KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)

Chapter 4.1: Treatment of CKD-MBD targeted at lowering high serum phosphorus and maintaining serum calcium

Kidney International (2009) 76 (Suppl 113), S50-S99; doi:10.1038/ki.2009.192

INTRODUCTION

The overall phosphate balance is positive in patients with chronic kidney disease (CKD) stages 4-5D,310 and therapeutic strategies are aimed at correcting this. Approaches include reducing phosphate intake by dietary modifications,³¹¹ reducing intestinal absorption using phosphate-binding agents,³¹² and in patients with CKD stage 5D, enhancing dialytic clearance with more dialysis.^{313, 314}

RECOMMENDATIONS

4.1.1In patients with CKD stages 3-5, we suggest maintaining serum phosphorus in the normal range (2C). In patients with CKD stage 5D, we suggest lowering elevated phosphorus levels toward the normal range (2C).

4.1.2In patients with CKD stages 3-5D, we suggest maintaining serum calcium in the normal range (2D).

4.1.3In patients with CKD stage 5D, we suggest using a dialysate calcium concentration between 1.25 and 1.50 mmol/l (2.5 and 3.0 mEq/l) (2D).

4.1.4In patients with CKD stages 3-5 (2D) and 5D (2B), we suggest using phosphate-binding agents in the treatment of hyperphosphatemia. It is reasonable that the choice of phosphate binder takes into account CKD stage, presence of other components of CKD-MBD, concomitant therapies, and side-effect profile (not graded).

4.1.5In patients with CKD stages 3-5D and hyperphosphatemia, we recommend restricting the dose of calcium-based phosphate binders and/or the dose of calcitriol or vitamin D analog in the presence of persistent or recurrent hypercalcemia (1B).In patients with CKD stages 3-5D and hyperphosphatemia, we suggest restricting the dose of calcium-based phosphate binders in the presence of arterial calcification (2C) and/or adynamic bone disease (2C) and/or if serum PTH levels are persistently low (2C).

4.1.6In patients with CKD stages 3-5D, we recommend avoiding the long-term use of aluminum-containing phosphate binders and, in patients with CKD stage 5D, avoiding dialysate aluminum contamination to prevent aluminum intoxication (1C).

4.1.7In patients with CKD stages 3-5D, we suggest limiting dietary phosphate intake in the treatment of hyperphosphatemia alone or in combination with other treatments (2D).

4.1.8In patients with CKD stage 5D, we suggest increasing dialytic phosphate removal in the treatment of persistent hyperphosphatemia (2C).

Summary of rationale for recommendations

• Hyperphosphatemia has been associated with poor outcomes and mortality in CKD stage 5D, and high normal serum phosphorus levels have been associated with mortality in non-CKD patients and in CKD stage 3 patients.
• Many patients with CKD stages 4-5D have a high serum phosphorus level that is linked to the development of aspects of CKD-MBD, including secondary hyperparathyroidism (HPT), reduced serum calcitriol levels, abnormal bone remodeling, and soft-tissue calcification.
• Laboratory-based experimental data suggest that hyperphosphatemia may directly cause or exacerbate other aspects of CKD-MBD, specifically secondary HPT, a reduction in calcitriol levels, bone disease, and arterial calcification.
• There is no evidence that lowering serum phosphorus to a specific target range leads to improved clinical outcomes in patients with CKD. Recommended goals of therapy must therefore be based on observational data.
• Despite a lack of evidence from randomized controlled trials (RCTs) demonstrating that lowering phosphorus levels impact clinical outcomes, it is reasonable to lower phosphorus in CKD patients with hyperphosphatemia using phosphate binders. Additional options to lower phosphorus include limiting dietary phosphate intake (while ensuring adequate protein intake) and/or increasing the frequency or duration of dialysis (in those who require renal replacement therapy).
• There is insufficient evidence that any specific phosphate binder significantly impacts patient-level outcomes. Thus, the choice of phosphate binder should be individualized, and the guidance offered in this recommendation is based on the effects of available agents on a range of clinical parameters, rather than on phosphorus lowering alone.

BACKGROUND

Hyperphosphatemia is an important and inevitable clinical consequence of the advanced stages of CKD. The rationale for controlling serum phosphorus is based on epidemiological evidence suggesting that hyperphosphatemia is an important risk factor, not only for secondary HPT but also for cardiovascular disease (CVD).^{205, 315} Long-standing hyperphosphatemia, together with an elevated serum Ca X P, is associated with an increased risk of vascular, valvular, and other soft-tissue calcification in patients with CKD.²⁶² Large epidemiological studies have consistently shown the importance of hyperphosphatemia as a predictor of mortality in CKD stage 5 patients receiving dialysis.^{205, 316, 317 and 318} Taken together, these observational data suggest that there is a need to control serum phosphorus in patients with CKD. Experimental data suggest a direct causal relationship between phosphorus and several components of CKD-MBD, specifically secondary HPT,^{319, 320} bone abnormalities,³²¹ calcitriol deficiency,³²² and extraskeletal calcification,³²³ providing biological plausibility to support these human observational studies.

The use of phosphate-restricted diets in combination with oral phosphate binders has become well established in the management of patients with CKD stages 3-5 (including CKD stage 5D), and this strategy has been endorsed by previous guidelines, with appropriate education and counseling to ensure adequate protein intake.5 Aluminum hydroxide is a potent phosphate binder, but concern about skeletal, hematological, and neurological toxicity led to a preferential use of calcium salts (carbonate and acetate) in the 1990s. The use of large doses of calcium-containing phosphate binders subsequently led to concerns about calcium overload because of a potential for generating a positive calcium balance. Table 19 lists phosphate binders that are presently in use or that have been used in the recent past. Unfortunately, the true benefits of phosphate lowering with respect to hard clinical end points have not been established, and most studies evaluate surrogate end points. In addition, because of ethical concerns regarding a prolonged lack of treatment, most studies evaluating these newer agents against placebo have been short term, with longer term studies using calcium salts as the comparator.

The following tables are found at the end of this chapter: Table 20 summarizes the RCTs of phosphate binders in children with CKD. For CKD stages 3 and 4, only one sevelamer-HCl study met the inclusion criteria and is described in Tables 21 and 22. The evidence matrix, a table that describes the methodologic quality of all of the included studies for CKD stage 5D, and the evidence profile, a table that provides an overall assessment of the quality of the evidence and balance of potential benefits and harm are Tables 23 and 24 for sevelamer-HCl compared to calcium containing phosphate binders, and Tables 25 and 26 for lanthanum carbonate compared to other binders. A narrative review of the literature on the topic of alternate hemodialysis regimens can be found in Tables 27, 28 and 29. These studies are discussed in the rationale for each recommendation. Additional detailed information about the studies of phosphate binders reviewed in this chapter are further described in detail in the Supplementary Tables 14-23.

RATIONALE

4.1.1In patients with CKD stages 3-5, we suggest maintaining serum phosphorus in the normal range (2C). In patients with CKD stage 5D, we suggest lowering elevated phosphorus levels toward the normal range (2C).

No prospective studies have specifically examined the benefits of targeting different phosphorus levels to determine the effect on patient-level end points. Epidemiological data suggest that serum phosphorus levels above the normal range are associated with increased morbidity and mortality (Supplementary Table 14). Higher levels of serum phosphorus, even within the normal range, have been associated with increased risk of cardiovascular events and/or mortality (all-cause or cardiovascular mortality) in patients with a normal renal function who were free of CVD,³²⁴ in patients with coronary artery disease and normal renal function,³²⁵ and in patients with CKD stages 3-5.³¹⁶ Not all studies find these relationships. A subanalysis of the modification of diet in renal disease (MDRD) study failed to identify phosphorus as an independent risk factor for increased mortality in patients with CKD who were not on dialysis.³²⁶

In patients on dialysis, multiple studies from different parts of the world have shown that higher levels of serum phosphorus have been associated with an increased relative risk (RR) of mortality. In most of these studies, the observed risk associations were robust and 'dose dependent', with progressive increases in risk with higher levels of serum phosphorus. The inflection point or range at which phosphorus becomes significantly associated with increased all-cause mortality varies among studies for the reasons cited above, 5.0-5.5 mg/dl (1.6-1.8 mmol/l),205 >5.5 mg/dl (>1.8 mmol/l),327 6.0-7.0 mg/dl (1.9-2.3 mmol/l),³²⁸ and >6.5 mg/dl (>2.1 mmol/l).^{33, 329, 330} A recent Dialysis Outcomes and Practice Pattern Study (DOPPS) analysis shows that the relationship between elevations in serum phosphorus and the RR of mortality is consistent across all countries analyzed.³³ The study by Noordzij et al.³²⁷ also found similar relationships in peritoneal dialysis (PD) and hemodialysis (HD) patients. These observational data are consistent with animal and other experimental data, providing biological plausibility to the association, and leading the Work Group to recommend interventions that lower phosphorus toward the normal range. Hypophosphatemia may also be problematic. In the DOPPS series, there is an increased risk of mortality for CKD stage 5D patients with a phosphorus level less than 2.0 mg/dl (0.65 mmol/l). However, fewer than 5% of patients are in this risk category. Analyses of DOPPS data by a dialysis unit (which was randomly selected) showed that if a facility had 10% more patients with phosphorus levels between 6.1-7.0 and >7.0 mg/dl (1.97-2.26 and >2.26 mmol/l), the mortality risk was 5.3 and 4.3% higher, respectively.³³

In summary, although the benefits of lowering serum phosphorus on patient-level clinical outcomes (for example, hospitalization, bone fracture, cardiovascular events, and mortality) have not been studied, numerous epidemiological data show a positive association, although not a causal link, between higher serum phosphorus levels and RR of mortality, independent of CKD stage. Experimental data support the biological plausibility of a direct effect of phosphorus on PTH secretion and parathyroid cell proliferation,^{320, 331, 332} and on vascular calcification.³³³ However, the use of phosphate binders is associated with side effects, especially gastrointestinal, and with a high pill burden. Thus, in some patients, treatment to achieve a serum phosphorus level within the normal range may not be possible or may lead to a reduction in quality of life. Therefore, in the absence of a prospective RCT showing outcome benefits at any level of phosphate control, it seems reasonable that therapy is individualized. However, it is generally accepted and biologically plausible that elevated serum phosphorus levels should be lowered in patients with CKD stages 3-5D in an effort to control complications of CKD-MBD. The lack of data showing that patient-centered outcomes are improved by lowering serum phosphorus means that the strength of this recommendation is level 2 or 'weak', as it is based on observational and experimental data.

4.1.2In patients with CKD stages 3-5D, we suggest maintaining serum calcium in the normal range (2D).

In patients with CKD stages 3-5, there are no data to support an increased risk of mortality or fracture with an increasing serum calcium concentration. The association in CKD stage 5D patients is generally similar to that of serum phosphorus. The inflection point or range at which calcium becomes significantly associated with an increased RR of all-cause mortality varies among studies for the reasons cited above, from being >9.5 mg/dl (>2.38 mmol/l)205 to >10.1 mg/dl (>2.53 mmol/l),³³ >10.4 mg/dl (>2.60 mmol/l),³³⁰ >10.5 mg/dl (>2.63 mmol/l),328 and to >11.4 mg/dl (>2.85 mmol/l).329 Globally, 50% of CKD stage 5D patients have serum calcium levels above 9.4 mg/dl (>2.35 mmol/l) and, of these, 25% have serum calcium levels above 10.0 mg/dl (>2.50 mmol/l).³³ At the low end, there is little evidence of an increase in RR until serum levels fall below 8.4 mg/dl (<2.10 mmol/l).³³ In another study from the United States, the increased RR of mortality with a low serum calcium was reversed when adjusted for covariates.205 It is therefore unclear at what level of low serum calcium is there an increased risk. It is also important to realize that none of these studies evaluated patients receiving cinacalcet, which lowers calcium by its effects on the calcium-sensing receptor (CaR) while also increasing the receptor's sensitivity to the cation. Treatment leads to an expected decrease in the total serum calcium concentration. Thus, we do not know whether patients with low serum calcium levels due to cinacalcet have a similar risk as those with identical calcium levels who are not on the drug. Overall, the interpretation of serum calcium, similar to other biochemical values, should be evaluated on the basis of trends, which may be related to specific medications that raise (calcium-based phosphate binders, vitamin D sterols) or lower (cinacalcet) serum calcium values.

4.1.3In patients with CKD stage 5D, we suggest using a dialysate calcium concentration between 1.25 and 1.50 mmol/l (2.5 and 3.0 mEq/l) (2D).

There was a discussion among the Work Group members as to whether the optimal dialysate calcium concentration should be adapted to each patient's individual needs, whenever possible. The final vote on this recommendation was 16 in favor and 1 vote against. The vote against was to argue that a 1.0 mmol/l (2.0 mEq/l) of calcium dialysate was also helpful in some patients to reduce their positive calcium balance.

Calcium balance during HD is important in determining short-term cardiovascular function, as it influences the hemodynamic tolerability of dialysis. In the longer term, calcium flux during HD is an important determinant of overall calcium balance. The calcium concentration of the dialysate therefore should be adjusted to optimize the total body calcium load.³³⁴ Theoretically, this strategy should help to improve bone health by reducing calcium flux during dialysis in patients with adynamic bone disease and extraskeletal calcification, and by inducing positive calcium flux during dialysis in patients with hypocalcemia. However, these possibilities have not been tested prospectively. The percentage of total body calcium that is dialyzable is very small, and studies that evaluate calcium balance are limited. The total amount of calcium removed with each dialysis treatment will depend not only on calcium concentration but also on the patient's serum-ionized calcium level, the intradialytic interval, and the rate of ultrafiltration.335 Studies that have measured spent dialysate for calcium to determine net flux have found near-neutral calcium flux in patients with a dialysis concentration of 1.25 mmol/l (2.5 mEq/l).^{336, 337} A more recent study used more frequent assessments of spent dialysate and found a mean calcium flux with each dialysis session of -187+ -232 mg (-46+ -58 mmol) on a 1.25 mmol/l (2.5 mEq/l) of calcium dialysate. However, six of the 52 patients had positive calcium balance, supporting the fact that calcium flux with dialysis is not uniform in all patients.³³⁸ Thus, the Work Group felt that, in general, a dialysate calcium concentration of 1.25 mmol/l (2.5 mEq/l) would be a near-neutral calcium balance for most patients. However, it is important to point out that a low dialysate calcium concentration may also predispose to cardiac arrhythmias and hemodynamic instability during dialysis sessions, with intradialytic hypotension.^{339, 340} At present, it is probably wise to maintain flexibility with dialysate calcium concentrations, which should be individualized, whenever possible, to meet specific patient requirements.

Similar considerations apply to PD, in which dialysate calcium concentration should be tailored to the individual patient's needs, if possible. Compared with patients receiving HD, patients receiving PD are exposed to a given dialysate calcium concentration for longer periods of time. Therefore, peritoneal dialysate calcium concentrations as high as 3.5 mEq/l (1.75 mmol/l) are generally avoided to prevent calcium overload and the induction of adynamic bone disease. Concentrations between 1.25 and 1.50 mmol/l (2.5 and 3.0 mEq/l) are recommended.

4.1.4In patients with CKD stages 3-5 (2D) and 5D (2B), we suggest using phosphate-binding agents in the treatment of hyperphosphatemia. It is reasonable that the choice of phosphate binder takes into account CKD stage, the presence of other components of CKD-MBD, concomitant therapies, and side-effect profile (not graded).

A systematic review of all RCTs examining phosphate binders was undertaken and considered in the context of the review of calcium-based binders published in the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines.5 These studies showed that all medications currently used as phosphate binders (calcium salts, aluminum salts, magnesium salts, sevelamer-HCl, and lanthanum carbonate) are effective in lowering serum phosphorus levels. The non-phosphorus-lowering effects are discussed in detail in the remainder of the chapter. The use of sevelamer, compared with the use of calcium-based salts, has been shown to attenuate progression of arterial calcification in one RCT involving patients with CKD stages 3-5²⁸⁶ and two RCTs involving patients with CKD stage 5D.^{284, 285} However, two more recent RCTs have not reproduced these results and have found high and similar rates of progression of vascular calcification in patients receiving sevelamer-HCl as compared with those receiving calcium acetate.^{287, 288} The effect of other binders on progression of vascular calcification has not been systematically studied. Most importantly, it is not clear whether slowing vascular calcification translates into improvements in clinical outcomes or whether other non-calcium-containing binders (for example, lanthanum carbonate) have similar effects. The use of lanthanum carbonate and sevelamer-HCl does not adversely affect bone histology in short-term studies and, when compared with calcium-based binders, may be less likely to lead to adynamic bone disease. Comparative studies of phosphate binders have shown differences in effects on the biochemical parameters of CKD-MBD. For example, the use of calcium salts is generally associated with higher serum calcium (and more frequent episodes of hypercalcemia) and lower serum PTH levels when compared with the use of sevelamer-HCl or lanthanum carbonate. The effects of different binders on biochemical end points, on surrogate markers of bone and vascular calcification, or on mortality, are described in the rationale following Recommendation 4.1.5. Overall, there is insufficient comparative efficacy data on clinical outcomes to make a recommendation for the use of a specific binder for all patients.

4.1.5In patients with CKD stages 3-5D and hyperphosphatemia, we recommend restricting the dose of calcium-based phosphate binders and/or the dose of calcitriol or vitamin D analog in the presence of persistent or recurrent hypercalcemia (1B).In patients with CKD stages 3-5D and hyperphosphatemia, we suggest restricting the dose of calcium-based phosphate binders in the presence of arterial calcification (2C) and/or adynamic bone disease (2C) and/or if serum PTH levels are persistently low (2C).

The Work Group asked if there were differences between the various phosphate binders in terms of their effects on biochemical indices of CKD-MBD, bone, vascular calcification, or clinical end points. The group felt that there were inconclusive data to indicate that any one binder has beneficial effects on mortality or other patient-centered outcomes when compared with any other binder, and thus the strength of this recommendation is graded as level 2. The specific recommendations regarding limiting calcium intake from phosphate binders were extensively discussed. As detailed below, there are consistent data regarding the risk of inducing hypercalcemia and calcium overload in patients on calcium-based phosphate binders, necessitating dose reduction. The Work Group also felt that the available bone biopsy data suggested that patients receiving calcium-based binders were more likely to develop adynamic bone disease. There was extensive discussion with respect to the role of calcium- vs non-calcium-based binders in the pathogenesis of vascular calcification. The Work Group acknowledged that the evidence was not conclusive and that more research is needed. However, the majority of the Work Group felt that limiting calcium intake in the form of phosphate binders was justified until further research is available on the basis of our knowledge of calcium balance in CKD patients. It was noted that at least some studies in humans showed a beneficial effect of sevelamer-HCl compared with calcium-based binders on progression of arterial calcification. The majority of the Work Group (16 of 17 members) felt that, given the high cardiovascular burden, recommending a limited calcium intake was likely to be more beneficial than harmful. A single member of the Work Group felt that this recommendation had the potential for too large an impact with too little data to support it, bringing the final vote to 16 in favor and 1 vote against.

Results of evidence review

The KDOQI guidelines⁵ extensively reviewed trials evaluating calcium carbonate and calcium acetate. No additional studies fulfilling our screening criteria were identified, with the exception of those comparing a calcium-containing phosphate binder with sevelamer-HCl or lanthanum carbonate. The KDOQI guidelines concluded that both calcium carbonate and calcium acetate were effective in lowering serum phosphorus when compared with placebo, but that both were associated with hypercalcemia and gastrointestinal side effects. A meta-analysis performed for the KDOQI guidelines indicated that calcium acetate is less hypercalcemic than is calcium carbonate.5 None of these studies assessed bone histology, vascular calcification, or hard clinical end points and thus will not be further reviewed. The KDOQI guidelines also evaluated aluminum hydroxide as a phosphate binder, but again no data on vascular calcification or hard clinical end points were identified. However, studies have shown that aluminum may induce osteomalacia, microcytic anemia, and central nervous system toxicity.^{341, 342} Thus, in the absence of a clear benefit beyond phosphorus lowering, and because of known potential toxicity, the Work Group felt that the use of aluminum hydroxide should be restricted.

The remaining studies identified by our systematic search compared sevelamer-HCl or lanthanum with calcium-based binders, or lanthanum with a previously prescribed binder (a calcium salt or sevelamer). These studies are listed in tables by treatment comparisons and are reviewed below by end point.

a) Patient-centered end points: Studies of phosphate binders comparing sevelamer-HCl and calcium-based binders that have mortality as the primary end point have been inconsistent.

The largest of these studies, the Dialysis Clinical Outcomes Revisited (DCOR) study, randomized 2103 prevalent CKD stage 5D patients to either sevelamer-HCl or a calcium-based phosphate binder (70% calcium acetate or 30% calcium carbonate), (Table 24; Supplementary Tables 15-18).266 Patients were allowed to receive other medications according to current standards of care and were followed up for a mean of approximately 20 months. The trial was designed to evaluate all-cause mortality as the primary end point and had 80% power to detect a 22% difference between the groups, assuming a mortality rate of 20 per 100 patient-years in the calcium-treated group and a two-sided alpha (alpha;) of 0.05. The study had a high early discontinuation rate and collected only 90 days of follow-up data on discontinued patients, providing limited information on these individuals. The overall dropout rate was 47% in the sevelamer-HCl arm and 51% in the calcium-based binder arm. More patients discontinued because of adverse events (AEs) in the sevelamer-HCl arm (8 vs 5%), but types of events and event rates were not comprehensively reported. The study was extended because the mortality rate in the control group was lower than expected. No details of interventions, treatment targets, or dose-titration protocols were provided, neither were baseline biochemical parameters available. Only 1068 patients completed the study, and there were no differences in all-cause or cause-specific mortality rates when comparing sevelamer-HCl (mortality rate 15.0 per 100 patient-years) with calcium-treated patients (16.1 per 100 patient-years), hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.79-1.10, log rank P=0.40. There were also no differences in cardiovascular mortality and hospitalization on the basis of data from case-report forms. Much attention has been focused on the analysis of subgroups, particularly patients over 65 years of age (a prespecified analysis) and those receiving treatment for more than 2 years in whom benefits associated with allocation to sevelamer-HCl therapy have been claimed. However, the Work Group took the view that, in light of the equivalence of the two therapies with respect to the primary end point in the overall cohort, such analyses could be, at best, considered hypothesis generating and should be interpreted with extreme caution. The ERT graded the quality of this study as C (low quality) with respect to all outcomes because of several factors, including the lack of an intention-to-treat analysis and possible bias resulting from the limited (90-day) follow-up of discontinued patients, as well as a lack of documentation of baseline biochemical parameters and AEs.

A secondary preplanned analysis of the DCOR study by St Peter et al.²⁶⁷ using Medicare claims data (rather than data collected at the study sites on case-report forms) showed no effect of phosphate-binder allocation on overall mortality (primary outcome), cause-specific mortality, morbidity, or first or cause-specific hospitalization (secondary outcomes).²⁶⁷ This study did show a beneficial effect of sevelamer-HCl on the secondary outcomes of multiple all-cause hospitalizations (1.7 vs 1.9 admissions per patient-year, P=0.02) and hospital days (12.3 vs 13.9 days per patient-year, P=0.03).²⁶⁷ This study was graded as 'B' (that is, moderate quality) for mortality outcome. The study ascertainment for mortality was complete and allowed a true intention-to-treat analysis, having included many patients lost to follow-up in the original publication; however, this could not overcome the high dropout rate.²⁶⁶ The quality of data for hospitalization was graded as low (or 'C'). The analysis by St Peter et al.²⁶⁷ using claims data described a higher rate of hospitalization in a smaller group of patients with a shorter duration of follow-up than that reported by Suki et al.,²⁶⁶ as a result of the fact that the denominator for hospitalization rates did not include days spent in the hospital. Thus, although both analyses showed a trend toward lower hospitalization rates, the fact that the difference between patients allocated to different binders was of statistical significance in the analysis by St Peter et al.²⁶⁷ was not considered to be robust. Furthermore, hospitalizations from CVD as ascertained from the administrative data did not differ, lending no support to the study's hypothesis that sevelamer-HCl reduces CVD morbidity.

The second study examining clinical outcomes data, RIND, randomized a smaller group of 148 incident HD patients (patients new to dialysis) to either sevelamer-HCl or calcium-based binder, but followed up these patients for a longer period. Only 127 patients received baseline electron-beam CT (EBCT) scans and the dropout rate was 26% in the sevelamer-HCl arm and 27% in the calcium-based phosphate-binder arm. At a median of 44 months, there was a difference in the unadjusted mortality rate for patients assigned to calcium-containing binders, which was 10.6 per 100 patient-years (CI 6.3-14.9), compared with 5.3 per 100 patient-years (CI 2.2-8.5) for patients assigned to sevelamer-HCl, with the HR for mortality in the univariate analysis for calcium vs sevelamer being 1.98 (P=0.06). However, in multivariate analysis, which included 10 variables (felt to be a large number considering that there had only been 34 deaths), the difference between the groups was significant (HR 3.1, P=0.016), suggesting an imbalance with respect to the covariates entered into the model and raising the possibility of an unsuccessful randomization. As a result of this concern, the Work Group downgraded the methodological quality of this study to B or 'moderate.'

No data on cardiovascular events other than death, fractures, or parathyroidectomy rates were available from either of these studies, making it impossible to draw conclusions on the impact of using sevelamer-HCl instead of a calcium-based phosphate binder on such outcomes. In addition, no studies have examined the effects of lanthanum carbonate or indeed any other phosphate binder (including calcium- and aluminum-based compounds) on patient-level outcomes.

b) Vascular calcification: The use of sevelamer-HCl attenuates the progression of arterial calcification in patients with CKD stages 3-5 and stage 5D when compared with the use of calcium-based salts in some, but not all, studies. The effect of other binders on progression of vascular calcification has not been systematically studied. Most important, it is not clear whether slowing vascular calcification translates into improvements in clinical outcomes.

Three of the five randomized trials (Supplementary Tables 15, 16), as reported in multiple publications, comparing sevelamer-HCl with calcium-based binders ^{284, 285 and 286, 288, 343, 344} studied the impact of phosphate-binder therapy on arterial calcification, assessed using computerized tomography imaging techniques. One examined the effect of these two oral phosphate-binder approaches on valvular calcification,345 and one compared the effect of sevelamer-HCl with calcium-based binders, adding atorvastatin treatment to both arms as required to reach a comparable low-density lipoprotein cholesterol target.²⁸⁷ Only one of these trials involved patients with CKD stages 3-4,²⁸⁶ whereas the remaining four recruited patients with CKD stage 5D. ^{284, 285, 287, 288, 343, 344 and 345}

In their study involving 90 binder-naive Italian patients with CKD stages 3-5 who were not receiving dialysis, Russo et al.²⁸⁶ (Tables 21, 22) randomized patients (30 per group) into either a low-phosphate diet alone group, a low-phosphate diet in combination with fixed doses of calcium carbonate (2 g/d) group, or a low-phosphate diet in combination with sevelamer-HCl (1600 mg/d) group, and followed up these individuals for 2 years. The primary end point of the study was progression of cornary artery calcification (CAC), assessed as the total calcium score using multislice computed tomography. Among the 84 patients who completed the study, the final CAC scores were greater than the initial scores in those receiving diet alone (P<0.001) or diet in combination with calcium carbonate (P<0.001), whereas there was no progression of calcification in the diet-plus-sevelamer-HCl-treated group. In patients with CKD stage 5D, four studies have examined the effect of sevelamer-HCl compared with that of calcium-containing phosphate binders on the progression of CAC (Supplementary Tables 15, 16). One of the secondary aims of the 'Treat to Goal' study was to assess the progression of cardiovascular calcification in 200 prevalent HD patients randomized to receive either sevelamer-HCl or a calcium-based phosphate binder (107 calcium acetate in the United States and 93 calcium carbonate in Europe) in an open-label design.²⁸⁴ The study was conducted in the United States, Germany, and Austria, and was powered to achieve a serum Ca X P difference of 10 mg2/dl2 (124 mmol2/l2). Patients were randomized after a 2-week 'washout' period and investigators were instructed to manage blood calcium, phosphorus, and PTH levels to achieve prespecified targets for the remaining 50 weeks (hence, the 'Treat to Goal' study). During this period, absolute calcium scores in the coronary arteries and aorta increased in the calcium-treated patients, but not in those receiving sevelamer-HCl. Many dropouts were reported, with 37% of the sevelamer-treated patients and 31% of the calcium-treated patients missing from the analysis at week 52. These data were partially duplicated in a publication that describes 93 patients from the European cohort343 (with 21 additional patients whose origin is unclear); in a third article that also reported valvular calcification, its progression did not differ when the two groups were compared at the start and end of a 52-week study period.³⁴⁵ Another report suggested that patients randomized to receive calcium salts, compared with those randomized to sevelamer-HCl, experienced greater trabecular (but not cortical) bone loss on the basis of changes in thoracic bone mineral density (BMD) on EBCT scans in a subset of 132 patients in whom the necessary imaging was available.³⁴⁶ At the end of the 52-week study period, a European subgroup of 72 patients out of the initial 'Treat to Goal' cohort chose to remain under follow-up and attended for subsequent EBCT scans approximately 2 years after enrollment into the study (although no longer randomized to different phosphate binders beyond 52 weeks). This approach to subject retention may well have introduced biases. Data from this extended follow-up, during which 53% of the patients dropped out, were reported to endorse the observation that assignment to a calcium-based binder was associated with progressive arterial calcification and decreased trabecular bone density when compared with assignment to sevelamer-HCl treatment.³⁴⁴ Changes in bone density and vascular calcification did not correlate. As measurement of thoracic vertebral radiolucency by EBCT is not a valid measure of BMD or mass, and bearing in mind the high dropout rate, the Work Group was concerned with regard to the validity of these bone data and graded all these substudies of 'Treat to Goal' as being of low quality.

Assessment of changes in CAC at 12 months was the primary outcome of the RIND study²⁸⁵ (Supplementary Tables 15, 16). Of the 127 patients who underwent baseline EBCT, 26% did not receive follow-up EBCT scans. At 1 year, there was no statistically significant difference in calcification. The mean annual rates of progression of calcification were 13.4 and 25.3% for sevelamer-HCl and the calcium-based binder groups, respectively, P=0.06. The median increase in the calcification score at 18 months was 11-fold higher in the calcium-treated group compared with the sevelamer-HCl-treated group (an increase of 127 points from a baseline of 667+ -1248 vs 11 points from a baseline of 648+ -1499, respectively, P=0.01). In a subgroup analysis, patients with a baseline CAC score of >30 Agatston units confirmed a trend for higher absolute and percentage increases in calcium-treated patients. In the RIND trial, the amount of calcium consumed in calcium-based binders was not associated with the rate of progression of calcification.

In the CARE 2 study, chronic HD patients from the United States were randomized to receive either calcium acetate or sevelamer-HCl.287 Patients in both groups received atorvastatin to achieve a low-density lipoprotein cholesterol goal of 70 mg/dl (1.81 mmol/l). The study was designed to assess non-inferiority, evaluating CAC using EBCT at 6 and 12 months after randomization. Before 1 year, 30% of the patients in the selevamer arm and 43% in the calcium acetate arm dropped out. Although achieving comparable levels of serum cholesterol, no difference in the progression of arterial calcification was noted when comparing the two treatment arms (annual progression of coronary calcification was 29 and 30% in the calcium acetate and sevelamer-HCl groups, respectively, P=0.90). Although the study had a high percentage of loss of follow-up, several sensitivity analyses (including some that imputed missing values under different assumptions) showed the findings to be robust. Furthermore, this is the only study that defined a metric for the primary calcification outcome up front. However, the study was downgraded from 'high' to 'moderate' quality, because the selection of the upper 95% confidence limit for outcome was not explained and, in the study design, it was not intuitive what the 'upper bound for the non-inferiority margin of 1.8' means in terms of clinically relevant differences in progression of calcification. It is noteworthy that CARE 2 showed that the combination of sevelamer-HCl and atorvastatin was associated with a much higher rate of progression of CAC than that in 'Treat to Goal',²⁸⁴ instead of showing a delay in CAC progression with the combination of calcium acetate and statin in accordance with the initial study hypothesis. One of the possible explanations for the equivalent progression of calcification in the two treatment arms of CARE 2, as opposed to less calcification in the sevelamer-HCl compared with the calcium arm in the 'Treat to Goal' study, is that the patient population was exposed to a greater number of cardiovascular risk factors in the CARE 2 study.²⁸⁹

The BRIC study investigated the effects of calcium acetate vs sevelamer-HCl on CAC progression and bone histomorphometry in chronic HD patients from Brazil. The authors randomized 49 patients to calcium acetate and 52 patients to sevelamer-HCl.288 The primary goal of the study was to test the hypothesis that treatment with calcium-containing phosphate binders has a negative impact on bone remodeling and this contributes to a more rapid progression of CAC compared with sevelamer-HCl treatment. The annual rates of progression of coronary calcification scores were 27 and 26% for sevelamer-HCl and calcium acetate, respectively, P=NS. The authors also found that neither CAC progression rates nor indices of bone remodeling differed between the two phosphate-binder arms. However, this study was hampered by several significant confounders, including small sample size, differences in baseline CAC scores between the two study arms (675+ -1267 for calcium acetate and 507+ -814 for sevelamer, P=0.38), the use of high dialysate calcium concentrations (1.75 mmol/l (3.5 mEq/l)) in most patients, resulting in a positive calcium balance, and multiple interventions during the course of the study based on bone biopsy results.

The inconsistencies between the results of the recent BRIC and CARE 2 studies on the one hand and those of the previous studies on the other hand cast some doubt on the hypothesis of a major role of calcium loading in the progression of arterial calcification, with the CARE 2 and BRIC study results not duplicating the beneficial effects observed with sevelamer-HCl in the other three trials. Taken together, the data on vascular calcification overall are only of low quality, bearing in mind that changes in the rate of calcium deposition have not been validated as a predictor of benefit in terms of clinical outcomes in CKD patients. Given the present uncertainty in this field, further trials comparing phosphate binders and examining hard clinical end points are needed.

c) Bone histology: Clinical trials comparing calcium carbonate with lanthanum carbonate or sevelamer-HCl do not show major differences among treatments. The changes in bone turnover with both calcium- and non-calcium-based binders are heterogeneous, with some patients showing worsening and others showing improvement. The results are also influenced by baseline turnover rates.

Sevelamer-HCl. Two clinical trials compared sevelamer-HCl with calcium carbonate, yielding a moderately high quality for this outcome, and a smaller study compared these therapies in children (Supplementary Table 17).

In the first adult study comparing the effects of sevelamer-HCl and calcium carbonate on bone histology, Ferreira et al.¹⁰⁴ enrolled 119 HD patients in a 54-week randomized, open-label study. Of them, 100 patients underwent baseline and 68 underwent follow-up bone biopsies after 1 year. Serum calcium was lower and serum intact PTH (iPTH) was higher in those patients assigned to sevelamer-HCl. Neither overall bone volume nor mineralization changed after 1 year in an intention-to-treat analysis when compared with that at baseline in either of the two groups, but turnover increased in the sevelamer group compared with that in calcium-treated patients (P=0.02). The turnover worsened by becoming higher in 12% of sevelamer-HCl and 3% of calcium groups; on the other hand, it worsened by becoming lower (development of adynamic disease) in 17% of calcium patients and 9% of sevelamer-HCl patients. Turnover improved in 26% of calcium and 15% of sevelamer-HCl patients. Change in bone volume was almost the same in both groups (the volume increased by 0.9% in the calcium vs sevelamer-HCl group).

The second adult study, the BRIC study, also compared the effects of sevelamer-HCl and calcium acetate on bone histology.²⁸⁸ Among the 101 HD patients randomized, 27 in the calcium acetate arm and 37 in the sevelamer-HCl arm had an interpretable repeat bone biopsy after a 12-month treatment period. Overall, there were no significant changes in the main bone parameters. Turnover: The resulting 12-month bone-formation rates were not statistically different between groups. The mean bone-formation rate increased by 76% with calcium treatment, which was not statistically significant for the before and after within-arm comparison, and by 93% with sevelamer-HCl treatment, which was significant (P<0.05) for the before and after within-group comparison. The authors then separately analyzed those who initially had a high or low bone turnover. In those with a low bone turnover, there was a similar improvement with both treatments. In those with a high bone turnover, there was no mean change in bone formation with either treatment. Mineralization: There was no significant change in the mineralization lag time (MLT) with either treatment. In the low-turnover group, there was improvement with both treatments. It is noteworthy that bone aluminum surface was 21.1+ -28.7% in the calcium-treated group and 27.6+ -27.4% in the sevelamer-treated group, although the number of patients who had positive aluminum staining was not provided. Volume: There was a significant (P<0.05) but slight improvement with calcium treatment and no change with sevelamer-HCl treatment.

A third study in children did not show differences between calcium and sevelamer-HCl for turnover or mineralization, and the same number developed adynamic disease.¹⁷

In all three of the studies, bone volume was slightly improved with calcium treatment compared with sevelamer-HCl treatment, but the results were not significant.

Lanthanum carbonate. Three studies compared the effects of lanthanum carbonate with those of calcium carbonate on bone histomorphometry (Supplementary Table 22). The larger studies^{13, 103} were of moderate quality, with some inconsistencies in data reporting, and the third study⁹⁸ was limited by a small sample size.

In the first study by D'Haese et al.,12 98 HD patients underwent baseline bone biopsy, and paired iliac crest bone biopsies were measured after 1 year from 63 patients, 33 of whom received lanthanum carbonate and 30 of whom received calcium carbonate. These biopsy results were reported in three publications.^{12, 13, 21} The first report presented data in a categorical form. The second report presented changes in activation frequency (a marker of bone turnover), which were considered to have improved if they became closer to normal.13 Data were extracted from a figure that presented individual changes in the bone-formation rate per bone surface. The third report presented changes in activation frequency, and defined improvement in terms of 1 s.d.21 When all three reports of the same biopsy study were taken together, an improvement in turnover was seen in 36-45% of patients receiving lanthanum and in 20-23% of those receiving calcium. The turnover worsened in 30% with calcium treatment (20% developed adynamic disease) and in 12% with lanthanum treatment (6% developed adynamic disease). Mineralization changes were similar in both treatment groups. Volume was not reported. Overall, the results favored lanthanum carbonate treatment.

The second study by Malluche et al.103 evaluated 2 years of treatment. Paired bone biopsy samples for histomorphometric analysis were available at baseline and at 1 year in 32 lanthanum carbonate-treated HD patients and in 33 HD patients receiving standard care, and at baseline and 2 years in 32 lanthanum carbonate-treated patients and in 24 patients receiving standard care. The majority of patients in the standard-care group (>80%) received calcium-containing phosphate binders.¹⁰³ Turnover: At 1 year, turnover worsened in 45% of the calcium group and in 42% of the lanthanum group, and improved in 3% of the calcium group and in 12% of the lanthanum group. At 2 years, the turnover had worsened in 72% of the calcium group (29% decreasing toward adynamic lesions) and in 40% of the lanthanum group (23% decreasing), with improvement being similar in both groups. Therefore, at 2 years, the results showed a better turnover with lanthanum carbonate treatment. Mineralization worsened in two patients receiving lanthanum carbonate and in none receiving standard-care treatment. Volume was slightly better in the lanthanum carbonate group at 2 years.

The third study by Spasovski et al.98 included 20 new HD patients randomly treated with lanthanum carbonate or calcium carbonate for 1 year, thereafter with calcium carbonate for an additional 2 years. Bone biopsies were performed at baseline, 1, and 3 years. Turnover: None of the patients in the lanthanum carbonate group developed low bone turnover at the 1-year biopsy in contrast to three patients developing adynamic bone disease in the calcium carbonate group. The bone-formation rate showed a nonsignificant increase in the first year and a return to baseline in year 3 in the lanthanum carbonate group, whereas it decreased slightly in the calcium group. Mineralization and volume were not reported.

In summary, there are only minor overall changes observed in response to non-calcium-containing phosphate binders, compared with calcium-containing phosphate binders, when patients are considered as a group. The changes in bone turnover are heterogeneous and influenced by initial bone turnover. None of the studies had enough power to provide adequate evidence for a change in volume. The studies did not identify consistent beneficial or adverse effects on bone with the administration of any of the phosphate binders in the doses used.

The Work Group felt it was important to acknowledge that existing adynamic bone or the development of a low-turnover disease may be related to the development of arterial calcification as described earlier. A cross-sectional study found that arterial calcification is higher in patients whose bone formation was below the median value. The mean calcium intake was higher in those with adynamic bone and in those with aortic calcification. Furthermore, in those with adynamic bone disease, calcium intake was directly related to the degree of aortic calcification.117 In the study by Barreto et al.,119 the relationship between bone histology and progression of arterial calcification was evaluated. In patients who began the 1-year study with a low-turnover disease, those who had coronary calcification progression were more likely to have a persistent low-turnover disease at the 12-month biopsy (58 vs 17%; P=0.01). Logistic regression analysis showed the diagnosis of a low-turnover bone state at the 12-month bone biopsy as being the only independent predictor for coronary artery progression (P=0.04; beta;-coefficient=4.5; 95% CI 1.04-19.39). The mechanism for this effect may be that adynamic bone is an ineffective reservoir for excess calcium intake. A study showed that HD patients with biopsy-proven adynamic bone disease had minimal radio-labeled calcium influx into bone, whereas those with a high-turnover bone disease had a marked influx of calcium into the bone.347 The RCTs detailed above show that some patients develop adynamic bone disease with calcium-containing phosphate binders more often than do those with non-calcium-based binders in some,12, 104 but not all, studies.103, 118 This raises a concern with respect to excessive calcium intake and the risk of vascular calcification, but the amount of calcium intake that is safe remains to be determined and is likely to not be a uniform amount across all patients. Despite these limitations, the Work Group recommended limiting calcium intake in the presence of low-turnover bone disease or adynamic bone disease, but acknowledged that this is a low-quality evidence and thus graded it as 2C. Formal balance research studies are needed.

d) Biochemical end points: Comparative studies of phosphate binders have shown differences in the biochemical parameters of CKD-MBD. For example, the use of calcium salts is generally associated with higher serum calcium (and more frequent episodes of hypercalcemia) and lower serum PTH levels when compared with sevelamer-HCl or lanthanum carbonate.

Sevelamer-HCl. All eight RCTs reported biochemical parameters reflecting a mineral-bone disorder (blood levels of calcium, phosphorus, and PTH) with broadly consistent results.^{104, 266, 267, 284, 285, 286, 287 and 288} In the context of these studies, sevelamer-HCl and calcium salts were equally effective as phosphate binders. In the population with CKD stages 3-5 studied by Russo et al.286 (Tables 21, 22), there were no differences in serum calcium, phosphorus, or PTH when comparing diet, diet plus calcium, or diet-plus-sevelamer-HCl-treated patients at the end of the 2-year study period. Compared with baseline, urinary phosphate excretion increased in the diet-only-treated patients but decreased in those receiving phosphate binders. Among-group comparisons of serum calcium, phosphorus, and PTH were not reported. Concerns with regard to this study included the imbalance between baseline levels of biochemical parameters, the lack of blinding, a high dropout rate (10% in the sevelamer-HCl arm), and the lack of a power analysis.

The DCOR investigators reported time-weighted biochemical parameters (but not baseline values). Patients receiving sevelamer-HCl had a lower serum calcium, but higher phosphorus and higher PTH serum levels than those receiving calcium-based binders. Serum calcium levels were also lower in the sevelamer-HCl-treated patients in the 'Treat to Goal' study²⁸⁴ and overt hypercalcemia was less common in such patients.²⁸⁴ These findings were broadly reflected in the RIND study results reported after 18 months of treatment,²⁸⁵ and in the CARE 2 study after 12 months.²⁸⁷ Ferreira et al.104 reported similar results after 13.5 months of follow-up, although biochemical data were only included for those patients undergoing a second bone biopsy, potentially biasing the results. In BRIC, those patients randomized to sevelamer-HCl had both higher PTH and alkaline phosphatase (ALP) levels after 12 months of treatment, although there were no differences in serum calcium or in the frequency of hypercalcemic episodes.²⁸⁸ Thus, in all of these eight comparative studies, a randomization to sevelamer-HCl was associated with higher serum iPTH levels, and in all but one study (BRIC), with a lower serum calcium concentration. The Work Group considered these biochemical data to be of high quality, although the importance of laboratory outcomes was considered to be low, the increase in PTH may or may not reflect a desirable change depending on the end point, and most importantly, the true relationship of biochemical measures with clinical end points has not been established.

Lanthanum carbonate. Of the three randomized studies comparing lanthanum carbonate with other binders (Supplementary Tables 20-22), only the study by Hutchison et al.³⁴⁸ reported biochemical parameters reflecting mineral bone disorder (serum phosphorus, calcium, Ca X P, and PTH) as the primary end point. However, this study compared the ability of the binders to maintain phosphorus control only in those patients who achieved serum phosphorus levels <5.58 mg/dl (1.8 mmol/l) within the initial dose-titration phase. The ERT therefore considered these data to be of limited applicability and was concerned with regard to potential bias introduced by the exclusion of study participants after randomization. The results of the other two studies were broadly consistent in that lanthanum carbonate was as effective as calcium carbonate in controlling serum phosphorus, but neither of these studies were primarily designed to compare efficacy in phosphorus lowering or to examine other biochemical end points.13, ³⁴⁹

In a longer term study,349 46% of patients in the lanthanum carbonate group (maximum daily dose of 3000 mg elemental lanthanum) achieved control of serum phosphorus levels to <1.9 mmol/l (5.9 mg/dl) compared with 49% in the standard-therapy group (P=0.5) after 2 years of treatment. However, there was a higher frequency of hypercalcemia reported as an AE in the calcium carbonate group (20.2%) compared with that in those receiving lanthanum carbonate therapy (0.4%). Serum PTH levels attained the range recommended by the KDOQI guidelines for patients with CKD stage 5 (150-300 pg/ml (15.9-31.8 pmol/l)) during titration in the lanthanum carbonate group, but remained below this range throughout the study period in the standard-therapy group. The Work Group considered these data on biochemical markers to be of low quality. First, the study was designed for safety analysis and not for efficacy. In addition, there was no option to switch treatments in the event of inefficacy in the lanthanum group. Patients in the lanthanum group were required to withdraw if they experienced AEs or if the investigator decided that additional therapy was required. However, patients randomized to the standard-therapy group were permitted to change to other phosphate binders or to receive additional binders. Furthermore, the lanthanum group was subjected to a dose-titration phase, whereas the standard-therapy group was placed on previously known and likely efficacious doses of phosphate binders. Overall, 38% of patients dropped out of the study. Dropouts due to AEs were higher in the lanthanum arm (14%) than in the 'other binder' arm (4%). The Work Group considered that these issues could bias efficacy results in favor of the standard-therapy group, who were more likely to complete the study.

In the smallest study involving 98 patients,13 serum calcium, phosphorus, Ca X P, and calcitriol values were similar in both groups and did not change from baseline throughout the study. The mean serum PTH also remained constant throughout treatment in the lanthanum carbonate group, but a reduction in levels was observed in calcium carbonate-treated patients. Overall, the Work Group considered these data on biochemical markers to be of moderate quality. However, in both studies,13, 349 there was concern with regard to the directness of PTH data for the same reasons expressed above.

4.1.6In patients with CKD stages 3-5D, we recommend avoiding the long-term use of aluminum-containing phosphate binders and, in patients with CKD stage 5D, avoiding dialysate aluminum contamination to prevent aluminum intoxication (1C).

The use of aluminum-containing phosphate binders has been extensively evaluated in the KDOQI Bone and Mineral Metabolism Guidelines.⁵ The major toxicities are neurotoxicity and impairment of bone mineralization, both of which can be prevented by minimizing aluminum exposure. However, the Work Group acknowledged that the literature, as detailed in the KDOQI guidelines,5 supports that the most severe cases of aluminum toxicity occurred in patients whose dialysate was contaminated with aluminum, and that aluminum-based binders only played a secondary role. The quantity of aluminum-based phosphate binders that is safe is unknown. Moreover, several conditions may favor intestinal aluminum absorption, such as diabetes mellitus, secondary HPT, vitamin D status, and a high citrate intake.³⁵⁰ Therefore, the Work Group felt that as numerous alternative phosphate binders have become available, and there is no ability to predict a safe aluminum dose, the long-term use of aluminum-based phosphate binders should be avoided. This was a unanimous vote.

4.1.7In patients with CKD stages 3-5D, we suggest limiting dietary phosphate intake in the treatment of hyperphosphatemia alone or in combination with other treatments (2D).

Only one RCT, by Russo et al.,²⁸⁶ (Tables 21, 22) has specifically assessed the effect of dietary phosphate restriction on CAC. However, it was not designed to show a superiority or an equivalence of dietary phosphate modification when compared with oral phosphate binders. The investigators recruited 90 phosphate-binder-naive patients with CKD stages 3-5 who were not on dialysis. Of these patients, 30 were randomized to a low-phosphate diet alone, with the remaining 60 patients receiving the diet in combination with fixed doses of calcium carbonate (2 g/d) or sevelamer-HCl (1600 mg/d) over a 2-year follow-up period. Final CAC scores were increased in the group receiving phosphate-restricted diet alone and in the group receiving diet in combination with calcium carbonate. There was no progression of calcification in the diet-plus-sevelamer-HCl-treated group (as discussed under Rationale 4.1.5). It is noteworthy that the prescription of phosphate restriction alone did not lead to a decrease in urinary phosphate excretion. Thus, a low-phosphate diet alone did not prevent CKD-associated progression of CAC in patients not receiving dialysis.

In the absence of other RCTs, the Work Group then searched for studies that compared diet with an active or placebo control including more than 25 patients in each arm (or less for bone biopsy studies) with a follow-up of more than 6 months. The only two studies^{351, 352} that met these extended criteria evaluated biochemical data, although one also assessed bone parameters and vascular calcification.³⁵² Zeller et al.³⁵¹ showed that the restriction of dietary protein and phosphate intake was feasible with the maintenance of nutritional parameters in a study of 35 type I diabetes patients with nephropathy. In relation to the biochemical markers of CKD-MBD, they found a significant reduction in urinary phosphate excretion in the group assigned a protein/phosphate restriction as compared with patients receiving a control diet. They did not examine markers of bone turnover. Using bone biopsy in 16 patients with CKD stages 4-5, Lafage-Proust et al.³⁵³ reported that after 5 years of a very-low-protein, low-phosphorus diet (supplemented with essential amino acids and their ketoanalogs), the bone-formation rate was normal or high in 10 patients, and low in the remaining six. They did not observe any low-protein-associated malnutrition in these patients.

Thus, there are insufficient data at present to strongly endorse dietary phosphate restriction as the primary intervention for the management of CKD-MBD, especially stage 5D. It is biologically plausible that such diets are helpful in early CKD and as an adjunct to phosphate binders and dialytic removal in dialysis patients. The limited safety data suggest that dietary phosphate restriction does not compromise nutrition in a monitored setting.

4.1.8In patients with CKD stage 5D, we suggest increasing dialytic phosphate removal in the treatment of persistent hyperphosphatemia (2C).

A narrative review of the literature addressing this issue was carried out. Although research in this area is becoming more abundant, studies are typically small in sample size and lack the rigor required to direct practice. One prospective RCT has reported the impact of alternative dialysis therapies using biochemical markers of CKD-MBD as a secondary end point.314 In this study, Culleton et al.314 (Tables 27, 28 and 29) compared the effect of a nocturnal prolonged-duration HD six times weekly (26 patients) with that of standard HD given thrice weekly for 4 h each session (25 patients) in a parallel design, reporting serum calcium, phosphorus, Ca X P, and iPTH. The authors found significant decreases in serum phosphorus and iPTH in patients allocated to frequent nocturnal HD, as compared with those on standard HD treatment. Serum calcium was comparable in the two groups. The amount of oral phosphate binder needed to control hyperphosphatemia was also reduced. These data suggest that frequent nocturnal HD can lead to an improvement in mineral metabolism (see Tables 27, 28 and 29). Thus, in efforts to control hyperphosphatemia, dialysis regimens that allow an increase in phosphate removal may be an alternative in patients who cannot tolerate phosphate binders or are not willing to take sufficient amounts of them.

SPECIAL CONSIDERATIONS IN CHILDREN

Of all the available binders, only sevelamer-HCl and calcium carbonate have been examined in children, with a total of 47 children studied in two RCTs to date (see Table 20). In one study, 29 children on maintenance dialysis were assigned to either sevelamer-HCl or calcium carbonate, as well as to either calcitriol or doxercalciferol in a factorial design.17 During sevelamer-HCl treatment, levels of serum phosphorus control were similar when compared with those with calcium treatment during the 8 months of study. Serum PTH was lower in the calcium arm compared with that in the sevelamer-HCl arm. There were more episodes of hypercalcemia in the calcium arms compared with that in the sevelamer-HCl arms. There was a 31% dropout rate in this study, but among those who attended for a second biopsy at the end of the study, bone histomorphometric data did not differ between the two groups. In the other study, which had a cross-over design and involved 18 children with CKD stages 3-5 not on dialysis, there was equivalent serum phosphorus control between the groups.354 Given the small number of children studied, the only conclusion that can be derived from these studies is that an avoidance of hypercalcemia may be easier to achieve with the use of sevelamer-HCl. There have been no studies on the use of lanthanum carbonate in children.

ADVERSE EVENTS

Sevelamer-HCl. (Supplementary Table 18) Compared with calcium-based phosphate binders, sevelamer-HCl seems to be well tolerated. Although European patients participating in the 'Treat to Goal' study reported more gastrointestinal side effects with sevelamer-HCl,343 this difference was not seen in the study cohort as a whole.²⁸⁴ As mentioned above, hypercalcemia was more commonly seen in patients treated with calcium-based binders participating in 'Treat to Goal' study,284 and accounted for several of the withdrawals in the calcium-treated arm of the DCOR study.²⁶⁶ In the two studies that reported total serious AEs,266, 284 there was no difference between calcium-based phosphate binder and sevelamer-HCl treatment. This observation is consistent with the conclusion reached by Tonelli et al.355 in a recently published systematic review of the clinical efficacy and safety of sevelamer-HCl in dialysis patients.

Lanthanum carbonate. (Supplementary Table 23) Lanthanum carbonate was shown to be generally well tolerated. The most notable difference between lanthanum carbonate and calcium carbonate was the frequency of clinically significant hypercalcemia with the use of calcium carbonate reported as an AE, as discussed earlier. The incidence of other AEs showed no clinically important differences between lanthanum carbonate and calcium carbonate groups.^{13, 348, 349}

Cognitive function was assessed in the substudy by Altmann et al.³⁵⁶ using the Cognitive Drug Research computerized assessment system. This showed that the use of lanthanum carbonate did not adversely affect cognitive function in HD patients compared with those undergoing standard therapy. Both groups showed a similar decline in cognitive function over a 2-year time period.

The plasma and bone lanthanum levels were assessed and compared as a primary end point in the study by Spasovski et al.98 Plasma lanthanum levels reached a steady state of around 0.6 ng/ml after 36 weeks of treatment. Six weeks after the cessation of 1 year of lanthanum treatment, plasma lanthanum levels had declined to a value of 0.17+ -0.12 ng/ml (P<0.05) and after 2 years to 0.09+ -0.03 ng/ml. The mean bone lanthanum concentration in patients receiving lanthanum carbonate increased from 0.05+ -0.03 to 2.3+ -1.6 mu;g/g (P<0.05) after 1 year and slightly decreased at the end of the study to 1.9+ -1.6 mu;g/g (P<0.05). The mean bone lanthanum concentration in the calcium carbonate group was 0.1+ -0.04 mu;g/g at the 1-year biopsy and 0.15+ -0.06 mu;g/g at the end of 3 years. These data, together with the bone histomorphometry findings, suggested that bone lanthanum deposition was not associated with aluminum-like toxicity.

RESEARCH RECOMMENDATIONS

Advancing the evidence base for phosphorus-lowering therapies

The Work Group considered that robust studies of a large sample size addressing the following issues should be given priority.

• Does lowering serum phosphorus with any phosphate binder improve clinical outcomes, including mortality, cardiovascular events, bone pain, or fracture in patients with CKD stages 3-5 and 5D?
• Does the use of lanthanum carbonate improve cardiovascular calcification compared with the use of calcium-based phosphate binders in patients with CKD stage 5D?
• Is slower progression of arterial calcification (as observed in association with the use of non-calcium-based phosphate binders, such as sevelamer, in comparison with calcium-containing phosphate binders) associated with better survival?
• Can aluminum hydroxide be used safely, at least in the short term, in selected CKD stage 5D patients, provided dialysis water is free of this metal?
• Do improvements in the biochemical parameters that have been associated with alternative dialysis regimens translate into an improvement in clinical outcomes of CKD-MBD?
• Studies are needed to evaluate the clinical benefits associated with the use of dietary intervention in patients with CKD stages 3-5D and stages 1-5T.
• Studies are needed to identify the presence and degree of phosphate additives in foods and their impact on phosphate metabolism.
• More studies in children with CKD-MBD are needed, especially to evaluate cardiovascular end points.

 

 

 

 

 

 

 

 

 

 

Chapter 4.2: Treatment of abnormal PTH levels in CKD-MBD

INTRODUCTION

Patients with CKD and HPT may develop abnormalities of all components of CKD-MBD. Bone effects include an increased bone turnover that may be associated with marrow fibrosis and abnormal mineralization, described as osteitis fibrosa and mixed uremic osteodystrophy. Patient-level consequences may include increased bone and muscle pain, weakness, postural instability, and fracture, whereas marrow fibrosis may exacerbate the anemia of CKD. Severe HPT may lead to pruritus, worsening of residual kidney function caused by hypercalcemia, calciphylaxis, CVD, neuromuscular disturbances, and death. Over the years, approaches to the management of secondary HPT have included using oral calcium salts and increasing dialysate calcium levels to raise serum calcium levels, the prescription of vitamin D, calcitriol or its analogs, parathyroidectomy, and—more recently—the use of calcimimetics, alone or in combination with other drugs. However, some patients with CKD have PTH levels that are inappropriately suppressed, leading to a low bone turnover or adynamic bone disease, conditions that may be exacerbated by the measures listed above.

RECOMMENDATIONS

4.2.1 In patients with CKD stages 3-5 not on dialysis, the optimal PTH level is not known. However, we suggest that patients with levels of intact PTH (iPTH) above the upper normal limit of the assay are first evaluated for hyperphosphatemia, hypocalcemia, and vitamin D deficiency (2C).

It is reasonable to correct these abnormalities with any or all of the following: reducing dietary phosphate intake and administering phosphate binders, calcium supplements, and/or native vitamin D (not graded).

4.2.2 In patients with CKD stages 3-5 not on dialysis, in whom serum PTH is progressively rising and remains persistently above the upper limit of normal for the assay despite correction of modifiable factors, we suggest treatment with calcitriol or vitamin D analogs (2C).

4.2.3 In patients with CKD stage 5D, we suggest maintaining iPTH levels in the range of approximately two to nine times the upper normal limit for the assay (2C).

We suggest that marked changes in PTH levels in either direction within this range prompt an initiation or change in therapy to avoid progression to levels outside of this range (2C).

4.2.4 In patients with CKD stage 5D and elevated or rising PTH, we suggest calcitriol, or vitamin D analogs, or calcimimetics, or a combination of calcimimetics and calcitriol or vitamin D analogs be used to lower PTH (2B).

• It is reasonable that the initial drug selection for the treatment of elevated PTH be based on serum calcium and phosphorus levels and other aspects of CKD-MBD (not graded).
• It is reasonable that calcium or non-calcium-based phosphate binder dosage be adjusted so that treatments to control PTH do not compromise levels of phosphorus and calcium (not graded).
• We recommend that, in patients with hypercalcemia, calcitriol or another vitamin D sterol be reduced or stopped (1B).
• We suggest that, in patients with hyperphosphatemia, calcitriol or another vitamin D sterol be reduced or stopped (2D).
• We suggest that, in patients with hypocalcemia, calcimimetics be reduced or stopped depending on severity, concomitant medications, and clinical signs and symptoms (2D).
• We suggest that, if the intact PTH levels fall below two times the upper limit of normal for the assay, calcitriol, vitamin D analogs, and/or calcimimetics be reduced or stopped (2C).

4.2.5 In patients with CKD stages 3-5D with severe hyperparathyroidism (HPT) who fail to respond to medical/pharmacological therapy, we suggest parathyroidectomy (2B).

Summary of rationale for recommendations

• CKD may lead to a rise in the circulating PTH level, which is a component of CKD-MBD. Lowering serum PTH has been a primary focus of therapy for over 30 years.
• Severe HPT is associated with morbidity and mortality in patients with CKD stages 3-5D. Observational studies consistently report an increased RR of death in CKD stage 5D patients who have PTH values at the extremes (less than two or greater than nine times the upper normal limit of the assay).
• Once developed, severe HPT may be resistant to medical/pharmacological therapy and may persist after transplantation. Thus, progressive increases of PTH should be avoided.
• However, there is difficulty in establishing narrow target ranges for serum iPTH because of the following reasons:
  • Cross-sectional studies in the CKD population show that the median iPTH increases and the range widens with progressive CKD.
  • There are methodological problems with regard to the measurement of PTH, because assays differ in their measurement of accumulating PTH fragments and there is interassay variability (see Chapter 3.1).
  • With a progressive deterioration of kidney function, bone becomes increasingly resistant to the actions of PTH.
  • The predictive value of PTH for underlying bone histology is poor when PTH values are between approximately two and nine times the upper normal laboratory range.
• In RCTs of patients with CKD stages 3-4, calcitriol and vitamin D analogs each lower levels of serum PTH compared with placebo.
• In RCTs of patients with CKD stage 5D, calcitriol, vitamin D analogs, and calcimimetics each lower levels of serum PTH compared with placebo.
• In CKD stages 3-5D, calcitriol and vitamin D analogs may increase serum calcium and phosphorus levels compared with placebo.
• Laboratory-based experimental data show differences in the efficacy and adverse effects of calcitriol and vitamin D analogs, but an analysis of the limited comparative studies in humans fails to show consistent differences.
• In studies of patients with CKD stage 5D, calcimimetics may lower serum calcium and phosphorus levels compared with placebo.
• There are no comparative RCTs that evaluate the use of calcitriol or vitamin D analogs compared with calcimimetics alone.
• There is a lack of RCT data in patients with CKD stages 3-5D that directly shows that the change in PTH with vitamin D (cholecalciferol and ergocalciferol), calcidiol, calcitriol, vitamin D analogs, or cinacalcet leads to improved clinical outcomes or adequately describes potential harm.
• Therefore, these recommendations remain weak.

BACKGROUND

Secondary HPT is a common complication of CKD that, before currently available medical and surgical therapies, resulted in considerable morbidity and mortality, including crippling bone disease. Recently, many observational studies have reported associations between levels of serum PTH, calcium and/or phosphorus and the RR of cardiovascular and all-cause mortality. Experimental and clinical data support the hypothesis that abnormalities of mineral metabolism constitute important 'nontraditional' cardiovascular risk factors. Over the past few years, recommended target ranges have been promoted for serum calcium, phosphorus, and PTH, and an increasing number of therapies are available that assist in achieving these targets. Traditionally, these have included calcium salts, calcitriol, and alfacalcidol. More recently, active vitamin D analogs, cinacalcet hydrochloride, and non-calcium- or aluminum-based phosphate binders have become available. Surgical parathyroidectomy remains a definitive therapy.

Vitamin D

The nomenclature for vitamin D has become unnecessarily complicated over the last several years, although the terms are well defined in chemical and endocrinology literature. The term vitamin D represents both vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Ergocalciferol is synthesized in plants and yeasts after an ultraviolet radiation-catalyzed conversion of its precursor, ergosterol, and, together with some cholecalciferol from oily fish, is a dietary source of vitamin D in humans. However, over 90% of human vitamin D requirements come from exposure of the skin to ultraviolet-B solar radiation. Sunlight converts 7-dehydrocholesterol to previtamin D3, which undergoes a rapid, temperature-dependent isomerization to vitamin D3 or cholecalciferol. Both vitamin D2 and D3 are hydroxylated in the liver to metabolites specified as 25-hydroxyergocalciferol (ercalcidiol), 25-hydroxycholecalciferol (calcidiol), or commonly without specificity as 25-hydroxyvitamin D (25(OH)D). Further, 1-alpha;-hydroxylation occurs mainly in the kidney and also at extrarenal sites. The most active, naturally occurring vitamin D derivative in man is calcitriol (1,25-dihydroxycholecalciferol; commonly abbreviated as 1,25(OH)2D3).

The therapeutic forms of vitamin D sterols available for use in patients with CKD include naturally occurring ergocalciferol, cholecalciferol, 25(OH)D, and calcitriol. Synthetic vitamin D2 analogs include paricalcitol and doxercalciferol, and synthetic vitamin D3 analogs include alfacalcidol, falecalcitriol, and 22-oxacalcitriol (maxacalcitol). Doxercalciferol and alfacalcidol, which are 1-alpha; vitamin D derivatives, require 25-hydroxylation by the liver for activity and are commonly referred to as 'prodrugs.'

Vitamin D has an established role in mineral homeostasis and musculoskeletal function and is recognized to have pleiotropic extraskeletal effects, including modulation of endothelial and immune function, inflammatory responses, and cell cycle regulation. The rate of calcitriol production and inactivation is tightly regulated. In the setting of normal kidney function, a reduction in the levels of calcitriol is sensed by parathyroid gland vitamin D receptors, with a consequent increase in the production and release of PTH. Increased PTH levels increase the activity of renal 1-alpha;-hydroxylase and the conversion of 25(OH)D to calcitriol, which suppresses PTH to its former level. In addition to a transient rise in levels of PTH, this feedback loop may result in a reduction in the levels of serum 25(OH)D. In the presence of CKD, most patients have reduced circulating levels of calcitriol. Initially, this is related to reduced phosphate excretion and a rise in the levels of serum phosphate and fibroblast growth factor-23, both of which suppress renal 1-alpha;-hydroxylase activity. Lower calcitriol levels (and reduced intestinal calcium uptake) facilitate a rise in PTH production, and for a time, this restores levels of serum calcitriol, increases renal phosphate excretion, and improves renal calcium conservation. However, despite increasing circulating levels of PTH, these homeostatic mechanisms inevitably fail if CKD progresses and the number of functioning nephrons decline.

Vitamin D, calcitriol, and vitamin D analogs are used in CKD stages 3-5 and CKD stage 5D to improve abnormal mineral homeostasis and to reduce the risk of secondary HPT developing and progressing. An evaluation of this therapy has generally focused on maintaining levels of serum PTH and calcium within predetermined 'target' ranges, or gauged by bone histomorphometry. A number of preclinical (animal) studies have shown differences in PTH suppression, gastrointestinal calcium absorption, incidence of hypercalcemia and hyperphosphatemia, vascular calcification, and bone histology between calcitriol and some synthetic vitamin D analogs.^{299, 358, 359, 360, 361 and 362} However, the evaluation of these drugs in patients with CKD has only rarely shown similar clear-cut differences. It is well known that, in humans, such a demonstration is inherently difficult, particularly when drugs such as calcium-based phosphate binders are used concomitantly.

The use of cholecalciferol and ergocalciferol has received relatively little attention because of an earlier, widely held view that the kidneys were the only sites of 1-alpha;-hydroxylation of calcidiol and that, in the presence of kidney failure, serum 25(OH)D levels were of less significance. On the other hand, recent data suggest a potential role for 25(OH)D in a number of tissues, independent of renal conversion.^{363, 364, 365 and 366} In patients with CKD, levels of serum 25(OH)D are commonly insufficient or deficient.^{48, 180} Thus, consideration may need to be given to both the management of endocrine (PTH lowering and calcium increasing) and autocrine (local inflammation and cell cycle regulation) effects of vitamin D and calcitriol and its analogs.

Calcimimetics

Physiological studies in animals and humans in the 1980s showed that there was a rapid release of PTH in response to small reductions in serum-ionized calcium,³⁶⁷ lending support to the existence of a calcium sensor in parathyroid glands. This CaR was cloned in 1993,³⁶⁸ leading to a revolutionary understanding of the mechanisms by which cells adjust to changes in extracellular calcium. It is now known that the CaR is expressed in many organs controlling calcium homeostasis, including parathyroids, thyroid C cells, intestine, kidneys, and other tissues. In parathyroids, an activation of CaR stimulates cell-signaling pathways to mobilize intracellular calcium and decreases PTH secretion, whereas an inactivation reduces intracellular calcium and increases PTH secretion.

Calcimimetics are a group of drugs that are allosteric modulators of CaR, augmenting the signal caused by the binding of extracellular ionized calcium to CaR to increase intracellular calcium and decrease PTH release.369 Thus, these drugs 'mimic' an increase in levels of extracellular calcium. Cinacalcet, the only clinically available calcimimetic agent, does not enhance intestinal calcium and phosphorus absorption, and this action differentiates it from vitamin D sterols and their analogs in that it can lower PTH without an increase in circulating levels of calcium and phosphate.

The following tables are found at the end of this chapter: Table 30 summarizes the RCTs of calcitriol or vitamin D analogs in children with CKD. The evidence matrix, a table that describes the methodologic quality of the included studies, and the evidence profile, a table that provides an overall assessment of the quality of the evidence and balance of potential benefits and harm are Tables 31, 32 (CKD stages 3-5) for calcitriol or vitamin D analogs compared to placebos; Tables 33, 34 (CKD stage 5D) for calcitriol compared to vitamin D analogs; and Tables 35, 36 (CKD stage 5D) for calcimimetics. Additional detailed information about the studies of vitamin D, calcitriol and its analogs reviewed in this chapter are further described in detail in the Supplementary Tables 24-38.

 

 

 

 

 

 

RATIONALE

4.2.1 In patients with CKD stages 3-5 not on dialysis, the optimal PTH level is not known. However, we suggest that patients with levels of intact PTH (iPTH) above the upper normal limit of the assay are first evaluated for hyperphosphatemia, hypocalcemia, and vitamin D deficiency (2C).It is reasonable to correct these abnormalities with any or all of the following: reducing dietary phosphate intake and administering phosphate binders, calcium supplements, and/or native vitamin D (not graded).

In patients with CKD stages 3-5, the optimal level of PTH is unknown. There are no strong associative data sets to link elevated PTH to patient-centered outcomes and, unfortunately, at this time, no RCTs have assessed the balance between therapeutic risk and benefit when modest PTH rises are suppressed in patients with CKD stages 3-5. Furthermore, in earlier stages of CKD, secondary HPT with modest increases in levels of PTH represents an appropriate adaptive response to declining kidney function that maintains phosphate, calcitriol, and calcium homeostasis. It is not yet clear how to differentiate an appropriate response from a maladaptive response, but it is likely that future studies evaluating urinary phosphate excretion or fibroblast growth factor-23 levels early in the course of CKD will clarify this issue. In addition, it is possible that a patient whose PTH level is always low is quite different from a patient who has a history of a sustained elevation in PTH and has the level lowered to the same value. Thus, prevention and treatment may not require similar approaches. When patients have very high PTH levels, it is more difficult to lower those levels because of marked parathyroid gland hyperplasia and possible clonal parathyroid cell proliferation, with a reduced or absent ability of the gland to involute.³⁷⁰

Given this lack of data, yet a desire for guidance in the management of patients with CKD stages 3-5, the Work Group felt that continuous increases in PTH over time likely represent a maladaptive response, and it is the persistent rise that should prompt therapy more than an absolute value. In addition, because modest increases in PTH may represent adaptations to a number of underlying factors in patients with CKD stages 3-5, it is appropriate to consider all modifiable factors that may have led to secondary HPT, in addition to the loss of GFR.

Calcium

Both historical use and experimental data support the efficacy of calcium supplementation in lowering PTH, but these findings are not supported by RCTs in patients with CKD stages 3-5 that fulfill our criteria for inclusion into evidence tables. In the absence of such RCTs, it is unknown if benefits outweigh the possible harm associated with calcium overload and AEs of hypercalcemia. In a secondary analysis of one RCT designed to assess the effect of calcium supplementation or placebo on bone density and fracture in postmenopausal women without CKD, a trend was reported toward an increased risk for myocardial infarction and a composite end point of myocardial infarction, stroke, or sudden death in the calcium-treated group.³⁷¹ However, this finding is controversial; investigators in the much larger Women's Health Initiative did not detect an association between supplementation with calcium/vitamin D and myocardial infarction, coronary heart disease, or stroke.³⁷² Russo et al.²⁸⁶ examined the effects of calcium supplementation on serum iPTH in patients with CKD stages 3-5. The administered daily dose was 2 g of calcium carbonate over a time period of 2 years. Serum iPTH levels did not change in response to this treatment (172 vs 176 pg/ml or 18.2 vs 18.7 pmol/l), whereas the GFR remained remarkably stable over the same time period. However, there was an increase in coronary calcification scores (see Chapter 4.1).

Thus, although historically calcium is efficacious in lowering PTH in patients with CKD stages 3-5, it is important to realize that the potential harm has not been adequately evaluated.

Hyperphosphatemia

There are no RCTs in patients with CKD stages 3-5 that specifically evaluate the effect of phosphate binders and lowering of serum phosphorus on PTH that fulfilled our inclusion criteria. However, a recent 8-week RCT in patients with CKD stages 3-4 with hyperphosphatemia found a decrease in PTH in lanthanum-treated patients compared with those with placebo.³⁷³ In addition, secondary HPT is known to be a compensatory response to phosphate retention, hence this approach has theoretical efficacy.

Low serum 25(OH)D levels

Vitamin D insufficiency and deficiency occur commonly in the general population and in patients with CKD. A recent post hoc analysis of the Vitamin D, Calcium, Lyon Study II was conducted by Kooienga et al.³⁷⁴ (Supplementary Tables 25-26). This study assessed the impact of treatment with cholecalciferol 800 IU plus calcium 1200 mg daily vs placebo on biochemical parameters in 610 elderly French women, of whom 322 had estimated glomerular filtration rate (eGFR) values <60 ml/min per 1.73 m², using the MDRD formula. Similar improvements in the proportion of individuals achieving 25(OH)D levels >30 ng/ml (75 nmol/l) at 6 months were seen in all kidney function groups. The proportion of individuals with a >30% reduction in iPTH at 6 months was 50% in all eGFR groups receiving treatment with cholecalciferol plus calcium compared with 6-9% for those on placebo (P<0.001 for all). However, this study was unable to distinguish between the effects of calcium and vitamin D, because the treatments were given in combination and the results may not be applicable to other demographic groups. In patients with CKD stages 3 and 4 with 25(OH)D levels<30 ng/ml (75 nmol/l) and elevated levels of PTH, an observational treatment study using ergocalciferol reported a normalization of the mean 25(OH)D levels in both CKD stages.³⁷⁵ A significant reduction in the median levels of PTH was seen in patients with CKD stage 3, with a trend toward reduced median PTH levels in CKD stage 4.³⁷⁵

4.2.2 In patients with CKD stages 3-5 not on dialysis, in whom serum PTH is progressively rising and remains persistently above the upper limit of normal for the assay despite correction of modifiable factors, we suggest treatment with calcitriol or vitamin D analogs (2C).

Calcitriol or its analogs

Four RCTs were identified that assessed patients with CKD stages 3-5 and met inclusion criteria (Tables 31, 32; Supplementary Tables 25-26). These trials compared the use of doxercalciferol, paricalcitol, alfacalcidol, or calcitriol with placebo. The study evaluating doxercalciferol included 55 patients³⁷⁶ and the study evaluating paricalcitol included 220 patients.377 Both assessed laboratory biochemical end points. African-Americans contributed toward one-quarter to one-half of study participants, with the remainder predominantly Caucasians. The study using alfacalcidol included 176 patients⁹⁷ and the study using calcitriol included 30 patients.¹⁰² Both assessed laboratory values and bone histomorphometry. These latter studies were from 1995 and 1998, respectively, which creates problems of interpretation because of changing patient demographics and altered clinical practices. Many patients in these studies were treated with aluminum-based phosphate binders, and the racial distribution of participants in the European studies was not provided. These studies will be discussed with respect to their end points.

a) Patient-centered end points: For CKD stages 3-5, data on mortality were available from safety analyses of two studies,97, 377 on clinical CVD and cerebrovascular disease from one study,376 and on other clinical outcomes from three studies97, 102, 376 (see Evidence Profile for stages CKD 3-5, Table 32). However, because these data were based on safety and toxicity rather than on end points identified a priori, the information suffered from serious methodological limitations such that treatment effects could not be assessed for these outcomes. Data were absent for hospitalization, fracture, parathyroidectomy, quality-of-life measures, and for changes in BMD.

b) Vascular calcification: No study has evaluated the role of calcitriol or its analogs or of cinacalcet on vascular calcification in CKD stages 3-5.

c) Bone histomorphometry: Three studies evaluated the effect of calcitriol or its analogs on bone histology in CKD stages 3-5: (Tables 31, 32 and Supplementary Table 27)

Nordal and Dahl¹⁰²: In this study published in 1988, 30 patients had bone biopsies at baseline and 28 patients had bone biopsies after 8 months of treatment with calcitriol or placebo. Turnover: The mean bone-formation rate decreased significantly in the calcitriol group and increased in the placebo group, with a significant difference between treatment groups. Approximately 25% of the calcitriol-treated patients had low bone formation (adynamic bone disease) at the end of the study. The eroded surfaces showed a similar pattern, so that calcitriol treatment decreased bone turnover. Fibrosis disappeared in all but four of the biopsies in the calcitriol group, but in none of those taking placebo. Mineralization: Median mineralization, assessed by MLT, was similar and normal in both groups and did not change with either therapy. Volume: Median bone volume was normal in both groups and there was no significant change with either therapy. Overall, calcitriol treatment was effective in treating osteitis fibrosa. The report was limited because adynamic bone disease was not discussed. Approximately 25% of calcitriol-treated patients developed low bone formation after therapy, but none of them had osteomalacia. However, the exact number was not reported.

Hamdy et al.97: In this study published in 1995, bone biopsies were performed in 176 patients at baseline and in 134 patients after treatment with alfacalcidol or placebo. The biopsies were initially placed into diagnostic categories, but later some of the abnormalities were felt to be unimportant. The criteria for 'important' abnormalities were not specified. The measurements were analyzed separately in those patients with unimportant abnormalities at baseline; this was therefore a post hoc subgroup analysis. The paper did not report the changes in measurements according to the entire group of placebo vs the entire group of alfacalcidol-treated patients. There was also an apparent error in the mineralization lag-time calculation in the placebo group. Although detailed measurements were made in a large number of biopsies, the presentation does not allow a critical evaluation of the results. Turnover: The following percentages were deduced from the results section: for patients treated with alfacalcidol, biopsies improved in 32% (improved osteitis fibrosa) and worsened (developed adynamic disease) in 11%. Placebo biopsies improved in 3% and worsened in 13% (6% developed adynamic disease and the rest developed worsened osteitis fibrosis). Mineralization: MLT and osteoid width improved in the alfacalcidol group. There was an increase (worsening) in the osteoid width in some of the placebo-treated patients. Volume: The mean bone volume did not change significantly in any of the groups. Overall, the alfacalcidol treatment resulted in bone histological improvement (related to improvement in osteitis fibrosa and mineralization) more often than did the placebo treatment. However, adynamic bone disease developed more frequently.

Birkenhager-Frenkel et al.³⁷⁸: This study examined the effect of 24,25(OH)2D in subjects who were already taking alfacalcidol. The study met our inclusion criteria, but 24,25(OH)2D is not commercially available so we have not included this in our evidence tables. Interpretation of the biopsy data was limited because the final biopsies were taken close to the site of a biopsy performed 9 months earlier, which alters the results. Also, the treatment group had a significantly different prior response to alfacalcidol so the groups were not comparable at the beginning of the study.

d) Biochemical end points: For patients with CKD stages 3-5, studies using doxercalciferol,376 paricalcitol,377 and alfacalcidol97 (as compared with placebo) assessed laboratory biochemical outcomes. The doxercalciferol study was a 24-week-duration, double-blind, intention-to-treat analysis with a <20% loss to follow-up. In the paricalcitol and alfacalcidol studies, premature patient withdrawal averaged 20-22%. Alfacalcidol doses were adjusted to maintain calcium levels at the upper limit of the laboratory reference range. Compared with placebo, PTH levels fell significantly with these active treatments. Only one study of patients with CKD stages 3-5 was included that compared calcitriol with placebo.102 Over 8 months, the levels of PTH fell significantly in the calcitriol arm compared with the baseline values and the end-of-study placebo values. However, this study enrolled only 15 individuals in each arm and, although it was included in this guideline because of the bone biopsy data, it did not achieve entry criteria for biochemical outcomes.

In studies of patients with CKD stages 3-4, calcium levels trended upward for paricalcitol and doxercalciferol,^{376, 377} whereas calcium levels increased significantly for alfacalcidol.97 Phosphate levels and the calcium phosphorus product significantly increased for doxercalciferol, with an upward trend for paricalcitol and alfacalcidol.

In CKD stages 3-4, levels of bone-specific ALP (b-ALP) were assessed in two studies,^{376, 377} and fell significantly with doxercalciferol compared with placebo (28% for doxercalciferol with no outcome value provided for the placebo arm; P<0.05) and with paricalcitol vs placebo (P<0.001). Total ALP levels were assessed in the alfacalcidol study97 and fell significantly in the active treatment arm (P<0.001).

ADVERSE EVENTS (Supplementary Table 28)
For paricalcitol vs placebo, the percentage of patients reported with hypercalcemia (>2.62 mmol/l) over two consecutive measurements was 2 vs 0%, respectively, and the incidence of hyperphosphatemia was reported to be similar between groups.³⁷⁷ Twelve percent of paricalcitol-treated patients and 6% of placebo-treated patients had two consecutive measurements of Ca X P>4.44 mmol2/l2. For doxercalciferol vs placebo, neither hypercalcemia (defined as >2.67 mmol/l and reported in 4% of both active- and placebo-treated groups) nor hyperphosphatemia differed significantly between active and placebo arms.³⁷⁶ For doxercalciferol, serum phosphorus levels>5.0 mg/dl (1.61 mmol/l) and >6.0 mg/dl (1.94 mmol/l) occurred in 8.5 and 2.6% of patients, respectively, vs 6.5 and 0.5%, respectively, for those in the placebo-treated group, this difference being nonsignificant. Nevertheless, at 24 weeks, serum phosphorus levels were higher in the doxercalciferol group, as were levels of Ca X P. Levels of serum calcium were not significantly different. One patient in the doxercalciferol arm had treatment suspended twice because of hypercalcemia; one had a suppression of serum iPTH to <150 pg/ml (15.9 pmol/l) at week 24; and doxercalciferol treatment was reduced in three patients because of low levels of iPTH. In the alfacalcidol vs placebo study from 1995, hypercalcemia (>10.5 mg/dl or 2.62 mmol/l) occurred in 14% of alfacalcidol-treated patients vs 3% of placebo-treated patients (0.05<P<0.01 between groups),97 and in the calcitriol vs placebo study from 1998, eight calcitriol-treated patients developed hypercalcemia (undefined) vs zero placebo-treated patients.102 Study discontinuation due to AEs ranged from 0 to 12%, with no patient reported to have discontinued treatment because of abnormal laboratory results. When reported, the incidence of other AEs was high for both active treatment and placebo arms.

Calcimimetics

Only one RCT which assessed the effect of the calcimimetic cinacalcet treatment in patients with CKD not receiving dialysis met our inclusion criteria.379 This study assessed biochemical outcomes and AEs. It was not designed to assess effects on vascular calcification, bone histomorphometry, or other clinical outcomes. Patients meeting entry criteria with CKD stage 3 were enrolled, if iPTH levels were >100 pg/ml (10.6 pmol/l) and patients with CKD stage 4 were enrolled if iPTH levels were >160 pg/ml (16.8 pmol/l). The study, conducted over 32 weeks with a 16-week dose titration and a 16-week drug efficacy phase, allowed the concomitant use of vitamin D sterols and/or calcium supplementation. Compared with placebo, cinacalcet reduced plasma iPTH (43 vs 1%), but at the price of frequent, generally asymptomatic decreases in serum calcium (two consecutive values<8.4 mg/dl (2.1 mmol/l) in 62% of participants taking cinacalcet) and increases in levels of serum phosphorus and 24-h urinary calcium excretion. More patients taking cinacalcet than placebo received vitamin D sterols (46 vs 25%). The proportion of participants receiving phosphate binders/calcium supplements increased from 19 to 58% for those taking cinacalcet and from 18 to 20% for those taking placebo. In CKD stages 3 and 4, the effect on bone turnover of this reduction in PTH is unknown, as is the change in urinary calcium. The long-term impact of increased levels of serum phosphorus combined with increased calcium supplementation is of concern, and thus the Work Group felt more data were needed before suggesting that calcimimetics could be used in CKD stages 3-5.

4.2.3 In patients with CKD stage 5D, we suggest maintaining iPTH levels in the range of approximately two to nine times the upper normal limit for the assay (2C).We suggest that marked changes in PTH levels in either direction within this range prompt an initiation or change in therapy to avoid progression to levels outside of this range (2C).

The target PTH in the KDOQI guidelines for CKD stage 5D was based on the predictive ability of PTH, using a Nichols iPTH assay, to predict low- and high-turnover bone disease.5 Unfortunately, that assay is no longer available, and recent studies have shown that iPTH levels within a range of 150-300 pg/ml (15.9-31.8 pmol/l) are not predictive of underlying bone histology (see Chapter 3.2)229 or fractures (Figure 15).

Figure 15 | Comparison of PTH levels to underlying bone histology in chronic hemodialysis patients. Intact PTH levels <150 pg/ml presented a 50% sensitivity, an 85% specificity, and an 83% positive predictive value for the diagnosis of low bone turnover (LT). In contrast, iPTH levels>300 pg/ml presented a 69% sensitivity, a 75% specificity, and a 62% positive predictive value for the diagnosis of high bone turnover (HT). iPTH, intact parathyroid hormone; n, number of patients; NL, normal bone turnover. Reprinted with permission from Barreto et al.²²⁹

Thus, additional evidence in the form of observational data determining associations between PTH and patient-level end points (mortality, cardiovascular death, and fractures) was evaluated by the Work Group (Supplementary Table 24). However, an important caveat is that conclusions based on these reports are limited, because of residual confounding and artificial constraints induced by statistical modeling. Some studies find a 'U'-shaped association with increased risk at both ends,³²⁸ although more current international analyses (DOPPS) often find only an increased RR of all-cause but not cardiovascular mortality when the PTH is >600 pg/ml (63.6 pmol/l).33 The inflection point or range at which PTH becomes significantly associated with increased all-cause mortality varies among studies for the reasons cited above, and ranges from >400 pg/ml (42.4 pmol/l)328 to >480 pg/ml (50.9 pmol/l),³²⁹ >500 pg/ml (53 pmol/l),³³⁰ >511 pg/ml (54.2 pmol/l),317 and >600 pg/ml (>63.6 pmol/l).205 All PTH analyses have been complicated by problems with assay methods and poor precision, as detailed in Chapter 3.1. Unfortunately, most of these analyses either do not indicate the assay type, or the data come from PTH measured with multiple assays. Another confounding factor for these analyses is that many studies feature single-baseline PTH values or infrequent (quarterly or less) measurements. One report has suggested that the 1-84 PTH 'bio-intact' or 'whole' assay is a better predictor of mortality than so-called iPTH assays.³⁰ However, this finding needs to be confirmed. Therefore, the Work Group does not recommend the routine use of 1-84 ('bio-intact' or 'whole') PTH assays at present. On the basis of these observational data, the Work Group considered that levels of iPTH less than two or greater than nine times the upper limit of normal for the PTH assay used represent extreme ranges of risk.

It is important to recognize that there are no RCTs showing that treatment to achieve a specific PTH level results in improved outcomes. In addition, there are no interventional RCTs that establish a 'cause and effect' relationship between the observed outcomes and the measured biochemical variables; the observational data cannot fully evaluate benefits and harm and are inherently biased. The analysis of such relationships is further complicated by the clinical 'reality' that these laboratory parameters do not move in isolation from one another, but rather change in often unpredictable ways depending on the levels of other parameters. This is best demonstrated by the work of Stevens et al.,³⁸⁰ which assessed various biochemical combinations in concert with dialysis vintage and found that specific risks varied significantly according to three-pronged constellations. Thus, the RR for mortality was greatest when levels of serum calcium and phosphorus were elevated in conjunction with low levels of iPTH, and was lowest with normal levels of serum calcium and phosphorus in combination with high levels of iPTH. In addition, duration of dialysis significantly affected the results. A DOPPS study also evaluated combinations of serum parameters of mineral metabolism and reached slightly different conclusions.³³ For example, in the setting of an elevated serum PTH (>300 pg/ml (31.8 pmol/l)), hypercalcemia (>10 mg/dl (2.5 mmol/l)) was associated with increased mortality risk even with normal serum phosphorus levels (Figure 16).

Figure 16 | Risk of all-cause mortality associated with combinations of baseline serum phosphorus and calcium categories by PTH level. HR, hazard ratio; PTH, parathyroid hormone. Reprinted with permission from Tentori et al.³³

Thus, future studies aimed at risk-stratifying patients with CKD should look at combinations of various biochemical abnormalities, rather than isolated parameters. At present, the Work Group felt that clinicians should avoid extreme ranges of PTH, and interpret changes in PTH together with calcium and phosphorus levels to guide therapy. Serum PTH, calcium, and phosphorus are all expected to change with PTH-altering treatments. As extreme values of these biochemical parameters have been linked to adverse patient outcomes in large observational studies, it is important to monitor serum levels of calcium and phosphorus during PTH-altering treatments more frequently.

4.2.4 In patients with CKD stage 5D and elevated or rising PTH, we suggest calcitriol, or vitamin D analogs, or calcimimetics, or a combination of calcimimetics and calcitriol or vitamin D analogs be used to lower PTH (2B).

• It is reasonable that the initial drug selection for the treatment of elevated PTH be based on serum calcium and phosphorus levels and other aspects of CKD-MBD (not graded).
• It is reasonable that calcium or non-calcium-based phosphate binder dosage be adjusted so that treatments to control PTH do not compromise levels of phosphorus and calcium (not graded).
• We recommend that, in patients with hypercalcemia, calcitriol or another vitamin D sterol be reduced or stopped (1B).
• We suggest that, in patients with hyperphosphatemia, calcitriol or another vitamin D sterol be reduced or stopped (2D).
• We suggest that, in patients with hypocalcemia, calcimimetics be reduced or stopped depending on severity, concomitant medications, and clinical signs and symptoms (2D).
• We suggest that, if the intact PTH levels fall below two times the upper limit of normal for the assay, calcitriol, vitamin D analogs, and/or calcimimetics be reduced or stopped (2C).

The Work Group asked if there were differences between the various therapies used to lower PTH in their effects on biochemical indices of CKD-MBD, bone, vascular calcification, or clinical end points. A systematic search was undertaken to evaluate RCTs of vitamin D, calcitriol, or any vitamin D analog vs each other or with placebo in individuals with CKD stage 5D. The a priori criteria chosen by the Work Group for inclusion of an RCT were duration of at least 6 months and a sample size of at least 50, except for bone biopsy studies and studies evaluating children, which were included with a sample size of 10. Importantly, our recommendations parallel recent Cochrane reviews, which were inclusive of all studies and found similar results for calcitriol and its analogs8 and for calcimimetics.³⁸¹ Studies evaluated with the KDIGO systematic review are reviewed below by end point (see Tables 33, 34, 35 and 36).

a) Patient-centered end points: No RCTs of patients with CKD have specifically evaluated the effect of vitamin D, calcitriol, or vitamin D analogs on patient-level outcomes (mortality, fracture, quality of life, hospital admission, and cardiovascular outcomes), and observational data are inconclusive.

There are no studies of either moderate or high quality that show a beneficial or harmful effect of calcimimetics on mortality, CVD, hospitalization, fractures, or quality of life.

Vitamin D, calcitriol, or its analogs

(Tables 34, 35) Patients with all stages of CKD, particularly those on dialysis, have greatly increased mortality and morbidity compared with the general population. Patient-level outcomes of vitamin D therapy that were considered to be of critical or high importance included mortality, cardiovascular events, rates of hospital admission, parathyroidectomy, fracture, musculoskeletal pain, and quality of life. No RCT evaluated mortality, cardiovascular events, hospitalizations, quality of life, or fracture as a primary or secondary end point.

Although the effects of vitamin D therapy on mortality have not been studied in prospective RCTs, recent retrospective observational studies have suggested that survival on dialysis may be improved by vitamin D therapy.^{45, 328, 382, 383} Furthermore, in the large historical cohort study that compared treatment with the vitamin D2 derivative, paricalcitol, with calcitriol, treatment with the former was reported to provide a survival advantage over the latter.³⁸⁴ However, this finding was not confirmed (after adjustment for laboratory values and clinical standardized mortality) in another report that also assessed the vitamin D2 derivative, doxercalciferol,³⁸³ or in a more recent DOPPS analysis.³⁸⁵ In addition, in the latter analysis, no relationship was detected between the use of vitamin D and outcome using an instrumental-variable approach. However, using a patient-level approach, there was an apparent survival benefit for vitamin D usage, as previously reported, suggesting a significant degree of residual confounding. Therefore, evidence from these observational studies could not be used in the development of this guideline when applying the Grades of Recommendation Assessment, Development, and Evaluation approach (GRADE), which requires consistent evidence of an association with an RR>2 (or an HR<0.5) from two or more observational studies, with no plausible confounders. None of these studies achieved an RR>2 (or an HR<0.5). Furthermore, authors of these studies pointed to a number of potential confounders and, importantly, there is inconsistency in findings among the published studies. Thus, RCTs are needed to confirm these findings.

Calcimimetics

All-cause hospitalization, quality of life, fractures, and parathyroidectomy were defined as outcomes of high importance and were evaluated in a secondary analysis³⁸⁶ of prospective RCTs³⁸⁷, ³⁸⁸ that evaluated cinacalcet vs placebo (with the majority of both groups receiving calcitriol or an analog). This analysis reported no statistically significant differences in mortality or all-cause hospitalizations, but a reduction in cardiovascular hospitalization. No differences in quality of life were detected using the Cognitive Functioning scale from the Kidney Disease Quality of Life instrument, but improvements were seen in some domains using the Medical Outcomes Study Short Form 36 (SF-36). The number of fractures and parathyroidectomies in cinacalcet-treated patients was significantly reduced compared with that in those receiving placebo. However, data were sparse for fracture and, although the RR for parathyroidectomy was 0.07 (95% CI 0.01-0.55), there was no description of the indications or protocol for parathyroidectomy, hence the overall quality for both these outcomes was classified as very low.

For all of these clinical outcomes, there were serious methodological limitations, because they were not predefined as either primary or secondary outcomes for RCTs and were taken from the safety data of prospective trials, creating a probable reporting bias. Furthermore, the length of the follow-up varied among patients and, at most, 266 had a 1-year follow-up from the total of 1184, with some having only a 6-month follow-up. More of the control patients agreed to follow-up (138 placebo vs 128 cinacalcet), although a much higher number were randomized to cinacalcet. In addition, quality of life was measured at variable points during the study, but the results were evaluated together, and only 876 out of 1184 individuals had their quality of life data evaluated. In both the Block et al.³⁸⁷ and Lindberg et al.³⁸⁸ studies, the percentage of dropouts was high, and it was not clear whether those who dropped out when their PTH was <250 pg/ml (26.5 pmol/l) were counted as successes or failures. The overall quality of evidence for mortality, hospitalization, and quality of life was thus deemed low.

b) Vascular calcification: There are no conclusions as to the effect of calcitriol or vitamin D analogs or calcimimetics on cardiovascular calcification, as these relationships have not been adequately evaluated in humans.

Only one RCT of calcitriol that met our inclusion criteria evaluated any measure of cardiovascular calcification.101 In that study of calcitriol vs placebo, plain X-rays of the hands, chest, pelvis, and feet were assessed. No differences were reported for the development or progression of CAC or for the calcification of the vessels of the hands, feet, or pelvis. However, vascular calcification was only evaluated in patients without radiological evidence of bone disease, and this number was not provided, creating a potential bias. Furthermore, aluminum hydroxide was used for phosphate control, the dialysate calcium level was 1.65 mmol/l (3.3 mEq/l), and hypercalcemia was common. There are no studies evaluating the effect of cinacalcet on vascular calcification in humans. Thus, the Work Group felt these data were insufficient to reach any conclusions.

c) Bone histology: On the basis of bone biopsy studies, the use of calcitriol or vitamin D analogs is associated with an improvement of osteitis fibrosa and mineralization, and a reduction of bone turnover. The latter may increase the risk of developing adynamic bone disease.There are insufficient data to determine the effect of cinacalcet on bone histomorphometry.

Calcitriol and its analogs

(Supplementary Table 32) Two studies evaluated patients with CKD stage 5D, one in adults and one in children.

Baker et al.101:

Bone biopsies were taken from 54 patients at baseline and from 20 patients after 12-57 months of follow-up; the results were published in 1986. The bone biopsies were separated into categories of normal, osteomalacia, osteitis fibrosa, and mixed osteodystrophy on the basis of a visual assessment by the investigator. No tetracycline labels were given; therefore, some of the patients who were designated as normal could have had adynamic bone disease. The majority of the patients had positive aluminum staining. Turnover: None of the follow-up biopsies showed an improvement in turnover as indicated by a change to the normal category. Bone turnover became too high (normal to osteitis fibrosa or mixed) in 50% of patients taking placebo and in 10% of those taking calcitriol, and too low (normal to osteomalacia) in 30% of the calcitriol group. Thus, turnover worsened in 50% of the placebo and in 40% of the calcitriol-treated individuals. Mineralization: It worsened (normal to osteomalacia or mixed) in 40% of placebo-treated patients and in 30% of calcitriol-treated patients. Volume: No data were provided. Overall, calcitriol may have retarded the development of osteitis fibrosa, but it may have contributed to low bone turnover.

Salusky et al.18:

This clinical trial included 46 children undergoing PD. They were randomly assigned to oral or intraperitoneal calcitriol for 12 months. The group receiving intraperitoneal dosing had lower PTH values, but the bone biopsy data were not significantly different between groups. Turnover: Improvement was seen in 23% of oral and in 36% of intraperitoneal treatment groups (all from improved osteitis fibrosa), but a worsening of turnover was seen in 41% of those receiving oral treatment and in 44% of those given intraperitoneal treatment (mostly development of adynamic bone disease). Mineralization: This parameter improved in 6% of the oral treatment group. Volume: No changes were reported. Overall, there were no significantly different bone biopsy findings between these two different routes of administration.

Calcimimetics

(Supplementary Table 36) There is only one RCT on the effect of cinacalcet vs standard treatment on bone histomorphometry in patients with CKD stage 5D, using repeat bone biopsies at time zero and 12 months.³⁸⁹ Patients receiving HD who had HPT, defined by serum iPTH>300 pg/ml (31.8 pmol/l), were randomly given cinacalcet or placebo for a year. Tetracyline-labeled bone biopsies were performed before and after therapy in 13 placebo and in 19 cinacalcet patients. Although all had a high serum PTH, five patients did not have an increased bone turnover at baseline. Turnover: In placebo biopsies, 45% showed an improved turnover (one patient increased from adynamic to normal and the rest decreased toward normal) and 23% showed an increased (worsened) turnover. In cinacalcet biopsies, 26% showed a decreasing (improved) turnover and 26% showed a worsened turnover (three patients developed adynamic bone disease and, in two patients, an abnormally high turnover became higher). Mineralization: None of the patients had overt osteomalacia, and the change in median MLT was the same in placebo and cinacalcet groups. Some of the biopsies had an abnormally high MLT, but details were not presented. Bone volume: It increased slightly but not significantly in the cinacalcet group, and did not change in the placebo group. Overall, there were no significant differences between groups on the basis of histomorphometry. The study was limited by a small sample size.

d) Biochemical end points: The use of calcitriol or vitamin D analogs is effective in decreasing serum PTH levels and ALP levels, but may increase calcium and phosphorus levels.The use of cinacalcet lowers serum PTH, calcium, phosphorus, the calcium phosphorus product, and b-ALP in patients with CKD stage 5D.

Vitamin D

Despite potential theoretical benefits, data are lacking in CKD stage 5D patients to support treatment to increase levels of 25(OH)D in patients on dialysis. No RCTs of treatment with cholecalciferol or ergocalciferol were identified, but one uncontrolled study reported biochemical responses to 6 months of treatment with oral 25(OH)D3 given to patients on HD.390 In that study, levels of b-ALP improved toward the normal range over 6 months and levels of PTH, calcium, and phosphorus improved toward the KDOQI target ranges in some patients. AEs, such as hyperphosphatemia, were infrequent.

Calcitriol and its analogs

PTH suppression: (Tables 34 and 35) In patients with CKD stage 5D, PTH levels were effectively suppressed by calcitriol compared with placebo in a study by Baker et al.101 conducted from 1977 to 1982.¹⁰¹ The placebo arm of that study had a higher median PTH level at baseline. (Supplementary Tables 30, 31) Levels of calcium increased for calcitriol compared with placebo. In another study of calcitriol compared with maxacalcitol (available in Japan), within-arm PTH levels fell significantly in both groups.391 In that study, doses of calcitriol and maxacalcitol were reduced or ceased if levels of calcium were >2.87 mmol/l or levels of iPTH were <15.9 pmol/l. Within-arm calcium levels rose significantly and there was a trend toward increased phosphate levels, which did not differ between the arms. An average of 20% of patients withdrew from this study, which was not powered adequately to show differences between the treatment groups. Sprague et al.³⁹² studied CKD stage 5D patients randomized in 1995-1996 to calcitriol and paricalcitol, using a 1:4 dosing ratio of calcitriol to paricalcitol. Doses were titrated at 4-week intervals to achieve a 50% or more reduction in levels of PTH, with doses modified when calcium levels exceeded 2.87 mmol/l, Ca X P exceeded 6.05 mmol2/l2 for 2 weeks, or levels of PTH were <10.6 pmol/l. PTH levels fell significantly in both arms, and approximately 60% of patients in both groups achieved a >50% reduction in levels of PTH at the end of the study period. Hypercalcemia occurred at least once in 68% of calcitriol-treated patients and in 83% of paricalcitol-treated patients (a nonsignificant difference), and hyperphosphatemic episodes were reported to be comparable. In a secondary analysis of this study, patients treated with paricalcitol showed more rapid reductions of PTH with fewer sustained episodes of hypercalcemia and/or an elevation of Ca X P (18 vs 38%, P=0.008). This composite outcome was defined as two consecutive measurements of corrected total calcium>11.5 mg/dl (2.87 mmol/l) and/or Ca X P>75 mg2/dl2 (6.05 mmol2/l2) for at least one period of four consecutive blood draws. The authors point out that lower doses of paricalcitol (using a 1:3 ratio) may have increased the time taken by paricalcitol to lower levels of PTH but decreased the incidence of hypercalcemia and hyperphosphatemia in paricalcitol-treated subjects.

Calcium: Support for the use of newer vitamin D analogs (22-oxacalcitriol, doxercalciferol, paricalcitol, and falecalcitriol) is based on experimental studies showing a similar or superior dose-equivalent suppression of PTH with less calcemic and/or phosphatemic activity.393 Therefore, the included RCTs were assessed for these end points. For calcitriol vs 22-oxacalcitriol (maxacalcitol),³⁹¹ there were no significant between-arm differences in any laboratory biochemical parameter, although initially, calcium levels rose more rapidly in response to therapy with maxacalcitol. Outcomes of the earlier (1995-1996) study of calcitriol vs paricalcitol have been described above.³⁹²

Alkaline phosphatases: For CKD stage 5D, median total ALP values were lower for calcitriol than for placebo,101 and b-ALP values did not differ between treatments with calcitriol and maxacalcitol.³⁹¹ Similar findings were reported in a recent meta-analysis that assessed responses to vitamin D compounds in CKD using more liberal inclusion criteria.⁸ This review also found no differences in levels of total ALP for intravenous (i.v.) vs oral vitamin D therapy (four studies) or for intermittent vs daily therapy (two studies).

Route of administration: Another question is the relative efficacy of the administration of i.v. compared with oral calcitriol or its analogs. Owing to a lack of comparative data in the included studies, no conclusions could be reached for preferred routes of administration or for dosing frequency. A meta-analysis of vitamin D therapy that included additional studies has reported that i.v. administration of vitamin D was superior to oral administration in reducing end-of-treatment PTH levels.8 However, there was significant heterogeneity in this analysis, and when one study that used higher i.v. doses of vitamin D was removed,³⁹⁴ there were no differences in the levels of PTH. Levels of serum phosphorus were marginally but significantly lower for the i.v. route (weighted mean difference -0.10 mmol; CI -0.19 to -0.01) with no differences in episodes of hypercalcemia or in levels of ALP. No differences were observed for daily compared with less-frequent intermittent administration.

Calcimimetics. A change in PTH was deemed as a moderately important outcome at the outset of the review (Tables 35, 36 and Supplementary Tables 34, 35). The primary outcome in the RCTs conducted by Block et al.³⁸⁷ and Lindberg et al.³⁸⁸ was the percentage of patients with iPTH<26.5 pmol/l. In both studies, significantly more patients achieved this outcome with cinacalcet (43% in Block's study and 39% in Lindberg's). The percentage of patients with a >30% reduction in iPTH was also significantly higher for cinacalcet. The methodological quality of these studies was graded B because of the relatively short duration of follow-up (26 weeks), the relatively high percentage of patients who dropped out before the evaluation time point (26-32% in cinacalcet-treated subjects vs 22-24% in the control arm), and because of concerns with regard to the generalizability of the studies to patient care because the assay for PTH (the primary measured end point) suffers from methodological problems, including reproducibility (see Chapter 3.1). In addition, one study³⁹⁵ was not analyzed on an intention-to-treat basis, the outcome definitions were shifted compared with the parent protocol, and one of the three studies differed with respect to the inclusion criteria governing the percentage of individuals with very high baseline levels of PTH. Both Block's and Lindberg's studies^{387, 388} showed that cinacalcet significantly reduced the mean percentage of serum calcium, phosphorus, and Ca X P, which were secondary outcomes of both, with no major inconsistencies. The study by Moe et al.³⁹⁵ showed that significantly more patients achieved the KDOQI targets when given cinacalcet than when they underwent the optimal standard treatment. The methodological quality for these end points was graded B because of the dropout rate and the other outcomes reported in the paragraph on PTH above. The quality of evidence for these moderately important outcomes was moderate overall. The study by Block et al.³⁸⁷ reported a lowering of the circulating levels of b-ALP (a bone turnover marker) toward normal in the cinacalcet compared with the control arms. No ALP data (total or bone specific) were provided in other studies.

The ACHIEVE study assessed the use of cinacalcet plus paricalcitol/doxercalciferol vs flexible vitamin D analog therapy,³⁹⁶ although this study did not fulfill our inclusion criteria in terms of duration. The proportion of patients reaching the KDOQI targets for PTH and Ca X P was higher with the combined therapy (21 vs 14%), although this did not reach significance. Of those using cinacalcet plus vitamin D analogs, 19% had iPTH levels <150 pg/ml and only 8% achieved all KDOQI targets for calcium, phosphorus, PTH, and Ca X P compared with 0% using flexible vitamin D analog treatment. No other RCTs comparing calcitriol or vitamin D analogs with calcimimetics, nor comparing different combinations of therapy, are available. Thus, the Work Group could not recommend one therapy, or combination therapy, over another.

Integrating therapies that alter PTH and phosphorus levels. Therapeutic interventions to suppress PTH, but which may compromise levels of calcium and phosphorus, may not be beneficial. Therefore, the use of phosphate binders is an important component of any integrated approach to PTH control, because a dose modification of binders can ameliorate unwanted changes in levels of calcium and phosphorus caused by calcitriol, vitamin D analogs, and calcimimetics. In addition, phosphate binders affect levels of iPTH independently. Calcium-based binders increase serum calcium, which suppresses PTH through the CaR, whereas a reduction in serum phosphorus by calcium- or non-calcium-based binders reduces PTH production at the posttranscriptional level.

SPECIAL CONSIDERATIONS IN CHILDREN

Calcitriol has been studied in RCTs in 102 children with CKD stage 5D and in some children with earlier stages of CKD (Table 30). Only one study was placebo controlled (Greenbaum, n=42),³⁹⁷ whereas the others compared varying dosages (daily vs twice weekly; oral vs i.v.). In 46 patients on PD studied for 1 year, equivalent calcitriol doses were given either i.v. or orally thrice weekly. The groups showed a similar improvement in histomorphometric changes of secondary HPT at follow-up bone biopsy and adynamic bone disease developed in both groups. Intravenously administered calcitriol reduced iPTH levels significantly and raised calcium levels, whereas orally administered calcitriol did not lead to a reduction in the levels of iPTH (values remaining above KDOQI suggested target levels), but increased serum phosphorus. In a 12-week study, calcitriol therapy led to a >30% decrease in iPTH when compared with placebo, and in 24 patients studied for 1 year, daily calcitriol was superior to twice weekly calcitriol for the control of secondary HPT. Another study of paricalcitol compared with placebo in 29 children on maintenance HD showed a >30% reduction in iPTH over a 12-week period. There are insufficient data to recommend one vitamin D sterol over another. In addition, there are no studies evaluating calcimimetics in children.

ADVERSE EVENTS

Calcitriol and its analogs. (Supplementary Table 28) For the study comparing calcitriol and placebo, 16% of patients treated with calcitriol and 5% treated with placebo discontinued treatment because of hypercalcemia.101 Parathyroidectomy rates were 13% for calcitriol (five patients with parathyroid hyperplasia) and 5% for placebo (one patient with a parathyroid adenoma and one with hyperplasia). For maxacalcitol vs calcitriol, calcium levels>11.5 mg/dl (2.87 mmol/l) occurred in 5 vs 2%, respectively (two measurements in two patients vs two measurements in one patient), and phosphorus levels >6.1 mg/dl (1.94 mmol/l) occurred in 68 vs 64%,391 but no patient discontinued treatment because of adverse effects of therapy. For paricalcitol vs calcitriol, calcium levels >11.5 mg/dl (2.87 mmol/l) and/or a Ca X P>6.05 mmol2/l2 occurred in 68% of paricalcitol- and 64% of calcitriol-treated patients.³⁹²

Calcimimetics. (Supplementary Table 37) Nausea and vomiting are the most frequently reported AEs in studies by Block et al.,³⁸⁷ Lindberg et al.,³⁸⁸ and Moe et al.³⁹⁵ In the cinacalcet-treated group, nausea occurred consistently, approximately one-and-a-half times more frequently, and vomiting occurred about twice as often. Serious AEs that may or may not have been treatment related occurred in about a quarter of patients in both the treatment and placebo groups in Lindberg's study. Approximately twice as many patients in the cinacalcet group, in both Block's (15%) and Lindberg's (9%) studies, discontinued treatment because of side effects, principally nausea, vomiting, and other gastrointestinal events. In both Block's and Lindberg's studies, 5% of patients in the cinacalcet groups and less than 1% of those in the control groups had serum calcium values that fell below 7.5 mg/dl (1.9 mmol/l). Hypocalcemic episodes were transient and rarely associated with symptoms. In a safety and efficacy 26- to 52-week extension study reported by Sterrett et al.,¹⁵ treatment with cinacalcet was considered to be safe and effective. AEs (principally nausea and vomiting) caused the discontinuation of therapy in 10% of those treated with cinacalcet and in 0% of controls, whereas 3% of controls withdrew for parathyroidectomy but none treated with cinacalcet. At 12 months, there was no difference in the use of vitamin D (64 vs 63%: cinacalcet vs placebo) or phosphate binders (92 vs 96%), and elemental calcium ingested per meal did not differ between the groups (930+ -641 vs 940+ -625 mg).

4.2.5 In patients with CKD stages 3-5D with severe hyperparathyroidism (HPT) who fail to respond to medical/pharmacological therapy, we suggest parathyroidectomy (2B).

There are no studies evaluating parathyroidectomy of either moderate or high quality that show a beneficial or harmful effect of this treatment on mortality, CVD, hospitalization, fractures, or quality of life; on bone and cardiovascular outcome; or on biochemical outcomes. However, parathyroidectomy performed by an expert surgeon generally results in a marked, sustained reduction in levels of serum PTH, calcium, and phosphorus. Subtotal parathyroidectomy or total parathyroidectomy with autotransplantation effectively reduces elevated levels of iPTH, calcium, phosphorus, and ALP. An improvement in these biochemical parameters is reported to be maintained at 1, 2, and up to 5 years postoperatively, despite a relatively high incidence of recurrent HPT or persisting hypoparathyroidism in some studies.^{401, 402, 403 and 404} There is no evidence that total parathyroidectomy with immediate ectopic parathyroid tissue reimplantation is superior or inferior to subtotal parathyroidectomy. Total parathyroidectomy without immediate parathyroid tissue reimplantation may be contraindicated in patients with CKD stage 5D on a waiting list for kidney transplantation.

Most patients who undergo parathyroidectomy exhibit an improvement in biochemical parameters, but comparisons between medical and surgical therapy for outcomes of morbidity and mortality are difficult to assess. In the absence of RCTs, the available observational studies that compare surgically and medically managed patients are open to important patient selection biases that limit the validity of their findings. Individuals considered for parathyroidectomy differ from those who enrolled in cinacalcet studies. The study with the largest sample size is that of Kestenbaum et al.,⁴⁰⁵ showing lower long-term mortality in patients who underwent parathyroidectomy compared with a matched cohort. However, this is a retrospective, observational study. Short-term, postoperative mortality was high at 3.1% and the better long-term outcome after parathyroidectomy may be due to selection bias, as in the study by Trombetti et al.406 In that study, patients undergoing parathyroidectomy were younger and had fewer comorbidities. However, when the authors proceeded toward a case-control analysis, this difference was no longer significant.

Owing to a lack of RCTs of medical vs surgical therapy of HPT, these management strategies are difficult to compare. For patients unsuitable for surgery or awaiting elective surgery, a case can be made for the availability of medical therapies, including cinacalcet. For patients able to undergo surgery, parathyroidectomy is generally considered when HPT is severe and refractory to medical management, usually after a therapeutic trial of calcitriol, a vitamin D analog, or cinacalcet as suggested above.

Parathyroidectomy could also be considered when medical management to reduce levels of iPTH results in unacceptable rises in levels of serum calcium and/or phosphorus (as occurs frequently using calcitriol or vitamin D analogs), or when medical management is not tolerated because of AEs. Determining what constitutes 'refractory HPT' may be difficult. Clearly, the higher the PTH, the less likely the gland is to involute in response to medical therapy. When severe HPT is present, with levels of PTH>800 pg/ml (85 pmol/l) using a second-generation PTH assay, 22% of patients are reported to achieve levels of iPTH<300 pg/ml (32 pmol/l) with cinacalcet therapy. On the other hand, 81% with mild HPT (iPTH 300-500 pg/ml (32-53 pmol/l)) and 60% with moderate HPT (iPTH 500-800 pg/ml (53-85 pmol/l)) are reported to achieve reductions in serum iPTH to <300 pg/ml (32 pmol/l).395

RESEARCH RECOMMENDATIONS

Well-designed RCTs on the use of vitamin D, calcitriol, and vitamin D analogs in CKD stages 3-5 and stage 5D are required to address a number of issues of clinical importance. These trials should include reporting of allocation concealment, blinding of participants, investigators and outcome assessments, patients lost to follow-up, and AEs:

• In a prospective RCT, does the use of vitamin D, calcitriol, or a vitamin D analog influence patient-level outcomes, including cardiovascular events, rates of hospital admission, parathyroidectomy, fracture, musculoskeletal pain, quality of life or, in CKD stages 3-5, the risk of progression or of requiring renal replacement therapy?
• In a prospective RCT, do any of the newer vitamin D analogs provide a survival advantage over the use of alfacalcidol or calcitriol?
• In a prospective RCT to assess the current dialysis population, do laboratory outcomes differ for newer vitamin D analogs vs doses of calcitriol or alfacalcidol, which are equipotent for PTH lowering?
• In a prospective RCT, what is the influence of cholecalciferol or ergocalciferol on patient-level outcomes, surrogate biochemical outcomes, and AEs in CKD stages 3-5 and stage 5D?
• In a prospective RCT, what is the effect of vitamin D, calcitriol, or vitamin D analogs vs placebo or control on bone outcomes, particularly on the normalization of bone histomorphometry?
• In the management of secondary HPT, particularly in relation to patient-level and bone outcomes, how do vitamin D, calcitriol, or vitamin D analogs compare in terms of efficacy and AEs with calcimimetic cinacalcet?
• When using vitamin D, calcitriol, or vitamin D analogs, does the route of administration or the dosing schedule influence efficacy or AEs?
• RCTs with a sufficient length of follow-up are required to determine whether clinical outcomes—including all-cause mortality, cardiovascular and cerebrovascular morbidity, fractures, bone pain, hospitalization, parathyroidectomy rate, and quality of life—are improved by cinacalcet administration in patients with HPT associated with CKD. There is an ongoing study, EVOLVE (NCT00345839, www.clinicaltrials.com), which is evaluating a primary end point of all-cause mortality, nonfatal cardiovascular events, time to mortality, and time to cardiovascular events after a 4-year follow-up. EVOLVE is due to report in 2012. AEs should be recorded to provide a balanced view of benefit vs harm.
• Further RCTs are required to directly compare treatment of HPT with cinacalcet vs calcitriol/vitamin D analogs, and to establish the optimal use of cinacalcet in combination with phosphate binders and vitamin D sterols.

Chapter 4.3: Treatment of bone with bisphosphonates, other osteoporosis medications, and growth hormone

INTRODUCTION

Abnormal bone is a common component of CKD-MBD. Patients with CKD have an increased risk of fractures compared with age-matched controls, with a resultant significant disability and mortality.^{82, 90, 158} In children, linear height deficit (short stature) is one of the cardinal features of progressive CKD, and is also a component of CKD-MBD. Both fractures and abnormal linear growth can lead to a decreased quality of life, and therefore, treatments to reduce these complications of CKD-MBD are needed. However, clinical studies in patients with CKD stages 4-5 are very limited.

RECOMMENDATIONS

4.3.1 In patients with CKD stages 1-2 with osteoporosis and/or high risk of fracture, as identified by World Health Organization criteria, we recommend management as for the general population (1A).

4.3.2 In patients with CKD stage 3 with PTH in the normal range and osteoporosis and/or high risk of fracture, as identified by World Health Organization criteria, we suggest treatment as for the general population (2B).

4.3.3 In patients with CKD stage 3 with biochemical abnormalities of CKD-MBD and low BMD and/or fragility fractures, we suggest that treatment choices take into account the magnitude and reversibility of the biochemical abnormalities and the progression of CKD, with consideration of a bone biopsy (2D).

4.3.4 In patients with CKD stages 4-5D having biochemical abnormalities of CKD-MBD, and low BMD and/or fragility fractures, we suggest additional investigation with bone biopsy prior to therapy with antiresorptive agents (2C).

4.3.5 In children and adolescents with CKD stages 2-5D and related height deficits, we recommend treatment with recombinant human growth hormone when additional growth is desired, after first addressing malnutrition and biochemical abnormalities of CKD-MBD (1A).

Summary of rationale for recommendations

• Patients with late stages of CKD have a high risk of fractures that are painful and disabling.
• In patients with age-related osteoporosis, surrogate measurements such as low BMD relate to clinical outcomes. This does not necessarily apply in patients with CKD stages 3-5D, in whom the fracture risk is high, regardless of BMD.
• In postmenopausal osteoporosis, medication-related increases in BMD are not always directly responsible for reductions in fracture incidence. Improved BMD does not necessarily parallel bone quality, which is an important factor contributing to bone fragility fractures.
• Studies evaluating medications for the treatment of postmenopausal osteoporosis (risedronate, alendronate, teriparatide, and raloxifene) specifically excluded patients with an elevated serum creatinine level, HPT, or abnormal ALPs. However, post hoc analyses found that these drugs had similar efficacy, improved BMD, and reduced fractures in individuals with a moderately reduced eGFR compared with those with a mildly decreased or normal eGFR.
• No studies meeting evidence-based criteria have evaluated these therapies in patients with CKD stages 3-5D who have biochemical evidence of CKD-MBD.
• There are multiple additional factors that contribute to fractures in patients with CKD stages 3-5D compared with those in the general population. The bone is frequently of abnormal quality because of metabolic abnormalities specific to CKD stages 3-5D and therapies that are used. In addition, patients with CKD may have an increased risk of falling.
• The pathogenesis of bone disease in patients with CKD-MBD is different from that in postmenopausal osteoporosis; therefore, extrapolating results of studies from osteoporosis to patients with CKD stages 3-5D may not be valid, especially with concerns of long-term safety. Thus, when evaluating treatment options for low BMD and/or fracture prevention, patients with CKD stages 1-3 who have no evidence of CKD-MBD must be differentiated from patients with CKD stages 3-5D who do have evidence of CKD-MBD.
• In children, linear growth abnormalities are common and can be corrected with rhGH.

BACKGROUND

Fractures and bone quality

Fractures occur when the bone is subjected to a force that is greater than the bone strength. Bone strength reflects the integration of two main features: BMD and bone quality.^{407, 408 and 409} These 'quality' factors include the rate of bone turnover or remodeling, bone shape and architecture, trabecular connectivity, mineralization, collagen cross-linking, crystal size, intrinsic biomechanical properties of strength and toughness, amount of microdamage, and viability of bone cells. For example, in some diseases such as osteopetrosis and skeletal fluorosis, bone fracture incidence is increased, despite high BMD, because bone quality is poor.

Bone quality in CKD

The pathogenesis of bone disease in patients with CKD-MBD is different from that in postmenopausal osteoporosis.⁴¹⁰ In patients with CKD-MBD, BMD does not predict fracture risk as it does in the general population (as detailed in Chapter 3.2), implying an abnormal bone quality. This limits the ability to extrapolate data from studies of patients with postmenopausal osteoporosis to patients with CKD-MBD. For example, in a report of 1429 bone biopsies from patients with CKD stage 5D, 52 patients had osteoporosis, and 49 of them had adynamic bone disease.411 Another biopsy study of patients with CKD found low bone volume in 46% of the patients, who were younger than the usual patients with idiopathic osteoporosis. Regression analysis revealed that the duration of amenorrhea, being Caucasian, and the OPG/RANK-L ratio influenced bone volume. This study also showed low bone-formation rates in those with low bone volumes.²³¹ Many patients with CKD have abnormal mineralization and increased osteoid. These findings are very different from studies of patients with postmenopausal osteoporosis, who frequently show increased bone turnover and rarely show abnormal mineralization.

Similarly, CKD-MBD may alter bone and cartilage structure and function in children, resulting in an abnormal linear growth in children. Thus, the management of bone disease in patients with CKD is challenging.

Gonadal hormones and bone strength

Many women with CKD have hypoestrogenism, and thus it may seem logical to administer patients estrogen. In postmenopausal women from the general population, estrogen-replacement therapy has been conclusively shown to reduce the incidence of hip, vertebral, and nonvertebral fractures.⁴¹² However, the combined administration of estrogen and progestin may also increase the risk of breast cancer, thromboembolic events, and coronary and cerebrovascular disease, with risks dependent on age and years since menopause.⁴¹³ A current theory is that estrogen can help prevent CACs if given to women who have normal coronary arteries, but can cause plaque rupture and myocardial infarctions in women who already have coronary artery disease.⁴¹⁴ Given that women with CKD frequently have coronary artery disease, the Work Group felt that these drugs should be used with caution. In premenopausal women with CKD, there are not enough data to make any recommendations with regard to estrogen use. Similarly, men with advanced CKD may have reduced testosterone levels,⁴¹⁵ which also may contribute to abnormal bone. However, there are no studies that have specifically evaluated the effect of testosterone therapy on bone in CKD patients.

Abnormal height and CKD

Linear height deficit (short stature) is one of the cardinal features of progressive CKD in pediatric patients. On the basis of the NAPRTCS 2006 Data Report,²⁵² more than one-third of patients are less than the third percentile for height. Baseline kidney function, by height Z-score, shows that there are patients with severe height deficits, even though they have a relatively good function (>25 ml/min). Of patients with a calculated CrCl between 50 and 75 ml/min, 18.2% (379/1720) had a height Z-score worse than -1.88. The mechanisms of linear growth failure include the presence of chronic metabolic acidosis, renal osteodystrophy, nutrient wasting, chronic inflammation, functional hypogonadism (in some adolescents), and dysregulation of the growth hormone-insulin-like growth factor-1 endocrine axis. Since 1988, rhGH has been licensed by the Food and Drug Administration in the United States for the treatment of linear growth failure in children with CKD.

RATIONALE

4.3.1 In patients with CKD stages 1-2 with osteoporosis and/or high risk of fracture, as identified by World Health Organization criteria, we recommend management as for the general population (1A).

Although osteoporosis is a major cause of disability among older men and women, studies from around the world have reported that many patients with osteoporotic fractures are not receiving treatment. The majority of patients with fragility fractures admitted to hospitals are not treated.⁴¹⁶ The disease is considered to be a consequence of aging, despite the fact that therapies can reduce fracture incidence and improve the quality of life. Approximately 85% of elderly women with postmenopausal osteoporosis have CKD.¹²²

Often patients with osteoporosis and CKD stages 1-2 are ignored, even though studies show that medications can reduce fractures and improve the quality of life. The Work Group felt it was important to indicate that bisphosphonates, raloxifene, and teriparatide could be used in these patients with early CKD, who otherwise would be appropriate candidates for therapy in the absence of CKD.

Osteoporosis in the general population

Overview. It was beyond the scope of this report to review all the studies on osteoporosis. The WHO has developed a clinical risk prediction algorithm that will help physicians determine the risk of a fracture within the subsequent decade (http://www.shef.ac.uk/FRAX/index.htm; last accessed on 25 March 2009); treatment decisions will depend on the cost and long-term studies on efficacy and safety; moreover, the exact thresholds for intervention are not yet determined.¹⁸⁵

Currently, it is cost effective to prescribe alendronate for patients with a BMD T-score lower than -2.5 or who haveexperienced a vertebral compression fracture or nontraumatic hip fracture.⁴¹⁷ In patients with osteoporosis, the approved drugs reduce fracture incidence by about 50%. A recent meta-analysis did not find any drug that was superior to others.⁴¹⁸ We focus on medications for which there are data in patients with CKD. It is important to remember that vitamin D and calcium supplements have been used as co-therapies in all of the major clinical trials.

Importance of bone turnover. Idiopathic osteoporosis, seen most often in elderly men and women, has a multifactorial pathophysiology. The bone turnover, for example, ranges from high to suppressed. Within the cancellous bone, the trabeculae become thin and disconnected, and lose the normal plate-like structure.⁴¹⁹ Further perforations of the trabecular plates can lead to an accelerated loss of strength. Medications that inhibit the osteoclastic resorption of the bone prevent this deterioration of bone strength.⁴²⁰ Most of the currently effective medications for osteoporosis (bisphosphonates, estrogen, calcitonin, and raloxifene) act by inhibiting resorption; as a consequence, bone formation is secondarily decreased. Thus, there are only minor changes, if any, in bone volume. Fractures are prevented because trabecular perforations are prevented. The decreased bone resorption and formation also leads to more mineralization in the bone, so that the bone becomes harder. This may also contribute to improving bone strength,⁴²¹ although overmineralization is associated a with more brittle bone.⁴²²

The reason BMD increases in patients with osteoporosis who are treated with antiresorbing medications is that bone becomes more mineralized. In clinical trials of antiresorbing medications, the decrease in fracture rate is not entirely explained by changes in BMD. Changes in the serum markers of bone cell activity suggest that fracture reduction is more closely related to a decrease in bone turnover than to an increase in BMD.^{247, 249}

In clinical trials of osteoporosis medications, fracture rates are decreased by about 50%. This suggests that about half of the individuals did not respond to therapy, and investigators would like to identify which patients are most likely to have a benefit. A recent post hoc evaluation of a large alendronate study found fracture benefit in women with the highest tertile of baseline bone turnover markers, but no difference in fracture rate in those with baseline low markers of bone turnover.²⁴⁸

Bisphosphonates

Overview. Bisphosphonates have been studied extensively and have been shown to effectively decrease bone fractures in patients with osteoporosis in studies with durations up to 5 years.

Pharmacokinetics. Several features with regard to bisphosphonate actions and pharmacokinetics are important in the context of CKD. Bisphosphonates bind very tightly to mineral, with a half-life of over 10 years.⁴²³ In patients with normal kidney function, about half of the administered dose is bound to the bone and the rest is excreted within several hours by the kidney, hence most of the tissues have only a brief exposure to the drugs.⁴²³ Serum calcium decreases and PTH increases.

Vascular calcifications. Although bisphosphonates are usually prescribed for bone diseases, the first-generation bisphosphonate (etidronate) inhibits calcification and has been used to treat ectopic calcifications. Vascular calcifications are an important component of CKD-MBD, and therefore, the effects of bisphosphonates on extraskeletal calcifications are important, and there may be differences between etidronate and the newer aminobisphosphonates. The effect of ibandronate on aortic calcifications was also studied in two 3-year RCTs involving 474 women with postmenopausal osteoporosis. One trial used oral doses and the other i.v. doses. Aortic calcifications increased significantly in both studies in the women taking ibandronate, although a similar increase was also seen in the patients taking a placebo.424 Another study of CACs, measured using EBCT, found increased calcium deposition in 56 elderly women after 2 years of alendronate, but the rate was not significantly greater than that in control women.⁴²⁵ There are no published studies of aminobisphosphonates and vascular calcification in patients with CKD stages 4-5D, although the older bisphosphonate etidronate did prevent arterial calcification progression in a small uncontrolled study of dialysis patients.⁴²⁶

Adverse events. Oral doses commonly cause upper gastrointestinal irritation. Intravenous dosing commonly causes an acute-phase reaction with fever, leukopenia, and bone pain. Severe hypocalcemia has been reported when these medications are administered to patients with a vitamin D deficiency.^{427, 428}

Unusual adverse effects of bisphosphonates include osteonecrosis of the jaw, ocular inflammation, atrial fibrillation, esophageal ulceration, bone pain, and nephrotic syndrome. It is important to realize that the clinical trials in patients with osteoporosis that show a decreased incidence of fractures with bisphosphonates have controls for only 5 years. Currently, there is a debate with regard to the possibility of oversuppression of bone formation with long-term use of bisphosphonates. There are several anecdotal reports of unusual fractures in patients who took bisphosphonates and whose bone biopsies showed no tetracycline labels. There may be a higher risk of subtrochanteric fractures, noted in a small study from Singapore⁴²⁹ and New York.⁴³⁰ Ten-year observational studies of patients who have taken bisphosphonates, however, have not revealed any increased incidence of fractures.⁴³¹ Further follow-up of these patients will be important.

Intermittent administration of 1-34 PTH

The only currently available medication that increases the formation of new bone is teriparatide (recombinant human 1-34 PTH). This anabolic drug has a totally different mechanism of action than bisphosphonates: the BMD increases because there is more bone.^{432, 433} The duration of the anabolic effect of PTH is about 12-18 months; thereafter, bone-formation rates return to baseline.⁴³² An earlier or concurrent use of bisphosphonates attenuates the anabolic effect within cancellous bone.^{434, 435} Teriparatide is particularly effective in cancellous bone.125 Early studies suggested that PTH could increase cancellous bone at the expense of cortical bone;⁴³⁶ the effects have been shown to be complex in cortical bone, with an increase in cortical thickness,⁴³² as well as an increase in cortical porosity⁴³⁷ and a decrease in the volumetric density of the hip as measured by quantitative computed tomography (qCT).⁴³⁴ Bone density at the radius decreases with teriparatide.^{125, 434, 435} This could have implications for the treatment of patients with CKD, who frequently have lower BMD at the radius compared with other skeletal sites (see Chapter 3.2). Furthermore, it is not known if 1-34 PTH will be anabolic in patients who already have high PTH, or in patients with PTH resistance.

Raloxifene

Raloxifene is a selective estrogen receptor modulator that is approved for treatment of postmenopausal osteoporosis. Several large clinical trials have documented a reduction in vertebral fracture incidence, but not in nonvertebral fractures.^{438, 439} This drug acts through estrogen receptors in the bone, but is antagonistic to estrogen effects in the breast and uterus. Similar to estrogen, there is enhanced coagulation and more frequent episodes of thrombophlebitis. The lipid profile improves (lower low-density lipoprotein cholesterol and higher high-density lipoprotein cholesterol), but the effect on CVD in women with preexisting coronary artery disease is similar to that of placebo. In women who have documented coronary artery disease or a history of myocardial infarction, the risk of a fatal stroke was increased with raloxifene.⁴³⁹ The incidence of strokes was not increased in studies of women with osteoporosis or of women with a high risk of breast cancer. The incidence of breast cancer, particularly estrogen-receptor-positive cases, is about half of that seen with placebo and similar to the beneficial effect on breast cancer found with tamoxifen.⁴⁴⁰ Side effects include hot flashes and leg cramps. Raloxifene is not indicated in premenopausal women because it may interfere with native estrogen.4.3.2 In patients with CKD stage 3 with PTH in the normal range and osteoporosis and/or high risk of fracture, as identified by World Health Organization criteria, we suggest treatment as for the general population (2B).

There are no clinical trials of antiresorbing drugs specifically designed for patients with CKD stages 3-5, and such patients were specifically excluded from most osteoporosis treatment trials. However, because of the use of serum creatinine, and not GFR, as an inclusion criteria, patients with CKD stages 3-4 by eGFR were inadvertently enrolled in these studies. Importantly, in all of these studies, patients were excluded if the PTH was elevated or if there were other biochemical abnormalities of CKD-MBD. Specifically, post hoc analyses of trials of bisphosphonates, teriparatide, or raloxifene have evaluated the effect of these agents on BMD and fractures, and are discussed below.

Bisphosphonates in CKD

Two post hoc analyses of trials in patients with osteoporosis have been published (Tables 37, 38 and Supplementary Tables 39-42). Miller et al.¹²⁶ reported a pooled analysis of nine trials using risedronate for treatment of osteoporosis. The primary trials were designed to exclude patients with significant systemic disease, hence individuals with serum creatinine >1.1 times the upper limit of normal were excluded. The individuals were elderly; therefore, most of them had some age-related decline in renal function as estimated by the Cockcroft and Gault method. There were 4071 patients with CKD stage 3, with a mean age of 77 years, and 572 patients with CKD stage 4, with a mean age of 83 years, with a mean serum creatinine of 1.3 mg/dl. These patients showed a reduction in vertebral fracture rates and improvements in bone density, which were similar to those with eGFR above 80 ml/min per 1.73 m²; however, in the CKD stage 4 patients, there was no difference in the femoral neck bone density with risedronate compared to placebo. In most of the primary studies, one-third of the patients were treated with 2.5 mg/d of risedronate, but these patients were not included in this pooled analysis. Bone biopsies were measured in 57 patients, but only 14 had moderate decreases in eGFR and none had CKD stage 4. Mineralizing surface decreased 68% with risedronate. No data with regard to other aspects of the bone biopsies were reported. An important limitation of this study is that the nonvertebral fracture rates were not mentioned, even though they are included in the primary reports.

 

This study provides C-quality evidence that risedronate is effective in elderly women with age-related CKD stage 3. Dropout rates were not represented and the end points from the studies were different; nevertheless, the results were pooled. Finally, the fracture data were incomplete as paired X-ray data were not uniformly available. These results may not apply to men or younger women. The evidence for efficacy in CKD stage 4 is weak, because these women did not show the classical bone abnormalities seen in patients with CKD stage 4. First, they were excluded if serum PTH or ALP values were higher than normal. Second, the mean eGFR was 27 ml/min per 1.73 m² and the interquartile range was 24.5-28.7 ml/min per 1.73 m², hence the eGFR was barely lower than that in CKD stage 4. Third, the mean age was 83 years, by which time the Cockcroft-Gault method becomes less accurate. Using the MDRD method, the average woman in the CKD stage 4 group had an eGRF of 42 ml/min per 1.73 m², hence most of these women did not meet the KDOQI definition of CKD stage 4. Fourth, fewer than half of the patients in the CKD stage 4 group had vertebral fractures measured. Finally, patients with severe CKD usually have more bone loss in the cortical bone (measured at the femoral neck) relative to cancellous bone (measured at the spine). Femoral neck bone density did not show any improvement with risedronate in the CKD stage 4 group.

A similar post hoc analysis of an osteoporosis trial was reported by Jamal et al.¹²⁷ Data from the alendronate fracture intervention trial were re-analyzed according to GFR as estimated by a modified equation using lean body mass from dual-energy X-ray absorptiometry studies. Verification of this method was not included in the report. In this study, as well as in the one conducted by Miller et al.,¹²⁶ the intent of the original trial was to exclude women with kidney disease, but because of their age many individuals did have mild-to-moderate decreases in eGFR. Data extrapolated from a figure in the paper show that fewer than 20 individuals had CKD stage 4, and those with abnormal serum calcium, PTH, or ALP values were excluded. This makes it unlikely that any patient had CKD-MBD. The authors found that the women with an eGFR less than 45 ml/min per 1.73 m² had similar improvements in BMD and decreases in relative fracture risk than those with higher eGFR. The original study was powered to detect differences in fracture rates, but there was inadequate power to detect a fracture benefit in this subgroup analysis. The study was graded as C quality, as the sample size was small and dropout rates were not provided.

Teriparatide in CKD

Miller et al.126 reported a post hoc study that used data from the Fracture Prevention Trial¹²⁵ (Supplementary Tables 43-45) to evaluate patients with postmenopausal osteoporosis, excluding patients with a serum creatinine>2 mg/dl. Using the Cockcroft-Gault formula, the patients were divided on the basis of kidney function into normal (GFR>80 ml/min per 1.73 m², N=885), mildly impaired (GFR 50-79 ml/min per 1.73 m², N=444), or moderately impaired (GFR 30-49 ml/min per 1.73 m², N=83); five patients with an eGFR less than 30 ml/min per 1.73 m² were in the study, but not in the analysis. These women did not carry a diagnosis of kidney disease, and they were thin and elderly. Importantly, the study excluded individuals with elevations in serum calcium, phosphorus, or PTH, or with vitamin D deficiency. The two treatment arms (different doses of teriparatide) were combined in the analysis. The study found that vertebral fracture incidence, detected by changes in radiographs, was greater in individuals with an abnormal renal function compared with those with a normal renal function for all levels of abnormal GFR; however, this difference was not found for nonvertebral fragility fracture. Teriparatide reduced vertebral fracture incidence in all groups; there were no nonvertebral fractures in the group with a moderately decreased eGFR. In addition, teriparatide improved lumbar spine BMD, femoral neck BMD, and collegen cross-link biomarkers in a similar manner in normal, mild, and moderately impaired GFR. The treatment increased serum calcium and uric acid in all subgroups, but the percentage of patients with hypercalcemia and hyperuricemia was greater in the moderately impaired GFR group.

Owing to the post hoc nature of this study, the different groupings of GFR depending on the end point of the study, and the inability to generalize to the 'usual' CKD stage 3 patient because of the exclusion criteria of abnormal biochemistries of CKD-MBD, the study was considered to be of low ('C') quality. In women with postmenopausal osteoporosis who have normal serum biochemistry levels, CKD stages 2-3 do not seem to be a contraindication to teriparatide therapy.

Raloxifene in CKD

A post hoc study used data from the Multiple Outcomes of Raloxifene Evaluation trial to evaluate the efficacy of raloxifene in patients with reduced kidney function (Supplementary Tables 43-45).⁴⁴¹ The original trial included 7705 postmenopausal women aged 31-80 year. Women were randomly assigned to receive placebo, raloxifene 60 mg/d, or raloxifene 120 mg/d, in addition to daily calcium supplements of 500 mg and 400-600 IU of vitamin D. The trial included women at least 2 years postmenopausal, with osteoporosis defined by low BMD or radiographical evidence of vertebral fractures. Women with a serum creatinine level>2.6 mg/dl (225 mu;mol/l) at baseline were excluded. For the post hoc analysis, some sites that did not use the central lab for creatinine were excluded, with a total of 7316 postmenopausal women being included. CKD was defined using the Cockcroft-Gault formula, and divided by kidney function into CrCl>60 ml/min (N=2343), CrCl 45-59 ml/min (N=3293), or CrCl<45 ml/min (N=1480). In the latter group, the median CrCl was 40.6 (range 20-44.9) and only 55 individuals had CrCl<30 ml/min; thus, this group represents CKD stage 3 patients. Importantly, the study excluded individuals with elevations in serum PTH, or with vitamin D deficiency, and the levels of PTH were normal in all of the CKD groups. The two treatment arms (different doses of raloxifene) were combined in the analysis. The study found that femoral neck and spine BMD increased with raloxifene compared with treatment using placebo. The femoral neck BMD increase was greatest in patients with lower CrCl compared with those in other kidney disease groups, but this difference disappeared when the MDRD formula was used instead of that of Cockcroft-Gault. There was a significant reduction in vertebral fractures in the overall cohort of raloxifine-treated patients, with no difference in the three (CrCl) groups. The odds ratio for vertebral fracture was 0.60 for those with a normal kidney function, 0.54 with eGFR 45-59 ml/min per 1.73 m², and 0.74 if eGFR was <45 ml/min per 1.73 m². In the latter group, this was not significant, but only 282 women were in that group. In contrast, there was no difference in nonvertebral fracture incidence in raloxifene-treated patients compared with those on placebo in the overall cohort (consistent with the results of the primary study), or within the groups defined by eGFR. AEs were greater in patients with a reduced kidney function, but there was no difference based on treatment assignment. This study was graded to be of 'B' quality, limited because of the post hoc analyses.

4.3.3 In patients with CKD stage 3 with biochemical abnormalities of CKD-MBD and low BMD and/or fragility fractures, we suggest that treatment choices take into account the magnitude and reversibility of the biochemical abnormalities and the progression of CKD, with consideration of a bone biopsy (2D).

At CKD stage 3, some patients have already developed abnormalities of CKD-MBD, in particular, secondary HPT. The large randomized trials of osteoporosis medications detailed above excluded those with known kidney disease, but many of the patients had early CKD stage 3. As kidney disease progresses, bone disease changes from idiopathic osteoporosis to renal osteodystrophy. This disease progression has not been characterized very well and is probably variable from patient to patient, but it seems to begin around a GFR of 40-50 ml/min per 1.73 m², when the biochemical manifestations of CKD-MBD initially appear.^{28, 233} The clinical trials of bisphosphonates, raloxifene, and teriparatide have excluded individuals with abnormal PTH values, hence the beneficial effects of these therapies cannot be assumed to apply to patients whose disease has progressed to those stages of CKD when biochemical abnormalities, and related bone remodeling abnormalities start to appear (that is, CKD-MBD, see Chapter 3.2). Given the heterogeneity of this population in terms of progressive CKD, duration of CKD, and severity of CKD-MBD, these patients must be evaluated on an individual basis. The Work Group recommends that secondary HPT be addressed first, as in Chapter 4.2. In patients in whom HPT has been corrected, the GFR is stable, and the risk of a fracture outweighs the potential long-term risk of inducing an irreversible low bone turnover, therapy with bisphosphonates may be considered. However, bisphosphonates are likely to prevent fractures only in those patients who have increased bone resorption. Therefore, the Work Group recommends consideration of a bone biopsy whenever feasible.

4.3.4 In patients with CKD stages 4-5D, having biochemical abnormalities of CKD-MBD, and low BMD and/or fragility fractures, we suggest additional investigation with bone biopsy prior to therapy with antiresorptive agents (2C).

The effectiveness of long-term bisphosphonate, teriparatide, or raloxifene therapy in CKD stages 4-5D with biochemical abnormalities of CKD-MBD is currently unknown. The Work Group could therefore not recommend the routine use of these agents, especially in light of safety concerns that are highlighted below.

Bisphosphonates in CKD stages 4-5D

A small study of 12 dialysis patients given pamidronate found reduced serum calcium and increased PTH.⁴⁴² A recent abstract presented by Amerling et al.⁴⁴³ found that patients with CKD stages 2-5 who were taking oral alendronate had low-turnover bone disease with absent tetracycline uptake. These patients had all been referred to the renal clinic. Thus, the bisphophonates could cause adynamic bone disease in patients with CKD-MBD. This is an important consideration for patients with CKD-MBD stage 5D, in whom the prevalence of low-turnover bone disease is high (28% of patients, range 4-60%; see Chapter 3.2).

We have no definite evidence that bisphosphonates are harmful to patients with CKD stages 4-5. Bisphosphonates could potentially be beneficial to those with a low bone density and a high bone turnover, with well-controlled serum PTH and minerals. An RCT is needed for this population. In addition, the pharmacodynamics of these drugs in CKD should be better defined.

Teriparatide in CKD stages 4-5D

There are no data on teriparatide in patients with CKD stage 3 who have biochemical abnormalities (high serum PTH, abnormal serum ALPs or 25(OH)D), and also no data in patients with CKD stages 4-5. There is a theoretical concern that preexisting HPT would be exacerbated by teriparatide, and the anabolic effects may not be able to overcome the resorptive effects. Moreover, patients with CKD-MBD show resistance to skeletal actions of PTH, hence they may not respond to intermittent injections of usual 1-34 PTH doses. One could speculate that teriparatide might be useful in patients with surgical hypoparathyroidism and adynamic bone disease, but there is currently no evidence to support this.

Raloxifene in CKD stages 4-5D

There was a single RCT evaluating raloxifene in dialysis patients,⁴⁴⁴ with 25 patients randomized to 60 mg/d raloxifene and 25 randomized to placebo for 1 year. The patients were postmenopausal by at least 2 years, and the BMD T-score was below -2.0 s.d. In the raloxifene-treated patients, the results showed a significant improvement in lumbar spine, but not hip BMD, after 1 year. Serum levels of pyridinoline (a marker of bone resorption) and of low-density lipoprotein cholesterol decreased after 6 months in the raloxifene-treated patients compared with those on placebo. There were no side effects noted. This study was graded of 'B' quality because of small sample size and the question of generalizability of the end point of BMD, as BMD in dialysis patients may not predict fracture risk as it does in the general population. This small study was not felt to be adequate for raloxifene to be recommended for routine use in dialysis patients.

From the physiological point of view, raloxifene is expected to be beneficial to bone in postmenopausal women with CKD-MBD, and reduction in breast cancer could be an important additional benefit. However, raloxifene increases the risk of thromboembolism, and larger studies are needed to determine whether the risks of thromboembolism or dialysis access thrombosis are seen in women with CKD stage 5D. There are also insufficient data with regard to the pharmacokinetics of raloxifene in dialysis patients. The drug is excreted through hepatic metabolism, unlike bisphosphonates. The effect of abnormal protein binding has not been studied, but this is an important factor for estrogen. The free estradiol levels in women with CKD stage 5D are twice as high as in women with normal kidney function when given the same dose.²⁰⁴ Most importantly, the patients enrolled in the MORE trial⁴⁴¹ had no biochemical evidence of CKD-MBD, and thus fracture efficacy may not be generalizable to patients with CKD stages 3-5D with CKD-MBD, in whom bone quality may be altered for reasons other than estrogen deficiency.

4.3.5 In children and adolescents with CKD stages 2-5D and related height deficits, we recommend treatment with recombinant human growth hormone when additional growth is desired, after first addressing malnutrition and biochemical abnormalities of CKD-MBD (1A).

There was a 2006 Cochrane Review on the use of rhGH in children with CKD.19 We searched using PEDS PICCOD criteria to determine if there were additional RCT studies not included or published, and found none. The Cochrane article19 reviewed 15 RCTs (629 children) that compared rhGH therapy with placebo. No studies have been published since then. These studies showed an improvement in height s.d. score, height velocity, and height velocity s.d. score. Depending on the study, the effects were evaluated at 6, 12, or 24 months, with positive results at all time points. However, across all growth outcomes, there was a consistent pattern of waning effect with longer duration of treatment. Thus, rhGH administration is efficacious in standard measures of growth in children. Available RCT data suggest that children with CKD should be treated with 28 IU/m²/week of rhGH. Compared with a dose of 14 IU/m²/week, the larger dose increases height by about 1.5 cm/year over 1 year, but increasing the dose to 56 IU/m²/week did not result in a statistically significant improvement in growth indices. However, these conclusions are based on only 18 patients. There are limited bone biopsy data in children treated with rhGH. The consistency of the positive benefits of rhGH across studies and in AEs was considered a high-quality evidence, leading to a strong guideline recommending its use in children with CKD height deficits.

The benefits to growth need to be balanced with AEs and the difficulty of adhering to a daily subcutaneous injection regimen. In a recent case series of children with CKD treated with rhGH for 2 years, children who responded to rhGH reported that they would choose treatment again, and those who did not respond generally reported that they would not choose treatment again.⁴⁴⁵ These data suggest that treatment response overrides concerns about injections. Adherence to treatment was time dependent, so that 41% of parents reported noncompliance at 1 year, whereas 91% reported missing injections at 2 years (when response to treatment had waned). When most parents are asked to trade-off the growth potential of their children against the burden of daily injections, they opt for rhGH treatment. In general, AEs were usually minor.

RESEARCH RECOMMENDATIONS

The following research studies are needed:

• A randomized, placebo-controlled clinical trial of men and women with CKD stages 4-5D, with controlled serum PTH, phosphorous, and calcium but low bone density, treated with bisphosphonates. The study should evaluate bone density, bone biopsy in at least a subset, serum PTH, calcium and ALP, fracture incidence, and measures of vascular calcification.
• A pharmacokinetic study of postmenopausal women with CKD stage 5D should evaluate serum levels of raloxifene and teriparatide after administration.
• An RCT in women with CKD stages 4-5D comparing the effects of raloxifene vs placebo on bone density, bone biopsy in at least a subset, serum PTH, calcium, phosphorous, ALP, cholesterol, incidence of fractures, breast cancer, heart disease, stroke, and blood/access clots.
• A prospective study of patients with CKD stage 5D with adynamic bone disease and low serum PTH levels using teriparatide to determine markers of bone formation and resorption, bone biopsies, and serum calcium/phosphorous/ALP.
• An RCT of pediatric CKD-MBD patients treated with rhGH therapy compared with those on placebo to evaluate bone histomorphometry, height, skeletal age, and fractures.

SUPPLEMENTARY MATERIAL

Supplementary Table 14. Overview table of selected studies demonstrating the risk relationships between biochemical parameters of Ca, P, Ca X P, and mortality in CKD stages 3-5 and 5D.
Supplementary Table 15. Summary table of RCTs examining the treatment of CKD-MBD with sevelamer-HCl vs calcium-containing phosphate binders in CKD stage 5D—description of population at baseline.
Supplementary Table 16. Summary table of RCTs examining the treatment of CKD-MBD with sevelamer-HCl vs calcium-containing phosphate binders in CKD stage 5D—intervention and results.
Supplementary Table 17. Summary table of RCTs examining the treatment of CKD-MBD with sevelamer-HCl vs calcium-containing phosphate binders in CKD stage 5D—bone biopsy results.
Supplementary Table 18. Adverse events of sevelamer-HCl vs calcium-containing phosphate binders in CKD stages 3-5 and 5D.
Supplementary Table 19. Ongoing RCTs examining the effect of phosphate binders on CKD-MBD.
Supplementary Table 20. Summary table of the treatment of CKD-MBD with lanthanum carbonate vs other phosphate binders in CKD stage 5D—description of population at baseline.
Supplementary Table 21. Summary table of the treatment of CKD-MBD with lanthanum carbonate vs other phosphate binders in CKD stage 5D—intervention and results.
Supplementary Table 22. Summary table of the treatment of CKD-MBD with lanthanum carbonate vs other phosphate binders in CKD stage 5D—bone biopsy results.
Supplementary Table 23. Adverse events of lanthanum carbonate vs other phosphate binders in CKD stage 5D.
Supplementary Table 24. Overview table of selected studies demonstrating the risk relationships between hormonal parameters of PTH, vitamin D, and mortality in CKD stages 3-5 and 5D.
Supplementary Table 25. Summary table of the treatment of CKD-MBD with calcitriol or vitamin D analogs vs placebo in CKD stages 3-5—description of population at baseline.
Supplementary Table 26. Summary table of the treatment of CKD-MBD with calcitriol or vitamin D analogs vs placebo in CKD stages 3-5—intervention and results.
Supplementary Table 27. Summary table of the treatment of CKD-MBD with calcitriol or vitamin D analogs vs placebo in CKD stages 3-5—bone biopsy results.
Supplementary Table 28. Adverse events of calcitriol or vitamin D analogs in CKD stages 3-5D.
Supplementary Table 29. Ongoing RCTs examining the effect of vitamin D, calcitriol, or vitamin D analogs on CKD-MBD in CKD stages 3-5.
Supplementary Table 30. Summary table of the treatment of CKD-MBD with calcitriol vs placebo or vitamin D analogs in CKD stage 5D—description of population at baseline.
Supplementary Table 31. Summary table of the treatment of CKD-MBD with calcitriol vs placebo or vitamin D analogs in CKD stage 5D—intervention and results.
Supplementary Table 32. Summary table of the treatment of CKD-MBD with calcitriol vs placebo or vitamin D analogs in CKD stage 5D—bone biopsy results.
Supplementary Table 33. Ongoing RCTs examining the effect of vitamin D, calcitriol, or vitamin D analogs on CKD-MBD in CKD stage 5D.
Supplementary Table 34. Summary table of RCTs examining the treatment of CKD-MBD with calcimimetics in CKD stage 5D—description of population at baseline.
Supplementary Table 35. Summary table of RCTs examining the treatment of CKD-MBD with calcimimetics in CKD stage 5D—intervention and results.
Supplementary Table 36. Summary table of RCTs examining the treatment of CKD-MBD with calcimimetics in CKD stage 5D—bone biopsy results.
Supplementary Table 37. Adverse events of calcimimetics vs placebo in CKD stage 5D.
Supplementary Table 38. Ongoing RCTs examining the effect of calcimimetics on CKD-MBD.
Supplementary Table 39. Summary table of the treatment of CKD-MBD with bisphosphonates in CKD stages 3-5—description of population at baseline.
Supplementary Table 40. Summary table of the treatment of CKD-MBD with bisphosphonates in CKD stages 3-5—intervention and results.
Supplementary Table 41. Adverse events of bisphosphonates in CKD stages 3-5.
Supplementary Table 42. Ongoing RCTs examining the effect of bisphosphonates on CKD-MBD.
Supplementary Table 43. Summary table of the treatment of CKD-MBD with other bone treatments in CKD stages 3-5 and 5D—description of population at baseline.
Supplementary Table 44. Summary table of the treatment of CKD-MBD with other bone treatments in CKD stages 3-5 and 5D—intervention and results.
Supplementary Table 45. Adverse events of other bone treatments in CKD stages 3-5 and 5D.
Supplementary material is linked to the online version of the paper at http://www.nature.com/ki