Kidney bone disease and mortality in CKD: revisiting the role of vitamin D, calcimimetics, alkaline phosphatase, and minerals

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1 review & 2010 International Society of Nephrology Kidney bone disease and mortality in CKD: revisiting the role of vitamin D, calcimimetics, alkaline phosphatase, and minerals Kamyar Kalantar-Zadeh 1,2,3,4, Anuja Shah 1,2, Uyen Duong 1, Rulin C. Hechter 1,2, Ramanath Dukkipati 1,2 and Csaba P. Kovesdy 5,6 1 Harold Simmons Center for Chronic Disease Research and Epidemiology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA; 2 Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA; 3 David Geffen School of Medicine at UCLA, Los Angeles, California, USA; 4 Department of Epidemiology, UCLA School of Public Health, Los Angeles, California, USA; 5 Division of Nephrology, Salem Veterans Affairs Medical Center, Salem, Virginia, USA and 6 Department of Medicine, University of Virginia, Charlottesville, Virginia, USA Recent evidence suggests that the traditional syndromes known as renal osteodystrophy, secondary hyperparathyroidism, and vitamin D deficiency are related to mortality in persons with moderate to advanced chronic kidney disease (CKD). The so-called kidney bone disease, also known as mineral and bone disorders, is defined to include bone disorders, mineral disarrays, and vascular calcification. We have identified 14 common and clinically relevant conditions of contemporary nature that are related to the kidney bone disease, including calcitriol (active vitamin D) deficiency, 25(OH)-vitamin D deficiency, biochemical hyperparathyroidism, relatively low parathyroid hormone (PTH) level, increased serum alkaline phosphatase (hyperphosphatasemia), elevated fibroblast growth factor (FGF)-23, high turnover bone disease, adynamic bone disease, uremic osteoporosis, vascular calcification, hyperand hypophosphatemia, and hyper- and hypocalcemia. We present a critical review of these 14 conditions with emphasis on patient survival pertinent clinical outcomes. We also review unresolved controversies surrounding the management of these conditions by administration of nutritional vitamin D (ergocalciferol and cholecalciferol), vitamin D receptor activators (calcitriol, alphacalcidiol, doxercalciferol), D-mimetics (paricalcitol, maxacalcitol), calcimimetics (cinacalcet), recombinant PTH (teriparatide), and receptor activator of nuclear factor-jb ligandmodulators (denosumab); compare mortality predictability of PTH and alkaline phosphatase; and examine potential risks of bone disorders and mineral disarrays in CKD. ; doi: /ki KEYWORDS: alkaline phosphatase; calcimimetic; D-mimetic; hyerparathyroidism; hypocalcemia; hypophosphatemia Correspondence: Kamyar Kalantar-Zadeh, Harold Simmons Center for Chronic Disease Research and Epidemiology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 West Carson Street, C1-Annex, Torrance, California , USA. TO CITE THIS ARTICLE: Kalantar-Zadeh K, Shah A, Duong U, Hechter RC, Dukkipati R, Kovesdy CP. Kidney bone disease and mortality in CKD: revisiting the role of vitamin D, calcimimetics, alkaline phosphatase, and minerals. Kidney Int 2010; 78 (Suppl 117): S10 S21. Bone disorders, mineral disarrays, and vascular calcification are the three closely interrelated and common conditions in individuals with moderate to advanced chronic kidney disease (CKD). 1,2 These conditions seem to be related to a progressive deficiency of active vitamin D and worsening secondary hyperparathyroidism (SHPT), which happen with gradual loss of renal function and lead to renal osteodystrophy. 3 Some leaders have suggested the designation of CKD-mineral and bone disorder for the constellation of the foregoing disorders. 1,2 Even though the term CKD mineral and bone disorder may sound more inclusive than the traditional term renal osteodystrophy, many physicians and health-care professionals, as well as many, continue to refer to these disorders as renal bone disease 4,5 or simply kidney bone disease. 6,7 Table 1 includes the list of the most commonly encountered conditions related to kidney bone disease in individuals with CKD. We present a critical review of the 14 conditions listed in Table 1, with emphasis on CKD patient survival pertinent clinical outcomes. CALCITRIOL (ACTIVE VITAMIN D) DEFICIENCY SHPT is engendered, at least in part, as a result of the progressive decline in the circulating level of 1,25 dihydroxycholecalciferol (1,25(OH) 2 D 3 or calcitriol), also known as activate (hormone) vitamin D, across worsening stages of CKD Replacement of active vitamin D has thus become the main strategy in the treatment of SHPT. The introduction of a number of analogs of the active vitamin D molecule, together also known as vitamin D receptor activators (VDRAs), including synthetic 1-a hydroxylated prehormones such as doxercalciferol (D2) and a-calcidiol (D3), has not only broadened our therapeutic armamentarium 11,12 but has S10

2 K Kalantar-Zadeh et al.: Kidney bone disease review Table 1 Disorders related to kidney bone disease Disorder/condition Possible cause Potential consequence Management 1 1,25 dihydroxy vitamin D (calcitriol) deficiency Insufficient and/or inhibited 1-a hydroxylation, m FGF-23, hyperphosphatemia, m PTH 2 25(OH) vitamin D deficiency Nutritional (reflecting background population?), MICS 3 Hyperparathyroidism k Calcitriol, hypocalcemia, hyperphosphatemia, k vitamin D receptor, k -sensing receptor, PTH resistance, m FGF-23 4 Low PTH MICS, load, administration of native or active vitamin D or calcimimetics, PTH assay error/ variability 5 Hyperphosphatasemia SHPT, calcitriol deficiency, (increased level of high-turnover bone disease circulating alkaline phosphatase) Probably the main driver of SHPT and renal osteodystrophy; may be associated with MICS, vascular calcification, atherosclerotic CV disease and death. MICS, vascular calcification, atherosclerotic CV disease and death Renal osteodystrophy, uremic toxin, vascular calcification, atherosclerotic CV disease and death, poor survival, refractory anemia resistant to ESA Questionable causal link to adynamic bone disease or other outcomes Worsening renal osteodystrophy, osteoporosis, vascular calcification, atherosclerotic CV disease and death, poor survival 6 Elevated FGF-23 k GFR, hyperphosphatemia Phosphaturic effect (with adequate residual renal function), inhibition of 1-a hydroxylation, k calcitriol, hypocalcemia(?) 7 High-turnover bone disease 8 Adynamic bone disease SHPT, calcitriol deficiency, 25(OH) D deficiency (?), uremia Calcium load (both high bath and high p.o. intake), diabetes mellitus, peritoneal dialysis, intake of vitamin D and calcimimetic (?), aluminum deposition 9 Osteoporosis Aging, uremia, MICS, vitamin D deficiency, hypocalcemia 10 Vascular calcification MICS, diabetes mellitus, vitamin D deficiency, SHPT 11 Hyperphosphatemia k GFR, increased phosphorus ingestion in protein and preservatives, k FGF-23, vitamin D analogs, calcimimetics (in NDD-CKD) 12 Hypophosphatemia MICS, protein-energy wasting, low protein intake, imposed (overzealous) dietary restrictions, calcimimetics (in dialysis ) 13 Hypercalcemia Calcium load, -based binder, dialysate, vitamin D, refractory (tertiary) hyperparathyroidism, adynamic bone disease Renal osteodystrophy, decreased bone mineral density, osteitis fibrosa, pathological (spontaneous) fractures, hyperphosphatasemia Hypercalcemia (cause vs consequence?), bone fracture (?) Pathological (spontaneous) fractures; higher death risk Peripheral vascular disease, CV disease and death, poor survival m SHPT, m FGF-23, m vascular calcification, m mortality Increased death risk (as a surrogate of malnutrition and poor p.o. intake) m Vascular calcification (?), m mortality 14 Hypocalcemia k GFR, calcimimetics Osteoporosis, potential risk of arrhythmias, possible increased risk of death VDRA, D-mimetic, nutritional D (?), phosphorus binder (?) Nutritional D (?), VDRA, D-mimetic VDRA, D-mimetic, calcimimetic, phosphorus binder Lower dialysate concentration, lower load, nutritional and anti-inflammatory interventions (?) VDRA, D-mimetic, calcimimetic, phosphorus binder (?), avoid inorganic phosphorus (processed food) Phosphorus binder (?), avoid inorganic phosphorus (processed food), calcimimetics (?) VDRA, D-mimetic, calcimimetic, phosphorus binder Lower dialysate concentration, lower load, avoid nonselective VDRA RANK ligand modulation, VDRA, D-mimetics (?), calcimimetic (?) VDRA, D-mimetics, calcimimetics Phosphorus binder, avoid inorganic phosphorus (processed food), calcimimetic (?), convert nonselective VDRA to D-mimetic Increase dietary protein intake, VDRA Calcimimetics, bisphosphonates, convert nonselective VDRA to D-mimetic VDRA, D-mimetic, avoid calcimimetic Abbreviations: CKD, chronic kidney disease; CV, cardiovascular; FGF, fibroblast growth factor; GFR, glomerular filtration rate; MICS, malnutrition inflammation complex syndrome; NDD-CKD, nondialysis-dependent CKD; PTH, parathyroid hormone; p.o., per os; RANK, receptor activator of nuclear factor-kb; SHPT; secondary hyperparathyroidism; VDRA, vitamin D receptor activators. also made decisions regarding which drug to use more complicated. 13 We recently examined the rationale for the therapeutic use of VDRAs, alone or in combination with other therapeutic agents such as -sensing receptor agonists, also known as calcimimetics such as cinacalcet, and/or nutritional vitamin D, that is, precursor of 25(OH) vitamin D, such as ergocalciferol and cholecalciferol. 3,12 In particular, we reviewed the recent observational data on the association of VDRA and survival in CKD. 3,12 There are an increasing number of observational studies indicating survival advantages of VDRA in CKD, including several studies in maintenance dialysis and two additional studies in nondialysis-dependent CKD. 22,23 To our knowledge, only one observational study has not uniformly confirmed the association of vitamin D agents and CKD S11

3 review K Kalantar-Zadeh et al.: Kidney bone disease survival, in which apparently both VDRAs and nutritional vitamin D agents, combined as one treatment group, were examined. 24 The consistency of the epidemiological data is remarkable, making a strong point about the potential of causality, given other features of Hill s causality criteria 25 such as biological plausibility and scientific coherence. 3 Some experimental studies using animal models have shown an association between VDRA and vascular calcification or myocardial fibrosis, 29 whereas other studies have shown salutary effects, including improved left ventricular hypertrophy 30 or lack of vascular calcification with more selective VDRAs that may have less effect on vitamin D receptors of the gastrointestinal tract, leading to less and phosphorus absorption. 31 Recently, the World Health Organization has reclassified some selective VDRAs, along with calcimimetics, out of vitamin D agents and under other anti-parathyroid agents. We propose the term D-mimetics for selective VDRA agents with less calcemic effect, such as paricalcitol (D 2 ) 32 and maxacalcitol (22-oxacalcitriol, D 3 ). 33 Nevertheless, the survival advantages of VDRAs or D-mimetics should eventually be tested in randomized controlled trials, not withstanding the fact that many fundamental beliefs of contemporary medicine and public health, such as the association between smoking and lung cancer, have never been tested in any randomized controlled trial. 12 Differences in survival advantages between D-mimetics such as paricalcitol and nonselective VDRAs such as calcitriol observed in a large epidemiological study 34 may also be explained by virtue of their differential effects on diverse parathyroid hormone (PTH) segments. Monier-Faugere et al. 35 found that calcitriol and paricalcitol have trivial but biologically significant differences between their effects on circulating levels of PTH-(1 84), intact PTH, large C-terminal PTH fragments, as well as on the ratio of PTH- (1 84) to C-terminal PTH fragment or PTH-(7 84), that is, ipth minus PTH-(1 84). PTH-(7 84) has been shown to function as a partial antagonist of PTH-(1 84), with opposite biological activities. 36,37 In CKD, reduction in renal function is accompanied by a higher increase in C-terminal PTH than in PTH-(1 84). 38 The administration of cinacalcet to dialysis with SHPT 39 or to with parathyroid cancer 40 does not change the ratio between intact PTH and PTH-(1 84). 36 Among VDRAs, paricalcitol has less hypercalcemic and hyperphosphatemic effects and does not induce low bone turnover in a rat model of renal failure. 41 Furthermore, the affinity of paricalcitol for vitamin D receptor is three times less than that of calcitriol, whereas its calcemic and phosphatemic effects have been shown to be 10 times lower. 35 Biologically plausible mechanisms that can explain survival advantages of different VDRAs are yet to be discovered and confirmed in clinical trials. 25(OH) VITAMIN D DEFICIENCY The Kidney Disease Outcome Quality Initiative (KDOQI) guidelines recommend measuring 25(OH) D (calcidiol) levels in individuals with CKD and hyperparathyroidism and, if below 30 ng/ml, replacing it with nutritional (inactive) vitamin D 2 (ergocalciferol) or D 3 (cholecalciferol). 42 The recommended ergocalciferol dose is 50,000 units (one pill) per week every month for 3 6 months, according to the severity of vitamin D deficiency. 43 Assuming liver function is intact, the administered nutritional (inactive) vitamin D precursor or substrate is expected to be converted to 25(OH) D and ready for further 1a-hydroxylation in the kidney or in nonrenal (peripheral) organs. 12 Although many studies have shown meaningful epidemiological or pathophysiological association between low 25(OH) D level and outcomes in the general population, 44 such findings need to be confirmed in observational or interventional studies in CKD patient populations. 45 A recent prospective cohort study showed that lower levels of 25(OH) D were associated with increased mortality in incident hemodialysis, but VDRA administration virtually nullified the mortality predictability of 25(OH) D deficiency. 46 Before the introduction of VDRA, nutritional (inactive or native) vitamin D agents such as ergocalciferol or cholecalciferol were used with less success in dialysis. A controlled trial by Berl et al. 47 found that vitamin D 3 was not effective in decreasing serum PTH level in dialysis, whereas calcitriol was. Nine of 12 on D 3 showed a histological deterioration of bone disease, whereas in six of seven who received calcitriol, an improved-to-unchanged status of bone histology was observed. 47 In another study by Malluche et al., 48 vitamin D 3, in doses that normalized intestinal absorption of, failed to restore bone histology to normal, although mineralization and collagen texture of osteoid were consistently improved. There is ongoing debate as to whether in the absence of renal 1a-hydroxylation in renal failure peripheral (nonrenal) 1a-hydroxylase is adequate to generate the required magnitude of circulating 1,25(OH) 2 D, especially if the availability of the substrate, that is, 25(OH) D, is enhanced by increasing the intake of nutritional vitamin D. 49 Apart from the above unanswered question, 25(OH) vitamin D may have a more widespread role, besides being a mere precursor or substrate to activate vitamin D. 45 Even though currently there are no convincing data about the usefulness of nutritional vitamin D in CKD, 12 there is heightened debate in pharmaceutical industry-related circles as to whether the combination of nutritional D and a calcimimetic can be as good as active vitamin D alone. Despite less encouraging results pertaining to the administration of nutritional D to dialysis in the past, it is possible that the combination of nutritional vitamin D and a calcimimetic 50 is more promising than nutritional D alone, a hypothesis that needs to be tested in well-designed randomized controlled trials. BIOCHEMICAL HYPERPARATHYROIDISM In individuals with a normal renal function, a serum-intact PTH of 65 pg/ml or above is considered abnormal and likely S12

4 K Kalantar-Zadeh et al.: Kidney bone disease review to be a sign of primary hyperparathyroidism. Indeed, in the face of a normal-to-high serum level, even PTH levels in mid-to-high 50s pg/ml may be abnormal. 51 However, the most recent version of the KDOQI has recommended higher cutoff levels as the definition of treatment-eligible SHPT, that is, PTH levels above 75, 110, and 300 pg/ml for CKD stages 3, 4, and 5, respectively. 51 Whereas the Kidney Disease Initiative Global Outcome has proposed the target range within approximately 2 9 times higher than the upper PTH threshold level of each region or country, both KDOQI and the Kidney Disease Initiative Global Outcome guidelines recommend PTH target levels that are much higher than the normal range of the general US population (o65 pg/ml). Assuming that PTH is a uremic toxin and associated with poor survival in CKD, as recently shown by Kovesdy et al., 52 normalization of PTH levels using active or nutritional vitamin D agents or calcimimetics seems prudent, provided reliable PTH assays can be used. 53 The Japanese Society for Dialysis Therapy ( recommends a PTH target range of pg/ml for Japanese dialysis 54 in whom median serum PTH is closer to 150 pg/ml (Figure 1), 55 compared with US dialysis with a median PTH above 200 pg/ml. 15 A recent study showed that in over 58,000 US American maintenance hemodialysis, PTH levels above 300 pg/ml were associated with increased death risk (Figure 2). 15 In this epidemiological analysis using timedependent models, intact PTH levels in pg/ml were incrementally associated with higher death risk when compared with the pg/ml (reference) group. However, PTH levels above 600 pg/ml, although still associated with a high death risk, did not show further increase in mortality, as would be expected for a dose response phenomenon. The aforementioned attenuated mortality with a PTH above 600 pg/ml may be due to the fact that most dialysis with very high PTH levels often received higher than usual doses of active vitamin D analogs (Figure 2). 15 Consistent with this notion, a recent study showed that the survival advantages of African American dialysis, who usually have higher PTH levels, can also be explained by virtue of their higher likelihood of receiving active vitamin D agents. 21 In another recent study, the ratio of paricalcitol dose per unit of PTH was linearly associated with greater survival. 20 SYNDROME OF APPARENT LOW SERUM PTH The KDOQI guidelines recommend against PTH levels below 150 pg/ml in CKD stage 5 to mitigate the risk of adynamic bone disease. 42 However, significant discrepancies may exist between the histopathological diagnosis of adynamic bone and the biochemical detection of low PTH. A recent epidemiological study in nondialysis-dependent CKD found that the lower the PTH the greater the survival. 52 Interestingly, a large epidemiological study in maintenance hemodialysis showed a similar trend in a conventional Cox model using baseline PTH measures at the start of the cohort, whereas a time-dependent survival model showed that a low PTH seemed to be associated with higher death risk, that is, a so-called U-shaped phenomenon (Figure 2). 15 This may be due to several reasons listed in Table 2 and depicted in Figure 3. In particular, the KDOQI guidelines recommend withholding active vitamin D agents and calcimimetics when JSDT target pg/ml N=130,525 prevalent Japanese hemodialysis in 2007 KDOQI target pg/ml intact PTH (pg/ml) Figure 1 Parathyroid hormone (PTH) distribution in 130,525 prevalent Japanese hemodialysis in Median dialysis vintage is 4 years. Data are abstracted from the Japanese Society for Dialysis Therapy registry of dialysis ( which recommends a PTH target range of pg/ml. 54 KDOQI, Kidney Disease Outcome Quality Initiative. S13

5 review K Kalantar-Zadeh et al.: Kidney bone disease All-cause death hazard ratio Increased death risk in PTH<150: Less likely to receive VDRA, D-mimetics, or calcimimetics, and more likely to have MICS? KDOQI target: Time-dependent model with repeated measures Attenuated mortality rise in PTH>600: Result of high doses of VDRA, D-mimetics, or calcimimetic? < intact PTH (pg/ml) Figure 2 The U-shaped association between serum intact parathyroid hormone (PTH) and survival in 58,058 maintenance hemodialysis over 2 years (adapted from Kalantar-Zadeh et al. 15 ). KDOQI, Kidney Disease Outcome Quality Initiative; MICS, malnutrition inflammation complex; VDRA, vitamin D receptor activator. 700 Table 2 Causes of biochemically measured, relatively low serum intact PTH level in CKD, for example, PTH o150 pg/ml, using conventional PTH assays Calcium-based binders Calcium rich diet Higher concentration in dialysate bath Metabolic syndrome Diabetes mellitus Malnutrition inflammation complex Oxidative stress Carbonyl (pentosidine) stress Peritoneal dialysis Advanced age Caucasian race PTH assay errors Administration of nutritional D, VDRA, or D-mimetics Administration of calcimimetics Administration of recombinant PTH (teriparatide) a Administration of RANK ligand modulators(?) Adynamic bone disease Abbreviations: CKD, chronic kidney disease; PTH, parathyroid hormone; RANK, receptor activator of nuclear factor-kb; VDRA, vitamin D receptor activator. a Administration of recombinat PTH, known as teriparatide (injectable Forteo), may suppress the measurable naive PTH level based on the PTH assay used. Malnutrition inflammation wasting (MICS)? Real adynamic bone disease VDRA and D-mimetics Calcimimetics PTH assay variability Advanced age white race comorbidities?? Calcium load Decreased PTH level Guidelines Misinterpreted as adynamic bone disease? Secondary hyperparathyroidism High-turnover bone disease alkaline phosphatase Vascular calcification death Withholding VDRA, D-mimetics and/or calcimimetics Figure 3 Schematic representation of the links between components of kidney bone disease and vascular calcification. Note potential contributors of low parathyroid hormone (PTH) level and its confounded association with poor outcomes. MICS, malnutrition inflammation complex; VDRA, vitamin D receptor activator. PTH is below a certain range, 42 and this recommendation may indeed lead to increased death risk as discussed above. A high load from -based binders 56 or from a dialysate bath 57 may lead to vascular calcification and cardiovascular death and may also suppress PTH, at the same time exaggerating the artificial association between low PTH and poor outcomes. PTH level may also be confounded by such nonbone-related factors such as obesity 58 or pentosidine-mediated carbonyl stress. 59 PTH assay discrepancies may lead to seemingly low PTH levels as well. 60,61 Different subtypes and/or fragments of PTH may be measured by different assays, such as the inhibitory (7 84) S14

6 K Kalantar-Zadeh et al.: Kidney bone disease review portion that is related to one of the large carboxy-terminals and is measured along with active (1 84) PTH when the so-called intact PTH assay is used. 4 Finally, the administration of teriparatide, a synthetic recombinant 1 34 PTH, 62 to osteoporotic with or without CKD, may increase bone turnover by stimulating osteoblasts more than osteoclasts, leading to elevated serum and suppressed serum phosphorus and circulating (measurable) intact PTH levels. A recent case report indicated that teriparatide was successfully used in a parathyoridectomized CKD patient with severe hypocalcemia due to hungry bone syndrome. 63 Currently, there are no data available about the consequences of teriparatide therapy in uremia. A recent epidemiological study found that, even among dialysis with an intact PTH below 150 pg/ml, a high serum alkaline phosphatase (4120 IU/l) was associated with higher death risk compared with lower alkaline phosphatase levels. 64 In a large cohort of Japanese dialysis, low PTH (o150 pg/ml) was associated with the highest survival. 65 We have recently found that low PTH is yet another facet of the malnutrition inflammation complex and that, after adjusting for this confounder, the PTH in the 100 to 150 pg/ml range is associated with the best 5-year survival in a cohort of hemodialysis. 66 INCREASED SERUM ALKALINE PHOSPHATASE Hyperphosphatasemia or hyperphosphatasia refers to disorders that feature elevated serum alkaline phosphatase activity in the blood. 67 The high serum alkaline phosphatase level in CKD is usually from excesses of the bone isoforms of the enzyme, but it may also happen in certain types of liver disorders and biliary obstruction. 68,69 Whereas serum alkaline phosphatase used to be a traditional measure for the management of kidney bone disease, in recent years, it seemed to have fallen out of favor, probably because the KDOQI guidelines did not include it in its recommendations, nor did they suggest any cutoff levels or target ranges for it. 42 A recent epidemiological study has shown robust associations between higher serum alkaline phosphatase (especially if 4120 U/l) and poor survival in hemodialysis. 64 Indeed, compared with serum PTH, which has a U-shaped association with mortality (Figure 2), serum alkaline phosphatase seems to have a linear and incremental association with both all-cause and cardiovascular mortality (Figure 4), and this association seems to hold across different PTH strata, including PTH below 150 pg/ml. 15 As lower alkaline phosphatase is associated with lower PTH (and ultimately with hypodynamic bone), some might expect a higher, rather than lower, mortality associated with low serum levels. Our epidemiological findings 15,64 are contrary to this expectation, suggesting that alkaline phosphatase may be more than a mere marker of bone turnover. Higher alkaline phosphatase has indeed been shown to result in increased hydrolysis of pyrophosphate, 70,71 which is a potent inhibitor of vascular calcification The effect of alkaline phosphatase on pyrophosphate could be the link that Death risk Intact PTH level Alkaline phosphatase explains why lower levels of the former are associated with a linear decrease in mortality. 75 Indeed, a recent epidemiological study found that higher levels of alkaline phosphatase, and no other biomarkers such as PTH or minerals, were associated with coronary artery calcification in hemodialysis. 76 Another possible explanation for the observed association is a link between higher alkaline phosphatase levels and lower 25(OH) vitamin D levels, which is per se associated with increased mortality. 46 Alkaline phosphatase is a marker of bone resorption, and its rise in CKD is associated with worsening bone mineral density. 80 Alkaline phosphatase can be effectively lowered by both active vitamin D products 12,81,82 and calcimimetics. 83 Indeed, a recent meta-analysis, which questioned the PTH-lowering effect of active vitamin D analogs, showed that these agents can decrease serum alkaline phosphatase effectively. 84 Recent data indicate a link between pyrophosphate and tissuenonspecific alkaline phosphatase as a causative pathway to vascular calcification. 70,75 A recent study suggested that the lower serum alkaline phosphatase is the better would be the response of dialysis to erythropoietin-stimulating agents during anemia management. 85 The consistency of epidemiological and experimental data on alkaline phosphatase and the fact that vitamin D and calcimimetics can both lower its circulating level make this traditional marker a promising tool for the management of kidney bone disease, notwithstanding the lack of adequate recommendations by current KDOQI guidelines. FIBROBLAST GROWTH FACTOR-23 Similar to PTH, fibroblast growth factor (FGF)-23 has phosphaturic properties; however, it also inhibits 1-a hydroxylation, and may hence aggravate calcitriol deficiency, leading to further PTH production and release. 86,87 It is unclear to what extent the different pathophysiological mechanisms, that is, intrinsic loss of enzymatic activity vs suppression by FGF-23, contribute to the lower 1-a hydroxylase activity, but the net effect is a progressive decline in activate vitamin D levels with advancing stages of CKD. It is speculated that VDR activation may increase, whereas calcimimatic administration may decrease FGF The latter may explain why Death risk level Figure 4 A comparison between survival predictability of serum parathyroid hormone (PTH) (as shown in Figure 2) and serum alkaline phosphatase in dialysis. S15

7 review K Kalantar-Zadeh et al.: Kidney bone disease calcimimetics lead to paradoxical hyperphosphatemia in with CKD stages 3 and 4 and some urine output, whereas in dialysis with no significant residual renal function, serum phosphorus tends to decrease, similar to hungry bone syndrome after parathyroidectomy. 87 Similar to hyperglycemia-associated increase in A1c levels, 88 persistent hyperphosphatemia may lead to higher FGF-23 levels, which, per se, independent of serum phosphorus is associated with both increased death risk and increased serum alkaline phosphatase in maintenance dialysis. 89 Further epidemiological and clinical studies are needed to examine the association between FGF-23 with vascular calcification and mortality in CKD. HIGH-TURNOVER BONE DISEASE AND OSTEOPOROSIS Even though changes in bone structure in histopathological examinations are the hallmarks of high-turnover bone disease, biomarkers such as increased serum PTH and/or alkaline phosphatase are often used as screening and detection tools. 4,90 To date, no reliable biomarker of bone histopathology has been found. Diminished bone mineral density may be observed with this or other types of renal osteodystrophy. 91,92 Indeed, low bone mineral density and osteoporosis are often associated with increased risk of aortic calcification in the general population. 93 A recent study showed that diminished bone mineral density was related to protein-energy wastage and poor survival in dialysis. 94 Additional studies examining the association between the nature of bone disease or its histopathology and survival in the CKD patient population are needed to show the consistency of such findings. Nevertheless, emerging studies that indicate robust and incremental association between serum alkaline phosphatase and mortality (see above) may indicate the deleterious effect of highturnover bone disease on survival. ADYNAMIC (LOW TURNOVER) BONE Notwithstanding the pathognomonic histopathological features of adynamic bone disease in CKD, recent evidence implies that adynamic bone status might indeed be a secondary phenomenon and a consequence of the malnutrition inflammation complex syndrome, which is per se associated with hypoalbuminemia, increased serum levels of proinflammatory cytokines, protein-energy wastage, 95 and increased cardiovascular disease and death in maintenance dialysis. 96 A recent study in 44 chronic peritoneal dialysis showed that low serum albumin was associated with adynamic bone. 97 Although we are not aware of any study that indicates a direct causal effect of inflammation on adynamic bone disease in CKD, in vitro PTH secretion is suppressed by interleukin-6, 98 a strong proinflammatory cytokine that is associated with poor outcome in maintenance dialysis. Interleukin-1b (IL-1b), another proinflammatory cytokine, may also suppress PTH secretion; in another in vitro study, PTH secretion from cultured parathyroid tissue slices was significantly inhibited in media containing IL-1b. 99 This effect may be mediated through the specific IL-1 receptors that upregulate sensing receptor mrna, leading to apparent low bone turnover. 99 Indeed, in the foregoing study, the inhibitory effect of IL-1b could be counteracted by the IL-1 receptor antagonist, 99 indicating that the inflammation-induced suppression of PTH can potentially be overcome by treatment of malnutrition inflammation complex syndrome in individuals with CKD. Hence, interventions that can improve hypoalbuminemia and kidney disease wasting by correcting malnutrition and/or by mitigating inflammation, for example, through agents that counteract tumor necrosis factor-a or other proinflammatory cytokines, 100 may be more promising approaches for the management of adynamic bone disease, rather than decreasing the dose of or withholding activated vitamin D analogs or calcimimetics. UREMIC OSTEOPOROSIS The use of the term osteoporosis for CKD, distinct from hyperparathyroidism-associated renal osteodystrophy, is a matter of debate. 101 Trials of therapeutic interventions to prevent fractures in nonuremic populations with osteoporosis cannot be generalized to CKD. 101 Taal et al. 102 showed that total hip bone mass predicts survival in hemodialysis. Bone mineral density is lower in CKD with higher PTH levels, 92 although a recent study indicated that worse bone mineral density is associated with higher averaged serum alkaline phosphatase levels (Figure 5) and that a serum alkaline phosphatase level above 120 U/l is the only significant and independent predictor of osteoporosis in these. 80 Denosumab is a human monoclonal antibody to the receptor activator of nuclear factor-kb ligand that blocks its binding to receptor activator of nuclear factor-kb, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. 103 Although in non-ckd alkaline phosphatase (U/L) to Bone mineral density Figure 5 Mean serum alkaline phosphatase according to the tertiles of T score 154 maintenance hemodialysis (adapted from Park et al. 80 ). S16

8 K Kalantar-Zadeh et al.: Kidney bone disease review denosumab is associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis, its use in the setting of uremia remains to be examined. 104 VASCULAR CALCIFICATION The recent literature is oversaturated with exponential numbers of studies indicating a high prevalence of vascular calcification in CKD 105,106 and its association with death risk. 107,108 Medial calcification, which happens more frequently in CKD, is associated with increased death risk as compared with no vascular calcification, but intimal calcification has the strongest association with death risk. 109 There are mixed data about the association of -based phosphorus binders and vascular calcification. 110,111 A recent controlled trial did not show any conclusive association between type of binder and short-term survival, even though a trend toward better survival was observed with non binder sevelamer. 112,113 Another trial showed no advantage of sevelamer over acetate in conjunction with statin, but both treatment arms were associated with increased calcification. 114 There are conflicting data and opinions about the association of vitamin D or calcimemtics with worsening or amelioration of vascular calcification. 13 The highly competitive nature of the binder marketing in the current environment and a lack of conclusive data has lead to major confusion among both physicians and as to whether any medication or intervention is associated with significant vascular calcification, and if so, whether the calcification that is engendered in this way is related to poor survival. 13 HYPERPHOSPHATEMIA The link between phosphorus retention and SHPT has been known for decades. 115 Recent evidence emphasizes the FGF- 23 pathway as the link between hyperphosphatemia and active vitamin D deficiency due to inhibition of 1-a hydroxylation of 25(OH) vitamin D. Several recent epidemiological studies have found an incremental association between phosphorus levels above 6 or 7 mg/dl and increased death risk. 15,116 Determination of which cutoff level of serum phosphorus is accepted in which stage of CKD is a matter of ongoing debate, despite the clear-cut cutoff levels recommended by KDOQI guidelines. 42 Organic phosphorus in dietary protein is less absorbable through the gastrointestinal tract (30 40% in plant proteins with phytates and 40 60% in animal proteins) compared with inorganic phosphorus in additives of enhanced food (up to 100% absorbable). 117,118 Higher phosphorus intake is associated with death risk, as is the intake of food with a higher phosphorus to protein ratio. 119 A recent study suggested that dietary protein restriction to lower serum phosphorus may cause more harm, that is, increased mortality, than good in dialysis. 120 A similar concern seems to exist with regard to restricting or discontinuing active vitamin D medications to lower serum phosphorus levels, especially in the current era of ongoing performance pressure of achieving a good phosphorus level at all costs. HYPOPHOSPHATEMIA Two large epidemiological studies from Fresenius 116 and DaVita national databases 15 showed that even after extensive multivariate adjustment including surrogates of malnutrition, serum phosphorus levels below 3.0 g/dl were associated with increased death risk in maintenance hemodialysis. Indeed, in unadjusted survival models, consistent with the real world of dialysis, a low serum phosphorus, which is often observed in with the malnutrition inflammation complex, is by far a stronger marker of poor survival than normal to high serum phosphorus. 121 Because of the high risk of death associated with low appetite 122 and poor protein intake, 123 it is possible that imposing protein restriction to control phosphorus levels may cause more harm in CKD patient populations. 115 Hence, more diligent use of potent phosphorus binders and more emphasis on restricting nonprotein sources of phosphorus, such as in preservatives or fast food, may be the preferred future approache to this end. HYPERCALCEMIA Whereas several epidemiological studies have shown an increased association between high serum mineral level and mortality in dialysis, 116,124 a recent epidemiological study found somewhat different threshold levels above which mortality starts to increase, that is, 8.5 vs 10.5 mg/dl, when a conventional Cox survival model with fixed and time-dependent survival models using calendar quarterly varying values were used, respectively. 15 As shown in Figure 6, in a conventional (nontime dependent) model, only baseline values at the start of the cohort are used, whereas changes over time are ignored. It is not clear which of these two models are more consistent with the real-world scenario, but conventional models that ignore changes in biochemical value over time and that assume that baseline values represent subsequent values may be far fetched. HYPOCALCEMIA Much more controversy exists as to whether a low serum, for example, below the KDOQI recommended level of 8.4 mg/dl, is harmful or not. 125,126 In the postcalcimimetic era, such low values in dialysis are not rare, not to mention a lowering trend of dialysate concentration (bath) from 3.5 meq/l in the 1990s to 2.5 or even 2.25 meq/l in recent years. Lowered levels may lead to more frequent use of -based binders, as shown in some controlled trials in which more -based binders are in use in the calcimimetic arm by the end of the study. 130 Time-dependent survival analyses recently showed that such low levels, similar to high values, may be associated with increased death risk. 15 Furthermore, a decline in the serum level over 6 months was associated with increased death risk in the same study. 15 S17

9 review K Kalantar-Zadeh et al.: Kidney bone disease Traditional cohort with baseline (fixed, once measured) variables Baseline data Start and other Changes in serum are ignored! End months Dynamic cohort with quarterly-varying (time-dependent) repeated measures Start 1st Q: 2nd Q: 3rd Q: 4th Q: 5th Q: 6th Q: 7th Q: 8th Q: End months Figure 6 Comparing conventional (fixed covariate) survival models vs time-dependent (repeated measure) models in examining the association between serum and survival in chronic kidney disease. A low serum level may be associated with cardiac arrhythmias. 131 A recent epidemiological study showed that a low level showed a tendency toward higher rates of CKD progression in a group of male nondialysis-dependent CKD. 132 Nevertheless, calcimimetics also offer a number of important advantages including reduction of fracture rate and parathyroidectomy. 133 The concomitant use of active vitamin D analogs with calcimimetics may reduce the risk of severe hypocalcemia and reinforce their beneficial effect. Future studies are required to better address the issue of hypocalcemia in CKD. Epilogue The SHPT, vitamin D deficiency, and mineral disarrays are associated with multiple skeletal and cardiovascular disorders in CKD. There is a large volume of epidemiological evidence suggesting a broader beneficial effect from treatment of kidney bone disease by modulating vitamin D and -sensing receptors. Whereas there are insufficient well-designed randomized controlled trials in the field, this shortcoming should not lead to a nihilistic approach to the relevant clinical problems of CKD. Nevertheless, because of insufficient clinical data, a single treatment modality, be it nutritional or activate vitamin D, calcimimetics, phosphorus binders, or recombinant PTH, may not claim to be uniformly superior to the others, and a wider therapeutic window often prompts the use of a combination of these agents. As the ultimate goal is to improve the poor survival of CKD, any suggested approach for the management of kidney bone disease should be tested to this end. DISCLOSURE KK-Z has received grants and/or honoraria from Genzyme, the manufacturer of Sevelamer (Renagel and RenVela) and doxercalciferol (Hectoral), from Abbott Laboratories, the manufacturer of paricalcitol (Zemplar) and calcitriol (Calcijex), from Shire Pharmaceuticals, the manufacturer of lanthanum carbonate (Fosrenol), and/or from Amgen, the manufacturer of cinacalcet hydrochloride (Sensipar), as well as from NIH and Watson Pharmaceuticals. CPK has served as ad-hoc consultant for Genzyme and received grant support from Abbot, Genzyme, Shire and the NIH. ACKNOWLEDGMENTS KK-Z has been funded by research grants from the National Institute of Diabetes, Digestive and Kidney Disease of the National Institute of Health (R01 DK078106, R21DK078012, and R21 DK077341), an American Heart Association grant ( Y), a research grant from DaVita Clinical Research and a philanthropic grant from Mr Harold Simmons. REFERENCES 1. Moe SM, Drueke T, Lameire N et al. Chronic kidney disease-mineral-bone disorder: a new paradigm. Adv Chronic Kidney Dis 2007; 14: Kovesdy CP, Kalantar-Zadeh K. Bone and mineral disorders in pre-dialysis CKD. Int Urol Nephrol 2008; 40: Kovesdy CP, Kalantar-Zadeh K. Vitamin D receptor activation and survival in chronic kidney disease. Kidney Int 2008; 73: Drueke TB. Is parathyroid hormone measurement useful for the diagnosis of renal bone disease? Kidney Int 2008; 73: Lee JH, Stodell M, Fowler JC. Renal bone disease. J R Soc Med 2005; 98: S18

10 K Kalantar-Zadeh et al.: Kidney bone disease review 6. Lee GH, Benner D, Regidor DL et al. Impact of kidney bone disease and its management on survival of on dialysis. J Ren Nutr 2007; 17: Proceedings of the 18th Annual Meeting of the Japanese Society for Kidney Bone Disease, February 24, 2007, Tokyo, Japan. Ther Apher Dial 2007; 11(Suppl 1): S1 S Levin A, Bakris GL, Molitch M et al. Prevalence of abnormal serum vitamin D, PTH,, and phosphorus in with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int 2007; 71: Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol 2005; 289: F8 F Andress DL, Coyne DW, Kalantar-Zadeh K et al. Management of secondary hyperparathyroidism in stages 3 and 4 chronic kidney disease. Endocr Pract 2008; 14: Brown AJ, Slatopolsky E. Drug insight: vitamin D analogs in the treatment of secondary hyperparathyroidism in with chronic kidney disease. Nat Clin Pract Endocrinol Metab 2007; 3: Kalantar-Zadeh K, Kovesdy CP. Clinical outcomes with active versus nutritional vitamin D compounds in chronic kidney disease. Clin J Am Soc Nephrol 2009; 4: Kovesdy CP, Mehrotra R, Kalantar-Zadeh K. Battleground: chronic kidney disorders mineral and bone disease obsession, vitamin d, and binder confusion. Clin J Am Soc Nephrol 2008; 3: Teng M, Wolf M, Ofsthun MN et al. Activated injectable vitamin d and hemodialysis survival: a historical cohort study. J Am Soc Nephrol 2005; 16: Kalantar-Zadeh K, Kuwae N, Regidor DL et al. Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis. Kidney Int 2006; 70: Melamed ML, Eustace JA, Plantinga L et al. Changes in serum, phosphate, and PTH and the risk of death in incident dialysis : a longitudinal study. Kidney Int 2006; 70: Shoji T, Shinohara K, Kimoto E et al. Lower risk for cardiovascular mortality in oral 1alpha-hydroxy vitamin D3 users in a haemodialysis population. Nephrol Dial Transplant 2004; 19: Tentori F, Hunt WC, Stidley CA et al. Mortality risk among hemodialysis receiving different vitamin D analogs. Kidney Int 2006; 70: Naves-Diaz M, Alvarez-Hernandez D, Passlick-Deetjen J et al. Oral active vitamin D is associated with improved survival in hemodialysis. Kidney Int 2008; 74: Shinaberger CS, Kopple JD, Kovesdy CP et al. Ratio of paricalcitol dosage to serum parathyroid hormone level and survival in maintenance hemodialysis. Clin J Am Soc Nephrol 2008; 3: Wolf M, Betancourt J, Chang Y et al. Impact of activated vitamin D and race on survival among hemodialysis. J Am Soc Nephrol Kovesdy CP, Ahmadzadeh S, Anderson JE et al. Association of activated vitamin D treatment and mortality in chronic kidney disease. Arch Intern Med 2008; 168: Shoben AB, Rudser KD, de Boer IH et al. Association of oral calcitriol with improved survival in nondialyzed CKD. J Am Soc Nephrol 2008; 19: Tentori F, Albert JM, Young EW et al. The survival advantage for haemodialysis taking vitamin D is questioned: findings from the Dialysis Outcomes and Practice Patterns Study. Nephrol Dial Transplant 2009; 24: Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965; 58: Niederhoffer N, Bobryshev YV, Lartaud-Idjouadiene I et al. Aortic calcification produced by vitamin D3 plus nicotine. J Vasc Res 1997; 34: Fleckenstein-Grun G, Thimm F, Frey M et al. Progression and regression by verapamil of vitamin D3-induced calcific medial degeneration in coronary arteries of rats. J Cardiovasc Pharmacol 1995; 26: Kingma Jr JG, Roy PE. Ultrastructural study of hypervitaminosis D induced arterial calcification in Wistar rats. Artery 1988; 16: Repo JM, Rantala IS, Honkanen TT et al. Paricalcitol aggravates perivascular fibrosis in rats with renal insufficiency and low calcitriol. Kidney Int 2007; 72: Bodyak N, Ayus JC, Achinger S et al. Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals. Proc Natl Acad Sci USA 2007; 104: Mizobuchi M, Finch JL, Martin DR et al. Differential effects of vitamin D receptor activators on vascular calcification in uremic rats. Kidney Int 2007; 72: Brown AJ, Finch J, Slatopolsky E. Differential effects of 19-nor-1,25- dihydroxyvitamin D(2) and 1,25-dihydroxyvitamin D(3) on intestinal and phosphate transport. J Lab Clin Med 2002; 139: Hirata M, Katsumata K, Endo K et al. In subtotally nephrectomized rats 22-oxacalcitriol suppresses parathyroid hormone with less risk of cardiovascular calcification or deterioration of residual renal function than 1,25(OH)2 vitamin D3. Nephrol Dial Transplant 2003; 18: Teng M, Wolf M, Lowrie E et al. Survival of undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 2003; 349: Monier-Faugere MC, Mawad H, Malluche HH. Opposite effects of calcitriol and paricalcitol on the parathyroid hormone-(1 84)/large carboxy-terminal-parathyroid hormone fragments ratio in with stage 5 chronic kidney disease. Clin J Am Soc Nephrol 2007; 2: Drueke TB, Fukagawa M. Whole or fragmentary information on parathyroid hormone? Clin J Am Soc Nephrol 2007; 2: Langub MC, Monier-Faugere MC, Wang G et al. Administration of PTH-(7 84) antagonizes the effects of PTH-(1 84) on bone in rats with moderate renal failure. Endocrinology 2003; 144: Donadio C, Ardini M, Lucchesi A et al. Parathyroid hormone and large related C-terminal fragments increase at different rates with worsening of renal function in chronic kidney disease. A possible indicator of bone turnover status? Clin Nephrol 2007; 67: Martin KJ, Juppner H, Sherrard DJ et al. First- and second-generation immunometric PTH assays during treatment of hyperparathyroidism with cinacalcet HCl. Kidney Int 2005; 68: Rubin MR, Silverberg SJ, D Amour P et al. An N-terminal molecular form of parathyroid hormone (PTH) distinct from hpth(1 84) is overproduced in parathyroid carcinoma. Clin Chem 2007; 53: Slatopolsky E, Cozzolino M, Lu Y et al. Efficacy of 19-Nor-1,25-(OH)2D2 in the prevention and treatment of hyperparathyroid bone disease in experimental uremia. Kidney Int 2003; 63: National Kidney Foundation I, Kidney Disease-Dialysis Outcome Quality Initiative. K/DOQI Clinical Practice Guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003; 42: S1 S Saab G, Young DO, Gincherman Y et al. Prevalence of vitamin D deficiency and the safety and effectiveness of monthly ergocalciferol in hemodialysis. Nephron Clin Pract 2007; 105: c132 c Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357: London GM, Guerin AP, Verbeke FH et al. Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25- hydroxyvitamin D deficiency. J Am Soc Nephrol 2007; 18: Wolf M, Shah A, Gutierrez O et al. Vitamin D levels and early mortality among incident hemodialysis. Kidney Int 2007; 72: Berl T, Berns AS, Hufer WE et al. 1,25 dihydroxycholecalciferol effects in chronic dialysis. A double-blind controlled study. Ann Intern Med 1978; 88: Malluche HH, Ritz E, Werner E et al. Long-term administration of vitamin D steroles in incipient and advanced renal failure: effect on bone histology. Clin Nephrol 1978; 10: Dusso AS, Finch J, Brown A et al. Extrarenal production of calcitriol in normal and uremic humans. J Clin Endocrinol Metab 1991; 72: Block GA, Zeig S, Sugihara J et al. Combined therapy with cinacalcet and low doses of vitamin D sterols in with moderate to severe secondary hyperparathyroidism. Nephrol Dial Transplant Irvin III GL, Carneiro DM. Management changes in primary hyperparathyroidism. JAMA 2000; 284: Kovesdy CP, Ahmadzadeh S, Anderson JE et al. Secondary hyperparathyroidism is associated with higher mortality in men with moderate to severe chronic kidney disease. Kidney Int 2008; 73: Salusky IB, Juppner H. PTH assays and renal osteodystrophy. Pediatr Nephrol 2004; 19: Guideline Working Group, Japanese Society for Dialysis Therapy. Clinical practice guideline for the management of secondary hyperparathyroidism in chronic dialysis. Ther Apher Dial 2008; 12: Nakai S, Masakane I, Shigematsu T et al. An overview of regular dialysis treatment in Japan (as of 31 December 2007). Ther Apher Dial 2009; 13: Galassi A, Spiegel DM, Bellasi A et al. Accelerated vascular calcification and relative hypoparathyroidism in incident haemodialysis diabetic receiving binders. Nephrol Dial Transplant 2006; 21: S19

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