Control of Secondary Hyperparathyroidism by Vitamin D Receptor Agonists in Chronic Kidney Disease

Mini-Review

Stuart M. Sprague* and Daniel Coyne† *NorthShore University HealthSystem and University of Chicago Pritzker School of Medicine, Evanston, Illinois; and †Division of Renal Diseases, Washington University in St. Louis, St. Louis, Missouri

Effective treatment options for managing secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) have advanced steadily since the early 1980s, from surgical removal of the parathyroid gland to pharmacologic intervention focused on reestablishing hormonal and mineral balances. In addition, earlier recognition of CKD via estimated GFR and educational efforts have led to advancements in diagnosis and treatment of elevated parathyroid hormone (PTH) and vitamin D deficiency. Clinical studies support the efficacy and safety of vitamin D receptor (VDR) agonists as effective treatments for SHPT. A number of considerations to ensure optimal SHPT control in CKD patients are apparent. VDR agonists effectively treat SHPT and vitamin D deficiency, but dosing needs to be optimized for each patient because the patient responds in an individualized manner to treatment to suppress and stabilize PTH levels. VDR agonist therapy should be continuous to ensure continued PTH suppression, coupled with strict monitoring of calcium and phosphorus to ensure compliance within target ranges. Awareness of the complex and beneficial effects of VDR agonists contributes to improved benefits in bone mineral disease and lower mortality risks. Clin J Am Soc Nephrol 5: 512–518, 2010. doi: 10.2215/CJN.03850609

reatment of secondary hyperparathyroidism (SHPT) in vitamin D (25-hydroxyvitamin D (25-D) and 1,25-dihydroxyvi- chronic kidney disease (CKD) has evolved over the last tamin D (1,25-D)) levels are associated with CKD progression T few decades, with a better understanding of the under- (7) as well as increased risk of mortality beginning at stage 3 lying pathophysiology and the development of advanced and CKD (7,8). Administration of oral or injectable vitamin D safer medications. Management of SHPT remains a challenge and/or VDR agonists (e.g., calcitriol) in patients on dialysis or because of the complex interrelationship of hormones, bone with stages 3 and 4 CKD has been correlated with improved health, diet, and mineral balances within the body. Bone and survival in observational studies (8–11). Additional observa- mineral guidelines were recently updated by the Kidney Dis- tional analyses have shown that treatment with paricalcitol, an ease: Improving Global Outcomes (KDIGO) working group analog of calcitriol with fewer calcemic and phosphatemic ef- from the 2003 National Kidney Foundation Kidney Disease fects, is associated with enhanced survival in patients under- Outcomes Quality Initiative (KDOQI), with the goal of provid- going long-term hemodialysis compared with those who did ing guidance in managing CKD patients (1,2). At the time of the not receive vitamin D analogs (12). Another study showed release of the 2003 guidelines, clinical studies in patients with enhanced survival benefit of paricalcitol compared with calcit- moderate to severe CKD and SHPT showed that treatment with riol (13). Although use of these and other VDR agonists (Table vitamin D receptor (VDR) agonists lowered elevated parathy- 1) to treat low endogenous 1,25-D hormonal levels is hypothe- roid hormone (PTH) levels but caused variable increases in sized to account for clinical benefits that include improved serum calcium (Ca) and phosphorus (P) (3,4). Although the survival, prospective randomized, controlled trials are neces- target ranges for PTH per each CKD stage have been updated sary to validate these findings. On the basis of results from in the new KDIGO guidelines to be more reflective of current clinical studies and through the practical use of therapies trends, changes in Ca and P outside of normal levels are still to control elevated PTH, replete vitamin D levels, and treat viewed as potentially harmful by experts (2). bone mineral disease, a number of considerations when using Observational data have shown a more complex and even VDR agonists have arisen that should be taken into account contradictory relationship of Ca and P to mortality, challenging for providing optimal SHPT control in patients with CKD theories that any increase in these mineral ions increases risk to (Table 2). the patient (5,6). Observational studies have shown that low CKD, SHPT, and Vitamin D Deficiency An estimated 16 million people in the United States have Published online ahead of print. Publication date available at www.cjasn.org. stage 3 or 4 CKD (eGFR 15–59 ml/min per 1.73 m2), with Correspondence: Dr. Stuart M. Sprague, NorthShore University HealthSys- diabetes mellitus and hypertension as major underlying causes tem, University of Chicago, Pritzker School of Medicine, 2650 North Ridge Avenue, Evanston, IL 60201. Phone: 847-570-2512; Fax: 847-570-1696; E-mail: (14). Despite the high prevalence of CKD in the adult popula- [email protected] tion, less than 20% of patients who have moderately decreased

Table 1. Vitamin D nomenclature

Vitamin D Term Sterol Type of Vitamin D

Vitamin D Cholecalciferol D3 Ergocalciferol D2 25-Hydroxyvitamin D Calcidiol (25(OH)D3) D3 Ercalcidiol (25(OH)D2) D2 a Vitamin D receptor agonist prohormone Alfacalcidol (1(OH)D3) D3; Synthetic prohormone Doxercalciferol D2; Synthetic prohormone (1(OH)D2) Vitamin D receptor agonist Calcitriol (1,25(OH)2D3) D3; Natural analog Paricalcitol D2; Synthetic analog (19nor,1,25(OH)2D2) Maxacalcitol D3; Synthetic analog (22oxa,1,25(OH)2D3) aRequires 25-hydroxylation by the liver to become an active analog.

Table 2. VDR agonists and SHPT control ment options for patients with early stages of CKD are less established. Considerations for Use of VDR Agonists for SHPT Control

• CKD patients should be identified on the basis of Vitamin D Deficiency and Treatment to Modulate SHPT in eGFR, and PTH and vitamin D levels should be CKD Patients There is ongoing debate regarding a clear definition for what evaluated early (e.g., stage 3 CKD). is considered vitamin D (25-D and/or 1,25-D) deficiency. Vita- • VDR agonists effectively suppress SHPT in a dose- min D deficiency is usually defined as concentrations Ͻ10 dependent manner. ng/ml (25 nmol/L), whereas vitamin D insufficiency is defined • When administering a VDR agonist to lower and as levels between 10 and 32 ng/mL (80 nmol/L). Vitamin D maintain steady PTH levels and avoid concentrations between 32 and 80 ng/mL (200 nmol/L) are hypercalcemia, dosing should be determined on generally considered sufficient (2). Vitamin D (25-D and/or the basis of individual patient response. 1,25-D) sufficiency is less well defined because numerous fac- • VDR agonist therapy should be continuous, rather tors contribute to achieving adequate endogenous vitamin D than intermittent, to ensure continued PTH levels, and the nomenclature for endogenous and exogenous suppression and replacement of low endogenous vitamin D is very similar (Table 1). Because 1,25-D functions as 1,25-D. a native hormone, providing complex, tissue-specific signaling • Dietary phosphate restriction, phosphate binders, throughout the body, it is a challenge to accurately measure the and repletion of nutritional vitamin D stores are relative contribution of exogenously administered vitamin D effective complementary treatments. with signaling that is occurring through autocrine/paracrine feedback loops (20). The interrelated effects between native and supplemented vitamin D are reiterated in a study examining the effects of exogenously administered 1,25D (i.e., calcitriol) in kidney function are aware of this impairment (15). A prospec- healthy volunteers and uremic patients. Gallieni et al. (21) tive, observational study of 1814 CKD patients with a recent showed that although dialysis patients have impaired uptake historic eGFR of Ͻ60 ml/min per 1.73 m2 confirmed that 78% of and metabolism of 25-D, treatment with calcitriol not only patients had stage 3, 4, or 5 CKD with elevated PTH and repleted serum 1,25-D levels but also increased the uptake of significantly reduced 1,25-D levels (16). Rising PTH levels were 25-D (as examined in monocytes). Thus, with exogenous 1,25-D inversely correlated with declining 1,25-D and 25-D levels; administration, there are potential complementary benefits to Ͻ 1,25-D levels were approaching very low levels ( 25 pg/ml) as both 1,25-D and 25-D in an effort to rebalance the hormonal eGFR measurements signified stage 3 CKD. eGFR continued to system. decline thereafter. These and other study findings substantiate a high incidence of SHPT and low endogenous vitamin D (25-D Treatment of Vitamin D Deficiency and SHPT in Patients and/or 1,25-D) levels in CKD patients, supporting the KDIGO with Stages 3 and 4 CKD recommendations for early and continued measurement of Deficiencies in 25-D and/or 1,25-D have been associated with these parameters throughout disease progression (2,9,16–19). an elevated risk of cardiovascular disease and mortality in the These observations support the view that SHPT occurs early general population (22,23). Suboptimal levels of vitamin D and, if left untreated, worsens over time. VDR agonist therapy contribute to the development of SHPT through reduced intes- for dialysis patients has been well documented; however, treat- tinal Ca absorption, increased PTH production, and parathy- 514 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 5: 512–518, 2010 roid cell proliferation (24). Elevated PTH may also initiate Doxercalciferol (a prohormone that can be hepatically acti- increased Ca and P resorption from bone and promote vascular vated into a VDR agonist) was originally investigated as a calcification (24,25). Despite elevation in PTH and reductions in treatment for osteoporosis (36) and later demonstrated its effi- endogenous vitamin D (i.e., 25-D and 1,25-D), serum Ca and P cacy by reducing PTH in hemodialysis patients, albeit with usually remain within normal physiologic range in stages 3 and elevations in serum Ca and P (37,38). Unfortunately, there have 4 CKD (16,17). been no studies directly comparing doxercalciferol with other Inactive forms of supplementary vitamin D, ergocalciferol VDR agonists. Alphacalcidol (not approved for use in the ␣ (vitamin D2), and cholecalciferol (vitamin D3), significantly in- United States) is 1 -hydroyvitamin D3, which is rapidly con- crease 25-D and 1,25-D levels in patients with stages 3 and 4 verted in the liver to 1,25-dihydroxy vitamin D3 (39). Vitamin- CKD and suppress, but do not normalize, PTH concentrations resistant disorders, such as renal bone disease, hypoparathy- (26–28). Beginning with stage 4 CKD, the ability of vitamin D roidism, and pseudodeficiency rickets, which usually require supplements to correct elevated PTH concentrations is signifi- large amounts of vitamin D, respond to physiologic doses of cantly reduced compared with earlier stages of CKD (26,28). alphacalcidol. Alphacalcidol may cause hypercalcemia. In a These supplements are generally considered ineffective for randomized prospective phase III study, IV paricalcitol 0.04 to PTH suppression in usual doses in patients with stage 5 CKD 0.24 ␮g (given for up to 32 weeks) showed similar or improved (before or in those receiving dialysis), although they may pre- PTH suppression and fewer hypercalcemic episodes compared vent osteomalacia due to vitamin D deficiency and possibly with IV calcitriol 0.01 to 0.06 ␮g (40). have other benefits. The biologically active VDR agonists calcitriol and paricalci- Optimal PTH Suppression through Individualized Dosing tol, and the prohormone doxercalciferol, suppress PTH in a and Continuous VDR Agonist Therapy dose-related fashion independent of the stage of CKD. Placebo- In 2003, KDOQI experts offered CKD stage-specific PTH controlled trials of these exogenously administered agents in target ranges; these targets lacked rigorous trial evidence and patients with stages 3 and 4 CKD demonstrated that calcitriol are no longer considered adequate for management of the and doxercalciferol elevated serum Ca, although doxercalcif- individual patient (1). Bone biopsy series in dialysis patients erol may have been less calcemic than calcitriol (3,29,30). Trials indicate a high prevalence of adynamic bone (low bone turn- of paricalcitol showed significant and sustained control of PTH, over) despite PTH levels in or above the KDOQI recommended with minimal alterations in Ca and P compared with placebo range, and this is thought to be due to overly aggressive treat- (30). Although the changes observed in Ca and P in these ment of SHPT in many patients (41). Black dialysis patients in studies are consistent with animal data showing differences in particular may require maintenance of a higher PTH level to the calcemic and phosphatemic effects of these agents (31,32), avoid adynamic bone (42). Although a patient may not reach definitive claims of differences between compounds await ran- PTH levels within KDOQI ranges, continued use of VDR ago- domized trials comparing these agents in patients with CKD nists usually leads to significantly reduced PTH that remains stages 3 and 4. Markers of bone formation, such as bone- stable over time and is accompanied by normalization of other specific alkaline phosphatase, were also significantly reduced markers of high bone turnover, such as bone-specific alkaline by VDR agonist treatment (3,29,30). Current KDIGO guidelines phosphatase and osteocalcin (30,43,44). In the clinical setting, do not recommend bone mineral density measurements for the optimal level of PTH suppression by VDR agonists has been CKD but do suggest that stages 3 to 5 CKD patients be mea- a matter of discussion because PTH levels are lowered and sured for serum PTH or bone-specific alkaline phosphatase to steady themselves at varying levels on the basis of individual predict for low or high bone turnover (2). patient response to therapy. Hypercalcemia after VDR agonist therapy may be an indication of ensuing adynamic bone and Treatment of SHPT in Dialysis Patients also suggests that the dose of VDR agonist should be reduced In the late 1980s, intravenous (IV) calcitriol was recom- (45). In the recently released KDIGO guidelines, target ranges mended as an alternative therapy to either oral calcitriol or for PTH are set in context with the upper limit of normal per the parathyroidectomy in dialysis patients with SHPT. Long-term PTH assay used (2). However, the guidelines do not make intermittent infusions of IV calcitriol 1 to 2.5 ␮g thrice weekly formal recommendations for PTH levels in CKD patients. Ide- for an average of 11.5 months in dialysis patients with concom- ally, an optimal PTH level would result in a nearly normal bone itant osteitis fibrosa achieved significant reductions in PTH and formation rate (BFR). Unfortunately, PTH has only a weak alkaline phosphatase, and resulted in fewer episodes of hyper- correlation with BFR; therefore, despite achieving otherwise calcemia than experienced with prior therapy (33). In the late “normal” PTH levels, individuals may have low, normal, or 1990s, investigators demonstrated that by lowering the level of high BFR. In general, patients with CKD stages 3 to 5 who are PTH in hemodialysis patients, IV calcitriol 2 ␮g twice weekly not on dialysis should achieve stable PTH levels near the upper not only attenuated the SHPT effects but also displayed cardio- limit of normal that are maintained with VDR agonist therapy protective effects (34). Interestingly, the increased use of calcit- while avoiding hypercalcemia and hyperphosphatemia. In di- riol as a therapeutic intervention has been associated with a alysis patients, PTH levels should, in general, be stable and reduction in parathyroidectomy rates in the late 1990s to Ͻ1% maintained at two or more times the upper limit of normal with and a shift in the treatment paradigm from a surgical interven- VDR agonist therapy while avoiding hypercalcemia. The tion to pharmacologic management of SHPT (35). KDIGO guidelines suggest a PTH goal of two to nine times the Clin J Am Soc Nephrol 5: 512–518, 2010 SHPT Control by VDR Agonists in CKD 515 upper limit for the assay being used in patients with CKD stage ing signaling through the VDR, because of either knockout of 5D (2). An elevated alkaline phosphatase level is suggestive of the VDR (53) or 1␣-vitamin D hydroxylase (54), develop left inadequately suppressed PTH, and therapy should be intensi- ventricular hypertrophy (LVH), whereas treatment of the latter fied to further suppress PTH. knockout model with 1,25-D prevents LVH (54). The Dahl Similar to treating other hormone-deficient diseases (e.g., hy- salt-sensitive rat develops severe hypertension, LVH, and vita- pothyroidism) (46), it is the authors’ opinion that VDR agonist min D deficiency when maintained on a high-salt diet. Cotreat- treatment should in general be continuous in dialysis patients ment of the Dahl salt-sensitive rats with paricalcitol has been so that patients can maintain normal to nearly normal levels of shown to prevent LVH while not altering hypertension (55). vitamin D hormone rather than being treated for episodic vi- More importantly, use of 1,25-D in dialysis patients has been tamin D deficiencies and/or rising PTH levels. These patients shown to reduce LVH (34). Prospective cohort studies of peri- show moderate to severe 1,25-D deficiency (8) in addition to toneal dialysis and hemodialysis patients with deficient or in- commonly having hyperphosphatemia and relative or absolute sufficient 25-D (i.e., Յ30 ng/ml) have demonstrated signifi- hypocalcemia. The hormonal and mineral imbalances (i.e., cantly elevated risk of cardiovascular-related mortality (8,56). 1,25-D, Ca, and P) are potent inducers for PTH secretion and This increased risk was significantly diminished in patients parathyroid proliferation. Uninterrupted use of VDR agonists receiving VDR agonists (8). Collectively, these preclinical and can therefore remove the PTH stimulatory effect of 1,25-D clinical data provide a plausible mechanism by which use of deficiency and help maintain normal serum Ca, although VDR agonist therapy may attenuate cardiovascular-related greater use of phosphate binders may be necessary. This ratio- mortality. nale is also consistent with the hypothesis that treatment of the Effects of VDR Agonist Treatment on Survival in Patients 1,25-D hormonal deficiency plays a role in maintaining health with Stages 3 and 4 CKD. The relationship between the use via activation of the VDR in multiple organ systems, such as of VDR agonists with survival in CKD stages 3 and 4 patients kidney, immunologic, and cardiovascular systems (reviewed has only recently been explored in observational studies. Use of by Andress (47)). oral VDR agonist is associated with significantly better survival, and a lower risk of initiating dialysis compared with PTH Control by VDR Agonists and Survival those not prescribed treatment (9,11). As expected, the addition Effects of Vitamin D Receptor Agonist Treatment on Sur- of vitamin D therapy suppressed PTH (9,11), and episodes of vival in Dialysis Patients. Numerous observational studies hypercalcemia and/or hyperphosphatemia were more frequent in dialysis patients have shown improved survival after VDR in calcitriol recipients (9,11). agonist therapy (8,10,12,48,49). Increased risks of all-cause mortality were observed in patients with elevated mineral levels Conclusions outside of KDOQI-based normal ranges (12). Hypercalcemia, Optimal SHPT control is important in managing the course of hyperphosphatemia, and increased Ca ϫ P were significantly CKD, as well as reestablishing PTH, mineral, and vitamin D associated with an increased risk of death. The reverse also balances in the CKD patient. It is clear that vitamin D deficiency appeared to be true; abnormally low mineral levels elevated a contributes to the development of SHPT in CKD patients. De- patient’s risk of death, rounding out a U-shaped effect on pending on the stage of kidney dysfunction, repletion of both mortality. In addition, the Kalantar-Zadeh et al. study (12) took inactive (25-D) and active (1,25-D) vitamin D may be needed to into account patients who received VDR agonist therapy and adequately replace and balance physiologic levels, because sig- demonstrated that treatment, compared with no treatment, was naling pathways are disrupted owing to a reduction in VDR associated with a trend toward improved survival. activity. Characteristics and some of the challenges associated Injectable VDR agonists have been associated with a survival with vitamin D therapies for SHPT in CKD patients are pre- advantage that appears to be independent of Ca, P, and PTH sented in Table 3. levels (48). The benefit with paricalcitol was evident at essen- Guidelines for the treatment of CKD patients with SHPT tially all baseline strata of Ca, P, and PTH. In a historic cohort were recently updated by the KDIGO working group to include study evaluating patients who changed VDR agonist therapy, a more recent perspective on SHPT treatment in CKD patients those crossing over from calcitriol to paricalcitol also demon- since the prior 2003 guidelines; comprehensive study details strated a survival advantage at 2 years compared with the are presented by the KDIGO group (1,2). Taking the KDIGO inverse crossover regimen (13). Cardiovascular-related mortal- guidance into account, as well as practical patient management ity rates (at all basal levels of Ca, P, or PTH) were also signif- experiences, several considerations are proposed to ensure op- icantly different for patients receiving paricalcitol versus pa- timal SHPT control in CKD patients, including early recogni- tients who did not (13). Patients with advancing stages of CKD tion of reduced eGFR, evaluation of PTH, 25-D, and/or 1,25-D are at correlative increasing risk for cardiovascular-related starting at stage 3 CKD; optimizing VDR agonist dosing per events (50). Low vitamin D and 1,25-D levels correlate with PTH response in the individual patient; maintenance of contin- increased cardiovascular disease and deaths, whereas use of uous VDR agonist therapy to ensure continued PTH suppres- VDR agonist therapy may be cardioprotective (23,48). Cardiac sion; and vigilant monitoring of Ca and P to conform with myocytes express the VDR (51), and vitamin D-deficient ani- target ranges (Table 2). The authors believe that it is a rational mals have significantly higher left ventricular systolic pressures approach to maintain continuous VDR agonist therapy; how- compared with vitamin D-sufficient animals (52). Animals lack- ever, there are no data to support the effectiveness of inter- 516 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 5: 512–518, 2010

Table 3. Effects and challenges with vitamin D to treat SHPT in CKD patients

Vitamin D Term Biologic and Clinical Effect Challenges of Use

Alphacalcidol • Effective in repleting 25-D and • Requires activation in kidney to generate 1,25-D in patients with early-stage active 1,25-D CKD and adequate kidney function Ergocalciferol, cholecalciferol • Effective in repleting 25-D and • Requires activation in kidney to generate 1,25-D in patients with early-stage active 1,25-D CKD and adequate kidney • Provides only partial suppression of function PTH in later-stage CKD patients Calcitriol • Biologically active VDR agonist • Hypercalcemia, hypercalciuria, and • Effectively suppresses SHPT hyperphosphatemia evident at higher • Reduces abnormal high bone doses turnover Doxercalciferol • Suppresses SHPT similar to or • Requires activation in liver to generate better than calcitriol active 1,25-D • Noted reduction in serum bone- • Induces significant elevation of serum P, specific alkaline phosphatase and elevating need for phosphate binder use osteocalcin Paricalcitol • Biologically active VDR agonist • Minimal elevation in Ca, P, and Ca ϫ P • Effectively suppresses SHPT product, requiring Ca and P monitoring • Noted reduction in serum bone- specific alkaline phosphatase and osteocalcin

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