Pediatr Nephrol (2004) 19:705–708DOI 10.1007/s00467-004-1478-0

E D I T O R I A L C O M M E N T A R Y

John Cunningham

New vitamin D analogues for osteodystrophyin chronic kidney disease

Received: 9 January 2004 / Revised: 17 March 2004 / Accepted: 22 March 2004 / Published online: 13 May 2004� IPNA 2004

Abstract Vitamin D therapy for patients with chronickidney disease has until recently comprised alfacalcidol orcalcitriol, both of which effectively attenuate secondaryhyperparathyroidism and the target organ consequencesthereof. Unfortunately, both these agents also have sig-nificant calcaemic and phosphataemic actions leading tofrequent episodes of hypercalcaemia, hyperphosphataemiaand an increase in the CaxP product. It is likely that thesein turn have adverse effects on cardiovascular and survivaloutcomes by promoting soft tissue and vascular calcifi-cation. These drawbacks have fuelled a search for vitaminD compounds with a wider therapeutic window. Experi-mentally, some of these have exhibited remarkable dis-sociation between their ability to suppress parathyroidhormone (PTH) and concomitant calcaemic actions. Inthe case of 22-oxacalcitriol, the calcaemic potency relativeto parathyroid suppression is 100th of that of calcitriol.22-oxacalcitriol, with paricalcitol and doxercalciferol, arenow widely used. Clinical studies of these agents, whileconfirming efficacy that is at least as good as alfacalcidol/calcitriol, have not consistently shown benefit in headto head comparison. Experience with these agents in thepaediatric arena is very limited. One placebo-controlledstudy has now been completed in children—paricalcitolappeared effective and well tolerated. Calcimimetics,which simultaneously lower PTH, calcium and the CaxPproduct are about to enter the clinical arena—early studiesin adults look promising, although they will need carefulevaluation in children. These two therapies are likely to beadditive and will probably complement one another ef-fectively.

Keywords Vitamin D · Non-calcaemic analogues ·Chronic kidney disease

In the late 1980s reports first appeared describing vitaminD-like sterols that bound to the vitamin D receptor andwhose action on target tissues appeared quite differentfrom those of the naturally occurring hormonal form ofvitamin D, calcitriol. The feature of these compounds thataroused the interest of nephrologists was an ability toexert a suppressive action on overactive, or potentiallyoveractive, parathyroid glands, with less tendency to raiseextracellular calcium and phosphorus concentrations viaactions on bone and intestinal target tissues [1, 2]. This inturn would have a bearing on current attempts to reducethe calcium burden faced by dialysis patients conven-tionally treated with cacitriol and calcium-based phos-phate binders [3, 4]. Three of these agents, namely 22-oxacalcitriol (Maxacalcitol), paricalcitol (Zemplar) anddoxercalciferol (Hectorol), are now in clinical use for thetreatment of secondary hyperparathyroidism. The mainexperience with 22-oxacalcitriol is in Japan and that withparicalcitol and doxercalciferol in the United States. 22-oxacalcitriol differs from calcitriol only in the substitu-tion of the carbon 22 with an oxygen atom, while bothparicalcitol and doxercalciferol are vitamin D2 (ergocal-ciferol) analogues. Doxercalciferol (1a-hydroxyvitaminD2) is the vitamin D2 equivalent of alfacalcidol and likealfcalcidol is a prodrug requiring hepatic 25-hydroxyla-tion for full activation [5]. Unlike alfcalcidol, how-ever, doxercalciferol administration leads to generationof 1,24S-dihydroxyvitamin D2 in addition to 1,25-dihy-droxyvitamin D2 [6, 7]. Both of these are potent vitaminD metabolites. Licensed indications are at present con-fined to adults with secondary hyperparathyroidism andadvanced chronic kidney disease. Unsurprisingly, there issubstantial and largely unreported experience of theseagents outside the strict parameters outlined above andpreliminary reports of studies in children are now be-ginning to appear. It is therefore timely to considerwhether the accumulating experience in the clinical arenais proving to be consistent with the underlying basicscience, not least because attempts to refine ‘conven-tional’ vitamin D therapies using intravenous and oralpulsed regimens have been disappointing [8, 9, 10].

J. Cunningham ())Department of Nephrology, The Middlesex Hospital,University College London Hospitals,Mortimer Street, London W1N 8AA, UKe-mail: drjohncunningham@aol.comTel.: +44-207-3809366Fax: +44-207-3809199

These compounds have been developed with the aimof selecting out some, but not all, of the classical actionsof vitamin D as normally mediated via the binding ofcalcitriol to its specific nuclear receptor [the vitamin Dreceptor (VDR)] [11]. This binding leads to a conforma-tional change in the VDR that permits heterodimerisationwith the retinoid X receptor (RXR). The VDR/RXRheterodimer complex binds to a specific portion of thevitamin D-responsive element (VDRE), which, dependingon the target tissue, increases (e.g., intestinal calbindin D9 k) or decreases [e.g., parathyroid hormone (PTH)] genetranscription. Thus, both calcitriol and its therapeuticanalogues function in the manner of a classical steroidhormone [12, 13]. Additionally, the existence of two otherVDRs has been reported, namely a membrane-associatedreceptor for calcitriol (mVDR) and a separate membranereceptor that binds 24,25-dihydroxyvitamin D [14, 15].The functional role of these latter receptors is uncertain—24-hydroxylation of 25-hydroxyvitamin D has been seenmainly as a catabolic pathway and further evidence isneeded regarding the physiological role of the membrane-bound 24,25-dihydroxyvitamin D receptor and themVDR.

However, there is no doubt that the principle actions ofvitamin D and its analogues are mediated via the nuclearVDR. The new vitamin D analogues, as well as manyothers that have not reached the clinical arena, are knownto possess widely differing affinities for the VDR, towhich all of them must bind to exert their biological ac-tions. This suggests that, apart from the issue of potency,little difference would be expected in the biological out-comes given the apparent constancy of the final commonpath of action. Things are not that simple, however, andon both theoretical and experimental grounds it can beseen that there are many ways in which structural modi-fication could, and in some cases clearly does, lead topotentially important tissue-specific differences in action.

Vitamin D compounds differ importantly in their me-tabolism and pharmacokinetics [16, 17]. All are carried inthe circulation bound to an a-globulin [vitamin D-bindingprotein (DBP)]. Naturally occurring vitamin D metabo-lites are bound to DBP at high affinity, serving to reducesubstantially the concentration of free hormone and there-by to limit its access to many tissues. Conversely, it ispossible that binding to DBP enhances presentation atother sites, as well as greatly slowing catabolism andextending half-life. Synthetic and semi-synthetic ana-logues with low affinity for DBP exhibit much shorterplasma half-lives than calcitriol and by this mechanismcould select out specific target tissues on the basis ofduration of presentation of ligand. For example, 22-oxa-calcitriol has lower binding affinity for DBP and a muchshorter plasma half-life than calcitriol, which may explainits relatively low potency in some target tissues such asintestine where 22-oxacalcitriol effects on calbindin D 9 ksynthesis and calcium transport were less sustained thanthose of calcitriol [17]. In the case of doxercalciferol,metabolism to two distinct sterols, 1,24S-dihydroxyvit-

amin D2 and 1,25-dihydroxyvitamin D2, potentially in-creases the scope of target tissue interactions [18].

Changes in the binding affinity for the VDR, whileclearly accounting for differences in potency, would re-quire additional factors relating to, for example, accessi-bility of the VDR, to operate selectively in different tis-sues. Again, supporting evidence is relatively weak. It isalso possible that the VDR/RXR heterodimer complexmay bind to the VDRE in a manner influenced by thespecific ligand that triggered VDR/RXR heterodimerisa-tion. Target organ selectivity by this mechanism would,however, only arise if such conformational changes werealso tissue specific.

One of the more plausible explanations for target tissueselectivity is based on events subsequent to binding of theVDR/RXR heterodimer to the VDRE. Co-activators andco-repressors can powerfully influence vitamin D-depen-dent transcription and there is good evidence that differentvitamin D sterols are capable of initiating strikingly dif-ferent patterns of co-activator or co-repressor recruitment[19, 20].

Finally, it is possible that the rate of catabolism ofthese ligands is tissue specific, although it has proveddifficult to establish evidence that convincingly showsthis as a mechanism for differential potency or targetorgan selectivity in bone or parathyroid [21, 22].

22-oxacalcitriol was in the vanguard of these new vi-tamin D compounds. In early experiments it exhibited astriking dissociation between PTH suppression in vitro(roughly equipotent with calcitriol) and dose-limitingcalcaemia in vivo (approximately 100-fold less potentthan calcitriol) [2]. Of course, this profile is extremelyappealing to clinicians, interested as they are in therapiesthat are capable of suppressing parathyroid activitywithout dangerous or dose-limiting calcaemia. Paricalci-tol also showed promise in early experimental studies,albeit with less spectacular dissociation than that seenwith 22-oxacalcitriol [23]. It was therefore with bothsurprise and disappointment that nephrologists saw theresults of the early emerging clinical studies. Withoutquestion, these two agents suppressed elevated parathy-roid hormone in patients with hyperparathyroidism atleast as well as did calcitriol [24, 25, 26, 27, 28] and inplacebo-controlled studies, it appeared that adverse ef-fects on plasma calcium, phosphorus and the CaxPproduct were possibly less marked than with calcitriol.Unfortunately, the results from studies comparing either22-oxacalcitriol or paricalcitol with current best therapyusing calcitriol lead us to be more circumspect. In thecase of 22-oxacalcitriol, the comparative data are ex-tremely limited and there is no evidence for a clinicallyrelevant benefit of 22-oxacalcitriol over standard treat-ment with calcitriol. Both suppress the parathyroids ef-fectively and both are associated with a similar incidenceof hypercalcaemia and elevation of the CaxP product asbest can be judged from uncontrolled or placebo-con-trolled studies.

The case of paricalcitol is less clear. Comparativestudies conducted as part of the regulatory process were

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filed with the American Food and Drug Administra-tion (FDA), but not published at the time. These FDAdata indicate that paricalcitol and calcitriol given intra-venously with each haemodialysis did not differ in theirability to decrease PTH or in their propensity to causehypercalcaemia or elevation of the CaxP product [10, 29].However, further analyses of that database have nowbeen published and appear to show a clear-cut, if modest,benefit of paricalcitol over calcitriol. Thus, patients treat-ed with paricalcitol experienced more rapid reduction ofPTH and fewer episodes of sustained hypercalcaemia and/or increased CaxP product [30, 31]. Of course, “head tohead” studies of this type are critically dependent on ac-curate prior assessment of dose comparability and failureto achieve this can have the effect of spuriously disad-vantaging one or another compound.

Intravenous paricalcitol in children has recently beenreported as an effective and well-tolerated treatment forsecondary hyperparathyrodism in a placebo-controlledstudy [32]. As yet, comparative studies in children havenot been reported. Preliminary work has been publishedin abstract form reporting experience with a new capsuleformulation of paricalcitol. These early reports are gen-erally encouraging, showing substantial reduction of PTHwith minimal change of calcium or the CaxP product. In aplacebo-controlled study of 150 patients, oral paricalcitolshowed good efficacy and acceptability [33]. If parical-citol does indeed have a significant clinical edge overcalcitriol, this oral formulation is a useful developmentthat should simplify treatment of patients on continuousambulatory peritoneal dialysis and those with less severechronic kidney disease and not yet on dialysis. As hasbeen the case with the intravenous preparations, com-parative studies are required before reaching a firm con-clusion as to the benefits, if any, of paricalcitol capsulesover oral alfacalcidol/calcitriol.

No studies comparing doxercalciferol with a currentestablished therapy (calcitriol, alfacalcidol or paricalcitol)have been published, although undoubtedly doxercalcif-erol is an effective treatment for secondary hyperpara-thyroidism as judged by placebo controlled assessments[5, 34]. As with other vitamin D analogues, hypercal-caemia complicates the otherwise good therapeutic re-sponse in a minority of cases.

An intriguing, and as yet unexplained, set of obser-vations has recently been published in which it appearsthat adult haemodialysis patients treated with paricalcitolexperienced slightly lower mortality than did apparentlycomparable patients treated with calcitriol [35]. Thiswas a very large retrospective study with the inevitablestrengths and weaknesses inherent in such a design. Onthe face of it, such an observation appears counterintuitiveand the lack of perfect comparability between paricalcitoland calcitriol groups (slightly more blacks and a longerperiod of dialysis pre enrolment in the paricalcitol group)is potentially confounding. The issue is clearly of greatimportance and requires further exploration by way of arandomized prospective study as well as investigation ofpotential mechanisms.

In conclusion, while the emerging picture is of the new“non-calcaemic” vitamin D analogues being at least aseffective and safe as calcitriol and alfacalcidol, clinicallyrelevant advantages over current best therapy are harder todemonstrate. Alfacalcidol and calcitriol are effective ifimperfect drugs—a description that can also be applied tothe current crop of new vitamin D compounds. The dis-crepancy between the experimental data showing strikingbenefits of the new agents and the clinical experience ofmodest benefit in the case of paricalcitol, and none in thecases of 22-oxacalcitriol and doxercalciferol, remainspuzzling and disappointing. Paediatric experience with thenew compounds remains limited or non-existent. Fur-thermore, the scenario is about to change—calcimimeticagents are in phase 3 clinical studies and are just enteringroutine clinical practice in the United States. The earlyresults look very encouraging [36] and, despite the wide-spread distribution of the calcium sensing receptor (CaR),unforeseen side effects have not been a feature of thestudies conducted in adults thus far. In children, however,great care will be needed in the clinical evaluation of thesecompounds. The CaR is probably expressed in bone cellsand also in growth plate chondrocytes—the potential forharm is obvious. It will be interesting to see how thesecomplementary and additive treatments for hyperpara-thyroidism develop alongside one another.

References

1. Abe J, Takita Y, Nakano T, Miyaura C, Suda T, Nishii Y(1989) A synthetic analogue of vitamin D3, 22-oxa-1 alpha, 25-dihydroxyvitamin D3, is a potent modulator of in vivo im-munoregulating activity without inducing hypercalcemia inmice. Endocrinology 124:2645–2647

2. Brown AJ, Ritter CR, Finch JL, Morrissey J, Martin KJ,Murayama E, Nishii Y, Slatopolsky E (1989) The noncalcemicanalogue of vitamin D, 22-oxacalcitriol, suppresses parathyroidhormone synthesis and secretion. J Clin Invest 84:728–732

3. Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, SiderD, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM,Salusky IB (2000) Coronary-artery calcification in young adultswith end-stage renal disease who are undergoing dialysis. NEngl J Med 342:1478–1483

4. Oh J, Wunsch R, Turzer M, Bahner M, Raggi P, Querfeld U,Mehls O, Schaefer F (2002) Advanced coronary and carotidarteriopathy in young adults with childhood-onset chronic renalfailure. Circulation 106:100–105

5. Coburn JW, Tan AU Jr, Levine BS, Mazess RB, Kyllo DM,Knutson JC, Bishop CW (1996) 1 alpha-Hydroxy-vitamin D2: anew look at an ‘old’ compound. Nephrol Dial Transplant 11[Suppl 3]:153–157

6. Knutson JC, LeVan LW, Valliere CR, Bishop CW (1997)Pharmacokinetics and systemic effect on calcium homeostasisof 1 alpha,24-dihydroxyvitamin D2 in rats. Comparison with 1alpha,25-dihydroxyvitamin D2, calcitriol, and calcipotriol.Biochem Pharmacol 53:829–837

7. Mawer EB, Jones G, Davies M, Still PE, Byford V, SchroederNJ, Makin HL, Bishop CW, Knutson JC (1998) Unique 24-hydroxylated metabolites represent a significant pathway ofmetabolism of vitamin D2 in humans: 24-hydroxyvitamin D2and 1,24-dihydroxyvitamin D2 detectable in human serum.J Clin Endocrinol Metab 83:2156–2166

707

8. Coburn JW (1990) Use of oral and parenteral calcitriol in thetreatment of renal osteodystrophy. Kidney Int [Suppl] 29:S54–S61

9. Mazess RB, Elangovan L (2003) A review of intravenousversus oral vitamin D hormone therapy in hemodialysis pa-tients. Clin Nephrol 59:319–325

10. Steddon SJ, Schroeder NJ, Cunningham J (2001) Vitamin Danalogues: how do they differ and what is their clinical role?Nephrol Dial Transplant 16:1965–1967

11. Haussler MR, Haussler CA, Jurutka PW, Thompson PD, HsiehJC, Remus LS, Selznick SH, Whitfield GK (1997) The vitaminD hormone and its nuclear receptor: molecular actions anddisease states. J Endocrinol 154 [Suppl]:S57–S73

12. Haussler MR, Jurutka PW, Hsieh JC, Thompson PD, SelznickSH, Haussler CA, Whitfield GK (1995) New understanding ofthe molecular mechanism of receptor-mediated genomic ac-tions of the vitamin D hormone. Bone 17:33S–38S

13. Haussler MR, Whitfield GK, Haussler CA, Hsieh JC, Thomp-son PD, Selznick SH, Dominguez CE, Jurutka PW (1998) Thenuclear vitamin D receptor: biological and molecular regulatoryproperties revealed. J Bone Miner Res 13:325–349

14. Boyan BD, Bonewald LF, Sylvia VL, Nemere I, Larsson D,Norman AW, Rosser J, Dean DD, Schwartz Z (2002) Evidencefor distinct membrane receptors for 1 alpha,25-(OH)(2)D(3)and 24R,25-(OH)(2)D(3) in osteoblasts. Steroids 67:235–246

15. Nemere I, Yazzie-Atkinson D, Johns DO, Larsson D (2002)Biochemical characterization and purification of a bindingprotein for 24,25-dihydroxyvitamin D3 from chick intestine.J Endocrinol 172:211–219

16. Bailie GR, Johnson CA (2002) Comparative review of thepharmacokinetics of vitamin D analogues. Semin Dial 15:352–357

17. Brown AJ, Finch J, Grieff M, Ritter C, Kubodera N, Nishii Y,Slatopolsky E (1993) The mechanism for the disparate actionsof calcitriol and 22-oxacalcitriol in the intestine. Endocrinology133:1158–1164

18. Horst R, Prapong S, Reinhardt T, Koszewski N, Knutson J,Bishop C (2000) Comparison of the relative effects of 1,24-dihydroxyvitamin D(2) [1, 24-(OH)(2)D(2)], 1,24-dihydroxy-vitamin D(3) [1,24-(OH)(2)D(3)], and 1,25-dihydroxyvitaminD(3) [1,25-(OH)(2)D(3)] on selected vitamin D-regulatedevents in the rat. Biochem Pharmacol 60:701–708

19. MacDonald PN, Baudino TA, Tokumaru H, Dowd DR, ZhangC (2001) Vitamin D receptor and nuclear receptor coactivators:crucial interactions in vitamin D-mediated transcription. Ster-oids 66:171–176

20. Issa LL, Leong GM, Sutherland RL, Eisman JA (2002) VitaminD analogue-specific recruitment of vitamin D receptor coacti-vators. J Bone Miner Res 17:879–890

21. Schroeder NJ, Burrin JM, Noonan K, Makin HL, Cunningham J(2003) Effects of ‘non-calcaemic’ vitamin D analogues on 24-hydroxylase expression in MG-63 osteoblast-like cells. Neph-ron Physiol 94:62–73

22. Brown AJ, Berkoben M, Ritter C, Kubodera N, Nishii Y,Slatopolsky E (1992) Metabolism of 22-oxacalcitriol by a vi-tamin D-inducible pathway in cultured parathyroid cells. Bio-chem Biophys Res Commun 189:759–764

23. Slatopolsky E, Finch J, Ritter C, Takahashi F (1998) Effects of19-nor-1,25(OH)2D2, a new analogue of calcitriol, on sec-

ondary hyperparathyroidism in uremic rats. Am J Kidney Dis32:S40–S47

24. Kurokawa K, Akizawa T, Suzuki M, Akiba T, Ogata E,Slatopolsky E (1996) Effect of 22-oxacalcitriol on hyperpara-thyroidism of dialysis patients: results of a preliminary study.Nephrol Dial Transplant 11 [Suppl] 3:121–124

25. Kinugasa E, Akizawa T, Takahashi J, Nabeshima K, Ogata H,Nakayama F, Ideura T (2002) Effects of 1,25-dihydroxy-22-oxavitamin D(3) on parathyroid gland function in haemodial-ysis patients with secondary hyperparathyroidism. Nephrol DialTransplant 17 [Suppl] 10:20–27

26. Doi S, Yorioka N, Usui K, Shigemoto K, Harada S (2003)Effect of 22-oxacalcitriol on secondary hyperparathyroidism inhemodialysis patients. Intern Med 42:955–959

27. Lindberg J, Martin KJ, Gonzalez EA, Acchiardo SR, Valdin JR,Soltanek C (2001) A long-term, multicenter study of the effi-cacy and safety of paricalcitol in end-stage renal disease. ClinNephrol 56:315–323

28. Llach F, Keshav G, Goldblat MV, Lindberg JS, Sadler R,Delmez J, Arruda J, Lau A, Slatopolsky E (1998) Suppressionof parathyroid hormone secretion in hemodialysis patients by anovel vitamin D analogue: 19-nor-1,25-dihydroxyvitamin D2.Am J Kidney Dis 32:S48–S54

29. Cunningham J (1999) What is the optimal regimen for vitaminD? Kidney Int [Suppl] 73:S59–S64

30. Sprague SM, Lerma E, McCormmick D, Abraham M, Batlle D(2001) Suppression of parathyroid hormone secretion in he-modialysis patients: comparison of paricalcitol with calcitriol.Am J Kidney Dis 38:S51–S56

31. Sprague SM, Llach F, Amdahl M, Taccetta C, Batlle D (2003)Paricalcitol versus calcitriol in the treatment of secondary hy-perparathyroidism. Kidney Int 63:1483–1490

32. Kommala D, Benador N, Goldstein S, Pardes A, MattinglyS, Amdhal MG, L, Williams LA, Salusky I (2003) Paricalcitol(Zemplar) injection for the treatment of secondary hyperpara-thyroidism in pediatric hemodialysis patients. Proceedings ofthe American Society of Nephrology, San Diego

33. Llach F, Qiu EA, Ross EA, Abboud H, Mere CC, Wojtak A,Hippensteel R, Williams LA, Block G (2003) Paricalcitol(Zemplar) capsule controls secondary hyperparathyroidism inchronic hemodialysis patients. Proceedings of the AmericanSociety of Nephrology, San Diego

34. Frazao JM, Elangovan L, Maung HM, Chesney RW, AcchiardoSR, Bower JD, Kelley BJ, Rodriguez HJ, Norris KC, RobertsonJA, Levine BS, Goodman WG, Gentile D, Mazess RB, KylloDM, Douglass LL, Bishop CW, Coburn JW (2000) Intermittentdoxercalciferol (1alpha-hydroxyvitamin D(2)) therapy for sec-ondary hyperparathyroidism. Am J Kidney Dis 36:550–561

35. Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, ThadhaniR (2003) Survival of patients undergoing hemodialysis withparicalcitol or calcitriol therapy. N Engl J Med 349:446–456

36. Quarles LD, Sherrard DJ, Adler S, Rosansky SJ, McCary LC,Liu W, Turner SA, Bushinsky DA (2003) The calcimimeticAMG 073 as a potential treatment for secondary hyperpara-thyroidism of end-stage renal disease. J Am Soc Nephrol 14:575–583

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