Kidney International, Vol. 62 (2002), pp. 367–374

PERSPECTIVES IN RENAL MEDICINE

Update on vitamin D and its newer analogues: Actions andrationale for treatment in chronic renal failure

HARTMUT H. MALLUCHE, HANNA MAWAD, and NICHOLAS J. KOSZEWSKI

Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, Kentucky, USA

Update on vitamin D and its newer analogues: Actions and Recent research shows that the biological actions ofrationale for treatment in chronic renal failure. Vitamin D is vitamin D extend well beyond these classic functions toan important hormone for mineral homeostasis and the proper include effects on immunity, muscle and vasculature,formation and maintenance of bone. In addition, vitamin D

reproduction, and the growth and differentiation ofhas broader functions in the body that expand its traditionallymany cell types [1, 2]. Target cells for vitamin D areknown role in mineral balance. In chronic renal failure, calcitriol

deficiency contributes to the development and progression of found in the intestine, kidneys, bone, bone marrow, para-secondary hyperparathyroidism, bone disorders, and altered thyroid glands, skin, liver, muscle, lymphoid tissue, andmineral metabolism. Recent revelations of the broader role of

other organs, suggesting diverse biological roles for thisvitamin D also suggest calcitriol deficiency may contribute tohormone [3, 4]. These properties have made vitamin Ddecreased cardiac and immune function in chronic renal failure

patients. Research on vitamin D has led to a more complete an attractive potential therapeutic agent for various typesunderstanding of the actions of vitamin D at the transcriptional of cancers, skin disorders, and autoimmune diseases, inlevel and with respect to the clinical use of vitamin D and its addition to its current use for the treatment of secondaryanalogs to control parathyroid hormone overactivity and to

hyperparathyroidism (s-HPT) [1].replace the other D hormone-dependent actions in patientsActive vitamin D hormone is generated from the pre-with renal failure. Limitations of vitamin D and its metabolites

include hypercalcemia, hyperphosphatemia and suppression of cursors vitamin D3 (cholecalciferol) and vitamin D2 (er-bone turnover with the risk of adynamic bone disease. Vitamin gocalciferol) obtained from animal and plant sources,D analogs may offer greater selectivity and potentially greater respectively, in the diet. A good source of vitamin D3 alsosafety as compared to calcitriol because of their altered relative

is provided by the conversion of 7-dehydrocholesterolpotency on calcium and phosphorus metabolism. This reviewfocuses on the current understanding of the biological actions (provitamin D3) in the skin upon exposure to ultravioletof vitamin D and its analogs and the rationale for treating light. The liver and kidneys are necessary for convertingpatients with chronic renal failure. these vitamin D hormone precursors into biologically

active forms in the body. In the liver, vitamin D is hydrox-ylated to form 25-hydroxyvitamin D. In the kidney, a

Evolution in the understanding of vitamin D and its second hydroxyl group is added to form 1,25-dihydrox-broad actions has led to major advances in the treatment yvitamin D (calcitriol), the most biologically active formof chronic renal disease and other disorders. Research of the hormone. Both the vitamin D2 and D3 forms of theon the classic actions of vitamin D has shown that its active hormone are biologically potent in the body [5].primary function is the stimulation of dietary calciumabsorption, which is vital for overall mineral balance andfor the development and maintenance of bone. As a VITAMIN D AND ITS RECEPTORsteroid endocrine hormone, the other primary action Calcitriol binds with high affinity to its nuclear recep-of vitamin D is the regulation of parathyroid hormone tor, the vitamin D receptor (VDR, NR1I1) [6], to elicit(PTH) through the inhibition of prepro-PTH mRNA changes in gene transcription inside of target cells (com-production by the parathyroid glands. prehensively reviewed in [7]). Sensitive detection meth-

ods have revealed that nearly every organ in the bodypossesses some cell types that express the VDR [8, 9].Key words: calcitriol, hemodialysis, mineral homeostasis, bone forma-

tion, progressive renal disease, hyperparathyroidism. This includes the classical target organs for hormoneaction such as the intestine, kidney, bone, and parathy-Received for publication September 11, 2001roid gland, but the receptor also has been found in suchand in revised form January 7, 2002

Accepted for publication January 8, 2002 organs as the skin, prostate, spleen, heart, and brain.Thus, the hormone has the potential to affect gene tran- 2002 by the International Society of Nephrology

367

Malluche et al: Vitamin D and analogues in renal failure368

scription events in a wide range of organs throughout the mRNA have been detected by restriction enzymedigestion of the corresponding cDNA molecule. One ofthe body.

The VDR, like other members of the nuclear receptor the most intensively studied VDR polymorphisms occursin the 3� untranslated region of the mRNA and is charac-family, is comprised of distinct structural domains within

the protein. These include a ligand binding domain terized by the presence or absence of sensitivity to theBsmI enzyme [25]. Genotyping studies in populations of(LBD), a DNA binding domain (DBD), and regions

involved in transactivation. Binding of the natural hor- renally impaired patients indicated that those lackingthe BsmI restriction site (BB) may be more prone tomone is thought to bring about a conformational change

in the receptor structure that increases interactions with possessing lower serum PTH concentrations [26–29].Perhaps a more intriguing finding has been the identifi-DNA and other proteins. Recently, crystal structure and

molecular modeling have provided detailed insights into cation of a FokI polymorphism in the start site codingregion for the VDR that results in the synthesis of athe LBD of the receptor and amino acids that the hor-

mone interacts within the binding cleft [10, 11]. Eventu- slightly smaller isoform of the protein [30]. Although farfewer studies have been conducted to date regarding theally, this understanding may afford the opportunity to

create vitamin D analogs that target interactions with FokI polymorphism, Jurutka et al have shown that thereare differences in the interactions of these receptor iso-specific amino acid residues to elicit specific transcrip-

tional responses. forms with transcription factor IIB (TFIIB) [31]. Becausethis polymorphism exists in the coding region and canRecent experiments have indicated the existence of

co-activators or transcriptional intermediary factors that produce a receptor with altered transcriptional sensitivi-ties, it may be of interest to see if populations of renalcan interact with the activating domains of nuclear recep-

tors [12]. Several silencers or co-repressors also have patients exhibit differences in this particular polymor-phism.been identified that appear to associate with unliganded

receptors to suppress transcription of the target gene[13, 14]. Similar to the other members of the nuclear

RATIONALE FOR VITAMIN D TREATMENT INreceptor superfamily, the VDR has been shown to inter-

PATIENTS WITH RENAL FAILUREact with several types of transcription factors and co-A lowered serum calcitriol concentration is a majoractivator proteins [15–18]. In addition, a large, multi-

factor in the pathogenesis of s-HPT in chronic renalsubunit complex of proteins, referred to as the DRIPfailure. The failing kidney’s reduced capacity to producecomplex, has been affinity purified using the ligandedcalcitriol contributes to PTH oversecretion by the para-LBD of the VDR [19]. Thus, a current working modelthyroid glands directly through genomic control of pre-for activation of a target gene includes a conformationalpro-PTH mRNA and indirectly through lower serumchange induced by hormone binding that results in thecalcium levels [32]. Recent data show that s-HPT in thedissociation of repressor molecules from the nuclear re-early stages or development of renal osteodystrophy mayceptor complex followed by the recruitment of co-activa-be an adaptive response to maintain calcium, phosphorustors that then mediate an increase in transcriptional ac-and calcitriol balance [33–35]. We showed an elevationtivity [20].in serum PTH in patients and experimental dogs withFar less is currently known in general about how nu-moderate renal failure with prevailing normocalcemia,clear receptors interact in a hormone-dependent fashionnormophosphatemia and normal calcitriol concentra-to repress gene transcription. DNA elements now havetions [36]. Under physiologic conditions elevated PTHbeen identified that are linked to the repression of PTHconcentrations would be expected to drive the synthesisgene transcripts by vitamin D [21–23]. It will be of inter-of calcitriol, but the further loss of kidney function, ac-est to determine if repression of gene transcription occurscentuated by impaired phosphorus excretion, furtherby a similar mechanism as proposed for gene activation,stimulates PTH production while lowering circulatingthat is, the hormone-dependent recruitment of co-modu-calcium and calcitriol levels, which worsens the syn-lator proteins that would result in a decrease of genedrome. Calcitriol deficiency thus plays a major role intranscription. Determining what other factors are re-the development and severity of renal osteodystrophyquired for mediating the vitamin’s repressive effects onin renal failure [32].PTH gene transcription therefore also might lead to the

development of other treatments that would comple-Replacement of the deficient vitamin D hormonement vitamin D therapy in the control of s-HPT.

The replacement of deficient vitamin D hormone lev-Interestingly, the VDR gene itself has been toutedels to restore the diverse actions of vitamin D is a majorfor its predictive value in assessing the severity of bonetherapeutic goal for the treatment of patients withabnormalities, although considerable controversy sur-chronic renal failure. The rationale is to promote normalrounds this issue [24]. In the case of polymorphisms in

the VDR gene, several variations in the sequence of physiology and mineral metabolism, and to prevent com-

Malluche et al: Vitamin D and analogues in renal failure 369

plications due to calcitriol deficiency by maintaining ap- be used with caution because of the risk of inducinghypercalcemia, soft tissue calcification and further sup-propriate levels of the missing hormone [37]. While the

current clinical indication for vitamin D and its analogues pression of PTH levels and bone turnover [45–47]. Acertain minimum level of bone activity is required forin chronic renal failure patients is for the treatment of

secondary hyperparathyroidism, the broader biological the bone’s ability to control mineral homeostasis throughaccretion and release of calcium [48].effects of the hormone suggest additional benefits for

this population. Parathyroid hormone monitoring and bone biopsy arethe best diagnostic approaches to assess the value ofRestoring calcium balance. Hypocalcemia is a com-

mon condition in chronic renal disease because of declin- long-term vitamin D therapy for patients with symptom-atic bone disorders [33, 34, 41, 49]. For example, seruming serum levels of calcitriol. Without adequate levels

of this hormone, active transport of dietary calcium by PTH levels above 500 pg/mL are reasonably predictiveof hyperparathyroid bone disease [47] that would mostlythe intestine is hampered, and calcium absorption occurs

mainly through passive mechanisms. Rising serum phos- likely benefit from vitamin D therapy. Conversely, intactPTH levels between 100 and 450 pg/mL are not pre-phorus levels due to impaired phosphorus excretion by

the kidneys further contribute to hypocalcemia by low- dictive of bone turnover status, and bone biopsy is neces-sary to determine the level of bone turnover to applyering serum ionized calcium levels and by inhibiting the

action of calcitriol [32, 38]. In end-stage renal disease the appropriate therapy [47, 49]. Studies are in progressin our laboratory to evaluate the diagnostic value of the(ESRD), the compensatory effects of increased PTH

that initially offset changes in calcium and phosphorus novel “whole” 1-84 PTH assay [50], and the ratio of1-84/N-terminal fragments as a noninvasive assessmentlevels eventually fail, causing profound calcitriol defi-

ciency, hyperphosphatemia, and hypocalcemia [32, 33, of bone turnover [51].Additional potential benefits. Research on vitamin D38]. Treatment with vitamin D restores the PTH-cal-

cium-vitamin D endocrine feedback loop that helps has uncovered a wide range of biological actions thatextend its primary function in mineral homeostasis. Formaintain normal serum calcium levels and mineral ho-

meostasis. example, vitamin D has been shown to stimulate theactivity of monocytes and macrophages and improve hostPreventing and treating bone disorders. Vitamin D is

critical for maintaining serum calcium and phosphate defense against infection and tumor cell growth [2].These actions suggest potential benefits in chronic renallevels that allow normal bone mineralization. Stimula-

tion of intestinal absorption of these minerals is believed failure patients who typically have depressed immunefunction.to be the primary benefit of vitamin D for proper bone

formation [2]. However, vitamin D also has direct effects Besides its effects on immunity, vitamin D also appearsto have direct effects on cardiac and skeletal musclethat stimulate the synthesis of bone matrix protein, bone

resorption, and bone cell activity [2, 39]. function. In animal studies, vitamin D controlled hyper-trophy in cardiac myocytes in rats [2, 52]. Similarly, inAbnormal bone histology is a nearly universal condi-

tion in ESRD due to reduced calcitriol concentrations, a prospective study of hemodialysis patients with s-HPT(iPTH levels �450 pg/mL), treatment with calcitriolelevated PTH levels, hypocalcemia, hyperphosphatemia,

metabolic acidosis, and other factors [2, 33, 34, 40, 41]. caused a regression of myocardial hypertrophy, as as-sessed by reductions in ventricular wall thickness andRenal bone disorders include the high turnover condi-

tions, predominant hyperparathyroid bone disease and left ventricle mass index [53]. Changes in serum PTHlevels as well as a reduction in angiotensin II may bemixed uremic osteodystrophy, as well as the low turnover

disorders, adynamic uremic bone disease and osteoma- responsible for the favorable effects of vitamin D in thisstudy. These potential benefits of vitamin D deservelacia.

Vitamin D has proved successful in the prevention more extensive research, given that cardiac abnormali-ties are so common in ESRD patients.and amelioration of renal bone disorders in patients with

mild to moderate renal insufficiency [42, 43]. In ESRD,Control of PTH oversecretionhowever, the potential benefits of vitamin D for these

disorders are highly dependent on the underlying causes Secondary hyperparathyroidism continues to affect alarge percentage of ESRD patients [54], increasing theof the abnormality. In high turnover disease states, vita-

min D improves bone structure primarily through the risk of death, cardiac abnormalities, bone disorders, andother complications in this population [55, 56]. Pro-control of PTH overproduction [44]. Mixed uremic os-

teodystrophy benefits from vitamin D therapy, de- longed PTH exposure appears to have toxic effects onmany organs, including the heart, bones, skeletal muscle,pending on the extent of hyperparathyroid bone disease

and abnormal mineralization [41]. Conversely, with ady- nerves, and reproductive system [55, 57, 58].The controlling effect of vitamin D on parathyroidnamic bone disorders—which are associated with low,

normal or high PTH levels—vitamin D therapy should gland overactivity is the primary indication for initiating

Malluche et al: Vitamin D and analogues in renal failure370

therapy and the major benefit of vitamin D treatment. phate binders [70, 71]. These adverse effects can limitthe maximum dose achievable and/or preclude the useVitamin D ameliorates secondary hyperparathyroidism

in several ways: by the direct inhibition of prepro-PTH of vitamin D or calcium-based phosphate binders untilmineral levels or serum levels of calcitriol are controlledmRNA production by the parathyroid glands, by the

inhibition of parathyroid gland hyperplasia, and by in- [36, 67, 72]. Temporarily discontinuing vitamin D ther-apy due to side effects can cause PTH levels to reboundcreasing serum calcium concentrations. Early control of

PTH production is crucial because sustained overactivity and further worsen secondary hyperparathyroidism [67,72, 73]. Additionally, an elevated Ca � P product (�55)of the parathyroid glands can lead to nodular forms of

hyperplasia that are resistant to vitamin D and calcium increases the risk of metastatic calcification, a complica-tion associated with cardiac dysfunction and death [56,regulation, are largely irreversible, and typically require

parathyroidectomy [38, 59–61]. 74, 75].Overall responsiveness to vitamin D can be affectedVitamin D therapy has led to significant improvements

in pathologic PTH secretion, bone histology, and cardiac by the reduced VDR content of the parathyroid gland,especially in nodules that have been shown to containabnormalities in many patient populations with mild to

severe secondary hyperparathyroidism [42, 43, 62, 63]. lower VDR concentrations [61, 76]. The potential effecton serum phosphorus levels through the stimulation ofPulse oral and intravenous forms of calcitriol appear to

have similar efficacy in patients with s-HPT [60, 64], intestinal phosphorus absorption is another factor thatmay limit vitamin D treatment. Hyperphosphatemiaalthough others have observed more beneficial effects

with pulse parenteral administration [65, 66]. However, worsens s-HPT by stimulating the proliferation of para-thyroid cells [38, 77] and promoting resistance to vitaminin a placebo controlled study we found more frequent

episodes of hypercalcemia with pulse oral and more hy- D and failure of treatment [67, 78, 79]. These limitationsof vitamin D therapy have been the impetus for theperphosphatemia with intermittent IV calcitriol therapy

(abstract, Faugere et al, J Am Soc Nephrol 5:695, 1993). development of less or non-calcemic, non-phosphatemicThe success of vitamin D therapy for treatment of s-HPT analogs for the treatment of s-HPT.depends on adequate dosing, careful monitoring of sideeffects, proper assessment of bone status, and appro-

FUTURE OUTLOOK: VITAMIN D ANALOGUESpriate timing and initiation of therapy. Proper dosing toThe development of vitamin D analogs that preventachieve sustained and effective control of PTH remains

hyperactivity of the parathyroid gland and retain othera central issue in vitamin D therapy. Underdosing cangenomic effects without induction of hypercalcemia andresult in ineffective control of PTH with continued riskhyperphosphatemia has been a major area of researchof hyperphosphatemia and eventually hypercalcemiaover the past decade. Several vitamin D analogs withsecondary to increased calcium and phosphate releasepotentially selective action are approved in the U.S.,from bone, whereas overdosing can oversuppress bonewhile others are under clinical investigation [1, 80–87].turnover and induce hypercalcemia and hyperphospha-Paricalcitol (19-nor-1,25-dihydroxy-vitamin D2; Zem-temia secondary to the bones’ inability to maintain nor-plar�, Abbott Laboratories, North Chicago, IL, USA)mal mineral accretion rates [33, 40, 67]. The response toand doxercalciferol (1�-hydroxyvitamin D2; Hectorol�vitamin therapy also can vary widely depending on theCapsules and Injection; Bone Care International, Middle-severity of s-HPT, bone status, mineral status, type oftown, WI, USA) are two vitamin D analogs that may havevitamin D analog used, concomitant use of phosphateless calcemic action have been recently approved for thebinders, and other factors [33, 68, 69]. It appears reason-treatment of secondary hyperparathyroidism in the U.S.able to state that the “pulse” administration of calcitriolOther analogs that have garnered interest include 22-oxa-is preferable for controlling PTH oversecretion, whilecalcitriol (Chugai Pharmaceuticals, Tokyo, Japan) and thedaily administration mimics more closely the physiologichexafluorinated analog falecalcitriol, although their ap-production, which should be preferable for optimal re-proval for the treatment of secondary hyperparathyroid-placement of the missing hormone.ism is pending approval of regulatory agencies in Japan.

Limitations of vitamin D treatment Paricalcitol is an injectable calcitriol analog that hasbeen shown in clinical trials to decrease serum PTH levelsWhile calcitriol is effective for controlling PTH over-in hemodialysis patients with secondary hyperparathy-production and improving bone histology, its stimulatoryroidism, with no significant increase in the incidence ofeffects on intestinal absorption of both calcium and phos-hypercalcemia or hyperphosphatemia as compared tophorous combined with its suppressive effects on boneplacebo [82, 88]. Regrettably, no studies including boneturnover can cause elevations in serum calcium, phos-histology before and after paricalcitol are available. Inphorous and calcium-phosphorus (Ca � P) product. Theanimal studies, paricalcitol appeared to have potent ef-risk of hypercalcemia and elevated Ca � P product is

greater if patients are also taking calcium-based phos- fects on the parathyroid glands but lesser effects on intes-

Malluche et al: Vitamin D and analogues in renal failure 371

tinal VDR levels as compared to calcitriol [89]. In rat These distinct vitamin D analogs may offer greaterselectivity and potentially less toxicity as compared tostudies, paricalcitol was less potent than calcitriol in mo-

bilizing calcium and phosphorus from bone [90]. In a re- calcitriol for the treatment of secondary hyperparathy-roidism. They appear to have similar efficacy and im-cent review, Brown noted that paricalcitol has a blunted

effect on intestinal calcium transport and bone resorp- proved safety profiles as compared to calcitriol, althoughdirect comparative studies with the natural hormone intion after repeated dosing [81]. Preliminary results from

a subpopulation of patients enrolled in a double-blind, a clinical setting of patients with reduced kidney functionhave been limited [91]. Bone studies are currently inrandomized, multi-center comparing paricalcitol with

calcitriol indicated a more rapid decline in serum PTH progress. Additional studies also are needed to under-stand the basis of selectivity in these analogs as well asconcentrations and lower incidences of hyperphosphate-

mia with paricalcitol [91]; however, further analysis of to evaluate their effects on bone turnover and to directlycompare their efficacy and safety to calcitriol. There arethe data from all centers involved in that study will need

to be incorporated to clearly establish superiority of pari- many factors that can influence the effectiveness of avitamin D analog, including binding to the serum vitamincalcitol over calcitriol.

Doxercalciferol is a prohormone that is converted in D binding protein, catabolic metabolism, and ability tobind to and alter the conformation of the VDR. Particu-the liver to active 1�,25-dihydroxyvitamin D2. A unique

feature of this analog is its partial conversion at higher larly confounding is the observation that numerous ana-logs appear to exhibit reduced binding affinity for thedoses to 1�,24-dihydroxyvitamin D2, a biologically active

vitamin D2 metabolite that has low calcemic activity and VDR compared to calcitriol, yet are able to elicit invitro responses at much lower concentrations than thereduced toxicity as compared to calcitriol [92, 93]. Doxer-

calciferol has undergone clinical trials in hemodialysis hormone (an extensive listing of vitamin D compoundsis in [101]). One intriguing possibility receiving increasedpatients. Oral doses of this analog reduced average se-

rum PTH levels in dialysis patients, with low incidence attention in this regard is to examine how binding ofof hypercalcemia and hyperphosphatemia [83, 94]. An an analog to the VDR may effectively alter subsequentinjectable form of doxercalciferol has also been approved interactions with co-activator proteins [102–104]. Thisrecently. may lead to the advent of analogs that possess more

22-Oxacalcitriol has shown promise in in vitro and in selective actions with respect to cellular differentiatingvivo studies. In rats, a controlling effect on PTH overse- or antiproliferative effects. The former would be a morecretion with less hypercalcemia than calcitriol was ob- desirable property if replacement of the missing hor-served [95, 96]. This has been ascribed to a more rapid mone were the major goal of therapy, while the latterpharmacokinetic profile [97]. In experimental dogs, PTH would be useful for control of parathyroid gland hyper-oversecretion was prevented or corrected without the plasia.slowdown in bone turnover observed with calcitriol [80]. One must exercise caution in extrapolating results us-A small clinical trial involving three patients suffering ing vitamin D analogs that were obtained from in vitrofrom renal failure indicated that 22-oxacalcitriol was ef- studies or short-term treatments in animal models offective in controlling PTH oversecretion [98]. Additional disease with the complexities involved with treating hu-clinical reports on the use of this analog have been forth- man patients suffering from renal insufficiency. How-coming [86], but further studies will be necessary to as- ever, together with data from the crystal structure andsess the safety and efficacy of this analog in comparison modeling of the VDR protein, the future holds promisewith calcitriol. for synthetic versions of vitamin D that can selectively

Finally, the hexafluorinated analog, falecalcitriol, also target subsets of vitamin D responsive genes for morehas generated interest as a potential therapeutic agent refined clinical outcomes.in the management of hyperparathyroid patients. Thisanalog was more potent in stimulating transcriptional

CONCLUSIONSactivity in cell culture and in inducing formation of aOur understanding of vitamin D and its biologicalVDR-DNA complex than calcitriol [99]. In addition, fa-

actions has increased tremendously over the past fewlecalcitriol was more potent than calcitriol in suppressingdecades. Vitamin D, first shown to be a potent hormonePTH secretion from bovine parathyroid cells and wasessential for mineral homeostasis, is now known to havemore slowly degraded in these cells [100]. A crossoverwide-ranging effects in the body, from regulation of im-study comparing falecalcitriol and alfacalcidol in the sup-mune function to effects on skeletal muscle, heart, skin,pression of serum PTH in hemodialysis patients has beenand many other cell types. A deficiency in vitamin Dreported [87]. Falecalcitriol was apparently more effec-contributes to the development and worsening of sec-tive in controlling PTH levels, although the results wereondary hyperparathyroidism, bone disorders, and abnor-hampered by the low patient numbers enrolled in the

study. mal mineral metabolism. Vitamin D treatment to control

Malluche et al: Vitamin D and analogues in renal failure372

involved in vitamin D-mediated transcription. J Biol ChemPTH levels and to supply adequate amounts of the hor-273:16434–16441, 1998

mone has proved successful for the management of 17. Gill RK, Atkins LM, Hollis BW, Bell NH: Mapping the do-chronic renal failure. Limitations of vitamin D, including mains of the interaction of the vitamin D receptor and steroid

receptor coactivator-1. Mol Endocrinol 12:57–65, 1998the tendency to induce hypercalcemia, suppression of18. Jurutka PW, Remus LS, Whitfield GK, et al: Biochemical evi-

bone turnover and hyperphosphatemia, are addressed dence for a 170-kilodalton, AF-2-dependent vitamin D receptor/through the development of new vitamin D analogs. The retinoid X receptor coactivator that is highly expressed in osteo-

blasts. Biochem Biophys Res Commun 267:813–819, 2000goal of these analogs is to control parathyroid gland19. Rachez C, Suldan Z, Ward J, et al: A novel protein complexhyperactivity without induction of adynamic bone, hyper- that interacts with the vitamin D3 receptor in a ligand-dependent

calcemia and hyperphosphatemia. Additional research on manner and enhances VDR transactivation in a cell-free system.Genes Dev 12:1787–1800, 1998these analogs will clarify the basis of their selectivity,

20. Xu L, Glass CK, Rosenfeld MG: Coactivator and corepressormode of action, and long-term efficacy. complexes in nuclear receptor function. Curr Opin Genet Dev9:140–147, 1999

21. Hawa NS, O’Riordan JL, Farrow SM: Functional analysis ofACKNOWLEDGMENTvitamin D response elements in the parathyroid hormone gene

Support for this study was provided by an unrestricted educational and a comparison with the osteocalcin gene. Biochem Biophysgrant from Bone Care International. Res Commun 228:352–357, 1996

22. Mackey SL, Heymont JL, Kronenberg HM, Demay MB: VitaminD receptor binding to the negative human parathyroid hormoneReprint requests to Hartmut H. Malluche, M.D., Division of Nephrol-vitamin D response element does not require the retinoid x recep-ogy, Bone and Mineral Metabolism, University of Kentucky, 800 Rosetor. Mol Endocrinol 10:298–305, 1996Street, Room MN 564, Lexington, Kentucky 40536-0298, USA.

E-mail: hhmall@pop.uky.edu 23. Liu SM, Koszewski N, Lupez M, et al: Characterization of aresponse element in the 5�-flanking region of the avian (chicken)PTH gene that mediates negative regulation of gene transcription

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