Vitamin D and Bone Authors
Skeletal Regulations (D Gaddy, Section Editor)
First Online: 29 April 2012 DOI:
Cite this article as: Bikle, D.D. Curr Osteoporos Rep (2012) 10: 151. doi:10.1007/s11914-012-0098-z
All cells comprising the skeleton—chondrocytes, osteoblasts, and osteoclasts—contain both the vitamin D receptor and the enzyme CYP27B1 required for producing the active metabolite of vitamin D, 1,25 dihydroxyvitamin D. Direct effects of 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D on these bone cells have been demonstrated. However, the major skeletal manifestations of vitamin D deficiency or mutations in the vitamin D receptor and CYP27B1, namely rickets and osteomalacia, can be corrected by increasing the intestinal absorption of calcium and phosphate, indicating the importance of indirect effects. On the other hand, these dietary manipulations do not reverse defects in osteoblast or osteoclast function that lead to osteopenic bone. This review discusses the relative importance of the direct versus indirect actions of vitamin D on bone, and provides guidelines for the clinical use of vitamin D to prevent/treat bone loss and fractures.
Vitamin D receptor
1,25 dihydroxyvitamin D
24,25 dihydroxyvitamin D
References Papers of particular interest, published recently, have been highlighted as: • Of importance
Holick MF, MacLaughlin JA, Clark MB, et al. Photosynthesis of previtamin D3 in human skin and the physiologic consequences. Science. 1980;210:203–5.
• Bikle DD. Extra renal synthesis of 1,25 dihydroxyvitamin D and its Health Implications. Clin Rev in Bone and Min Metab. 2009;7:114–25.
This review of extrarenal production of 1,25(OH)
D provides a good perspective for understanding the importance of the ability of tissues including bone to make their own 1,25(OH)
van Driel M, Koedam M, Buurman CJ, et al. Evidence for auto/paracrine actions of vitamin D in bone: 1alpha-hydroxylase expression and activity in human bone cells. Faseb J. 2006;20:2417–9.
Xie Z, Munson SJ, Huang N, et al. The mechanism of 1,25-dihydroxyvitamin D(3) autoregulation in keratinocytes. J Biol Chem. 2002;277:36987–90.
Schwartz Z, Ehland H, Sylvia VL, et al. 1alpha,25-dihydroxyvitamin D(3) and 24R,25-dihydroxyvitamin D(3) modulate growth plate chondrocyte physiology via protein kinase C-dependent phosphorylation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase. Endocrinology. 2002;143:2775–86.
Bikle DD, Gee E, Halloran B, et al. Free 1,25-dihydroxyvitamin D levels in serum from normal subjects, pregnant subjects, and subjects with liver disease. J Clin Invest. 1984;74:1966–71.
Bikle DD, Siiteri PK, Ryzen E, et al. Serum protein binding of 1,25-dihydroxyvitamin D: a reevaluation by direct measurement of free metabolite levels. J Clin Endocrinol Metab. 1985;61:969–75.
Pike JW. Genome-wide principles of gene regulation by the vitamin D receptor and its activating ligand. Mol Cell Endocrinol. 2011;347:3–10.
Smith CL, O’Malley BW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev. 2004;25:45–71.
Zanello LP, Norman AW. Rapid modulation of osteoblast ion channel responses by 1alpha,25(OH)2-vitamin D3 requires the presence of a functional vitamin D nuclear receptor. Proc Natl Acad Sci U S A. 2004;101:1589–94.
• Chen J, Olivares-Navarrete R, Wang Y, et al. Protein-disulfide isomerase-associated 3 (Pdia3) mediates the membrane response to 1,25-dihydroxyvitamin D3 in osteoblasts. J Biol Chem. 2010;285:37041–50.
This study addresses the rapid actions of 1,25(OH)
D on bone as mediated by a receptor other than VDR. Both VDR and Pdia3 are likely involved in these rapid, nongenomic actions.
Nemere I, Garbi N, Hammerling GJ, et al. Intestinal cell calcium uptake and the targeted knockout of the 1,25D3-MARRS (membrane-associated, rapid response steroid-binding) receptor/PDIA3/Erp57. J Biol Chem. 2010;285:31859–66.
Li YC, Pirro AE, Amling M, et al. Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci U S A. 1997;94:9831–5.
Yoshizawa T, Handa Y, Uematsu Y, et al. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet. 1997;16:391–6.
Dardenne O, Prud’homme J, Arabian A, et al. Targeted inactivation of the 25-hydroxyvitamin D(3)-1(alpha)-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets. Endocrinology. 2001;142:3135–41.
Panda DK, Miao D, Tremblay ML, et al. Targeted ablation of the 25-hydroxyvitamin D 1alpha-hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction. Proc Natl Acad Sci U S A. 2001;98:7498–503.
Johnson JA, Grande JP, Roche PC, et al. Ontogeny of the 1,25-dihydroxyvitamin D3 receptor in fetal rat bone. J Bone Miner Res. 1996;11:56–61.
Miller SC, Halloran BP, DeLuca HF, et al. Studies on the role of vitamin D in early skeletal development, mineralization, and growth in rats. Calcif Tissue Int. 1983;35:455–60.
Narbaitz R, Stumpf WE, Sar M, et al. Autoradiographic localization of target cells for 1 alpha, 25-dihydroxyvitamin D3 in bones from fetal rats. Calcif Tissue Int. 1983;35:177–82.
Boivin G, Mesguich P, Pike JW, et al. Ultrastructural immunocytochemical localization of endogenous 1,25-dihydroxyvitamin D3 and its receptors in osteoblasts and osteocytes from neonatal mouse and rat calvaria. Bone Miner. 1987;3:125–36.
Atkins GJ, Anderson PH, Findlay DM, et al. Metabolism of vitamin D3 in human osteoblasts: evidence for autocrine and paracrine activities of 1 alpha,25-dihydroxyvitamin D3. Bone. 2007;40:1517–28.
Masuyama R, Stockmans I, Torrekens S, et al. Vitamin D receptor in chondrocytes promotes osteoclastogenesis and regulates FGF23 production in osteoblasts. J Clin Invest. 2006;116:3150–9.
Anderson PH, O’Loughlin PD, May BK, et al. Modulation of CYP27B1 and CYP24 mRNA expression in bone is independent of circulating 1,25(OH)2D3 levels. Bone. 2005;36:654–62.
Kogawa M, Anderson PH, Findlay DM, et al. The metabolism of 25-(OH)vitamin D3 by osteoclasts and their precursors regulates the differentiation of osteoclasts. J Steroid Biochem Mol Biol. 2010;121:277–80.
• Kogawa M, Findlay DM, Anderson PH, et al. Osteoclastic metabolism of 25(OH)-vitamin D3: a potential mechanism for optimization of bone resorption. Endocrinology. 2010;151:4613–25.
This study demonstrated that osteoclast precursors can produce 1,25(OH)2D, and that such production stimulates osteoclast differentiation, but surprisingly reduces their resorptive function at least in an osteoclast cell line (RAW264.7).
• Naja RP, Dardenne O, Arabian A, et al. Chondrocyte-specific modulation of Cyp27b1 expression supports a role for local synthesis of 1,25-dihydroxyvitamin D3 in growth plate development. Endocrinology. 2009;150:4024–32.
This study of mice in which CYP27B1 was deleted from chondrocytes demonstrated decreased endochondral bone formation similar to the results from Masuyama et al.
in which VDR was specifically deleted in chondrocytes. These are strong arguments for a direct action of vitamin D on bone.
Balsan S, Garabedian M, Larchet M, et al. Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D. J Clin Invest. 1986;77:1661–7.
Underwood JL, DeLuca HF. Vitamin D is not directly necessary for bone growth and mineralization. Am J Physiol. 1984;246:E493–8.
Li YC, Amling M, Pirro AE, et al. Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice. Endocrinology. 1998;139:4391–6.
Amling M, Priemel M, Holzmann T, et al. Rescue of the skeletal phenotype of vitamin D receptor-ablated mice in the setting of normal mineral ion homeostasis: formal histomorphometric and biomechanical analyses. Endocrinology. 1999;140:4982–7.
al-Aqeel A, Ozand P, Sobki S, et al. The combined use of intravenous and oral calcium for the treatment of vitamin D dependent rickets type II (VDDRII). Clin Endocrinol (Oxf). 1993;39:229–37.
Dardenne O, Prud’homme J, Hacking SA, et al. Correction of the abnormal mineral ion homeostasis with a high-calcium, high-phosphorus, high-lactose diet rescues the PDDR phenotype of mice deficient for the 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1). Bone. 2003;32:332–40.
Weinstein RS, Underwood JL, Hutson MS, et al. Bone histomorphometry in vitamin D-deficient rats infused with calcium and phosphorus. Am J Physiol. 1984;246:E499–505.
• Xue Y, Fleet JC. Intestinal vitamin D receptor is required for normal calcium and bone metabolism in mice. Gastroenterology. 2009;136:1317–27. e1311–1312.
This study provides strong evidence for an indirect effect of vitamin D on bone in that replacing the VDR in the intestine of VDR null mice corrected most of the skeletal abnormalities
• Bikle DD. Vitamin D: an ancient hormone. Exp Dermatol. 2010;20:7–13.
This perspective argues for the dual actions of calcium and vitamin D on most tissues such that lack of either can be at least partially compensated for by the other—a situation relevant to an understanding of the relative roles for indirect and direct actions of vitamin D on bone.
Morales O, Faulds MH, Lindgren UJ, et al. 1Alpha,25-dihydroxyvitamin D3 inhibits GH-induced expression of SOCS-3 and CIS and prolongs growth hormone signaling via the Janus kinase (JAK2)/signal transducers and activators of transcription (STAT5) system in osteoblast-like cells. J Biol Chem. 2002;277:34879–84.
Chenu C, Valentin-Opran A, Chavassieux P, et al. Insulin like growth factor I hormonal regulation by growth hormone and by 1,25(OH)2D3 and activity on human osteoblast-like cells in short- term cultures. Bone. 1990;11:81–6.
Kurose H, Yamaoka K, Okada S, et al. 1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] increases insulin-like growth factor I (IGF-I) receptors in clonal osteoblastic cells. Study on interaction of IGF-I and 1,25-(OH)2D3. Endocrinology. 1990;126:2088–94.
Scharla SH, Strong DD, Mohan S, et al. 1,25-Dihydroxyvitamin D3 differentially regulates the production of insulin-like growth factor I (IGF-I) and IGF-binding protein-4 in mouse osteoblasts. Endocrinology. 1991;129:3139–46.
Moriwake T, Tanaka H, Kanzaki S, et al. 1,25-Dihydroxyvitamin D3 stimulates the secretion of insulin-like growth factor binding protein 3 (IGFBP-3) by cultured human osteosarcoma cells. Endocrinology. 1992;130:1071–3.
Sato T, Ono T, Tuan RS. 1,25-Dihydroxy vitamin D3 stimulation of TGF-beta expression in chick embryonic calvarial bone. Differentiation. 1993;52:139–50.
Wang DS, Yamazaki K, Nohtomi K, et al. Increase of vascular endothelial growth factor mRNA expression by 1,25-dihydroxyvitamin D3 in human osteoblast-like cells. J Bone Miner Res. 1996;11:472–9.
Lacey DL, Grosso LE, Moser SA, et al. IL-1-induced murine osteoblast IL-6 production is mediated by the type 1 IL-1 receptor and is increased by 1,25 dihydroxyvitamin D3. J Clin Invest. 1993;91:1731–42.
Lacey DL, Erdmann JM, Tan HL, et al. Murine osteoblast interleukin 4 receptor expression: upregulation by 1,25 dihydroxyvitamin D3. J Cell Biochem. 1993;53:122–34.
Nambi P, Wu HL, Lipshutz D, et al. Identification and characterization of endothelin receptors on rat osteoblastic osteosarcoma cells: down-regulation by 1,25-dihydroxy- vitamin D3. Mol Pharmacol. 1995;47:266–71.
Owen TA, Aronow MS, Barone LM, et al. Pleiotropic effects of vitamin D on osteoblast gene expression are related to the proliferative and differentiated state of the bone cell phenotype: dependency upon basal levels of gene expression, duration of exposure, and bone matrix competency in normal rat osteoblast cultures. Endocrinology. 1991;128:1496–504.
Sooy K, Sabbagh Y, Demay MB. Osteoblasts lacking the vitamin D receptor display enhanced osteogenic potential in vitro. J Cell Biochem. 2005;94:81–7.
Tanaka H, Seino Y. Direct action of 1,25-dihydroxyvitamin D on bone: VDRKO bone shows excessive bone formation in normal mineral condition. J Steroid Biochem Mol Biol. 2004;89–90:343–5.
Anderson PH, Atkins GJ, Findlay DM, et al. RNAi-mediated silencing of CYP27B1 abolishes 1,25(OH)2D3 synthesis and reduces osteocalcin and CYP24 mRNA expression in human osteosarcoma (HOS) cells. J Steroid Biochem Mol Biol. 2007;103:601–5.
Baldock PA, Thomas GP, Hodge JM, et al. Vitamin D action and regulation of bone remodeling: suppression of osteoclastogenesis by the mature osteoblast. J Bone Miner Res. 2006;21:1618–26.
Gardiner EM, Baldock PA, Thomas GP, et al. Increased formation and decreased resorption of bone in mice with elevated vitamin D receptor in mature cells of the osteoblastic lineage. Faseb J. 2000;14:1908–16.
Demay MB, Gerardi JM, DeLuca HF, et al. DNA sequences in the rat osteocalcin gene that bind the 1,25-dihydroxyvitamin D3 receptor and confer responsiveness to 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci U S A. 1990;87:369–73.
Kerner SA, Scott RA, Pike JW. Sequence elements in the human osteocalcin gene confer basal activation and inducible response to hormonal vitamin D3. Proc Natl Acad Sci U S A. 1989;86:4455–9.
Noda M, Vogel RL, Craig AM, et al. Identification of a DNA sequence responsible for binding of the 1,25-dihydroxyvitamin D3 receptor and 1,25-dihydroxyvitamin D3 enhancement of mouse secreted phosphoprotein 1 (SPP-1 or osteopontin) gene expression. Proc Natl Acad Sci U S A. 1990;87:9995–9.
Zhang R, Ducy P, Karsenty G. 1,25-dihydroxyvitamin D3 inhibits Osteocalcin expression in mouse through an indirect mechanism. J Biol Chem. 1997;272:110–6.
Wronski TJ, Halloran BP, Bikle DD, et al. Chronic administration of 1,25-dihydroxyvitamin D3: increased bone but impaired mineralization. Endocrinology. 1986;119:2580–5.
Hock JM, Gunness-Hey M, Poser J, et al. Stimulation of undermineralized matrix formation by 1,25 dihydroxyvitamin D3 in long bones of rats. Calcif Tissue Int. 1986;38:79–86.
Kyeyune-Nyombi E, Lau KH, Baylink DJ, et al. 1,25-Dihydroxyvitamin D3 stimulates both alkaline phosphatase gene transcription and mRNA stability in human bone cells. Arch Biochem Biophys. 1991;291:316–25.
Irving JT, Wuthier RE. Histochemistry and biochemistry of calcification with special reference to the role of lipids. Clin Orthop. 1968;56:237–60.
Howell DS, Marquez JF, Pita JC. The nature of phospholipids in normal and rachitic costochondral plates. Arthritis Rheum. 1965;8:1039–46.
Dean DD, Boyan BD, Muniz OE, et al. Vitamin D metabolites regulate matrix vesicle metalloproteinase content in a cell maturation-dependent manner. Calcif Tissue Int. 1996;59:109–16.
Plachot JJ, Du Bois MB, Halpern S, et al. In vitro action of 1,25-dihydroxycholecalciferol and 24,25-dihydroxycholecalciferol on matrix organization and mineral distribution in rabbit growth plate. Metab Bone Dis Relat Res. 1982;4:135–42.
St-Arnaud R, Arabian A, Travers R, et al. Deficient mineralization of intramembranous bone in vitamin D-24-hydroxylase-ablated mice is due to elevated 1,25-dihydroxyvitamin D and not to the absence of 24,25-dihydroxyvitamin D. Endocrinology. 2000;141:2658–66.
Boyan BD, Schwartz Z, Carnes Jr DL, et al. The effects of vitamin D metabolites on the plasma and matrix vesicle membranes of growth and resting cartilage cells in vitro. Endocrinology. 1988;122:2851–60.
Schwartz Z, Boyan B. The effects of vitamin D metabolites on phospholipase A2 activity of growth zone and resting zone cartilage cells in vitro. Endocrinology. 1988;122:2191–8.
Swain LD, Schwartz Z, Caulfield K, et al. Nongenomic regulation of chondrocyte membrane fluidity by 1,25-(OH)2D3 and 24,25-(OH)2D3 is dependent on cell maturation. Bone. 1993;14:609–17.
Sylvia VL, Schwartz Z, Schuman L, et al. Maturation-dependent regulation of protein kinase C activity by vitamin D3 metabolites in chondrocyte cultures. J Cell Physiol. 1993;157:271–8.
Pedrozo HA, Schwartz Z, Rimes S, et al. Physiological importance of the 1,25(OH)2D3 membrane receptor and evidence for a membrane receptor specific for 24,25(OH)2D3. J Bone Miner Res. 1999;14:856–67.
Suda T, Takahashi N, Abe E. Role of vitamin D in bone resorption. J Cell Biochem. 1992;49:53–8.
Rodan GA, Martin TJ. Role of osteoblasts in hormonal control of bone resorption—a hypothesis. Calcif Tissue Int. 1981;33:349–51.
Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A. 1998;95:3597–602.
Takeda S, Yoshizawa T, Nagai Y, et al. Stimulation of osteoclast formation by 1,25-dihydroxyvitamin D requires its binding to vitamin D receptor (VDR) in osteoblastic cells: studies using VDR knockout mice. Endocrinology. 1999;140:1005–8.
Panda DK, Miao D, Bolivar I, et al. Inactivation of the 25-hydroxyvitamin D 1alpha-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis. J Biol Chem. 2004;279:16754–66.
• Anderson PH, Atkins GJ, Turner AG, et al. Vitamin D metabolism within bone cells: effects on bone structure and strength. Mol Cell Endocrinol. 2011;347:42–7.
This review summarizes some of the data supporting a direct action of vitamin D on bone.
• Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96:53–8.
This controversial report sets a recommended floor and ceiling for vitamin D supplementation and optimal serum 25OHD levels.
Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. Jama. 2005;293:2257–64.
• Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med. 2009;169:551–61.
This meta-analysis suggests that the lower limits recommended by the Institute of Medicine report are too low to prevent fractures optimally.
Avenell A, Gillespie WJ, Gillespie LD, et al. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev (Online) 2009.CD000227.
Ensrud KE, Taylor BC, Paudel ML, et al. Serum 25-hydroxyvitamin D levels and rate of hip bone loss in older men. J Clin Endocrinol Metab. 2009;94:2773–80.
Heaney RP, Dowell MS, Hale CA, et al. Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. J Am Coll Nutr. 2003;22:142–6.
Bischoff-Ferrari HA, Kiel DP, Dawson-Hughes B, et al. Dietary calcium and serum 25-hydroxyvitamin D status in relation to BMD among U.S. adults. J Bone Miner Res. 2009;24:935–42.
Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al. Effect of Vitamin D on falls: a meta-analysis. Jama. 2004;291:1999–2006.
Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999;69:842–56.
Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–81.
Heaney RP, Davies KM, Chen TC, et al. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr. 2003;77:204–10.
Hathcock JN, Shao A, Vieth R, et al. Risk assessment for vitamin D. Am J Clin Nutr. 2007;85:6–18.
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