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Prolonged 25-OH Vitamin D Deficiency Does Not Impair Bone Mineral Density in Adult Patients With Vitamin D 25-Hydroxylase Deficiency (CYP2R1)


Vitamin D-dependent rickets type 1B (VDDR1B) is an autosomal semidominant genetic disorder caused by a deficiency in CYP2R1, which encodes vitamin D 25-hydroxylase, an enzyme that plays a crucial role in the conversion of vitamin D to 25-dihydroxyvitamin D3. VDDR1B is a severe form of rickets that occurs during infancy and which is responsive to 25-OH vitamin D supplementation. We studied three adult patients from a multi-consanguineous family with VDDR1B. They have been diagnosed with pseudo-nutritional rickets and treated during their adolescence with 25-OH vitamin D. These patients stopped their treatments at the end of adolescence and were contacted 14 to 17 years later when VDDR1B diagnosis was carried out in their niece and nephews. These three patients had undetectable 25-OH vitamin D, but normal levels of plasma 1–25(OH)2 vitamin D. All patients had a hip bone mineral density and a normal vertebral despite osteoarthritis degenerative lesions which may impact BMD evaluation. These findings show that vitamin D supplementation has a questionable effect, if any, for osteoporosis prevention in adulthood in contrast to its crucial importance during infancy and adolescence.

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  1. Henry HL (2011) Regulation of vitamin D metabolism. Best practice & research. J Clin Endocr Metab 25:531–541

    CAS  Google Scholar 

  2. Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW (2004) Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci USA 101:7711–7715

    Article  CAS  Google Scholar 

  3. Lewiecki EM, Bilezikian JP, Giangregorio L, Greenspan SL, Khosla S, Kostenuik P, Krohn K, McClung MR, Miller PD, Pacifici R (2019) Proceedings of the 2018 Santa Fe Bone Symposium: advances in the management of osteoporosis. J Clin Densitom 22:1–19

    Article  Google Scholar 

  4. Weaver CM, Alexander DD, Boushey CJ, Dawson-Hughes B, Lappe JM, LeBoff MS, Liu S, Looker AC, Wallace TC, Wang DD (2016) Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis from the National Osteoporosis Foundation. Osteoporos Int 27:367–376

    Article  CAS  Google Scholar 

  5. Murad MH, Drake MT, Mullan RJ, Mauck KF, Stuart LM, Lane MA, Abu Elnour NO, Erwin PJ, Hazem A, Puhan MA, Li T, Montori VM (2012) Clinical review. Comparative effectiveness of drug treatments to prevent fragility fractures: a systematic review and network meta-analysis. J Clin Endocrinol Metab 97:1871–1880

    Article  CAS  Google Scholar 

  6. Liu GF, Wang ZQ, Liu L, Zhang BT, Miao YY, Yu SN (2018) A network meta-analysis on the short-term efficacy and adverse events of different anti-osteoporosis drugs for the treatment of postmenopausal osteoporosis. J Cell Biochem 119:4469–4481

    Article  CAS  Google Scholar 

  7. Rizzoli R (2018) Postmenopausal osteoporosis: assessment and management. Best practice & research. Clin Endocrinol Metab 32:739–757

    Google Scholar 

  8. Molin A, Wiedemann A, Demers N, Kaufmann M, Do Cao J, Mainard L, Dousset B, Journeau P, Abeguile G, Coudray N, Mittre H, Richard N, Weryha G, Sorlin A, Jones G, Kottler ML, Feillet F (2017) Vitamin D-dependent rickets type 1B (25-hydroxylase deficiency): a rare condition or a misdiagnosed condition? J Bone Miner Res 32:1893–1899

    Article  CAS  Google Scholar 

  9. Casella SJ, Reiner BJ, Chen TC, Holick MF, Harrison HE (1994) A possible genetic defect in 25-hydroxylation as a cause of rickets. J Pediatr 124:929–932

    Article  CAS  Google Scholar 

  10. Thacher TD, Fischer PR, Singh RJ, Roizen J, Levine MA (2015) CYP2R1 mutations impair generation of 25-hydroxyvitamin D and cause an atypical form of vitamin D deficiency. J Clin Endocrinol Metab 100:E1005–1013

    Article  CAS  Google Scholar 

  11. Thacher TD, Levine MA (2017) CYP2R1 mutations causing vitamin D-deficiency rickets. J Steroid Biochem Mol Biol 173:333–336

    Article  CAS  Google Scholar 

  12. Fraser D, Kooh SW, Kind HP, Holick MF, Tanaka Y, DeLuca HF (1973) Pathogenesis of hereditary vitamin-D-dependent rickets. An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D. N Engl J Med 289:817–822

    Article  CAS  Google Scholar 

  13. Brooks MH, Bell NH, Love L, Stern PH, Orfei E, Queener SF, Hamstra AJ, DeLuca HF (1978) Vitamin-D-dependent rickets type II. Resistance of target organs to 1,25-dihydroxyvitamin D. N Engl J Med 298:996–999

    Article  CAS  Google Scholar 

  14. Damiani FM, Martin RM, Latronico AC, Ferraz-de-Souza B (2015) Normal bone mass and normocalcemia in adulthood despite homozygous vitamin D receptor mutations. Osteoporos Int 26:1819–1823

    Article  CAS  Google Scholar 

  15. Zhu JG, Ochalek JT, Kaufmann M, Jones G, Deluca HF (2013) CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo. Proc Natl Acad Sci USA 110:15650–15655

    Article  CAS  Google Scholar 

  16. Black DM, Rosen CJ (2016) Postmenopausal osteoporosis. N Engl J Med 374:2096–2097

    Article  Google Scholar 

  17. Miras A, Boveda MD, Leis MR, Mera A, Aldamiz-Echevarria L, Fernandez-Lorenzo JR, Fraga JM, Couce ML (2013) Risk factors for developing mineral bone disease in phenylketonuric patients. Mol Genet Metab 108:149–154

    Article  CAS  Google Scholar 

  18. van Wegberg AMJ, MacDonald A, Ahring K, Belanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Gizewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, van Spronsen FJ (2017) The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis 12:162

    Article  Google Scholar 

  19. Mollard E, Bilek L, Waltman N (2018) Emerging evidence on the link between depressive symptoms and bone loss in postmenopausal women. Int J Women's Health 10:1–9

    Article  CAS  Google Scholar 

  20. de Oliveira DL, Hirotsu C, Tufik S, Andersen ML (2017) The interfaces between vitamin D, sleep and pain. J Endocrinol 234:R23–R36

    Article  Google Scholar 

  21. Babaei M, Esmaeili Jadidi M, Heidari B, Gholinia H (2018) Vitamin D deficiency is associated with tibial bone pain and tenderness. A possible contributive role. Int J Rheum Dis 21:788–795

    Article  CAS  Google Scholar 

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Correspondence to Arnaud Wiedemann.

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Arnaud Wiedemann, Emeline Renard, Arnaud Molin, Georges Weryha, Abderrahim Oussalah, Jean-Louis Guéant, and François Feillet declare that they have no conflict of interest in relation to the present work.

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Wiedemann, A., Renard, E., Molin, A. et al. Prolonged 25-OH Vitamin D Deficiency Does Not Impair Bone Mineral Density in Adult Patients With Vitamin D 25-Hydroxylase Deficiency (CYP2R1). Calcif Tissue Int 107, 191–194 (2020).

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