Skip to main content
SpringerLink
Log in

Use of vitamin D with anti-osteoporotic drugs: are available clinical trials telling us the whole story?

  • Viewpoint
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

There is a strong rationale for using vitamin D in combination with anti-osteoporotic drugs. Still, available trials do not give clear indications in this setting, presenting a suboptimal and heavily inhomogeneous experimental design. Health authorities should revise requirements for using vitamin D in anti-osteoporotic drug trials to maximise their effect and produce reliable indications for clinical practice in this setting.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. G. Mazziotti, J. Bilezikian, E. Canalis, D. Cocchi, A. Giustina, New understanding and treatments for osteoporosis. Endocrine 41(1), 58–69 (2012). https://doi.org/10.1007/s12020-011-9570-2

    Article  CAS  PubMed  Google Scholar 

  2. J.P. Bilezikian, A.M. Formenti, R.A. Adler et al. Vitamin D: dosing, levels, form, and route of administration: does one approach fit all? Rev Endocr Metab Disord 22(4), 1201–1218 (2021). https://doi.org/10.1007/s11154-021-09693-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. A.G. Need, P.D. O’Loughlin, H.A. Morris, P.S. Coates, M. Horowitz, B.E. Nordin, Vitamin D metabolites and calcium absorption in severe vitamin D deficiency. J Bone Miner Res 23(11), 1859–1863 (2008). https://doi.org/10.1359/jbmr.080607

    Article  CAS  PubMed  Google Scholar 

  4. M. Kužma, P. Jackuliak, Z. Killinger, J. Payer, Parathyroid hormone-related changes of bone structure. Physiol Res 70(Suppl 1), S3–S11 (2021). https://doi.org/10.33549/physiolres.934779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. L. di Filippo, A. Allora, M. Locatelli et al. Hypocalcemia in COVID-19 is associated with low vitamin D levels and impaired compensatory PTH response. Endocrine 74(2), 219–225 (2021). https://doi.org/10.1007/s12020-021-02882-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. A. Giustina, R. Bouillon, N. Binkley et al. Controversies in Vitamin D: a statement from the third international conference. JBMR Plus 4(12), e10417 (2020). https://doi.org/10.1002/jbm4.10417

    Article  PubMed  PubMed Central  Google Scholar 

  7. S.H. Ralston, N. Binkley, S. Boonen et al. Randomized trial of alendronate plus vitamin D3 versus standard care in osteoporotic postmenopausal women with vitamin D insufficiency. Calcif Tissue Int 88(6), 485–494 (2011). https://doi.org/10.1007/s00223-011-9482-4

    Article  CAS  PubMed  Google Scholar 

  8. A. Catalano, F. Bellone, D. Santoro et al. Vitamin D boosts alendronate tail effect on bone mineral density in postmenopausal women with osteoporosis. Nutrients 13(6), 1878 (2021). https://doi.org/10.3390/nu13061878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. C. Roux, N. Binkley, S. Boonen, et al. Vitamin D status and bone mineral density changes during alendronate treatment in postmenopausal osteoporosis [published correction appears in Calcif Tissue Int. 2014 Feb;94(2):158. Regnister, Jean-Yves [corrected to Reginster, Jean-Yves]]. Calcif Tissue Int 94(2), 153–157 (2014). https://doi.org/10.1007/s00223-013-9763-1

  10. S. Adami, G. Isaia, G. Luisetto et al. Fracture incidence and characterization in patients on osteoporosis treatment: the ICARO study. J Bone Miner Res 21(10), 1565–1570 (2006). https://doi.org/10.1359/jbmr.060715

    Article  CAS  PubMed  Google Scholar 

  11. S. Adami, S. Giannini, G. Bianchi et al. Vitamin D status and response to treatment in post-menopausal osteoporosis. Osteoporos Int 20(2), 239–244 (2009). https://doi.org/10.1007/s00198-008-0650-y

    Article  CAS  PubMed  Google Scholar 

  12. A. Deane, L. Constancio, I. Fogelman, G. Hampson, The impact of vitamin D status on changes in bone mineral density during treatment with bisphosphonates and after discontinuation following long-term use in post-menopausal osteoporosis. BMC Musculoskelet Disord 8, 3 (2007). https://doi.org/10.1186/1471-2474-8-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. M. Ishijima, Y. Sakamoto, M. Yamanaka et al. Minimum required vitamin D level for optimal increase in bone mineral density with alendronate treatment in osteoporotic women. Calcif Tissue Int 85(5), 398–404 (2009). https://doi.org/10.1007/s00223-009-9295-x

    Article  CAS  PubMed  Google Scholar 

  14. A. Catalano, N. Morabito, A. Di Stefano et al. Vitamin D and bone mineral density changes in postmenopausal women treated with strontium ranelate. J Endocrinol Invest 38(8), 859–863 (2015). https://doi.org/10.1007/s40618-015-0299-2

    Article  CAS  PubMed  Google Scholar 

  15. A. Barone, A. Giusti, G. Pioli et al. Secondary hyperparathyroidism due to hypovitaminosis D affects bone mineral density response to alendronate in elderly women with osteoporosis: a randomized controlled trial. J Am Geriatr Soc 55(5), 752–757 (2007). https://doi.org/10.1111/j.1532-5415.2007.01161.x

    Article  PubMed  Google Scholar 

  16. J.L. Geller, B. Hu, S. Reed, J. Mirocha, J.S. Adams, Increase in bone mass after correction of vitamin D insufficiency in bisphosphonate-treated patients. Endocr Pract 14(3), 293–297 (2008). https://doi.org/10.4158/EP.14.3.293

    Article  PubMed  Google Scholar 

  17. G.A. Heckman, A. Papaioannou, R.J. Sebaldt et al. Effect of vitamin D on bone mineral density of elderly patients with osteoporosis responding poorly to bisphosphonates. BMC Musculoskelet Disord 3, 6 (2002). https://doi.org/10.1186/1471-2474-3-6

    Article  PubMed  PubMed Central  Google Scholar 

  18. R. Okazaki, R. Muraoka, M. Maehara, D. Inoue, Factors associated with inadequate responses to risedronate in Japanese patients with osteoporosis. J Bone Miner Metab 37(1), 185–197 (2019). https://doi.org/10.1007/s00774-018-0931-2

    Article  CAS  PubMed  Google Scholar 

  19. O.C. Kwon, J.S. Oh, M.C. Park, Y.G. Kim, Effect of Vitamin D supplementation on bone mineral density in rheumatoid arthritis patients with osteoporosis. Front Med 7, 443 (2020). https://doi.org/10.3389/fmed.2020.00443

    Article  Google Scholar 

  20. U.A. Liberman, S.R. Weiss, J. Bröll et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 333(22), 1437–1443 (1995). https://doi.org/10.1056/NEJM199511303332201

    Article  CAS  PubMed  Google Scholar 

  21. D.M. Black, S.R. Cummings, D.B. Karpf et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 348(9041), 1535–1541 (1996). https://doi.org/10.1016/s0140-6736(96)07088-2

    Article  CAS  PubMed  Google Scholar 

  22. S.R. Cummings, D.M. Black, D.E. Thompson et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 280(24), 2077–2082 (1998). https://doi.org/10.1001/jama.280.24.2077

    Article  CAS  PubMed  Google Scholar 

  23. K.G. Saag, R. Emkey, T.J. Schnitzer et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group. N Engl J Med 339(5), 292–299 (1998). https://doi.org/10.1056/NEJM199807303390502

    Article  CAS  PubMed  Google Scholar 

  24. B. Ettinger, D.M. Black, B.H. Mitlak et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators [published correction appears in JAMA 1999 Dec 8;282(22):2124]. JAMA. 282(7), 637–645 (1999). https://doi.org/10.1001/jama.282.7.637

    Article  CAS  PubMed  Google Scholar 

  25. S.T. Harris, N.B. Watts, H.K. Genant et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA 282(14), 1344–1352 (1999). https://doi.org/10.1001/jama.282.14.1344

    Article  CAS  PubMed  Google Scholar 

  26. E. Orwoll, M. Ettinger, S. Weiss et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med 343(9), 604–610 (2000). https://doi.org/10.1056/NEJM200008313430902

    Article  CAS  PubMed  Google Scholar 

  27. S. Wallach, S. Cohen, D.M. Reid et al. Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy. Calcif Tissue Int 67(4), 277–285 (2000). https://doi.org/10.1007/s002230001146

    Article  CAS  PubMed  Google Scholar 

  28. J. Reginster, H.W. Minne, O.H. Sorensen et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 11(1), 83–91 (2000). https://doi.org/10.1007/s001980050010

    Article  CAS  PubMed  Google Scholar 

  29. M.R. McClung, P. Geusens, P.D. Miller et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med 344(5), 333–340 (2001). https://doi.org/10.1056/NEJM200102013440503

    Article  CAS  PubMed  Google Scholar 

  30. J.D. Adachi, K.G. Saag, P.D. Delmas, et al., Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial. Arthritis Rheum 44(1), 202–211 (2001). https://doi.org/10.1002/1529-0131(200101)44:1<202::AID-ANR27>3.0.CO;2-W

    Article  CAS  PubMed  Google Scholar 

  31. R.M. Neer, C.D. Arnaud, J.R. Zanchetta et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344(19), 1434–1441 (2001). https://doi.org/10.1056/NEJM200105103441904

    Article  CAS  PubMed  Google Scholar 

  32. E. Barrett-Connor, D. Grady, A. Sashegyi et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA 287(7), 847–857 (2002). https://doi.org/10.1001/jama.287.7.847

    Article  CAS  PubMed  Google Scholar 

  33. C.H. Chesnut 3rd, A. Skag, C. Christiansen et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 19(8), 1241–1249 (2004). https://doi.org/10.1359/JBMR.040325

    Article  CAS  PubMed  Google Scholar 

  34. P.J. Meunier, C. Roux, E. Seeman et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 350(5), 459–468 (2004). https://doi.org/10.1056/NEJMoa022436

    Article  CAS  PubMed  Google Scholar 

  35. E. McCloskey, P. Selby, M. Davies et al. Clodronate reduces vertebral fracture risk in women with postmenopausal or secondary osteoporosis: results of a double-blind, placebo-controlled 3-year study. J Bone Miner Res 19(5), 728–736 (2004). https://doi.org/10.1359/JBMR.040116

    Article  CAS  PubMed  Google Scholar 

  36. J.Y. Reginster, E. Seeman, M.C. De Vernejoul, et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab 90(5), 2816–2822 (2005). https://doi.org/10.1210/jc.2004-1774

    Article  CAS  PubMed  Google Scholar 

  37. D.M. Black, P.D. Delmas, R. Eastell et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356(18), 1809–1822 (2007). https://doi.org/10.1056/NEJMoa067312

    Article  CAS  PubMed  Google Scholar 

  38. K.G. Saag, E. Shane, S. Boonen et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med 357(20), 2028–2039 (2007). https://doi.org/10.1056/NEJMoa071408

    Article  CAS  PubMed  Google Scholar 

  39. K.W. Lyles, C.S. Colón-Emeric, J.S. Magaziner et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 357(18), 1799–1809 (2007). https://doi.org/10.1056/NEJMoa074941

    Article  CAS  PubMed  Google Scholar 

  40. E.V. McCloskey, M. Beneton, D. Charlesworth et al. Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study. J Bone Miner Res 22(1), 135–141 (2007). https://doi.org/10.1359/jbmr.061008

    Article  CAS  PubMed  Google Scholar 

  41. S.L. Silverman, C. Christiansen, H.K. Genant et al. Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res 23(12), 1923–1934 (2008). https://doi.org/10.1359/jbmr.080710

    Article  CAS  PubMed  Google Scholar 

  42. S.R. Cummings, J. San Martin, M.R. McClung et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis [published correction appears in N Engl J Med. 2009 Nov 5;361(19):1914]. N Engl J Med. 361(8), 756–765 (2009). https://doi.org/10.1056/NEJMoa0809493

    Article  CAS  PubMed  Google Scholar 

  43. F. Cosman, D.B. Crittenden, J.D. Adachi et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 375(16), 1532–1543 (2016). https://doi.org/10.1056/NEJMoa1607948

    Article  CAS  PubMed  Google Scholar 

  44. K.G. Saag, J. Petersen, M.L. Brandi et al. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. N Engl J Med 377(15), 1417–1427 (2017). https://doi.org/10.1056/NEJMoa1708322

    Article  CAS  PubMed  Google Scholar 

  45. P.R. Ebeling, R.A. Adler, G. Jones et al. Management of endocrine disease: therapeutics of vitamin D. Eur J Endocrinol 179(5), R239–R259 (2018). https://doi.org/10.1530/EJE-18-0151

    Article  CAS  PubMed  Google Scholar 

  46. M. Rossini, S. Adami, F. Bertoldo et al. Linee guida per la diagnosi, la prevenzione ed il trattamento dell’osteoporosi. Reumatismo 68(1), 1–42 (2016)

    Article  CAS  PubMed  Google Scholar 

  47. M.F. Holick, The vitamin D deficiency pandemic: approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord 18(2), 153–165 (2017). https://doi.org/10.1007/s11154-017-9424-1

    Article  CAS  PubMed  Google Scholar 

  48. European Medicines Agency: evaluation of new medicinal products in the treatment of primary osteoporosis - Scientific guideline. London, November 2006. Doc. Ref. CPMP/EWP/552/95 Rev. 2. www.ema.europa.eu/en/evaluation-new-medicinal-products-treatment-primary-osteoporosis-scientific-guideline

  49. M. Hiligsmann, W. Ben Sedrine, O. Bruyère, S.M. Evers, V. Rabenda, J.Y. Reginster, Cost-effectiveness of vitamin D and calcium supplementation in the treatment of elderly women and men with osteoporosis. Eur J Public Health 25(1), 20–25 (2015). https://doi.org/10.1093/eurpub/cku119

    Article  PubMed  Google Scholar 

  50. S. Minisola, L. Colangelo, C. Cipriani, J. Pepe, D.P. Cook, C. Mathieu, Screening for hypovitaminosis D: cost-effective or not? Eur J Endocrinol 180(3), D1–D7 (2019). https://doi.org/10.1530/EJE-18-0977

    Article  CAS  PubMed  Google Scholar 

  51. C.T. Sempos, A.C. Heijboer, D.D. Bikle, J. Bollerslev, R. Bouillon, P.M. Brannon, H.F. DeLuca, G. Jones, C.F. Munns, J.P. Bilezikian, A. Giustina, N. Binkley, Vitamin D assays and the definition of hypovitaminosis D: results from the First International Conference on Controversies in Vitamin D. Br J Clin Pharmacol 84(10), 2194–2207 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author contributions

All authors contributed to the review conception and design. LdF performed material preparation and data collection. The first draft of the manuscript was written by LdF and FMU. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Author information

Authors and Affiliations

  1. Institute of Endocrine and Metabolic Sciences, San Raffaele Vita-Salute University and IRCCS Hospital, Milan, Italy

    Luigi di Filippo, Fabio Massimo Ulivieri & Andrea Giustina

  2. Emeritus Professor of Internal Medicine, University of Siena, Siena, Italy

    Ranuccio Nuti

Authors
  1. Luigi di Filippo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fabio Massimo Ulivieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ranuccio Nuti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrea Giustina
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fabio Massimo Ulivieri.

Ethics declarations

Conflict of interest

A.G. is consultant for Abiogen Pharma S.p.A. and Takeda and received research grant to Institution from Takeda. The other authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

di Filippo, L., Ulivieri, F.M., Nuti, R. et al. Use of vitamin D with anti-osteoporotic drugs: are available clinical trials telling us the whole story?. Endocrine 83, 342–348 (2024). https://doi.org/10.1007/s12020-023-03551-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-023-03551-z

Search

Navigation