Skip to main content

Vitamin D history part III: the “modern times”—new questions for orthopaedic practice: deficiency, cell therapy, osteomalacia, fractures, supplementation, infections

Abstract

Purpose

The nutritional basis for rickets was described between 1880 and 1915, at the same period of discovery of other “vital substances” or vitamins. In contrast, rickets could also be prevented or cured by sunshine. But as the capacity to produce vitamin D depends on exposure to ultraviolet B rays (UVB) from sunlight or artificial sources, vitamin D became one of the most frequently used “drugs” in the twentieth century to compensate for insufficient exposure to UVB of humans. Furthermore, as the understanding of vitamin D metabolism grew during the twentieth century, other concerns than rickets occurred for the orthopaedic surgeon: In recent history, deficiency is explored as being an associated factor of different bone pathologies as fracture or prosthetic infection. The aim of this review is to analyze these new data on vitamin D.

Materials and methods

During the twentieth century, there were many concerns for the orthopaedic surgeon: sources and synthesis of vitamin D, regulation of the calcium deposition process for both children and adults, when vitamin D deficiency is observed, and what the best method of vitamin D supplementation is. As target genes regulated by vitamin D are not limited to those involved in mineral homeostasis, orthopedists recently discovered that vitamin D might prevent periprosthetic infection.

Results

The primary source (80%) of vitamin D is dermal synthesis related to the sun. Dietary sources (20%) of vitamin D are fat fishe, beef, liver, and eggs. Vitamin D is produced industrially to be used in fortified foods and supplements. Maintenance of skeletal calcium balance is mediated through vitamin D receptors. Progenitor cells, chondrocytes, osteoblasts, and osteoclasts contain these receptors which explains the role of vitamin D in cell therapy, in the prevention of rickets and osteomalacia. Despite fortified foods, the prevalence of deficiency remains endemic in north latitudes. However, the definition of vitamin D insufficiency or deficiency remains controversial. Vitamin D has been evaluated in patients undergoing fractures and elective orthopaedic procedures Although supplementation may not be able to prevent or cure all the orthopaedic pathologies, oral supplementation is able to improve the vitamin D levels of deficient patients. These vitamin D level improvements might be associated with better functional and clinical outcomes after some surgical procedures and improvement of immunity to decrease the risk of infection in arthroplasties.

Conclusion

Vitamin D deficiency is frequent and concerns millions of people in the world. It is therefore normal to find hypovitaminosis in various orthopaedic populations including trauma and arthroplasties. However, we do not know exactly if this phenomenon only reflects the general prevalence of vitamin D deficiency or has an influence on the outcome of some pathologies on specific populations at risk. After the success of treatment of rickets, it is disappointing that we are still wondering in the twenty-first century whether supplementation of a substance synthetized millions of years ago by plankton and necessary for growth of all the animals may improve (or not) clinical and functional outcomes of a simple fracture in humans.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13

References

  1. Hernigou P, Auregan JC, Dubory A (2018) Vitamin D: part I; from plankton and calcified skeletons (500 million years ago) to rickets. Int Orthop 42(9):2273–2285. https://doi.org/10.1007/s00264-018-3857-3

    Article  PubMed  Google Scholar 

  2. Hernigou P, Auregan JC, Dubory A (2019) Vitamin D: part II cod liver oil, ultraviolet radiation, and eradication of rickets. Int Orthop. https://doi.org/10.1007/s00264-019-04288-z

  3. DeLuca HF (2004) Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr 80(6 Suppl):1689S–1696S

    Article  CAS  PubMed  Google Scholar 

  4. Pike JW, Meyer MB, Benkusky NA, Lee SM, St John H, Carlson A, Onal M, Shamsuzzaman S (2016) Genomic determinants of vitamin D-regulated gene expression. Vitam Horm 100:21–44

    Article  CAS  PubMed  Google Scholar 

  5. Baker AR, McDonnell DP, Hughes M, Crisp TM, Mangelsdorf DJ, Haussler MR, Pike JW, Shine J, O’Malley BW (1988) Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci U S A 85(10):3294–3298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Holick MF, MacLaughlin JA, Clark MB, Holick SA, Potts JT Jr, Anderson RR, Blank IH, Parrish JA, Elias P (1980) Photosynthesis of previtamin D3 in human skin and the physiologic consequences. Science 210(4466):203–205

    Article  CAS  PubMed  Google Scholar 

  7. Borel P, Caillaud D, Cano NJ (2015) Vitamin D bioavailability: state of the art. Crit Rev Food Sci Nutr 55:1193–1205

    Article  CAS  PubMed  Google Scholar 

  8. Koh JS, Kang H, Choi SW, Kim HO (2002) Cigarette smoking associated with premature facial wrinkling: image analysis of facial skin replicas. Int J Dermatol 41(1):21–27

    Article  PubMed  Google Scholar 

  9. Kennedy C, Bastiaens M, Bajdik C, Willemze R, Westerndorp R, Bouwes Bavinck J et al (2003) Effect of smoking and sun on the aging skin. J Investig Dermatol 120:548–554

    Article  CAS  PubMed  Google Scholar 

  10. Ross AC, Manson JE, Abrams SA et al (2011) 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 96:53–58

    Article  CAS  PubMed  Google Scholar 

  11. Ross A, Taylor C, Yaktine A (2011) Institute of Medicine (US) committee to review dietary reference intakes for vitamin D and calcium. National Academies Press, Washington, DC. https://doi.org/10.17226/13050

    Book  Google Scholar 

  12. DeLuca HF (1988) The vitamin D story: a collaborative effort of basic science and clinical medicine. FASEB J 2(3):224–236

    Article  CAS  PubMed  Google Scholar 

  13. Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW (2003) De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase. J Biol Chem 278(39):38084–38093

    Article  CAS  PubMed  Google Scholar 

  14. 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 U S A 101(20):7711–7715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bouillon R, Van Cromphaut S, Carmeliet G (2003) Intestinal calcium absorption: molecular vitamin D mediated mechanisms. J Cell Biochem 88(2):332–339

    Article  CAS  PubMed  Google Scholar 

  16. Olivares-Navarrete R, Sutha K, Hyzy SL, Hutton DL, Schwartz Z, McDevitt T, Boyan BD (2012) Osteogenic differentiation of stem cells alters vitamin D receptor expression. Stem Cells Dev 21:1726–1735

    Article  CAS  PubMed  Google Scholar 

  17. Woeckel VJ, Bruedigam C, Koedam M, Chiba H, van der Eerden BC, van Leeuwen JP (2014) 1α,25-Dihydroxyvitamin D3 and rosiglitazone synergistically enhance osteoblast-mediated mineralization. Gene 512:438–443

    Article  CAS  Google Scholar 

  18. Van de Peppel J, van Leeuwen JP (2013) Vitamin D and gene networks in human osteoblasts. Front Physiol 5:137

    Google Scholar 

  19. Zhou S, Glowacki J, Kim SW, Hahne J, Geng S, Mueller SM, Shen L, Bleiberg I, LeBoff MS (2012) Clinical characteristics influence in vitro action of 1,25-dihydroxyvitamin D (3) in human marrow stromal cells. J Bone Miner Res 27:1992–2000

    Article  CAS  PubMed  Google Scholar 

  20. Hernigou P, Dubory A, Homma Y, Guissou I, Flouzat Lachaniette CH, Chevallier N, Rouard H (2018) Cell therapy versus simultaneous contralateral decompression in symptomatic corticosteroid osteonecrosis: a thirty year follow-up prospective randomized study of one hundred and twenty five adult patients. Int Orthop 42(7):1639–1649. https://doi.org/10.1007/s00264-018-3941-8

    Article  PubMed  Google Scholar 

  21. Hernigou P, Auregan JC, Dubory A, Flouzat-Lachaniette CH, Chevallier N, Rouard H (2018) Subchondral stem cell therapy versus contralateral total knee arthroplasty for osteoarthritis following secondary osteonecrosis of the knee. Int Orthop 42(11):2563–2571. https://doi.org/10.1007/s00264-018-3916-9

    Article  PubMed  Google Scholar 

  22. Heidari B, Heidari P, Hajian-Tilaki K (2011) Association between serum vitamin D deficiency and knee osteoarthritis. Int Orthop 35(11):1627–1631. https://doi.org/10.1007/s00264-010-1186-2

    Article  PubMed  Google Scholar 

  23. Eguchi M, Shibata K, Wada F, Kawamura H, Shimauchi T, Shiota E, Sugioka Y (1987) A comparative study of the calcification-promoting action of 1,25 (OH)2D3 and calcitonin on the growth cartilage of rats with 1-hydroxyethylidene-1, 1-biphosphonic acid (HEBP)-induced rickets. Int Orthop 11(1):77–82

    Article  CAS  PubMed  Google Scholar 

  24. Eguchi M, Kaibara N (1980) Treatment of hypophosphataemic vitamin D-resistant rickets and adult presenting hypophosphataemic vitamin D-resistant osteomalacia. Int Orthop 3(4):257–264

    Article  CAS  PubMed  Google Scholar 

  25. Antonucci R, Locci C, Clemente MG, Chicconi E, Antonucci L (2018) Vitamin D deficiency in childhood: old lessons and current challenges. J Pediatr Endocrinol Metab 31:247–260

    Article  PubMed  Google Scholar 

  26. Uday S, Högler W (2018) Prevention of rickets and osteomalacia in the UK: political action overdue. Arch Dis Child 103:901–906

    Article  PubMed  Google Scholar 

  27. Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–268

    Article  CAS  PubMed  Google Scholar 

  28. Dusso AS, Brown AJ, Slatopolsky E (2005) Vitamin D. Am J Physiol Renal Physiol 289:F8–F28

    Article  CAS  PubMed  Google Scholar 

  29. Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B (2006) Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 84:18–28

    Article  CAS  PubMed  Google Scholar 

  30. Anderson PH (2017) Vitamin D activity and metabolism in bone. Curr Osteoporos Rep 15:443–449

    Article  PubMed  Google Scholar 

  31. Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 348:1535–1541

    Article  CAS  PubMed  Google Scholar 

  32. Moan J, Porojnicu AC, Dahlback A, Setlow RB (2008) Addressing the health benefits and risks, involving vitamin D or skin cancer, of increased sun exposure. Proc Natl Acad Sci U S A 105:668–673

    Article  PubMed  PubMed Central  Google Scholar 

  33. Nagpal S, Na S, Rathnachalam R (2005) Noncalcemic actions of vitamin D receptor ligands. Endocr Rev 26:662–687

    Article  CAS  PubMed  Google Scholar 

  34. Bikle D (2009) Nonclassic actions of vitamin D. J Clin Endocrinol Metab 94:26–34

    Article  CAS  PubMed  Google Scholar 

  35. Malabanan A, Veronikis IE, Holick MF (1998) Redefining vitamin D insufficiency. Lancet. 351:805–806

    Article  CAS  PubMed  Google Scholar 

  36. Chapuy MC, Preziosi P, Maamer M, Arnaud S, Galan P, Hercberg S et al (1997) Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int 7:439–443

    Article  CAS  PubMed  Google Scholar 

  37. Rovner AJ, O’Brien KO (2008) Hypovitaminosis D among healthy children in the United States: a review of current evidence. Arch Pediatr Adolesc Med 162:513–519

    Article  PubMed  Google Scholar 

  38. Looker AC, Pfeiffer CM, Lacher DA, Schleicher RL, Picciano MF, Yetley EA (2008) Serum 25-hydroxyvitamin D status of the US population: 1988-1994 compared with 2000-2004. Am J Clin Nutr 88:1519–1527

    Article  CAS  PubMed  Google Scholar 

  39. Hyppönen E, Power C (2007) Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr 85:860–868

    Article  PubMed  Google Scholar 

  40. Koenig J, Elmadfa I (2000) Status of calcium and vitamin D of different population groups in Austria. Int J Vitam Nutr Res 70(5):214–220

    Article  CAS  PubMed  Google Scholar 

  41. Adams JS, Hewison M (2010) Update in vitamin D. J Clin Endocrinol Metab 95:471–478

  42. Hintzpeter B, Mensink GB, Thierfelder W, Müller MJ, Scheidt-Nave C (2008) Vitamin D status and health correlates among German adults. Eur J Clin Nutr 62(9):1079–1089

    Article  CAS  PubMed  Google Scholar 

  43. Lamberg-Allardt CJ, Outila TA, Kärkkainen MU, Rita HJ, Valsta LM (2001) Vitamin D deficiency and bone health in healthy adults in Finland: could this be a concern in other parts of Europe? Bone Miner Res 16:2066–2073

    Article  CAS  Google Scholar 

  44. Rockell JE, Skeaff CM, Williams SM, Green TJ (2006) Serum 25-hydroxyvitamin D concentrations of new Zealanders aged 15 years and older. Osteoporos Int 17:1382–1389

    Article  CAS  PubMed  Google Scholar 

  45. McKenna MJ (1992) Differences in vitamin D status between countries in young adults and the elderly. Am J Med 93:69–77

    Article  CAS  PubMed  Google Scholar 

  46. Calvo MS, Whiting SJ, Barton CN (2004) Vitamin D fortification in the United States and Canada: current status and data needs. In: Vitamin D and health in the 21st century: bone and beyond. Am J Clin Nutr 80:1710S–1716S

    Article  CAS  PubMed  Google Scholar 

  47. Farrell CJ, Martin S, McWhinney B, Straub I, Williams P, Herrmann M (2012) State-of-the-art vitamin D assays: a comparison of automated immunoassays with liquid chromatography tandem mass spectrometry methods. Clin Chem 58:531–542

    Article  CAS  PubMed  Google Scholar 

  48. Carter GD, Jones JC (2009) Use of a common standard improves the performance of liquid chromatography-tandem mass spectrometry methods for serum 25-hydroxyvitamin-D. Ann Clin Biochem 46:79–81

    Article  CAS  PubMed  Google Scholar 

  49. Fraser WD (2009) Standardization of vitamin D assays: art or science? Ann Clin Biochem 46:3–4

    Article  PubMed  Google Scholar 

  50. Phinney KW, Bedner M, Tai SS, Vamathevan VV, Sander LC, Sharpless KE, Wise SA, Yen JH, Schleicher RL, Chaudhary-Webb M, Pfeiffer CM, Betz JM, Coates PM, Picciano MF (2012) Development and certification of a standard reference material for vitamin D metabolites in human serum. Anal Chem 84:956–962

    Article  CAS  PubMed  Google Scholar 

  51. Inkrott BP, Koberling JL, Noel CR (2016) Hypovitaminosis D in patients undergoing shoulder arthroplasty: a single-center analysis. Orthopedics 39(4):e651–e656

    Article  PubMed  Google Scholar 

  52. Michelson JD, Charlson MD (2016) Vitamin D status in an elective orthopedic surgical population. Foot Ankle Int 37(2):186–191

    Article  PubMed  Google Scholar 

  53. Shin KY, Park KK, Moon SH, Yang IH, ChoiHJ LWS (2017) Vitamin D deficiency adversely affects early post-operative functional outcomes after total knee arthroplasty. Knee Surg Sports Traumatol Arthrosc 25(11):3424–3430. https://doi.org/10.1007/s00167-016-4209-8

    Article  PubMed  Google Scholar 

  54. Maier GS, Maus U, Lazovic D, Horas K, Roth KE, Kurth AA (2016) Is there an association between low serum 25-OH-D levels and the length of hospital stay in orthopaedic patients after arthroplasty? J Orthop Traumatol 17(4):297–302

    Article  PubMed  PubMed Central  Google Scholar 

  55. Sprague S, Bhandari M, Devji T, Scott T, Petrisor B, McKay P, Slobogean GP (2016) Prescription of vitamin D to fracture patients: a lack of consensus and evidence. J Orthop Trauma 30(2):e64–e69. https://doi.org/10.1097/BOT.0000000000000451

    Article  PubMed  Google Scholar 

  56. Bee CR, Sheerin DV, Wuest TK, Fitzpatrick DC (2013) Serum vitamin D levels in orthopaedic trauma patients living in the northwestern United States. J Orthop Trauma 27(5):e103–e106

    Article  PubMed  Google Scholar 

  57. Breer S, Krause M, Marshall RP, Oheim R, Amling M, Barvencik F (2012) Stress fractures in elderly patients. Int Orthop 36(12):2581–2587. https://doi.org/10.1007/s00264-012-1708-1

    Article  PubMed  PubMed Central  Google Scholar 

  58. Sorbi R, Aghamirsalim MR (2012) Knowledge of orthopaedic surgeons in managing patients with fragility fracture. Int Orthop 36(6):1275–1279. https://doi.org/10.1007/s00264-012-1482-0

    Article  PubMed  PubMed Central  Google Scholar 

  59. Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM (1996) Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial. Ann Intern Med 124(4):400–406

    Article  CAS  PubMed  Google Scholar 

  60. Meyer HE, Smedshaug GB, Kvaavik E, Falch JA, Tverdal A, Pedersen JI (2002) Can vitamin D supplementation reduce the risk of fracture in the elderly? A randomized controlled trial. J Bone Miner Res 17(4):709–715

    Article  CAS  PubMed  Google Scholar 

  61. Zhao JG, Zeng XT, Wang J, Liu L (2017) Association between calcium or vitamin D supplementation and fracture incidence in community-dwelling older adults: a systematic review and meta-analysis. JAMA 318(24):2466–2482. https://doi.org/10.1001/jama.2017.19344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ettehad H, Mirbolook A, Mohammadi F, Mousavi M, Ebrahimi H, Shirangi A (2014) Changes in the serum level of vitamin D during healing of tibial and femoral shaft fractures. Trauma Mon 19(1):e10946. https://doi.org/10.5812/traumamon.10946

    Article  PubMed  PubMed Central  Google Scholar 

  63. Holick MF, Matsuoka LY, Wortsman J (1989) Age, vitamin D, and solar ultraviolet. Lancet 2:1104–1105

    Article  CAS  PubMed  Google Scholar 

  64. Clemens TL, Henderson SL, Adams JS, Holick MF (1982) Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet 1:74–76

    Article  CAS  PubMed  Google Scholar 

  65. Matsuoka LY, Ide L, Wortsman J, MacLaughlin J, Holick MF (1987) Sunscreens suppress cutaneous vitamin D3 synthesis. J Clin Endocrinol Metab 64:1165–1168

    Article  CAS  PubMed  Google Scholar 

  66. Webb AR, Kline L, Holick MF (1988) Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab 67:373–378

    Article  CAS  PubMed  Google Scholar 

  67. Hewison M (2012) Vitamin D and the immune system: new perspectives on an old theme. Rheum Dis Clin North Am 38(1):125–139. https://doi.org/10.1016/j.rdc.2012.03.012

    Article  PubMed  Google Scholar 

  68. Herrera G (1949) Vitamin D in massive doses as an adjuvant to the sulfones in the treatment of tuberculoid leprosy. Int J Lepr 17:35–42

    CAS  PubMed  Google Scholar 

  69. Liu PT, Stenger S, Tang DH, Modlin RL (2007) Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol 179:2060–2063

    Article  CAS  PubMed  Google Scholar 

  70. White JH (2010) Vitamin D as an inducer of cathelicidin antimicrobial peptide expression: past, present and future. J Steroid Biochem Mol Biol 121:234–238

    Article  CAS  PubMed  Google Scholar 

  71. Kim EW, Teles RMB, Haile S, Liu PT, Modlin RL (2018) Vitamin D status contributes to the antimicrobial activity of macrophages against Mycobacterium leprae. PLoS Negl Trop Dis 12

  72. Maier GS, Horas K, Seeger JB, Roth KE, Kurth AA, Maus U (2014) Is there an association between periprosthetic joint infection and low vitamin D levels? Int Orthop 38(7):1499–1504. https://doi.org/10.1007/s00264-014-2338-6

    Article  PubMed  PubMed Central  Google Scholar 

  73. Hegde V, Dworsky EM, Stavrakis AI, Loftin AH, Zoller SD, Park HY, Richman S, Johansen D, Hu Y, Taylor JA, Hamad CD, Chun RF, Xi W, Adams JS, Bernthal NM (2017) Single-dose, preoperative vitamin-D supplementation decreases infection in a mouse model of Periprosthetic joint infection. J Bone Joint Surg Am 99(20):1737–1744. https://doi.org/10.2106/JBJS.16.01598

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Philippe Hernigou.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hernigou, P., Sitbon, J., Dubory, A. et al. Vitamin D history part III: the “modern times”—new questions for orthopaedic practice: deficiency, cell therapy, osteomalacia, fractures, supplementation, infections. International Orthopaedics (SICOT) 43, 1755–1771 (2019). https://doi.org/10.1007/s00264-019-04334-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00264-019-04334-w

Keywords

  • Vitamin D and orthopaedic surgery
  • Cell therapy and vitamin D
  • Fracture healing and vitamin D
  • Osteomalacia
  • Osteoporosis
  • Arthroplasty infection and vitamin D
  • Supplementation