Vitamin D and musculoskeletal health

Article metrics


Vitamin D is critical for calcium homeostasis. Following cutaneous synthesis or ingestion, vitamin D is metabolized to 25(OH)D and then to the active form 1,25(OH)2D. Low serum vitamin D levels are common in the general population and cause a decline in calcium absorption, leading to low serum levels of ionized calcium, which in turn trigger the release of parathyroid hormone, promoting skeletal resorption and, eventually, bone loss or osteomalacia. Vitamin D deficiency is generally defined as a serum 25(OH)D concentration <25–37 nmol/l (<10–15 ng/ml), but the definition of the milder state of vitamin D insufficiency is controversial. Three recent meta-analyses concluded that vitamin D must be administered in combination with calcium in order to substantially reduce the risk of nonvertebral fracture in adults over the age of 50 years. Fracture protection is optimal when patient adherence to medication exceeds 80% and vitamin D doses exceed 700 IU/day. In addition to disordered calcium homeostasis, low vitamin D levels might have effects on cell proliferation and differentiation and immune function. Randomized, double-blind, placebo-controlled trials are needed to clarify whether vitamin D supplementation is beneficial in cancer, autoimmune disease and infection. This Review focuses on the pathophysiology, clinical correlates, evaluation and treatment of hypovitaminosis D.

Key Points

  • Hypovitaminosis D, encompassing both vitamin D insufficiency and deficiency, is common in the general population

  • The optimal serum 25(OH)D level required for calcium homeostasis and skeletal health is debated

  • Evidence indicates that vitamin D must be administered with calcium to increase bone mineral density in adults

  • Three recent meta-analyses concluded that vitamin D must be administered with calcium to reduce the risk of fracture in adults over age 50 years

  • Hypovitaminosis D causes sarcopenia, muscle weakness, and contributes to an increased risk of falls

  • Recent research suggests that vitamin D has a role in cancer risk and innate immunity

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The vitamin D metabolic pathway.
Figure 2: A strategy for assessing vitamin D status in patients with normal renal function.
Figure 3: Simplified example of a pathway by which vitamin D might stimulate innate immunity and enhance antimicrobial activity via interaction with TLRs.


  1. 1

    Matsuoka LY et al. (1987) Sunscreens suppress cutaneous vitamin D3 synthesis. J Clin Endocrinol Metab 64: 1165–1168

  2. 2

    Holick MF et al. (1981) Regulation of cutaneous previtamin D3 photosynthesis in man: skin pigment is not an essential regulator. Science 211: 590–593

  3. 3

    Vieth R (1999) Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 69: 842–856

  4. 4

    Jacques PF et al. (1997) Plasma 25-hydroxyvitamin D and its determinants in an elderly population sample. Am J Clin Nutr 66: 929–936

  5. 5

    Holick MF and Garabedian M (2006) Vitamin D: Photobiology, Metabolism, Mechanism of Action, and Clinical Applications. In Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, edn 6, 106–114 (Ed. Favus MJ) Washington, DC: American Society for Bone and Mineral Research

  6. 6

    Vazquez G et al. (1997) Stimulation of Ca2+ release-activated Ca2+ channels as a potential mechanism involved in non-genomic 1,25(OH)2-vitamin D3-induced Ca2+ entry in skeletal muscle cells. Biochem Biophys Res Commun 239: 562–565

  7. 7

    Mosekilde L (2005) Vitamin D and the elderly. Clin Endocrinol (Oxf) 62: 265–281

  8. 8

    Zittermann A (2003) Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr 89: 552–572

  9. 9

    Peacock M et al. (1985) Vitamin D deficiency, insufficiency, and intoxication. What do they mean? In Vitamin D: Chemical, Biochemical and Clinical Update, 569–570 (Eds Norman AW et al.) Berlin: Walter de Gruyter

  10. 10

    Dawson-Hughes B et al. (2005) Estimates of optimal vitamin D status. Osteoporos Int 16: 713–716

  11. 11

    Binkley N et al. (2004) Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. J Clin Endocrinol Metab, 89: 3152–3157

  12. 12

    Thomas MK et al. (1998) Hypovitaminosis D in medical inpatients. N Engl J Med 338: 777–783

  13. 13

    Sahota O et al. (1999) Vitamin D insufficiency increases bone turnover markers and enhances bone loss at the hip in patients with established vertebral osteoporosis. Clin Endocrinol (Oxf) 51: 217–221

  14. 14

    Chapuy MC et al. (1997) Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int 7: 439–443

  15. 15

    Lips P et al. (2001) A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. J Clin Endocrinol Metab 86: 1212–1221

  16. 16

    Heaney RP et al. (2003) Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. J Am Coll Nutr 22: 142–146

  17. 17

    Rivlin RS (1983) Nutrition and the health of the elderly. A growing concern for all ages. Arch Intern Med 143: 1200–1201

  18. 18

    Souberbielle JC et al. (2001) Vitamin D status and redefining serum parathyroid hormone reference range in the elderly. J Clin Endocrinol Metab 86: 3086–3090

  19. 19

    Gomez-Alonso C et al. (2003) Vitamin D status and secondary hyperparathyroidism: the importance of 25-hydroxyvitamin D cut-off levels. Kidney Int 85 (Suppl): S44–S48

  20. 20

    Holick MF et al. (2005) Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab 90: 3215–3224

  21. 21

    Andersen R et al. (2001) Towards a strategy for optimal vitamin D fortification (OPTIFORD). Nutr Metab Cardiovasc Dis 11 (Suppl 4): 74–77

  22. 22

    Bolland MJ et al. (2007) Defining vitamin D deficiency. NZ Med J 120: U2760

  23. 23

    Vieth R et al. (2003) Age-related changes in the 25-hydroxyvitamin D versus parathyroid hormone relationship suggest a different reason why older adults require more vitamin D. J Clin Endocrinol Metab 88: 185–191

  24. 24

    Brot C et al. (2001) Vitamin D status and its adequacy in healthy Danish perimenopausal women: relationships to dietary intake, sun exposure and serum parathyroid hormone. Br J Nutr 86 (Suppl 1): S97–S103

  25. 25

    Sahota O et al. (2004) The relationship between vitamin D and parathyroid hormone: calcium homeostasis, bone turnover, and bone mineral density in postmenopausal women with established osteoporosis. Bone 35: 312–319

  26. 26

    Aloia JF et al. (2006) Optimal vitamin D status and serum parathyroid hormone concentrations in African American women. Am J Clin Nutr 84: 602–609

  27. 27

    Malabanan A et al. (1998) Redefining vitamin D insufficiency. Lancet 351: 805–806

  28. 28

    Patel R et al. (2001) The effect of season and vitamin D supplementation on bone mineral density in healthy women: a double-masked crossover study. Osteoporos Int 12: 319–325

  29. 29

    Binkley N et al. (2007) Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab 92: 2130–2135

  30. 30

    Hansen KE et al. (2008) Vitamin D insufficiency: disease or no disease. J Bone Miner Res 23: 1052–1060

  31. 31

    Utiger RD (1998) The need for more vitamin D. N Engl J Med 338: 828–829

  32. 32

    Du X et al. (2004) School-milk intervention trial enhances growth and bone mineral accretion in Chinese girls aged 10–12 years in Beijing. Br J Nutr 92: 159–168

  33. 33

    Viljakainen et al. (2006) A positive dose-response effect of vitamin D supplementation on site-specific bone mineral augmentation in adolescent girls: a double-blinded randomized placebo-controlled 1-year intervention. J Bone Miner Res 21: 836–844

  34. 34

    Cranney A et al. (2007) Effectiveness and safety of vitamin D in relation to bone health. Evid Rep Technol Assess (Full Rep) 158: 1–235

  35. 35

    Chapuy MC et al. (2002) Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study. Osteoporos Int 13: 257–264

  36. 36

    Dawson-Hughes B et al. (1997) Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 337: 670–676

  37. 37

    Baeksgaard L et al. (1998) Calcium and vitamin D supplementation increases spinal BMD in healthy, postmenopausal women. Osteoporos Int 8: 255–260

  38. 38

    Grados F et al. (2003) Prediction of bone mass density variation by bone remodeling markers in postmenopausal women with vitamin D insufficiency treated with calcium and vitamin D supplementation. J Clin Endocrinol Metab 88: 5175–5179

  39. 39

    Komulainen MH et al. (1998) HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial. Maturitas 31: 45–54

  40. 40

    Ooms ME et al. (1995) Prevention of bone loss by vitamin D supplementation in elderly women: a randomized double-blind trial. J Clin Endocrinol Metab 80: 1052–1058

  41. 41

    Cooper L et al. (2003) Vitamin D supplementation and bone mineral density in early postmenopausal women. Am J Clin Nutr 77: 1324–1329

  42. 42

    Jensen C et al. (2002) Long-term effects of nutrient intervention on markers of bone remodeling and calciotropic hormones in late-postmenopausal women. Am J Clin Nutr 75: 1114–1120

  43. 43

    Tang BM et al. (2007) Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 370: 657–666

  44. 44

    Boonen S et al. (2007) Need for additional calcium to reduce the risk of hip fracture with vitamin D supplementation: evidence from a comparative metaanalysis of randomized controlled trials. J Clin Endocrinol Metab 92: 1415–1423

  45. 45

    Grant AM (2005) Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 365: 1621–1628

  46. 46

    Porthouse JS et al. (2005) Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ 330: 1003

  47. 47

    Jackson RD et al. (2006) Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 354: 669–683

  48. 48

    Szulc P et al. (2004) Hormonal and lifestyle determinants of appendicular skeletal muscle mass in men: the MINOS study. Am J Clin Nutr 80: 496–503

  49. 49

    Visser M et al. (2003) Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. J Clin Endocrinol Metab 88: 5766–5772

  50. 50

    Lau EM et al. (2005) Prevalence of and risk factors for sarcopenia in elderly Chinese men and women. J Gerontol A Biol Sci Med Sci 60: 213–216

  51. 51

    Skaria J et al. (1975) Myopathy and neuropathy associated with osteomalacia. Acta Neurol Scand 51: 37–58

  52. 52

    Sørensen OH et al. (1979) Myopathy in bone loss of ageing: improvement by treatment with 1 alpha-hydroxycholecalciferol and calcium. Clin Sci (Lond) 56: 157–161

  53. 53

    Simpson RU et al. (1985) Identification of 1,25-dihydroxyvitamin D3 receptors and activities in muscle. J Biol Chem 260: 8882–8891

  54. 54

    Bischoff HA et al. (2003) Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res 18: 343–351

  55. 55

    Glerup H et al. (2000) Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement. Calcif Tissue Int 66: 419–424

  56. 56

    Latham NK et al. (1979) Effects of vitamin D supplementation on strength, physical performance, and falls in older persons: a systematic review. J Am Geriatr Soc 51: 1219–1226

  57. 57

    Pfeifer M et al. (2000) Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res 15: 1113–1118

  58. 58

    Gloth FM et al. (1995) Functional improvement with vitamin D replenishment in a cohort of frail, vitamin D-deficient older people. J Am Geriatr Soc 43: 1269–1271

  59. 59

    Dukas L et al. (2004) Alfacalcidol reduces the number of fallers in a community-dwelling elderly population with a minimum calcium intake of more than 500 mg daily. J Am Geriatr Soc 52: 230–236

  60. 60

    Binder EF (1995) Implementing a structured exercise program for frail elderly nursing home residents with dementia. J Aging Phys Activity 3: 383–395

  61. 61

    Latham NK et al. (2003) A randomized, controlled trial of quadriceps resistance exercise and vitamin D in frail older people: the Frailty Interventions Trial in Elderly Subjects (FITNESS). J Am Geriatr Soc 51: 291–299

  62. 62

    Graafmans WC et al. (1996) Falls in the elderly: a prospective study of risk factors and risk profiles. Am J Epidemiol 143: 1129–1136

  63. 63

    Sato Y et al. (1999) Amelioration of osteopenia and hypovitaminosis D by 1alpha-hydroxyvitamin D3 in elderly patients with Parkinson's disease. J Neurol Neurosurg Psychiatry 66: 64–68

  64. 64

    Lappe JM et al. (2007) Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 85: 1586–1591

  65. 65

    Borissova AM et al. (2003) The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients. Int J Clin Pract 57: 258–261

  66. 66

    Hypponen E et al. (2001) Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 358: 1500–1503

  67. 67

    Merlino LA et al. (2004) Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study. Arthritis Rheum 50: 72–77

  68. 68

    Holick MF (2007) Vitamin D deficiency. N Engl J Med 357: 266–281

  69. 69

    Wu K et al. (2007) A nested case control study of plasma 25-hydroxyvitamin D concentrations and risk of colorectal cancer. J Natl Cancer Inst 99: 1120–1129

  70. 70

    Wactawski-Wende J et al. (2006) Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 354: 684–696

  71. 71

    Hayes CE (2000) Vitamin D: a natural inhibitor of multiple sclerosis. Proc Nutr Soc 59: 531–535

  72. 72

    Mahon BD et al. (2003) Cytokine profile in patients with multiple sclerosis following vitamin D supplementation. J Neuroimmunol 134: 128–132

  73. 73

    Liu PT et al. (2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311: 1770–1773

  74. 74

    Nursyam EW et al. (2006) The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion. Acta Med Indones 38: 3–5

  75. 75

    Martineau AR et al. (2007) A single dose of vitamin D enhances immunity to mycobacteria. Am J Respir Crit Care Med 176: 208–213

  76. 76

    McAlindon TE et al. (1996) Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study. Ann Intern Med 125: 353–359

  77. 77

    Lane NE et al. (1999) Serum vitamin D levels and incident changes of radiographic hip osteoarthritis: a longitudinal study. Study of Osteoporotic Fractures Research Group. Arthritis Rheum 42: 854–860

  78. 78

    Felson DT et al. (2007) Low levels of vitamin D and worsening of knee osteoarthritis: results of two longitudinal studies. Arthritis Rheum 56: 129–136

  79. 79

    Institute of Medicine (1997) Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D and Flouride. Washington, DC: National Academy Press

  80. 80

    Saadi HF et al. (2007) Efficacy of daily and monthly high-dose calciferol in vitamin D-deficient nulliparous and lactating women. Am J Clin Nutr 85: 1565–1571

  81. 81

    Chel V et al. (2008) Efficacy of different doses and time intervals of oral vitamin D supplementation with or without calcium in elderly nursing home residents: reply to comment by Vieth. Osteoporos Int 19: 723

  82. 82

    Wu FT et al. (2003) Efficacy of an oral, 10-day course of high-dose calciferol in correcting vitamin D deficiency. NZ Med J 116: U536

  83. 83

    National Kidney Foundation (2003) K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 42 (Suppl 3): S1–S201

Download references


Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

Author information

Correspondence to Karen E Hansen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wolff, A., Jones, A. & Hansen, K. Vitamin D and musculoskeletal health. Nat Rev Rheumatol 4, 580–588 (2008) doi:10.1038/ncprheum0921

Download citation

Further reading