Vitamin D and Musculoskeletal Health

Matsuoka LY et al. (1987) Sunscreens suppress cutaneous vitamin D₃ synthesis. J Clin Endocrinol Metab 64: 1165–1168
Holick MF et al. (1981) Regulation of cutaneous previtamin D₃ photosynthesis in man: skin pigment is not an essential regulator. Science 211: 590–593
Vieth R (1999) Vitamin D supplementation, 25- hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 69: 842–856
Jacques PF et al. (1997) Plasma 25-hydroxyvitamin D and its determinants in an elderly population sample. Am J Clin Nutr 66: 929–936
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
Vazquez G et al. (1997) Stimulation of Ca2+ releaseactivated 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
Mosekilde L (2005) Vitamin D and the elderly. Clin Endocrinol (Oxf) 62: 265–281
Zittermann A (2003) Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr 89: 552–572
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
Dawson-Hughes B et al. (2005) Estimates of optimal vitamin D status. Osteoporos Int 16: 713–716
Binkley N et al. (2004) Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. J Clin Endocrinol Metab, 89: 3152–3157
Thomas MK et al. (1998) Hypovitaminosis D in medical inpatients. N Engl J Med 338: 777–783
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
Chapuy MC et al. (1997) Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int 7: 439–443
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
Heaney RP et al. (2003) Calcium absorption varies within the reference range for serum 25- hydroxyvitamin D. J Am Coll Nutr 22: 142–146
Rivlin RS (1983) Nutrition and the health of the elderly. A growing concern for all ages. Arch Intern Med 143: 1200–1201
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
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
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
Andersen R et al. (2001) Towards a strategy for optimal vitamin D fortification (OPTIFORD). Nutr Metab Cardiovasc Dis 11(Suppl 4): 74–77
Bolland MJ et al. (2007) Defining vitamin D deficiency. NZ Med J 120: U2760
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
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
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
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
Malabanan A et al. (1998) Redefining vitamin D insufficiency. Lancet 351: 805–806
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
Binkley N et al. (2007) Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab 92: 2130–2135
Hansen KE et al. (2008) Vitamin D insufficiency: disease or no disease? J Bone Miner Res 23: 1052–1060
Utiger RD (1998) The need for more vitamin D. N Engl J Med 338: 828–829
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
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
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
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
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
Baeksgaard L et al. (1998) Calcium and vitamin D supplementation increases spinal BMD in healthy, postmenopausal women. Osteoporos Int 8: 255–260
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
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
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
Cooper L et al. (2003) Vitamin D supplementation and bone mineral density in early postmenopausal women. Am J Clin Nutr 77: 1324–1329
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
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
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
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 placebocontrolled trial. Lancet 365: 1621–1628
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
Jackson RD et al. (2006) Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 354: 669–683
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
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
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
Skaria J et al. (1975) Myopathy and neuropathy associated with osteomalacia. Acta Neurol Scand 51: 37–58
Sørensen OH et al. (1979) Myopathy in bone loss of ageing: improvement by treatment with 1 alphahydroxycholecalciferol and calcium. Clin Sci (Lond) 56: 157–161
Simpson RU et al. (1985) Identification of 1,25- dihydroxyvitamin D₃ receptors and activities in muscle. J Biol Chem 260: 8882–8891
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
Glerup H et al. (2000) Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement. Calcif Tissue Int 66: 419–424
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
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
Gloth FM et al. (1995) Functional improvement with vitamin D replenishment in a cohort of frail, vitamin Ddeficient older people. J Am Geriatr Soc 43: 1269–1271
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
Binder EF (1995) Implementing a structured exercise program for frail elderly nursing home residents with dementia. J Aging Phys Activity 3: 383–395
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
Graafmans WC et al. (1996) Falls in the elderly: a prospective study of risk factors and risk profiles. Am J Epidemiol 143: 1129–1136
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
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
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
Hypponen E et al. (2001) Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 358: 1500–1503
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
Holick MF (2007) Vitamin D deficiency. N Engl J Med 357: 266–281
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
Wactawski-Wende J et al. (2006) Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 354: 684–696
Hayes CE (2000) Vitamin D: a natural inhibitor of multiple sclerosis. Proc Nutr Soc 59: 531–535
Mahon BD et al. (2003) Cytokine profile in patients with multiple sclerosis following vitamin D supplementation. J Neuroimmunol 134: 128–132
Liu PT et al. (2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311: 1770–1773
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
Martineau AR et al. (2007) A single dose of vitamin D enhances immunity to mycobacteria. Am J Respir Crit Care Med 176: 208–213
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
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
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
Institute of Medicine (1997) Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D and Flouride. Washington, DC: National Academy Press
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
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
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
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

As an organization accredited by the ACCME, Medscape, LLC requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.

Medscape, LLC encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.

Author(s)

Anne E. Wolff, MD

Consultant Rheumatologist, Centracare Rheumatology Clinic, St. Cloud, Minnesota

Disclosures

Disclosure: Anne E. Wolff, MD, has disclosed no relevant financial relationships.

Andrea N. Jones, MA

Research Specialist, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

Disclosures

Disclosure: Andrea N. Jones, MA, has disclosed no relevant financial relationships.

Karen E. Hansen, MD

Assistant Professor of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

Disclosures

Disclosure: Karen E. Hansen, MD, has disclosed no relevant financial relationships.

Editor

Elizabeth Poll

Locum Editor, Nature Clinical Practice Rheumatology

Disclosures

Disclosure: Elizabeth Poll has disclosed no relevant financial relationships.

processing....

Summary and Introduction

Summary

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.

Introduction

Hypovitaminosis D, encompassing both vitamin D insufficiency and deficiency, is highly prevalent in the general population and has potentially deleterious musculoskeletal effects. Hypovitaminosis D results from several factors, including reduced cutaneous vitamin D synthesis as a consequence of sunscreen use,^[1] increased skin pigmentation, inadequate sun exposure,^[2] poor nutrition, comorbid diseases, such as celiac sprue, and the use of certain medications, such as anticonvulsants.^[3] Using questions to assess diet and sun exposure in elderly individuals, one research group^[4] reported associations between 25(OH)D levels and season of measurement, BMI, age, time spent indoors, vitamin D intake and plasma creatinine level. Here, we review the pathophysiology, clinical correlates, evaluation and treatment of hypovitaminosis D.