Recent developments in vitamin D deficiency and muscle weakness among elderly people
1 14 Lucas Road, High Wycombe HP13 6QG
Introduction
Elderly people's liability to falls and fractures is increased by many factors, including visual impairment, neurological disorders, orthopaedic disabilities, and drug effects. In one study showing that more than a third of people aged over 65 fell each year, the main risk factor was muscle weakness.1 Poor muscle strength and weakness may be associated with vitamin D deficiency, which is common among elderly people2 because the capacity of the skin to synthesise the provitamin calcidiol (25-hydroxycholecalciferol) decreases with age. Serious deficiency of vitamin D is common among elderly housebound people in old people's homes, nursing homes, and long stay wards and has been identified as an important public health problem.2-5 In this review I discuss recent developments in screening and treating vitamin D deficiency among elderly housebound people aimed at reducing the incidence of falls and fractures.
, http://www.100md.com
Sources and selection criteria
This review is based on material identified through Medline searches and the author's personal library, and through discussions with researchers.
Evidence of association
Higher plasma concentrations of calcidiol are associated with muscle strength, physical activity, and ability to climb stairs and lower concentrations with falls among elderly people.6 7 Indeed, in a randomised controlled trial elderly women given 800 IU vitamin D daily with calcium had a 47% reduction in falls and fractures compared with controls receiving calcium alone over 12 months.8 In another trial with three month follow up, the incidence of falls was almost halved and musculoskeletal function improved among elderly people who had 800 IU vitamin D with calcium compared with calcium alone.9
, 百拇医药
Being housebound as a risk factor
The prevalence of falls at age 85 is double that at ages 65-75.10 Most studies of osteoporosis among elderly people cover a wide age range and do not focus specifically on those who are housebound, despite the fact that age and being housebound are independently associated with vitamin D deficiency. Among the least disabled group in the Women's Health and Ageing Study, the frequency of severe vitamin D deficiency was 8.3% in those aged 65-74, 14.5% at ages 75-84, and 17.4% at 85 and over.2
, 百拇医药
Recent developments
The prevalence of vitamin D deficiency in elderly people is much greater than previously realised, especially among those who are housebound
Vitamin D deficiency is associated with muscle weakness as well as osteomalacia
Deficiency is also associated with falls and fractures among elderly people that are not explained by reduced bone density
, 百拇医药 Supplementation of 800 IU of vitamin D daily is needed to have an effect on falls
This may not reflect cause and effect. Nevertheless, this phenomenon could be explained by reduced concentrations of 7-dehydrocholesterol, which is needed to synthesise calcidiol, in ageing skin.5 And housebound elderly people often do not get adequate exposure to sunlight. They probably also get less exercise than other elderly people, and exercise training can reduce the incidence of falls.11
, http://www.100md.com
The best evidence for an association between deficiency and being housebound comes from a study in Finland. This found that mean plasma calcidiol concentrations were low among people over 85 living in their own homes but even lower among people aged 75-84 living in old people's homes.12 Other studies in a long stay geriatric ward13 and in nursing and residential homes, which excluded patients with osteomalacia, confirm the association.14 15 There are other associations as well as age and housebound status: the prevalence of vitamin D deficiency is ten times higher in African-American than in white women in America,16 and deficiency seems to be more common in Europe than in the United States.17 18
, http://www.100md.com
Problem of inadequate doses
Scanning electron micrograph of skeletal muscle fibres
Credit: STEVE G SCHEISSNER/SPL
If vitamin D deficiency is associated with musculoskeletal weakness and falls among elderly people, why does supplementation with the vitamin sometimes fail to help The explanation seems to be inadequate dose. Two randomised controlled trials have found 400 IU/day of vitamin D to be ineffective in reducing the frequency of fractures,15 19 and two descriptive studies have noted deficiency despite supplementation at a dose of 400 IU daily.13 14 Furthermore, one trial of high dose treatment showed no evidence of reduction in falls among frail outpatients.20 But vitamin D deficiency is only one risk factor for falls and fractures among elderly people, and in this study the patients who received placebo had near normal mean calcidiol concentrations and still had a high frequency of falls, probably because they had other disabilities that were not amenable to vitamin D treatment.
, 百拇医药
In contrast, five randomised controlled trials have shown that 800 IU/day of vitamin D significantly reduces the incidence of falls8 9 and fractures.21 22 The fifth trial showed a reduction in fractures using 100 000 IU of vitamin D every four months (a dose equivalent to 800 IU/day).23 These high dose studies strengthen the evidence for and the public health importance of preventive treatment with adequate doses of vitamin D among housebound elderly people and suggest priorities for future research. But are there enough data on the safety of high dose vitamin D
, 百拇医药
Safety of high dose supplementation
Vitamin D is usually given in the form of cholecalciferol. A comprehensive review article of data on toxic hypocalcaemia during vitamin D therapy for a variety of conditions found that the lowest level at which an adverse effect was observed was a serum calcidiol concentration of 200 nmol/l, corresponding to a daily intake of 40 000 IU.24 A dose of 800 IU daily (or 100 000 IU three times a year) therefore has a 50-fold margin of safety. That review was primarily concerned with establishing the safe upper limit for daily dose but also included data on the safety of very large single doses up to 600 000 IU. In 3443 patients closely observed in clinical trials, no adverse effects occurred at a dose of 800 IU daily or 100 000 IU at various intervals.
, 百拇医药
Although administration of 800 IU of cholecalciferol to residents of old people's homes is safe, it is important to remember that cholecalciferol is ineffective in patients with renal or hepatic failure. The kidney is involved in the first step in metabolism of cholecalciferol to calcidiol, the form in which it is stored, and the liver in the final conversion to the active hormone calcitriol. For this reason patients with kidney or liver disease require treatment with calcitriol rather than cholecalciferol.
, 百拇医药
Conclusion
Vitamin D deficiency among elderly people is much more common than previously recognised. It constitutes a serious public health problem for residents of old people's homes, nursing homes, and long stay wards and housebound people in the community. The consequences include muscle weakness, body sway, and a tendency to falls and fractures, as well as osteomalacia.
Exercise is one evidence based approach to preventing falls, but not all elderly people are able to access or take up exercise training owing to disability and other factors. Treating elderly housebound people with 800 IU daily of vitamin D (or equivalent, such as 100 000 IU every 4 months) should also be seriously considered.23 But the research on this so far has been carried out with cholecalciferol, which is not available in the United Kingdom except as 400 IU tablets with added calcium. Some patients find this awkward to take. Vitamin D2 (ergocalciferol) is available at a dose of 50 000 IU, which could be taken once every two months to provide an equivalent dose, but this needs testing in clinical trials.
, http://www.100md.com
Further educational resources
For doctors
Vitamin D and lower-extremity function in the elderly. Bandolier. www.jr2.ox.ac.uk/bandolier/booth/Arthritis/VDmusceld.html (accessed 1 Feb 2005)
Janssen HC, Samson MM, Verhaar HJ. Vitamin D deficiency, muscle function, and falls in elderly people. Am J Clin Nutr 2002;75: 611-5
Compston JE. Vitamin D deficiency: time for action. BMJ 1998;317: 1466-7
, 百拇医药
Grant WB. Vitamin D largely overlooked in review of interventions for the prevention of falls in older adults. Rapid response 19 Mar 2004 http://bmj.bmjjournals.com/cgi/eletters/328/7441/680#53950
For patients
Health and Age. The role of vitamin D in preserving muscle strength in seniors. www.healthandage.com/PHome/gm=20!gid2=1826 (accessed 1 Feb 2005)
Looksmart. Vitamin D's muscle-strengthening effect and fracture prevention. www.findarticles.com/p/articles/mi_m0815/is_6_29/ai_n6134289 (accessed 1 Feb 2005)
, 百拇医药
The question of whether to treat all elderly people living in the community is problematic. Two thirds are not deficient in vitamin D, yet 250 would need to be treated for one year to prevent a fracture.23 This number could probably be reduced by confining treatment to people aged 80 or older.2 Treating only women with known vitamin D deficiency could prevent one fall for every five women treated for a year8 and treating 20-25 women in nursing homes and old people's homes for a year without screening for vitamin D status would prevent one fracture.21
, 百拇医药
Finally, devotees of anecdote based medicine who need an example of the dramatic effect of vitamin D on muscle weakness (in a different clinical context) may wish to note the case report of "A woman who left her wheelchair" after three weeks of calcitriol for extremely severe vitamin D deficiency with progressive muscular weakness.25
I thank Richard Doll and Larry Ramsay for encouraging me to undertake this review.
Competing interests: GV is a semiretired independent consultant in pharmaceutical medicine. He spent most of his working life in the industry with responsibility for the clinical development of new drugs. He also worked as a medical assessor with the Committee on Safety of Medicines responsible for evaluating the efficacy and safety of new drugs. The review was prompted after participating in a five year randomised controlled trial of vitamin D for the prevention of fractures in elderly people by the realisation that appropriate preparations of vitamin D are not readily available in England.
, http://www.100md.com
References
Blake AJ, Morgan K, Bendall MJ, Dallosso H, Ebrahim SB, Arie TH, et al. Falls by elderly people at home: prevalence and associated factors. Age Ageing 1988;17: 365-72.
Semba RD, Garrett E, Johnson BA, Guralnik JM, Fried LP. Vitamin D deficiency among older women with and without disability. Am J Clin Nutr 2000;72: 1529-34.
Jacques PF, Felson DT, Tucker KL, Mahnken B, Wilson PW, Rosenberg IH, et al. Plasma 25 hydroxy vitamin D and its determinants in an elderly population sample. Am J Clin Nutr 1997;66: 929-36.
, http://www.100md.com
Institute of Medicine. Dietary reference intakes. Washington, DC: National Academic Press, 1997.
Holick MF. Vitamin D: a millennium perspective. J Cell Biochem 2003;88: 296-307.
Mowé M, Haug E, Bohmer T. Low serum calcidiol concentration in older adults with reduced muscular function. J Am Geriatr Soc 1999;47: 220-6.
Dhesi JK, Bearne LM, Moniz C, Hurley MV, Jackson SH, Swift CG, et al. Neuromuscular and psychomotor function in elderly subjects who fall and the relationship with vitamin D status. J Bone Miner Res 2002;17: 891-7.
, 百拇医药
Pfeiffer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C. Effects of a short term Vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res 2000;15: 1113-8.
Bischoff HA, Sthelin HB, Dick W, Akos R, Knecht M, Salis C, et al. Effects of vitamin D and calcium supplements on falls: a randomised controlled trial. J Bone Miner Res 2003;18: 343-51.
Evans JG. Falls and fractures. Age Ageing 1988;17: 361-4.
, 百拇医药
Chang JT, Morton SC, Rubenstein LZ, Mojica WA, Maglione M, Suttorp MJ, et al. Interventions for the prevention of falls in older adults: systematic review and meta-analysis of randomised clinical trials. BMJ 2004;328: 680.
Heikinheimo RJ, Inkovaara JA, Harju EJ, Haavisto MV, Kaarela RH, Kataja JM, et al. Annual injection of vitamin D and fractures of aged bones. Calcif Tissue Int 1992;51: 105-10.
Egsmose C, Lund B, McNair P, Lund B, Storm T, Sorensen OH, et al. Low serum levels of 25-hydroxy vitamin D and 1,25 dihydroxy vitamin D in institutionalized old people: influence of solar exposure and vitamin D supplementation. Age Ageing 1987;16: 35-40.
, http://www.100md.com
Gloth FM, Gundberg CM, Hollis BW, Haddad JG Jr, Tobin JD. Vitamin D deficiency in homebound elderly persons. JAMA 1995;274: 1683-6.
Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM. Vitamin D supplementation and fracture incidence in elderly persons: a randomized placebo-controlled trial. Ann Intern Med 1996;124: 400-6.
Nesby-O'Dell S, Scanlon KS, Cogswell ME, Gillespie C, Hollis BW, Looker AC, et al. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994. AmJClin Nutr 2002;76: 187-92.
, 百拇医药
Gallagher JC, Kinyamu HK, Fowler SE, Dawson-Hughes B, Dalsky GP, Sherman SS, al. Calciotropic hormones and bone markers in the elderly. J Bone Miner Res 1998;13: 475-82.
McKenna MJ. Differences in vitamin D status between countries in young adults and the elderly. Am J Med 1992;93: 69-77.
Meyer HE, Smedshaug GB, Kvaavik E, Falch JA, Tverdal A, Pedersen JI. Can vitamin D supplementation reduce the risk of fracture in the elderly A randomized controlled trial. J Bone Miner Res 2002;17: 709-15.
, 百拇医药
Latham NK, Anderson CS, Lee A, Bennett DA, Moseley A, Cameron ID, et al. 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 2003;51: 291-9.
Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992; 327-42.
, 百拇医药 Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997;337: 670-6.
Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 2003;326: 469-72.
Vieth R. Vitamin D supplementation, 25-hydroxy vitamin D concentrations and safety. Am J Clin Nutr 1999;69: 842-56.
Mingrone G, Greco AV, Castagneto M, Gasbarrini G. A woman who left her wheelchair. Lancet 1999;353: 806., 百拇医药(Geoff Venning)
Introduction
Elderly people's liability to falls and fractures is increased by many factors, including visual impairment, neurological disorders, orthopaedic disabilities, and drug effects. In one study showing that more than a third of people aged over 65 fell each year, the main risk factor was muscle weakness.1 Poor muscle strength and weakness may be associated with vitamin D deficiency, which is common among elderly people2 because the capacity of the skin to synthesise the provitamin calcidiol (25-hydroxycholecalciferol) decreases with age. Serious deficiency of vitamin D is common among elderly housebound people in old people's homes, nursing homes, and long stay wards and has been identified as an important public health problem.2-5 In this review I discuss recent developments in screening and treating vitamin D deficiency among elderly housebound people aimed at reducing the incidence of falls and fractures.
, http://www.100md.com
Sources and selection criteria
This review is based on material identified through Medline searches and the author's personal library, and through discussions with researchers.
Evidence of association
Higher plasma concentrations of calcidiol are associated with muscle strength, physical activity, and ability to climb stairs and lower concentrations with falls among elderly people.6 7 Indeed, in a randomised controlled trial elderly women given 800 IU vitamin D daily with calcium had a 47% reduction in falls and fractures compared with controls receiving calcium alone over 12 months.8 In another trial with three month follow up, the incidence of falls was almost halved and musculoskeletal function improved among elderly people who had 800 IU vitamin D with calcium compared with calcium alone.9
, 百拇医药
Being housebound as a risk factor
The prevalence of falls at age 85 is double that at ages 65-75.10 Most studies of osteoporosis among elderly people cover a wide age range and do not focus specifically on those who are housebound, despite the fact that age and being housebound are independently associated with vitamin D deficiency. Among the least disabled group in the Women's Health and Ageing Study, the frequency of severe vitamin D deficiency was 8.3% in those aged 65-74, 14.5% at ages 75-84, and 17.4% at 85 and over.2
, 百拇医药
Recent developments
The prevalence of vitamin D deficiency in elderly people is much greater than previously realised, especially among those who are housebound
Vitamin D deficiency is associated with muscle weakness as well as osteomalacia
Deficiency is also associated with falls and fractures among elderly people that are not explained by reduced bone density
, 百拇医药 Supplementation of 800 IU of vitamin D daily is needed to have an effect on falls
This may not reflect cause and effect. Nevertheless, this phenomenon could be explained by reduced concentrations of 7-dehydrocholesterol, which is needed to synthesise calcidiol, in ageing skin.5 And housebound elderly people often do not get adequate exposure to sunlight. They probably also get less exercise than other elderly people, and exercise training can reduce the incidence of falls.11
, http://www.100md.com
The best evidence for an association between deficiency and being housebound comes from a study in Finland. This found that mean plasma calcidiol concentrations were low among people over 85 living in their own homes but even lower among people aged 75-84 living in old people's homes.12 Other studies in a long stay geriatric ward13 and in nursing and residential homes, which excluded patients with osteomalacia, confirm the association.14 15 There are other associations as well as age and housebound status: the prevalence of vitamin D deficiency is ten times higher in African-American than in white women in America,16 and deficiency seems to be more common in Europe than in the United States.17 18
, http://www.100md.com
Problem of inadequate doses
Scanning electron micrograph of skeletal muscle fibres
Credit: STEVE G SCHEISSNER/SPL
If vitamin D deficiency is associated with musculoskeletal weakness and falls among elderly people, why does supplementation with the vitamin sometimes fail to help The explanation seems to be inadequate dose. Two randomised controlled trials have found 400 IU/day of vitamin D to be ineffective in reducing the frequency of fractures,15 19 and two descriptive studies have noted deficiency despite supplementation at a dose of 400 IU daily.13 14 Furthermore, one trial of high dose treatment showed no evidence of reduction in falls among frail outpatients.20 But vitamin D deficiency is only one risk factor for falls and fractures among elderly people, and in this study the patients who received placebo had near normal mean calcidiol concentrations and still had a high frequency of falls, probably because they had other disabilities that were not amenable to vitamin D treatment.
, 百拇医药
In contrast, five randomised controlled trials have shown that 800 IU/day of vitamin D significantly reduces the incidence of falls8 9 and fractures.21 22 The fifth trial showed a reduction in fractures using 100 000 IU of vitamin D every four months (a dose equivalent to 800 IU/day).23 These high dose studies strengthen the evidence for and the public health importance of preventive treatment with adequate doses of vitamin D among housebound elderly people and suggest priorities for future research. But are there enough data on the safety of high dose vitamin D
, 百拇医药
Safety of high dose supplementation
Vitamin D is usually given in the form of cholecalciferol. A comprehensive review article of data on toxic hypocalcaemia during vitamin D therapy for a variety of conditions found that the lowest level at which an adverse effect was observed was a serum calcidiol concentration of 200 nmol/l, corresponding to a daily intake of 40 000 IU.24 A dose of 800 IU daily (or 100 000 IU three times a year) therefore has a 50-fold margin of safety. That review was primarily concerned with establishing the safe upper limit for daily dose but also included data on the safety of very large single doses up to 600 000 IU. In 3443 patients closely observed in clinical trials, no adverse effects occurred at a dose of 800 IU daily or 100 000 IU at various intervals.
, 百拇医药
Although administration of 800 IU of cholecalciferol to residents of old people's homes is safe, it is important to remember that cholecalciferol is ineffective in patients with renal or hepatic failure. The kidney is involved in the first step in metabolism of cholecalciferol to calcidiol, the form in which it is stored, and the liver in the final conversion to the active hormone calcitriol. For this reason patients with kidney or liver disease require treatment with calcitriol rather than cholecalciferol.
, 百拇医药
Conclusion
Vitamin D deficiency among elderly people is much more common than previously recognised. It constitutes a serious public health problem for residents of old people's homes, nursing homes, and long stay wards and housebound people in the community. The consequences include muscle weakness, body sway, and a tendency to falls and fractures, as well as osteomalacia.
Exercise is one evidence based approach to preventing falls, but not all elderly people are able to access or take up exercise training owing to disability and other factors. Treating elderly housebound people with 800 IU daily of vitamin D (or equivalent, such as 100 000 IU every 4 months) should also be seriously considered.23 But the research on this so far has been carried out with cholecalciferol, which is not available in the United Kingdom except as 400 IU tablets with added calcium. Some patients find this awkward to take. Vitamin D2 (ergocalciferol) is available at a dose of 50 000 IU, which could be taken once every two months to provide an equivalent dose, but this needs testing in clinical trials.
, http://www.100md.com
Further educational resources
For doctors
Vitamin D and lower-extremity function in the elderly. Bandolier. www.jr2.ox.ac.uk/bandolier/booth/Arthritis/VDmusceld.html (accessed 1 Feb 2005)
Janssen HC, Samson MM, Verhaar HJ. Vitamin D deficiency, muscle function, and falls in elderly people. Am J Clin Nutr 2002;75: 611-5
Compston JE. Vitamin D deficiency: time for action. BMJ 1998;317: 1466-7
, 百拇医药
Grant WB. Vitamin D largely overlooked in review of interventions for the prevention of falls in older adults. Rapid response 19 Mar 2004 http://bmj.bmjjournals.com/cgi/eletters/328/7441/680#53950
For patients
Health and Age. The role of vitamin D in preserving muscle strength in seniors. www.healthandage.com/PHome/gm=20!gid2=1826 (accessed 1 Feb 2005)
Looksmart. Vitamin D's muscle-strengthening effect and fracture prevention. www.findarticles.com/p/articles/mi_m0815/is_6_29/ai_n6134289 (accessed 1 Feb 2005)
, 百拇医药
The question of whether to treat all elderly people living in the community is problematic. Two thirds are not deficient in vitamin D, yet 250 would need to be treated for one year to prevent a fracture.23 This number could probably be reduced by confining treatment to people aged 80 or older.2 Treating only women with known vitamin D deficiency could prevent one fall for every five women treated for a year8 and treating 20-25 women in nursing homes and old people's homes for a year without screening for vitamin D status would prevent one fracture.21
, 百拇医药
Finally, devotees of anecdote based medicine who need an example of the dramatic effect of vitamin D on muscle weakness (in a different clinical context) may wish to note the case report of "A woman who left her wheelchair" after three weeks of calcitriol for extremely severe vitamin D deficiency with progressive muscular weakness.25
I thank Richard Doll and Larry Ramsay for encouraging me to undertake this review.
Competing interests: GV is a semiretired independent consultant in pharmaceutical medicine. He spent most of his working life in the industry with responsibility for the clinical development of new drugs. He also worked as a medical assessor with the Committee on Safety of Medicines responsible for evaluating the efficacy and safety of new drugs. The review was prompted after participating in a five year randomised controlled trial of vitamin D for the prevention of fractures in elderly people by the realisation that appropriate preparations of vitamin D are not readily available in England.
, http://www.100md.com
References
Blake AJ, Morgan K, Bendall MJ, Dallosso H, Ebrahim SB, Arie TH, et al. Falls by elderly people at home: prevalence and associated factors. Age Ageing 1988;17: 365-72.
Semba RD, Garrett E, Johnson BA, Guralnik JM, Fried LP. Vitamin D deficiency among older women with and without disability. Am J Clin Nutr 2000;72: 1529-34.
Jacques PF, Felson DT, Tucker KL, Mahnken B, Wilson PW, Rosenberg IH, et al. Plasma 25 hydroxy vitamin D and its determinants in an elderly population sample. Am J Clin Nutr 1997;66: 929-36.
, http://www.100md.com
Institute of Medicine. Dietary reference intakes. Washington, DC: National Academic Press, 1997.
Holick MF. Vitamin D: a millennium perspective. J Cell Biochem 2003;88: 296-307.
Mowé M, Haug E, Bohmer T. Low serum calcidiol concentration in older adults with reduced muscular function. J Am Geriatr Soc 1999;47: 220-6.
Dhesi JK, Bearne LM, Moniz C, Hurley MV, Jackson SH, Swift CG, et al. Neuromuscular and psychomotor function in elderly subjects who fall and the relationship with vitamin D status. J Bone Miner Res 2002;17: 891-7.
, 百拇医药
Pfeiffer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C. Effects of a short term Vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res 2000;15: 1113-8.
Bischoff HA, Sthelin HB, Dick W, Akos R, Knecht M, Salis C, et al. Effects of vitamin D and calcium supplements on falls: a randomised controlled trial. J Bone Miner Res 2003;18: 343-51.
Evans JG. Falls and fractures. Age Ageing 1988;17: 361-4.
, 百拇医药
Chang JT, Morton SC, Rubenstein LZ, Mojica WA, Maglione M, Suttorp MJ, et al. Interventions for the prevention of falls in older adults: systematic review and meta-analysis of randomised clinical trials. BMJ 2004;328: 680.
Heikinheimo RJ, Inkovaara JA, Harju EJ, Haavisto MV, Kaarela RH, Kataja JM, et al. Annual injection of vitamin D and fractures of aged bones. Calcif Tissue Int 1992;51: 105-10.
Egsmose C, Lund B, McNair P, Lund B, Storm T, Sorensen OH, et al. Low serum levels of 25-hydroxy vitamin D and 1,25 dihydroxy vitamin D in institutionalized old people: influence of solar exposure and vitamin D supplementation. Age Ageing 1987;16: 35-40.
, http://www.100md.com
Gloth FM, Gundberg CM, Hollis BW, Haddad JG Jr, Tobin JD. Vitamin D deficiency in homebound elderly persons. JAMA 1995;274: 1683-6.
Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM. Vitamin D supplementation and fracture incidence in elderly persons: a randomized placebo-controlled trial. Ann Intern Med 1996;124: 400-6.
Nesby-O'Dell S, Scanlon KS, Cogswell ME, Gillespie C, Hollis BW, Looker AC, et al. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994. AmJClin Nutr 2002;76: 187-92.
, 百拇医药
Gallagher JC, Kinyamu HK, Fowler SE, Dawson-Hughes B, Dalsky GP, Sherman SS, al. Calciotropic hormones and bone markers in the elderly. J Bone Miner Res 1998;13: 475-82.
McKenna MJ. Differences in vitamin D status between countries in young adults and the elderly. Am J Med 1992;93: 69-77.
Meyer HE, Smedshaug GB, Kvaavik E, Falch JA, Tverdal A, Pedersen JI. Can vitamin D supplementation reduce the risk of fracture in the elderly A randomized controlled trial. J Bone Miner Res 2002;17: 709-15.
, 百拇医药
Latham NK, Anderson CS, Lee A, Bennett DA, Moseley A, Cameron ID, et al. 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 2003;51: 291-9.
Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992; 327-42.
, 百拇医药 Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997;337: 670-6.
Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 2003;326: 469-72.
Vieth R. Vitamin D supplementation, 25-hydroxy vitamin D concentrations and safety. Am J Clin Nutr 1999;69: 842-56.
Mingrone G, Greco AV, Castagneto M, Gasbarrini G. A woman who left her wheelchair. Lancet 1999;353: 806., 百拇医药(Geoff Venning)