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Age and Ageing 2005 34(6):542-544; doi:10.1093/ageing/afi184
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© The Author 2005. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Vitamin D and fracture prevention—treatment still indicated but clarification needed

The publication of Chapuy’s 1992 paper, ‘Vitamin D3 and calcium to prevent hip fractures in elderly women’, was a turning point in fracture prevention in older adults. It was the first large-scale study to demonstrate that simple, oral, daily administration of calcium and vitamin D supplements could cause a substantial reduction in hip fractures with a relative risk of 0.74 over 3 years [1]. The mechanism for the reduction in fracture risk is probably a combination of improved bone health and neuromuscular changes. The latter may reduce falls risk or improve neuroprotective reflexes, so a fall is less likely to result in a serious injury. Chapuy’s study included 3,270 women aged over 70 years, living in residential care. This paper was followed by a number of others, which reinforced the view that vitamin D alone, or with calcium, could reduce peripheral fractures in older adults. These studies extended the populations likely to benefit including men as well as women, those living in their own homes as well as in residential care and slightly younger adults, down to the age of 65 years [2–5]. The apparent benefits, cost effectiveness (numbers needed to treat 17 to prevent one hip fracture of women living in residential care) and relative safety have meant that many national and local guidelines advocate the widespread prescription of calcium and vitamin D supplements to prevent fractures in adults aged 65 years and over.

However, not all studies of the effects of calcium and vitamin D supplementation on fracture rates in older people have had positive findings [6–8]. The publication of three high-profile, negative studies within the past year calls these recommendations into doubt [9–11]. Two of these were primary prevention studies. The Wessex fracture prevention study was a population-based study of 9,440 men and women, aged over 75, who received an annual injection of vitamin D (ergocalciferol 300,000 IU) for 3 years [12]. The study by Porthouse and colleagues [9] looked at 3,314 women aged over 70 years who were treated with calcium (1 g/day) and vitamin D (cholecalciferol 800 IU/day). The third study (RECORD) investigated secondary prevention of fractures in 5,292 men and women, aged over 70 years, who had suffered a fragility fracture within the previous 10 years. In a factorial design, they were given calcium (1 g/day), vitamin D (cholecalciferol 800 IU/day), both or neither [10]. It is unlikely that the conclusions of the studies demonstrating benefit were wrong, so what is it about the populations studied, the nature of the interventions or the ascertainment of outcomes that can explain these differences?

The variables that are likely to be significant in altering the outcome of such studies are the likelihood of vitamin D deficiency or insufficiency in the population being studied, the calcium intake of subjects, the rate of fracture in that population (in turn related to the duration of follow-up) and the dose and type of vitamin D administered. Furthermore, adherence to treatment may differ depending on the setting and the treatment regime, so that studies in care homes or those using intermittent bolus vitamin D may have higher adherence rates and, therefore, be more likely to have positive results compared to population-based studies such as RECORD where compliance may have been as low as 45%. Finally, self-selection of study subjects, particularly in population-based studies [9–11], may bias the sample towards fitter and more active older people, so the studies may be missing frailer, housebound people, the very group who are at higher risk of vitamin D deficiency, falls and fractures.

The likelihood of vitamin D deficiency in the populations studied and the dose and type of vitamin D supplements administered warrant further discussion.

Increasing age and housebound lifestyle are important determinants of vitamin D status [13]. High rates of vitamin D deficiency have been demonstrated in community-based samples of older people [14] and high-risk groups such as people with falls [15] or fractures [16]. The majority of studies looking at the efficacy of vitamin D in fracture prevention, particularly those with a large sample size, have not ascertained vitamin D status in all subjects, presuming that the population under study will have a high prevalence of vitamin D deficiency. Vitamin D and parathyroid hormone (PTH) levels (since PTH is an important mediator of bone loss and osteoporosis in later life), before and during supplementation, were either measured in small subgroups [1, 4, 10, 12] or not measured at all [9]. Scrutiny of this data shows a wide range of levels of vitamin D with improvements with treatment which still leave many subjects in the deficient/insufficient range and modest changes in PTH (if measured). Furthermore, the vitamin D status of the vast majority of subjects is unknown.

Since the publication of the papers by Chapuy [1] and then by Dawson-Hughes [3], 7–800 IU of cholecalciferol/day with or without calcium has been widely accepted as an appropriate dose of vitamin D for supplemental use; however, these doses may not be sufficient. Useful guidelines on interventional studies with vitamin D suggest that doses of 3,000–10,000 IU cholecalciferol/day are necessary [17, 18] and can be safely administered without toxicity. Ergocalciferol (vitamin D2) is at least threefold less potent than cholecalciferol (vitamin D3) [19], which may account for the negative findings in the Wessex hip fracture prevention study [12] in which an ergocalciferol injection was used. Finally, it is not known whether activated vitamin D would be a more effective supplement for widespread use in older adults. Calcitriol can reduce vertebral fractures in postmenopausal women with osteoporosis [20], and alpha-calcidol has been shown to reduce falls in frail older adults with low calcium intake or renal impairment [21]. Given that many older adults have low calcium intake and low glomerular filtration rate, activated vitamin D has theoretical advantages in this respect, although the major disadvantage is the risk of hypercalcaemia. In contrast, supplementation with cholecalciferol and ergocalciferol is unlikely to lead to hypercalcaemia due to homeostatic regulation of activation of vitamin D. If calcitriol were used on a routine ‘whole population’ basis, the need for monitoring of calcium levels would lead to increased cost and inconvenience.

Where does the current body of literature leave us with regard to using calcium and vitamin D supplements for peripheral fracture prevention in older adults?

The situation is best summarised as follows:

  1. For older women, aged over 70 years, living in residential or nursing care, the evidence for population-based supplements is good. This could still reasonably be extrapolated to frail, housebound adults of both genders. Oral supplements of cholecalciferol 800 IU with calcium 1 g a day are preferable to an injection, and intermittent oral dosing of cholecalciferol may aid compliance.
  2. For secondary fracture prevention, since the publication of National Institute of Clinical Excellence (NICE) guidance on the secondary prevention of osteoporotic fracture [22], all women over 75 and postmenopausal women under 75 who meet criteria based on bone densitometry should now be treated with bone-strengthening drugs, usually a bisphosphonate. The guidance specifically says that all patients should have adequate calcium and vitamin D levels before treatment, and it is important that patients treated with bisphophonates are calcium and vitamin D replete, so it is good practice to co-prescribe calcium and vitamin D supplements to this group too. Although NICE does not address osteoporosis treatment in men, this recommendation also applies to men being treated for osteoporosis.
  3. In postmenopausal women under 75 who have fractured, but do not meet bone densitometry criteria for specific treatment, there is no evidence at present to give vitamin D supplements. However, between 20 and 50% will be vitamin D deficient and, given that they have already fractured, it would be good practice to check vitamin D levels and replace if deficient or insufficient.
  4. For primary prevention of fractures in ‘younger’ older adults, there is currently no evidence to support population-based administration of calcium and vitamin D.

It is clear that there is a need for more research on this subject, particularly using higher doses of vitamin D or activated vitamin D. Whether vitamin D needs to be combined with calcium supplements is also not clear. It should be remembered that vitamin D deficiency is common, and untreated vitamin D deficiency has adverse effects throughout the body, including an increased risk of falls, increased vascular risk and a higher incidence of cancer. So, reducing fracture rates is not the only desirable outcome of vitamin D supplementation in older adults.

Theresa J. Allain

North Bristol NHS Trust, Southmead Hospital, Bristol, UK

Email: theresa.allain{at}nbt.nhs.uk

References

  1. Chapuy MC, Arlot ME, DuBoeuf F et al. Vitamin D and calcium to prevent hip fractures in elderly women. N Engl J Med. 1992; 327: 1637–42.[Abstract]
  2. Heikinheimo RJ, Inkovaara JA, Harju EJ et al. Annual injection of vitamin D and fracture of aged bones. Calcif Tissue Int 1992; 51: 105–10.[CrossRef][Web of Science][Medline]
  3. 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.[Abstract/Free Full Text]
  4. 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.[Abstract/Free Full Text]
  5. Larsen ER, Mosekilde L, Foldspang A. Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study. J Bone Miner Res 2004; 19: 370–8.[CrossRef][Web of Science][Medline]
  6. Inkovaara J, Gothoni G, Halttula R, Heikinheimo R, Tokola O. Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial. Age Ageing 1983; 12: 124–30.[Abstract/Free Full Text]
  7. Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM. Vitamin D supplementation and fracture incidence in elderly persons: a randomised, placebo-controlled clinical trial. Ann Intern Med 1996; 124: 400–6.[Abstract/Free Full Text]
  8. 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.[CrossRef][Web of Science][Medline]
  9. Porthouse J, Cockayne S, King C et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ 2005; 330: 1003.[Abstract/Free Full Text]
  10. Grant AM, Avenell A, Campbell MK et al. 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 2005; 365: 1621–8.[CrossRef][Web of Science][Medline]
  11. Smith HE, Anderson FH, Raphael HM, Crozier SR, Cooper C. Effect of annual intramuscular vitamin D3 supplementation on fracture risk: population based, randomised, double-blind, placebo-controlled trial. Osteoporos Int 2004; 15: S8 OC10.
  12. Anderson FH, Smith HE, Raphael HM, Crozier SR, Cooper C. Effect of annual intramuscular vitamin D3 supplementation on fracture risk in 9440 community-living older people: the Wessex Fracture Prevention Trial. J Bone Miner Res 2004; 19: S57.
  13. Jacques PF, Felson DT, Tucker KL et al. Plasma 25-hydroxyvitamin D and its determinants in an elderly population sample. Am J Clin Nutr 1997; 66: 929–36.[Abstract/Free Full Text]
  14. van der Wielen RPJ, Lowik MRH, van den Berg H, de Groot LCPGM, Haller J, Morieras O. Serum vitamin D concentrations among elderly people in Europe. Lancet 1995; 346: 207–10.[CrossRef][Web of Science][Medline]
  15. Dhesi JK, Moniz C, Close JC, Allain TJ. A rationale for vitamin D prescribing in a falls clinic population. Age Ageing 2002; 31: 267–71.[Abstract/Free Full Text]
  16. Harwood RH, Sahota O, Gaynor K, Masud T, Hosking DJ. A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study. Age Ageing 2004; 33: 45–51.[Abstract/Free Full Text]
  17. Veith R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations and safety. Am J Clin Nutr 1999; 69: 842–56.[Abstract/Free Full Text]
  18. Vasquez A, Manso G, Cannell J. The clinical importance of vitamin D (cholecalciferol): a paradigm shift with implications for all healthcare providers. Altern Ther Health Med 2004; 10: 28–36.[Web of Science][Medline]
  19. Armas LA, Hollis BW, Heaney RP. Vitamin D2 is much less effective than vitamin D3 in humans. Clin Endocrinol Metab 2004; 89: 5387–91.[Abstract/Free Full Text]
  20. Tilyard MW, Spears GF, Thomson J, Dovey S. Treatment of postmenopausal osteoporosis with calcitriol or calcium. N Engl J Med 1992; 6: 406–8.
  21. Dukas L, Schacht E, Mazor Z, Stahelin HB. Treatment with alfacalcidol in elderly people significantly decreases the high risk of falls associated with a low creatinine clearance of <65 ml/min. Osteoporos Int 2004; 16: 198–203.
  22. NICE. The secondary prevention of osteoporotic fracture in postmenopausal women. Technology Appraisal No. 87. DOH 2005.

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