NPC Archive Item: Vitamin D alone may not prevent fractures

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23 February 2010

A meta-analysis found that daily calcium and vitamin D supplementation significantly reduced the overall risk of fracture across a wide age range of people, irrespective of sex and fracture history. In contrast, vitamin D alone in doses equivalent to 10 to 20 micrograms (400 to 800 units) per day did not prevent fractures.

Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.

Healthcare professionals should follow the two NICE technology appraisals on the use of drugs for the primary and secondary prevention of osteoporotic fragility fractures in postmenopausal women with osteoporosis, and the NICE guideline on the assessment and prevention of falls in older people. The technology appraisals assume that women who receive drug treatment for osteoporotic fragility fractures have an adequate calcium intake and are vitamin D replete. Unless clinicians are confident that women who receive treatment meet these criteria, calcium and/or vitamin D supplementation should be considered. There are a number of licensed preparations that will supply the evidence-based doses of 1g per day for calcium (measured as elemental calcium) and around 20 micrograms (800 units) per day for vitamin D.

What is the background to this?
Although a rationale exists for the use of vitamin D to prevent fractures in older people, it is unclear what dose should be used, or whether co-supplementation with calcium is necessary. This meta-analysis by the DIPART group analysed individual patient data from seven randomised controlled trials (RCTs, n=68,517) of vitamin D, with or without calcium. It aimed to identify whether patient characteristics influenced the efficacy of vitamin D or vitamin D plus calcium in reducing fractures and assessed the influence of dosing regimens and co-administration of calcium.

What does this study claim?
The study found that vitamin D alone at daily doses of 10 to 20 microgram (400 to 800 units) did not significantly reduce the risk of fracture. However, vitamin D plus calcium significantly reduced the overall risk of fracture (hazard ratio [HR] 0.92, 95%CI 0.86 to 0.99, P=0.025), irrespective of age and fracture history. Lower dose vitamin D (10microgram/day) plus calcium significantly reduced the risk of hip fracture (HR 0.74 95%CI 0.61 to 0.91, P=0.005). However, higher doses (20microgram/day) did not show a statistically significant reduction in the risk of hip fracture (HR 1.30, 95%CI 0.88 to 1.92, P=0.19). The trials of this dose included substantially fewer patients than those of the lower dose, and so the comparison may have lacked sufficient power to detect a true effect.

The relative reduction in risk was small (16% or less) and rates of fracture were low in most studies. The authors calculated that 213 people would need to be treated (NNT) with vitamin D plus calcium for three years to prevent one suffering from any fracture.

How does this relate to other studies?
These results are consistent with the results of a Cochrane review, which found that vitamin D alone (10 RCTs, n=25,016) did not significantly reduce the risk of hip fracture, vertebral fracture or any new fracture. Vitamin D with calcium significantly reduced the risk of hip fractures (8 RCTs, n=46,658; relative risk [RR] 0.84, 95%CI 0.73 to 0.96), but the review did not find a significant reduction in risk of all non-vertebral fractures or vertebral fractures with vitamin D plus calcium.

The authors of the meta-analysis discussed here recommend a daily dose of at least 10micrograms (400 units) vitamin D plus calcium 1000mg. However, another meta-analysis (12 RCTs, n=42,279) concluded that prevention of non-vertebral fractures with vitamin D was dose dependent (482 to 770 units), and independent of calcium supplementation. The two meta-analyses include different studies. In addition, as an editorial points out, in two studies of higher dose vitamin D that were included in the DIPART meta-analysis, compliance with treatment was poor. The other meta-analysis adjusted for compliance by multiplying the dose by the percentage of adherence to estimate the mean received dose for each trial. The DIPART group made no such adjustment, which may explain the contrasting conclusions. Also, information relating to baseline vitamin D (diet, sunlight and supplements) and calcium intake was not available for most of the studies included in the DIPART meta-analysis and is likely to vary widely due to differences in the nationality, age and mobility of the study populations.

As discussed in a previous blog, another meta-analysis found that high-dose vitamin D supplements reduced the relative risk of falling by 19% in individuals aged 65 years or more. Falls were not significantly reduced by low-dose vitamin D supplements.

So what?
Risk assessment is important in osteoporosis to target the effective therapies to those at highest risk of falls and fracture. For the lower-risk population, advice to ensure sufficient calcium and vitamin D intake, perhaps using educational materials, is probably appropriate. Supplementation may be considered for those with diets that have poor intake of calcium-rich foods or who have limited exposure to sunlight. The Food Standards Agency website outlines which foods are good sources of calcium and vitamin D.

Those at higher risk of falls and fracture, such as those in nursing or residential homes, or certain people receiving long term corticosteroids, should be considered for additional supplementation with calcium and vitamin D, at evidence-based doses. Importantly, this includes those on a bisphosphonate or other osteoporosis treatment, as all of the trials for these drugs were conducted in people with optimal calcium and vitamin D intake. For postmenopausal women receiving treatment for the primary or secondary prevention of osteoporotic fractures, NICE states that calcium and vitamin D supplements may be considered for those who do not have an adequate calcium intake and who may not be vitamin D replete. There are a number of licensed preparations that will supply the evidence-based doses of 1g per day for calcium and around 800 units per day for vitamin D, and practitioners should ensure that this is the case when prescribing, dispensing or administering this treatment. See the BNF for more details.

The NICE guidance on falls prevention does not currently make any recommendations on the use of calcium and vitamin D. It points out that there is evidence that vitamin D deficiency and insufficiency are common among older people and that, when present, they impair muscle strength and possibly neuromuscular function.

NICE is developing a clinical guideline on ‘Osteoporosis: assessment of fracture risk and the prevention of osteoporotic fractures in individuals at high risk’. The development of this is currently being reviewed following the publication of the technology appraisals.

Further information on the management of osteoporosis is available in a suite of materials on the osteoporosis section of NPC. In addition a recent MeReC Bulletin illustrates use of the two NICE technology appraisals and outlines some issues for healthcare professionals to consider.

Study details:
The DIPART Group. Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ 2010;340:b5463

Design: Individual patient data analysis using pooled data from RCTs with at least one intervention arm in which vitamin D was given, fracture as an outcome, and at least 1000 participants. Eleven RCTs were identified. Authors of seven (6 individually randomised and one cluster randomised) provided patient level data.

Patients: 68,517 participants (mean age 69.9 years, range 47 to 107 years, 14.7% men).

Intervention and comparison: The meta-analysis looked at the efficacy of vitamin D or vitamin D plus calcium with respect to any fracture, hip fracture, and clinical vertebral fracture and assessed the influence of patient characteristics, dosing regimens and co-administration of calcium

Outcomes and results: Information on fracture history was not available in one study. All studies reported incident hip fractures and other non-vertebral fractures. All but one reported on clinical vertebral fractures.

Trials using vitamin D with calcium showed a reduced overall risk of fracture (HR 0.92, 95%CI 0.86 to 0.99, P=0.025) but not hip fracture (HR 0.84, 95%CI 0.70 to 1.01, P=0.07). Studies using 10 micrograms of vitamin D given with calcium significantly reduced the risk of fracture (HR 0.74, 95%CI 0.60 to 0.91, P=0.005) and any fracture (HR 0.91, 95%CI 0.85 to 0.99, p=0.02) However, the 20microgram doses did nor significantly reduce the risk of any fracture or hip fracture. For vitamin D alone in daily doses of 10 or 20 micrograms no significant effects on fracture were found. No interaction was found between fracture history and treatment response, nor any interaction with age, sex, or hormone replacement therapy.

Sponsorship: National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services, UK Medical Research Council and Chief Scientist Office of the Scottish Government Health Directorates.

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