News Author: Laurie Barclay, MD

May 2, 2005 — Calcium and vitamin D₃ supplementation do not reduce fractures in those at risk, according to the results of two studies, one published in the April 28 Early Online Publication issue of The Lancet and the other in the April 30 issue of the BMJ. The findings do not support routine oral supplementation, with either supplement alone or in combination, to prevent further fractures in previously mobile elderly people. The commentator points out a study limitation of not measuring vitamin D₃ levels in the study population.

"Policies for secondary prevention should therefore consider other strategies," Adrian M. Grant, MD, lead author of The Lancet study, from the University of Aberdeen, U.K., said in a news release. "The main pharmacological intervention is antiresorptive drugs, such as bisphosphonates, which have rarely been assessed in patients who have not been taking calcium or vitamin D."

The authors note that vitamin D₃ and calcium, alone or in combination, are often recommended for prevention of osteoporotic fractures. Inadequate intake of vitamin D₃ and calcium intake might increase fracture risk by increasing bone resorption and loss from secondary hyperparathyroidism, and vitamin D₃ may also protect against falls resulting in fracture. Data from randomized trials suggest that the combination of calcium and vitamin D₃ may be helpful.

In the factorial-design Randomised Evaluation of Calcium Or vitamin D₃ (RECORD) trial, 5,292 elderly people who were mobile before developing a low-trauma fracture were randomized to receive 800 IU per day of oral vitamin D₃, 1,000 mg of calcium, 800 IU daily of oral vitamin D₃ combined with 1,000 mg per day of calcium, or placebo. Of the 5,292 subjects, 4,481 (85%) were women; all were 70 years or older. Follow-up for participants recruited from 21 U.K. hospitals ranged from 24 to 62 months. The main outcome measure was new low-energy fractures, and analysis was by intent-to-treat.

Of 5,292 participants, 698 (13%) had a new low-trauma fracture, of which 183 (26%) were of the hip. The incidence of new, low-trauma fractures was not significantly different between participants receiving calcium and those who did not (331 [12.6%] of 2,617 vs 367 [13.7%] of 2,675; hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.81 - 1.09]); between participants receiving vitamin D₃ and those who did not (353 [13.3%] of 2,649 vs 345 [13.1%] of 2,643; HR,1.02; 95% CI, [0.88 - 1.19]); or between those receiving combination treatment and those receiving placebo (165 [12.6%] of 1,306 vs 179 [13.4%] of 1,332; HR for interaction term, 1.01 [0.75 - 1.36]).

Incidence of all new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life did not differ between groups.

At 24-month follow-up, 2,886 (54.5%) of 5,292 were still taking their assigned tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn from the study, and 1,897 (35.8%) had stopped taking their assigned tablets but were still providing data for at least the main outcomes. Compliance with consumption of calcium tablets was significantly lower (difference, 9.4% [95% CI, 6.6 - 12.2]), in part due to gastrointestinal tract symptoms, but potentially serious adverse events were uncommon and no different between groups.

"Our trial indicates that routine supplementation with calcium and vitamin D₃, either alone or in combination, is not effective in the prevention of further fractures in people who had a recent low-trauma fracture," Dr. Grant said.

Study limitations include possible underestimation of true differences because of chance, difficulty in maintaining compliance, different rates of questionnaire response in the trial groups, and inability to directly address whether supplementation should be used as a primary prevention measure or for those who live in a care-home environment.

The Shire Pharmaceuticals Group supported this study and has various financial arrangements with three of its authors, one of whom also has financial arrangements with Nycomed, supplier of vitamin supplements.

In an accompanying comment, Philip N. Sambrook, from Royal North Shore Hospital in Sydney, Australia, notes that interpretation of these findings is limited by two main factors.

"First, compliance with medication was only moderate. It declined to 63% after 2 years and might have been as low as 45% when non-responders to the questionnaire about compliance were included," Dr. Sambrook writes. "Second, the study perpetuates the limitations of most previous studies by measuring 25-hydroxyvitamin D in only a small sample. Thus the vitamin D status of the trial population at baseline remains largely unknown, although, because the patients were younger than in other studies, ambulatory, and living in the community, they were less likely to have vitamin D deficiency."

Dr. Sambrook reports no conflict of interest.

The objective of the second randomized trial, led by Jill Porthouse, MD, from the University of York, England, U.K., was to determine whether supplementation with calcium and cholecalciferol (vitamin D₃) reduces fracture risk in community-dwelling older women with one or more risk factors for hip fracture.

At nurse-led clinics in primary care, 3,314 women aged 70 years and older with one or more risk factors for hip fracture were randomized to receive or not to receive daily oral supplementation with 1,000 mg of calcium and 800 IU of cholecalciferol. Both groups received an information leaflet on dietary calcium intake and fall prevention. Risk factors were defined as any previous fracture, low body weight (< 58 kg), smoking, family history of hip fracture, or fair or poor self-reported health. The primary outcome was all clinical fractures, and secondary outcomes were treatment adherence, falls, and quality of life measured with the Short-Form 12.

At 24 months, 69% of women who completed the follow-up questionnaire were still taking supplements (55% when randomized participants known to be alive were included). After a median follow-up period of 25 months (range, 18 - 42 months), clinical fracture rates were lower than expected in both groups. However, the rate for all clinical fractures was not significantly different between groups (odds ratio [OR] for fracture in supplemented group, 1.01; 95% CI, 0.71 - 1.43).

The OR for hip fracture was 0.75 (95% CI, 0.31 - 1.78). The odds of a woman having a fall at six months was 0.99, and at 12 months was 0.98. Quality of life did not significantly differ between the groups.

Study limitations include lack of placebo control; fewer fractures than anticipated, reducing the power to detect modest differences between groups; and treatment adherence rates of approximately 60% at 12 months.

"Although we found no evidence of a benefit on fractures in older community dwelling women given calcium and vitamin D supplementation, we cannot exclude a clinically significant benefit of supplementation owing to the relatively wide confidence intervals around our estimate of effect," the authors write.

Northern and Yorkshire National Health Service research and development, healthy ageing programme, Shire, and Nycomed funded this study. Shire supplied the calcium and vitamin D₃ supplements and has financial arrangements with three of the authors, one of whom also has financial arrangements with Nycomed.