Boning Up on Calcium: Does it Help Prevent Fractures?

By Mary Hardy, MD Dr. Hardy is Associate Director, UCLA Center for Dietary Supplement Research: Botanicals, and Medical Director, Cedars-Sinai Integrative Medicine Program, Los Angeles, CA. Dr. Hardy reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.

Source: Jackson RD, et al. Women's Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-683.

Abstract: The efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal. The authors recruited 36,282 postmenopausal women, 50-79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. Participants were randomly assigned to receive 1,000 mg/d of elemental calcium as calcium carbonate with 400 IU/d of vitamin D3 or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers. Hip bone density was 1.06% higher in the calcium plus vitamin D group than in the placebo group (P < 0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95% confidence interval [CI] 0.72-1.08), 0.90 for clinical spine fracture (CI 0.74-1.10), and 0.96 for total fractures (CI 0.91-1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio 1.17; CI 1.02-1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (CI 0.52-0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels. Among healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones.

Comments

Most women in the united states know that they are supposed to take calcium and vitamin D to prevent osteoporosis and fractures, a major cause of morbidity and mortality in postmenopausal women. This is the most widely recognized public health message in the United States today. However, physicians, and their patients, may be surprised to hear that the medical literature on this topic has not been uniformly positive. On the one hand, two recent Cochrane reviews reported small but positive effects. In the first, calcium supplementation alone showed a statistically significant, albeit small, increase in bone mineral density but only a non-statistically significant trend toward a decrease in vertebral body fractures.1 No effect was demonstrated on the rate of non-vertebral fractures. A second review, focused on vitamin D, concluded that high-risk patients (frail elderly) may sustain fewer fractures overall if given vitamin D (at least 700 IU/d) in conjunction with adequate calcium.2 There was no clear cut benefit for vitamin D alone with respect to fracture prevention. However, a recent publication from the Women's Health Initiative (WHI) study cast doubt on this conclusion3—or does it?

The WHI study, a very large prospective controlled trial of almost 40,000 American women, assigned subjects to receive either calcium carbonate, equivalent to 1,000 mg/d of elemental calcium, plus 400 IU/d of vitamin D or placebo for the duration of the trial (an average of seven years). The women were postmenopausal, between 50 and 79 years of age, and were not necessarily at high risk for the development of osteoporosis. Throughout the trial, women were allowed to take their own personal calcium supplementation, regardless of group assignment, as well as bisphosphonates, if prescribed. The majority of women also were taking hormone replacement therapy until that portion of the study was stopped several years ago. The authors found a 1% increase in bone mineral density in the treatment group (P < 0.01) but an intention-to-treat analysis showed no decrease in the fracture risk, at any site, compared to placebo. A 17% increase in the incidence of renal calculi also was reported in the treatment group. The authors therefore concluded that despite the small increase in bone density, calcium and vitamin D, at the levels tested, did not decrease the risk of fracture and seemed to increase the risk of kidney stones. This study raises the question of whether we should continue to recommend routine calcium and vitamin D supplementation to postmenopausal women.

This trial was reported in the popular press as "proving" that calcium doesn't help bones, but a closer look and a consideration of additional factors paints a more complicated picture. First, the dose of vitamin D in this study was likely too low. Trials conducted after the start of the WHI study showed that less than 700 IU/d vitamin D was much less likely to be effective and a dose of 400 IU/d was considered ineffective to prevent fractures.4 Second, there may have been some issues with the calcium formulation chosen. Calcium carbonate is less bioavailable in general compared to other calcium salts.5 This effect is even more pronounced in patients, like many elderly, with low stomach acid. So, the dose of the vitamin D was too low and the calcium formulation may not have been optimal.

Although this study was well conducted and appropriately designed, there were some inherent problems with its design. More than half of the women were on hormone replacement therapy, itself a potent antiresorptive agent, which could have masked a milder effect of calcium and vitamin D. Also, 64% of the women in the placebo group took at least 800 mg/d of calcium through diet and supplementation and 42% also took vitamin D. This use decreased the differences between the placebo and treatment groups, making it harder to demonstrate a statistically significant difference between groups. The authors further reported that the expected rate of hip fractures in the placebo group was half of what they had expected, and so this study may not have been sensitive enough to demonstrate a difference in hip fractures, the most debilitating type of fracture. However, there were large enough numbers of fractures at other sites to show a lack of difference overall between groups for all other kinds of fractures. The most telling analysis may be of the patients who were the most compliant with their supplements. The women who took calcium and vitamin D more than 80% of the time for the duration of the study did show a significant decrease in their risk of hip fracture (hazard ratio 0.71; 95 % confidence interval 0.52-0.97). So apparently, calcium and vitamin D work better if you actually take them.

Finally, it is important to remember that vitamin D has additional positive benefits. It has been shown to decrease falls in the frail elderly,6 probably by increasing muscle mass, and also has been associated with a decreased risk of colon cancer in conjunction with calcium supplementation.7,8

Unfortunately, the WHI has not given the definitive answers regarding calcium and vitamin D supplementation it was intended to provide, but it does suggest that the effects of supplementation are modest. Therefore, in advising our perimenopausal patients, it is important to continue to reduce all possible risk factors for osteoporosis and to encourage exercise, both weight-bearing and resistance training. To accrue the benefits of supplementation, patients must continue to take adequate doses of appropriate formulations, so we need to continue to reinforce the directive to be adherent with supplementation. Further, we should not depend on calcium and vitamin D alone to prevent osteoporosis, but should monitor patients to start more aggressive therapy if needed. Finally, despite the increase it renal calculi, the benefits of adequate vitamin D (800 IU/d at least) and appropriate calcium supplementation (citrate or malate if elderly and/or achlorhydric) likely outweigh the small risk and should be continued until further data clarifies which patients are the most likely to benefit from supplementation.

References

1. Shea B, et al; Osteoporosis Methodology Group; Osteoporosis Research Advisory Group. Calcium supplementation on bone loss in postmenopausal women. Cochrane Database Syst Rev 2004;(1):CD004526.

2. Avenell A, et al. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and postmenopausal osteoporosis. Cochrane Database Syst Rev 2005;(3):CD000227.

3. Jackson RD, et al; Women's Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-683. Erratum in: N Engl J Med 2006;354:1102.

4. Bischoff-Ferrari HA, et al. Fracture prevention with vitamin D supplementation: A meta-analysis of randomized controlled trials. JAMA 2005;293:2257-2264.

5. Hanzlik RP, et al. Relative bioavailability of calcium from calcium formate, calcium citrate, and calcium carbonate. J Pharmacol Exp Ther 2005;313:1217-1222.

6. Bischoff-Ferrari HA, et al. Effect of vitamin D on falls: A meta-analysis. JAMA 2004;291:1999-2006.

7. Hartman TJ, et al; Polyp Prevention Study Group. The association of calcium and vitamin D with risk of colorectal adenomas. J Nutr 2005;135:252-259.

8. Harris DM, Go VL. Vitamin D and colon carcinogenesis. J Nutr 2004;134(12 Suppl):3463S-3471S.