PERTH, Australia – Calcium supplements can help prevent fractures in older women, but only if patients are compliant, according to a 5-year, double-blind, placebo-controlled study led by Richard L. Prince, MD, of the University of Western Australia in Perth, Australia.¹

The new findings, which appear in the April 24, 2006, issue of the Archives of Internal Medicine, echo those of the recently published Calcium/Vitamin D Trial, an arm of the ongoing Women's Health Initiative (WHI).² The WHI study also showed that calcium (plus vitamin D) does not decrease risk of any of the fracture endpoints, including hip, spine, and total body. However, a subgroup analysis of women who largely adhered to the protocol did suggest that calcium with vitamin D supplementation reduces the risk of hip fracture.

Compliance is key

In the new report by Prince and colleagues, 1460 non-vitamin D-deficient ambulatory women >70 years were randomized to calcium carbonate supplements (600 mg twice a day) or placebo, and a total of 236 women (16.1%) had one or more osteoporotic fractures. An intention-to-treat analysis of the entire group found that calcium supplementation did not significantly reduce the fracture risk (hazard ratio, 0.87; 95% CI, 0.67–1.12), indicating that supplementation was ineffective.

However, in an analysis of 830 compliant women (56.8% of all the women), only 10.2% of the 310 calcium patients had fractures, compared with 15.4% of the 320 placebo patients, the study showed.

While calcium supplementation may be ineffective as a public health intervention due to lack of compliance, "all women at relatively high risk of minimal trauma fracture due to the fact that they have survived to 70 years of age should take calcium tablets twice a day for 5 years to reduce their risk of fracture of any bone from 15.4% to 10.2% (RR 0.66)," Dr. Prince told CIAOMed.

In the study, calcium-treated patients had improved quantitative ultrasonography findings of the heel, femoral neck, and whole-body dual x-ray absorptiometry data, and bone strength compared with placebo-treated patients. These findings support calcium's effect in improving bone mass and possibly architecture, the researchers conclude. In the calcium group, the researchers reported a reduction in all-site clinical fractures (HR 0.66; 95% CI, 0.45–0.97), appendicular fractures (HR 0.65; 95% CI, 0.43–0.97), and upper-limb fractures (HR 0.44; 95% CI, 0.21–0.92). Analysis of fractures in the noncompliant calcium group showed no difference in the number or type of fractures compared with the placebo patients.

In the study, 43% of women were noncompliant, which was defined as taking <80% of the prescribed supplements. Researchers checked compliance by counting returned tablets at each 12-month review and calculating the returns as a percentage of the optimum. Average yearly compliance of <80% was classified as noncompliant.

Did vitamin D status affect results?

The vitamin D status of the study population may have also played a role in the less-than-stellar results, the researchers speculate. "Although substantially better than that encountered in studies in higher latitudes, [it] may have been insufficient to allow optimal absorption and disposal of calcium to the skeleton," they write.

Of the 92,000 adverse events recorded, constipation was the only event increased by the treatment. Specifically, 13.4% of patients in the calcium group were constipated, compared with 9.1% of those given placebo. The risks of kidney stones, ischemic heart disease, or other adverse events did not increase, the study showed.

Slow-release calcium tablets needed

"The physiological reason [that calcium prevents fractures] is likely to be that one of the major causes of postmenopausal and age-related osteoporosis is a continual small loss of extra calcium in the urine due to low levels of estrogen in postmenopausal women, coupled with a slight reduction in calcium absorption from food, also due to low estrogen levels," Dr. Prince explained. "Thus, what we need is slow-release calcium to suppress the consequent rise in parathyroid hormone, which is the direct cause of the bone loss via the stimulation of action of osteoclasts—the cells that cause the bone loss, and which are very effectively inhibited by bisphosphonates such as Fosamax®," he said, adding that calcium can be considered an antiresorptive agent that acts further up the causative pathway, "but because of its short duration of action high compliance is critical to its effect."

Dr. Prince said that like other agents it must be taken as directed, "but many of us cannot do this regularly for many years." Improving compliance may come with explaining this physiological mechanism of action to patients, follow-up by a health professional, and reinforcement by all health professionals. "[Patients'] bone status is often ignored until they fracture, even though the risks are often higher than having a myocardial infraction," Dr. Prince said.

References

1. Prince RL, Devine A, Dhaliwal SS, et al. Effects of calcium supplementation on clinical fracture and bone structure. Arch Intern Med. 2006;166:869-875.
2. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and risk of fractures. New Engl J Med. 2006;354:669-683.