Feb. 15, 2006 — Calcium and vitamin D supplementation in postmenopausal and elderly women improves bone density, but does not reduce fracture risk and increases risk for kidney stones, according to the results of a 7-year follow-up randomized study from the Women's Health Initiative (WHI) reported in the February 16 issue of The New England Journal of Medicine. A second analysis showed that supplementation did not reduce the risk for colorectal cancer, but the investigators suggest that this may have been related to the short follow-up and/ or insufficient dose.

"The efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal," write Rebecca D. Jackson, MD, from Ohio State University in Columbus, and colleagues from the WHI Investigators. "In two recent randomized trials, calcium plus vitamin D supplements (1,000 mg of elemental calcium and 800 IU of vitamin D₃) did not reduce the risk of nonvertebral fractures among older women."

The investigators recruited 36,282 postmenopausal women, aged 50 to 79 years, who were already enrolled in WHI. and they randomized them to receive 1,000 mg of elemental calcium as calcium carbonate with 400 IU of vitamin D₃ daily or placebo. During an average follow-up period of 7.0 years, fractures were ascertained and bone density was measured at 3 WHI centers.

Compared with the placebo group, the calcium plus vitamin D group had 1.06% higher hip bone density (P < .01). Based on intent-to-treat analysis, the supplemented group had a hazard ratio [HR] of 0.88 for hip fracture (95% confidence interval [CI], 0.72 - 1.08), 0.90 for clinical spine fracture (95% CI, 0.74 - 1.10), and 0.96 for total fractures (95% CI, 0.91 - 1.02).

However, the group receiving calcium plus vitamin D had increased risk for renal calculi (HR, 1.17; 95% CI, 1.02 - 1.34). Censoring data from women who became noncompliant with the study medication reduced the HR for hip fracture to 0.71 (95% CI, 0.52 - 0.97). Prerandomization serum vitamin D levels did not significantly affect these findings.

Study limitations include lack of data on higher doses of vitamin D than were used in the WHI; failure of many women to adhere to the study treatment; inability to separate the independent effects of calcium and vitamin D; participants in both groups allowed to take multivitamins as well as calcium and vitamin D up to specified levels; and insufficient power to detect a small effect on reducing the risk for hip fracture.

"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," the authors write. "Although the statistically null primary effect argues against recommending universal calcium with vitamin D supplementation for already calcium-replete women, the findings provide evidence of a positive effect of calcium with vitamin D on bone health in older postmenopausal women."

The National Heart, Lung, and Blood Institute and the General Clinical Research Center program of the National Center for Research Resources, Department of Health and Human Services, supported this study. GlaxoSmithKline Consumer Healthcare supplied the active study drug and placebo. Some of the authors have disclosed having various financial relationships with Procter & Gamble Pharmaceuticals, the Alliance for Better Bone Health, Novartis, Pfizer, Schering-Plough, the National Cancer Institute of Canada, Lilly, Merck, the Egg Nutrition Council, and/or General Mills.

In an accompanying editorial, Joel S. Finkelstein, MD, from Massachusetts General Hospital in Boston, notes that the trial was well conducted, but the results leave many questions unanswered in large part due to study limitations. A subgroup analysis of women who largely adhered to the protocol suggested that calcium with vitamin D supplementation reduces the risk for hip fracture.

"It seems reasonable to recommend that women consume the recommended daily levels of calcium and vitamin D through diet, supplements, or both," Dr. Finkelstein writes. "But one message is clear: calcium with vitamin D supplementation by itself is not enough to ensure optimal bone health. Clinicians and patients should be aware that even if a woman is receiving adequate calcium with vitamin D supplementation, she may still be at risk for fracture, particularly if she has low bone mineral density or other clinical risk factors."

Dr. Finkelstein has disclosed no relevant financial relationships.

In an additional analysis from the randomized, double-blind, placebo-controlled trial described above, the incidence of pathologically confirmed colorectal cancer was the designated secondary outcome. A nested case-control study also determined baseline levels of serum 25-hydroxyvitamin D.

"Higher intake of calcium and vitamin D has been associated with a reduced risk of colorectal cancer in epidemiologic studies and polyp recurrence in polyp-prevention trials," write Jean Wactawski-Wende, PhD, and colleagues from the WHI Investigators. "However, randomized-trial evidence that calcium with vitamin D supplementation is beneficial in the primary prevention of colorectal cancer is lacking."

Invasive colorectal cancer developed in 168 women assigned to calcium plus vitamin D supplementation and in 154 women assigned to placebo (HR, 1.08; 95% CI, 0.86 - 1.34; P = .51). Tumor characteristics, frequency of colorectal-cancer screening, and abdominal symptoms were similar in both groups. There were no significant treatment interactions with baseline characteristics.

"Daily supplementation of calcium with vitamin D for seven years had no effect on the incidence of colorectal cancer among postmenopausal women," the authors write. "The long latency associated with the development of colorectal cancer, along with the seven-year duration of the trial, may have contributed to this null finding. Ongoing follow-up will assess the longer-term effect of this intervention."

Study limitations include high baseline intakes of calcium with vitamin D; calcium and vitamin D doses used may have been insufficient to demonstrate a protective effect; a high fraction of participants not fully adherent throughout the study; the protocol did not require participants to undergo bowel examinations; timing of administration of the intervention; and the length of follow-up.

"These results do not provide support for the general use of calcium plus vitamin D supplementation to prevent colorectal cancer," the authors conclude.

In an accompanying editorial, Michele R. Forman, PhD, and Bernard Levin, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, note the differences between women in this study and those in the Third National Health and Nutrition Examination Survey, and they recommend additional research.

"The conclusion of Wactawski-Wende et al. about the role of calcium plus vitamin D supplementation in the prevention of colorectal cancer needs to be interpreted in the light of the complexities of the WHI study and the probability that the doses of these substances may have been too low to achieve the desired effect," Drs. Forman and Levin write.

The editorialists have disclosed no relevant financial relationships.

N Engl J Med. 2006;354:669--696, 750-754