Calcium Supplementation in Postmenopausal Women to Reduce the Risk of Osteoporotic Fractures

Mikayla Spangler, Pharm.D., BCPS; Beth Bryles Phillips, Pharm.D., FCCP, BCPS; Mary B. Ross, M.B.A.; Kevin G. Moores, Pharm.D.

Disclosures

Am J Health Syst Pharm. 2011;68(4):309-318. 

In This Article

Literature Review

A search of the medical literature was performed using the terms calcium, postmenopausal women, osteoporosis, fractures, and bone fractures. Only controlled clinical trials involving human subjects and published in English were selected for this review. Additional references were obtained by cross-referencing selected articles.

Five studies have been published since 2004 that question whether calcium supplementation should continue to be recommended for postmenopausal women to reduce the risk of osteoporotic fractures.[17–21] Postmenopausal women were included in all five studies, three of which included women over age 70. Baseline calcium intake was higher than the national average in most of the studies, and many women were considered at low risk for osteoporotic fracture.

Studies in Healthy Postmenopausal Women

The Women's Health Initiative (WHI) was notable for its study design and large number of participants.[17] It was a large-scale project, with multiple substudies, to explore three chronic diseases associated with high rates of morbidity and mortality in postmenopausal women: cardiovascular disease, cancer, and osteoporosis. The osteoporosis substudy included more than 36,000 women, 50–79 years of age, who were randomized to receive either 500 mg of elemental calcium (calcium carbonate) plus 200 IU of vitamin or placebo, twice daily with food. D3 Personal supplementation with up to 1000 mg of calcium and up to 600 IU of vitamin D (increased to 1000 IU in response to IOM recommendations issued in 1999) was allowed.

Baseline BMD measurements in about 7% of the trial participants showed that about 58% of those tested had normal bone density, 38% were osteopenic, and 4% had a BMD in the osteoporotic range.[30] After 9 years of treatment, hip BMD was about 1% higher in the treatment group than in the placebo group (p < 0.01). BMD of the spine and total body did not differ significantly between the two groups at 9 years. The intention-to-treat analysis indicated that after an average of 7 years of follow-up, there was no difference in fracture rates between the treatment and placebo groups. However, at an average of 3.9 years of follow-up, the researchers censored data on some women due to nonadherence (i.e., taking less than 80% of their assigned calcium or placebo doses). Among the adherent women, there was a 29% reduction in hip fractures (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52–0.97) among women consistently taking calcium and vitamin D (68 versus 99 fractures in the placebo group). There were no significant differences with regard to other fracture sites.

The WHI researchers concluded that the doses of calcium and vitamin D studied may not affect fracture rates and that any benefit of calcium plus vitamin D in decreasing fractures may be seen only in adherent subjects. At the end of the study, only 59% of participants were taking at least 80% of the study medication. Subgroup analysis showed a significant decrease in hip fractures among women greater than 60 years of age (n = 22,860), with 186 fractures in the placebo group versus 146 fractures in the calcium-plus-vitamin D group (HR, 0.79; 95% CI, 0.64–0.98). A decrease in fractures was also seen in those with no history of a fall before initiation of the study (n = 22,393), with 117 fractures in the placebo group versus 87 fractures in the calcium-plus-vitamin D group (HR, 0.74; 95% CI, 0.56–0.98).

There are several points to consider when interpreting the results of the WHI study. The participants were generally healthy, living in the community, and highly educated (41% had at least a college degree); thus the results may not be generalizable to women with worse health status or less education. Also, the average daily calcium intake at baseline was about 1,150 mg, and the study protocol permitted all participants to take up to 1,000 mg of supplemental calcium per day; thus, some women assigned to placebo may have been consuming up to 1,678 mg of elemental calcium per day during the trial. The study did not specify how many women in the placebo group might have been using more than 1,000 mg of supplemental calcium per day, but the researchers reported that daily calcium supplement intake increased an average of 100 mg in both placebo and intervention groups, while dietary intake remained stable from baseline. In addition, the participants' generally high baseline calcium intake may have made it more difficult to detect a difference in fracture rate. Because the observed hip fracture rate (16 per 10,000 persons per year) was less than half of the projected rate of 34 per 10,000 persons per year, the statistical power of this study was greatly diminished. The study was designed to detect an 18% reduction in the risk of hip fracture with calcium plus vitamin D. Factors that may have contributed to the lower-than-expected observed fracture rate include the participants' relative lack of comorbidities, high rate of estrogen use (more than 50%), and high calcium intake at baseline. Although there was no overall difference in fracture rates between the treatment and placebo groups, most studies showing a benefit with calcium supplementation also included at least 600 IU of vitamin D in the treatment group. After publication of the WHI study results, NOF indicated it had no plans to revise its calcium and vitamin D supplementation guidelines.[31]

In a second large study of calcium supplementation in healthy postmenopausal women, Reid et al.[18] followed 1471 women not receiving any therapy for osteoporosis. These women had not used hormone replacement therapy, glucocorticoids, or bisphosphonates within the prior year, and participants' baseline BMD was within the normal range. Study participants were randomized to take either 400 mg of elemental calcium (calcium citrate) before breakfast and another 600 mg in the evening, or placebo twice daily, for five years. All women were consuming approximately 850 mg of dietary calcium daily. This study was designed to have 80% power to detect a 40% decrease in fracture rate. Compared with the placebo group, patients receiving calcium experienced a greater increase in BMD of the lumbar spine (1.8%, p < 0.0001), total hip (1.6%, p < 0.0001), and total body (1.2%, p < 0.0001). However, in the intention-to-treat analysis, more hip fractures occurred in the calcium group than in the placebo group (17 versus 5; HR, 3.55; 95% CI, 1.31–9.63). The researchers stated that was a surprise and most likely a chance finding related to the small number of hip fractures that occurred in the study population. No significant differences were observed in the rates of any symptomatic fracture, or in the rates of vertebral or forearm fractures, between the two groups. When participants who were less than 60% adherent, or diagnosed with cancer during follow-up, or used bone-active medication (e.g., bisphosphonates, estrogen, glucocorticoids) were excluded from the analysis, a significant decrease in the rate of distal forearm fractures was noted in patients taking calcium versus placebo (12 and 29 fractures, respectively; HR, 0.43; 95% CI, 0.22–0.85). Only 58% of the placebo group and 55% of the calcium group were considered adherent for the entire study. The researchers concluded that calcium supplement use can result in sustained reductions in bone loss and turnover, but poor long-term adherence limits those benefits, and its effect on fracture rates remains uncertain.

There are several issues to consider when interpreting the results of the study by Reid et al.[18] First, supplemental vitamin D was not included in the treatment protocol. Second, the participants were healthy community-dwelling women recruited by advertisements and by mailings using electoral rolls; therefore, the study may have attracted participants of higher socioeconomic status, leading to selection bias. Also, the women were considered adherent if they were taking 60% of their assigned medication doses by the end of the study, so it is possible that women in the treatment group were consuming only 600 mg more elemental calcium per day than those in the placebo group. More benefit on fracture risk may have been shown with calcium use if the authors had used a higher adherence threshold. In addition, 10% of participants withdrew from the study due to illness or personal reasons, reducing the amount of data available for analysis.

Studies in Australia and the United Kingdom

Prince et al.[19] evaluated 1460 women in Western Australia who were randomized to receive 600 mg of calcium carbonate (contains 240 mg of elemental calcium) or placebo twice daily with meals for five years. Average daily calcium intake was about 900 mg at baseline. BMD changes during follow-up were not significantly different between the calcium and placebo groups. In the intention-to-treat analysis, calcium supplementation did not lead to significant reductions in fracture risk. In a subgroup analysis of 830 women who were considered to be adherent (i.e., took 80% or more of their assigned tablets), those in the calcium group had a significant decrease in fractures of the upper limb (10 versus 22 in the placebo group; HR, 0.44; 95% CI, 0.21–0.92), any appendicular site (39 versus 58 in the placebo group; HR, 0.65; 95% CI, 0.43–0.97), or any skeletal site (43 versus 63 in the placebo group; HR, 0.66; 95% CI, 0.45–0.97). A subgroup analysis of nonadherent patients showed no significant difference in fracture rates between the two groups. The researchers stated that the intention-to-treat analysis probably didn't show a significant benefit of calcium therapy due to subjects' poor adherence (57%) to the calcium regimen. They concluded that although the tested calcium regimen cannot be recommended as a public health approach to fracture prevention because of problems with long-term adherence, the study results support the continued use of calcium supplements by women who can remain adherent.

Among other limitations, the Australian study did not include supplemental vitamin D in the treatment regimen, and the treatment group received only 480 mg per day of elemental calcium, an amount lower than that recommended for fracture prevention. This study also had a low adherence rate and a high withdrawal rate (11.3%).

Porthouse et al.[20] evaluated 3314 elderly women with one or more self-reported risk factors for hip fracture, including a history of previous fracture, low body weight (less than 58 kg), a maternal history of hip fracture, tobacco use, and poor or fair health. Participants randomized to the treatment group received 500 mg of elemental calcium (calcium carbonate) and 400 IU of vitamin D3 twice daily, advice on fracture risk reduction by a general-practice clinic nurse, and a leaflet on how to obtain recommended amounts of calcium and vitamin D from dietary sources and how to prevent falls; the control group received only the leaflet. The exclusion criteria included a daily intake of more than 500 mg of calcium supplementation prior to randomization; however, self-reported dietary intake of calcium was close to 1100 mg per day. Study participants had no baseline or follow-up BMD measurements. They were followed for a median of 25 months, and only 3.5% withdrew from the study. No significant difference was found in the rates of all fractures, hip fractures, or combined hip and wrist fractures between the intervention and control groups. The researchers concluded that in women with one or more risk factors for osteoporotic fracture, using calcium and vitamin D supplementation does not reduce the risk of such fractures. However, they stated that the study results do not rule out the possibility of a clinically significant benefit given the wide confidence intervals reported.

Limitations of the study by Porthouse et al.[20] included the lack of a placebo group; a lower-than-anticipated fracture rate in the control group (projected rate of 10%, actual rate of 5%), which lowered the statistical power to detect a difference in fracture risk between the calcium and control groups; the low adherence rate; the high average baseline calcium intake; and the relatively short follow-up of two years.

The final study included in this review, conducted by researchers based in the United Kingdom, included 5292 participants (85% women) with a previous osteoporotic fracture.[21] The purpose of this study was to determine if use of calcium or vitamin D alone or in combination can prevent secondary fractures. The exclusion criteria included daily use of more than 200 IU of vitamin D or more than 500 mg of calcium via supplements; use of fluoride, bisphosphonates, calcitonin, tibo-lone, hormone replacement therapy, or selective estrogen-receptor modulators during the previous five years; and having received vitamin D by injection during the previous year. The participants were randomized to one of four protocols: 800 IU of vitamin D3, 1000 mg of calcium carbonate, plus 1000 mg 800 IU of vitamin D3 of calcium, or placebo. BMD was not reported at baseline or follow-up in this trial. Participants were followed for a median of 45 months, and only about 1% withdrew from the study by 24 months; an additional 35.8% of patients discontinued the use of the medication by month 24 but still provided data for the main outcome.

No differences were seen in the rate of new fractures among the different treatment groups. There were also no differences in treatment outcomes between adherent versus nonadherent patients. In reporting the study results, the researchers concluded that calcium and vitamin D, alone or in combination, are not effective for preventing secondary osteoporotic fractures. Limitations of this study included the lack of baseline calcium intake evaluations and a poor adherence rate of 60%.[21]

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