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.

Implications for Clinical Practice

In the WHI study, more women taking calcium and vitamin D developed kidney stones compared with women in the placebo group (449 versus 381, respectively; HR, 1.17; 95% CI, 1.02–1.34).^[17] An increase in kidney stones in study subjects taking calcium was not reported in the other studies, but significantly more constipation and gastrointestinal adverse effects were reported in subjects treated with calcium.^[18,19,21] Porthouse et al.^[20] did not report on adverse effects.

When applying the results of these five trials to clinical practice, there are several issues to consider. The first is that adherence rates were low (55–60%) in all of the studies. When nonadherent participants were excluded from analysis, significant reductions in fracture rates were seen in three of the five studies.^[17–19] Poor adherence may be one key reason fracture reduction did not reach statistical significance in the intention-to-treat analyses.

In two of the studies, the statistical power to detect the primary outcome of decreased fractures was lower than planned due to lower-than-predicted observed fracture rates.^[17,20] A number of factors could have contributed to this, including evaluation of women at low risk for osteoporotic fracture in the WHI study^[17] and high calcium intake at baseline. Also, if supplementation was allowed in the control group, or if the dietary calcium intake was high, the participants randomized to placebo may have been, in effect, taking the same amount of calcium as those in the intervention group. This would reduce the possibility of detecting a difference in fracture rates between the two groups.

In four of the five studies, subjects enrolled in the treatment group were given calcium carbonate, a substance that requires an acidic environment for absorption and may not be an optimal source of calcium for the elderly.^[17,19–21] Porthouse et al.^[20] did not specify whether the calcium carbonate used in their study was taken with meals, an important determinant of calcium absorption. In other studies, participants were instructed to take calcium supplementation with meals;^[17,19,21] if they were also consuming calcium from dietary sources, they were probably absorbing only about 500 mg of elemental calcium per meal, and any additional calcium intake likely conferred no benefit.^[27,32] Also, in three of the studies, vitamin D was not included in the treatment arm^[17] or was used in amounts insufficient for optimal calcium absorption.^[18,19] Vitamin D is known to increase calcium absorption,^[33] and combined use of both substances has been shown to reduce the risk of fractures.

Most medications to prevent or treat other diseases are available by prescription only. Because calcium supplements can be obtained without a prescription, they may not be perceived as medication by many in the general public, and their use may be considered optional. Our patients should be informed that they must take calcium and vitamin D supplements consistently and as recommended if they are to attain any potential benefit in decreased fracture risk.

There is minimal risk associated with the use of calcium supplements. Although its impact on fracture risk is uncertain, calcium supplementation appears to confer some preventive benefits in women who are adherent to therapy. The cost and resulting morbidity and mortality of an osteoporotic fracture are great. In light of these factors, it is suggested that postmenopausal women who are unable to achieve the recommended daily amount of calcium through diet alone continue to use calcium supplementation. Pharmacists can play a key role educating women on the importance of good adherence in achieving the benefits of calcium supplementation.

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Cite this: Calcium Supplementation in Postmenopausal Women to Reduce the Risk of Osteoporotic Fractures - Medscape - Feb 15, 2011.

Table 1. Randomized Controlled Trials Evaluating Effects of Calcium Supplementation on Fracture Risk in Postmenopausal Women^a
Reference	Study Population	Treatment	BMD Changes per Intention-to-Treat Analysis	Effects on Incident Fractures or Fracture Risk
Reference	Study Population	Treatment	BMD Changes per Intention-to-Treat Analysis	Per Intention-to-Treat Analysis	Per Protocol Analysis
10	78 healthy women; mean age, 58 yr; median dietary calcium intake, 700 mg at baseline, 670 mg at 2 yr, 640 mg at 4 yr	Calcium lactate–gluconate + calcium carbonate (1,000 mg elemental calcium) daily or placebo for 4 yr	Increase in total body BMD over 4 yr greater with calcium vs. placebo (p = 0.002). Significant treatment effects also seen over 4 yr at lumbar spine (p = 0.03), femoral neck (p = 0.03), and trochanter (p = 0.01)	Incident fractures (all sites) Calcium: 2 Placebo: 7 (p < 0.05)	NA
11	197 women, 47% with preexisting fractures; mean age, 74 yr; mean baseline dietary calcium intake, 432 mg	Calcium carbonate (480 mg elemental calcium) per day or placebo for 4.3 ± 1.1 yr	Change in forearm BMD with preexisting fracture Calcium: 0.31% ± 0.25% per yr (p < 0.05) Placebo: −1.24% ± 0.38% per yr Change in forearm BMD with no preexisting fracture Calcium: 0 ± 0.26% per yr (p > 0.05) Placebo: −0.39% ± 0.27% per yr	Incident fractures with preexisting fracture Calcium: 15 Placebo: 21 (p < 0.05) Incident fractures with no preexisting fracture Calcium: 12 Placebo: 13 (p > 0.05)	NA
12	2,790 healthy women; mean age, 84 yr; baseline dietary calcium intake, 513 mg	Tricalcium phosphate (1,200 mg elemental calcium) + 800 IU vitamin D₃ per day or placebo for 1.5 yr	Change in femoral neck BMD at 1.5 yr Calcium: 2.7% Placebo: −4.6% (p < 0.001)	Nonvertebral fractures (no.) Treatment: 160 Placebo: 215 (p < 0.001) Hip fractures (no.) Treatment: 80 Placebo: 110 (p < 0.05)	Subgroup analysis (n = 1,765) of new fracture incidence, by fracture site Nonvertebral Treatment: 66 Placebo: 97 (p < 0.05) Hip Treatment: 21 Placebo: 37 (p < 0.05)
13	2,303 healthy women; mean age, 84 yr; baseline dietary calcium intake, 513 mg	Tricalcium phosphate (1,200 mg elemental calcium) + 800 IU vitamin D₃ per day or placebo for 3 yr	Not reported	Nonvertebral fractures (no.) Treatment: 255 Placebo: 308 (p < 0.05) OR for decreased probability of fracture, 0.72 (95% CI, 0.50–0.84) Hip fractures (no.) Treatment: 137 Placebo: 178 (p < 0.05) OR for decreased probability of fracture 0.73 (95% CI, 0.62–0.84)	Subgroup analysis (n = 1,765) of probability and OR (treatment vs. placebo) of new fracture, by fracture site/type Nonvertebral: −24% (p < 0.01); OR, 0.70 (95% CI, 0.51–0.91) Hip: −29% (p < 0.01); OR, 0.70 (95% CI, 0.62–0.78)
15	389 healthy women and men; mean age, 72 yr; baseline dietary calcium intake, 746 mg in women, 728 mg in men	Calcium citrate (500 mg elemental calcium) + 700 IU vitamin D per day or placebo for 3 yr	BMD change with treatment vs. placebo greater at femoral neck (0.5% vs. −0.7%; p = 0.02), lumbar spine (2.12% vs. 1.22%; p = 0.04), and for total body (0.06% vs. −1.09%; p < 0.001)	RR of first nonvertebral fracture with treatment vs. placebo, 0.4 (95% CI, 0.2–1.0; p < 0.05)	Cumulative incidence of first nonvertebral fracture Treatment: 5.9% Placebo: 12.9% (p < 0.05) RR (treatment vs. placebo) of first nonvertebral fracture, 0.5 (95% CI, 0.2–0.9)
16	583 women; mean age, 85 yr; baseline dietary calcium intake, 558 mg/day; baseline vitamin D intake, 41 IU/day	Tricalcium phosphate (1,200 mg elemental calcium) + 800 IU vitamin D₃ per day or placebo for 2 yr	Change in femoral neck BMD Calcium: 0.29% (p = 0.09) Placebo: −2.36%	Hip fracture incidence Treatment: 6.9% Placebo: 11.1% (p = 0.07) RR of hip fracture with treatment vs. placebo, 1.69 (95% CI, 0.96–3.00) Nonvertebral fracture incidence Treatment: 17.8% Placebo: 17.9% (difference NS)	NA
17, 30	36,282 healthy women; mean age, 62 yr; mean baseline calcium intake from all sources, 1,148–1,154 mg/day; mean baseline calcium intake from diet alone, 678 mg/day	Calcium carbonate (500 mg elemental calcium) + 200 IU vitamin D₃ twice daily or placebo for 9 yr	Increase in hip BMD at 9 yr 1.06% greater with treatment vs. placebo (p < 0.01); differences in spine and total body BMD changes with treatment vs. placebo at 9 yr NS	HR (treatment vs. placebo) for fracture, by fracture site Hip: 0.88 (95% CI, 0.72–1.08); NS Vertebra: 0.90 (95% CI, 0.74–1.10); NS Lower arm or wrist: 1.01 (95% CI, 0.90–1.14); NS All sites: 0.96 (95% CI, 0.91–1.02); NS	HR (treatment vs. placebo) for fracture, by fracture site Hip: 0.71 (95% CI, 0.52–0.97) Vertebra: 0.89 (95% CI, 0.67–1.19) Lower arm or wrist: 1.05 (95% CI, 0.90–1.23) Total fractures: 0.94 (95% CI, 0.87–1.02)
18	1,471 healthy women; mean age, 74 yr; baseline daily calcium intake, 861 mg in treatment group, 853 mg in placebo group	Calcium citrate (500 mg elemental calcium) twice daily or placebo for 5 yr	BMD increases at 5 yr with calcium vs. placebo 1.6% greater for hip (p < 0.0001), 1.8% greater for lumbar spine (p < 0.0001), and 1.2% greater for total body (p < 0.0001)	HR (treatment vs. placebo) for fracture, by fracture site/type Hip: 3.55 (95% CI, 1.31–9.63) Symptomatic: 0.91 (95% CI, 0.71–1.17); NS Osteoporotic: 0.87 (95% CI, 0.67–1.14); NS Vertebra: 0.72 (95% CI, 0.44–1.18); NS Distal forearm: 0.64 (95% CI, 0.40–1.03); NS	HR (treatment vs. control) for fracture, by fracture site/type Hip: 2.12 (95% CI, 0.72–6.19) Symptomatic: 0.87 (95% CI, 0.67–1.14); NS Osteoporotic: 0.83 (95% CI, 0.62–1.10); NS Vertebra: 0.61 (95% CI, 0.33–1.11); NS Distal forearm: 0.43 (95% CI, 0.22–0.85)
19	1,460 women; mean age, 75 yr; baseline daily calcium intake, 909 mg in treatment group, 934 mg in placebo group	Calcium carbonate (240 mg elemental calcium) twice daily or placebo for 5 yr	NA	HR (treatment vs. placebo) for fracture, by site Upper limb: 0.93 (95% CI, 0.56–1.54); NS Wrist or hand: 1.10 (95% CI, 0.60–2.02); NS Rib or pelvis: 0.99 (95% CI, 0.55–1.78); NS Proximal femur: 1.84 (95% CI, 0.68–4.96); NS Lower limb: 0.58 (95% CI, 0.32–1.03); NS Any appendicular site: 0.88 (95% CI, 0.65–1.18); NS Spine: 0.98 (95% CI, 0.63–1.54); NS Any site: 0.87 (95% CI, 0.67–1.12); NS	HR (treatment vs. placebo) for fracture, by fracture site Upper limb: 0.44 (95% CI, 0.21–0.92) Any appendicular site: 0.65 (95% CI, 0.43–0.97) Any site: 0.66 (95% CI, 0.45–0.97) Wrist or hand: 0.81 (95% CI, 0.35–1.88); NS Rib or pelvis: 0.71 (95% CI, 0.33–1.55); NS Proximal femur: 1.64 (95% CI, 0.39–6.87); NS Lower limb: 0.54 (95% CI, 0.25–1.18); NS Spine: 1.10 (95% CI, 0.42–2.84); NS
20	3,314 women with at least one risk factor for osteoporosis; mean age, 77 yr; baseline daily calcium intake, 1,075–1,084 mg	Calcium carbonate (500 mg elemental calcium) + 400 IU vitamin D twice daily for 2 yr + informational leaflet or leaflet only	NA	HR (treatment vs. control) for fracture, by fracture site Hip: 0.75 (95% CI, 0.31–1.78); NS Hip and wrist: 0.89 (95% CI, 0.56–1.44); NS All fractures: 1.01 (95% CI, 0.71–1.43); NS	HR (treatment vs. control) for all fracture sites, 1.03 (95% CI, 0.68–1.56); NS
21	5,292 men and women (85% women) with previous osteoporotic fracture; mean age, 77 yr; baseline daily calcium intake not reported	Calcium carbonate (1,000 mg elemental calcium) alone vs. calcium carbonate + 800 IU vitamin D₃ or placebo for 2–5 yr	NA	HR for new low-trauma fracture, by treatment variable Calcium carbonate vs. no calcium carbonate: 0.94 (95% CI, 0.81–1.09); NS Vitamin D₃ vs. no vitamin D₃: 1.01 (95% CI, 0.88–1.17); NS Calcium carbonate + vitamin D₃ vs. placebo: 1.01 (95% CI, 0.75–1.36); NS	HR for new fracture, by treatment variable Calcium carbonate vs. no calcium carbonate: 1.01 (95% CI, 0.70–1.48) Vitamin D₃ vs. no vitamin D₃: 1.01 (95% CI, 0.70–1.45)

^aBMD = bone mineral density, CI = confidence interval, HR = hazard ratio, NA = not applicable, NS = not significant, OR = odds ratio, RR = relative risk.

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