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Calcium supplementation, hormone replacement therapy, and osteoporosis

Note: This report represents the medical/scientific literature on this subject as of June 1997.

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Resolution 503 (I-95), introduced by the Medical Student Section, asked:

That the American Medical Association [AMA] amend Policy 525.997 [AMA Policy Compendium] to read (additions italicized; deletion in brackets): "...Estrogens are effective in the treatment and/or prevention of vasomotor flushes, atrophic urogenital conditions, and (in conjunction with calcium supplementation) [probably] osteoporosis."

This resolution was referred to the Board of Trustees. 

The Council on Scientific Affairs (CSA) previously addressed the issue of calcium supplementation in CSA Report 3 (I-95), "Intake of Dietary Calcium to Reduce the Incidence of Osteoporosis" (PDF summary, 114 KB). A large body of evidence now supports the concept that calcium intake is an important determinant of bone mass at all phases of life. Calcium nutrition appears to influence the quantity of new bone accretion into the skeleton during growth, and may therefore be a determinant of peak bone mass in young adult life. Considerable evidence also supports the concept that calcium supplementation can slow bone loss in older adults, with the effects appearing to become greater as age increases. This report reviews and evaluates the supportive evidence for the utility of calcium supplementation along with standard pharmacological therapy for the prevention and treatment of osteoporosis.

Calcium supplementation

Childhood: Two recent controlled clinical trials in twins demonstrated that bone mass increases faster in growing twins supplemented with calcium compared to placebo-treated twins.1,2 In both studies this effect was seen primarily in prepubertal children, in part because at puberty

the effects of calcium become masked by the effects of the hormonal milieu. Since calcium is a major component of bone, adequate calcium intake is clearly necessary to ensure appropriate growth of the skeleton, along with other nutritional requirements. Furthermore, the efficiency of calcium absorption by the intestine is higher in young growing individuals than it is in mature adults.3 The data support the results of a cross-sectional evaluation of bone mass in adults (aged 30 to 39 years), which suggested that those with the greatest peak bone mass had the highest intakes of calcium, both as children and as young adults.4 The authors predicted that a lifelong  change in calcium intake from 800 to 1200 mg/day would result in a 6 percent increment in peak bone mass in the femoral neck. A 6 percent change equates to half of one standard deviation in bone mass. This change, if maintained into old age, would reduce the lifetime relative risk of hip fracture by approximately 25 percent.

Premenopausal women: Four controlled intervention studies5 in premenopausal women, of 1 to 3 years duration, suggested that calcium intakes between 1500 and 2500 mg/day will produce an annual mean percentage difference in bone mass of 1.32 percent (95 percent confidence limit=1.21-1.42) in several skeletal sites (radius, humerus, lumbar spine, total body). This modest difference in bone loss would be meaningful if it were continued for the entire premenopausal period.

Postmenopausal women: A 1990 meta-analysis of  6 calcium supplementation studies suggested that an intake of about 1200 mg/day of calcium would decrease bone loss by approximately 0.8 percent/year in the forearm and lumbar spine (no data for the hip were available) in women with a mean age of 54 years.6 A later review of calcium supplementation trials concluded that calcium supplementation is more effective in older postmenopausal women compared to women within 5 years of menopause, when the effects of estrogen deficiency dominate.7 Furthermore, bone mass at the hip and forearm was more responsive to calcium supplementation than the spine.

That such effects can be seen until very old age is supported by the data of Chapuy et al8 who provided supplemental calcium and vitamin D to elderly patients in France and were able to demonstrate a 20 percent reduction in the relative risk of hip fracture. These data also support the concept that secondary hyperparathyroidism, which occurs with increasing frequency as age advances, is an important determinant of bone loss, especially in the femoral neck. Secondary hyperparathyroidism probably occurs in most individuals due to declining calcium intake, decreasing intestinal calcium absorption efficiency, and declining renal function. Increasing calcium intake can largely overcome this phenomenon.

The original meta-analysis9 has extended to a total of 18 studies of calcium supplementation in postmenopausal women (mean duration=2.3 years) with a mean age of 59 years. When calcium intake is doubled from approximately 700 mg/day to 1500 mg/day, there is a 40 percent reduction in bone loss from the lumbar spine, from 0.9 percent in the placebo group to 0.4 percent loss with calcium supplementation. There was a much greater effect in the femoral neck and in the forearm, where there was no evidence of bone loss in the calcium-supplemented group in comparison to a loss of approximately 1 percent in the placebo group. 

Summary: Together, the data suggest that in growing children, in premenopausal women, and in postmenopausal women, increasing lifelong calcium intake to between 1000 and 1500 mg/day will have positive effects on bone mass and will presumably reduce the risk of fractures. Since fractures of the hip account for the majority of costs associated with osteoporosis, the effects of calcium on bone mass are likely to be both clinically meaningful and economically important.

Calcium and estrogens

There is clear evidence that estrogen deficiency causes bone loss and that estrogen intervention reverses that process by reducing bone turnover and re-establishing the balance between formation and resorption of bone.10 Calcium deficiency might be expected to exacerbate the effects of estrogen deficiency on the skeleton. However, it is unclear whether calcium intake needs to be increased when hormone replacement therapy (HRT) is given in order to obtain the maximum benefit on bone mass. In one small, open prospective study, a dose of 0.3 mg/day of conjugated equine estrogens (CEE) was more effective when calcium intake was increased to 1500 mg/day. The effect of this combination on bone mass was equivalent to the effect of 0.625 mg of CEE prescribed without calcium supplementation.11 No controlled, blinded clinical trials exist to determine if there is an additive or synergistic effect between calcium intake and HRT.

To determine whether estrogen effects on bone may be dependent on the level of calcium intake, the published literature has been analyzed.12 Only clinical trials of HRT in healthy postmenopausal women without secondary causes for osteoporosis that were published in the peer-reviewed literature, excluding observational studies, were considered. The outcome measure was bone mass measured by a standard technique, single or dual photon absorptiometry or dual energy x-ray absorptiometry. To allow evaluation across studies, changes in bone mass were assessed as percent change per year from baseline, and the effects in the calcium-supplemented estrogen-treated groups and the non-supplemented estrogen-treated groups were compared, using standard statistical tests. Inclusion was limited to those studies in which a dose of 0.625 mg CEE or its equivalent was provided.

Thirty-three studies11, 13-45 were found in the literature, of which 16 had used a calcium supplement, bringing the average total calcium intake to 1400 mg/day. Seventeen studies used estrogen alone, with an average total calcium intake of 600 mg/day. Baseline data for these studies were evaluated, and there were no significant differences for any important variable between the estrogen-alone and estrogen-plus-calcium groups (e.g., age, years since menopause, baseline bone mineral density, duration of study, etc.).

The estrogen response in the lumbar spine was greater when calcium supplementation was provided with estrogen. Calcium and estrogen led to an increase in lumbar spine of 3.63 percent per year as compared to estrogen alone, where the increase in lumbar spine bone mass was 2.37 percent per year (p=0.07). In the femoral neck, the average mean increment in bone mass was 2.4 percent per year when calcium supplementation was given with estrogen as compared to estrogen alone, where the annual increase in bone mass was 0.8 percent (p=0.04). In the forearm, estrogen alone led to an annual mean increase in bone mass of 0.57 percent in contrast to combination therapy where the annualized mean increment was 2.27 percent. Weighted means were calculated for the change in bone mass at each skeletal site, and results were similar to those reported above. This analysis suggests that calcium supplementation potentiates the positive effect of estrogen on bone mass.

These statements are based on an analysis of published data; however, this analysis is subject to the same biases that affect any review or meta-analysis of the literature. No attempt was made to find and include unpublished data.

Among postmenopausal women, the major contributor to bone loss is estrogen deficiency. The effects are maximal in the spine where surface area is greatest. Consequently, estrogen intervention has its greatest effect at that site. Analysis of the published data suggests that only a portion of vertebral bone loss can be considered calcium-sensitive, and it is partially masked by the more potent antiresorptive effects of estrogen. Bone loss in the femoral neck appears to continue into old age, suggesting a prolonged effect of estrogen deficiency and, probably, the addition of other insults to the skeleton. The demonstration that calcium supplementation can reduce bone loss at this site suggests that bone loss in the hip is related to known impairments in calcium supply and handling with increasing age. Consequently, it might be argued that HRT and calcium supplementation would have important separate impacts on bone loss at that site. That the effects of calcium superimposed on estrogen are more marked in the hip than at the spine is therefore not unexpected. It is consistent with analysis of calcium supplementation studies, where a greater effect in the hip than in the spine was also found.

Conclusion:  Several meta-analyses in a large body of literature now support the concept that calcium intake is an important determinant of bone mass throughout life. Since it is known that bone mass is the most important determinant of fracture risk, it follows that calcium supplementation may be expected to reduce the risk of fractures in the aging population. Furthermore, data support the concept that standard doses of estrogen (0.625 mg CEE or its equivalent) are effective in the preservation of bone mass in the spine. The addition of calcium can further increase the effectiveness. Furthermore, estrogen will produce significantly greater increments in bone mass in the femoral neck and in the forearm (i.e., peripheral sites) when calcium intake is increased to an average of 1400 mg/day. These data support the value of calcium supplementation along with standard antiresorptive therapy for osteoporosis.

Recommendations

The following statements, recommended by the Council on Scientific Affairs, were adopted by the AMA House of Delegates as AMA policy at the 1997 AMA Annual Meeting.

  1. That Policy 525.997 be amended to read: "Estrogens are effective in the treatment and/or prevention of cardiovascular disorders, vasomotor flushes, atrophic urogenital conditions, and probably osteoporosis."   
  2. Adequate calcium intake is essential in the prevention of osteoporosis during growth years. Maintenance of adequate calcium intake during the growth years, perimenopausal years, and post-menopausal years is extremely important. The effects of estrogen on bone density can be improved significantly by calcium supplementation, particularly for cortical bone such as in the femoral neck.   
  3. In the late postmenopausal period, increased calcium intake will improve bone density in those patients with calcium deficiency or poor absorption of calcium. Therefore, it follows that increasing dietary calcium, if necessary by calcium supplementation in proper doses, may be expected to decrease the risk of osteoporosis and fractures in the aging population. Increasing calcium intake also appears to potentiate the positive effects of estrogen on bone mass. Therefore, increased intake, including appropriate supplementation, is also important in patients on such osteoporosis therapies. 

References

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