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Effect of Low-Dose Hormone Replacement Therapy on Bone



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Am Fam Physician. 2000 Jan 15;61(2):525-526.

Osteoporosis prevention through the use of hormone replacement therapy (HRT) has been clearly documented. However, the dose-related side effects of HRT have limited its acceptance, and many times patients do not even fill their HRT prescriptions. In addition, the lowest available dosages of HRT have not been tested for efficacy in preventing bone loss, particularly in elderly women. Several studies have shown an inconsistent benefit in the prevention of bone loss with low-dose HRT. The lowest dosage that produces bone effects has been thought to be 0.625 mg of conjugated equine estrogens per day or the equivalent. Recker and associates hypothesized that spinal bone loss would be prevented in elderly, postmenopausal women who received continuous therapy with 0.3 mg per day of conjugated equine estrogen combined with 2.5 mg per day of medroxyprogesterone, supplemented by adequate calcium and vitamin D intake.

White women over age 65 with mild spinal bone mineral loss who had not previously received any other medication or treatment that would affect bone density were recruited for the study of three and one half years. Women who smoked more than 10 cigarettes per day, had vaginal thickening on transvaginal ultrasonography or had a history of breast cancer were excluded from the study.

A total of 128 women met study criteria and were randomly assigned to receive low-dose HRT or placebo. All patients noted to have calcium intakes of less than 1 g per day received calcium carbonate supplementation (300 mg of calcium per tablet) in an amount sufficient to raise their daily dietary intake of calcium to the 1-g level. Patients with low serum levels of 25-hydroxyvitamin D (less than 28.86 ng per mL [75 nmol per L]) received oral 25-hydroxyvitamin D supplementation in an amount sufficient to raise serum levels to at least 28.86 ng per mL. These levels were monitored and maintained throughout the study.

Bone mineral density of the spine increased significantly in the HRT-treated group. This increase occurred most rapidly during the first six months of therapy and peaked at three years, with an overall increase of 4 percent. The value at the end of the study was 3.23 percent. Radius bone mineral density also increased significantly in the HRT-treated group. Femoral neck bone density steadily increased in the HRT-treated group for the first one and one half years, then decreased somewhat by the end of the study. Overall, the treatment effect of bone mineral density did not reach statistical significance.

Of the 128 study participants, 107 completed the study; all dropouts occurred during the first year. The dropout rate was similar in both study groups. Side effects thought to be related to HRT were mild and brief. In the HRT-treated group, the most common side effect included vaginal spotting or a change in the nature of vaginal discharge. Most side effects from HRT disappeared within six months.

The authors conclude that continuous oral therapy with 0.3 mg per day of conjugated equine estrogen and 2.5 mg per day of medroxyprogesterone combined with adequate calcium and vitamin D intake has a significant bone-sparing effect in elderly women. The increase in bone mineral density demonstrated with low-dose HRT is equal to that reported with higher dosages of HRT. Undesirable side effects were rare and brief. The risk of endometrial cancer is likely to be less with lower doses of estrogen, but this requires further investigation.

Recker RR, et al. The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women. Ann Intern Med. June 1, 1999;130:897–904.



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