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The Effect of Low-Dose Continuous Estrogen and Progesterone Therapy with Calcium and Vitamin D on Bone in Elderly Women: A Randomized, Controlled Trial

Robert R. Recker, MD; K. Michael Davies, PhD; Rachel M. Dowd, RN; and Robert P. Heaney, MD
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From Osteoporosis Research Center, School of Medicine, Creighton University, Omaha, Nebraska.

Ann Intern Med. 1999;130(11):897-904. doi:10.7326/0003-4819-130-11-199906010-00005
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Background: Hormone replacement therapy (HRT), the mainstay of osteoporosis prevention, is limited because of dose-related risks, side effects, and patient acceptance. The bone-sparing efficacy and tolerability of the lowest available doses of HRT have not been adequately studied in elderly women.

Objective: To determine the bone-sparing effect of continuous low-dose HRT in elderly women.

Design: Randomized, double-blind, placebo-controlled trial.

Setting: University osteoporosis research and clinical center.

Patients: 128 healthy white women (age > 65 years) with low bone mass recruited by word of mouth and by local advertisement. The principal eligibility criterion was spinal bone mineral density of 0.90 g/cm2 or less.

Intervention: Continuous therapy with conjugated equine estrogen, 0.3 mg/d, and medroxyprogesterone, 2.5 mg/d, or matching placebo. Sufficient calcium supplementation was given to bring all calcium intakes above 1000 mg/d in both groups; supplemental oral 25-hydroxyvitamin D was given to maintain serum 25-hydroxyvitamin D levels of at least 75 nmol/L in both groups.

Measurements: Bone mineral density of the spine, hip, total body, and forearm; serum total alkaline phosphatase and serum osteocalcin levels at 6-month intervals; and 24-hour urine creatinine and hydroxyproline excretion at baseline, 12 months, and 42 months.

Results: During 3.5 years of observation, spinal bone mineral density increased by 3.5% (P < 0.001) in an intention-to-treat analysis and by 5.2% among patients with greater than 90% adherence to therapy. Significant increases were seen in total-body and forearm bone density (P < 0.01). Symptoms related to HRT (breast tenderness, spotting, pelvic discomfort, and mood changes) were mild and short-lived.

Conclusions: Continuous low-dose HRT with conjugated equine estrogen and oral medroxyprogesterone combined with adequate calcium and vitamin D provides a bone-sparing effect that is similar or superior to that provided by other, higher-dose HRT regimens in elderly women. This combination is well tolerated by most patients.


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Figure 1.
Results of randomization.

HRT = hormone replacement therapy.

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Figure 2.
Percentage change in spine bone mineral density (BMD) (top left), femoral neck bone mineral density (bottom left), total-body bone mineral content (BMC) (top right), and forearm bone mineral density (bottom right) in the hormone replacement therapy group (diamonds) and placebo group (squares).PP

The effect of hormone replacement therapy was significant at all sites ( < 0.01) except the femoral neck ( = 0.19). Bone mass remained the same or increased in the placebo group at the spine, total body, and femoral neck and decreased at the forearm. Error bars represent SEs.

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Figure 3.
Total alkaline phosphatase level (top left), 24-hour urinary hydroxyproline:creatinine ratio (bottom left), osteocalcin level (top right), and 24-hour urinary calcium:creatinine ratio (bottom right) in the hormone replacement therapy group (diamonds) and placebo group (squares).

Values shown are the mean ± SE. The treatment effect of hormone replacement therapy was significant for all four bone markers. To convert alkaline phosphatase values to µkat/L, multiply by 0.01667. To convert osteocalcin values to nmol/L, multiply by 0.0171.

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