Issn Print: 0029-7828

Publication Date: 1995/05/01


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Parathyroid Hormone for the Prevention of Bone Loss Induced by Estrogen Deficiency

Joel S. Finkelstein; Anne Klibanski; Elizabeth H. Schaefer; Mark D. Hornstein; Isaac Schiff; Robert M. Neer

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Excerpt

Osteopenia is common in young women with hypogonadism caused by hyperprolactinemia, excessive exercise, anorexia nervosa, or hypothalamic amenorrhea. It also occurs in women with endometriosis or uterine leiomyomas who are treated with an analog of gonadotropin-releasing hormone (GnRH) to induce hypogonadism. This bone loss is reversible if treatment with the GnRH analog is limited to 6 months, but concern about permanent bone loss has prevented long-term treatment with GnRH analogs. Simultaneous treatment with calcitonin does not prevent spinal bone loss and the concomitant use of estrogen or a progestin may diminish the efficacy of the analog and progestins lower HDL levels. A treatment that prevented bone loss induced by the GnRH analog without compromising its benefits would be valuable. Although continuous administration of parathyroid hormone (PTH) decreases bone mass, intermittent administration increases bone formation more than it increases bone resorption, leading to increased bone mass. The authors hypothesized that the intermittent administration of low doses of PTH would prevent bone loss in young women with endometriosis who had hypogonadism induced by therapy with a GnRH analog.
Fifty women between the ages of 20 and 44 with symptomatic, laparoscopically proven endometriosis were studied. All women had normal serum calcium, phosphate, alkaline phosphatase, bilirubin, creatinine, thyroxine, thyrotropin, and prolactin concentrations. Oral contraceptives and danazol were discontinued for at least 2 months and GnRH-analog therapy was discontinued for at least 9 months before the start of the study. Thirteen normal women, 23 to 45 years of age, without endometriosis, who met all the other entrance criteria were also studied to determine whether bone densities and markers of bone turnover were normal in women with endometriosis.
Between days 6 and 10 of their menstrual cycles, the women had measurements of bone mineral density (BMD) of the radius, spine, and proximal femur. Hydroxyproline, free pyridinoline plus deoxypyridinoline, and creatinine levels in the second urine specimens obtained the morning after an overnight fast were measured and alkaline phosphatase, osteocalcin, calcium, phosphate, PTH, calcidiol, calcitriol, total and fractionated cholesterol, and estradiol concentrations in fasting serum samples were also obtained. The women's daily calcium intake, body-mass index, and percentage of body fat were also determined. Histories of the women's involvement in running, weight lifting, and aerobic exercise were obtained. The women with endometriosis were randomly assigned to receive either the GnRH analog nafarelin acetate at a dose of 200 microgram intranasally twice a day for 6 months (group 1, 22 women) or nafarelin acetate plus the fragment of human PTH consisting of the first 34 amino acids (hPTH-[1-34]) at a dose of 40 microgram (500 units) S.C. per day for 6 months (group 2, 28 women). The women were asked to maintain a daily calcium intake of approximately 1200 mg through diet and calcium carbonate supplements, but they were not asked to change their exercise habits. Forty women (20 in each group) completed the study and were reevaluated after 3 and 6 months, including assessments of side effects and reported relief of symptoms. BMD at the radius, lumbar spine, and femoral neck was determined by dual-energy x-ray absorptiometry. Measurements of the nondominant radius were made at the junction of the proximal two thirds and the distal one third of the radial shaft. Serum intact PTH and osteocalcin were measured with immunoradiometric assays. Serum calcidiol, calcitriol, and estradiol concentrations were determined by radioimmunoassay. Urinary hydroxyproline excretion was measured with automated spectrophotometric analysis. Urinary-free pyridinolines were measured with an enzyme-linked immunosorbent assay.
The clinical characteristics of the women are shown in Table 1.
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