Effect of Hormone Replacement Therapy on Bone Mineral Density in Postmenopausal Women with Mild Primary Hyperparathyroidism

Primary hyperparathyroidism occurs most frequently in postmenopausal women; the prevalence of this condition in such women may be as high as 3% [1]. The management of persons with mild disease is controversial. Although surgical intervention has been advocated for all affected patients [2], the recognition that the condition is asymptomatic in at least 50% of patients and that most persons who receive the diagnosis are elderly [3, 4] has led others to recommend a conservative approach if the condition causes no complications [5-7]. Interest in the effects of mild primary hyperparathyroidism on the skeleton has recently been increasing. Some investigators, but not all, have reported that the disorder is associated with osteopenia, which primarily affects cortical bone [8-15]; other reports have noted that the disorder is associated with an increased risk for osteoporotic fracture [16, 17]. Thus, asymptomatic primary hyperparathyroidism is considered to be one of the four indications for measurement of bone mineral density [18], and osteopenia in persons with primary hyperparathyroidism is considered an indication for surgical intervention [19]. However, medical therapies for osteopenia have not been rigorously assessed in patients with primary hyperparathyroidism. In eucalcemic elderly postmenopausal women, estrogen-progestin therapy (hormone replacement therapy) increases bone mineral density [20-23] and reduces the incidence of osteoporotic fractures [22, 24]. This treatment may have the same effects in women with primary hyperparathyroidism, but only limited data on this condition are available. Although high doses of estrogen suppress biochemical markers of bone turnover and reduce serum calcium levels in women with this disorder [25-27], cross-sectional studies of bone mineral density in affected women treated with estrogen have had conflicting results [28, 29]. In an uncontrolled study of postmenopausal women with primary hyperparathyroidism [30], norethisterone preserved bone mineral density of the forearm. However, because this agent has progestogenic and androgenic as well as estrogenic activity, these data are difficult to interpret. Because skeletal status now has an important influence on the management of persons with primary hyperparathyroidism, the efficacy of potential therapies in preventing bone loss must be clearly delineated. We report the results of a 2-year, randomized, double-blind, placebo-controlled study of the effect of hormone replacement therapy on bone mineral density in postmenopausal women with mild primary hyperparathyroidism. Methods Patients Seventy-three postmenopausal women with mild primary hyperparathyroidism were identified from the Auckland Hospital Endocrinology Clinic, to which most patients with this condition who live in the Auckland area are referred. In each patient, hypercalcemia was detected incidentally on routine blood testing, and primary hyperparathyroidism was confirmed by the presence of a concomitant elevation of serum ionized calcium and intact parathyroid hormone levels. No patient had a family history of hypercalcemia. Exclusion criteria were concurrent systemic illness; untreated thyroid disease; hepatic or renal dysfunction; undiagnosed genital bleeding; estrogen therapy within the past 6 months; any history of bisphosphonate or fluoride therapy; and current use of a glucocorticoid drug, an anticonvulsant agent, or a thiazide diuretic. Three patients were initially excluded on the basis of these criteria (two patients had histories of breast cancer and uterine cancer, and one patient was currently using glucocorticoid drugs). Information about the study was mailed to the remaining 70 women: Seven of these women could not be contacted, and 3 were ineligible for the study because they were taking estrogen. Of the 60 women who could be contacted and were eligible, 42 (70%) agreed to participate. Because no other selection criteria were applied, the patients are representative of postmenopausal women with mild hyperparathyroidism. None of the five patients receiving thyroid hormone replacement therapy had a suppressed serum thyroid-stimulating hormone level. Two patients who had previously received hormone replacement therapy had discontinued this treatment 18 and 11 years, respectively, before study entry. Study Protocol Patients were randomly assigned to receive either continuous combined therapy with conjugated equine estrogens, 0.625 mg/d, and medroxyprogesterone acetate, 5 mg/d, or identical placebo tablets for 2 years. Patients who had had hysterectomy were not given progestin. One woman in the hormone replacement therapy group, who developed substantial mastalgia while receiving 0.625 mg of conjugated estrogens per day, completed the protocol by consuming 0.3 mg/d. Randomization was done manually by an independent researcher who followed a predetermined strategy. The researcher documented the randomization and had no knowledge of the patients' clinical details. This person then supervised the dispensing of the appropriate medication into bottles labeled with the patient's study number. Treatment codes could be accessed only by this researcher and only after a patient was withdrawn from the study. No attempt was made to influence dietary habits during the study period. The women were seen 1, 2, 3, and 6 months after the study began and every 6 months thereafter until the study ended. The patients' medical history and compliance with trial medication (assessed by tablet counts) between visits were recorded at each 6-month visit. Patients with vaginal bleeding were referred to an independent clinician, who was then notified of the patient's treatment allocation. Placebo recipients with vaginal bleeding were to have endometrial biopsy; hormone recipients were routinely investigated only if bleeding occurred after they had been receiving therapy for 12 months. This practice is consistent with that used in our institution. Nine women (4 in the hormone replacement therapy group and 5 in the placebo group) withdrew from the study during the 2-year period. In the hormone replacement therapy group, 1 woman withdrew because of mood disturbance, 1 because of the development of thyrotoxicosis, 1 because of diffuse aching in the lower limbs, and 1 because of personal reasons. In the placebo group, 2 women withdrew because of personal reasons, 1 because of seronegative polyarticular arthritis, 1 because of renal impairment, and 1 because of symptomatic hypercalcemia that required parathyroidectomy. Thus, 33 women (17 receiving hormone replacement therapy and 16 receiving placebo) completed the protocol. The local ethics committee approved the study, and each patient gave written informed consent. Measurements Bone mineral density was measured using dual-energy x-ray absorptiometry (DPX-L, Lunar, Madison, Wisconsin). Scans of the whole body, lumbar spine (vertebrae L2 to L4), proximal femur, and forearm were obtained every 6 months and were analyzed using the manufacturer's software (version 1.3). The whole-body scans were used to assess the densities of the subregions as well as the density of the total body. In our laboratory, the precisions of these measurements of bone mineral density are 0.4% for the total body, 1.0% for the lumbar spine, 1.4% for the femoral neck, 2.9% for the Ward triangle, and 1.6% for the trochanter. Lateral spine radiography was done at study entry, and any deformed vertebrae were excluded from subsequent analysis. Calcium intake was determined by a validated food-frequency questionnaire [31]. The levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D (Nichols Institute, San Juan Capistrano, California) were measured at study entry. At baseline, 6 months, and 2 years, fasting blood samples were collected for measurement of serum levels of ionized calcium, phosphate, total alkaline phosphatase, and intact parathyroid hormone (Nichols Institute); second-urination fasting urine samples were also collected at these times for measurement of levels of hydroxyproline, N-telopeptides (Ostex International, Seattle, Washington), calcium, and creatinine. The methods used to measure these substances have been described previously [32]. Statistical Analysis We used the SAS statistical package (SAS Institute, Cary, North Carolina) for all statistical analyses. We compared baseline characteristics in the treatment groups using the Student t-test for continuous variables and the chi-square test for categorical variables. Data that were not normally distributed were appropriately transformed before analysis. Within-group changes in biochemical variables (at 6 months and 2 years) and bone mineral density (at 2 years only) from baseline were assessed using the Student t-test for paired data or the Wilcoxon signed-rank test for data that were not normally distributed. Differences between the study groups in absolute changes from baseline values in bone mineral density and biochemical variables were assessed by repeated-measures analysis of variance using data from all time points. For ease of presentation, bone density results are expressed as the percentage of the baseline value. We examined several covariates that putatively affect bone mineral density (including baseline values), but none was found to significantly influence the bone density response. With the exception of serum phosphate levels, results of between-group comparisons of the biochemical data did not significantly change when we included baseline values in the model. Because all comparisons were made a priori, we made no adjustment to . Only the results from the 33 women who completed the study were included in the main analyses. To accommodate an analysis of data from all patients, including those for whom observations were missing, the mixed SAS procedure (version 6.11) was used to estimate random-effects variables for a repeated-measures design. Maximum likelihood was used to estimat