Joanne P. Stapleton

The effect of the antiestrogen tamoxifen on bone mineral density in normal late postmenopausal women

PURPOSE To assess the effect of the antiestrogenic agent tamoxifen on bone mineral density in normal late postmenopausal women. METHODS A randomized, double-blind, placebo-controlled trial was performed with 57 healthy, late postmenopausal women (mean 11 +/- 7 years since menopause). Subjects were assigned to take either tamoxifen 20 mg/d or placebo for 2 years. Total body, lumbar spine, and proximal femoral (femoral neck, Wards triangle, trochanter) bone mineral densities were measured every 6 months using dual-energy x-ray absorptiometry. Serum and urine indices of bone turnover were measured at baseline, 6 months, and 2 years. RESULTS In the women given tamoxifen, the mean bone mineral density of the lumbar spine increased by 1.4%, while that in the women given placebo declined by 0.7% (P < 0.01 for difference between groups). Total body bone mineral density declined in both groups, but less so in the tamoxifen-treated women (P < 0.05). At both sites, the effect of tamoxifen was maximal after 1 year, with no further separation of the groups thereafter. There was no significant effect of tamoxifen on bone mineral density in the proximal femur. Tamoxifen produced significant falls in serum alkaline phosphatase (P < 0.0001), ionized calcium (P < 0.0001), and phosphate (P < 0.01), and in urinary excretion of hydroxyproline, n-telopeptides, and calcium (P < 0.05 for each). CONCLUSIONS In normal late postmenopausal women, tamoxifen at a dose of 20 mg/d exerts a small protective effect on bone mineral density, comparable in magnitude to that of calcium supplementation and less than that of either estrogen or the bisphosphonates. Tamoxifen is unlikely to supersede any of these therapies in the management of postmenopausal osteoporosis.

Body weight and bone mineral density in postmenopausal women with primary hyperparathyroidism.

Primary hyperparathyroidism is the third most common endocrine disorder and has its highest incidence in postmenopausal women [1]. The advent of multichannel biochemical analysis has led to the recognition that mild, asymptomatic disease occurs frequently [2], and the correct approach to the management of persons with such disease is much debated [3, 4]. In recent years, attention has focused on the long-term skeletal effects of primary hyperparathyroidism. Asymptomatic primary hyperparathyroidism is considered to be one of the four indications for bone mineral density measurement [5], and osteopenia in patients with primary hyperparathyroidism is regarded as an indication for surgical intervention [6]. Several investigators, using single-photon absorptiometry, have reported reductions in bone mineral content in the proximal forearm, a site of predominantly cortical bone [3, 7-17], but these reductions have not been a universal finding [18]. Few data have been reported on bone mineral density in the proximal femur, an important site of osteoporotic fracture, where a combination of cortical and trabecular bone is found. No data on total body bone mineral density in primary hyperparathyroidism have been reported. Both reduced [11, 12, 18] and normal [8, 16] values have been reported for bone mineral density at the trabecular-rich lumbar spine. Many of the investigators who have done bone mineral density studies [3, 8-15, 17, 18] have neither reported body weight in the study groups nor indicated what adjustment was made for this important determinant of bone density [19]. In our study, we did a comprehensive assessment of bone mineral density (including that for the proximal femur, the lumbar spine in the posteroanterior and lateral projections, and the total body) in a cohort of postmenopausal women with primary hyperparathyroidism and compared the results with those observed in healthy eucalcemic women. Methods Participants Postmenopausal women with mild, asymptomatic primary hyperparathyroidism were recruited by postal invitation from the Auckland Hospital Endocrinology Clinic and local general practices. Invitations were sent to 70 women, 7 of whom had moved and were not locatable, and 3 of whom were ineligible because they were taking estrogen. Of the 60 women who were both contactable and eligible, 41 (68%) agreed to participate. In each participant, hypercalcemia was detected incidentally during routine blood testing and primary hyperparathyroidism was confirmed by the presence of a concomitant increase in serum ionized calcium and intact parathyroid hormone. No participant had evidence of malignancy or a family history of hypercalcemia. None was taking any medication or had any disease other than primary hyperparathyroidism known to influence bone metabolism. Twenty-five patients (61%) were taking antihypertensive medications, and 7 (17%) had known ischemic heart disease. Five (12%) were currently employed. Controls Forty-three normal postmenopausal women from the same community as the patients with primary hyperparathyroidism provided control data. These participants were part of a larger group of healthy postmenopausal women who were recruited by newspaper advertisement and whose clinical and demographic characteristics have previously been reported [20]. Those who were similar in age to the patients with primary hyperparathyroidism were selected by an independent statistician, who was unaware of their bone mineral density and body weight, to provide an age-matched control group. None had any condition or was taking any medication known to influence bone metabolism. Three (7%) were taking antihypertensive medications, and 2 (5%) had known ischemic heart disease. Seven (16%) were currently employed. Bone Density and Body Composition Bone mineral density was assessed using a Lunar DPX-L dual-energy x-ray absorptiometer (Lunar Radiation Corporation, Madison, Wisconsin). Separate scans of the whole body, the lumbar spine in both the posteroanterior (L2-L4) and lateral projections (L3), and the proximal femur (femoral neck, Wards triangle, and trochanter) were done and analyzed using the manufacturers version 1.3 software. Because previous studies had often measured mid-radius bone mineral content, analyses of the bone mineral density of the arms subregion of the total body scans were done to provide an assessment of appendicular cortical bone. Total body fat mass and lean mass were also quantified from the whole body scans [21]. The precision (coefficient of variation) of the bone mineral density measurements in our laboratory was 0.4% for total body, 1.0% for posteroanterior lumbar spine, 3.1% for lateral lumbar spine, and 1.4% for femoral neck. The precision of the body composition measurements was 2.7% for total body fat mass and 0.8% for lean body mass. Android (waist) and gynoid (thigh) fat were measured by regional analysis of the total body scans [22]. The waist region was defined by a box whose superior border was the uppermost part of the 12th thoracic vertebra, whose inferior border was at the level of the iliac crests, and whose lateral borders were the outermost soft tissue to either side. The thigh region was defined by a box of equal dimensions, positioned so that its uppermost border was level with the inferior pubic rami. Fat distribution was assessed by calculating the ratio of android to gynoid fat in each participant. In the 43 controls, the android-to-gynoid fat ratio derived in this manner correlated with the waist-to-hip ratio as assessed by tape measure (r = 0.73, P < 0.0001). Radiologic Studies Lateral radiographs of the lumbar spine were obtained from each patient with primary hyperparathyroidism and each control. Any vertebrae affected by fracture were excluded from bone mineral density analysis. Biochemical Studies Intact parathyroid hormone concentrations were measured using a two-site immunoradiometric assay (Nichols Institute, San Juan Capistrano, California) with a coefficient of variation of 8% (normal range, 1 to 5 pmol/L). Ionized calcium was measured using an ion-specific electrode (Radiometer, Copenhagen, Denmark; normal range, 1.17 to 1.28 mmol/L). Body Mass Weight was measured using electronic scales; body mass index was calculated by dividing weight (kg) by the square of height (m). Socioeconomic Status Population census data were used to assign each study participant to one of five groups, according to average household income in their residential suburbs within the Auckland urban area [23]. Statistical Analysis Baseline data in the two groups were compared using the Student t-test and the chi-square test. Further analysis of the bone mineral density data was done using the GLM procedures of the SAS statistical package (SAS Institute, Cary, North Carolina). Least-squares mean bone mineral density values at each site were generated by analysis of covariance, with body weight as a covariate, and then the values of the controls were compared with those of patients with primary hyperparathyroidism. A significance level of = 0.05 was used for all analyses. Results are presented as mean SE unless otherwise specified. The study was approved by the Auckland Area Health Board Ethics Committee, and each participant gave written, informed consent. Results The mean (SD) ionized calcium level for patients with primary hyperparathyroidism was 1.42 0.08 mmol/L (range, 1.30 to 1.63 mmol/L); the mean level of parathyroid hormone was 9.4 4.7 pmol/L (range, 3.4 to 25.5 pmol/L). Clinical and body composition data for patients with primary hyperparathyroidism and controls are shown in Table 1. The two groups were comparable for age, height, and cigarette smoking. Patients with primary hyperparathyroidism weighed, on average, 9 kg more than controls. This difference was almost entirely due to an increased total body fat mass in the patients with primary hyperparathyroidism. Lean mass did not differ between the groups. The ratio of android-to-gynoid fat in patients with primary hyperparathyroidism was greater than that in the controls. No difference existed between patients with primary hyperparathyroidism and controls in socioeconomic status, which was assessed according to residential area (P = 0.3). Table 1. Clinical and Anthropometric Findings in Patients with Primary Hyperparathyroidism and in Controls* Body weight correlated with bone mineral density at all sites in the controls (0.52 < r < 0.69, P < 0.001) and with total body and proximal femoral bone mineral density in the patients with primary hyperparathyroidism (0.45 < r < 0.58, P < 0.005). Figure 1 shows the bone mineral density results, unadjusted for weight, in each of the two groups. There were no significant differences between the primary hyperparathyroidism group and the control group at any site. Figure 1. Unadjusted bone mineral density results in postmenopausal women with primary hyperparathyroidism (n = 41) and eucalcemic controls (n = 43). Bone mineral density results adjusted for body weight are shown in (Figure 2). After adjustment for body weight, total body, proximal femoral, and arm bone mineral densities were significantly lower in patients with primary hyperparathyroidism than in controls. The mean reduction was 6% in total body bone mineral density, 12% in femoral neck bone mineral density, 10% in Wards triangle bone mineral density, 7% in bone mineral density in the trochanteric region, and 7% in arm bone mineral density. No difference was found between patients with primary hyperparathyroidism and controls in spinal bone mineral density assessed in either projection. Figure 2. Bone mineral density results in postmenopausal women with primary hyperparathyroidism (n = 41) and eucalcemic controls (n = 43), adjusted for body weight. P P P Discussion Our study showed that postmenopausal women with primary hyperparathyroidism are significantly heavier, have greater total body fat mass, and have proportionally

Accelerated bone loss in post-menopausal women with mild primary hyperparathyroidism

OBJECTIVES Osteopenia is regarded as an indication for parathyroidectomy in primary hyperparathyroidism. However, uncertainty exists as to the extent and degree of the skeletal effects in those with mild disease. We sought to determine whether mild primary hyperparathyroidism affects the rate of bone loss in post‐menopausal women.