Margaret C. Evans

Effect of Calcium Supplementation on Bone Loss in Postmenopausal Women

BACKGROUND The use of calcium supplements slows bone loss in the forearm and has a beneficial effect on the axial bone density of women in late menopause whose calcium intake is less than 400 mg per day. However, the effect of a calcium supplement of 1000 mg per day on the axial bone density of postmenopausal women with higher calcium intakes is not known. METHODS We studied 122 normal women at least three years after they had reached menopause who had a mean dietary calcium intake of 750 mg per day. The women were randomly assigned to treatment with either calcium (1000 mg per day) or placebo for two years. The bone mineral density of the total body, lumbar spine, and proximal femur was measured every six months by dual-energy x-ray absorptiometry. Serum and urine indexes of calcium metabolism were measured at base line and after 3, 12, and 24 months. RESULTS The mean (+/- SE) rate of loss of total-body bone mineral density was reduced by 43 percent in the calcium group (-0.0055 +/- 0.0010 g per square centimeter per year) as compared with the placebo group (-0.0097 +/- 0.0010 g per square centimeter per year, P = 0.005). The rate of loss of bone mineral density was reduced by 35 percent in the legs (P = 0.02), and loss was eliminated in the trunk (P = 0.04). Calcium use was of significant benefit in the lumbar spine (P = 0.04), and in Wards triangle the rate of loss was reduced by 67 percent (P = 0.04). Calcium supplementation had a similar effect whether dietary calcium intake was above or below the mean value for the group. Serum parathyroid hormone concentrations tended to be lower in the calcium group, as were urinary hydroxyproline excretion and serum alkaline phosphatase concentrations. CONCLUSIONS Calcium supplementation significantly slowed axial and appendicular bone loss in normal post-menopausal women.

Long-term effects of calcium supplementation on bone loss and fractures in postmenopausal women: A randomized controlled trial

PURPOSE To determine the long-term effects of calcium supplements or placebo on bone density in healthy women at least 3 years postmenopause. PATIENTS AND METHODS Eighty-six women from our previously reported 2-year study agreed to continue on their double-blind treatment allocation (1 g elemental calcium or placebo) for a further 2 years, with 78 women (40 on placebo) reaching the 4-year end point. Median (interquartile range) dietary calcium intakes for the whole group were 700 mg (range 540 to 910) per day at baseline, 670 mg (range 480 to 890) per day at 2 years, and 640 mg (range 460 to 880) per day at 4 years. The bone mineral density (BMD) of the total body, lumbar spine, and proximal femur was measured every 6 months by dual-energy, x-ray absorptiometry. RESULTS There was a sustained reduction in the rate of loss of total body BMD in the calcium group throughout the 4-year study period (P = 0.002), and bone loss was significantly less in the calcium-treated subjects in years 2 through 4 also (difference between groups 0.25% +/- 0.11% per year, P = 0.02). In the lumbar spine, bone loss was reduced in the calcium group in year 1 (P = 0.004), but not subsequently. There was, however, a significant treatment effect at this site over the whole 4-year period (P = 0.03). In the proximal femur, the benefit from calcium treatment also tended to be greater in the first year and was significant over the 4-year study period in the femoral neck (P = 0.03) and the trochanter (P = 0.01). Nine symptomatic fractures occurred in 7 subjects in the placebo group and 2 fractures in 2 subjects receiving calcium (P = 0.037). CONCLUSIONS Calcium supplementation produces a sustained reduction in the rate of loss of total body BMD in healthy postmenopausal women.

Effects of calcium supplementation on serum lipid concentrations in normal older women:: A randomized controlled trial

PURPOSE To determine the effect of supplementation with calcium citrate on circulating lipid concentrations in normal older women. SUBJECTS AND METHODS As part of a study of the effects of calcium supplementation on fractures, we randomly assigned 223 postmenopausal women (mean [+/- SD] age, 72 +/- 4 years), who were not receiving therapy for hyperlipidemia or osteoporosis, to receive calcium (1 g/d, n = 111) or placebo (n = 112) for 1 year. Fasting serum lipid concentrations, including high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, were obtained at baseline, and at 2, 6, and 12 months. RESULTS After 12 months, HDL cholesterol levels and the HDL cholesterol to LDL cholesterol ratio had increased more in the calcium group than in the placebo group (mean between-group differences in change from baseline: for HDL cholesterol, 0.09 mmol/L (95% confidence interval [CI]: 0.02 to 0.17; P = 0.01); for HDL/LDL cholesterol ratio, 0.05 (95% CI: 0.02 to 0.08; P = 0.001). This was largely due to a 7% increase in HDL cholesterol levels in the calcium group, with a nonsignificant 6% decline in LDL cholesterol levels. There was no significant treatment effect on triglyceride level (P = 0.48). CONCLUSION Calcium citrate supplementation causes beneficial changes in circulating lipids in postmenopausal women. This suggests that a reappraisal of the indications for calcium supplementation is necessary, and that its cost effectiveness may have been underestimated.

Hydrochlorothiazide reduces loss of cortical bone in normal postmenopausal women: a randomized controlled trial ☆

PURPOSE Thiazide diuretics reduce urine calcium excretion and might therefore reduce postmenopausal bone loss. In some, but not all, case-control studies, their use has been associated with a reduced incidence of hip fractures. We studied the effects of hydrochlorothiazide on bone loss in normal postmenopausal women. SUBJECTS AND METHODS We performed a randomized, double-blind, 2-year trial of the effects of hydrochlorothiazide (50 mg per day) and placebo on bone mineral density in normal postmenopausal women. Participants were not required to have either low bone mineral density or hypertension. Bone mineral density was measured using dual-energy x-ray absorptiometry. RESULTS One hundred eighty-five women entered the study, of whom 138 completed 2 years of follow-up. In an intention-to-treat analysis, hydrochlorothiazide produced significant benefits on bone mineral density of the total body (between-group difference at 2 years of 0.8%, 95% confidence interval [CI]: 0.3% to 1.3%, P <0.0001), legs (0.9%, 95% CI: 0.2% to 1.7%, P <0.0001), mid-forearm (1.2%, 95% CI: 0.2% to 2.2%, P = 0.02), and ultradistal forearm (1.7%, 95% CI: 0.1% to 3.2%, P = 0.04). There was no effect in the lumbar spine (0.5%, 95% CI: -0.5% to 1.6%) or femoral neck (0.2%, 95% CI: 1.3% to 1.7%). The between-group changes tended to be greatest during the first 6 months, except in the mid-forearm where there appeared to be a progressive divergence. An as-treated analysis produced similar results. Urine calcium excretion and indices of bone turnover decreased in the thiazide group, but parathyroid hormone concentrations did not differ between the groups. Treatment was tolerated well. CONCLUSIONS Hydrochlorothiazide (50 mg per day) slows cortical bone loss in normal postmenopausal women. It may act directly on bone as well as on the renal tubule. The small size of the effect suggests that thiazides may have a role in the prevention of postmenopausal bone loss, but that they are not an appropriate monotherapy for treating osteoporosis.

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.

Recovery of bone density in women who stop using medroxyprogesterone acetate

In order to determine whether the loss in bone density seen in users of depot medroxyprogesterone acetate is reversible, a comparative study was undertaken in three groups of women. Group 1 consisted of 14 women who had used the contraceptive for at least 3 years and then discontinued use. Group 2 was 22 longterm users, and Group 3 contained 18 women who had never used the drug and served as controls. Estrogen production resumed in all of the Group 1 women after discontinuation. Two bone density measurements were taken twice in each woman. At first measurement, lumbar spine density was an average of 9% lower in Groups 1 and 2 than in controls. At the second measurement, however, lumbar spine density had significantly increased in Group 1 while it remained the same for the other groups. No significant changes in femoral neck density were observed. Additional measurements in 8 women from Group 1 taken 2 years after discontinuation revealed a further significant increase in lumbar spine bone density. Thus, it was concluded that bone density loss is reversible, even in cases where women experience a significant weight loss after discontinuation.

Normal bone mineral density following cure of Cushing's syndrome

objective Both endogenous and exogenous glucocorti‐cold excess are well established as causes of osteoporosis. However, there are few data describing bone mineral density in these subjects following the restoration of normal steroid levels. The present study addresses this issue

Volumetric bone density of the lumbar spine is related to fat mass but not lean mass in normal postmenopausal women

We have previously found that fat mass but not lean body mass is related to bone mineral density (BMD) in women. In these and most other studies of the dependence of BMD on body composition, areal rather than volumetric bone density was measured. It is possible that the dependence of this variable on body size introduced a scale artifact that contributed to the previous findings. The present study addresses this issue by measuring thevolumetric density of the third lumbar vertebra from simultaneous anteroposterior (AP) and lateral scans using dual-energy X-ray absorptiometry in 119 normal postmenopausal women. Whole body fat and lean body mass were also measured using this technique. In the AP projection, BMD was similarly related to body weight and to fat mass (r=0.44,p<0.0001 for both) but not to lean body mass (r=0.17, NS). BMD in the lateral projection was less closely related to body composition than was AP BMD, but the greater impact of fat (r=0.25,p<0.01) than lean body mass (r=0.09, NS) was still evident. When AP or lateral BMDs were divided by height, arm span or the square root of the scan area to produce an index with the dimensions of volumetric density, the dependence of BMD on body weight and fat mass were not affected but the relationship to lean body mass was eliminated (−0.02<r<0.09). Similarly, the volumetric density of the third lumbar vertebra was related to fat mass (r=0.21,p=0.02) but not to lean body mass (r=0.01). It is concluded that BMD is related to fat mass and that previously reported associations between lean body mass and BMD are probably contributed to by a scaling factor arising from failure to measure volumetric bone density.

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

Bone mineral density of the proximal femur and lumbar spine in glucocorticoid-treated asthmatic patients

The importance of the proximal femur as a site of osteoporotic fractures, the development of techniques for bone mineral density (BMD) measurement at this site and the apparent selectivity of the osteopenic effects of glucorticoids have focused attention on the assessment of proximal femoral BMD in steroid-treated subjects. We have, therefore, measured BMD (Lunar DPX) in the lumbar spine and proximal femur of 31 asthmatic patients receiving long-term glucocorticoid therapy (mean ± SEM dose 16 ± 1 mg prednisone/day, mean duration 10 ± 2 years). BMD values expressed as the percentage of normal age- and sex-appropriate mean values, after weight adjustment, were as follows: lumbar spine 80 ± 2%, femoral neck 83 ± 2%, Wards triangle 78 ± 3% and trochanter 86 ± 2%. All these values were significantly less than control (p<0.0001) and the decrement in BMD was more marked in Wards triangle than at the other two femoral sites (p<0.05). In all regions BMD was unrelated to dose or duration of steroid treatment. It is concluded that there are reductions in the BMD of the lumbar spine and proximal femur in glucocorticoid-treated asthmatics, probably reflecting the mixed cortical/trabecular makeup of both regions.