The effect of treatment with a thiazide diuretic for 4 years on bone density in normal postmenopausal women.

SUMMARY: We performed a 2-year extension of our previous 2-year randomized controlled trial of the effects of hydrochlorothiazide on bone mineral density. The improvements in bone density seen in the first 2 years were sustained throughout the extension study. Thiazides provide a further option in the prevention of postmenopausal bone loss. INTRODUCTION: Thiazide diuretics reduce urinary calcium excretion and therefore might prevent osteoporosis. Previously we reported a 2-year randomized controlled trial of hydrochlorothiazide treatment in 185 postmenopausal women that showed positive benefits of hydrochlorothiazide on bone density. Here, we report the results of a 2-year extension to that study. METHODS: Of 185 healthy postmenopausal women, 122 agreed to continue in a double-blinded 2-year extension taking 50 mg hydrochlorothiazide or placebo daily. Measurements of bone density occurred every 6 months and of calcium metabolism at 2 and 4 years. RESULTS: The improvements in bone density seen in the first 2 years of the trial were sustained throughout the extension. There were significant between-groups differences in the change in bone density over 4 years at the total body (0.9%, P<0.001), legs (1.0%, P=0.002), mid-forearm (1.1%, P=0.03), and ultradistal forearm (1.4%, P=0.04). At the lumbar spine (0.9%, P=0.76) and femoral neck (0.4%, P=0.53) the between-groups differences did not reach statistical significance. CONCLUSIONS: Hydrochlorothiazide produces small positive benefits on cortical bone density that are sustained for at least the first 4 years of treatment. They provide a further option in the prevention of postmenopausal bone loss, especially for women with hypertension or a history of kidney stones.

Determinants of vitamin D status in older men living in a subtropical climate.

INTRODUCTION: Previously we reported seasonal variation in 25-hydroxyvitamin D (25OHD) levels in postmenopausal women living in a subtropical climate. Because studies have suggested that there are gender differences in 25OHD levels, we sought to determine (1) the levels and determinants of 25OHD in men drawn from the same community, (2) whether seasonal variation of 25OHD occurs in men at this latitude (37 degrees S), and (3) whether these findings were comparable to those we previously observed in postmenopausal women. METHODS: Cross-sectional study of 378 healthy, middle-aged and older community-dwelling men in Auckland, New Zealand. RESULTS: The mean 25OHD (SD) level was 85 (31) nmol/l. We found significant seasonal variation in 25OHD levels (peak in autumn 103 nmol/l, nadir in spring 59 nmol/l). Vitamin D insufficiency (25OHD <50 nmol/l) was uncommon (prevalence in summer 0-17%, in winter 0-20%). The major determinants of 25OHD were month of blood sampling, fat percentage, physical activity, and serum albumin. Men had higher levels of 25OHD throughout the year than women did, a finding that persisted after adjusting for potential confounding factors. In men and women the determinants of 25OHD were similar. CONCLUSION: There is significant seasonal variation in 25OHD levels in men living in a subtropical climate. In contrast to postmenopausal women, men have low rates of suboptimal vitamin D status, even in winter. Routine vitamin D supplementation for this population of men is not warranted.

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 past use of the injectable contraceptive depot medroxyprogesterone acetate on bone mineral density in normal post-menopausal women.

OBJECTIVE: Depot medroxyprogesterone acetate (DMPA), an injectable progestogen, is a widely used contraceptive acting primarily by inhibiting secretion of pituitary gonadotrophins, thus producing oestrogen deficiency. Cross-sectional and prospective studies in pre-menopausal women have shown DMPA use to be associated with reduced bone density, but bone density increases following discontinuation of the drug. Because fracture rates are low in pre-menopausal women, the principal concern arising from the effects of DMPA on bone is that there may be residual osteopenia in former users such that their post-menopausal fracture risk is increased. The present study addresses this question. DESIGN: Cross-sectional study of bone density in post-menopausal former users of DPMA and controls. SUBJECTS: Three hundred and forty-six normal post-menopausal women, of whom 34 had previously used DMPA. The median age at which DMPA use began was 41 years and the median duration of use was 3.0 years. MEASUREMENTS: Bone density was measured in the spine, proximal femur and total body by dual-energy, X-ray absorptiometry. RESULTS: There were no significant differences in bone density at any site between the women who had previously used DMPA and the others in the cohort. However, in those who had used DMPA for > 2 years there was a trend towards bone densities being lower in the former users, the differences from non-users being 1.6% in the lumbar spine (P = 0.6), 3.1% in the femoral neck (P = 0.4) and 0.5% in the total body (P = 0.8). There was no correlation between bone densities and the duration of DMPA use, the age at discontinuation of DMPA, or the time between DMPA discontinuation and the menopause. CONCLUSIONS: Any residual effects of depot medroxyprogesterone acetate use on post-menopausal bone density are small and therefore unlikely to have a substantial impact on fracture risk in the post-menopausal years.

PIP: The possibility that use of depot medroxyprogesterone acetate (DMPA) has residual effects on postmenopausal bone mineral density was assessed in a cross-sectional study of 346 postmenopausal former users of DMPA and controls from Auckland, New Zealand. 34 women (10%) reported past use of DMPA, for a median duration of 3 years, starting at a median age of 41 years. Dual-energy, x-ray absorptiometry failed to reveal significant differences between past users of DMPA and never-users in bone density in the spine, proximal femur, or total body. However, in women who had used DMPA for more than 2 years, there was a nonsignificant trend toward lower bone densities in former users compared with never-users. The difference between mean measurements was 1.6% in the lumbar spine (p = 0.6), 3.1% in the femoral neck (p = 0.4), and 0.5% in the total body (p = 0.8). There was no correlation between bone densities and the duration of DMPA use, age at discontinuation of DMPA use, or the time between DMPA discontinuation and menopause. These findings suggest that any residual effects of DMPA use on postmenopausal bone density are likely to be small and without a substantial impact on fracture risk.

Premature hair graying and bone mineral density.

In a recent case-control study, premature hair graying was found to be associated with osteopenia, suggesting that this might be a clinically useful risk factor for osteoporosis. We report a reexamination of this possibility in 293 healthy postmenopausal women. Subjects experiencing onset of hair graying in their 20s tended to have lower bone mineral density throughout the skeleton (adjusted for age and weight) than those with onset of graying later in life. The same was true for those in whom the majority of their hair was gray by the age of 40 yr (n = 16), in whom bone density was reduced by 7% in the femoral neck, 8% in the femoral trochanter, and 4% in the total body (P < 0.05) when compared with those not prematurely gray. Bone density at the lumbar spine and Ward's triangle showed similar trends that were not significant. However, premature hair graying explained only 0.6-1.3% of the variance in bone mineral density within the population. We conclude that premature hair graying is associated with low bone density, but that its infrequency in the normal postmenopausal population leads to its accounting for only a tiny fraction of the variance of bone density.

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, Ward's 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.

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.

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 the volumetric 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 was 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).(ABSTRACT TRUNCATED AT 250 WORDS)

Determinants of the rate of bone loss in normal postmenopausal women.

Despite a large number of studies assessing relationships between putative risk factors and bone density, it is not known which factors influence the rate of axial bone loss in normal postmenopausal women. We have examined the relationships between the rate of bone loss (delta BMD) and variables related to calcium metabolism, lifestyle, diet (calcium, sodium, caffeine, and protein), body composition, muscle strength, sex hormones, and spinal osteophytosis in 122 normal postmenopausal women participating in a 2-yr prospective randomized placebo-controlled trial of calcium supplementation. Univariate correlation coefficients indicated that delta BMD at most sites was inversely related to baseline BMD and positively related to rate of change in body weight (0.10 < r < 0.36) and fat mass (0.11 < r < 0.42) during the study. Lean mass and its rate of change showed no consistent relationship to delta BMD. There was no correlation between delta BMD and any of the lifestyle, muscle strength, dietary, or hormonal indices or with the severity of spinal osteophytosis. Multiple regression analysis indicated that delta BMD in the total body was directly related to fat mass (P < 0.0001), the rate of change in fat mass (P < 0.0001), the renal tubular reabsorption of calcium (P < 0.01), and calcium treatment (P < 0.01) and inversely to the initial BMD (P < 0.0001; r2 = 0.42; P < 0.0001). Similar effects were seen throughout the skeleton, although the fraction of the variance accounted for was less in the subregions, consistent with the lower precision of measurement of regional bone density. It is concluded that baseline bone density, fat mass, and renal calcium handling are important factors influencing bone loss in normal postmenopausal women.

Circulating insulin levels are related to bone density in normal postmenopausal women.

We recently established that the dependence of bone mineral density (BMD) on body weight in women is mainly attributable to a close relationship between total body fat mass and BMD. The present study assesses whether this latter relationship might be contributed to by the hormones insulin or amylin, both of which may influence fat mass and calcium metabolism. Fifty-three normal postmenopausal women underwent a 75-g glucose tolerance test with measurement of plasma insulin and amylin concentrations every 30 min for 2 h. Body composition and BMD/height (to provide a quantity with the dimensions of volumetric density that is independent of body size) were measured by dual-energy X-ray absorptiometry, and volumetric density of the third lumbar vertebral body was calculated. Circulating insulin concentrations correlated with BMD/height and volumetric density of the third lumbar vertebral body (r = 0.28-0.52). They also were related to body weight (r = 0.34-0.56) and fat mass (r = 0.38-0.56) but were not independently related to lean mass on multiple regression. There were no consistent relationships between amylin levels and these variables. Multiple-regression analyses with fat mass and insulin levels as independent variables indicated that BMD/height of total body and femoral trochanter were primarily related to fat mass, whereas, in femoral neck, the significant relationship was with insulin. Volumetric density of the third lumbar vertebral body was related to insulin levels alone on this analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone mineral density and body composition in adult patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis is a multisystem disease characterised by chronic pulmonary sepsis and malnutrition. To ascertain whether osteoporosis is a feature of cystic fibrosis in adult patients, total body and regional bone mineral density (BMD) was measured in a group of eight men and eight women aged 17-42 years. METHODS: Total body and regional BMD (lumbar spine L2-L4, femoral neck, trochanteric, and Ward's triangle), as well as total body fat and lean mass, were measured by dual energy x ray absorptiometry. A range of biochemical, lifestyle, and anthropometric variables was also assessed. RESULTS: Patients with cystic fibrosis had significantly reduced bone density at all sites compared with normal young adults. The mean reductions ranged from 7% at Ward's triangle to 13% at the trochanter. Body mass index (BMI) was positively correlated with BMD at four sites and disease severity negatively correlated with BMD at two sites. Other biochemical and anthropometric variables were not predictive of bone density. Total body fat mass was reduced by 30% compared with normal young adults. CONCLUSIONS: Bone density is decreased in adult patients with cystic fibrosis and BMI and disease severity are independent predictors of bone density.

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 Ward's 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.

Intraluminal chemistry of zinc in milks.

The solubility of both free and low molecular weight ligand complexed calcium, magnesium, and zinc in skimmed human and bovine milks over intestinal luminal pH ranges (approximately 3-7) was measured using ultrafiltration techniques. Some of the experimental difficulties associated with the separation of labile metal ion ligand components from milks by ultrafiltration techniques are discussed. Experimental methods designed to minimize interferences in mineral ultrafiltrations from milks are outlined. Mineral solubilities in skimmed human and bovine milks are compared to data obtained in a previous study using milk models. The solubility of zinc in both skimmed bovine and bovine model milks is less than in human and human model milks at the higher pHs, characteristic of the luminal region where zinc absorption is thought to occur. The decrease in zinc solubility is caused by the coprecipitation of zinc with calcium phosphate, particularly in bovine milk samples. If solubility at the higher pHs is a requisite for zinc absorption then the enhanced bioavailability of zinc from human milk may be related to the detrimental element-compound interaction discussed in this study.

Effect of pH on the speciation and solubility of divalent metals in human and bovine milks.

Computer models estimated the ligand speciation and solubility of calcium, magnesium, zinc, and copper over a pH range for low molecular weight fractions characteristic of either human or bovine milks. Above pH 4 calcium is the only metal predicted to precipitate. Most of the remaining soluble calcium, magnesium, and zinc should be complexed with citrate. The solubility of calcium, magnesium, and zinc in human and bovine milks was measured experimentally from pH 2 to 7. The solubility of all three metals decreased as the pH increased. Calcium and zinc were soluble over a narrower pH range in bovine milk than in human milk. Increasing the levels of either calcium or inorganic phosphate alone in decaseinated human milk did not affect the solubility of zinc, but when both calcium and inorganic phosphate were added at levels comparable to bovine milk the solubility of zinc decreased at the higher pH's. The decreased solubility of zinc in skimmed milks in pH's characteristic of the small intestine is likely due to coprecipitation of zinc with calcium phosphate--a reaction not predicted for milk systems from known chemical solubility product data.