Ruth Ames

Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial

Objective To determine the effect of calcium supplementation on myocardial infarction, stroke, and sudden death in healthy postmenopausal women. Design Randomised, placebo controlled trial. Setting Academic medical centre in an urban setting in New Zealand. Participants 1471 postmenopausal women (mean age 74): 732 were randomised to calcium supplementation and 739 to placebo. Main outcome measures Adverse cardiovascular events over five years: death, sudden death, myocardial infarction, angina, other chest pain, stroke, transient ischaemic attack, and a composite end point of myocardial infarction, stroke, or sudden death. Results Myocardial infarction was more commonly reported in the calcium group than in the placebo group (45 events in 31 women v 19 events in 14 women, P=0.01). The composite end point of myocardial infarction, stroke, or sudden death was also more common in the calcium group (101 events in 69 women v 54 events in 42 women, P=0.008). After adjudication myocardial infarction remained more common in the calcium group (24 events in 21 women v 10 events in 10 women, relative risk 2.12, 95% confidence interval 1.01 to 4.47). For the composite end point 61 events were verified in 51 women in the calcium group and 36 events in 35 women in the placebo group (relative risk 1.47, 0.97 to 2.23). When unreported events were added from the national database of hospital admissions in New Zealand the relative risk of myocardial infarction was 1.49 (0.86 to 2.57) and that of the composite end point was 1.21 (0.84 to 1.74). The respective rate ratios were 1.67 (95% confidence intervals 0.98 to 2.87) and 1.43 (1.01 to 2.04); event rates: placebo 16.3/1000 person years, calcium 23.3/1000 person years. For stroke (including unreported events) the relative risk was 1.37 (0.83 to 2.28) and the rate ratio was 1.45 (0.88 to 2.49). Conclusion Calcium supplementation in healthy postmenopausal women is associated with upward trends in cardiovascular event rates. This potentially detrimental effect should be balanced against the likely benefits of calcium on bone. Trial registration Australian Clinical Trials Registry ACTRN 012605000242628.

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.

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.

Randomized Controlled Trial of Calcium Supplementation in Healthy, Nonosteoporotic, Older Men

BACKGROUND There is no consistent evidence, to our knowledge, that calcium supplementation affects bone mineral density (BMD) in men, despite male osteoporosis being a common clinical problem. METHODS To determine the effects of calcium supplementation (600 mg/d, 1200 mg/d, or placebo) on BMD in men, we conducted a double-blind, randomized controlled trial for a 2-year period at an academic clinical research center. A total of 323 healthy men at least 40 years old (mean age, 57 years) were recruited by newspaper advertisement. Complete follow-up was achieved in 96% of subjects. RESULTS The BMD increased at all sites in the group receiving calcium, 1200 mg/d, by 1% to 1.5% more than those receiving placebo. The results for the group receiving calcium, 600 mg/d, were not different from the placebo group at any BMD site. There was no interaction between the BMD treatment effect and either age or dietary calcium intake. There were dosage-related, sustained decreases in serum parathyroid hormone (P < .001), total alkaline phosphatase activity (P = .01), and procollagen type 1 N-terminal propeptide (P < .001) amounting to 25%, 8%, and 20%, respectively, in the group receiving calcium, 1200 mg/d, at 2 years. Tooth loss, constipation, and cramps were unaffected by calcium supplementation, falls tended to be less frequent in the group receiving calcium, 1200 mg/d, but vascular events tended to be more common in the groups receiving calcium vs the group receiving placebo. CONCLUSION Calcium, 1200 mg/d, has effects on BMD in men comparable with those found in postmenopausal women but a dosage of 600 mg/d is ineffective for treating BMD. TRIAL REGISTRATION actr.org.au Identifier: 012605000274673.

Evaluation of the FRAX and Garvan fracture risk calculators in older women

Fracture risk calculators estimate the absolute risk of osteoporotic fractures. We investigated the performance of the FRAX and Garvan Institute fracture risk calculators in healthy, older, New Zealand, postmenopausal women with normal bone mineral density (BMD) for their age. Fractures were ascertained in women initially enrolled in a 5‐year trial of calcium supplements and followed on average for 8.8 years. Baseline data (1422 women, mean age 74 years, mean femoral neck BMD T‐score –1.3) were used to estimate fracture risk during follow‐up using the FRAX and Garvan calculators. The FRAX–New Zealand tool was used both with and without baseline BMD. The discrimination of the calculators was assessed using the area under the curve (AUC) of receiver operating characteristic curves. The calibration was assessed by comparing estimated risk of fracture with fracture incidence across a range of estimated fracture risks and clinical factors. For each fracture subtype, the calculators had comparable moderate predictive discriminative ability (AUC range: hip fracture 0.67–0.70; osteoporotic fracture 0.62–0.64; any fracture 0.60–0.63) that was similar to that of models using only age and BMD. The Garvan calculator was well calibrated for osteoporotic fractures but overestimated hip fractures. FRAX with BMD underestimated osteoporotic and hip fractures. FRAX without BMD underestimated osteoporotic and overestimated hip fractures. In summary, none of the calculators provided better discrimination than models based on age and BMD, and their discriminative ability was only moderate, which may limit their clinical utility. The calibration varied, suggesting that the calculators should be validated in local cohorts before clinical use.

Vitamin D insufficiency and health outcomes over 5 y in older women

BACKGROUND Vitamin D insufficiency was shown to be associated with adverse musculoskeletal and nonskeletal outcomes in numerous observational studies. However, some studies did not control for confounding factors such as age or seasonal variation of 25-hydroxyvitamin D [25(OH)D]. OBJECTIVE We sought to determine the effect of vitamin D status on health outcomes. DESIGN Healthy community-dwelling women (n = 1471) with a mean age of 74 y were followed in a 5-y trial of calcium supplementation. 25(OH)D was measured at baseline in all women. Skeletal and nonskeletal outcomes were evaluated according to seasonally adjusted vitamin D status at baseline. RESULTS Fifty percent of women had a seasonally adjusted 25(OH)D concentration <50 nmol/L. These women were significantly older, heavier, and less physically active and had more comorbidities than women with a seasonally adjusted 25(OH)D concentration > or =50 nmol/L. Women with a seasonally adjusted 25(OH)D concentration <50 nmol/L had an increased incidence of stroke and cardiovascular events that did not persist after adjustment for between-group differences in age or comorbidities. Women with a seasonally adjusted 25(OH)D concentration <50 nmol/L were not at increased risk of adverse consequences for any musculoskeletal outcome, including fracture, falls, bone density, or grip strength or any nonskeletal outcomes, including death, myocardial infarction, cancer, heart failure, diabetes, or adverse changes in blood pressure, weight, body composition, cholesterol, or glucose. CONCLUSIONS Vitamin D insufficiency is more common in older, frailer women. Community-dwelling older women with a seasonally adjusted 25(OH)D concentration <50 nmol/L were not at risk of adverse outcomes over 5 y after control for comorbidities. Randomized placebo-controlled trials are needed to determine whether vitamin D supplementation in individuals with vitamin D insufficiency influences health outcomes. This trial was registered at www.anzctr.org.au as ACTRN 012605000242628.