Anne Horne

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.

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.

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.

Imatinib promotes osteoblast differentiation by inhibiting PDGFR signaling and inhibits osteoclastogenesis by both direct and stromal cell-dependent mechanisms.

Several lines of evidence suggest that imatinib may affect skeletal tissue. We show that inhibition by imatinib of PDGFR signaling in osteoblasts activates osteoblast differentiation and inhibits osteoblast proliferation and that imatinib inhibits osteoclastogenesis by both stromal cell‐dependent and direct effects on osteoclast precursors.

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.

Effects of calcium supplementation on lipids, blood pressure, and body composition in healthy older men: a randomized controlled trial

BACKGROUND Calcium supplementation has been suggested to have beneficial effects on serum lipids, blood pressure, and body weight, but these possibilities have not been rigorously assessed in men. OBJECTIVE This study evaluated the effect of calcium supplementation on the change in the ratio of HDL to LDL cholesterol (primary endpoint) and on changes in cholesterol fractions, triglycerides, blood pressure, and body composition (secondary endpoints). DESIGN We carried out a randomized controlled trial of calcium supplementation in 323 generally healthy men over a period of 2 y. Subjects were randomly assigned to take placebo, 600 mg Ca/d, or 1200 mg Ca/d. RESULTS There was no significant treatment effect on the ratio of HDL to LDL cholesterol (P = 0.47) nor on weight, fat mass, lean mass, triglycerides, or total, LDL, or HDL cholesterol (P > 0.28 for all). There were downward trends in systolic and diastolic blood pressures within the calcium-supplemented groups, but there were no significant treatment effects over the whole trial period (P > 0.60). In a post hoc analysis of those with baseline calcium intakes below the median value (785 mg/d), blood pressures showed borderline treatment effects (P = 0.05-0.06 for changes at 2 y in those who received 1200 mg Ca/d compared with placebo: systolic, -4.2 mm Hg; diastolic, -3.3 mm Hg). Low magnesium intake showed a similar interaction. No treatment effects on weight or body composition were found. CONCLUSIONS These data do not show significant effects of calcium supplementation on serum lipids or body composition. Calcium supplementation in those with low dietary intakes may benefit blood pressure control. This trial was registered with the Australian Clinical Trials Registry as ACTRN 012605000274673.

The antiresorptive effects of a single dose of zoledronate persist for two years: a randomized, placebo-controlled trial in osteopenic postmenopausal women.

CONTEXT Annual iv administration of 5 mg zoledronate decreases fracture risk. The optimal dosing interval of 5 mg zoledronate is not known. OBJECTIVE Our objective was to determine the duration of antiresorptive action of a single 5-mg dose of iv zoledronate. DESIGN, SETTING, AND PARTICIPANTS We conducted a double-blind, randomized, placebo-controlled trial over 2 yr at an academic research center, in a volunteer sample of 50 postmenopausal women with osteopenia. INTERVENTION Intervention included 5 mg zoledronate. MAIN OUTCOME MEASURES Biochemical markers of bone turnover and bone mineral density of the lumbar spine, proximal femur, and total body. RESULTS Compared with placebo, zoledronate treatment decreased mean levels of each of four markers of bone turnover by at least 38% (range 38-45%) for the duration of the study (P < 0.0001 for each marker). After 2 yr, bone mineral density was higher in the zoledronate group than the placebo group by an average of 5.7% (95% confidence interval = 4.0-7.4) at the lumbar spine, 3.9% (2.2-5.7) at the proximal femur, and 1.7% (0.8-2.5) at the total body (P < 0.0001 for each skeletal site). Between-groups differences in markers of bone turnover and bone mineral density were similar at 12 and 24 months. Mild secondary hyperparathyroidism was present throughout the study in the zoledronate group. CONCLUSION The antiresorptive effects of a single 5-mg dose of zoledronate are sustained for at least 2 yr. The magnitudes of the effects on markers of bone turnover and bone mineral density are comparable at 12 and 24 months. Administration of zoledronate at intervals of up to 2 yr may be associated with antifracture efficacy; clinical trials to investigate this possibility are justified.

Relationships between vascular calcification, calcium metabolism, bone density, and fractures†

Factors involved with calcium metabolism, such as serum calcium and phosphate and calcium intake, have been associated with vascular disease in different populations. We investigated whether this association is mediated via increased vascular calcification by assessing relationships between these factors and abdominal aortic calcification (AAC) and coronary artery calcification (CAC). A total of 1471 healthy postmenopausal women participated in a 5‐year randomized, placebo‐controlled trial of calcium 1 g/day, and 323 healthy middle‐aged and older men participated in a 2‐year randomized, placebo‐controlled trial of calcium 600 or 1200 mg/day. AAC was assessed on vertebral morphometric images at baseline and follow‐up. Based on computed tomography, 163 men had CAC assessed, on average, 1.5 years after study completion. In elderly women, AAC was positively related to serum calcium (p < .001), phosphate (p = .04), and the calcium‐phosphate product (p = .003), but changes in AAC over time and incidence of cardiovascular events were not related to these variables. In middle‐aged men, AAC and CAC were not consistently related to these variables. Neither dietary calcium intake nor calcium supplementation was associated with changes in the prevalence of AAC over time, and calcium supplementation also was not related to CAC scores in men. After adjusting for age, AAC was not associated with low bone mineral density (BMD) at baseline, changes in BMD over time, or fracture incidence. CAC also was not related to baseline BMD. In summary, serum calcium and phosphate are associated with AAC in older women, but dietary calcium intake and calcium supplementation were not associated with changes in AAC over 2 to 5 years.