Richard L. Prince

Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women with Osteoporosis

BACKGROUND Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown. METHODS We randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone (1-34) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study (median duration of observation, 21 months) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry. RESULTS New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent, respectively, of the women in the 20-microg and 40-microg parathyroid hormone groups; the respective relative risks of fracture in the 20-microg and 40-microg groups, as compared with the placebo group, were 0.35 and 0.31 (95 percent confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95 percent confidence intervals, 0.25 to 0.88 and 0.25 to 0.861). As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points. Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo. Parathyroid hormone had only minor side effects (occasional nausea and headache). CONCLUSIONS Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects.

Hypovitaminosis D in Medical Inpatients

BACKGROUND Vitamin D deficiency is a major risk factor for bone loss and fracture. Although hypovitaminosis D has been detected frequently in elderly and housebound people, the prevalence of vitamin D deficiency among patients hospitalized on a general medical service is unknown. METHODS We assessed vitamin D intake, ultraviolet-light exposure, and risk factors for hypovitaminosis D and measured serum 25-hydroxyvitamin D, parathyroid hormone, and ionized calcium in 290 consecutive patients on a general medical ward. RESULTS A total of 164 patients (57 percent) were considered vitamin D-deficient (serum concentration of 25-hydroxyvitamin D, < or = 15 ng per milliliter), of whom 65 (22 percent) were considered severely vitamin D-deficient (serum concentration of 25-hydroxyvitamin D, <8 ng per milliliter). Serum 25-hydroxyvitamin D concentrations were related inversely to parathyroid hormone concentrations. Lower vitamin D intake, less exposure to ultraviolet light, anticonvulsant-drug therapy, renal dialysis, nephrotic syndrome, hypertension, diabetes mellitus, winter season, higher serum concentrations of parathyroid hormone and alkaline phosphatase, and lower serum concentrations of ionized calcium and albumin were significant univariate predictors of hypovitaminosis D. Sixty-nine percent of the patients who consumed less than the recommended daily allowance of vitamin D and 43 percent of the patients with vitamin D intakes above the recommended daily allowance were vitamin D-deficient. Inadequate vitamin D intake, winter season, and housebound status were independent predictors of hypovitaminosis D in a multivariate model. In a subgroup of 77 patients less than 65 years of age without known risk factors for hypovitaminosis D, the prevalence of vitamin D deficiency was 42 percent. CONCLUSIONS Hypovitaminosis D is common in general medical inpatients, including those with vitamin D intakes exceeding the recommended daily allowance and those without apparent risk factors for vitamin D deficiency.

Modelling in Ecomomic Evaluation: An Unavoidable Fact of Life

The role of modelling in economic evaluation is explored by discussing, with examples, the uses of models. The expanded use of pragmatic clinical trials as an alternative to models is discussed. Some suggestions for good modelling practice are made.

Prevention of Postmenopausal Osteoporosis: A Comparative Study of Exercise, Calcium Supplementation, and Hormone-Replacement Therapy

Abstract Background. Osteoporosis among older women is a major public health problem. We studied the effects of three approaches to the prevention of osteoporosis in women with low bone density. Methods. One hundred twenty postmenopausal women (mean [±SD] age, 56±4) who were selected because they had low forearm bone density were enrolled in a double-blind, placebo-controlled, randomized study comparing the effects of an exercise regimen (exercise group, n = 41), exercise plus dietary calcium supplementation (exercise—calcium group, n = 39), and exercise plus continuous replacement of estrogen and progesterone (exercise—estrogen group, n = 40). Periodically during the two-year study period, we measured the womens bone density at three forearm sites, measured indexes of calcium metabolism, and recorded symptom scores. A comparison group of 42 women (mean age, 55.5 ±3.1) with normal bone density was also followed for two years. Results. Significant bone loss in the distal forearm occurred in the group with...

Comparison of the Effect of Denosumab and Alendronate on BMD and Biochemical Markers of Bone Turnover in Postmenopausal Women With Low Bone Mass : A Randomized, Blinded, Phase 3 Trial

Denosumab is a fully human monoclonal antibody that inhibits bone resorption by neutralizing RANKL, a key mediator of osteoclast formation, function, and survival. This phase 3, multicenter, double‐blind study compared the efficacy and safety of denosumab with alendronate in postmenopausal women with low bone mass. One thousand one hundred eighty‐nine postmenopausal women with a T‐score ≤ −2.0 at the lumbar spine or total hip were randomized 1:1 to receive subcutaneous denosumab injections (60 mg every 6 mo [Q6M]) plus oral placebo weekly (n = 594) or oral alendronate weekly (70 mg) plus subcutaneous placebo injections Q6M (n = 595). Changes in BMD were assessed at the total hip, femoral neck, trochanter, lumbar spine, and one‐third radius at 6 and 12 mo and in bone turnover markers at months 1, 3, 6, 9, and 12. Safety was evaluated by monitoring adverse events and laboratory values. At the total hip, denosumab significantly increased BMD compared with alendronate at month 12 (3.5% versus 2.6%; p < 0.0001). Furthermore, significantly greater increases in BMD were observed with denosumab treatment at all measured skeletal sites (12‐mo treatment difference: 0.6%, femoral neck; 1.0%, trochanter; 1.1%, lumbar spine; 0.6%, one‐third radius; p ≤ 0.0002 all sites). Denosumab treatment led to significantly greater reduction of bone turnover markers compared with alendronate therapy. Adverse events and laboratory values were similar for denosumab‐ and alendronate‐treated subjects. Denosumab showed significantly larger gains in BMD and greater reduction in bone turnover markers compared with alendronate. The overall safety profile was similar for both treatments.

Recreational physical activity levels in healthy older women: the importance of fear of falling.

OBJECTIVES: To examine whether fear of falling is a probable cause of reduced recreational physical activity levels in healthy older women.

Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk

Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55–85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or −4.0 to −1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD–associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies.

A Case–Control Study of Quality of Life and Functional Impairment in Women with Long–Standing Vertebral Osteoporotic Fracture

Abstract: There have been several studies of the impact of vertebral osteoporotic fracture on the quality of life and functionality of individual subjects. To date, however, no direct comparisons with age-matched normal subjects without vertebral fracture have been made. The radiographs of 145 female clinic patients with vertebral fractures were reviewed by the study physicians. The controls were recruited from the electoral role and by media appeal. One hundred and sixty-seven women had radiographs taken to determine those without vertebral fracture. Fracture subjects and controls had to be ambulant and were excluded if they had significant radiologic evidence of degenerative disk or joint disease of the spine. One hundred cases and one hundred controls were matched by 5-year age groups. The number, position and severity of the vertebral fracture on the lateral radiographs of the cases was recorded. Quality of life was measured using the Short Form-36 (SF-36) (maximum score 100) and a utility score calculated from thesese results (maximum score 1). Two measurements of functionality were employed: the Modified Barthel Index (MBI) to assess the activities of daily living (maximum score 100) and the Timed ‘Up & Go’ (TUG) that measured the time taken for the subject to rise from sitting in a chair, walk 3 m along a line, return to the chair and sit down. The fracture subjects had 2.9 + 1.6 (mean + SD) vertebral fractures and the time since last fracture was 5.1 + 4.8 years. The SF-36 physical function component summary index results were: fracture subjects 36 + 11, controls 48 + 9 (p < 0.001). The SF-36 mental health component summary index results were: fracture subjects 50 + 11, controls 54 + 8 (p <0.05). The utility scores were: fracture subjects 0.64 + 0.08, controls 0.72 + 0.07 (p <0.001). The MBI results were: fracture subjects 97 + 5, controls 99 + 1 (p< 0.01). The TUG results were: fracture subjects 13.8 + 7.3 s, controls 10.1 + 4.1 s (p <0.01). TUG and MBI scores correlated well with SF-36 scores; however, no domain of the SF-36 or functional measure correlated with either the number of vertebral fractures or the time since last vertebral fracture. Thus, clinically reported vertebral fractures impair both the quality of life and functionality of these subjects. The adverse impact of vertebral fracture on quality of life and functionality needs to be recognized by medical practitioners, subjects and the community, so that adequate health resources can be devoted to the prevention and treatment of this debilitating condition condition.

Calcium supplementation and the risks of atherosclerotic vascular disease in older women: Results of a 5-year RCT and a 4.5-year follow-up

Concern has been expressed that calcium supplementation, a key intervention for preventing osteoporotic fracture in older women, may increase the risk of atherosclerotic vascular disease. To evaluate the risk further, an examination of complete verified atherosclerotic vascular hospitalization and mortality data from a 5‐year randomized, controlled trial (RCT) of calcium carbonate and 4.5 years of posttrial follow‐up was undertaken. This study used data from a published 5‐year randomized, double‐blinded, placebo‐controlled trial [Calcium Intake Fracture Outcome Study (CAIFOS)]. The participants were 1460 women aged 75.1 ± 2.7 years at baseline (1998) recruited from the general population and randomized to receive 1200 mg of calcium carbonate daily or an identical placebo. All hospital admission and deaths during the 5‐year study and the 4.5‐year follow‐up were derived from the Western Australian Data Linkage Service (WADLS). Hazard ratios (HRs) for the combined endpoint of atherosclerotic vascular mortality or first hospitalization were calculated using prespecified intention‐to‐treat and per‐protocol models. The intervention group that received calcium supplementation did not have a higher risk of death or first‐time hospitalization from atherosclerotic vascular disease in either the 5‐year RCT [multivariate‐adjusted HR = 0.938, 95% confidence interval (CI) 0.690–1.275] or during the 9.5 years of observational study (multivariate‐adjusted HR = 0.919, 95% CI 0.737–1.146). Further analysis suggested that calcium supplementation may reduce the risk of hospitalization and mortality in patients with preexisting atherosclerotic cardiovascular disease. This trial provides compelling evidence that calcium supplementation of 1200 mg daily does not significantly increase the risk of atherosclerotic vascular disease in elderly women.

Effects of Ergocalciferol Added to Calcium on the Risk of Falls in Elderly High-Risk Women

BACKGROUND Ergocalciferol (vitamin D(2)) supplementation plays a role in fall prevention, but the effect in patients living in the community in sunny climates remains uncertain. We evaluated the effect of ergocalciferol and calcium citrate supplementation compared with calcium alone on the risk of falls in older women at high risk of falling. METHODS A 1-year population-based, double-blind, randomized controlled trial of 302 community-dwelling ambulant older women aged 70 to 90 years living in Perth, Australia (latitude, 32 degrees S), with a serum 25-hydroxyvitamin D concentration of less than 24.0 ng/mL and a history of falling in the previous year. Participants were randomized to receive ergocalciferol, 1000 IU/d, or identical placebo (hereinafter, ergocalciferol and control groups, respectively). Both groups received calcium citrate, 1000 mg/d. Fall data were collected every 6 weeks. RESULTS Ergocalciferol therapy reduced the risk of having at least 1 fall over 1 year after adjustment for baseline height, which was significantly different between the 2 groups (ergocalciferol group, 53.0%; control group, 62.9%; odds ratio [OR], 0.61; 95% confidence interval [CI], 0.37-0.99). When those who fell were grouped by the season of first fall or the number of falls they had, ergocalciferol treatment reduced the risk of having the first fall in winter and spring (ergocalciferol group, 25.2%; control group, 35.8%; OR, 0.55; 95% CI, 0.32-0.96) but not in summer and autumn, and reduced the risk of having 1 fall (ergocalciferol group, 21.2%; control group, 33.8%; OR, 0.50; 95% CI, 0.28-0.88) but not multiple falls. CONCLUSION Patients with a history of falling and vitamin D insufficiency living in sunny climates benefit from ergocalciferol supplementation in addition to calcium, which is associated with a 19% reduction in the relative risk of falling, mostly in winter.