Celeste J. Hamilton

The effects of exercise and physical activity participation on bone mass and geometry in postmenopausal women: a systematic review of pQCT studies

The cumulative risk of fracture for a postmenopausal woman over the age of 50 can reach up to 60%. Exercise has the potential to modify fracture risk in postmenopausal women through its effects on bone mass and geometry; however, these effects are not well characterized. To determine the effects of exercise on bone mass and geometry in postmenopausal women, we conducted a systematic review of the literature. We included all randomized controlled trials, cross-sectional studies, and prospective studies that used peripheral quantitative computed tomography to assess the effects of exercise on bone mass and geometry in this population. Exercise effects appear to be modest, site-specific, and preferentially influence cortical rather than trabecular components of bone. Exercise type also plays a role, with the most prominent mass and geometric changes being observed in response to high-impact loading exercise. Exercise appears to positively influence bone mass and geometry in postmenopausal women. However, further research is needed to determine the types and amounts of exercise that are necessary to optimize improvements in bone mass and geometry in postmenopausal women and determine whether or not these improvements are capable of preventing fractures.

Effect of nitroglycerin ointment on bone density and strength in postmenopausal women: a randomized trial.

CONTEXT Nitroglycerin stimulates bone formation and inhibits bone resorption, is inexpensive, and is widely available. Its effects on bone density, bone structure, and bone strength are unknown. OBJECTIVES To determine if nitroglycerin increases lumbar spine bone mineral density (BMD) and to evaluate changes in hip BMD, bone geometry, and density at the radius and tibia, and markers of bone turnover. DESIGN, SETTING, AND PARTICIPANTS A single-center, double-blind, placebo-controlled randomized trial conducted in Toronto, Ontario, Canada, for 24 months starting in November 2005 and completed in March 2010, of 243 postmenopausal women with lumbar spine T scores of between 0 and -2.0 who completed a 1-week run-in period taking nitroglycerin ointment. Intervention Nitroglycerin ointment (15 mg/d) or placebo applied at bedtime for 24 months. MAIN OUTCOME MEASURES Areal BMD at the lumbar spine, femoral neck, and total hip. Secondary outcomes included indices of bone geometry and strength at the distal radius and tibia, and biomarkers of bone formation (bone-specific alkaline phosphatase) and bone resorption (urine N -telopeptide). RESULTS At 2 years, women randomized to the nitroglycerin group had significant increases in areal BMD at the lumbar spine (from 1.05 to 1.14 g/cm(2) vs placebo from 1.06 to 1.08 g/cm(2); percentage change, 6.7%; 95% confidence interval [CI], 5.2%-8.2%; P < .001); total hip (from 0.92 to 0.97 g/cm(2) vs placebo from 0.93 to 0.92 g/cm(2); 6.2%; 95% CI, 5.6%-7.0%; P < .001); and femoral neck (from 0.88 to 0.93 g/cm(2) vs placebo from 0.87 to 0.86 g/cm(2); 7.0%; 95% CI, 5.5%-8.5%; P < .001). At 2 years, nitroglycerin also increased volumetric trabecular BMD (11.9% and 8.5%), cortical thickness (13.9% and 24.6%), periosteal circumference (7.4% and 2.9%), polar section modulus (10.7% and 9.8%), and polar moment of inertia (7.3% and 14.5%) at the radius and tibia, respectively (all P < .001); and increased bone-specific alkaline phosphatase by 34.8% and decreased urine N -telopeptide by 54.0% (P < .001). Incidence of serious adverse events did not differ between nitroglycerin (5 [4.2%]) and placebo (5 [4.3%]) groups. Among those women who continued treatment for 24 months, headaches were reported by 40 (35%) in nitroglycerin and 6 (5.4%) in placebo groups during the first month, decreasing substantially after 12 months. CONCLUSION Among postmenopausal women, nitroglycerin ointment modestly increased BMD and decreased bone resorption. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN94484747.

The effects of organic nitrates on osteoporosis: a systematic review

Current treatments for osteoporosis are limited by lack of effect on cortical bone, side effects, and, in some cases, cost. Organic nitrates, which act as nitric oxide donors, may be a potential alternative. This systematic review summarizes the clinical data that reports on the effects of organic nitrates and bone. Organic nitrates, which act as nitric oxide donors, are novel agents that have several advantages over the currently available treatments for osteoporosis. This systematic review summarizes the clinical data that reports on the effects of organic nitrates on bone. We searched Medline (1966 to November 2012), EMBASE (1980 to November 2012), and the Cochrane Central Register of Controlled Trials (Issue 11, 2012). Keywords included nitrates, osteoporosis, bone mineral density (BMD), and fractures. We identified 200 citations. Of these, a total of 29 were retrieved for more detailed evaluation and we excluded 19 manuscripts: 15 because they did not present original data and four because they did not provide data on the intervention or outcome of interest. As such, we included ten studies in literature review. Of these ten studies two were observational cohort studies reporting nitrate use was associated with increased BMD; two were case control studies reporting that use of nitrates were associated with lower risk of hip fracture; two were randomized controlled trials (RCT) comparing alendronate to organic nitrates for treatment of postmenopausal women and demonstrating that both agents increased lumbar spine BMD. The two largest RCT with the longest follow-up, both of which compared effects of organic nitrates to placebo on BMD in women without osteoporosis, reported conflicting results. Headaches were the most common adverse event among women taking nitrates. No studies have reported on fracture efficacy. Further research is needed before recommending organic nitrates for the treatment of postmenopausal osteoporosis.

Evidence for impaired skeletal load adaptation among Canadian women with type 2 diabetes mellitus: Insight into the BMD and bone fragility paradox

OBJECTIVE Recent data suggest that women with type 2 diabetes mellitus (T2DM) might be more susceptible to fractures due to an impaired adaptive response to mechanical load, despite reportedly higher bone mineral density (BMD). The purpose of this study was to use an engineering beam analysis to calculate and compare the load stresses on the femurs of healthy women and women with T2DM and compare these levels to conventional measures of femoral neck BMD. MATERIALS/METHODS We studied 3658 women who participated in the Canadian Multicentre Osteoporosis Study (CaMos), and who had available Hip Structure Analysis (HSA) data from baseline dual energy x-ray absorptiometry (DXA) scans. Women were categorized into two groups based on the presence or absence of self-reported T2DM. We computed stress in megapascals (MPa) at the infero-medial margin of the femoral neck in a one-legged stance using an engineering beam analysis incorporating dimensions and geometry from DXA scans using the HSA method. We used linear regression (SAS 9.3) to determine the association between T2DM status and stress. We also determined the association between T2DM status and femoral neck BMD. RESULTS Stresses were 4.5% higher in T2DM women than in non-diabetics (11.03±0.18 vs. 10.56±0.04 MPa; p=0.0093). Femoral neck BMD was 4.2% greater in women with T2DM than in non-diabetics (0.74±0.002 vs. 0.71±0.01 g/cm(2); p=0.0008). CONCLUSIONS Despite higher femoral neck BMD, higher stress indicates weaker skeletal geometry for a given load, and suggests an impaired skeletal adaptive response to load may be present in women with T2DM.

Nitric Oxide Donors for the Treatment of Osteoporosis

The number of osteoporotic fractures is increasing worldwide as populations age. An inexpensive and widely available treatment is necessary to alleviate this increase in fractures. Current treatments decrease fractures at trabecular bone sites (spine) but have limited effects at cortical sites (hip, legs, forearm, and upper arm)—the most common sites of osteoporotic fracture. Treatments are also limited by costs, side effects, and lack of availability. Nitric oxide is a novel agent that has the potential to influence cortical bone, is inexpensive, is widely available, and has limited side effects. In this review we evaluate the in vitro and in vivo data which support the concept that nitric oxide is important in bone cell function, review the observational and case–control studies reporting on subjects taking organic nitrates that act as nitric oxide donors, and review the effects of nitrates on bone mineral density measurements and fracture risk.

Associations between leisure physical activity participation and cortical bone mass and geometry at the radius and tibia in a Canadian cohort of postmenopausal women

Few studies have examined the effects of leisure physical activity (PA) participation on bone mass and geometry in postmenopausal women using peripheral quantitative computed tomography (pQCT). The purpose of this study was to determine associations between leisure PA participation and bone mass and geometry at the radius and tibia in a Canadian cohort of healthy postmenopausal women (n=234, mean age 62 years). Leisure PA participation was assessed using the Minnesota Leisure Time Physical Activity Questionnaire and by generating a total activity score (TAS, mean=105, range=0-840). Bone mass and geometry at the distal and midshaft sites of the non-dominant radius and tibia were measured using pQCT. Associations between TAS and bone mass and geometry variables were determined using linear regression models adjusted for clinically relevant confounding variables. TAS was positively and significantly associated with total content, total area, cortical content and cortical area at the midshaft sites of the radius and tibia (p<0.05 for all associations). TAS was also positively and significantly associated with bone bending and torsional strength parameters at the midshaft radius and tibia (p<0.05 for all associations). No associations were observed between TAS and trabecular bone parameters. Leisure PA participation is positively associated with cortical bone mass and geometry as well as bending and torsional strength at weight-bearing and non-weight-bearing bone sites and may have the potential to modify bone strength and influence bone fragility in postmenopausal women.

The effects of organic nitrates on osteoporosis: a randomized controlled trial (ISRCTN94484747)

BackgroundOsteoporotic fractures are common and are associated with increased morbidity, mortality and health care costs. The most effective way to moderate increases in health care costs and the sickness and premature death associated with osteoporotic fractures, is to prevent osteoporosis. Several lines of evidence suggest that nitrates, drugs typically prescribed for the treatment of angina, may be effective in preventing postmenopausal osteoporosis.MethodsWe have designed a multicentre randomized controlled trial to determine the effects of nitrates on bone. The trial consists of two studies. The objective of the first study is to determine whether isosorbide mononitrate at 20 mg/day or nitroglycerin ointment at 15 mg/day leads to fewer headaches. The nitrate that is best tolerated will be used in a second study with one main objective: To determine if postmenopausal women with a T-score at the lumbar spine (L1 to L4) between 0 and -2.0 randomized to two years of treatment with intermittent nitrates have a greater increase in spine bone mineral density as compared to women randomized to placebo.We hypothesize that: 1. Women will report fewer headaches when they are randomized to intermittent nitroglycerin ointment at 15 mg/day compared to intermittent oral isosorbide mononitrate at 20 mg/day, and, 2. After two years, women randomized to intermittent nitrates will have a greater percent increase in lumbar spine bone mineral density compared with women randomized to placebo.DiscussionWe have completed our pilot study and found that transdermal nitroglycerin was associated with fewer headaches than oral isosorbide mononitrate. We are currently recruiting patients for our second main study.

Organic nitrates for osteoporosis: an update

The number of osteoporotic fractures is increasing worldwide as populations age. An inexpensive and widely available treatment is necessary to alleviate this increase in fractures. Current treatments decrease fractures at trabecular bone sites (spine) but have limited effects at cortical sites (hip, legs, forearm and upper arm)-the most common sites of osteoporotic fracture. Treatments are also limited by costs, side effects and lack of availability. Nitric oxide (NO) is a novel agent that has the potential to influence cortical bone, is inexpensive, widely available and has limited side effects. In this review, we will evaluate the in vitro and in vivo data that support the concept that NO is important in bone cell function, review the observational, case control and randomized trial data on organic nitrates and the effects of these agents on bone turnover, geometry and strength.

Lasofoxifene in osteoporosis and its place in therapy

Selective estrogen-receptor modulators (SERMs), which have estrogen-like effects on bone and “antiestrogen effects” on other tissues, have been in development for osteoporosis prevention and treatment in postmenopausal women as a safer alternative to long-term estrogen. We conducted a literature review of the skeletal and extraskeletal effects of lasofoxifene, a new generation SERM approved by the European Commission for osteoporosis treatment. Published data on the effects of lasofoxifene are based on 23 clinical pharmacology studies with over 10,000 participants from 17 phase 2 and 3 randomized controlled trials (RCTs). In RCTs, lasofoxifene decreases bone turnover markers (BTMs), increases bone mineral density (BMD) at the spine and hip, and decreases the incidence of vertebral and nonvertebral nonhip fractures compared with placebo. Compared with raloxifene, lasofoxifene gave greater decreases in BTMs, and greater increases in lumbar spine BMD. Lasofoxifene also decreased the risk of breast cancer, major coronary heart disease events, and stroke, but—similar to raloxifene—there was an increased risk of venous thromboembolism. In one trial, endometrial hypertrophy and uterine polyps were more common with lasofoxifene than with placebo, but endometrial cancer and hyperplasia were not. Lasofoxifene is probably most appropriate for use among women in their early or middle menopausal years (age 55-65) who have, or are at risk of developing, osteoporosis and in particular vertebral fractures. At the time of publication, lasofoxifene is not approved for use by the US Food and Drug Administration, and as such is not used in North America.

Heterogeneity in Skeletal Load Adaptation Points to a Role for Modeling in the Pathogenesis of Osteoporotic Fracture

Genetic, environmental, or hormonal factors may cause heterogeneity in skeletal load response. Individuals with reduced sensitivity to load should require higher strains to generate an adaptive response, consequently have weaker bones and fracture more frequently. The purpose of our study was to determine if stresses (proportional to strains) at the femoral neck under equivalent loads were higher in women with a history of fractures compared with women without fractures. We studied postmenopausal women participating in the Canadian Multicentre Osteoporosis Study who had available hip structure analysis data from dual-energy X-ray absorptiometry scans (n = 2168). Women were categorized into 2 groups based on their number of self-reported fractures. We computed stress (megapascals) at the inferomedial margin of the femoral neck in a one-legged stance mode using a 2-dimensional engineering beam analysis. We used linear regression (SAS 9.3) to determine associations between stress, geometry parameters, and number of fractures. Postmenopausal women with 1 or more fractures had higher stress (2.6%), lower narrow neck bone mineral density (4.2%), cross-sectional area (3.9%), and section modulus (9.6%) than postmenopausal women without fractures (all p < 0.05). These findings provide evidence of heterogeneity in load response and suggest an important role for modeling in the pathogenesis of osteoporotic fracture.