K. Shawn Davison

Bisphosphonate Therapy for Osteoporosis: Benefits, Risks, and Drug Holiday

The amino-bisphosphonates are first-line therapy for the treatment of most patients with osteoporosis, with proven efficacy to reduce fracture risk at the spine, hip, and other nonvertebral skeletal sites. Further, bisphosphonates have been associated with a significant decrease in morbidity and increase in survival. Following the use of bisphosphonates in millions of patients in clinical practice, some unexpected possible adverse effects have been reported, including osteonecrosis of the jaw, atypical femur fractures, atrial fibrillation, and esophageal cancer. Because bisphosphonates are incorporated into the skeleton and continue to exert an antiresorptive effect for a period of time after dosing is discontinued, the concept of a drug holiday has emerged, whereby the risk of adverse effects might be decreased while the patient still benefits from antifracture efficacy. Patients receiving bisphosphonates who are not at high risk for fracture are potential candidates for a drug holiday, while for those with bone mineral density in the osteoporosis range or previous history of fragility fracture, the benefits of continuing therapy probably far outweigh the risk of harm.

Creatine supplementation combined with resistance training in older men.

PURPOSE To study the effect of creatine (Cr) supplementation combined with resistance training on muscular performance and body composition in older men. METHODS Thirty men were randomized to receive creatine supplementation (CRE, N = 16, age = 70.4 +/- 1.6 yr) or placebo (PLA, N = 14, age = 71.1 +/- 1.8 yr), using a double blind procedure. Cr supplementation consisted of 0.3-g Cr.kg(-1) body weight for the first 5 d (loading phase) and 0.07-g Cr.kg(-1) body weight thereafter. Both groups participated in resistance training (36 sessions, 3 times per week, 3 sets of 10 repetitions, 12 exercises). Muscular strength was assessed by 1-repetition maximum (1-RM) for leg press (LP), knee extension (KE), and bench press (BP). Muscular endurance was assessed by the maximum number of repetitions over 3 sets (separated by 1-min rest intervals) at an intensity corresponding to 70% baseline 1-RM for BP and 80% baseline 1-RM for the KE and LP. Average power (AP) was assessed using a Biodex isokinetic knee extension/flexion exercise (3 sets of 10 repetitions at 60 degrees.s(-1) separated by 1-min rest). Lean tissue (LTM) and fat mass were assessed using dual energy x-ray absorptiometry. RESULTS Compared with PLA, the CRE group had significantly greater increases in LTM (CRE, +3.3 kg; PLA, +1.3 kg), LP 1-RM (CRE, +50.1 kg; PLA +31.3 kg), KE 1-RM (CRE, +14.9 kg; PLA, +10.7 kg), LP endurance (CRE, +47 reps; PLA, +32 reps), KE endurance (CRE, +21 reps; PLA +14 reps), and AP (CRE, +26.7 W; PLA, +18 W). Changes in fat mass, fat percentage, BP 1-RM, and BP endurance were similar between groups. CONCLUSION Creatine supplementation, when combined with resistance training, increases lean tissue mass and improves leg strength, endurance, and average power in men of mean age 70 yr.

Peak Bone Mass From Longitudinal Data: Implications for the Prevalence, Pathophysiology, and Diagnosis of Osteoporosis

We estimated peak bone mass (PBM) in 615 women and 527 men aged 16 to 40 years using longitudinal data from the Canadian Multicentre Osteoporosis Study (CaMos). Individual rates of change were averaged to find the mean rate of change for each baseline age. The age range for PBM was defined as the period during which bone mineral density (BMD) was stable. PBM was estimated via hierarchical models, weighted according to 2006 Canadian Census data. Lumbar spine PBM (1.046 ± 0.123 g/cm2) occurred at ages 33 to 40 years in women and at 19 to 33 years in men (1.066 ± 0.129 g/cm2). Total hip PBM (0.981 ± 0.122 g/cm2) occurred at ages 16 to 19 years in women and 19 to 21 years in men (1.093 ± 0.169 g/cm2). Analysis of Canadian geographic variation revealed that the levels of PBM and of mean BMD in those over age 65 sometimes were discordant, suggesting that PBM and subsequent rates of bone loss may be subject to different genetic and/or environmental influences. Based on our longitudinally estimated PBM values, the estimated Canadian prevalences of osteoporosis (T‐score < –2.5) were 12.0% (L1–L4) and 9.1% (total hip) in women aged 50 years and older and 2.9% (L1–L4) and 0.9% (total hip) in men aged 50 years and older. These were higher than prevalences using cross‐sectional PBM data. In summary, we found that the age at which PBM is achieved varies by sex and skeletal site, and different reference values for PBM lead to different estimates of the prevalence of osteoporosis. Furthermore, lack of concordance of PBM and BMD over age 65 suggests different determinants of PBM and subsequent bone loss.

Bone turnover markers in the management of postmenopausal osteoporosis

Osteoporosis is the most common cause of fragility fractures. Bone remodelling is essential for repairing damaged areas within bone to preserve bone strength and for assisting in mineral homeostases. In young adults, bone remodelling is usually balanced with approximately as much bone replaced as is removed during each remodelling cycle. However, when remodelling becomes accelerated in combination with an imbalance that favours bone resorption over formation, such as during menopause, precipitous losses in bone mass occur. Bone turnover markers (BTMs) measure the rate of bone remodelling allowing for a dynamic assessment of skeletal status and hold promise in identifying those at highest risk of rapid bone loss and subsequent fracture. Further, the use of BTMs to monitor individuals administered osteoporosis therapy is attractive as monitoring anti-fracture efficacy with bone mineral density has significant limitations. This review details remodelling biology, pre-analytical and analytical sources of variability for BTMs, describes the most commonly used resorption and formation markers, and offers some guidelines for their use and interpretation in the laboratory and the clinic.

Management of corticosteroid-induced osteoporosis.

OBJECTIVES To educate scientists and health care providers about the effects of corticosteroids on bone, and advise clinicians of the appropriate treatments for patients receiving corticosteroids. METHODS This review summarizes the pathophysiology of corticosteroid-induced osteoporosis, describes the assessment methods used to evaluate this condition, examines the results of clinical trials of drugs, and explores a practical approach to the management of corticosteroid-induced osteoporosis based on data collected from published articles. RESULTS Despite our lack of understanding about the biological mechanisms leading to corticosteroid-induced bone loss, effective therapy has been developed. Bisphosphonate therapy is beneficial in both the prevention and treatment of corticosteroid-induced osteoporosis. The data for the bisphosphonates are more compelling than for any other agent. For patients who have been treated but continue to lose bone, hormone replacement therapy, calcitonin, fluoride, or anabolic hormones should be considered. Calcium should be used only as an adjunctive therapy in the treatment or prevention of corticosteroid-induced bone loss and should be administered in combination with other agents. CONCLUSIONS Bisphosphonates have shown significant treatment benefit and are the agents of choice for both the treatment and prevention of corticosteroid-induced osteoporosis.

Size-corrected BMD decreases during peak linear growth: Implications for fracture incidence during adolescence

Peak adolescent fracture incidence at the distal end of the radius coincides with a decline in size‐corrected BMD in both boys and girls. Peak gains in bone area preceded peak gains in BMC in a longitudinal sample of boys and girls, supporting the theory that the dissociation between skeletal expansion and skeletal mineralization results in a period of relative bone weakness.

Change in bone mineral density as a function of age in women and men and association with the use of antiresorptive agents

Background: Measurement of bone mineral density is the most common method of diagnosing and assessing osteoporosis. We sought to estimate the average rate of change in bone mineral density as a function of age among Canadians aged 25–85, stratified by sex and use of antiresorptive agents. Methods: We examined a longitudinal cohort of 9423 participants. We measured the bone mineral density in the lumbar spine, total hip and femoral neck at baseline in 1995–1997, and at 3-year (participants aged 40–60 years only) and 5-year follow-up visits. We used the measurements to compute individual rates of change. Results: Bone loss in all 3 skeletal sites began among women at age 40–44. Bone loss was particularly rapid in the total hip and was greatest among women aged 50–54 who were transitioning from premenopause to postmenopause, with a change from baseline of –6.8% (95% confidence interval [CI] –7.5% to –4.9%) over 5 years. The rate of decline, particularly in the total hip, increased again among women older than 70 years. Bone loss in all 3 skeletal sites began at an earlier age (25–39) among men than among women. The rate of decline of bone density in the total hip was nearly constant among men 35 and older and then increased among men older than 65. Use of antiresorptive agents was associated with attenuated bone loss in both sexes among participants aged 50–79. Interpretation: The period of accelerated loss of bone mineral density in the hip bones occurring among women and men older than 65 may be an important contributor to the increased incidence of hip fracture among patients in that age group. The extent of bone loss that we observed in both sexes indicates that, in the absence of additional risk factors or therapy, repeat testing of bone mineral density to diagnose osteoporosis could be delayed to every 5 years.

The Relationship Between Proton Pump Inhibitor Use and Longitudinal Change in Bone Mineral Density: A Population-Based From the Canadian Multicentre Osteoporosis Study (CaMos)

OBJECTIVES:Proton pump inhibitor (PPI) use has been identified as a risk factor for hip and vertebral fractures. Evidence supporting a relationship between PPI use and osteoporosis remains scant. Demonstrating that PPIs are associated with accelerated bone mineral density (BMD) loss would provide supportive evidence for a mechanism through which PPIs could increase fracture risk.METHODS:We used the Canadian Multicentre Osteoporosis Study data set, which enrolled a population-based sample of Canadians who underwent BMD testing of the femoral neck, total hip, and lumbar spine (L1–L4) at baseline, and then again at 5 and 10 years. Participants also reported drug use and exposure to risk factors for osteoporosis and fracture. Multivariate linear regression was used to determine the independent association of PPI exposure and baseline BMD, and on change in BMD at 5 and 10 years.RESULTS:In all, 8,340 subjects were included in the baseline analysis, with 4,512 (55%) undergoing year 10 BMD testing. After adjusting for potential confounders, PPI use was associated with significantly lower baseline BMD at the femoral neck and total hip. PPI use was not associated with a significant acceleration in covariate-adjusted BMD loss at any measurement site after 5 and 10 years of follow-up.CONCLUSIONS:PPI users had lower BMD at baseline than PPI non-users, but PPI use over 10 years did not appear to be associated with accelerated BMD loss. The reasons for discordant findings between PPI use at baseline and during follow-up require further study.

Association Between Change in BMD and Fragility Fracture in Women and Men

Our objective was to estimate the relationship between longitudinal change in BMD and fragility fractures. We studied 3635 women and 1417 men 50–85 yr of age in the Canadian Multicentre Osteoporosis Study who had at least two BMD measurements (lumbar spine, femoral neck, total hip, and trochanter) within the first 5 yr of the study and fragility fractures (any, main, forearm/wrist, ribs, hip) within the first 7 yr. Multiple logistic regression was used to model the relationship between baseline BMD, BMD change, and fragility fractures. We found that, among nonusers of antiresorptives, independent of baseline BMD, a decrease of 0.01 g/cm2/yr in total hip BMD was associated with an increased risk of fragility fracture with ORs of 1.15 (95% CI: 1.01; 1.32) in women and 1.34 (95% CI: 1.02; 1.78) in men. The risk of fragility fractures in subgroups such as fast losers and those with osteopenia was better estimated by models that included BMD change than by models that included baseline BMD but excluded BMD change. Although the association between baseline BMD and fragility fractures was similar in users and nonusers of antiresorptives, the association was stronger in nonusers compared with users. These results show that BMD change in both men and women is an independent risk factor for fragility fractures and also predicts fracture risk in those with osteopenia. The results suggest that BMD change should be included with other variables in a comprehensive fracture prediction model to capture its contribution to osteoporotic fracture risk.

Calcium and Vitamin D Intake and Mortality: Results from the Canadian Multicentre Osteoporosis Study (CaMos)

CONTEXT Calcium and vitamin D are recommended for bone health, but there are concerns about adverse risks. Some clinical studies suggest that calcium intake may be cardioprotective, whereas others report increased risk associated with calcium supplements. Both low and high serum levels of 25-hydroxyvitamin D have been associated with increased mortality. OBJECTIVE The purpose of this study was to determine the association between total calcium and vitamin D intake and mortality and heterogeneity by source of intake. DESIGN The Canadian Multicentre Osteoporosis Study cohort is a population-based longitudinal cohort with a 10-year follow-up (1995-2007). SETTING This study included randomly selected community-dwelling men and women. PARTICIPANTS A total of 9033 participants with nonmissing calcium and vitamin D intake data and follow-up were studied. EXPOSURE Total calcium intake (dairy, nondairy food, and supplements) and total vitamin D intake (milk, yogurt, and supplements) were recorded. OUTCOME The outcome variable was all-cause mortality. RESULTS There were 1160 deaths during the 10-year period. For women only, we found a possible benefit of higher total calcium intake, with a hazard ratio of 0.95 (95% confidence interval, 0.89-1.01) per 500-mg increase in daily calcium intake and no evidence of heterogeneity by source; use of calcium supplements was also associated with reduced mortality, with hazard ratio of 0.78 (95% confidence interval, 0.66-0.92) for users vs nonusers with statistically significant reductions remaining among those with doses up to 1000 mg/d. These associations were not modified by levels of concurrent vitamin D intake. No definitive associations were found among men. CONCLUSIONS Calcium supplements, up to 1000 mg/d, and increased dietary intake of calcium may be associated with reduced risk of mortality in women. We found no evidence of mortality benefit or harm associated with vitamin D intake.