George Ioannidis

Relation between fractures and mortality: results from the Canadian Multicentre Osteoporosis Study

Background: Fractures have largely been assessed by their impact on quality of life or health care costs. We conducted this study to evaluate the relation between fractures and mortality. Methods: A total of 7753 randomly selected people (2187 men and 5566 women) aged 50 years and older from across Canada participated in a 5-year observational cohort study. Incident fractures were identified on the basis of validated self-report and were classified by type (vertebral, pelvic, forearm or wrist, rib, hip and “other”). We subdivided fracture groups by the year in which the fracture occurred during follow-up; those occurring in the fourth and fifth years were grouped together. We examined the relation between the time of the incident fracture and death. Results: Compared with participants who had no fracture during follow-up, those who had a vertebral fracture in the second year were at increased risk of death (adjusted hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.1–6.6); also at risk were those who had a hip fracture during the first year (adjusted HR 3.2, 95% CI 1.4–7.4). Among women, the risk of death was increased for those with a vertebral fracture during the first year (adjusted HR 3.7, 95% CI 1.1–12.8) or the second year of follow-up (adjusted HR 3.2, 95% CI 1.2–8.1). The risk of death was also increased among women with hip fracture during the first year of follow-up (adjusted HR 3.0, 95% CI 1.0–8.7). Interpretation: Vertebral and hip fractures are associated with an increased risk of death. Interventions that reduce the incidence of these fractures need to be implemented to improve survival.

The influence of osteoporotic fractures on health-related quality of life in community-dwelling men and women across Canada.

Abstract: Health-related quality of life (HRQL) was examined in relation to prevalent fractures in 4816 community-dwelling Canadian men and women 50 years and older participating in the Canadian Multicentre Osteoporosis Study (CaMos). Fractures were of three categories: clinically recognized main fractures, subclinical vertebral fractures and fractures at other sites. Main fractures were divided and analyzed at the hip, spine, wrist/forearm, pelvis and rib sites. Baseline assessments of anthropometric data, medical history, therapeutic drug use, spinal radiographs and prevalent fractures were obtained from all participants. The SF-36 instrument was used as a tool to measure HRQL. A total of 652 (13.5%) main fractures were reported. Results indicated that hip, spine, wrist/forearm, pelvis and rib fractures had occurred in 78 (1.6%), 40 (0.8%), 390 (8.1%), 19 (0.4%) and 125 (2.6%) individuals, respectively (subjects may have had more than one main fracture). Subjects who had experienced a main prevalent fracture had lower HRQL scores compared with non-fractured participants. The largest differences were observed in the physical functioning (−4.0; 95% confidence intervals (CI): −6.0, −2.0) and role-physical functioning domains (−5.8; 95% CI: −9.5, −2.2). In women, the physical functioning domain was most influenced by hip (−14.9%; 95% CI: −20.9, −9.0) and pelvis (−18.1; 95% CI: −27.6, −8.6) fractures. In men, the role-physical domain was most affected by hip fractures (−35.7; 95% CI: −60.4, −11.1). Subjects who experienced subclinical vertebral fractures had lower HRQL scores than those without prevalent fractures. In conclusion, HRQL was lower in the physical functioning domain in women and the role-physical domain in men who sustained main fractures at the hip. Subclinical vertebral fractures exerted a moderate effect on HRQL.

The impact of incident vertebral and non-vertebral fractures on health related quality of life in postmenopausal women

BackgroundLittle empirical research has examined the multiple consequences of osteoporosis on quality of life.MethodsHealth related quality of life (HRQL) was examined in relationship to incident fractures in 2009 postmenopausal women 50 years and older who were seen in consultation at our tertiary care, university teaching hospital-affiliated office and who were registered in the Canadian Database of Osteoporosis and Osteopenia (CANDOO) patients. Patients were divided into three study groups according to incident fracture status: vertebral fractures, non-vertebral fractures and no fractures. Baseline assessments of anthropometric data, medical history, therapeutic drug use, and prevalent fracture status were obtained from all participants. The disease-targeted mini-Osteoporosis Quality of Life Questionnaire (mini-OQLQ) was used to measure HRQL.ResultsMultiple regression analyses revealed that subjects who had experienced an incident vertebral fracture had lower HRQL difference scores as compared with non-fractured participants in total score (-0.86; 95% confidence intervals (CI): -1.30, -0.43) and the symptoms (-0.76; 95% CI: -1.23, -0.30), physical functioning (-1.12; 95% CI: -1.57, -0.67), emotional functioning (-1.06; 95% CI: -1.44, -0.68), activities of daily living (-1.47; 95% CI: -1.97, -0.96), and leisure (-0.92; 95% CI: -1.37, -0.47) domains of the mini-OQLQ. Patients who experienced an incident non-vertebral fracture had lower HRQL difference scores as compared with non-fractured participants in total score (-0.47; 95% CI: -0.70, -0.25), and the symptoms (-0.25; 95% CI: -0.49, -0.01), physical functioning (-0.39; 95% CI: -0.65, -0.14), emotional functioning (-0.97; 95% CI: -1.20, -0.75) and the activities of daily living (-0.47; 95% CI: -0.73, -0.21) domains.ConclusionQuality of life decreased in patients who sustained incident vertebral and non-vertebral fractures.

The impact of incident fractures on health-related quality of life: 5 years of data from the Canadian Multicentre Osteoporosis Study

Background Vertebral fractures in patients with cystic fibrosis (CF) may contribute to an accelerated decline in lung function and can be a contraindication to lung transplantation. In this study, we examined longitudinal change in bone mineral density (BMD) and the prevalence of vertebral fractures in adult CF patients, without lung-transplant, attending a Canadian specialty clinic. Methods Retrospective chart review of all patients attending an Adult Cystic Fibrosis Clinic at Hamilton Health Sciences in Hamilton, Canada. Forty-nine of 56 adults met inclusion criteria. Chest radiographs were graded by consensus approach using Genant’s semi-quantitative method to identify and grade fractured vertebrae. Dual x-ray absorptiometry (DXA) scans were also reviewed. Results The mean age of the cohort was 25.2 years (SD 9.4), 43% were male. The mean body mass index (BMI) was 19.8 (2.8) for males and 21.7 (5.1) for females. At baseline, the rate of at least one vertebral fracture was 16.3%; rising to 21.3% (prevalent and incident) after a 3-year follow-up. The mean BMD T-or Z-scores at baseline were −0.80 (SD 1.1) at the lumbar spine, −0.57 (SD 0.97) at the proximal femur, and −0.71 (SD 1.1) at the whole body. Over approximately 4-years, the mean percent change in BMD was −1.93% at the proximal femur and −0.73% at the lumbar spine. Conclusion Approximately one in five CF patients demonstrated at least one or more vertebral fractures. Moderate declines in BMD were observed. Given the high rate of vertebral fractures noted in this cohort of adult CF patients, and the negative impact they have on compromised lung functioning, regular screening for vertebral fractures should be considered on routine chest radiographs.

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.

Associations among disease conditions, bone mineral density, and prevalent vertebral deformities in men and women 50 years of age and older: Cross-sectional results from the canadian Multicentre Osteoporosis Study

This cross‐sectional cohort study of 5566 women and 2187 men 50 years of age and older in the population‐based Canadian Multicentre Osteoporosis Study was conducted to determine whether reported past diseases are associated with bone mineral density or prevalent vertebral deformities. We examined 12 self‐reported disease conditions including diabetes mellitus (types 1 or 2), nephrolithiasis, hypertension, heart attack, rheumatoid arthritis, thyroid disease, breast cancer, inflammatory bowel disease, neuromuscular disease, Pagets disease, and chronic obstructive pulmonary disease. Multivariate linear and logistic regression analyses were performed to determine whether there were associations among these disease conditions and bone mineral density of the lumbar spine, femoral neck, and trochanter, as well as prevalent vertebral deformities. Bone mineral density measurements were higher in women and men with type 2 diabetes compared with those without after appropriate adjustments. The differences were most notable at the lumbar spine (+0.053 g/cm2), femoral neck (+0.028 g/cm2), and trochanter (+0.025 g/cm2) in women, and at the femoral neck (+0.025 g/cm2) in men. Hypertension was also associated with higher bone mineral density measurements for both women and men. The differences were most pronounced at the lumbar spine (+0.022 g/cm2) and femoral neck (+0.007 g/cm2) in women and at the lumbar spine (+0.028 g/cm2) in men. Although results were statistically inconclusive, men reporting versus not reporting past nephrolithiasis appeared to have clinically relevant lower bone mineral density values. Bone mineral density differences were −0.022, −0.015, and −0.016 g/cm2 at the lumbar spine, femoral neck, and trochanter, respectively. Disease conditions were not strongly associated with vertebral deformities. In summary, these cross‐sectional population‐based data show that type 2 diabetes and hypertension are associated with higher bone mineral density in women and men, and nephrolithiasis may be associated with lower bone mineral density in men. The importance of these associations for osteoporosis case finding and management require further and prospective studies.

The association between osteoporotic fractures and health-related quality of life as measured by the Health Utilities Index in the Canadian Multicentre Osteoporosis Study (CaMos)

Osteoporotic fractures can be a major cause of morbidity. It is important to determine the impact of fractures on health-related quality of life (HRQL). A total of 3,394 women and 1,122 men 50 years of age and older, who were recruited for the Canadian Multicentre Osteoporosis Study (CaMos), participated in this cross-sectional study. Minimal trauma fractures of the hip, pelvis, spine, lower body (included upper and lower leg, knee, ankle, and foot), upper body (included arm, elbow, sternum, shoulder, and clavicle), wrist and hand (included forearm, hand, and finger), and ribs were studied. Participants with subclinical vertebral deformities were also examined. The Health Utilities Index Mark II and III Systems were used to assess HRQL. Past osteoporotic fractures varied in prevalence from 1.2% (pelvis) to 27.8% (lower body) in women and 0.3% (pelvis) to 29.3% (wrist) in men. Multivariate linear regression analyses [parameter estimates and corresponding 95% confidence intervals (CI)] indicated that minimal trauma fractures were negatively associated with HRQL and that this relationship depends on fracture type and gender. The multi-attribute scores for the Mark II system were negatively related to hip (−0.05; 95% CI: −0.09, −0.01), lower body (−0.02; 95% CI: −0.03, −0.000), and subclinical vertebral fractures (−0.02; 95% CI: −0.03, −0.00) for women. The multi-attribute scores for the Mark III system were negatively related to hip (−0.09; 95% CI: −0.14, −0.03) and rib fractures (−0.06; 95% CI: −0.11, −0.00) for women, and rib fractures (−0.06; 95% CI: −0.12, −0.00) for men. In conclusion, this study demonstrates a negative association between osteoporotic fractures and quality of life in both women and men.

The osteoporosis care gap in Canada

BackgroundThe presence of a fragility fracture is a major risk factor for osteoporosis, and should be an indicator for osteoporosis diagnosis and therapy. However, the extent to which patients who fracture are assessed and treated for osteoporosis is not clear.MethodsWe performed a review of the literature to identify the practice patterns in the diagnosis and treatment of osteoporosis in adults over the age of 40 who experience a fragility fracture in Canada. Searches were performed in MEDLINE (1966 to January 2, 2003) and CINAHL (1982 to February 1, 2003) databases.ResultsThere is evidence of a care gap between the occurrence of a fragility fracture and the diagnosis and treatment of osteoporosis in Canada. The proportion of individuals with a fragility fracture who received an osteoporosis diagnostic test or physician diagnosis ranged from 1.7% to 50%. Therapies such as hormone replacement therapy, bisphosphonates or calcitonin were being prescribed to 5.2% to 37.5% of patients. Calcium and vitamin D supplement intake was variable, and ranged between 2.8% to 61.6% of patients.ConclusionMany Canadians who experience fragility fracture are not receiving osteoporosis management for the prevention of future fractures.

Adherence to bisphosphonates and hormone replacement therapy in a tertiary care setting of patients in the CANDOO database

Therapies for osteoporosis must be taken for at least 1 year to be effective. The purpose of this study was to determine the difference in adherence to etidronate, alendronate and hormone replacement therapy in a group of patients seen at our tertiary care centres. The Canadian Database of Osteoporosis and Osteopenia (CANDOO), a prospective observational database designed to capture clinical data, was searched for patients who started therapy following entry into CANDOO. There were 1196 initiating etidronate, 477 alendronate and 294 hormone replacement therapy women and men aged (mean, SD) 65.8 (8.7) years in the study. A Cox proportional hazards regression model was used to assess differences between treatment groups in the time to discontinuation of therapy. Several potential covariates such as anthropometry, medications, illnesses, fractures and lifestyle factors were entered into the model. A forward selection technique was used to generate the final model. Hazard ratios and 95% confidence intervals (CI) were calculated. Adjusted results indicated that alendronate-treated patients were more likely to discontinue therapy as compared with etidronate-treated patients (1.404; 95% CI: 1.150, 1.714). After 1 year, 90.3% of patients were still taking etidronate compared with 77.6% for alendronate. No statistically significant differences were found between hormone replacement therapy and etidronate users (0.971; 95% CI: 0.862, 1.093) and hormone replacement therapy and alendronate users (0.824; 95% CI: 0.624, 1.088) after controlling for potential covariates. After 1 year, 80.1% of patients were still taking hormone replacement therapy, which decreased to 44.5% after 6 years. Increasing age and presence of incident non-vertebral fractures were found to be independent predictors of adherence. In conclusion, alendronate users were more likely to discontinue therapy than etidronate users over the follow-up period. Potential barriers to long-term patient adherence to osteoporosis therapies need to be evaluated.

Construction and validation of a simplified fracture risk assessment tool for Canadian women and men: results from the CaMos and Manitoba cohorts

SummaryA procedure for creating a simplified version of fracture risk assessment tool (FRAX®) is described. Calibration, fracture prediction, and concordance were compared with the full FRAX tool using two large, complementary Canadian datasets.IntroductionThe Canadian Association of Radiologists and Osteoporosis Canada (CAROC) system for fracture risk assessment is based upon sex, age, bone mineral density (BMD), prior fragility fracture, and glucocorticoid use. CAROC does not require computer or web access, and categorizes 10-year major osteoporotic fracture risk as low (<10%), moderate (10–20%), or high (>20%).MethodsBasal CAROC fracture risk tables (by age, sex, and femoral neck BMD) were constructed from Canadian FRAX probabilities for major osteoporotic fractures (adjusted for prevalent clinical risk factors). We assessed categorization and fracture prediction with the updated CAROC system in the CaMos and Manitoba BMD cohorts.ResultsThe new CAROC system demonstrated high concordance with the Canadian FRAX tool for risk category in both the CaMos and Manitoba cohorts (89% and 88%). Ten-year fracture outcomes in CaMos and Manitoba BMD cohorts showed good discrimination and calibration for both CAROC (6.1–6.5% in low-risk, 13.5–14.6% in moderate-risk, and 22.3–29.1% in high-risk individuals) and FRAX (6.1–6.6% in low-risk, 14.4–16.1% in moderate-risk, and 23.4–31.0% in high-risk individuals). Reclassification from the CAROC risk category to a different risk category under FRAX occurred in <5% for low-risk, 20–24% for moderate-risk, and 27–30% for high-risk individuals. Reclassified individuals had 10-year fracture outcomes that were still within or close to the original nominal-risk range..ConclusionThe new CAROC system is well calibrated to the Canadian population and shows a high degree of concordance with the Canadian FRAX tool. The CAROC system provides s a simple alternative when it is not feasible to use the full Canadian FRAX tool.