P. Sambrook

Osteoporosis: trends in epidemiology, pathogenesis and treatment

Osteoporosis is a serious public health issue. The past 10 years have seen great advances in our understanding of its epidemiology, pathophysiology, and treatment, and further advances are rapidly being made. Clinical assessment will probably evolve from decisions mainly being made on the basis of bone densitometry, to use of algorithms of absolute fracture risk. Biochemical markers of bone turnover are also likely to become more widely used. Bisphosphonates will probably remain the mainstay of therapy, but improved understanding of the optimum amount of remodelling suppression and duration of therapy will be important. At the same time, other diagnostic and therapeutic approaches, including biological agents, are likely to become more widespread.

Obesity is not protective against fracture in postmenopausal women: GLOW

OBJECTIVEnTo investigate the prevalence and incidence of clinical fractures in obese, postmenopausal women enrolled in the Global Longitudinal study of Osteoporosis in Women (GLOW).nnnMETHODSnThis was a multinational, prospective, observational, population-based study carried out by 723 physician practices at 17 sites in 10 countries. A total of 60,393 women aged ≥ 55 years were included. Data were collected using self-administered questionnaires that covered domains that included patient characteristics, fracture history, risk factors for fracture, and anti-osteoporosis medications.nnnRESULTSnBody mass index (BMI) and fracture history were available at baseline and at 1 and 2 years in 44,534 women, 23.4% of whom were obese (BMI ≥ 30 kg/m(2)). Fracture prevalence in obese women at baseline was 222 per 1000 and incidence at 2 years was 61.7 per 1000, similar to rates in nonobese women (227 and 66.0 per 1000, respectively). Fractures in obese women accounted for 23% and 22% of all previous and incident fractures, respectively. The risk of incident ankle and upper leg fractures was significantly higher in obese than in nonobese women, while the risk of wrist fracture was significantly lower. Obese women with fracture were more likely to have experienced early menopause and to report 2 or more falls in the past year. Self-reported asthma, emphysema, and type 1 diabetes were all significantly more common in obese than nonobese women with incident fracture. At 2 years, 27% of obese women with incident fracture were receiving bone protective therapy, compared with 41% of nonobese and 57% of underweight women.nnnCONCLUSIONSnOur results demonstrate that obesity is not protective against fracture in postmenopausal women and is associated with increased risk of ankle and upper leg fractures.

Bone Loss, Physical Activity, and Weight Change in Elderly Women: The Dubbo Osteoporosis Epidemiology Study

The present study examined the effects of physical activity, weight, and weight change on femoral bone loss in relation to age in elderly women. Baseline and follow‐up measurements at an average interval of 2.7 years of femoral neck bone mineral density (BMD) were reanalyzed for 827 women who were part of the Dubbo Osteoporosis Epidemiology Study. Physical activity was assessed based on hours per day spent in each of various activities according to its expected oxygen consumption. The rate of loss of BMD progressively increased with age, i.e., −0.6 ± 0.1, −1.1 ± 0.2, and −2.1 ± 0.6% per year (mean ± SEM) for the 60–69, 70–79, and ≥80 age groups, respectively (p < 0.001). After adjustment for age, physically inactive women lost more (−1.4 ± 0.2% per year; p < 0.001), compared with physically active women (−0.5 ± 0.3% per year; p = 0.15). Thinner women experienced more rapid bone loss, and women whose weight decreased (≥5%) over the study period lost more bone (−1.7 ± 0.4% per year) than those whose weight was stable (−0.8 ± 0.1% per year) or increased (+0.1 ± 0.3% per year; p < 0.01, analysis of variance). Furthermore, women whose BMD was high (>0.81 g/cm2) at baseline experienced greater loss (−1.1 ± 0.2%) compared with those in the middle tertile (1.0 ± 0.2%) or lowest tertile (−0.5 ± 0.3%). Independent predictors of rate of bone loss included age, baseline BMD, weight, weight change, and physical activity; collectively these factors accounted for 13% of total variance of bone loss by multiple regression analysis. It is concluded that a physically active lifestyle and stable weight in the later decades of life may retard proximal femur bone loss and thus contribute to reduction of fracture risk.

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, nu200a=u200a1055, or −4.0 to −1.5, nu200a=u200a900), with replication in cohorts of women drawn from the general population (nu200a=u200a20,898). 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 framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis

SummaryThis paper provides a framework for the development of national guidelines for the management of glucocorticoid-induced osteoporosis in men and women aged 18xa0years and over in whom oral glucocorticoid therapy is considered for 3xa0months or longer.IntroductionThe need for updated guidelines for Europe and other parts of the world was recognised by the International Osteoporosis Foundation and the European Calcified Tissue Society, which set up a joint Guideline Working Group at the end of 2010.Methods and resultsThe epidemiology of GIO is reviewed. Assessment of risk used a fracture probability-based approach, and intervention thresholds were based on 10-year probabilities using FRAX. The efficacy of intervention was assessed by a systematic review.ConclusionsGuidance for glucocorticoid-induced osteoporosis is updated in the light of new treatments and methods of assessment. National guidelines derived from this resource need to be tailored within the national healthcare framework of each country.

Effect of co-morbidities on fracture risk: Findings from the Global Longitudinal Study of Osteoporosis in Women (GLOW)

INTRODUCTIONnGreater awareness of the relationship between co-morbidities and fracture risk may improve fracture-prediction algorithms such as FRAX.nnnMATERIALS AND METHODSnWe used a large, multinational cohort study (GLOW) to investigate the effect of co-morbidities on fracture risk. Women completed a baseline questionnaire detailing past medical history, including co-morbidity history and fracture. They were re-contacted annually to determine incident clinical fractures. A co-morbidity index, defined as number of baseline co-morbidities, was derived. The effect of adding the co-morbidity index to FRAX risk factors on fracture prevention was examined using chi-squared tests, the May-Hosmer test, c index and comparison of predicted versus observed fracture rates.nnnRESULTSnOf 52,960 women with follow-up data, enrolled between October 2006 and February 2008, 3224 (6.1%) sustained an incident fracture over 2 years. All recorded co-morbidities were significantly associated with fracture, except for high cholesterol, hypertension, celiac disease, and cancer. The strongest association was seen with Parkinsons disease (age-adjusted hazard ratio [HR]: 2.2; 95% CI: 1.6-3.1; P<0.001). Co-morbidities that contributed most to fracture prediction in a Cox regression model with FRAX risk factors as additional predictors were: Parkinsons disease, multiple sclerosis, chronic obstructive pulmonary disease, osteoarthritis, and heart disease.nnnCONCLUSIONnCo-morbidities, as captured in a co-morbidity index, contributed significantly to fracture risk in this study population. Parkinsons disease carried a particularly high risk of fracture; and increasing co-morbidity index was associated with increasing fracture risk. Addition of co-morbidity index to FRAX risk factors improved fracture prediction.

The Global Longitudinal Study of Osteoporosis in Women (GLOW): rationale and study design

SummaryThe Global Longitudinal study of Osteoporosis in Women (GLOW) is a prospective cohort study involving 723 physicians and 60,393 women subjects ≥55xa0years. The data will provide insights into the management of fracture risk in older women over 5xa0years, patient experience with prevention and treatment, and distribution of risk among older women on an international basis.IntroductionData from cohort studies describing the distribution of osteoporosis-related fractures and risk factors are not directly comparable and do not compare regional differences in patterns of patient management and fracture outcomes.MethodsThe GLOW is a prospective, multinational, observational cohort study. Practices typical of each region were identified through primary care networks organized for administrative, research, or educational purposes. Noninstitutionalized patients visiting each practice within the previous 2xa0years were eligible. Self-administered questionnaires were mailed, with 2:1 oversampling of women ≥65xa0years. Follow-up questionnaires will be sent at 12-month intervals for 5xa0years.ResultsA total of 723 physicians at 17 sites in ten countries agreed to participate. Baseline surveys were mailed (October 2006 to February 2008) to 140,416 subjects. After the exclusion of 3,265 women who were ineligible or had died, 60,393 agreed to participate.ConclusionsGLOW will provide contemporary information on patterns of management of fracture risk in older women over a 5-year period. The collection of data in a similar manner in ten countries will permit comparisons of patient experience with prevention and treatment and provide insights into the distribution of risk among older women on an international basis.

Influence of BMI on Health‐related Quality of Life: Comparison Between an Obese Adult Cohort and Age‐matched Population Norms

The aim of this study was to determine health‐related quality of life and fatigue measures in obese subjects and to compare scores with age‐ and gender‐matched population norms. A total of 163 obese subjects were recruited from laparoscopic‐adjustable gastric banding or exercise and diet weight loss programs between March 2006 and December 2007. All subjects completed the Medical Outcomes Study Short Form 36 (SF‐36), Assessment of Quality of Life (AQoL), and Multidimensional Assessment of Fatigue (MAF) questionnaires. One‐sample t‐tests were used to compare transformed scores with age‐ and gender‐matched population norms and controls. Obese subjects have significantly lower SF‐36 physical and emotional component scores, significantly lower AQoL utility scores and significantly higher fatigue scores compared to age‐matched population norms. Within the study cohort, the SF‐36 physical functioning, role physical and bodily pain scores, and AQoL utility index were even lower in subjects with clinical knee osteoarthritis (OA). However, obese individuals without OA still had significantly lower scores compared to population norms. Obesity is associated with impaired health‐related quality of life and disability as measured by the SF‐36, AQoL, and fatigue score (MAF) compared to matched population norms.

Previous fractures at multiple sites increase the risk for subsequent fractures: the Global Longitudinal Study of Osteoporosis in Women.

Previous fractures of the hip, spine, or wrist are well‐recognized predictors of future fracture, but the role of other fracture sites is less clear. We sought to assess the relationship between prior fracture at 10 skeletal locations and incident fracture. The Global Longitudinal Study of Osteoporosis in Women (GLOW) is an observational cohort study being conducted in 17 physician practices in 10 countries. Women aged ≥55 years answered questionnaires at baseline and at 1 and/or 2 years (fractures in previous year). Of 60,393 women enrolled, follow‐up data were available for 51,762. Of these, 17.6%, 4.0%, and 1.6% had suffered 1, 2, or ≥3 fractures, respectively, since age 45 years. During the first 2 years of follow‐up, 3149 women suffered 3683 incident fractures. Compared with women with no previous fractures, women with 1, 2, or ≥3 prior fractures were 1.8‐, 3.0‐, and 4.8‐fold more likely to have any incident fracture; those with ≥3 prior fractures were 9.1‐fold more likely to sustain a new vertebral fracture. Nine of 10 prior fracture locations were associated with an incident fracture. The strongest predictors of incident spine and hip fractures were prior spine fracture (hazard ratio [HR]u2009=u20097.3) and hip (HRu2009=u20093.5). Prior rib fractures were associated with a 2.3‐fold risk of subsequent vertebral fracture, and previous upper leg fracture predicted a 2.2‐fold increased risk of hip fracture. Women with a history of ankle fracture were at 1.8‐fold risk of future fracture of a weight‐bearing bone. Our findings suggest that a broad range of prior fracture sites are associated with an increased risk of incident fractures, with important implications for clinical assessments and risk model development.

Burden of non-hip, non-vertebral fractures on quality of life in postmenopausal women : The Global Longitudinal study of Osteoporosis in Women (GLOW)

SummaryAmong 50,461 postmenopausal women, 1,822 fractures occurred (57% minor non-hip, non-vertebral [NHNV], 26% major NHNV, 10% spine, 7% hip) over 1xa0year. Spine fractures had the greatest detrimental effect on EQ-5D, followed by major NHNV and hip fractures. Decreases in physical function and health status were greatest for spine or hip fractures.IntroductionThere is growing evidence that NHNV fractures result in substantial morbidity and healthcare costs. The aim of this prospective study was to assess the effect of these NHNV fractures on quality of life.MethodsWe analyzed the 1-year incidences of hip, spine, major NHNV (pelvis/leg, shoulder/arm) and minor NHNV (wrist/hand, ankle/foot, rib/clavicle) fractures among women from the Global Longitudinal study of Osteoporosis in Women (GLOW). Health-related quality of life (HRQL) was analyzed using the EuroQol EQ-5D tool and the SF-36 health survey.ResultsAmong 50,461 women analyzed, there were 1,822 fractures (57% minor NHNV, 26% major NHNV, 10% spine, 7% hip) over 1xa0year. Spine fractures had the greatest detrimental effect on EQ-5D summary scores, followed by major NHNV and hip fractures. The number of women with mobility problems increased most for those with major NHNV and spine fractures (both +8%); spine fractures were associated with the largest increases in problems with self care (+11%), activities (+14%), and pain/discomfort (+12%). Decreases in physical function and health status were greatest for those with spine or hip fractures. Multivariable modeling found that EQ-5D reduction was greatest for spine fractures, followed by hip and major/minor NHNV. Statistically significant reductions in SF-36 physical function were found for spine fractures, and were borderline significant for major NHNV fractures.ConclusionThis prospective study shows that NHNV fractures have a detrimental effect on HRQL. Efforts to optimize the care of osteoporosis patients should include the prevention of NHNV fractures.