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The aims of this study were to determine common international risk factors for hip fracture in women aged 50 years or more. We studied women aged 50 years or more who sustained a hip fracture in 14 centers from Portugal, Spain, France, Italy, Greece, and Turkey over a 1-year period. Women aged 50 years or more selected from the neighborhood or population registers served as controls. Cases and controls were interviewed using a structured questionnaire on work, physical activity, exposure to sunlight, reproductive, history and gynecologic status, height, weight, mental score, and consumption of tobacco, alcohol, calcium, coffee, and tea. Significant risk factors identified by univariate analysis included low body mass index (BMI), short fertile period, low physical activity. lack of sunlight exposure, low milk consumption, no consumption of tea, and a poor mental score. No significant adverse effects of coffee or smoking were observed. Moderate intake of spirits was a protective factor in young adulthood, but otherwise no significant effect of alcohol intake was observed. For some risks, a threshold effect was observed. A low BMI and milk consumption were significant risks only in the lowest 50% and 10% of the population, respectively. A late menarche, poor mental score, low BMI and physical activity, low exposure to sunlight, and a low consumption of calcium and tea remained independent risk factors after multivariate analysis, accounting for 70% of hip fractures. Excluding mental score and age at menarche (not potentially reversible), the attributable risk was 56%. Thus, about half of the hip fractures could be explained on the basis of the potentially reversible risk factors sought. In contrast, the use of risk factors to "predict" hip fractures had moderate sensitivity and specificity. We conclude that variations in lifestyle factors are associated with significant differences in the risk of hip fracture, account for a large component of the total risk, and may be of some value in selecting individuals at high risk.

Altogether 733 postmenopausal women were interviewed with regard to their age at menopause. Subsequent fragility fractures over an 11 year period were recorded. Fragility fractures had occurred in 212 women. These women had an earlier menopause, but the deviation from the nonfracture group was significant only in those who were less than 70 years at the beginning of the fracture catchment period. Women 50-69 years of age, in the lowest quartile of menopausal age, sustained 50% more fragility fractures than those in the highest quartile. In older women menopausal age does not predict fragility fractures. Women less than 70 with an early menopause had a significantly lower initial bone mass.

Summary A fracture risk assessment tool (FRAX™) is developed based on the use of clinical risk factors with or without bone mineral density tests applied to the UK. Introduction The aim of this study was to apply an assessment tool for the prediction of fracture in men and women with the use of clinical risk factors (CRFs) for fracture with and without the use of femoral neck bone mineral density (BMD). The clinical risk factors, identified from previous meta-analyses, comprised body mass index (BMI, as a continuous variable), a prior history of fracture, a parental history of hip fracture, use of oral glucocorticoids, rheumatoid arthritis and other secondary causes of osteoporosis, current smoking, and alcohol intake 3 or more units daily. Methods Four models were constructed to compute fracture probabilities based on the epidemiology of fracture in the UK. The models comprised the ten-year probability of hip fracture, with and without femoral neck BMD, and the ten-year probability of a major osteoporotic fracture, with and without BMD. For each model fracture and death hazards were computed as continuous functions. Results Each clinical risk factor contributed to fracture probability. In the absence of BMD, hip fracture probability in women with a fixed BMI (25 kg/m2) ranged from 0.2% at the age of 50 years for women without CRF’s to 22% at the age of 80 years with a parental history of hip fracture (approximately 100-fold range). In men, the probabilities were lower, as was the range (0.1 to 11% in the examples above). For a major osteoporotic fracture the probabilities ranged from 3.5% to 31% in women, and from 2.8% to 15% in men in the example above. The presence of one or more risk factors increased probabilities in an incremental manner. The differences in probabilities between men and women were comparable at any given T-score and age, except in the elderly where probabilities were higher in women than in men due to the higher mortality of the latter. Conclusion The models provide a framework which enhances the assessment of fracture risk in both men and women by the integration of clinical risk factors alone and/or in combination with BMD.

Few economic or quality-of-life studies have investigated the long-term consequences of fragility fractures. This prospective observational data collection study assessed the cost and quality of life related to hip, vertebral, and wrist fracture 13-18 months after the fracture, based on 684 patients surviving 18 months after fracture.Data regarding resource use and quality of life related to fractures was collected using questionnaires at 7 research centers in Sweden. Information was collected using patient records, register sources, and by asking the patient. Quality of life was estimated using the EQ-5D questionnaire. Direct and indirect costs were estimated from a societal standpoint.The mean fracture-related cost 13-18 months after a hip, vertebral, or wrist fracture were estimated to be euro2,422, euro3,628, and euro316, respectively. Between 12 and 18 months after hip, vertebral, and wrist fracture, utility increased by 0.03, 0.05, and 0.02, respectively. Compared to prefracture levels, the mean loss in quality of life between 13 and 18 months after fracture was estimated to be 0.05, 0.11, and 0.005 for hip, vertebral, and wrist fracture.The sample of vertebral fracture patients was fairly small and included a high proportion of fractures leading to hospitalization, but the results indicate higher long-term costs and greater loss in quality of life related to vertebral fracture than previously believed.

INTRODUCTION: It has been suggested that bone mineral density (BMD) measurements should be made at multiple sites, and that the lowest T-score should be taken for the purpose of diagnosing osteoporosis. PURPOSE: The aim of this study was to examine the use of BMD measurements at the femoral neck and lumbar spine alone and in combination for fracture prediction. METHODS: We studied 19,071 individuals (68% women) from six prospective population-based cohorts in whom BMD was measured at both sites and fracture outcomes documented over 73,499 patient years. BMD values were converted to Z-scores, and the gradient of risk for any osteoporotic fracture and for hip fracture was examined by using a Poisson model in each cohort and each gender separately. Results of the different studies were merged using weighted beta-coefficients. RESULTS: The gradients of risk for osteoporotic fracture and for hip fracture were similar in men and women. In men and women combined, the risk of any osteoporotic fracture increased by 1.51 [95% confidence interval (CI)=1.42-1.61] per standard deviation (SD) decrease in femoral-neck BMD. For measurements made at the lumbar spine, the gradient of risk was 1.47 (95% CI=1.38-1.56). Where the minimum of the two values was used, the gradient of risk was similar (1.55; 95% CI=1.45-1.64). Higher gradients of risk were observed for hip fracture outcomes: with BMD at the femoral neck, the gradient of risk was 2.45 (95% CI=2.10-2.87), with lumbar BMD was 1.57 (95% CI=1.36-1.82), and with the minimum value of either femoral neck and lumbar spine was 2.11 (95% CI=1.81-2.45). Thus, selecting the lowest value for BMD at either the femoral neck or lumbar spine did not increase the predictive ability of BMD tests. By contrast, the sensitivity increased so that more individuals were identified but at the expense of specificity. Thus, the same effect could be achieved by using a less stringent T-score for the diagnosis of osteoporosis. CONCLUSIONS: Since taking the minimum value of the two measurements does not improve predictive ability, its clinical utility for the diagnosis of osteoporosis is low.

Recent advances in the understanding of the epidemiology of osteoporosis suggest that certain parts of the current European guidelines for the registration of drugs in osteoporosis might be no longer substantiated. The object of this review is to provide the European regulatory authorities with an evidence-based working document providing suggestions for the revision of the "Note for guidance for the approval of drugs to be used in postmenopausal osteoporosis" (CPMP/EWP/552/95). Following an extensive review of the literature (1990-2004), the Group for the Respect of Ethics and Excellence in Science (GREES) organized a workshop including European regulators, academic scientists and representatives of the pharmaceutical industry. The outcomes of this meeting reflect the personal views of those who attended and should not, in any case, be seen as an official position paper of any regulatory agency. The group identified a certain number of points that deserve discussion. They mainly relate to the nature of the indication being granted to new chemical entities (treatment of osteoporosis in women at high risk of fracture instead of prevention and treatment of osteoporosis), the requirements of showing an anti-fracture efficacy on all or on major nonvertebral fractures (instead of the hip), the duration of pivotal trials (2 years instead of 3) and the possibility of considering bridging studies for new routes of administration, new doses or new regimens of previously approved drugs. The group also recommends that an indication could be granted for the treatment of osteoporosis in males on the basis of a placebo-controlled study, with bone mineral density changes after 1 year as the primary endpoint, for medications approved in the treatment of osteoporosis in women at high risk of fractures. © International Osteoporosis Foundation and National Osteoporosis Foundation 2005.

The International Society for Clinical Densitometry (ISCD) has published position statements on topics relating to the use and interpretation of measurements of bone mineral density (BMD). The most recent appeared in the Journal of Clinical Densitometry (1) and was republished in the Journal of Endocrinology and Metabolism and in Osteoporosis International (2,3). The topics included the indications for testing with BMD, the use of central dual energy X-ray absorptiometry (DXA) for the diagnosis of osteoporosis, the use of the Z-score and some recommendations for the spelling of the T-score and Z-score. Although these topics were chosen in an attempt to produce international consistency and consensus, most of the position statements lack a scientific basis. (Less)

The objectives of the present study were to estimate 10-year probabilities of clinical vertebral fractures in women, according to age and bone mineral assessment using phalangeal quantitative ultrasound (QUS). Risks were computed from UK derived data on the incidence of a first symptomatic vertebral fracture and mortality rates for each year of age using Poisson models. The 10-year probability of vertebral fracture was determined as the proportion of individuals fracture-free at that site from the age of 45 years. We assumed that the risk of fracture increased with decreasing QUS as assessed by an independent re-analysis of a previously published, multicenter cross-sectional study. For amplitude-dependent speed of sound (AD-SoS) information was available from 8,502 women, and vertebral fracture risk increased 1.7-fold for each SD decrease in measurement. For fast wave amplitude (FWA), available in 6,573 women, the risk gradient was 2.4/SD. In a subset of the population ( n =1,572) in whom bone mineral density was measured at the lumbar spine, the gradient of risk was 2.3/SD, with similar gradients of risk noted for AD-SoS (1.8/SD) and FWA (2.6/SD). Ten-year probabilities increased with age and decreasing Z -score. The use of absolute risk permits information from different types of bone mineral measurements to be applied for the assessment of patients, either alone or in combination with other independent risk factors.

The aim of this study was to determine the threshold of fracture probability at which interventions became cost-effective in women based on data from the UK. We modelled the effects of an intervention costing pound 350 per year given for 5 years that decreased the risk of all osteoporotic fractures by 35% followed by a waning of effect (offset time) for a further 5 years. Sensitivity analyses included a range of treatment duration (3-10 years), intervention costs (pound 300-400/year) and offset times (0-15 years). Data on costs and risks were from the UK. Costs included direct costs, but excluded indirect costs due to morbidity. A threshold for cost-effectiveness of pound 30,000/QALY gained was used. With the base case ( pound 350 per year; 35% efficacy) treatment in women was cost-effective with a 10-year hip fracture probability that ranged from 1.1% at the age of 50 years to 9.0% at the age of 85 years. Intervention thresholds were sensitive to the assumed costs and offset time. The exclusion of osteoporotic fractures other than hip fracture significantly increased the cost-effectiveness ratio because of the substantial morbidity from such other fractures, particularly at younger ages. Cost-effective scenarios were found for women at the threshold for osteoporosis from the age of 60 years. Treatment of established osteoporosis was cost-effective irrespective of age. We conclude that the inclusion of all osteoporotic fractures has a marked effect on intervention thresholds, that these vary with age and that available treatments can be targeted cost-effectively to individuals from the UK at moderately increased fracture risk.

A low intake of calcium is widely considered to be a risk factor for future fracture. The aim of this study was to quantify this risk on an international basis and to explore the effect of age, gender and bone mineral density (BMD) on this risk. We studied 39,563 men and women (69% female) from six prospectively studied cohorts comprising EVOS/EPOS, CaMos, DOES, the Rotterdam study, the Sheffield study and a cohort from Gothenburg. Cohorts were followed for 152,000 person-years. The effect of calcium intake as judged by the intake of milk on the risk of any fracture, any osteoporotic fracture and hip fracture alone was examined using a Poisson model for each sex from each cohort. Covariates examined were age and BMD. The results of the different studies were merged by using the weighted beta-coefficients. A low intake of calcium (less than 1 glass of milk daily) was not associated with a significantly increased risk of any fracture, osteoporotic fracture or hip fracture. There was no difference in risk ratio between men and women. When both sexes were combined there was a small but non-significant increase in the risk of osteoporotic and of hip fracture. There was also a small increase in the risk of an osteoporotic fracture with age which was significant at the age of 80 years (RR = 1.15; 95% CI = 1.02-1.30) and above. The association was no longer significant after adjustment for BMD. No significant relationship was observed by age for low milk intake and hip fracture risk. We conclude that a self-reported low intake of milk is not associated with any marked increase in fracture risk and that the use of this risk indicator is of little or no value in case-finding strategies.

The diagnosis of osteoporosis is based on the measurement of bone mineral density (BMD). There are a number of clinical risk factors that provide information on fracture risk over and above that given by BMD. The assessment of fracture risk thus needs to be distinguished from diagnosis to take account of the independent value of the clinical risk factors. These include age, a prior fragility fracture, a parental history of hip fracture, smoking, use of systemic corticosteroids, excess alcohol intake and rheumatoid arthritis. The independent contribution of these risk factors can be integrated by the calculation of fracture probability with or without the use of BMD. Treatment can then be offered to those identified to have a fracture probability greater than an intervention threshold.

Several osteoporotic fractures such as hip fractures have a very high morbidity and mortality, and there are similar new findings for vertebral fractures. There have been several definitions of an osteoporotic fracture, and recently updated definitions have specified fractures occurring at a site associated with low BMD and which increase in incidence after the age of 50 years. Other definitions are based on clinical diagnosis. Lifetime risk of any osteoporotic fracture is very high and lies within the range of 40-50% in women and 13-22% for men. Measuring the true burden of osteoporotic fractures involves multiplying the morbidity of hip fractures according to age group: for women aged 50-54 years, the disability caused by osteoporotic fractures is 6.07 times that accounted for by hip fracture alone, and for women aged 80-84 years, the incidence of hip fractures should be multiplied by 1.55; for men aged 50-54 years, the incidence of hip fractures should be multiplied by 4.48, and for those aged 80-84 years by 1.50.

Previous fracture is a well-documented risk factor for future fracture. The aim of this study was to quantify this risk on an international basis and to explore the relationship of this risk with age, sex, and bone mineral density (BMD). We studied 15259 men and 44902 women from 11 cohorts comprising EVOS/EPOS, OFELY, CaMos, Rochester, Sheffield, Rotterdam, Kuopio, DOES, Hiroshima, and two cohorts from Gothenburg. Cohorts were followed for a total of 250000 person-years. The effect of a prior history of fracture on the risk of any fracture, any osteoporotic fracture, and hip fracture alone was examined using a Poisson model for each sex from each cohort. Covariates examined were age, sex, and BMD. The results of the different studies were merged by using the weighted beta-coefficients. A previous fracture history was associated with a significantly increased risk of any fracture compared with individuals without a prior fracture (RR = 1.86; 95% CI = 1.75-1.98). The risk ratio was similar for the outcome of osteoporotic fracture or for hip fracture. There was no significant difference in risk ratio between men and women. Risk ratio (RR) was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any fracture (8%) and for hip fracture (22%). The risk ratio was stable with age except in the case of hip fracture outcome where the risk ratio decreased significantly with age. We conclude that previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by measurement of BMD. Its validation on an international basis permits the use of this risk factor in case finding strategies.

The aim of this study was to examine the effects of risedronate (5 mg/daily) in patients identified solely on the basis of a prior fragility fracture, without BMD as an inclusion criterion. A total of 1,802 patients were examined from the VERT-NA and VERT-MN clinical trials. Lateral radiographs (T4 to L4) were obtained at baseline and annually; incident fractures were evaluated using quantitative and semiquantitative methods at the central facility. BMD was measured at the lumbar spine and femoral neck by dual-energy X-ray absorptiometry. Secondary analyses evaluated vertebral fracture efficacy in patient subgroups categorized according to the presence of risk factors for osteoporosis at baseline (age, femoral neck BMD, lumbar spine BMD, more severe BMD, height, weight, body mass index, prevalent nonvertebral fracture status, smoking, and bone turnover marker levels). Over 3 years, risedronate reduced the risk of new vertebral fractures by 44% (95% CI, 28% to 56%) compared with placebo. In patients subgrouped according to the presence or absence of putative risk factors, the efficacy of risedronate was comparable across all groups (all treatment-by-non BMD subgroup interactions por =0.210). Adjustment for age, baseline BMD, and prevalent vertebral fractures on fracture risk gave results similar to the unadjusted analysis. In patients taking placebo, the incidence of new vertebral fracture was higher in several of the high-risk categories (elderly, T-scoreor = -2.5 SD). In conclusion, the findings of this study suggest that risedronate is effective in patients identified solely on the basis of a prior fragility fracture and that the efficacy of risedronate in the reduction of vertebral fractures is largely independent of the presence of clinical risk factors for osteoporotic fracture.

Smoking is widely considered a risk factor for future fracture. The aim of this study was to quantify this risk on an international basis and to explore the relationship of this risk with age, sex and bone mineral density (BMD). We studied 59,232 men and women (74% female) from ten prospective cohorts comprising EVOS/EPOS, DOES, CaMos, Rochester, Sheffield, Rotterdam, Kuopio, Hiroshima and two cohorts from Gothenburg. Cohorts were followed for a total of 250,000 person-years. The effect of current or past smoking, on the risk of any fracture, any osteoporotic fracture and hip fracture alone was examined using a Poisson model for each sex from each cohort. Covariates examined were age, sex and BMD. The results of the different studies were merged using the weighted beta-coefficients. Current smoking was associated with a significantly increased risk of any fracture compared to non-smokers (RR=1.25; 95% Confidence Interval (CI)=1.15-1.36). Risk ratio (RR) was adjusted marginally downward when account was taken of BMD, but it remained significantly increased (RR=1.13). For an osteoporotic fracture, the risk was marginally higher (RR=1.29; 95% CI=1.13-1.28). The highest risk was observed for hip fracture (RR=1.84; 95% CI=1.52-2.22), but this was also somewhat lower after adjustment for BMD (RR=1.60; 95% CI=1.27-2.02). Risk ratios were significantly higher in men than in women for all fractures and for osteoporotic fractures, but not for hip fracture. Low BMD accounted for only 23% of the smoking-related risk of hip fracture. Adjustment for body mass index had a small downward effect on risk for all fracture outcomes. For osteoporotic fracture, the risk ratio increased with age, but decreased with age for hip fracture. A smoking history was associated with a significantly increased risk of fracture compared with individuals with no smoking history, but the risk ratios were lower than for current smoking. We conclude that a history of smoking results in fracture risk that is substantially greater than that explained by measurement of BMD. Its validation on an international basis permits the use of this risk factor in case finding strategies.

Randomized, double-blind, controlled studies have shown that treatment with risedronate reduces the risk of vertebral fracture in postmenopausal women with established vertebral osteoporosis. They also show that the drug decreases the risk of non-vertebral fractures in women with osteoporosis. The aim of this study was to investigate the cost-effectiveness of risedronate in postmenopausal women with osteoporosis. A Markov model was applied to a UK setting. Treatment effects were computed by meta-analysis of randomized, controlled trials and given over 5 years to subjects aged between 60 and 80 years. Quality-adjusted life years (QALYs) and life years gained were used as outcome measures. Intervention with risedronate was cost-effective in women aged 60 years and older. Cost savings were also found for postmenopausal women aged 70 years and older with established vertebral osteoporosis (a prior spine fracture and BMD T-scoreor =-2.5 SD). This treatment was cost-effective for women aged 65 years and older who had a prior vertebral fracture and a BMD T-score at the threshold of osteoporosis ( T-score=-2.5 SD), and in women with a T-scoreor =-2.5 SD, but without a prior vertebral fracture. In women aged 60-80 years and at the threshold of osteoporosis ( T-score=-2.5 SD) but without a prior vertebral fracture, treatment exceeded the threshold for cost-effectiveness. However, if an additional, independent risk factor was assumed (e.g., corticosteroid use) treatment became cost-effective.

Background : One third of all the hip fractures occur in men. The risk for mortality following hip fracture is higher for men compared to women. The Fracture Intervention Trial (FIT) showed that the bisphosphonate alendronate reduces the risk of fractures and increases bone mineral density (BMD) in osteoporotic women. Similar effects of alendronate were observed in men in some other trials. There are also results demonstrating alendronate to be cost-effective in the treatment of osteoporosis in women. Objective : To investigate the cost effectiveness of alendronate for male osteoporosis in Sweden by assuming the same relative risk reduction of fractures in men as for women, based on the FIT trial. Design : A Markov model earlier used to analyze cost effectiveness of alendronate in treatment of postmenopausal osteoporosis in Sweden was adapted to fit a cohort of Swedish men. Cost effectiveness of alendronate vs. no treatment was assessed by transitioning men in the model over time between different health states. Time horizon : The patients were followed from start of intervention until 100 years of age or death. In the base-case alendronate was assumed to have a fracture-risk-reducing effect for 10 years; a treatment duration period of 5 years followed by a 5-year period where the effect declined linearly to zero. Results : Taking a societal perspective treating a 71-year-old man (mean age in the FIT) with low BMD and prior vertebral fracture (VFA) with alendronate was found to be associated with a cost of €14,843 per quality adjusted life year (QALY) gained. Conclusions : The results in this study indicate that treating osteoporotic men with alendronate was projected to be cost-effective, under the assumption of the same fracture-risk-reducing effect of alendronate for men as for women.

Vertebral fractures are associated with back pain and disability. There are, however, few prospective data looking at back pain and disability following identification of radiographic vertebral fracture. The aim of this analysis was to determine the impact of radiographically identified vertebral fracture on the subsequent occurrence of back pain and disability. Women aged 50 years and over were recruited from population registers in 18 European centers for participation in the European Prospective Osteoporosis Study. Participants completed an interviewer-administered questionnaire which included questions about back pain in the past year and various activities of daily living, and they had lateral spine radiographs performed. Participants in these centers were followed prospectively and had repeat spine radiographs performed a mean of 3.7 years later. In addition they completed a questionnaire with the same baseline questions concerning back pain and activities of daily living. The presence of prevalent and incident vertebral fracture was defined using established morphometric criteria. The data were analyzed using logistic regression with back pain or disability (present or absent) at follow-up as the outcome variable with adjustment made for the baseline value of the variable. The study included 2,260 women, mean age 62.2 years. The mean time between baseline and follow-up survey was 5.0 years. Two hundred and forty participants had prevalent fractures at the baseline survey, and 85 developed incident fractures during follow-up. After adjustment for age, center, and the baseline level of disability, compared with those without baseline prevalent fracture, those with a prevalent fracture (odds ratio [OR] = 1.4; 95% confidence interval [CI] 1.0 to 2.0) or an incident fracture (OR = 1.7; 95% CI, 0.9 to 3.2) were more likely to report disability at follow-up, though the confidence intervals embraced unity. Those with both a prevalent and incident fracture, however, were significantly more likely to report disability at follow-up (OR = 3.1; 95% CI, 1.4 to 7.0). After adjustment for age, center, and frequency of back pain at baseline, compared with those without baseline vertebral fracture, those with a prevalent fracture were no more likely to report back pain at follow-up (OR = 1.2; 95% CI, 0.8 to 1.7). There was a small increased risk among those with a preexisting fracture who had sustained an incident fracture during follow-up (OR = 1.6; 95% CI, 0.6 to 4.1) though the confidence intervals embraced unity. In conclusion, although there was no significant increase in the level of back pain an average of 5 years following identification of radiographic vertebral fracture, women who suffered a further fracture during follow-up experienced substantial levels of disability with impairment in key physical functions of independent living.

Global aging superimposed on existing infectious diseases and trauma will aggravate competition for health care resources to diagnose and treat osteoporosis. Efforts to implement public health measures are needed, but the targeted approach to assessment and treatment of high-risk individuals must also be refined. Increases in the elderly population worldwide will cause a dramatic rise in osteoporotic fractures, but other age-related diseases will increase as well. Changes will be superimposed on existing public health problems (e.g., malaria, alcoholism), and these acute health care needs will take priority in some areas. Societies in most parts of the world may have to limit osteoporosis control to broad public health measures, and such efforts (e.g., calcium and vitamin D supplementation) should be supported. In these regions, clinical decision-making will generally be limited to treating patients with fractures (who presumably have already failed any public health measures in place), or in a few wealthy countries, to patients with low bone density identified by case-finding. Case-finding approaches will vary with the resources available, although unselective (mass) screening by bone densitometry is largely ineffective and unaffordable anywhere. The key to clinical decision-making on behalf of individuals will be an assessment of absolute fracture risk, and the tools needed to predict the risk of an osteoporotic fracture over the next 10 years are now being developed. These include bone density measures, but also incorporate other risk factors (e.g., fracture history, corticosteroid use), which may allow extension of fracture risk prediction to nonwhite populations and to men. Even with a universal risk prediction tool, cost-effective treatment thresholds will vary by country based on the level of fracture risk in the region and on the resources available for health care. To better compete for these resources, efforts should be made to lower the cost of osteoporosis interventions. Additionally, evidence is needed that these interventions are really effective in reducing fractures in the community.

BACKGROUND. in this retrospective data base study, the authors sought to estimate direct costs for bone fractures in women age 65 years with early-stage breast carcinoma and to compare those costs with treatment costs for bone fractures in older women without early-stage breast carcinoma. METHODS. Direct costs for bone fractures in patients with early-stage breast carcinoma, which consist of excess treatment costs for bone fracture and excess costs of long-term care for bone fracture, were evaluated by using the 1997-1998 Standard Analytical File. The statistical significance of the difference in inpatient costs, medical treatment costs, and long-term care admission rates were determined with the t test and the Fisher chi-square test, respectively. RESULTS. For older women with early-stage breast carcinoma, the direct costs for bone fracture were estimated at $45,579, and 57% of those costs came from treating the bone fracture (32% came from inpatient hospital costs, and 25% came from noninpatient hospital costs), 25% came from other excess treatment costs, and 18% came from excess long-term care costs. The women who had early-stage breast carcinoma and sustained bone fracture did not differ significantly from the women without early-stage breast carcinoma who sustained a bone fracture. CONCLUSIONS. Bone fracture was associated with high direct costs in older women with early-stage breast carcinoma. Additional research should include appropriate, incidence-based studies to investigate the potential benefit of an intervention for preventing bone fracture in this increasingly large patient population. (Less)

An excess mortality is well described after vertebral fracture. Deaths are in part related to co-morbidity, but could also be due to the fracture event itself, either directly or indirectly. The aim of this study was to examine the quantum and pattern of mortality following vertebral fracture. We identified 16,051 men and women aged 50 years or more with a vertebral fracture that required hospitalization in 28.8 million person years from the patient register of Sweden. Mortality after vertebral fracture was examined using Poisson models applied to fracture patients and compared to that of the general population. At all ages, the risk of death was markedly increased immediately after the event. After a short period of declining risk, the risk increased with age at a rate that was higher than that of the general population and comparable to that 1 year after hip fracture. The latter function was assumed to be due to deaths related to co-morbidity and the residuum assumed to be due to the vertebral fracture. Causally related deaths comprised 28% of all deaths associated with vertebral fracture (depending on age). We conclude that a minority of deaths following hospitalization for vertebral fracture are attributable to the fracture itself under the assumptions we used.

The aim of this study was to examine the pattern of fracture risk following a prior fracture at the spine, shoulder or hip. We studied 1918 patients with fractures at these sites identified from the Department of Radiology in Malmo who were followed for 5 years. Poisson regression was used to compute fracture rates immediately after the initial fracture and at 5 years thereafter in men and women aged 60 or 80 years. Immediate fracture risk was higher than that of the general population, more markedly so at the age of 60 than at 80 years. At the age of 60 years, the risk of hip, forearm and spine fractures were significantly increased following a prior spine, hip or shoulder fracture in men. A similar pattern was seen in women, except that the increase in risk of forearm fracture following a spine or hip fracture was not statistically significant. The incidence of further fractures at the shoulder, spine or hip fell with time after the first fracture, a fall that was significant for all fractures after a shoulder fracture, hip fracture after a spine fracture, and hip and spine fractures after a hip fracture. We conclude that the risk of a subsequent fracture immediately after an osteoporotic fracture is highest immediately after the event. This provides a rationale for very early intervention immediately after fractures to avoid recurrent fractures.

We studied the appearance and frequency of the medial epiarticular osteophyte in human femoral heads. Specimens were sampled from 24 men and 31 women who underwent total hip arthroplasty. On radiography, medial epiarticular osteophytes were present in two thirds of the cases. However, histological examination revealed endochondral ossification in all. Presumably, the bone formation was preceded by the formation of canals and cavities containing vessels. Due to the ossification around these canals and cavities, the histological picture frequently featured two layers of cartilage with bone in the middle. Also in the marginal osteophytes, bone was formed by endochondral ossification. However, this bone appeared more irregular. The new bone formation most likely indicates a reactivated growth as an attempt to repair the osteoarthritic lesions rather than a process of degradation.

Raloxifene reduces vertebral fracture risk in postmenopausal women with osteoporosis and established osteoporosis, but its efficacy in women with osteopenia has not been studied. The objective of this study was to evaluate the effect of raloxifene hydrochloride on the risk of vertebral fractures in postmenopausal women with osteopenia and to compare this effect with that in women with osteoporosis as defined by the bone mineral density (BMD) T-score at the hip. We studied the 3204 postmenopausal women with osteopenia or osteoporosis without vertebral fractures at baseline in the Multiple Outcomes of Raloxifene Evaluation trial. Compared with placebo, 60 mg/day raloxifene reduced the risk of new vertebral fractures at 3 years independent of baseline total hip BMD. The relative risk for new vertebral fractures for the raloxifene group compared with placebo was 0.53 (95% CI, 0.32-0.88) for those with osteopenia and 0.31 (0.06-0.71) for those with osteoporosis. In raloxifene-treated women the rate of vertebral fracture was similar in women with osteoporosis (2%) to that in women with osteopenia (1.9%). For clinically apparent vertebral fractures, the relative risk of fracture in the osteopenia group for raloxifene was 0.25 (0.04-0.63) compared with placebo. There were no new clinical vertebral fractures in women with osteoporosis receiving raloxifene, whereas four occurred in the placebo group. We conclude that treatment with 60 mg/day raloxifene significantly decreases the risk of new vertebral fractures and new clinical vertebral fractures in postmenopausal women without baseline vertebral fracture who have osteopenia or osteoporosis.

The quality of the subchondral bone in total knee arthroplasty (TKA) may be important for the outcome. We correlated a histomorphologic analysis of the prosthetic bone bed to micromotion as analyzed by roentgen stereophotogrammetric analysis (RSA). Twenty-three knees, both osteo- and rheumatoid arthritic were studied. The mean migration after 1 year was 1 mm (0.21–2.68), with no correlation to the bone variables or diagnosis. One patient underwent revision after 3 years because of pain. One patient underwent revision after 15 years because of aseptic loosening. This patient appeared stable according to changes in maximum total point motion (MTPM), but the prosthesis migrated continuously according to segment motion. Prosthetic migration increased after 10 years, zones started to evolve, and the patient became symptomatic after 13 years. A biopsy of the bone bed was taken in all patients. A larger percentage of trabecular bone and a larger relative area of unmineralized osteoid surface were found in patients with rheumatoid arthritis compared with those with osteoarthritis. The latter finding is probably a result of increased bone turnover. In conclusion, no support currently exists for the idea that preoperative bone quality, evaluated as bone histomorphometry, has any impact on prosthetic micromotion in knee prostheses.

A high excess mortality is well described after hip fracture. Deaths are in part related to comorbidity and in part due directly or indirectly to the hip fracture event itself (causally related deaths). The aim of this study was to examine the quantum and pattern of mortality following hip fracture. We studied 160,000 hip fractures in men and women aged 50 years or more, in 28.8 million person-years from the patient register of Sweden, using Poisson models applied to hip fracture patients and the general population. At all ages the risk of death was markedly increased compared with population values immediately after the event. Mortality subsequently decreased over a period of 6 months, but thereafter remained higher than that of the general population. The latter function was assumed to account for deaths related to comorbidity and the residuum assumed to be due to the hip fracture. Causally related deaths comprised 17-32% of all deaths associated with hip fracture (depending on age) and accounted for more than 1.5% of all deaths in the population aged 50 years or more. Hip fracture was a more common cause for mortality than pancreatic or stomach cancer. Thus, interventions that decreased hip fracture rate by, say, 50% would avoid 0.75% or more of all deaths.

The prevalence of vertebral deformity, estimated in lateral spine radiographs (Th4-L4) using quantitative morphometry, in 64 men and 132 women with hip fractures was compared with the prevalence of vertebral deformity in individuals in two population-based studies. A vertebral deformity of a specific vertebra was defined as a 3, 4, or 5 SD reduction from the normal mean of any of three ratios describing that specific vertebra. The age-adjusted prevalence of individuals with vertebral deformities was higher among the hip fracture patients than among the reference subjects in both genders, with an odds ratio of 3.6 [95% confidence interval (CI) 1.9-6.6] in men and 2.6 (95% CI 1.7-4.1) in women using deformity criterion -3 SD. Also, the number of vertebrae with deformities (-3 SD) in individuals with one deformity or more was greater among the hip fracture patients than among the reference subjects (in men mean 2.3 versus 1.8, P = 0.007; in women mean 3.3 versus 2.0, P0.001). Adjusted for age there were more vertebrae with deformities (-3 SD) among female than among male hip fracture patients (mean 3.3 versus 2.3, P = 0.01). We found no differences in the vertebral deformity rates when comparing patients with a per- or subtrochanteric hip fracture with patients with a cervical hip fracture. In conclusion, there is a relationship between vertebral deformities and hip fractures suggesting that a prevalent vertebral deformity could predict an increased hip fracture risk.

The Fracture Intervention Trial (FIT) demonstrated that the bisphosphonate alendronate reduces the risk of hip, spine and wrist fracture in osteoporotic women by approximately one half.To use data from FIT to conduct a cost-effectiveness analysis of alendronate.A Markov model was developed for a cohort of Swedish women, comparable in relative fracture risk to the women enrolled in the FIT vertebral fracture arm (i.e. age 71 years with low bone mass plus at least one prior spine fracture). The women in the model (with low bone mass and a previous spine fracture) were exposed to alendronate therapy and transitioned over time from a 'well' health state to health states of 'hip fracture', 'spine fracture', 'wrist fracture' or 'death'. All costs were calculated in 2000 Swedish kronors (SEK).In the Markov model our base-case treatment duration was 5 years followed by a 5-year period where the benefit declined linearly to 0.We found that treating 71-year-old osteoporotic women with a prior spine fracture with alendronate resulted in a cost per quality-adjusted life-year (QALY) gained of SEK76000, which is well below the threshold for cost effectiveness of SEK300000. For women aged 65 years, the cost-effectiveness ratio increased to SEK173000 and for women aged 77 years, the cost-effectiveness ratio decreased to SEK52000.Treating older osteoporotic women with alendronate was more cost effective than treating younger women with osteoporosis, and treating osteoporotic women with prior spine fracture was more cost effective than treating osteoporotic women without prior spine fracture. However, the costs per QALY gained for all populations studied were below generally accepted thresholds for cost effectiveness.

The aim of this study was to determine the threshold of fracture probability at which interventions become cost-effective. We modeled the effects of a treatment costing $500/year, given for 5 years, that decreased the risk of all osteoporotic fractures by 35%, followed by a waning of effect for 5 years. Sensitivity analyses included a range of effectiveness (10%-50%) and a range of intervention costs (200-500 dollars/year). Data on costs and risks were from Sweden. Costs included direct costs and costs in added years of life, but excluded indirect costs due to morbidity. A threshold for cost-effectiveness of 60,000 dollars per quality-adjusted life-year (QALY) gained was used. Costs of added years were excluded in a sensitivity analysis for which a threshold value of 30,000 dollars per QALY was used. In the base case, intervention was cost-effective when treatment was targeted to women at average risk at age of >or=65 years. Irrespective of the efficacy modeled (10%-50%) or of cost of intervention (200-500 dollars/year) segments of the population at average risk could be targeted cost-effectively: The lower the intervention cost and the higher the effectiveness, the lower the age at which intervention was cost-effective. With the base case (500 dollars/year; 35% efficacy) treatment in women was cost-effective with a 10 year hip fracture probability that ranged from 1.4% at the age of 50 years to 4.4% at the age of 65 years. The exclusion of osteoporotic fractures other than hip fracture would increase the threshold to a 9%-11% 10 year probability because of the substantial morbidity from fractures other than hip fracture, particularly at younger ages. We conclude that the inclusion of all osteoporotic fractures has a marked effect on intervention thresholds, that these vary with age, and that available treatments can be cost-effectively targeted to individuals at moderately increased risk.

There is a need for studying the effects of long-term inhaled corticosteroid therapy on bone mineral density (BMD) and vertebral fracture rates in patients with mild chronic obstructive pulmonary disease (COPD).Patients (n=912, mean age 52 yrs) with mild COPD (mean forced expiratory volume in one second (FEV1) 77% of predicted; mean FEV1/slow vital capacity ratio 62%) were randomized to receive budesonide 400 mug, or placebo twice daily via Turbuhaler R. BMD was measured at the L2-L4 vertebrae and the femoral neck, trochanter and Ward's triangle by dual-energy X-ray absorptiometry at baseline and after 6, 12, 24 and 36 months (n=161). Radiographs of the thoracic and lumbar spine were obtained at the beginning and end of treatment (n=653).Previous fractures were present at baseline in 43 budesonide-treated patients (13.4%) and 38 placebo-treated patients (11.5%). New fractures occurred in five budesonide-treated patients, compared with three in the placebo group (p=0.50). There were no significant changes in BMD at any site in budesonide-treated patients. compared with the placebo group, during the course of the study. Budesonide treatment was associated with a slight but statistically significant decrease in the area under the concentration-time curve for serum osteocalcin.In the present study, involving a large group of patients with chronic obstructive pulmonary disease, long-term treatment with budesonide 800 mug.day(-1) via Turbuhaler R had no clinically significant effects on bone mineral density or fracture rates.

The advent of effective agents for the treatment of osteoporosis has led to the view that placebo-controlled trials to test new agents for efficacy are no longer appropriate since proven treatments are available. In this review we argue that, if new agents are to be developed, there is still a place for the placebo-controlled trial. A move to studies of equivalence or non-inferiority raises more problems than it resolves.

Background: Surgical removal of the stomach (gastrectomy, Gx) induces osteopenia. In this study we compared the osteopenic effect of Gx with that induced by calcium (Ca) deficiency. Methods: Young male rats were subjected to Gx and/or low Ca diet (-Ca). A group of Gx rats received standard diet + oral Ca supplementation (+ Ca). The rats were killed at various times after the operation/start of treatment (longest time 12 weeks). After 8 weeks on low Ca diet, the blood Ca 2 concentration was lowered slightly in both Sham-operated and Gx rats. The calvariac were subjected to transillumination analysis and quantitative histomorphometry. Also the tibiae were subjected to histomorphometry. Results: Transillumination of the calvariae revealed extensive bone loss in the rats that had been subjected to Gx and/or low Ca diet, Gx + Ca induced the same bone loss as Gx alone. These observations were later confirmed in quantitative terms by histomorphometry (Sham-Ca 56%, Gx 35%, Gx + Ca 32%, Gx - Ca 58% less bone area than in Sham). The osteopenia induced by Gx+ low Ca diet seemed more rapid in onset than that induced by Gx or low Ca diet alone. Tibiae from Gx rats and rats given a low Ca diet displayed a reduced trabecular bone volume (Sham-Ca 27%, remaining, Gx 36%, Gx + Ca 44%, Gx - Ca 1711) and reduced trabecular number (Sham-Ca 44% remaining, Gx 41%, Gx + Ca 56%, Gx - Ca 33%). The trabecular thickness was reduced in the Gx rats and Gx - Ca rats (Gx 78% remaining, Gx-Ca 63%) but not in Sham-operated rats receiving a low Ca-dict (95% remaining). Conclusion: Although the pattern of osteopenia was qualitatively quite similar in Gx rats and Ca-deficient rats, in quantitative terms the low Ca diet was more detrimental to bone than Gx. Ca deficiency induced a similar degree of osteopenia in both Sham and Gx rats. Ca supplementation failed to prevent the Gx-induced osteopenia. (Less)

Interpretation of data in epidemiological cohort studies may be confounded if differences exist between non-participants and participants. In the Malmo part of the European Vertebral Osteoporosis Study (EVOS), which was designed to evaluate the prevalence of vertebral deformity in 50-80-year-old persons, we compared 74 men and 95 women who had been invited, but declined to participate with age- and gender-matched participants as regards alcohol abuse, previous fractures and subsequent mortality, factors known to affect the prevalence of vertebral deformity. We found more men with alcohol abuse, more men with a previous fragility fracture and a tendency to more men with a previous clinical vertebral fracture among the non-participants than in the male partici- pants. In contrast, there were fewer female non-partici- pants than female participants with a previous clinical vertebral fracture. The mortality rate during the decade after the baseline examination was higher among both male and female non-participants. The "true" prevalence of vertebral deformity in the whole male population at risk in Malmo seems to be underestimated in the EVOS study. In women, it is more dife cult to estimate the combined result of the confounding factors. Conclusions based on the EVOS participants may not be applicable to the whole popula- tion at risk. n

This review examines the hypothesis that there are gender differences in the relationship between bone mineral density (BMD) and fracture risk. Prospective studies of spine and hip fracture risk drawn from population samples suggest that the fracture risk increases as BMD decreases in men in the same way as that described in women. Moreover, for any given BMD at the spine, heel, or proximal femur the risk in men is similar to that in women. Although data are limited, prior fragility fractures increase subsequent fracture risks in both men and women. These studies suggest that the same BMD criteria used to diagnose osteoporosis in women can be applied to men.

The aim of this study was to assess the relationship between morbidity from hip fracture and that from other osteoporotic fractures by age and sex based on the population of Sweden. Osteoporotic fractures were designated as those associated with low bone mineral density (BMD) and those that increased in incidence with age after the age of 50 years. Severity of fractures was weighted according to their morbidity using utility values based on those derived by the National Osteoporosis Foundation. Morbidity from fractures other than hip fracture was converted to hip fracture equivalents according to their disutility weights. Excess morbidity was 3.34 and 4.75 in men and women at the age of 50 years, i.e. the morbidity associated with osteoporotic fractures was 3–5 times that accounted for by hip fracture. Excess moribidity decreased with age to approximately 1.25 between the ages of 85 and 89 years. On the assumption that the age- and sex-specific pattern of fractures due to osteoporosis is similar in different communities, the computation of excess morbidity can be utilized to determine the total morbidity from osteoporotic fractures from knowledge of hip fracture rates alone. Such data can be used to weight probabilities of hip fracture in different countries in order to take into account the morbidity from fractures other than hip fracture, and to modify intervention thresholds based on hip fracture risk alone. If, for example, a 10-year probability of hip fracture of 10% was considered an intervention threshold, this would be exceeded in women with osteoporosis aged 65 years and more, but when weighted for other osteoporotic fractures would be exceeded in all women (and men) with osteoporosis.

The aims of this study were to determine whether treatments that reduce the incidence of hip fracture might be used in the general female population rather than screening or case-finding strategies. Cost-effectiveness, measured as cost per quality-adjusted life-year (QALY) gained using threshold values for cost-effectiveness of $20,000 or $30,000/QALY gained, was assessed during and after treatment using a computer simulation model applied to the female population of Sweden. The base case assumed a 5-year intervention that reduced the risk of hip fracture by 35% during the treatment period, and an effect that reversed to the pretreatment risk during the next 5 years. Sensitivity analyses included the effects of age, different treatment costs and effectiveness. Cost-effectiveness was critically dependent upon the age and costs of intervention. Reasonable cost-effectiveness was shown even with relatively high intervention costs for women at average risk at the age of 84 years or more. For the cheapest interventions ($63/year) cost-effectiveness could be found from the age of 53 years. Variations in effectiveness (15-50% risk reduction) had marked effects on the age that treatment was worthwhile. We conclude that segments of the apparently healthy population could be advantaged by treatment if efficacy were supported by randomized controlled studies.

The aims of this study were to determine the magnitude of the increase in risk of further fracture following hospitalization for vertebral fracture, and in particular to determine the time course of this risk. The records of the Swedish Patient Register were examined from 1987 to 1994 to identify all patients who were admitted to hospital for thoracic or lumbar vertebral fractures. Vertebral fractures were characterized as due to high- or low-energy trauma. Patients were followed for subsequent hospitalizations for hip fracture, and for all fractures combined. A Poisson model was used to determine the absolute risk of subsequent nonvertebral fracture and compared with that of the general population. We analyzed 13.4 million hospital admissions from which 28,869 individuals with vertebral fracture were identified, of which 60% were associated with low-energy trauma. There was a marked increase in subsequent incidence of hip and all fractures within the first year following hospitalization for vertebral fracture in both men and women. Thereafter, fracture incidence declined toward, but did not attain, baseline risk. Increased risks were particularly marked in the young. The increase in fracture risk was more marked following low-energy vertebral fracture than in the case of high-energy trauma. We conclude that the high incidence of new fractures within a year of hospitalization for vertebral fractures, irrespective of the degree of trauma involved, indicates that such patients should be preferentially targeted for treatment. It is speculated that short courses of treatment at the time of first vertebral fracture could provide important therapeutic dividends.

On the basis of cross-sectional studies in elite athletes and longitudinal studies, physical activity in growing children has been suggested to enhance bone mineral acquisition and prevent osteoporosis later in life. The level of exercise in most of these studies is not applicable in a population on a day-to-day basis. The aim of this study was to determine whether moderate increased exercise within the school curriculum from age 12 to 16 years would have anabolic bone effects. In a population-based setting of 40 boys and 40 girls the school curriculum was enhanced to physical education 4 times per week for 3-4 years. Controls were 82 boys and 66 girls who had had physical education twice a week over a corresponding period. Both cases and controls were measured at age 16 years. Bone mineral content (BMC), areal bone mineral density (aBMD), bone size (femoral neck width) and volumetric BMD (vBMD) were measured in total body, spine and femoral neck (FN) by dual-energy X-ray absorptiometry. Data are presented as mean +/- SD. BMC (8 +/- 15%, p = 0.04), aBMD (9 +/- 13%, p = 0.002) and vBMD (9 +/- 15%, p = 0.001) were all higher in FN in the male intervention group compared with controls. FN bone size was no higher in the intervention group than in the controls. In girls, no differences were found when comparing the intervention group with controls. The results remained after adjusting for confounding factors such as weight, height, milk intake and activity after school. In summary, we report that increased bone mass can be achieved in a population-based cohort of boys (but not in girls) by moderate increased physical activity within the school curriculum from age 12 to 16 years. We speculate that the same results can be seen in girls if intervention starts at an earlier age. We conclude that increasing the physical education content of the Swedish school curriculum may improve bone mass in at least peripubertal boys.

These guidelines are for practicing orthopedic surgeons who do not have a special interest in treatment of osteoporosis or prevention of falls, but who should have basic knowledge about how to prevent new fractures.

We have investigated patients with hip fracture between 1992–1997 in two regions in southern Sweden, the urban city of Malmo and the rural Hassleholm-Kristianstad (HK). All patients with hip fracture over 65 years of age were included, resulting in a total of 5201 consecutive hip fractures in 4891 patients. The annual incidence of hip fracture for the period 1992–1997 was in Malmo 69/10 000 for men and 138/10 000 for women, and 62/10 000 for men and 125/10 000 for women in HK. The 6/12 month mortality rate was in Malmo 25%/31.6% for men and 15.9%/20.3% for women, while it was 23.1%/28.9% for men and 12.8%/17.4% for women in HK. We found significantly lower incidence of hip fracture among the rural population in both sexes and also lower mortality rates among the population with hip fracture in the rural area.

Vertebral fractures may be minor or lead to pain, decreased physical function, immobility, social isolation and depression, which together contribute to quality of life. A Working Party of the European Foundation for Osteoporosis has developed a specific questionnaire for patients with vertebral fractures. This questionnaire, QUALEFFO, includes questions in the domains pain, physical function, social function, general health perception and mental function. QUALEFFO was validated in a multicenter study in seven countries. The study was done in 159 patients aged 55-80 years with clinical osteoporosis, i.e., back pain and other complaints with at least one vertebral fracture and lumbar bone mineral density T-score /=0.70. The internal consistency of the five domains was adequate, with Crohnbach alpha around 0.80. All except five questions discriminated significantly between patients and controls. The median scores of QUALEFFO were significantly higher in patients with vertebral fractures than in controls in all five domain (p /=3 SD severity, in contrast with 7 controls (4%). Significant correlations existed between scores of similar domains of QUALEFFO and the SF-36, especially for pain, physical function and mental function. All five domains within each questionnaire discriminated significantly between fracture cases and controls. The odds ratios for pain and social function were greater for QUALEFFO, while general health perception was more discriminating using the SF-36. The ROC curve analysis of QUALEFFO indicated that all five domains were significantly predictive of vertebral fractures. When comparing similar domains of the two questionnaires, QUALEFFO domains demonstrated significantly better performance for pain, physical function and social function. The QUALEFFO total score and SF-36 physical composite score showed similar performance. In conclusion, QUALEFFO is repeatable, coherent and discriminates well between patients with vertebral fractures and control subjects. The results of this study confirm the decreased quality of life in patients with vertebral fractures.

The aims of this study were to identify risk factors for hip fracture in men aged 50 years or more. We identified 730 men with hip fracture from 14 centers from Portugal, Spain, France, Italy, Greece and Turkey during the course of a prospective study of hip fracture incidence and 1132 age-stratified controls selected from the neighborhood or population registers. The questionnaire examined aspects of work, physical activity past and present, diseases and drugs, height, weight, indices of co-morbidity and consumption of tobacco, alcohol, calcium, coffee and tea. Significant risk factors identified by univariate analysis included low body mass index (BMI), low sunlight exposure, a low degree of recreational physical activity, low consumption of milk and cheese, and a poor mental score. Co-morbidity including sleep disturbances, loss of weight, impaired mental status and poor appetite were also significant risk factors. Previous stroke with hemiplegia, prior fragility fractures, senile dementia, alcoholism and gastrectomy were associated with significant risk, whereas osteoarthrosis, nephrolithiasis and myocardial infarction were associated with lower risks. Taking medications was not associated with a difference in risk apart from a protective effect with the use of analgesics independent of co-existing osteoarthrosis and an increased risk with the use of anti-epileptic agents. Of the potentially ‘reversible’ risk factors, BMI, leisure exercise, exposure to sunlight and consumption of tea and alcohol and tobacco remained independent risk factors after multivariate analysis, accounting for 54% of hip fractures. Excluding BMI, 46% of fractures could be explained on the basis of the risk factors sought. Of the remaining factors low exposure to sunlight and decreased physical activity accounted for the highest attributable risks (14% and 9% respectively). The use of risk factors to predict hip fractures had relatively low sensitivity and specificity (59.6% and 61.0% respectively). We conclude that lifestyle factors are associated with significant differences in the risk of hip fracture. Potentially remediable factors including a low degree of physical exercise and a low BMI account for a large component of the total risk.

Background: Gastrectomy induces osteopenia. In this study, we tested if resection of defined parts of the stomach could reproduce the gastrectomy-evoked osteopenia. Methods: Rats were subjected to gastrectomy (surgical removal of the glandular part of the stomach), fundectomy (extirpation of the acid-producing part, fundus) or antrectomy (extirpation of the gastrin-producing part, antrum). Calvariae, tibiae and femurs were examined at various times after the operations. The calvariae were subjected to transillumination. Calvariae and tibiae were sectioned and analysed by histomorphometry, tibia sections by the aid of a Merz grid and calvaria sections using computer-assisted image analysis. The intact femurs were subjected to computerized microtomography. Results: Gastrectomy (hypogastrinemia) and fundectomy (hypergastrinemia) resulted in osteopenia, while antrectomy (hypogastrinemia) had less effect on bone. Gastrectomy/fundectomy were associated with loss of trabecules in the tibia and with reduced bone volume in both tibia and calvaria. In contrast, there was only little reduction of cortical bone in the femur. Conclusion: Gastrectomy-evoked osteopenia can be reproduced by selective resection of the acid-producing part of the rat stomach (i.e. fundectomy). Antrectomy was less effective. In the long bones, the osteopenia was manifested primarily in trabecular bone and less in cortical bone. The calvaria displayed marked osteopenia. Although the findings indicate that the stomach, notably the acid-producing (oxyntic) mucosa, is important for bone metabolism, the precise mechanisms behind the gastrectomy/fundectomy-evoked osteopenia remain unidentified. Clearly, lack of gastrin is not responsible. The oxyntic mucosa is rich in peptide hormone-producing cells (the so-called ECL cells), with unidentified physiological significance. The ECL cells, which operate under the control of gastrin, have been put forward as a possible source of an osteotropic hormone.

Use of postmenopausal hormone replacement therapy (HRT) has been associated with a reduced risk of osteoporotic fractures. However, it is uncertain whether this risk reduction is modified by other risk factors for hip fracture. In a population-based case-control study in Sweden, we investigated the association between HRT and hip fracture risk within categories of age, body measures and lifestyle factors in postmenopausal women, 50-81 years of age. Mailed questionnaires and telephone interviews were used to collect data. Of those eligible, 1328 incident cases with hip fracture (82.5%) and 3312 randomly selected controls (81.6%) answered the questionnaire. Ever use of HRT in women less than 75 years old was associated with an odds ratio (OR) of 0.66 (95% confidence interval: 95% CI 0.50-0.87) for hip fracture compared with OR 0.40 (95% CI 0.21-0.77) in women 75 years or older. We found a significant interaction between HRT and both weight and physical activity (p < 0.05). The protective effect of HRT was particularly pronounced in lean women: compared with never HRT users, ever users weighing under 60 kg had an OR of 0.44 (95% CI 0.30-0.66) whereas women weighing more than 70 kg had an OR of 0.91 (95% CI 0.53-1.56). Women with low recent leisure physical activity (less than 1 h/week) similarly benefited more from HRT for hip fracture prevention than women with a higher degree of recreational physical activity. The observed interactions with weight and physical activity suggest that HRT has the best protective effect against hip fracture among high-risk women.

Estimates of lifetime risk of osteoporotic fracture have assumed that mortality rates do not change. Since mortality in the elderly is decreasing in all regions of the world we assessed the effect of this on lifetime risks for hip fracture using Sweden as a reference country. Lifetime risks of hip fracture at the age of 50 years were 4.6% and 13.9% in men and women respectively, assuming all survive to current average life expectancy. Estimates increased to 8.1% and 19.5% when based on present mortality and to 11.1% and 22.7% respectively based on predicted mortality. We conclude that lifetime risks of hip fracture have been considerably underestimated.

Hip fracture is a major public health problem, but with a potential for prevention. Data from a European multicentre study on hip fracture epidemiology with a case control design, the MEDOS study, were used to describe and analyse circumstances around falls associated with hip fracture. The study includes 2185 fracture cases age > 50 years from 14 centres in southern Europe: Portugal, Spain, France, Italy, Greece and Turkey. Information was collected by a standardized and validated questionnaire translated into six languages and administered by trained interviewers. Circumstances around the fall were categorized according to: (1) place, age group and time of day; (2) functional disability; (3) drug consumption including alcohol; and (4) environmental factors. Possibilities for prevention were also analysed. High risk falls were identified using seven reasonably well-established risk factors, and similarly eight risk factors were used to identify high risk fallers. Selected trains of events were also studied. A pattern of great diversity was found both among the fallers and the environment in which they fell and fractured the hip. Those with more than one factor involved constituted only 14.7% of female and 19.7% of male fractures. A majority of cases were not physically disabled before the fall. A majority (66.5%) fell and fractured their hip indoors and only 4.3% outside in darkness. Cardiovascular and cerebrovascular comborbidity were observed with 4.9 and 7.8%, of falls respectively. Falls in a stairway comprised 11% of falls. The correlation between the number of the risk factors of the faller and in the environment was 0.07 and there was no difference between males and females. The pattern of causality behind falls that cause hip fracture and therefore of prevention comprises many sometimes small groups and intricate time sequence. The results suggest that global preventive strategies could presently not be implemented. Instead, the pattern of prevention should include different target groups and be country and site specific. For the high risk group of institutionalized patients prevention can be implemented without delay.

Objective: To determine the relative risk of hip fracture associated with postmenopausal hormone replacement therapy including the effect of duration and recency of treatment, the addition of progestins, route of administration, and dose. Design: Population based case-control study. Setting: Six counties in Sweden. Subjects: 1327 women aged 50-81 years with hip fracture and 3262 randomly selected controls. Main outcome measure: Use of hormone replacement therapy. Results: Compared with women who had never used hormone replacement therapy, current users had an odds ratio of 0.35 (95 % confidence interval 0.24 to 0.53) for hip fracture and former users had an odds ratio of 0.76 (0.57 to 1.01). For every year of therapy, the overall risk decreased by 6% (3% to 9%): 4% (1% to 8%) for regimens without progestin and 11% (6% to 16%) for those with progestin. Last use between one and five years previously, with a duration of use more than five years, was associated with an odds ratio of 0.27 (0.08 to 0.94). After five years without hormone replacement therapy the protective effect was substantially diminished (7% to 48%). With current use, an initiation of therapy nine or more years after the menopause gave equally strong reduction in risk for hip fracture as an earlier start. Oestrogen treatment with skin patches gave similar risk estimates as oral regimens. Conclusions: Recent use of hormone replacement therapy is required for optimum fracture protection, but therapy can be started several years after the menopause. The protective effect increases with duration of use, and an oestrogen-sparing effect is achieved when progestins are included in the regimen. Key messages Hormone replacement therapy should be continued for long periods for optimal protection of hip fracture No overall substantial hip fracture protection remains after five years without hormone replacement therapy Therapy can be initiated several years after menopause without loss of fracture protection Oral or transdermal therapy are equally effective in reducing the risk of hip fracture The addition of progestins permits lower doses of oestrogens

In a population-based, retrospective study, we investigated the effect of a previous fracture on the risk of a later fracture. A questionnaire was mailed to 46,353 postmenopausal women aged 50-80 years and 29,802 (64%) responded. Questions were asked about fractures after age 25 and in what year they had occurred. The fractures were grouped according to whether they occurred within 5 and 10 years before answering the questionnaire. The occurrence of a fracture preceding these time intervals increased the odds ratio (OR) of having sustained a hip fracture to 1.6 (95% CI 1.1-2.3) for a previous ankle fracture and to 3.5 (95% CI 2.4-5.0) for a previous humerus fracture. Corresponding figures for having sustained a spine fracture were 1.5 (95% CI 1.1-2.1) for a previous ankle fracture and 4.5 (95% CI 3.4-5.9) for a previous spine fracture. It seems possible to select women for evaluation and intervention against osteoporosis by using information on previous fragility fractures.

A body of evidence points towards a close connection between susceptibility to fractures and osteoporosis. The incidence of osteoporotic fractures, both in absolute figures and in age-specific figures, has increased worldwide throughout this century. Although some reports show that the age-specific incidence is levelling-off, there will be a continuously increasing number of individuals with such fractures that will have implications from an economical point of view not only for the affected individual but for society as a whole. The outcome after such fractures, especially those of the hip, is by no means always favourable, partly due to insufficient results after orthopaedic treatment and partly due to an already high comorbidity. Therefore, trying to prevent osteoporotic fractures by non-pharmacological or pharmacological regimens is of utmost importance.

The aim of this study was to describe the course of untreated or conservatively treated arthrosis of the knee joint. Of 265 patients presenting with knee pain who had weightbearing radiographs taken between 1970 and 1973, 132 (33 men and 99 women) responded to and participated in a clinical followup 20 years later using the Hospital for Special Surgery score and new weightbearing radiographs. Arthrosis was defined as an equal to or greater than 50% joint space narrowing. In 75 of 132 knees of Ahlbäck Class 0 (57%) and 20 of 52 knees of Ahlbäck Class I (39%), the classification remained unchanged. The Hospital for Special Surgery score at followup was compared with the Ahlbäck classes in the 1970s for the 110 cases for which surgery was not done. A higher Ahlbäck class at the time of presentation was associated with lower functional score (Hospital for Special Surgery) 20 years later. In addition, in the contralateral knee a reduction of joint space may occur. In the arthrosis group with total joint space reduction or attrition there was a clinical and radiographic deterioration that would merit surgical intervention to avoid unnecessary loss of function. However, in knees with equal to or greater than 50% joint space reduction (Ahlbäck I) and pain, a considerable number (39%) did not deteriorate radiographically during a 20-year period, and 25% remain free of pain. It appears that the long-term prognosis of mild knee arthrosis is not necessarily poor. A substantial number of these patients will not have progression of the arthrosis.