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SummaryThe risk of a recurrent fragility fracture is particularly high immediately following the fracture. This study provides adjustments to FRAX-based fracture probabilities accounting for the site of a recent fracture.IntroductionThe recency of prior fractures affects subsequent fracture risk. The aim of this study was to quantify the effect of a recent sentinel fracture, by site, on the 10-year probability of fracture determined with FRAX.MethodsThe study used data from the Reykjavik Study fracture register that documented prospectively all fractures at all skeletal sites in a large sample of the population of Iceland. Fracture probabilities were determined after a sentinel fracture (humeral, clinical vertebral, forearm and hip fracture) from the hazards of death and fracture. Fracture probabilities were computed on the one hand for sentinel fractures occurring within the previous 2 years and on the other hand, probabilities for a prior osteoporotic fracture irrespective of recency. The probability ratios provided adjustments to conventional FRAX estimates of fracture probability for recent sentinel fractures.ResultsProbability ratios to adjust 10-year FRAX probabilities of a major osteoporotic fracture for recent sentinel fractures were age dependent, decreasing with age in both men and women. Probability ratios varied according to the site of sentinel fracture with higher ratios for hip and vertebral fracture than for humerus or forearm fracture. Probability ratios to adjust 10-year FRAX probabilities of a hip fracture for recent sentinel fractures were also age dependent, decreasing with age in both men and women with the exception of forearm fractures.ConclusionThe probability ratios provide adjustments to conventional FRAX estimates of fracture probability for recent sentinel fractures.

SummaryThe risk of major osteoporotic fracture (MOF) after a first MOF is increased over the whole duration of follow-up, but the imminent risk is even higher. If the acute increment in risk in the few years following MOF is amenable to therapeutic intervention, then immediate short-term treatments may provide worthwhile clinical dividends in a very cost-effective manner.IntroductionA history of fracture is a strong risk factor for future fractures. The aim of the present study was to determine whether the predictive value of a past MOF for future MOF changed with time.MethodsThe study was based on a population-based cohort of 18,872 men and women born between 1907 and 1935. Fractures were documented over 510,265 person-years. An extension of Poisson regression was used to investigate the relationship between the first MOF and the second. All associations were adjusted for age and time since baseline.ResultsFive thousand thirty-nine individuals sustained one or more MOFs, of whom 1919 experienced a second MOF. The risk of a second MOF after a first increased by 4% for each year of age (95% CI 1.02–1.06) and was 41% higher for women than men (95% CI 1.25–1.59). The risk of a second MOF was highest immediately after the first fracture and thereafter decreased with time though remained higher than the population risk throughout follow-up. For example, 1 year after the first MOF, the risk of a second fracture was 2.7 (2.4–3.0) fold higher than the population risk. After 10 years, this risk ratio was 1.4 (1.2–1.6). The effect was more marked with increasing age.ConclusionsThe risk of MOF after a first MOF is increased over the whole follow-up, but the imminent risk is even higher. If the acute increment in risk in the few years following MOF is amenable to therapeutic intervention, then immediate short-term treatments may provide worthwhile clinical dividends in a very cost-effective manner, particularly in the elderly.

SummaryThe risk of a recurrent fragility fracture varies by age and sex, as by site and recency of sentinel fracture.IntroductionThe recency of prior fractures affects subsequent fracture risk. Variable recency may obscure other factors that affect subsequent fracture risk. The aim of this study was to quantify the effect of a sentinel fracture by site, age, and sex where the recency was held constant.MethodsThe study used data from the Reykjavik Study fracture register that documented prospectively all fractures at all skeletal sites in a large sample of the population of Iceland. Fracture incidence was compared to that of the general population determined at fixed times after a sentinel fracture (humeral, clinical vertebral, forearm, hip, and minor fractures). Outcome fractures comprised a major osteoporotic fracture and hip fracture.ResultsSentinel osteoporotic fractures were identified in 9504 men and women. Of these, 3616 individuals sustained a major osteoporotic fracture as the first subsequent fracture, of whom 1799 sustained a hip fracture. Hazard ratios for prior fracture were consistently higher in men than in women and decreased progressively with age. Hazard ratios varied according to the site of sentinel fracture with higher ratios for hip and vertebral fracture than for humerus, forearm, or minor osteoporotic fracture.ConclusionThe risk of a recurrent fragility fracture varies by age, sex, and site of sentinel fracture when recency is held constant.

SummaryThe present study, drawn from a sample of the Icelandic population, quantified high immediate risk and utility loss of subsequent fracture after a sentinel fracture (at the hip, spine, distal forearm and humerus) that attenuated with time.IntroductionThe risk of a subsequent osteoporotic fracture is particularly acute immediately after an index fracture and wanes progressively with time. The aim of this study was to quantify the risk and utility consequences of subsequent fracture after a sentinel fracture (at the hip, spine, distal forearm and humerus) with an emphasis on the time course of recurrent fracture.MethodsThe Reykjavik Study fracture registration, drawn from a sample of the Icelandic population (n = 18,872), recorded all fractures of the participants from their entry into the study until December 31, 2012. Medical records for the participants were manually examined and verified. First sentinel fractures were identified. Subsequent fractures, deaths, 10-year probability of fracture and cumulative disutility using multipliers derived from the International Costs and Utilities Related to Osteoporotic fractures Study (ICUROS) were examined as a function of time after fracture, age and sex.ResultsOver 10 years, subsequent fractures were sustained in 28% of 1498 individuals with a sentinel hip fracture. For other sentinel fractures, the proportion ranged from 35 to 38%. After each sentinel fracture, the risk of subsequent fracture was highest in the immediate post fracture interval and decreased markedly with time. Thus, amongst individuals who sustained a recurrent fracture, 31–45% did so within 1 year of the sentinel fracture. Hazard ratios for fracture recurrence (population relative risks) were accordingly highest immediately after the sentinel fracture (2.6–5.3, depending on the site of fracture) and fell progressively over 10 years (1.5–2.2). Population relative risks also decreased progressively with age. The utility loss during the first 10 years after a sentinel fracture varied by age (less with age) and sex (greater in women). In women at the age of 70 years, the mean utility loss due to fractures in the whole cohort was 0.081 whereas this was 12-fold greater in women with a sentinel hip fracture, and was increased 15-fold for spine fracture, 4-fold for forearm fracture and 8-fold for humeral fracture.ConclusionHigh fracture risks and utility loss immediately after fracture suggest that treatment given as soon as possible after fracture would avoid a higher number of new fractures compared with treatment given later. This provides the rationale for very early intervention immediately after a sentinel fracture.

SummaryIn a population-based study, we found that computed tomography (CT)-based bone density and strength measures from the thoracic spine predicted new vertebral fracture as well as measures from the lumbar spine, suggesting that CT scans at either the thorax or abdominal regions are useful to assess vertebral fracture risk.IntroductionPrior studies have shown that computed tomography (CT)-based lumbar bone density and strength measurements predict incident vertebral fracture. This study investigated whether CT-based bone density and strength measurements from the thoracic spine predict incident vertebral fracture and compared the performance of thoracic and lumbar bone measurements to predict incident vertebral fracture.MethodsThis case-control study of community-based men and women (age 74.6 ± 6.6) included 135 cases with incident vertebral fracture at any level and 266 age- and sex-matched controls. We used baseline CT scans to measure integral and trabecular volumetric bone mineral density (vBMD) and vertebral strength (via finite element analysis, FEA) at the T8 and L2 levels. Association between these measurements and vertebral fracture was determined by using conditional logistic regression. Sensitivity and specificity for predicting incident vertebral fracture were determined for lumbar spine and thoracic bone measurements.ResultsBone measurements from T8 and L2 predicted incident vertebral fracture equally well, regardless of fracture location. Specifically, for predicting vertebral fracture at any level, the odds ratio (per 1-SD decrease) for the vBMD and strength measurements at L2 and T8 ranged from 2.0 to 2.7 (p < 0.0001) and 1.8 to 2.8 (p < 0.0001), respectively. Results were similar when predicting fracture only in the thoracic versus the thoracolumbar spine. Lumbar and thoracic spine bone measurements had similar sensitivity and specificity for predicting incident vertebral fracture.ConclusionThese findings indicated that like those from the lumbar spine, CT-based bone density and strength measurements from the thoracic spine may be useful for identifying individuals at high risk for vertebral fracture.

Summary The incidence of the most common fracture types in Iceland is reported based on individual data from the Reykjavik Study 1967–2008. Time trend is reported for the major osteoporotic fractures (MOS) 1989–2008. Introduction This study aims to assess the incidence of all fractures in Iceland, with emphasis on the rate of hip fractures, and compare the incidence with other populations as well as examine the secular changes. Methods Individuals from the prospective population-based cohort Reykjavik Study were examined between 1967 and 2008 (follow-up 26.5 years), which consisted of 9,116 men and 9,756 women born in 1907–1935, with age range 31–81 years. First fracture incidence was estimated using life table methods with age as the timescale. Results Fracture rate increased proportionally with age between the sexes for vertebral and proximal humerus but disproportionally for hip and distal forearm fractures. The ratio of first fracture incidence between the sexes varied considerably by site: 2.65 for hip fractures and the highest for distal forearm fractures at 4.83. By the age of 75, 36.7 % of women and 21 % of men had sustained a fracture, taking into account competing risk of death. The incidence of hip fractures was similar to results previously published from USA, Sweden, Norway, and Scotland. The incidence of MOS fractures in both sexes decreased over the last decade, except hip fractures in men, which remained unchanged, as reflected in the women/men ratio for the hip, which changed from 2.6 to 1.7. Conclusion This study adds information to scarce knowledge on the relative fracture incidence of different fractures. The incidence of MOS fractures increased in the latter part of the last century in both sexes and declined during the last decade, less dramatically for men. This information is important for planning health resources.

SummaryThe increase in fracture risk associated with a recent fragility fracture is more appropriately captured using a 10-year fracture probability than 2- or 5-year probabilities.IntroductionThe recency of prior fractures affects subsequent fracture risk. The aim of this study was to quantify the effect of a recent sentinel fracture, by site, on the 2-, 5-, and 10-year probability of fracture.MethodsThe study used data from the Reykjavik Study fracture register that documented prospectively all fractures at all skeletal sites in a large sample of the population of Iceland. Fracture probabilities were determined after a sentinel fracture (humeral, clinical vertebral, forearm and hip fracture) occurring within the previous 2 years and probabilities for a prior osteoporotic fracture irrespective of recency. The probability ratios were used to adjust fracture probabilities over a 2-, 5-, and 10-year time horizon.ResultsAs expected, probabilities decreased with decreasing time horizon. Probability ratios varied according to age and the site of sentinel fracture. Probability ratios to adjust for a prior fracture within the previous 2 years were higher the shorter the time horizon, but the absolute increases in fracture probabilities were much reduced. Thus, fracture probabilities were substantially lower with time horizons less than 10 years.ConclusionThe 10-year probability of fractures is the appropriate metric to capture the impact of the recency of sentinel fractures. The probability ratios provide adjustments to conventional FRAX estimates of fracture probability for recent sentinel fractures, adjustments which can readily inform clinical decision-making.

SummaryPoor physical function and body composition my partly predict the risk of falls leading to fracture regardless of bone mineral density.IntroductionTo examine the relationship between body composition, physical function, and other markers of health with hip fractures in older community-dwelling Icelandic adults.MethodsA prospective cohort of 4782 older adults from the AGES-Reykjavik study. Baseline recruitment took place between 2002 and 2006, and information on hip fractures occurring through 2012 was extracted from clinical records. Using multivariate regression analyses, baseline measures of bone health, physical function, and body composition were compared between those who later experienced hip fractures and to those who did not. Associations with the risk of fractures were quantified using Cox regression.ResultsMean age was 76.3 years at baseline. After adjustment for age, regression showed that male hip fracture cases compared with non-cases had (mean (95% confidence interval)) significantly lower thigh muscle cross-sectional area − 5.6 cm2 (− 10.2, − 1.1), poorer leg strength – 28 N (− 49, − 7), and decreased physical function as measured by longer timed up and go test 1.1 s (0.5, 1.7). After adjustment for age, female cases had, compared with non-cases, lower body mass index − 1.5 kg/m2 (− 2.1, − 0.9), less lean mass − 1.6 kg (− 2.5, − 0.8), thigh muscle cross-sectional area − 4.4 cm2 (− 6.5, − 2.3), and worse leg strength − 16 N (− 25, − 6). These differences largely persisted after further adjustment for bone mineral density (BMD), suggesting that body composition may contribute to the risk of fracture independent of bone health. When examining the association between these same factors and hip fractures using Cox regression, the same conclusions were reached.ConclusionsAfter accounting for age and BMD, older adults who later experienced a hip fracture had poorer baseline measures of physical function and/or body composition, which may at least partly contribute to the risk of falls leading to fracture.

Summary Association between serum bone formation and resorption markers and cortical and trabecular bone loss and the concurrent periosteal apposition in a population-based cohort of 1069 older adults was assessed. BTM levels moderately reflect the cellular events at the endosteal and periosteal surfaces but are not associated with fracture risk. Introduction We assessed whether circulating bone formation and resorption markers (BTM) were individual predictors for trabecular and cortical bone loss, periosteal expansion, and fracture risk in older adults aged 66 to 93 years from the AGES-Reykjavik study. Methods The sample for the quantitative computed tomography (QCT)-derived cortical and trabecular BMD and periosteal expansion analysis consisted of 1069 participants (474 men and 595 women) who had complete baseline (2002 to 2006) and follow-up (2007 to 2011) hip QCT scans and serum baseline BTM. During the median follow-up of 11.7 years (range 5.4–12.5), 54 (11.4 %) men and 182 (30.6 %) women sustained at least one fracture of any type. Results Increase in BTM levels was associated with faster cortical and trabecular bone loss at the femoral neck and proximal femur in men and women. Higher BTM levels were positively related with periosteal expansion rate at the femoral neck in men. Markers were not associated with fracture risk. Conclusion This data corroborates the notion from few previous studies that both envelopes are metabolically active and that BTM levels may moderately reflect the cellular events at the endosteal and periosteal surfaces. However, our results do not support the routine use of BTM to assess fracture risk in older men and women. In light of these findings, further studies are justified to examine whether systemic markers of bone turnover might prove useful in monitoring skeletal remodeling events and the effects of current osteoporosis drugs at the periosteum.

Osteoarthritis is an increasingly important health problem for which the main treatment remains joint replacement. Therapy developments have been hampered by a lack of biomarkers that can reliably predict disease, while 2D radiographs interpreted by human observers are still the gold standard for clinical trial imaging assessment. We propose a 3D approach using computed tomography—a fast, readily available clinical technique—that can be applied in the assessment of osteoarthritis using a new quantitative 3D analysis technique called joint space mapping (JSM). We demonstrate the application of JSM at the hip in 263 healthy older adults from the AGES-Reykjavík cohort, examining relationships between 3D joint space width, 3D joint shape, and future joint replacement. Using JSM, statistical shape modelling, and statistical parametric mapping, we show an 18% improvement in prediction of joint replacement using 3D metrics combined with radiographic Kellgren & Lawrence grade (AUC 0.86) over the existing 2D FDA-approved gold standard of minimum 2D joint space width (AUC 0.73). We also show that assessment of joint asymmetry can reveal significant differences between individuals destined for joint replacement versus controls at regions of the joint that are not captured by radiographs. This technique is immediately implementable with standard imaging technologies.