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The relative contributions of factors such as muscle strength, falls risk and low bone mineral density (BMD) to increased fracture risk in Parkinson's Disease (PD) were examined in an analysis of 5212 community-dwelling women age 75 years or more recruited to a randomised, double-blind, placebo-controlled study of the oral bisphosphonate, clodronate. Similar number of PD and non-PD subjects received treatment. Each participant had measurements of hip and forearm BMD, muscle strength (hand grip strength and maximum isometric quadriceps strength), ability in the sit-to-stand test, and postural stability. Incident radiographic and/or surgically verified fractures, and deaths, were recorded over an average follow-up of 3.8 years. A diagnosis of PD was made if it was self-reported and appropriate medication was recorded at the study entry. 47 of the women (0.9 %) had a diagnosis of PD at baseline. They were of similar age to those without PD, but reported higher disability scores and lower quality of life. While BMD at the forearm and hip regions was lower in PD, this only reached statistical significance at the femoral neck (0.61 ± 0.12 vs 0.65 ± 0.12 g/cm 2 , p = 0.037). Right hand grip strength was non-significantly lower in PD, but maximum right quadriceps strength was much reduced (96.9 ± 49.3 vs 126.3 ± 59.2 N, p = 0.003). Eleven (23.4 %) of the women with PD sustained 12 fractures, while 609 women (11.8 %) without PD sustained 742 osteoporotic fractures. The risk of osteoporotic fracture associated with PD was 2.24-fold higher in women with PD (Cox-regression HR 2.24, 95 % CI 1.23-4.06) and this remained high when adjusted for death as a competing risk (2.17, 95 % CI 1.17-4.01, p = 0.013). Following adjustment for femoral neck BMD, PD remained a significant predictor of fracture (HR 2.04, 1.12-3.70, p = 0.020). Entering PD as a risk variable using the rheumatoid arthritis input as a surrogate resulted in a reduction in PD as a FRAX-independent risk factor, particularly when BMD was included in FRAX (1.65, 95 % CI), but the relationship between PD and fracture risk appears to remain of clinical significance. The study suggests that PD may be an independent input in future iterations of FRAX, possibly due to non-skeletal components of risk such as reduced lower limb muscle strength. Introducing measures of muscle strength and performance in FRAX could also be considered., Competing Interests: Declaration of competing interest MS No conflicts of interest in relation to this study. PB No conflicts of interest in relation to this study. HS No conflicts of interest in relation to this study. HJ No conflicts of interest in relation to this study. NCH No conflicts of interest in relation to this study. ML has received lecture fees from Astellas, Amgen, Lilly, UCB Pharma, Radius Health, Meda/Mylan, GE-Lunar and Santax Medico/Hologic, all outside the submitted work. JAK No conflicts of interest in relation to this study. EVM No conflicts of interest in relation to this study., (Copyright © 2022. Published by Elsevier Inc.)

Background: Lumbar spine TBS, a texture index derived from lumbar spine dual-energy x-ray absorptiometry (DXA) images, enhances fracture prediction. No studies to date have studied a broad range of clinical variables to determine which patients might experience the greatest benefit from the use of TBS., Methods: Using the Manitoba BMD Registry, we identified 37,176 subjects with baseline DXA, FRAX®-based fracture probability, lumbar spine TBS, and minimum 5 years of observation. Subgroups considered were based on sex, age, body mass index (BMI), prior fracture, chronic obstructive lung disease (COPD), high alcohol use, rheumatoid arthritis (RA), high glucocorticoid use, osteoporotic femoral neck T-score, number of comorbidities, diabetes, secondary osteoporosis, and prior osteoporosis treatment. Non-traumatic major osteoporotic fractures (MOF, n = 3741) and hip fractures (HF, n = 1008) were identified using population-based health services data. We analyzed baseline TBS using analysis of covariance (ANCOVA). FRAX-adjusted hazard ratios (HR) per SD reduction in TBS were estimated and tested for interactions. Categorical net reclassification improvement (NRI) was estimated using fixed FRAX-based intervention cut-offs., Results: Adjusted baseline TBS was significantly lower (p ≤ 0.001) for women (-4.2%), osteoporotic hip T-score (-4.0%), COPD (-2.8%), diabetes (-2.6%), high alcohol use (-2.3%), prior fracture (-2.2%), glucocorticoid use (-1.5%), RA (-0.9%) and secondary osteoporosis (-0.8%), whereas recent osteoporosis therapy was associated with greater TBS (+1.5%). HRs per SD reduction in TBS for fracture prediction were larger for age < 65 vs 65+ (MOF p-interaction = 0.004, HF p-interaction < 0.001), without vs with prior fracture (MOF p-interaction = 0.003, HF p-interaction = 0.048), without vs with glucocorticoid use (HF p-interaction = 0.029), lower vs higher comorbidity score (HF p-interaction < 0.001), and without vs with osteoporosis treatment (MOF p-interaction = 0.005). NRI for using the TBS adjustment to FRAX in all subjects was 1.2% for MOF (p = 0.002) and 1.7% for HF (p = 0.016). NRI was greater in subjects age < 65 y (MOF:1.7%, HF:5.6%), no prior fracture (HF: 2.4%), non-osteoporotic T-score (HF: 3.0%), and high glucocorticoid use (MOF: 3.9%)., Conclusion: TBS is sensitive to the effects of multiple risk factors for fracture. TBS-adjusted fracture risk assessment resulted in significant improvements for multiple subgroups., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Trabecular bone score (TBS) is a recently-developed analytical tool that performs novel grey-level texture measurements on lumbar spine dual X-ray absorptiometry (DXA) images, and thereby captures information relating to trabecular microarchitecture. In order for TBS to usefully add to bone mineral density (BMD) and clinical risk factors in osteoporosis risk stratification, it must be independently associated with fracture risk, readily obtainable, and ideally, present a risk which is amenable to osteoporosis treatment. This paper summarizes a review of the scientific literature performed by a Working Group of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis. Low TBS is consistently associated with an increase in both prevalent and incident fractures that is partly independent of both clinical risk factors and areal BMD (aBMD) at the lumbar spine and proximal femur. More recently, TBS has been shown to have predictive value for fracture independent of fracture probabilities using the FRAX® algorithm. Although TBS changes with osteoporosis treatment, the magnitude is less than that of aBMD of the spine, and it is not clear how change in TBS relates to fracture risk reduction. TBS may also have a role in the assessment of fracture risk in some causes of secondary osteoporosis (e.g., diabetes, hyperparathyroidism and glucocorticoid-induced osteoporosis). In conclusion, there is a role for TBS in fracture risk assessment in combination with both aBMD and FRAX., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Summary: Aspects of osteoporosis in men, such as screening and identification strategies, definitions of diagnosis and intervention thresholds, and treatment options (both approved and in the pipeline) are discussed., Introduction: Awareness of osteoporosis in men is improving, although it remains under-diagnosed and under-treated. A European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) workshop was convened to discuss osteoporosis in men and to provide a report by a panel of experts (the authors)., Methods: A debate with an expert panel on preselected topics was conducted., Results and Conclusions: Although additional fracture data are needed to endorse the clinical care of osteoporosis in men, consensus views were reached on diagnostic criteria and intervention thresholds. Empirical data in men display similarities with data acquired in women, despite pathophysiological differences, which may not be clinically relevant. Men should receive treatment at a similar 10-year fracture probability as in women. The design of mixed studies may reduce the lag between comparable treatments for osteoporosis in women becoming available in men., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Use of antidepressant medications that act on the serotonin system has been linked to detrimental impacts on bone mineral density (BMD), and to osteoporosis. This article reviews current evidence for such effects, and identifies themes for future research. Serotonin receptors are found in all major types of bone cell (osteoblasts, osteocytes, and osteoclasts), indicating an important role of the neuroendocrine system in bone. Observational studies indicate a complex relationship between depression, antidepressants, and fracture. First, the presence of depression itself increases fracture risk, in relation with decreased BMD and an increase in falls. A range of aspects of depression may operate, including behavioral factors (e.g., smoking and nutrition), biological changes, and confounders (e.g., comorbidities and concomitant medications). A substantial proportion of depressed patients receive antidepressants, mostly selective serotonin reuptake inhibitors (SSRIs). Some of these have been linked to decreased BMD (SSRIs) and increased fracture risk (SSRIs and tricyclic agents). Current use of SSRIs and tricyclics increases fracture risk by as much as twofold versus nonusers, even after adjustment for potential confounders. While there is a dose-response relationship for SSRIs, the effect does not appear to be homogeneous across the whole class of drugs and may be linked to affinity for the serotonin transporter system. The increase in risk is the greatest in the early stages of treatment, with a dramatic increase after initiation, reaching a peak within 1 month for tricyclics and 8 months for SSRIs. Treatment-associated increased risk diminishes towards baseline in the year following discontinuation. The body of evidence suggests that SSRIs should be considered in the list of medications that are risk factors for osteoporotic fractures., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: An important aspect of cost-effectiveness analysis of osteoporosis is to accurately model the fracture risk and mortality related to the patient groups in the analysis. The estimation of fracture risk is based on a number of factors, such as the level of general risk of the normal population, the effect of treatment and the prevalence of clinical risk factors (CRFs) for fracture. Fracture risk has traditionally been calculated with risk adjustments based on age, bone mineral density and prior vertebral fracture. The treatment effect has been derived from clinical trials and, in the absence of subgroup analyses, the same efficacy has been assumed irrespective of the fracture risk of the population. The FRAX tool enables the estimation of risk based on a wider range of risk factors, and treatment efficacy that is dependent on the level of risk in the analyzed population. The objective was to describe the implementation of the FRAX algorithms into health economic osteoporosis models and to highlight how it differs from traditional risk assessment., Methods: The selective estrogen receptor modulator, bazedoxifene, was evaluated in a Swedish setting with traditional and FRAX-based risk assessment in a previously developed Markov model that included fractures and thromboembolic events, and also was adapted to accommodate risk-dependent efficacy, which is available for bazedoxifene., Results: The traditional approach gave lower ICERs at ages up to 60 years compared to the FRAX method when only considering age, BMD and prior fracture. At 70 years and older and when adding more CRFs with the FRAX approach, the FRAX ICER decreased and fell below the traditional approach. The risk dependant efficacy was the main reason for lower ICERs with FRAX in women at higher risk of fracture., Discussion: FRAX applied in cost-effectiveness analyses is a more granular method for the estimation of fracture risk, mortality and efficacy compared to previous approaches that can also improve case finding. Furthermore, it facilitates the estimation of cost-effectiveness for various types of patients with different combinations of CRFs, which more closely matches patients in clinical practice., (Copyright 2010 Elsevier Inc. All rights reserved.)

The effect of bisphosphonates on trabecular microarchitecture may contribute to the reduced risk of vertebral fracture with treatment independent of the bone volume. Trabecular structure was examined at the twelfth thoracic vertebra after 2 years of treatment of two groups of ovariectomized baboons on high and low doses of alendronate, compared with ovariectomized and non-ovariectomized controls. Standard 2D histological measurements showed that alendronate treatment of ovariectomized animals resulted in significantly higher total trabecular length and a lower marrow star volume in comparison with ovariectomized controls indicating preservation of connectivity. Similarly when the vertebrae were examined using a novel thick slice technique that combines 2D and 3D information, ovariectomy produced a significantly higher number of "real" trabecular termini in comparison with normal. When ovariectomized animals were treated with increasing doses of alendronate, fewer "real" termini were seen. MicroCT analysis (2D and 3D) correlated well with the histological measurements, although more variability and less discrimination between groups was seen, with no statistically significant differences with alendronate treatment. Reduced vertebral fracture risk with alendronate may be due to a combination of factors including the increased bone volume, reduced turnover and greater mineralization reported by others. Added to this is now suggested the preservation of several aspects of vertebral cancellous architecture, with microscopy the most sensitive method of analysis.

The aims of the present study were to determine whether a parental history of any fracture or hip fracture specifically are significant risk factors for future fracture in an international setting, and to explore the effects of age, sex and bone mineral density (BMD) on this risk. We studied 34,928 men and women from seven prospectively studied cohorts followed for 134,374 person-years. The cohorts comprised the EPOS/EVOS study, CaMos, the Rotterdam Study, DOES and cohorts at Sheffield, Rochester and Gothenburg. The effect of family history of osteoporotic fracture or of hip fracture in first-degree relatives, BMD and age on all clinical fracture, osteoporotic fracture and hip fracture risk alone was examined using Poisson regression in each cohort and for each sex. The results of the different studies were merged from the weighted beta coefficients. A parental history of fracture was associated with a modest but significantly increased risk of any fracture, osteoporotic fracture and hip fracture in men and women combined. The risk ratio (RR) for any fracture was 1.17 (95% CI=1.07-1.28), for any osteoporotic fracture was 1.18 (95% CI=1.06-1.31), and for hip fracture was 1.49 (95% CI=1.17-1.89). The risk ratio was higher at younger ages but not significantly so. No significant difference in risk was seen between men and women with a parental history for any fracture (RR=1.17 and 1.17, respectively) or for an osteoporotic fracture (RR=1.17 and 1.18, respectively). For hip fracture, the risk ratios were somewhat higher, but not significantly higher, in men than in women (RR=2.02 and 1.38, respectively). A family history of hip fracture in parents was associated with a significant risk both of all osteoporotic fracture (RR 1.54; 95CI=1.25-1.88) and of hip fracture (RR=2.27; 95% CI=1.47-3.49). The risk was not significantly changed when BMD was added to the model. We conclude that a parental history of fracture (particularly a family history of hip fracture) confers an increased risk of fracture that is independent of BMD. Its identification on an international basis supports the use of this risk factor in case-finding strategies.

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.

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.

There is important geographic variation in the occurrence of the major osteoporotic fractures across Europe. The aim of this study was to determine whether between-center variation in limb fracture rates across Europe could be explained by variation in the incidence of falls. Men and women, aged 50-79 years, were recruited from population-based registers in 30 European centers. Subjects were followed by postal questionnaire to ascertain the occurrence of incident fractures, and were also asked about the occurrence and number of recent falls. Self-reported fractures were confirmed, where possible, by review of the radiographs, medical record, or subject interview. The age- and gender-adjusted incidence of falls was calculated by center using Poisson regression. Poisson regression was also used to assess the extent to which between-center differences in the incidence of limb fractures could be explained by differences in the age- and gender-adjusted incidence of falls at those centers. In all, 6302 men (mean age 63.9 years) and 6761 women (mean age 63.1 years) completed at least one questionnaire concerning fractures and falls. During a median follow-up time of 3 years, 3647 falls were reported by men and 4783 by women. After adjusting for age and gender, there was evidence of significant between-center differences in the occurrence of falls. There was also between-center variation in the occurrence of upper limb, lower limb, and distal forearm fractures. Variation in the age- and gender-adjusted center-specific fall rates explained 24%, 14%, and 6% of the between-center variation in incidence of distal forearm and upper and lower limb fractures, respectively. Given the constraints inherent in such an analysis, in men and women aged 50-79 years, variation in fall rates could explain a significant proportion of the between-center variation in the incidence of limb fracture across Europe., (Copyright 2002 by Elsevier Science Inc.)

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.

The aim of this study was to model the effect of short (3 year) treatments for osteoporosis at different times after menopause on the risk of osteoporotic fracture and to assess the impact of strategies to target high-risk individuals. Treatment efficacy for hip, proximal forearm, shoulder, and spine fracture were computed from the relationship between bone mineral density (BMD) and fracture in women from Sweden. Treatment that increased hip bone mineral density by 6% over untreated women saved 126 vertebral, hip, proximal humerus, and forearm fractures per 1000 women at the age of 50 years, provided that the effects of treatment persisted. Targeting women with osteoporosis at this age would save an additional 50% of fractures. With age, the number of fractures saved decreased moderately. At the age of 70 years, 133 fractures would be saved in women with osteoporosis compared to 198 in women with osteoporosis at the age of 50 years. Where the effect of treatment was assumed to wear off over 20 years after stopping treatment, the efficacy of treatment was reduced at all ages, but most markedly at the age of 50 years. Where all women aged 50 years were treated, the number of fractures saved per 1000 women decreased from 127 to 15 and, in the case of targeting women with osteoporosis, decreased from 198 to 27 per 1000 women. By contrast, with a persisting effect of treatment, the number of fractures saved increased markedly with advancing age. If all women were targeted at the age of 50 years, 15 fractures would be saved, whereas this increased to 55 per 1000 women at the age of 70 years. When treatment effects wore off more rapidly with an offset half-time of 2.5 years only 5 fractures were saved per 1000 women at the age of 50 years. This figure rose to 23 per 1000 at the age of 70 years. We conclude that, although uncertainty exists concerning the offset of effect of treatments, treatments should be optimally given to women without prior fractures in later life.

Bone mineral density (BMD) measurements are widely used to estimate the risk of osteoporotic fractures. In addition, many other risk factors have been identified, some of which are known to add to the risk independently of BMD measurements. The combination of BMD with such risk factors increases the gradient of risk/standard deviation (SD) than that achieved by BMD alone. In this paper, we report the fracture probabilities according to age, gender, and relative risk, and have investigated the effects of changes in the gradient of risk for osteoporotic fractures on the sensitivity and specificity of assessments, modeled on the population of Sweden. Ten-year risks of hip, clinical vertebral, forearm, or proximal humeral fracture were computed with increments in gradient of risk that varied from 1.5 to 6.0 per SD change in skeletal risk. The identification of high-risk groups had little effect on the specificity of assessments, but increased the sensitivity over a wide range of assumptions. The inclusion of all four fracture types had little effect on sensitivity, but increased the positive predictive value of the test. Positive predictive value also increased with age, so that values greater than 50% were obtained testing women at the age of 65 years with modest gradient of risk of 2.0-2.5/SD when small segments of the population were targeted (0.5-5%). Screening of women to direct intervention at the age of 65 years and targeting 25% of the population could save up to 23% of all fractures in women over the next 10 years by the use of multiple tests with a moderate gradient of risk (RR = 2.0/SD). Such gradients might be achieved with the use of multiple risk factors to identify patients at risk.

The aim of this study was to determine whether clodronate reduced the incidence of vertebral fractures in patients with osteoporosis. We report here the interim analysis after 1 year of a 3-year double-blind placebo-controlled study. The objectives of the interim analysis were to determine whether there was a trend in fracture frequency and to examine the effects of clodronate on bone mineral density (BMD). Patients with densitometrically proven osteoporosis (T-score <-2.5 and <-3 for women and men, respectively) or with at least one prevalent vertebral fracture were recruited to a 3-year double-blind, controlled study. Patients were randomized to three strata, namely women with postmenopausal osteoporosis (stratum I, n = 483), women with secondary osteoporosis (II, n = 110), and men with osteoporosis of any causation (III, n = 84). They received either clodronate 800 mg daily by mouth or an identical placebo, and all patients received a calcium supplement of 500 mg daily. BMD was measured at six monthly intervals, and lateral spine radiographs for vertebral morphometry were obtained at baseline and 1 year. Treatment with clodronate was associated with a significant increase in BMD at the spine of 3.2 +/- 0.3% (p < 0.0001 vs. baseline) compared with a nonsignificant change of 0.5 +/- 0.3% in the placebo group (p < 0.0001 between treatments). At the hip, clodronate was associated with a significant increase in total hip BMD of 1.3 +/- 0.3% (p = 0.018 vs. baseline) compared with a small decrease of 0.4 +/- 0.3% in the placebo group (p = 0.027 for the difference between treatment groups). The mean changes at the spine and hip were similar in all three strata. Incident vertebral fractures were observed in 27 patients at 1 year in the placebo group (9.0%) and in 14 patients receiving clodronate (4.9%) (relative risk 0.54; 95% CI 0.29-1.02; p = 0.07). A trend was observed in all treatment strata. Treatment was well tolerated, with no significant adverse events attributable to clodronate treatment. We conclude that clodronate 800 mg daily is effective in preventing bone loss, and at 1 year, there is a trend consistent with antifracture efficacy in patients with established osteoporosis regardless of causation.

Bone affected by Paget's disease is known to be dense but more prone to fractures. It is proposed that dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS) assess different aspects of the skeletal status. In this study, we used Paget's disease of the tibia as a model to explore this. Ten patients with Paget's disease affecting a single tibia were investigated with the normal side acting as the control within each individual. Tibial speed of sound (SOS) was measured at the midpoint of the affected and control tibiae using a Soundscan 2000 (Myriad Ultrasound System, Rehovot, Israel) device. Bone mineral density (BMD) of the tibia was measured at a level corresponding to the site of the tibial ultrasound using a QDR-2000+ (Hologic, Inc., Waltham, MA). The mean bone area and estimated volume in the pagetic tibia was greater than that in the normal tibia (bone area: 25.10 +/- 8.00 vs. 20.23 +/- 5.43 cm(2), p = 0.017; estimated bone volume: 68.79 +/- 41.99 vs. 43.62 +/- 22.56 cm(3), p = 0.02), reflecting the bone expansion characteristic of Paget's disease. The bone mineral content (BMC) was more markedly increased in the pagetic tibia (27.38 +/- 12.98 vs. 14.39 +/- 6.14 g, p = 0.003) and, consequently, areal bone mineral density (BMD) was also markedly increased in the pagetic bone (1.09 +/- 0.38 vs. 0.77 +/- 0.44 g/cm(2), p = 0.018). There was no significant difference in the estimated volumetric BMD between the pagetic and the normal tibia (0.48 +/- 0.24 vs. 0.47 +/- 0.51 g/cm(3), p = 0.96). In contrast, the mean tibial SOS in the leg affected by Paget's disease was significantly lower than in the unaffected leg (3228 +/- 234 vs. 3840 +/- 164 m/sec, p < 0.001). When expressed as a z score using the normal limb as reference, areal BMD was 0.72 SD higher in the affected limb, whereas tibial SOS was 3.72 SD lower. We conclude that tibial SOS detects important changes in bone quality in Paget's disease of bone, which are unrelated to calcium content.

There is a well-established relationship between bone mineral density (BMD) and fracture risk. Estimates of the relative risk of fracture from BMD have been derived mainly from short-term studies in which the correlation between BMD at assessment and BMD in later life ranged from 0.8 to 0.9. Because individuals lose bone mineral at different rates throughout later life, the long-term predictive value of low BMD is likely to decrease progressively with time. This article examines and formalizes the relationship between current BMD, correlation coefficients, and long-term risk. The loss of predictive value has important implications for early assessment and supports the view that measurements should be optimally targeted at the time interventions are contemplated and, when necessary, repeated in later life.

Hip fracture is the most serious complication of osteoporosis and the incidence is rising worldwide. Bone mineral density measurements can be used not only to diagnose osteoporosis at the hip, but also to give prognostic information on the lifetime risk of hip fracture. A number of additional risk factors enhance the ability of density measurements to assess risk. Candidates include markers of bone resorption, prior fragility fractures, hip axis length, and estimates of postural integrity, each of which improve prognostic value independently of bone mineral assessments. Their use in the stratification of risk will help define intervention thresholds for treatments and improve the design of population screening policies, particularly in elderly women in whom the burden of hip fracture is greatest.

We studied retrospectively 51 patients with Paget's disease of bone treated with oral clodronate, 1600 mg daily given for 1 (n = 23), 3 (n = 13), or 6 months (n = 15), to compare the effect of a variable length of treatment on the response rate to treatment and the duration of disease suppression. Activity of alkaline phosphatase and urinary hydroxyproline excretion were measured before treatment at monthly intervals for a year and every 3 months thereafter until biochemical relapse. Before treatment, patients given the three regimens had similar disease activity as judged by serum alkaline phosphatase and urinary hydroxyproline values. There was no significant difference in the time to response between groups (median = 2 months). The proportion of patients attaining normal values of alkaline phosphatase activity was significantly higher in patients treated for 6 months (71%, p < 0.03) compared with those treated for 1 or 3 months (23% and 39%, respectively). The time to relapse from the start of treatment was significantly shorter in patients treated for 1 month compared with those treated for 3 or 6 months (median = 11, 18, and 23 months, respectively). Thus, at 2 years all patients treated for 1 month had relapsed, whereas 31% and 40% were still relapse-free in patients receiving treatment for 3 and 6 months, respectively. The length of treatment was the only variable identified by stepwise linear regression that significantly affected the duration of response. We conclude that oral clodronate (1600 mg daily) suppresses disease activity in the vast majority of patients with Paget's disease of bone. The magnitude of the response and its duration depend on the duration of treatment or the total dose administered, so that several months of treatment with oral clodronate are required when a durable response is desired.

The variability of different primary tumors in the susceptibility to metastatic bone disease is poorly understood. Factors that determine the viability of metastatic cells are also poorly understood, but may depend in part upon gene expression of PTHrP and the vitamin D receptor. In contrast, much more is known of the manner in which metastatic disease affects bone remodeling to induce osteolytic bone disease. Mechanisms include a generalized increase in activation frequency at sites close to metastatic tissue, an imbalance between the amount of bone formed and that resorbed within resorption cavities, and uncoupling of bone formation from bone resorption. The greatest morbidity from metastatic bone disease arises from osteolytic disease and gives rise to hypercalcemia, bone pain, and fractures. Because osteolysis is primarily mediated by the activation of osteoclasts, there has been a great deal of interest in the use of agents which primarily affect bone metabolism to alter the natural history of metastatic bone disease. Nonsteroidal antiinflammatory agents and cytotoxic agents are capable of inducing responses in bone, but are limited by their toxicity when effective doses are utilized. The use of calcitonin in the long-term suppression of osteolysis has also been disappointing. The bisphosphonates are, however, capable of inducing sustained decreases in osteoclast activity and numbers in patients with osteolytic bone disease. There are now several studies which have examined the effects of the bisphosphonates on skeletal morbidity in breast cancer. Both clodronate and pamidronate decrease the incidence of hypercalcemia, bone pain, and pathological fractures, but do not significantly alter mortality.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied bone biopsies from 65 normocalcaemic women with breast cancer and predominantly osteolytic bone metastases in order to examine the pathophysiology of bone destruction in metastatic bone disease. Quantitative histomorphometric measurements were made at sites of tumour involvement, at sites adjacent to tumour tissue and at sites distant from tumour tissue. There were no significant differences in bone volume or in indices of bone resorption or formation between biopsies taken from sites distant from tumour and the controls. Bone resorption, as judged by eroded surface, increased progressively from bone distant from tumour to tumour-laden bone. The number of osteoclasts was significantly increased in bone immediately adjacent to tumour and within metastases. There was no decrease in the ratio of osteoclast to eroded surface in breast cancer compared to controls suggesting that increased resorption in breast cancer was mainly osteoclast mediated and locally activated by the tumour. Two thirds of the biopsies taken from tumour involved regions showed osteosclerosis with woven bone formation. The volume of the pre-existing lamellar trabecular bone was lower than normal in 75% of these biopsies, suggesting that bone resorption must have been increased before the onset of woven bone formation. Since all patients were receiving hormonal treatment or chemotherapy, it is likely that osteosclerosis at sites of previous resorption mainly resulted from the basic cancer treatment as a sign of response to treatment. Osteoclastic bone resorption was, however, not completely inhibited by the active cancer treatment.

The Mediterranean osteoporosis (MEDOS) study was carried out in 14 centres from six countries in Southern Europe to determine the incidence rates and risk factors associated with hip fracture over the age of 50 years. This paper discusses both the validity and relevance of the data, that is, whether the number of collected cases of hip fracture and the size and age distribution of the population are representative of the population as a whole, and whether the incidence measures used in the study are suitable for comparing the risk of hip fracture between populations and for predicting future risk within populations. Five measures of risk were assessed at each centre: crude incidence over the age of 50 years; age-standardised incidence; risk increase/fracture doubling time by age; computed incidence at 50 years; and excess morbidity. Three standardised populations were used for comparison: the MEDOS population (incidences standardised to the overall age and sex distribution of all the participating centres); the weighted MEDOS population (only including the age range 60 to 84 years); and the Swedish population at the start of the study. The MEDOS study showed that the incidence of hip fracture increased exponentially with age in both sexes at all centres. The regression slope of incidence against age was affected by the age distribution of the population, but not by the absolute size of the population. Methods used to define the population of the catchment areas did not introduce errors of a greater magnitude than would the occasional addition or removal of single fracture cases.(ABSTRACT TRUNCATED AT 250 WORDS)

This is increasing evidence that interventions with drugs affecting bone metabolism decrease the risk of hip fracture. The use of such agents is increasing in Europe, and there is a need to develop the strategies for optimum means of intervention. This paper assesses the impact of the increasing use of such agents on hip fracture outcome using several sets of assumptions. Since hip fractures occur largely after the age of 70 years, intervention directed at this age has a significant impact on hip fractures prevented. Indeed, the gains are greater if the effects of a 5-year treatment wear off once treatment has stopped. The targeting of intervention to those with the lowest values of bone mineral density increases the efficiency of intervention on hip fracture outcome by 70-140%, depending on the gradient of risk associated with decreasing bone mineral density.

Fragility fractures are now recognised as a major problem of public health. Although the prevalence of all fractures is similar among men and women, the vast majority of osteoporotic fractures occur in elderly women. These comprise vertebral compression fractures, Colles fractures at the wrist, and hip fracture, and to a lesser extent fractures at other sites. The incidence of vertebral and hip fracture increases exponentially with age. The reasons for this relate in part to the lower bone density of women at the time of maturity (peak bone density), and the accelerated bone loss that occurs after the menopause. Women live significantly longer than men, so that the prevalence of osteoporosis amongst elderly women is six-fold that of men. The age- and sex-specific incidence of osteoporotic fracture is rising in many countries, and if the current trends in the United Kingdom continue, then the number of hip fractures each year will more than double over the next 20 years. There is a marked geographic distribution in the incidence of hip fracture, and probably of other osteoporotic fractures. Indeed, the difference in incidence between communities is greater than the difference in incidence between sexes within communities. This suggests that the importance of gonadal insufficiency in women has been over-emphasised and that other factors, probably relating to life-style factors affecting peak bone density, account for ecological differences in incidence between communities and secular trends within communities.

The association of haemochromatosis and osteoporosis is well established, but it is unclear whether this is due to iron overload, hypogonadism, liver disease, or diabetes mellitus. We describe a young eugonadal male patient with osteoporotic fractures as a presenting feature of haemochromatosis, suggesting that factors other than hypogonadism contribute to osteoporosis.

Neoplasia affecting the skeleton is an important cause of morbidity, which includes hypercalcaemia, bone pain and fracture. In most instances these events are mediated by an increase in the resorption of bone which decreases bone density and disrupts skeletal architecture, either at focal sites or generally throughout the skeleton. Neoplastic activation of bone resorption in heterogeneous, but there is now good evidence that this is due to the increased activation of osteoclasts, the cells which mediate bone resorption in health. Bisphosphonates are specific inhibitors of osteoclast-mediated bone resorption and are capable of inhibiting osteoclastic activation independent of the mechanism of its stimulation. This provides the rationale for the use of bisphosphonates in the hypercalcaemia of malignancy. Despite refinements in the use of endocrine therapy, chemotherapy and radiotherapy these interventions have had relatively little impact on the skeletal morbidity or mortality of common malignancies affecting the skeleton, particularly breast cancer and myelomatosis. In addition, there is good evidence that skeletal disease is progressive in many patients despite the use of chemotherapy and radiotherapy. Since accelerated bone resorption can be inhibited by long-term treatment with bisphosphonates, their use is likely to decrease skeletal complications such as bone pain and fracture. The bisphosphonates, therefore, hold great promise as agents to improve the quality of life of such patients.

Biopsies from the diseased bones of patients with familial expansile osteolysis (FEO) were examined by light and electron microscopy. Focal concentrations of multinuclear osteoclasts were present, and these contained viral-like microcylindrical inclusions which appeared exclusive to their nuclei. No consistent relationship was found between osteoclast size and the number of osteoclast nuclei containing microcylindrical inclusions. Quantitative histomorphometry showed evidence of increased bone remodelling with high bone cell densities and a decrease of the reversal period in bone remodelling. The lesions contained prominent woven bone and fibrovascular tissue, together with mononuclear cells and adipocytes. Little bone was found in the most radiolucent lesions, which were almost totally occupied by adipocytes and fibrovascular tissue. Serology did not reveal any significant differences between the viral antibody titres of patients and their age- and sex-matched controls. The present study suggests that intranuclear viral-like microcylindrical inclusions of osteoclasts are not a specific feature of Paget's disease, and are found in other disorders of osteoclast function, including pycnodysostosis, osteopetrosis, giant cell tumours, and familial expansile osteolysis.