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Rationale: Comorbidities are common in fracture patients, but the interaction between fracture and comorbidities remains unclear. This study aimed to define specific multimorbidity clusters in older adults and quantify the association between the multimorbidity clusters and fracture risk., Methods: This nationwide cohort study includes 1.7 million adults in Denmark aged ≥50 years who were followed from 2001 through 2014 for an incident low-trauma fracture. Chronic diseases and fractures were identified from the Danish National Hospital Discharge Register. Latent class analysis and Cox's regression were conducted to define the clusters and quantify fracture risk, respectively., Results: The study included 793 815 men (age: 64 ± 10) and 873 524 women (65.5 ± 11), with a third having ≥1 chronic disease. The pre-existent chronic diseases grouped individuals into low-multimorbidity (80.3% in men, 83.6% in women), cardiovascular (12.5%, 10.6%), malignant (4.1%, 3.8%), diabetic (2.4%, 2.0%) and hepatic clusters (0.7%, men only). These clusters distinguished individuals with advanced, complex, or late-stage disease from those having earlier-stage disease. During a median follow-up of 14 years (IQR: 6.5, 14), 95 372 men and 212 498 women sustained an incident fracture. The presence of multimorbidity was associated with a significantly greater risk of fracture, independent of age and sex. Importantly, the multimorbidity clusters had the highest discriminative performance in assessing fracture risk, whereas the strength of their association with fracture risk equalled or exceeded that of both the individual chronic diseases most prevalent in each cluster and of counts-based comorbidity indices., Conclusions: Future fracture prevention strategies should take comorbidities into account. Multimorbidity clusters may provide greater insight into fracture risk than individual diseases or counts-based comorbidity indices., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Context: Fragility fracture is a significant public health problem because it is associated with increased mortality. We want to find out whether the risk of fracture can be predicted from the time of birth., Objective: To examine the association between a polygenic risk score (PRS) and lifetime fracture risk., Methods: This population-based prospective study involved 3515 community-dwelling individuals aged 60+ years who have been followed for up to 20 years. Femoral neck bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry. A PRS was created by summing the weighted number of risk alleles for each single nucleotide polymorphism using BMD-associated coefficients. Fragility fractures were radiologically ascertained, whereas mortality was ascertained through a state registry. Residual lifetime risk of fracture (RLRF) was estimated by survival analysis., Results: The mortality-adjusted RLRF for women and men was 36% (95% CI, 34%-39%) and 21% (18%-24%), respectively. Individuals with PRS > 4.24 (median) had a greater risk (1.2-fold in women and 1.1-fold in men) than the population average risk. For hip fracture, the average RLRF was 10% (95% CI, 8%-12%) for women and ∼5% (3%-7%) for men; however, the risk was significantly increased by 1.5-fold and 1.3-fold for women and men with high PRS, respectively., Conclusion: A genetic profiling of BMD-associated genetic variants is associated with the residual lifetime risk of fracture, suggesting the potential for incorporating the polygenic risk score in personalized fracture risk assessment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Muscle strength and performance are associated with fractures. However, the contribution of their rate of decline is unclear., Objective: To assess the independent contribution of the rate of decline in muscle strength and performance to fracture risk., Design, Setting, and Participants: Community-dwelling women (n = 811) and men (n = 440) aged 60 years or older from the prospective Dubbo Osteoporosis Epidemiology Study followed from 2000 to 2018 for incident fracture. Clinical data, appendicular lean mass/height2 (ht)2, bone mineral density, quadricep strength/ht (QS), timed get-up-and-go (TGUG), 5 times repeated sit-to-stand (5xSTS), and gait speed (GS) measured biennially. Rates of decline in muscle parameters were calculated using ordinary least squares regression and fracture risk was assessed using Cox's models., Main Outcome: Incident low-trauma fracture ascertained by x-ray report., Results: Apart from lean mass in women, all muscle parameters declined over time. Greater rates of decline in physical performance were associated with increased fracture risk in women (Hazard ratios [HRs] ranging from 2.1 (95% CI: 1.5-2.9) for GS to 2.7 (95% CI: 1.9-3.6) for 5xSTS, while in men only the decline in GS was associated with fracture risk (HR: 3.4 [95% CI: 1.8-6.3]). Baseline performance and strength were also associated with increased fracture risk in men (HRs ranging from 1.8 (95% CI: 1.1-3.0) for QS to 2.5 (95% CI: 1.5-4.1) for TGUG, but not in women., Conclusion: Rate of decline in physical performance in both genders, and baseline strength and performance in men, contributed independently to fracture risk. Sit-to-stand and GS were the tests most consistently associated with fractures. Further studies are required to determine whether muscle strength and/or performance improve the predictive accuracy of fracture prediction models., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Although bone mineral density (BMD) is strongly associated with fracture and postfracture mortality, the burden of fractures attributable to low BMD has not been investigated., Objectives: We sought to estimate the population attributable fraction of fractures and fracture-related mortality that can be attributed to low BMD., Design and Setting: This study is a part of an ongoing population-based prospective cohort study, the Dubbo Osteoporosis Epidemiology study. In total, 3700 participants aged ≥50 years participated in the study. Low-trauma fracture was ascertained by X-ray reports, and mortality was ascertained from the Birth, Death and Marriage Registry., Results: Overall, 21% of women and 11% of men had osteoporotic BMD. In univariable analysis, 21% and 16% of total fractures in women and men, respectively, were attributable to osteoporosis. Osteoporosis combined with advancing age (>70 years) accounted for 34% and 35% of fractures in women and men, respectively. However, these two factors accounted for ∼60% of hip fractures. About 99% and 66% of postfracture mortality in women and men, respectively, were attributable to advancing age, osteoporosis, and fracture; however, most of the attributable proportion was accounted for by advancing age., Conclusions: A substantial health care burden of fracture is on people aged <70 years or nonosteoporosis, suggesting that treatment of people with osteoporosis is unlikely to reduce a large number of fractures in the general population., (Copyright © 2019 Endocrine Society.)

Context: Little is known about long-term excess mortality following fragility nonhip fractures., Objective: The study aimed to determine which fracture was associated with excess mortality and for how long the postfracture excess mortality persisted., Design, Setting, and Patients: This nationwide registry-based follow-up study included all individuals in Denmark aged 50+ years who first experienced fragility fractures in 2001 and were followed up for up to 10 years for their mortality risk., Main Outcome Measure: The contribution of fracture to mortality at precise postfracture time intervals was examined using relative survival analysis, accounting for time-related mortality changes in the background population., Results: There were 21,123 women (aged 72 ± 13 years) and 9481 men (aged 67 ± 12 years) with an incident fragility fracture in 2001, followed by 10,668 and 4745 deaths, respectively. Excess mortality was observed following all proximal and lower leg fractures. The majority of deaths occurred within the first year after fracture, and thereafter excess mortality gradually declined. Hip fractures were associated with the highest excess mortality (33% and 20% at 1 year after fracture in men and women, respectively). One-year excess mortality after fracture of a femur or pelvis was 20% to 25%; vertebrae, 10%; humerus, rib, or clavicle, 5% to 10%; and lower leg, 3%. A significant although smaller excess mortality was still observed until 10 years for hip fractures and ~5 years after femur, other proximal, and lower leg fractures., Conclusion: This study highlights the important contribution of a wide variety of fragility fractures to long-term excess mortality and thus the potential for benefit from early intervention.

Context: Hip fracture incidence has been declining and life expectancy improving. However, trends of postfracture outcomes are unknown., Objectives: The objective of the study was to compare the refracture risk and excess mortality after osteoporotic fracture between two birth cohorts, over 2 decades., Design: Prospective birth cohorts were followed up over 2 decades (1989-2004 and 2000-2014)., Setting: The study was conducted in community-dwelling participants in Dubbo, Australia., Participants: Women and men aged 60-80 years, participating in Dubbo Osteoporosis Epidemiology Study 1 (DOES 1; born before 1930) and Dubbo Osteoporosis Epidemiology Study 2 (DOES 2; born after 1930) participated in the study., Main Outcome Measure: Age-standardized fracture and mortality over two time intervals: (1989-2004 [DOES 1] and 2000-2014 [DOES 2]) were measured., Results: The DOES 2 cohort had higher body mass index and bone mineral density and lower initial fracture rate than DOES 1, but similar refracture rates [age-standardized refracture rates per 1000 person-years: women: 53 (95% confidence interval [CI] 42-63) and 51 (95% CI 41-60) and men: 53 (95% CI 38-69) and 55 (95% CI 40-71) for DOES 2 and DOES 1, respectively). Absolute postfracture mortality rates declined in DOES 2 compared with DOES 1, mirroring the improvement in general-population life expectancy. However, when compared with period-specific general-population mortality, there was a similar 2.1- to 2.6-fold increased mortality risk after a fracture in both cohorts (age-adjusted standardized mortality ratio, women: 2.05 [95% CI 1.43-2.83] and 2.43 [95% CI 1.95-2.99] and men: 2.56 [95% CI 1.78-3.58] and 2.48 [95% CI 1.87-3.22] for DOES 2 and DOES 1, respectively)., Conclusion: Over the 2 decades, despite the decline in the prevalence of fracture risk factors, general-population mortality, and initial fracture incidence, there was no improvement in postfracture outcomes. Refracture rates were similar and fracture-associated mortality was 2-fold higher than expected. These data indicate that the low postfracture treatment rates are still a major problem.

Context: Increased bone resorption predicts mortality and bone resorption heightens during critical illness. Bisphosphonates are potent inhibitors of bone resorption. Whether bisphosphonate impacts clinical outcome of intensive care unit (ICU) admission is unknown., Objective: We investigated the relationship between preadmission bisphosphonate use and clinical outcome in critically ill patients., Design: This was a retrospective hospital-based analysis., Setting: The study was conducted at a tertiary referral hospital ICU., Patients: A total of 7830 critically ill patients between 2003 and 2014 participated in the study., Interventions: The intervention included bisphosphonate treatment., Main Outcome Measures: In-hospital mortality in the main study (n = 7830) and bone density loss and biochemical and hematological changes in the mechanistic substudy (n = 111) were measured., Results: A total of 245 patients received preadmission bisphosphonate. Bisphosphonate users were older (66 ± 16 vs 58 ± 18 y, P < .01) and had greater comorbid disease burden (Charlson comorbidity index: 5.7 ± 3.6 vs 4.6 ± 3.8, P < .01), yet bisphosphonate use was associated with a lower in-hospital mortality (mortality rate ratio: 0.41, 95% confidence interval 0.24-0.71, P < .01), which remained significant after adjusting for age, sex, principal diagnosis, admitting unit, comorbidities and admission year. Bisphosphonate-associated survival benefit was independent of vitamin D, but bisphosphonate/vitamin D co-use was associated with additive reduction in mortality (mortality rate ratio 0.38, 95% confidence interval 0.20-0.71, P < .01). Bone density decreased during ICU admission (-13% ± 19% per week, P < .01) but was significantly attenuated among bisphosphonate users compared with nonusers (-3% ± 13% per week v. -15% ± 14% per week, P < .01), despite similar disease severity on admission. All bisphosphonate users in the substudy survived, whereas six nonusers died., Conclusions: Preadmission bisphosphonate use was associated with superior survival among critically ill patients. Prospective studies examining the effects of bisphosphonate in critical illness are required.

Background: Serum testosterone can be measured by LC-MS/MS and RIA. We investigated whether the testosterone-fracture relationship was affected by the method of measurement., Methods: We measured total testosterone (TT) by LC-MS/MS (TTLC-MS/MS) and RIA (TTRIA) in serum samples collected from 602 men whose incident fractures had been continuously ascertained by x-ray reports from 1989 to 2010. We measured bone mineral density (BMD) by dual-energy x-ray absorptiometry. The association between TT and fracture risk was assessed by the Cox proportional hazards model, taking into account the effect of age and BMD., Results: Mean TTLC-MS/MS was higher than TTRIA by 27 ng/dL (95% CI 13-41). The concordance correlation coefficient between TTLC-MS/MS and TTRIA was 0.72 (95% CI 0.68-0.76). The Deming regression equation linking the 2 measurements was ln(TTLC-MS/MS + 10) = 0.87 + 0.87 × ln(TTRIA + 10). The hazard ratio of fracture per SD decrease in TT was 1.32 (95% CI 1.12-1.54) for TTLC-MS/MS and 1.23 (1.06-1.43) for TTRIA. The correlation between predicted probabilities of fracture by TTLC-MS/MS and TTRIA was r = 0.96, with the mean difference being 0.01% (95% CI -6.1% to 6.2%). Slightly more patients were classified as having hypogonadism if TTRIA was used (29% vs 26%)., Conclusions: The concordance between LC-MS/MS and RIA in the measurement of serum TT was moderate. Moreover, the magnitude of association between testosterone and fracture risk in older men was largely unaffected by the method of measurement., (© 2015 American Association for Clinical Chemistry.)

Context: Nonhip nonvertebral fractures represent half of all osteoporotic fractures; however, their contribution to the burden of refracture and premature mortality is unclear., Objectives: To examine the risk and burden of subsequent fracture and mortality associated with an initial nonhip nonvertebral fracture., Setting and Participants: This is a prospective cohort from the Dubbo Osteoporosis Epidemiology Study, 1989-2010 of community dwelling participants aged 60+ with incident fractures., Outcome Measures: Relative risk of all subsequent fractures and age-adjusted standardized mortality ratios were calculated according to initial fracture type. The total burden of adverse events was assessed using competing risk models with four potential outcomes: mortality after initial fracture, mortality after subsequent fracture, subsequent fracture and alive, or event-free., Results: Of the 952 fractures in women and 343 in men, over half were nonhip nonvertebral fractures (486 in women and 173 in men). Nonhip nonvertebral fractures were associated with increased risk of any subsequent fracture (1.95 [1.67-2.27] for women and 2.47 [1.82-3.35] for men), hip refracture (2.11 [1.04-4.28] for women and 2.63 [1.35-5.13] for men), and vertebral refracture (1.89 [1.43-2.48] for women and 2.13 [1.20-3.79] for men). More importantly, nonhip nonvertebral fractures were associated overall with 20% excess mortality for the first 5 years postfracture, of which approximately half were due to initial fracture and the remaining due to subsequent fractures. Proximal fractures were associated with increased mortality risk per se, whereas distal fractures were associated with increased mortality risk only in the group who sustained subsequent fractures., Conclusion: Nonhip nonvertebral fractures are associated with significant risk of subsequent fracture including hip and vertebral refracture, and premature mortality. Due to their high prevalence, about half of all subsequent fractures and a quarter of all fracture-related excess mortality were attributable to nonhip nonvertebral fracture. Thus nonhip nonvertebral fracture warrants early investigation and appropriate intervention.

Context: Higher body weight is associated with greater bone mineral density (BMD) and lower fracture risk. However, the relationship between abdominal fat mass (aFM) and fracture risk is unclear because of limited prospective data. The present study sought to examine the association between aFM, BMD, and fracture risk., Methods: The study was designed as a prospective investigation, in which a sample of 1126 participants (360 men and 766 women) aged 50 years or older had been continuously followed up for an average of 5 years. The mean age of participants was 71 years (range, 57-94 years). At baseline, BMD at the femoral neck and lumbar spine and aFM were measured by dual-energy X-ray absorptiometry. The incidence of low-trauma and nonpathological fractures was ascertained prospectively from X-ray reports., Results: During the follow-up period, 19 men and 107 women had sustained a fracture. In women, each 1-kg lower aFM was associated with a 50% higher risk of fracture (hazard ratio [HR], 1.50; 95% confidence interval [CI], 1.10-2.05) after adjustment for age, femoral neck BMD, falls, stature, physical activity, and prior fracture. Subgroup analysis by fracture type found that the association was mainly observed in clinical vertebral fracture (HR, 1.96; 95% CI, 1.22-3.13). In men, although there was no statistically significant association between aFM and fracture risk (HR, 1.15; 95% CI, 0.58-2.25), the strength of this finding is affected negatively by the low number of fractures., Conclusions: Lower abdominal fat was significantly associated with an higher fracture risk in women.

Context: Osteoporotic fractures are associated with premature mortality. Antiresorptive treatment reduces refracture but mortality reduction is unclear., Objective: The objective of the study was to examine the effect of osteoporosis treatment [bisphosphonates (BP), hormone therapy (HT), and calcium ± vitamin D only (CaD)] on mortality risk., Design: This was a prospective cohort study (April 1989 to May 2007)., Setting: The study was conducted with community-dwelling elderly (aged 60+ yr) subjects in Dubbo, a semiurban city, Australia., Subjects: Subjects included 1223 and 819 women and men in the Dubbo Osteoporosis Epidemiology Study., Main Outcome Measure: Mortality according to treatment group was recorded., Results: There were 325 (BP, n = 106; HT, n = 77; CaD, n = 142) women and 37 men (BP, n = 15; CaD, n = 22) on treatment. In women, mortality rates were lower with BP 0.8/100 person-years (0.4, 1.4) and HT 1.2/100 person-years (0.7, 2.1) but not CaD 3.2/100 person-years (2.5, 4.1) vs. no treatment 3.5/100 person-years (3.1, 3.8). Accounting for age, fracture occurrence, comorbidities, quadriceps strength, and bone mineral density, mortality risk remained lower for women on BP [hazard ratio (HR) 0.3 (0.2, 0.6)] but not HT [HR 0.8 (0.4, 1.8)]. For 429 women with fractures, mortality risk was still reduced in the BP group [adjusted HR 0.3 (0.2, 0.7)], not accounted for by a reduction in subsequent fractures. In men, lower mortality rates were observed with BP but not CaD [BP 1.0/100 person-years (0.3, 3.9) and CaD 3.1/100 person-years (1.5, 6.6) vs. no treatment 4.3/100 person-years (3.9, 4.8)]. After adjustment, mortality was similar, although not significant [HR 0.5 (0.1, 2.0)]., Conclusions: Osteoporosis therapy appears to reduce mortality risk in women and possibly men.

Background: Cross-sectional studies from different populations show a variable decline in blood testosterone concentrations as men age. Few population representative cohorts have been followed up over time., Objective: The objective of the study was to quantify longitudinally the change in serum testosterone and SHBG concentrations with age in two well-defined, representative but geographically widely separated regional Australian cohorts., Subjects and Setting: The Busselton cohort comprises individuals aged 18-90 yr residing in Western Australia assessed prospectively since 1981. Sera were assayed from 910 men, from whom further samples were available 14 yr later in 480. The Dubbo cohort involves individuals aged 61-90 yr living in Eastern Australia. Baseline sera were collected from 610 men and additional sera on a second (n = 370) and third (n = 200) occasion from 1989 to 2004. Men from both cohorts are community dwelling and of predominately European origin., Results: Longitudinal analyses show the following: 1) total testosterone declines comparably (P > 0.9) by 1.3% (Busselton) and 0.9% (Dubbo) per annum with the same rates of decline when analyses were restricted to men older than 60 yr of age; 2) annual changes in SHBG were also very similar in age-restricted analyses (2.3% vs. 2.5%, P = 0.48); and 3) the annual increase in SHBG was steeper in middle-aged and older men (P < 10(-3) vs. young men). These longitudinal changes were all up to 4-fold greater in magnitude, compared with cross-sectional analyses of baseline data., Conclusion: In two separate regional Australian populations, blood testosterone fell and SHBG increased comparably with age. Age-related changes in blood testosterone and SHBG previously described in urban-dwelling men are the same in men who reside in smaller regional cities of another continent.

Context and Objective: It is not known which factors are associated with fracture in nonosteoporotic elderly. The aim of this study was to assess the association between fall-related risk factors and fracture risk in men and women without osteoporosis., Design: This study was part of the ongoing Dubbo Osteoporosis Epidemiology Study, which was designed as a prospective population-based cohort investigation., Participants: At baseline, 924 women and 723 men aged 60+ yr did not have osteoporosis [bone mineral density (BMD) T-scores > -2.5]. The individuals have been followed for up to 15 yr., Main Outcome Measures: Atraumatic fractures were prospectively identified through radiologists' reports., Risk Factors: At baseline, femoral neck BMD (FNBMD) was measured by dual energy x-ray absorptiometry (DXA); history of fall, postural stability, and quadriceps strength was obtained., Results: During the follow-up period, among the nonosteoporotic group, 221 women and 105 men had sustained a fracture, accounting for 55 and 74% of total fractures in the entire Dubbo Osteoporosis Epidemiology Study sample, respectively. The following factors were independent risk factors for any fracture: in women, age per sd (hazard ratio, 1.2; 95% CI, 1.0-1.3), postural sway per sd (1.1, 1.0-1.2), FNBMD per sd (1.6, 1.3-1.9), fall in the previous 12 months (2.1, 1.6-2.7), and prior fracture (1.8, 1.2-2.7); in men, age (1.4, 1.1-1.6), postural sway (1.2, 1.0-1.3), FNBMD (1.2, 1.0-1.5), and fall in the previous 12 months (1.9, 1.2-3.0). Exposure to at least one of the risk factors could account for 49% (women) and 39% (men) of any fractures in this population., Conclusion: In nonosteoporotic elderly, the combination of low BMD, advancing age, fall during the last 12 months, and prior fracture could identify a subgroup of individuals with high risk of fracture.

Context and Objective: Hip fracture is partially genetically determined. The present study was designed to examine the contributions of vitamin D receptor (VDR) and collagen I alpha1 (COLIA1) genotypes to the liability to hip fracture in postmenopausal women., Design: The study was designed as a prospective population-based cohort investigation., Subjects: Six hundred seventy-seven postmenopausal women of Caucasian background, aged 70 +/- 7 yr (mean +/- SD), have been followed for up to 14 yr. Sixty-nine women had sustained a hip fracture during the period., Main Outcome: Atraumatic hip fractures were prospectively identified through radiologists' reports. Bone mineral density (BMD) at the hip and lumbar spine was measured by dual-energy x-ray absorptiometry. GENOTYPES: The TaqI and SpI COLIA1 polymorphisms of the VDR and COLIA1 genes were determined. Using the Single Nucleotide Polymorphism database, VDR TT, Tt, and tt genotypes were coded as TT, TC, and CC, whereas COLIA1 SS, Ss, and ss were coded as GG, GT, and TT., Results: Women with VDR CC genotype (16% prevalence) and COLIA1 TT genotype (5% prevalence) had an increased risk of hip fracture [odds ratio (OR) associated with CC, 2.6; 95% confidence interval (CI), 1.2-5.3; OR associated with TT, 3.8; 95% CI, 1.3-10.8] after adjustment for femoral neck BMD (OR, 3.4 per SD; 95% CI, 2.3-5.0) and age (OR, 1.4 per 5 yr; 95% CI, 1.1-1.7). Approximately 20 and 12% of the liability to hip fracture was attributable to the presence of the CC genotype and TT genotype, respectively., Conclusion: The VDR CC genotype and COLIA1 TT genotype were associated with increased hip fracture risk in Caucasian women, and this association was independent of BMD and age.

Measurements of bone density using dual-energy x-ray absorptiometry are generally based on the areal projection, which incompletely accounts for size. The larger areal bone density in older men compared with older women is primarily due to their larger bone size, conferring a biomechanical advantage that may be a major factor contributing to lower hip fracture rates. The aim of this study was to evaluate estimated volumetric bone density at the hip in men and women with and without fractures to better determine the role of estimated volumetric density vs. size in hip fracture risk. This prospective population-based study compared 852 women and 635 men without fractures with 73 women and 23 men with hip fractures. As expected, areal bone mineral density (BMD) and cross-sectional area were lower in women than men, and areal bone density was lower in those with hip fractures compared with nonfracture subjects. However, estimated volumetric BMD was the only parameter, apart from age, that was the same in women and men both without hip fractures (0.31 +/- 0.06 and 0.31 +/- 0.06 g/cm3, respectively) and with hip fractures (0.25 +/- 0.04 and 0.26 +/- 0.04 g/cm3, respectively). Using the World Health Organization 2.5 SD cut-off for osteoporosis for hip fracture prediction, estimated volumetric BMD was more sensitive than areal BMD in men (70 vs. 43%; P = 0.04) and similar to that in women, in whom sensitivity was similar for both areal (73%) and estimated volumetric (78%) BMD cut-offs. Thus, men and women have hip fractures at the same estimated femoral neck volumetric BMD, which is largely independent of the size artifact inherent in areal BMD. This aspect of estimated femoral neck volumetric BMD suggests that it can provide a single measure that could be used in men and women. It needs further exploration for a role in assessment of hip fracture risk across the sexes and particularly in men.

This study was designed to test the hypothesis of a major gene influence on the variation in bone mineral density (BMD). BMD and bone mineral content at the lumbar spine and femoral neck were measured in 330 men and 413 women, aged 18-90 yr, from 107 nuclear and complex families (including 5 large pedigrees with 194 individuals who were identified through an index case with moderately high BMD at the femoral neck (z-score, >or=1.28)). After adjusting for age and body weight, familial factors accounted for up to 72% of the total variation in BMD. In complex segregation analysis, for all variables examined the best-fitting most parsimonious model consistently suggested the Mendelian transmission of a major gene locus with significant residual correlations among siblings. This genetic model suggested that the proportion of a total variance (adjusted for significant covariates) attributable to a putative major gene effect ranged between 0.30 +/- 0.09 for femoral neck BMD and 0.53 +/- 0.07 for the principal component obtained on BMD and corresponding bone mineral content measures. These findings clearly support the hypothesis that a large component of the variance in BMD is under genetic control, with strong evidence for a major gene locus influencing BMD transmission.

The vitamin D(3) receptor (VDR) is a ubiquitously expressed nuclear hormone receptor, and its ligand, calcitriol, has diverse biological effects. The extent to which transcriptional coactivators are involved in modulating tissue-specific functions of the VDR is unclear. Hence, the current studies investigated the role of p160 coactivators in regulating VDR function and interaction with RXR. Two p160 coactivators, glucocorticoid receptor-interacting protein-1 (GRIP1) and receptor-associated coactivator-3 (RAC3), which are expressed in an inverse fashion in cell lines representative of calcitriol target tissues, interacted directly with the VDR, both in vitro and in yeast cells, but only in the presence of calcitriol. Deletional analyses of VDR indicated that GRIP1 and RAC3 required an intact VDR activation function (AF-2) domain for efficient interaction as well as additional but distinct regions of the VDR. Coexpression experiments in yeast cells indicated that both GRIP1 and RAC3 coassemble with the VDR to form an active transcriptional complex. They also form ternary complexes with VDR homodimers and VDR:RXRalpha heterodimers. In mammalian cells, GRIP1 augmented VDR activation of the osteocalcin promoter, whereas RAC3 enhanced VDR activation indirectly through RXR. These data suggest different coactivators regulate VDR function via distinct mechanisms and support the hypothesis that the VDR recruits different coactivators depending on specific gene and cellular contexts.

Fractures of the proximal humerus, forearm, and wrist account for approximately one third of total osteoporotic fractures in the elderly. Several risk factors for these fractures were evaluated in this prospective study of 739 men and 1,105 women aged > or =60 years in Dubbo, Australia. During follow-up (1989-1996), the respective incidences of humerus and of forearm and wrist fractures, per 10,000 person-years, were 22.6 and 33.8 for men and 54.8 and 124.6 for women. Independent predictors of humerus fracture were femoral neck bone mineral density (FNBMD) (relative risk (RR) = 2.3, 95% confidence interval (CI): 1.2, 4.5) in men and FNBMD (RR = 2.4, 95% CI: 1.7, 3.5) and height loss (RR = 1.1, 95% CI: 1.0, 1.2) in women. For forearm and wrist fractures, risk factors were FNBMD (men: RR = 1.5, 95% CI: 1.0, 2.3; women: RR = 1.5, 95% CI: 1.2, 1.9) and height loss (men: RR = 1.2, 95% CI: 1.0, 1.3; women: RR = 1.1, 95% CI: 1.0, 1.2). In addition, dietary calcium (men: RR = 2.0, 95% CI: 1.0, 3.6) and a history of falls (women: RR = 1.9, 95% CI: 1.4, 2.6) were also significant. These data suggest that elderly men and women largely share common risk factors for upper limb fractures and that FNBMD is the primary risk factor.

There is clear evidence of genetic modulation of bone phenotype parameters including bone density, quantitative ultrasound, bone size, and bone turnover. At any particular age and phase of life, genetic factors explain about 70% of the variance in bone phenotype after adjustment for major medical and disease factors. Hormonal factors, diet, and lifestyle interact with those genetic factors over time. Common allelic variation in the VDR was the first of several genes and now chromosomal loci to be implicated in the genetic determination of bone phenotype. The VDR polymorphisms have an effect weaker than originally reported, and part of the allelic effects may be mediated by effects on body size and development and even other hormonal regulators such as PTH or insulin. Irrespective of the strength or mechanism of these associations, these initial findings on the VDR stimulated the field of the genetics of osteoporosis with targeted genetic studies and now genome scan approaches. Intronic polymorphisms of the collagen I alpha 1 gene have been shown to be related to bone density and to fracture risk in several studies, although not all findings concur. Common allelic variations have now been associated with bone density for the estrogen receptor, TGF beta receptor, and TGF beta 1, for the insulin-like growth factor-I pathway, for interleukin-4 and -6 and the interleukin-1 receptor antagonist, for calcitonin and the PTH receptors and for apolipoprotein E. Of considerable interest, chromosomal loci, notably 11q 12-13, have now been linked to bone phenotypes in human and mouse studies. The mouse strain studies seem likely to be powerful tools providing insight to important human loci based on the mouse-human chromosomal synteny. Variability of genetic findings across studies seems to be the rule rather than the exception. This variability may relate to interaction of particular loci with specific environmental or even other genetic loci. The importance of genetic heterogeneity, including ethnicity, as well as environmental and hormonal confounders, such as calcium and vitamin D intake, hormonal status and skeletal and body size, will need to be taken into account in future gene search approaches. Genome scans in relation to bone density and fracture end-points will need to account for such important potential confounders in each target population. Interactions between genetic and environmental factors, including lifestyle, have been investigated initially for the VDR polymorphisms in relation to the response of bone density and turnover to calcium intake and treatment with simple vitamin D and active vitamin D compounds. Gene-gene and gene-environment interactions in human and animal models will be critical targets for future research. Further genes with positive and negative effects on bone phenotype are certain to be identified in the near future. Each of these will need to be evaluated in relation to potential environmental modulators in pharmacogenetic models. Understanding the molecular physiology of such gene effects is likely to lead to more specific treatments and to allow the selection of more appropriate and effective treatment options.

The extent to which changes in several hormonal and biochemical parameters are involved in the pathogenesis of osteoporosis in men remains controversial. This study examined the roles of free testosterone (T), estradiol (E2), sex hormone-binding globulin (SHBG), 25-hydroxyvitamin D, PTH, and insulin-like growth factor I in the determination of bone mineral density (BMD) in 437 community-dwelling elderly men. Age, height, weight, quadriceps strength, and femoral neck (FN) and lumbar spine (LS) BMD were also obtained. In multiple regression analysis, after adjusting for age and weight, low E2 (P = 0.01), and high SHBG (P = 0.0002) levels were common determinants of FN and LS BMD. In addition, high PTH (P = 0.03) was an independent predictor of FN BMD, and low free T (P = 0.02) was an independent predictor of LS BMD. Low free T was associated with FN BMD in univariate analysis only. The hormonal measurements collectively accounted for 5% and 7% of the age- and weight-adjusted variance of FN and LS BMD, respectively. The sex steroids, SHBG and insulin-like growth-I were found to be interrelated using a technique of path analysis that examines the intercorrelation between these variables. A subject with any one abnormal serum parameter had a 4-fold increase in the risk of osteoporosis, whereas three abnormal parameters were associated with an 11-fold increased risk, although the latter group only applied to 1% of the study population. Although the precise causal effects these biochemical parameters may have on the development of osteoporosis remains to be determined, the present findings support an important interrelated role for these hormonal and biochemical parameters on changes in bone density in elderly men.

The initial findings on the vitamin D receptor have opened the field of the genetics of osteoporosis to targeted genetic studies and may open the way to genome scan approaches. Interaction between genetics, the environment, and lifestyle factors will also be an important target for future research. Understanding the physiology of such gene effects will likely open the way to more specific treatments and the selection of more appropriate and effective treatment options.

The contributions of genetic and environmental factors to the association among bone mineral density (BMD), lean mass, and fat mass were assessed in the Sydney Twin Study of Osteoporosis (Australia), 1995-1996, in 57 monozygotic and 55 dizygotic female twin pairs of Caucasian background, aged 52.8 (standard deviation, 13) years. In multiple regression analysis, lean mass was a significant determinant of areal BMD; however, fat mass was a principal determinant of volumetric BMD. Univariate model-fitting analyses indicated that 80% and 65% of variance of lean mass and fat mass, respectively, were attributable to genetic factors. The estimated heritability of BMD for lumbar spine, femoral neck, and total body BMD was 78%, 76%, and 79%, respectively. Multivariate analyses suggested that, while the association between lean mass and fat mass was attributable mainly to environmental factors (re = 0.53, p < 0.01), the association among the three BMD sites was attributable to both genetic and environmental factors (rg = 0.64-0.75, p < 0.001; re = 0.57-0.70, p < 0.001). Furthermore, genetic factors that affect lean mass or fat mass have minor effects on BMD. It is concluded that lean mass and fat mass, as well as bone density, are under strong genetic regulation. However, the associations between BMD and fat mass or between lean mass and fat mass appear to be mediated mainly via environmental influences.

Osteoporosis is recognized as an important cause of morbidity and mortality in aging women, but there have been few epidemiologic studies in men. Potential risk factors for osteoporotic fractures were assessed in 220 elderly men aged 60 years or above in the city of Dubbo (Australia). During the follow-up period of 1989-1994, the overall incidence of fractures (determined from x-ray reports) was 220 fractures per 10,000 person-years. Higher risk of fracture was associated with lower femoral neck bone mineral density (BMD), quadriceps weakness, higher body sway, falls in the preceding 12 months, a history of fractures in the previous 5 years, lower body weight, and shorter current height. Use of thiazide diuretics, higher physical activity, and moderate alcohol intake were protective against fracture. In multivariate analysis (Cox's proportional hazards model), femoral neck BMD (odd ratio (OR) = 1.47, 95% confidence interval (CI) 1.25-1.73 per 0.12 g/cm2), quadriceps strength (OR = 1.43, 95% CI 1.18-1.73 per 10 kg), and body sway (OR = 1.25, 95% CI 1.07-1.45 per 5.15 cm2) were independent risk factors. Preventive measures for bone loss and maintaining a physically active, healthy life-style and modification of risk factors for falls in the elderly could yield beneficial effects in the reduction of the incidence of osteoporotic fracture and hence improve the survival among men.

The risk of osteoporotic fracture is related to peak bone mass achieved at skeletal maturity and subsequent bone loss. Although premature menopause is a risk factor for osteoporosis, the effect of exposure to endogenous estrogen during a woman's reproductive years is poorly characterized. We analyzed the relationship between reproductive factors and estrogen exposure on bone mineral density (BMD) and incidence of atraumatic fracture in data from 1091 women (age: 70 +/- 7.2 yr; mean +/- SD) participating in the Dubbo Osteoporosis Epidemiology Study. Age- and weight-adjusted BMD among women who had used estrogen replacement therapy (ERT) for more than 5 yr was higher at the lumbar spine and femoral neck by 13.7% and 10.2% (P < 0.001), respectively, compared with women who had used ERT for less than 5 yr or nonusers. Duration of exposure to estrogen (years of menstruation plus postmenopausal ERT use) was associated with higher BMD, such that BMD increased by 2-3% for every 10-yr increase in years of estrogen exposure; thus women who menstruated for more than 40 yr had a 6-8% higher BMD than did women who menstruated for less than 30 yr. Higher BMD was also significantly associated with high parity, such that nulliparous women had 5-6% lower BMD than did their peers of the same age and weight. The incidence of atraumatic fractures among non-ERT users was higher than that of ERT-users [odds ratio (OR): 1.06; 95% confidence interval (CI): 0.94-1.16] and was significantly lower among parous women than among nulliparous women (OR 0.94; 95% CI: 0.84-0.98) in univariate analysis. Longer duration of menstruation was associated with lower fracture incidence (OR for 1 SD = 6.6 yr: 0.93; 95% CI: 0.86-1.02). Moreover, when all of these factors were considered simultaneously, parity remained a significant determinant of fracture as well as femoral neck BMD. We conclude that high parity and longer duration of exposure to estrogen, either through natural menstruation or postmenopausal ERT, have protective effects on BMD and are associated with a reduced incidence of atraumatic fracture in a population-based study.

Identification of the major contribution of genetic factors in determination of peak bone mass at skeletal maturity and possibly on subsequent age-related bone loss has led to efforts to identify possible mechanisms. Recent evidence suggests one mechanism relates to genetic effects on bone turnover mediated via the vitamin D system. This field of research has potential for reducing osteoporotic fracture risk by allowing interventions at different stages in life to reduce this increasing problem of ageing societies.

Circulating osteocalcin, a marker of bone formation, is under strong genetic influence, and this effect is related to the genetic influence on bone density. To examine genetic influences on bone turnover further, other markers of bone formation (serum carboxyterminal propeptide of type I procollagen, PICP), bone resorption (serum pyridinoline cross-linked carboxyterminal telopeptide of type I collagen, ICTP), and nonosseous connective tissue synthesis (serum aminoterminal propeptide of type III procollagen, PIIINP) were studied in 82 female twin pairs: 42 monozygotic (MZ) and 40 dizygotic (DZ) twin pairs (mean age, MZ; 48.4 yr; DZ; 45.6 yr). The intraclass correlation coefficients of MZ twin pairs, rMZ, for serum PICP (0.78) and serum ICTP (0.68) were significantly greater than the corresponding rDZ (0.31 and 0.36, respectively), but a genetic effect on serum PIIINP was not demonstrable. Within DZ twin pair differences in serum PICP predicted differences in lumbar spine bone density (r = -0.37); higher serum PICP levels indicating the twin with the lower lumbar spine bone density. Also within pair differences in serum ICTP and PICP predicted differences in bone density at the lumbar spine independent of serum osteocalcin. These data indicate that both synthesis and degradation of type I collagen are genetically determined and that this phenomenon is related to the genetic regulation of bone density.

Genetic factors are major determinants of adult bone density, however, it is unknown how these effects may be mediated. Since bone mineral density is the net result of bone formation and bone resorption we studied biochemical indices of bone formation (serum osteocalcin) and resorption [fasting urinary calcium:creatinine (Ca/Crt) and hydroxyproline:creatinine (OH/Crt)] in adult female twins; 39 monozygotic (MZ) and 31 dizygotic (DZ) twin pairs (age, mean +/- SEM, MZ: 51.1 +/- 1.5 yrs; DZ: 46.5 +/- 1.5 yrs, P = NS). Of these subjects, 18 MZ twin pairs and 10 DZ twin pairs were postmenopausal. The MZ twin pair correlations (rMZ) for each index of bone turnover exceeded that between DZ pairs (rDZ), but this difference was only significant for osteocalcin (rMZ = 0.81, rDZ = 0.21, P less than 0.001). Similarly, in the postmenopausal group examined alone, the rMZ (r = 0.84) for serum osteocalcin was significantly greater than rDZ (r = -0.003, P less than 0.03). These osteocalcin data imply that 80% of the variance in serum osteocalcin could be explained by genetic factors. Although genetic effects on fasting urinary hydroxyproline:creatine and calcium:creatinine were not demonstrable, these indices may be less precise and specific. The data indicate that circulating osteocalcin, and therefore bone formation, is strongly genetically determined. These studies suggest at least one of the mechanisms of the genetic effect on bone mass relates to the regulation of bone turnover.

Somatomedin-C (Sm-C) or insulin-like growth factor-I, GH and physical fitness decline with age. Physical fitness and muscle strength are important determinants of bone density, and the age-related decline in bone density may be related in part to a decline in fitness and muscle strength. Also, Sm-C has been shown to stimulate osteoblasts in vitro and may effect skeletal muscle mass. We postulated that the age-related decline in GH and Sm-C levels may be related to an age-related decline in physical fitness and/or muscle strength, and the effect of physical fitness and muscle strength on bone may be mediated by Sm-C. We, therefore, examined the relationship between circulating GH and Sm-C levels and physical fitness, as determined by predicted maximal oxygen uptake (VO2max) in 134 normal women, 34 of whom were postmenopausal. In a subgroup of 62 women overall muscle strength was estimated as the sum of the Z-sores for biceps, quadriceps, and grip strength. Overall muscle strength correlated with GH levels (r = 0.28; P less than 0.02), but not with Sm-C levels. There was a significant positive relationship between plasma Sm-C levels and VO2max in all women (r = 0.47; P less than 0.001) and in the postmenopausal group alone (r = 0.05; P less than 0.01). Although there was a significant negative relationship between Sm-C and age (r = -0.36; P = 0.001), VO2max was a better independent predictor than age (r = 0.47; P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Human breast cancer cells have been shown to be targets of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]action with specific dose-dependent effects on growth in vitro. These cells possess specific, high affinity receptors for 1,25-(OH)2D3. We have studied the interaction of the vitamin D hormone with its receptor in these intact human target cells. Specific binding of tritium-labeled 1,25-(OH)2D3 by these cells reaches a maximum with 3-9 h depending on hormone concentration; subsequently there is a rapid loss of hormone-binding activity to virtually undetectable levels by 12-24 h. Although the hormone induces its own metabolism in these cells, binding cannot be restored by the addition of fresh hormone. This loss of hormone-binding activity of the receptor, is analogous to the processing of the estrogen receptor in estrogen receptor-positive cells. Two inhibitors of DNA transcription, actinomycin D and cordycepin, delay the onset and slow the processing of receptor if added with the hormone. They are ineffective if added after hormone binding is maximal. Inhibitors of protein synthesis have no protective effect at all and, in fact, these agents inhibit both the attainment of maximum specific binding and the recovery of receptor over the subsequent 24-72 h. These data demonstrate for the first time that the 1,25-(OH)2D3 receptor undergoes regulation in the intact human target cell. This event, which resembles processing of the estrogen receptor and down-regulation of peptide-hormone receptors, likely represents a nuclear mechanism for the control of cellular responsiveness to hormone in the intact cell.

The early biochemical events following exposure of human target cells to 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] have been difficult to study due to the lack of suitable in vitro systems. We have studied the T47 D human breast cancer cell line, which possesses specific high affinity receptors for 1,25-(OH)2D3 and responds to the hormone with changes in cellular replication, as a functional model of 1,25-(OH)2D3-responsive human cells. Specific uptake and binding of [3H]1,25-(OH)2D3 by T47 D cells follows a time course of relatively slow rise and decline. The time of peak binding is delayed relative to that of other steroid hormones in the same system. We have studied the kinetics of 1,25-(OH)2D3 specific uptake and binding in intact cells and Scatchard analysis in broken cell preparations of three T47 D sublines: the wild-type and the 10 and M1 sublines. Binding parameters varied among the three sublines. Thus, peak binding capacity was highest in the wild-type cell and lowest in the M1 subline; ranging from 10-65 fmol/10(6) cells in intact cell studies and from 23-148 fmol/mg protein (approximately 2.8-12.7 fmol/10(6) cells) in broken cell preparations. Receptor affinity in the three sublines ranged from 1.1-2.8 x 10(-11) M. The half-life of occupied receptor was estimated in intact cells of all three sublines by incubation in the presence of the protein synthesis inhibitor puromycin. Similar analyses were made of apparent half-life of unoccupied receptor in broken cell preparations of the wild-type and T47-10 cells. The half-life of occupied 1,25-(OH)2D3 receptor was estimated to be 2.8 +/- 0.4 h in intact wild-type T47 D cells compared with 3.1 +/- 0.7 and 1.4 +/- 0.2 hours in intact T47 D-10 and T47 D-M1 cells, respectively. The half-life of unoccupied 1,25-(OH)2D3 receptor was estimated in broken cell preparations to be 4.1 +/- 0.7 h in wild-type T47 D and 4.2 +/- 0.6 h in the T47 D-10 cells. Receptor half-lives in the wild-type and T47 D-10 cells were not different in either intact or broken cell preparations; however, receptor half-life was 40% longer (P less than 0.05) in broken cell preparations (4.2 +/- 0.4 h) than in the intact cells (3.0 +/- 0.4 h) of the two cell sublines.(ABSTRACT TRUNCATED AT 400 WORDS)

Human breast cancer and malignant melanoma cells possess specific, high affinity receptors for 1 alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3). The replication of these cells is affected by 1,25-(OH)2D3 with a biphasic dose response, i.e. stimulation at low concentration and inhibition at high concentration. Several 1,25-(OH)2D3 metabolites hydroxylated at the 23,24 and 26 carbons have reduced affinity for the receptors but are still able to inhibit cell replication at high concentrations; none of these metabolites are able to stimulate cell growth. In this context, it is of considerable interest that T47-D breast cancer cells in culture actively metabolize 1,25-(OH)2D3 to chloroform- and aqueous-soluble compounds. Based on multiple solvent high pressure liquid chromatography, double label studies, and periodate sensitivity it is apparent that metabolism occurs about the 23,24 and 26,27 carbon atoms. Three metabolites have been tentatively identified as 1,24,25-(OH)3D3 and the 24-oxo derivatives of 1,25-(OH)2D3 and 1,23,25-trihydroxyvitamin D3. Although calcitroic acid may be produced, other aqueous-soluble metabolites with partially intact side chains are major metabolic products. The metabolic activity is low in the 1,25-(OH)2D3-depleted cell and is induced in 3-4 h by a process requiring new protein synthesis. The induction by 1,25-(OH)2D3 is highly specific since 25-OH D3 is quite ineffective. The studies reported here carried out in intact cells in culture demonstrate unequivocally that 1,25-(OH)2D3 metabolism, through chloroform-soluble to aqueous-soluble metabolites, occurs entirely within a proven target cell of 1,25-(OH)2D3 action. Since other 1,25-(OH)2D3 metabolites hydroxylated at the 23,24 and 26 carbons lack the ability to stimulate cell replication, it is hypothesized that the hormone-inducible metabolic activity represents a sensitive mechanism for the control of cellular responsiveness to 1,25-(OH)2D3.

Age-related bone loss has been attributed to a decline in bone formation due to decreased osteoblast function. However, studies examining the relationship between age or menopausal status and indices of bone formation such as serum osteocalcin have yielded conflicting results. To examine these relationships we studied indices of bone formation and resorption and bone mineral density in 247 normal women, including 96 postmenopausal women ranging in age from 20-75 yr. A cubic polynomial regression best fit the relationship between age and serum osteocalcin (r = 0.32; n = 228; P = 0.0001) and urinary hydroxyproline/creatinine excretion (r = 0.40; n = 228; P = 0.0001), with both indices declining before the menopause, rising at the menopause, and subsequently falling through the seventh and eighth decades. While a significant decline in osteocalcin levels was observed in the postmenopausal group older than 60 yr, levels in subjects older than 60 yr remained higher (+31%) than those in late premenopausal subjects. Urinary calcium to creatinine excretion rose in the premenopausal years, increased markedly after the menopause, and remained at this level subsequently. Urinary hydroxyproline/creatinine, but not serum osteocalcin or urinary calcium/creatinine excretion, was a significant predictor of bone mineral density at the lumbar spine and the femoral neck independent of age. These data are consistent with the hypothesis that age-related bone loss after the menopause occurs in the presence of initially increased but subsequently decreasing bone turnover with maintenance of a relative excess of bone resorption.