We have proposed 24-mo between-treatment difference (active-placebo) in mean percent change in total hip bone mineral density (%THBMD) be used to evaluate whether a drug will likely reduce fracture risk, such that a mean %THBMD change greater than the surrogate threshold effect (STE) would indicate fracture benefit. However, this approach does not consider trial size. Here, we investigate using the lower limit of the 95% confidence interval (LCL) of %THBMD as an alternative to the mean to account for the impact that trial size has on estimator uncertainty. We compared the performance of these two measures (mean and LCL of %THBMD) in indicating fracture risk reduction relative to the STE by simulating trials of various sizes (100, 250, 500, 750, and 1000) based on data re-sampling from existing large trials with THBMD at 24 mo; this included 11 studies with radiographic vertebral fracture, three studies with hip fracture, and five studies with all clinical fractures. We re-sampled the THBMD data from each study 1000 times with equal numbers in treatment groups to estimate the reliability of these measures in being consistent with the observed fracture risk reduction due to treatment. Concordance between the %THBMD-STE comparisons and observed fracture risk reduction generally converged at a sample size of 500 (250 per treatment group). For vertebral fracture using mean %THBMD, 9 of the 11 studies had ≥90% of trials consistent with the observed fracture risk reduction if the sample size exceeded 500, which decreased to 7 of the 11 studies using the LCL. For both hip and all clinical fracture, all included studies had ≥90% of trials consistent with the observed fracture risk reduction if the sample size exceeded 500, regardless of using mean or LCL. Overall, the %THBMD-STE comparisons were generally consistent with the original studies' fracture risk reduction observed.

BACKGROUND CONTEXT:There are a number of risk factors- from biological, psychological, and social domains- for nonspecific chronic low back pain (cLBP). Many cLBP treatments target risk factors on the assumption that the targeted factor is not just associated with cLBP but is also a cause (ie, a causal risk factor). In most cases this is a strong assumption, primarily due to the possibility of confounding variables. False assumptions about the causal relationships between risk factors and cLBP likely contribute to the generally marginal results from cLBP treatments. PURPOSE:The objectives of this study were to a) using rigorous confounding control compare associations between modifiable causal risk factors identified by Mendelian randomization (MR) studies with associations in a cLBP population and b) estimate the association of these risk factors with cLBP outcomes. STUDY DESIGN/SETTING:Cross sectional analysis of a longitudinal, online, observational study. PATIENT SAMPLE:A total of 1,376 participants in BACKHOME, a longitudinal observational e-Cohort of U.S. adults with cLBP that is part of the NIH Back Pain Consortium (BACPAC) Research Program. OUTCOME MEASURES:Pain, Enjoyment of Life, and General Activity (PEG) Scale. METHODS:Five risk factors were selected based on evidence from MR randomization studies: sleep disturbance, depression, BMI, alcohol use, and smoking status. Confounders were identified using the ESC-DAG approach, a rigorous method for building directed acyclic graphs based on causal criteria. Strong evidence for confounding was found for age, female sex, education, relationship status, financial strain, anxiety, fear avoidance and catastrophizing. These variables were used to determine the adjustment sets for the primary analysis. Potential confounders with weaker evidence were used for a sensitivity analysis. RESULTS:Participants had the following characteristics: age 54.9±14.4 years, 67.4% female, 60% never smokers, 29.9% overweight, 39.5% obese, PROMIS sleep disturbance T-score 54.8±8.0, PROMIS depression T-score 52.6±10.1, Fear-avoidance Beliefs Questionnaire 11.6±5.9, Patient Catastrophizing Scale 4.5±2.6, PEG 4.4±2.2. In the adjusted models, alcohol use, sleep disturbance, depression, and obesity were associated with PEG, after adjusting for confounding variables identified via a DAG constructed using a rigorous protocol. The adjusted effect estimates- the expected change in the PEG outcome for every standard deviation increase or decrease in the exposure (or category shift for categorical exposures) were the largest for sleep disturbance and obesity. Each SD increase in the PROMIS sleep disturbance T-score resulted in a mean 0.77 (95% CI: 0.66, 0.88) point increase in baseline PEG score. Compared to participants with normal BMI, adjusted mean PEG score was slightly higher by 0.37 points (95% CI: 0.09, 0.65) for overweight participants, about 0.8 to 0.9 points higher for those in obesity classes I and II, and 1.39 (95% CI: 0.98, 1.80) points higher for the most obese participants. Each SD increase in the PROMIS depression T-score was associated with a mean 0.28 (95% CI: 0.17, 0.40) point increase in baseline PEG score, while each SD decrease in number of alcoholic drinks per week resulted in a mean 0.12 (95% CI: 0.01, 0.23) increase in baseline PEG score in the adjusted model. CONCLUSIONS:Several modifiable causal risk factors for cLBP - alcohol use, sleep disturbance, depression, and obesity- are associated with PEG, after adjusting for confounding variables identified via a DAG constructed using a rigorous protocol. Convergence of our findings for sleep disturbance, depression, and obesity with the results from MR studies, which have different designs and biases, strengthens the evidence for causal relationships between these risk factors and cLBP. The estimated effect of change in a risk factor on change in PEG were the largest for sleep disturbance and obesity. Future analyses will evaluate these relationships with longitudinal data.

Disclosure: T. Vilaca: Pharmacosmos. L. Lui: None. M. Schini: UCB. S. Ewing: None. A.R. Thompson: None. E. Vittinghoff: None. D. Bauer: None. D. Bauer: None. D.M. Black: None. M. Bouxsein: Angitia Bio, Keros Therapeutics. R. Eastell: Alexion Pharmaceuticals, Inc., Sandoz, Immunodiagnostic Systems,, Angitia, CL Bio, Cureteq. Objectives In the SABRE Study, we showed that treatment-related differences in 24-month total hip bone mineral density (THBMD) changes are strongly associated with reduced fracture risk in placebo-controlled trials. We also determined the surrogate threshold effect (STE): the minimum THBMD change in a trial that would predict a significant reduction in fracture risk in trials. However, the availability of osteoporosis therapies limits use of placebo-controlled trials, and the need to sustain bone mineral density gains after anabolic therapies leads to the use of sequential therapy. This analysis aimed to determine if these associations and STEs apply to trials using active control or sequential therapies.Material and methods We used individual patient data from 19 trials: 16 randomized, placebo-controlled trials (14 anti-resorptive, 1 teriparatide, 1 odanacatib), and 3 trials with active control or sequential therapy (1 abaloparatide/alendronate and 2 romosozumab/alendronate or denosumab).For each trial, we calculated the treatment-related difference in mean percentage change in THBMD at 24 months and the risk reductions for the entire follow-up period. We used logistic regression for radiologic vertebral fractures and Cox regression for all clinical fractures (combination of non-vertebral and clinical vertebral fractures). We performed linear meta-regression to estimate the study-level association (r2 and 95% CI) between treatment-related differences in THBMD changes and fracture risk reduction, including the 16 placebo-controlled trials only and all the trials including 3 active control/sequential therapy trials and verified if the change in THBMD observed in the trials with active control or sequential therapy was greater than the STE calculated from placebo-controlled trials.Results We found consistent associations between treatment-related THBMD changes and fracture risk reduction for placebo-controlled trials only and all trials for vertebral fractures [r2 (CI)= 0.73 (0.33, 0.84) vs. 0.71 (0.36, 0.82)] and for all clinical fractures [0.71 (0.32, 0.83) vs.0.72 (0.39, 0.83)] respectively. In trials with active control or sequential therapy, the increase in THBMD was greater than STE and associated with a significant decrease in fracture risk: the increase in THBMD was 4.57%; 3.69% and 3.12% respectively for romosozumab/denosumab, romosozumab/alendronate and abaloparatide/alendronate trials, and the STE was 1.43% for vertebral and 2.04% for all clinical fractures. Conclusion Our findings show that treatment-related changes in THBMD predict anti-fracture efficacy equally well, regardless of the trial design. Presentation: Saturday, July 12, 2025

Emerging anti-osteoporosis therapies might present varied mechanisms of action and demand active control groups or sequential therapies due to ethical or mechanistic reasons. We previously showed a strong association between treatment-induced changes in total hip BMD (THBMD) at 12 and 24 mo and reduced fracture risk in placebo-controlled trials. We determined the surrogate threshold effect: the minimum THBMD difference (active-placebo) in a trial that would predict a significant reduction in fracture risk in trials. In this analysis, we investigated whether these associations are influenced by drug mechanism of action or trial design, including treatment with an anabolic followed by an antiresorptive compared to active control or placebo. We analyzed individual patient data from 22 randomized, placebo-controlled trials (17 antiresorptive, 3 PTH analogs, 1 odanacatib, and 1 romosozumab placebo-controlled phase), and 3 trials of an anabolic followed by an antiresorptive (1 PTH analog and 2 romosozumab). We established treatment-related differences in THBMD changes, calculated fracture risk reductions for radiologic vertebral and all clinical fractures, and estimated study-level associations between these features via meta-regression. We found consistent associations between treatment-related THBMD changes and fracture risk reduction across different drug mechanisms and trial designs. Among placebo-controlled trials, the r(2) values for vertebral fractures were 0.73 (p = .0001) and 0.78 (p = .0002) at 24 mo, and 0.59 (p = .0003) and 0.70 (p = .0007) at 12 mo for all drugs vs only antiresorptive drugs, respectively. Similarly, for all clinical fractures, the r(2) were 0.71 (p < .0001) and 0.65 (p = .0009) at 24 mo and 0.46 (p = .0007) and 0.51 (p = .002) at 12 mo for all drugs vs only antiresorptive drugs. For trials of an anabolic followed by an antiresorptive, the association between THBMD change and fracture risk reduction was similar to that for the placebo-controlled monotherapy trials. Our analyses indicate robust associations between treatment-induced THBMD changes and fracture risk reduction across various anti-osteoporosis therapies and trial designs, suggesting that treatment-induced changes in THBMD predict anti-fracture efficacy regardless of drug mechanism or trial design.

Context Fracture risk is higher in type 2 diabetes (T2D) for a given bone mineral density (BMD) level. Increased oxidative stress in T2D induces diabetic complications and may affect T2D bone fragility. Objective To investigate whether the levels of plasma F2-isoprostanes, a reliable oxidative stress marker, are associated with incident clinical fracture risk in older adults with diabetes. Methods An observational cohort study was conducted in a well-characterized cohort from Health, Aging, and Body Composition study. Participants Older Black and White ambulatory adults with baseline plasma F2-isoprostanes measurements (baseline age 70-79 years, T2D: N = 132; nondiabetes: N = 571) were selected from the study cohort of 3075 individuals. Risk of incident clinical fractures was assessed. Results In the Cox proportional hazard model with multivariate adjustments (including BMD, medications, and other risk factors), a 93% increase in incident clinical fracture risk was significantly associated with each SD increase in log plasma F2-isoprostanes in the T2D group (hazard ratio [HR] = 1.93 [95% CI, 1.26-2.9] P = .002), but there was no evidence of an association in the nondiabetes group (HR = 0.98 [95% CI 0.81-1.18] P = .79, P for interaction <.001). Log plasma F2-isoprostanes were moderately correlated with a decline in baseline total hip BMD (r = -0.25, P = .003), and with a 4-year decrease in total hip BMD (r = -0.28, P = .008) in T2D. There was no evidence of correlation between log plasma F2-isoprostanes and circulating glycoxidation markers or bone turnover markers in either group. Conclusion Plasma F2-isoprostanes levels in individuals with diabetes are associated with increased incident clinical fracture risk independently of baseline BMD.

We have proposed to the Food and Drug Administration (FDA) that treatment-related increases in total hip BMD (TH BMD) at 2 yr could be a surrogate endpoint for fracture risk reduction in clinical trials. The qualification of a surrogate includes a strong association of the surrogate with the clinical outcome. We compiled a large database of individual patient data (IPD) through the Foundation for the National Institutes of Health-American Society for Bone and Mineral Research- A Study to Advance BMD as a Regulatory Endpoint (FNIH-ASBMR-SABRE) project, and this analysis aimed to assess the relationship between baseline BMD and fracture risk in the placebo groups. We estimated the association of baseline TH, femoral neck (FN), and lumbar spine (LS) BMD with fracture risk using IPD from the combined placebo groups, which included data from 46 666 placebo participants in 25 RCTs. We estimated the relative risk (RR) of fracture per SD decrease in baseline BMD using logistic regression models for radiographic vertebral fractures and proportional hazards models for hip, non-vertebral, "all," and "all clinical" fractures. Total person-years in the combined placebo groups was 250 662 (mean baseline age 70.2 +/- 7.2 yr, mean TH BMD T-score -1.97 +/- 0.90). We observed significant relationships between baseline TH BMD and vertebral (RR = 1.55/SD), hip (RR = 2.27), non-vertebral (RR = 1.31), all (RR = 1.43), and all clinical (RR = 1.35) fracture risk. Fracture risk estimates were similar for FN BMD and after adjustment for age, race, and study. Fracture incidence increased with decreasing TH BMD quintile, confirming the strong graded association between TH BMD and fracture risk. There was a strong relationship between LS BMD and vertebral fracture risk (RR = 1.56/SD), but only a weak association with non-vertebral (RR = 1.07) and no association with hip (RR = 1.01) fracture risk. These data support the very strong relationship between hip BMD and fracture risk and provide supporting rationale for change in TH BMD as a surrogate for fracture risk reduction in future RCTs. Bone mineral density (BMD) is the standard of care for the diagnosis of osteoporosis. In this study, we analyzed data from more than 40 000 placebo participants in 25 RCTs of medications used for osteoporosis. We showed that there is a strong relationship between low total hip BMD (TH BMD) and high risk of fractures.

Bone marrow adipose tissue (BMAT) expansion and distinct BMAT composition profiles, including lower unsaturated levels, are cross-sectionally associated with older age. Prospective changes in BMAT composition with aging and the effect of serum follicle stimulating hormone (FSH), which influences both bone and fat metabolism, are unknown. We examined these associations in the AGES-Reykjavik Bone Marrow Adipose cohort, using sex-stratified linear regression models adjusted for covariates including estradiol and testosterone. At baseline, 236 women and 245 men had mean age 81 (SD 4) and 83 (4) years, respectively. Over a mean 3.3 years for 154 women and 2.6 years for 151 men, there was no significant change in total or saturated BMAT. However, mean unsaturated BMAT increased in women (+0.26 %/year, 95 % CI +0.21 %/year to +0.32 %/year) and men (+0.24 %/year, 95 % CI +0.18 %/year to +0.30 %/year). Among women, greater increases in unsaturated BMAT were associated with significantly greater reductions in vertebral trabecular volumetric BMD. At baseline, women in the highest FSH quartile had highest total (66.6 %, 95 % CI 64.3 %-69.0 %) and saturated BMAT (95 % CI 49.3 %, 47.5 %-51.0 %). No relationship existed between FSH and unsaturated BMAT in women or any BMAT outcome in men. Longitudinally, in women, higher FSH was associated with greater increase in unsaturated BMAT. There was no relationship between FSH and change in total or saturated BMAT in women or any change outcome in men. In older adults, total BMAT was stable, but BMAT composition changed with increases in unsaturated BMAT. In women, higher FSH correlated cross-sectionally with higher saturated BMAT but longitudinally with greater gain in unsaturated BMAT. These novel findings warrant further longitudinal studies to better characterize BMAT changes and the role of FSH.

There is a common belief that antiosteoporosis medications are less effective in older adults. This study used data from randomized controlled trials (RCTs) to determine whether the anti-fracture efficacy of treatments and their effects on BMD differ in people ≥70 compared to those <70 yr. We used individual patient data from 23 RCTs of osteoporosis medications collected as part of the FNIH-ASBMR SABRE project. We assessed the following fractures: radiographic vertebral, non-vertebral, hip, all clinical, and all fractures. We used Cox proportional hazard regression to estimate treatment effect for clinical fracture outcomes, logistic regression for the radiographic vertebral fracture outcome, and linear regression to estimate treatment effect on 24-mo change in hip and spine BMD in each age subgroup. The analysis included 123 164 (99% female) participants; 43% being ≥70 yr. Treatment with anti-osteoporosis drugs significantly and similarly reduced fractures in both subgroups (eg, odds ratio [OR] = 0.47 and 0.51 for vertebral fractures in those below and above 70 yr, interaction P = .19; hazard ratio [HR] for all fractures: 0.72 vs 0.70, interaction P = .20). Results were similar when limited to bisphosphonate trials with the exception of hip fracture risk reduction which was somewhat greater in those <70 (HR = 0.44) vs ≥70 (HR = 0.79) yr (interaction P = .02). Allocation to anti-osteoporotic drugs resulted in significantly greater increases in hip and spine BMD at 24 mo in those ≥70 compared to those <70 yr. In summary, anti-osteoporotic medications similarly reduced the risk of fractures regardless of age, and the few small differences in fracture risk reduction by age were of uncertain clinical significance.

BACKGROUND: Tools, such as the STarTBack Screening Tool (SBT), have been developed to identify risks of progressing to chronic disability in low back pain (LBP) patients in the primary care population. However, less is known about predictors of change in function after treatment in the specialty care population. OBJECTIVE: We pursued a retrospective observational cohort study involving LBP patients seen in a multidisciplinary specialty clinic to assess which features can predict change in function at follow-up. METHODS: The SBT was administered at initial visit, and a variety of patient characteristics were available in the chart including the presence of chronic overlapping pain conditions (COPCs). Patient Reported Outcomes Measurement Information System-10 (PROMIS-10) global physical health (PH) and global mental health (MH) were measured at baseline and at pragmatic time points during follow-up. Linear regression was used to estimate adjusted associations between available features and changes in PROMIS scores. RESULTS: 241 patients were followed for a mean of 17.0 +/- 7.5 months. Mean baseline pain was 6.7 (SD 2.1), PROMIS-10 global MH score was 44.8 (SD 9.3), and PH score was 39.4 (SD 8.6). 29.7% were low-risk on the SBT, 41.8% were medium-risk, and 28.5% were high-risk. Mean change in MH and PH scores from baseline to the follow-up questionnaire were 0.86 (SD 8.11) and 2.39 (SD 7.52), respectively. Compared to low-risk patients, high-risk patients had a mean 4.35 points greater improvement in their MH score (p = 0.004) and a mean 3.54 points greater improvement in PH score (p = 0.006). Fewer COPCs also predicted greater improvement in MH and PH. CONCLUSIONS: SBT and the presence of COPC, which can be assessed at initial presentation to a specialty clinic, can predict change in PROMIS following treatment. Effort is needed to identify other factors that can help predict change in function after treatment in the specialty care setting.

Some osteoporosis drug trials have suggested that treatment is more effective in those with low BMD measured by DXA. This study used data from a large set of randomized controlled trials (RCTs) to determine whether the anti-fracture efficacy of treatments differs according to baseline BMD. We used individual patient data from 25 RCTs (103 086 subjects) of osteoporosis medications collected as part of the FNIH-ASBMR SABRE project. Participants were stratified into FN BMD T-score subgroups (≤-2.5, > -2.5). We used Cox proportional hazard regression to estimate treatment effect for clinical fracture outcomes and logistic regression for the radiographic vertebral fracture outcome. We also performed analyses based on BMD quintiles. Overall, 42% had a FN BMD T-score ≤ -2.5. Treatment with anti-osteoporosis drugs led to significant reductions in fractures in both T-score ≤ -2.5 and > -2.5 subgroups. Compared to those with FN BMD T-score > -2.5, the risk reduction for each fracture outcome was greater in those with T-score ≤ -2.5, but only the all-fracture outcome reached statistical significance (interaction P = .001). Results were similar when limited to bisphosphonate trials. In the quintile analysis, there was significant anti-fracture efficacy across all quintiles for vertebral fractures and with greater effects on fracture risk reduction for non-vertebral, all, and all clinical fractures in the lower BMD quintiles (all interaction P ≤ .03). In summary, anti-osteoporotic medications reduced the risk of fractures regardless of baseline BMD. Significant fracture risk reduction with treatment for 4 of the 5 fracture endpoints was seen in participants with T-scores above -2.5, though effects tended to be larger and more significant in those with baseline T-scores <-2.5.

Abstract Disclosure: T. Vilaca: None. M.T. Schini: None. A.R. Thompson: None. E. Vittinghoff: None. L. Lui: None. S.K. Ewing: None. D.C. Bauer: None. D.M. Black: None. M. Bouxsein: None. R. Eastell: Consulting Fee; Self; Immunodiagnostic Systems, CL Bio, CureTeQ, Biocon, Takeda, UCB. Grant Recipient; Self; Alexion Pharmaceuticals, Inc., Osteolabs. Speaker; Self; Pharmacosmos, Alexion Pharmaceuticals, Inc., Amgen Inc, UCB. Introduction: To date, trials of new anti-osteoporosis therapies have used fractures as primary endpoints. In the FNIH-ASBMR-SABRE project, we posited that the treatment-related change in total hip BMD (THBMD) could be used as a surrogate endpoint for fractures in future clinical trials of new osteoporosis therapies. To demonstrate this, we compiled a large dataset of individual patient data (IPD) from randomized trials and showed a strong association between the change in THBMD at 24 months and reduction in fracture risk. To further explore the use of THBMD as a surrogate endpoint, here we examine whether the association is robust across drugs with different mechanisms of action. Methods: We used IDP (n>120,000 participants) from 22 randomized, placebo-controlled, double-blind trials of osteoporosis medications (17 anti-resorptive, 3 PTH analogs, 1 odanacatib, and 1 romosozumab). We calculated the treatment-related difference (active-placebo) in mean % change in THBMD at 12, 18, and 24 months for each trial. We determined the treatment-related fracture risk reductions for the entire follow-up period, using logistic regression for radiologic vertebral fractures and Cox regression for all clinical fractures (a combination of non-vertebral and clinical vertebral fractures). We used meta-regression to estimate the study-level association (r2) between treatment-related differences in THBMD changes and fracture risk reduction, including only the 17 trials of anti-resorptive drugs and then using the entire set of 22 trials. Since there were only 3 trials of anabolic drugs, we did not perform separate analyses for the anabolic trials. Results: The r2 values were similar between all trials and antiresorptive trials only for both fracture outcomes at all time points. Specifically, for vertebral fractures, the r2 was 0.59 vs 0.70 at 12 mo, 0.69 vs 0.74 at 18 mo, and 0.73 vs 0.78 at 24 mo for all trials vs anti-resorptive trials only. For all clinical fractures, the r2 was 0.46 vs 0.51 at 12 mo, 0.64 vs 0.60 at 18 mo, and 0.71 vs 0.65 at 24 mo for all trials vs anti-resorptive trials only. Conclusion: These results demonstrate that the associations between treatment-related changes in THBMD and fracture risk reductions are robust across anti-osteoporosis therapies with varying mechanisms of action. We conclude that the treatment-related difference in THBMD change would predict fracture reduction equally well for drugs with different mechanisms of action. Presentation: 6/2/2024

There is a strong association between total hip bone mineral density (THBMD) changes after 24 mo of treatment and reduced fracture risk. We examined whether changes in THBMD after 12 and 18 mo of treatment are also associated with fracture risk reduction. We used individual patient data (n = 122 235 participants) from 22 randomized, placebo-controlled, double-blind trials of osteoporosis medications. We calculated the difference in mean percent change in THBMD (active-placebo) at 12, 18, and 24 mo using data available for each trial. We determined the treatment-related fracture reductions for the entire follow-up period, using logistic regression for radiologic vertebral fractures and Cox regression for hip, non-vertebral, "all" (combination of non-vertebral, clinical vertebral, and radiologic vertebral) fractures and all clinical fractures (combination of non-vertebral and clinical vertebral). We performed meta-regression to estimate the study-level association (r2 and 95% confidence interval) between treatment-related differences in THBMD changes for each BMD measurement interval and fracture risk reduction. The meta-regression revealed that for vertebral fractures, the r2 (95% confidence interval) was 0.59 (0.19, 0.75), 0.69 (0.32, 0.82), and 0.73 (0.33, 0.84) for 12, 18, and 24 mo, respectively. Similar patterns were observed for hip: r2 = 0.27 (0.00, 0.54), 0.39 (0.02, 0.63), and 0.41 (0.02, 0.65); non-vertebral: r2 = 0.27 (0.01, 0.52), 0.49 (0.10, 0.69), and 0.53 (0.11, 0.72); all fractures: r2 = 0.44 (0.10, 0.64), 0.63 (0.24, 0.77), and 0.66 (0.25, 0.80); and all clinical fractures: r2 = 0.46 (0.11, 0.65), 0.64 (0.26, 0.78), and 0.71 (0.32, 0.83), for 12-, 18-, and 24-mo changes in THBMD, respectively. These findings demonstrate that treatment-related THBMD changes at 12, 18, and 24 mo are associated with fracture risk reductions across trials. We conclude that BMD measurement intervals as short as 12 mo could be used to assess fracture efficacy, but the association is stronger with longer BMD measurement intervals.

CONTEXT:Higher levels of FSH are associated with bone loss among women during the perimenopausal transition and among older men, independent of estradiol and testosterone levels, but whether higher FSH is an independent fracture risk factor is unknown. OBJECTIVE:To determine whether baseline FSH level predicts subsequent hip fracture in older adults. SETTING, DESIGN, PARTICIPANTS:Using a case-cohort design, we randomly sampled 295 participants stratified by sex from the Age, Gene/Environment Susceptibility-Reykjavik cohort, including 25 participants with incident hip fracture within 10 years after baseline. We sampled an additional 230 sex-stratified participants with incident hip fracture. Serum FSH and sex hormone levels were measured at baseline. Robust weighted Cox proportional hazards models were used to determine the relationship between FSH and hip fracture risk. MAIN OUTCOME:Incident hip fracture. RESULTS:As no interaction was identified between FSH and sex for the relationship with fracture, men and women were pooled for analysis. Higher levels of FSH were associated with a significantly increased risk of incident hip fracture in models adjusted for age and sex [hazard ratio (HR) 1.24 (95% CI 1.04-1.48, P = .02)] and after further adjustment for estradiol, testosterone, and SHBG levels [HR 1.20 (95% CI 1.01-1.44, P = .04) per sex-specific SD increase in FSH level]. CONCLUSION:Higher FSH is associated with an increased risk of subsequent hip fracture. Our findings support a growing body of evidence for the direct pleiotropic effects of FSH on bone and for a role for FSH in aging and disability independent of sex hormone levels.

Objective:The University of California, San Francisco (UCSF) Core Center for Patient-centric, Mechanistic Phenotyping in Chronic Low Back Pain (REACH) is one of the three NIH Back Pain Consortium (BACPAC) Research Programs Mechanistic Research Centers (MRCs). The goal of UCSF REACH is to define cLBP phenotypes and pain mechanisms that can lead to effective, personalized treatments for patients across the population. The primary objective of this research project is to address the critical need for new diagnostic and prognostic markers, and associated patient classification protocols for chronic low back pain (cLBP) treatment. Design:To meet this objective, REACH is conducting two large investigator-initiated translational research cohort studies called: The Longitudinal Clinical Cohort for Comprehensive Deep Phenotyping of Chronic Low-Back Pain (cLBP) Adults Study (comeBACK) and the Chronic Low-Back Pain (cLBP) in Adults Study (BACKHOME). Setting:comeBACK is a longitudinal multicenter in-person observational study of 450 adults with chronic low back pain designed to perform comprehensive deep phenotyping. While, the BACKHOME study is a site-less longitudinal observational e-cohort of approximately 3000 U.S. adults with cLBP. To our knowledge, BACKHOME is the largest prospective remote registry of nationwide adults with cLBP. Methods:Both the comeBACK and BACKHOME studies are collecting a robust and comprehensive set of risk factors, outcomes, and covariates in order to perform deep phenotyping of cLBP patients based on combined biopsychosocial variables to: define cLBP subtypes, establish phenotyping tools for routine clinical evaluation, and lead to improved cLBP outcomes in the future. The data from both studies will be used to establish techniques to develop a patient-centric definition of treatment success and to analyze cLBP patient traits to define clinically useful cLBP phenotypes, using a combination of traditional data analyses and deep learning methods. Conclusions:These 2 pivotal studies, in conjunction with the ancillary studies being performed in both comeBACK and BACKHOME, and the other BACPAC-consortium research projects, we will be able to address a number of diagnostic and therapeutic issues in this complex and diverse patient population with cLBP. These studies will help clarify biopsychosocial mechanisms of cLBP with the aim to provide a foundation to improve the evaluation of treatment effectiveness and to spur new avenues of therapeutic research, including personalized outcome measures that constitute a clinically meaningful treatment effect for individual cLBP patients.