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The presented guidelines are an update of the position paper, endorsed by the International Osteoporosis Foundation (IOF), on nomenclature of bone markers published over 2 decades ago. Novel insight into bone biology and pathophysiology of bone disorders has highlighted the increasing relevance of new and known mediators implicated in various aspects of bone metabolism. This updated guideline proposes the nomenclature Bone Status Indices (BSI) as the comprehensive classification rather than bone turnover markers, bone markers, metabolic markers of bone turnover or metabolic markers of bone turnover, that are currently in use for the implicated molecules. On behalf of the IFCC Committee on Bone Metabolism and the Joint IOF Working Group and IFCC Committee on Bone Metabolism, the authors propose standardized nomenclature, abbreviations and measurement units for the bone status indices., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Upon denosumab discontinuation, an observed overshoot phenomenon in bone turnover may occur, potentially leading to a reduction in bone mineral density and the occurrence of vertebral fractures. Several theories have been proposed to explain this phenomenon, one of which is that osteoclast precursors might be accumulating during treatment. Our aim was to study the effects of denosumab on osteoclast precursors in postmenopausal women. This cross-sectional observational study included 30 postmenopausal women with osteopenia or osteoporosis, divided into two groups: 15 treated with denosumab (mean duration 4 years, range 6 months-9 years) and 15 treatment-naïve controls. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and were stained for CD14, MCSFR, CD11b and TNFRII. Osteoclast precursors (CD14+/MCSFR+, CD14+/CD11b + OR CD14+/TNFRII+) were identified with fluorescent activated cell sorting (FACS). The proportion of osteoclasts was determined by calculating their percentage of the total cell population in each whole blood sample. To confirm the expected suppression of bone turnover in the subjects treated with denosumab, we measured serum PINP, CTX and TRACP5b. Denosumab-treated patients exhibited a significantly higher count of CD14+/CD11b + osteoclast precursors compared to controls (median 4% vs 0.75%, P=.011). There was no correlation with the duration of treatment. Bone turnover markers were significantly lower in the group treated with denosumab than controls. Our findings indicate an increase in osteoclast precursors, which could explain the overshoot phenomenon observed after discontinuing denosumab., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

The overarching goal of osteoporosis management is to prevent fractures. A goal-directed approach to long-term management of fracture risk helps ensure that the most appropriate initial treatment and treatment sequence is selected for individual patients. Goal-directed treatment decisions require assessment of clinical fracture history, vertebral fracture identification (using vertebral imaging as appropriate), measurement of bone mineral density (BMD), and consideration of other major clinical risk factors. Treatment targets should be tailored to each patient's individual risk profile and based on the specific indication for beginning treatment, including recency, site, number and severity of prior fractures, and BMD levels at the total hip, femoral neck, and lumbar spine. Instead of first-line bisphosphonate treatment for all patients, selection of initial treatment should focus on reducing fracture risk rapidly for patients at very high and imminent risk, such as in those with recent fractures. Initial treatment selection should also consider the probability that a BMD treatment target can be attained within a reasonable period of time and the differential magnitude of fracture risk reduction and BMD impact with osteoanabolic versus antiresorptive therapy. This position statement of the ASBMR/BHOF Task Force on Goal-Directed Osteoporosis Treatment provides an overall summary of the major clinical recommendations about treatment targets and strategies to achieve those targets based on the best evidence available, derived primarily from studies in older postmenopausal women of European ancestry., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Purpose: Sandoz biosimilar denosumab (GP2411 [SDZ-deno]; Jubbonti/Wyost) is approved by the US FDA, EMA and Health Canada for all indications of reference denosumab (REF-deno; Prolia/Xgeva), a fully human IgG2κ monoclonal antibody that binds with high affinity and specificity to receptor activator of nuclear factor kappa-B ligand (RANKL). Denosumab blocks RANKL, preventing bone resorption and loss of bone density/architecture in conditions characterized by excessive bone loss such as osteoporosis in postmenopausal women and metastatic bone disease, among others., Methods: This narrative review summarizes the totality of evidence (ToE) for SDZ-deno that supported its approval as Jubbonti/Wyost in the EU and US., Findings: Analytical evaluation indicated that SDZ-deno has high purity and structural homology with REF-deno. SDZ-deno also demonstrated similar binding affinities, size and charge variants, and disulfide isoforms to REF-deno, and did not trigger clinically meaningful antibody-dependent cellular cytotoxicity. In clinical evaluation, SDZ-deno was similar to REF-deno in pharmacokinetics (PK) and pharmacodynamics (PD) in a 39-week Phase I study in 502 healthy male participants, and to REF-deno in a 72-week Phase III study in 527 postmenopausal women with osteoporosis. In both studies, the 90% and 95% confidence intervals (for PK and PD endpoints, respectively) of the geometric mean ratios for AUC inf , C max (and AUC last in the Phase I study; PK endpoints), and area under the effect versus time curve of percent change from baseline in serum carboxy-terminal crosslinked telopeptide of type I collagen (PD endpoint), were fully contained within the prespecified equivalence margins (0.80, 1.25). The Phase III study also demonstrated SDZ-deno is similar in efficacy to REF-deno in postmenopausal women with osteoporosis, as the difference in percent change from baseline in lumbar spine bone mineral density at week 52 between REF-deno and SDZ-deno was fully contained within the prespecified equivalence margins (-1.45, 1.45). SDZ-deno was well tolerated in both studies. As the ToE has established biosimilarity of SDZ-deno and REF-deno, extrapolation to all indications is justified based on the common mechanism of action and the comparable PK, safety, and immunogenicity across all indications., Implications: The ToE for SDZ-deno suggests it will be an effective biosimilar to REF-deno, and its lower unit price is anticipated to increase the number of appropriate patients who will benefit., Competing Interests: Declaration of competing interest BV, JP, AS, SS, NK, and OR, are employees of Hexal AG (a Sandoz company). AS owns shares in Sandoz Group. AK has received consulting fees from AbbVie, Coval, Ecor1, Fresenius Kabi, Genzyme, Gilead, Grunenthal, GSK, Halia, Horizon, Janssen, Prime, Prometheus, Selecta, Synact, Takeda, UCB, and XBiotech; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, GSK, Eli Lilly, Pfizer, Sanofi-Regeneron, AbbVie, and UCB; been part of a board or advisory board for Fresenius Kabi, Horizon, Janssen, Novartis, Princeton Biopartners, and UCB; and has stock or stock options in Pfizer, GSK, Gilead, Novartis, and Amgen. JJB has received consultancy funding or lecture fees from Amgen, Cole Pharma, and UCB; and grant funding from UCB. RE has received consultancy funding from Biocon, CL Bio, CureTeQ, Immunodiagnostic Systems, Samsung, Sandoz, Takeda, UCB; has given meeting presentations for Pharmacosmos, Alexion, Amgen and UCB; received support for attending meetings from CL Bio and Samsung; received grant funding from Alexion and Osteolabs; and has chaired a Data Safety Monitoring Board or Advisory Board for Biocon, CuRaTEQ, and STOPFOP., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Context: SB16 is a proposed biosimilar to reference denosumab (DEN; brand name: Prolia)., Objective: This phase 3 randomized, double-blind, multicenter study evaluated the biosimilarity of SB16 to DEN in women with postmenopausal osteoporosis (PMO; NCT04664959)., Design: The study included 457 PMO patients who had a lumbar spine or total hip T-score between -2.5 and -4. Patients were randomized in a 1:1 ratio to receive either 60 mg of SB16 or DEN subcutaneously at Month 0 and Month 6. At Month 12, patients were re-randomized to continue with the assigned treatment or switch from DEN to SB16 up to Month 18. This report includes results up to Month 12., Methods: The primary endpoint was the percent change from baseline in lumbar spine bone mineral density (BMD) at Month 12. Secondary endpoints including the percent change from baseline in BMD of the lumbar spine (except for Month 12), total hip and femoral neck; pharmacokinetic, pharmacodynamic (serum C-telopeptide of type I collagen [CTX] and procollagen type I N-terminal propeptide [P1NP]), safety, and immunogenicity profiles were measured up to Month 12., Results: The least-squares mean differences in percent change from baseline in lumbar spine BMD at Month 12 were 0.33% (90% confidence interval [CI]: -0.25, 0.91) in the full analysis set and 0.39% (95% CI: -0.36, 1.13) in the per-protocol set; both within the pre-defined equivalence margin. The secondary endpoints were comparable between the two treatment groups., Conclusion: The reported efficacy, PK, PD, safety, and immunogenicity data support the biosimilarity of SB16 to DEN., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

High dose bolus cholecalciferol supplementation has been associated with falls and fracture, and this does not appear to be due to hypercalcaemia. The primary aim of this study was to determine the change in free vitamin D and metabolites after high dose bolus supplementation. This was a single centre, double-blinded, randomised, controlled trial of three different oral bolus doses of vitamin D 3 (50,000 IU, 150,000 IU, and 500,000 IU) in otherwise healthy, vitamin D deficient (total 25-hydroxylated vitamin 25(OH)D < 30 nmol/L) postmenopausal women. Thirty-three women were randomized to one of the three treatment groups. Twenty-seven vitamin D sufficient (25(OH)D > 50 nmol/L) postmenopausal women were recruited as a concurrent control group. Participants attended five study visits over three months. We measured total 25(OH)D 3 and free 25(OH)D, total and free 1,25(OH) 2 D, parathyroid hormone, fibroblast-growth factor-23, serum calcium, ionised calcium, urinary calcium excretion, and bone turnover markers (procollagen I N-propeptide (PINP), serum C-telopeptides of type I collagen (CTX-I) and Osteocalcin (OC)). We assessed muscle strength and function with grip strength and a short physical performance battery. Postural blood pressure and aldosterone:renin ratio (ARR) was also measured. Total 25(OH)D 3 and free 25(OH)D increased in response to dose, and there were proportionate increases in total and free metabolites. Treatment did not affect serum calcium, postural blood pressure, ARR, or physical function. Bone turnover markers increased transiently one week after administration of 500,000 IU. High dose bolus cholecalciferol supplementation does not cause disproportionate increases in free vitamin D or metabolites. We did not identify any effect on blood pressure regulation or physical function that would explain increased falls after high dose treatment. A transient increase in bone turnover markers one week after a 500,000 IU bolus suggests that very high doses can have acute effects on bone metabolism, but the clinical significance of this transient increase is uncertain.

Background: Growth differentiation factor 15 (GDF-15) is a member of the TGFβ superfamily secreted by many cell types and found at higher blood concentrations as chronological age increases (1). Given the emergence of GDF-15 as a key protein associated with aging, it is important to understand the multitude of conditions with which circulating GDF-15 is associated., Methods: We pooled data from 1,174 randomly selected Health ABC Study (Health ABC) participants and 1,503 Cardiovascular Health Study (CHS) participants to evaluate the risk of various conditions and age-related outcomes across levels of GDF-15. The primary outcomes were (1) risk of mobility disability and falls; (2) impaired cognitive function; (3) and increased risk of cardiovascular disease and total mortality., Results: The pooled study cohort had a mean age of 75.4 +/-4.4 years. Using a Bonferroni-corrected threshold, our analyses show that high levels of GDF-15 were associated with a higher risk of severe mobility disability (HR: 2.13 [1.64, 2.77]), coronary heart disease (HR: 1.47 [1.17, 1.83]), atherosclerotic cardiovascular disease (HR: 1.56 [1.22, 1.98]), heart failure (HR: 2.09 [1.66, 2.64]), and mortality (HR: 1.81 [1.53, 2.15]) when comparing the highest and lowest quartiles. For CHS participants, analysis of extreme quartiles in fully adjusted models revealed a 3.5-fold higher risk of dementia (HR: 3.50 [1.97, 6.22])., Conclusions: GDF-15 is associated with several age-related outcomes and diseases, including mobility disability, impaired physical and cognitive performance, dementia, cardiovascular disease, and mortality. Each of these findings demonstrates the importance of GDF-15 as a potential biomarker for many aging-related conditions.

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Introduction: Androgen Deprivation Therapy (ADT) for prostate cancer (PC) has substantial negative impacts on the musculoskeletal system and body composition. Many studies have focused on the effects of ADT on areal bone mineral density (aBMD), but aBMD does not capture key determinants of bone strength and fracture risk, for example volumetric bone density (vBMD), geometry, cortical thickness and porosity, trabecular parameters and rate of remodelling. More specialist imaging techniques such as high-resolution peripheral quantitative computed tomography (HR-pQCT) have become available to evaluate these parameters. Although it has previously been demonstrated that bone microarchitectural deterioration occurs in men undergoing ADT, the aim of the ANTELOPE study was to examine longitudinal changes in bone microstructure alongside a range of musculoskeletal parameters and frailty, comparing men with PC receiving ADT alone or ADT plus chemotherapy for metastatic disease, with a healthy age-matched population., Methods: We used HR-pQCT to investigate effects of 12 months of ADT on vBMD and microstructural parameters, complemented by assessment of changes in aBMD, serum bone turnover markers, sex hormones, body composition, grip strength, physical and muscle function, frailty and fracture risk. We studied three groups: Group A - men with localised/locally advanced PC due to commence ADT; Group B - men with newly diagnosed hormone-sensitive, metastatic PC, starting ADT alongside docetaxel chemotherapy and steroids; Group C - healthy, age-matched men. The primary endpoint was change in vBMD (Group A vs Group C) at the distal radius., Results: Ninety-nine participants underwent baseline study assessments (Group A: n = 38, Group B: n = 30 and Group C: n = 31). Seventy-five participants completed all study assessments (Group A (29), Group B (18), Group C (28). At baseline, there were no significant differences between Groups A and C in any of the BMD or bone microstructure outcomes of interest. After 12 months of ADT treatment, there was a significantly greater decrease in vBMD (p < 0.001) in Group A (mean 12-month change = -13.7 mg HA/cm 3 , -4.1 %) compared to Group C (mean 12-month change = -1.3 mg HA/cm 3 , -0.4 %), demonstrating achievement of primary outcome. Similar effects were observed when comparing the change in vBMD between Group B (mean 12-month change = -13.5 mg HA/cm 3 , -4.3 %) and Group C. These changes were mirrored in aBMD. ADT resulted in microstructural deterioration, a reduction in estimated bone strength and an increase in bone turnover. There was evidence of increase in total fat mass and trunkal fat mass in ADT-treated patients, with marked loss in upper limb mass, along with BMI gain. Frailty increased and physical performance and strength deteriorated in both ADT groups, relative to the healthy control group., Conclusion: The study showed that ADT has profound effects on vBMD, aBMD, bone microstructure and strength and body composition, and important impacts on frailty and physical performance. Whilst DXA remains a valuable tool (changes in aBMD are of the same magnitude as those observed for vBMD), HR-pQCT should be considered for assessing the effects of anti-androgens and other newer PC therapies on bone, as well as potential mitigation by bone-targeted agents., Competing Interests: CH – Fellowship funding from Weston Park Cancer Charity MAP – none RJ – none FG – none RE receives consultancy funding from Immunodiagnostic Systems, Sandoz, Samsung, CL Bio, CureTeQ, Biocon, Takeda, UCB, meeting presentations for Pharmacosmos, Alexion, UCB and Amgen, and grant funding from Alexion and Osteolabs. JSW – none JEB – has served as a consultant or adviser for Novartis, Ipsen, Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, and Bayer; honoraria from Novartis, Ipsen, Amgen, Merck Sharp & Dohme, BristolMyers Squibb, and Bayer; research funding paid to their institution from the National Institute for Health and Care Research and Weston Park Cancer Charity; and travel expenses from Ipsen., (© 2024 Published by Elsevier GmbH.)

Competing Interests: DMB and MLB report grants awarded to University of California, San Francisco, from the Foundation for the National Institutes of Health, American Society for Bone and Mineral Research, and US Food and Drug Administration. MLB has served as president for the American Society for Bone and Mineral Research. RE reports grants from Alexion and Osteolabs; consulting fees from AstraZeneca, Immunodiagnostic Systems, Sandoz, Samsung, CL Bio, CureTeq, Biocon, Takeda, and UCB; and honoraria from Pharmacosmos, Alexion, UCB, and Amgen. ART declares no competing interests.

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Context: Collagen type I C-telopeptide (CTX) and procollagen type I N-terminal propeptide (PINP) are reference bone resorption and formation markers, respectively., Objective: To characterize CTX and PINP trajectories across the menopause transition (MT)., Methods: This 18-year longitudinal analysis of a community-based cohort from the Study of Women's Health Across the Nation included 541 women (126 Black, 90 Chinese, 87 Japanese, 238 White) who transitioned from pre- to postmenopause. Multivariable mixed effects regression fit piecewise linear models of CTX or PINP relative to years from final menstrual period (FMP); covariates were race/ethnicity, body mass index (BMI), and age at FMP. In the referent participant (White, 52.46 years at FMP, BMI 27.12 kg/m2), CTX and PINP were stable until 3 years pre-FMP (premenopause). During the MT (3 years before to 3 years after the FMP), CTX and PINP increased 10.3% (P < .0001) and 7.5% (P < .0001) per year, respectively; MT-related gains totaled 61.9% for CTX and 45.2% for PINP. Starting 3 years post-FMP (postmenopause), CTX and PINP decreased 3.1% (P < .0001) and 2.9% (P < .0001) per year, respectively. Compared with the White participants, during the MT, Chinese participants had larger gains in CTX (P = .01), and Japanese women experienced greater increases in CTX (P < .0001) and PINP (P = .02). In postmenopause, CTX (P = .01) and PINP (P = .01) rose more in Japanese relative to White women., Conclusion: CTX and PINP are stable in premenopause, increase during the MT, and decrease in postmenopause. During the MT and postmenopause, bone turnover change rates vary by race/ethnicity., (© 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.)

Background: Previous studies have indicated that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) may enhance bone formation and have neutral or beneficial effects on fracture risk. We evaluated the effect of the GLP-1RA semaglutide on the bone formation marker Procollagen type I N-terminal propeptide (PINP) in adults with increased fracture risk., Methods: This randomised, placebo-controlled, double-blinded, phase 2 clinical trial was conducted at two public hospitals in Denmark. We enrolled 64 men and women with increased fracture risk based on a T-score < -1.0 at the total hip or lumbar spine and/or low-energy fracture within three years of recruitment. Participants were randomised (1:1) to receive once-weekly subcutaneous semaglutide 1.0 mg or placebo. The primary outcome was changes in plasma (P)-PINP from baseline to week 52. Primary and safety outcomes were assessed and evaluated for all participants. This trial is complete and registered with ClinicalTrials.gov, NCT04702516., Findings: Between March 24 and December 8, 2021, 55 (86%) postmenopausal women and nine men with a mean age of 63 years (SD 5.5) and BMI of 27.5 kg/m 2 (SD 4.5) were enrolled. There was no effect on changes in P-PINP from baseline to week 52 between the two groups (estimated treatment difference (ETD) semaglutide versus placebo 3.8 μg/L [95% CI -5.6 to 13.3]; p = 0.418), and no difference in P-PINP levels between groups at week 52 (semaglutide 64.3 μg/L versus placebo 62.3 μg/L [95% CI -10.8 to 15.0]; p = 0.749). The secondary outcomes showed higher plasma levels of bone resorption marker Collagen type I cross-linked C-terminal telopeptide (P-CTX) in the semaglutide group than in the placebo group (ETD 166.4 ng/L [95% CI 25.5-307.3]; p = 0.021). Compared to placebo, lumbar spine and total hip areal bone mineral densities (aBMD) were lower in the semaglutide group after 52 weeks ((ETD lumbar spine -0.018 g/cm 3 [95% CI -0.031 to -0.005]; p = 0.007); ETD total hip -0.020 g/cm 2 ([95% CI -0.032 to -0.008]; p = 0.001). Treatment differences in femoral neck aBMD were not observed ([95% CI [-0.017 to 0.006]; p = 0.328). Further, body weight was lower in the semaglutide group than in the placebo group after 52 weeks (ETD -6.8 kg [95% CI -8.8 to -4.7]; p < 0.001). Thirty-one [97%] in the semaglutide group and 18 [56%] in the placebo group experienced at least one adverse event, including four serious events (two in each group). No episodes of hypoglycaemia or deaths were reported., Interpretation: In adults with increased fracture risk, semaglutide once weekly did not increase bone formation based on the bone formation marker P-PINP. The observed increase in bone resorption in the semaglutide group may be explained by the accompanying weight loss., Funding: Region of Southern Denmark, Novo Nordisk Foundation, and Gangsted Foundation. Novo Nordisk provided the investigational drug and placebo., Competing Interests: EMW, SJ, SGH, JJM, and CE declare no conflicts of interest. MSH and MF have received funding from the Novo Nordisk Foundation. RE receives consultancy funding from Immunodiagnostic Systems, Sandoz, Samsung, CL Bio, Biocon, Takeda, UCB, meeting presentations for Pharmacosmos, Alexion, UCB and Amgen, and grant funding from Alexion. NRJ has received assays and reagents from IDS and Roche for clinical studies. MF has received consultancy funding from Novo Nordisk and is shareholder at Novo Nordisk and Eli Lily. Novo Nordisk, Denmark, provided the investigational drug and placebo., (© 2024 The Author(s).)

Areal bone mineral density (aBMD) currently represents the clinical gold standard for hip fracture risk assessment. Nevertheless, it is characterised by a limited prediction accuracy, as about half of the people experiencing a fracture are not classified as at being at risk by aBMD. In the context of a progressively ageing population, the identification of accurate predictive tools would be pivotal to implement preventive actions. In this study, DXA-based statistical models of the proximal femur shape, intensity (i.e., density) and their combination were developed and employed to predict hip fracture on a retrospective cohort of post-menopausal women. Proximal femur shape and pixel-by-pixel aBMD values were extracted from DXA images and partial least square (PLS) algorithm adopted to extract corresponding modes and components. Subsequently, logistic regression models were built employing the first three shape, intensity and shape-intensity PLS components, and their ability to predict hip fracture tested according to a 10-fold cross-validation procedure. The area under the ROC curves (AUC) for the shape, intensity, and shape-intensity-based predictive models were 0.59 (95%CI 0.47-0.69), 0.80 (95%CI 0.70-0.90) and 0.83 (95%CI 0.73-0.90), with the first being significantly lower than the latter two. aBMD yielded an AUC of 0.72 (95%CI 0.59-0.82), found to be significantly lower than the shape-intensity-based predictive model. In conclusion, a methodology to assess hip fracture risk uniquely based on the clinically available imaging technique, DXA, is proposed. Our study results show that hip fracture risk prediction could be enhanced by taking advantage of the full set of information DXA contains., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Denosumab is a monoclonal antibody used to reduce risk of fractures in osteoporosis. ROSALIA was a multicenter, double-blind, randomized, integrated phase I/phase III study comparing the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and safety of proposed biosimilar denosumab GP2411 with reference denosumab (REF-DMAb) (Prolia®; Amgen). Postmenopausal women with osteoporosis were randomized 1:1 to 2 60-mg doses of GP2411 or REF-DMAb, one at study start and one at week 26. At week 52, the REF-DMAb group was re-randomized 1:1 to a third dose of REF-DMAb or switch to GP2411. The primary efficacy endpoint was percentage change from baseline (%CfB) in LS-BMD at week 52. Secondary efficacy endpoints were %CfB in LS-BMD, FN-BMD, and TH-BMD at weeks 26 and 78 (and week 52 for FN-BMD and TH-BMD). Primary PK and PD endpoints were the area under the serum concentration-time curve extrapolated to infinity and maximum drug serum concentration at week 26, and the area under the effect-time curve of the %CfB in serum CTX at week 26. Secondary PK and PD endpoints included drug serum concentrations and %CfB in serum CTX and P1NP during the study period. Similar efficacy was demonstrated at week 52, with 95% CIs of the difference in %CfB in LS-BMD between treatment groups fully contained within prespecified equivalence margins. Similarity in PK and PD was demonstrated at week 26. Immunogenicity was similar between groups and was not impacted by treatment switch. The rate of new vertebral fractures was comparable. Treatment-emergent adverse events were comparable between groups (63.6% [GP2411/GP2411]; 76.0% [REF-DMAb/REF-DMAb]; 76.6% [REF-DMAb/GP2411]). In conclusion, ROSALIA showed similar efficacy, PK and PD, and comparable safety and immunogenicity of GP2411 to REF-DMAb in postmenopausal osteoporosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

MicroRNAs are involved in post-transcriptional regulation of gene expression. Due to their regulatory role, microRNAs are differently expressed during specific conditions in healthy and diseased individuals, so microRNAs circulating in the blood could be used as diagnostic and prognostic biomarkers for various diseases and conditions. We want to investigate the variability of circulating microRNAs and bone turnover markers in weekly time intervals in older women. In a single-site longitudinal study, a panel of 19 bone-related miRNAs was measured using the osteomiR RT-qPCR assay in serum samples of 35 postmenopausal women divided into 3 groups: healthy controls ( n  = 12), low BMD ( n  = 14), and vertebral fractures ( n  = 9). Blood samples for measurement of CTX, PINP, OC, and bone ALP were collected once per week for 8 weeks at 9:00 AM after overnight fasting. Serum samples from all participants were analyzed for 19 microRNA bone biomarkers and 4 bone turnover markers over 8 weeks. We analyzed the data using a mixed model analysis of variance and found no significant changes between week-by-week time points in any of the groups. To estimate intraindividual variability between weekly time points, we have calculated the median coefficient of variation (CV). This was between 28.4% and 80.2% for microRNA, with an assay CV of 21.3%. It was between 8.5% and 15.6% for bone turnover markers, with an assay CV of 3.5% to 6.5%. The intraindividual variability was similar between groups. Circulating microRNAs measured in serum had a higher weekly intraindividual variability than bone turnover markers due in part to a higher assay CV., Competing Interests: M.H. and J.G. are co-founders of TAmiRNA. TAmiRNA employs M.H. J.G. is a scientific advisor to TAmiRNA. M.H. and J.G. hold patents related to the application of circulating microRNAs as biomarkers for the diagnosis of bone disorders. R.E. receives grant funding from TAmiRNA and Immunodiagnostics Systems. The remaining authors have nothing to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Type 1 diabetes mellitus (T1DM) has been linked to increased osteocyte apoptosis, local accumulation of mineralized lacunar spaces, and microdamage suggesting an impairment of the mechanoregulation network in affected individuals. Diabetic neuropathy might exacerbate this dysfunction through direct effects on bone turnover, and indirect effects on balance, muscle strength, and gait. However, the in vivo effects of impaired bone mechanoregulation on bone remodeling in humans remain underexplored. This longitudinal cohort study assessed consenting participants with T1DM and varying degree of distal symmetric sensorimotor polyneuropathy (T1DM, n = 20, median age 46.5 yr, eight female) and controls (CTRL; n = 9, median age 59.0 yr, four female) at baseline and 4-yr follow-up. Nerve conduction in participants with T1DM was tested using DPNCheck and bone remodeling was quantified with longitudinal high-resolution peripheral quantitative-computed tomography (HR-pQCT, 82 μm) at the standard distal sites. Local trabecular bone formation (Tb.F) and resorption (Tb.R) sites were captured by implementing 3D rigid image registration of HR-pQCT images, and the mechanical environment across the bone microarchitecture at these sites was simulated using micro-finite element analysis. We calculated odds ratios to determine the likelihood of bone formation (ORF) and resorption (ORR) with increasing/decreasing strain in percent as markers for mechanoregulation. At the distal radius, Tb.F was 47% lower and Tb.R was 59% lower in T1DM participants compared with CTRL (P < .05). Tb.F correlated positively with nerve conduction amplitude (R = 0.69, P < .05) in participants with T1DM and negatively with glycated hemoglobin (HbA1c) (R = -0.45, P < .05). Additionally, ORF was 34% lower and ORR was 18% lower in T1DM compared with CTRL (P < .05). Our findings represent in vivo evidence suggesting that bone remodeling in individuals with T1DM is in a state of low responsiveness to mechanical stimuli, resulting in impaired bone formation and resorption rates; these correlate to the degree of neuropathy and level of diabetes control., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

There is a dearth of data on Se status in very old adults. The aims of this study were to assess Se status and its determinants in 85-year-olds living in the Northeast of England by measuring serum Se and selenoprotein P (SELENOP) concentrations and glutathione peroxidase 3 (GPx3) activity. A secondary aim was to examine the interrelationships between each of the biomarkers. In total, 757 participants (463 women, 293 men) from the Newcastle 85+ Study were included. Biomarker concentrations were compared with selected cut-offs (serum Se: suboptimal 70 µg/l and deficient 45 µg/l; SELENOP: suboptimal 4·5 mg/l and deficient 2·6 mg/l). Determinants were assessed using linear regressions, and interrelationships were assessed using restricted cubic splines. Median (inter-quartile range) concentrations of serum Se, SELENOP and of GPx3 activity were 53·6 (23·6) µg/l, 2·9 (1·9) mg/l and 142·1 (50·7) U/l, respectively. Eighty-two percentage and 83 % of participants had suboptimal serum Se (< 70 µg/l) and SELENOP (< 4·5 mg/l), and 31 % and 40 % of participants had deficient serum Se (< 45 µg/l) and SELENOP (< 2·6 mg/l), respectively. Protein intake was a significant determinant of Se status. Additional determinants of serum Se were sex, waist:hip ratio, self-rated health and disease, while sex, BMI and physical activity were determinants of GPx3 activity. There was a linear association between serum Se and SELENOP, and nonlinear associations between serum Se and GPx3 activity and between SELENOP and GPx3 activity. These findings indicate that most participants had suboptimal Se status to saturate circulating SELENOP.

Adjuvant bisphosphonates are often recommended in postmenopausal women with early breast cancer at intermediate-to-high risk of disease recurrence, but the magnitude and duration of their effects on bone mineral density (BMD) and bone turnover markers (BTMs) are not well described. We evaluated the impact of adjuvant zoledronate on areal BMD and BTMs in a sub-group of patients who had completed the large 5-yr randomized Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial. About 224 women (recurrence free) who had completed the AZURE trial within the previous 3 mo were recruited from 20 UK AZURE trial sites. One hundred twenty had previously been randomized to zoledronate (19 doses of 4 mg over 5 yr) and 104 to the control arm. BMD and BTMs were assessed at sub-study entry, 6 (BTMs only), 12, 24, and 60 mo following the completion of AZURE. As expected, mean BMD, T-scores, and Z-scores at sub-study entry were higher in the zoledronate vs the control arm. At the lumbar spine, the mean (SD) standardized BMD (sBMD) was 1123 (201) and 985 (182) mg/cm2 in the zoledronate and control arms, respectively (P < .0001). The baseline differences in sBMD persisted at all assessed skeletal sites and throughout the 5-yr follow-up period. In patients completing zoledronate treatment, BTMs were significantly lower than those in the control arm (α- and β-urinary C-telopeptide of type-I collagen, both P < .00001; serum intact pro-collagen I N-propeptide, P < .00001 and serum tartrate-resistant acid phosphatase 5b, P = .0001). Some offset of bone turnover inhibition occurred in the 12 mo following the completion of zoledronate treatment. Thereafter, during the 60 mo of follow-up, all BTMs remained suppressed in the zoledronate arm relative to the control arm. In conclusion, in addition to the known anti-cancer benefits of adjuvant zoledronate, there are likely to be positive, lasting benefits in BMD and bone turnover., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose of the Review: The purpose of the review is to summarise the current scientific evidence on the efficacy of osteoporosis medications in patients with type 2 diabetes., Recent Findings: Type 2 diabetes (T2D) is a growing global epidemic. The highest prevalence is observed in the elderly, the same population affected by osteoporosis. Despite normal or even increased bone mineral density and low bone turnover, T2D is associated with an increased risk of fractures in most skeletal sites. These findings raised concerns over the efficacy of anti-osteoporosis drugs in this population. There is no randomised controlled trial designed specifically for people with T2D. However, observational studies and post-hoc analyses of randomised controlled trials have provided valuable insights into the effects of various anti-osteoporosis treatments in this population. Overall, most anti-osteoporosis drugs seem to have similar efficacy and safety profiles for people with and without type 2 diabetes. However, continued research and long-term safety data are needed to optimise treatment strategies and improve bone health outcomes in this population. The current evidence suggests that most anti-osteoporosis drugs exhibit comparable efficacy in people with and without T2D., (© 2023. The Author(s).)

Diabetes is characterized by hyperglycemia, but the two main types, type 1 diabetes (T1D) and type 2 diabetes (T2D), have distinct pathophysiology and epidemiological profiles. Individuals with T1D and T2D have an increased risk of fractures, particularly of the hip, upper arm, ankle, and nonvertebral sites. The risk of fractures is higher in T1D compared to T2D. The diagnosis of osteoporosis in individuals with T1D and T2D follows similar criteria as in the general population, but treatment thresholds may differ. Antiresorptive therapies, the first-line treatment for osteoporosis, are effective in individuals with T2D. Observational studies and post hoc analyses of previous trials have indicated that antiresorptive drugs, such as bisphosphonates and selective estrogen receptor modulators, are equally effective in reducing fracture risk and increasing bone mineral density (BMD) in individuals with and without T2D. Denosumab has shown similar effects on vertebral fracture risk but increases the risk of nonvertebral fractures. Considering the low bone turnover observed in T1D and T2D, anabolic therapies, which promote bone formation and resorption, have emerged as a potential treatment option for bone fragility in this population. Data from observational studies and post hoc analyses of previous trials also showed similar results in increasing BMD and reducing the risk of fractures in people with or without T2D. However, no evidence suggests that anabolic therapy has greater efficacy than antiresorptive drugs. In conclusion, there is an increased risk of fractures in T1D and T2D. Reductions in BMD cannot solely explain the relationship between T1D and T2D and fractures. Bone microarchitecture and other factors play a role. Antiresorptive and anabolic therapies have shown efficacy in reducing fracture risk in individuals with T2D, but the evidence is more robust for antiresorptive drugs. Evidence in T1D is scant. Further research is needed to fully understand the underlying mechanisms and optimize management strategies for bone fragility in T1D and T2D. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., (© 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

The incidence of major osteoporotic fractures has declined in men and women in Western countries over the last two decades. Although fracture risk is higher in persons with diabetes mellitus, trends of fractures remain unknown in men and women with diabetes. We investigated the trends in fracture incidence rates (IRs) in men and women with type 1 diabetes mellitus (T1D) and type 2 diabetes mellitus (T2D) in Denmark between 1997 and 2017. We identified men and women aged 18+ years who sustained a fracture (excluding skull and facial fractures) between 1997 and 2017 using the Danish National Patient Registry. We calculated sex-specific IRs of fractures per 10,000 person-years separately in persons with T1D, T2D, or without diabetes. Furthermore, we compared median IRs of the first 5 years (1997-2002) to the median IRs of the last 5 years (2012-2017). We identified 1,235,628 persons with fractures including 4863 (43.6% women) with T1D, 65,366 (57.5% women) with T2D, and 1,165,399 (54.1% women) without diabetes. The median IRs of fractures declined 20.2%, 19.9%, and 7.8% in men with T1D, T2D, and without diabetes, respectively ( p -trend <0.05). The median IRs decreased 6.4% in women with T1D ( p -trend = 0.35) and 25.6% in women with T2D ( p -trend <0.05) but increased 2.3% in women without diabetes ( p -trend = 0.08). Fracture IRs decreased in men with both diabetes types and only in women with T2D, highlighting the need for further attention behind the stable trend observed in women with T1D. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., (© 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Context: Bone turnover markers (BTMs) are lower in type 2 diabetes mellitus (T2D). The relationships between bone turnover, β-cell function, and insulin sensitivity in T2D are uncertain., Objective: To investigate if fasting levels of BTMs in persons with T2D are associated with β-cell function or insulin sensitivity., Methods: We defined three T2D phenotypes, the insulinopenic (low β-cell function, high insulin sensitivity), the classical (low β-cell function, low insulin sensitivity), and the hyperinsulinemic (high β-cell function, low insulin sensitivity) phenotypes, in the Danish Centre for Strategic Research T2D cohort using the homeostatic model assessment. We selected age- and gender-matched subgroups to represent the three T2D phenotypes, yielding 326 glucose-lowering treatment-naïve persons with T2D. Median values of BTMs between the three T2D phenotypes were compared. Regression models were applied to assess the association between BTMs, β-cell function, and insulin sensitivity adjusted for potential confounders., Results: Median serum levels of procollagen type I N-terminal propeptide, C-terminal telopeptide of type I collagen, and osteocalcin were higher in the insulinopenic phenotype (52.3 μg/L, IQR 41.6, 63.3; 259.4 ng/L, IQR 163.4, 347.7; and 18.0 μg/L, IQR 14.4, 25.2, respectively) compared with the classical (41.4, IQR 31.0, 51.4; 150.4 IQR 103.5, 265.1; 13.1, IQR 10.0, 17.6, respectively) and the hyperinsulinemic (43.7, IQR 32.3, 57.3; 163.3, IQR 98.9, 273.1; 15.7 IQR 10.2, 20.8, respectively) phenotypes (all P < .01). These differences persisted after adjustment for age, sex, waist to hip ratio, or fasting plasma glucose (P < .01)., Conclusion: BTMs are lower in newly diagnosed persons with T2D characterized by low insulin sensitivity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: The risk of fragility fractures is increased in both type 1 and type 2 diabetes. Numerous biochemical markers reflecting bone and/or glucose metabolism have been evaluated in this context., Objective: This review summarizes current data on biochemical markers in relation to bone fragility and fracture risk in diabetes., Methods: A group of experts from the International Osteoporosis Foundation and European Calcified Tissue Society reviewed the literature focusing on biochemical markers, diabetes, diabetes treatments, and bone in adults., Results: Although bone resorption and bone formation markers are low and poorly predictive of fracture risk in diabetes, osteoporosis drugs seem to change bone turnover markers (BTMs) in diabetics similarly to nondiabetics, with similar reductions in fracture risk. Several other biochemical markers related to bone and glucose metabolism have been correlated with bone mineral density and/or fracture risk in diabetes, including osteocyte-related markers such as sclerostin, glycated hemoglobin A1c (HbA1c) and advanced glycation end products, inflammatory markers, and adipokines, as well as insulin-like growth factor-1 and calciotropic hormones., Conclusion: Several biochemical markers and hormonal levels related to bone and/or glucose metabolism have been associated with skeletal parameters in diabetes. Currently, only HbA1c levels seem to provide a reliable estimate of fracture risk, while BTMs could be used to monitor the effects of antiosteoporosis therapy., (© 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.)

Bone turnover markers (BTMs) are used widely, in both research and clinical practice. In the last 20 years, much experience has been gained in measurement and interpretation of these markers, which include commonly used bone formation markers (bone alkaline phosphatase, osteocalcin, and procollagen I N-propeptide); and commonly used resorption markers (serum C-telopeptides of type I collagen, urinary N-telopeptides of type I collagen, and tartrate-resistant acid phosphatase type 5b). BTMs are usually measured by enzyme-linked immunosorbent assay or automated immunoassay. Sources contributing to BTM variability include uncontrollable factors (eg, age, gender, ethnicity) and controllable factors, particularly relating to collection conditions (eg, fasting/feeding state, and timing relative to circadian rhythms, menstrual cycling, and exercise). Pregnancy, season, drugs, and recent fracture(s) can also affect BTMs. BTMs correlate with other methods of assessing bone turnover, such as bone biopsies and radiotracer kinetics, and can usefully contribute to diagnosis and management of several diseases such as osteoporosis, osteomalacia, Paget's disease, fibrous dysplasia, hypophosphatasia, primary hyperparathyroidism, and chronic kidney disease-mineral bone disorder., Competing Interests: Conflict of Interest M.S. received funding for her fellowship from the Medical Research Council Centre of Excellence for Musculoskeletal Ageing and from the Osteoporosis 2000 support group, grant funding from Roche Diagnostics, and honorarium from Kyowa Kirin. T.V. received consultancy and grant funding from Pharmacosmos. F.G. has no disclosures. S.S. received project grant funding from Immunodiagnostic Systems. R.E. receives consultancy funding from Immunodiagnostic Systems, Sandoz, Samsung, Haoma Medica, CL Bio, Biocon, Amgen, Pharmacosmos, and Takeda and grant funding from Roche Diagnostics, Pharmacosmos, and Alexion., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Senescent cells and senescence-associated secretory phenotype (SASP) proteins are involved in age-related bone loss. Growth differentiation factor 15 (GDF 15), a stress-responsive cytokine member of the transforming growth factor-β (TGF-β) superfamily, is one of the key SASP proteins. It is strongly associated with age and higher levels correlate with frailty and are detected in several conditions and diseases. It also modulates appetite and body weight through the binding to its receptor glial cell- derived neurotrophic factor family receptor alpha- like (GFRAL) in the brainstem. The GDF 15 involvement in bone metabolism has been studied in several murine models, however, it is still unclear in humans. Therefore, this study aims to determine whether GDF 15 is associated with bone mineral density (BMD) and bone turnover, and to establish the effect of age and gender on its levels. Serum GDF 15 was measured with an ELISA from R&D Systems in 180 healthy women and men from the "XtremeCT study", divided into three age groups which represent different stages of skeletal development (16-18, 30-32, over 70 years). We also measured bone resorption marker C-terminal telopeptide of type I collagen (CTX) and bone formation markers N-terminal propeptide of type I collagen (PINP), osteocalcin (OC) and bone alkaline phosphatase (BAP) using iSYS-IDS analyser. Parathyroid hormone (PTH), 25hydroxyvitamin D (25OH-vitamin D), Insulin-like Growth Factor I (IGF-1), estradiol and testosterone were measured using the Cobas automated analyser (Roche Diagnostics). We assessed BMD at spine and total hip by dual-energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HRpQCT) of the radius and tibia. Univariate analysis of variance with the post-hoc Sheffe test and multiple linear regression has been used to assess the effect of age and gender. Spearman's rank correlation was used to evaluate the associations between GDF 15 and the other variables. We found GDF 15 levels significantly associated with age ( p  < 0.001) and gender ( p  = 0.008), with a significant gender ∗ age interaction ( p  < 0.001). Significantly higher levels of GDF 15 were found in subjects aged over 70 compared with the younger people (p < 0.001) and significantly higher levels were detected in men. We did not find any significant correlation between GDF 15 and bone turnover markers (BTMs), BMD, HRpQCT measures and hormones in any of the age groups. In conclusion, age and gender are determinants of GDF15 and much higher levels are found in older people and in men. Since no association was found between GDF 15 and bone health measures, we hypothesize that the effect of GDF 15 on bone might be exert by other tissue, such as muscle., Competing Interests: LM: no disclosures. FG: no disclosures. JW: Speaker's honoraria from Eli Lilly and Sandoz, grant funding from Alexion, donation of drug from Eli Lilly for clinical studies, consulting fees from Mereo Biopharma. RE: receives consultancy funding from Immunodiagnostic Systems, Sandoz, Samsung, Haoma Medica, CL Bio, Biocon, Takeda, meeting presentations for Pharmacosmos, Alexion and Amgen, and grant funding from Roche, Pharmacosmos and Alexion., (©2023PublishedbyElsevierInc.)

Glucocorticoids prescribed to limit inflammation, have significant adverse effects. As 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoid, we investigated whether 11β-HSD1 inhibition with AZD4017 could mitigate adverse glucocorticoid effects without compromising their anti-inflammatory actions. We conducted a proof-of-concept, randomized, double-blind, placebo-controlled study at Research Unit, Churchill Hospital, Oxford, UK (NCT03111810). 32 healthy male volunteers were randomized to AZD4017 or placebo, alongside prednisolone treatment. Although the primary endpoint of the study (change in glucose disposal during a two-step hyperinsulinemic, normoglycemic clamp) wasn't met, hepatic insulin sensitivity worsened in the placebo-treated but not in the AZD4017-treated group. Protective effects of AZD4017 on markers of lipid metabolism and bone turnover were observed. Night-time blood pressure was higher in the placebo-treated but not in the AZD4017-treated group. Urinary (5aTHF+THF)/THE ratio was lower in the AZD4017-treated but remained the same in the placebo-treated group. Most anti-inflammatory actions of prednisolone persisted with AZD4017 co-treatment. Four adverse events were reported with AZD4017 and no serious adverse events. Here we show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects., (© 2023. The Author(s).)

This narrative review summarizes data on classical and nonclassical manifestations of primary hyperparathyroidism (PHPT). It is based on a rigorous literature search, inclusive of a Medline search for systematic reviews from 1940 to December 2020, coupled with a targeted search for original publications, covering four databases, from January 2013-December 2020, and relevant articles from authors' libraries. We present the most recent information, identify knowledge gaps, and suggest a research agenda. The shift in the presentation of PHPT from a predominantly symptomatic to an asymptomatic disease, with its varied manifestations, has presented several challenges. Subclinical nephrolithiasis and vertebral fractures are common in patients with asymptomatic disease. The natural history of asymptomatic PHPT with no end organ damage at diagnosis is unclear. Some observational and cross-sectional studies continue to show associations between PHPT and cardiovascular and neuropsychological abnormalities, among the different disease phenotypes. Their causal relationship is uncertain. Limited new data are available on the natural history of skeletal, renal, cardiovascular, neuropsychological, and neuromuscular manifestations and quality of life. Normocalcemic PHPT (NPHPT) is often diagnosed without the fulfillment of rigorous criteria. Randomized clinical trials have not demonstrated a consistent long-term benefit of parathyroidectomy (PTX) versus observation on nonclassical manifestations. We propose further refining the definition of asymptomatic disease, into two phenotypes: one without and one with evidence of target organ involvement, upon the standard evaluation detailed in our recommendations. Each of these phenotypes can present with or without non-classical manifestations. We propose multiple albumin-adjusted serum calcium determinations (albumin-adjusted and ionized) and exclusion of all secondary causes of high parathyroid hormone (PTH) when establishing the diagnosis of NPHPT. Refining the definition of asymptomatic disease into the phenotypes proposed will afford insights into their natural history and response to interventions. This would also pave the way for the development of evidence-based guidance and recommendations. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Higher selenium status has been associated with lower bone turnover markers (BTM) in epidemiological studies. However, the long-term impact of selenium supplementation on BTMs has not been studied. We investigated the effects of selenium supplementation on BTMs including osteocalcin (OC), procollagen type I N-terminal propeptide (PINP), collagen type I cross-linked C-telopeptide (CTX), and bone alkaline phosphatase (BALP) in the short (6 months) and long term (5 years). A total of 481 Danish men and women (60-74 years) were randomized to receive placebo-yeast versus 100, 200, or 300 μg selenium as selenium-enriched yeast daily for 5 years. Plasma selenium concentration was measured using inductively coupled plasma mass spectrometry, and BTMs were measured in nonfasted samples at baseline, 6 months, and 5 years. Data were analyzed by ANCOVA to investigate the shape of the dose-response relationships. Covariates included age, body mass index, baseline selenium status, baseline BTM, smoking, alcohol, supplement use, and medication. Plasma selenium concentration (mean 86.5 μg/d at baseline) increased significantly with increasing selenium supplementation to 152.6, 209.1, and 253.7 μg/L after 6 months and remained elevated at 5 years (158.4, 222.4, and 275.9 μg/L for 100, 200, and 300 μg supplemental selenium/d, respectively (p < 0.001)). There was no change in plasma selenium concentration in the placebo-treated group. There was no significant effect of selenium supplementation on OC (6 months p = 0.37; 5 years p = 0.63), PINP (6 months p = 0.37; 5 years p = 0.79), CTX (6 months p = 0.91; 5 years p = 0.58) or BALP (6 months p = 0.17; 5 years p = 0.53). The relatively replete baseline selenium status in the study participants may explain this lack of effect. Testing in more deficient populations may provide further insights into the impact of selenium supplementation on bone health. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Type 2 diabetes (T2D) is associated with increased risk of fractures. However, it is unclear whether current osteoporosis treatments reduce fractures in individuals with diabetes. The aim of the study was to determine whether presence of T2D influences the efficacy of antiresorptive treatment for osteoporosis using the Foundation for the National Institutes of Health (FNIH)-American Society for Bone and Mineral Research (ASBMR)-Study to Advance Bone Mineral Density (BMD) as a Regulatory Endpoint (SABRE) cohort, which includes individual patient data from randomized trials of osteoporosis therapies. In this study we included 96,385 subjects, 6.8% of whom had T2D, from nine bisphosphonate trials, two selective estrogen receptor modulator (SERM) trials, two trials of menopausal hormone therapy, one denosumab trial, and one odanacatib trial. We used Cox regression to obtain the treatment hazard ratio (HR) for incident nonvertebral, hip, and all fractures and logistic regression to obtain the treatment odds ratio (OR) for incident morphometric vertebral fractures, separately for T2D and non-DM. We used linear regression to estimate the effect of treatment on 2-year change in BMD (n = 49,099) and 3-month to 12-month change in bone turnover markers (n = 12,701) by diabetes status. In all analyses, we assessed the interaction between treatment and diabetes status. In pooled analyses of all 15 trials, we found that diabetes did not impact treatment efficacy, with similar reductions in vertebral, nonvertebral, all, and hip fractures, increases in total hip and femoral neck BMD, and reductions in serum C-terminal cross-linking telopeptide (CTX), urinary N-telopeptide of type I collagen/creatinine (NTX/Cr) and procollagen type 1 N propeptide (P1NP) (all interactions p > 0.05). We found similar results for the pooled analysis of bisphosphonate trials. However, when we considered trials individually, we found a few interactions within individual studies between diabetes status and the effects of denosumab and odanacatib on fracture risk, change in BMD or bone turnover markers (BTMs). In sum, these results provide strong evidence that bisphosphonates and most licensed antiresorptive drugs are effective at reducing fracture risk and increasing BMD irrespective of diabetes status. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

The anti-fibroblast growth factor 23 monoclonal antibody burosumab corrects hypophosphatemia in adults with X-linked hypophosphatemia (XLH) and improves pain, stiffness, physical function, and fatigue. This post hoc subgroup analysis used data from the 24-week placebo-controlled period of a phase 3 study in 134 adults with XLH (ClinicalTrials.gov NCT02526160), to assess whether the benefits of burosumab are evident in 14 clinically relevant subgroups defined by baseline demographic and functional criteria, including sex, Brief Pain Inventory-short form (BPI-SF) Average And Worst Pain, region, race, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®) Stiffness, Physical Function and Pain domains and total score, use of opioid/other pain medication, active fractures/pseudo-fractures, and 6-min walk test distance. There were no statistically significant interactions between any of the subgroups and treatment arm for any endpoint. Higher proportions of subjects achieved mean serum phosphate concentration above the lower limit of normal (the primary endpoint) with burosumab than with placebo in all subgroups. For the key secondary endpoints (WOMAC Stiffness and Physical Function; BPI-SF Worst Pain) individual subgroup categories showed improvements with burosumab relative to placebo. For additional efficacy endpoints, burosumab was favored in some subgroups but differences were not significant and confidence intervals were wide. For some endpoints the treatment effect is small at 24 weeks in all subjects. This subgroup analysis shows that burosumab was largely superior to placebo across endpoints in the 14 clinically relevant subgroup variables at 24 weeks and is likely to benefit all symptomatic adults with active XLH., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The risk of osteoporotic fracture is inversely related to bone mineral density (BMD), but how spatial BMD pattern influences fracture risk remains incompletely understood. This study used a pixel-level spatiotemporal atlas of proximal femoral BMD in 13,338 white European women (age 20-97 years) to quantitate age-related texture variation in BMD maps and generate a "reference" map of bone aging. We introduce a new index, called Densitometric Bone Age (DBA), as the age at which an individual site-specific BMD map (the proximal femur is studied here) best matches the median aging trajectory at that site in terms of the root mean squared error (RMSE). The ability of DBA to predict incident hip fracture and hip fracture pattern over 5 years following baseline BMD was compared against conventional region-based BMD analysis in a subset of 11,899 women (age 45-97 years), for which follow-up fracture records exist. There were 208 subsequent incident hip fractures in the study populations (138 femoral necks [FNs], 52 trochanteric [TR], 18 sites unspecified). DBA had modestly better performance compared to the conventional FN-BMD, TR-BMD, and total hip (TOT)-BMD in identifying hip fractures measured as the area under the curve (AUC) using receiver operating characteristics (ROC) curve analysis by 2% (95% confidence interval [CI], -0.5% to 3.5%), 3% (95% CI, 1.0% to 4.0%), and 1% (95% CI, 0.4% to 1.6%), respectively. Compared to FN-BMD T-score, DBA improved the ROC-AUC for predicting TR fractures by ~5% (95% CI, 1.1% to 9.8%) with similar performance in identifying FN fractures. Compared to TR-BMD T-score, DBA improved the ROC-AUC for the prediction of FN fractures by ~3% (95% CI, 1.1% to 4.9%), with similar performance in identifying TR fractures. Our findings suggest that DBA may provide a spatially sensitive measure of proximal femoral fragility that is not captured by FN-BMD or TR-BMD alone. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)