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Background and Purpose: This study seeks to perform a survey of patterns of practice among the different physicians involved in the bone metastases management, with special focus on external beam radiotherapy (EBRT).Methods and Materials: A questionnaire about bone metastases based on clinical cases and supplemented with general questions, including medical therapies, EBRT and metabolic radiotherapy strategies, surgery, and supportive care approaches, was sent to 4,706 French-speaking physicians in Belgium, France, Luxemburg, and Switzerland.Results: Overall, 644 questionnaires were analyzed. Twenty-eight percent concerned the radiotherapy approach and were judged adequate to respond to the part dedicated to EBRT. Sixty-nine percent of physicians used a total dose irradiation of 30 Gy delivered in ten fractions. A large majority (75%) used two opposed fields prescribed at mid-depth (30%), or with non-equally weighted fields (45%). Seventy percent irradiated also above and below the concerned vertebra. A dosimetry planning treatment was done in 85% and high-energy megavoltage photons were used in 42%. Moreover, 54% physicians used short course radiotherapy in routine.Conclusions: Radiotherapy remains the mainstay of treatment of bone metastases, but there is substantial heterogeneity in clinical practice. Guidelines and treatment protocols are required to improve the treatment quality. [ABSTRACT FROM AUTHOR]

Background: The proto-oncogene Src is an important non-receptor protein tyrosine kinase involved in signaling pathways that control cell adhesion, growth, migration and differentiation. It negatively regulates osteoblast activity, and, as such, its inhibition is a potential means to prevent bone loss. Dasatinib is a new dual Src/Bcr-Abl tyrosine kinase inhibitor initially developed for the treatment of chronic myeloid leukemia. It has also shown promising results in preclinical studies in various solid tumors. However, its effects on the differentiation of human osteoblasts have never been examined.Methods: We evaluated the effects of dasatinib on bone marrow-derived mesenchymal stromal cells (MSC) differentiation into osteoblasts, in the presence or absence of a mixture of dexamethasone, ascorbic acid and beta-glycerophosphate (DAG) for up to 21 days. The differentiation kinetics was assessed by evaluating mineralization of the extracellular matrix, alkaline phosphatase (ALP) activity, and expression of osteoblastic markers (receptor activator of nuclear factor kappa B ligand [RANKL], bone sialoprotein [BSP], osteopontin [OPN]).Results: Dasatinib significantly increased the activity of ALP and the level of calcium deposition in MSC cultured with DAG after, respectively, 7 and 14 days; it upregulated the expression of BSP and OPN genes independently of DAG; and it markedly downregulated the expression of RANKL gene and protein (decrease in RANKL/OPG ratio), the key factor that stimulates osteoclast differentiation and activity.Conclusions: Our results suggest a dual role for dasatinib in both (i) stimulating osteoblast differentiation leading to a direct increase in bone formation, and (ii) downregulating RANKL synthesis by osteoblasts leading to an indirect inhibition of osteoclastogenesis. Thus, dasatinib is a potentially interesting candidate drug for the treatment of osteolysis through its dual effect on bone metabolism. [ABSTRACT FROM AUTHOR]

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.)

Low serum vitamin D levels have been associated with a variety of health conditions which has led the medical community but also the general population to evaluate vitamin D status quite liberally. Nevertheless, there remain questions about the efficacy and cost-effectiveness of such a broad and untargeted approach. This review therefore aims to summarize the current evidence and recommendations on when and how to evaluate vitamin D status in human health and disease. For the general population, most guidelines do not recommend universal screening but suggest a targeted approach in populations at risk. Also, some guidelines do not even recommend evaluating vitamin D status when vitamin D substitution is indicated anyway, such as in children or patients receiving anti-osteoporosis drugs. In those guidelines that recommend the screening of vitamin D status, serum 25(OH)D levels are universally proposed as the preferred screening tool. However, little attention is given to analytical considerations and almost no guidelines discuss the timing and frequency of screening. Finally, there is the known variability in diagnostic thresholds for defining vitamin D insufficiency and deficiency. Overall, the existing guidelines on the evaluation of vitamin D status differ broadly in screening strategy and screening implementation, and none of these guidelines discusses alternative screening modes, for instance, the vitamin metabolic ratio. Efforts to harmonize these different guidelines are needed to enhance their efficacy and cost-effectiveness.

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.)

Only previous glucocorticoid use and rheumatoid arthritis were predictors of an early fracture (< 2 years after inclusion). A shorter 'time to first fracture' was not an independent clinical risk factor for imminent fractures., Purpose: Risk factors for fragility fractures independent of BMD were assessed in several prediction models. However, predictors of a shorter 'time to first fracture' and its impact on imminent fractures are unknown., Methods: We studied the concept of 'time to first fracture' in the FRISBEE ("Fracture RIsk Brussels Epidemiological Enquiry") cohort (3560 postmenopausal women). Validated fractures were divided into 3 groups: first fracture < 2 years, 2-5 years, and > 5 years after inclusion. Factors associated with first fracture risk were evaluated with uni- and multivariate analyses using Cox modeling. We examined 'time to first fracture' as a risk factor for imminent fractures in untreated subjects and in those receiving pharmacological treatment., Results: Classical risk factors (age, prior fracture, fall history and low BMD) were associated with first fracture in all groups. Previous glucocorticoids and rheumatoid arthritis (RA) were predictors for fracture < 2 years. Imminent fractures were similar in subjects with or without osteoporosis treatment, despite a higher estimated 10-year risk of fragility fracture in those treated, suggesting that treatment is efficient. 'Time to first fracture' was not an independent risk factor for imminent fractures., Conclusion: Among the risk factors considered, previous glucocorticoid use and RA were predictors for early fracture, consistent with the concept of very high risk. The 'time to first validated fracture' was not an independent risk factor for imminent fractures. Patients with a first osteoporotic fracture should thus be considered at very high risk for re-fracture, independent of the 'time to first fracture'., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Our imminent model was less sensitive but more selective than FRAX® in the choice of treatment to prevent imminent fractures. This new model decreased NNT by 30%, which could reduce the treatment costs. In the Belgian FRISBEE cohort, the effect of recency further decreased the selectivity of FRAX®., Purpose: We analyzed the selection for treatment of patients at high risk of fracture by the Belgian FRISBEE imminent model and the FRAX® tool., Methods: We identified in the FRISBEE cohort subjects who sustained an incident MOF (mean age 76.5 ± 6.8 years). We calculated their estimated 10-year risk of fracture using FRAX® before and after adjustment for recency and the 2-year probability of fracture using the FRISBEE model., Results: After 6.8 years of follow-up, we validated 480 incident and 54 imminent MOFs. Of the subjects who had an imminent fracture, 94.0% had a fracture risk estimated above 20% by the FRAX® before correction for recency and 98.1% after adjustment, with a specificity of 20.2% and 5.9%, respectively. The sensitivity and specificity of the FRISBEE model at 2 years were 72.2% and 55.4%, respectively, for a threshold of 10%. For these thresholds, 47.3% of the patients were identified at high risk in both models before the correction, and 17.2% of them had an imminent MOF. The adjustment for recency did not change this selection. Before the correction, 34.2% of patients were selected for treatment by FRAX® only, and 18.8% would have had an imminent MOF. This percentage increased to 47% after the adjustment for recency, but only 6% of those would suffer a MOF within 2 years., Conclusion: In our Belgian FRISBEE cohort, the imminent model was less sensitive but more selective in the selection of subjects in whom an imminent fracture should be prevented, resulting in a lower NNT. The correction for recency in this elderly population further decreased the selectivity of FRAX®. These data should be validated in additional cohorts before using them in everyday practice., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Objective: To review the comparative effectiveness of osteoporosis treatments, including the bone anabolic agents, abaloparatide and romosozumab, on reducing the risk of fractures in postmenopausal women, and to characterise the effect of antiosteoporosis drug treatments on the risk of fractures according to baseline risk factors., Design: Systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials., Data Sources: Medline, Embase, and Cochrane Library to identify randomised controlled trials published between 1 January 1996 and 24 November 2021 that examined the effect of bisphosphonates, denosumab, selective oestrogen receptor modulators, parathyroid hormone receptor agonists, and romosozumab compared with placebo or active comparator., Eligibility Criteria for Selecting Studies: Randomised controlled trials that included non-Asian postmenopausal women with no restriction on age, when interventions looked at bone quality in a broad perspective. The primary outcome was clinical fractures. Secondary outcomes were vertebral, non-vertebral, hip, and major osteoporotic fractures, all cause mortality, adverse events, and serious cardiovascular adverse events., Results: The results were based on 69 trials (>80 000 patients). For clinical fractures, synthesis of the results showed a protective effect of bisphosphonates, parathyroid hormone receptor agonists, and romosozumab compared with placebo. Compared with parathyroid hormone receptor agonists, bisphosphonates were less effective in reducing clinical fractures (odds ratio 1.49, 95% confidence interval 1.12 to 2.00). Compared with parathyroid hormone receptor agonists and romosozumab, denosumab was less effective in reducing clinical fractures (odds ratio 1.85, 1.18 to 2.92 for denosumab v parathyroid hormone receptor agonists and 1.56, 1.02 to 2.39 for denosumab v romosozumab). An effect of all treatments on vertebral fractures compared with placebo was found. In the active treatment comparisons, denosumab, parathyroid hormone receptor agonists, and romosozumab were more effective than oral bisphosphonates in preventing vertebral fractures. The effect of all treatments was unaffected by baseline risk indicators, except for antiresorptive treatments that showed a greater reduction of clinical fractures compared with placebo with increasing mean age (number of studies=17; β=0.98, 95% confidence interval 0.96 to 0.99). No harm outcomes were seen. The certainty in the effect estimates was moderate to low for all individual outcomes, mainly because of limitations in reporting, nominally indicating a serious risk of bias and imprecision., Conclusions: The evidence indicated a benefit of a range of treatments for osteoporosis in postmenopausal women for clinical and vertebral fractures. Bone anabolic treatments were more effective than bisphosphonates in the prevention of clinical and vertebral fractures, irrespective of baseline risk indicators. Hence this analysis provided no clinical evidence for restricting the use of anabolic treatment to patients with a very high risk of fractures., Systematic Review Registration: PROSPERO CRD42019128391., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare support from UCB and Amgen for the submitted work: MNH, IC, CvB, JFR, AU, SMN, and RC report grants from UCB and Amgen paid to the Parker Institute to conduct the study; J-JB reports personal fees from UCB during the conduct of the study and personal fees from UCB and Sandoz outside the submitted work; MLB reports fees as honorarium, speaker, grants, and consultant from Amgen, Bruno Farmaceutici, Calcilytix, Kyowa Kirin, UCB, Abiogen, Alexion, Echolight, Eli Lilly, Kyowa Kirin, SPA, Theramex, and Amolyt outside the submitted work; AD-P has received speaker fees from Amgen, Lilly, and Theramex and is a shareholder of Active Life; PH reports personal fees from UCB during the conduct of the study and personal fees from UCB, Amgen, Gedeon Richter, Stada, and Theramex outside the submitted work; MKJ reports personal fees and non-financial support from UCB during the conduct of the study, and grants, personal fees, and non-financial support from Amgen and UCB outside the submitted work; MKJ was also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre and the views expressed are those of the author and not necessarily those of the NHS, the NIHR, or the Department of Health; WFL reports speakers fee/advisory board from UCB, Amgen, Pfizer, and Lilly; XN has received fees for consulting from UCB and Amgen and for lectures from UCB, Amgen, and Lilly; CR reports personal fees from UCB during the conduct of the study, and grants and personal fees from Alexion, Regeneron, Sanofi, and Amgen outside the submitted work; SM reports fees as speaker and advisory board from Abiogen, Amgen, Bruno Farmaceutici, Diasorin, Eli Lilly, Shire, Sandoz, Takeda, Abiogen, Kyowa Kirin, Pfizer and UCB outside the submitted work; TT reports personal fees from UCB during the conduct of the study, personal fees from Amgen, Arrow, and Biogen, personal fees from Grunenthal, Jansen, LCA, Lilly, MSD, Nordic, Novartis, Pfizer, Sanofi, Thuasne, and Theramex, grants and personal fees from Chugai and UCB, and grants from Bone Therapeutics outside the submitted work; SLF reports grants from Amgen, consulting and lecture honorarium from UCB, consulting honorarium from Radius, and grants and consulting honorarium from Agnovos outside the submitted work; DP-A's department received consultancy fees related to this work, DP-A reports grants and fees for speaker services and advisory board membership from Amgen, grants, non-financial support, and fees for consultancy services from UCB Biopharma, grants from Les Laboratoires Servier and UCB outside the submitted work, DP-A is an HTA Funding Committee membership, and Janssen, on behalf of Innovative Medicines Initiative (IMI) funded European Health Data and Evidence Network (EHDEN) and European Medical Information Framework (EMIF) consortiums, and Synapse Management Partners, have supported training programmes organised by DP-A's department that are open to external participants; BL reports personal fees from UCB during the conduct of the study and BL has received funding to her institution from Amgen and Novo Nordisk and personal fees from Amgen, UCB, Eli Lilly, Gedeon-Richter, and Gilead outside the submitted work; BA reports personal fees from UCB during the conduct of the study, grants and personal fees from UCB and Kyowa-Kirin UK, personal fees from Amgen, grants from Novartis, and grants and personal fees from Pharmacosmos outside the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study showed additional clinical risk factors for the occurrence of multiple fractures with regards to a single fracture, with often higher hazard ratios. It would be important to include the risk of the occurrence of multiple fractures in future prediction models., Purpose: To identify clinical risk factors (CRFs) which would specifically increase the risk of multiple fractures., Methods: Data of the 3560 postmenopausal women of the FRISBEE study were analysed. The CRFs and the fractures are collected annually. The cohort was divided into three groups: those who had no incident fracture, those who had a single incident fracture and those who had 2 two or more incident fractures (i.e. multiple fractures). Statistical analyses were performed using Cox proportional hazards models., Results: Among the 3560 subjects (followed for 9.1 (7.2-10.6) years), 261 subjects had two or more validated fractures during follow-up (146 were major osteoporotic fractures (MOFs)), 628 had one fracture (435 MOFs), 2671 had no fracture (2979 had no MOF); 157 subjects had two or more central fractures, 389 had only one and 3014 had none. The risk factors for those with multiple fractures at any site were age, history of fracture, history of fall, total hip bone mineral density (BMD), spine BMD and rheumatoid arthritis. For those with multiple MOFs, significant CRFs were age, history of fracture, parental hip fracture, total hip BMD and rheumatoid arthritis., Conclusion: We found in a prospective cohort study that there were more CRFs and higher hazard ratios for the occurrence of multiple fractures than for a single fracture., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with progressive bone pain, muscle weakness, and fragility fractures. TIO is characterized by hypophosphatemia, excess renal phosphate excretion, and low/inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH) 2 D) levels. Rarity and enigmatic clinical presentation of TIO contribute to limited awareness among the medical community. Accordingly, appropriate diagnostic tests may not be requested, leading to delayed diagnosis and poorer patient outcomes. We have developed a global guidance document to improve the knowledge of TIO in the medical community, enabling the recognition of patients with TIO and appropriate referral. We provide recommendations aiding diagnosis, referral, and treatment, helping promote a global standard of patient management. We reviewed the literature and conducted a three-round Delphi survey of TIO experts. Statements were drafted based on published evidence and expert opinions (≥70% consensus required for final recommendations). Serum phosphate should be measured in patients presenting with chronic muscle pain or weakness, fragility fractures, or bone pain. Physical examination should establish features of myopathy and identify masses that could be causative tumors. Priority laboratory evaluations should include urine/serum phosphate and creatinine to assess renal tubular reabsorption of phosphate and TmP/GFR, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25(OH) 2 D, and FGF23. Patients with the clinical/biochemical suspicion of TIO should be referred to a specialist for diagnosis confirmation, and functional imaging should be used to localize causative tumor(s). Recommended treatment is tumor resection or, with unresectable/unidentifiable tumors, phosphate salts plus active vitamin D, or burosumab., (© 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Introduction: Prediction models, especially the FRAX®, are largely used to estimate the fracture risk at ten years, but the current algorithm does not take into account the time elapsed after a fracture. Kanis et al. recently proposed correction factors allowing to adjust the FRAX® score for fracture recency. The objective of this work was to analyze the effect of fracture recency in the FRISBEE cohort., Methods: We identified in the FRISBEE cohort subjects who sustained a validated fracture during the first 5 years following an incident MOF. We calculated their estimated 5-year risk of fracture using FRAX® uncorrected, adjusted for recency and further adjusted for the MOF/hip ratios calibration factors previously derived for the Belgian FRAX®. We compared the fracture risk estimated by FRAX® before and after these corrections to the observed incidence of validated fractures in our cohort., Results: In our ongoing cohort, 376 subjects had a first non-traumatic incident validated MOF after inclusion; 81 had a secondary fracture during the 5 years follow-up period after this index fracture. The FRAX® score significantly under-evaluated the observed incidence of fractures in our cohort by 54.7 % (fracture rate of 9.7 %; 95 % CI, 6.8-12.9 %) if uncorrected (p < 0.001) and by 32.6 % after correction for recency (14.5 %; 95 % CI, 11.1-18.2 %) (p = 0.01). The calibration for MOF/hip ratios improved the prediction (17.5 %; 95 % CI: 13.7-21.4 %) (p = 0.2). After correcting for recency and for calibration, the predicted value was over-evaluated by 22 % (fracture rate of 26.1 %; 95 % CI, 21.6-30.5 %) but this over-evaluation was not significant (p = 0.1)., Conclusion: Our data indicate that the correction of the FRAX® score for fracture recency improves fracture prediction. However, correction for calibration and recency tends to overestimate fracture risk in this population of elderly women., Competing Interests: We wish to declare that there are no known conflicts of interest associated with this publication that could be perceived as prejudicing the impartiality of the research reported., (© 2023 The Authors.)

Five-year fracture risk prediction from the Fracture Risk Brussels Epidemiological Enquiry (FRISBEE) models was externally tested in 9716 Canadian women and demonstrated good discrimination but consistently overestimated risk., Introduction: Five-year risk prediction models for all fractures, major osteoporotic fractures (MOFs) and central fractures (proximal to forearm and ankle) from the FRISBEE cohort demonstrated good performance in the original derivation cohort. Our aim was to externally validate the FRISBEE-based 5-year prediction models in routine practice., Methods: Using the population-based Manitoba Bone Mineral Density (BMD) registry, we identified women aged 60-85 years undergoing baseline BMD assessment from September 1, 2012 to March 31, 2018. Five-year probabilities of all fractures, MOFs and central fractures were calculated using the FRISBEE prediction models. We identified incident non-traumatic fractures up to 5 years from population-based healthcare data sources. Performance characteristics included area under the receiver operating characteristic curve (AUROC), gradient of risk (hazard ratio [HR] per SD increase and across risk tertiles) from Cox regression analysis, and calibration (ratio 5-year observed cumulative incidence to predicted fracture probability)., Results: We included 9716 women (mean age 70.7 + / - SD 5.3 years). During a mean observation time of 2.5 years, all fractures, MOFs and central fractures were identified in 377 (3.9%), 264 (2.7%) and 259 (2.7%) of the women. AUROC showed significant fracture risk stratification with the FRISBEE models (all fractures 0.69 [95%CI 0.67-0.72], MOFs 0.71 [95%CI 0.68-0.74], central fractures 0.72 [95%CI 0.69-0.75]). There was a strong gradient of risk for predicting fracture outcomes per SD increase (HRs from 1.98 to 2.26) and across risk tertiles (HRs for middle vs lowest from 2.25 to 2.41, HRs for highest vs lowest from 4.70 to 6.50). However, risk was overestimated for all fractures (calibration-in-the-large 0.63, calibration slope 0.63), MOF (calibration-in-the-large 0.51, calibration slope 0.57) and central fractures (calibration-in-the-large 0.55, calibration slope 0.60)., Conclusions: FRISBEE 5-year prediction models were externally validated to stratify fracture risk similar to the derivation cohort, but would need recalibration for Canada as risk was overestimated., (© 2022. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Tumor-induced osteomalacia (TIO) is a rare and largely underdiagnosed paraneoplastic condition. Previous reviews often reported incomplete data on clinical aspects, diagnosis or prognosis. The aim of this study was to present a systematic clinical review of all published cases of TIO. A search was conducted in Pubmed, Embase, Web of Science from inception until April 23rd, 2020. We selected case reports and case series of patients diagnosed with TIO, with information on tumor localization and serum phosphate concentration. Two reviewers independently extracted data on biochemical and clinical characteristics including bone involvement, tumor localization and treatment. 468 articles with 895 unique TIO cases were included. Median age was 46 years (range 9 months-90 years) and 58.3% were males. Hypophosphatemia and inappropriately low or normal 1,25-dihydroxyvitamin D levels, characteristic for TIO, were present in 98% of cases. Median tumor size was 2.7 cm (range 0.5 to 25.0 cm). Serum fibroblast growth factor 23 was related to tumor size (r = 0.344, P < 0.001). In 32% of the cases the tumor was detected by physical examination. Data on bone phenotype confirmed skeletal involvement: 62% of cases with BMD data had a T-score of the lumbar spine ≤ - 2.5 (n = 61/99) and a fracture was reported in at least 39% of all cases (n = 346/895). Diagnostic delay was longer than 2 years in more than 80% of cases. 10% were reported to be malignant at histology. In conclusion, TIO is a debilitating disease characterized by a long diagnostic delay leading to metabolic disturbances and skeletal impairment. Increasing awareness of TIO should decrease its diagnostic delay and the clinical consequences., (© 2022. The Author(s).)

The association between obesity and fracture sites in postmenopausal women has been little studied. We examined the most common types of fractures in obese and overweight postmenopausal women compared to subjects with a normal BMI in the FRISBEE study, a cohort of postmenopausal women followed since 9.1 (7.2-10.6) years. Chi-squared tests and logistic regressions were used to compare the percentages of fracture sites in overweight/obese subjects to subjects with a normal BMI. Their mean (± SD) age was 76.7 ± 6.9 years and their mean BMI was 26.4 ± 4.4. Seven hundred seventy-seven subjects suffered at least one validated fragility fracture with a total of 964 fractures in the whole cohort. Subjects with a BMI higher than 25 had significantly more ankle fractures and less pelvic fractures than subjects with a normal BMI (OR 1.63, 95% CI 1.02-2.56, P = 0.04 and OR 0.55, 95% CI 0.34-0.89, P = 0.01, respectively). There were no significant differences between overweight and obese subjects. Among those older than 75, there were significantly fewer pelvic fractures in overweight/obese subjects (OR 0.49, 95% CI 0.27-0.87, P = 0.01), but before 75, ankle fractures were significantly more frequent in overweight/obese subjects than in subjects with a normal BMI (OR 1.89, 95% CI 1.01-3.57, P = 0.04). In conclusion, the proportion of ankle and pelvic fractures in obese and overweight subjects differs from that in subjects with a normal BMI, but these differences are age dependent. Fracture prevention strategies should take into account the differential effects of excess weight according to age and the site of fracture., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Glucocorticoids are effective immunomodulatory drugs used for many inflammatory disorders as well as in transplant recipients. However, both iatrogenic and endogenous glucocorticoid excess are also associated with several side effects including an increased risk of osteoporosis and fractures. Glucocorticoid-induced osteoporosis (GIOP) is a common secondary cause of osteoporosis in adults. Despite availability of clear evidence and international guidelines for the prevention of GIOP, a large treatment gap remains. In this narrative review, the Belgian Bone Club (BBC) updates its 2006 consensus recommendations for the prevention and treatment of GIOP in adults. The pathophysiology of GIOP is multifactorial. The BBC strongly advises non-pharmacological measures including physical exercise, smoking cessation and avoidance of alcohol abuse in all adults at risk for osteoporosis. Glucocorticoids are associated with impaired intestinal calcium absorption; the BBC therefore strongly recommend sufficient calcium intake and avoidance of vitamin D deficiency. We recommend assessment of fracture risk, taking age, sex, menopausal status, prior fractures, glucocorticoid dose, other clinical risk factors and bone mineral density into account. Placebo-controlled randomized controlled trials have demonstrated the efficacy of alendronate, risedronate, zoledronate, denosumab and teriparatide in GIOP. We suggest monitoring by dual-energy X-ray absorptiometry (DXA) and vertebral fracture identification one year after glucocorticoid initiation. The trabecular bone score might be considered during DXA monitoring. Extended femur scans might be considered at the time of DXA imaging in glucocorticoid users on long-term (≥ 3 years) antiresorptive therapy. Bone turnover markers may be considered for monitoring treatment with anti-resorptive or osteoanabolic drugs in GIOP. Although the pathophysiology of solid organ and hematopoietic stem cell transplantation-induced osteoporosis extends beyond GIOP alone, the BBC recommends similar evaluation, prevention, treatment and follow-up principles in these patients. Efforts to close the treatment gap in GIOP and implement available effective fracture prevention strategies into clinical practice in primary, secondary and tertiary care are urgently needed., Competing Interests: ML has received consultancy and lecture fees from Alexion, Amgen, Daiichi Sankyo, Kyowa Kirin, Menarini, Orifarm, Sandoz, Takeda, UCB, and Will Pharma. SG has received consultancy, lecture and travel fees from Alexion, Amgen, MSD, Novartis, Takeda, UCB, and Will Pharma. CV has received travel fees from Boehringer Ingelheim. JB has received consultancy, lecture fees and travel support from Alexion, Amgen, Bayer, Sandoz, Takeda, UCB and Will-Pharma. OB has received consultancy fees from Amgen, Biophytis, IBSA, MEDA, Servier, SMB, Teva, TRB Chemedica, and UCB. EC has received consultancy fees from bioMérieux, DiaSorin, Fujirebio, IDS, Menarini, and Nittobo. SR has received travel and consultancy fees from Abbott, Bayer, Eurogenerics, Gedeon Richter, Mylan, Takeda, Theramex, UCB and Will-Pharma. EG has received travel and consultancy fees from Amgen, Alexion, Daiichi Sankyo, Sandoz, Takeda, UCB, and Will Pharma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Laurent, Goemaere, Verroken, Bergmann, Body, Bruyère, Cavalier, Rozenberg, Lapauw and Gielen.)

The association of hip fractures with adverse outcomes is well established, but for non-hip fractures this association still needs to be further investigated. The objective of this narrative review is to describe the state of the art with regards to the health impact of clinically relevant non-hip fracture locations in postmenopausal women. PubMed and Scopus databases were searched from January 2010 until December 2020. Studies were included when the crude rates and/or relative risk of 1-year subsequent fractures and/or mortality were reported as well as the precise fracture site. Twenty-three studies met the inclusion criteria. Regarding mortality rates, there was a high variability between studies, with higher rates for vertebral, proximal humerus and pelvic fractures. There was a small or no impact of wrist, ankle or tibia fractures. The mortality rate increased with age after vertebral, proximal humerus and wrist fractures. Moreover, proximal humerus and vertebral fractures were associated with a higher mortality risk. This narrative review indicates that, besides fractures of the hip, fractures of the vertebrae, proximal humerus or pelvis deserve more attention when trying to prevent adverse outcomes of osteoporosis. More studies on the topic of non-hip fractures are urgently needed.

Context: Individualized fracture risk may help to select patients requiring a pharmacological treatment for osteoporosis. FRAX and the Garvan fracture risk calculators are the most used tools, although their external validation has shown significant differences in their risk prediction ability., Objective and Methods: Using data from the Fracture Risk Brussels Epidemiological Enquiry study, a cohort of 3560 postmenopausal women aged 60 to 85 years, we aimed to construct original 5-year fracture risk prediction models using validated clinical risk factors (CRFs). Three models of competing risk analysis were developed to predict major osteoporotic fractures (MOFs), all fractures, and central fractures (femoral neck, shoulder, clinical spine, pelvis, ribs, scapula, clavicle, sternum)., Results: Age, a history of fracture, and hip or spine BMD were predictors common to the 3 models. Excessive alcohol intake and the presence of comorbidities were specific additional CRFs for MOFs, a history of fall for all fractures, and rheumatoid arthritis for central fractures. Our models predicted the fracture probability at 5 years with an acceptable accuracy (Brier scores ≤ 0.1) and had a good discrimination power (area under the receiver operating curve of 0.73 for MOFs and 0.72 for central fractures) when internally validated by bootstrap. Three simple nomograms, integrating significant CRFs and the mortality risk, were constructed for different fracture sites. In conclusion, we derived 3 models predicting fractures with an acceptable accuracy, particularly for MOFs and central fractures. The models are based on a limited number of CRFs, and we constructed nomograms for use in clinical practice., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Antiresorptive therapy significantly reduces fracture risk in patients with benign bone disease and skeletal-related events (SREs) in patients with bone metastases (BM). Osteonecrosis of the jaw (ONJ) is a rare but severe condition manifested as necrotic bone lesion or lesions of the jaws. ONJ has been linked to the use of potent antiresorptive agents, termed medication-related ONJ (MRONJ)., Objective: We aimed to identify the differences various aspects of MRONJ among distinct patient categories and provide recommendations on how to mitigate the risk and optimally manage MRONJ in each of them., Methods: A working group of the European Calcified Tissue Society (ECTS) and 2 experts performed an updated detailed review of existing literature on MRONJ incidence, characteristics, and treatment applied in bone diseases with variable severity of skeletal insult, ranging from osteoporosis to prevention of cancer treatment-induced bone loss and SREs in cancer patients with BM., Results: The risk for MRONJ is much higher in patients with advanced malignancies compared to those with benign bone diseases because of the higher doses and more frequent administration of antiresorptive agents in individuals with compromised general health, along with coadministration of other medications that predispose to MRONJ. The overall risk for MRONJ is considerably lower than the benefits in all categories of patients., Conclusion: The risk for MRONJ largely depends on the underlying bone disease and the relevant antiresorptive regimen applied. Physicians and dentists should keep in mind that the benefits of antiresorptive therapy far outweigh the risk for MRONJ development., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Patients who sustain a fracture are at greatest risk of recurrent fracture during the next 2 years. We propose three models to identify subjects most at risk of an imminent fracture, according to fracture site (any fracture, major osteoporotic fracture [MOF] or central). They were constructed using data of the prospective Frisbee cohort, which includes 3560 postmenopausal women aged 60 to 85 years who were followed for at least 5 years. A total of 881 subjects had a first incident validated fragility fracture before December 2018. Among these, we validated 130 imminent fractures occurring within the next 2 years; 79 were MOFs, and 88 were central fractures. Clinical risk factors were re-evaluated at the time of the index fracture. Fine and Gray proportional hazard models were derived separately for each group of fractures. The following risk factors were significantly associated with the risk of any imminent fracture: total hip bone mineral density (BMD) (p < 0.001), a fall history (p < 0.001), and comorbidities (p = 0.03). Age (p = 0.05 and p = 0.03, respectively) and a central fracture as the index fracture (p = 0.04 and p = 0.005, respectively) were additional predictors of MOFs and central fractures. The three prediction models are presented as nomograms. The calibration curves and the Brier scores based on bootstrap resampling showed calibration scores of 0.089 for MOF, 0.094 for central fractures, and 0.132 for any fractures. The predictive accuracy of the models expressed as area under the receiver operating characteristic (AUROC) curve (AUC) were 0.74 for central fractures, 0.72 for MOFs, and 0.66 for all fractures, respectively. These AUCs compare well with those of FRAX and Garvan to predict the 5- or 10-year fracture probability. In summary, five predictors (BMD, age, comorbidities, falls, and central fracture as the incident fracture) allow the calculation with a reasonable accuracy of the imminent risk of fracture at different sites (MOF, central fracture, and any fracture) after a recent sentinel fracture. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)

Context: Numerous studies have demonstrated detrimental skeletal consequences following bariatric surgery., Methods: A working group of the European Calcified Tissue Society (ECTS) performed an updated review of existing literature on changes of bone turnover markers (BTMs), bone mineral density (BMD), and fracture risk following bariatric surgery and provided advice on management based on expert opinion., Literature Review: Based on observational studies, bariatric surgery is associated with a 21-44% higher risk of all fractures. Fracture risk is time-dependent and increases approximately 3 years after bariatric surgery. The bariatric procedures that have a malabsorptive component (including Roux-en-Y Gastric bypass (RYGB) and biliopancreatic diversion (BPD)) have clearly been associated with the highest risk of fracture. The extent of high-turnover bone loss suggests a severe skeletal insult. This is associated with diminished bone strength and compromised microarchitecture. RYGB was the most performed bariatric procedure worldwide until very recently, when sleeve gastrectomy (SG) became more prominent. There is growing evidence that RYGB is associated with greater reduction in BMD, greater increase in BTMs, and higher risk of fractures compared with SG but RCTs on optimal management are still lacking., Expert Opinion: In all patients, it is mandatory to treat vitamin D deficiency, to achieve adequate daily calcium and protein intake and to promote physical activity before and following bariatric surgery. In post-menopausal women and men older than 50 years, osteoporosis treatment would be reasonable in the presence of any of the following criteria: i) history of recent fragility fracture after 40 years of age, ii) BMD T-score ≤ -2 at hip or spine, iii) FRAX score with femoral neck BMD exceeding 20% for the 10-year major osteoporotic fracture probability or exceeding 3% for hip fracture. Zoledronate as first choice should be preferred due to intolerance of oral formulations and malabsorption. Zoledronate should be used with caution due to hypocemia risk. It is recommended to ensure adequate 25-OH vitamin D level and calcium supplementation before administering zoledronate., Conclusions: The bariatric procedures that have a malabsorptive component have been associated with the highest turnover bone loss and risk of fracture. There is a knowledge gap on osteoporosis treatment in patients undergoing bariatric surgery. More research is necessary to direct and support guidelines., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The ratio between major osteoporotic fractures (MOFs) and hip fractures in the Belgian FRAX® tool to predict fractures is currently based on Swedish data. We determined these ratios in a prospective cohort of Belgian postmenopausal women. 3560 women, aged 60-85 years (70.1 ± 6.4 years), were included in a prospective study from 2007 to 2013 and surveyed yearly (FRISBEE). We analyzed the number of validated incident fractures until October 2020 by age and sites and compared the MOFs/hip ratios in this cohort with those from the Swedish databases. We registered 1336 fractures (mean follow-up of 9.1 years). The MOFs/hip ratios extracted from the FRISBEE cohort were 10.7 [95% CI: (5.6-20.5)], 6.4 [4.7-8.7], and 5.0 [3.9-6.5] for women of 60-69, 70-79, and 80-89 years old, respectively. These ratios were 1.7-1.8 times higher for all age groups than those from the Swedish data, which decreased from 6.5 (60-64 years group) down to 1.8 (85-89 age group). The overall MOFs/hip ratio in Frisbee was 6.0 [5.9-6.1], which was higher than any Swedish ratio between 65 and 85 years. Nevertheless, the decrease of the ratios with age paralleled that observed in Sweden. In this Brussels prospective cohort, MOFs/hip ratios were 1.7-1.8 times those observed in Sweden currently used for MOFs prediction in the Belgian FRAX® version. This discrepancy can greatly modify the estimation of the risk of MOFs, which is among the main criteria used to recommend a pharmacological treatment for osteoporosis in several countries., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Probabilistic models including clinical risk factors with or without bone mineral density (BMD) have been developed to estimate the 5- or 10-year absolute fracture risk. We investigated the performance of the FRAX and Garvan tools in a well-characterized population-based cohort of 3560 postmenopausal, volunteer women, aged 60 to 85 years at baseline, included in the Fracture Risk Brussels Epidemiological Enquiry (FRISBEE) cohort, during 5 years of follow-up. Baseline data were used to calculate the estimated 10-year risk of hip and major osteoporotic fractures (MOFs) for each participant using FRAX (Belgium). We computed the 5-year risk according to the Garvan model with BMD. For calibration, the predicted risk of fracture was compared with fracture incidence across a large range of estimated fracture risks. The accuracy of the calculators to predict fractures was assessed using the area under the receiver operating characteristic curves (AUC). The FRAX tool was well calibrated for hip fractures (slope 1.09, p  < 0.001; intercept -0.001, p  = 0.46), but it consistently underestimated the incidence of major osteoporotic fractures (MOFs) (slope 2.12, p  < 0.001; intercept -0.02, p  = 0.06). The Garvan tool was well calibrated for "any Garvan" fractures (slope 1.05, p  < 0.001; intercept 0.01, p  = 0.37) but largely overestimated the observed hip fracture rate (slope 0.32, p  < 0.001; intercept 0.006, p  = 0.05). The predictive value for hip fractures was better for FRAX (AUC: 0.841, 95% confidence interval [CI] 0.795-0.887) than for Garvan (AUC: 0.769, 95% CI 0.702-0.836, p  = 0.01). The Garvan AUC for "any Garvan" fractures was 0.721 (95% CI 0.693-0.749) and FRAX AUC for MOFs was 0.708 (95% CI 0.675-0.741). In conclusion, in our Belgian cohort, FRAX estimated quite well hip fractures but underestimated MOFs, while Garvan overestimated hip fracture risk but showed a good estimation of "any Garvan" fractures. Both models had a good discriminatory value for hip fractures but only a moderate discriminatory ability for MOFs or "any Garvan" fractures. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., (© 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)