Fragility hip fractures in older adults are a major burden for the individual and the society, as they result in increased morbidity, mortality and substantial health care expenditure. Most fragility hip fractures are caused by falls, resulting in an impact on the postero-lateral aspect of the hip, inducing a force that exceeds the femoral bone strength. The risk of fracture depends on the rate of falling, the fall-induced impact force, and the femoral bone strength. This article presents the framework of a novel fragility hip fracture risk calculator based on a combined mechanistic and stochastic modelling approach. The model integrates the stochastic aspects of a fall and its dynamics together with a 1D mechanical model predicting the impact force in the hip to calculate a one-year absolute fracture risk. The required input parameters are based on QCT images, but can be substituted with more accessible anthropometric and densitometric data. To demonstrate how the parameters are extracted from clinical data and how the model is calibrated, data from the AFFIRM-CT cohort were used. A sensitivity analysis was conducted, confirming that the fall rate, the trochanteric soft tissue thickness and the bone strength are the dominating parameters influencing the risk of fragility hip fractures. Furthermore, output variables such as the predicted impact velocity and impact force aligned well with experimental data. Thus, the model is able to reflect observations from empirical data, indicating that it can capture the intrinsic aspects that define the risk of fragility hip fractures.

Monoclonal gammopathy of undetermined significance (MGUS) is a frequent hematological condition that occurs in later life. MGUS is associated with increased fragility fractures that mix individual osteoporotic risk factors, MGUS-related comorbidities, and direct MGUS bone impact such as senescence of plasma cells. This International Osteoporosis Foundation (IOF) position statement aims at evaluating the potential relationship between MGUS and fracture risk, as well as methods for evaluating bone involvement in MGUS. Finally, we propose the first bone clinical guidance for patients with MGUS to improve their bone health. Monoclonal gammopathy of undetermined significance is a prevalent hematological condition in adults, characterized by the presence of an abnormal monoclonal protein in the blood without concomitant symptoms or malignancy. MGUS is of considerable bone significance and contributes to fragility fractures in adults. In this review, data pertaining to bone fragility were collected, including epidemiological fracture data in patients with MGUS, bone mineral density (BMD), bone microarchitecture, bone turnover marker, and bone histomorphometry data. Collectively, these findings suggest an elevated risk of fractures, especially in presence of osteoporotic risk factors or comorbidities, and a diminished BMD due to augmented bone resorption. Studies focusing on the treatment of this condition are limited. Based on this analysis, we present the International Osteoporosis Foundation (IOF) position statement for bone evaluation and management of these patients. We recommend a risk-adapted treatment strategy. A proposal of bone clinical guidance dedicated to patients with MGUS is presented, suggesting bisphosphonates as the preferred treatment option.

Osteoporosis is a prevalent condition characterized by a rapid decline in bone mineral density and distorted microarchitecture, which leads to increased bone fragility. The gut microbiota and its metabolites play a crucial role in the development and progression of osteoporosis by influencing gut permeability, nutrient digestion and absorption, pH balance, and immune regulation. Nutritional interventions aimed at modulating gut microbiota, through postbiotics (butyrate), probiotics (Bifidobacterium animalis or Lacticaseibacillus rhamnosus LGG), prebiotics (fructo-oligosaccharides), synbiotics, and specific dietary patterns (e.g. Mediterranean and vegetarian diets) have emerged as promising strategies to mitigate bone loss associated with aging. This review investigates the communication between the gut and bone, summarizing the underlying mechanisms and providing an updated review on microbial metabolites. Additionally, it examines recent research on probiotics and their metabolic contributions, highlighting potential gaps in the current understanding of this field.

This study investigated the timing and effects of zoledronate infusions in long-term denosumab users having reached T-score targets (BMD > -2.0 T-score). Findings support that early and multiple zoledronate injections are needed to preserve as much BMD as possible after stopping denosumab. This study evaluated the effects of zoledronate (Zol) administration and the need for multiple infusions to prevent bone loss after stopping denosumab (Dmab) in long-term users, and the influence of previous bisphosphonates (BPs) exposure. This was a multicentric, randomized, open-label study, including 44 post-menopausal women treated with Dmab > 2 years and reaching BMD T-scores > -2.0. Patients without pre-Dmab BPs were randomized into 3 groups receiving Zol at 6 months (6 M, n = 12) or 9 months (9 M, n = 11) after the last Dmab, or to a group receiving Zol if CTX > 644 ng/l or BMD decreased ≥ 5

Although areal bone mineral density (aBMD) measured by DXA is a good predictor of fractures, nearly half of low-trauma fractures occur in individuals without osteoporosis (T-score > -2.5 SD). This study investigated whether femoral strength estimated from 3D DXA-based finite element (FE) analysis enhances the prediction of incident fractures compared with conventional 2D DXA-derived aBMD. Baseline hip DXA scans from 740 postmenopausal women in the Geneva Retirees Cohort were analyzed. 3D reconstructions of the proximal femur were generated to estimate femoral strength using FE analysis and to derive structural bone parameters. Over a mean follow-up of 5.7 ± 1.5 years, 100 low-trauma fractures were recorded, including 44 major osteoporotic fractures (MOF), 89% at non-hip sites. Femoral strength, total and trabecular vBMD, some cortical parameters, and conventional areal BMD were all significantly associated with incident low-trauma fractures (risk increase of 23-38% per SD decrease) and major osteoporotic fractures (36-59%), with femoral strength showing hazard ratios (95% confidence interval) of 1.32 (1.08-1.60) and 1.50 (1.12-2.01), respectively. A strength threshold of 2600 N improved fracture risk classification beyond conventional aBMD thresholds and outperformed the previously proposed fragile strength 3000 N threshold. Notably, 25% of women with low-trauma fractures and 27% with MOF were non-osteoporotic by aBMD but exhibited fragile femoral strength (≤3000 N), with 14% and 16% respectively below the very fragile threshold (≤2600 N). In conclusion, 3D DXA-derived femoral strength provides complementary value to aBMD in identifying women at elevated fracture risk, particularly those not classified as osteoporotic by conventional criteria.

Denosumab is a monoclonal antibody targeting the receptor activator of nuclear factor kappa-b ligand widely used for the prevention of skeletal-related events in patients with bone metastases. This Phase 1 randomized, double-blind, two-arm, parallel-group study assessed the equivalence in pharmacokinetics (PK) and compared the pharmacodynamics (PD), safety, and immunogenicity of the proposed biosimilar RGB-14-X and reference denosumab in healthy males. Participants were randomized 1:1 to a single subcutaneous 60 mg dose of RGB-14-X or reference denosumab, with 252 days of follow-up. Primary PK endpoints were maximum observed serum concentration (Cmax) and area under the concentration-time curve from time 0 to last quantifiable concentration (AUC0-last) and extrapolated to infinity (AUC0-inf). Secondary objectives were to compare additional PK parameters, safety and tolerability, PD and immunogenicity between groups. Of 165 participants randomized, 162 (98.2%) completed the study. The geometric mean ratios and corresponding 90% confidence intervals of RGB-14-X versus reference denosumab for Cmax, AUC0-last, and AUC0-inf were within the pre-specified range of 0.80-1.25, demonstrating equivalence. No notable differences were observed in secondary PK or PD parameters between groups; maximum reduction in concentration of the bone resorption marker serum C-terminal telopeptide of type I collagen (CTX) and the extent and duration of reduction in CTX levels over time were similar. RGB-14-X was well tolerated with a similar safety profile to reference denosumab. No anti-drug or neutralizing antibodies were detected in either group. RGB-14-X demonstrated biosimilarity to reference denosumab, with equivalent PK and similar PD, safety, and immunogenicity outcomes in healthy males.

Current contouring software for high-resolution peripheral quantitative CT (HR-pQCT) requires manual correction, which can be subjective and time-consuming. In this study, we externally validated a deep learning (DL) model for automatic periosteal and endosteal contouring in second-generation HR-pQCT scans of the distal radius and tibia. Additionally, we compared the DL model's contours with uncorrected standard automatic periosteal and endosteal HR-pQCT contours (AUTO) in second-generation HR-pQCT scans and evaluated its performance in first-generation HR-pQCT scans. In 939 second-generation HR-pQCT scans, median Dice (DSC) and Jaccard (JSC) similarity coefficients for periosteal and endosteal DL contours were >0.92 and median average (ASSD) and maximum (HD) symmetric surface distances <1.15 mm when compared with our reference contours (AUTO with manual periosteal correction). Most HR-pQCT parameters differed significantly when comparing DL and reference contours, but differences were small (median between -0.6% and +6.6%) and correlations high (>0.78). Comparison with AUTO gave considerably larger maximum HDs and differences in HR-pQCT parameters - predominantly due to erroneous AUTO contours. In 300 first-generation HR-pQCT scans, median DSC and JSC were >0.98 and median ASSD and HD <0.49 mm when comparing periosteal DL contours with manually-guided snake-based periosteal contours (SNAKE). Most HR-pQCT parameters from standard morphological and extended cortical analysis differed significantly when comparing periosteal DL and SNAKE contours combined with standard automatic endosteal contours, but differences were small (median between -1.2% and +4.1%) and correlations high (>0.95). To conclude, the DL model performed well for automatic periosteal and endosteal contouring on second-generation HR-pQCT and for automatic periosteal contouring on first-generation HR-pQCT.

The growing interest in 3D-DXA reconstructions for possible uses in fracture risk prediction or patient follow-up, e.g., in conjunction with finite element analyses, asks for precision data to increase the interpretability of results making use of the 3D-DXA technique. Using two datasets and a total of 2427 DXA scans of the proximal femur we evaluated the short- and long-term precision of standard DXA measurements. All the available scans were reconstructed using 3D-Shaper software and processed through a nonlinear finite element pipeline for femoral strength estimation. Short- and long-term precision were computed for thirty 3D-DXA-based parameters as well as femoral strength in fall and stance configurations. Precision errors were related to change rates of the respective parameters by calculating the trend assessment interval (TAI). Simultaneously, spatially resolved precision errors were computed for cortical parameters and error progression from DXA to 3D-DXA and FEA was considered. Precision errors were amplified through the different processing steps. Long-term precision errors were 1.6%, 2.0% and 7.5% for total hip aBMD, total hip integral vBMD and strength in fall, respectively. Errors between processing steps were only weakly correlated. Higher change rates for vBMD and strength compensated the larger precision errors, resulting in similar TAIs for total hip aBMD (5.5 years), total hip integral vBMD (4.6) and strength (5.8), respectively. Relative local precision errors of cortical parameters were largest in the superior and anterior neck region and above the lesser trochanter. 3D-DXA and thereon based FEA may offer interesting insights into the densitometric and mechanical quality of the proximal femur. The here reported results should offer a help for the interpretation of sequential measurements where these are required.

Calcium supplements are often prescribed with osteoporosis medications without considering dietary adequacy. In calcium-replete older women, calcium supplements had little effect on the response to antiresorptives, whereas low protein intake blunted their benefits. Calcium supplementation may be unnecessary when intake is adequate, and nutrition should be optimized for osteoporosis treatment. Osteoporosis medications (OM) are commonly prescribed with calcium supplements (CaS) without considering dietary adequacy. We investigated whether calcium and protein intakes influence the effect of OM on total hip bone mineral density (BMD) and strength in calcium-replete women. Data from 586 women (median age 67 years) from the Geneva Retirees Cohort were analyzed: 101 on menopausal hormone therapy (MHT), 67 on antiresorptives (AR) (bisphosphonates, denosumab or raloxifene), and 418 without OM. Annual changes in total hip BMD, strength, and structure were assessed over a median 3.5 years using 2D/3D-DXA and finite element analysis. Calcium and protein intakes were assessed by food frequency questionnaire; CaS use was recorded at baseline and follow-up. Total calcium intake (diet + supplements) was 1503 mg/day; 71 http://www.isrctn.com/ISRCTN11865958

In 2025, osteoporosis management in Switzerland benefited from the introduction of abaloparatide, an anabolic PTHrP analogue that effectively reduces the risk of vertebral and non-vertebral fractures, with reimbursement criteria identical to those of romosozumab. Zoledronate, administered preventively only twice at a five-year interval in recently menopausal, non-osteoporotic women, lowers 10-year fracture risk by about 40 %. Calcium and/or vitamin D supplements are now subject to reimbursement restrictions. Burosumab, an anti-FGF23 antibody, has become the treatment of choice for X-linked hypophosphatemic rickets, though access remains limited in Switzerland. Finally, artificial intelligence is emerging as a valuable tool for radiographic diagnosis and opportunistic screening of osteoporotic fractures.

In this meta-analysis of international cohorts, current smoking is confirmed as a significant BMD-independent predictor of future fracture with a stronger relationship in men than in women. A causative and reversible effect of smoking on fracture risk is suggested by past smoking having a significantly lower risk than current smoking. In this meta-analysis of international cohorts, the aim was to examine the relationship of current and past smoking with fracture risk to provide an update for future iterations of the FRAX tool. The risk of fracture associated with current and past smoking was estimated using an extended Poisson model applied separately to each of 58 prospective international cohort studies. Covariates included current time since start of follow up, current age, and in an additional model, BMD at the femoral neck. The results of the different studies were merged by using inverse-variance weighted β-coefficients. This analysis included a total of 1,691,024 participants (61.2

The relationship between bone mineral density (BMD) at the femoral neck and fracture risk was determined in a meta-analysis of primary data of 307205 men and women from 53 cohort studies. Low BMD was an important predictor of fracture risk, particularly for hip fracture. This study aimed to quantify the relationship between DXA-measured femoral neck BMD and fracture risk and examine the effect of age, sex, time since measurement, and initial BMD value on fracture risk, with a view to updating FRAX®. We studied 307,205 men and women from within 53 predominately population-based cohorts followed up for an average of 8.7 years and a total of 2,683,185 person-years. The association of BMD and fracture risk was examined using a Poisson model in each cohort separately by sex. Results were expressed as a gradient of risk (GR, hazard ratio/standard deviation decrease in BMD). The different studies were then merged using weighted coefficients. Most hip fractures arose in men and women with low bone mass or osteoporosis at baseline (73 = 0.12 for women and p = 0.89 for men). A significant decrease in GR for hip fracture was observed with increasing duration of follow-up, but the magnitude of the effect was modest compared with the effect of age. For other fracture outcomes, including non-hip major osteoporotic fracture, the gradient of risk was lower than for hip fracture. Femoral neck BMD is a risk factor for fracture of substantial importance, particularly for future hip fracture. The lower magnitude of association at older age is consistent with other non-skeletal factors contributing to hip fracture risk with advancing age. Its validation on an international basis supports its use in case finding strategies. Its use should, however, take account of the variations in predictive value of BMD with age, sex, length of follow-up, and BMD.

The risk of fracture is increased in patients with type 1 and type 2 diabetes. Bone mineral density (BMD) tends to be decreased in type 1 diabetes and increased in type 2 diabetes. BMD and the fracture risk assessment tool (FRAX) underestimate the fracture risk in patients with type 2 diabetes, and specific adjustments may be required. Poor glycemic control is the main fracture risk predictor. Conventional treatments for osteoporosis have not been specifically evaluated in non-osteoporotic diabetic patients. However, they can be prescribed to diabetics at high risk for fractures if there are no contraindications. Preventing the risk of falls and optimizing muscle health are essential in older diabetic patients.

In the largest meta-analysis of international cohorts to date, a family history of fracture is confirmed as a significant BMD-independent predictor of future fracture risk. Parental and sibling histories of fracture carry the same significance for future fracture, including the impact of family hip fracture on future hip fracture risk. PURPOSE:We have undertaken a meta-analysis of international prospective cohorts to quantify the relationship between a family history of fracture and future fracture incidence. METHODS:The analysis dataset comprised 350,542 men and women from 42 cohorts in 29 countries followed for 2.8 million person-years. We investigated the relationship between family history of hip fracture or any fracture and the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture (MOF), and hip fracture alone using an extended Poisson model in each cohort. Models were adjusted for current age, sex, BMD, and follow-up time. RESULTS:As no difference in influence of family history of fracture was seen between genders, results are presented for men and women combined. A parental history of hip fracture was associated with a higher risk of incident fracture across all fracture outcome categories, with a stronger relationship with future hip fracture (hazard ratios (HR, 95% CI) for hip and MOF 1.37, 1.23-1.52 and 1.19, 1.12-1.27, respectively). Associations were slightly reduced but remained significant when additionally adjusted for BMD and did not vary by baseline offspring age, follow-up time, or parent affected. In a more limited analysis, parental history of any fracture or a sibling history of hip or any fracture showed similar associations to those observed with parental history of hip fracture. CONCLUSIONS:A family history of fracture is confirmed as a significant BMD-independent predictor of future fracture risk. While parental hip fracture appears the strongest factor for future hip fracture, a family history of other fractures might be appropriate for inclusion in future iterations of the FRAX tool.

Background: Women with hormone-responsive breast cancer who receive adjuvant endocrine treatment with aromatase inhibitors (AI) are known to be at higher fracture risk due to a marked increase in bone resorption. In 2017, several interdisciplinary cancer and bone societies involved in the management of women with AI-associated bone loss (AIBL) published a joint position statement comprising evidence-based recommendations and a practical management algorithm for the assessment of fracture risk and optimal treatment of this patient population. Patients and methods: In order to provide updated recommendations that reflect recent advances in the assessment and management of AIBL since publication of the 2017 joint position statement, a systematic literature review was undertaken to identify relevant studies for analysis, including systematic reviews and meta-analyses. Individual trials identified were assessed for their level of evidence based on design, size, follow-up, and evaluation of safety, as well as the impact of bone directed treatments on breast cancer outcomes. Results: New evidence was combined with the existing recommendations to provide an updated joint position statement regarding fracture risk assessment and implementation of bone-directed therapy. Conclusion: Current published literature, including recent clinical trial reports, systematic reviews and meta-analyses, continue to affirm the high risk of fractures in women with breast cancer who are receiving adjuvant AI treatment, a risk which has been observed to increase with the commonly used approach of extended duration AI therapy (>5 years). Risk factors for fracture and risk assessment in this patient population as well as the most suitable treatment modalities have been updated. Finally, the influence of bone protective treatments on breast cancer outcomes such as incidence of bone metastasis and breast cancer related overall survival have been included.

Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic syndrome caused by a mesenchymal tumor secreting a phosphaturic hormone called FGF23. Patients present with bone pain, fragility fractures and muscle weakness. Biochemical results show hypophosphatemia, raised serum alkaline phosphatase and reduced calcitriol. We report the case of a 44-year-old man who presented to the Emergency Departement with acute low back pain revealing extensive subchondral fractures between D2 and L5. Investigations showed partial Fanconi syndrome; nevertheless, he had profound hypophosphatemia, low 1,25-OH vitamin D and raised FGF23 levels suggesting a diagnosis of tumor-induced osteomalacia. A subcutaneous lesion was identified in the left leg on a PET-CT initially performed to rule out malignancy in the context of Fanconi syndrome. Tumorectomy enabled complete resolution of the electrolyte disturbances within days of surgery. This case shows that TIO may present as partial Fanconi syndrome, highlighting the importance of testing other electrolytes in cases of hypophosphatemia and the need to look for TIO in cases of partial Fanconi with severe hypophosphatemia.

The relationship between rheumatoid arthritis (RA) and fracture risk was estimated in an international meta-analysis of individual-level data from 29 prospective cohorts. RA was associated with an increased fracture risk in men and women, and these data will be used to update FRAX®. RA is a well-documented risk factor for subsequent fracture that is incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between rheumatoid arthritis and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD) with a view to updating FRAX. The resource comprised 1,909,896 men and women, aged 20–116 years, from 29 prospective cohorts in which the prevalence of RA was 3

The risk of fracture is increased in patients with type 1 and type 2 diabetes. Bone mineral density (BMD) tends to be decreased in type 1 diabetes and increased in type 2 diabetes. BMD and the fracture risk assessment tool (FRAX) underestimate the fracture risk in patients with type 2 diabetes, and specific adjustments may be required. Poor glycemic control is the main fracture risk predictor. Conventional treatments for osteoporosis have not been specifically evaluated in non-osteoporotic diabetic patients. However, they can be prescribed to diabetics at high risk for fractures if there are no contraindications. Preventing the risk of falls and optimizing muscle health are essential in older diabetic patients.

Although weight loss has many health benefits for people with overweight/obesity, its potential negative impact on bone health needs to be considered. This review provides a comprehensive overview of the effects of intentional weight loss achieved by lifestyle changes on bone health outcomes in adults with overweight/obesity and discusses potential mechanisms underlying the observed skeletal effects and protective measures to preserve bone health in this context. Weight loss achieved through lifestyle modifications increases surrogate markers of bone resorption and small but persistent reductions in bone mineral density at clinically relevant sites (mainly at the level of the hip). Based on limited available data, weight loss achieved by lifestyle modifications may increase fragility fractures. Combating sedentary lifestyles and promoting exercise, particularly resistance exercise, adequate intakes of calcium (diets and/or supplements), vitamin D supplementation, and higher dietary protein intakes could attenuate but not fully prevent the increased bone turnover or bone loss often associated with intentional weight loss. Further research needs to explore the skeletal effects of pragmatic interventions that match clinical scenarios, verify if changes in bone macro- and/or microstructure translate to an increased fracture risk, and investigate novel/combined strategies to improve bone health due to weight loss.