Impact of osteoporosis and osteoporosis medications on fracture healing: a narrative review.

Antiresorptive medications do not negatively affect fracture healing in humans. Teriparatide may decrease time to fracture healing. Romosozumab has not shown a beneficial effect on human fracture healing. BACKGROUND: Fracture healing is a complex process. Uncertainty exists over the influence of osteoporosis and the medications used to treat it on fracture healing. METHODS: Narrative review authored by the members of the Fracture Working Group of the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF), on behalf of the IOF and the Société Internationale de Chirurgie Orthopédique et de Traumatologie (SICOT). RESULTS: Fracture healing is a multistep process. Most fractures heal through a combination of intramembranous and endochondral ossification. Radiographic imaging is important for evaluating fracture healing and for detecting delayed or non-union. The presence of callus formation, bridging trabeculae, and a decrease in the size of the fracture line over time are indicative of healing. Imaging must be combined with clinical parameters and patient-reported outcomes. Animal data support a negative effect of osteoporosis on fracture healing; however, clinical data do not appear to corroborate with this. Evidence does not support a delay in the initiation of antiresorptive therapy following acute fragility fractures. There is no reason for suspension of osteoporosis medication at the time of fracture if the person is already on treatment. Teriparatide treatment may shorten fracture healing time at certain sites such as distal radius; however, it does not prevent non-union or influence union rate. The positive effect on fracture healing that romosozumab has demonstrated in animals has not been observed in humans. CONCLUSION: Overall, there appears to be no deleterious effect of osteoporosis medications on fracture healing. The benefit of treating osteoporosis and the urgent necessity to mitigate imminent refracture risk after a fracture should be given prime consideration. It is imperative that new radiological and biological markers of fracture healing be identified. It is also important to synthesize clinical and basic science methodologies to assess fracture healing, so that a convergence of the two frameworks can be achieved.

Cerebellum Purkinje cell vulnerability in aged rats with memory impairment.

The cerebellum is involved in higher order cognitive function and is susceptible to age-related atrophy. However, limited evidence has directly examined the cerebellum's role in cognitive aging. To interrogate potential substrates of the relationship between cerebellar structure and memory in aging, here we target the Purkinje cells (PCs). The sole output neurons of the cerebellum, PC loss and/or degeneration underlie a variety of behavioral abnormalities. Using a rat model of normal cognitive aging, we immunostained sections through the cerebellum for the PC-specific protein, calbindin-D28k. Although morphometric quantification revealed no significant difference in total PC number as a function of age or cognitive status, regional cell number was a more robust correlate of memory performance in the young cerebellum than in aged animals. Parallel biochemical analysis of PC-specific protein levels in whole cerebellum additionally revealed that calbindin-D28k and Purkinje cell protein-2 (pcp-2) levels were lower selectively in aged rats with spatial memory impairment compared to both young animals and aged rats with intact memory. These results suggest that cognitive aging is associated with cerebellum vulnerability, potentially reflecting disruption of the cerebellum-medial temporal lobe network.

Trial Forge Guidance 4: a guideline for reporting the results of randomised Studies Within A Trial (SWATs).

BACKGROUND: Evidence to support decisions on trial processes is minimal. One way to generate this evidence is to use a Study Within A Trial (SWAT) to test trial processes or explore methodological uncertainties. SWAT evidence relies on replication to ensure sufficient power and broad applicability of findings. Prompt reporting is therefore essential; however, SWAT publications are often the first to be abandoned in the face of other time pressures. Reporting guidance for embedded methodology trials does exist but is not widely used. We sought therefore to build on these guidelines to develop a straightforward, concise reporting standard, which remains adherent to the CONSORT guideline. METHODS: An iterative process was used to develop the guideline. This included initial meetings with key stakeholders, development of an initial guideline, pilot testing of draft guidelines, further iteration and pilot testing, and finalisation of the guideline. RESULTS: We developed a reporting guideline applicable to randomised SWATs, including replications of previous evaluations. The guideline follows the Consolidated Standards for Reporting Trials (CONSORT) statement and provides example text to ensure ease and clarity of reporting across all domains. CONCLUSIONS: The SWAT reporting guideline will aid authors, reviewers, and journal editors to produce and review clear, structured reports of randomised SWATs, whilst also adhering to the CONSORT guideline. TRIAL REGISTRATION: EQUATOR Network - Guidelines Under Development ( https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-clinical-trials/#SWAT ). Registered on 25 March 2021.

Previous fracture and subsequent fracture risk: a meta-analysis to update FRAX.

A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX. INTRODUCTION: The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD). METHODS: We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted ß-coefficients. RESULTS: A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination. CONCLUSION: A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies.

Development, implementation and evaluation of a multinational FLS mentorship programme in Latin America.

Realising the benefits of systematic secondary fracture prevention requires supporting local sites to get started and becoming effective. We here describe the development, implementation and impact of a regional fracture liaison service (FLS) mentorship programme in Latin America that led to 64 FLS getting started and coverage of 17,205 patients. INTRODUCTION: Despite treatments and service models to deliver effective secondary fracture prevention, most patients are left untreated after a fragility fracture. To improve the capability to get FLS started and more effective, we describe the development, implementation and evaluation of an international programme to develop national communities of FLS mentors as part of the Capture the Fracture Partnership in Latin America. METHODS: The IOF regional team and the University of Oxford developed the curriculum and associated resources for training mentors in setting up FLS, service improvement and mentorship. Mentors were selected during a preparatory meeting, trained using live online sessions followed by regular mentor-led post-training meetings. The programme was evaluated using a pre-training needs assessment and post-training evaluation based on Moore's outcomes. RESULTS: The mentorship programme was initiated in Mexico, Brazil, Colombia and Argentina. The mentors were multidisciplinary, including orthopaedic surgery, rehabilitation, rheumatology, endocrinology, geriatrics, gynaecology and internal medicine. There was 100% participation in training sessions and reported satisfaction with the training. Since the initiation of the training programme, 22 FLS have been set up in Mexico, 30 in Brazil, 3 in Colombia and 9 in Argentina, in comparison with two in Chile and none in any other LATAM countries that were not involved in the mentorship programme. This equates to approximately 17,025 additional patients identified from 2019 to 2021 after initiation of mentorship. The mentors have engaged with 58 FLS for service development. Post-training activities include two published national best practice guidelines and other country-specific resources for FLS in the local language. CONCLUSION: Despite the COVID pandemic, the mentorship pillar of the Capture the Fracture Partnership has developed a community of FLS mentors with measurable improvement in national FLS provision. The programme is a potentially scalable platform to develop communities of mentors in other countries.

The Capture the Fracture® Partnership: an overview of a global initiative to increase the secondary fracture prevention care for patient benefit.

The Capture the Fracture® Partnership (CTF-P) is a unique collaboration between the International Osteoporosis Foundation, academic units and industry partners to enhance the implementation of effective, efficient fracture liaison services (FLSs) with a good patient experience. CTF-P has generated valuable resources for the specific countries as well as the broader FLS community to improve the initiation, effectiveness and sustainability of FLS in a wide range of healthcare settings.

Influence of cold-water immersion on lower limb muscle oxygen consumption, as measured by near-infrared spectroscopy.

CONTEXT: Cold-water immersion (CWI) is reported to reduce tissue metabolism post immersion, yet there is a lack of physiologic data regarding muscle metabolic response to its application. Near-infrared Spectroscopy (NIRS) is a non-invasive optical technique that can inform upon muscle haemodynamics and tissue metabolism. OBJECTIVE: The purpose of our study was to investigate the effects of CWI at two different water temperatures (10°C and 15°C) upon NIRS calculated measurements of muscle oxygen consumption (mVO2). DESIGN: A randomised, crossover design. SETTING: University Sports Rehabilitation Centre. PARTICIPANTS: Eleven long-distance runners (age; 23.4 ± 3.4 years, mean adipose tissue thickness; 6.7 ± 2.7 mm) (NCAA Division 2), adult males. MAIN OUTCOME MEASURE(S): mVO2 was calculated pre and post immersion at both 10°C and 15°C. Changes in tissue oxyhaemoglobin (O2Hb), deoxyhaemoglobin (HHb), total haemoglobin (tHb), haemoglobin difference (Hbdiff) and tissue saturation index (TSI %) were measured during both 20 minute immersion temperatures. RESULTS: There was a significant decrease in mVO2 following both the 10°C and 15°C immersion (P = 0.001). During the 20 min immersion at both temperatures there was a significant main effect of time for O2Hb (P = 0.001)), HHb (P = 0.009) tHb (P = 0.001), and Hbdiff (P = 0.020), in which they decreased over the course of the 20 min immersion. Post-hoc pairwise comparisons showed these changes occurred within the final 5 minutes of immersion for tHb and O2Hb. CONCLUSIONS: Our results demonstrated that a 20 min CWI at 10°C and 15°C led to a significant reduction in mVO2. The reduction in mVO2 was greater following 10°C immersion. The reduction in mVO2 suggests a decrease in muscle metabolic activity i.e. O2 utilisation following CWI. Calculating mVO2 via the NIRS-occlusion technique may offer further insight into muscle metabolic responses, beyond what is attainable from observing the NIRS primary signals.

Associations of baseline and longitudinal change in cerebellum volume with age-related changes in verbal learning and memory.

The cerebellum is involved in higher-order cognitive functions, e.g., learning and memory, and is susceptible to age-related atrophy. Yet, the cerebellum's role in age-related cognitive decline remains largely unknown. We investigated cross-sectional and longitudinal associations between cerebellar volume and verbal learning and memory. Linear mixed effects models and partial correlations were used to examine the relationship between changes in cerebellum volumes (total cerebellum, cerebellum white matter [WM], cerebellum hemisphere gray matter [GM], and cerebellum vermis subregions) and changes in verbal learning and memory performance among 549 Baltimore Longitudinal Study of Aging participants (2,292 visits). All models were adjusted by baseline demographic characteristics (age, sex, race, education), and APOE e4 carrier status. In examining associations between change with change, we tested an additional model that included either hippocampal (HC), cuneus, or postcentral gyrus (PoCG) volumes to assess whether cerebellar volumes were uniquely associated with verbal learning and memory. Cross-sectionally, the association of baseline cerebellum GM and WM with baseline verbal learning and memory was age-dependent, with the oldest individuals showing the strongest association between volume and performance. Baseline volume was not significantly associated with change in learning and memory. However, analysis of associations between change in volumes and changes in verbal learning and memory showed that greater declines in verbal memory were associated with greater volume loss in cerebellum white matter, and preserved GM volume in cerebellum vermis lobules VI-VII. The association between decline in verbal memory and decline in cerebellar WM volume remained after adjustment for HC, cuneus, and PoCG volume. Our findings highlight that associations between cerebellum volume and verbal learning and memory are age-dependent and regionally specific.

A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites.

Radical cure of Plasmodium vivax malaria must include elimination of quiescent 'hypnozoite' forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets, we screened the Repurposing, Focused Rescue, and Accelerated Medchem library against P. vivax liver stages and identified the DNA methyltransferase inhibitors hydralazine and cadralazine as active against hypnozoites. We then used bisulfite sequencing and immunostaining to identify cytosine modifications in the infectious stage (sporozoites) and liver stages, respectively. A subsequent screen of epigenetic inhibitors revealed hypnozoites are broadly sensitive to histone acetyltransferase and methyltransferase inhibitors, indicating that several epigenetic mechanisms are likely modulating hypnozoite persistence. Our data present an avenue for the discovery and development of improved radical cure antimalarials.

Inequalities in energy drink consumption among UK adolescents: a mixed-methods study.

OBJECTIVE: To examine energy drink consumption among adolescents in the United Kingdom (UK) and associations with deprivation and dietary inequalities. DESIGN: Quantitative dietary and demographic data from the National Diet and Nutrition Survey (NDNS) repeated cross-sectional survey were analysed using logistic regression models. Qualitative data from semi-structured interviews were analysed using inductive thematic analysis. SETTING: UK. PARTICIPANTS: Quantitative data: nationally representative sample of 2587 adolescents aged 11-18 years. Qualitative data: 20 parents, 9 teachers, and 28 adolescents from Hampshire, UK. RESULTS: NDNS data showed adolescents' consumption of energy drinks was associated with poorer dietary quality (OR 0.46 per SD; 95% CI 0.37, 0.58; p<0.001). Adolescents from more deprived areas and lower income households were more likely to consume energy drinks than those in more affluent areas and households (OR 1.40; 95%CI 1.16, 1.69; p<0.001; OR 0.98 per £1000; 95%CI, 0.96, 0.99; p<0.001 respectively). Between 2008 and 2016, energy drink consumption among adolescents living in the most deprived areas increased, but decreased among those living in the most affluent neighbourhoods (p=0.04). Qualitative data identified three themes. First, many adolescents drink energy drinks because of their friends and because the unbranded drinks are cheap. Second, energy drink consumption clusters with other unhealthy eating behaviours and adolescents don't know why energy drinks are unhealthy. Third, adolescents believe voluntary bans in retail outlets and schools do not work. CONCLUSIONS: This study supports the introduction of age-dependent legal restrictions on the sale of energy drinks which may help curb existing socio-economic disparities in adolescents' energy drink intake.

Upgrades to the gamma ray imager on DIII-D enabling access to high flux hard x-ray measurements during the runaway electron plateau phase (invited).

The Gamma Ray Imager (GRI) is a pinhole camera providing 2D imaging of MeV hard x-ray (HXR) bremsstrahlung emission from runaway electrons (REs) over the poloidal cross section of the DIII-D tokamak. We report a series of upgrades to the GRI expanding the access to RE scenarios from the diagnosis of a trace amount of REs to high flux HXR measurements during the RE plateau phase. We present the implementation of novel gamma ray detectors based on LYSO and YAP crystals coupled to multi-pixel photon counters, enabling a count rate in excess of 1 MHz. Finally, we highlight new insights into the RE physics discovered during the current quench and RE plateau phase experiments as the result of these upgrades.

Stability of a Novel PEGylation Site on a Putative Haemoglobin-Based Oxygen Carrier.

PEGylation of protein sulfhydryl residues is a common method used to create a stable drug conjugate to enhance vascular retention times. We recently created a putative haemoglobin-based oxygen carrier using maleimide-PEG to selectively modify a single engineered cysteine residue in the α subunit (αAla19Cys). However, maleimide-PEG adducts are subject to deconjugation via retro-Michael reactions, with consequent cross-conjugation to endogenous plasma thiols such as those found on human serum albumin or glutathione. In previous studies mono-sulfone-PEG adducts have been shown to be less susceptible to deconjugation. We therefore compared the stability of our maleimide-PEG Hb adduct with one created using a mono-sulfone PEG. The corresponding mono-sulfone-PEG adduct was significantly more stable when incubated at 37 °C for 7 days in the presence of 1 mM reduced glutathione, 20 mg/mL human serum albumin, or human serum. In all cases haemoglobin treated with mono-sulfone-PEG retained >90% of its conjugation whereas maleimide-PEG showed significant deconjugation, especially in the presence of 1 mM reduced glutathione where <70% of the maleimide-PEG conjugate remained intact. Although maleimide-PEGylation of Hb seems adequate for an oxygen therapeutic intended for acute use, if longer vascular retention is required reagents such as mono-sulfone-PEG may be more appropriate.

Morbidities among older workers and work exit: the HEAF cohort.

BACKGROUND: Governments need people to work to older ages, but the prevalence of chronic disease and comorbidity increases with age and impacts work ability. AIMS: To investigate the effects of objective health diagnoses on exit from paid work amongst older workers. METHODS: Health and Employment After Fifty (HEAF) is a population cohort of adults aged 50-64 years recruited from English GP practices which contribute to the Clinical Practice Research Datalink (CPRD). Participants have completed questionnaires about health and work at baseline and annually for 2 years: their responses were linked with their objective health diagnoses from the CPRD and data analysed using Cox regression. RESULTS: Of 4888 HEAF participants ever in paid work, 580 (25%) men and 642 (25%) women exited employment, 277 of them mainly or partly for a health reason (health-related job loss (HRJL)). Amongst HEAF participants who remained in work (n = 3666) or who exited work but not for health reasons (n = 945), there was a similar prevalence of background health conditions. In men and women, HRJL was associated with inflammatory arthritis, sleep disorders, common mental health conditions and musculoskeletal pain. There were however gender differences: widespread pain and lower limb osteoarthritis were associated with HRJL in women but hypertension and cardiovascular disease in men. CONCLUSIONS: Improved diagnosis and management of common conditions might be expected to increase working lives. Workplace well-being interventions targeting obesity and increasing mobility might contribute to extended working lives. Employers of predominantly female, as compared with male workforces may need different strategies to retain older workers.

The APPLE Tree programme: Active Prevention in People at risk of dementia through Lifestyle, bEhaviour change and Technology to build REsiliEnce-randomised controlled trial.

BACKGROUND: Large-scale trials of multidomain interventions show that modifying lifestyle and psychological risk factors can slow cognitive decline. We aim to determine if a lower intensity, personally tailored secondary dementia prevention programme for older people with subjective or mild objective memory decline, informed by behaviour change theory, reduces cognitive decline over 2 years. METHODS: A multi-site, single-blind randomised controlled trial recruiting 704 older adults at high dementia risk due to mild cognitive impairment (MCI) or subjective cognitive decline (SCD). Participants are randomised using 1:1 allocation ratio to the APPLE Tree intervention versus control arm (dementia prevention information), stratified by site. The intervention explores and implements strategies to promote healthy lifestyle, increase pleasurable activities and social connections and improve long-term condition self-management. Two facilitators trained and supervised by a clinical psychologist deliver ten, 1-h group video call sessions over 6 months (approximately every fortnight), video-call 'tea breaks' (less structured, facilitated social sessions) in intervening weeks and individual goal-setting phone calls every 2 weeks. From 6 to 12 months, participants meet monthly for 'tea breaks', with those not attending receiving monthly goal-setting phone calls. Participants receive a food delivery, pedometer and website access to cognitive training and information about lifestyle modification. Follow-ups for all outcome measures are at 12 and 24 months. The primary outcome is cognition (Neuropsychological Test Battery (NTB) score) at 24 months. Secondary outcomes are quality of life, cost per quality-adjusted life year (QALY) and wellbeing and lifestyle factors the intervention targets (diet, vascular risk, body weight, activity, sleep, anxiety, depression, social networks and loneliness, alcohol intake and smoking). Participants from purposively selected sites participate in qualitative process evaluation interviews, which will be analysed using thematic analytic methods. DISCUSSION: If effective, the intervention design, involving remote delivery and non-clinical facilitators, would facilitate intervention roll-out to older people with memory concerns. TRIAL REGISTRATION: ISRCTN17325135 . Registration date 27 November 2019.

Is it time to consider population screening for fracture risk in postmenopausal women? A position paper from the International Osteoporosis Foundation Epidemiology/Quality of Life Working Group.

The IOF Epidemiology and Quality of Life Working Group has reviewed the potential role of population screening for high hip fracture risk against well-established criteria. The report concludes that such an approach should strongly be considered in many health care systems to reduce the burden of hip fractures. INTRODUCTION: The burden of long-term osteoporosis management falls on primary care in most healthcare systems. However, a wide and stable treatment gap exists in many such settings; most of which appears to be secondary to a lack of awareness of fracture risk. Screening is a public health measure for the purpose of identifying individuals who are likely to benefit from further investigations and/or treatment to reduce the risk of a disease or its complications. The purpose of this report was to review the evidence for a potential screening programme to identify postmenopausal women at increased risk of hip fracture. METHODS: The approach took well-established criteria for the development of a screening program, adapted by the UK National Screening Committee, and sought the opinion of 20 members of the International Osteoporosis Foundation's Working Group on Epidemiology and Quality of Life as to whether each criterion was met (yes, partial or no). For each criterion, the evidence base was then reviewed and summarized. RESULTS AND CONCLUSION: The report concludes that evidence supports the proposal that screening for high fracture risk in primary care should strongly be considered for incorporation into many health care systems to reduce the burden of fractures, particularly hip fractures. The key remaining hurdles to overcome are engagement with primary care healthcare professionals, and the implementation of systems that facilitate and maintain the screening program.

Comparative effectiveness and cardiovascular safety of abaloparatide and teriparatide in postmenopausal women new to anabolic therapy: A US administrative claims database study.

Real-world evidence on the comparative effectiveness and safety of abaloparatide versus teriparatide in women with osteoporosis may help inform treatment decisions. Following 18 months of treatment, abaloparatide was comparable to teriparatide for prevention of nonvertebral fractures, resulted in a 22% risk reduction for hip fractures, and demonstrated similar cardiovascular safety. Osteoporotic fracture risk can be reduced with anabolic or antiresorptive medications. In addition to efficacy and safety data from controlled clinical trials, real-world evidence on comparative effectiveness and safety may help inform treatment decisions. INTRODUCTION: The real-world effectiveness of abaloparatide versus teriparatide on nonvertebral fracture (NVF) incidence and cardiovascular safety during the 19-month period after treatment initiation were evaluated (NCT04974723). METHODS: Anonymized US patient claims data from Symphony Health, Integrated Dataverse (IDV)®, May 1, 2017 to July 31, 2019, included women aged ≥ 50 years with ≥ 1 prescription of abaloparatide or teriparatide and no prior anabolic therapy. Most were enrolled in commercial and Medicare health plans. Index was the date of the initial prescription dispensed during the identification period. In 1:1 propensity score matched cohorts, time to first NVF following index date, major adverse cardiovascular events (MACE), and MACE + heart failure (HF) were compared between cohorts using a Cox proportional hazards model. RESULTS: Propensity score matching yielded 11,616 patients per cohort. Overall median age (interquartile range) was 67 (61, 75) years, and 25.6% had a fracture history. Over 19 months, 335 patients on abaloparatide and 375 on teriparatide had a NVF (hazard ratio [95% confidence interval]: 0.89 [0.77, 1.03]), and 121 and 154 patients, respectively, had a hip fracture [HR (95% CI): 0.78 (0.62, 1.00)]. The MACE and MACE + HF rates were similar between cohorts. CONCLUSIONS: Following 18 months of treatment, abaloparatide was comparable to teriparatide for prevention of NVF and similar cardiovascular safety was demonstrated between cohorts.

Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan.

We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. INTRODUCTION: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors. METHODS: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible. RESULTS: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed. CONCLUSIONS: These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).