Reduce Fracture Risk Research Articles

Integrated model of secondary fracture prevention in primary care (INTERCEPT): protocol for a cluster randomised controlled multicentre trial

BackgroundOsteoporotic fractures signal severely compromised bone strength and are associated with a greatly increased risk of refracture. Despite the availability of effective and safe medications that reduce fracture risk, 70–80% of patients are inadequately investigated or treated for osteoporosis following an initial fracture, constituting a significant ‘osteoporosis care gap’. Optimal methods of bridging this gap with primary care at the forefront of secondary fracture prevention remain undetermined. This protocol describes a cluster randomised controlled trial to evaluate the effectiveness of a novel integrated model of secondary fracture prevention and management in primary care.MethodsThe cluster randomised controlled trial involves multiple branches of a community-based radiology provider (CRP), a hospital-based secondary fracture prevention program (SFPP) and numerous primary care practices in metropolitan Sydney that refer to either the CRP or SFPP. Using natural language processing tools, patients diagnosed with a potential osteoporotic fracture will be identified by automatically screening radiology reports generated at the CRP or SFPP. The primary care practices that these patients attend will be randomised (1:1) to either the intervention or usual care. The intervention consists of (i) electronic and fax alerts informing the practice/primary care physician that their patient has been diagnosed with a potential osteoporotic fracture; (ii) provision of osteoporosis management guidelines and (iii) follow-up surveys at 4 weeks and 6 months. Practices in the usual care (control) group will receive no alerts and provide usual care. The primary outcome is the proportion of patients undergoing a bone density scan and/or filling a prescription for osteo-protective pharmacotherapy within 3 months of the initial diagnostic imaging report. Secondary outcomes are the proportion of patients: (i) undergoing an osteoporosis-related blood test within 3 months of the initial diagnostic imaging report; (ii) initiated on a chronic disease management plan within 3 months of the diagnostic report, and (iii) filling a second prescription for osteo-protective pharmacotherapy within 9 months post initial diagnostic imaging report. Outcomes will be obtained through de-identified linked data from Medical Benefits Schedule and Pharmaceutical Benefits Scheme held by the Australian Institute of Health and Welfare.DiscussionThis is the first randomised trial to integrate case-detection of potential osteoporotic fractures in a hospital and community setting with direct alerts to the patient’s primary care provider. This study will determine whether such an intervention is effective in improving investigation and/or treatment rates of osteoporosis in patients with a potential osteoporotic fracture.Trial registrationThis study is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12623000658617p.

The relationship between treatment-related changes in total hip BMD measured after 12, 18, and 24mo and fracture risk reduction in osteoporosis clinical trials: the FNIH-ASBMR-SABRE project.

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

Nutrition and Osteoporosis Prevention.

Osteoporosis affects 50% of women and 20% of men after the age of 50. Fractures are associated with significant morbidity, increased mortality and altered quality of life. Lifestyle measures for fragility fracture prevention include good nutrition including adequate protein and calcium intakes, vitamin D sufficiency, and regular weight bearing physical exercise. Dietary protein is one of the most important nutritional considerations as it affects bone mineral density, trabecular and cortical microstructure, and bone strength. When calcium intake is sufficient, higher dietary protein intake is associated with lower risk of fracture. Dairy products are a valuable source of calcium and high quality protein. Dairy product consumption, particularly fermented dairy products, are associated with a lower risk of hip fracture and vegan diets are associated with increased fracture risk. Other dietary factors associated with reduced fracture risk include at least 5 servings per day of fruits and vegetables, regular tea drinking, adherence to a Mediterranean diet and other dietary patterns which provide fibers, polyphenols and fermented dairy products. Such dietary patterns may confer health benefits through their effect on gut microbiota composition and/or function. A balanced diet including minerals, protein, fruits and vegetables is an important element in the prevention of osteoporosis and of fragility fracture.

Treating Osteoporosis in Patients with Atypical Femoral Fracture.

Patients who have suffered an atypical femoral fracture while on bisphosphonates or denosumab may continue to be at risk for typical osteoporotic fractures. There are no studies to provide guidance on safe treatment for such patients. Instead, using an illustrative case, 5 principles of management are provided that may lead to decreased osteoporotic fracture risk. The first principle is to discontinue the anti-resorptive medications, which may be challenging in the patient on denosumab because of rebound vertebral fractures reported in patients stopping denosumab. The second principle is to maximize non-pharmacologic management to reduce falls and fractures. Home safety, other methods of fall risk reduction, adequate nutrition, and an exercise prescription should help reduce fracture risk. Investigating potential secondary causes of osteoporosis, particularly if the original workup was not comprehensive, is the third principle because treatment of some specific causes may lower fracture risk. Reviewing the medication list is the fourth principle, with the goal of eliminating drugs that may increase fracture risk; and considering thiazides for some patients, which may lower fracture risk. Finally, some patients may benefit from anabolic therapy. One potential (but not FDA-approved) method is to use long-term cyclic teriparatide or abaloparatide on a three-months on, three-months off schedule. Tailoring the approach to each patient is important, based on the five clinical principles, in the absence of evidence-based management recommendations.

A nationwide cohort study of inflammatory bowel disease, histological activity and fracture risk

SummaryBackgroundIndividuals with inflammatory bowel disease (IBD) are at increased risk of fracture. It is unclear if this risk varies by recent histological activity.AimsTo determine the fracture risk in IBD during periods with and without histological inflammation.MethodsWe studied a nationwide cohort of 54,591 individuals diagnosed with IBD in 1990–2016 with longitudinal data on ileo‐colorectal biopsies. Fractures were identified by inpatient and hospital‐based outpatient diagnoses. We derived Cox regression estimated hazard ratios (HRs) for fracture during 12 months following a histological inflammation (vs. histological remission) record after adjusting for socio‐demographics, comorbidities, IBD duration, IBD‐related surgery and hospitalization. We adjusted sensitivity analyses for medical IBD treatment including corticosteroids.ResultsMean age of patients was 44.0 (SD = 18.3) and 45.5 (SD = 17.1) years at biopsy with histological inflammation and remission, respectively. For histological inflammation, there were 1.37 (95% CI 1.29–1.46) fractures per 100 years' follow‐up versus 1.31 (95% CI 1.19–1.44) for remission (adjusted [a]HR 1.12; 95% CI 1.00–1.26; p = 0.04). HRs were similar with histological inflammation of Crohn's disease (1.11; 95% CI 0.91–1.36) and ulcerative colitis (1.18; 95% CI 1.02–1.36). Estimates were consistent across age groups. An overall small excess risk of any fracture remained after accounting for corticosteroids. A more prominently raised fracture risk was observed in corticosteroid‐naïve IBD patients with histological inflammation versus histological remission (aHR 1.41; 95% CI 1.07–1.85). The aHR of hip fracture following histological inflammation was 1.29 (95% CI 0.87–1.92).ConclusionsHistological inflammation in IBD predicted a small increase in short‐term fracture risk. Measures to reduce disease activity may reduce fracture risk in IBD.

Bone Loss and Fractures in Post-Menopausal Women Living with HIV: A Narrative Review.

Post-menopausal women living with Human Immunodeficiency Virus (WLHIV) face an increased risk of bone fractures due to the relationship between HIV-related factors and menopause. This narrative review aims to summarise the current knowledge about fracture risk among post-menopausal WLHIV in particular looking at hormonal changes, combined antiretroviral therapy (cART), lifestyle factors, and psychosocial implications. We also profiled a summary of the significant, recent studies of post-menopausal WLHIV residing in low-income countries (LIC). A thorough search of the literature was performed across PubMed, Medline, Scopus, and Google Scholar, focussing on studies published between 2000 and 2024. Inclusion criteria entailed original research, reviews, and meta-analyses addressing bone mineral density (BMD), fracture incidence, and related risk factors in post-menopausal WLHIV. The review identified 223 relevant studies. Post-menopausal WLHIV exhibit significantly lower BMD and higher fracture rates compared to both HIV-negative post-menopausal women and pre-menopausal WLHIV. cART, particularly tenofovir disoproxil fumarate (TDF), contributes to reduced BMD. Menopausal status exacerbates this risk through decreased oestrogen levels, leading to increased bone resorption. Moreover, lifestyle choices such as smoking, alcohol consumption, and low physical activity are more prevalent in PWHIV, which further elevates fracture risk. Different psychosocial factors may make WLWHIV more vulnerable at this stage of their life, such as depression, isolation, stigma, and housing and nutritional issues. Women living in LICs face a variety of challenges in accessing HIV care. There are gaps in research related to the prevalence of osteoporosis and bone loss in post-menopausal WLHIV in LICs. Post-menopausal women living with HIV face a significantly higher risk of bone loss and fractures due to the combined effects of HIV and menopause. Antiretroviral therapy (particularly TDF), lifestyle factors, and psychosocial challenges exacerbate this risk. There is a need for careful selection of cART, hormone replacement therapy (HRT), and emerging treatments such as Abaloparatide. A holistic approach including lifestyle changes and psychosocial support is crucial to reduce fracture risk in WLHIV, especially in low-income countries.

Metformin acts on miR-181a-5p/PAI-1 axis in stem cells providing new strategies for improving age-related osteogenic differentiation decline.

A general decline in the osteogenic differentiation capacity of human bone marrow mesenchymal stem cells (hBMSCs) in the elderly is a clinical consensus, with diverse opinions on the mechanisms. Many studies have demonstrated that metformin (MF) significantly protects against osteoporosis and reduces fracture risk. However, the exact mechanism of this effect remains unclear. In this study, we found that the decreased miR-181a-5p expression triggered by MF treatment plays a critical role in recovering the osteogenic ability of aging hBMSCs (derived from elderly individuals). Notably, the miR-181a-5p expression in hBMSCs was significantly decreased with prolonged MF (1000 μM) treatment. Further investigation revealed that miR-181a-5p overexpression markedly impairs the osteogenic ability of hBMSCs, while miR-181a-5p inhibition reveals the opposite result. We also found that miR-181a-5p could suppress the protein translation process of plasminogen activator inhibitor-1 (PAI-1), as evidenced by luciferase assays and western blots. Additionally, low PAI-1 levels were associated with diminished osteogenic ability, whereas high levels promoted it. These findings were further validated in human umbilical cord mesenchymal stem cells (hUCMSCs). Finally, our in vivo experiment with a bone defects rat model confirmed that the agomiR-181a-5p (long-lasting miR-181a-5p mimic) undermined bone defects recovery, while the antagomiR-181a-5p (long-lasting miR-181a-5p inhibitor) significantly promoted the bone defects recovery. In conclusion, we found that MF promotes bone tissue regeneration through the miR-181a-5p/PAI-1 axis by affecting MSC osteogenic ability, providing new strategies for the treatment of age-related bone regeneration disorders.

Knee Osteoporosis Diagnosis Based on Deep Learning

Osteoporosis, a silent yet debilitating disease, presents a significant challenge due to its asymptomatic nature until fractures occur. Rapid bone loss outpaces regeneration, leading to pain, disability, and loss of independence. Early detection is pivotal for effective management and fracture risk reduction, yet current diagnostic methods are time-consuming. Despite its importance, research addressing early diagnosis remains limited. Deep learning, particularly convolutional neural networks (CNNs), has emerged as a potent tool in image analysis. This paper presents a novel approach utilizing transfer learning with CNNs for osteoporosis detection from X-ray images. The proposed approach not only achieves a high accuracy of osteoporosis diagnosis but also offers a revealed feature map that can guide medical professionals for osteoporosis diagnosis. The innovation lies in a dual strategy: (i) a model integrating transfer learning from CNN architectures such as AlexNet, VGG-16, ResNet-50, VGG-19, InceptionNet, XceptionNet, and a custom CNN, and (ii) a dataset collection augmentation mechanism to enhance learning accuracy. The study includes binary and multiclass classification of knee joint X-ray images into normal, osteopenia, and osteoporosis groups, utilizing a dataset of 1947 knee X-rays for training and testing. Performance comparisons against state-of-the-art models reveal the proposed VGG-19 model achieves the highest accuracy at 92.0% for multiclass and 97.5% for binary. These findings underscore the potential of deep learning with transfer learning in aiding early osteoporosis detection, thereby mitigating fracture risks.

The role of short-chain fatty acids in the regulation of osteoporosis: new perspectives from gut microbiota to bone health: A review.

Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration, resulting in increased fracture risk. With an aging population, osteoporosis imposes a heavy burden worldwide. Current pharmacotherapies such as bisphosphonates can reduce fracture risk but have limitations. Emerging research suggests that gut microbiota regulates bone metabolism through multiple mechanisms. Short-chain fatty acids (SCFAs) produced from microbial fermentation of dietary fiber beneficially impact bone health. Preclinical studies indicate that SCFAs such as butyrate and propionate prevent bone loss in osteoporosis models by inhibiting osteoclastogenesis and immune modulation. Early clinical data also suggest that SCFA supplementation may improve bone turnover markers in postmenopausal women. SCFAs likely act via inhibition of osteoclast differentiation, stimulation of osteoblast activity, regulation of T cells, and other pathways. However, optimal dosing, delivery methods, and long-term safety require further investigation. Modulating the gut-bone axis via supplementation, prebiotics/probiotics, diet, and lifestyle interventions represents an innovative therapeutic approach for osteoporosis. Harnessing the interplay between microbiome, metabolism, immunity, and bone may provide new directions for managing osteoporosis in the future.

Can Bisphosphonate Therapy Reduce Overall Mortality in Patients With Osteoporosis? A Meta-analysis of Randomized Controlled Trials.

For patients with osteoporosis, bisphosphonate therapy can reduce the risk of fractures, but its effect on reducing mortality remains unclear. Previous studies on this topic have produced conflicting results and generally have been too small to definitively answer the question of whether bisphosphonate therapy reduces mortality. Therefore, a meta-analysis may help us arrive at a more conclusive answer. In a large meta-analysis of placebo-controlled randomized controlled trials (RCTs), we asked: (1) Does bisphosphonate use reduce mortality? (2) Is there a subgroup effect based on whether different bisphosphonate drugs were used (zoledronate, alendronate, risedronate, and ibandronate), different geographic regions where the study took place (Europe, the Americas, and Asia), whether the study was limited to postmenopausal female patients, or whether the trials lasted 3 years or longer? We conducted a systematic review using multiple databases, including Embase, Web of Science, Medline (via PubMed), Cochrane Library, and ClinicalTrials.gov, with each database searched up to November 20, 2023 (which also was the date of our last search), following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We included randomized, placebo-controlled clinical trials with participants diagnosed with osteoporosis and receiving bisphosphonate treatment. We excluded papers posted to preprint servers, other unpublished work, conference abstracts, and papers that were registered on ClinicalTrials.gov but were not yet published. We collected 2263 records. After excluding records due to study type, study content not meeting the inclusion criteria, and duplicates, our meta-analysis included 47 placebo-controlled RCTs involving 59,437 participants. Data extraction, quality assessment, and statistical analyses were performed. The evaluation of randomized trials for potential bias was conducted using the revised Cochrane Risk of Bias tool. This assessment encompassed factors such as sequence generation, allocation concealment, subject blinding, outcome assessor blinding, incomplete outcome data, and reporting bias. Some studies did not provide explicit details regarding random sequence generation, leading to a high risk of selection bias. A few studies, due to their open-label nature, were unable to achieve double-blind conditions for both the subjects and the researchers, resulting in intermediate performance bias. Nevertheless, the overall study quality was high. Due to the low heterogeneity among the studies, as evidenced by the low statistical heterogeneity (that is, a low I2 statistic), we opted for a fixed-effects model, indicating that the effect size is consistent across the studies. In such cases, the fixed-effects model can provide more precise estimates. According to the results of the funnel plot, we did not find evidence of publication bias. The use of bisphosphonates did not reduce the overall risk of mortality in patients with osteoporosis (risk ratio 0.95 [95% CI 0.88 to 1.03]). Subgroup analyses involving different bisphosphonate drugs (zoledronate, alendronate, risedronate, and ibandronate), regions (Europe, the Americas, and Asia), diverse populations (postmenopausal female patients and other patients), and trials lasting 3 years or longer revealed no associations with reduced overall mortality. Based on our comprehensive meta-analysis, there is high-quality evidence suggesting that bisphosphonate therapy for patients with osteoporosis does not reduce the overall risk of mortality despite its effectiveness in reducing the risk of fractures. The primary consideration for prescribing bisphosphonates to individuals with osteoporosis should continue to be centered on reducing fracture risk, aligning with clinical guidelines. Long-term studies are needed to investigate potential effects on mortality during extended treatment periods. Level I, therapeutic study.

Statin use associated with a reduced risk of hip fracture in patients with gout

Studies show that statins users are at reduced risk of fracture and improved bone mineral density. However, the clinical effectiveness of statin use in patients with gout has not been investigated. This retrospective cohort study used data from Taiwan's National Health Insurance Research Database, consisting of 3443 patients with gout using statins aged 50 years and above and 6886 gout patients of non-statin users matched by sex, age and propensity score. The Cox proportional hazards regression analysis showed that statin use was associated with a reduced risk of hip fracture (adjusted hazard ratio [aHR] = 0.78, 95 % confidence interval [CI] = 0.64–0.94) after controlling for potential confounding factors. The association was significant in both genders aged 50–64 years, with aHRs of near 0.35, but not in the elderly. In addition, women aged 50–64 years who used statins also exhibited a lower risk of vertebral fracture (aHR = 0.70, 95 % CI = 0.50–0.99), but not men. In conclusion, the stating use in gout patients could reduce fracture risk for younger patients. Further research is warranted to confirm these findings.

Is orthotic treatment beneficial for fresh osteoporotic vertebral fractures? A propensity score matching study

BACKGROUND CONTEXTOrthotic treatment is a common option for the conservative treatment of osteoporotic vertebral fractures (OVF). However, there is insufficient evidence of its clinical benefit. PURPOSETo investigate the effectiveness of orthotic treatment for OVF. STUDY DESIGN/SETTINGRetrospective cohort study with data from two prospective studies. PATIENT SAMPLEThis study included 160 patients with fresh OVF enrolled in 2012 and 2020 prospective cohort studies. OUTCOME MEASURESThe visual analog scale (VAS) score for low back pain was used for clinical outcomes, and radiographic parameters included the percent height of the vertebra and angular change of the vertebral body. Moreover, the occurrence of secondary vertebral fractures was followed-up over time. METHODSThe patients were divided into brace and no-brace groups and were matched according to propensity score for age, sex, anterior percent height at the initial examination, and presence of old OVFs. Hazard ratio for the cumulative incidence of secondary vertebral fractures with and without bracing were calculated and analyzed using the generalized Wilcoxon test. In addition, the brace group was divided into soft and rigid brace groups and compared with the no-brace group. RESULTSEach group had 61 cases after propensity score matching. There were no significant differences in the VAS improvement for low back pain and the change in percent height of the anterior and posterior walls from initial examination to 6 months after injury (p=.87, p=.39 and p=.14, respectively, mixed-effect models). Meanwhile, the mean angular change of fractured vertebrae was 4.3° / 3.2° initially and 1.2° / 2.5° at 6 months (the brace group / no-brace group, respectively; p=.007, mixed-effect models). A significant difference was also observed between the rigid brace group and the no-brace group (p=.008, mixed effect models). The incidence of secondary vertebral fractures was 1.6% / 11.4% at 1 month, indicating a significant difference (the brace group / no-brace group, respectively; p = .028). The hazard ratio for the cumulative incidence of secondary fractures due to orthotic treatment was 0.47 (95% confidence interval 0.20–1.09, p=.054). CONCLUSIONSAlthough orthotic treatment for fresh OVF did not relieve pain, it might contribute to the stabilization of the fractured vertebra, especially using a rigid brace. Moreover, it might influence a reduction of the imminent vertebral fracture risk immediately after the onset of OVF. ClassificationsClinical study

Goal-directed osteoporosis treatment: ASBMR/BHOF task force position statement 2024.

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

Reconstruction of remodeling units reveals positive effects after 2 and 12months of romosozumab treatment.

Romosozumab treatment results in a transient early increase in bone formation and sustained decrease in bone resorption. Histomorphometric analyses revealed that the primary bone-forming effect of romosozumab is a transient early stimulation of modeling-based bone formation on cancellous and endocortical surfaces. Furthermore, preclinical studies have demonstrated that romosozumab may affect changes in the remodeling unit, resulting in positive bone balance. To further investigate the effects of romosozumab on bone balance, mo 12 (M12) and mo 2 (M2) (to analyze early effects) unpaired bone biopsies from the FRAME clinical trial were analyzed using remodeling site reconstruction to assess whether positive changes in bone balance on cancellous/endocortical surfaces may contribute to the progressive improvement in bone mass/structure and reduced fracture risk in osteoporotic women at high fracture risk. At M12, bone balance was higher with romosozumab vs placebo on cancellous (+6.1 vs +1.5μm; P =.012) and endocortical (+5.2 vs -1.7μm; P =.02) surfaces; higher bone balance was due to lower final erosion depth (40.7 vs 43.7μm; P =.05) on cancellous surfaces and higher completed wall thickness (50.8 vs 47.5μm; P =.037) on endocortical surfaces. At M2, the final erosion depth was lower on the endocortical surfaces (42.7 vs 50.7μm; P =.021) and was slightly lower on the cancellous surfaces (38.5 vs 44.6μm; P =.11) with romosozumab vs placebo. Sector analysis of early endocortical formative sites revealed higher osteoid thickness (29.9 vs 19.2μm; P = .005) and mineralized wall thickness (18.3 vs 11.9μm; P =.004) with romosozumab vs placebo. These evolving bone packets may reflect the early stimulation of bone formation that contributes to the increase in completed wall thickness at M12. These data suggest that romosozumab induces a positive bone balance due to its effects on bone resorption and formation at the level of the remodeling unit, contributing to the positive effects on bone mass, structure, and fracture risk.

Radium-223 Treatment Produces Prolonged Suppression of Resident Osteoblasts and Decreased Bone Mineral Density in Trabecular Bone in Osteoblast Reporter Mice.

Radium 223 (Ra-223) is an α-emitting bone-homing radiopharmaceutical that targets tumor-induced osteoblasts and is used to reduce bone pain and prolong overall survival in men with bone-metastatic, castrate-resistant prostate cancer. However, increased fracture risk in skeletal sites with no bone metastasis has been observed in patients treated with Ra-223. Both luciferase- or green fluorescence protein (GFP)-labeled osteoblast reporter mice were used to monitor the effect of Ra-223 on resident osteoblasts and normal bone structure. Upon Ra-223 treatment, 70% of resident osteoblasts were reduced within 2 days, and the osteoblast reduction lasted for at least 18 weeks without detectable recovery, as measured by in vivo bioluminescent imaging. In GFP-labeled osteoblast reporter mice, Ra-223 mainly reduced osteoblasts localized in the trabecular bone areas; the osteoblasts in the growth plates were less affected. Micro-computed tomography analyses showed that Ra-223 significantly reduced bone mineral density and bone microstructure in the trabecular area of femurs but not in the cortical bone. Tumor-induced bone was generated by inoculating osteogenic TRAMP-BMP4 prostate cancer cells into the mouse femurs; Ra-223 treatment significantly reduced tumor-induced osteoblasts. Our study shows that Ra-223 affects bone structures that are not involved in bone metastasis. Strategies that improve bone health may reduce fracture risk in patients receiving Ra-223.

Lower Parathyroid Hormone Levels are Associated With Reduced Fracture Risk in Japanese Patients on Hemodialysis

Secondary hyperparathyroidism (SHPT) affects bone metabolism and may lead to bone fragility. However, there is conflicting evidence as to whether parathyroid hormone (PTH) levels are associated with fracture risk and whether the relationship is linear or U-shaped. We examined the association between PTH levels and the risk of any fracture and site-specific fractures in a nationwide cohort of 180,333 patients on hemodialysis. We also examined the association between the percent change in PTH levels during the preceding 1 year and subsequent fracture. At baseline, the median intact PTH level was 141 pg/ml (interquartile range, 78-226 pg/ml). During 1 year of follow-up, there were a total of 3762 fractures requiring hospitalization (1361 hip, 551 vertebral, and 1850 other). In an adjusted analysis, higher baseline PTH levels were associated with an incrementally increased risk of any fracture (odds ratio [OR] per doubling of intact PTH, 1.06; 95% confidence interval, 1.03-1.09). The association between PTH levels and fracture risk was more pronounced for hip fractures but not found for vertebral fractures. The absolute risk difference associated with higher PTH levels appeared to be more pronounced in older individuals, females, and those with lower body mass index (BMI). Change in PTH levels was also associated with fracture risk: the adjusted OR for fracture decreased linearly with decreasing PTH levels over 1 year, regardless of the preceding PTH levels. Lower PTH levels are associated with a graded reduction in fracture risk. Further studies are needed to determine whether intensive PTH control reduces fracture risk.

Proton pump inhibitor use and bone fractures in patients with chronic kidney disease.

Patients with chronic kidney disease (CKD) are at high risk for bone fractures, which are associated with high morbidity and mortality. Proton pump inhibitors (PPI) have been linked to an increased risk for fractures in the general population as well as in patients with need for hemodialysis, but studies in patients with CKD are currently missing. We performed a population-based observational case-control study exploring a sample of patients with CKD derived from the IQVIATM Disease Analyzer database. Patients with and without fractures were matched using the 1:1 nearest neighbor propensity score matching method. To investigate the association between PPI use and fractures, multivariable logistic regression analyses were performed adjusting for confounding factors. In total, 6076 patients with and 6076 patients without fractures were matched and subsequently available for analyses. In the total cohort, PPI use was associated with an increased risk for fractures (OR 1.68; 95% CI 1.55-1.83). This association was noted for nearly all types of fractures. The strongest association between PPI use and fractures was found in patients below the age of 60 with a PPI prescription for longer than two years (OR 6.85, 95% CI 1.85-25.38). The same was true, when analyzing cumulative PPI doses. Here, patients below the age of 60 with a cumulative PPI dose above 16000mg (highest quartile) had the highest risk for fractures (OR 4.62, 95% CI 1.87-11.44). There was no difference between men or women regarding the association between PPI use and fractures. This study provides evidence that PPI use is associated with fractures in patients with CKD. Deprescription of PPI in patients without an indication for treatment could be a modifiable risk factor to reduce fracture risk in this high-risk group.

Clinical effects of teriparatide, abaloparatide, and romosozumab in postmenopausal osteoporosis.

In the management of osteoporosis, anti-resorptive agents serve as a primary therapeutic approach. However, in cases where individuals exhibit an increased susceptibility to fractures, such as those characterized by severe low bone mass or a history of vertebral or hip fractures that markedly diminish life expectancy, the immediate reduction of fracture risk through the administration of osteoanabolic agents could be beneficial. Teriparatide, available in daily, once-weekly, or twice-weekly dosages, along with abaloparatide and romosozumab, constitutes a trio of such agents. Each of these medications is defined by unique characteristics, distinct efficacy profiles, and specific adverse effects. There is growing evidence to suggest that these agents have a superior effect on enhancing bone mineral density and reducing fracture incidence when compared to traditional bisphosphonate therapies. Nonetheless, their employment demands thorough consideration of clinical indications, which includes evaluating economic factors, the frequency of injections required, and the potential for adverse effects. The objective of this review is to consolidate the current evidence focusing primarily on the efficacy of these agents, with the goal of enhancing understanding and aiding in making more informed treatment decisions, particularly for those individuals who are at an elevated risk of fractures.

Roles of collagen cross-links and osteon collagen/lamellar morphotypes in equine third metacarpals in tension and compression tests.

Many bones experience bending, placing one side in net compression and the other in net tension. Because bone mechanical properties are relatively reduced in tension compared with compression, adaptations are needed to reduce fracture risk. Several toughening mechanisms exist in bone, yet little is known of the influences of secondary osteon collagen/lamellar 'morphotypes' and potential interplay with intermolecular collagen cross-links (CCLs) in prevalent/predominant tension- and compression-loaded regions. Paired third metacarpals (MC3s) from 10 adult horses were prepared for mechanical testing. From one MC3/pair, 5 mm cubes were tested in compression at several mid-shaft locations. From contralateral bones, dumbbell-shaped specimens were tested in tension. Hence, habitual/natural tension- and compression-loaded regions were tested in both modes. Data included: elastic modulus, yield and ultimate strength, and energy absorption (toughness). Fragments of tested specimens were examined for predominant collagen fiber orientation (CFO; representing osteonal and non-osteonal bone), osteon morphotype score (MTS, representing osteonal CFO), mineralization, porosity and other histological characteristics. As a consequence of insufficient material from tension-tested specimens, CCLs were only examined in compression-tested specimens (HP, hydroxylysylpyridinoline; LP, lysylpyridinoline; PE, pentosidine). Among CCLs, only LP and HP/LP correlated significantly with mechanical parameters: LP with energy absorption, HP/LP with elastic modulus (both r=0.4). HP/LP showed a trend with energy absorption (r=-0.3, P=0.08). HP/LP more strongly correlated with osteon density and mineralization than CFO or MTS. Predominant CFO more strongly correlated with energy absorption than MTS in both testing modes. In general, CFO was found to be relatively prominent in affecting regional toughness in these equine MC3s in compression and tension.

Following hip fracture, hospital organisational factors associated with prescription of anti-osteoporosis medication on discharge, to address imminent refracture risk: a record-linkage study.

Patients who sustain a hip fracture are known to be at imminent refracture risk. Their complex multidisciplinary rehabilitation needs to include falls prevention and anti-osteoporosis medication (AOM) to prevent such fractures. This study aimed to determine which hospital-level organisational factors predict prescription of post-hip fracture AOM, and refracture risk. A cohort of 178 757 patients aged ≥60years who sustained a hip fracture in England and Wales (2016-19) was examined and followed for 1year. Patient-level hospital admission datasets from 172 hospitals, the National Hip Fracture Database, and mortality data were linked to 71 metrics extracted from 18 hospital-level organisational reports. Multilevel models determined organisational factors, independent of patient case-mix, associated with (i) AOM prescription, (ii) refracture (by ICD10 coding). Patients were mean (SD) 82.7 (8.6) years old, 71% female, with 18% admitted from care homes. Overall, 101 735 (57%) were prescribed AOM during admission; while 50 354 (28%) died during 1-year follow-up, 12 240 (7%) refractured. Twelve organisational factors were associated with AOM prescription, e.g., orthogeriatrician-led care compared to traditional care models (OR 4.65 [95%CI: 2.25-9.59]); AOM was 9% (95%CI: 6%-13%) more likely to be prescribed in hospitals providing routine bone health assessment to all patients. Refracture occurred at median 126days (IQR 59-234). Eight organisational factors were associated with refracture risk; hospitals providing orthogeriatrician assessment to all patients within 72-hours of admission had an 18% (95%CI: 2-31%) lower refracture risk, weekend physiotherapy provision an 8% (95%CI: 3-14%) lower risk, and where occupational therapists attended clinical governance meetings, a 7% (95%CI: 2-12%) lower risk. Delays initiating post-discharge community rehabilitation were associated with a 15% (95%CI: 3-29%) greater refracture risk. These novel, national findings highlight the importance of orthogeriatrician, physiotherapist and occupational therapist involvement in secondary fracture prevention post hip fracture; notably fracture risk reductions were seen within 12months of hip fracture.