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Age-associated osteoporosis (AAOP) poses a significant health burden, characterized by increased fracture risk due to declining bone mass and strength. Effective prevention and early treatment strategies are crucial to mitigate the disease burden and the associated healthcare costs. Current therapeutic approaches effectively target the individual contributing factors to AAOP. Nonetheless, the management of AAOP is complicated by the multitude of variables that affect its development. Main intrinsic and extrinsic factors contributing to AAOP risk are reviewed here, including mechanical unloading, nutrient deficiency, hormonal disbalance, disrupted metabolism, cognitive decline, inflammation and circadian disruption. Furthermore, it is discussed how these can be targeted for prevention and treatment. Although valuable as individual targets for intervention, the interconnectedness of these risk factors result in a unique etiology for every patient. Acknowledgement of the multifaceted nature of AAOP will enable the development of more effective and sustainable management strategies, based on a holistic, patient-centered approach.

Osteoporosis is characterized by reduced bone mass due to imbalanced bone metabolism. Exosomes derived from bone mesenchymal stem cells (BMSCs) have been shown to play roles in various diseases. This study aimed to clarify the regulatory function and molecular mechanism of BMSCs-derived exosomes in osteogenic differentiation and their potential therapeutic effects on osteoporosis. Exosomes were extracted from BMSCs. Bone marrow-derived macrophages (BMDMs) were cultured and internalized with BMSCs-derived exosomes. Real-time quantitative PCR was used to detect the expression of macrophage surface markers and tripartite motif (TRIM) family genes. BMDMs were co-cultured with human osteoblasts to assess osteogenic differentiation. Western blot was performed to analyze the ubiquitination of triggering receptor expressed on myeloid cell 1 (TREM1) mediated by TRIM25. An ovariectomized mice model was established to evaluate the role of TRIM25 and exosomes in osteoporosis. Exosomes were successfully isolated from BMSCs. BMSCs-derived exosomes upregulated TRIM25 expression, promoting M2 macrophage polarization and osteogenic differentiation. TRIM25 facilitated the ubiquitination and degradation of TREM1. Overexpression of TREM1 reversed the enhanced M2 macrophage polarization and osteogenic differentiation caused by TRIM25 overexpression. TRIM25 enhanced the protective effect of BMSCs-derived exosomes against bone loss in mice. These findings suggested that BMSCs-derived exosomes promoted osteogenic differentiation by regulating M2 macrophage polarization through TRIM25-mediated ubiquitination and degradation of TREM1. This mechanism might provide a novel approach for treating osteoporosis., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the Ethics Committee of Capital Medical University Affiliated Beijing Jishuitan Hospital. All experiments were performed in accordance with the ARRIVE guidelines. Consent for publication Not applicable. Competing interests The authors confirm that no competing interests exist in this work., (© 2024. The Author(s).)

We aim to evaluate the Osteopontin (OPN) levels in patients with Celiac disease (CD) at diagnosis and exploring its association with mucosal atrophy and osteoporosis. The study included celiac patients at diagnosis and age and sex matched healthy controls. Subjects with additional intestinal pathology, other known inflammatory and autoimmune disease accompanying CD, and patients with signs of infection were excluded. Demographics, presenting symptoms, concurrent disorders, physical examination findings, laboratory results, celiac serology and histopathological assessment were recorded. A total of 36 celiac patients (23 girls, 13 boys, mean age 9.4 ± 4.5 years) and 36 healthy controls (22 girls, 14 boys, mean age 8.7 ± 4 years) were included. The median OPN level was significantly higher in patients [10.41 (9.34-13.47) ng/ml vs. 9.42 (7.56-10.19) ng/ml, p < 0.001]. The median OPN levels of patients with osteoporosis was significantly higher than those with normal BMD values [20.7 (10.12-21.22) vs. 9.87 (9.16-10.75), respectively, p = 0.006)]. A serum OPN level of 10.74 ng/ml was found to be a cut-off value for the patient with osteoporosis with 66.7% sensitivity, 66.7% specificity, 50% positive predictive value, and 80% negative predictive value. Patients' OPN levels were 9.53 (9.3-10.42) ng/ml in Marsh type 3a, 9.78 (8.62-15.28) ng/ml in Marsh type 3b and 11.51 (9.88-19.75) ng/ml in Marsh type 3c. Marsh-Oberhuber type 3c was found to have higher median OPN levels than type 3a and type 3b (p = 0.027). When patients were stratified based on their manifestations of either intestinal or extraintestinal symptoms, along with the presence of anemia, tissue TG IgA levels exceeding ten times the upper normal limit, and a deficiency in vitamin D, the median OPN levels exhibited no significant differences across these groups., Conclusions:  In conclusion, it is suggested that serum OPN could potentially serve as an indicator of the extent of mucosal atrophy at the initial diagnosis and may have predictive value for osteoporosis., What Is Known: • There is currently no routinely utilized marker that can ascertain the extent of histological involvement in celiac disease. • Bone mineral density evaluation is not routinely recommendable at diagnosis in celiac disease, as no clinical predictor is available for low bone mineral density in children., What Is New: • Celiac patients have a higher level of osteopontin at diagnosis. • Osteopontin could potentially serve as an indicator of the extent of mucosal atrophy at the initial diagnosis and may have predictive value for osteoporosis., Competing Interests: Declarations Ethics Approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Eskisehir Osmangazi University (Date:19.03.2020/No:07). Consent to Participate Written informed consent was obtained from the parents. Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Context: Type 2 diabetes mellitus is associated with more rapid bone loss in women, but less evidence is available for men or those with prediabetes., Objective: To determine whether bone loss rate is affected by diabetes status in older men, we analyzed data from the Osteoporotic Fractures in Men (MrOS) study., Methods: The multisite MrOS study enrolled 5994 men aged ≥ 65 years. Diabetes status was defined by self-report, diabetes medication use, or elevated fasting serum glucose at baseline. Hip bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA) at baseline and a follow-up visit after 4.6 ± 0.4 years. This analysis included 4095 men, excluding those without follow-up DXA or with unknown diabetes status. Changes in hip BMD in participants with normoglycemia (NG), prediabetes, or type 2 diabetes, excluding thiazolidinedione (TZD) users, were evaluated using generalized linear models (GLM). Diabetes medication use and BMD loss among those with type 2 diabetes were also evaluated with GLM., Results: In adjusted models, hip BMD loss was greater in men with type 2 diabetes (- 2.23%; 95% CI: -2.54 to -1.91; P < .001) but not in men with prediabetes (-1.45%; 95% CI -1.63 to -1.26; P = .33) compared with NG (-1.57%; 95% CI -1.73 to -1.41). Among men with type 2 diabetes, TZD, insulin, and sulfonylurea use were associated with greater hip BMD loss., Conclusion: Men with type 2 diabetes, but not prediabetes, experienced accelerated bone loss compared to participants with normoglycemia. More rapid bone loss predicts increased risk of fractures and mortality in broader populations., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The accumulating evidence has made it clear that iron overload is a crucial mechanism in bone loss. Protocatechualdehyde (PCA) has also been used to prevent osteoporosis in recent years. Whether PCA can reverse the harmful effects of iron overload on bone mass in aged rats is still unknown. Therefore, this study aimed to assess the role of PCA in iron overload-induced bone loss in senile rats. In the aged rat model, we observed that iron overload affects bone metabolism and bone remodeling, manifested by bone loss and decreased bone mineral density. The administration of PCA effectively mitigated the detrimental effects caused by iron overload, and concomitant reduction in MDA serum levels and elevation of SOD were noted. In addition, PCA-treated rats were observed to have significantly increased bone mass and elevated expression of SIRT3，BMP2，SOD2 and reduced expression of TNF-α in bone tissue. We also observed that PCA was able to reduce oxidative stress and inflammation and restore the imbalance in bone metabolism. When MC3T3-E1 and RAW264.7 cells induced osteoblast and osteoclasts differentiation, PCA intervention could significantly recover the restriction of osteogenic differentiation and up-regulation of osteoclast differentiation treated by iron overload. Further, by detecting changes in ROS, SOD, MDA, expression of SIRT3 and mitochondrial membrane potentials, we confirm that the damage caused to cells by iron overload is associated with decreased SIRT3 activity, and that 3-TYP have similar effects on oxidative stress caused by FAC. In conclusion, PCA can resist iron overload-induced bone damage by improving SIRT3 activity, anti-inflammatory and anti-oxidative stress., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Employing a two-sample Mendelian randomization (MR) analysis, we aimed to investigate the potential causal effect of Parkinson disease (PD) on osteoporosis. We conducted an in-depth MR analysis by leveraging extensive genome-wide association study datasets from the International Parkinson Disease Genomics Consortium and the Genetic Factors for Osteoporosis Consortium. We meticulously selected instrumental variables based on strict criteria, including significance thresholds, linkage disequilibrium, and the exclusion of confounding single-nucleotide polymorphisms. Our investigation utilized diverse MR methods, including inverse variance weighted, MR Egger regression, weighted median, and MR-PRESSO, to robustly evaluate the causal relationship. Our comprehensive analysis revealed noteworthy associations between PD and distinct measures of bone mineral density (BMD) (forearm BMD, femoral neck BMD, lumbar spine BMD). Specifically, the inverse variance weighted method underscored potential significant relationships between PD and forearm BMD (P = .037; odds ratio [OR], 1.04; 95% confidence interval [CI], 1.00-1.09), femoral neck BMD (P = .034; OR, 1.02; 95% CI, 1.00-1.05), and lumbar spine BMD (P = .043; OR, 1.03; 95% CI, 1.00-1.06). The consistency of results across various methods and sensitivity analyses indicated both robustness and minimal pleiotropy concerns. Through a two-sample MR approach, this study establishes a plausible causal relationship between PD and decreased BMD. The outcomes underscore the urgency of targeted interventions to mitigate bone loss and manage osteoporosis in individuals with PD., Competing Interests: The authors have no conflicts of interests to disclose, (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by the synovitis and bone erosion. The combination therapy of glucocorticoids (GCs) and methotrexate (MTX) is recommended in early RA management, although the precise underlying mechanism of action remains unclear. This study is aimed to clarify the mechanism of MTX in combined with GC in treating RA., Methods: GC-induced osteoporosis (GIOP) mouse model was used to investigate the bone-protective role of MTX. Lipopolysaccharide-induced arthritis mouse model was used to evaluate the anti-inflammatory effects of GCs and MTX. Functional role of MTX on osteoclastogenesis was assessed by trap staining and micro-computer tomography. Western blot, RT-qPCR and coimmunoprecipitation were used to explore the underlying mechanisms., Results: We demonstrate that GCs, but not MTX, rapidly inhibited synovitis in arthritis model. MTX treatment was observed to inhibit osteoclastogenesis induced by GC in vitro and mitigate bone loss attributed by GIOP. GCs were found to augment the interaction between the membrane GC receptor (mGR) and signal transducer and activator of transcription 1 (STAT1), leading to the suppression of IFN-γR/STAT1 signalling pathways. Interestingly, MTX was found to inhibit osteoclastogenesis induced by GCs through the enhancement of the A2AR and IFN-γR interaction, thereby activating the IFN-γR/STAT1 signalling cascade. Consequently, this process results in a reduction in the mGR and STAT1 interaction., Conclusions: Our study provides compelling evidence that MTX can make GCs effectively to suppress synovitis and reduce bone loss induced by GCs. This sheds light on the potential mechanistic insights underlying the efficacy of GCs in conjunction with MTX for treating RA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background and Aims: The nutritional status and consequences of malnutrition among older adults with ulcerative colitis (UC) are not known., Methods: We conducted a retrospective study of patients 65 years ≥ with Ulcerative colitis (UC). Malnutrition was defined using the European Society for Clinical Nutrition and Metabolism (ESPEN) definition. Eight micronutrients and nutrition-related outcomes were measured. The Saskatchewan Inflammatory Bowel Disease-Nutrition Risk Tool was utilized to identify patients at risk for malnutrition. Data were summarized using descriptive statistics. Characteristics of patients with and without malnutrition were compared using Chi-Square test or Fisher's exact tests (analysis of variance for age)., Results: Two-hundred and ninety patients with a mean age of 73.4 years were included. 54% of patients had moderate-to-severe UC, with 52% receiving advanced therapy. Fifty-one patients (18%) met criteria for malnutrition, 17% were moderate-high risk for malnutrition, and 87% were low risk. Two-hundred and twenty patients (76%) had at least one micronutrient deficiency: 38% vitamin D, 43% iron, and 11% B12. Half of patients had osteoporosis or osteopenia (49%), however, only 39% of high-risk patients had undergone a DEXA scan., Conclusions: The majority of patients were not found to have malnutrition, however, the prevalence of micronutrient deficiencies among older adults with UC was high. This population is at particularly high risk for bone-related disease, yet a significant proportion of patients are not undergoing guideline-directed bone density testing. These findings illustrate the need for regular screening for malnutrition, micronutrient deficiency, and bone-related disease in older adults with UC., Competing Interests: Declarations Conflict of interest ZM—consultant for Neptune Medical. AT—none. CD—none. UM—consultant: Abbvie, Bristol Myers Squibb, Boeringher Ingelheim, Celltrion, Enveda, Gilead, Janssen, Lilly, Merck, Pfizer, Protagonist, Rani Therapeutics, Roivant, and Takeda. KB—site-specific principle investigator for AbbVie, Gilead, and NorthSea Clinical Trials. Ethical approval This study was approved by the Institutional Review Board (IRB) at the University of California San Francisco (IRB number 23-39463) and was conducted in accordance with the University’s research and patient-specific guidelines. All personnel involved in this study underwent CITI Human Subjects Protection Training. As this was a retrospective study, using de-identified data, the requirement for informed consent was waived., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The role of gut bacteria in preventing and delaying osteoporosis has been studied. However, the causal relationship between gut bacteria, plasma proteins, circulating metabolites and osteoporosis (OP) risk has not been fully revealed., Materials and Methods: In this study, a two-sample Mendelian randomization study (MR) approach was used to assess the causal associations between gut bacteria, plasma proteins and circulating metabolites, and osteoporosis risk using Genome Wide Association Study (GWAS) data from gut bacteria(n=8208), plasma proteins(n=2263), circulating metabolites (n=123), and osteoporosis (3203 cases and 16380452 controls). Inverse-variance weighted (IVW) was used as the main analytical method to estimate the MR causal effect and to perform directional sensitivity analysis of causality. Finally, the mediating effect values for the influence of gut flora on OP pathogenesis through circulating metabolites were calculated by univariate MR analysis, and multivariate MR analysis. Next, we evaluated the effect of Phosphatidylcholine on the osteogenic function of bone marrow mesenchymal stem cells (BMSCs) through relevant experiments, including Edu detection of cell proliferation, alkaline phosphatase (ALP) staining, Alizarin red staining to evaluate osteogenic function, qPCR and WB detection of osteogenic differentiation related gene expression., Results: A total of 9 gut microbial taxa, 15 plasma proteins and eight circulating metabolites were analysed for significant causal associations with the development of OP. Significant causal effects of 7 on gut bacteria, plasma proteins and circulating metabolites were analysed by univariate MR analysis and these results were used as exposure factors for subsequent multivariate MR. Multivariate MR analyses yielded a significant effect of circulating metabolites Phosphatidylcholine and other cholines on OP (P<0.05). Further mediation effect analysis showed that the mediation effect of Bifidobacteriaceae affecting OP through the circulating metabolite Phosphatidylcholine and other cholines was -0.0224, with a 95 % confidence interval for the mediation effect that did not include 0, and the complete mediation effect was significant. Phosphatidylcholine can promote BMSCs proliferation and osteogenesis., Conclusion: Our study demonstrated significant causal associations of gut bacteria, plasma proteins and circulating metabolites on OP, and that Bifidobacteriaceae affect OP through the circulating metabolites Phosphatidylcholine and other cholines. Phosphatidylcholine affects the osteogenic ability of BMSCs. Further exploration of potential microbiota-associated mechanisms of bone metabolism may offer new avenues for osteoporosis prevention and treatment of osteoporosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The aim of the study was to explore the clinical efficacy of bisphosphonates in patients with osteoporosis in diabetes patients by meta-analysis. Six databases were systematically searched from inception to January 30,2023. Studies evaluating the treatment of diabetic osteoporosis with bisphosphonates were included. Key outcome measures, such as bone mineral density (BMD), bone metabolism markers, pain improvement, and safety assessments, were extracted and analyzed. STATA MP V17.0 was used to calculate the combined effect size. After searching Chinese and English databases, 15 studies met the inclusion criteria of this study. The results of the meta-analysis showed that the BMD of patients with osteoporosis in diabetes increased significantly after bisphosphonate treatment, and the lumbar BMD increased by 0.08 g/cm² (95% CI: 0.05-0.11). Femoral neck BMD increased by 0.06 g/cm² (95% CI: 0.01-0.11); Ward's triangle BMD increased 0.07 g/cm² (95% CI: 0.04-0.09); and trochanter BMD increased by 0.06 g/cm² (95% CI: 0.04-0.08). In addition, bone alkaline phosphatase increased 1.95 μg/l (95% CI: 1.18-2.72), while serum tartrate-resistant acid phosphatase-5b decreased 1.28 U/l (95% CI: -1.81-0.75). Moreover, improvements in pain were statistically significant. The effects of bisphosphonates on osteocalcin (MD: -0.07; 95% CI: -1.12-1.25), serum calcium (MD: 0.01; 95% CI: -0.03-0.04), serum phosphorus (MD: 0.04; 95% CI: -0.03-0.10) and medication safety (OR: 1.75; 95% CI: 1.29-2.37) were not statistically significant. Bisphosphonates have a significant positive effect on bone mineral density and bone metabolism in patients with osteoporosis in diabetes and have good safety., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

The study aimed to explore the role of the irisin receptor (integrin αVβ5) signaling pathway in obesity-induced osteoporosis and its potential mechanism. The integrin αVβ5 gene of bone marrow mesenchymal stem cells (BMSCs) was silenced and overexpressed, and the cells were exposed to irisin treatment and mechanical stretch. Mouse models of obesity were established by feeding mice a high-fat diet, and 8-week caloric restriction/aerobic exercise regimens were implemented. The results showed that after silencing the integrin αVβ5, the osteogenic differentiation of BMSCs was significantly reduced. While overexpression of the integrin αVβ5 increased the osteogenic differentiation of BMSCs. Besides, mechanical stretch promoted the osteogenic differentiation of BMSCs. Obesity did not affect integrin αVβ5 expression in the bone, but it downregulated the expression of irisin and osteogenic factors, upregulated the expression of adipogenic factors, increased bone marrow fat, reduced bone formation, and destroyed the bone microstructure. Caloric restriction, exercise, and a combined regimen reversed these effects and improved obesity-induced osteoporosis, with the combined treatment exhibiting the most potent effect. This study confirms that the irisin receptor signaling pathway has a significant part in transmitting 'mechanical stress' and regulating 'osteogenic/adipogenic differentiation' of BMSCs via recombinant irisin, mechanical stretch, and overexpression/silencing of the integrin αVβ5 gene.

Pulsatilla koreana Nakai ( P. koreana ) is a perennial herb traditionally used to treat malaria and fever. Although the pharmacological properties of P. koreana have been explored in various contexts, its effects on bone diseases, such as osteoporosis, remain poorly studied. In this study, we investigated the effects of water extracts of P. koreana (WEPK) on osteoclasts, which play a crucial role in bone remodeling, and an ovariectomized (OVX) mouse model, which mimics osteoporosis. Phytochemical profiling of WEPK revealed several compounds that regulate bone or fat metabolism. WEPK suppressed osteoclast differentiation by downregulating the expression of receptor activator of nuclear factor-κB ligand (RANKL), a cytokine that induces osteoclastogenesis. Additionally, WEPK directly inhibited RANKL-induced differentiation of osteoclast precursors by downregulating nuclear factor of activated T cells 1 (NFATc1), the master transcription factor for osteoclastogenesis, by modulating its upstream regulators. In vivo, oral administration of WEPK suppressed bone loss, reduced weight gain, and mitigated fat accumulation in the liver and gonadal tissues of OVX mice. Given its positive impact on bone and fat accumulation under estrogen deficiency, WEPK may serve as a promising alternative therapy for postmenopausal osteoporosis, especially when accompanied by other metabolic disorders, such as obesity and fatty liver.

Background: Anorexia Nervosa is a highly lethal illness that is also associated with many medical complications. Food restriction and weight loss define this illness. Most of its physical complications are reversible with weight restoration, with the notable exception of the loss of bone density, which is commonly present in anorexia nervosa., Methods: A comprehensive scientific literature review was performed in order to explore bone disease in anorexia nervosa., Results: The pathophysiology of the loss of bone mineral density in anorexia nervosa was elucidated, along with the diagnosis and treatment of osteoporosis in patients with anorexia nervosa, including the nutritional approach to weight restoration., Conclusions: Loss of bone mineral density in anorexia nervosa is very aggressive. Nutritional rehabilitation is a cornerstone to treating this, along with medicinal considerations.

Objective: It is known that fracture risk is increased in patients with psoriatic arthritis (PsA); however, there is no consensus on the association with osteoporosis. The purpose of this study was to elicit the rate of osteoporosis and the risk factors of osteoporosis in patients with PsA at our institution., Methods: The data in this study were extracted from 163 patients with PsA. Osteoporosis and osteopenia were defined based on the WHO definition. Osteoporosis was also diagnosed when a fragility vertebral compression fracture was observed., Results: The osteoporosis and osteopenia rates for PsA patients were 11.7% and 33.1%, respectively. The rates of osteoporosis and osteopenia in males were particularly high compared to previous reports, at 9.3% and 34.3%, respectively. Trabecular bone score was considered age-appropriate for both males and females. Body mass index and Trabecular bone score were significantly lower in patients with osteoporosis., Conclusions: In patients with PsA, males are at elevated risk of osteoporosis and associated fragility fractures even if they are under 50 years. Body mass index was significantly lower in osteoporotic cases, suggesting the importance of bone mineral density testing and treatment in such cases., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Chronic kidney disease (CKD) is a significant global health issue and often involves CKD-mineral and bone disorder (MBD) and sarcopenia. Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of fibrinolysis. PAI-1 has been implicated in the pathogenesis of osteoporosis and muscle wasting induced by inflammatory conditions. However, the roles of PAI-1 in CKD-MBD and sarcopenia remain unknown. Therefore, the present study investigated the roles of PAI-1 in bone loss and muscle wasting induced by adenine in PAI-1-deficient mice. CKD was induced in PAI-1+/+ and PAI-1-/- mice by administration of adenine for ten weeks. Muscle wasting was assessed by grip strength test, quantitative computed tomography (CT) analysis and muscle weight measurement. Osteoporosis was assessed by micro-CT analysis of femoral microstructural parameters. PAI-1 deficiency did not affect adenine-induced decreases in body weight and food intake or renal dysfunction in male or female mice. PAI-1 deficiency also did not affect adenine-induced decreases in grip strength, muscle mass in the lower limbs, or the tissue weights of the gastrocnemius, soleus, and tibialis anterior muscles in male or female mice. PAI-1 deficiency aggravated trabecular bone loss in CKD-induced male mice, but significantly increased trabecular bone in CKD-induced female mice. On the other hand, PAI-1 deficiency did not affect cortical bone loss in CKD-induced mice. In conclusion, PAI-1 is not critical for the pathophysiology of CKD-MBD or CKD-induced sarcopenia in mice. However, PAI-1 may be partly related to bone metabolism in trabecular bone in the CKD state with sex differences., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Mizukami et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Extensive observational data suggest a link between celiac disease (CeD) and osteoporosis, but the causality and mediating mechanism remain undetermined. Herein, we performed a Mendelian randomization (MR) study to address these concerns., Methods: We obtained the summary-level statistics for CeD from a large genome-wide association study (GWAS) comprising 4,533 cases and 10,750 controls of European ancestry. The GWAS data for osteoporosis-related traits and inflammatory cytokines were derived from the UK Biobank, FinnGen, IEU OpenGWAS database, or GWAS catalog. Two-sample MR with the inverse variance-weighted methods were employed to evaluate the genetic association between CeD and osteoporosis-related traits. The potential inflammatory mediators from CeD to osteoporosis were explored using two-step mediation analyses., Results: The primary MR analyses demonstrated causal associations between genetically predicted CeD and osteoporosis (odds ratio [OR]: 1.110, 95% confidence interval [CI]: 1.043-1.182, p =0.001), total body bone mineral density (β: -0.025, p =0.039), and osteoporotic fracture (OR: 1.124, 95% CI: 1.009-1.253, p =0.034). Extensive sensitivity analyses consolidated these findings. Among the candidate inflammatory cytokines, only interleukin-18 was observed to mediate the effects of CeD on osteoporosis, with an indirect OR of 1.020 (95% CI: 1.000-1.040, p =0.048) and a mediation proportion of 18.9%. The mediation effects of interleukin-18 could be validated in other datasets (OR: 1.015, 95% CI: 1.001-1.029, p =0.041). Bayesian colocalization analysis supported the role of interleukin-18 in osteoporosis., Conclusion: The present MR study reveals that CeD is associated with an increased risk of developing osteoporosis, which may be partly mediated by upregulation of interleukin-18., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xiang, Zheng, Luo and Yang.)

Angiogenesis-osteogenesis coupling is critical for proper functioning and maintaining the health of bones. Any disruption in this coupling, associated with aging and disease, might lead to loss of bone mass. Osteoporosis (OP) is a debilitating bone metabolic disorder that affects the microarchitecture of bones, gradually leading to fracture. Computational analysis revealed that normal angiogenesis is disrupted during the progression of OP, especially postmenopausal osteoporosis (PMOP). The genes associated with OP and PMOP were retrieved from the DisGeNET database. Hub gene analysis and molecular pathway enrichment were performed via the Cytoscape plugins STRING, MCODE, CytoHubba, ClueGO and the web-based tool Enrichr. Twenty-eight (28) hub genes were identified, eight of which were transcription factors (HIF1A, JUN, TP53, ESR1, MYC, PPARG, RUNX2 and SOX9). Analysis of SNPs associated with hub genes via the gnomAD, I-Mutant2.0, MUpro, ConSurf and COACH servers revealed the substitution F201L in IL6 as the most deleterious. The IL6 protein was modeled in the SWISS-MODEL server and the substitution was analyzed via the YASARA FoldX plugin. A positive ΔΔG (1.936) of the F201L mutant indicates that the mutated structure is less stable than the wild-type structure is. Thirteen hub genes, including IL6 and the enriched molecular pathways were found to be profoundly involved in angiogenesis/endothelial function and immune signaling. Mechanical loading of bones through weight-bearing exercises can activate osteoblasts via mechanotransduction leading to increased bone formation. The present study suggests proper mechanical loading of bone as a preventive strategy for PMOP, by which angiogenesis and the immune status of the bone can be maintained. This in silico analysis could be used to understand the molecular etiology of OP and to develop novel therapeutic approaches., (© 2024. The Author(s).)

Objective: To investigate the prevalence of low bone mineral density (BMD) along with its possible risk factors in male Han Chinese patients with alcohol dependence (AD)., Methods: This retrospective, cross-sectional study included male patients with AD, classified into normal and low BMD groups according to bone densitometry T scores. Demographic and alcohol-related data, and routine laboratory parameters were compared between the two groups. Binary logistic regression analysis was employed to evaluate risk factors associated with low BMD, and correlations between the T-score and demographic, alcohol-related, and routine laboratory data were evaluated., Results: Among a total of 107 patients with AD included in the study, the prevalence of low BMD was 70.09% (75/107). Patients with low BMD were older, consumed more alcohol daily, and had higher lactate dehydrogenase (LDH) and lower Ca 2+ levels than patients with normal BMD. Regression analysis revealed that increased daily alcohol intake, low serum Ca 2+ levels, high serum LDH levels, and comorbid hypertension was related to low BMD in patients with AD. Further correlation analysis revealed a positive association between T-score and serum Ca 2+ levels., Conclusion: Increased daily alcohol intake, low serum Ca 2+ levels, high serum LDH levels, and comorbid hypertension may be risk factors for low BMD., Competing Interests: Declaration of conflicting interestThe authors declare that there is no conflict of interest.

Sarcopenia and osteoporosis do not develop independently. Rather, there is a close physiological and pathological relationship between them, often leading to the condition known as osteo-sarcopenia. This relationship also provides a basis for exploring the common mechanisms of muscle regeneration and bone remodeling. In the process of muscle and bone degeneration, inflammation is an important mechanism for disease progression, and the balance between regulatory T cells (Tregs) and Th17 cells is an important regulatory mechanism for immune equilibrium and inflammatory response. If the number and function of Tregs are impaired, coupled with an increase in the activity of Th17 cells, an imbalance between Tregs and Th17 cells occurs, leading to an increase in inflammatory response and an accumulation of tissue damage, and ultimately impairing myogenic and osteogenic functions. By regulating the Treg/Th17 cell immune balance, symptoms of muscle and bone degeneration can be improved.

Bone loss, commonly seen in osteoporosis, is a condition that entails a progressive decline of bone mineral density and microarchitecture, often seen in post-menopausal women. Bone loss has also been widely reported in astronauts exposed to a plethora of stressors and in patients with osteoporosis following radiotherapy for cancer. Studies on mechanisms are well documented but the causal connectivity of events to bone loss development remains incompletely understood. Herein, the adverse outcome pathway (AOP) framework was used to organize data and develop a qualitative AOP beginning from deposition of energy (the molecular initiating event) to bone loss (the adverse outcome). This qualitative AOP was developed in collaboration with bone loss research experts to aggregate relevant findings, supporting ongoing efforts to understand and mitigate human system risks associated with radiation exposures. A literature review was conducted to compile and evaluate the state of knowledge based on the modified Bradford Hill criteria. Following review of 2029 studies, an empirically supported AOP was developed, showing the progression to bone loss through many factors affecting the activities of bone-forming osteoblasts and bone-resorbing osteoclasts. The structural, functional, and quantitative basis of each proposed relationship was defined, for inference of causal changes between key events. Current knowledge and its gaps relating to dose-, time- and incidence-concordance across the key events were identified, as well as modulating factors that influence linkages. The new priorities for research informed by the AOP highlight areas for improvement to enable development of a quantitative AOP used to support risk assessment strategies for space travel or cancer radiotherapy., (© 2024 The Author(s). Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagenesis and Genomics Society.)

Competing Interests: ERSC receives research funding from Arnold Ventures. GRM's institution has received funding as part of him being a site principal investigator on a Janssen phase 3 trial, and GRM has received royalties for writing from MashupMD. SZ declares no competing interests.

Osteoporosis (OP) was long viewed as an inevitable process of aging, due to an imbalance between osteoclast bone resorbing and osteoblast bone formation function, leading to a negative balance in bone remodeling. This leads to low bone mass and increased bone fragility putting the patient at risk for fracture. While this view still holds, a better understanding disclosed that OP can occur at any age, as a comorbidity or a complication of many diseases and treatments. Differentiation, maturation, and function of osteoclasts and osteoblasts are affected by many factors from different morbidities: endocrine, metabolic, mechanical and inflammatory. Inflammatory diseases are often complicated by a generalized bone loss that subsequently leads to OP. Factors such as glucocorticoid treatment, immobilization, malnutrition, and insufficient intake of vitamin D play a role. However, the inflammatory process itself is involved and the resulting bone loss is termed immune-mediated bone loss. Experiments on animals and on humans, in addition to clinical studies, shed light on the role of inflammation in OP., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: The aim of this systematic review and meta-analysis was to analyze the factors associated of osteoporosis in patients with rheumatoid arthritis (RA) in China., Methods: PubMed, Embase, Web of Science, Cochrane Library, CINAHL, and four Chinese electronic databases were searched for observational studies without language restrictions that reported the factors associated of osteoporosis from inception to February 2023. A modified Newcastle-Ottawa Scale evaluated the risk of bias. Statistical heterogeneity among the included studies was analyzed using Cochran Q and I2 tests. Begg and Egger tests were used to assess the publication bias., Results: A total of 15 studies were finally included. The meta-analysis showed that 10 factors were grouped into three themes with statistical significance: (1) demographics theme: age ≥50 (odds ratio [OR] = 1.161; 95% CI, 1.111-1.231; p < 0.001), low body mass index (BMI) (OR = 1.248; 95% CI, 1.192-1.312; p < 0.001), female (OR = 5.174; 95% CI, 3.058-7.290; p < 0.001), and menopause (OR = 4.917; 95% CI, 1.558-15.523; I2 = 0.0%; p = 0.007); (2) RA-related factor theme: disease duration (OR = 1.083; 95% CI, 1.038-1.127; p < 0.001), and glucocorticoids (OR = 2.740; 95% CI, 2.000-3.750; p < 0.001); (3) relevant physiological indicators or scores theme: low 25(OH)D 3 (OR = 1.009; 95% CI, 1.003-1.016; p < 0.001), erythrocyte sedimentation rate (ESR) (OR = 1.489; 95% CI, 1.041-2.130; p = 0.029), high Disease Activity Score in 28 joints (DAS28) score (OR = 2.5991; 95% CI, 1.094-6.138; p < 0.001); and β-isomerized C-terminal telopeptide (β-CTx) (OR = 1.009; 95% CI, 1.003-1.016; p = 0.005)., Conclusion: Osteoporosis in patients with RA is associated with various factors. Therefore, patients with RA should be monitored in a timely manner and targeted interventions should be taken. In addition, further longitudinal studies are needed to confirm the direct link between multiple factors and osteoporosis., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Background: Periprosthetic bone loss is a well-known phenomenon following total hip arthroplasty (THA). However, the choice of drugs for prevention remains controversial. Therefore, the aim of this study was to determine the best drug to treat periprosthetic bone loss by comparing changes in bone mineral density (BMD) at different times after THA., Methods: A comprehensive search of five databases and two clinical trial registration platforms was undertaken from their inception through to August 31, 2023 to identify eligible randomized controlled trials. A Bayesian network meta-analysis (NMA) was carried out for calculating the standardized mean difference (SMD) and the surface under cumulative ranking curve (SUCRA) of the BMD in calcar (Gruen zone 7) at 6 months, 12 months, and 24 months and over., Results: Twenty-nine trials involving 1427 patients and 10 different interventions were included. The results demonstrated that at 6 months, denosumab had the highest ranking (SUCRA = 0.90), followed by alendronate (SUCRA = 0.76), and zoledronate (SUCRA = 0.73). At 12 months, clodronate ranked highest (SUCRA = 0.96), followed by denosumab (SUCRA = 0.84) and teriparatide (SUCRA = 0.82). For interventions with a duration of 24 months and over, denosumab had the highest SUCRA value (SUCRA = 0.96), followed by raloxifene (SUCRA = 0.90) and zoledronate (SUCRA = 0.75)., Conclusion: Investigating the existing body of evidence revealed that denosumab demonstrates potential as an intervention of superior efficacy at the three specifically examined time points. However, it remains crucial to conduct further research to confirm these findings and determine the most effective treatment strategy., (© 2024 The Author(s). Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.)

The clinical data analysis found that, compared with the traditional obesity index, the waist-weight ratio (WWR) has more advantages in predicting abnormal bone mineral density in subjects with type 2 diabetes. WWR may serve as a new predictive indicator for osteoporosis in T2DM patients., Purpose: This study was designed to explore the correlation between obesity-related indices and bone mineral density (BMD) and its influencing factors in type 2 diabetes mellitus (T2DM) patients., Methods: A total of 528 patients with type 2 diabetes were recruited. Glucose tolerance, insulin stimulation, and blood biochemical tests were conducted on all participants. All subjects underwent dual-energy X-ray bone density testing and were grouped based on the bone density results., Results: Compared with those in the normal BMD group, the waist-to-body weight ratio (WWR) and weight-adjusted-waist index (WWI) in the osteopenia and osteoporosis groups were significantly greater, while body mass index (BMI) was significantly lower (P < 0.05). The logistic regression results showed that the WWR, WWI, and BMI were independently correlated with abnormal BMD in T2DM patients (P < 0.05). WWR and the WWI were negatively correlated with the T-value of bone density in various parts of the body, while BMI was positively correlated with the T-value of bone density (P < 0.05). The area under the working characteristic curve (AUC) for T2DM patients with abnormal bone mass predicted by the WWR [0.806, 95% CI = (0.770-0.843), P < 0.001] was greater than that for patients with other obesity indicators, such as the WWI and BMI., Conclusion: We found a positive correlation between the WWR and bone density in T2DM patients. Compared with other obesity indicators, such as BMI and WWI, the WWR has a stronger discriminative ability for T2DM patients with abnormal bone density. Therefore, more attention should be given to the WWR in T2DM patients., (© 2024. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Objective: This study aimed to compare bone mineral density (BMD) values in patients with lumbar osteoarthritis (OA) with and without osteoporosis (OP). This study evaluated the effect of lumbar osteoarthritis in patients with osteoporosis on Dexa scores using the Lane and Wilke scale., Methods: A total of 51 individuals with OA, 20 with OP, and 31 without OP were included in the study. Lumbar osteoarthritis was assessed and recorded using the Lane and Wilke scale. BMD was measured by dual-energy X-ray absorptiometry (DEXA) at the waist and hip (femoral neck, lumbar vertebrae). Frax assessed the risk of osteoporosis and fracture risk., Results: The mean age of patients with OP was 68.1±8.2 years, and the mean age of patients without OP was 68.6±9.4 years. There was a significant decrease between the lumbar vertebrae and femoral neck BMD values of the two groups in favor of the osteoporosis group. The t-scores of the OP group were significantly lower (p = 0.045). All variables showed a statistically significant difference between the group with OP and those without OP (p<0.05). The median values of L1-L2, L2-L3, L3-L4, and total L1-L4 were higher in absolute value in the group with OP. In frax hip and frax primary osteoporosis, the median values were higher in the group with OP than in the group without OP (p = 0.023/p = 0.020). All L1-L2, L2-L3, and L3-L4 dexa parameters with and without OP were not significantly different between the groups according to the Lane and Wilke classification (p > 0.05)., Conclusion: There was no statistically significant difference between DEXA parameters in osteoporosis and non-osteoporosis patients with low back osteoarthritis (according to the Lane and Wilke classification)., Competing Interests: Declaration of conflicting interest The authors declared no conflicts of interest with respect to the authorship and/or publication of this article., (Copyright © 2024 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Background: The present study aimed to identify the risk factors of periprosthetic femoral fracture (PFF) after cementless total hip arthroplasty and rank them based on importance., Methods: The age, sex, body mass index (BMI), osteoporosis, canal flare index (CFI), canal bone ratio (CBR), canal calcar ratio (CCR), stem design, and stem canal fill ratio (P1, P2, P3, and P4) of the proximal femoral medullary cavity of 111 total hip arthroplasty patients who had PFF and 388 who did not have PFF were analyzed. Independent-samples student t-tests were used for continuous variables, and Chi-square tests were used for categorical variables. The importance rankings of influencing factors were assessed using a random forest algorithm. Dimensionally reduced variables were then incorporated into a binary logistic regression model to determine the PFF-related risk factors., Results: The mean age, BMI, CBR, CCR, and incidence of osteoporosis were higher in cases of PFF (all P < .001), while the mean CFI, P1, P2, P3, and P4 were lower in cases of PFF (P < .001, P = .033, P = .008, P < .001, and P < .001, respectively). Additionally, the stem design was also statistically associated with PFF (P < .001). Multivariate logistic regression revealed that advanced age, higher BMI, osteoporosis, stem design, lower CFI, higher CBR, higher CCR, lower P1, lower P2, lower P3, and lower P4 were the risk factors of PFF (P < .001, P < .001, P < .001, P < .001, P < .001, P = .010, P < .001, P = .002, P < .001, P < .001, and P = .007, respectively). The ranked importance of the risk factors for PFF was P3, CFI, osteoporosis, CBR, age, P4, P1, stem design, CCR, BMI, and P2., Conclusions: Lower P3, lower CFI, osteoporosis, higher CBR, advanced age, lower P4, lower P1, stem design, higher CCR, higher BMI, and lower P2 increased the risk of PFF., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: People with multiple sclerosis (PwMS) exhibit reduced bone mineral density (BMD) across several anatomical regions. Studies have indicated that PwMS are at a heightened risk of fractures due to decreased BMD and increased prevalence of osteopenia and osteoporosis. This study aimed to investigate the prevalence and risk of osteopenia, osteoporosis, and fracture among PwMS., Methods: Relevant studies were identified through comprehensive searches of databases (PubMed/MEDLINE, Scopus, Embase, and Web of Science) from January 1, 2000, to January 21, 2024. R software version 4.4.0 and random-effects models were employed to estimate the pooled prevalence, odds ratio (OR), and risk ratio (RR) of osteopenia, osteoporosis, and fracture among PwMS, along with their respective 95 % confidence intervals (CIs)., Results: From a total of 2039 articles, 51 studies with 1,503,785 PwMS met our inclusion criteria. The pooled prevalence of osteopenia, osteoporosis, and overall fracture among PwMS was 41.41 % (95 % CI: 36.14% to 46.69 %, I 2 =97 %), 14.21 % (95 % CI: 10.75 % to 17.68 %, I 2 =99 %), and 12.84 % (95 % CI: 8.49 % to 17.19 %, I 2 = 100 %), respectively. The likelihood of osteopenia (OR=2.02, 95 % CI: 1.46 to 2.8, p-value<0.01, I 2 =17 %) and osteoporosis (OR=1.71, 95 % CI: 1.27 to 2.31, p-value<0.01, I 2 =74 %), as well as the probability of overall fracture (RR=1.86, 95 % CI: 1.61 to 2.14, p-value<0.01, I 2 =74 %) were significantly higher in PwMS than healthy controls (HCs)., Conclusion: PwMS were at a substantially increased risk of developing osteopenia (2-fold), osteoporosis (1.7-fold), and overall fractures (1.9-fold). Well-designed studies are needed to explore these associations further., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sarcopenic obesity (SO) and osteoporosis (OP) are associated with aging and obesity. The pathogenesis of SO is complex, including glucolipid and skeletal muscle metabolic disorders caused by inflammation, insulin resistance, and other factors. Growing evidence links muscle damage to bone loss. Muscle-lipid metabolism disorders of SO disrupt the balance between bone formation and bone resorption, increasing the risk of OP. Conversely, bones also play a role in fat and muscle metabolism. In the context of aging and obesity, the comprehensive review focuses on the effects of mechanical stimulation, mesenchymal stem cells (MSCs), chronic inflammation, myokines, and adipokines on musculoskeletal, at the same time, the impact of osteokines on muscle-lipid metabolism were also analyzed. So far, exercise combined with diet therapy is the most effective strategy for increasing musculoskeletal mass. A holistic treatment of musculoskeletal diseases is still in the preliminary exploration stage. Therefore, this article aims to improve the understanding of musculoskeletal -fat interactions in SO and OP, explores targets that can provide holistic treatment for SO combined with OP, and discusses current limitations and challenges. We hope to provide relevant ideas for developing specific therapies and improving disease prognosis in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: This comprehensive review discusses the complex relationship between Alzheimer's disease (AD) and osteoporosis, two conditions that are prevalent in the aging population and result in adverse complications on quality of life. The purpose of this review is to succinctly elucidate the many commonalities between the two conditions, including shared pathways, inflammatory and oxidative mechanisms, and hormonal deficiencies., Recent Findings: AD and osteoporosis share many aspects of their respective disease-defining pathophysiology. These commonalities include amyloid beta deposition, the Wnt/β-catenin signaling pathway, and estrogen deficiency. The shared mechanisms and risk factors associated with AD and osteoporosis result in a large percentage of patients that develop both diseases. Previous literature has established that the progression of AD increases the risk of sustaining a fracture. Recent findings demonstrate that the reverse may also be true, suggesting that a fracture early in the life course can predispose one to developing AD due to the activation of these shared mechanisms. The discovery of these commonalities further guides the development of novel therapeutics in which both conditions are targeted. This detailed review delves into the commonalities between AD and osteoporosis to uncover the shared players that bring these two seemingly unrelated conditions together. The discussion throughout this review ultimately posits that the occurrence of fractures and the mechanism behind fracture healing can predispose one to developing AD later on in life, similar to how AD patients are at an increased risk of developing fractures. By focusing on the shared mechanisms between AD and osteoporosis, one can better understand the conditions individually and as a unit, thus informing therapeutic approaches and further research. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Most periprosthetic fractures following total hip arthroplasty (THA) are fragility fractures that qualify patients for osteoporosis diagnoses. However, it remains unknown how many patients were diagnosed who had osteoporosis before injury or received the proper evaluation, diagnosis, and treatment after injury., Methods: We identified 171 Vancouver B2 (109) and B3 (62) periprosthetic femur fractures treated with a modular fluted tapered stem from 2000 to 2018 at 1 institution. The mean patient age was 75 years (range, 35 to 94), 50% were women, and the mean body mass index was 29 (range, 17 to 60). We identified patients who had osteoporosis or osteopenia diagnoses, a fracture risk assessment tool (FRAX), bone mineral density (BMD) testing, an endocrinology consult, and osteoporosis medications. Age-appropriate BMD testing was defined as no later than 1 year after the recommended ages of 65 (women) or 70 years (men). The mean follow-up was 11 years (range, 4 to 21)., Results: Falls from standing height caused 94% of fractures and thus, by definition, qualified as osteoporosis-defining events. The prevalence of osteoporosis diagnosis increased from 20% before periprosthetic fracture to 39% after (P < .001). The prevalence of osteopenia diagnosis increased from 13% before the fracture to 24% after (P < .001). The prevalence of either diagnosis increased from 24% before fracture to 44% after (P < .001). No patients had documented FRAX scores before fracture, and only 2% had scores after. The prevalence of BMD testing was 21% before fracture and 22% after (P = .88). By the end of the final follow-up, only 16% had received age-appropriate BMD testing. The proportion of patients who had endocrinology consults increased from 6% before the fracture to 25% after (P < .001). The proportion on bisphosphonate therapy was 19% before fracture and 25% after (P = .08)., Conclusions: Although most periprosthetic fractures following THA are fragility fractures that qualify patients for osteoporosis diagnoses, there remain major gaps in diagnosis, screening, endocrinology follow-up, and treatment. Like nonarthroplasty fragility fractures, a systematic approach is needed after periprosthetic fractures., Level of Evidence: Level III, retrospective cohort study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Diabetic peripheral neuropathy (DPN) and diabetic osteoporosis (DOP) are conditions that significantly impact the quality of life of patients worldwide. Rehmanniae Radix Preparata, a component of traditional Chinese medicine with a history spanning thousands of years, has been utilized in the treatment of osteoporosis and diabetes. Specifically, Rehmannia glutinosa Libosch polysaccharide (RGP), a key bioactive compound of Rehmanniae Radix Preparata, has demonstrated immune-modulating properties and beneficial effects on hyperglycemia, hyperlipidemia, and vascular inflammation in diabetic mice. Despite these known actions, the precise mechanisms of RGP in addressing DOP and DPN remain unclear. Our study aimed to explore the impact of RGP on osteoporosis and peripheral neuropathic pain in diabetic mice induced by streptozotocin (STZ). The findings revealed that RGP not only improved hyperglycemia and osteoporosis in STZ-induced diabetic mice but also enhanced osteogenesis, insulin production, and nerve health. Specifically, RGP alleviated distal pain, improved nerve conduction velocity, nerve fiber integrity, and immune cell balance in the spleen. Mechanistically, RGP was found to upregulate HDAC6 mRNA expression in regulatory T cells, potentially shedding light on novel pathways for preventing DOP and DPN. These results offer promising insights for the development of new therapeutic approaches for diabetic complications., Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To investigate whether a diagnosis of precancer poor bone mineral density (PBMD) is associated with higher risk of urological cancer bone metastasis., Methods: The PearlDiver Database was utilized to conduct a retrospective, propensity-matched cohort analysis of adult patients diagnosed with kidney, bladder, prostate, and testicular cancer with and without a prior diagnosis of PBMD, defined as osteopenia or osteoporosis. Unadjusted and adjusted odds ratios (OR) and 95% confidence intervals are used to compare the rate of newly diagnosed bone metastases between 6months and 3years of the initial cancer diagnosis between the experimental and control cohorts., Results: Among 685,066 patients with urological cancers, precancer PBMD was associated with increased odds of bone metastasis at various time periods (1week, 6months, 1, 2, and 3years). The strongest association was appreciated within 1week of cancer diagnosis (kidney: adjusted odds ratio [aOR], 2.37, P <.001; bladder: [aOR], 2.37, P <.001; prostate: [aOR], 2.84, P <.001; testicular: [aOR], 4.45, P <.001). Bisphosphonates were associated with reduced risk of kidney ([aOR], 0.46, P <.001), bladder ([aOR], 0.61, P <.001), and prostate ([aOR], 0.66, P <.001) cancer bone metastasis., Conclusion: Our findings suggest urology patients with PBMD may be predisposed to forming bone metastases as well as presenting with metastatic disease at time of cancer diagnosis. As such, further studies are needed to elucidate whether PBMD plays a role in bone tropism and whether bone health pertains to prolonging bone-free metastasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Abnormalities in osteoclastic generation or activity disrupt bone homeostasis and are highly involved in many pathologic bone-related diseases, including rheumatoid arthritis, osteopetrosis, and osteoporosis. Control of osteoclast-mediated bone resorption is crucial for treating these bone diseases. However, the mechanisms of control of osteoclastogenesis are incompletely understood. In this study, we identified that inosine 5'-monophosphate dehydrogenase type II (Impdh2) positively regulates bone resorption. By histomorphometric analysis, Impdh2 deletion in mouse myeloid lineage cells (Impdh2 LysM-/- mice) showed a high bone mass due to the reduced osteoclast number. qPCR and western blotting results demonstrated that the expression of osteoclast marker genes, including Nfatc1, Ctsk, Calcr, Acp5, Dcstamp, and Atp6v0d2, was significantly decreased in the Impdh2 LysM-/- mice. Furthermore, the Impdh inhibitor MPA treatment inhibited osteoclast differentiation and induced Impdh2-cytoophidia formation. The ability of osteoclast differentiation was recovered after MPA deprivation. Interestingly, genome-wide analysis revealed that the osteoclastic mitochondrial biogenesis and functions, such as oxidative phosphorylation, were impaired in the Impdh2 LysM-/- mice. Moreover, the deletion of Impdh2 alleviated ovariectomy-induced bone loss. In conclusion, our findings revealed a previously unrecognized function of Impdh2, suggesting that Impdh2-mediated mechanisms represent therapeutic targets for osteolytic diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Considering the prevalence of type 2 diabetes (T2D), osteoporosis should be considered a serious complication. However, an effective tool for the assessment of low bone mass mineral density (BMD) in T2D patients is not currently available. Therefore, the aim of our study was to establish a simple-to-use risk assessment tool by exploring risk factors for low BMD in T2D patients., Methods: This study included 436 patients with a low BMD and 381 patients with a normal BMD. Multiple logistic regression analysis was performed to evaluate risk factors for low BMD in T2D patients. A nomogram was then developed from these results. A receiver operating characteristic (ROC) curve, calibration plot, and goodness-of-fit test were used to validate the nomogram. The clinical utility of the nomogram was also assessed., Results: Multivariate logistic regression indicated that age, sex, education, body mass index (BMI), fasting C-peptide, high-density cholesterol (HDL), alkaline phosphatase (ALP), estimated glomerular filtration rate (eGFR), and type I collagen carboxy terminal peptide (S-CTX) were independent predictors for low BMD in T2D patients. The nomogram was developed from these variables using both the unadjusted area under the curve (AUC) and the bootstrap-corrected AUC (0.828). Calibration plots and the goodness-of-fit test demonstrated that the nomogram was well calibrated., Conclusions: The nomogram-illustrated model can be used by clinicians to easily predict the risk of low BMD in T2D patients. Our study also revealed that common factors are independent predictors of low BMD risk. Our results provide a new strategy for the prediction, investigation, and facilitation of low BMD in T2D patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Individuals with spinal cord injury (SCI) experience a notable decrease in bone mass below the level of injury. While studies have primarily focused on the acute phase with a small cohort, this study aimed to provide comprehensive insights into bone loss patterns over time. A total of 427 individuals with SCI who underwent dual-energy X-ray absorptiometry (DXA) testing at the Korea National Rehabilitation Center (2010-2021) were included and analyzed by categorizing the DXA results into 1-year intervals based on postinjury duration. Demographic characteristics (age, sex, body mass index, and alcohol/smoking history) and SCI-related factors (etiology, severity, extent of injury, motor score, and Korean Spinal Cord Independence Measure 3rd edition) were collected and analyzed. Linear mixed models and Bonferroni post hoc tests were performed to assess temporal changes in bone mass and linear regression analysis to assess the associations between possible risk factors and bone loss. DXA results revealed that substantial annual bone loss occurred in the total hip site up to 3 years postinjury and in the femoral neck site up to 2 years postinjury. Old age, women, and low body mass index were significant risk factors for bone loss in the SCI population. Additionally, during the chronic phase, lower Korean Spinal Cord Independence Measure 3rd edition scores were associated with low bone mass. Significant annual bone loss in the hip region persists for up to 3 years postinjury in individuals with SCI. While prioritizing the risk factors for osteoporosis commonly used in the general population, applying the SCIM score in the chronic phase may provide additional information on bone loss risk., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Osteoporosis (OP) is characterized by decreased bone mineral density (BMD) and increased fracture risk, poses a significant global health burden. Recent research has shed light on the bidirectional relationship between gut microbiota (GM) and bone health, presenting a novel avenue for understanding OP pathogenesis and developing targeted therapeutic interventions. This review provides a comprehensive overview of the GM-bone axis, exploring the impact of GM on OP development and management. We elucidate established risk factors and pathogenesis of OP, delve into the diversity and functional changes of GM in OP. Furthermore, we examine experimental evidence and clinical observations linking alterations in GM composition or function with variations in BMD and fracture risk. Mechanistic insights into microbial mediators of bone health, such as microbial metabolites and products, are discussed. Therapeutic implications, including GM-targeted interventions and dietary strategies, are also explored. Finally, we identify future research directions and challenges in translating these findings into clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hao, Yan, Huang and Li.)

Introduction and Objective: The medical records were examined of 222 patients of the Osteoporosis Treatment Clinic at the Central Clinical Hospital of the Medical University of Łódź, Poland. The influence was analyzed of 27 clinical risk factors on the occurrence of low-energetic fractures in this population. The aim of the research was to find possible dependencies between different risk factors, and the actual fractures that were recorded in the database., Material and Methods: For each risk factor and for each category (e.g., patients with diabetes and patients without diabetes), the percentage was computed of patients who had incidents osteoporotic fractures, and the percentage of those without fractures. Student's t-test and Pearson's chi-squared test were used to find statistically significant risk factors., Results: Statistically significant risk factors were found: age, chronic kidney disease, T-scores of the femoral neck and T-score of the lumbar spine, serum phosphate levels, FRAX-BMD, FRAX-BMI, and the type of diet., Conclusions: Some observations concerning the influence of individual risk factors on the occurrence of fractures are consistent with those presented in the literature. However, it was also noticed that the patients with hyperthyroidism, rheumatic diseases, diabetes, cancer or gastrointestinal diseases, had a smaller percentage of fractures than the patients who did not have these diseases. This may be explained by the small number of those having these diseases, or by the fact that they had already received appropriate treatment.

A cross-sectional study was performed in healthy adults (mean age 28 y, 67% women) whose habitual diet was an omnivore, lacto-ovo vegetarian, or vegan diet. The total sample ( n = 297) was divided into two groups according to the parathormone (PTH) cut-off value of 65 pg/mL of either normal-PTH ( n = 228) or high-PTH ( n = 69). Vitamin D status (25-hydroxycholecalciferol, 25-OHD), PTH, and bone formation (bone alkaline phosphatase, BAP) and bone resorption (N-telopeptides of type I collagen, NTx) markers were determined. Hematocrit, erythrocytes, hemoglobin, platelets, serum iron, serum transferrin, transferrin saturation, and serum ferritin were also measured. In the total sample, 25-OHD and PTH were negatively correlated, and all subjects with high PTH presented vitamin D insufficiency (25-OHD < 75 nmol/L). High bone remodeling was observed in the high-PTH group, with significantly higher NTx and marginally higher BAP compared to the normal-PTH group. Hematocrit and ferritin were significantly lower in the high-PTH compared to the normal-PTH group. However, serum iron was higher in the high-PTH group, which was only observed for the lacto-ovo vegetarian and vegan subjects. It is concluded that both low vitamin D and low iron status are associated with elevated PTH and bone resorption, more in vegetarians than omnivores, which is in line with the hypothesis that chronic iron deficiency in adulthood mainly predisposes to osteoporosis in postmenopausal women and the elderly.

Treatment for breast cancer, including endocrine therapies, can contribute to bone loss and increase the risk of osteoporosis and fractures. Management of bone health in patients with cancer is often coordinated between oncologists, endocrinologists, and primary care physicians. In this article, we discuss the approach to screening for fracture risk among patients initiating treatments for breast cancer and recommendations for lifestyle modifications to optimize bone health. We will review 3 indications for pharmacologic bone-targeted therapies: prevention of cancer treatment-induced bone loss, adjuvant therapy to reduce recurrence, and management of bone metastases., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Diabetic neuropathy is one of the most common diabetes mellitus complications associated with mediocalcinosis of the lower extremities, a significant decrease in feet bone mineral density, and a high incidence of cardiovascular disease. In most cases, calcium-phosphorus metabolism changes occur in patients with diabetic neuroarthropathy, or Charcot foot, when we can observe feet local osteoporosis, which in 90% of cases associated with a vessel's calcification of the lower extremities in the majority of diabetes population. A large number of studies presented literature have demonstrated that patients with Charcot foot can have accelerated bone metabolism and increased bone resorption. Patients with Charcot foot often have crucial abnormalities in the calcium-phosphorus parameters, bone metabolism, and levels of vitamin D and its metabolites. In addition, the duration of diabetes mellitus, the degree of its compensation widely affects the development of its micro- and macrovascular complications, which could also accelerate the development of mineral and bone disorders in these types of patients. Multifactorial pathogenesis of these disorders complicates the management of patients with a long and complicated course of diabetes mellitus. This review discusses the peculiarities of vitamin D metabolism, the importance of timely diagnosis in phosphorus-calcium disorders, and the specifics of therapy in these patients. Special attention is paid to the timely diagnosis of the Charcot's foots acute stage based on the bone marrow edema by MRI evaluation and the possibility of reducing the immobilization period.

The intricate link between childhood obesity and adult osteoporosis has been a subject of numerous clinical inquiries, yet the genetic underpinnings of this association remain enigmatic. Our research aims to unravel the association between adult osteoporosis and childhood obesity using genome-wide association study data for Mendelian randomization (MR) analysis. Utilizing a pool of single-nucleotide polymorphism data associated with childhood obesity obtained from a previous genome-wide association study report involving a study population of 13,848 people in Europe, alongside data of adult osteoporosis sourced from Neale Lab (5266 cases and 331,893 controls). Various methods for MR were used in our research, including weighted mode, simple mode, weighted median, MR-Egger, and the inverse-variance weighted (IVW). We also used Cochran Q test of IVW to assess for heterogeneity, MR-Egger intercept and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analysis for pleiotropy, and leave-one-out analysis for the result stability. The instrumental variables associated with 11 single-nucleotide polymorphisms were selected. MR analyses unveiled a noteworthy link between genetically forecasted childhood obesity and the onset of adult osteoporosis based on the odds ratio, 95% confidence interval, and P-value from the results of IVW, MR-Egger, weighted median: simple mode, and weighted mode analyses. No significant heterogeneity was found by the assessment using MR-Egger and IVW. Similarly, there was no indication of pleiotropy based on the MR-PRESSO and MR-Egger analyses. Leave-one-out analysis confirmed the stability of the results. Our research suggests that childhood obesity, as predicted by genetic factors, may pose a significant risk for the development of osteoporosis in adulthood., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Alveolar bone loss in elderly populations is highly prevalent and increases the risk of tooth loss, gum disease susceptibility, and facial deformity. Unfortunately, there are very limited treatment options available. Here, we developed a bone-targeted gene therapy that reverses alveolar bone loss in patients with osteoporosis by targeting the adaptor protein Schnurri-3 (SHN3). SHN3 is a promising therapeutic target for alveolar bone regeneration, because SHN3 expression is elevated in the mandible tissues of humans and mice with osteoporosis while deletion of SHN3 in mice greatly increases alveolar bone and tooth dentin mass. We used a bone-targeted recombinant adeno-associated virus (rAAV) carrying an artificial microRNA (miRNA) that silences SHN3 expression to restore alveolar bone loss in mouse models of both postmenopausal and senile osteoporosis by enhancing WNT signaling and osteoblast function. In addition, rAAV-mediated silencing of SHN3 enhanced bone formation and collagen production of human skeletal organoids in xenograft mice. Finally, rAAV expression in the mandible was tightly controlled via liver- and heart-specific miRNA-mediated repression or via a vibration-inducible mechanism. Collectively, our results demonstrate that AAV-based bone anabolic gene therapy is a promising strategy to treat alveolar bone loss in osteoporosis., Competing Interests: Declaration of interests G.G. and J.H.S. have submitted a patent application concerning the methodology described in this study. G.G. and J.H.S. are scientific co-founders of AAVAA Therapeutics and hold equity in this company. G.G. is also a scientific co-founder of Voyager Therapeutics, Adrenas Therapeutics, and Aspa Therapeutics, and holds equity in these companies. G.G. is an inventor on patents with potential royalties licensed to Voyager Therapeutics, Adrenas Therapeutics, Aspa Therapeutics, and other biopharmaceutical companies., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Previous studies have shown that inflammatory bowel disease (IBD) is associated with osteoporosis (OP) and bone mineral density (BMD), but the underlying genetic mechanisms are unclear. Our study wanted to explore the genetic and causal relationship between IBD and OP., Materials and Methods: Based on large-scale genome-wide association summary statistics and individual-level datasets (i.e., the UK Biobank), this study performed linkage disequilibrium score regression (LDSC), pleiotropic analysis under the composite null hypothesis (PLACO), and Mendelian randomization (MR) analyses to explore the genetic association, the pleiotropic genes and the causal relationship between IBD and BMD., Results: LDSC revealed significant genetic correlations between IBD and BMD (e.g., forearm BMD (rg = -0.3479, P = 0.019) and femoral neck BMD (rg = -0.1335, P = 0.0307). PLACO identified 14 overlapping pleiotropic loci, 1 shared risk gene (CDYL), and multiple shared pathways, revealing possible mechanisms for IBD and OP. MR analysis demonstrated a causal association between IBD and BMD., Conclusions: Our study indicates that IBD may increase the risk of OP and reveals a complex genetic mechanism linking IBD and the risk of osteoporosis, which has important implications for diagnosing and treating IBD and OP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Early-onset osteoporosis is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT). It remains unknown if physical training can improve bone formation in these patients, as the transplantation procedure may cause sustained dysregulation of the bone-forming osteoblast progenitor cells., Objective: We aimed to explore the effect of resistance training on bone remodeling in long-term survivors of pediatric HSCT., Procedure: In this prospective, controlled intervention study, we included seven HSCT survivors and 15 age- and sex-matched healthy controls. The participants completed a 12-week heavy load, lower extremity resistance training intervention with three weekly sessions. We measured fasting serum levels of the bone formation marker "N-terminal propeptide of type I procollagen" (P1NP), and the bone resorption marker "C-terminal telopeptide of type I collagen" (CTX). The hypothesis was planned before data collection began. The trial was registered at Clinicaltrials.gov before including the first participant, with trial registration no. NCT04922970., Results: Resistance training led to significantly increased levels of fasting P1NP in both patients (from 57.62 to 114.99 ng/mL, p = .03) and controls (from 66.02 to 104.62 ng/mL, p < .001). No significant changes in fasting CTX levels were observed., Conclusions: Despite previous high-dose cytotoxic therapy, long-term survivors of pediatric HSCT respond to resistance training with improvement of bone formation, comparable to that of healthy controls. This suggests that resistance training might be a promising non-pharmacological approach to prevent the early decline in bone mass, and should be considered as part of a follow-up program to counteract long-term sequela after pediatric HSCT., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

For women under age 65, varying recommendations and the need to apply clinical risk calculators can lead to underscreening for osteoporosis. The resulting undertreatment may lead to a risk of osteoporotic fractures with significant morbidity and impact on functional status. Factors that must be considered when deciding to screen a woman under age 65 include a history of fragility fractures, race, family history, body mass index, smoking, high alcohol use, and secondary causes of osteoporosis. Secondary causes of osteoporosis are much more common in younger women. These include common conditions such as glucocorticoid use, hyperthyroidism, hypogonadism, chronic kidney disease, diabetes, anticonvulsant use, rheumatoid arthritis, malabsorption, and a history of anorexia nervosa. The reasons why these conditions confer an increased risk of osteoporosis are discussed. Recommendations are provided for the clinician to be aware of when screening women under age 65 for osteoporosis and initiating treatment when indicated., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This article reviews bone metabolism, bone mass, and bone structure changes expected during and after pregnancy and lactation, as well as the condition of pregnancy and lactation-associated osteoporosis (PLO)-a presentation with fragility fracture(s) in the context of these physiologic changes. Clinical implications of physiologic bone changes will be addressed, as will specific management considerations that apply to premenopausal women with PLO., Competing Interests: Disclosure The author has received research funding from Amgen and Eli Lilly., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Calcium supplements are commonly prescribed to prevent fractures in patients with osteoporosis. Nonetheless, they are generally eschewed in hemodialysis patients because they increase vascular calcification and induce cardiovascular disease. This retrospective cohort study aimed to investigate the effect of calcium-based phosphate binders (CBPB) on bone mineral density (BMD) in hemodialysis patients., Methods: Outpatients on dialysis who underwent BMD measurement from January to December 2017, whose data on BMD trends and CBPB administration were recorded over the next 4 years, were enrolled. Patients receiving anti-osteoporotic medications were excluded. The association between the presence and duration of CBPB administration and changes in BMD was evaluated., Results: The femoral neck's BMD decreased from 0.836 g/cm 2 (0.702-0.952) to 0.764 g/cm 2 (0.636-0.896) (P < 0.001) in the non-CBPB group (patients who never received CBPB over 4 years, n = 32). The CBPB group (n = 56) exhibited only a minute decrease from 0.833 g/cm 2 (0.736-0.965) to 0.824 g/cm 2 (0.706-0.939) (P = 0.004). Multivariate linear regression analysis revealed better BMD maintenance in the CBPB group [β-coefficient (95% CI): 0.033 (0.001-0.065); P = 0.046] than in the non-CBPB group. Additionally, the prolonged-CBPB administration group showed superior BMD preservation [β-coefficient (95% CI): 0.038 (0.001-0.076); P = 0.042]., Conclusion: CBPB administration may be associated with BMD maintenance., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Introduction: Patients undergoing radical cystectomy with urinary diversions (UD) are at increased risk of bone fractures compared to the general population. Although a loss of bone mineral density (BMD) has been described in patients with UD, we still do not know with certainty why these patients follow this tendency., Objective: We performed a systematic review of the available literature to analyze the prevalence of osteoporosis and bone alterations in patients with ileal UD and the possible associated risk factors., Evidence Acquisition: We systematically searched PubMed® and Cochrane Library for original articles published before December 2022 according to PRISMA guidelines., Evidence Synthesis: A total of 394 publications were identified. We selected 12 studies that met the inclusion criteria with 496 patients included. Six of the twelve studies showed decreased BMD values. Prevalence of osteoporosis was specified in three articles, with values ranging ​​from 0% to 36%. Risk factors such as age, sex, body mass index, metabolic acidosis and renal function appear to have an impact on bone tissue reduction, while type of UD, follow-up, 25-hydroxyvitamin D and parathormone had less evidence or contradictory data. The heterogeneity of the studies analyzed could led to interpretation bias., Conclusions: UD are associated with multiple risk factors for osteoporosis and bone fractures. Identifying patients at highest risk and establishing diagnostic protocols in routine clinical practice are essential to reduce the risk of fractures and the resulting complications., (Copyright © 2023 AEU. Published by Elsevier España, S.L.U. All rights reserved.)

Osteoporosis is a worldwide common disease characterised by reduced bone mass and increased risk of fractures.Many genetic variants are associated with the disease, but they account for only a small percentage of variance in individual bone mineral density and fragility fracture risk. Only recently have researchers recognised the role of a broad variety of environmental factors in the pathogenesis of osteoporosis, which has led to a further step: how genetic and environmental factors can interact, which is the next frontier in research on bone fragility.