Bone loss and fracture in people with multiple sclerosis: A systematic review and meta-analysis.

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 %, I2=97 %), 14.21 % (95 % CI: 10.75 % to 17.68 %, I2=99 %), and 12.84 % (95 % CI: 8.49 % to 17.19 %, I2 = 100 %), respectively. The likelihood of osteopenia (OR=2.02, 95 % CI: 1.46 to 2.8, p-value<0.01, I2=17 %) and osteoporosis (OR=1.71, 95 % CI: 1.27 to 2.31, p-value<0.01, I2=74 %), as well as the probability of overall fracture (RR=1.86, 95 % CI: 1.61 to 2.14, p-value<0.01, I2=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.

Associations between new obesity indices and abnormal bone density in type 2 diabetes mellitus patients.

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.

Artificial intelligence-enhanced opportunistic screening of osteoporosis in CT scan: a scoping Review.

PURPOSE: This scoping review aimed to assess the current research on artificial intelligence (AI)--enhanced opportunistic screening approaches for stratifying osteoporosis and osteopenia risk by evaluating vertebral trabecular bone structure in CT scans. METHODS: PubMed, Scopus, and Web of Science databases were systematically searched for studies published between 2018 and December 2023. Inclusion criteria encompassed articles focusing on AI techniques for classifying osteoporosis/osteopenia or determining bone mineral density using CT scans of vertebral bodies. Data extraction included study characteristics, methodologies, and key findings. RESULTS: Fourteen studies met the inclusion criteria. Three main approaches were identified: fully automated deep learning solutions, hybrid approaches combining deep learning and conventional machine learning, and non-automated solutions using manual segmentation followed by AI analysis. Studies demonstrated high accuracy in bone mineral density prediction (86-96%) and classification of normal versus osteoporotic subjects (AUC 0.927-0.984). However, significant heterogeneity was observed in methodologies, workflows, and ground truth selection. CONCLUSIONS: The review highlights AI's promising potential in enhancing opportunistic screening for osteoporosis using CT scans. While the field is still in its early stages, with most solutions at the proof-of-concept phase, the evidence supports increased efforts to incorporate AI into radiologic workflows. Addressing knowledge gaps, such as standardizing benchmarks and increasing external validation, will be crucial for advancing the clinical application of these AI-enhanced screening methods. Integration of such technologies could lead to improved early detection of osteoporotic conditions at a low economic cost.

Latent metabolic bone disease, skeletal dysplasia and other conditions related to low bone formation among 38 patients with subtrochanteric femoral fractures: a retrospective observational study.

Subtrochanteric femoral fracture is rare and intractable due to the possible association with low bone formation. Retrospective analysis of 38 patients with subtrochanteric femoral fractures revealed that four patients suffered from disorders related to low bone formation and there were specific treatments for two of them. PURPOSE: The main aim of this study was to detect latent metabolic bone diseases and skeletal dysplasia associated with low bone formation among patients with morphologic atypical femoral fracture (AFF). A second aim was to evaluate the frequency of recognized risk factors, such as antiresorptive agents, glucocorticoids, and age. METHODS: Clinical information was retrospectively analyzed among 38 Japanese patients who were admitted to the Department of Orthopedic Surgery and Spinal Surgery and the Division of Emergency and Critical Care Medicine at the University of Tokyo Hospital with diagnoses of subtrochanteric fractures between February 2012 and March 2022. RESULTS: Among 38 patients (including 30 females), 21 patients were aged 75 and over. Ten patients had past oral glucocorticoid use, and 18 had past antiresorptive agent use. Two patients were diagnosed with hypophosphatemic osteomalacia after the development of fractures. One patient was suspected to be a carrier of a loss-of-function variant of alkaline phosphatase, biomineralization associated (ALPL), and one other patient had previously been genetically diagnosed with pycnodysostosis. Among four patients with a diagnosis or suspicion of these metabolic bone diseases and skeletal dysplasia, four had past clinical fractures, two had past subtrochanteric femoral fractures, and two had subtrochanteric femoral fractures on both sides. CONCLUSION: If clinicians encounter patients with morphologic AFF, latent diseases related to low bone formation should be carefully differentiated because appropriate treatment may prevent delayed union and recurrent fractures. Additionally, it may be desirable to exclude these bone diseases in advance before initiating long-term use of antiresorptive agents in osteoporotic patients by screening with serum alkaline phosphatase levels to reduce the risk of morphologic AFF.

Gamified Exercise with Kinect: Can Kinect-Based Virtual Reality Training Improve Physical Performance and Quality of Life in Postmenopausal Women with Osteopenia? A Randomized Controlled Trial.

BACKGROUND: Osteopenia, caused by estrogen deficiency in postmenopausal women (PMW), lowers Bone Mineral Density (BMD) and increases bone fragility. It affects about half of older women's social and physical health. PMW experience pain and disability, impacting their health-related Quality of Life (QoL) and function. This study aimed to determine the effects of Kinect-based Virtual Reality Training (VRT) on physical performance and QoL in PMW with osteopenia. METHODOLOGY: The study was a prospective, two-arm, parallel-design, randomized controlled trial. Fifty-two participants were recruited in the trial, with 26 randomly assigned to each group. The experimental group received Kinect-based VRT thrice a week for 24 weeks, each lasting 45 min. Both groups were directed to participate in a 30-min walk outside every day. Physical performance was measured by the Time Up and Go Test (TUG), Functional Reach Test (FRT), Five Times Sit to Stand Test (FTSST), Modified Sit and Reach Test (MSRT), Dynamic Hand Grip Strength (DHGS), Non-Dynamic Hand Grip Strength (NDHGS), BORG Score and Dyspnea Index. Escala de Calidad de vida Osteoporosis (ECOS-16) questionnaire measured QoL. Both physical performance and QoL measures were assessed at baseline, after 12 weeks, and after 24 weeks. Data were analyzed on SPSS 25. RESULTS: The mean age of the PMW participants was 58.00 ± 5.52 years. In within-group comparison, all outcome variables (TUG, FRT, FTSST, MSRT, DHGS, NDHGS, BORG Score, Dyspnea, and ECOS-16) showed significant improvements (p < 0.001) from baseline at both the 12th and 24th weeks and between baseline and the 24th week in the experimental group. In the control group, all outcome variables except FRT (12th week to 24th week) showed statistically significant improvements (p < 0.001) from baseline at both the 12th and 24th weeks and between baseline and the 24th week. In between-group comparison, the experimental group demonstrated more significant improvements in most outcome variables at all points than the control group (p < 0.001), indicating the positive additional effects of Kinect-based VRT. CONCLUSION: The study concludes that physical performance and QoL measures were improved in both the experimental and control groups. However, in the group comparison, these variables showed better results in the experimental group. Thus, Kinect-based VRT is an alternative and feasible intervention to improve physical performance and QoL in PMW with osteopenia. This novel approach may be widely applicable in upcoming studies, considering the increasing interest in virtual reality-based therapy for rehabilitation.

Association between socioeconomic deprivation and bone health status in the UK biobank cohort participants.

The effect of deprivation on total bone health status has not been well defined. We examined the relationship between socioeconomic deprivation and poor bone health and falls and we found a significant association. The finding could be beneficial for current public health strategies to minimise disparities in bone health. PURPOSE: Socioeconomic deprivation is associated with many illnesses including increased fracture incidence in older people. However, the effect of deprivation on total bone health status has not been well defined. To examine the relationship between socioeconomic deprivation and poor bone health and falls, we conducted a cross-sectional study using baseline measures from the United Kingdom (UK) Biobank cohort comprising 502,682 participants aged 40-69 years at recruitment during 2006-2010. METHOD: We examined four outcomes: 1) low bone mineral density/osteopenia, 2) fall in last year, 3) fracture in the last five years, and 4) fracture from a simple fall in the last five years. To measure socioeconomic deprivation, we used the Townsend index of the participant's residential postcode. RESULTS: At baseline, 29% of participants had low bone density (T-score of heel < -1 standard deviation), 20% reported a fall in the previous year, and 10% reported a fracture in the previous five years. Among participants experiencing a fracture, 60% reported the cause as a simple fall. In the multivariable logistic regression model after controlling for other covariates, the odds of a fall, fracture in the last five years, fractures from simple fall, and osteopenia were respectively 1.46 times (95% confidence interval [CI] 1.42-1.49), 1.26 times (95% CI 1.22-1.30), 1.31 times (95% CI 1.26-1.36) and 1.16 times (95% CI 1.13-1.19) higher for the most deprived compared with the least deprived quantile. CONCLUSION: Socioeconomic deprivation was significantly associated with poor bone health and falls. This research could be beneficial to minimise social disparities in bone health.

The role of thiol-disulfide homeostasis and ischemia-modified albumin in osteosarcopenia.

BACKGROUND: Oxidative stress results from an imbalance between the induction of reactive oxygen species and the ability of cells to metabolize them. Numerous markers can be used to assess the level of oxidative stress. Thiol-disulfide homeostasis (TDH) and ischemia-modified albumin (IMA) are some of them. The aim of this study is to investigate the role of TDH and IMA, which are indicators of oxidative stress, in older patients with osteosarcopenia (OS). METHODS: The study was conducted cross-sectionally in a geriatrics outpatient clinic. Patients who applied to the outpatient clinic for three months were included in the study. Patients with acute infection, delirium, malignancy, severe liver, heart or kidney dysfunction and who did not give their consent for the study were excluded from the study. The study was conducted with 136 patients. Sarcopenia was diagnosed according to muscle ultrasonography (USG) and handgrip strength (HGS) results. Osteopenia/osteoporosis was diagnosed according to bone mineral densitometry (BMD) results. The combination of osteopenia/osteoporosis and sarcopenia was accepted as OS. RESULTS: Native thiol, total thiol value and nativethiol /totalthiol*100 values were significantly lower in the group with OS (respectively; value = 265 ± 53.8 standard deviation (SD) µmol/L, p = ≤ 0.001; value = 295.33 ± 55.77 SD µmol/L, p = 0.001; value = 90.06 (2.8) interquartile ranges (IQR), p = 0.033). Disulfide/native thiol*100 and disulfide/total thiol*100 values were significantly higher in the group with OS (respectively; value = 5.5 (1.7) IQR, p = 0.033; value = 4.97 (1.4) IQR, p = 0.034). CONCLUSION: In our study, the role of oxidative stress in OS was demonstrated by using TDH as an oxidative stress parameter.

A comprehensive meta-analysis of risk factors associated with osteosarcopenic obesity: a closer look at gender, lifestyle and comorbidities.

This study reviewed the risk factors of Osteosarcopenic obesity (OSO), a condition linking weak bones, muscle loss, and obesity. Notable associations were found with female gender, physical inactivity, hypertension, and frailty. Recognizing these early can aid targeted prevention, emphasizing further research for improved understanding and strategies. PURPOSE: Osteosarcopenic obesity (OSO) represents a confluence of osteopenia/osteoporosis, sarcopenia, and obesity, contributing to increased morbidity and mortality risks. Despite escalating prevalence, its risk factors remain under-explored, necessitating this comprehensive systematic review and meta-analysis. METHODS: A diligent search of PubMed, Scopus, and Cochrane databases was conducted for pertinent studies until June 2023. The random-effects model was employed to compute pooled odds ratios (ORs) and 95% confidence intervals (CIs), scrutinizing various risk factors like age, gender, lifestyle factors, and common comorbidities. RESULTS: Our meta-analysis incorporated 21 studies comprising 178,546 participants. We identified significant associations between OSO and factors such as female gender (OR 1.756, 95% CI 1.081 to 2.858), physical inactivity (OR 1.562, 95% CI 1.127-2.165), and hypertension (OR 1.482, 95% CI 1.207-1.821). Conversely, smoking (OR 0.854, 95% CI 0.672-1.084), alcohol consumption (OR 0.703, 95% CI 0.372-1.328), and dyslipidemia (OR 1.345, 95% CI 0.982-1.841) showed no significant associations. Remarkable heterogeneity was observed across studies, indicating considerable variation in effect sizes. Notably, OSO was strongly associated with frailty (OR 6.091; 95% CI 3.576-10.375). CONCLUSIONS: Our study underscored the substantial role of female gender, physical inactivity, and hypertension in the development of OSO, whilst suggesting a strong link between OSO and frailty. These findings emphasize the importance of early risk factor identification and targeted interventions in these groups. Further research is warranted to decode the complex pathophysiological interplay and devise effective prevention and management strategies.

The risk of revision following total hip arthroplasty in patients with inflammatory bowel disease, a registry based study.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the intestinal tract and is associated with decreased bone mineral density. IBD patients are at higher risk of osteopenia, osteoporosis and fracture compared to non-IBD patients. The impact of IBD on the performance of orthopedic implants has not been well studied. We hypothesized that a history of IBD at the time of primary total hip arthroplasty (THA) would increase the risk of subsequent failure as assessed by revision surgery. A retrospective implant survival analysis was completed using the Swedish Hip Arthroplasty Registry and the Sweden National Patient Register. A total of 150,073 patients undergoing THA for osteoarthritis within an 18-year period were included in the study. THA patients with (n = 2,604) and without (n = 147,469) a history of IBD at the time of THA were compared with primary revision as the main endpoint and adjusted using sex, age category and comorbidity (Elixhauser scores) as covariates. We found that patients with a history of IBD had a relatively higher risk of revision surgery for septic causes while the non-IBD patients had a relatively higher risk of revision for aseptic causes (p = 0.004). Our findings suggest there may be an association between gut health and THA performance.

Induction of somatopause in adult mice compromises bone morphology and exacerbates bone loss during aging.

Somatopause refers to the gradual declines in growth hormone (GH) and insulin-like growth factor-1 throughout aging. To define how induced somatopause affects skeletal integrity, we used an inducible GH receptor knockout (iGHRKO) mouse model. Somatopause, induced globally at 6 months of age, resulted in significantly more slender bones in both male and female iGHRKO mice. In males, induced somatopause was associated with progressive expansion of the marrow cavity leading to significant thinning of the cortices, which compromised bone strength. We report progressive declines in osteocyte lacunar number, and increases in lacunar volume, in iGHRKO males, and reductions in lacunar number accompanied by ~20% loss of overall canalicular connectivity in iGHRKO females by 30 months of age. Induced somatopause did not affect mineral/matrix ratio assessed by Raman microspectroscopy. We found significant increases in bone marrow adiposity and high levels of sclerostin, a negative regulator of bone formation in iGHRKO mice. Surprisingly, however, despite compromised bone morphology, osteocyte senescence was reduced in the iGHRKO mice. In this study, we avoided the confounded effects of constitutive deficiency in the GH/IGF-1 axis on the skeleton during growth, and specifically dissected its effects on the aging skeleton. We show here, for the first time, that induced somatopause compromises bone morphology and the bone marrow environment.

Effect of Ginseng Extracts on the Improvement of Osteopathic and Arthritis Symptoms in Women with Osteopenia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Ginsenosides are active compounds that are beneficial to bone metabolism and have anti-osteoporosis properties. However, very few clinical investigations have investigated the effect of ginseng extract (GE) on bone metabolism. This study aims to determine the effect of GE on improving bone metabolism and arthritis symptoms in postmenopausal women with osteopenia. A 12-week randomized, double-blind, placebo-controlled clinical trial was conducted. A total of 90 subjects were randomly divided into a placebo group, GE 1 g group, and GE 3 g group for 12 weeks based on the random 1:1:1 assignment to these three groups. The primary outcome is represented by bone metabolism indices consisting of serum osteocalcin (OC), urine deoxypyridinoline (DPD), and DPD/OC measurements. Secondary outcomes were serum CTX, NTX, Ca, P, BsALP, P1NP, OC/CTX ratio, and WOMAC index. The GE 3 g group had a significantly increased serum OC concentration. Similarly, the GE 3 g group showed a significant decrease in the DPD/OC ratio, representing bone resorption and bone formation. Moreover, among all the groups, the GE 3 g group demonstrated appreciable improvements in the WOMAC index scores. In women with osteopenia, intake of 3 g of GE per day over 12 weeks notably improved the knee arthritis symptoms with improvements in the OC concentration and ratios of bone formation indices like DPD/OC.

Congenital Metabolic Bone Disorders as a Cause of Bone Fragility.

Bone fragility is a pathological condition caused by altered homeostasis of the mineralized bone mass with deterioration of the microarchitecture of the bone tissue, which results in a reduction of bone strength and an increased risk of fracture, even in the absence of high-impact trauma. The most common cause of bone fragility is primary osteoporosis in the elderly. However, bone fragility can manifest at any age, within the context of a wide spectrum of congenital rare bone metabolic diseases in which the inherited genetic defect alters correct bone modeling and remodeling at different points and aspects of bone synthesis and/or bone resorption, leading to defective bone tissue highly prone to long bone bowing, stress fractures and pseudofractures, and/or fragility fractures. To date, over 100 different Mendelian-inherited metabolic bone disorders have been identified and included in the OMIM database, associated with germinal heterozygote, compound heterozygote, or homozygote mutations, affecting over 80 different genes involved in the regulation of bone and mineral metabolism. This manuscript reviews clinical bone phenotypes, and the associated bone fragility in rare congenital metabolic bone disorders, following a disease taxonomic classification based on deranged bone metabolic activity.

Modeling Sympathetic Hyperactivity in Alzheimer's Related Bone Loss.

BACKGROUND: A significant subset of patients with Alzheimer's disease (AD) exhibit low bone mineral density and are therefore more fracture-prone, relative to their similarly aged neurotypical counterparts. In addition to chronic immune hyperactivity, behavioral dysregulation of effector peripheral sympathetic neurons-which densely innervate bone and potently modulate bone remodeling-is implicated in this pathological bone reformation. OBJECTIVE: Thus, there exists a pressing need for a robust in vitro model which allows interrogation of the paracrine interactions between the putative mediators of AD-related osteopenia: sympathetic neurons (SNs) and mesenchymal stem cells (MSCs). METHODS: Toward this end, activated SN-like PC12 cells and bone marrow derived MSCs were cultured in poly(ethylene glycol) diacrylate (PEGDA) hydrogels in the presence or absence of the AD-relevant inflammatory cytokine tumor necrosis factor alpha (TNF-α) under mono- and co-culture conditions. RESULTS: PC12s and MSCs exposed separately to TNF-α displayed increased expression of pro-inflammatory mediators and decreased osteopontin (OPN), respectively. These data indicate that TNF-α was capable of inducing a dysregulated state in both cell types consistent with AD. Co-culture of TNF-α-activated PC12s and MSCs further exacerbated pathological behaviors in both cell types. Specifically, PC12s displayed increased secretion of interleukin 6 relative to TNF-α stimulated monoculture controls. Similarly, MSCs demonstrated a further reduction in osteogenic capacity relative to TNF-α stimulated monoculture controls, as illustrated by a significant decrease in OPN and collagen type I alpha I chain. CONCLUSION: Taken together, these data may indicate that dysregulated sympathetic activity may contribute to AD-related bone loss.

Biomechanics of the Femoral Head Cartilage and Subchondral Trabecular Bone in Osteoporotic and Osteopenic Fractures.

This study aimed to investigate the relationship between the micro structural properties of the subchondral trabecular bone (STB) and the macro mechanical properties of the articular cartilage (AC) in patients with osteoporotic (OP) and osteopenic (OPE) fractures. Sixteen femoral head samples (OP;OPE, n = 8 each) were obtained from female patients who underwent hip hemiarthroplasty. STB and AC specimens were harvested from those heads. Bone specimens were scanned using µ-CT to determine the micro structural properties. In-situ nondestructive compressive tests were performed for the cartilages to obtain elastic properties. The finite element technique was implemented on STB models created from µ-CT data to compute apparent elastic modulus. In addition, dynamic cyclic destructive tests were performed on STB and AC specimens to assess failure cycles. The results demonstrated that STB specimens in OPE group have more interconnected structure and higher cyclic dynamic strength than those in OP group. Furthermore, bone mineral density, failure cycle, and trabecular number of STB were positively correlated with the cartilage failure cycle, which indicates that STB alteration may affect the macroscopic mechanical properties of AC. The findings suggest that STB loss correlates with a decrease in cartilage strength and that improving of bone quality may prevent cartilage weakness.

Recovery of the maternal skeleton after lactation is impaired by advanced maternal age but not by reduced IGF availability in the mouse.

BACKGROUND: Lactation results in substantial maternal bone loss that is recovered following weaning. However, the mechanisms underlying this recovery, and in particular the role of insulin-like growth factor 1 (IGF-I), is not clear. Furthermore, there is little data regarding whether recovery is affected by advanced maternal age. METHODS: Using micro-computed tomography, we studied bone recovery following lactation in mice at 2, 5 and 7 months of age. We also investigated the effects of reduced IGF-I availability using mice lacking PAPP-A2, a protease of insulin-like growth factor binding protein 5 (IGFBP-5). RESULTS: In 2 month old mice, lactation affected femoral trabecular and cortical bone, but only cortical bone showed recovery 3 weeks after weaning. This recovery was not affected by deletion of the Pappa2 gene. The amount of trabecular bone was reduced in 5 and 7 month old mice, and was not further reduced by lactation. However, the recovery of cortical bone was impaired at 5 and 7 months compared with at 2 months. CONCLUSIONS: Recovery of the maternal skeleton after lactation is impaired in moderately-aged mice compared with younger mice. Our results may be relevant to the long-term effects of breastfeeding on the maternal skeleton in humans, particularly given the increasing median maternal age at childbearing.

Neutralization of oxidized phospholipids attenuates age-associated bone loss in mice.

Oxidized phospholipids (OxPLs) are pro-inflammatory molecules that affect bone remodeling under physiological conditions. Transgenic expression of a single-chain variable fragment (scFv) of the antigen-binding domain of E06, an IgM natural antibody that recognizes the phosphocholine (PC) moiety of OxPLs, increases trabecular and cortical bone in adult male and female mice by increasing bone formation. OxPLs increase with age, while natural antibodies decrease. Age-related bone loss is associated with increased oxidative stress and lipid peroxidation and is characterized by a decline in osteoblast number and bone formation, raising the possibility that increased OxPLs, together with the decline of natural antibodies, contribute to age-related bone loss. We show here that transgenic expression of E06-scFv attenuated the age-associated loss of spinal, femoral, and total bone mineral density in both female and male mice aged up to 22 and 24 months, respectively. E06-scFv attenuated the age-associated decline in trabecular bone, but not cortical bone, and this effect was associated with an increase in osteoblasts and a decrease in osteoclasts. Furthermore, RNA-seq analysis showed that E06-scFv increased Wnt10b expression in vertebral bone in aged mice, indicating that blocking OxPLs increases Wnt signaling. Unlike age-related bone loss, E06-scFv did not attenuate the bone loss caused by estrogen deficiency or unloading in adult mice. These results demonstrate that OxPLs contribute to age-associated bone loss. Neutralization of OxPLs, therefore, is a promising therapeutic target for senile osteoporosis, as well as atherosclerosis and non-alcoholic steatohepatitis (NASH), two other conditions shown to be attenuated by E06-scFv in mice.

The Impact of the "Osteo" Component of Osteosarcopenia on Fragility Fractures in Post-Menopausal Women.

Osteosarcopenia, the coexistence of bone and muscle loss, is common in older adults, but its definition lacks international consensus. This cross-sectional study (n = 1199 post-menopausal women) aimed to determine the association between osteosarcopenia and fragility fractures and to investigate the impact of the definition of the "osteo" component. Bone mineral density and bone microarchitecture were measured by dual-energy X-ray absorptiometry and the trabecular bone score (TBS), respectively. The "osteo" component of osteosarcopenia was classified as osteoporosis (T-score ≤ -2.5 SD), osteopenia/osteoporosis (T-score < -1 SD), and high-fracture-risk osteopenia (-2.5 SD < T-score < -1 SD)/osteoporosis (T-score ≤ -2.5 SD). The Fracture Risk Assessment Tool was used to identify high-fracture-risk osteopenia. Altogether, 30.3%, 32.2%, 14.4%, and 23.1% of participants had osteosarcopenia, osteoporosis alone, sarcopenia alone, and neither condition, respectively. The odds ratios between osteosarcopenia and fragility fractures were 3.70 (95% CI: 1.94-7.04) for osteosarcopenia, 2.48 (95% CI: 1.30-4.71) for osteoporosis alone, and 1.87 (95% CI: 0.84-4.14) for sarcopenia alone. Women with osteosarcopenia also had lower TBS, indicating worse bone microarchitecture. In conclusion, women with osteosarcopenia were more likely to have previously sustained a fracture compared to those without osteosarcopenia, with sarcopenia alone, and with osteoporosis alone. The relationship between osteosarcopenia and fracture risk may be best identified when considering high-fracture-risk osteopenia and osteoporosis.

Detraining Effects on Muscle Quality in Older Men with Osteosarcopenia. Follow-Up of the Randomized Controlled Franconian Osteopenia and Sarcopenia Trial (FrOST).

The present study aimed to determine the effect of detraining on muscle quality (MQ) in older men with osteosarcopenia. Forty-three community-dwelling older men (78 ± 4 years) were randomly allocated to a consistently supervised high-intensity resistance exercise training (HIRT) group (n = 21) or a control group (CG, n = 22). The HIRT scheduled a periodized single set protocol twice weekly. After the intervention, the men were subjected to six months of detraining. Muscle quality (MQ), defined as maximum isokinetic hip/leg extensor strength per unit of mid-thigh intra-fascia volume, was determined by magnetic resonance imaging (MRI) or per unit of thigh muscle mass assessed by dual-energy X-ray absorptiometry (DXA). Intention-to-treat analysis with multiple imputations was applied. We observed significant exercise effects for MQ (p = 0.001). During detraining, the HIRT group lost about one-third of the intervention-induced gain and displayed significantly (p = 0.001) higher MQ reductions compared to the CG. Nevertheless, after training and detraining, the overall intervention effect on MQ remained significant (p ≤ 0.004). In summary, six months of absence from HIRT induce a significant deleterious effect on MQ in older osteosarcopenic men. We conclude that intermitted training programs with training breaks of six months and longer should be replaced by largely continuous exercise programs, at least when addressing MQ parameters.

Omega-3 fatty acid-rich fish oil supplementation prevents rosiglitazone-induced osteopenia in aging C57BL/6 mice and in vitro studies.

Rosiglitazone is an effective insulin-sensitizer, however associated with bone loss mainly due to increased bone resorption and bone marrow adiposity. We investigated the effect of the co-administration of fish oil rich in omega-3 fatty acids (FAs) on rosiglitazone-induced bone loss in C57BL/6 mice and the mechanisms underlying potential preventive effect. Mice fed the iso-caloric diet supplemented with fish oil exhibited significantly higher levels of bone density in different regions compared to the other groups. In the same cohort of mice, reduced activity of COX-2, enhanced activity of alkaline phosphatase, lower levels of cathepsin k, PPAR-γ, and pro-inflammatory cytokines, and a higher level of anti-inflammatory cytokines were observed. Moreover, fish oil restored rosiglitazone-induced down-regulation of osteoblast differentiation and up-regulation of adipocyte differentiation in C3H10T1/2 cells and inhibited the up-regulation of osteoclast differentiation of RANKL-treated RAW264.7 cells. We finally tested our hypothesis on human Mesenchymal Stromal Cells differentiated to osteocytes and adipocytes confirming the beneficial effect of docosahexaenoic acid (DHA) omega-3 FA during treatment with rosiglitazone, through the down-regulation of adipogenic genes, such as adipsin and FABP4 along the PPARγ/FABP4 axis, and reducing the capability of osteocytes to switch toward adipogenesis. Fish oil may prevent rosiglitazone-induced bone loss by inhibiting inflammation, osteoclastogenesis, and adipogenesis and by enhancing osteogenesis in the bone microenvironment.

Changes in Body Composition and Cardiometabolic Health After Detraining in Older Men with Osteosarcopenia: 6-Month Follow-Up of the Randomized Controlled Franconian Osteopenia and Sarcopenia Trial (FrOST) Study.

PURPOSE: Temporary cessation of exercise but maintenance of habitual physical activity might be a frequent situation in older people's lives. Particularly the COVID-19 induced lockdown of exercise training facilities with individual outdoor activities still being allowed might be a blueprint for this potentially harmful scenario. Thus, the aim of the present study was to determine the effects of 6 months of detraining after 18 months of high-intensity resistance exercise (HIT-RT) on body composition and cardiometabolic outcomes in predominately obese older men with osteosarcopenia. MATERIALS AND METHODS: Community-dwelling predominately obese men 72-91 years old with low muscle and bone mass (n=43) were randomly assigned to an 18-month HIT-RT (EG: n=21) or a non-training control group (CG, n=22). After the intervention, participants of the EG discontinued HIT-RT for 6 months, but increased their habitual physical activity. Study outcomes were group differences in detraining changes ("effects") for lean body mass (LBM), total and abdominal body fat rate (determined by dual-energy x-ray absorptiometry) and the Metabolic Syndrome Z-Score (MetSZ). We applied an intention-to-treat analysis with multiple imputation to analyze the data. RESULTS: After the 18-month HIT-RT, we observed significant positive training effects for LBM, total and abdominal body fat rate and the MetSZ (all p<0.001). Abrupt cessation of HIT-RT for 6 months resulted in significantly higher unfavorable changes in the HIT-RT compared with the CG for LBM (p=0.001), total body fat (p=0.003) and the MetSZ (p=0.003), apart from abdominal body fat (p=0.059). However, significant overall effects were still present after 24 months for LBM and body fat indices but not for the MetSZ. CONCLUSION: The present study clearly indicates the unfavorable effects of 6 months of detraining after HIT-RT. Correspondingly, exercise protocols particularly for older people should focus on continuous exercise with short regeneration periods rather than on intermitted protocols with pronounced training breaks.