Efficacy of manual therapy on shoulder pain and function in patients with rotator cuff injury: A systematic review and meta­analysis.

To critically evaluate the effects of manual therapy (MT) on pain and functional improvement in patients with rotator cuff injury (RCI), a systematic review of all randomized controlled trials (RCTs) on MT for RCI was conducted in the following databases: PubMed, Cochrane Central Register of Controlled Trials, Embase, Web of Science, Physiotherapy Evidence Database, Chinese National Knowledge Infrastructure, Wan-fang Data, Chinese Scientific Journal Database, and Chinese Biomedical Literature database from inception to March 28, 2023. A total of 1,110 participants from 24 eligible RCTs were included in the analysis. Compared with placebo, MT could not effectively relieve pain [standardized mean difference (SMD)=-0.25; 95% CI: -0.51 to 0.01; P=0.06], although its impact on functional improvement appears limited (SMD=0.20; 95% CI: -0.09 to 0.49; P=0.18). Combining MT with exercise had significant advantages over exercise alone, as combined therapy contributed to both pain reduction (SMD=0.36; 95% CI: 0.08 to 0.64; P=0.01) and functional enhancement (SMD=0.32; 95% CI: 0.11 to 0.52; P=0.002). Furthermore, MT combined with multimodal physiotherapy showed additional benefits in pain reduction (mean difference=1.57; 95% CI: 0.18 to 2.96; P=0.03) and functional improvement (SMD=0.77; 95% CI: 0.43 to 1.12; P<0.0001) compared with multimodal physiotherapy alone. These findings highlight the superior pain alleviation and functional improvement provided by MT when combined with exercise or physiotherapy. Consequently, MT has emerged as a pivotal component of therapeutic intervention for RCI.

Aconine attenuates osteoclast-mediated bone resorption and ferroptosis to improve osteoporosis via inhibiting NF-κB signaling.

Osteoporosis (OP), a prevalent public health concern primarily caused by osteoclast-induced bone resorption, requires potential therapeutic interventions. Natural compounds show potential as therapeutics for postmenopausal OP. Emerging evidence from in vitro osteoclastogenesis assay suggests that aconine (AC) serves as an osteoclast differentiation regulator without causing cytotoxicity. However, the in vivo functions of AC in various OP models need clarification. To address this, we administered intraperitoneal injections of AC to ovariectomy (OVX)-induced OP mice for 8 weeks and found that AC effectively reversed the OP phenotype of OVX mice, leading to a reduction in vertebral bone loss and restoration of high bone turnover markers. Specifically, AC significantly suppressed osteoclastogenesis in vivo and in vitro by decreasing the expression of osteoclast-specific genes such as NFATc1, c-Fos, Cathepsin K, and Mmp9. Importantly, AC can regulate osteoclast ferroptosis by suppressing Gpx4 and upregulating Acsl4, which is achieved through inhibition of the phosphorylation of I-κB and p65 in the NF-κB signaling pathway. These findings suggest that AC is a potential therapeutic option for managing OP by suppressing NF-κB signaling-mediated osteoclast ferroptosis and formation.

Efficacy of Combining Traditional Chinese Manual Therapy (Tuina) and Specific Therapeutic Neck Exercise in Young Adults with Non-Specific Chronic Neck Pain: Study Protocol for a Randomized Controlled Trial.

Purpose: Non-specific chronic neck pain (NSCNP) is an increasingly common musculoskeletal disease and an important issue in the global healthcare system. Some studies have shown that the combination of manual therapy and exercise is effective in treating NSCNP but still with several limitations. Traditional Chinese manual therapy (tuina) is a Chinese manual therapy that consists of soft tissue manipulation and spinal manipulation. This study aims to design a randomized controlled trial to assess the effect of a tuina combined with specific therapeutic neck exercise modified protocol for NSCNP patients. Patients and Methods: This is a study protocol for a randomized, participant-, assessor- and analyst-blinded controlled trial. Eighty-eight eligible NSCNP patients will be randomly allocated into tuina combined with specific therapeutic neck exercise group (TSTE group) and tuina combined with sham therapeutic neck exercise group (TS group) in a ratio of 1:1. All participants will receive 8 treatment sessions applied in 4 weeks and then be followed up for another 12 weeks. Clinical data will be collected at baseline, during treatment phase (at the 2- and 4-week) and at the 8-, 12-, 16-week follow-ups. The primary outcome is the changes in neck pain intensity (visual analogue scale). The secondary outcomes include neck disability (Neck Disability Index), cervical range of motion (ROM), neck muscle endurance, cervical muscle cross-sectional area, cervical curvature and analgesic consumption. Adverse events will be collected and recorded throughout the study. Conclusion: We will discuss whether our tuina combined with specific therapeutic neck exercise modified protocol is more effective at improving pericervical muscle endurance, ROM, cervical muscle cross-sectional area and cervical curvature than tuina alone, thereby decreases neck pain and disability in individuals with NSCNP more effectively. Trial Registration: Chinese Clinical Trials Registry, ChiCTR2300067903. Registered on 31 January 2023.

Bioinformatics analysis identification of AKT3 and RAC1 as key genes in postmenopausal osteoporosis.

Postmenopausal osteoporosis (PMO) is an aging-associated disease that manifests as degradation of bone tissue microstructure leading to decreased bone mass and increased bone fragility. Differentiation of peripheral blood mononuclear cells into osteoclasts is an important process in the development of PMO and identification of key genes that drive differentiation is essential to reveal the mechanism of PMO. The present study combined bioinformatics analysis of a Gene Expression Omnibus dataset of PMO and drug (bisphosphonate) target prediction using the STITCH database to identify hub genes in patients with PMO. Next, the expression of candidate hub genes was assessed in osteoclasts differentiated from THP-1 cells and small interfering RNA assays were performed to assess the function of selected hub genes. The present study identified 10 hub genes including WNT1, AKT3, disheveled segment polarity protein 1, cyclin D1, H2B clustered histone 17, JUN, EGFR, RAC1, actinin α1 (ACTN1) and ACTN2. Among these, AKT3 and RAC1 were highly upregulated during osteoclast differentiation, and knockdown of AKT3 and RAC1 using small interfering RNA enhanced the inhibitory effect of bisphosphonates on osteoclast differentiation and apoptosis of monocytes as assessed by tartrate-resistant acid phosphatase staining and flow cytometry examining Annexin V-FITC/PI staining, respectively. In conclusion, AKT3 and RAC1 were key for development of PMO and inhibiting AKT3 and RAC1 may improve the therapeutic efficacy of bisphosphonates.

Quercetin Attenuates Osteoporosis in Orchiectomy Mice by Regulating Glucose and Lipid Metabolism via the GPRC6A/AMPK/mTOR Signaling Pathway.

Quercetin, a flavonoid found in natural medicines, has shown a role in disease prevention and health promotion. Moreover, because of its recently identified contribution in regulating bone homeostasis, quercetin may be considered a promising agent for improving bone health. This study aimed to elucidate the role of quercetin in androgen deprivation therapy-induced osteoporosis in mice. C57BL/6 mice were subjected to orchiectomy, followed by quercetin treatment (75 and 150 mg/kg/d) for 8 weeks. Bone microstructure was then assessed by micro-computed tomography, and a three-point bending test was used to evaluate the biomechanical parameters. Hematoxylin and eosin (H&E) staining was used to examine the shape of the distal femur, gastrocnemius muscle, and liver. The balance motion ability in mice was evaluated by gait analysis, and changes in the gastrocnemius muscle were observed via Oil red O and Masson's staining. ELISA and biochemical analyses were used to assess markers of the bone, glucose, and lipid metabolism. Western blotting analyses of glucose and lipid metabolism-related protein expression was performed, and expression of the GPCR6A/AMPK/mTOR signaling pathway-related proteins was also assessed. After 8 weeks of quercetin intervention, quercetin-treated mice showed increased bone mass, bone strength, and improved bone microstructure. Additionally, gait analysis, including stride length and frequency, were significantly increased, whereas a reduction of the stride length and gait symmetry was observed. H&E staining of the gastrocnemius muscle showed that the cross-sectional area of the myofibers had increased significantly, suggesting that quercetin improves balance, motion ability, and muscle mass. Bone metabolism improvement was defined by a reduction of serum levels of insulin, triglycerides, total cholesterol, and low-density lipoprotein, whereas levels of insulin-like growth factor-1 and high-density lipoprotein were increased after quercetin treatment. Expression of proteins involved in glucose uptake was increased, whereas that of proteins involved in lipid production was decreased. Moreover, the GPRC6A and the phospho-AMPK/AMPK expression ratio was elevated in the liver and tibia tissues. In contrast, the phospho-mTOR/mTOR ratio was reduced in the quercetin group. Our findings indicate that quercetin can reduce the osteoporosis induced by testosterone deficiency, and its beneficial effects might be associated with the regulation of glucose metabolism and inhibition of lipid metabolism via the GPCR6A/AMPK/mTOR signaling pathway.

Role of skeletal muscle satellite cells in the repair of osteoporotic fractures mediated by ß-catenin.

BACKGROUND: Osteoporosis is a metabolic disease, and osteoporotic fracture (OPF) is one of its most serious complications. It is often ignored that the influence of the muscles surrounding the fracture on the healing of OPF. We aimed to clarify the role of skeletal muscle satellite cells (SMSCs) in promoting OPF healing by ß-catenin, to improve our understanding of SMSCs, and let us explore its potential as a therapeutic target. METHODS: Skeletal muscles were obtained from control non-OPF or OPF patients for primary SMSCs culture (n = 3, 33% females, mean age 60 ± 15.52). Expression of SMSCs was measured. In vivo, 3-month-old female C57BL/6 mice underwent OVX surgery. Three months later, the left tibia fracture model was again performed. The control and the treatment group (n = 24, per group, female). The treatment group was treated with an agonist (osthole). Detection of SMSCs in muscles and fracture healing at 7, 14, and 28 three time points (n = 8, 8, 8, female). To further clarify the scientific hypothesis, we innovatively used Pax7-CreERT2/+ ;ß-cateninfx/fx transgenic mice (n = 12, per group, male). Knock out ß-catenin in SMSC to observe the proliferation and osteogenic differentiation of SMSCs, and OPF healing. In vitro primary cells of SMSCs from 3-month-old litter-negative ß-cateninfx/fx transgenic mice. After adenovirus-CRE transfection, the myogenic and osteogenic differentiation of SMSC was observed. RESULTS: We find that human SMSCs reduced proliferation and osteogenic differentiation in patients with OPF (-38.63%, P < 0.05). And through animal experiments, it was found that activation of ß-catenin promoted the proliferation and osteogenic differentiation of SMSC at the fracture site, thereby accelerating the healing of the fracture site (189.47%, P < 0.05). To prove this point of view, in the in vivo Pax7-CreERT2/+ ;ß-cateninfx/fx transgenic mouse experiment, we innovatively found that knocking out ß-catenin in SMSC will cause a decrease in bone mass and bone microstructure, and accompanied by delayed fracture healing (-35.04%, P < 0.001). At the same time, through in vitro SMSC culture experiments, it was found that their myogenic (-66.89%, P < 0.01) and osteogenic differentiation (-16.5%, P < 0.05) ability decreased. CONCLUSIONS: These results provide the first practical evidence for a direct contribution of SMSCs to promote the healing of OPF with important clinical implications as it may help in the treatment of delayed healing and non-union of OPFs, and mobilization of autologous stem cell therapy in orthopaedic applications.

Osthole enhances the bone mass of senile osteoporosis and stimulates the expression of osteoprotegerin by activating ß-catenin signaling.

INTRODUCTION: Osthole has a potential therapeutic application for anti-osteoporosis. The present study verified whether osthole downregulates osteoclastogenesis via targeting OPG. METHODS: In vivo, 12-month-old male mice were utilized to evaluate the effect of osthole on bone mass. In vitro, bone marrow stem cells (BMSCs) were isolated and extracted from 3-month-old OPG-/- mice and the littermates of OPG+/+ mice. Calvaria osteoblasts were extracted from 3-day-old C57BL/6J mice or 3-day-old OPG-/- mice and the littermates of OPG+/+ mice. RESULTS: Osthole significantly increased the gene and protein levels of OPG in primary BMSCs in a dose-dependent manner. The deletion of the OPG gene did not affect ß-catenin expression. The deletion of the ß-catenin gene inhibited OPG expression in BMSCs, indicating that osthole stimulates the expression of OPG via activation of ß-catenin signaling. CONCLUSION: Osthole attenuates osteoclast formation by stimulating the activation of ß-catenin-OPG signaling and could be a potential drug for the senile osteoporosis.

Urban-Rural Differences in Bone Mineral Density and its Association with Reproductive and Menstrual Factors Among Older Women.

PURPOSE: This study aimed to compare the bone mineral density (BMD) of older women living in rural and urban areas, and evaluate the potential factors affecting the risk of osteoporosis. METHODS: We recruited 574 women aged 65 years or older from rural areas and 496 from urban areas in Shanghai, China. The BMD values of the lumbar vertebrae and total left hip were measured by a dual energy X-ray absorptiometry densitometer. We also recorded information about education level, family income, medications, reproductive and menstrual history, diet, smoking, and alcohol consumption. RESULTS: Women in urban areas had significantly higher BMD in their lumbar spine, and there was a dramatic increase in the proportion of women with osteoporosis in rural areas. The age at menarche was significantly higher among women living in rural areas, and there were more years from menarche to menopause among urban women. Rural women had significantly higher numbers of both pregnancies and parity, and a significantly lower age at first parity. In multiple linear regression analyses, years from menarche to menopause was independently related to high lumbar spine BMD, while age at menarche and parity was independently related to low lumbar spine BMD. CONCLUSION: More older women in rural areas had osteoporosis. Later menarche, less years from menarche to menopause and higher parity might partially contribute to decreased BMD among women in rural areas. More attention should be paid to women in rural areas to prevent bone loss and further bone and health impairment.

Association between serum vitamin B6 concentration and risk of osteoporosis in the middle-aged and older people in China: a cross-sectional study.

OBJECTIVE: To determine the relationship between serum vitamin B6 (Vit B6) concentration and the status of bone mineral density and identify the relationship between serum Vit B6 and bone metabolism parameters in middle-aged and older people in China. DESIGN: The present study was a cross-sectional study within the framework of an ongoing prospective population-based cohort study. SETTING AND PARTICIPANTS: A total of 1829 residents (men ≥50 years and women ≥45 years) from two subdistricts were recruited from July 2015 to February 2016 in Shanghai, China. MEASURES: Recruited residents were grouped (control, osteopenia and osteoporosis) according to their lumbar spine bone mineral density, measured through dual-energy X-ray absorptiometry. Serum Vit B6 concentrations, bone turnover marker concentrations and calcium and phosphorus metabolism parameters were assessed. RESULTS: No significant linear trend between serum Vit B6 concentrations and lumbar bone mass was observed in the men. In the women, the average osteoporosis risk was 61% higher at serum Vit B6 concentrations of <19.2 µg/L than at those of >26.9 µg/L (OR 1.61, 95% CI 1.00 to 2.58). However, there was no significance after controlling of serum 25-hydroxy-vitamin D concentration and parathyroid hormone concentration, respectively. In the osteoporotic women, the serum Vit B6 concentration was significantly negatively correlated to concentrations of bone turnover marker including N-terminal propeptide of type I collagen, ß-C-terminal telopeptide of type I collagen and osteocalcin. It was also positively related to the serum 25-hydroxy-vitamin D concentration and inversely related to the serum parathyroid hormone concentration. CONCLUSIONS: A relatively low serum Vit B6 concentration, even in the normal range, may be a risk factor for osteoporosis in postmenopausal women, which is dependent on serum 25-hydroxy-vitamin D concentration and parathyroid hormone concentration. TRIAL REGISTRATION NUMBER: NCT02958020; Post-results.

Efficacy and safety of Shaoyang Xibi decoction in patients with knee osteoarthritis: a multi-center, single-blind, randomized controlled trial.

PURPOSE: To observe the efficacy and safety of Shaoyang Xibi decoction (SYXBD) in patients with knee osteoarthritis (KOA), and to verify that the theory of ""Shaoyang dominating bone"" in Traditional Chinese Medicine (TCM) can be applied to KOA treatment. METHODS: Participants were randomly allocated to two groups: SYXBD (treatment group, n = 66) and Meloxicam (control group, n = 66). Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and 36-Item Short Form Health Survey (SF-36) were used to assess efficacy before the treatment and 8 weeks after the treatment. RESULTS: Baseline data before the treatment between the two groups were similar. The WOMAC scores significantly decreased and the SF-36 scores significantly increased after 8- week treatment in both groups compared with before the treatment (P < 0.05). SYXBD significantly decreased pain scores (P < 0.001), physical function scores (P < 0.001) and the total scores (P < 0.001) in WOMAC compared to Meloxicam. SYXBD significantly improved physical function (P = 0.021), bodily pain (P = 0.002) and general health (P = 0.014), with no significant difference in role emotional (P = 0.053), role physical (P = 0.517), vitality (P = 0.241), social function (P = 0.712) and mental health (P = 0.800) in SF-36 compared to Meloxicam. No adverse events were reported in the treatment group while 13 adverse events happened in the control group during the study. CONCLUSION: SYXBD, prepared based on the theory of ""Shaoyang dominating bone"", has a better curative efficay and safety in patients with KOA compared with Meloxicam. The TCM theory of ""Shaoyang dominating bone"" may be useful in KOA treatment.