Advances in mechanism and management of bone homeostasis in osteonecrosis: a review article from basic to clinical applications.

Osteonecrosis, characterized by bone cell death leading to impaired bone recovery, causes challenges in bone homeostasis maintenance. Bone homeostasis relies on the delicate balance between osteoclasts and osteoblasts, encompassing a series of complex and strictly regulated biological functions. Current treatments, including conservative therapies and surgeries, often fall short of expected outcomes, necessitating a reorientation towards more effective therapeutic strategies according to the pathogenesis. In this review, we hierarchically outlined risk factors, emerging mechanisms, and last-decade treatment approaches in osteonecrosis. By connecting mechanisms of bone homeostasis, we proposed future research directions should be focused on elucidating risk factors and key molecules, performing high-quality clinical trial, updating practice, and accelerating translational potential.

Telehealth-Supported Exercise or Physical Activity Programs for Knee Osteoarthritis: Systematic Review and Meta-Analysis.

BACKGROUND: The integration of telehealth-supported programs in chronic disease management has become increasingly common. However, its effectiveness for individuals with knee osteoarthritis (KOA) remains unclear. OBJECTIVE: This study aimed to assess the effectiveness of telehealth-supported exercise or physical activity programs for individuals with KOA. METHODS: A comprehensive literature search encompassing Embase, MEDLINE, CENTRAL, Web of Science, PubMed, Scopus, PEDro, GreyNet, and medRxiv from inception to September 2023 was conducted to identify randomized controlled trials comparing telehealth-supported exercise or physical activity programs to a control condition for KOA. Data were extracted and qualitatively synthesized across eligible studies, and a meta-analysis was performed to evaluate the effects. The study was reported according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020. RESULTS: In total, 23 studies met eligibility criteria, with 20 included in the meta-analysis. Results showed that telehealth-supported exercise or physical activity programs reduced pain (g=-0.39; 95% CI -0.67 to -0.11; P<.001), improved physical activity (g=0.13; 95% CI 0.03-0.23; P=.01), and enhanced physical function (g=-0.51; 95% CI -0.98 to -0.05; P=.03). Moreover, significant improvements in quality of life (g=0.25; 95% CI 0.14-0.36; P<.001), self-efficacy for pain (g=0.72; 95% CI 0.53-0.91; P<.001), and global improvement (odds ratio 2.69, 95% CI 1.41-5.15; P<.001) were observed. However, self-efficacy for physical function (g=0.14; 95% CI -0.26 to 0.53; P=.50) showed insignificant improvements. Subgroup analyses based on the World Health Organization classification of digital health (pain: χ22=6.5; P=.04 and physical function: χ22=6.4; P=.04), the type of teletechnology in the intervention group (pain: χ24=4.8; P=.31 and function: χ24=13.0; P=.01), and active or inactive controls (pain: χ21=5.3; P=.02 and physical function: χ21=3.4; P=.07) showed significant subgroup differences. CONCLUSIONS: Telehealth-supported exercise or physical activity programs might reduce knee pain and improve physical activity, physical function, quality of life, self-efficacy, and global improvement in individuals with KOA. Future research should consider longer implementation durations and assess the feasibility of incorporating wearables and standardized components into large-scale interventions to evaluate the effects. TRIAL REGISTRATION: PROSPERO CRD42022359658; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=359658.

Mechanisms and applications of the regenerative capacity of platelets-based therapy in knee osteoarthritis.

Osteoarthritis (OA) is the most prevalent joint disease in the elderly population and its substantial morbidity and disability impose a heavy economic burden on patients and society. Knee osteoarthritis (KOA) is the most common subtype of OA, which is characterized by damage to progressive articular cartilage, synovitis, and subchondral bone sclerosis. Most current treatments for OA are palliative, primarily aim at symptom management, and do not prevent the progression of the disease or restore degraded cartilage. The activation of α-granules in platelets releases various growth factors that are involved in multiple stages of tissue repair, suggesting potential for disease modification. In recent years, platelet-based therapies, such as platelet-rich plasma, platelet-rich fibrin, and platelet lysates, have emerged as promising regenerative treatments for KOA, but their related effects and mechanisms are still unclear. Therefore, this review aims to summarize the biological characteristics and functions of platelets, classify the products of platelet-based therapy and related preparation methods. Moreover, we summarize the basic research of platelet-based regeneration strategies for KOA and discuss the cellular effects and molecular mechanisms. Further, we describe the general clinical application of platelet-based therapy in the treatment of KOA and the results of the meta-analysis of randomized controlled trials.

A comparison of different physical stimulation combined with platelet-rich plasma for the treatment of knee osteoarthritis: study protocol for a randomized controlled trial.

BACKGROUND: Platelet-rich plasma (PRP) contains various growth factors and inflammatory regulators, which can effectively reduce inflammation in joints and promote tissue repair. Multiple studies have proved its effectiveness in the treatment of knee osteoarthritis (KOA). Low-intensity focused ultrasound (LIFU) and transcutaneous electrical nerve stimulation (TENS) are non-invasive and safe physical therapy methods for KOA. This study is the first to propose the treatment of KOA with physical stimulation after PRP treatment, and to observe the clinical efficacy of the treatment method. METHODS: This is a protocol paper that outlines a randomized controlled trial, patients will be assigned randomly to the PRP group, PRP+LIFU group, PRP+TENS group, and PRP+LIFU combined TENS group. The patients will be followed at 12-week and 24-week time points to evaluate the primary and secondary outcomes of the study. The primary outcome is the VAS pain score. Secondary outcomes include Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and International Knee Documentation Committee scores (IKDC). After baseline examination, all patients will sign a written informed consent for study participation after a full explanation of the treatment protocol. We have planned a total of 120 patients (30 patients per group). DISCUSSION: The objective of this clinical trial is to evaluate the effect of different physical stimulation after PRP treatment for KOA. The data will be published after the completion of the study. TRIAL REGISTRATION: This study has been registered with the Chinese Clinical Trials Registry. REGISTRATION NUMBER: ChiCTR2200065119 (registered date: 10/28/2022).

Exoskeleton-Assisted Walking for Pulmonary and Exercise Performances of SCI Individuals.

OBJECTIVE: To determine whether exoskeleton-assisted walking (EAW) improves pulmonary ventilation function, motor function and related body structure, and activities equivalently as the conventional exercise program for people with spinal cord injury (SCI). METHODS: Forty participants (7 females and 33 males; age 37.1±12.0 years) with thoracic SCI were randomized into two groups and undertook 16 sessions of 50-60 min training (4 days/week). Participants in the EAW group received EAW trainings, such as assisted standing, walking, and climbing the stairs. The control group received a conventional exercise program. Outcomes were measured at baseline and upon completion of treatment. RESULTS: After trainings, the EAW group improved more than the control group in the forced vital capacity (FVC, 0.53 L [0.01-1.06 L]), predicted FVC% (19.59 [6.63-32.54]) and forced expiratory volume in 1s (0.61 L [0.15-1.07 L]), basic activities of daily living (BADL) (19.75 [10.88-28.62]), and distal femoral cartilage. Participants in the EAW group completed 6-minute walk test with median 17.3 meters while wearing the exoskeleton. There was no difference in trunk and lower extremity motor function, bone mineral density, and adverse events ( P > 0.05). CONCLUSION: In people with lower thoracic neurological level of SCI, EAW training has potential benefits to facilitate pulmonary ventilation function, walking, BADL and thickness of cartilage comparing to a conventional excise program. SIGNIFICANCE: This study provided more evidence for using EAW in clinic, and partly proved EAW had equivalent effects as conventional exercise program, which may combine with conventional exercise program for reducing burden of therapists in the future.

The Effect of Different Frequencies of Pulsed Electromagnetic Fields on Cartilage Repair of Adipose Mesenchymal Stem Cell-Derived Exosomes in Osteoarthritis.

BACKGROUND: The intra-articular injection of mesenchymal stem cell (MSC)-derived exosomes has already been proved to reverse osteoarthritic cartilage degeneration. Pulsed electromagnetic field (PEMF) has been found to regulate the biogenic function of MSCs. However, the effect of PEMF on MSC-derived exosomes has not yet been characterized. The aim of this study was to elucidate the regulatory role of different frequencies of PEMF in promoting the osteoarthritic cartilage regeneration of MSC-derived exosomes. METHODS: The adipose tissue-derived MSCs (AMSCs) were extracted from the epididymal fat of healthy rats and further exposed to the PEMF at 1 mT amplitude and a frequency of 15, 45, and 75 Hz, respectively, in an incubator. The chondrocytes were treated with interlukin-1ß (IL-1ß) and the regenerative effect of co-culturing with PEMF-exposed AMSC-derived exosomes was assessed via Western blot, quantitative polymerase chain reaction, and ELISA assays. A rat model of osteoarthritis was established by anterior cruciate ligament transection (ACLT) surgery and received 4 times intra-articular injection of PEMF-exposed AMSC-derived exosomes once a week. After 8 weeks, the knee joint specimens of rats were collected for micro-computed tomography and histologic analyses. RESULTS: PEMF-exposed AMSC-derived exosomes could be endocytosed with IL-1ß-induced chondrocytes. Compared with the AMSC-derived exosomes alone, the PEMF-exposed AMSC-derived exosomes substantially suppressed the inflammation and extracellular matrix degeneration of IL-1ß-induced chondrocytes as shown by higher expression of transcripts and proteins of COL2A1, SOX9, and ACAN and lower expression of MMP13 and caspase-1. Of these, the 75-Hz PEMF presented a more significant inhibitive effect than the 15-Hz and 45-Hz PEMFs. Furthermore, the intra-articular injection of 75-Hz PEMF-exposed exosomes could obviously increase the number of tibial epiphyseal trabeculae, lead to a remarkable decrease in Osteoarthritis Research Society International score, and upregulate the COL2A1 and ACAN protein level of the degenerated cartilage. CONCLUSION: The present study demonstrated that PEMF stimulation could effectively promote the regeneration effects of AMSC-derived exosomes on osteoarthritic cartilage. Compared with other frequency parameters, the PEMF at a frequency of 75 Hz showed a superior positive effect on AMSC-derived exosomes in suppressing the IL-1ß-induced chondrocyte inflammation and extracellular matrix catabolism, as well as the osteoarthritic cartilage degeneration.

Mesenchymal stromal cell-based therapy for cartilage regeneration in knee osteoarthritis.

Osteoarthritis, as a degenerative disease, is a common problem and results in high socioeconomic costs and rates of disability. The most commonly affected joint is the knee and characterized by progressive destruction of articular cartilage, loss of extracellular matrix, and progressive inflammation. Mesenchymal stromal cell (MSC)-based therapy has been explored as a new regenerative treatment for knee osteoarthritis in recent years. However, the detailed functions of MSC-based therapy and related mechanism, especially of cartilage regeneration, have not been explained. Hence, this review summarized how to choose, authenticate, and culture different origins of MSCs and derived exosomes. Moreover, clinical application and the latest mechanistical findings of MSC-based therapy in cartilage regeneration were also demonstrated.

Exoskeleton-assisted walking improves pulmonary function and walking parameters among individuals with spinal cord injury: a randomized controlled pilot study.

BACKGROUND: Exoskeleton-assisted walking (EAW) is expected to improve the gait of spinal cord injury (SCI) individuals. However, few studies reported the changes of pulmonary function (PF) parameters after EAW trainings. Hence, we aimed to explore the effect of EAW on PF parameters, 6-min walk test (6MWT) and lower extremity motor score (LEMS) in individuals with SCI and to compare those with conventional trainings. METHODS: In this prospective, single-center, single-blinded randomized controlled pilot study, 18 SCI participants were randomized into the EAW group (n = 9) and conventional group (n = 9) and received 16 sessions of 50-60 min training (4 days/week, 4 weeks). Pulmonary function parameters consisting of the forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), forced expiratory flow (FEF), peak expiratory flow, and maximal voluntary ventilation, 6MWT with assisted devices and LEMS were reported pre- and post-training. RESULTS: Values of FVC (p = 0.041), predicted FVC% (p = 0.012) and FEV1 (p = 0.013) were significantly greater in EAW group (FVC: 3.8 ± 1.1 L; FVC% pred = 94.1 ± 24.5%; FEV1: 3.5 ± 1.0 L) compared with conventional group (FVC: 2.8 ± 0.8 L; FVC% pred = 65.4 ± 17.6%; FEV1: 2.4 ± 0.6 L) after training. Participants in EAW group completed 6MWT with median 17.3 m while wearing the exoskeleton. There was no difference in LEMS and no adverse event. CONCLUSIONS: The current results suggest that EAW has potential benefits to facilitate PF parameters among individuals with lower thoracic neurological level of SCI compared with conventional trainings. Additionally, robotic exoskeleton helped walking. TRIAL REGISTRATION: Registered on 22 May 2020 at Chinese Clinical Trial Registry (ChiCTR2000033166). http://www.chictr.org.cn/edit.aspx?pid=53920&htm=4 .

Conservative treatment of partial-thickness rotator cuff tears and tendinopathy with platelet-rich plasma: A systematic review and meta-analysis.

OBJECTIVE: To assess the effect of platelet-rich plasma as a conservative therapy in individuals with partial-thickness rotator cuff tears or tendinopathy on pain, and function. DATA SOURCES: Embase, MEDLINE, CENTRAL, Web of Science, CINAHL, PEDro, and the grey literature (to 31 March 2021). METHODS: Randomized controlled trials in English that reported short-term (6 ± 1 months), or long-term (⩾1 year) outcomes (shoulder pain or function) were conducted. Two independent reviewers screened the literature, completed the assessment of the Cochrane's risk of bias and extracted the data. Mean difference or standardized mean difference was used for continuous data. Heterogeneity was identified with I2 test. RESULTS: A total of 11 studies were eligible, and nine studies (n = 629) were included in this meta-analysis, that showed statistically significant short-term effects of platelet-rich plasma on pain relief (MD = -1.56; 95% CI -2.82 to -0.30), Constant-Murley score (MD = 16.48; 95% CI 12.57 to 20.40), and Shoulder Pain and Disability Index (MD = -18.78; 95% CI -36.55 to -1.02). Nonetheless, no long-term effect was observed on pain and function, except Constant-Murley score (MD = 24.30; 95% CI 23.27 to 25.33). The results of minimal important difference reached the minimal clinically important difference, except American Shoulder and Elbow Surgeons. For subgroup analysis, differences of pain relief were statistically significant in platelet-rich plasma-treated groups with double centrifugation, single injection, and post-injection rehabilitation. CONCLUSION: Our results suggested platelet-rich plasma had positive effects on pain relief and functional improvement for partial-thickness rotator cuff tears and rotator cuff tendinopathy, although the effects may not last for a long time.

The safety and feasibility of a new rehabilitation robotic exoskeleton for assisting individuals with lower extremity motor complete lesions following spinal cord injury (SCI): an observational study.

STUDY DESIGN: A pre-post observational study. OBJECTIVES: To evaluate the safety and feasibility of a new rehabilitation robotic device for assisting individuals with lower extremity motor complete lesions following spinal cord injury (SCI). SETTING: Three hospitals in Sichuan Province, China. METHODS: Individuals aged 15-75 years with an SCI between vertebrae six (T6) and lumbar 1 (L1) and complete motor paralysis participated in an exoskeletal-assisted walking (EAW) programme (2 weeks, 5 days/week, 30 min/day). Data were collected pre-, mid- (week 1) and post-intervention (week 2). RESULTS: Twenty-eight individuals (mean age = 41.3, 71% males) participated in the EAW programme. The distance walked during the 6-min walking test (6MWT) increased relative to that at baseline, during week 1 (13.0 ± 5.3 m) and week 2 (16.2 ± 5.3 m) when wearing the exoskeleton. The walking speed during the 10-m walking test (10MWT) increased from 0.039 ± 0.016 to 0.045 ± 0.016 m/s. The Hoffer walking ability grade, the Spinal Cord Independence Measure (SCIM), and the Walking Index for SCI II (WISCI II) changed after 2 weeks of EAW. No improvement in lower extremity motor score (LEMS) was observed. The rates of adverse events and serious adverse events were 21% and 4%, respectively. CONCLUSIONS: The EAW programme with the new robotic exoskeleton provided potential meaningful improvements in mobility for individuals with SCI and had few adverse events.

Pulsed electromagnetic fields for postmenopausal osteoporosis and concomitant lumbar osteoarthritis in southwest China using proximal femur bone mineral density as the primary endpoint: study protocol for a randomized controlled trial.

BACKGROUND: Osteoporosis (OP) and osteoarthritis (OA) are prevalent skeletal disorders among postmenopausal women. Coexistence is common especially that of postmenopausal osteoporosis (PMO) and lumbar OA. An hypothesis has been raised that OP and OA might share the same pathogenic mechanism, and pulsed electromagnetic fields (PEMFs) were reported to have anti-osteoporosis and anti-osteoarthritis properties, but this suggestion was based primarily on biomarker data. Therefore, whether these two effects could take place simultaneously has not yet been investigated. This randomized controlled trial (RCT) is designed to explore the effect of PEMFs for PMO and concomitant lumbar OA. METHODS/DESIGN: The study will include PMO patients (postmenopausal women; aged between 50 and 70 years; have been postmenopausal for at least 5 years and diagnosed with OP using proximal femur T-score) with concomitant lumbar OA (patients with confounding disorders like diabetes, hypertension, hyperlipidemia, and previous fracture history, etcetera, will be excluded) will be randomly assigned to two arms: PEMFs group and sham PEMFs group. There will be 25 participants in each arm (50 in total) and the outcome assessment, including the primary endpoint (proximal femur bone mineral density), will be performed at 5 weeks, 3 months and 6 months after enrollment. DISCUSSION: PMO and lumbar OA are prominent public health problem, especially for postmenopausal women. We hope this RCT will provide scientific evidence to primary care of the postmenopausal women regarding the use of these nonpharmaceutical, noninvasive modalities, PEMFs, in managing PMO and lumbar OA. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR-TRC-14005156 (28 August 2014).

Pulsed electromagnetic fields on postmenopausal osteoporosis in Southwest China: a randomized, active-controlled clinical trial.

A randomized, active-controlled clinical trial was conducted to examine the effect of pulsed electromagnetic fields (PEMFs) on women with postmenopausal osteoporosis (PMO) in southwest China. Forty-four participants were randomly assigned to receive alendronate or one course of PEMFs treatment. The primary endpoint was the mean percentage change in bone mineral density of the lumbar spine (BMDL), and secondary endpoints were the mean percentage changes in left proximal femur bone mineral density (BMDF), serum 25OH vitamin D3 (25(OH)D) concentrations, total lower-extremity manual muscle test (LE MMT) score, and Berg Balance Scale (BBS) score. The BMDL, BMDF, total LE MMT score and BBS score were recorded at baseline, 5, 12, and 24 weeks. Serum concentrations of 25(OH)D were measured at baseline and 5 weeks. Using a mixed linear model, there was no significant treatment difference between the two groups in the BMDL, BMDF, total LE MMT score, and BBS score (P ≥ 0.05). For 25(OH)D concentrations, the effects were also comparable between the two groups (P ≥ 0.05) with the Mann-Whitney's U-test. These results suggested that a course of PEMFs treatment with specific parameters was as effective as alendronate in treating PMO within 24 weeks.

Motor function and activities of daily living capacity of patients with fractures sustained during the Wenchuan earthquake.

BACKGROUND: On the afternoon of May 12, 2008, a 8.0-magnitude earthquake hit Sichuan Province, a mountainous region in Western China, killing about 70 000 people and leaving over 18 000 missing. What about the survivors motor functions and activities of daily living (ADL) capacity, especially for fractures? We need the data to guide the rehabilitation for the seismic wounded and it's important to collect the data for the future. We study the survivors to understand the motor functions and ADL capacity of patients with fractures sustained in the Wenchuan earthquake, to provide a basis for rehabilitation and treatment. METHODS: We used the Manual Muscle Testing method to evaluate muscle strength, the joint angle scale to measure joint range of motion (ROM), and the Barthel index to evaluate the activities of daily living status. SPSS 13.0 software was used to analyze the data and the results were tested using one-way analysis of variance (ANOVA). RESULTS: The number of seismic wounded amounted to 487; 81.1% of patients had fractures. Most of the injured had fractures in multiple regions (53.9% of all fracture patients), followed by fractures of the upper limb (34.0% of patients); cranial fractures were rare (2.3%). Totally 82.0% had restricted range of motion, 23.5% had decreased muscle force, and 72.2% of the patients had restricted activities of daily living capacities. With time the activities of daily living capacity of female increased (P < 0.05), compared with the male fracture patients who did not show any relative improvement (P > 0.05). The difference between the patients' ages and ADL capacities did not reach statistical significance (P > 0.05), nor was there a significant difference between their ages and the numbers of days in hospital (P > 0.05). CONCLUSIONS: Fractures were the main issue in the seismic wounded, many of them had reductions in the ROM, muscle force and ADL capacities. The physicians involved in rehabilitation should pay greater attention to muscle force exercises, joint mobilization, and occupational therapy during the early phases post disaster.

Clinical update of pulsed electromagnetic fields on osteoporosis.

OBJECTIVE: To understand the effects of low-frequency pulsed electromagnetic fields (PEMFs) on chronic bony pain, bone mineral density (BMD), bone strength and biochemical markers of bone metabolism in the patients of osteoporosis. DATA SOURCES: Using the key words "pulsed electromagnetic fields" and "osteoporosis", we searched the PubMed for related studies published in English from January 1996 to December 2007. We also searched the China National Knowledge Infrastructure (CNKI) for studies published in Chinese from January 1996 to December 2007. INCLUSION CRITERIA: (1) all articles which referred to the effects of low-frequency pulsed magnetic fields on osteoporosis either in primary osteoporosis or secondary osteoporosis; (2) either observational studies or randomized controlled studies. EXCLUSION CRITERIA: (1) articles on experimental studies about osteoporosis; (2) repetitive studies; (3) case reports; (4) meta analysis. RESULTS: Totally 111 related articles were collected, 101 of them were published in Chinese, 10 were in English. Thirty-four were included and the remaining 84 were excluded. CONCLUSIONS: Low-frequency PEMFs relieves the pain of primary osteoporosis quickly and efficiently, enhances bone formation and increases BMD of secondary osteoporosis. But the effects of PEMFs on bone mineral density of primary osteoporosis and bone resorption were controversial.

[Association of physical activities and bone mass density of lumbar spines in men].

OBJECTIVE: To determine the association of physical activities and bone mineral density of lumbar vertebrae in men. METHODS: A total of 1169 men who sought medical attentions in the West China Hospital of Sichuan University from August, 2003 to December, 2005 because of ostealgia and arthralgia were given a dual-energy X-ray absorptiometry for the L2-L4 bone mineral density. The height, weight, smoking history, and diseases (eg. diabetes and hypertension) of the participants were recorded. A questionnaire survey was undertaken to assess the physical activities of the participants. The participants were classified into group A (frequent exercise), B (occasional exercise) and C (no exercise) according to the frequencies of physical activities. The bone mass densities of lumbar vertebrae of the three groups were compared. RESULTS: Group A had greater bone mineral density and mineral content in L2-L4, greater average bone mineral density, and greater all bone mineral content and T-score than group C (P<0.05 or P<0.01), although Group A had similar body mass index as Group C, was older and had greater prevalence of smoking and hypertension than Group C (P<0.01). Group B had similar age and body mass index as Group C and greater smoking rate and prevalence of diabetes and hypertension than Group C (P>0.05). But the differences of bone mineral density and mineral content of L2-L4, average bone mineral density, and all bone mineral content and T-score between Group B and C were not statistical significant (P>0.05). CONCLUSION: Physical activities can increase bone mineral density of lumbar vertebrae in men. But frequent and persistent exercises are needed to prevent decreasing mineral densities due to ageing, smoking and diseases.