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Hui-Ming Peng,1 Zong-Ke Zhou,2 Fei Wang,3 Shi-Gui Yan,4 Peng Xu,5 Xi-Fu Shang,6 Jia Zheng,7 Qing-Sheng Zhu,8 Li Cao,9 Xi-Sheng Weng1 1Department of Orthopedics, Peking Union Medical College Hospital, CAMS & PUMC, Beijing, 100730, People’s Republic of China; 2Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People’s Republic of China; 3Department of Orthopedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, Hebei Province, People’s Republic of China; 4Department of Orthopedic Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang Province, People’s Republic of China; 5Department of Adult Joint Reconstruction, Xi’ an Honghui Hospital, Xi’ An, 710054, Shaanxi Province, People’s Republic of China; 6Department of Orthopedic Surgery, First Affiliated Hospital of University of Science and Technology of China, Hefei, 230001, Anhui Province, People’s Republic of China; 7Department of Orthopedic Surgery, Henan Provincial People’s Hospital, Zhengzhou, 450003, Henan Province, People’s Republic of China; 8Department of Orthopedic Surgery, Xijing Hospital of Air Force Medical University, Xi’ An, 710032, Shanxi Province, People’s Republic of China; 9Department of Orthopedic Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, Xinjiang, People’s Republic of ChinaCorrespondence: Xi-Sheng WengDepartment of Orthopedics, Peking Union Medical College Hospital, CAMS & PUMC, No. 1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, People’s Republic of ChinaTel/Fax +86-10-69152710Email drweng_wxs1377@163.comBackground and Aim: Periprosthetic joint infection (PJI) is one of the most devastating complications after total joint arthroplasty (TJA). However, the antibiotic resistance of infecting pathogens can significantly vary in different parts of the country. In the current study, we analyzed the demographic and microbiological profiles of knee and hip PJI over three years and compared the microbiological differences between them.Methods: A multicenter retrospective study of PJI patients in 34 referral medical centers in mainland China from January 2015 to November 2017 was performed.Results: A total of 925 PJI patients were recruited, 452 were identified as knee PJIs, and 473 were hip PJIs. The most common causative pathogens were Staphylococcus aureus (26.5%) and coagulase-negative staphylococci (14.3%). Methicillin-resistant staphylococci were involved in 25.6% (237/925) of all PJI cases. Mycobacterium and fungus only accounted for 6.5% (61) of all cases. Enteric gram-negative bacilli, anaerobes, and polymicrobial pathogens were more common in hip joint prostheses than in knee PJI (P = 0.014; P = 0.006; P = 0.002, respectively).Conclusion: While the majority of causative pathogens in PJI cases are staphylococcal species, the prevalence of atypical organisms and resistant pathogens should also be given attention and warrant the need for empiric antibiotic treatment.Keywords: arthroplasty, hips, knees, microorganism, prosthetic joint infection

Wear particle-induced periprosthetic osteolysis is mainly responsible for joint replacement failure and revision surgery. Curculigoside is reported to have bone-protective potential, but whether curculigoside attenuates wear particle-induced osteolysis remains unclear. In this study, titanium particles (Ti) were used to stimulate osteoblastic MC3T3-E1 cells in the presence or absence of curculigoside, to determine their effect on osteoblast differentiation. Rat osteoclastic bone marrow stromal cells (BMSCs) were cocultured with Ti in the presence or absence of curculigoside, to evaluate its effect on osteoclast formation in vitro. Ti was also used to stimulate mouse calvaria to induce an osteolysis model, and curculigoside was administrated to evaluate its effect in the osteolysis model by micro-CT imaging and histopathological analyses. As the results indicated, in MC3T3-E1 cells, curculigoside treatment attenuated the Ti-induced inhibition on cell differentiation and apoptosis, increased alkaline phosphatase activity (ALP) and cell mineralization, and inhibited TNF-α, IL-1β, and IL-6 production and ROS generation. In BMSCs, curculigoside treatment suppressed the Ti-induced cell formation and suppressed the TNF-α, IL-1β, and IL-6 production and F-actin ring formation. In vivo, curculigoside attenuated Ti-induced bone loss and histological damage in murine calvaria. Curculigoside treatment also reversed the RANK/RANKL/OPG and NF-κB signaling pathways, by suppressing the RANKL and NF-κB expression, while activating the OPG expression. Our study demonstrated that curculigoside treatment was able to attenuate wear particle-induced periprosthetic osteolysis in in vivo and in vitro experiments, promoted osteoblastic MC3T3-E1 cell differentiation, and inhibited osteoclast BMSC formation. It suggests that curculigoside may be a potential pharmaceutical agent for wear particle-stimulated osteolysis therapy.

ObjectivesTo evaluate the morphine-sparing effects of the sequential treatment versus placebo in subjects undergoing total knee arthroplasty (TKA), the effects on pain relief, inflammation control and functional rehabilitation after TKA and safety.DesignDouble-blind, pragmatic, randomised, placebo-controlled trial.SettingFour tertiary hospitals in China.Participants246 consecutive patients who underwent elective unilateral TKA because of osteoarthritis (OA).InterventionsPatients were randomised 1:1 to the parecoxib/celecoxib group or the control group. The patients in the parecoxib/celecoxib group were supplied sequential treatment with intravenous parecoxib 40 mg (every 12 hours) for the first 3 days after surgery, followed by oral celecoxib 200 mg (every 12 hours) for up to 6 weeks. The patients in the control group were supplied with the corresponding placebo under the same instructions.Primary and secondary outcome measuresThe primary endpoint was the cumulative opioid consumption at 2 weeks post operation (intention-to-treat analysis). Secondary endpoints included the Knee Society Score, patient-reported outcomes and the cumulative opioid consumption.ResultsThe cumulative opioid consumption at 2 weeks was significantly smaller in the parecoxib/celecoxib group than in the control group (median difference, 57.31 (95% CI 34.66 to 110.33)). The parecoxib/celecoxib group achieving superior Knee Society Scores and EQ-5D scores and greater Visual Analogue Scale score reduction during 6 weeks. Interleukin 6, erythrocyte sedation rate and C-reactive protein levels were reduced at 72 hours, 2 weeks and 4 weeks and prostaglandin E2 levels were reduced at 48 hours and 72 hours in the parecoxib/celecoxib group compared with the placebo group. The occurrence of adverse events (AEs) was significantly lower in the parecoxib/celecoxib group.ConclusionsThe sequential intravenous parecoxib followed by oral celecoxib regimen reduces morphine consumption, achieves better pain control and functional recovery and leads to less AEs than placebo after TKA for OA.Trial registration numberClinicalTrials.gov (ID:NCT02198924).

Cellular senescence plays both beneficial and detrimental roles in embryonic development and tissue regeneration, while the underlying mechanism remains elusive. Recent studies disclosed the emerging roles of heat‐shock proteins in regulating muscle regeneration and homeostasis. Here, we found that Hsp90β, but not Hsp90α isoform, was significantly upregulated during muscle regeneration. RNA‐seq analysis disclosed a transcriptional elevation of p21 in Hsp90β‐depleted myoblasts, which is due to the upregulation of p53. Moreover, knockdown of Hsp90β in myoblasts resulted in p53‐dependent cellular senescence. In contrast to the notion that Hsp90 interacts with and protects mutant p53 in cancer, Hsp90β preferentially bound to wild‐type p53 and modulated its degradation via a proteasome‐dependent manner. Moreover, Hsp90β interacted with MDM2, the chief E3 ligase of p53, to regulate the stability of p53. In line with these in vitro studies, the expression level of p53‐p21 axis was negatively correlated with Hsp90β in aged mice muscle. Consistently, administration of 17‐AAG, a Hsp90 inhibitor under clinical trial, impaired muscle regeneration by enhancing injury‐induced senescence in vivo. Taken together, our finding revealed a previously unappreciated role of Hsp90β in regulating p53 stability to suppress senescence both in vitro and in vivo.

The regenerative process of injured muscle is dependent on the fusion and differentiation of myoblasts derived from muscle stem cells. Hsp70 is important for maintaining skeletal muscle homeostasis and regeneration, but the precise cellular mechanism remains elusive. In this study, we found that Hsp70 was upregulated during myoblast differentiation. Depletion or inhibition of Hsp70/Hsc70 impaired myoblast differentiation. Importantly, overexpression of p38 mitogen-activated protein kinase α (p38MAPKα) but not AKT1 rescued the impairment of myogenic differentiation in Hsp70- or Hsc70-depleted myoblasts. Moreover, Hsp70 interacted with MK2, a substrate of p38MAPK, to regulate the stability of p38MAPK. Knockdown of Hsp70 also led to downregulation of both MK2 and p38MAPK in intact muscles and during cardiotoxin-induced muscle regeneration. Hsp70 bound MK2 to regulate MK2-p38MAPK interaction in myoblasts. We subsequently identified the essential regions required for Hsp70-MK2 interaction. Functional analyses showed that MK2 is essential for both myoblast differentiation and skeletal muscle regeneration. Taken together, our findings reveal a novel role of Hsp70 in regulating myoblast differentiation by interacting with MK2 to stabilize p38MAPK.

Osteoporosis is a common health problem worldwide caused by an imbalance of bone formation vs. bone resorption. However, current therapeutic approaches aimed at enhancing bone formation or suppressing bone resorption still have some limitations. In this study, we demonstrated for the first time that cepharanthine (CEP, derived from Stephania cepharantha Hayata) exerted a protective effect on estrogen deficiency-induced bone loss. This protective effect was confirmed to be achieved through inhibition of bone resorption in vivo, rather than through enhancement of bone formation in vivo. Furthermore, the in vitro study revealed that CEP attenuated receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast formation, and suppressed bone resorption by impairing the c-Jun N-terminal kinase (JNK) and phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathways. The inhibitory effect of CEP could be partly reversed by treatment with anisomycin (a JNK and p38 agonist) and/or SC79 (an AKT agonist) in vitro. Our results thus indicated that CEP could prevent estrogen deficiency-induced bone loss by inhibiting osteoclastogenesis. Hence, CEP might be a novel therapeutic agent for anti-osteoporosis therapy.

We studied the effect of molecular polyethylene particles on local heterotopic ossification. A total of 36 healthy Sprague-Dawley rats were randomly divided into the control group (n=18) and the observation group (n=18). High molecular polyethylene particles were injected to rupture Achilles tendon position in the observation group, and normal saline was injected in the control group. X-ray examinations were conducted on Achilles tendon in the 4th, 8th and 12th week after operation. The incidence rate of heterotopic ossification was evaluated, and bone trabecula morphological structure was studied under optical microscope after hematoxylin and eosin staining. Bone morphogenetic protein 2 (BMP-2), transforming growth factor-β (TGF-β), interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), runt-related transcription factor 2 (Runx2) and matrix metalloproteinase-9 (MMP-9) expression levels were also measured. Our results showed that heterotopic ossification incidence in the observation group was significantly lower than that in the control group. Achilles tendon structure in the control group increased in volume, and its texture was harder and cartilage-like. In the observation group, trabecular bone volume, thickness and quantity were more than those observed in the control group. BMP-2, TGF-β, IL-1, TNF-α, Runx2 and MMP-9 levels in the observation group were significantly lower than those in the control group. We concluded that, high molecular polyethylene particles had a significant inhibiting effect on local heterotopic ossification.

The osteonecrosis of femoral head (ONFH) has been a common disorder in clinical orthopaedic practice. ONFH is the relative contraindication of hip arthroplasty for the young and active patients since they suffer a high rate of revision and inferior function postoperatively. The primary importance in therapy is to prevent the progression of the disease and the collapse of the articular surface in order to keep away from hip arthroplasty. Low-intensity pulsed ultrasound (LIPUS) has been indicated to enhance the osteogenic differentiation of mesenchymal stem cells, stimulate the differentiation and the proliferation of osteoblasts, inhibit osteoclasts, improve the local blood perfusion and the angiogenesis, and accelerate the healing process of the stress fracture. We present a hypothesis that LIPUS may be an appropriate non-invasive modality for bone repair in the early stage of ONFH so that the progressive collapse of the articular surface and the subsequent arthroplasty would be avoided.

Osteonecrosis of the femoral head (ONFH) is a devastating disease that can result in a femoral head collapse. By proteomics analysis, we identified 1,967 proteins with two or more unique peptides from ONFH and from control bones with a false discovery rate of 4.8%. Using spectral counting, we identified 141 overexpressed and 56 underexpressed proteins comparing ONFH bones to the controls. GSEA (gene set enrichment analysis) revealed that proteins overexpressed in ONFH are enriched for gene sets related to multiple myeloma and adult T-cell lymphoma (ATL), and to JAK2-dependent genes. We confirmed the underexpression of CHST2 (isoform 1 of carbohydrate sulfotransferase 2), a key protein involved in biosynthesis of chondroitin sulfate proteoglycans, and the underexpression of GPCR26 (G-protein coupled receptor 26), a protein that mediates intracellular calcium mobilization, in ONFH bones compared to controls. Taken together, our data suggest that biosynthesis of chondroitin sulfate proteoglycans and cation transport and mobilization may be a key process involved in the pathogenesis of ONFH. Our analysis sheds new light on the understanding of the pathogenesis of ONFH.

Rhizoma drynariae is used commonly in the treatment of osteoporosis and bone nonunion in traditional Chinese medicine. Modern pharmacological research indicates that naringin is the main effective component of rhizoma drynariae, which can induce the expression of the osteogenic marker in the osteoblast cell line. However, no former study has described its effect on bone mesenchymal stem cells (BMSCs). In our experiment, we co-cultured human BMSCs with different concentrations of naringin solution, then the osteogenic differentiation markers and proliferation ability were analyzed. The results indicated that a certain concentration (1–100 μg/ml) of the naringin solution may enhance the proliferation and osteogenic differentiation of human BMSCs. Also, our research explains excellently the anti-osteoporotic and bone nonunion treatment mechanism of rhizoma drynariae, thus contributing to the exploration of osteogenic differentiation agents from Chinese herbs.

In this cross-sectional study, we examined whether hyperuricemia is associated with hypertension and the association exists in a Chinese population at a high risk of hypertension. The study population included 813 consecutively clinical patients with suspected cardiovascular disease, including the subjects with the current use of antihypertensive medications and self-reported diagnosis of hypertension. The subjects underwent three measures of blood pressure and were divided into two groups: 502 non-hypertensive subjects and 311 hypertensive subjects. Clinical and biochemical variables were measured. Results showed that uric acid level, fasting glucose, low-density lipoprotein (LDL)-cholesterol, total cholesterol and urea nitrogen were significantly higher (all p0.05) in hypertension subjects than in non-hypertension subjects. The risk of hypertension was significantly higher in the group with higher uric acid (400 micromol/l), compared with that with lower uric acid (200 micromol/l) (odds ratio: 2.09, 95% CI 1.13-3.88). The odds ratio was 1.73, 95% CI 1.05-2.85 in the higher uric acid (200-400 micromol/l) group, compared with that with lower uric acid. In addition, age, gender, weight, fasting glucose, triglycerides and total cholesterol were also significantly associated with the incidence of hypertension. In age-adjusted logistic regression analysis, the effect of uric acid concentration on hypertension was attenuated. In conclusion, hyperuricemia is associated with hypertension in a Chinese population at a high risk of hypertension.

To evaluate the effectiveness of the cell-material in situ on joint resurfacing, a woven fabric polyglycolic acid (PGA) treated with fresh chondrocytes was used for repairing cartilage defects. Full-thickness defects were created in the weight-bearing surfaces of the femoral intercondylar fossa in a rabbit model. The defect was filled with and without PGA under surgical condition. Before implantation, chondrocytes were co-cultured with PGA for one day. The animals were sacrificed at eight weeks after implantation and evaluated grossly and histological score. Morphological examination showed that for PGA/chondrocytes group, the repaired tissue appeared similar in color and texture to the surrounding articular surface. While for the untreated control, no cartilage-like tissue was observed at all defects, but connective fibrous tissue. Histological analysis revealed neochondrogenesis and clusters of cartilage matrix with specific safranin-O staining for the PGA/cell group. The Gross and histological evaluation indicated a significantly higher score for PGA/cell group than for PGA and control group. These results suggest that the woven fabric PGA may facilitate the formation of cartilage tissues by providing a biodegradable and good-handle vehicle for the delivery to and retention of organized cell matrix constructs in vivo site. It might therefore enhance neochondrogenesis because of the superior biodegradable and biocompatible of PGA scaffold sheet, while the more suitable biological environment might sustain cell growth and in situ cell function, suggesting a promising candidate for functional tissue engineering of clinical environment.

Osteonecrosis of femoral head (ONFH) is a common joint disease with high morbidity in mainland China. We performed a retrospective case investigation based on the widest range of patients ever to reveal the demographic and clinical characteristics of ONFH in mainland China. We collected data from hospitalized patients of nine large tertiary hospitals in China, focusing on the aetiology of ONFH. Medical records and self-design questionnaires were used to collect data. We determined the patients’ aetiology according to established guidelines and categorized patients into different subgroups. We further analysed the underlying illness of the steroid-induced osteonecrosis of femoral head. A total of 6,395 patients with complete medical records were included in the study. The age (mean ± SD) of the patients was 46.45 ± 13.80 years. Males dominate with 70.1 % of all ONFH patients. In all the ONFH patients, 24.1 % are steroid induced, 30.7 % are alcoholic, 16.4 % are traumatic and 28.8 % are idiopathic. Among steroid-induced osteonecrosis of femoral head patients, 546 patients have autoimmune disorder (46.63 %), which is the most common underling illness, among these, the most common disease is systemic lupus erythematosus (SLE). The most common age when ONFH occurs is between 40 and 50 years old. Male patients developed ONFH 3.4 years earlier than female patients. The number of the male patients is greater than the female, reaching the overall gender proportion of 7:3. Autoimmune disease is the primary cause of steroid-induced ONFH, among which SLE is the most common disease.

Monotropein, the primary iridoid glycoside isolated from Morindacitrifolia, has been previously reported to possess potent antioxidant and antiosteoporotic properties. However, there is no direct evidence correlating the antiosteoporotic effect of monotropein with its observed antioxidant capacity, and the molecular mechanisms involved in mediating these processes remain unclear. Therefore, the aim of the present study was to investigate the protective effects of monotropein against oxidative stress in osteoblasts and the mechanisms involved in mediating this process. Osteoblast viability was evaluated using the MTT assay. The mitochondrial membrane potential and reactive oxygen species were detected by flow cytometry analyses. Western blotting and enzyme‑linked immunosorbent assays were performed to detect protein expression levels. A significant reduction in osteoblast viability was observed at 24 h following exposure to various concentrations (100‑1,000 µM) of H2O2 compared with untreated osteoblasts. The cytotoxic effect of H2O2 was notably reversed when osteoblasts were pretreated with 1‑10 µg/ml monotropein. Pretreatment with 1-10 µg/ml monotropein increased the mitochondrial membrane potential and reduced the generation of reactive oxygen species in osteoblasts following exposure to H2O2. In addition, the H2O2‑induced increase in apoptotic markers (caspase-3 and caspase-9) and H2O2-induced reduction in sirtuin 1 levels were significantly reversed following pretreatment of cells with monotropein. Furthermore, monotropein significantly reduced H2O2‑induced stimulation of NF‑κB expression, in addition to the expression of a number of proinflammatory mediators. These results indicate that monotropein suppresses apoptosis and the inflammatory response in H2O2‑induced osteoblasts through the activation of the mitochondrial apoptotic signaling pathway and inhibition of the NF‑κB signaling pathway.

Though it is well accepted that low-intensity pulsed ultrasound (LIPUS) can accelerate the healing process of a fracture with very good results, we should still pay attention to its side effects and further improve its application in detail, such as the appropriate time and point for the application. In the early phase of a bone fracture, there are millions of oxygen radicals released by neutrophils in the injured area. This article focuses on whether the increased permeability of normal cell membranes by LIPUS makes the concentration of oxygen radicals increase to such a high degree that damage occurs to healthy tissue cells. It is proposed that it may be better not to use LIPUS in the acute phase of a fracture (i.e. within 1week after injury) but instead delay its application until after any inflammatory reaction has weakened to yield better results.

Dear Editor, We read with great interest the article by Sener et al. [1] and would like to bring four issues to your attention. First, the authors analysed the difference in the bacterial density between four groups with repetitive Mann-Whitney U test. Unavoidably, type I error (α) would be magnified [2]. It would be appropriate to calibrate the P value as: [2]. Thus, we made a second statistical analysis (Table 1). The data showed, however, no difference was found between group 2 and group 3 nor between group 3 and group 4. Combined with the inferior performance of group 3 in both radiological findings and macroscopic findings, antibiotic-loaded bone cement did not show superiority over other treatment modalities. Table 1 Statistical results of subgroup comparison in microbiological evaluation Second, the results showed that teicoplanin-loaded bone graft could not help, and could even interfere, with the infection control. Apart from the mechanisms discussed by the authors, other interpretations may be considered (Fig. 1). For example, local subacute inflammation was assumed two weeks after the bacterial inoculation. Less encapsulation of granulation tissue and bone callus, more osteolysis and exudation, and greater hyperemia were anticipated compared with chronic osteomyelitis [3]. Also, teicoplanin releasing systems were placed at the fracture site, a more open space than the medullary cavity. As a result, the adopted model of implant-related infection might present greater dilution, absorption, distribution, and elimination of teicoplanin than that of chronic osteomyelitis [4]. Some hidden or distant bacteria might be spared from the locally compromised teicoplanin level and account for recurrence of infection. Moreover, it was reported that the length of time during which the local antibiotic level exceeded minimal inhibition concentration (T>MIC) highly predicted antimicrobial potency of glycopeptide releasing systems [4]. Applying morselised cancellous bone, lengthening the duration of immersion in antibiotic solution, and the technique of iontophoresis would facilitate the teicoplanin impregnation into bone and prolong the T>MIC [5]. The authors simply immersed the corticocancellous grafts in teicoplanin solution for only one hour. The adsorption was possibly far below the saturation threshold, which may underestimate the antimicrobial efficacy of teicoplanin-loaded bone grafts. To our disappointment, no in vivo investigation was attempted on the kinetics of antibiotic release from bone. Also, implant removal is a prerequisite for thorough debridement; however, the authors retained the infected implant, where bacteria colonised and biofilm probably developed (Fig. 1). It was difficult to reach effective antibiofilm concentrations of teicoplanin around the implant. Fig. 1 Schematic diagram of osteomyelitis models of subacute infection (a) and chronic infection (b). In comparison with the model of chronic osteomyelitis (b), the subacute animal model (a) had less encapsulation of granulation tissue and bone callus, more ... Third, substantial details concerning the fabrication of teicoplanin-loaded bone grafts and acrylic beads [5], such as the concentration and pH of teicoplanin solution, the surface area, the bulk volume and the weight of bone grafts and acrylic beads, were not mentioned, which made comparison on antimicrobial efficacy impossible. Fourth and finally, the authors indicated that use of antibiotic-loaded beads was superior to debridement and systematic antibiotic treatment while antibiotic-loaded autogenous bone was not. This did not seem reasonable. In fact, debridement and systematic teicoplanin treatment were also offered in groups 3 and 4. What differed from group 2 was additional teicoplanin-loaded beads and teicoplanin-loaded autogenous bone in groups 3 and 4, respectively. It seems more appropriate to conclude that the inhibition by both antibiotic delivery systems was inferior to their aggravation of infection.

Spinal cord injury (SCI)-induced bone loss represents the most severe osteoporosis with no effective treatment. Past animal studies have focused primarily on long bones at the acute stage using adolescent rodents. To mimic chronic SCI in human patients, we performed a comprehensive analysis of long-term structural and mechanical changes in axial and appendicular bones in adult rats after SCI. In this experiment, 4-month-old Fischer 344 male rats received a clinically relevant T13 contusion injury. Sixteen weeks later, sublesional femurs, tibiae, and L4 vertebrae, supralesional humeri, and blood were collected from these rats and additional non-surgery rats for micro-computed tomography (µCT), micro-finite element, histology, and serum biochemical analyses. At trabecular sites, extreme losses of bone structure and mechanical competence were detected in the metaphysis of sublesional long bones after SCI, while the subchondral part of the same bones showed much milder damage. Marked reductions in bone mass and strength were also observed in sublesional L4 vertebrae but not in supralesional humeri. At cortical sites, SCI induced structural and strength damage in both sub- and supralesional long bones. These changes were accompanied by diminished osteoblast number and activity and increased osteoclast number and activity. Taken together, our study revealed site-specific effects of SCI on bone and demonstrated sustained inhibition of bone formation and elevation of bone resorption at the chronic stage of SCI.