Frozen shoulder. An overview of pathology and biology with hopes to novel drug therapies.

Frozen shoulder (FS) is a common disorder characterized by spontaneous onset of shoulder pain accompanied by progressive loss of range-of-motions. The cause of FS is still unclear, and radical therapy has not been established. With the final aim of preventing or curing FS at an earlier stage, we reviewed the pathological and biological features of this disease. Many studies indicate that the main pathology of FS is inflammation initially and fibrosis later. There are inflammatory cytokines, immune cells, fibrotic growth factors, and type-III collagen in the synovium and the joint capsule. The immune cell landscape switches from the macrophages to T cells. Activated fibroblasts seem to regulate the inflammatory and fibrotic processes. The imbalance between matrix metalloproteinases and tissue inhibitors of metalloproteases might promote fibrosis. Additionally, advanced glycation end-products are noted in the FS synovium. Diabetes mellitus and hypothyroidism are closely related to the development of FS. In terms of nonsurgical treatment, oral or intra-articular glucocorticoids are the only drugs that provide early benefit. Some other anti-inflammatory or antifibrotic drugs may potentially control the FS, but have not been proven effective in the clinical setting. Future studies should be targeted to develop steroid-sparing agents that inhibit biological events in FS.

Changes in knee joint destruction patterns among patients with rheumatoid arthritis undergoing total knee arthroplasty in recent decades.

OBJECTIVES: This study aimed to investigate the trend of joint destruction patterns on knee radiographs of patients with rheumatoid arthritis (RA) undergoing total knee arthroplasty (TKA) over the past 16 years. METHOD: Medial joint space, lateral joint space, medial spur area, lateral spur area (L-spur), and femoro-tibial angle were obtained from 831 preoperative knee radiographs of patients with RA who underwent TKA between 2006 and 2021 using software capable of automatic measurements. Non-hierarchical clustering was performed based on these five parameters. Trends in the five individual radiographic parameters and the ratio of each cluster were investigated during the target period. Moreover, clinical data from 244 cases were compared among clusters to identify factors associated with this trend. RESULTS: All parameters, except for L-spur, showed significant increasing trends from 2006 to 2021. The radiographs were clustered into groups according to the characteristic pattern of radiographic findings: cluster 1 (conventional RA type), with bicompartmental joint space narrowing (JSN), less spur formation, and valgus alignment; cluster 2 (osteoarthritis type), with medial JSN, medial osteophytes, and varus alignment; and cluster 3 (less destructive type), with mild bicompartmental JSN, less spur formation, and valgus alignment. The ratio of cluster 1 showed a significantly decreasing trend contrary to the significantly increasing trend in clusters 2 and 3. The DAS28-CRP of cluster 3 was higher than those of clusters 1 and 2. CONCLUSIONS: Radiographs of TKA recipients with RA are increasingly presenting osteoarthritic features in recent decades. Key Points • Using automated measurement software, morphological parameters were measured from radiographs of 831 patients with rheumatoid arthritis who had undergone TKA in the past 16 years. • Cluster analysis based on the radiographic parameters revealed that the radiographs of patients with end-stage knee arthritis requiring total knee arthroplasty were classified into three groups. • In patients with rheumatoid arthritis who have undergone total knee arthroplasty in the past 16 years, the proportion of clusters with features of osteoarthritis and difficult-to-treat rheumatoid arthritis has increased, while the proportion of conventional rheumatoid arthritis has decreased.

Increasing trend of radiographic features of knee osteoarthritis in rheumatoid arthritis patients before total knee arthroplasty.

To investigate the trend and factors related to the occurrence of osteoarthritis (OA)-like features on knee radiographs of rheumatoid arthritis (RA) patients undergoing total knee arthroplasty (TKA) in the recent decades. To classify antero-posterior knee radiographs into 'RA' and 'OA-like RA' groups, a deep learning model was developed by training the network using knee radiographs of end-stage arthropathy in RA patients obtained during 2002-2005 and in primary OA patients obtained during 2007-2009. We used this model to categorize 796 knee radiographs, which were recorded in RA patients before TKA during 2006-2020, into 'OA-like RA' and 'RA' groups. The annual ratio of 'OA-like RA' was investigated. Moreover, univariate and multivariate analyses were performed to identify the factors associated with the classification as OA-like RA using clinical data from 240 patients. The percentage of 'OA-like RA' had significant increasing trend from 20.9% in 2006 to 67.7% in 2020. Higher body mass index, use of biologics, and lower level of C-reactive protein were identified as independent factors for 'OA-like RA'. An increasing trend of knee radiographs with OA-like features was observed in RA patients in the recent decades, which might be attributed to recent advances in pharmacotherapy.

Effect of TNF inhibitors with bisphosphonates vs bisphosphonates alone on bone mineral density and bone and cartilage biomarkers at 1 year in patients with rheumatoid arthritis: A prospective study.

BACKGROUND: The present study aimed prospectively to investigate the effect of a combination of tumour necrosis factor inhibitors and bisphosphonates (TNFi with BP) on bone mineral density (BMD) and bone and cartilage biomarkers compared to that of BP alone at 1 year in patients with rheumatoid arthritis (RA). METHODS: Two groups of patients with RA and osteoporosis were enrolled. One group (37 patients) had already received BP, while the other group (37 patients) had already received TNFi with BP. The serum bone resorption and formation markers, cartilage markers, BMD in the lumbar spine, femoral neck, and distal radius were prospectively investigated at the beginning of the study and at 6 and 12 months. RESULTS: The percentages of change recorded for the various assessment categories were as follows in the TNFi with BP group: (1) tartrate-resistant acid phosphatase-5b had significantly decreased and osteocalcin had increased; (2) matrix metalloproteinase-3 and cartilage oligomeric matrix protein had significantly decreased; and (3) each BMD did not differ significantly between the groups. CONCLUSION: Our data suggested that TNFi with BP therapy not only suppressed cartilage degradation and bone resorption but also increased bone formation; however, this treatment did not affect the BMD at 1 year.

Midterm clinical outcomes of reverse shoulder arthroplasty in Japanese patients with rheumatoid arthritis using patient-reported outcome measures (Shoulder36).

BACKGROUND: Reverse shoulder arthroplasty normally has adequate functional outcomes in patients with cuff tear arthropathy. The present study aimed to investigate the midterm clinical outcomes of reverse shoulder arthroplasty in Japanese patients with rheumatoid arthritis. METHODS: Between July 2014 and May 2016, reverse shoulder arthroplasty was performed in 14 rheumatic shoulders with joint destruction and rotator cuff tears. The range of motion, Constant score, and Shoulder36, which is a patient-reported outcome measure, were compared preoperatively and postoperatively. The prevalence of subscapular notching, subscapular osteophytes, postoperative fractures, and stress shielding of the humeral stem were evaluated by X-ray. RESULTS: Range of motion significantly improved from 77 to 122 degrees in flexion and from 67 to 111 degrees in abduction at four years. The Constant score significantly improved from 27 to 62, and each domain of Shoulder36 also significantly increased at four years. There was no dislocation, infection, or loosening of the prosthesis. Three shoulders presented scapular notching, and three cemented humeral stems showed stress shielding in the proximal humeral cortical bone. CONCLUSION: Reverse shoulder arthroplasty performed in Japanese patients with rheumatoid arthritis not only decreased the pain and improved the function of the shoulder joint but also significantly improved patients' health and activity of daily living in midterm results.

Disease activity affects the recurrent deformities of the lesser toes after resection arthroplasty for rheumatoid forefoot deformity.

OBJECTIVES: The purpose of this study was to clarify the effect of disease activity on recurrent deformities after resection arthroplasty for forefoot deformities in patients with rheumatoid arthritis (RA). METHODS: This study included 83 feet in 58 patients with RA who underwent resection arthroplasty of all metatarsal heads, with a minimum follow-up of 2 years. The patients' demographic characteristics, preoperative radiographic findings, and RA disease activity evaluated using the 28-joint disease activity score based on the erythrocyte sedimentation rate (determined preoperatively and at the final follow-up) were compared between feet with and without postoperative recurrent deformities of the toes. Recurrent deformities were assessed separately for the hallux and lesser toes. RESULTS: Recurrence in the hallux and lesser toes occurred in 23 feet (27.7%) and 13 feet (15.7%), respectively. With respect to recurrent hallux deformity, only the preoperative severity of hallux deformity was associated with recurrence. On the other hand, postoperative deformity of the lesser toes was positively associated with disease activity alone and not with other preoperative factors. CONCLUSION: Postoperative control of RA disease activity was associated with recurrent deformity of the lesser toes but not that of the hallux after resection arthroplasty of all metatarsals for rheumatoid forefoot deformities.

Factors affecting bone union after distal shortening oblique osteotomy of the lesser metatarsals.

Objectives: There have been few reports on factors affecting bone union after metatarsal osteotomies. The purpose of this study was to clarify the factors affecting bone union after distal shortening oblique osteotomy of the lesser metatarsals.Methods: Patients who underwent distal shortening oblique osteotomy of the lesser metatarsals were retrospectively investigated. Failure to achieve bone union at 6 months after surgery was defined as delayed union. Background characteristics and radiographic measurements were compared between patients with and those without delayed union, and factors affecting bone union were assessed using multivariate analysis.Results: Among 204 toes in 58 patients evaluated in this study, delayed union occurred in 28%. In multivariate analysis, corticosteroid use (odds ratio (OR), 3.68; 95% confidence interval (CI), 1.65-8.16; p< .01), larger preoperative overlap between the metatarsal and the proximal phalanx (OR, 1.11 (per 1 mm increase); 95% CI, 1.02-1.21; p= .02), and larger gap at the osteotomy site (OR, 3.02 (per 1 mm increase); 95% CI, 1.76-5.16; p< .01) were identified as independent risk factors of delayed union.Conclusion: The identified risk factors of delayed union after distal shortening metatarsal osteotomies were corticosteroid use, preoperative overlap between the metatarsal and the proximal phalanx, and a gap at the osteotomy site.

Vertebral fractures affect functional status in postmenopausal rheumatoid arthritis patients.

Functional disability is a major concern in patients with rheumatoid arthritis (RA). This retrospective study investigated the risk factors for vertebral fractures (VFs) in postmenopausal RA patients and determined the impact of VFs on functional status. Data from a cohort of 200 postmenopausal RA patients in a single hospital registry were analyzed. Demographic and clinical data, imaging data from spine radiographs, and bone mineral density (BMD) data were collected from the patients at baseline and at the final visit (a mean of 2.9 years after the first visit). Risk factors for incident VFs and their impact on the modified health assessment questionnaire (mHAQ) were analyzed. Twenty-eight patients (14%) developed new VFs (NVFs). Logistic regression analysis adjusted for age, BMI, and disease duration revealed that daily dose of prednisolone, femoral neck BMD, use of active vitamin D3, and use of a bisphosphonate at baseline were factors associated with NVF, with odds ratios (95% confidence interval) of 1.27 (1.05-1.54), 0.94 (0.91-0.97), 0.34 (0.13-0.89), and 0.31 (0.12-0.82), respectively. Patients with NVF exhibited worse mHAQ scores and a greater increase in mHAQ scores from baseline compared with those without NVF. In conclusion, incident VFs were associated with reduced functional status in postmenopausal patients with RA. It is important to prevent VFs to maintain the functional status of RA patients.

Regulation of bone resorption and sealing zone formation in osteoclasts occurs through protein kinase B-mediated microtubule stabilization.

We investigated the role of protein kinase B (Akt), a downstream effector of phosphatidylinositol 3-kinase, in bone-resorbing activity of mature osteoclasts. Treatment with a specific Akt inhibitor disrupted sealing zone formation and decreased the bone-resorbing activity of osteoclasts. The normal microtubule structures were lost and the Akt inhibitor reduced the amount of acetylated tubulin, which reflects stabilized microtubules, whereas forced Akt activation by adenovirus vectors resulted in the opposite effect. Forced Akt activation increased the binding of the microtubule-associated protein adenomatous polyposis coli (APC), the APC-binding protein end-binding protein 1 (EB1) and dynactin, a dynein activator complex, with microtubules. Depletion of Akt1 and Akt2 resulted in a disconnection of APC/EB1 and a decrease in bone-resorbing activity along with reduced sealing zone formation, both of which were recovered upon the addition of LiCl, a glycogen synthase kinase-3ß (GSK-3ß) inhibitor. The Akt1 and Akt2 double-knockout mice exhibited osteosclerosis due to reduced bone resorption. These findings indicate that Akt controls the bone-resorbing activity of osteoclasts by stabilizing microtubules via a regulation of the binding of microtubule associated proteins.

Patellar fracture after total knee arthroplasty for rheumatoid arthritis.

Patellar fracture is one of the most challenging complications of total knee arthroplasty, but relatively, little is known about it in patients with rheumatoid arthritis. We retrospectively analyzed 329 total knee arthroplasties performed in 230 female patients with rheumatoid arthritis to identify the incidence and risk factors for postoperative patellar fractures. The mean age was 61.8 years, and the mean follow-up period was 6.2 years. Patellar resurfacing was performed in all cases. Five postoperative patellar fractures (1.51%) were identified, and a thin residual patellar thickness and the use of posterior-stabilizing components were identified as significant risk factors, although the number of fractures was small in both groups. There was also tendency of higher age and greater joint line change observed in patients with fracture compared with those without fracture.

Osteogenesis and osteoclast inhibition in rheumatoid arthritis patients treated with bisphosphonates alone or in combination with pitavastatin over an 18-month follow-up after more than 4 years of treatment with bisphosphonates.

INTRODUCTION: To investigate the effects of bisphosphonates (Bis) (etidronate, alendronate, and risedronate), alone and in combination with statin, on the BMD (bone mineral density) and bone metabolism of rheumatoid arthritis (RA) patients. METHODS: Seventy-seven RA patients who had been receiving prednisolone (PSL) and Bis for over 4 years were divided into two groups: Bis and Bis + statin (n = 42 and 35; average age, 66.4 and 65.3 years; average disease duration, 24.9 and 20.8 years; average PSL dose, 2.4 and 2.7 mg, respectively). Serum levels of NTX (N-terminal telopeptide of type I collagen), TRACP-5b (tartrate-resistant acid phosphate-5b), PICP (C-terminal propeptide of type I procollagen), and RANKL (receptor activator of NF-κB ligand) were measured over an 18-month period of treatment and follow-up. The BMD levels of the two groups at the radius, lumbar spine, and femoral neck were compared using DXA (dual-energy x-ray absorptiometry). RESULTS: A significant increase was only observed in the BMD of the lumbar spine at 18-months, but the BMDs of the radius and femoral neck decreased during the follow-up period in the Bis group. Meanwhile, a significant increase was observed in the BMD of the lumbar spine in the Bis + statin group during administration and the BMDs of the radius and femoral neck stayed at baseline. Among the markers of bone metabolism, serum NTX was up-regulated after 6 months in the Bis + statin group. Serum TRACP-5b was significantly increased during the follow-up period in the Bis + statin group, but only at 18 months in the Bis group. Serum PICP recovered to base line in the Bis + statin group, whereas that in the Bis group did not observably recover during the post-administration follow-up, but rather decreased. CONCLUSION: Our findings suggest that both bone resorption and bone formation were inhibited by long-term administration of Bis alone, whereas combination therapy with Bis + statin may be associated with a less marked inhibition of bone metabolism. Cardiovascular disease is highly prevalent in RA patients and some patients are prescribed statins and bisphosphonate. Bis + statin may confer more benefit to the bone metabolism of these patients compared to Bis alone.

[Biomarker of bone destruction].

Patients with rheumatoid arthritis (RA) often have progression of bone destruction owing to chronic inflammation. Treatment for bone destruction is still insufficient in these patients although goal of treatment has become remission since biologics have been used widely. It is shown that collagen cross-linked C-peptide (CTX- I ) and tartrate-resistant acid phosphatase (TRACP) have correlated with bone destruction in patients with RA, in addition, evidence of new biomarker such as hepatocyte growth factor and macrophage inhibitory factor have been accumulated recently. These biomarkers may help evaluation of bone quality clinically.

Distinguishing the proapoptotic and antiresorptive functions of risedronate in murine osteoclasts: role of the Akt pathway and the ERK/Bim axis.

OBJECTIVE: Nitrogen-containing bisphosphonates are one of the most successful therapeutics for osteoporosis. The aim of this study was to elucidate the functional mechanism of one of the typical nitrogen-containing bisphosphonates, risedronate. METHODS: Osteoclasts generated from murine bone marrow macrophages were treated with risedronate in vitro, and its effects on apoptosis and bone-resorbing activity were examined. The mechanism of action of risedronate was examined by gene induction of constitutively active Akt-1 and constitutively active MEK-1, and by gene deletion of Bim. Bim(-/-) mice, in which osteoclasts were resistant to apoptosis, were treated with risedronate and analyzed radiographically, biochemically, and histologically. RESULTS: Risedronate induced osteoclast apoptosis through the mitochondria-dependent pathway with an increased expression of Bim, and the proapoptotic effect of risedronate was suppressed by Bim deletion and constitutively active MEK-1 introduction. In contrast, the risedronate-induced suppression of bone resorption was completely reversed by inducing constitutively active Akt-1, but not by Bim deletion or constitutively active MEK-1 introduction. These results suggested that apoptosis and bone-resorbing activity of osteoclasts were regulated through the ERK/Bim axis and the Akt pathway, respectively, both of which were suppressed by risedronate. Although osteoclast apoptosis in response to risedronate administration was suppressed in the Bim(-/-) mice, risedronate treatment increased bone mineral density in Bim(-/-) mice at a level equivalent to that in wild-type mice. CONCLUSION: Our findings indicate that the antiresorptive effect of risedronate in vivo is mainly mediated by the suppression of the bone-resorbing activity of osteoclasts and not by the induction of osteoclast apoptosis.

[Odanacatib (MK-0822)].

Bone homeostasis is maintained by delicate balance between bone resorption by osteoclasts and bone formation by osteoblasts. Bisphosphonates are widely used nowadays by suppressing bone resorption to treat patients with osteoporosis, which results from high bone turnover, causing excessive bone resorption phase. While bisphosphonates increase bone mineral density and improve back pain due to spinal compression fracture, they may have some problems such as osteonecrosis of jaw and excessive suppression of bone turnover. Cathepsin K inhibitor, which has a new mechanism in addition to function of suppressing bone resorption, is recently focused. Cathepsin K is a protease which specifically expresses in osteoclasts and plays an important role in resolution of bone collagen. Cathepsin K inhibitor has a potential of inhibiting bone resorption without suppressing bone formation and could be an attractive therapeutic target of osteoporosis.

Risk factors for pulmonary embolism and the effects of fondaparinux after total hip and knee arthroplasty: a retrospective observational study with use of a national database in Japan.

BACKGROUND: Clinical evidence demonstrating the effectiveness of pharmacological and mechanical thromboprophylaxis for the prevention of pulmonary embolism is limited because the prevalence of postoperative pulmonary embolism following total hip and knee arthroplasty is very low. Our purposes were to characterize a patient population with in-hospital pulmonary embolism, to identify perioperative risk factors associated with pulmonary embolism, and to analyze the effect of combining fondaparinux with mechanical prophylaxis on the prevalence of pulmonary embolism following total hip and knee arthroplasty. METHODS: We retrospectively identified 27,542 patients who underwent total hip or knee arthroplasty at 793 hospitals, using data from the Diagnosis Procedure Combination database, collected from July 1 to December 31 in 2007 and 2008. We extracted data on patient sex, age, primary diagnoses, and comorbidities that could potentially affect the prevalence of pulmonary embolism. The dates of pharmacological and mechanical thromboprophylaxis were identified for each patient. Logistic regression analysis was performed to analyze the concurrent effects of various factors on the prevalence of postoperative pulmonary embolism. RESULTS: The mean age (and standard deviation) of the patients at the time of arthroplasty was 69.9 ± 10.3 years, and 23,783 patients (86.4%) were diagnosed as having osteoarthritis. The overall mean duration of anesthesia was 159 ± 84 minutes. The overall prevalence of postoperative pulmonary embolism was 0.55% (151 of 27,542). Significant risk factors for postoperative pulmonary embolism included age, number of comorbidities, diagnosis of rheumatoid arthritis, type of anesthesia, and duration of anesthesia. Multivariate analysis found that the prevalence of postoperative pulmonary embolism was significantly reduced when fondaparinux was used in combination with mechanical prophylaxis, compared with the use of mechanical prophylaxis alone (0.40% versus 0.66%; odds ratio, 0.60; 95% confidence interval, 0.42 to 0.84; p = 0.003). CONCLUSIONS: These findings could help to identify patients at higher risk of postoperative pulmonary embolism after total hip or knee arthroplasty. Our results demonstrate the effectiveness of fondaparinux in combination with mechanical prophylaxis for the prevention of postoperative pulmonary embolism after total hip or knee arthroplasty.

Antiapoptotic molecule Bcl-2 is essential for the anabolic activity of parathyroid hormone in bone.

The antiapoptotic molecule Bcl-2 inhibits apoptosis by preventing cytochrome c release from mitochondria. Although several studies have indicated the importance of Bcl-2 in maintaining skeletal integrity, the detailed cellular and molecular mechanisms remain elusive. Since Bcl-2(-/-) mice die before six weeks of age on account of renal failure and cannot be compared to adult wild-type mice, we generated Bcl-2(-/-)Bim(+/-) mice, in which a single Bim allele was inactivated, and compared them with their Bcl-2(+/-)Bim(+/-) littermates. Bcl-2(-/-)Bim(+/-) mice grew normally, but exhibited decreased bone mass compared to Bcl-2(+/-)Bim(+/-) mice, mainly due to impaired osteoblast function. Interestingly, the anabolic effect of parathyroid hormone (PTH) was not observed in Bcl-2(-/-)Bim(+/-) mice. This data demonstrates that Bcl-2 is indispensable for the anabolic activity of PTH in bone.

Anti-apoptotic molecule Bcl-2 regulates the differentiation, activation, and survival of both osteoblasts and osteoclasts.

The anti-apoptotic molecule Bcl-2 inhibits apoptosis by preventing cytochrome c release from mitochondria. Although several studies have indicated the importance of Bcl-2 in maintaining skeletal integrity, the detailed cellular and molecular mechanisms remain elusive. Bcl-2(-/-) mice are growth-retarded and exhibit increased bone volume of the primary spongiosa, mainly due to the decreased number and dysfunction of osteoclasts. Osteoblast function is also impaired in Bcl-2(-/-) mice. Ex vivo studies on osteoblasts and osteoclasts showed that Bcl-2 promoted the differentiation, activation, and survival of both cell types. Because Bcl-2(-/-) mice die before 6 weeks of age due to renal failure and cannot be compared with adult wild type mice, we generated Bcl-2(-/-)Bim(+/-) mice, in which a single Bim allele was inactivated, and compared them with their Bcl-2(+/-)Bim(+/-) littermates. Loss of a single Bim allele restored normal osteoclast function in Bcl-2(-/-) mice but did not restore the impaired function of osteoblasts, and the mice exhibited osteopenia. These data demonstrate that Bcl-2 promotes the differentiation, activity, and survival of both osteoblasts and osteoclasts. The balance between Bcl-2 and Bim regulates osteoclast apoptosis and function, whereas other pro-apoptotic members are important for osteoblasts.

The antiapoptotic protein Bcl-xL negatively regulates the bone-resorbing activity of osteoclasts in mice.

The B cell lymphoma 2 (Bcl-2) family member Bcl-xL has a well-characterized antiapoptotic function in lymphoid cells. However, its functions in other cells--including osteoclasts, which are of hematopoietic origin--and other cellular processes remain unknown. Here we report an unexpected function of Bcl-xL in attenuating the bone-resorbing activity of osteoclasts in mice. To investigate the role of Bcl-xL in osteoclasts, we generated mice with osteoclast-specific conditional deletion of Bcl-x (referred to herein as Bcl-x cKO mice) by mating Bcl-xfl/fl mice with mice in which the gene encoding the Cre recombinase has been knocked into the cathepsin K locus and specifically expressed in mature osteoclasts. Although the Bcl-x cKO mice grew normally with no apparent morphological abnormalities, they developed substantial osteopenia at 1 year of age, which was caused by increased bone resorption. Bcl-x deficiency increased the bone-resorbing activity of osteoclasts despite their high susceptibility to apoptosis, whereas Bcl-xL overexpression produced the opposite effect. In addition, Bcl-x cKO osteoclasts displayed increased c-Src activity, which was linked to increased levels of vitronectin and fibronectin expression. These results suggest that Bcl-xL attenuates osteoclastic bone-resorbing activity through the decreased production of ECM proteins, such as vitronectin and fibronectin, and thus provide evidence for what we believe to be a novel cellular function of Bcl-xL.

Potential involvement of p53 in ischemia/reperfusion-induced osteonecrosis.

Idiopathic osteonecrosis of the femoral head (ION) is a devastating pathological condition of unknown etiology. In this study, we developed a simple murine model of osteonecrosis and investigated the underlying molecular mechanisms. In this model, the central portion of the tails of male C57BL/6 mice were tightly ligated to produce ischemic regions at sites distal to the ligatures. The occlusive ligatures were maintained for the indicated periods and then removed to induce reperfusion. The tails were histologically examined, and gene expression was analyzed by PCR array. The effect of p53 expression on osteocytes apoptosis was examined using preosteocytic MLO-A5 cells. In addition, the expression of p53 was analyzed in the femoral head samples obtained from hip osteoarthritis (OA) patients and ION patients. Caudal vertebrae distal to the ligatures (distal region) exhibited histological changes mimicking those observed in ION. Expression of p53 was increased in the distal region, and overexpression of p53 induced apoptosis in MLO-A5 cells. Treatment with a p53 inhibitor suppressed osteocyte apoptosis in the distal region. Strong p53 immunostaining was observed in osteocytes, vascular endothelial cells, and bone marrow cells in the femoral heads from ION patients but not from OA patients. Ischemia/reperfusion of the caudal vertebrae is a useful murine model of osteonecrosis, mimicking the histological changes found in ION. Using this model, we found the possible involvement of p53 in the osteocyte apoptosis observed in ION. Therapeutics targeting p53 might be a useful approach to ameliorating or even preventing osteonecrosis in ION patients.