Summary Statement. The effects of local glucocorticoid on tendon appear broadly negative and this supports the emerging clinical evidence which points toward significant long term harms associated with this treatment modality. Introduction. The use of locally administered glucocorticoid is widespread in the treatment of painful tendinopathy. Despite evidence of short term benefit, the emerging evidence points toward significant long term harms associated with this method of treatment, including an increased risk of recurrence, rupture and worsened clinical outcomes (1, 2). Our primary purpose was to summarise the known effects of locally administered glucocorticoid on tendon tissue and tendon cells. Methods. We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines of the Medline database using specific search criteria. Only studies analysing the effects of locally administered glucocorticoid on tendon tissue or tendon cells with adequate controls were included. Specific attention was paid to histological and biomechanical findings. Inclusion was agreed upon by two independent researchers after review of abstracts or full text. The search yielded 4424 results, of which 42 met the inclusion criteria. The final 42 articles consisted of 13 human in vitro studies, 15 animal in vivo studies and 14 animal in vitro studies. Results. Due to study heterogeneity, statistical pooling or meta-analysis of data was not possible. The results are therefore described qualitatively. Histologically, there was a loss of collagen structure (5 studies) and an increase in collagen necrosis (4 studies). The proliferation and viability of fibroblasts was reduced (11 studies). An increased inflammatory cell infiltrate was shown in 3 animal in vivo studies, while an increased fibroblast infiltrate was seen in 2 studies. Fibroblast migration was reduced in 2 in vitro studies. Collagen synthesis was reduced in 13 studies. An increased ratio of type 3 to type 1 Collagen was shown in 2 studies. Apoptosis was unaffected in 2 studies. 19 studies investigated the mechanical properties of tendon. Of these 7 showed deterioration in mechanical properties, 4 showed an improvement and 8 showed no difference. Discussion/Conclusion. Overall it is clear that the local administration of glucocorticoid has significant negative effects on tendon cells in vitro, such as reduced cell viability, cell proliferation and collagen synthesis. There is increased collagen disorganisation and necrosis as shown by animal in vivo studies. The mechanical effects are equivocal. This review supports emerging clinical evidence showing significant long term harms associated with glucocorticoid injections. There is clearly a significant need for better designed human trials with appropriate blinding and control arms to investigate the effects of glucocorticoid on both clinical outcomes and characteristics of tendon tissue

Clinical use of glucocorticoids engenders deleterious changes in bone fragility and initiates apoptosis in osteoblasts and osteocytes. The pathways leading to corticosteroid-induced death in bone remain unclear. Similarly little is known about the effects of ‘bone sparing’ bisphosphonates on osteocytes in vivo. We investigated the effects of bisphosphonates (BPs) on dexamethasone (Dex)-induced apoptosis in the murine osteocyte cell line, MLO-Y4 and studied the putative pathways involved by intervention with inhibitors of signalling molecules, such as p42/44 MAPK and protein kinase A (PKA). Cells were preincubated with N- & non N-containing BPs and/or inhibitors before insult with Dex or H. 2. O. 2. for 5 hrs. Apoptotic morphology was revealed by acridine orange staining. Activation of p42/44 was identified using Western blotting and in situ immunocytochemistry in the presence or absence of serum. Both N- & non N-containing BPs were shown to protect against cell death. The addition of inhibitors of p42/44 and PKA blocked the action of Dex. H. 2. O. 2. -induced apoptosis was not blocked by BPs or by any of the inhibitors. Dex appeared to activate p42/44 only in serum supplemented cultures. These data suggest that glucocorticoid but not oxidant-induced osteocyte apoptosis involves activation of p42/44 and that bisphosphonate engendered cell rescue is brought about by inhibition of these MAPK’s. Studies using truncated BPs that lack anti-resorptive activity, and therefore do not interrupt bone remodelling showed that these BPs were also able to protect osteocytes from glucocorticoid-induced death. The ability of bisphosphonates to influence MAPK activation and cell death in the osteocyte opens up exciting possibilities for pharmaceutical intervention during age and steroid hormone related osteocyte loss

Introduction. The objective of this study was to identify fat emboli in the arterioles of the femoral bone marrow by Scanning Electron Microscopy (SEM) after glucocorticoid administration. Methods. Female adult rabbits weighing 3.5 to 4.0 kg received a single injection of prednisolone at a dose of 4 mg/kg body weight. The day after injection was designated as day 1. Control rabbits were injected with only physiological saline and euthanized on day 14. The femoral bone marrow was obtained on days 5, 8, and 14, and processed for SEM. Aortic blood serum was passed through a filter, and the filter was processed for SEM. Some SEM specimens were embedded in a plastic resin and sectioned for correspondence of SEM-photomicroscopy or SEM-TEM. Results. In the controls, small fat globules were present in sinusoids and venules, but were absent from the arterioles. On day 5, fat globules were found in the lumina of both sinusoids and arterioles. Complete arteriolar occlusion was not found. On day 8, fat globules were often encountered in the venous and arteriolar lumina. Some small arterioles were completely occluded by fat emboli. On day 14, fat globules were present in the arterioles and some small and large arterioles were completely occluded. Blood drawn from the aorta contained fat globules in both the controls and rabbits injected with prednisolone. Conclusion. A small amount of prednisolone induced the presence of fat globules in arterioles as early as day 5, complete occlusion of small arterioles on day 8, and occlusion of large arterioles on day 14. The source of fat globules and the mechanism of arteriolar occlusion were discussed

There is a great need for suitable large animal models that closely resemble osteoporosis in humans, and that they have adequate bone size for bone prosthesis and biomaterial research. This study aimed to investigate effects of a 7 month glucocorticoid (GC) treatment alone without ovariectomy on the properties of sheep cancellous bone. Eighteen female sheep were randomly allocated into 3 groups: group 1 (GC-1) received GC (0.60mg/kg/day methylprednisolone) 5 days weekly for 7 months; group 2 (GC-2) received the same treatment regime for 7 months, and further observed for 3 months without GC; and group 3 served as the control group, and left untreated for 7 months. The sheep received restricted diet. After 7 months of GC treatment. Cancellous bone volume fraction of the 5th lumbar vertebra in the GC-1 group was reduced by −35%, trabecular thickness by −28%, and changed from typical plate structure to a combination of plate and rod structure with increased connectivity by 202%. Bone strength was reduced by 52%. Bone formation marker, serum osteocalcin of GC-1, was reduced by 71% at 7 months, but recovered with an increase of 45% at 10 month in the GC-2 group. Similar trends were also seen in the femur and tibia. At 10 months, the GC-2 group had microarchitectural and mechanical properties similar to the level of the control sheep. We have demonstrated in this study that 7 month high-dose GC on bone density and microarchitecture are comparable with those observed in human after long-term GC treatment. Moreover, we have shown that the bone quality with regard to strength and microarchitecture recovers after 3 months further observation without GC. This suggests that a prolonged administration of GC is needed for long-term observation to keep osteopenic bone. The model will be useful in pre-clinical studies

Objectives. The primary purpose of this meta-analysis was to determine whether statin usage could reduce the risk of glucocorticoid-related osteonecrosis in animal models. Methods. A systematic literature search up to May 2015 was carried out using the PubMed, Ovid, EBM reviews, ISI Web of Science, EBSCO, CBM, CNKI databases with the term and boolean operators: statins and osteonecrosis in all fields. Risk ratio (RR), as the risk estimate of specific outcome, was calculated along with 95% confidence intervals (CI). The methodological quality of individual studies was assessed using a quantitative tool based on the updated Stroke Therapy Academic Industry Roundtable (STAIR) recommendations. Results. A total of 11 eligible studies were included according to predetermined criteria. The pooled data demonstrated that animals with statin usage, either alone or combined with other treatments, were at a decreased risk of developing glucocorticoid-related osteonecrosis (RR = 2.06, 95% confidence interval (CI) 1.71 to 2.50). Moreover, subgroup analysis revealed that compared with statins alone, statins combined with other treatments significantly decreased the risk of osteonecrosis (RR = 1.23, 95% CI 1.02 to 1.47). However, we could find no significant risk difference for different gender, or for different time points. Conclusions. The present study suggests that statins combined with other treatments are efficient in preventing the development of glucocorticoid-related osteonecrosis in animals. These results might shed light on clinical practice when glucocorticoids are prescribed, and could be further investigated in high-quality clinical trials. Cite this article: Z. Yang, H. Liu, D. Li, X. Xie, T. Qin, J. Ma, P. Kang. The efficacy of statins in preventing glucocorticoid-related osteonecrosis in animal models: A meta-analysis. Bone Joint Res 2016;5:393–402. DOI: 10.1302/2046-3758.59.2000500

Introduction. Osteoarthritis (OA) often results from joint misloading, which affects chondrocyte calcium signaling through mechano-sensitive receptors such as Piezo1, -2, and TRPV4. Activation of Piezo1, especially under inflammatory conditions, can trigger premature chondrocyte apoptosis. Intra-articular glucocorticoid therapy, while beneficial against inflammation and pain in osteoarthritis, may induce oxidative stress and chondrotoxicity at higher doses. This study aims to assess the effects of glucocorticoids, particularly triamcinolone, on chondrocyte elasticity and mechanosignaling. Method. Chondrocytes isolated from articular condyles obtained from patients undergoing knee replacement surgery (n= 5) were cultured for 7 days in triamcinolone acetonide (TA) at different concentrations (0.2µM – 2mM). Cytoskeletal changes were assessed by F-actin labeling. Cell elasticity was measured using atomic force microscopy (AFM). Labeling cells (n=6 patients) with the calcium-sensitive dye (Fluo-4) enabled monitoring changes in intracellular calcium fluorescence intensity during guided single-cell mechanical indentation (500 nN) by AFM. Result. Cell exposure to 2 mM TA led to cell death and crystallization of TA in the cell culture media. However, the concentration of TA for intra-articular application is 46 times higher at 92.1 mM (40 mg/ml). The maximal pharmacological effect on viable cells was observed at 0.2 mM. AFM results showed a significant decrease of elasticity (p<0.001), alongside significantly higher calcium intensities both prior to and during mechanical stimulation in the TA-treated samples (p<0.05). Conclusion. Administration of TA significantly impacts the mechanical properties of chondrocytes, reducing cellular elasticity while simultaneously enhancing calcium-dependent mechanosensitivity. This data suggests a correlation between glucocorticoid-induced changes in cell elasticity and cell mechanosensitivity. Finding ways to minimize the effect of glucocorticoids on cell mechanosensitivity could help to make future therapies safer and reduce side effects

Osteoporosis is a common problem in postmenopausal women and the elderly. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a bi-directional enzyme that primarily activates glucocorticoids (GCs) in vivo, which is a considerable potential target as treatment for osteoporosis. Previous studies have demonstrated its effect on osteogenesis, and our study aimed to demonstrate its effect on osteoclast activation. In vivo, we used 11β-HSD1 knock-off (KO) and C57BL6/J mice to undergo the ovariectomy-induced osteoporosis (OVX). In vitro, In vivo, We used 11β-HSD1 knockoff (KO) and C57BL6/J mice to undergo the ovariectomy-induced osteoporosis (OVX). In vitro, bone marrow-derived macrophages (BMM) and bone marrow mesenchymal stem cell (BMSC) of KO and C57BL6/J mice were extracted to test their osteogenic and osteoclastic abilities. We then created osteoclastic 11β-HSD1 elimination mice (Ctsk::11β-HSD1fl/fl) and treated them with OVX. Micro-CT analysis, H&E, immunofluorescence staining, and qPCR were performed. Finally, we conducted the high-throughput sequencing to find out 11β-HSD1 and osteoclast activation related genes. We collected 6w samples after modeling. We found that KO mice were resistant to loss of bone trabeculae. The same effect was observed in osteoclastic 11β-HSD1 elimination mice. Meanwhile, BVT-2733, a classic inhibitor of 11β-HSD1, inhibited the osteoclast effect of cells without affecting osteogenic effect in vitro. High-throughput sequencing suggested that glucocorticoid receptor (GR) may play a key role in the activation of osteoclasts, which was verified by immunofluorescence staining and WB in vivo and in vitro. In the process of osteoporosis, 11β-HSD1 expression of osteoclasts is abnormally increased, which may be a new target for inhibiting osteoclast activation and treating osteoporosis

Glucocorticoid excess is shown to deteriorate bone tissue integrity, increasing the risk of osteoporosis. Marrow adipogenesis at cost of osteogenesis is a prominent feature of this osteoporosis condition. Epigenetic pathway histone deacetylase (HDAC)-mediated histone acetylation regulates osteogenic activity and bone mass. This study is aimed to figure out what role of acetylated histone reader bromodomain-containing protein 4 (BRD4) did play in glucocorticoid-induced osteoporosis. Bone-marrow mesenchymal stem cells were incubated in osteogenic medium with or without 1 μM dexamethasone. Mineralized matrix and adipocyte formation were probed using von Kossa and Nile Red O staining, respectively. Osteogenic and adipogenic marker expression were quantified using RT-PCR. The binding of acetylated histone to promoter of transcription factors were detected using chromatin immunoprecipitation-PCR. Bone mineral density and microstructure in osteoporotic bone were quantified with microCT system. Glucocorticoid repressed osteogenic transcription factor Runx2 expression and mineralized matrix formation along with a low level of acetylated lysine 9 at histone 3 (H3K9ac), whereas BRD4 signaling and adipocytic formation were increased in cell cultures. BRD4 knockdown reversed the H3K9ac enrichment in Runx2 promoter and osteogenesis, but downregulated adipogenic differentiation. Silencing BRD4 attenuated H3K9ac occupancy in forkhead box P1 (Foxp1) relevant to lipid metabolism upon glucocorticoid stress. Foxp1 interference downregulated adipogenic activities of glucocorticoid-treated cells. In vivo, treatment with BRD4 inhibitor JQ-1 compromised the glucocorticoid-induced bone mineral density loss, spare trabecular structure, and fatty marrow, as well as improved biomechanical properties of bone tissue. Taken together, BRD4-mediated Foxp1 pathways drive mesenchymal stem cells shifting toward adipocytic cells rather than osteogenic cells to aggravates excessive marrow adipogenesis in the process of glucocorticoid-induced osteoporosis. Pharmacological inhibition of BRD4 signaling protects bone tissue from bone loss and fatty marrow in glucocorticoid-treated mice. This study conveys a new molecular insight into epigenetic regulation of osteogenesis and adipogenesis in osteoporotic skeleton and highlight the remedial effect of BRD4 inhibitor on glucocorticoid-induced bone loss

Chronic glucocorticoid use causes osteogenesis loss, accelerating the progression of osteoporosis. Histone methylation is shown to epigenetically increase repressive transcription, altering lineage programming of mesenchymal stem cells (MSC). This study is undertaken to characterize the action of histone demethylase UTX to osteogenic lineage specification of bone-marrow MSC and bone integrity upon glucocorticoid treatment. Bone-marrow MSC were incubated in osteogenic medium containing supraphysiological dexamethasone. Osteogenic gene expression and mineralized nodule formation were probed using RT-PCR and von Kossa staining. The enrichment of trimethylated lysine 27 at histone 3 (H3K27me3) in Dkk1 promoter was quantified using chromatin immunoprecipitation-PCR. Bone mass and trabecular morphometry in methylprednisolone-treated skeletons were quantified using microCT analysis. Supraphysiological dexamethasone decreased osteogenic genes Runx2 and osteocalcin expression and mineralized matrix production along with reduced UTX expression in MSC. Forced UTX expression attenuated the glucocorticoid-mediated loss of osteogenic differentiation, whereas UTX knockdown provoked osteogenesis loss and cytoplasmic oil overproduction. UTX demethylated H3K27 and reduced the glucocorticoid-mediated the H3K27 enrichment in Dkk1 promoter, reversing beta-catenin signal, but downregulating Dkk1 production by MSC. In vivo, treatment with UTX inhibitor GSK-J4 significantly suppressed bone mineral density, trabecular volume, and thickness along with porous trabecular, fatty marrow and disturbed beta-catenin/Dkk1 histopathology comparable with glucocorticoid-induced osteoporosis condition. This study offers a productive insight into how UTX protects MSC from methylated histone-mediated osteogenesis repression in the development of glucocorticoid-induced osteoporosis

Background. Long-term glucocorticoid treatment increases incidence of osteoporotic or osteonecrotic disorders. Excessive bone loss and marrow fat accumulation are prominent features of glucocorticoid-induced osteoporosis. MicroRNA-29 (miR-29) family members reportedly modulate lineage commitment of stem cells. This study was undertaken to define the biological roles of miR-29a in skeletal and fat metabolism in the pathogenesis of glucocorticoid-induced osteoporosis. Methods. Osteoblast-specific miR-29a transgenic mice (Tg) driven by osteocalcin promoter (C57BL/6JNarl-TgOCN-mir29a) or wild-type (WT) mice were given methylprednisolone. Bone mass, trabecular and cortical bone microarchitecture were assessed by μCT. Comparative mRNA and protein expression was quantified by RT-PCR and immunoblotting. Primary bone-marrow mesenchymal cells were isolated for elucidating ex vivo osteogenic and adipogenic differentiation capacity. Results. Decremented miR-29a expression was associated with severe skeletal deterioration and excessive marrow adipogenesis in glucocorticoid-induced osteoporosis bone tissue. Tg mice had high bone mass, spacious trabecular bone and thick cortical bone microstructure. Tg mice also had modest responses to the deleterious actions of glucocorticoid on trabecular microstructure and histomorphological characteristics, mineral acquisition and attenuated marrow fat deposition and osteoclast resorption. Ex vivo, miR-29a overexpression promoted bone-marrow mesenchymal progenitor cells differentiation towards osteogenic cells and away from adipogenic lineage cells. Mechanistically, miR-29a via inhibiting histone deacetylase 4 (HDAC4) actions restored acetylation states of osteogenic regulators Runx2 and β-catenin and decreased osteoclastogenic factor RANKL and adipokine leptin expression in bone microenvironments. Conclusions. Glucocorticoid suppression of miR-29a disintegrates the homeostasis between osteogenic and adipogenic activities, thereby impairs bone formation and skeletal integrity. By suppressing HDAC4, miR-29a stabilizes Runx2 and β-catenin signalling that counteracts the adverse effects of glucocorticoid on bone mass and marrow adiposity. This study unveils the anabolic roles of miR-29a in the progression of glucocorticoid-induced bone loss. Sustained miR-29a action is beneficial for protecting against osteoporosis and excessive marrow adipogenesis. Level of evidence. I

The effects of dexamethasone (dex), during in vitro human osteogenesis, are contrasting. Indeed, dex downregulates SOX9 during osteogenic differentiation of human bone marrow mesenchymal stromal cells (HBMSCs). However, dex also promotes PPARG expression, resulting in the formation of adipocyte-like cells within the osteogenic monolayers. The regulation of both SOX9 and PPARG seems to be downstream the transactivation activity of the glucocorticoid receptor (GR), thus the effect of dex on SOX9 downregulation is indirect. This study aims at determining whether PPAR-γ regulates SOX9 expression levels, as suggested by several studies. HBMSCs were isolated from bone marrow of patients with written informed consent. HBMSCs were cultured in different osteogenic induction media containing 10 or 100 nM dex. Undifferentiated cells were used as controls. Cells were treated either with a pharmacological PPAR-γ inhibitor T0070907 (donors n=4) or with a PPARG-targeting siRNA (donors n=2). Differentiation markers or PPAR-γ target genes were analysed by RT-qPCR. Mineral deposition was assessed by ARS staining. Two-way ANOVA followed by a Tukey's multiple comparison test compared the effects of treatments. At day 7, T0070907 downregulated ADIPOQ and upregulated CXCL8, respectively targets of PPAR-γ-mediated transactivation and transrepression. RUNX2 and SOX9 were also significantly downregulated in absence of dex. PPARG was successfully downregulated by siRNA. ADIPOQ expression was also inhibited, while CXCL8 did not show any significant difference between siRNA treatment groups. RUNX2 was downregulated by the PPARG-siRNA treatment in presence of 100 nM dexamethasone, while SOX9 levels were not affected. ARS showed no change in the mineralization levels when PPARG expression or activity was inhibited. Understanding how dex regulates HBMSC differentiation is of pivotal importance to refine current in vitro models. These results suggest that PPARG does not mediate SOX9 downregulation. Unexpectedly, RUNX2 expression was also unaltered or even downregulated after PPAR-γ inhibition. Acknowledgements: AO Foundation, AO Research Institute (CH) and PRIN 2017 MUR (IT) for financial support

Introduction: Rotator cuff tears are a common injury which affects both the young athlete and the sedentary elderly alike. This condition is commonly treated with glucocorticoid injections as part of initial management. The effects, however, of these injections on the histology of collagen and the metabolism of tendon fibroblasts are still controversial. Materials and methods: In this study, samples from 19 patients with rotator cuff tears were taken during definitive surgery to manage these tears. There was a history of glucocorticoid injections in all of the patients. The samples were examined in terms of histopathology using light microscopy, in situ hybridization to detect the presence of glucocorticoid receptor mRNA and TUNEL assay to determine the incidence of apoptosis. Results: Light microscopy of hematoxylin-eosin stained samples from the study group showed marked cellularity although there were no signs of inflammation. The nuclei were noted to be rounded and a significant number showed pyknosis. Angiogenesis was also noted in the sections, consistent with previous finding of angio-fibroblastic hyperplasia as a characteristic of tendinosis. Collagen structure was noted to be abnormal, with longitudinal clefts and focal areas of marked disorganization of fibers. In situ hybridization showed a strong signal for glucocorticoid receptor mRNA in all of the samples. TUNEL assay also showed a strong signal for apoptosis of the tendon fibroblasts in the study group as compared to the control group which showed almost no signal. Conclusion: Our results suggest that although an overall picture of hypercellularity is seen in cases of tendinosis and tendon tears, a high percentage of these cells are undergoing apoptosis. This may reflect a natural high rate of turnover of cells during the process of repair or may be due to exogenous factors. Glucocorticoids almost certainly affect metabolism of tendon fibroblasts and subsequently collagen structure as seen by the abundant expression of the receptor mRNA. However, a causal relationship between glucocorticoids and apoptosis of tenocytes is yet to be established

Objectives. Intra-articular injections of local anaesthetics (LA), glucocorticoids (GC), or hyaluronic acid (HA) are used to treat osteoarthritis (OA). Contrast agents (CA) are needed to prove successful intra-articular injection or aspiration, or to visualize articular structures dynamically during fluoroscopy. Tranexamic acid (TA) is used to control haemostasis and prevent excessive intra-articular bleeding. Despite their common usage, little is known about the cytotoxicity of common drugs injected into joints. Thus, the aim of our study was to investigate the effects of LA, GC, HA, CA, and TA on the viability of primary human chondrocytes and tenocytes in vitro. Methods. Human chondrocytes and tenocytes were cultured in a medium with three different drug dilutions (1:2; 1:10; 1:100). The following drugs were used to investigate cytotoxicity: lidocaine hydrochloride 1%; bupivacaine 0.5%; triamcinolone acetonide; dexamethasone 21-palmitate; TA; iodine contrast media; HA; and distilled water. Normal saline served as a control. After an incubation period of 24 hours, cell numbers and morphology were assessed. Results. Using LA or GC, especially triamcinolone acetonide, a dilution of 1:100 resulted in only a moderate reduction of viability, while a dilution of 1:10 showed significantly fewer cell counts. TA and CA reduced viability significantly at a dilution of 1:2. Higher dilutions did not affect viability. Notably, HA showed no effects of cytotoxicity in all drug dilutions. Conclusion. The toxicity of common intra-articular injectable drugs, assessed by cell viability, is mainly dependent on the dilution of the drug being tested. LA are particularly toxic, whereas HA did not affect cell viability. Cite this article: P. Busse, C. Vater, M. Stiehler, J. Nowotny, P. Kasten, H. Bretschneider, S. B. Goodman, M. Gelinsky, S. Zwingenberger. Cytotoxicity of drugs injected into joints in orthopaedics. Bone Joint Res 2019;8:41–48. DOI: 10.1302/2046-3758.82.BJR-2018-0099.R1

Background: Comparison of intra-articular corticoid injections and oral corticosteroids in the treatment of adhesive capsulitis of the shoulder. Methods: In a prospective randomized evaluation two different treatment regimen were compared. 40 patients with idiopathic adhesive capsulitis of the shoulder were treated either with an oral (20) corticoid treatment regimen for 4 weeks or intra-articular (20) injection series of corticosteroids (3 injections- 4, 8, 12 weeks).Patient groups were comparable in sex, age and affected side. Follow-up periods were after 4,8,12 weeks, 6 and 12 months. For the clinical evaluation the Constant and Murley Score, the Simple Shoulder Test and visual analog scales for pain, function and satisfaction were used. Results: In the patients group treated with oral glucocorticoids significant improvements were found for the Constant and Murley Score (p< .0001), the Simple Shoulder Test (p=.035) and range of motion for flexion (p< .0001), abduction (p< .0001), external (p=.001) and internal rotation (p=.028) already at 4 weeks follow-up. The visual analog scales for pain, function and patient satisfaction also improved significantly after 4 weeks of treatment (p< .0001).). The patient group treated with an intra-articular glucocorticoid injection series also showed significant improvements for the Constant and Murley Score (p< .0001), the Simple Shoulder Test (p< .0001) and the visual analog scales for pain, function and patient satisfaction (p< .0001) after 4 weeks and also at any other follow up. Significant improvements were also seen in abduction (p< .0001), flexion (p< .0001) and external rotation (p=.001) and internal rotation (p=.035) after 4 weeks of treatment. These results were confirmed at any other follow up. Comparison of the two treatment regimen showed superior short term results for the intra-articular treatment regimen in range of motion, Constant Score and Simple Shoulder Test and patient satisfaction (p< .05). No significant differences were found in the visual analog scales for pain and function (p> .05). Conclusion: The use of cortisone in the treatment of idiopathic adhesive capsulitis of the shoulder leads to fast pain relief and improves range of motion. Intra-articular injections of glucocorticoids showed superior short term results in objective shoulder scores, range of motion and patient satisfaction compared with a short course of oral corticosteroids

Objective. The aim of this study was to investigate the clinical results of treatment for patients with periprosthetic joint infection (PJI) following total knee arthroplasty (TKA) in our department. Patients and Methods. Between April 2004 and March 2014, 9 patients with rheumatoid arthritis (RA) and 6 patients with osteoarthritis (OA) were identified as PJI following TKA and treated in our hospital. We investigated retrospectively the data of each patient, including the clinical background and the peri-operative data as well as the outcome at final follow-up. Results. The mean duration between the TKA and the onset of PJI was 5.8 years (1–234 months), and 3 cases were PJI within 1 year following TKA. In RA patients, 5 of 9 patients used glucocorticoids and the mean dosage was 4.4 mg per day (2–8 mg) and 4 of 9 patients were treated by using biologics. Intensive irrigation and synovectomy was done in 11 patients, one-stage revision surgery in 2 patients, removal of prosthesis with antibiotic-containing cement spacer in 1 patient, and treated conservatively in 1 patient due to severe renal dysfunction. At the final follow-up, the knee prosthesis was survived in all patients except the removal case. However, continuous usage of oral antibiotics were needed for long period to avoid recurrence of infection. Discussions and Conclusions. PJI is one of the most serious problems following total joint arthroplasty and intensive treatment was usually applied to control infection. This study showed that surgical intervention such as intensive irrigation and synovectomy was useful for treatment PJI. Although it remains controversial whether one-stage or two-stage revision surgery is suitable for treatment of PJI following TKA, one-stage revision surgery was useful in our cases. Because 12 of 15 cases were PJI more than 1 year after TKA, we should consider the risk of late-onset infection, especially in RA patients with usage of glucocorticoids or biologics

Perioperative glucocorticoids have been used as a successful non-opioid analgesic adjunct for various orthopaedic procedures. Here we describe an ongoing randomized control trial assessing the efficacy of a post-operative methylprednisolone taper course on immediate post-operative pain and function following surgical distal radius fixation. We hypothesize that a post-operative methylprednisolone taper course following distal radius fracture fixation will lead to improved patient pain and function. This study is a randomized control trial (NCT03661645) of a group of patients treated surgically for distal radius fractures. Patients were randomly assigned at the time of surgery to receive intraoperative dexamethasone only or intraoperative dexamethasone followed by a 6-day oral methylprednisolone (Medrol) taper course. All patients received the same standardized perioperative pain management protocol. A pain journal was used to record visual analog pain scores (VAS-pain), VAS-nausea, and number of opioid tablets consumed during the first 7 post-operative days (POD). Patients were seen at 2-weeks, 6-weeks, and 12-weeks post-operatively for clinical evaluation and collection of patient reported outcomes (Disabilities of the Arm, Shoulder and Hand Score [qDASH]). Differences in categorical variables were assessed with χ2 or Fischer's exact tests. T-tests or Mann-Whitney-U tests were used to compare continuous data. Forty-three patients were enrolled from October 2018 to October 2019. 20 patients have been assigned to the control group and 23 patients have been assigned to the treatment group. There were no differences in age (p=0.7259), Body Mass Index (p=0.361), race (p=0.5605), smoking status (p=0.0844), or pre-operative narcotic use (p=0.2276) between cohorts. 83.7% (n=36) of patients were female and the median age was 56.9 years. No differences were seen in pre-operative qDASH (p=0.2359) or pre-operative PRWE (p=0.2329) between groups. In the 7 days following surgery, patients in the control group took an average of 16.3 (±12.02) opioid tablets, while those in the treatment group took an average of 8.71 (±7.61) tablets (p=0.0270). We see that significant difference in Opioid consumption is formed at postoperative day two between the two groups with patients in the control group taking. Patient pain scores decreased uniformly in both groups to post-operative day 7. Patient pain was not statistically from POD0 to POD2 (p=0.0662 to 0.2923). However, from POD4 to POD7 patients receiving the methylprednisolone taper course reported decreased pain (p=0.0021 to 0.0497). There was no difference in qDASH score improvement at 6 or 12 weeks. Additionally, no differences were seen for wrist motion improvement at 6 or 12 weeks. A methylprednisolone taper course shows promise in reducing acute pain in the immediate post-operative period following distal radius fixation. Furthermore, although no statistically significant reductions in post-operative opioid utilization were noted, current trends may become statistically significant as the study continues. No improvements were seen in wrist motion or qDASH and continued enrollment of patients in this clinical trial will further elucidate the role of methylprednisolone for these outcomes

Osteoporosis is a disease when bone mass and tissue is lost, with a consequent increase in bone fragility and increase susceptibility to develop fracture. The osteoporosis prevalence increases markedly with age, from 2% at 50 years to more than 25% at 80 years. 1. in women. The vast majority of distal radius fractures (DRFs) can be considered fragility fractures. The DRF is usually the first medical presentation of these fractures. With an aging population, all fracture clinics should have embedded screening for bone health and falls risk. DRF is the commonest type of fracture in perimenopausal women and is associated with an increased risk of later non-wrist fracture of up to one in five in the subsequent decade. 2. . According to the national guidelines in managing the fragility fractures of distal radius with regards the bone health review, we, as orthopedic surgeons, are responsible to detect the risky patients, refer them to the responsible team to perform the required investigations and offer the treatment. We reviewed our local database (E-trauma) all cases of fracture distal radius retrospectively during the period from 01/08/2019 to 29/09/2019. We included total of 45 patients who have been managed conservatively and followed up in fracture clinic. Our inclusion criteria was: women aged 65 years and over, men aged 75 years and over with risk factors, patients who are more than 50 years old and sustained low energy trauma whatever the sex is or any patient who has major risk factor (current or frequent recent use of oral or systemic glucocorticoids, untreated premature menopause or previous fragility fracture). We found that 96% of patients were 50 years old or more and 84% of the patients were females. 71% of patients were not referred to Osteoporosis clinic and 11% were already under the orthogeriatric care and 18% only were referred. Out of the 8 referred patients, 3 were referred on 1st appointment, 1 on the 3rd appointment, 1 on discharge from fracture clinic to GP again and 3 were without clear documentation of the time of referral. We concluded that we as trust are not compliant to the national guidelines with regards the osteoporosis review for the DRF as one of the first common presentations of fragility fractures. We also found that the reason for that is that there is no definitive clear pathway for the referral in our local guidelines. We recommended that the Osteoporosis clinic referral form needs to be available in the fracture clinic in an accessible place and needs to be filled by the doctor reviewing the patient in the fracture clinic in the 1st appointment. A liaison nurse also needs to ensure these forms have been filled and sent to the orthogeriatric team. Alternatively, we added a portal on our online database (e-trauma), therefore the patient who fulfils the criteria for bone health review should be referred to the orthogeriatric team to review

Introduction: In the pathogenesis of steroid-associated femoral head necrosis only intra- and extravascular factors have been discussed. This study investigated the effect of long term glucocorticoid treatment on contraction of intraosseous femoral head arteries in a porcine model. Materials and Methods: From 24 immature female Danish Landrace pigs from 12 litters, 12 animals received 100 mg methylprednisolone daily for 3 months. Their 12 sister pigs served as controls and received no steroids. Resistance arteries (diameter approximately 250 μm) were isolated from the femoral head epiphyseal cancellous bone and mounted as ring preparations on a small vessel myograph for measurement of isometric force development. Results: Increasing doses of endothelin-1 evoked significantly stronger vasoconstriction after 3 months of methylprednisolone treatment. The vasocontractory response to increasing doses of noradrenaline was not altered by the previous methylprednisolone treatment. After submaximal precontraction by noradrenaline, vasorelaxation by bradykinin was not altered by methylprednisolone treatment. Discussion: The vasocontractory response of isolated intraosseous femoral head epiphyseal arteries to endothelin-1 after long term glucocorticoid treatment in the pig was enhanced. Enhanced contraction of FH lateral epiphyseal arteries can diminish femoral head blood flow as vessel diameter decreases. This may be a relevant cofactor in the early pathogenesis of steroid-associated femoral head necrosis

Introduction: Osteomyelitis often causes functional impairment due to tissue destruction and the incidence of this condition appears to be increasing. Antimicrobial peptides (AP) are effectors of the innate defence system and play a key role in host protection at cellular surfaces. Human beta-defensins (HBD) represent a major subclass of antimicrobial peptides and act as a first line defence through their broad spectrum of potent antimicrobial activity (1). The aim of the present in vitro and in vivo investigations was to study the expression and regulation of HBD-2 and -3 in the case of bacterial bone infection and to analyze the effects of immunosuppressive drugs on bone-derived AP-expression. Methods: Samples of healthy human bone, osteomyelitic bone and cultured osteoblasts (primary-, hFOB- and SAOS-2 cells) were assessed for the expression of HBD-2/-3 by RT-PCR, immunohistochemistry or ELISA. Regulation of HBD-2/-3 was studied after exposure to Staphylococcus aureus (SAS) or Pseudomonas aeruginosa (PAS), proinflammatory cytokines (IL-1, 10ng/ml) and immunosuppressive drugs (glucocorticoids, methotrexate) and was assayed by ELISA. An osteomyelitis mouse model was performed to demonstrate the regulation of the murine homologues of HBD-2/-3 by real time RT-PCR and immunohistochemistry. Results: ELISA experiments demonstrated, that samples of infected bone produce higher levels of endogenous antibiotics such as HBD-2 when compared with samples of healthy bone. After exposure of osteoblasts to bacteria or proinflammatory cytokines a clear HBD-2/-3 induction was observed. Additional treatment with glucocorticoids or methotrexate prevented bacteria mediated HBD-2 induction in cultured osteoblasts. The osteomyelitis mouse model demonstrated transcriptional up-regulation of the murine HBD-homologues in bone after intra-osseous contamination of the tibia. Discussion: Our study firstly demonstrate that osteoblasts are able to produce anti-inflammatory peptides such as HBD-2 in vitro and in an animal model of staphylococcal osteomyelitis. We provide evidence for a new role of osteoblasts during infection of bone tissues, namely, the ability to produce antimicrobial peptides and modulating immune responses in inflammatory bone diseases. Immunosuppressive drugs such as glucocorticoids or methotrexate may increase the susceptibility to bone infection by decreasing AP-expression levels in case of microbial challenge. Novel approaches to management are required particularly in the era of multi-resistant bacterial strains. Current investigation will focus on the regulation of human β-Defensins in bone and may allow artificial amplification for prevention of bacterial bone infection in the future

Fatty marrow and bone loss are prominent pathologic features of osteoporosis. DNA hypermethylation shifts mesenchymal stem cells towards adipocytes impairing bone formation. Brown adipocytes produce growth factors advantageous to osteogenesis, whereas white adipocytes secrete pro-inflammatory cytokines deleterious to bone homeostasis. We assess DNA methylation inhibitor action to brown and white adipocyte formation in marrow fat of osteoporotic skeletons. Osteoporotic skeletons in mice were induced by glucocorticoid, ovariectomy or ageing. Marrow adipose volume and bone structure were quantified using OsO4 contrast-μCT imaging. Brown and white adipocytes were probed using immunostaining, RT-PCR and primary bone-marrow mesenchymal stem cell cultures. Abundant marrow fat and spare trabecular bone existed in osteoporotic skeletons. Osteoporosis increased expressions of general adipogenic markers PPARγ2 and FABP4 and white adipocyte markers TCF21 and HOXc9, whereas expressions of brown adipocyte markers PGC-1α and UCP-1 and osteogenic markers Runx2 and osteocalcin were significantly decreased. Number of UCP-1 immunostaining-positive brown adipocytes also reduced in osteoporotic bone. In vitro, DNA methylation inhibitor 5'-aza-deoxycystidine significantly increased brown adipocyte formation and osteogenic differentiation and mitigated dexamethasone-induced white adipocyte formation in mesenchymal stem cells. 5'-aza-deoxycystidine control of brown adipogenesis and white fat formation appeared to be regulated by increasing Wnt3a/β-catenin and reducing Dkk1. Disintegrated brown adipocyte and white fat cell differentiation contribute to osteoporosis pathogenesis. Maintaining DNA hypomethylation promotes Wnt signalling and brown adipocyte differentiation facilitating osteogenic differentiation. This study shed a new light to the contribution of brown adipocytic cells to bone metabolism during osteoporosis