A balanced inflammatory response is important for successful fracture healing. The response of osteoporotic fracture healing is deranged and an altered inflammatory response can be one underlying cause. The objectives of this review were to compare the inflammatory responses between normal and osteoporotic fractures and to examine the potential effects on different healing outcomes. A systematic literature search was conducted with relevant keywords in PubMed, Embase, and Web of Science independently. Original preclinical studies and clinical studies involving the investigation of inflammatory response in fracture healing in ovariectomized (OVX) animals or osteoporotic/elderly patients with available full text and written in English were included. In total, 14 articles were selected. Various inflammatory factors were reported; of those tumour necrosis factor-α (TNF-α) and interleukin (IL)-6 are two commonly studied markers. Preclinical studies showed that OVX animals generally demonstrated higher systemic inflammatory response and poorer healing outcomes compared to normal controls (SHAM). However, it is inconclusive if the local inflammatory response is higher or lower in OVX animals. As for clinical studies, they mainly examine the temporal changes of the inflammatory stage or perform comparison between osteoporotic/fragility fracture patients and normal subjects without fracture. Our review of these studies emphasizes the lack of understanding that inflammation plays in the altered fracture healing response of osteoporotic/elderly patients. Taken together, it is clear that additional studies, preclinical and clinical, are required to dissect the regulatory role of inflammatory response in osteoporotic fracture healing. Cite this article: Bone Joint Res 2020;9(7):368–385

Aims. Fibrinolysis plays a key transition step from haematoma formation to angiogenesis and fracture healing. Low-magnitude high-frequency vibration (LMHFV) is a non-invasive biophysical modality proven to enhance fibrinolytic factors. This study investigates the effect of LMHFV on fibrinolysis in a clinically relevant animal model to accelerate osteoporotic fracture healing. Methods. A total of 144 rats were randomized to four groups: sham control; sham and LMHFV; ovariectomized (OVX); and ovariectomized and LMHFV (OVX-VT). Fibrinolytic potential was evaluated by quantifying fibrin, tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) along with healing outcomes at three days, one week, two weeks, and six weeks post-fracture. Results. All rats achieved healing, and x-ray relative radiopacity for OVX-VT was significantly higher compared to OVX at week 2. Martius Scarlet Blue (MSB) staining revealed a significant decrease of fibrin content in the callus in OVX-VT compared with OVX on day 3 (p = 0.020). Mean tPA from muscle was significantly higher for OVX-VT compared to OVX (p = 0.020) on day 3. Mechanical testing revealed the mean energy to failure was significantly higher for OVX-VT at 37.6 N mm (SD 8.4) and 71.9 N mm (SD 30.7) compared with OVX at 5.76 N mm (SD 7.1) (p = 0.010) and 17.7 N mm (SD 11.5) (p = 0.030) at week 2 and week 6, respectively. Conclusion. Metaphyseal fracture healing is enhanced by LMHFV, and one of the important molecular pathways it acts on is fibrinolysis. LMHFV is a promising intervention for osteoporotic metaphyseal fracture healing. The improved mechanical properties, acceleration of fracture healing, and safety justify its role into translation to future clinical studies. Cite this article: Bone Joint Res 2021;10(1):41–50

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Previous studies have suggested that selenium as a trace element is involved in bone health, but findings related to the specific effect of selenium on bone health remain inconclusive. Thus, we performed a meta-analysis by including all the relevant studies to elucidate the association between selenium status (dietary intake or serum selenium) and bone health indicators (bone mineral density (BMD), osteoporosis (OP), or fracture).

Aims. There is an increasing concern of osteoporotic fractures in the ageing population. Low-magnitude high-frequency vibration (LMHFV) was shown to significantly enhance osteoporotic fracture healing through alteration of osteocyte lacuno-canalicular network (LCN). Dentin matrix protein 1 (DMP1) in osteocytes is known to be responsible for maintaining the LCN and mineralization. This study aimed to investigate the role of osteocyte-specific DMP1 during osteoporotic fracture healing augmented by LMHFV. Methods. A metaphyseal fracture was created in the distal femur of ovariectomy-induced osteoporotic Sprague Dawley rats. Rats were randomized to five different groups: 1) DMP1 knockdown (KD), 2) DMP1 KD + vibration (VT), 3) Scramble + VT, 4) VT, and 5) control (CT), where KD was performed by injection of short hairpin RNA (shRNA) into marrow cavity; vibration treatment was conducted at 35 Hz, 0.3 g; 20 minutes/day, five days/week). Assessments included radiography, micro-CT, dynamic histomorphometry and immunohistochemistry on DMP1, sclerostin, E11, and fibroblast growth factor 23 (FGF23). In vitro, murine long bone osteocyte-Y4 (MLO-Y4) osteocyte-like cells were randomized as in vivo groupings. DMP1 KD was performed by transfecting cells with shRNA plasmid. Assessments included immunocytochemistry on osteocyte-specific markers as above, and mineralized nodule staining. Results. Healing capacities in DMP1 KD groups were impaired. Results showed that DMP1 KD significantly abolished vibration-enhanced fracture healing at week 6. DMP1 KD significantly altered the expression of osteocyte-specific markers. The lower mineralization rate in DMP1 KD groups indicated that DMP1 knockdown was associated with poor fracture healing process. Conclusion. The blockage of DMP1 would impair healing outcomes and negate LMHFV-induced enhancement on fracture healing. These findings reveal the importance of DMP1 in response to the mechanical signal during osteoporotic fracture healing. Cite this article: Bone Joint Res 2022;11(7):465–476

Objectives. The treatment of osteoporotic fractures is a major challenge, and the enhancement of healing is critical as a major goal in modern fracture management. Most osteoporotic fractures occur at the metaphyseal bone region but few models exist and the healing is still poorly understood. A systematic review was conducted to identify and analyse the appropriateness of current osteoporotic metaphyseal fracture animal models. Materials and Methods. A literature search was performed on the Pubmed, Embase, and Web of Science databases, and relevant articles were selected. A total of 19 studies were included. Information on the animal, induction of osteoporosis, fracture technique, site and fixation, healing results, and utility of the model were extracted. Results. Fracture techniques included drill hole defects (3 of 19), bone defects (3 of 19), partial osteotomy (1 of 19), and complete osteotomies (12 of 19). Drill hole models and incomplete osteotomy models are easy to perform and allow the study of therapeutic agents but do not represent the usual clinical setting. Additionally, biomaterials can be filled into drill hole defects for analysis. Complete osteotomy models are most commonly used and are best suited for the investigation of therapeutic drugs or noninvasive interventions. The metaphyseal defect models allow the study of biomaterials, which are associated with complex and comminuted osteoporotic fractures. Conclusion. For a clinically relevant model, we propose that an animal model should satisfy the following criteria to study osteoporotic fracture healing: 1) induction of osteoporosis, 2) complete osteotomy or defect at the metaphysis unilaterally, and 3) internal fixation. Cite this article: R. M. Y. Wong, M. H. V. Choy, M. C. M. Li, K-S. Leung, S. K-H. Chow, W-H. Cheung, J. C. Y. Cheng. A systematic review of current osteoporotic metaphyseal fracture animal models. Bone Joint Res 2018;7:6–11. DOI: 10.1302/2046-3758.71.BJR-2016-0334.R2

Aims. The optimal choice of management for proximal humerus fractures (PHFs) has been increasingly discussed in the literature, and this work aimed to answer the following questions: 1) what are the incidence rates of PHF in the geriatric population in the USA; 2) what is the mortality rate after PHF in the elderly population, specifically for distinct treatment procedures; and 3) what factors influence the mortality rate?. Methods. PHFs occurring between 1 January 2009 and 31 December 2019 were identified from the Medicare physician service records. Incidence rates were determined, mortality rates were calculated, and semiparametric Cox regression was applied, incorporating 23 demographic, clinical, and socioeconomic covariates, to compare the mortality risk between treatments. Results. From 2009 to 2019, the incidence decreased by 11.85% from 300.4 cases/100,000 enrollees to 266.3 cases/100,000 enrollees, although this was not statistically significant (z = -1.47, p = 0.142). In comparison to matched Medicare patients without a PHF, but of the same five-year age group and sex, a mean survival difference of -17.3% was observed. The one-year mortality rate was higher after nonoperative treatment with 16.4% compared to surgical treatment with 9.3% (hazard ratio (HR) = 1.29, 95% confidence interval (CI) 1.23 to 1.36; p < 0.001) and to shoulder arthroplasty with 7.4% (HR = 1.45, 95% CI 1.33 to 1.58; p < 0.001). Statistically significant mortality risk factors after operative treatment included age older than 75 years, male sex, chronic obstructive pulmonary disease (COPD), cerebrovascular disease, chronic kidney disease, a concomitant fracture, congestive heart failure, and osteoporotic fracture. Conclusion. Mortality risk factors for distinct treatment modes after PHF in elderly patients could be identified, which may guide clinical decision-making. Cite this article: Bone Joint Res 2023;12(2):103–112

Objectives. Osteoporosis has become an increasing concern for older people as it may potentially lead to osteoporotic fractures. This study is designed to assess the efficacy and safety of ten therapies for post-menopausal women using network meta-analysis. Methods. We conducted a systematic search in several databases, including PubMed and Embase. A random-effects model was employed and results were assessed by the odds ratio (OR) and corresponding 95% confidence intervals (CI). Furthermore, with respect to each outcome, each intervention was ranked according to the surface under the cumulative ranking curve (SUCRA) value. Results. With respect to preventing new vertebral fractures (NVF), all ten drugs outperformed placebo, and etidronate proved to be the most effective treatment (OR 0.24, 95% CI 0.14 to 0.39). In addition, zoledronic acid and parathyroid hormone ranked higher compared with the other drugs. With respect to preventing clinical vertebral fractures (CVF), zoledronic acid proved to be the most effective drug (OR = 0.25, 95% CI 0.08 to 0.92), with denosumab as a desirable second option (OR = 0.48, 95% CI 0.22 to 0.96), when both were compared with placebo. As for adverse events (AE) and severe adverse events (SAE), no significant difference was observed. According to SUCRA, etidronate ranked first in preventing CVF; parathyroid hormone and zoledronic acid ranked highly in preventing NVF and CVF. Raloxifene was safe with a high rank in preventing AEs and SAEs though performed unsatisfactorily in efficacy. Conclusions. This study suggests that, taking efficacy and safety into account, parathyroid hormone and zoledronic acid had the highest probability of satisfactory performance in preventing osteoporotic fractures. Cite this article: G. Wang, L. Sui, P. Gai, G. Li, X. Qi, X. Jiang. The efficacy and safety of vertebral fracture prevention therapies in post-menopausal osteoporosis treatment: Which therapies work best? a network meta-analysis. Bone Joint Res 2017;6:452–463. DOI: 10.1302/2046-3758.67.BJR-2016-0292.R1

Objectives. Insufficient protein ingestion may affect muscle and bone mass, increasing the risk of osteoporotic fractures in the elderly, and especially in postmenopausal women. We evaluated how a low-protein diet affects bone parameters under gonadal hormone deficiency and the improvement led by hormone replacement therapy (HRT) with 17β-oestradiol. Methods. Female Wistar rats were divided into control (C), ovariectomized (OVX), and 17β-oestradiol-treated ovariectomized (OVX-HRT) groups, which were fed a control or an isocaloric low-protein diet (LP; 6.6% protein; seven animals per group). Morphometric, serum, and body composition parameters were assessed, as well as bone parameters, mechanical resistance, and mineralogy. Results. The results showed that protein restriction negatively affected body chemical composition and bone metabolism by the sex hormone deficiency condition in the OVX group. The association between undernutrition and hormone deficiency led to bone and muscle mass loss and increased the fragility of the bone (as well as decreasing relative femoral weight, bone mineral density, femoral elasticity, peak stress, and stress at offset yield). Although protein restriction induced more severe adverse effects compared with the controls, the combination with HRT showed an improvement in minimizing these damaging effects, as it was seen that HRT had some efficacy in maintaining muscle and bone mass, preserving the bone resistance and minimizing some deleterious processes during the menopause. Conclusion. Protein restriction has adverse effects on metabolism, leading to more severe menopausal symptoms, and HRT could minimize these effects. Therefore, special attention should be given to a balanced diet during menopause and HRT. Cite this article: Bone Joint Res 2019;8:573–581

Objectives. Researchers continue to seek easier ways to evaluate the quality of bone and screen for osteoporosis and osteopenia. Until recently, radiographic images of various parts of the body, except the distal femur, have been reappraised in the light of dual-energy X-ray absorptiometry (DXA) findings. The incidence of osteoporotic fractures around the knee joint in the elderly continues to increase. The aim of this study was to propose two new radiographic parameters of the distal femur for the assessment of bone quality. Methods. Anteroposterior radiographs of the knee and bone mineral density (BMD) and T-scores from DXA scans of 361 healthy patients were prospectively analyzed. The mean cortical bone thickness (CBTavg) and the distal femoral cortex index (DFCI) were the two parameters that were proposed and measured. Intra- and interobserver reliabilities were assessed. Correlations between the BMD and T-score and these parameters were investigated and their value in the diagnosis of osteoporosis and osteopenia was evaluated. Results. The DFCI, as a ratio, had higher reliability than the CBTavg. Both showed significant correlation with BMD and T-score. When compared with DFCI, CBTavg showed better correlation and was better for predicting osteoporosis and osteopenia. Conclusion. The CBTavg and DFCI are simple and reliable screening tools for the prediction of osteoporosis and osteopenia. The CBTavg is more accurate but the DFCI is easier to use in clinical practice. Cite this article: Q-F. He, H. Sun, L-Y. Shu, Y. Zhu, X-T. Xie, Y. Zhan, C-F. Luo. Radiographic predictors for bone mineral loss: Cortical thickness and index of the distal femur. Bone Joint Res 2018;7:468–475. DOI: 10.1302/2046-3758.77.BJR-2017-0332.R1

Objectives. Venous thromboembolism (VTE) is a major potential complication following orthopaedic surgery. Subcutaneously administered enoxaparin has been used as the benchmark to reduce the incidence of VTE. However, concerns have been raised regarding the long-term administration of enoxaparin and its possible negative effects on bone healing and bone density with an increase of the risk of osteoporotic fractures. New oral anticoagulants such as rivaroxaban have recently been introduced, however, there is a lack of information regarding how these drugs affect bone metabolism and post-operative bone healing. Methods. We measured the migration and proliferation capacity of mesenchymal stem cells (MSCs) under enoxaparin or rivaroxaban treatment for three consecutive weeks, and evaluated effects on MSC mRNA expression of markers for stress and osteogenic differentiation. Results. We demonstrate that enoxaparin, but not rivaroxaban, increases the migration potential of MSCs and increases their cell count in line with elevated mRNA expression of C-X-C chemokine receptor type 4 (CXCR4), tumor necrosis factor alpha (TNFα), and alpha-B-crystallin (CryaB). However, a decrease in early osteogenic markers (insulin-like growth factors 1 and 2 (IGF1, IGF2), bone morphogenetic protein2 (BMP2)) indicated inhibitory effects on MSC differentiation into osteoblasts caused by enoxaparin, but not by rivaroxaban. Conclusions. Our findings may explain the adverse effects of enoxaparin treatment on bone healing. Rivaroxaban has no significant impact on MSC metabolism or capacity for osteogenic differentiation in vitro. Cite this article: Dr H. Pilge. Enoxaparin and rivaroxaban have different effects on human mesenchymal stromal cells in the early stages of bone healing. Bone Joint Res 2016;5:95–100. DOI: 10.1302/2046-3758.53.2000595

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This study intended to investigate the effect of vericiguat (VIT) on titanium rod osseointegration in aged rats with iron overload, and also explore the role of VIT in osteoblast and osteoclast differentiation.

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Symptomatic spinal stenosis is a very common problem, and decompression surgery has been shown to be superior to nonoperative treatment in selected patient groups. However, performing an instrumented fusion in addition to decompression may avoid revision and improve outcomes. The aim of the SpInOuT feasibility study was to establish whether a definitive randomized controlled trial (RCT) that accounted for the spectrum of pathology contributing to spinal stenosis, including pelvic incidence-lumbar lordosis (PI-LL) mismatch and mobile spondylolisthesis, could be conducted.

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The aim of this systematic review and meta-analysis was to gather epidemiological information on selected musculoskeletal injuries and to provide pooled injury-specific incidence rates.

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Osteoporosis is common in total hip arthroplasty (THA) patients. It plays a substantial factor in the surgery’s outcome, and previous studies have revealed that pharmacological treatment for osteoporosis influences implant survival rate. The purpose of this study was to examine the prevalence of and treatment rates for osteoporosis prior to THA, and to explore differences in osteoporosis-related biomarkers between patients treated and untreated for osteoporosis.

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The aim of this study was to create artificial intelligence (AI) software with the purpose of providing a second opinion to physicians to support distal radius fracture (DRF) detection, and to compare the accuracy of fracture detection of physicians with and without software support.

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Low-energy distal radius fractures (DRFs) are the most common upper arm fractures correlated with bone fragility. Vitamin D deficiency is an important risk factor associated with DRFs. However, the relationship between DRF severity and vitamin D deficiency is not elucidated. Therefore, this study aimed to identify the correlation between DRF severity and serum 25-hydroxyvitamin-D level, which is an indicator of vitamin D deficiency.

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This study explored the shared genetic traits and molecular interactions between postmenopausal osteoporosis (POMP) and sarcopenia, both of which substantially degrade elderly health and quality of life. We hypothesized that these motor system diseases overlap in pathophysiology and regulatory mechanisms.

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The distal radius is a major site of osteoporotic bone loss resulting in a high risk of fragility fracture. This study evaluated the capability of a cortical index (CI) at the distal radius to predict the local bone mineral density (BMD).

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With the ageing population, fragility fractures have become one of the most common conditions. The objective of this study was to investigate whether microbiological outcomes and fracture-healing in osteoporotic bone is worse than normal bone with fracture-related infection (FRI).