Introduction. This study was to investigate the association of developmental dysplasia of the hip (DDH) and primary protrusion acetabuli (PPA) with Vitamin D receptor polymorphisms TaqI and FokI and oestrogen receptor polymorphisms Pvu II and XbaI. Methods. 45 patients with DDH and 20 patients with PPA were included in the study. Healthy controls (n=101) aged 18-60 years were recruited from the same geographical area. The control subjects had a normal acetabular morphology based on a recent pelvic radiograph performed for an unrelated cause. DNA was obtained from all the subjects from peripheral blood. Genotype frequencies were compared in the three groups. The relationship between the genotype and morphology of the hip joint, severity of the disease, age at onset of disease and gender were examined. Results. The oestrogen receptor XbaI wild-type genotype (XX, compared with Xx and xx combined) was more common in the DDH group (55.8%) than controls (37.9%), though this just failed to achieve statistical significance (p=0.053, odds ratio=2.1, 95% CI=0.9-4.6). In the DDH group, homozygosity for the mutant TaqI Vitamin D receptor t allele was associated with higher acetabular index (Mann-Whitney U-test, p= 0.03). Pvu II pp oestrogen receptor genotype was associated with low centre edge angle (p=0.07). Conclusion. This study suggests a possible correlation between gene polymorphism in the oestrogen and vitamin D receptors and susceptibility to, and severity of DDH. The TaqI vitamin D receptor polymorphisms may be associated with abnormal acetabular morphology leading to DDH while the XbaI oestrogen receptor XX genotype may be associated with increased risk of developing DDH. No such correlations were found in the group with PPA

Introduction: Evidence exists concerning the anti-oxidant properties of oestrogen in protecting neuronal cells from oxidative stress. The withdrawal of oestrogen after menopause is the major factor determining age related bone loss and apoptotic death of osteocytes. While oestrogen replacement demonstrates clear oestrogen receptor mediated benefits to bone cells little is known regarding oestrogens’ anti-oxidant effects in bone. Methods: Here we have used MLO-Y4 osteocyte-like cell line to determine whether oestrogen saving effects on osteocytes involves its activities as an anti-oxidant. MLO-Y4 cells were treated with physiological doses (10. −8. )M of either 17-beta E. 2. or the oestrogen receptor inactive stereoisomer 17-alpha E. 2. with or without the specific oestrogen receptor antagonist ICI 182,780 prior to the addition of 0.4milliM 30% (v/v) H. 2. O. 2. Cellular apoptosis was determined using morphological and biochemical criteria. Results: H. 2. O. 2. induced an increase in apoptosis of MLO-Y4 (14.3 ± 3 SD vs control 1.4 ± 0.9). Pre-treatment of the cells with 17-beta E. 2. significantly reduced H. 2. O. 2. induced apoptosis (2.4 ± 0.96). Pre-treatment of cells with 17-alpha E. 2. or ICI 182,780 also reduced oxidant induced apoptosis to 3.4 ± 1.5 SD and 7.0 ± 2.3 respectively. The cellular production of reactive oxygen species was determined using the free radical indicator 2′7′- dichlorodihydrofluorescein diacetate. H. 2. O. 2. induced increases in the number of ROS positive cells (34.6 ± 9.07 SD vs control 0.22 ± 0.39 SD). In contrast pre-treatment with both 17-beta E. 2. and 17-alpha E. 2. reduced the number of ROS positive cells associated with H. 2. O. 2. treatment (Fig 1). Conclusion: These data suggest that oestrogens ability to save osteocytes from oxidant induced death is independent of the oestrogen receptor and may be related to oestrogens known activity as an anti-oxidant. This raises the possibility that loss of osteocytes during oestrogen insufficiency may occur through a failure to suppress the activity of naturally occurring or disease associated production of oxidant molecules

In the pubertal growth plate, sex hormones play important roles for the regulation of the proliferation, differentiation, maturation and programmed death of chondrocytes. Many studies have been reported on the regulation of oestrogen in long bone growth, however, some of the mechanisms have remained unclarified to date including its role for cell kinetics in the growth plate chondrocytes. The aim of this study was to clarify the effect of the deficiency of oestrogen on growth plate chondrocytes. We obtained the growth plates of femoral head from the normal and ovariectomized Japanese white rabbits at 10, 15, 20 and 25 weeks. Ovariectomy was performed at 8 weeks. The cell kinetics of chondrocytes as defined by the numbers of proliferating and programmed dying cells was investigated using immunohistological methods. The lengths of the femur were almost same both in the ovariectomised and normal rabbits. The height of the growth plate was larger in the former. The total number of chondrocytes in the ovariectomised rabbits was less than that of normal rabbits of the same age. Immunostaining of proliferating cell nucleous antigen (PCNA) showed a decrease number of proliferating chondrocytes and that of caspase-3 indicated a little increased number of apoptotic chondrocytes. Oestrogen regulates endochondral bone formation through several pathways. It directly binds oestrogen receptor alpha and beta, and the former accelerates longitudinal bone growth whereas the latter represses it. Another pathway is through the GH-IGF-I axis: it closely interacts with GH and IGF-I for the control of longitudinal bone growth. In addition, there might be other mediators including transforming growth factor-beta, other IGFs and still unknown paracrine or auto-crine factors as IHH PTHrP. Our study suggests that in the rabbit growth plate during puberty, oestrogen mainly acts through the GH-IGF-I axis since its defi-ciency declined the proliferating ability of chondrocytes, which led the decrease of the number of chondrocytes

There is a disparity in sport-related injuries between sexes, with females sustaining non-contact musculoskeletal injuries at a higher rate. Anterior cruciate ligament ruptures are between two and eight times more common than in males, and females also have a higher incidence of ankle sprains, patellofemoral pain, and bone stress injuries. The sequelae of such injuries can be devastating to an athlete, resulting in time out of sport, surgery, and the early onset of osteoarthritis. It is important to identify the causes of this disparity and introduce prevention programmes to reduce the incidence of these injuries. A natural difference reflects the effect of reproductive hormones in females, which have receptors in certain musculoskeletal tissues. Relaxin increases ligamentous laxity. Oestrogen decreases the synthesis of collagen and progesterone does the opposite. Insufficient diet and intensive training can lead to menstrual irregularities, which are common in female athletes and result in injury, whereas oral contraception may have a protective effect against certain injuries. It is important for coaches, physiotherapists, nutritionists, doctors, and athletes to be aware of these issues and to implement preventive measures. This annotation explores the relationship between the menstrual cycle and orthopaedic sports injuries in pre-menopausal females, and proposes recommendations to mitigate the risk of sustaining these injuries. Cite this article: Bone Joint J 2023;105-B(7):723–728

Introduction: Retrospective reports of adverse events following growth hormone administration to short-statured children indicate that the incidence of scoliosis is elevated, largely due to the higher incidence of scoliosis in Turner/other syndromes within the group. The aims of this study are to analyse risk factors for scoliosis in these children. Methods: Data on 184 of 267 (65%) current and recent Australian children from the Australian OZGROW program was collected in 2001/2002 (from three Australian States). This included medical records (including past history of known scoliosis), growth charts, timing of growth hormone and oestrogen administration and the presence and severity of scoliosis from clinical examination. Growth hormone dosage was controlled by Australian Health Department guidelines. Standard oestrogen dosage was similar for all pubertal girls. The cohort was noted to comprise many varying syndromes, some of whom were pituitary hormone deficient. Potential risk factors for the development of scoliosis were statistically analysed. Results: Of 45 subjects with Turner Syndrome, 13 (30%) have idiopathic scoliosis and 2 have a hemi-vertebra. Of the other 139 subjects, 15 have scoliosis but 11 have syndromes which would normally be associated with scoliosis. Therefore, the incidence of idiopathic scoliosis in the remaining 128 subjects is 3.1% (4/128), which is within the normal population range. All 4 have mild scoliosis < 20 degrees. For the 139 subjects with idiopathic short stature or a specific syndrome, the age of commencement and total amount of growth hormone and/or oestrogen did not affect the degree of scoliosis. Discussion: Having Turner Syndrome was the only variable identified as a risk factor for having scoliosis (p< .001). The incidence of scoliosis in growth hormone treated Turner Syndrome subjects is much larger than previously reported (11–12%). 1,. 2. To the authors’ knowledge, this is the first report derived from non-retrospective data on the incidence of scoliosis in a growth hormone–treated Turner Syndrome population. This stimulated the next study looking at the incidence of scoliosis in growth hormone-treated and non-growth hormone-treated subjects with Turner Syndrome

1. Twenty-one cases of congenital dislocation of the hip were found on examination of 1,881 consecutive neonates on the first day of life, giving an incidence of eleven per 1,000 live births. 2. Insignificant high-pitched "clicks" were noted in 10 per cent of newborn children. 3. Conversion of half of the patients with hip dislocation to normal occurred during the first post-natal week. 4. Joint laxity was not a feature of the newborn with congenital dislocation of the hip. 5. Oestradiol, oestrone and oestriol were estimated in twenty-fourhour urine samples collected from sixteen patients with congenital dislocation of the hip and nineteen matched controls during the first six days of life. No significant differences in oestrogen output between the two groups were found. 6. The hypothesis that congenital dislocation of the hip is a result of an inborn error of oestrogen metabolism in the newborn is not supported

Aims. To investigate the effects of senescent osteocytes on bone homeostasis in the progress of age-related osteoporosis and explore the underlying mechanism. Methods. In a series of in vitro experiments, we used tert-Butyl hydroperoxide (TBHP) to induce senescence of MLO-Y4 cells successfully, and collected conditioned medium (CM) and senescent MLO-Y4 cell-derived exosomes, which were then applied to MC3T3-E1 cells, separately, to evaluate their effects on osteogenic differentiation. Furthermore, we identified differentially expressed microRNAs (miRNAs) between exosomes from senescent and normal MLO-Y4 cells by high-throughput RNA sequencing. Based on the key miRNAs that were discovered, the underlying mechanism by which senescent osteocytes regulate osteogenic differentiation was explored. Lastly, in the in vivo experiments, the effects of senescent MLO-Y4 cell-derived exosomes on age-related bone loss were evaluated in male SAMP6 mice, which excluded the effects of oestrogen, and the underlying mechanism was confirmed. Results. The CM and exosomes collected from senescent MLO-Y4 cells inhibited osteogenic differentiation of MC3T3-E1 cells. RNA sequencing detected significantly lower expression of miR-494-3p in senescent MLO-Y4 cell-derived exosomes compared with normal exosomes. The upregulation of exosomal miR-494-3p by miRNA mimics attenuated the effects of senescent MLO-Y4 cell-derived exosomes on osteogenic differentiation. Luciferase reporter assay demonstrated that miR-494-3p targeted phosphatase and tensin homolog (PTEN), which is a negative regulator of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Overexpression of PTEN or inhibition of the PI3K/AKT pathway blocked the functions of exosomal miR-494-3p. In SAMP6 mice, senescent MLO-Y4 cell-derived exosomes accelerated bone loss, which was rescued by upregulation of exosomal miR-494-3p. Conclusion. Reduced expression of miR-494-3p in senescent osteocyte-derived exosomes inhibits osteogenic differentiation and accelerates age-related bone loss via PTEN/PI3K/AKT pathway. Cite this article: Bone Joint Res 2024;13(2):52–65

The purpose of this study was to evaluate whether epidural fibrosis formation around the spinal cord was affected by endogenous oestrogen deficient state after lumbar laminectomy in the rats. Thirty-six 12-month-old adult female Sprague-Dawley rats were used in this study. Bilaterally ooferectomy were done in 18 rats. Rats were divided into two groups: oophrectomised (oestrogen deficient) group and sham operated (oestrogen maintained) group. Three weeks after the ooferectomy each rat underwent complete bilaterally laminectomy at the L2 and L3 vertebral levels (two levels per rat). The rats were randomly divided into three equal groups (12 rats in each group). The rats were sacrificed at four, eight, and twelve weeks postoperatively and the lumbar spine excised en bloc, fixed and decalcified. Section stained with hematoxylin and eosin and Masson’s trichrome were used to evaluate epidural fibrosis, acute inflammatory cells, chronic inflammatory cells and vascular proliferation. Sections were analyzed by investigator blinded to the study and graded on a five-point grading system. Statistic were performed using Mann-Whitney U test when compare two variable and Kruskal-Wallis test when compare more than two variables. Compared with the oopherectomised group, the sham operated group showed decreased rate of epidural fibrosis and higher acute and chronic inflammatory cells response at four and eight weeks but this was no statistically significant (p> 0.05). The results of this study revealed that endogenous oestrogen may decrease epidural fibrosis formation after lumbar laminectomy in the rats

Aims: Hormone replacement therapy (HRT) reverses the menopausal decline in bone mineral density (BMD).We investigate if part of this response is through modulation of Interleukin-6 (IL-6) activity, which is known to be reduced by HRT. Methods: We have examined the association of the -174 G/C functional promoter polymorphism of the IL-6 gene with the BMD response to HRT (Prempak C: 0.625mg oestrogen per day and 0.15mg norgestrel). 65 women were genotyped for the IL-6 polymorphism, and differences in genotype related to changes in BMD over a one year follow up period. Results: Baseline BMD (0.75 g/cm. 2. ) was independent of IL-6 genotype. The rise in BMD with HRT (5% ± 3%, p < 0.00005 by paired t-test) was genotype-dependent, with BMD rising least amongst those of GG genotype (6% ± 3% for ≥1 C allele vs 4% ± 2% GG, p=0.03). In the HRT group, BMD rose most amongst those with the putatively ‘lowest IL-6’ genotype combination- namely ≥ 1 ACE I allele and ≥ 1 IL-6 C allele (n=14) (7% ± 3%), when compared with other genotype combinations (4% ± 2%) (n=16) (p=0.003). Conclusion: These are the first data to demonstrate an influence for IL-6 genotype in influencing response to oestrogen therapy, rather than its physiological withdrawal

Introduction: Large numbers of women are taking hormone replacement therapy (HRT) or an oestrogen containing contraceptive pill. They are being advised that these medications can increase their risk of developing deep vein thrombosis (DVT) and there has been considerable recent publicity. Aim: To determine the practice of New Zealand orthopaedic surgeons when women taking such medications present for major surgery. Method: A postal survey was sent to all New Zealand orthopaedic surgeons. The current practice was compared with recently revised national guidelines and manufacturers advice. Results: The response rate was 80% (118/148). There was wide variation in the beliefs surrounding the peri-operative use of both of these medications. Of the surgeons who replied, 44% indicated that they would routinely advise discontinuing the combined oral contraceptive pill peri-operatively for major surgery, 24% indicated that they would routinely advise discontinuing HRT peri-operatively. The mean duration that surgeons would discontinue the medication pre-operatively was 13 days for the contraceptive pill and nine days for HRT. The mean time for re-starting medication post-operatively was 18 days for the contraceptive pill and 13 days for HRT. Recently released New Zealand guidelines recommend that HRT should be stopped for at least 30 days prior to elective surgery and withheld for 90 days following surgery. Less than 3% of surgeons appeared to be routinely following this recommendation. Most manufacturers of combined oral contraceptive pills recommend stopping the medication for at least four weeks prior to elective surgery. Only 25% of surgeons routinely practice in accordance with these recommendations. Discussion: This survey demonstrated substantial differences between actual clinical practice, recently revised national guidelines and manufacturers’ advice. These differences need to be brought to the attention of surgeons and guideline producers alike. A review of international literature and recommendations revealed that these guidelines are very conservative and that strong evidence for them is lacking. Issues to be considered include the practicalities of implementing such recommendations; the associated risks of discontinuing medication; the presence of other risk factors; the type of surgery; the use of thromboprophylaxis and not least the wishes of the patient. The possible medico-legal implications are uncertain and caution in this area is advised

Abstract

Although effects of mechanical stimulation with high frequency, low magnitude vibrations on bone mass and bone mineral density in animal and clinical studies have been proven effective, its effects on fracture healing is less well described. 20 Sham and 20 ovarectomised (Ovx) Sprague Dawley rats at 22 weeks of age, had intra-medullary k-wire fixation followed by controlled mid-shaft fractures. The animals were divided into subgroups of 3 week Sham and Ovx treated and non-treated and 6 week Sham and Ovx treated and non-treated groups. The treated animals were vibrated for 20mins daily on a DMT (dynamic motion therapy) platform which had a frequency of 30hz, 8-micron vertical displacement and 3g force, the non treated animals allowed to move freely. Xrays, DEXA studies, micro computed tomography, Histological analysis and Mechanical studies performed at the end point. DMT treated animals had more bridging callus on radiographic and micro computed tomographic analysis compared to non-treated groups especially the OVX groups at 3 weeks compared to controls or Shams (using Image J software). DEXA studies showed increased bone mineral density and bone mineral content in the treated animals compared to the controls. Histological analysis showed increased callus and woven bone being laid down in the treated OVX groups. In the 6-week groups, the treated OVX groups had healed, remodelled fractures compared to the non-treated groups or Sham controls where the fracture gaps were still visible. Although significance was not achieved on mechanical analysis due to small sample size, in the OVX non-operated femora group that were treated with DMT there were indications that they were stronger than the control counterparts. High frequency low magnitude vibrations with the Juvent DMT device enhances fracture healing in oestrogen deficient models and this model could be used as a platform for clinical studies in future

Sclerostin (SOST) is an endogenous inhibitor of Wnt/β-catenin signalling pathway to impair osteogenic differentiation and bone anabolism. SOST immunotherapy like monoclonal antibody has been observed to control bone remodeling and regeneration. This study is aimed to develop a SOST vaccine and test its protective effects on estrogen deficiency-induced bone loss in mice. Gene sequences coded SOST peptide putative targeting Wnt co-receptor LRP5 were cloned and constructed into vectors expressing Fc fragment to produced SOST-Fc fusion protein. Mice were subcutaneously injected SOST-Fc to boost anti-SOST antibody. Bone mineral density, microstructure, and mechanical property were quantified using μCT scanning and material testing system. Serum bone formation and resorption markers and anti-SOST levels were measured using ELISA. SOST-Fc injections significantly increased serum anti-SOST antibody levels but reduced serum SOST concentrations. SOST-Fc vaccination significantly reduced estrogen deficiency-induced serum bone resorption markers CTX-1 increased serum bone formation marker osteocalcin. Of note, it significantly alleviated the severity of estrogen-induced loss of bone mineral density, trabecular morphometric properties, and biomechanical forces of bone tissue. Mechanistically, SOSF-Fc vaccination attenuated trabecular loss histopathology and restored immunostaining of Wnt pathway like Wnt3a, β-catenin, and TCF4 in bone tissue along with increased serum osteoclast inhibitor OPG levels but decreased serum osteoclast enhancer RANKL concentrations. Taken together, SOST-Fc vaccination boosts anti-SOST antibody to neutralize SOST and mitigates the estrogen deficiency-induced bone mass and microstructure deterioration through preserving Wnt signalling. This study highlights an innovative remedial potential of SOST vaccine for preventing osteoporosis.

The expression of the mechanosensor, integrin αvβ3, is reduced in osteoporotic bone cells compared to controls. MLO-Y4 osteocytes experience altered mechanotransduction under estrogen deficiency and it is unknown whether this is associated with defective αvβ3 expression or signalling. The objectives of this study are to (1) investigate αvβ3 expression and spatial organisation in osteocytes during estrogen deficiency, and (2) establish whether altered responses of osteocytes under estrogen deficiency correlate to defective αvβ3 expression and functionality. MLO-Y4 cells were cultured as follows: Ctrl (no added estradiol), E+ (10nM 17β-estradiol for 5 days), and Ew (10nM 17β-estradiol for 3 days and withdrawal for 2 days). Cells were cultured with/without 0.5µM IntegriSense750 (αvβ3 antagonist). Laminar oscillatory fluid flow of 1Pa at 0.5Hz was applied for 1hr. αvβ3 content was quantified using an ELISA. The location and quantity of αvβ3 and focal-adhesions was determined by immunocytochemistry. Estrogen withdrawal under static conditions led to lower cell and focal-adhesion area (p<0.05), compared to E+ cells. Fluid flow led to higher αvβ3 content (p<0.05) in all groups, compared to static counterparts, with αvβ3 blocking altering this response. Fluid flow on Ew cells had the highest αvβ3 levels (p<0.05), but αvβ3 did not localise at focal-adhesions sites. Cell morphologies were similar after treatment with the αvβ3 antagonist to the Ew group. These results suggest there are fewer functional focal-adhesion sites at which αvβ3 integrins localise to facilitate mechanotransduction. To further understand these results, we are analysing osteocyte mechanotransduction by quantifying PGE2 and gene expression (COX-2, RANKL, OPG, SOST).

Background

MicroRNAs are non-coding small RNAs that reportedly regulate mRNA targets or protein translation of various tissues in physiological and pathological contexts. This study was undertaken to characterise the contributions of microRNA-29a (miR-29a) to the progression of estrogen deficiency-mediated excessive osteoclast resorption and bone loss.

Aims

Deciphering the genetic relationships between major depressive disorder (MDD) and osteoarthritis (OA) may facilitate an understanding of their biological mechanisms, as well as inform more effective treatment regimens. We aim to investigate the mechanisms underlying relationships between MDD and OA in the context of common genetic variations.

3D cell culture studies more accurately represent the complex in vivo mechanical environment of human bone and are, thus, superior to 2D studies when testing the efficacy of osteoporosis therapies. As such, the objective of this study was to use a 3D model to investigate the effect of sclerostin antibodies. Sclerostin is a protein, which inhibits osteoblasts and is downregulated under mechanical stimulation. It is not yet known how expression of sclerostin mediates the site-specific and temporal changes in mineralisation. To address this, we developed a 3D cellular niche of MC3T3 osteoblasts encapsulated within gelatin and applied mechanical loading to the constructs using a custom-designed compression bioreactor system (0.5% strain at 0.5 Hz, 1 hr/day) (VizStim) under continuous perfusion of cell culture media. Osteoblasts were pretreated with estrogen for 14 days, followed by estrogen withdrawal (EW) to simulate postmenopausal conditions. 3D constructs were successfully fabricated and actin staining revealed the formation of dendritic cells under both static and stimulated conditions indicative of osteocyte-like cells. Under static conditions, estrogen treatment enhanced production of calcium by osteoblasts when compared to the same cells cultured under estrogen deficient conditions. Overall, preliminary results propose a link between mechanical stimulation, estrogen deficiency and mineral production by osteoblasts. Ongoing studies are comparing the static and stimulated groups after a longer culture period of 21 days using sclerostin antibodies. This research aims to deliver further understanding of the mechanical regulation of bone formation, and will inform novel approaches for regeneration of bone tissue and treatment of osteoporosis.

Osteoporosis has long been associated with weak bones but recent studies have shown that bone tissue mineral becomes more heterogeneous and the expression of mechanosensors are altered during estrogen deficiency in an animal model of osteoporosis. However, whether these changes occur as a primary response to estrogen deficiency is unknown. In this study we investigate whether matrix production and mineralisation by mechanically-stimulated osteoblasts are impaired as a direct consequence of estrogen depletion. Osteoblast-like MC3T3-E1 cells were cultured for 14 days with 10⁻⁸M of 17β-estradiol and subsequently cultured with osteogenic media only, or supplemented with estrogen or an estrogen antagonist (Fulvestrant, 10⁻⁷M). Physiological shear stress (1Pa) was applied using an orbital shaker (290rpm, 40min/day), which allows long-term culture and induces oscillatory flow on cells. Osteoblasts phenotype, extracellular matrix (ECM), mineralisation and mechanosensors were tracked by qRT-PCR (Runx2, Col1a1, Col1a2, Cox2, Bglap2, FN1), by biochemical assays (ALP activity, DNA and calcium content), by immunostaining (integrin α_v, BSP2, fibronectin) and by labelling with calcein the calcium. The results of this study demonstrate that after 7 days, estrogen depleted cells had less integrin α_v mechanosensors compared to those that received continuous estrogen treatment. By 14 days the ECM formation (calcium, fibronectin) by osteoblasts was altered under estrogen depletion, when compared to cells that were cultured continuously with estrogen. This study provides evidence of changes in osteoblast behaviour under estrogen depletion, which might explain the alteration in tissue mineral content and the decrease of integrins observed previously in ovariectomized rats in vivo.

Objectives. Osteoporosis is a metabolic disease resulting in progressive loss of bone mass as measured by bone mineral density (BMD). Physical exercise has a positive effect on increasing or maintaining BMD in postmenopausal women. The contribution of exercise to the regulation of osteogenesis in osteoblasts remains unclear. We therefore investigated the effect of exercise on osteoblasts in ovariectomized mice. Methods. We compared the activity of differentially expressed genes of osteoblasts in ovariectomized mice that undertook exercise (OVX+T) with those that did not (OVX), using microarray and bioinformatics. Results. Many inflammatory pathways were significantly downregulated in the osteoblasts after exercise. Meanwhile, IBSP and SLc13A5 gene expressions were upregulated in the OVX+T group. Furthermore, in in vitro assay, IBSP and SLc13A5 mRNAs were also upregulated during the osteogenic differentiation of MC3T3-E1 and 7F2 cells. Conclusion. These findings suggest that exercise may not only reduce the inflammatory environment in ovariectomized mice, indirectly suppressing the overactivated osteoclasts, but may also directly activate osteogenesis-related genes in osteoblasts. Exercise may thus prevent the bone loss caused by oestrogen deficiency through mediating the imbalance between the bone resorptive activity of osteoclasts and the bone formation activity of osteoblasts. Cite this article: W-B. Hsu, W-H. Hsu, J-S. Hung, W-J. Shen, R. W-W. Hsu. Transcriptome analysis of osteoblasts in an ovariectomized mouse model in response to physical exercise. Bone Joint Res 2018;7:601–608. DOI: 10.1302/2046-3758.711.BJR-2018-0075.R2

Purpose of the study: Oestrogen depletion leads to osteoclastic hyperactivity and subsequent postmenopausal osteoporosis. Little is known about interactions with bone absorption induced by wear particles from joint bearings. The purpose of this study was to evaluate bone response to polyethylene (PE) particles in a mouse model of oestrogen deficiency. Material and methods: Particles of PE were implanted in the calvaria of seven non-ovariectomised mice and in seven ovariectomised mice (OVX). Fourteen mice were operated on without implantation of the particles (7 non-OVX and 7 OVX, control groups). The mice were sacrificed at two weeks. The crania were studied under a microscanner and histologically without decalcification. Results: The microscanner showed that particles of PE induced a significant decrease in bone thickness in non-OVX mice (p=0.04), while the thickness remained unchanged in OVX mice who had received the particles (p=0.40). After implantation of the PE particles, the number of osteoclasts per mm of bone perimeter was 2.84±1.6 in the non-OVX mice and 1.74±1.3 in OVX mice (p=0.004). Compared with controls, the mean loss of bone was 12±10% in the non-OVX mice versus 4.7±0.9%in the OVX mice (p=0.004). Discussion: The volume of osteolysis induced by PE particles was smaller in OVX mice compared with non-OVX mice. Conclusion: These results suggest that a deficit in oestrogens has a protective effect against bone adsorption induced by PE particles

Objectives. Ligaments which heal spontaneously have a healing process that is similar to skin wound healing. Menopause impairs skin wound healing and may likewise impair ligament healing. Our purpose in this study was to investigate the effect of surgical menopause on ligament healing in a rabbit medial collateral ligament model. Methods. Surgical menopause was induced with ovariohysterectomy surgery in adult female rabbits. Ligament injury was created by making a surgical gap in the midsubstance of the medial collateral ligament. Ligaments were allowed to heal for six or 14 weeks in the presence or absence of oestrogen before being compared with uninjured ligaments. Molecular assessment examined the messenger ribonucleic acid levels for collagens, proteoglycans, proteinases, hormone receptors, growth factors and inflammatory mediators. Mechanical assessments examined ligament laxity, total creep strain and failure stress. Results. Surgical menopause in normal medial collateral ligaments initiated molecular changes in all the categories evaluated. In early healing medial collateral ligaments, surgical menopause resulted in downregulation of specific collagens, proteinases and inflammatory mediators at 6 weeks of healing, and proteoglycans, growth factors and hormone receptors at 14 weeks of healing. Surgical menopause did not produce mechanical changes in normal or early healing medial collateral ligaments. With or without surgical menopause, healing ligaments exhibited increased total creep strain and decreased failure stress compared with uninjured ligaments. Conclusions. Surgical menopause did not affect the mechanical properties of normal or early healing medial collateral ligaments in a rabbit model. The results in this preclinical model suggest that menopause may result in no further impairment to the ligament healing process. . Cite this article: Bone Joint Res 2015;4:38–44

1. In growing rats oestrogen, cortisone and thyroxine in high doses suppress bone formation, and this effect is probably part of a general suppression of body growth. 2. Growth hormone and thyroxine in small doses stimulate both body growth and bone formation. 3. Testosterone has no effect on bone formation. 4. Oestrogen and cortisone suppress bone resorption. The effect of cortisone may be modified in conditions of calcium depletion. 5. Thyroxine appears on the other hand to increase bone resorption. 6. Testosterone has no effect on bone resorption

Aims

This study examined whether systemic administration of melatonin would have different effects on osseointegration in ovariectomized (OVX) rats, depending on whether this was administered during the day or night.

Anterior cruciate ligament (ACL) injuries are among the most common and debilitating knee injuries in professional athletes with an incidence in females up to eight-times higher than their male counterparts. ACL injuries can be career-threatening and are associated with increased risk of developing knee osteoarthritis in future life. The increased risk of ACL injury in females has been attributed to various anatomical, developmental, neuromuscular, and hormonal factors. Anatomical and hormonal factors have been identified and investigated as significant contributors including osseous anatomy, ligament laxity, and hamstring muscular recruitment. Postural stability and impact absorption are associated with the stabilizing effort and stress on the ACL during sport activity, increasing the risk of noncontact pivot injury. Female patients have smaller diameter hamstring autografts than males, which may predispose to increased risk of re-rupture following ACL reconstruction and to an increased risk of chondral and meniscal injuries. The addition of an extra-articular tenodesis can reduce the risk of failure; therefore, it should routinely be considered in young elite athletes. Prevention programs target key aspects of training including plyometrics, strengthening, balance, endurance and stability, and neuromuscular training, reducing the risk of ACL injuries in female athletes by up to 90%. Sex disparities in access to training facilities may also play an important role in the risk of ACL injuries between males and females. Similarly, football boots, pitches quality, and football size and weight should be considered and tailored around females’ characteristics. Finally, high levels of personal and sport-related stress have been shown to increase the risk of ACL injury which may be related to alterations in attention and coordination, together with increased muscular tension, and compromise the return to sport after ACL injury. Further investigations are still necessary to better understand and address the risk factors involved in ACL injuries in female athletes.

Cite this article: Bone Jt Open 2024;5(2):94–100.

The anterior cruciate ligament (ACL) is frequently injured in elite athletes, with females up to eight times more likely to suffer an ACL tear than males. Biomechanical and hormonal factors have been thoroughly investigated; however, there remain unknown factors that need investigation. The mechanism of injury differs between males and females, and anatomical differences contribute significantly to the increased risk in females. Hormonal factors, both endogenous and exogenous, play a role in ACL laxity and may modify the risk of injury. However, data are still limited, and research involving oral contraceptives is potentially associated with methodological and ethical problems. Such characteristics can also influence the outcome after ACL reconstruction, with higher failure rates in females linked to a smaller diameter of the graft, especially in athletes aged < 21 years. The addition of a lateral extra-articular tenodesis can improve the outcomes after ACL reconstruction and reduce the risk of failure, and it should be routinely considered in young elite athletes. Sex-specific environmental differences can also contribute to the increased risk of injury, with more limited access to and availablility of advanced training facilities for female athletes. In addition, football kits are designed for male players, and increased attention should be focused on improving the quality of pitches, as female leagues usually play the day after male leagues. The kit, including boots, the length of studs, and the footballs themselves, should be tailored to the needs and body shapes of female athletes. Specific physiotherapy programmes and training protocols have yielded remarkable results in reducing the risk of injury, and these should be extended to school-age athletes. Finally, psychological factors should not be overlooked, with females’ greater fear of re-injury and lack of confidence in their knee compromising their return to sport after ACL injury. Both intrinsic and extrinsic factors should be recognized and addressed to optimize the training programmes which are designed to prevent injury, and improve our understanding of these injuries.

Cite this article: Bone Joint J 2023;105-B(10):1033–1037.

Aims

Transcription factor nuclear factor kappa B (NF-κB) plays a major role in the pathogenesis of chronic inflammatory diseases in all organ systems. Despite its importance, NF-κB targeted drug therapy to mitigate chronic inflammation has had limited success in preclinical studies. We hypothesized that sex differences affect the response to NF-κB treatment during chronic inflammation in bone. This study investigated the therapeutic effects of NF-κB decoy oligodeoxynucleotides (ODN) during chronic inflammation in male and female mice.

Aims

The association of auraptene (AUR), a 7-geranyloxycoumarin, on osteoporosis and its potential pathway was predicted by network pharmacology and confirmed in experimental osteoporotic mice.

Aims

Osteoporosis is characterized by decreased trabecular bone volume, and microarchitectural deterioration in the medullary cavity. Interleukin-19 (IL-19), a member of the IL-10 family, is an anti-inflammatory cytokine produced primarily by macrophages. The aim of our study was to investigate the effect of IL-19 on osteoporosis.

Aims

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.

Aims

The antidiabetic agent metformin inhibits fibrosis in various organs. This study aims to elucidate the effects of hyperglycaemia and metformin on knee joint capsule fibrosis in mice.

Aims

Currently, the effect of drug treatment for osteoporosis is relatively poor, and the side effects are numerous and serious. Melatonin is a potential drug to improve bone mass in postmenopausal women. Unfortunately, the mechanism by which melatonin improves bone metabolism remains unclear. The aim of this study was to further investigate the potential mechanism of melatonin in the treatment of osteoporosis.

Aims

Mechanical stimulation is a key factor in the development and healing of tendon-bone insertion. Treadmill training is an important rehabilitation treatment. This study aims to investigate the benefits of treadmill training initiated on postoperative day 7 for tendon-bone insertion healing.

Aims

Gap junction intercellular communication (GJIC) in osteocytes is impaired by oxidative stress, which is associated with age-related bone loss. Ageing is accompanied by the accumulation of advanced oxidation protein products (AOPPs). However, it is still unknown whether AOPP accumulation is involved in the impairment of osteocytes’ GJIC. This study aims to investigate the effect of AOPP accumulation on osteocytes’ GJIC in aged male mice and its mechanism.

Aims

This study was designed to develop a model for predicting bone mineral density (BMD) loss of the femur after total hip arthroplasty (THA) using artificial intelligence (AI), and to identify factors that influence the prediction. Additionally, we virtually examined the efficacy of administration of bisphosphonate for cases with severe BMD loss based on the predictive model.

Aims

Breast cancer survivors have known risk factors that might influence the results of total hip arthroplasty (THA) or total knee arthroplasty (TKA). This study evaluated clinical outcomes of patients with breast cancer history after primary THA and TKA.

Aims

Long non-coding RNAs (lncRNAs) act as crucial regulators in osteoporosis (OP). Nonetheless, the effects and potential molecular mechanism of lncRNA PCBP1 Antisense RNA 1 (PCBP1-AS1) on OP remain largely unclear. The aim of this study was to explore the role of lncRNA PCBP1-AS1 in the pathogenesis of OP.

Aims

This study aimed to investigate the role and mechanism of meniscal cell lysate (MCL) in fibroblast-like synoviocytes (FLSs) and osteoarthritis (OA).

Aims

Thresholds of acceptable early migration of the components in total knee arthroplasty (TKA) have traditionally ignored the effects of patient and implant factors that may influence migration. The aim of this study was to determine which of these factors are associated with overall longitudinal migration of well-fixed tibial components following TKA.

Aims

To explore the novel molecular mechanisms of histone deacetylase 4 (HDAC4) in chondrocytes via RNA sequencing (RNA-seq) analysis.

We report 12 patients with infiltrating muscular lipomas of the lower limbs all treated by wide resection. During follow-up averaging seven years, the tumour recurred in five patients. Our results and those reported by others suggest that, in order to avoid recurrence, this tumour, although benign, should be treated by total excision of the muscle or by compartmental resection. Hormonal imbalance was suspected in 9 of the patients but an oestrogen receptor analysis of the histological samples proved negative

Adolescent idiopathic scoliosis (AIS), defined by an age at presentation of 11 to 18 years, has a prevalence of 0.47% and accounts for approximately 90% of all cases of idiopathic scoliosis. Despite decades of research, the exact aetiology of AIS remains unknown. It is becoming evident that it is the result of a complex interplay of genetic, internal, and environmental factors. It has been hypothesized that genetic variants act as the initial trigger that allow epigenetic factors to propagate AIS, which could also explain the wide phenotypic variation in the presentation of the disorder. A better understanding of the underlying aetiological mechanisms could help to establish the diagnosis earlier and allow a more accurate prediction of deformity progression. This, in turn, would prompt imaging and therapeutic intervention at the appropriate time, thereby achieving the best clinical outcome for this group of patients.

Cite this article: Bone Joint J 2022;104-B(8):915–921.

Aims

We aimed to develop a gene signature that predicts the occurrence of postmenopausal osteoporosis (PMOP) by studying its genetic mechanism.

In 15 consecutive patients with slipped capital femoral epiphysis we recorded height, weight and skeletal maturity. Sexual maturity was assessed clinically and biochemically, and Harris's hypothesis that there is an increased ratio of serum growth hormone to oestrogen was tested in comparison with 15 age and sex matched controls. We found no difference in skeletal or sexual maturity between the groups, or any overt endocrine abnormality in the patients. However almost half the patients with slipped epiphysis were over the 90th weight percentile, suggesting that mechanical factors such as obesity are more important aetiologically than endocrine abnormalities

Four cases of slipped upper femoral epiphyses in patients with intracranial tumours causing hypopituitarism and chiasmal compression are presented. Detailed endocrine studies in three cases showed severe deficiencies of growth hormone as well as of gonadotrophin and sex hormones. The literature is reviewed and the aetiology is discussed with special reference to Harris's hypothesis that an increase in growth hormone relative to oestrogen predisposes to slipping of the upper femoral epiphysis in humans, which these cases do not seem to support. In all cases the slip was bilateral, and it is emphasised that surgical treatment can provide only temporary fixation because fusion is dependent on correct hormonal therapy

1. An apparatus was designed to determine the shearing strength of the upper tibial epiphysis in the rat. Observations were made with this instrumenton normal animals, on animals receiving growth-hormone, and on animals receiving oestrogen. 2. When the epiphysis separates from the diaphysis, the plane of cleavage is constant, passing through the third layer of the epiphysial plate. 3. Growth-hormone decreases and sex-hormone increases the shearing strength of the epiphysial plate. These changes are due to alterations produced by these two hormones in the thickness of the third layer of the epiphysial plate. 4. It is suggested that these findings may be of significance in providing an anatomical basis for slipping of the upper femoral epiphysis in man, especially when it is associated with the adiposo-genital syndrome or with rapid adolescent growth

Aims

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).

Introduction and aims: Minimal trauma fractures may be the first indication of osteoporosis [OP]. Available data suggests that the continuum of care [EDorthopaedic service-GP] is breaking down with respect to identification and treatment of osteoporosis. Our aim was to determine the extent of this breakdown in the Australasian context. Methods: Observational retrospective cohort study of patients aged 50 years or over who were treated and discharged with wrist fracture due to minimal trauma. Data collected included demographics, fracture details, cause of injury, bone density testing and osteoporosis-related medication change. Outcomes of interest were the proportion of patients who underwent bone density testing and treatment in the follow-up period. Results: 131 patients were studied; 83% were female with median age of 71 years. No patient was referred by ED or fracture clinic for bone density testing [0%, 95% CI 0–3.5%]. Telephone follow-up was obtained from 91 patients, of whom 28 [31%] reported having bone density testing after their fracture. 50% [14, 95% CI 32–67%] of these were found to have osteoporosis. Seven patients [8%] commenced treatment with a bisphosphonate and one [1%] commenced a selective oestrogen receptor modulator. Conclusion: Follow-up of ‘at risk’ patients suffering minimal trauma wrist fractures treated in the ED is poor. Systems to improve identification and treatment of osteoporosis in this group are needed if future osteoporotic fractures and their consequences are to be avoided. Possible models will be put forward

Introduction. Forelimb and tail amputations of 3-week-old C57BL/6 mice are known to yield spinal curves similar to adolescent idiopathic scoliosis (AIS). Our previous work showed that tamoxifen produces a significant decrease in severity of these curves. Vertebral osteoporosis was thought to be related to AIS. Interestingly, a histological pilot study has shown that scoliotic mice given tamoxifen were less osteoporotic than were controls. Raloxifene is an oestrogen receptor modulator (SERM) similar to tamoxifen with a more specific effect on bone and is commonly used to treat osteoporosis. We aimed to study and compare the effects of tamoxifen and raloxifene on the rate and magnitude of scoliosis on a C57BL/6 mice model. Methods. 90 female 3-week-old C57BL/6 mice underwent amputations of forelimbs and tails. 78 were available for analysis and were grouped as control (no medications; n=24), TMX group (10 mg tamoxifen/L drinking water; n=30), and RLX group (10 mg raloxifene/L drinking water; n=241). Seven mice from each group (including scoliotic ones) were killed for histological study at week 20 after posteroanterior (PA) scoliosis radiograph examinations. The rest were killed at the end of week 40 after PA radiographs were obtained. Radiographs were assessed for presence and magnitude of spinal curves. Results. Week 20 analysis showed that lower thoracic curve rate (LTr) was higher in RLX group (p=0·029) and thoracolomber rate (TLr) was higher in TMX group (p=0·33) than in the control group. TMX group had higher upper thoracic (UT) curve magnitudes than did the control group (p=0·021). Week analysis showed similar curve rates in all groups. The RLX group had significantly decreased upper (p<0·0001) and lower (p=0·014) thoracic curve magnitudes compared with the control group. The TMX group had significantly lower UT curve magnitudes than did the control group (p=0·014). Conclusions. Raloxifene is shown to be as effective as tamoxifen in decreasing the magnitude of spinal deformities in C57BL/6 mice model. These results suggest that SERMs might be useful to prevent progression of scoliotic curves. Models of higher animals may be warranted

The purpose of this study was to investigate the association of endocrine disease with calcific tendinitis and the effects that such disease has on its natural history. A retrospective observational cohort study of 102 consecutive patients (125 shoulders) with calcific tendinitis is presented. Seventy-three (71.6 %) female, 29 (28.4 %) male. Compared with population prevalences, significant levels of endocrine disorders were found in our study cohort. Sixty-six patients (81 shoulders, 62 female (93.9 %), 4 male (6.1 %), mean age 50.3 years) with associated endocrine disease were compared with 36 patients (44 shoulders, 11 female (30.6 %), 25 male (69.4 %), mean age 52.4 years) without endocrine disease. The endocrine cohort were significantly younger than the non-endocrine cohort when symptoms started (mean 40.9 years and 46.9 years respectively, p=0.0026), had significantly longer natural histories (mean 79.7 months compared with 47.1 months, p=0.0015) and a significantly higher proportion underwent operative treatment (46.9 % compared with 22.7 %, p=0.0014). Disorders of thyroid and oestrogen metabolism may contribute to calcific tendinitis aetiology. Classifying calcific tendinitis into Type I idiopathic and Type II secondary or endocrine-related aids prognosis and management

Introduction: Abnormal fracture healing in aged, post-menopausal or ovariectomised patients remains a clinical problem. Understanding the distribution and regulation of biomolecular factors in fracture healing in oestrogen deficient rats may have clinical implications for developing novel therapeutic strategies for enhancing osteoporotic fracture healing. Our previous work demonstrated that bone morphogenetic proteins (BMPs), transforming growth factor beta (TGF-ß) and their signal transducers, Smads, played important roles in normal fracture healing. Insulin-like growth factor I (IGF-I) has been indicated playing a role in the maintenance of bone mass. Matrix metalloproteinases (MMPs) has been indicated to play a role in bone matrix degradation. Those factors in ovariectomised fracture healing have not yet been reported. Aim: To investigate the expression of BMP-2, 7, TGF-ß, Smads1–7, IGF-I, IGF-I receptor 1a (IGF-IR1), MMPs and TIMPs by a quantitative immunohistochemistry in a fracture model in an ovariectomised rodent (OVX). Methods: Age-matched, normal, female rats served as controls. The animals were sacrificed in groups of six at one, two, three, four and six weeks after the fracture. Results: The highlights of our results were the lack of IGF-I in the early stage of fracture healing (up to two weeks) in OVX rats and the greater expression of MMP-1 in OVX rats at all groups when compared with the normal rats. Conclusions: Our data suggested that the regulation downward of IGF-I in the OVX fractures resulted from estrogen deficiency and may have the function to stimulate MMP-1 activity. Over-expressed MMP-1 degraded collagen matrix in the cortex and inhibited the woven bone matrix formation during OVX fracture healing

Background: To compare height-adjusted fat and fat-free mass components of body composition in girls with adolescent idiopathic scoliosis to young adolescents with eating disorders. Adolescent idiopathic scoliosis (AIS) has been linked with low bone densities. Animal and human studies have shown that bone densities are influenced by a wide variety of inter-related factors that includes body fat, oestrogen levels, nutritional status and energy balance. Anthropometric studies have reported girls with AIS as being taller and more slender than their age-matched peers and that they also exhibit complex patterns of body asymmetry, particularly in the upper limb. There are also some studies report eating disorders in this population. Methods: Height-adjusted fat and fat-free mass components of body composition were examined. Fat mass index (FMI) and fat-free mass index (FFMI) were calculated and normalised for height and were superimposed onto UK 1990 growth reference data. The data for left and right limb length was also compared. A sample of 325 girls with AIS referred to the specialist spinal unit in Liverpool during the period 1970–1990. Results: The fat mass index and fat-free mass index were reduced in this sample of AIS subjects compared with normal reference children, but were similar to those diagnosed with eating disorders (anorexia nervosa). The cohort also exhibited significant upper limb asymmetry. Conclusion: The findings suggest that this population has significantly low fat mass compared to normal, healthy reference values. Since fat mass reflects energy balance, nutritional status (possibly eating disorders) and is closely linked to endocrine function, the implications of reduced fat mass on growth, bone mass accretion and the aetiology of AIS merit further investigation

Nachemson (1996), drawing upon the theses of Sahlstrand (1977) and Lidström (1988), articulated the view there are more girls than boys with progressive AIS for the following reason. The maturation of postural mechanisms in the nervous system is complete about the same time in boys and girls. Girls enter their skeletal adolescent growth spurt with immature postural mechanisms – so that if they have a predisposition to develop a scoliosis curve, the spine deforms. In contrast boys enter their adolescent growth spurt with mature postural mechanisms so that they are protected from developing a scoliosis curve. There is evidence that postural sway improves with age in boys and girls until about 10 years of age after which it is similar between the sexes (Hirashawa 1973, Odenrick and Sandstedt 1984) findings which need further evaluation. We term Nachemson’s concept the neuro-ossesous timing of maturation (NOTOM) hypothesis. It may have an evolutionary basis through natural selection towards sexual and skeletal development during adolescence being earlier in girls and later in boys. The NOTOM hypothesis suggests a treatment to prevent progression of late-juvenile idiopathic scoliosis, early-AIS, and some secondary scolioses based on delaying the onset of puberty used therapeutically in girls with idiopathic precocious puberty (IPP, Grumbach and Styne 1998). The proposal is to administer a gonadorelin analogue which in the pituitary down-regulates the receptors to hypothalamic gonadotropin-releasing hormone (GnRH) causing a fall in both luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn causes a fall in oestrogens and androgens, and thereby delays or stops menarche and slows bone growth – as in girls and boys with IPP (Galluzzi et al 1998). Expert scrutiny of this therapeutic proposal is currently in progress

Introduction and Aims: Hormonal factors are one plausible explanation for differences in musculotendinous stiffness (MTS) and knee laxity between men and women, and the resulting higher risk for ACL injury in women. This study examined MTS and ACL laxity over the course of the menstrual cycle in women and investigated the interaction of warm-up. Method: Eight female netball players aged between 16–18 years (mean = 16.3 ± 0.8 years) participated in this study. None of the participants were using oral contraceptives and all demonstrated regular menstrual cycles. Venous blood samples and MTS data were collected each week over the 28-day menstrual cycle. MTS was assessed prior to, and following a standardised warm-up consisting of light cycling and jumping. ACL laxity was determined at the beginning of each test session using the KT2000™ knee arthrometer (MEDmetric Corporation, San Diego, USA). Results: Repeated measures ANOVA results revealed significant (p < 0.05) main effects of warm-up and test session on MTS. For the effect of warm-up, MTS was found to significantly decrease by 4.2% following the warm-up intervention, indicating that relatively low levels of activity can acutely alter the viscoelastic properties of muscle. Post hoc contrasts for test session revealed that MTS was significantly lower at week three (corresponding to the ovulatory phase), in contrast to weeks one and two (7% and 4.5% decrease, respectively). For ACL laxity, repeated measures ANOVA revealed no significant (p < 0.05) differences at 30 lb anterior force across the menstrual cycle. The results did however demonstrate a trend towards increased ACL laxity during ovulation (week three) when the lower limb musculature was most compliant. Conclusion: While there were no significant differences in static ACL laxity, reduced MTS is one of the main causes of prolonged electromechanical delay (EMD) and has particular relevance for ACL injury. In conclusion, females are at greater risk of incurring an ACL injury during ovulation when oestrogen levels are highest

Nachemson [2] drawing upon the theses of Sahlstrand [3] and Lidström [4] articulated the view there are more girls than boys with progressive AIS for the following reason. The maturation of postural mechanisms in the nervous system is complete about the same time in boys and girls. Girls enter their skeletal adolescent growth spurt with immature postural mechanisms – so if they have a predisposition to develop a scoliosis curve, the spine deforms. In contrast, boys enter their adolescent growth spurt with mature postural mechanisms so they are protected from developing a scoliosis curve. We term Nachemson’s concept the neuro-osseous timing of maturation (NOTOM) hypothesis [1,5] The earlier sexual and skeletal maturation of girls may have an evolutionary basis through natural selection. Curve progression in AIS is associated with acceleration of the adolescent growth spurt [6]. Postural sway involves proprioceptive, vestibular and visual input to the central nervous system. In normal children there is a significant reduction in postural sway amplitude between six to nine years and 10–14 years [7,8]. In 1071 normal children aged 6–14 years postural sway is more stable in girls from 6–9 years and over 10 years there is no sex effect [9]; all these findings fit the Nachemson concept. But in view of a subsequent report on 64 normal children aged 3–17 years showing the change with age is limited to boys [10] the age and sex effect of postural sway in healthy children needs further evaluation. In AIS children stabilometry findings are conflicting and observed greater postural sway may be secondary to the curve. In the siblings of scoliotics Lidström et al [11] concluded that postural aberration is a factor in the aetiology of AIS. Conclusion: The NOTOM hypothesis suggests a treatment to prevent progression of late-juvenile idiopathic scoliosis, early-AIS, and some secondary scolioses. It is based on delaying the onset of the adolescent growth spurt and puberty as used therapeutically in children with idiopathic precocious puberty (IPP)[12]. The proposal is to administer a gonadorelin analogue which in the pituitary down-regulates receptors to hypothalamic gonadotropin-releasing hormone (GnRH) causing a fall in both luteinizing hormone (LH) and follicle-stimulating stimulating hormone (FSH); in turn this causes a fall in oestrogens and androgens and thereby delays or stops menarche and slows bone growth – as in girls and boys with IPP [13]. Expert paediatric opinion is supportive. King [14] has suggested the use of a gonadorelin analogue (Lupron) to delay the onset of the adolescent growth spurt in progressive AIS

Introduction: Following an Australian study on the incidence of scoliosis in a population of short-statured children treated with human growth hormone (conducted during 2001–2002), it was determined that the only risk factor for the presence of idiopathic scoliosis was having Turner/another syndrome. The 30% incidence in Turner syndrome was noted to be much higher than previously reported (11–12%). The aim of this study is to determine the incidence of scoliosis in a group of growth hormone-treated and non-treated Turner Syndrome subjects who attended the International Turner Syndrome Society meeting in Sydney, Australia in July 2003 and to correlate the results with the Australian 2001–2002 results. Methods: 88 subjects were clinically examined for the presence and severity of idiopathic scoliosis. Their ages ranged from 11 to 60 years. All subjects provided information regarding previous growth hormone and/or oestrogen administration. Anthropometric data including sitting and standing height and arm span was also collated on this cohort. Results: 13 of 46 (28.3%) subjects who had no growth hormone treatment were found to have scoliosis. Five of 42 (12%) subjects who were growth hormone treated were found to have scoliosis. 12 curves were thoracic, five were thoracolumbar and one was lumbar. The 13 subjects with scoliosis and no growth hormone treatment had curves between10 and 20° Cobb angle. Three growth hormone-treated subjects had curves of 10°, one had a curve of 30° and the last subject had already undergone scoliosis surgery. Combining the results of this study with the three Australian States study from 2001–2002, 18 of 87 (21%) growth hormone-treated Turner syndrome subjects have idiopathic scoliosis. 13 of 46 (28%) non-growth hormone-treated Turner syndrome subjects also have idiopathic scoliosis. Of the total 133 subjects in this cohort, 31 (23%) have idiopathic scoliosis. Discussion: The incidence of idiopathic scoliosis in Turner syndrome appears to have been understated in previous studies. Data from this study would indicate that treating children who have Turner syndrome with adjuvant human growth hormone does not appear to result in a greater incidence or severity of idiopathic scoliosis. In this relatively small study, two of five children who had previous growth hormone treatment developed larger curves, one requiring corrective scoliosis surgery

Aims

Despite the interest in the association of gut microbiota with bone health, limited population-based studies of gut microbiota and bone mineral density (BMD) have been made. Our aim is to explore the possible association between gut microbiota and BMD.

Introduction. From the many human studies that attempt to identify genes for adolescent idiopathic scoliosis (AIS), the view emerging is that AIS is a complex genetic disorder with many predisposing genes exhibiting complex phenotypes through environmental interactions. Although advancements in genomic technology are transforming how we undertake genetic and genomic studies, only some success has been reached in deciphering complex diseases such as AIS. Moreover, the present challenge in AIS research is to understand the causative and correlative effects of discovered genetic perturbations. An important limitation to such investigations has been the absence of a method that can easily stratify patients with AIS. To overcome these challenges, we have developed a functional test that allows us to stratify patients with AIS into three functional subgroups, representing specific endophenotypes. Interestingly, in families with multiple cases of AIS, a specific endophenotype is shared among the affected family members, indicating that such a transmission is inherited. Moreover, increased vulnerability to AIS could be attributable to sustained exposure to osteopontin (OPN), a multifunctional cytokine that appears to be at the origin of the Gi-coupled receptor signalling dysfunction discovered in AIS. We examined the molecular expression profiles of patients with AIS and their response to OPN. Methods. Osteoblasts isolated from patients with AIS were selected for each functional subgroup and compared with osteoblasts obtained from healthy matched controls. We used the latest gene chip human genome array Affymetrix (HuU133 Plus 2.0 array) that allows for the analysis of the expression level of 38 000 well characterised human genes. Raw data were normalised with robust multiarray analysis method. Statistical analysis was done by the EB method with FlexArray software. Selection criteria for in-depth analysis include the magnitude of change in expression (at least □} 3-fold) and 5% false discovery rate as stringency selection. Validation of selected candidate genes was done by qPCR and at the protein level by Western blot and ELISA methods. Plasma OPN concentrations were measured by ELISA on a group of 683 consecutive patients with AIS and were compared with 262 healthy controls and 178 asymptomatic offspring, born from at least one scoliotic parent, and thus considered at risk of developing the disorder. The regulation of OPN signalling pathway in normal and AIS cells were validated in vitro by cellular dielectric spectroscopy (CDS). Results. Of 38 000 human genes tested, we have found eight genes specifically associated with the functional subgroup 1, 16 genes with the functional subgroup 2, and 11 genes with the functional subgroup 3. Interestingly, only 19 genes were shared and affected to the same extent in all AIS functional subgroups exhibiting a similar curve pattern (double major), suggesting their role in the formation of this curve pattern. Indeed, most of these genes encode for regulatory proteins such as transcription factors regulating axial skeleton, somite development, and extracellular matrix proteins. Mean plasma OPN concentrations were significantly increased in patients with AIS and correlated with disease severity. Increased plasma OPN concentrations were also detected in the asymptomatic at-risk group, suggesting that these changes precede scoliosis onset. CDS experiments clearly showed that OPN exposure triggers a Gi-coupled receptor signalling dysfunction, which is exacerbated by oestrogens. Conclusions. Our data further support our functional method of stratification of patients with AIS and allow the identification of genes triggering scoliosis onset versus those predisposing to the development of a specific curve pattern. Furthermore, our clinical and experimental data show that OPN is essential for scoliosis onset and curve progression, thus offering a first molecular concept to explain the pathomechanism leading to the asymmetrical growth of the spine in AIS. Acknowledgments. This research project was supported by grants from La Fondation Yves Cotrel de l'Institut de France, Canadian Institutes of Health Research, and Paradigm Spine LLC

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.

Osteoporosis (OP) is a chronic metabolic bone disease characterized by the decrease of bone tissue per unit volume under the combined action of genetic and environmental factors, which leads to the decrease of bone strength, makes the bone brittle, and raises the possibility of bone fracture. However, the exact mechanism that determines the progression of OP remains to be underlined. There are hundreds of trillions of symbiotic bacteria living in the human gut, which have a mutually beneficial symbiotic relationship with the human body that helps to maintain human health. With the development of modern high-throughput sequencing (HTS) platforms, there has been growing evidence that the gut microbiome may play an important role in the programming of bone metabolism. In the present review, we discuss the potential mechanisms of the gut microbiome in the development of OP, such as alterations of bone metabolism, bone mineral absorption, and immune regulation. The potential of gut microbiome-targeted strategies in the prevention and treatment of OP was also evaluated.

Cite this article: Bone Joint Res 2020;9(8):524–530.

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.

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.

Introduction: Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis, which appears to be caused by a melatonin signalling dysfunction proved recently in osteoblasts. This pathology occurs and progresses during the time of pre-puberty and puberty growth. This period is known to be under the hormonal control and coincides with many biological changes related to the secretion of estrogens, of which estradiol (E2) is the most active. The female prevalence of AIS disease is clearly evident. Indeed, in Quebec the spine deformities considered clinically significant (at least 11° of deformity) are found in a girl:boy ratio of approximately 2:1 for reduced scoliosis, and this ratio increases to 10:1 for scoliosis of more than 30o of deformation. However, the reason for this female prevalence as well as the role of estrogens and estrogen receptors in AIS is not clear despite the fact that these hormones are known for their impact on bone and bone growth, including the spine. The purpose of the present study was to investigate the role of E2 on the responsiveness of the AIS cells to the melatonin, to determine the expression of estrogens receptors (ERα and ERβ) in AIS tissues and to clarify the impact of estrogen receptor gene polymorphisms in the pathogenesis of AIS. Methodology: The effects of oestrogen on the AIS osteoblasts (n=10) response to the melatonin was determined by measuring the reduction of forskolin-induced cAMP accumulation. The forskolin treated osteoblasts were incubated in the presence of increasing amounts of melatonin (10–11 to 10-5 M) with or without physiological concentrations (10-10 M) of 17-β-estradiol for 16 hours, and the intracellular cAMP measured by radio-immunoassay using Biotrak Kit. Using RT-PCR, we determined ERα and ERβ mRNA expression in osteoblasts from AIS patients (n=14). Polymorphisms of the first intron of the ERα gene, which contains the XbaI and PvuII polymorphisms, were investigated by PCR following digestion with restriction enzyme and using the genomic DNA from lymphocytes isolated from scoliotic patients (n=33). Using the restriction enzymes XbaI and PvuII, the allelic variants XX, Xx, xx, PP, Pp, and pp were identified in 33 AIS patients (uppercase letters represent absence, and lowercase letters represent presence of restriction sites). Results: The intracellular level of cAMP was significantly increased (p< 0.01) in the presence of a physiological concentration of 17-β-estradiol (10-10 M) when compared to the level observed in the presence of melatonin alone (10-9 M) (melatonin + estradiol: 109.46 ± 20.07; melatonin 76.09 ± 12.32 (mean ± SD)). As previously described by Dr Moreau’s team, the same pattern (three type of response to melatonin) takes place in the presence of 17-β-estradiol. We observed the loss of ERβ gene expression in 8/ 14 AIS patients contrasting with ERα gene expression that was found in all AIS patients. The XbaI and PvuII polymorphisms were found in 70% (23/33) and 80% (26/33) of the cases respectively. Of the 33 cases, 21 presented both digestion sites, 24 presented PvuII digestion site (6 homozygote, 18 heterozygote) and 23 (8 homozygote, 15 heterozygote) presented XbaI digestion site. The allelic variants were found as follows: XX: n=8, Xx: n=15, xx: n=8, PP: n=6, Pp: n=18 and pp: n=6. Classified by their location in the spine, seven right thoracic, one left thoracic, one right thoracolumbar, three left thoracolumbar and nine right thoracic-left lumbar were found among the patients presenting PvuII positive polymorphism. Among the patients with XbaI positive polymorphism, six right thoracic, one left thoracic, one right thoracolumbar, three left thoracolumbar and eight right thoracic left lumbar were found. Conclusion: These results show the antagonistic effects of the 17-β-estradiol on AIS osteoblasts response to the melatonin. Thus estrogens interference with melatonin signalling activity would act as a triggering or aggravating factor in the pathogenesis of AIS. At the molecular level, it is possible that estrogens attenuate the response of AIS cells to melatonin through the desensitization of melatonin receptors. The loss of ERβ expression in a significant number of AIS patients appears to be important for the change of the ERα/ERβ receptors ratio that consequently may perhaps alter estrogens signalling pathways. The XbaI and PvuII polymorphisms are present in a significant number of AIS patients but this was not dependant of the curve pattern. These results clearly support the interplays and crosstalk between estrogens and melatonin signalling pathways in AIS aetiopathogenesis. Supported by the Fondation Yves Cotrel, Institut de France

Aims

The main aims were to identify risk factors predictive of a radiolucent line (RLL) around the acetabular component with an interface bioactive bone cement (IBBC) technique in the first year after THA, and evaluate whether these risk factors influence the development of RLLs at five and ten years after THA.

Relating the results of our investigations to the knowledge hitherto acquired about the etiology of osteoporosis (which I have already referred to), I am inclined to interpret the pathogenesis of osteoporosis in the following way: 1) Primary osteoblastic deficiency: congenital (Lobstein); involutive (senile osteoporosis?); 2) Reduced osteoblastic activity from absence of trophic stimuli: (inactivity, ovarian agenesia, eunuchoidism, menopause); 3) Reduced osteoblastic activity from inhibitory stimuli: (cortisone, adrenocorticotrophic hormone (A.C.T.H.), stress, Cushing's disease, thyrotoxicosis); 4) Normal osteoblastic activity but insufficiency of constructive material: (malnutrition, disturbances of the digestive system, insufficiency of vitamin C, diabetes, thyrotoxicosis, cortisone, A.C.T.H., stress, Cushing's disease). Osteoporosis may therefore be the consequence either of a congenital osteoblastic deficiency, such as that found in cases of osteogenesis imperfecta, or of reduced osteoblastic activity due to absence of trophic stimuli such as mechanical stress and the sex hormones, or of reduced activity of the bone cells due to anti-anabolic substances which inhibit them, such as cortisone and its derivatives and the thyroid hormone in strong doses, or lastly of reduced availability of construction material due to its introduction in reduced quantities (starvation, dysfunction of the digestive system) or due to hindering of synthesis (deficiency of vitamin C, diabetes, cortisone and its derivatives) or due to an excessive degree of destruction (thyrotoxicosis). In the case of anti-anabolic hormones from the adrenal cortex, the mechanism may thus be twofold: inhibition of the osteoblasts and deprivation of the osteoblasts of glucoprotein material due to a general anomaly of metabolism. This may perhaps explain the most serious forms of bone atrophy which are usually observable in cases of hyperfunction of the adrenal cortex. Senile osteoporosis should, in my opinion, be included in the first of our groups because it cannot be said to be brought about by any of the causes usually cited for osteoporosis– such as deficiency of sex hormones, excess of hormones from the adrenal cortex, deficiency of calcium, etc.–and in all probability it will depend on a progressive involution of the osteoblasts brought about by old age. Senile involution is an expression of the descending phase of life's parabola and it involves all the organs and all the parenchymatous tissues in the human body, but it does not cause a parallel reduction of functions and activities on all of them equally. The skeletal system is one of the first to feel these reductions, because in old age life necessarily becomes less intense. Consequently in the economy of the ageing subject the generally reduced level of metabolism brings about a sort of selection in the nourishment of the different organs and systems, and sometimes almost a dismantling of some of these in an attempt to fall in with the new and reduced level of activities of some of the parenchymatous tissues, activities which may be incomplete or even transferred elsewhere. We believe that the moment which originally determines the beginning of senile osteoporosis coincides with the involutional process of cellular metabolism that strikes at all parenchymatous tissue during old age–striking, in the case of osteoporosis, hardest of all at the bony tissues. There is, indeed, no doubt that certain essential processes of cellular metabolism do alter with age, and that the reduction in the activity of the gonads does have considerable importance. In any case, just as adolescence and old age cannot be explained only in terms of gonadal activity, so the involution of the skeleton cannot be due merely to the involution of the gonads. How should one then interpret the well known benefit afforded by administration of sex hormones in cases of osteoporosis? Probably the action of oestrogens and androgens is, in this case, of a pharmacological nature, and comparable, for instance, to the action of digitalis on the cardiac muscle. It will be remembered how digitalis acts almost exclusively on myofibrils which have become inadequate, and has little or no effect on a normal myocardium. Similarly, the sex hormones would seem to exert a stimulating action on osteoblasts that are on the way to involution, while they exert little or no action on normal osteoblasts. In support of this we have the findings of Urist and other workers, who demonstrated that the administration of sex hormones produces calcium and nitrogen retention only in osteoporotics, while in non-osteoporotic subjects of the same age it produces no effect. On the other hand, the action of the sex hormones might act in cases of senile osteoporosis by returning the changed level of protein metabolism to normal. From the data in the literature and from the results of our own investigations, I conclude that osteoporosis in general, and senile osteoporosis in particular, are first and foremost the result of a disturbance in the metabolism of bone, and that the metabolic disturbance is closely and exclusively related to the degree of activity and the state of activity of the cells in the bone. Lastly, I believe that senile osteoporosis should not be considered an actual disease but rather as one limited aspect of the normal descending parabola which affects to a greater or less degree all the tissues of the body

Bone is a dynamic tissue with a quarter of the trabecular and a fifth of the cortical bone being replaced continuously each year in a complex process that continues throughout an individual’s lifetime. Bone has an important role in homeostasis of minerals with non-stoichiometric hydroxyapatite bone mineral forming the inorganic phase of bone. Due to its crystal structure and chemistry, hydroxyapatite (HA) and related apatites have a remarkable ability to bind molecules. This review article describes the accretion of trace elements in bone mineral giving a historical perspective. Implanted HA particles of synthetic origin have proved to be an efficient recruiting moiety for systemically circulating drugs which can locally biomodulate the material and lead to a therapeutic effect. Bone mineral and apatite however also act as a waste dump for trace elements and drugs, which significantly affects the environment and human health.

Cite this article: Bone Joint Res 2020;9(10):709–718.

Aims

The aim of this study was to investigate the influence of age on the cost-effectiveness of arthroscopic rotator cuff repair.

Aims

To examine the relationship of sex steroid hormones with osteopenia in a nationally representative sample of men in the USA.

Objectives

MicroRNAs (miRNAs) have been reported as key regulators of bone formation, signalling, and repair. Fracture healing is a proliferative physiological process where the body facilitates the repair of a bone fracture. The aim of our study was to explore the effects of microRNA-186 (miR-186) on fracture healing through the bone morphogenetic protein (BMP) signalling pathway by binding to Smad family member 6 (SMAD6) in a mouse model of femoral fracture.

Objectives

Mesenchymal stem cells (MSCs) are of growing interest in terms of bone regeneration. Most preclinical trials utilize bone-marrow-derived mesenchymal stem cells (bMSCs), although this is not without isolation and expansion difficulties. The aim of this study was: to compare the characteristics of bMSCs and adipose-derived mesenchymal stem cells (AdMSCs) from juvenile, adult, and ovarectomized (OVX) rats; and to assess the effect of human parathyroid hormone (hPTH) 1-34 on their osteogenic potential and migration to stromal cell-derived factor-1 (SDF-1).

Objectives

Cellular movement and relocalisation are important for many physiologic properties. Local mesenchymal stem cells (MSCs) from injured tissues and circulating MSCs aid in fracture healing. Cytokines and chemokines such as Stromal cell-derived factor 1(SDF-1) and its receptor chemokine receptor type 4 (CXCR4) play important roles in maintaining mobilisation, trafficking and homing of stem cells from bone marrow to the site of injury. We investigated the differences in migration of MSCs from the femurs of young, adult and ovariectomised (OVX) rats and the effect of CXCR4 over-expression on their migration.

Objectives

The osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) balance is of the utmost importance in fracture healing. The aim of this study was therefore to investigate the impact of nonosteogenic factors on OPG and RANKL levels.

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.

Objectives

The aim of this study was to review the impact of smoking tobacco on the musculoskeletal system, and on bone fractures in particular.

Objectives

In order to screen the altered gene expression profile in peripheral blood mononuclear cells of patients with osteoporosis, we performed an integrated analysis of the online microarray studies of osteoporosis.

Osteoporosis is a systemic skeletal disorder characterized by reduced bone mass and deterioration of bone microarchitecture, which results in increased bone fragility and fracture risk. Casein kinase 2-interacting protein-1 (CKIP-1) is a protein that plays an important role in regulation of bone formation. The effect of CKIP-1 on bone formation is mainly mediated through negative regulation of the bone morphogenetic protein pathway. In addition, CKIP-1 has an important role in the progression of osteoporosis. This review provides a summary of the recent studies on the role of CKIP-1 in osteoporosis development and treatment.

Cite this article: X. Peng, X. Wu, J. Zhang, G. Zhang, G. Li, X. Pan. The role of CKIP-1 in osteoporosis development and treatment. Bone Joint Res 2018;7:173–178. DOI: 10.1302/2046-3758.72.BJR-2017-0172.R1.

Aims

The aim of this study was to investigate the effects of preoperative bisphosphonate treatment on the intra- and postoperative outcomes of arthroplasty of the shoulder. The hypothesis was that previous bisphosphonate treatment would adversely affect both intra- and postoperative outcomes.

Objectives

Oxidative stress plays a major role in the onset and progression of involutional osteoporosis. However, classical antioxidants fail to restore osteoblast function. Interestingly, the bone anabolism of parathyroid hormone (PTH) has been shown to be associated with its ability to counteract oxidative stress in osteoblasts. The PTH counterpart in bone, which is the PTH-related protein (PTHrP), displays osteogenic actions through both its N-terminal PTH-like region and the C-terminal domain.

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.

Aims

Surgical intervention in patients with bone metastases from breast cancer is dependent on the estimated survival of the patient. The purpose of this paper was to identify factors that would predict survival so that specific decisions could be made in terms of surgical (or non-surgical) management.

Objectives

Bisphosphonates are widely used as first-line treatment for primary and secondary prevention of fragility fractures. Whilst they have proved effective in this role, there is growing concern over their long-term use, with much evidence linking bisphosphonate-related suppression of bone remodelling to an increased risk of atypical subtrochanteric fractures of the femur (AFFs). The objective of this article is to review this evidence, while presenting the current available strategies for the management of AFFs.

Objectives

Previous genome-wide association studies (GWAS) have reported significant association of the single nucleotide polymorphism (SNP) rs8044769 in the fat mass and obesity-associated gene (FTO) with osteoarthritis (OA) risk in European populations. However, these findings have not been confirmed in Chinese populations.

Objectives

This study aims to evaluate if micro-CT can work as a method for the 3D assessment and analysis of cancellous bone by comparing micro-CT with undecalcified histological sections in OVX rats.

The ageing population and an increase in both the incidence and prevalence of cancer pose a healthcare challenge, some of which is borne by the orthopaedic community in the form of osteoporotic fractures and metastatic bone disease. In recent years there has been an increasing understanding of the pathways involved in bone metabolism relevant to osteoporosis and metastases in bone. Newer therapies may aid the management of these problems. One group of drugs, the antibody mediated anti-resorptive therapies (AMARTs) use antibodies to block bone resorption pathways. This review seeks to present a synopsis of the guidelines, pharmacology and potential pathophysiology of AMARTs and other new anti-resorptive drugs.

We evaluate the literature relating to AMARTs and new anti-resorptives with special attention on those approved for use in clinical practice.

Denosumab, a monoclonal antibody against Receptor Activator for Nuclear Factor Kappa-B Ligand. It is the first AMART approved by the National Institute for Health and Clinical Excellence and the US Food and Drug Administration. Other novel anti-resorptives awaiting approval for clinical use include Odanacatib.

Denosumab is indicated for the treatment of osteoporosis and prevention of the complications of bone metastases. Recent evidence suggests, however, that denosumab may have an adverse event profile similar to bisphosphonates, including atypical femoral fractures. It is, therefore, essential that orthopaedic surgeons are conversant with these medications and their safe usage.

Take home message: Denosumab has important orthopaedic indications and has been shown to significantly reduce patient morbidity in osteoporosis and metastatic bone disease.

Cite this article: Bone Joint J 2016;98-B:160–5.

Objectives

The biomembrane (induced membrane) formed around polymethylmethacrylate (PMMA) spacers has value in clinical applications for bone defect reconstruction. Few studies have evaluated its cellular, molecular or stem cell features. Our objective was to characterise induced membrane morphology, molecular features and osteogenic stem cell characteristics.

Sex hormones play important roles in the regulation of the proliferation, maturation and death of chondrocytes in the epiphyseal growth plate. We have investigated the effects of male castration on the cell kinetics of chondrocytes as defined by the numbers of proliferating and dying cells. The growth plates of normal rabbits and animals castrated at eight weeks of age were obtained at 10, 15, 20 and 25 weeks of age.

Our study suggested that castration led to an increase in apoptosis and a decrease in the proliferation of chondrocytes in the growth plate. In addition, the number of chondrocytes in the castrated rabbits was less than that of normal animals of the same age.

In patients with traumatic brain injury and fractures of long bones, it is often clinically observed that the rate of bone healing and extent of callus formation are increased. However, the evidence has been unconvincing and an association between such an injury and enhanced fracture healing remains unclear. We performed a retrospective cohort study of 74 young adult patients with a mean age of 24.2 years (16 to 40) who sustained a femoral shaft fracture (AO/OTA type 32A or 32B) with or without a brain injury. All the fractures were treated with closed intramedullary nailing. The main outcome measures included the time required for bridging callus formation (BCF) and the mean callus thickness (MCT) at the final follow-up. Comparative analyses were made between the 20 patients with a brain injury and the 54 without brain injury. Subgroup comparisons were performed among the patients with a brain injury in terms of the severity of head injury, the types of intracranial haemorrhage and gender. Patients with a brain injury had an earlier appearance of BCF (p < 0.001) and a greater final MCT value (p < 0.001) than those without. There were no significant differences with respect to the time required for BCF and final MCT values in terms of the severity of head injury (p = 0.521 and p = 0.153, respectively), the types of intracranial haemorrhage (p = 0.308 and p = 0.189, respectively) and gender (p = 0.383 and p = 0.662, respectively).

These results confirm that an injury to the brain may be associated with accelerated fracture healing and enhanced callus formation. However, the severity of the injury to the brain, the type of intracranial haemorrhage and gender were not statistically significant factors in predicting the rate of bone healing and extent of final callus formation.

The mammalian growth plate is a complex structure which is essential for the elongation of long bones. However, an understanding of how the growth plate functions at the cellular level is lacking. This review, summarises the factors involved in growth-plate regulation, its failure and the consequence of injury. We also describe some of the cellular mechanisms which underpin the increase in volume of the growth-plate chondrocyte which is the major determinant of the rate and extent of bone lengthening. We show how living in situ chondrocytes can be imaged using 2-photon laser scanning microscopy to provide a quantitative analysis of their volume. This approach should give better understanding of the cellular control of bone growth in both healthy and failed growth plates.

Corticosteroid use has been implicated in the development of osteonecrosis of the femoral head (ONFH). The exact mechanism and predisposing factors such as age, gender, dosage, type and combination of steroid treatment remain controversial. Between March and July 2003, a total of 539 patients with severe acute respiratory syndrome (SARS) were treated with five different types of steroid. There were 129 men (24%) and 410 women (76%) with a mean age of 33.7 years (21 to 59). Routine screening was undertaken with radiographs, MRI and/or CT to determine the incidence of ONFH.

Of the 129 male patients with SARS, 51 (39.5%) were diagnosed as suffering from ONFH, compared with only 79 of 410 female patients (19.3%). The incidence of ONFH in the patients aged between 20 and 49 years was much higher than that of the group aged between 50 and 59 years (25.9% (127 of 491) versus 6.3% (3 of 48); p = 0.018). The incidence of ONFH in patients receiving one type of steroid was 12.5% (21 of 168), which was much lower than patients receiving two different types (28.6%; 96 of 336) or three different types of steroid (37.1%; 13 of 35).

Cite this article: Bone Joint J 2014;96-B:259–62.

Adolescent idiopathic scoliosis affects about 3% of children. Non-operative measures are aimed at altering the natural history to maintain the size of the curve below 40° at skeletal maturity. The application of braces to treat spinal deformity pre-dates the era of evidence-based medicine, and there is a paucity of irrefutable prospective evidence in the literature to support their use and their effectiveness has been questioned.

This review considers this evidence. The weight of the evidence is in favour of bracing over observation. The most recent literature has moved away from addressing this question, and instead focuses on developments in the design of braces and ways to improve compliance.

Cite this article: Bone Joint J 2013;95-B:1308–16.

The long-term effects of metal-on-metal arthroplasty are currently under scrutiny because of the potential biological effects of metal wear debris. This review summarises data describing the release, dissemination, uptake, biological activity, and potential toxicity of metal wear debris released from alloys currently used in modern orthopaedics. The introduction of risk assessment for the evaluation of metal alloys and their use in arthroplasty patients is discussed and this should include potential harmful effects on immunity, reproduction, the kidney, developmental toxicity, the nervous system and carcinogenesis.

The June 2012 Research Roundup³⁶⁰ looks at: platelet-rich plasma; ageing, bone and mesenchymal stem cells; cytokines and the herniated intervertebral disc; ulcerative colitis, Crohn’s disease and anti-inflammatories; the effect of NSAIDs on bone healing; osteoporosis of the fractured hip; herbal medicine and recovery after acute muscle injury; and ultrasound and the time to fracture union.

Given the growing prevalence of obesity around the world and its association with osteoarthritis of the knee, orthopaedic surgeons need to be familiar with the management of the obese patient with degenerative knee pain. The precise mechanism by which obesity leads to osteoarthritis remains unknown, but is likely to be due to a combination of mechanical, humoral and genetic factors.

Weight loss has clear medical benefits for the obese patient and seems to be a logical way of relieving joint pain associated with degenerative arthritis. There are a variety of ways in which this may be done including diet and exercise, and treatment with drugs and bariatric surgery. Whether substantial weight loss can delay or even reverse the symptoms associated with osteoarthritis remains to be seen.

Surgery for osteoarthritis in the obese patient can be technically more challenging and carries a risk of additional complications. Substantial weight loss before undertaking total knee replacement is advisable. More prospective studies that evaluate the effect of significant weight loss on the evolution of symptomatic osteoarthritis of the knee are needed so that orthopaedic surgeons can treat this patient group appropriately.

Breast cancer is generally managed surgically with adjuvant agents which include hormone therapy, chemotherapy, radiotherapy and bisphosphonate therapy. However, some of these adjuvant therapies may cause adverse events, including wound infection, neutropenia, bone marrow suppression and fever. The simultaneous presentation of osteonecrosis and osteomyelitis has not previously been described in patients with breast cancer undergoing hormone therapy and chemotherapy.

We report a patient with breast cancer who developed bone infarcts in both legs as well as osteomyelitis in the right distal tibia after treatment which included a modified radical mastectomy, hormone therapy and chemotherapy. Simultaneous osteonecrosis and osteomyelitis should be considered in patients with breast cancer who are receiving chemotherapy and hormone therapy who present with severe bone pain, especially if there have been infective episodes during treatment.

Low bone mass and osteopenia have been described in the axial and peripheral skeleton of patients with adolescent idiopathic scoliosis (AIS). Recently, many studies have shown that gene polymorphism is related to osteoporosis. However, no studies have linked the association between IL6 gene polymorphism and bone mass in AIS. This study examined the association between bone mass and IL6 gene polymorphism in 198 girls with AIS. The polymorphisms of IL6-597 G→A, IL6-572 G→C and IL6-174 G→A and the bone mineral density in the lumbar spine and femoral neck were analysed and compared with their levels in healthy controls. The mean bone mineral density at both sites in patients with AIS was decreased compared with controls (p = 0.0022 and p = 0.0013, respectively). Comparison of genotype frequencies between AIS and healthy controls revealed a statistically significant difference in IL6-572 G→C polymorphism (p = 0.0305). There was a significant association between the IL6-572 G→C polymorphism and bone mineral density in the lumbar spine, with the CC genotype significantly higher with the GC (p = 0.0124) or GG (p = 0.0066) genotypes.

These results suggest that the IL6-572 G→C polymorphism is associated with bone mineral density in the lumbar spine in Korean girls with AIS.

The brachial artery is rarely injured after closed dislocation of the elbow. We describe an unusual variation of this injury, namely, a delayed thrombosis of the brachial artery after a closed dislocation sustained during a low-energy fall. This has not previously been described in the English literature, but may be more common than this suggests. We stress the importance of a thorough neurovascular examination and vigilance in regard to this potentially disastrous complication.

We describe a case of sciatic endometriosis in a 25-year-old woman diagnosed by MRI and histology with no evidence of intrapelvic disease.

The presentation, diagnosis and management of this rare condition are described. Early diagnosis and treatment are important to prevent irreversible damage to the sciatic nerve.

We performed a meta-analysis to evaluate the relative efficacy of regional and general anaesthesia in patients undergoing total hip or knee replacement. A comprehensive search for relevant studies was performed in PubMed (1966 to April 2008), EMBASE (1969 to April 2008) and the Cochrane Library. Only randomised studies comparing regional and general anaesthesia for total hip or knee replacement were included.

We identified 21 independent, randomised clinical trials. A random-effects model was used to calculate all effect sizes. Pooled results from these trials showed that regional anaesthesia reduces the operating time (odds ratio (OR) −0.19; 95% confidence interval (CI) −0.33 to −0.05), the need for transfusion (OR 0.45; 95% CI 0.22 to 0.94) and the incidence of thromboembolic disease (deep-vein thrombosis OR 0.45, 95% CI 0.24 to 0.84; pulmonary embolism OR 0.46, 95% CI 0.29 to 0.80).

Regional anaesthesia therefore seems to improve the outcome of patients undergoing total hip or knee replacement.

Little is known about the efficacy of graduated compression stockings in preventing venous thromboembolism after hip surgery. We conducted a prospective, randomised single-blind study to determine whether the addition of compression stockings to fondaparinux conferred any additional benefit.

The study included 874 patients, of whom 795 could be evaluated (400 in the fondaparinux group and 395 in the fondaparinux plus compression stocking group). Fondaparinux was given post-operatively for five to nine days, either alone or combined with wearing stockings, which were worn for a mean 42 days (35 to 49).

The study outcomes were venous thromboembolism, or sudden death before day 42. Duplex ultrasonography was scheduled within a week of day 42. Safety outcomes were bleeding and death from venous thromboembolism.

The prevalence of deep-vein thrombosis was similar in the two groups 5.5% (22 of 400) in the fondaparinux group and 4.8 (19 of 395) in the fondaparinux plus stocking group (odds ratio 0.88, 95% confidence interval 0.46 to 1.65, p = 0.69). Major bleeding occurred in only one patient.

The addition of graduated compression stockings to fondaparinux appears to offer no additional benefit over the use of fondaparinux alone.