Low Bone Research Articles

Systematic Review and Meta-Analysis of the Effect of Osteoporosis on Reoperation Rates and Complications after Surgical Management of Lumbar Degenerative Disease.

There is considerable heterogeneity in findings and a lack of consensus regarding the interplay between osteoporosis and outcomes in patients with lumbar degenerative spine disease. Therefore, the purpose of this systematic review and meta-analysis was to gather and analyze existing data on the effect of osteoporosis on radiographic, surgical, and clinical outcomes following surgery for lumbar degenerative spinal disease. A systematic review was performed to determine the effect of osteoporosis on the incidence of adverse outcomes after surgical intervention for lumbar degenerative spinal diseases. The approach focused on the radiographic outcomes, reoperation rates, and other medical and surgical complications. Subsequently, a meta-analysis was performed on the eligible studies. The results of the meta-analysis suggested that osteoporotic patients experienced increased rates of adjacent segment disease (ASD; p=0.015) and cage subsidence (p=0.001) while demonstrating lower reoperation rates than non-osteoporotic patients (7.4% vs. 13.1%; p=0.038). The systematic review also indicated that the length of stay, overall costs, rates of screw loosening, and rates of wound and other medical complications may increase in patients with a lower bone mineral density. Fusion rates, as well as patient-reported and clinical outcomes, did not differ significantly between osteoporotic and non-osteoporotic patients. Osteoporosis was associated with an increased risk of ASD, cage migration, and possibly postoperative screw loosening, as well as longer hospital stays, incurring higher costs and an increased likelihood of postoperative complications. However, a link was not established between osteoporosis and poor clinical outcomes.

DXA-derived lumbar bone strain index corrected for kyphosis is associated with vertebral fractures and trabecular bone score in acromegaly.

The bone strain index (BSI) is a marker of bone deformation based on a finite element analysis inferred from dual X-ray absorptiometry (DXA) scans, that has been proposed as a predictor of fractures in osteoporosis (i.e., higher BSI indicates a lower bone's resistance to loads with consequent higher risk of fractures). We aimed to investigate the association between lumbar BSI and vertebral fractures (VFs) in acromegaly. Twenty-three patients with acromegaly (13 males, mean age 58 years; three with active disease) were evaluated for morphometric VFs, trabecular bone score (TBS), bone mineral density (BMD) and BSI at lumbar spine, the latter being corrected for the kyphosis as measured by low-dose X-ray imaging system (EOS®-2D/3D). Lumbar BSI was significantly higher in patients with VFs as compared to those without fractures (2.90 ± 1.46 vs. 1.78 ± 0.33, p = 0.041). BSI was inversely associated with TBS (rho -0.44; p = 0.034), without significant associations with BMD (p = 0.151), age (p = 0.500), BMI (p = 0.957), serum IGF-I (p = 0.889), duration of active disease (p = 0.434) and sex (p = 0.563). Lumbar BSI corrected for kyphosis could be proposed as integrated parameter of spine arthropathy and osteopathy in acromegaly helping the clinicians in identifying patients with skeletal fragility possibly predisposed to VFs.

Evolutionary and functional analyses of LRP5 in archaic and extant modern humans

BackgroundThe human lineage has undergone a postcranial skeleton gracilization (i.e. lower bone mass and strength relative to body size) compared to other primates and archaic populations such as the Neanderthals. This gracilization has been traditionally explained by differences in the mechanical load that our ancestors exercised. However, there is growing evidence that gracilization could also be genetically influenced.ResultsWe have analyzed the LRP5 gene, which is known to be associated with high bone mineral density conditions, from an evolutionary and functional point of view. Taking advantage of the published genomes of archaic Homo populations, our results suggest that this gene has a complex evolutionary history both between archaic and living humans and within living human populations. In particular, we identified the presence of different selective pressures in archaics and extant modern humans, as well as evidence of positive selection in the African and South East Asian populations from the 1000 Genomes Project. Furthermore, we observed a very limited evidence of archaic introgression in this gene (only at three haplotypes of East Asian ancestry out of the 1000 Genomes), compatible with a general erasing of the fingerprint of archaic introgression due to functional differences in archaics compared to extant modern humans. In agreement with this hypothesis, we observed private mutations in the archaic genomes that we experimentally validated as putatively increasing bone mineral density. In particular, four of five archaic missense mutations affecting the first β-propeller of LRP5 displayed enhanced Wnt pathway activation, of which two also displayed reduced negative regulation.ConclusionsIn summary, these data suggest a genetic component contributing to the understanding of skeletal differences between extant modern humans and archaic Homo populations.

Technologically advanced running shoes reduce oxygen cost and cumulative tibial loading per kilometer in recreational female and male runners

Technologically advanced running shoes (TARS) improve performance compared to classical running shoes (CRS). Improved race performance has been attributed to metabolic savings in male runners, but it remains unclear if these same benefits are experienced among females and in recreational runners. The mechanisms behind these benefits are still not fully understood despite the need for optimisation, and their influence on injury mechanisms has not been explored. Here we combined biomechanical, physiological, and modelling approaches to analyse joint mechanics, oxygen uptake, and tibial load in nineteen male and female recreational runners running with CRS and TARS at their individual lactate threshold speed (12.4 ± 1.9 km/h). Oxygen uptake was 3.0 ± 1.5% lower in TARS than in CRS. Ankle dorsiflexion, joint moment and joint power were reduced in TARS compared to CRS at various phases of stance including midstance, while knee joint mechanics were mostly similar throughout. There were no significant differences for tibial bending moment during the stance phase but cumulative tibial damage per kilometre was 12 ± 9% lower in TARS compared to CRS. Our results suggest that running with TARS reduces oxygen cost in recreational female and male runners, which may partly be explained by differences in lower limb joint mechanics. The lower cumulative tibial bone load with TARS may allow runners to run longer distances in this type of shoe compared to CRS.

The influence of bone block graft position on bone dimensional changes in staged onlay horizontal ridge augmentation: A 6-month retrospective cohort study.

To analyze changes in bone dimensions and their modulating factor in bone dimensions 6 months after horizontal ridge augmentation using autogenous bone grafts. Thirty-eight patients with horizontally atrophic alveolar ridges of a single edentulous tooth at the maxillary anterior site were divided into two groups based on the fixation position of the bone block during ridge augmentation surgery (H0, vertical distance from the upper edge of the bone block to the alveolar crest). Patients were classified into a crestal level (CL) group if H0 ≤ 1 mm and a sub-crestal level (SCL) group if H0 > 1 mm. The width and height of the alveolar ridge were recorded using CBCT both before and 6 months after the augmentation procedure. The CL group comprised 20 patients with 23 implants, whereas the SCL group comprised 18 patients with 22 implants. All the augmentation sites exhibited vertical bone resorption. Vertical bone resorption in the SCL group (1.94 ± 2.11 mm) was significantly higher than that of the CL group (0.61 ± 0.64 mm). The SCL group showed significantly lower horizontal bone gain than the CL group (SCL: 1.02 ± 2.30 mm; CL: 3.19 ± 3.17 mm) at the cervical level. Peri-implant marginal bone loss increased significantly in the SCL group (1.00 ± 2.71 mm) compared to the CL group (0.64 ± 0.40 mm). The bone height decreased after horizontal ridge augmentation using autogenous onlay grafting. The fixation position of the bone block was a modulating factor. The SCL group showed more vertical bone loss, less horizontal bone gain 6 months after surgery, and more marginal bone loss after restoration.

#2215 Early molecular and cellular features of aortic remodeling in a mild CKD-MBD model with low bone turnover

Abstract Background and Aims Vascular calcification associated with a maladaptive bone response is common in CKD and is a major cause of mortality (up to 60% depending on CKD stage). Alterations in several intracellular signaling pathways have been reported during the cellular phenotype transition and vascular calcification, however the initial phases of vascular remodeling in early CKD-MBD remain poorly understood. The aim of this study was to investigate the early molecular and cellular features of aortic remodeling prior to calcification in a model of mild CKD-MBD with low bone turnover. Method We induced CKD-MBD by 3/4 nephrectomy (Nx, n = 8) in adult male spontaneously hypertensive rats (SHR) with normal phosphate (Pi) intake (0.6%). Controls were sham-operated Wistar rats (n = 8) and SHR (n = 8). Chronic kidney injury and Pi exchange parameters, serum levels of calciprotein particles (CPPs), intact PTH, intact FGF23, dickkopf-1 and sclerostin, static bone histomorphometry, aortic morphology (H&E, Masson's trichrome, calcein, von Kossa stain), CD31, aSMA, nestin, Col1a1, PDGFR-beta, PiT1, LGR4 and intracellular signaling molecules—phospho-ERK1/2, active (non-phospho) beta-catenin, Hes1, Gli1 were analyzed by IHC with quantitative morphometry and IF after 4 months. Confocal microscopy was performed at the Centre for Collective Use of the Pavlov Institute of Physiology, Russian Academy of Sciences (Zeiss LSM 710). Results The study found that Nx rats with chronic kidney injury comparable to human CKD S2 exhibited lower bone turnover (Fig. 1). The Nx group had higher serum levels of Pi and CPPs vs. control group, but there were no differences in Pi-regulatory factors (Figs 1, 2b). Additionally, the Nx group showed aorta remodeling, which was characterized by an increase in intima thickness, cellularity, and collagen accumulation in the medial layer (Figs 1, 2a). The histological parameters of intimal remodeling and perivascular fibrosis were found to be directly correlated with serum levels of Pi and CPPs. In Nx, there was a decrease in medial αSMA expression accompanied by an increase in phospho-ERK1/2, PiT1, nestin, Gli1, beta-catenin, dickkopf-1, and an decrease in Hes1 immunomorphological staining (Figs 1, 2a, c). αSMA-negative cells demonstrated the expression of osteogenesis-related molecules, such as phospho-ERK1/2 (Fig. 2a, c), and occasionally, RunX2 (Fig. 2a). Phospho-ERK1/2 and PiT1 were found to co-localize in Nx (Fig. 2c). Intimal remodeling was observed, characterized by increased beta-catenin and nestin expression (Fig. 2c). Conclusion In mild CKD-MBD with low bone turnover, early intimal and medial aortic remodeling was associated with higher serum Pi and CPPs levels, and upregulation of PiT1, ERK1/2. In addition, other signals likely related to osteogenesis (RunX2, LGR4) and regulation of vascular progenitor cells (Nestin, Wnt, Notch, Hedgehog) may be implicated.

#1552 The role of osteocytes in bone remodeling: comparison between biopsies from patients with osteitis fibrosa and mixed uremic osteodystrophy disease

Abstract Background and Aims Osteocytes represent about 95% of bone cells. They are located in mineralized bone tissue and connect with each other, with osteoblasts, osteoclasts, blood vessels and bone marrow cells. These cells express several proteins that regulate phosphorus-calcium metabolism and bone remodeling. Disorders of mineral metabolism resulting from chronic kidney disease – mineral bone disorder (CKD-MBD) alter tissue function leading to histological changes known as renal osteodystrophy (ROD). ROD is classified: in high turnover – osteitis fibrosa (OF) and mixed uremic osteodystrophy (MUO) and low turnover – adynamic bone disease and osteomalacia. The participation of osteocytes proteins in ROD pathogenesis is not fully explained. The aim of this study was to evaluate the expression of osteocytic proteins in bone biopsies from patients with OF and MUO and analyze clinical, biochemical and bone histomorphometric results. Method We evaluated patients with CKD on hemodialysis, who underwent bone biopsy to elucidate the diagnosis of ROD. Static and dynamic parameters by histomorphometry, including quantification of osteocytes, and the expression of proteins by immunohistochemistry (Sclerostin; Nuclear factor Kappa B ligand – RANKL; Osteoprotegerin – OPG; Dickkopf-related protein 1 - DKK1; Fibroblast growth factor 23 - FGF23; Dentin matrix protein 1 - DMP1; Matrix extracellular phosphoglycoprotein – MEPE; Phosphate regulatory gene with homologies to endopeptidases on the X chromosome – PHEX; podoplanin - E11; and CD44). Results We included 47 patients (24 with OF and 23 with MUO). Table 1 describes the results from the comparison between both groups. Patients with MUO were older and had lower serum P levels compared to patients with OF. Histomorphometric results showed that the structural parameter trabecular number was greater in patients with OF. The formation parameters, as osteoid volume, thickness and surface were greater in patients with MUO. Regarding mineralization, these patients also have lower bone formation rate, and mineralizing surface and a longer mineralization lag time. The expression of osteocytic proteins in both groups showed that DMP-1 was approximately 50% lower, near to statistical significance (p = 0.07) and RANKL was 23% lower in patients with MUO. In Table 2 are described the association found between proteins and histomorphometric parameters. The majority of the proteins involved in bone remodeling are negatively associated with histomorphometric parameters. Conclusion The clinical symptoms of CKD-BMD in patients with OF and MD are similar, and, except for serum P levels, other biochemical parameters did not contribute to differentiate Of and MUO. Bone biopsy, despite being an invasive procedure, revealed differences between the two pathologies, which could better guide clinical treatment, such as, vitamin D supplementation and VD analogs in patients with MUO who present an increase in osteoid parameters, which could improve bone mineralization. Regarding the expression of proteins in osteocytes, we found few differences between the two groups. However, several associations were observed between the expression of these proteins and structural, formation, reabsorption and mineralization parameters in high turnover bone disease.

Sophoraflavanone G Inhibits RANKL-Induced Osteoclastogenesis via MAPK/NF-κB Signaling Pathway.

Osteoporosis is a common chronic bone metabolism disorder characterized by decreased bone mass and reduced bone density in the bone tissue. Osteoporosis can lead to increased fragility of the skeleton, making it prone to brittle fractures. Osteoclasts are macrophage-like cells derived from hematopoietic stem cells, and their excessive activity in bone resorption leads to lower bone formation than absorption during bone remodeling, which is one of the important factors inducing osteoporosis. Therefore, how to inhibit osteoclast formation and reducing bone loss is an important direction for treating osteoporosis. Sophoraflavanone G, derived from Sophora flavescens Alt and Rhizoma Drynariae, is a flavonoid compound with various biological activities. However, there have been few studies on osteoporosis and osteoclasts so far. Therefore, we hypothesize that genistein G can inhibit osteoclast differentiation, alleviate bone loss phenomenon, and conduct in vitro and in vivo experiments for research and verification purposes.

#2708 Impact of dialysis modality on bone phenotype

Abstract Background and Aims Literature data suggest that low bone turnover is the prevailing bone phenotype in patients treated with peritoneal dialysis (PD) and point to high sclerostin as the central culprit. Lack of adequate controls, diagnostic heterogeneity, and a changing mineral metabolism landscape and armamentarium call for a cautious interpretation and confirmation in contemporary patients. Method Laboratory parameters of mineral metabolism (biointact parathyroid hormone (PTH), fibroblast growth factor 23 [FGF23] and sclerostin), bone turnover markers (bone alkaline phosphatase [BALP], intact procollagen type I N-terminal propeptide [PINP], tartrate-resistant acid phosphatase 5b [TRAP5b]) and bone mineral density (BMD) were assessed in 636 non-diabetic kidney transplant candidates of whom 447 were treated with hemodialysis (HD) and 189 with PD. A bone biopsy was performed in 204 patients (n = 134 HD; n = 70 PD), with bone sclerostin expression assessed in a subset (n = 52). Results Patients treated with PD had lower levels of PINP (79.6 vs 99.5 ug/L; p < 0.01) and BALP (20.2 vs 23.7 ug/L; p = 0.04) compared to those treated with HD. Histomorphometric parameters of bone formation were numerically lower in patients treated with PD, but significance was not reached. Bone mineralization was impaired in HD patients (osteoid width: 7.90 vs 6.75 µM; p = 0.01; osteoid maturation: 9 vs 6 days; p = 0.03), while frank osteomalacia was rare in both modalities (6.0%, both groups). BMD was higher in patients treated with PD compared to HD at skeletal sites rich in cortical bone (Z-score midshaft radius −0.4 ± 1.3 vs −0.9 ± 1.7; p = 0.04). PTH levels were comparable (150 vs 144 pg/mL, PD vs HD), while patients treated with PD showed higher serum phosphate (4.9 ± 1.3 vs 4.5 ± 1.6 mg/dl; p < 0.01) and FGF23 levels (3852 pg/ml vs 2361 pg/ml; p = 0.01). Circulating (1.82 ng/mL, both groups) and bone tissue expression (205 ± 126 vs 206 ± 112 positive osteocytes per mm2) of sclerostin did not differ between groups. Conclusion Patients treated with PD present a lower bone turnover, better mineralization, and higher cortical BMD than counterparts treated HD. Overall, differences are marginal and most probably clinically irrelevant. We speculate that inferior phosphate control may be in the causal pathway.

Impaired bone mineral density and microarchitecture in female adolescents with IgE-mediated cow's milk allergy.

Persistent immunoglobulin E (IgE)-mediated cow's milk allergy (CMA) may impair bone parameters and increase the risk of fractures. High-resolution peripheral quantitative computed tomography (HR-pQCT) is a novel methodology that not only assesses trabecular and cortical bone compartments and volumetric density measurements, but also evaluates bone microarchitecture and estimates biomechanical properties through finite element analysis (FEA). Both HR-pQCT and bone strength parameters derived from FEA have shown a strong correlation with fracture risk. To assess the bone density, microarchitecture, and bone strength of adolescents with persistent IgE-mediated CMA (IgE-CMA). This was an observational, cross-sectional study with female adolescents with persistent IgE-CMA and healthy control participants matched by female sex and sexual maturation. Bone parameters were assessed by areal bone mineral density (aBMD) through dual-energy X-ray absorptiometry (DXA), bone microarchitecture by HR-pQCT at the radius and tibia, and laboratory markers related to bone metabolism. The median age of adolescents with persistent IgE-CMA (n = 26) was 13.0years (interquartile range (IQR) 11.4-14.7) and of healthy control participants (n = 28) was 13.6years (IQR 11.9-14.9). Adolescents with IgE-CMA ingested 27.4% less calcium (p = 0.012) and 28.8% less phosphorus (p = 0.009) than controls. Adolescents with IgE-CMA had lower bone mineral content (BMC) (38.83g vs. 44.50g) and aBMD (0.796g/cm2 vs. 0.872g/cm2) at lumbar spine, and lower BMC (1.11kg vs. 1.27kg) and aBMD (0.823g/cm2 vs. 0.877g/cm2) at total body less head (TBLH) (p < 0.05). However, Z-scores BMC and Z-scores aBMD at lumbar spine and TBLH, when adjusted for Z-score height/age, were not significantly different between the groups. Moreover, CMA adolescents had lower bone strength at the distal tibia (S 169 kN/mm vs. 194 kN/mm; F Load 8030 N vs. 9223 N) (p < 0.05). Pairing of groups by the presence of menarche showed compromised parameters at the tibia-lower total volumetric BMD (Tt.vBMD) (293.9mg HA/cm3 vs. 325.9mg HA/cm3) and trabecular vBMD (Tb.vBMD) (170.8mg HA/cm3 vs. 192.2mg HA/cm3), along with lower cortical thickness (Ct.th) (1.02mm vs. 1.16mm) and bone strength (S 174 kN vs. 210 kN; F Load 8301 N vs. 9950 N)-and at the radius (S 61 kN/mm vs. 71 kN/mm; F Load 2920 N vs. 3398 N) (p < 0.05) among adolescents with IgE-CMA. Adolescents with IgE-CMA on a total exclusion diet (n = 12) showed greater impairment of bone features than those on a partial exclusion diet (n = 14), with lower lumbar spine Z-score BMC (- 0.65 vs. 0.18; p = 0.013), lumbar spine trabecular bone score (TBS) (1.268 vs. 1.383; p = 0.005), Z-score TBS (0.03 vs. 1.14; p = 0.020), TBLH Z-score BMC (- 1.17 vs. - 0.35; p = 0.012), TBLH Z-score aBMD (- 1.13 vs. - 0.33; p = 0.027), Tt.vBMD at the tibia (259.0mg HA/cm3 vs. 298.7mg HA/cm3; p = 0.021), Ct.th at the tibia (0.77mm vs. 1.04mm; p = 0.015) and Ct.th at the radius (0.16mm vs. 0.56mm; p = 0.033). Adolescents with persistent IgE-CMA had lower aBMD and compromised microarchitecture (impaired trabecular microarchitecture and lower bone strength). Adolescents on a partial exclusion diet had better bone parameters than those on a total exclusion diet.

Prospective associations between breast feeding, metabolic health, inflammation and bone density in women with prior gestational diabetes mellitus

IntroductionThe aim of the study is to investigate prospective associations between breastfeeding and metabolic outcomes, inflammation, and bone density in women with prior gestational diabetes mellitus (GDM).Research design and methodsWe...

Prediction of new vertebral compression fracture within 3 years after percutaneous vertebroplasty for osteoporotic vertebral compression fracture: Establishment and validation of a nomogram prediction model.

New vertebral compression fractures (NVCF) are common in patients with osteoporotic vertebral compression fractures (OVCF) who have undergone percutaneous vertebroplasty (PVP). We sought to develop a nomogram prediction model for better identification and prevention of NVCF within 3 years after PVP in patients with OVCF. The demographic, clinical, and imaging data of patients who underwent PVP for OVCF between January 2010 and December 2019 were reviewed. Multivariate logistic regression analysis was used to screen for risk factors for NVCF within 3 years after PVP. A nomogram prediction model was then developed and validated to visually predict NVCF. The samples in the model were randomly divided into training and validation sets at a ratio of 7:3. Twenty-seven percent of patients experienced NVCF in other segments within 3 years after PVP. Older age, lower bone mineral density (BMD), smoking, lack of anti-osteoporosis therapy, and postoperative trauma were risk factors for NVCF. The area under the receiver operating characteristic curve suggested good discrimination of this model: training set (0.781, 95% confidence interval: 0.731-0.831) and validation set (0.786, 95% confidence interval: 0.708-0.863). The calibration curve suggested good prediction accuracy between the actual and predicted probabilities in the training and validation sets. The DCA results suggested that, when the probability thresholds were 0.0452-08394 and 0.0336-0.7262 in the training and validation set, respectively, patients can benefit from using this model to predict NVCF within 3 years after PVP. In conclusion, this nomogram prediction model that included five risk factors (older age, lower BMD, smoking, postoperative minor trauma, and lack of anti-osteoporosis treatment can effectively predict NVCF within 3 years after PVP. Postoperative smoking cessation, standard anti-osteoporosis treatment, and reduction in incidental minor trauma are necessary and effective means of reducing the incidence of NVCF.

Humic Acid Derived from Agricultural Biomass Mitigates Alveolar Bone Loss and Modulates Systemic Inflammatory Cytokines in Rats with Periodontitis.

Humic acid (HA) is a bioproduct that can be extracted from different sources and has anti-inflammatory properties that have been little explored in the treatment and prevention of Periodontal Disease (PD). Thus, we aimed to investigate the effects of oral administration of HA on the progression of PD in rats. Twenty-four male Wistar rats were distributed into three experimental groups (Control/ Sham, PD, and PD + HA). HA was administered by gavage (80 mg/kg/day) for 28 days, and PD was induced 14 days after the beginning of treatment. Bone loss, bone topography, and surface elemental composition were analyzed. Circulating IL1-beta, TNF-alpha, and IL-10 levels were evaluated through Enzyme-Linked Immunosorbent Assay (ELISA). The animals treated with HA showed lower bone loss (p < 0.05). Calcium and phosphorus levels on the alveolar bone surface were lower in the PD group (p < 0.05) compared to the control group, whereas the animals treated with HA exhibited attenuation in this loss (p < 0.05). The animals treated with HA showed reduced TNF-alpha, IL1-beta, IL-10, and the TNF-alpha/IL-10 ratio compared to those with PD (p < 0.05). Treatment with HA attenuated the parameters of alveolar bone loss and modulated systemic inflammatory parameters in rats with ligature-induced PD.

The kinematics of pace bowling associated with lumbar bone stress injuries: Disparities observed in elite male and female cricketers

Elite cricket pace bowlers commonly sustain debilitating bone stress injuries. Lumbar bone stress injuries are more prominent in males, while lower limb bone stress injuries are more common in females. Bone stress injuries are partly attributable to bowling technique; however, scant research exists comparing bowling techniques of males and females as to better understand why males are more susceptible to lumbar bone stress injury. Three-dimensional pace bowling kinematics previously linked with lumbar bone stress injury were compared between 59 male and 19 female elite pace bowlers. Participants bowled 18 match-intensity deliveries indoors from a full run-up, whereby the mean of six deliveries was analyzed. Compared to females, males exhibited: a more extended thoraco-pelvic segment at back foot contact ( p = 0.039, g = 0.46), larger shoulder counter-rotation from back foot contact to front foot flat ( p = 0.021, g = 0.64), greater thoraco-pelvic lateral flexion at front foot flat ( p = 0.001, g = 0.95), larger front knee flexion at ball release ( p = 0.046, g = 0.57), and greater maximum front knee flexion from front foot flat to ball release ( p = 0.009, g = 0.57). Australian elite male pace bowlers performed techniques linked to lumbar bone stress injury to a much greater extent than their female counterparts. A straighter front leg technique observed in elite Australian females may be why they more commonly experience lower limb bone stress injuries via possibly higher vertical loading rates. This information may assist in developing sex-specific bone stress injury risk mitigation approaches.

Relationship between gut microbiome and bone deficits in primary hyperparathyroidism: A proof-of-concept pilot study.

Parathyroid hormone (PTH) interacts with components of the gut microbiota to exert its bone-regulating effects. This study aimed to investigate the gut microbial composition in patients with primary hyperparathyroidism (PHPT). Nine patients with PHPT and nine age-sex and body mass index-matched healthy controls were included. Gut microbial composition was assessed using 16S rRNA gene amplicon sequencing in both groups at baseline and 1 month after parathyroidectomy in the PHPT group. Data were imported into QIIME-2 and both QIIME-2 and R packages were used for microbiome analysis. Alpha and beta diversities were similar between the groups and remained unchanged after parathyroidectomy. The relative abundance of Subdoligranulum was significantly higher, whereas Ruminococcus, Alloprevotella, Phascolarctobacterium, and Clostridium sensu stricto_1 were significantly lower in PHPT than in controls (p < 0.001). After parathyroidectomy, the relative abundance of Subdoligranulum decreased, and Ruminococcus and Alloprevotella increased (p < 0.001). The PHPT group had lower total femoral and lumbar bone mineral density (BMD) than the controls (p < 0.05). At baseline, Alloprevotella abundance was positively correlated with serum phosphorus and Subdoligranulum was positively correlated with total lumbar BMD. Clostridium sensu stricto_1 was negatively correlated with serum calcium and positively correlated with femoral neck BMD. Postoperatively, Alloprevotella was positively correlated with baseline serum phosphorus and Phascolarctobacterium was positively correlated with distal radius BMD. This study demonstrated that the diversity of the gut microbiome was altered, possibly in response to electrolyte changes in PHPT, both before and after parathyroidectomy.

Long-term haplodeficency of DSPP causes temporomandibular joint osteoarthritis in mice

BackgroundExtracellular matrix (ECM) protein malfunction or defect may lead to temporomandibular joint osteoarthritis (TMJ OA). Dentin sialophophoprotein (DSPP) is a mandibular condylar cartilage ECM protein, and its deletion impacted cell proliferation and other extracellular matrix alterations of postnatal condylar cartilage. However, it remains unclear if long-term loss of function of DSPP leads to TMJ OA. The study aimed to test the hypothesis that long-term haploinsufficiency of DSPP causes TMJ OA.Materials and methodsTo determine whether Dspp+/– mice exhibit TMJ OA but no severe tooth defects, mandibles of wild-type (WT), Dspp+/–, and Dspp homozygous (Dspp−/−) mice were analyzed by Micro-computed tomography (micro-CT). To characterize the progression and possible mechanisms of osteoarthritic degeneration over time in Dspp+/– mice over time, condyles of Dspp+/– and WT mice were analyzed radiologically, histologically, and immunohistochemically.ResultsMicro-CT and histomorphometric analyses revealed that Dspp+/– and Dspp−/− mice had significantly lower subchondral bone mass, bone volume fraction, bone mineral density, and trabecular thickness compared to WT mice at 12 months. Interestingly, in contrast to Dspp−/− mice which exhibited tooth loss, Dspp+/– mice had minor tooth defects. RNA sequencing data showed that haplodeficency of DSPP affects the biological process of ossification and osteoclast differentiation. Additionally, histological analysis showed that Dspp+/– mice had condylar cartilage fissures, reduced cartilage thickness, decreased articular cell numbers and severe subchondral bone cavities, and with signs that were exaggerated with age. Radiographic data showed an increase in subchondral osteoporosis up to 18 months and osteophyte formation at 21 months. Moreover, Dspp+/– mice showed increased distribution of osteoclasts in the subchondral bone and increased expression of MMP2, IL-6, FN-1, and TLR4 in the mandibular condylar cartilage.ConclusionsDspp+/– mice exhibit TMJ OA in a time-dependent manner, with lesions in the mandibular condyle attributed to hypomineralization of subchondral bone and breakdown of the mandibular condylar cartilage, accompanied by upregulation of inflammatory markers.

Effect of abdominal tissue thickness on trabecular bone score and fracture risk in adults with diabetes: the Manitoba BMD registry.

Individuals with type 2 diabetes have lower trabecular bone score (TBS) and increased fracture risk despite higher bone mineral density. However, measures of trabecular microarchitecture from high-resolution peripheral computed tomography are not lower in type 2 diabetes. We hypothesized that confounding effects of abdominal tissue thickness may explain this discrepancy, since central obesity is a risk factor for diabetes and also artifactually lowers TBS. This hypothesis was tested in individuals aged 40years and older from a large DXA registry, stratified by sex and diabetes status. When DXA-measured abdominal tissue thickness was not included as a covariate, men without diabetes had lower TBS than women without diabetes (mean difference -0.074, P < .001). TBS was lower in women with versus without diabetes (mean difference -0.037, P < .001), and men with versus without diabetes (mean difference -0.007, P = .042). When adjusted for tissue thickness these findings reversed, TBS became greater in men versus women without diabetes (mean difference +0.053, P < .001), in women with versus without diabetes (mean difference +0.008, P < .001), and in men with versus without diabetes (mean difference +0.014, P < .001). During mean 8.7years observation, incident major osteoporotic fractures were seen in 7048 (9.6%). Adjusted for multiple covariates except tissue thickness, TBS predicted fracture in all subgroups with no significant diabetes interaction. When further adjusted for tissue thickness, HR per SD lower TBS remained significant and even increased slightly. In conclusion, TBS predicts fractures independent of other clinical risk factors in both women and men, with and without diabetes. Excess abdominal tissue thickness in men and individuals with type 2 diabetes may artifactually lower TBS using the current algorithm, which reverses after accounting for tissue thickness. This supports ongoing efforts to update the TBS algorithm to directly account for the effects of abdominal tissue thickness for improved fracture risk prediction.

Effect of Allele-Specific Clcn7G213R siRNA Delivered Via a Novel Nanocarrier on Bone Phenotypes in ADO2 Mice on 129S Background.

Autosomal dominant osteopetrosis type 2 (ADO2) is a rare inherited bone disorder characterised by dense but brittle bones. It displays striking phenotypic variability, with the most severe symptoms, including blindness and bone marrow failure. Disease management largely relies on symptomatic treatment since there is no safe and effective treatment. Most ADO2 cases are caused by heterozygous loss-of-function mutations in the CLCN7 gene, which encodes an essential Cl-/H+ antiporter for proper bone resorption by osteoclasts. Thus, siRNA-mediated silencing of the mutant allele is a promising therapeutic approach, but targeting bone for first-in-human translation remains challenging. Here, we demonstrate the utility of silicon-stabilised hybrid lipid nanoparticles (sshLNPs) as a next-generation nucleic acid nanocarrier capable of delivering allele-specific siRNA to bone. Using a Clcn7G213R knock-in mouse model recapitulating one of the most common human ADO2 mutations and based on the 129S genetic background (which produces the most severe disease phenotype amongst current models), we show substantial knockdown of the mutant allele in femur when siRNA targeting the pathogenic variant is delivered by sshLNPs. We observed lower areal bone mineral density in femur and reduced trabecular thickness in femur and tibia, when siRNA-loaded sshLNPs were administered subcutaneously (representing the most relevant administration route for clinical adoption and patient adherence). Importantly, sshLNPs have improved stability over conventional LNPs and enable 'post hoc loading' for point-of-care formulation. The treatment was well tolerated, suggesting that sshLNP-enabled gene therapy might allow successful clinical translation of essential new treatments for ADO2 and potentially other rare genetic bone diseases.

Caudal Agenesis: Classification Based on the Pathoembryogenesis of the Spinal Cord

BACKGROUND AND OBJECTIVES: Caudal agenesis (CA) is a congenital disease characterized by lower vertebral bone defects. Previous classifications for CA were based on the levels of bony defects or the conus medullaris. We created a new pathoembryogenic classification that takes into account the level of conus, considering both its shape and filum. We evaluated its accuracy in reflecting the neurological status and the need for untethering. METHODS: Patients with radiologic studies available on our institute's electronic image view system between 1985 and 2019 were reviewed. Our classification categorized patients with CA into 3 groups: the failure of formation (a conus level &gt; L1 or normal level conus with a blunt shape), the failure of regression (a conus level &lt; L3 or normal level conus with a thickened filum or a filar lipoma), and the normal (a normal level conus without specific abnormalities). We analyzed which of the following 3 classifications better reflects the neurological status and the probability of recommending untethering: classifications based on (1) bony defect level, (2) conus level, and (3) pathoembryogenic mechanism. RESULTS: A total of 89 patients were included in this study. The pathoembryogenic classification revealed more significant differences in motor or sensory deficits compared with other classifications (failure of formation: 42%; failure of regression: 16%; and normal: 0%, P = .039). In addition, the pathoembryogenic classification emerged as a significant or suggestive predictive factor for motor and sensory deficits (motor: odds ratio 11.66, P = .007; sensory: odds ratio 5.44, P = .066). Notably, only the pathoembryogenic classification exhibited a significant difference in the probabilities of recommending untethering between groups (failure of formation: 42%; failure of regression: 81%; and normal 12%, P &lt; .001). CONCLUSION: The correlation between bony classification and spinal cord abnormalities was exaggerated. Our new pathoembryogenic classification was valuable in prognosticating neurological status and identifying the patient group more likely to require untethering among patients with CA.

Sagittal Imbalance in Degenerative Kyphosis: Prevalence and Implication on Postoperative Mechanical Failure

BACKGROUND AND OBJECTIVES: To explore the patterns of sagittal imbalance in patients with lumbar or thoracolumbar degenerative kyphosis (DK) and determine its implication for the risk of mechanical complication (MC) after corrective surgery. METHODS: A total of 137 patients with DK who underwent corrective surgery were reviewed. The patients were divided into L group (with a kyphotic apex at L2 and below) and TL group (with kyphotic apex at L1 and above). Then, sacral slope (SS) (defined as S1 if SS &gt; 0 in TL, or SS &gt; 10 in L group) and sagittal vertical axis ≥ 5 cm (defined as +) were used as modifier sagittal balance. The Scoliosis Research Society (SRS)-22 questionnaire scores were analyzed, and the risk of mechanical failure was compared across groups. RESULTS: The distribution of subgroups was 38 (27.7%) in TLS1(−) group, 36 (26.3%) in TLS1(+) group, 16 (11.7%) in TLS0(−) group, and 5 (3.6%) in TLS0(+) group. For L group, the figure was 5 (3.6%) in LS1(−), 22 (16.1%) in LS1(+), 7 (5.2%) in LS0(−), and 8 (5.8%) in LS0(+). Patients in L group had significantly higher regional kyphosis, lower lumbar lordosis, and higher sagittal vertical axis, indicating a higher risk of global decompensation. The SRS function scores and pain scores were also lower in the L group compared with the TL group. At a minimum of 2 years of follow-up, χ2 test showed that the incidence of TLS0 (+), LS0 (−), and LS0 (+) had significantly higher rates of MC (&gt;40%). In both TL and L groups, patients with MC were found to have significantly lower bone mineral density than those without. CONCLUSION: The findings decipher the distinct patterns of sagittal imbalance in severe DK patients with kyphotic apex at thoracolumbar or lumbar spine. Patients with kyphotic apex apex at L2 or below, low SS, and global imbalance showed the highest risk of postoperative mechanical failure.