Osteoporosis is a worldwide disease resulting in the increase of bone fragility and enhanced fracture risk in adults. In the context of osteoporotic fractures, bone tissue engineering (BTE), i.e., the use of bone substitutes combining biomaterials, cells, and bone inducers, is a potential alternative to conventional treatments. Pre-clinical testing of innovative scaffolds relies on in vitro systems where the simultaneous presence of osteoblasts (OBs) and osteoclasts (OCs) is required to mimic their crosstalk and molecular cooperation for bone remodelling. To this aim, two composite materials based on type I collagen were developed, containing either strontium-enriched mesoporous bioactive glasses or rod-like hydroxyapatite nanoparticles. Following chemical crosslinking with genipin, the nanostructured materials were tested for 2–3 weeks with an indirect co-culture of human trabecular bone-derived OBs and buffy coat-derived OC precursors. The favourable structural and biological properties of the materials proved to successfully support the viability, adhesion, and differentiation of bone cells, encouraging a further investigation of the two bioactive systems as biomaterial inks for the 3D printing of more complex scaffolds for BTE

Abstract. Objective. This study assesses the prevalence of major and minor discordance between hip and spine T scores using Radiofrequency Echographic Multi-spectrometry (REMS). REMS is a novel technology that uses ultrasound and radiofrequency analysis to measure bone density and bone fragility at the hip and lumbar spine. The objective was to compare the results with the existing literature on Dual-Energy X-ray Absorptiometry (DEXA) the current “gold standard” for bone densitometry. REMS and DEXA have been shown to have similar diagnostic accuracy, however, REMS has less human input when carrying out the scan, therefore the rates of discordance might be expected to be lower than for DEXA. Discordance poses a risk of misclassification of patients’ bone health status, causing diagnostic ambiguity and potentially sub-optimal management decisions. Reduction of discordance rates therefore has the potential to significantly improve treatment and patient outcomes. Methods. Results from 1,855 patients who underwent REMS investigations between 2018 and 2022 were available. Minor discordance is defined as a difference of one World Health Organisation (WHO) diagnostic classification (Normal / Osteopenia or Osteopenia / Osteoporosis). Major discordance is defined as a difference of two WHO diagnostic classifications (Normal / Osteoporosis). The results were compared with reported DEXA discordance rates. Results. 1,732 individuals had both hip and spine T scores available for analysis. There were 267 cases of discordance. No instances of major discordance were observed. The minor discordance rate was 15.4%. 6.5% of the REMS scans with minor discordance showed > 1.0 standard deviation (SD) difference between the T scores of the hip and spine. 19.4% had differences of between 0.6 SD and 1.0 SD while 73.9% had ≤ 0.5 SD or less. In 24.5% of the cases of REMS discordance the hip T scores were greater than the spine and in 75.5% of cases the spine T score was greater than the hip. Conclusions. The current analysis is the largest of its kind. It demonstrates that REMS has an overall lower rate of discordance than reported DEXA rates. Major discordance rates with DEXA range from 2–17%, but REMS avoids many of the positioning problems and post-processing errors inherent in DEXA scanning, which might account for the absence of major discordance. Rates of minor discordance in DEXA scans range between 38–51%. The REMS minor discordance rate being much lower than these rates suggests that it has the potential to enhance diagnostic accuracy considerably. Most REMS discordance results showed ≤ 0.5 SD variance between the T scores of the two sites, indicating close correlation in the bone densitometry analysis. Most studies of DEXA discordant results confirm that spinal T scores are more often higher than at the hip. The REMS results concur with this observation. Considering the comparable accuracy rates that have been shown between REMS and DEXA, with its much lower discordance rate, REMS can potentially improve current medical practice and enhance patient care. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Fragility fractures are skeletal complications associated with type 2 diabetes (T2D) causing disability, hospitalization, impaired quality of life, and increased mortality. Increased circulating sclerostin and accumulation of advanced glycation end-products (AGEs) are two potential mechanisms underlying low bone turnover and increased fracture risk. We have recently shown that T2D affects the expression of genes controlling bone formation (SOST and RUNX2) and that accumulation of AGEs is associated with impaired bone formation in T2D. We hypothesized that Wnt/B- catenin target genes are down-regulated in bone of T2D subjects as a consequence of decreased SOST and AGEs accumulation. To this end, we studied gene expression in extracts of bone samples obtained from femoral heads of 14 subjects with relatively well-controlled T2D (HbA1c 6.5±1.7%) and 21 control, non-diabetic postmenopausal women (age >65 years) undergoing hip replacement. There were no differences in age (73.2± .8 vs. 75.2±8.5 years) or BMI (27.7±5.6 vs. 29.9±5.4 kg/m2) between control and T2D groups, respectively. Expression of LEF1 mRNA was significantly lower in T2D compared to non-diabetic subjects (p=0.002), while DKK1 was not different between groups (p=0.108). Correlation analysis showed that DKK1 (r2=0.038; p=0.043) and HbA1c (r2=0.503; p=0.048) increased with age in T2D. COL1A1 mRNA trended lower in T2D compared to controls (p=0.056). Bone volume (9,333 ± 1,443 vs. 15,53 ± 2,442 mm2; p=0.048), mineralized volume (9,278 ± 1,418 vs. 15,45 ± 2,444 mm. 2. ; p=0.048) and BV/TV (0,2125 ± 0,03114 vs. 0,3719 ± 0,03196 %; p=0.002) measured by bone histomorphometry were lower in T2D compared to controls. Our data show that even in patients with relatively good glycemic control, T2D decreases expression of Wnt/B-catenin target genes andCOL1A1, associated with decreased bone density. These results may help understand the mechanisms underlying bone fragility in T2D

Introduction and Objective. Individuals with type 2 diabetes (T2D) have a 3-fold increased risk of bone fracture compared to non-diabetics, with the majority of fractures occurring in the hip, vertebrae and wrists. However, unlike osteoporosis, in T2D, increased bone fragility is generally not accompanied by a reduction in bone mineral density (BMD). This implies that T2D is explained by poorer bone quality, whereby the intrinsic properties of the bone tissue itself are impaired, rather than bone mass. Yet, the mechanics remain unclear. The objective of this study is to (1) assess the fracture mechanics of bone at the structural and tissue level; and (2) investigate for changes in the composition of bone tissue along with measuring total fluorescent advanced glycation end products (fAGEs) from the skin, as T2D progresses with age in Zucker diabetic fatty (ZDF (fa/fa)) and lean Zucker (ZL (fa/+)) rats. Materials and Methods. Right ulnae and skin sections were harvested from ZDF (fa/fa) (T2D) and ZL (fa/+) (Control) rats at 12 and 46 weeks (wks) of age (n = 8, per strain and age) and frozen. Right ulnae were thawed for 12 hrs before micro-CT (μCT) scanning to assess the microstructure and measure BMD. After scanning, ulnae were loaded until failure via three-point bending. Fourier transform-infrared microspectroscopy (FTIR) was used to measure various bone mineral- and collagen-related parameters such as, mineral-to-matrix ratio and nonenzymatic cross-link ratio. Finally, fAGEs were measured from skin sections using fluorescence spectrometry and an absorbance assay, reported in units of ng quinine/ mg collagen. Results. At 12 and 46 wks bone size was significantly smaller in length (p < 0.01), cortical area (p < 0.001) and cross-sectional moment of inertia (p < 0.001) in T2D rats compared to age-matched controls. A slight reduction in BMD was observed in T2D rats compared to controls at both ages, however, this was not significant. Structural properties of T2D bone were significantly altered at 12 and 46 wks, with bending rigidity increasing approximately 2.5-fold and 1.5-fold in control and T2D rats with age, respectively (p < 0.0001). Similarly, yield and ultimate moment significantly reduced in T2D rats with age in comparison to controls (p < 0.0001). Energy absorbed to failure was significantly reduced in T2D rats at 46 weeks of age compared to controls (p < 0.01). The amount of energy absorbed to failure increased approximately 1.4-fold from 12 to 46 wks in control rats, however, in T2D rats a reduction was seen with age, although not significant. At 12 wks, there was no significant deficits in tissue material properties, whereas, at 46 wks a significant reduction in yield stress, yield strain and ultimate stress was observed for T2D rats in comparison to controls (p < 0.05). Conclusions. These findings show that longitudinal growth is impaired as early as 12 wks of age and by 46 wks bone size is significantly reduced in T2D rats compared to controls. The reduction in T2D structural properties is likely attributed to the bone geometry deficits. At 12 wks of age, the tissue material properties are not altered in T2D bone versus controls. However, at 46 wks, bone strength is reduced in T2D, leading to the conclusion that tissue properties are altered as the disease progresses

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

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

Introduction. DXA areal-bone-mineral-density (aBMD) is used clinically as a surrogate for true volumetric-BMD to assess bone fragility. Trabecular-Bone-Score (TBS) provides an assessment of bone quality based on the DXA-derived two-dimensional images. Calculated from bone area (BA), aBMD may under- or overestimate true BMD in individuals with relatively low and high BA respectively. This study investigated relationships between BA at the lumbar-spine (L1–L4) and measurements of BMD and TBS. Method. Lumbar spine scans were performed (GE Lunar Prodigy) on 114 women (mean 53 yrs). The study population was divided by L1–L4 BA using the 20th and 80th centiles, and BMD v TBS correlations calculated for the subgroups. BMD and TBS, converted to Z-scores, were correlated with BA. Results. For the whole group, r = 0.23 for BMD v BA, whereas r = −0.12 for TBS v. BA: the correlation between BMD and TBS was r=0.38. Correlations between BMD and TBS for BA subgroups were r = 0.23, r=0.44 and r=0.59 for the >20th, 20th −80th and >80th centile groups respectively. Conclusion. Low correlation between BMD and TBS for the entire group indicates that TBS reflects some bone quality properties unrelated to BMD. The correlation of BMD with BA suggests that it incorrectly estimates true BMD at BA extremes. Correlation for BMD v TBS in the lowest area-subgroup was substantially lower than for the middle and highest area subgroups suggesting that TBS may afford valuable complementary information on bone fragility at the lowest extreme of BA where distortions in BMD measurement potentially occur

Osteoporosis is a worldwide spread, silent disease steadily increasing due to demographic shift; it results in bone loss and increased porosity that lead to an increase in bone fragility and to low-energy fractures. In such a contest, we worked on the development of 3D scaffolds engineered to mimic the features of human healthy bone. Healthy and osteoporotic bone microCT scans were obtained from tissues discarded during surgical interventions (Istituto Ortopedico Rizzoli-Italy). The obtained .STL file was used to 3D print a type I collagen solution to mimic bone matrix whereas mesoporous bioactive glass/nano-hydroxyapatite were embedded within the collagen fibers to mimic the inorganic phase of human bone. The rheological properties of the Type I collagen/mesoporous glass suspensions were investigated at different collagen concentration and temperatures. The possibility of incorporating growth factors (IGF and β-TGF) in the scaffold struts was investigated proposing several approaches and their retained activity was assessed. Different co-culture of osteoblasts and osteoclasts set-ups were explored in order to define the influence of both chemical and topographical stimuli on the osteoblast-osteoclast coupling

Although osteoporosis reduces overall bone mass causing bone fragility, our recent studies have shown that bone tissue composition is altered at the microscopic level, which is undetectable by conventional diagnostic techniques (DEXA) but may contribute to bone fracture. However, the time sequence of changes in bone microarchitecture, mechanical environment and mineral distribution are not yet fully understood. This study quantified the longitudinal effects of estrogen deficiency on the trabecular microarchitecture and mineral distribution in the tibia of Female Wistar rats (6 months) that underwent ovariectomy (OVX, n=10) or sham surgery (SHAM, n=10). Weekly micro-CT scans of the proximal tibia were conducted at 15µm resolution for the first month of estrogen deficiency. Morphometric analysis was conducted to characterise the trabecular bone microarchitecture. The bone mineral composition was characterised with analysis of bone mineral density distributions (BMDD). There was significantly reduced trabecular bone volume fraction at 2 weeks in OVX rats compared to controls (p<0.01). There was no difference in mineral distribution between the OVX and control animals. This study provides the first evidence in uncovering the temporal nature of changes in bone microarchitecture and mineral distribution, showing that structure changes before composition. In-vivo µCT analysis for later time points (week 8, 14 and 34) is ongoing to comprehensively examine these longitudinal compositional changes. Moreover, we are conducting ex-vivo mechanical analysis (nanoindentation), and together these will uncover the time-sequence and respective contribution of changes in bone mass and composition to the integrity of the bone tissue at these stages of estrogen deficiency

Recent studies have shown that bone mineral distribution is more heterogeneous in bone tissue from an animal model of osteoporosis and osteoporotic human vertebral trabeculae. These tissue alterations may play a role in bone fragility seen in osteoporosis, albeit that they are not detectable by current diagnostic techniques (dual-energy X-ray absorptiometry, DXA). Type II Diabetes Mellitus (T2DM) also increases a patient's fracture risk beyond what can be explained or diagnosed by DXA, and is associated with impaired bone cell function, compromised collagen structure and reduced mechanical properties. However, it is not currently known whether osteoporosis or T2DM leads to an increased mineral heterogeneity in the femoral head of humans, a common osteoporotic fracture site. In this study, we examine bone microarchitecture, mineralisation and mechanical properties of trabecular bone from osteoarthritic, diabetic and osteoporotic patients. We report that while osteoporotic trabecular bone has significantly deteriorated mechanical properties and microarchitecture compared to the other groups, there is also a significant increase in mean mineral content. Moreover, the heterogeneity of the mineral content in osteoporotic bone is significantly higher than osteoarthritic (+35%) and diabetic (+13%) groups. We propose that the compromised architecture following bone loss at the onset of osteoporosis alters the mechanical environment, which initiates compensatory changes in mineral content. We show for the first time that trabecular bone mineralisation is significantly more heterogeneous (+20%) in T2DM compared to osteoarthritic controls. Interestingly, bone microarchitecture and mechanical properties are not significantly different between diabetic and osteoarthritic groups despite this increase in mineral heterogeneity

Objectives

Bisphosphonates (BP) are the first-line treatment for preventing fragility fractures. However, concern regarding their efficacy is growing because bisphosphonate is associated with over-suppression of remodelling and accumulation of microcracks. While dual-energy X-ray absorptiometry (DXA) scanning may show a gain in bone density, the impact of this class of drug on mechanical properties remains unclear. We therefore sought to quantify the mechanical strength of bone treated with BP (oral alendronate), and correlate data with the microarchitecture and density of microcracks in comparison with untreated controls.

The haematoma occurring at the site of a fracture is known to play an important role in bone healing. We have recently shown the presence of progenitor cells in human fracture haematoma and demonstrated that they have the capacity for multilineage mesenchymal differentiation. There have been many studies which have shown that low-intensity pulsed ultrasound (LIPUS) stimulates the differentiation of a variety of cells, but none has investigated the effects of LIPUS on cells derived from human fracture tissue including human fracture haematoma-derived progenitor cells (HCs). In this in vitro study, we investigated the effects of LIPUS on the osteogenic activity of HCs. Alkaline phosphatase activity, osteocalcin secretion, the expression of osteoblast-related genes and the mineralisation of HCs were shown to be significantly higher when LIPUS had been applied but without a change in the proliferation of the HCs. These findings provide evidence in favour of the use of LIPUS in the treatment of fractures.