Reduced Bone Strength Research Articles

Fractures following pregnancy in Osteogenesis imperfecta - A self-controlled case series using Danish Health Registers.

Osteogenesis imperfecta (OI) is a rare inherited connective tissue disorder with considerable clinical and genetic heterogeneity. The clinical hallmark of OI is liability to fractures due to reduced bone strength. Pregnancy and lactation are periods of increased calcium demand resulting in a decrease in maternal bone mineral density (BMD). This self-controlled case series evaluates fracture risk 12- and 19-months prior to conception compared to a period of 12- and 19months following childbirth in women with OI. This study is based on data from the Danish National Patient Register collected between 1995 and 2018. Modified Poisson models were fitted to estimate Incidence Rate Ratio in the post/pre-pregnancy period/s, adjusted by parity and age. The 12-month observation group included 111 women with 205 pregnancies, and the 19-month observation 108 women with 197 pregnancies. We calculated fracture rates (IR) of 48.78 [95%CI 18.55-79.01] per 1000 person years 12months prior to conception, and of 27.87 [95%CI 10.60-45.14] in the 12months post-delivery. Comparing pre- and post-pregnancy period we found an incidence rate ratio (IRR) of 1.00 [95%CI 0.42-2.40]. When adjusting for parity and age at delivery no significant change in the IRR was noted. In the 19months observation-period, the IR per 1000 person years prior to conception was 74.84 [95%CI 44.25-105.43] and the IR postpartum was 36.86 [95%CI 17.55-56.17], leading to an IRR of 0.61 [95%CI 0.31-1.18]. We could not identify any increased risk of fractures when comparing fracture rates during pregnancy and 12 or 19months postpartum to fracture rates 12 or 19months prior to conception.

Efficacy and safety of bisphosphonates on childhood osteoporosis secondary to chronic illness or its treatment: a meta-analysis.

Background:Bisphosphonates are a type of medication that prevents the loss of bone density. Secondary childhood osteoporosis reduces bone strength and results in an increased risk of fragility fracture. This meta-analysis aims to explore the efficacy and safety of bisphosphonates on secondary childhood osteoporosis.Methods:We performed a systematic search of PubMed, Cochrane library, and Web of Science databases up to 31 July 2022 to screen for random clinical trials (RCTs) on bisphosphonate treatment for childhood secondary osteoporosis. Data from selected studies, mainly changes in lumbar spine (LS) bone mineral density (BMD), changes in LS BMD Z-scores, fracture events, and adverse events (AEs), were extracted and analyzed.Results:Nine RCTs (n = 429 in total) were included in our meta-analysis. The meta-analysis indicated that bisphosphonates improved the changes in LS BMD [mean difference (MD) = 0.04, 95% confidence intervals (CIs) = 0.01–0.07, p < 0.01] and LS BMD Z-scores [MD = 0.52, 95% CI = 0.23–0.81, p < 0.01]. Use of bisphosphonates did not increase the risk of AEs [odds ratio (OR) = 1.61, 95% CI = 0.87–2.99, p = 0.13]. Subgroup analysis showed that routes of administration, but not causes of secondary osteoporosis, might influence the efficacy of bisphosphonates. IV bisphosphonates close to significantly improved the incidence of fracture (OR = 0.34, 95% CI: 0.11–1.08, p = 0.07).Conclusions:The use of bisphosphonates improves LS BMD without increasing AE rates, which supports the clinical use of bisphosphonates in secondary childhood osteoporosis. Further large RCTs are still warranted, especially for their long-term effects on fracture rates.

Biomechanical MRI Detects Reduced Bone Strength in Subjects with Vertebral Fractures

Biomechanical MRI Detects Reduced Bone Strength in Subjects with Vertebral Fractures

Hypobaric hypoxia deteriorates bone mass and strength in mice.

Mountaineers at high altitude are at increased risk of acute mountain sickness as well as high altitude pulmonary and cerebral edema. A densitometric study in mountaineers has suggested that expeditions at high altitude decrease bone mineral density. Surprisingly, the in vivo skeletal effects of hypobaric hypoxia are largely unknown, and have not been studied using advanced contemporary methods to assess bone microstructure. Eighty-four 22-week-old female mice were divided into seven groups with 12 mice in each group: 1. Baseline; 2. Normobaric, 4weeks; 3. Hypobaric hypoxia, 4weeks; 4. Normobaric, 8weeks; 5. Hypobaric hypoxia, 8weeks; 6. Normobaric, 12weeks; and 7. Hypobaric hypoxia, 12weeks. Hypobaric hypoxia mice were housed in hypobaric chambers at an ambient pressure of 500mbar (5500m altitude), while normobaric mice were housed at sea level atmospheric pressure for 4, 8, or 12weeks, respectively. Hypobaric hypoxia had a profound impact on femoral cortical bone and L4 trabecular bone, while the effect on femoral trabecular bone was less pronounced. Hypobaric hypoxia reduced the bone strength of the femoral mid-diaphysis and L4 at all time-points. At femoral cortical bone, hypobaric hypoxia reduced bone formation through fewer mineralizing surfaces and lower bone formation rate after 2weeks. In addition, bone strength decreased, and C-terminal telopeptide of type I collagen (CTX-I) increased independently of the duration of exposure to simulated high altitude. At L4, hypobaric hypoxia resulted in a substantial reduction in bone volume fraction, trabecular thickness, and trabecular number after 4weeks of exposure. Hypobaric hypoxia reduced bone strength and femoral bone mass, while femoral trabecular bone was much less affected, indicating the skeletal response to hypobaric hypoxia differ between cortical and trabecular bone. These findings provide initial preclinical support for future clinical studies in mountaineers to assess bone status and bone strength after exposure to prolonged high altitude exposure.

Craniospinal Surgery in Hajdu-Cheney Syndrome: A Review of Case Reports

Hajdu-Cheney syndrome (HCS) is a rare metabolic bone disorder that results in severe osteoporosis and various skeletal deformities. Craniospinal pathology is commonly associated with it, but surgical management is challenging due to the distorted anatomy, reduced bone strength, and fusion failure due to osteolysis. Hence, the surgical difficulty in these patients requires careful consideration. In this study, we systematically review all published operative cases and complications to provide a comprehensive review pertaining to the spine and/or cranium in patients with HCS. By highlighting these cases and their associated complications, we aim to prepare practitioners who treat this difficult pathology.

Reduced bone strength in adults with moderate or complex congenital heart disease

BackgroundWe aimed to study bone mineral density (BMD) and skeletal strength in the growing population of adults with moderate or complex congenital heart disease (CHD). MethodsPeripheral quantitative computed tomography (pQCT) was performed on the radius and tibia in 49 adults with moderate or complex CHD, and in 49 age and sex matched controls (n ​= ​23 [47%] female, mean age 36 ​± ​15.5 years.) Strength in the radius and tibia were presented, respectively, in terms of Strength-Strain Index (SSI). ResultsPatients had similar total BMD as controls in both the radius (807 ​± ​82 vs. 792 ​± ​75 ​mg/cm3, p ​= ​0.3) and tibia (663 ​± ​86 vs. 689 ​± ​67 ​mg/cm3, p ​= ​0.1). In the radius, patients had a lower xSSI than controls (154 ​± ​46 vs. 175 ​± ​54 ​mm3, p ​= ​0.04) but a similar ySSI (178 ​± ​58 vs. 195 ​± ​55 ​mm3, p ​= ​0.1). In the tibia, patients had a lower xSSI (1492 ​± ​399 vs. 1780 ​± ​372 ​mm3, p ​< ​0.001) as well as ySSI (1066 ​± ​304 vs. 1250 ​± ​281, p ​= ​0.002). In a multiple linear regression model, only height was independently associated with decreased skeletal strength in patients tibia in terms of xSSI [F(2,46) ​= ​40.002, p ​< ​0.001, R2 ​= ​0.635]. ConclusionAdults with moderate or complex CHD had reduced strength in the radius and tibia, despite a normal BMD as assessed with pQCT. Their reduced bone strength could increase the risk of future fractures.

Does Total Hip Arthroplasty Influence the Development and Localization of Sacral Insufficiency Fractures?

Background: Sacral insufficiency fractures (SIFs) are fractures related to reduced bone strength. In a previous study, we noticed that many patients with SIF had undergone total hip arthroplasty (THA). Therefore, the purpose of the present study was to research the localization of clinically apparent SIFs in relation to unilateral THA as well as the influence of unilateral THA on bone mineral density changes in the sacrum. Methods: In this retrospective study, 171 patients with SIFs were screened for unilateral THA. In the group of patients with SIF and THA, the rate of SIF ipsilateral and contralateral to the side of the THA was determined. In a second cohort of 39 THA patients with healthy bone, changes in bone mineral density at the sacral alae ipsilateral and contralateral to the THA were analyzed by use of computed tomography immediately postoperatively and at the 1-year follow-up. Results: Of the 171 patients with SIF, 50 (40 female; mean age, 79 years; range, 54 to 101 years) were previously treated with THA. Of the 50, 31 patients were treated with unilateral THA. The proportion of patients with an SIF contralateral to the THA was 42% (13 of 31) and ipsilateral to the THA was 19% (6 of 31). Twelve patients had bilateral SIFs. The mean age of the THA group without SIF was 62 years (range, 49 to 79 years); 17 were female. The median bone mineral density decreased significantly (p = 0.023), from 35.0 to 13.0 HU, at the sacral ala contralateral to the THA, whereas the decrease of ipsilateral bone mineral density, from 24.0 to 17.0 HU, was not significant (p = 0.361). Conclusions: The proportion of patients with an SIF contralateral to a THA was twice as high as that of patients with an SIF ipsilateral to a THA. These findings are supported by the second cohort’s decrease in bone mineral density at the sacral ala contralateral to the THA at 1 year after surgery. We conclude that THA can lead to spatially different remodeling of the sacrum, possibly affecting the development of SIFs. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

The Effects of Osteoporotic and Non-osteoporotic Medications on Fracture Risk and Bone Mineral Density.

Osteoporosis is a highly prevalent bone disease affecting more than 37.5 million individuals in the European Union (EU) and the United States of America (USA). It is characterized by low bone mineral density (BMD), impaired bone quality, and loss of structural and biomechanical properties, resulting in reduced bone strength. An increase in morbidity and mortality is seen in patients with osteoporosis, caused by the approximately 3.5 million new osteoporotic fractures occurring every year in the EU. Currently, different medications are available for the treatment of osteoporosis, including anti-resorptive and osteoanabolic medications. Bisphosphonates, which belong to the anti-resorptive medications, are the standard treatment for osteoporosis based on their positive effects on bone, long-term experience, and low costs. However, not only medications used for the treatment of osteoporosis can affect bone: several other medications are suggested to have an effect on bone as well, especially on fracture risk and BMD. Knowledge about the positive and negative effects of different medications on both fracture risk and BMD is important, as it can contribute to an improvement in osteoporosis prevention and treatment in general, and, even more importantly, to the individual’s health. In this review, we therefore discuss the effects of both osteoporotic and non-osteoporotic medications on fracture risk and BMD. In addition, we discuss the underlying mechanisms of action.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40265-021-01625-8.

Congenital Metabolic Bone Disorders as a Cause of Bone Fragility.

Bone fragility is a pathological condition caused by altered homeostasis of the mineralized bone mass with deterioration of the microarchitecture of the bone tissue, which results in a reduction of bone strength and an increased risk of fracture, even in the absence of high-impact trauma. The most common cause of bone fragility is primary osteoporosis in the elderly. However, bone fragility can manifest at any age, within the context of a wide spectrum of congenital rare bone metabolic diseases in which the inherited genetic defect alters correct bone modeling and remodeling at different points and aspects of bone synthesis and/or bone resorption, leading to defective bone tissue highly prone to long bone bowing, stress fractures and pseudofractures, and/or fragility fractures. To date, over 100 different Mendelian-inherited metabolic bone disorders have been identified and included in the OMIM database, associated with germinal heterozygote, compound heterozygote, or homozygote mutations, affecting over 80 different genes involved in the regulation of bone and mineral metabolism. This manuscript reviews clinical bone phenotypes, and the associated bone fragility in rare congenital metabolic bone disorders, following a disease taxonomic classification based on deranged bone metabolic activity.

In vivo Measurement of Intraosseous Vascular Haemodynamic Markers in Human Bone Tissue Utilising Near Infrared Spectroscopy.

Objective: Poor vascular health is associated with reduced bone strength and increased risk of fragility fracture. However, direct measurement of intraosseous vascular health is difficult due to the density and mineral content of bone. We investigated the feasibility of using a commercially available continuous wave near infrared spectroscopy (NIRS) system for the investigation of vascular haemodynamics in human bone in vivo.Approach: An arterial occlusion (AO) protocol was developed for obtaining haemodynamic measurements of the proximal tibia and lateral calf, including assessment of the protocol’s intra operator reproducibility. For 36 participants, intraosseous haemodynamics derived by NIRS were compared to alternative tests of bone health based on dual x-ray absorptiometry (DXA) testing and MRI.Main Results: Near infrared spectroscopy markers of haemodynamics of the proximal tibia demonstrated acceptable reproducibility, comparable with reproducibility assessments of alternative modalities measuring intraosseous haemodynamics, and the use of NIRS for measuring muscle. Novel associations have been demonstrated between haemodynamic markers of bone measured with NIRS and body composition and bone mineral density (BMD) measurements obtained with both DXA and MRI.Significance: Near infrared spectroscopy provides inexpensive, non-invasive, safe, and real time data on changes in oxygenated and deoxygenated haemoglobin concentration in bone at the proximal tibia. This study has demonstrated the potential for NIRS to contribute to research investigating the pathophysiological role of vascular dysfunction within bone tissue, but also the limitations and need for further development of NIRS technology.

Global Prevalence of Osteoporosis in Chronic Kidney Disease: Protocol for a Systematic Review

Abnormalities in mineral metabolism, soft tissue calcifications, and bone health are common in people with chronic kidney disease (CKD). In this scenario, osteoporosis is a highly prevalent skeletal disorder characterized by reduced bone strength predisposing patients to adverse health outcomes. We will summarize the evidence of the prevalence of osteoporosis in adults with CKD. Methods: We will perform a comprehensive literature search using MEDLINE, EMBASE, Web of Science, CINAHL, and LILACS databases, without date or language restrictions from inception until January 2021. We will include cross-sectional, case–control, or cohort studies that report prevalence data of osteoporosis in adults aged ≥18 years with CKD in stages 3a–5, including those receiving kidney replacement therapies. We will exclude conference abstracts and experimental studies. The primary outcome will be the prevalence of osteoporosis according to the World Health Organization criteria (T-score ≤ −2.5). Two independent reviewers will screen title and abstract, full-text review, critical appraisal of the quality of studies, risk of bias, heterogeneity, and data extraction. The quality of the included studies will be assessed with the Joanna Briggs Institute (JBI) appraisal checklist. The overall prevalence of the studies will be synthesized using random-effects meta-analysis. This systematic review will be reported according to the guidelines for Meta-Analyses and Systematic Reviews of Observational Studies (MOOSE) and the JBI methodological guidance for systematic reviews of observational epidemiological studies. The qualitative and quantitative results will be synthesized and presented in tables, figures or graphs.

Degenerations in Global Morphometry of Cancellous Bone in Rheumatoid Arthritis, Osteoarthritis and Osteoporosis of Femoral Heads are Similar but More Severe than in Ageing Controls.

We have recently revealed significant differences in microarchitectural properties (i.e. global and local morphometries) and mechanical properties between rheumatoid arthritis (RA), osteoarthritis (OA) and osteoporosis (OP) in cancellous bones. This study compared these properties with those of ageing controls by matching bone volume fraction (BV/TV), the most important determinant for bones' mechanical properties, to investigate whether these bones have similar properties and degenerative potentials. RA, OA and OP femoral heads were harvested from patients undergoing total hip replacement surgery. The selected patients were matched by similar cancellous bone BV/TV, with seven patients in each group. Four samples were prepared from each femoral head and scanned with micro-CT to quantify microarchitectural properties and compression tested to determine mechanical properties. In terms of global morphometry, no significant differences were observed between these diseased bones. In terms of local morphometry, the number of plates in the RA group was significantly greater than that of the OP and control groups. Plate volume density in the RA group was significantly greater than in the control group. Interestingly, the ultimate stresses in the three diseased groups were 77% to 195% lower than in the control group (p < 0.001). Degenerations of global morphometry of cancellous bones in these diseased femoral heads are similar but more severe than in ageing controls matched by BV/TV, as evidenced by pronounced reduction in bone strength. This phenomenon suggests that some local morphometric parameters, along with other factors, such as abnormal collagen, mineralisation, erosion and microdamage, may contribute to further compromising mechanical properties.

Mechano-structural alteration in proximal femora of individuals with alcoholic liver disease: Implications for increased bone fragility.

Although increased hip fracture risk is noted in patients with alcoholic liver disease (ALD), their femoral microstructural and mechanical properties were not investigated previously. The present study aimed to analyze the associations between subregional deteriorations in femoral mechano-structural properties and clinical imaging findings to explain increased femoral fracture risk among ALD patients. This study analyzed proximal femora of 33 male cadaveric donors, divided into ALD (n=13, 57±13years) and age-matched control group (n=20, 54±13years). After pathohistological verification of ALD stage, DXA and HSA measurements of the proximal femora were performed, followed by micro-CT and Vickers microindentation of the superolateral neck, inferomedial neck, and intertrochanteric region. Bone mineral density and cross sectional area of the femoral neck were deteriorated in ALD donors, compared with healthy controls (p<0.05). Significant ALD-induced degradation of trabecular and cortical microstructure and Vickers microhardness reduction were noted in the analyzed femoral regions (p<0.05). Still, the most prominent ALD-induced mechano-structural deterioration was noted in intertrochanteric region. Additionally, more severe bone alterations were observed in individuals with an irreversible stage of ALD, alcoholic liver cirrhosis (ALC), than in those with an initial ALD stage, fatty liver disease. Observed osteodensitometric and mechano-structural changes illuminate the basis for increased femoral fracture risk in ALD patients. Additionally, our data suggest bone strength reduction that may result in increased susceptibility to intertrochanteric femoral fracture in men with ALD. Thus, femoral fracture risk assessment should be advised for all ALD patients, especially in those with ALC.

Experimental testing and biomechanical CT analysis of Chinese cadaveric vertebrae with different modeling approaches

Osteoporosis is characterized by reduced bone strength predisposing to an increased risk of fracture. Biomechanical computed tomography (BCT), predicting bone strength via CT-based finite element analysis (FEA), is now clinically available in the USA for diagnosing osteoporosis or assessing fracture risk. However, it has not been previously validated using a cohort of only Chinese subjects. Additionally, the effect of various modeling approaches on BCT outcomes remains elusive. To address these issues, we performed DXA and QCT scanning, compression testing, and BCT analyses on thirteen vertebrae derived from Chinese donors. Three BCT models were created (voxBCT and tetBCT: voxel-based and tetrahedral element-based FE models generated by a commercial software; matBCT: tetrahedral element-based FE model generated by a custom MATLAB program). BCT-computed outcomes were compared with experimental measures or between different BCT models. Results showed that, DXA-measured areal bone mineral density (aBMD) showed weak correlations with experimentally-measured vertebral stiffness (R2 = 0.28) and strength (R2 = 0.34). Compared to DXA-aBMD, BCT-computed stiffness provided improved correlations with experimentally-measured stiffness (voxBCT: R2 = 0.82; tetBCT: R2 = 0.77; matBCT: R2 = 0.76) and strength (voxBCT: R2 = 0.55; tetBCT: R2 = 0.57; matBCT: R2 = 0.53); BCT-computed mechanical parameters (stiffness, stress and strain) of the three different models were highly correlated with each other, with coefficient of determination (R2) values of 0.89–0.98. These results, based on a cohort of Chinese vertebral cadavers, suggest that BCT is superior over aBMD to consistently predict vertebral mechanical characteristics, regardless of the modeling approaches of choice.

Recurrent Atraumatic Pelvic Fractures in a Patient With Cushing’s Disease - Is DEXA Scan Really Useful to Predict the Future Fracture Risk?

Background: Cushing’s disease may present with a variety of clinical features, including osteoporosis and fracture. Due to the inhibitory effects of cortisol on osteoblastic activity and enhancing effects on osteoclastic activity, these patients are more prone to have osteoporotic fractures. We report a case of ACTH dependent Cushing’s disease presenting with recurrent atraumatic pelvic fractures in a woman despite normal bone mineral density for her age. Clinical Case: A 56 year-old-woman was referred to the endocrinology department for suspected Cushing’s syndrome following a recent atraumatic fracture of right pubic ramus. She had a history of weight gain and easy fatigue. On examination, she had subtle changes suggestive of Cushing’s syndrome, including mild truncal obesity, minimal bruising and moon face. She had been taking hormone replacement therapy for 3 years for the post-menopausal symptoms. Her bone mineral density was normal for her age on a recent DEXA scan [femoral neck T score: -0.9, Z score: 0.1, lumbar spine (L1-L4) T score: -1.2, Z score: -0.1]. Her vitamin D, serum calcium and parathyroid hormone levels were normal. Her 24-hour urinary cortisol was 688 nmol/day (reference range: <200 nmol/day), low dose dexamethasone suppression cortisol 525 nmol/L (reference range: <50 nmol/day), ACTH 96 ng/L (reference range: <50 ng/L), indicating ACTH dependent Cushing syndrome. MRI pituitary showed 7 mm right sided hypoenhancing area suggestive of a pituitary microadenoma. CT neck, thorax, abdomen and pelvis did not show any source of ectopic ACTH secretion but did show generalised osteopenia, with old fractures of the ribs and left ilium. She was referred for trans-sphenoidal resection of pituitary tumour. While awaiting pituitary surgery she was treated with metyrapone: at this time she suffered a further atraumatic fracture of the left pubic ramus. Conclusion: Glucocorticoid excess predominantly affects trabecular bones (pelvis, ribs, lumbar spine) as compared to cortical bones. Due to micro-architectural changes, reduction in bone strength is disproportionately greater than would be expected from BMD measured by DEXA. Clinicians should be aware that recurrent fracture of trabecular bones may indicate Cushing’s disease even though other clinical features of cortisol excess are minimal or absent.

Osteocyte-Specific TGFβ Signaling Mitigates Obesity-Induced Deregulated Energy Metabolism and Compromised Bone Quality

Bone fragility associated with obesity is well recognized and is attributed to a cumulative decline in bone quality despite high BMD. Moreover, novel insights into skeletal physiology have revealed that bone-derived factors are key regulators of systemic energy balance. Despite the revelation that bone is both a target and a driver of energy metabolism, it is not entirely clear how obesity compromises the metabolic function of bone and whether deregulated energetics in bone play a causal role in declining bone quality.Transforming growth factor-beta (TGFβ), a key mediator of bone homeostasis, was recently shown by us to play a positive role in osteocytes, where its ablation (TβRIIocy-/-) compromised bone quality. TGFβ signaling has been previously implicated in etiologies of obesity and type 2 diabetes. Also, our unpublished unbiased transcriptomic analysis in TβRIIocy-/- mouse bones (osteocyte-enriched RNA) has shown that osteocytic ablation of TGFβ signaling causes profound changes in the expression of genes implicated in glucose and fatty metabolism. Together these observations led us to hypothesize that osteocytic TGFβ plays an integral role in regulating obesity impacted bone architecture and function in metabolism.Using hyperglycemia to model the metabolic milieu of obesity in vitro, we found that hyperglycemia upregulated TGFβ signaling in osteocytes. We also found that TGFβ acts similarly to hyperglycemia in reprogramming osteocyte cellular metabolism to promote glycolysis at the expense of oxidative phosphorylation. Thus, TGFβ may be a crucial mediator of hyperglycemia-induced metabolic reprogramming in osteocytes.In TβRIIocy-/- mice, inhibition of osteocyte-intrinsic TGFβ signaling reduced age-dependent weight gain and improved glycemic control relative to littermate controls. When subjected to a high-fat diet (HFD, 18 weeks), TβRIIocy-/- mice continued to be leaner, with lower food intake, and higher levels of activity and fatty acid metabolism in the liver compared to HFD fed littermate controls. This implicates osteocyte-intrinsic TGFβ signaling as a crucial regulator of systemic energy metabolism. TβRIIocy-/- mice on HFD also showed increased trabecular and cortical bone mass, increased bone mineral density, and protection against reduced bone strength compared to littermate controls on a similar diet.Overall, our study identifies a novel role for osteocytic TGFβ signaling in regulating energy metabolism and bone health in obesity.

In Vivo Effects of Osteoblast-Specific Overexpression of Gα s and Gα q/11 on Bone Formation and Bone Remodeling During Fracture Healing

Although the regenerative potential of bone is high, fracture healing is sometimes compromised resulting in fracture non-union. Successful prevention and treatment of non-union rely on accurate prognosis of fracture and treatment assignment but are often impeded by a high degree of heterogeneity in fracture pathogenesis and treatment response. Burgeoning evidence that indicates differential levels of G proteins among healthy populations offers a plausible explanation, since G protein signaling plays regulatory roles in bone development and remodeling. We previously demonstrated the in vivo effects of G protein level variation on bone development by characterizing the skeletal phenotypes of two transgenic mouse lines that overexpress normal Gα s (Gs-Tg) or Gα 11 (G11-Tg) in osteoblast lineage cells under the control of the 3.6-kb Col1a1 promoter. Gs-Tg mice showed high bone mass but diminished bone quality due to increased formation of woven bone and cortical porosity. Conversely, G11-Tg mice displayed a low bone mass phenotype with reduced bone strength primarily due to increased bone resorption. It still remains unclear, however, how variation in G protein signaling in osteoblasts affects the rate and quality of bone repair. To characterize bone healing in Gs-Tg and G11-Tg mice, we induced a stabilized transverse osteotomy in the tibia of wild-type, Gs-Tg or G11-Tg at 8 weeks of age and assessed the progression of bone healing at the tissue and molecular levels by Micro-CT, histomorphometry, and quantitative gene expression analysis at 1, 2, 3, and 4 weeks post-fracture. The effects of increased G protein signaling during repair on Wnt and Hh signaling, the two signaling pathways essential in osteogenesis, were also examined by assessing mRNA levels of key components of each pathway. Persistent upregulation of Wnt and Hh signaling in Gs-Tg fractures led to enhanced callus mineralization and new woven bone formation at the expense of cartilaginous callus formation and defective bone remodeling. G11-Tg fractures, in contrast, showed minimal changes in Wnt and Hh pathways and consequently led to only subtle changes in the healing response with a transient increase in callus mineralization followed by its rapid resorption. Our results indicate that G protein signaling in osteoblasts regulates bone formation and remodeling during fracture repair in part by tightly controlling the strength and duration of Wnt and Hh signaling pathways.

Prediction of Risk Factors for Pathological Fracture After Bone Tumor Biopsy Using Finite Element Analysis.

PurposeWe aimed to determine if finite element analysis (FEA) provides useful thresholds for bone biopsy practice patterns.MethodsThe femoral head compression test was performed on rabbit femurs, using FEA to identify the part of the bone that preferentially fractures (n=15/group). Four types of rectangular biopsy holes were made using finite element (FE) models. These models were divided into control (no defect), defect 1 (10% width), defect 2 (20% width), defect 3 (30% width), and defect 4 (40% width) groups (n=15 each). Three types of rectangular biopsy holes (defect A, 27% length; defect B, 40% length; defect C, 53% length) were also made using FE models (n=15 each). The load to failure was then predicted using FEA.ResultsAlmost all femurs with no defect were fractured at the femoral shaft in both the femoral head compression test and FEA. The experimental load to failure in intact femurs was predicted well by the FE models (R2=0.74, p<0.001). There was also a strong linear correlation of stiffness between compression test in femurs with no defect and the FEA (R2=0.68, p<0.001). Therefore, the femoral shaft was targeted for FEA. The median predicted loads by FEA were significantly higher for defect 1 than for the other types when testing the widths of the rectangular defects, but there were no significant differences among the three types when testing for defect length.ConclusionThe FEA results correlated well with those of the femoral head compression test. A width <10% of the circumference length in bone biopsy holes helps minimize bone strength reduction using FEA. It may be useful for orthopedic doctors to perform FEA to avoid pathological fractures after bone tumor biopsy.

Static magnetic field of 0.2–0.4 T promotes the recovery of hindlimb unloading-induced bone loss in mice

Purpose Bone loss is one of the most serious medical problem associated with prolonged weightlessness in long-term spaceflight mission. Skeletal reloading after prolonged spaceflight have indicated incomplete recovery of lost bone, which may lead to an increased risk of fractures in astronauts when returning to Earth. Substantial studies have revealed the capacity of static magnetic fields (SMFs) on treating various bone disorders, whereas it is unknown whether SMFs have the potential regulatory effects on bone quality in unloaded mice during unloading. This study was conducted to investigate the potential effects of whole-body SMF exposure with 0.2–0.4 T on the recovery of unloading-induced bone loss. Materials and methods Eight‐week‐old male C57BL/6J mice were subjected to hindlimb unloading (HLU) for 4 weeks, following the mice were reloaded for 4 weeks under geomagnetic field (GMF) and SMF of 0.2–0.4 T. Bone quality indexes, including bone mineral density (BMD) and bone mineral content (BMC), bone microarchitecture, and bone mechanical properties were examined by the measurement of dual energy X-ray absorptiometry (DEXA), micro-computed tomography (Micro-CT), and 3-point bending. Bone turnover was evaluated by bone histomorphometric and serum biochemical assay. Results We found that SMF exposure for 4 weeks significantly promoted the recovery in HLU-induced decrease of BMD and BMC, deterioration of bone microarchitecture, and reduction of bone strength. The results from bone turnover determination revealed that SMF exposure for 4 weeks induced lower osteoclast number of trabecular bone and serum TRAP-5b levels in reloaded mice, whereas SMF showed no significant alteration in skeletal osteoblast number and serum osteocalcin levels. Conclusions Together, our findings suggest that SMF of 0.2–0.4 T facilitated the recovery of unloading-induced bone loss by inhibiting the increase of bone resorption in reloaded mice, and indicate that SMF might become a promising biophysical countermeasure for maintaining bone health in astronauts after landing.

Plasma pentosidine levels are associated with prevalent fractures in patients with chronic liver disease.

Osteoporotic fractures negatively impact health-related quality of life and prognosis. Advanced glycation end products (AGEs) impair bone quality and reduce bone strength. The aim of this study was to determine the relationship between plasma levels of pentosidine, a surrogate marker for AGEs, and prevalent fractures in patients with chronic liver disease (CLD). This cross-sectional study included 324 patients with CLD. Vertebral fractures were evaluated using lateral thoracolumbar spine radiographs. Information on prevalent fractures was obtained through a medical interview, medical records, and/or radiography. The patients were classified into low (L), intermediate (I), and high (H) pentosidine (Pen) groups based on baseline plasma pentosidine levels. Of the 324 patients, 105 (32.4%) had prevalent fractures. The prevalence of liver cirrhosis (LC) and prevalent fractures significantly increased stepwise with elevated pentosidine levels. The H-Pen group had the highest prevalence of LC (88.6%, p < 0.001) and prevalent fractures (44.3%, p = 0.007), whereas the L-Pen group had the lowest prevalence of LC (32.1%, p < 0.001) and prevalent fractures (21.0%, p = 0.007). Multiple logistic regression analysis identified pentosidine as a significant independent factor related to prevalent fractures (odds ratio = 1.069, p < 0.001). Pentosidine levels increased stepwise and correlated with liver disease severity. They were markedly high in patients with decompensated LC. In multiple regression analysis, liver functional reserve factors (total bilirubin, albumin, and prothrombin time-international normalized ratio) significantly and independently correlated with pentosidine levels. Plasma pentosidine was significantly associated with prevalent fractures and liver functional reserve in patients with CLD. Pentosidine may be useful in predicting fracture risk and should be closely followed in CLD patients with advanced disease.