Impaired Bone Quality Research Articles

CircZNF367 promotes osteoclast differentiation and osteoporosis by interacting with FUS to maintain CRY2 mRNA stability

BackgroundOsteoporosis, characterized by reduced bone mass and deterioration of bone quality, is a significant health concern for postmenopausal women. Considering that the specific role of circRNAs in osteoporosis and osteoclast differentiation remains poorly understood, this study aims to shed light on their involvement in these processes to enhance our understanding and potentially contribute to improved treatment strategies for osteoporosis.MethodsAn osteoporotic model was constructed in vivo in ovariectomized mouse. In vitro, we induced osteoclast formation in bone marrow-derived macrophages (BMDMs) using M-CSF + RANKL. To assess osteoporosis in mice, we conducted HE staining. We used MTT and TRAP staining to measure cell viability and osteoclast formation, respectively, and also evaluated their mRNA and protein expression levels. In addition, RNA pull-down, RIP and luciferase reporter assays were performed to investigate interactions, and ChIP assay was used to examine the impact of circZNF367 knockdown on the binding between FUS and CRY2.ResultsWe observed increased expression of CircZNF367, FUS and CRY2 in osteoporotic mice and M-CSF + RANKL-induced BMDMs. Functionally, knocking down circZNF367 inhibited osteoporosis in vivo. Furthermore, interference with circZNF367 suppressed osteoclast proliferation and the expression of TRAP, NFATc1, and c-FOS. Mechanistically, circZNF367 interacted with FUS to maintain CRY2 mRNA stability. Additionally, knocking down CRY2 rescued M-CSF + RANKL-induced osteoclast differentiation in BMDMs promoted by circZNF367 and FUS.ConclusionThis study reveals that the circZNF367/FUS axis may accelerate osteoclasts differentiation by upregulating CRY2 in osteoporosis and suggests that targeting circZNF367 may have potential therapeutic effects on osteoporosis.

Micro-scale vertebral features in postmenopausal women with alcohol-associated and metabolic-associated fatty liver disease: ex vivo bone quality analyses.

Although epidemiological studies indicate increased fracture risk in women with alcohol-associated liver disease (AALD) and metabolic-associated fatty liver disease (MAFLD), data about their micro-scale bone features are still limited. We aimed to characterize bone quality changes in the anterior mid-transverse part of the first lumbar vertebral body collected from 32 adult postmenopausal females. Based on pathohistological assessment of the liver tissue, individuals were divided into AALD (n = 13), MAFLD (n = 9), and control group (n = 10). We analyzed trabecular and cortical micro-architecture (using micro-computed tomography), bone mechanical properties (using Vickers microhardness tester), osteocyte lacunar network and bone marrow adiposity morphology (using optic microscopy). Data were adjusted to elude the covariant effects of advanced age and body mass index on our results. Our data indicated a minor trend toward deteriorated bone quality in MAFLD women, presented in impaired trabecular and cortical micro-architectural integrity, which could be associated with bone marrow adiposity alterations noted in these women. Additionally, we observed a significant decline in micro-architectural, mechanical, and osteocyte lacunar features in lumbar vertebrae collected from the AALD group. Lastly, our data indicated that vertebral bone deterioration was more prominent in the AALD group than in the MAFLD group. Our data suggested that MAFLD and AALD are factors that could play a part in compromised vertebral strength of postmenopausal women. Also, our data contribute to understanding the multifactorial nature of bone fragility in these patients and highlight the necessity for developing more effective patient-specific diagnostic, preventive, and therapeutic strategies.

Automated, calibration-free quantification of cortical bone porosity and geometry in postmenopausal osteoporosis from ultrashort echo time MRI and deep learning.

Assessment of cortical bone porosity and geometry by imaging in vivo can provide useful information about bone quality that is independent of bone mineral density (BMD). Ultrashort echo time (UTE) MRI techniques of measuring cortical bone porosity and geometry have been extensively validated in preclinical studies and have recently been shown to detect impaired bone quality in vivo in patients with osteoporosis. However, these techniques rely on laborious image segmentation, which is clinically impractical. Additionally, UTE MRI porosity techniques typically require long scan times or external calibration samples and elaborate physics processing, which limit their translatability. To this end, the UTE MRI-derived Suppression Ratio has been proposed as a simple-to-calculate, reference-free biomarker of porosity which can be acquired in clinically feasible acquisition times. To explore whether a deep learning method can automate cortical bone segmentation and the corresponding analysis of cortical bone imaging biomarkers, and to investigate the Suppression Ratio as a fast, simple, and reference-free biomarker of cortical bone porosity. In this retrospective study, a deep learning 2D U-Net was trained to segment the tibial cortex from 48 individual image sets comprised of 46 slices each, corresponding to 2208 training slices. Network performance was validated through an external test dataset comprised of 28 scans from 3 groups: (1) 10 healthy, young participants, (2) 9 postmenopausal, non-osteoporotic women, and (3) 9 postmenopausal, osteoporotic women. The accuracy of automated porosity and geometry quantifications were assessed with the coefficient of determination and the intraclass correlation coefficient (ICC). Furthermore, automated MRI biomarkers were compared between groups and to dual energy X-ray absorptiometry (DXA)- and peripheral quantitative CT (pQCT)-derived BMD. Additionally, the Suppression Ratio was compared to UTE porosity techniques based on calibration samples. The deep learning model provided accurate labeling (Dice score 0.93, intersection-over-union 0.88) and similar results to manual segmentation in quantifying cortical porosity (R2≥0.97, ICC≥0.98) and geometry (R2≥0.82, ICC≥0.75) parameters in vivo. Furthermore, the Suppression Ratio was validated compared to established porosity protocols (R2≥0.78). Automated parameters detected age- and osteoporosis-related impairments in cortical bone porosity (P≤.002) and geometry (P values ranging from <0.001 to 0.08). Finally, automated porosity markers showed strong, inverse Pearson's correlations with BMD measured by pQCT (|R|≥0.88) and DXA (|R|≥0.76) in postmenopausal women, confirming that lower mineral density corresponds to greater porosity. This study demonstrated feasibility of a simple, automated, and ionizing-radiation-free protocol for quantifying cortical bone porosity and geometry in vivo from UTE MRI and deep learning.

Rapid Transition from a High-Fat, High-Fructose to a Low-Fat, Low-Fructose Diet Reverses Gains in Bone Mass and Strength.

Obesity is thought to negatively impact bone quality and strength despite improving bone mineral density. We hypothesized that 1) continuous consumption of a high-fat, high-sugar (HFS) diet would impair bone quality and strength, and 2) a change from an HFS diet to a low-fat, low-sugar (LFS) would reverse HFS-induced impairments to bone quality and strength. Six-week-old male C57Bl/6 mice ( n = 10/group) with access to a running wheel were randomized to an LFS diet or an HFS diet with simulated sugar-sweetened beverages (20% fructose in place of regular drinking water) for 13 wk. HFS mice were subsequently randomized to continuing HFS feeding (HFS/HFS) or transition to the LFS diet (HFS/LFS) for four additional weeks. HFS/HFS mice exhibited superior femoral cancellous microarchitecture (i.e., greater BV/TV, Tb.N, Tb.Th, and decreased Tb.Sp) and cortical bone geometry (i.e., lower Ct.CSA and pMOI) compared with all other groups. At the femoral mid-diaphysis, structural, but not material, mechanical properties were greatest in HFS/HFS mice. However, HFS/HFS exhibited greater femoral neck strength only when compared with mice assigned to diet transition (HFS/LFS). Osteoclast surface and the percentage of osteocytes staining positive for interferon-gamma were greater in HFS/LFS mice, consistent with reduced cancellous microarchitecture postdiet transition. HFS feeding enhanced bone anabolism and structural, but not material, mechanical properties in exercising mice. A change from an HFS to LFS diet returned the bone structure to that of continuously LFS-fed mice while compromising strength. Our results indicate rapid weight loss from obese states should be performed with caution to prevent bone fragility. A deeper analysis into the altered bone phenotype in diet-induced obesity from a metabolic standpoint is needed.

Diffuse idiopathic skeletal hyperostosis (DISH) and trabecular bone score (TBS) in postmenopausal women: The Camargo cohort

ObjectivesThe potential relationship between diffuse idiopathic skeletal hyperostosis (DISH) and bone microstructure has not been studied in women. We aimed to assess the association between the trabecular bone score (TBS) and DISH in postmenopausal women, as well as the role of other parameters related to bone metabolism, such as bone mineral density (BMD), calciotropic hormones, and bone remodeling markers. MethodsCross-sectional study, nested in a prospective population-based cohort (Camargo cohort). Clinical covariates, DISH, TBS, vitamin D, parathormone, BMD and serum bone turnover markers, were analyzed. ResultsWe have included 1545 postmenopausal women (mean age, 62±9 years). Those with DISH (n = 152; 8.2%) were older and had a significantly higher prevalence of obesity, metabolic syndrome, hypertension, and type 2 diabetes mellitus (p<0.05). Moreover, they had lower TBS values (p = 0.0001) despite having a higher lumbar spine BMD (p<0.0001) and a higher prevalence of vertebral fractures than women without DISH (28.6% vs. 15.1%; p = 0.002). When analyzing DISH through Schlapbach grades, women without DISH had a median TBS value consistent with a normal trabecular structure while the values for women with DISH from grades 1 to 3 were consistent with a partially degraded trabecular structure. Women with vertebral fractures and DISH had a mean TBS corresponding to a degraded trabecular structure (1.219±0.1). After adjusting for confounders, the estimated TBS means were 1.272 (1.253–1.290) in the DISH group, and 1.334 (1.328–1.339) in the NDISH group (p<0.0001). ConclusionAn association between DISH and TBS has been shown in postmenopausal women, in which hyperostosis has been significantly and consistently related to trabecular degradation and, therefore, to deterioration in bone quality after adjusting for confounding variables.

Role of Advanced Glycation End-Products and Oxidative Stress in Type-2-Diabetes-Induced Bone Fragility and Implications on Fracture Risk Stratification.

Type 2 diabetes (T2D) and osteoporosis (OP) are major causes of morbidity and mortality that have arelevant health and economic burden. Recent epidemiological evidence suggests that both of these disorders are often associated with each other and that T2D patients have an increased risk of fracture, making bone an additional target of diabetes. As occurs for other diabetic complications, the increased accumulation of advanced glycation end-products (AGEs) and oxidative stress represent the major mechanisms explaining bone fragility in T2D. Both of these conditions directly and indirectly (through the promotion of microvascular complications) impair the structural ductility of bone and negatively affect bone turnover, leading to impaired bone quality, rather than decreased bone density. This makes diabetes-induced bone fragility remarkably different from other forms of OP and represents a major challenge for fracture risk stratification, since either the measurement of BMD or the use of common diagnostic algorithms for OP have a poor predictive value. We review and discuss the role of AGEs and oxidative stress on the pathophysiology of bone fragility in T2D, providing some indications on how to improve fracture risk prediction in T2D patients.

Resveratrol prevents ovariectomy-induced bone quality deterioration byimprovingthemicroarchitectural and biophysicochemical properties of bone.

Osteoporosis is a major health problem that is very common worldwide and is characterized by both low bone density and deterioration in bone quality. New treatment options without side effects have become an active area of research in recent years. This study was designed to investigate the preventive effects of resveratrol on bone quality deterioration caused by ovariectomy. Sixty rats were randomly divided into five groups (12 animals per group): Control, Sham-operated (SHAM), ovariectomized (OVX), OVX + Resveratrol-40mg/kg/day (OVX + Res40), OVX + Resveratrol-80mg/kg/day (OVX + Res80). Resveratrol was administered by oral gavage (40 and 80mg/kg/day) for ten weeks. Micro-CT measurements, biomechanical testing, Raman spectroscopyanalysis, and RT-PCR analysis were performed. ALP, OCN, TAS, and TOS levels were also measured from blood serum. Bone strength, bone volume/total volume, trabecular volume, and trabecular thickness were higher in the OVX + RES-80 group than inthe OVX group. Resveratrol increased osteogenic differentiation, as the expression of osteogenic markers ALP, Col1A1, Runx2, OPG, OCN increased in both OVX + RES-80 and OVX + RES-40 groups compared to theOVX group. 80mg/kg/day resveratrol administration decreasedthe levels of ALP, OCN and TOS in ovariectomized rats. Raman spectroscopy findings showed a preventive effect of resveratrol administration against ovariectomy-induced deterioration in biophysiochemical properties of bone tissue. This study revealed that administration of different doses of 80 mg/kg/day and 40 mg/kg/day of resveratrol had protective effects on bone quality deterioration caused by ovariectomy.

Bone collagen quality in lumbar fusion patients: the association between volumetric bone mineral density and advanced glycation endproducts.

The sole determination of volumetric bone mineral density (vBMD) is insufficient to evaluate overall bone integrity. The accumulation of advanced glycation endproducts (AGEs) stiffens and embrittles collagen fibers. Despite the important role of AGEs in bone aging, the relationship between AGEs and vBMD is poorly understood. We hypothesized that an accumulation of AGEs, a marker of impaired bone quality, is related to decreased vBMD. Prospectively collected data of 127 patients undergoing lumbar fusion were analyzed. Quantitative computed tomography (QCT) measurements were performed at the lumbar spine. Intraoperative bone biopsies were obtained and analyzed with confocal fluorescence microscopy for fluorescent AGEs, both trabecular and cortical. Spearman's correlation coefficients were calculated to examine relationships between vBMD and fAGEs, stratified by sex. Multivariable linear regression analysis with adjustments for age, sex, body mass index (BMI), race, diabetes mellitus and HbA1c was used to investigate associations between vBMD and fAGEs. One-hundred and twenty-seven patients (51.2% female, 61.2years, BMI of 28.7kg/m2) with 107 bone biopsies were included in the final analysis, excluding patients on anti-osteoporotic drug therapy. In the univariate analysis, cortical fAGEs increased with decreasing vBMD at (r = -0.301; p = 0.030), but only in men. In the multivariable analysis, trabecular fAGEs increased with decreasing vBMD after adjusting for age, sex, BMI, race, diabetes mellitus and HbA1c (β = 0.99;95%CI=(0.994,1.000); p = 0.04). QCT-derived vBMD measurements were found to be inversely associated with trabecular fAGEs. Our results enhance the understanding of bone integrity by suggesting that spine surgery patients with decreased bone quantity may also have poorer bone quality.

Relationship between risk factors for impaired bone health and HR-pQCT in young adults with type 1 diabetes.

In type 1 diabetes, risk factors associated with impaired bone health contribute to increased risk of fracture. The aim of this study was to (1): compare the high-resolution peripheral quantitative computed tomography (HR-pQCT) parameters of young adults with type 1 diabetes with those of healthy controls (2), identify sex differences, and (3) evaluate the association between diabetes and bone health risk factors, with HR-pQCT. This is a cross-sectional study in young Canadian adults with childhood onset type 1 diabetes. Z-scores were generated for HR-pQCT parameters using a large healthy control database. Diet, physical activity, BMI, hemoglobin A1C (A1C) and bone health measures were evaluated, and associations were analyzed using multivariate regression analysis. Eighty-eight participants (age 21 ± 2.2 years; 40 males, 48 females, diabetes duration 13.9 ± 3.4 years) with type 1 diabetes were studied. Low trabecular thickness and elevated cortical geometry parameters were found suggesting impaired bone quality. There were no sex differences. Significant associations were found: Vitamin D (25(OH)D) with trabecular parameters with possible synergy with A1C, parathyroid hormone with cortical parameters, BMI with cortical bone and failure load, and diabetes duration with trabecular area. Our data suggests impairment of bone health as assessed by HR-pQCT in young adults with type 1 diabetes. Modifiable risk factors were associated with trabecular and cortical parameters. These findings imply that correction of vitamin D deficiency, prevention and treatment of secondary hyperparathyroidism, and optimization of metabolic control may reduce incident fractures.

Comprehensive Associations between Acidosis and the Skeleton in Patients with Kidney Disease.

Renal osteodystrophy (ROD) contributes substantially to morbidity in CKD, including increased fracture risk. Metabolic acidosis (MA) contributes to the development of ROD, but an up-to-date skeletal phenotype in CKD-associated acidosis has not been described. We comprehensively studied associations between acidosis and bone in patients with CKD using advanced methods to image the skeleton and analyze bone-tissue, along with biochemical testing. Cross-sectionally, acidosis was associated with higher markers of bone remodeling and female-specific impairments in cortical and trabecular bone quality. Prospectively, acidosis was associated with cortical expansion and trabecular microarchitectural deterioration. At the bone-tissue level, acidosis was associated with deficits in bone mineral content. Future work investigating acidosis correction on bone quality is warranted. Renal osteodystrophy is a state of impaired bone quality and strength. Metabolic acidosis (MA) is associated with alterations in bone quality including remodeling, microarchitecture, and mineralization. No studies in patients with CKD have provided a comprehensive multimodal skeletal phenotype of MA. We aim to describe the structure and makeup of bone in patients with MA in the setting of CKD using biochemistry, noninvasive imaging, and histomorphometry. The retrospective cross-sectional analyses included 180 patients with CKD. MA was defined as bicarbonate ≤22 mEq/L. We evaluated circulating bone turnover markers and skeletal imaging with dual energy x-ray absorptiometry and high-resolution peripheral computed tomography. A subset of 54 participants had follow-up. We assessed associations between baseline and change in bicarbonate with change in bone outcomes. Histomorphometry, microCT, and quantitative backscatter electron microscopy assessed bone biopsy outcomes in 22 participants. The mean age was 68±10 years, 54% of participants were male, and 55% were White. At baseline, acidotic subjects had higher markers of bone turnover, lower areal bone mineral density at the radius by dual energy x-ray absorptiometry, and lower cortical and trabecular volumetric bone mineral density and impaired trabecular microarchitecture. Over time, acidosis was associated with opposing cortical and trabecular effects: cortical expansion but trabecular deterioration. Bone-tissue analyses showed reduced tissue mineral density with increased heterogeneity of calcium distribution in acidotic participants. MA is associated with multiple impairments in bone quality. Future work should examine whether correction of acidosis improves bone quality and strength in patients with CKD.

A steered molecular dynamics investigation on the role of glycation on the energy dissipation capacity of osteopontin at mineral interfaces in bone.

Type-2 Diabetes (T2D) is associated with a 3-fold increase in bone fracture risk. T2D impairs bone quality, whereby the intrinsic material properties of the bone matrix are altered, through glycation of collagenous and non-collagenous proteins (NCPs). There is a distinct lack of understanding of how altered protein configurations impair whole-bone biomechanics, particularly in the case of NCPs since their structural roles in bone are only now emerging. In this study, the effect of glycation on the energy dissipation behaviour of OPN, the most abundant NCP, on HydroxyApatite (HAp) mineral surfaces was investigated. The adsorption modes of OPN on the surface was obtained by conventional MD by comparing the residues residence time for each protein orientation with their average values. Then, energy dissipation of OPN was obtained through Steered Molecular Dynamics (SMD) by pulling simulations perpendicular to the surface. Two different glycation possibilities were considered whereby (a) Glycation occurred prior to Adsorption (GA) or (b) Adsorption took place before Glycation (AG). The simulation results showed that AG has the same adsorption modes as the healthy OPN, while the GA experienced a different mode. It was found that energy dissipation in absence of glycation was EOPN = 2646 kcal/mol. For glycated groups energy dissipation values were EOPN-AG = 2324 kcal/mol and EOPN-GA = 773 kcal/mol. The simulation results showed that OPN had reduced capacity for energy dissipation for either glycation case. However, it was notable that if OPN glycation occurred before its adsorption on HAp, its energy dissipation capacity was greatly reduced, which was caused by changes to the adsorption mode itself. The current study for the first time showed that the glycation sequence could negatively affects energy dissipation behaviour of OPN, which could have consequence for bone toughness.

Calcium and vitamin D for increasing bone mineral density in premenopausal women.

Calcium and vitamin D for increasing bone mineral density in premenopausal women.

Impact of serum vitamin D level on selected bone-related markers in obese- type 2 diabetes patients

Background: Type 2 diabetes mellitus (T2DM) is accompanied by an increased risk for skeletal fractures. The causes are probably a mix of factors, including poor glycemic control, a higher risk of falling due to hypoglycemia, osteopenia, bone quality deterioration, and drug side effects related to bone fragility. Undercarboxylated osteocalcin (ucOC) is a protein generated by osteoblasts that affects insulin secretion and sensitivity. Methods: A total number of 47 obese (BMI ˃ 30) patients with confirmed type 2 diabetes were selected depending on the American Diabetes Association ADA criteria. The control participants were similar to the patients in age and gender, with a total number of 43 obese (BMI ˃ 30) and healthy subjects chosen from the general population. The selected subjects were grouped according to their serum vitamin D levels. Their blood specimen was used for assaying ucOC, parathyroid hormone (PTH), and vitamin D3 levels by specific ELISA kits, and to estimate calcium (Ca2+) levels and inorganic phosphate (PO43−) via enzymatic colorimetric methods. Results: Serum parathyroid hormone and inorganic phosphate median (IQR) values were markedly increased in patients with T2DM when compared to healthy controls, whereas serum calcium and ucOC levels were lowered significantly in diabetic patients when compared to healthy controls. This was irrespective of serum vitamin D levels. Conclusions: Elevated serum levels of PTH and PO43− values in obese type 2 diabetic patients compared to obese non-diabetic controls were accompanied by a significant decrease in ucOC and Ca2+ levels, irrespective of serum vitamin D levels. Hence, serum vitamin D3 levels had no significant impact on levels of ucOC, PTH, Ca2+, and PO43− in obese patients with type 2 diabetes.

MLK3 silence suppressed osteogenic differentiation and delayed bone formation via influencing the bone metabolism and disturbing MAPK signaling.

Mixed lineage kinase 3 (MLK3) is a member of a serine/threonine MAP3K family, and it has been demonstrated to play critical roles in various biological activities and disease progression. Previous studies showed that impaired skeletal mineralization and spontaneous tooth fracture in the MLK3-deficient mice, suggesting MLK3 actively participated in the bone formation. However, the detailed function and underlying mechanisms remain obscure. The MLK3 knockout (KO) mouse was applied in the present study, and multi-omics were performed to compare the metabolites and gene expression between wild type (WT) and KO mice. The bone fracture model was successfully established, and the healing process was evaluated by X-ray, micro-CT examination, histomorphometry and immunohistochemistry (IHC) staining. On the other hand, the effects of MLK3 on osteogenic differentiation were assessed by alkaline phosphatase (ALP) activity, Alizarin red S (ARS) staining and qRT-PCR examination. Finally, the downstream signaling pathways were screened out by RNA-sequencing (RNA-seq) and then validated by Western blotting. In the present study, imbalanced bone metabolism was observed in these MLK3 KO mice, suggesting MLK3 may participate in bone development. Moreover, MLK3 -/- mice displayed abnormal bone tissues, impaired bone quality, and delayed fracture healing. Further investigation showed that the inhibition of MLK3 attenuated osteoblast differentiation in vitro. According to the RNA-seq data, MAPK signaling was screened out to be a downstream pathway, and its subfamily members extracellular signal-regulated kinase (ERK), p38 and Jun N-terminal protein kinase (JNK) were subjected to Western blotting examination. The results revealed that although no differences in their expression were observed between MSCs derived from WT and KO mice, their phosphorylated protein levels were all suppressed in MLK3 -/- MSCs. In conclusion, our results demonstrated that loss of MLK3 suppressed osteoblast differentiation and delayed bone formation via influencing metabolism and disturbing MAPK signaling. The findings based on the current study demonstrated that MLK3 promoted osteogenesis, stimulated new bone formation and facilitated fracture healing, suggesting that MLK3 may serve as a potential therapeutic target for bone regeneration. MLK3 activator therefore may be developed as a therapeutic strategy for bone fracture.

Histological assessment of cortical bone changes in diabetic rats

BackgroundDiabetes mellitus weakens bone strength due to deterioration of bone quality; however, the histological mechanisms are still unknown. We hypothesized that histological assessment of cortical bone would enable us to determine the cause of the bone strength reduction associated with diabetes mellitus. Our aim was to evaluate the histomorphometric changes of cortical bone associated with deterioration of intrinsic bone properties and bone quality in diabetes mellitus.MethodsWe compared the outcomes of mechanical tests, bone mineral density measured using micro-computed tomography, and histological assessments, by applying Villanueva’s bone stain, to the tibial bones of 40-week-old diabetic and control male rats.ResultsWith respect to mechanical testing, the maximum load and energy absorption were significantly lower in the diabetic than in the control group, although fracture displacement and stiffness were not significantly different between the two groups. Bone mineral density was significantly higher in the diabetic group than in the control group. Bone histomorphometry revealed that the diabetic rats had fewer osteocytes, greater cortical porosity, and increased mineralization in cortical bone compared with the control group.ConclusionsIncreased mineralization of the cortical bone with greater cortical porosity leads to a weakening of bone strength in diabetes mellitus.

Simvastatin therapy in higher dosages deteriorates bone quality: Consistent evidence from population-wide patient data and interventional mouse studies

BackgroundCombining mouse experiments with big data analysis of the Austrian population, we investigated the association between high-dose statin treatment and bone quality. MethodsThe bone microarchitecture of the femur and vertebral body L4 was measured in male and ovariectomized female mice on a high-fat diet containing simvastatin (1.2 g/kg). A sex-specific matched big data analysis of Austrian health insurance claims using multiple logistic regression models was conducted (simvastatin 60–80 mg/day vs. controls; males: n = 138,666; females: n = 155,055). ResultsHigh-dose simvastatin impaired bone quality in male and ovariectomized mice. In the trabecular femur, simvastatin reduced bone volume (µm3: ♂, 213 ± 15 vs. 131 ± 7, p < 0.0001; ♀, 66 ± 7 vs. 44 ± 5, p = 0.02) and trabecular number (1/mm: ♂, 1.88 ± 0.09 vs. 1.27 ± 0.06, p < 0.0001; ♀, 0.60 ± 0.05 vs. 0.43 ± 0.04, p = 0.01). In the cortical femur, bone volume (mm3: ♂, 1.44 ± 0.03 vs. 1.34 ± 0.03, p = 0.009; ♀, 1.33 ± 0.03 vs. 1.12 ± 0.03, p = 0.0002) and cortical thickness were impaired (µm: ♂, 211 ± 4 vs. 189 ± 4, p = 0.0004; ♀, 193 ± 3 vs. 169 ± 3, p < 0.0001). Similar impairments were found in vertebral body L4. Simvastatin-induced changes in weight or glucose metabolism were excluded as mediators of deteriorations in bone quality. Results from mice were supported by a matched cohort analysis showing an association between high-dose simvastatin and increased risk of osteoporosis in patients (♂, OR: 5.91, CI: 3.17–10.99, p < 0.001; ♀, OR: 4.16, CI: 2.92–5.92, p < 0.001). ConclusionHigh-dose simvastatin dramatically reduces bone quality in obese male and ovariectomized female mice, suggesting that direct drug action accounts for the association between high dosage and increased risk of osteoporosis as observed in comparable human cohorts. The underlying pathophysiological mechanisms behind this relationship are presently unknown and require further investigation.

Trabecular Bone Score as an Index of Bone Fragility in Patients with Acromegaly: A Systematic Review and Meta-Analysis

Background: Acromegaly is characterized by impaired bone quality and increased fracture risk. However, due to the pathophysiology of acromegalic osteopathy, bone mineral density (BMD) does not represent a reliable predictor for fragility fractures in this setting. Trabecular bone score (TBS) has been recently evaluated as an alternative index of skeletal fragility in acromegalic patients. However, no conclusive data are still available in this regard. Methods: PubMed/Medline, EMBASE, Cochrane Library, Ovid, and CINAHL databases were systematically searched until June 2022 for studies reporting data either about the comparison of TBS values between acromegalic patients and non-acromegalic controls or about the relationship – within acromegalic patients – between TBS values and fracture risk. Effect sizes were pooled through a random-effect model. Results: Eight studies were eligible for inclusion in the meta-analysis, encompassing 336 acromegalic patients and 490 non-acromegalic controls. Overall, TBS was significantly lower in acromegalic patients compared to controls (−0.089, 95% CI: [−0.111, −0.067], p < 0.01), irrespective of acromegaly disease activity and gonadal status. With respect to fracture risk, TBS was significantly lower in acromegalic patients with vertebral fractures than in those without (−0.099, 95% CI: [−0.166, −0.032], p < 0.01). Conclusion: In this meta-analysis, we specifically assessed the role of TBS as an index of bone quality and fracture risk in patients with acromegaly. Our results support the notion that TBS could be of value in the assessment and management of skeletal fragility in acromegalic patients, especially in light of the poor information provided in this setting by BMD.

Roles of Gut Microbiome in Bone Homeostasis and Its Relationship with Bone-Related Diseases.

Simple SummaryIn recent years, there has been increasing evidence that communication between the skeletal system and the gut microbiome (GM) can influence bone health and that the GM is a key regulator of bone homeostasis. Here, we review the roles of GM in bone homeostasis. In addition, the relationship between GM composition and selected bone-related diseases (osteoporosis, osteoarthritis, rheumatoid arthritis, diabetes mellitus, obesity and bone cancer) is presented. It is also emphasized that a probiotic supplementation can play an important role in suppressing the symptoms of each of these diseases.The extended microbial genome—the gut microbiome (GM)—plays a significant role in host health and disease. It is able to influence a number of physiological functions. During dysbiosis, GM is associated with the development of various chronic diseases with impaired bone quality. In general, GM is important for bone homeostasis and can affect it via several mechanisms. This review describes the roles of GM in bone homeostasis through influencing the immune and endocrine functions, short-chain fatty acids production, calcium absorption and the gut–brain axis. The relationship between GM composition and several bone-related diseases, specifically osteoporosis, osteoarthritis, rheumatoid arthritis, diabetes mellitus, obesity and bone cancer, is also highlighted and summarized. GM manipulation may become a future adjuvant therapy in the prevention of many chronic diseases. Therefore, the beneficial effects of probiotic therapy to improve the health status of individuals with aforementioned diseases are provided, but further studies are needed to clearly confirm its effectiveness. Recent evidence suggests that GM is responsible for direct and indirect effects on drug efficacy. Accordingly, various GM alterations and interactions related to the treatment of bone-related diseases are mentioned as well.

2. The association between lumbar bone mineral density and advanced glycation end products derived from confocal fluorescence microscopy: a prospective investigation of bone biopsies in patients undergoing lumbar spinal fusion surgery

2. The association between lumbar bone mineral density and advanced glycation end products derived from confocal fluorescence microscopy: a prospective investigation of bone biopsies in patients undergoing lumbar spinal fusion surgery

Coexistence of bone and vascular disturbances in patients with endogenous glucocorticoid excess

PurposeBone and vascular diseases are considered to share pathogenic mechanisms. Excess glucocorticoids, key regulators of cardiovascular and metabolic homeostasis, may promote both diseases simultaneously. We used endogenous Cushing's syndrome (CS) to investigate whether glucocorticoid excess underlies coexisting bone and vascular diseases. MethodsWe included 194 patients with adrenal tumors (ATs): autonomous cortisol secretion (ACS, n = 97) and non-functional AT (n = 97). ACS was further classified into overt CS (n = 17) and subclinical CS (SCS, n = 80). Arterial stiffness was defined as a brachial-ankle pulse wave velocity (baPWV) ≥ 1800 cm/s. ResultsPatients with ACS had higher coexistence rates of vertebral fracture and arterial stiffness (23 % vs. 2 %; p < 0.001) and vertebral fracture and abdominal aortic calcification (22 % vs. 1 %; p < 0.001) than those with non-functional AT. In patients with ACS, baPWV was negatively correlated with trabecular bone score (TBS, r = −0.33; p = 0.002), but not with bone mineral density, and vertebral fracture was associated with arterial stiffness in the logistic regression analysis. In the multivariate analysis of variance, the degree of cortisol excess (defined as CS, SCS, and non-functional AT) determined the correlation between TBS and baPWV (partial η2 = 0.07; p < 0.001). In the analysis of covariance, patients with coexisting vertebral fracture and arterial stiffness had higher levels of serum cortisol after the 1-mg dexamethasone suppression test than those without. ConclusionIn endogenous glucocorticoid excess, bone and vascular diseases frequently coexisted, and deteriorated bone quality, not bone loss, was related to arterial stiffness. Thus, glucocorticoid excess may perturb the bone-vascular axis.