Shannon R Emerzian, F. Johannesdottir, E. W. Yu, M. Bouxsein
Diabetes, a disease marked by consistent high blood glucose levels, is associated with various complications such as neuropathy, nephropathy, retinopathy, and cardiovascular disease. Notably, skeletal fragility has emerged as a significant complication in both type 1 (T1D) and type 2 (T2D) diabetic patients. This review examines non-invasive imaging studies that evaluate skeletal outcomes in adults with T1D and T2D, emphasizing distinct skeletal phenotypes linked with each condition and pinpointing gaps in understanding bone health in diabetes. While traditional DXA-BMD does not fully capture the increased fracture risk in diabetes, recent techniques such as quantitative computed tomography (QCT), peripheral QCT (pQCT), high-resolution pqCT (HR-pQCT) and magnetic resonance imaging (MRI) provide insights into 3D bone density, microstructure, and strength. Notably, existing studies present heterogeneous results possibly due to variations in design, outcome measures, and potential misclassification between T1D and T2D. Thus, the true nature of diabetic skeletal fragility is yet to be fully understood. As T1D and T2D are diverse conditions with heterogeneous subtypes, future research should delve deeper into skeletal fragility by diabetic phenotypes, and focus on longitudinal studies in larger, diverse cohorts to elucidate the complex influence of T1D and T2D on bone health and fracture outcomes.
{"title":"Use of non-invasive imaging to identify causes of skeletal fragility in adults with diabetes: a review","authors":"Shannon R Emerzian, F. Johannesdottir, E. W. Yu, M. Bouxsein","doi":"10.1093/jbmrpl/ziae003","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae003","url":null,"abstract":"\u0000 Diabetes, a disease marked by consistent high blood glucose levels, is associated with various complications such as neuropathy, nephropathy, retinopathy, and cardiovascular disease. Notably, skeletal fragility has emerged as a significant complication in both type 1 (T1D) and type 2 (T2D) diabetic patients. This review examines non-invasive imaging studies that evaluate skeletal outcomes in adults with T1D and T2D, emphasizing distinct skeletal phenotypes linked with each condition and pinpointing gaps in understanding bone health in diabetes. While traditional DXA-BMD does not fully capture the increased fracture risk in diabetes, recent techniques such as quantitative computed tomography (QCT), peripheral QCT (pQCT), high-resolution pqCT (HR-pQCT) and magnetic resonance imaging (MRI) provide insights into 3D bone density, microstructure, and strength. Notably, existing studies present heterogeneous results possibly due to variations in design, outcome measures, and potential misclassification between T1D and T2D. Thus, the true nature of diabetic skeletal fragility is yet to be fully understood. As T1D and T2D are diverse conditions with heterogeneous subtypes, future research should delve deeper into skeletal fragility by diabetic phenotypes, and focus on longitudinal studies in larger, diverse cohorts to elucidate the complex influence of T1D and T2D on bone health and fracture outcomes.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139524644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alinie Pichone, Elicivaldo Lima Juvencio, Bernardo Crespo, Carlos Perez Gomes, Renata de Souza Mendes, Marise Rocha Godinho, Aline Cordeiro Fernandes Ladeira, Maurilo Leite, João Antônio Matheus Guimarães
Spontaneous rupture of the patellar (PTR) and quadriceps (QTR) tendon are infrequent. Systemic diseases such as diabetes mellitus, chronic kidney disease and secondary hyperparathyroidism (SHPT) are risk factors. The present cohort study aimed to evaluate risk factors associated with tendon rupture in hemodialysis (HD) patients with SHPT, as well as outcomes including surgical complications, re-ruptures and fracture. Baseline clinical, laboratorial data and radiographs were analyzed. Patients were followed up from March 2012 to March 2020. One-hundred thirty-one patients (≥18 years of age, on HD ≥ 6 months, with SHPT) were included. Incidence rates of PTR and QTR were 2.3 and 1.7/10000 HD patients/year, respectively. The mean age of patients with tendon rupture was 44.0 ± 11.2 years. These patients exhibited higher serum levels of phosphorus (6.3 ± 1.5 mg/dL vs 5.6 ± 1.1 mg/dL; p = 0.005), parathyroid hormone (2025.7 ± 667.6 pg/mL vs 1728.4 ± 684.8 pg/mL; p = 0.035), and C-reactive-protein (35.4 ± 32.9 mg/dL vs 17 ± 24.5 mg/dL; p = 0.002) compared to the group without tendon rupture. The mean follow-up was 56.7 ± 27.1 months. No patient required a new surgical approach or experienced re-rupture. Of all patients, 31% experienced hip fracture: 50% in the group with rupture (29.5 ± 17.4 months after the tendon rupture) vs 26% without tendon rupture (p = 0.015). After adjustment, the hazard ratio for hip fracture was 2.87 (CI 95% 1.27–6.49; p = 0.012). Patients with SHPT and high levels of phosphorus, parathyroid hormone, and inflammatory markers were at greater risk for tendon rupture. Surgical complication rates were low. However, results suggest that tendon rupture of knee extensor mechanism in hemodialysis patient with SHPT should be regarded as a “red flag” for future hip fracture.
{"title":"Patellar and quadriceps tendon rupture are associated with hip fracture in hemodialysis patients with severe hyperparathyroidism","authors":"Alinie Pichone, Elicivaldo Lima Juvencio, Bernardo Crespo, Carlos Perez Gomes, Renata de Souza Mendes, Marise Rocha Godinho, Aline Cordeiro Fernandes Ladeira, Maurilo Leite, João Antônio Matheus Guimarães","doi":"10.1093/jbmrpl/ziae008","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae008","url":null,"abstract":"\u0000 Spontaneous rupture of the patellar (PTR) and quadriceps (QTR) tendon are infrequent. Systemic diseases such as diabetes mellitus, chronic kidney disease and secondary hyperparathyroidism (SHPT) are risk factors. The present cohort study aimed to evaluate risk factors associated with tendon rupture in hemodialysis (HD) patients with SHPT, as well as outcomes including surgical complications, re-ruptures and fracture. Baseline clinical, laboratorial data and radiographs were analyzed. Patients were followed up from March 2012 to March 2020. One-hundred thirty-one patients (≥18 years of age, on HD ≥ 6 months, with SHPT) were included. Incidence rates of PTR and QTR were 2.3 and 1.7/10000 HD patients/year, respectively. The mean age of patients with tendon rupture was 44.0 ± 11.2 years. These patients exhibited higher serum levels of phosphorus (6.3 ± 1.5 mg/dL vs 5.6 ± 1.1 mg/dL; p = 0.005), parathyroid hormone (2025.7 ± 667.6 pg/mL vs 1728.4 ± 684.8 pg/mL; p = 0.035), and C-reactive-protein (35.4 ± 32.9 mg/dL vs 17 ± 24.5 mg/dL; p = 0.002) compared to the group without tendon rupture. The mean follow-up was 56.7 ± 27.1 months. No patient required a new surgical approach or experienced re-rupture. Of all patients, 31% experienced hip fracture: 50% in the group with rupture (29.5 ± 17.4 months after the tendon rupture) vs 26% without tendon rupture (p = 0.015). After adjustment, the hazard ratio for hip fracture was 2.87 (CI 95% 1.27–6.49; p = 0.012). Patients with SHPT and high levels of phosphorus, parathyroid hormone, and inflammatory markers were at greater risk for tendon rupture. Surgical complication rates were low. However, results suggest that tendon rupture of knee extensor mechanism in hemodialysis patient with SHPT should be regarded as a “red flag” for future hip fracture.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139526376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aleksandar Cirovic, Felix N Schmidt, Marko Vujačić, P. Sihota, Bojan Petrovic, Vladimir Živković, Zoran Bascarevic, S. Nikolić, D. Djonic, M. Djuric, Björn Busse, Petar Milovanovic
There is still limited understanding of the microstructural reasons for the higher susceptibility to fractures in individuals with type 2 diabetes mellitus (T2DM). In this study, we examined bone mineralization, osteocyte lacunar parameters, and microhardness of the femoral neck trabeculae in 18 individuals with T2DM who sustained low-energy fracture (T2DMFx: 78 ± 7 years, 15 women and 3 men) and 20 controls (74 ± 7 years, 16 women and 4 men). Femoral necks of the T2DMFx subjects were obtained at a tertiary orthopedic hospital, while those of the controls were collected at autopsy. T2DMFx individuals had lower trabecular microhardness (p = 0.023) and mineralization heterogeneity (p = 0.001), and a tendency to a lower bone area with mineralization above 95th percentile (p = 0.058) than the controls. There were no significant intergroup differences in the numbers of osteocyte lacunae per bone area, mineralized lacunae per bone area, and total lacunae per bone area (each p > 0.05). After dividing the T2DMFx group based on the presence of vascular complications (VD) to T2DMFxVD (VD present) and T2DMFxNVD (VD absent), we observed that microhardness was particularly reduced in the T2DMFxVD group (vs. control group, p = 0.02), while mineralization heterogeneity was significantly reduced in both T2DMFx subgroups (T2DMFxNVD vs. control, p = 0.002; T2DMFxVD vs. control, p = 0.038). The observed changes in mineralization and microhardness may contribute to the increased hip fracture susceptibility in individuals with T2DM.
{"title":"Lower microhardness along with less heterogeneous mineralization in the femoral neck of individuals with type 2 diabetes mellitus indicates higher fracture risk","authors":"Aleksandar Cirovic, Felix N Schmidt, Marko Vujačić, P. Sihota, Bojan Petrovic, Vladimir Živković, Zoran Bascarevic, S. Nikolić, D. Djonic, M. Djuric, Björn Busse, Petar Milovanovic","doi":"10.1093/jbmrpl/ziae005","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae005","url":null,"abstract":"\u0000 There is still limited understanding of the microstructural reasons for the higher susceptibility to fractures in individuals with type 2 diabetes mellitus (T2DM). In this study, we examined bone mineralization, osteocyte lacunar parameters, and microhardness of the femoral neck trabeculae in 18 individuals with T2DM who sustained low-energy fracture (T2DMFx: 78 ± 7 years, 15 women and 3 men) and 20 controls (74 ± 7 years, 16 women and 4 men). Femoral necks of the T2DMFx subjects were obtained at a tertiary orthopedic hospital, while those of the controls were collected at autopsy. T2DMFx individuals had lower trabecular microhardness (p = 0.023) and mineralization heterogeneity (p = 0.001), and a tendency to a lower bone area with mineralization above 95th percentile (p = 0.058) than the controls. There were no significant intergroup differences in the numbers of osteocyte lacunae per bone area, mineralized lacunae per bone area, and total lacunae per bone area (each p > 0.05). After dividing the T2DMFx group based on the presence of vascular complications (VD) to T2DMFxVD (VD present) and T2DMFxNVD (VD absent), we observed that microhardness was particularly reduced in the T2DMFxVD group (vs. control group, p = 0.02), while mineralization heterogeneity was significantly reduced in both T2DMFx subgroups (T2DMFxNVD vs. control, p = 0.002; T2DMFxVD vs. control, p = 0.038). The observed changes in mineralization and microhardness may contribute to the increased hip fracture susceptibility in individuals with T2DM.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139621866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Corinne E. Metzger, M. Kittaka, Alec N LaPlant, Yasuyoshi Ueki, Matthew R Allen
Skeletal fragility and high fracture rates are common in chronic kidney disease (CKD). A key component of bone loss in CKD with secondary hyperparathyroidism is high bone turnover and cortical bone deterioration through both cortical porosity and cortical thinning. We hypothesized that receptor activator of nuclear factor-κB ligand (RANKL) drives high bone resorption within cortical bone leading to the development of cortical porosity (Study 1) and that systemic inhibition of RANKL would mitigate the skeletal phenotype (Study 2). In Study 1 we assessed the skeletal properties of male and female Dmp1-cre RANKLfl/fl (cKO) and control genotype (Ranklfl/fl; Con) mice after 10 weeks of adenine-induced CKD (AD; 0.2% dietary adenine). All AD mice regardless of sex or genotype had elevated blood urea nitrogen and high parathyroid hormone (PTH). Con AD mice in both sexes had cortical porosity and lower cortical thickness as well as high osteoclast-covered trabecular surfaces and higher bone formation rate. cKO mice had preserved cortical bone microarchitecture despite high circulating PTH as well as no CKD-induced increases in osteoclasts. In Study 2, male mice with established adenine-induced CKD were given a single injection of an anti-RANKL antibody (5 mg/kg) 8 weeks post-induction or 3x/week dosing with risedronate (1.2 μg/kg) for 4 weeks. Anti-RANKL treatment significantly reduced bone formation rate as well as osteoclast surfaces at both trabecular and cortical surfaces; risedronate treatment had little effect on these bone parameters. In conclusion, these studies demonstrate that bone-specific RANKL is critical for the development of high bone formation/high osteoclasts and cortical bone loss in CKD with high PTH. Additionally, systemic anti-RANKL ligand therapy in established CKD may help prevent the propagation of cortical bone loss via suppression of bone turnover.
{"title":"Inhibition of RANKL improves the skeletal phenotype of adenine-induced chronic kidney disease in mice","authors":"Corinne E. Metzger, M. Kittaka, Alec N LaPlant, Yasuyoshi Ueki, Matthew R Allen","doi":"10.1093/jbmrpl/ziae004","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae004","url":null,"abstract":"\u0000 Skeletal fragility and high fracture rates are common in chronic kidney disease (CKD). A key component of bone loss in CKD with secondary hyperparathyroidism is high bone turnover and cortical bone deterioration through both cortical porosity and cortical thinning. We hypothesized that receptor activator of nuclear factor-κB ligand (RANKL) drives high bone resorption within cortical bone leading to the development of cortical porosity (Study 1) and that systemic inhibition of RANKL would mitigate the skeletal phenotype (Study 2). In Study 1 we assessed the skeletal properties of male and female Dmp1-cre RANKLfl/fl (cKO) and control genotype (Ranklfl/fl; Con) mice after 10 weeks of adenine-induced CKD (AD; 0.2% dietary adenine). All AD mice regardless of sex or genotype had elevated blood urea nitrogen and high parathyroid hormone (PTH). Con AD mice in both sexes had cortical porosity and lower cortical thickness as well as high osteoclast-covered trabecular surfaces and higher bone formation rate. cKO mice had preserved cortical bone microarchitecture despite high circulating PTH as well as no CKD-induced increases in osteoclasts. In Study 2, male mice with established adenine-induced CKD were given a single injection of an anti-RANKL antibody (5 mg/kg) 8 weeks post-induction or 3x/week dosing with risedronate (1.2 μg/kg) for 4 weeks. Anti-RANKL treatment significantly reduced bone formation rate as well as osteoclast surfaces at both trabecular and cortical surfaces; risedronate treatment had little effect on these bone parameters. In conclusion, these studies demonstrate that bone-specific RANKL is critical for the development of high bone formation/high osteoclasts and cortical bone loss in CKD with high PTH. Additionally, systemic anti-RANKL ligand therapy in established CKD may help prevent the propagation of cortical bone loss via suppression of bone turnover.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139530527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Beatriz Bermudez, Kenna Brown, G. Vahidi, Ana C F Ruble, Chelsea M Heveran, Cheryl L Ackert-Bicknell, Vanessa Sherk
Western diets are becoming increasingly common around the world. Western diets have high omega 6 (ω-6) and omega 3 (ω-3) fatty acids and are linked to bone loss in humans and animals. Dietary fats are not created equal; therefore, it is vital to understand the effects of specific dietary fats on bone. We aimed to determine how altering the endogenous ratios of ω-6:ω-3 fatty acids impacts bone accrual, strength, and fracture toughness. To accomplish this, we used the Fat-1 transgenic mice, which carry a gene responsible for encoding an ω-3 fatty acid desaturase that converts ω-6 to ω-3 fatty acids. Male and female Fat-1 positive mice (Fat-1) and Fat-1 negative littermates (WT) were given either a high-fat diet (HFD) or low-fat diet (LFD) at 4 weeks of age for 16 weeks. The Fat-1 transgene reduced fracture toughness in males. Additionally, male bone mineral density (BMD), measured from dual-energy x-ray absorptiometry (DXA), decreased over the diet duration for HFD mice. In males, neither HFD feeding nor the presence of the Fat-1 transgene impacted cortical geometry, trabecular architecture, or whole-bone flexural properties, as detected by main group effects. In females, Fat-1-LFD mice experienced increases in BMD compared to WT-LFD mice, however, cortical area, distal femur trabecular thickness, and cortical stiffness were reduced in Fat-1 mice compared to pooled WT controls. However, reductions in stiffness were caused by a decrease in bone size and were not driven by changes in material properties. Together, these results demonstrate that the endogenous ω-6:ω-3 fatty acid ratio influences bone material properties in a sex-dependent manner. In addition, Fat-1 mediated fatty acid conversion was not able to mitigate the adverse effects of HFD on bone strength and accrual.
{"title":"Sex-specific effects of Fat-1 transgene on bone material properties, size, and shape in mice","authors":"Beatriz Bermudez, Kenna Brown, G. Vahidi, Ana C F Ruble, Chelsea M Heveran, Cheryl L Ackert-Bicknell, Vanessa Sherk","doi":"10.1093/jbmrpl/ziad011","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad011","url":null,"abstract":"\u0000 Western diets are becoming increasingly common around the world. Western diets have high omega 6 (ω-6) and omega 3 (ω-3) fatty acids and are linked to bone loss in humans and animals. Dietary fats are not created equal; therefore, it is vital to understand the effects of specific dietary fats on bone. We aimed to determine how altering the endogenous ratios of ω-6:ω-3 fatty acids impacts bone accrual, strength, and fracture toughness. To accomplish this, we used the Fat-1 transgenic mice, which carry a gene responsible for encoding an ω-3 fatty acid desaturase that converts ω-6 to ω-3 fatty acids. Male and female Fat-1 positive mice (Fat-1) and Fat-1 negative littermates (WT) were given either a high-fat diet (HFD) or low-fat diet (LFD) at 4 weeks of age for 16 weeks. The Fat-1 transgene reduced fracture toughness in males. Additionally, male bone mineral density (BMD), measured from dual-energy x-ray absorptiometry (DXA), decreased over the diet duration for HFD mice. In males, neither HFD feeding nor the presence of the Fat-1 transgene impacted cortical geometry, trabecular architecture, or whole-bone flexural properties, as detected by main group effects. In females, Fat-1-LFD mice experienced increases in BMD compared to WT-LFD mice, however, cortical area, distal femur trabecular thickness, and cortical stiffness were reduced in Fat-1 mice compared to pooled WT controls. However, reductions in stiffness were caused by a decrease in bone size and were not driven by changes in material properties. Together, these results demonstrate that the endogenous ω-6:ω-3 fatty acid ratio influences bone material properties in a sex-dependent manner. In addition, Fat-1 mediated fatty acid conversion was not able to mitigate the adverse effects of HFD on bone strength and accrual.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139440019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Madison M Kelly, Karan Sharma, Christian S. Wright, Xin Yi, Perla C. Reyes Fernandez, Aaron T Gegg, Taylor A Gorrell, Megan L. Noonan, A. Baghdady, Jacob A Sieger, Annette C Dolphin, Stuart J Warden, Padmini J. Deosthale, Lilian I Plotkin, Uma Sankar, J. Hum, A. Robling, M. Farach-Carson, William R. Thompson
Voltage sensitive calcium channels (VSCCs) influence bone structure and function, including anabolic responses to mechanical loading. While the pore-forming (α1) subunit of VSCCs allows Ca2+ influx, auxiliary subunits regulate the biophysical properties of the pore. The α2δ1 subunit influences gating kinetics of the α1 pore and enables mechanically induced signaling in osteocytes; however, the skeletal function of α2δ1 in vivo remains unknown. In this work, we examined the skeletal consequences of deleting Cacna2d1, the gene encoding α2δ1. Dual energy X-ray absorptiometry (DEXA) and microcomputed tomography (μCT) imaging demonstrated that deletion of α2δ1 diminished bone mineral content and density in both male and female C57BL/6 mice. Structural differences manifested in both trabecular and cortical bone for males, while the absence of α2δ1 affected only cortical bone in female mice. Deletion of α2δ1 impaired skeletal mechanical properties in both sexes, as measured by three-point bending to failure. While no changes in osteoblast number or activity were found for either sex, male mice displayed a significant increase in osteoclast number, accompanied by increased eroded bone surface and upregulation of genes that regulate osteoclast differentiation. Deletion of α2δ1 also rendered the skeleton insensitive to exogenous mechanical loading in males. While previous work demonstrates that VSCCs are essential for anabolic responses to mechanical loading, the mechanism by which these channels sense and respond to force remained unclear. Our data demonstrate that the α2δ1 auxiliary VSCC subunit functions to maintain baseline bone mass and strength through regulation of osteoclast activity, and also provides skeletal mechanotransduction in male mice. These data reveal a molecular player in our understanding of the mechanisms by which VSCCs influence skeletal adaptation.
{"title":"Loss of the auxiliary α2δ1 voltage sensitive Calcium Channel subunit impairs bone formation and anabolic responses to mechanical loading","authors":"Madison M Kelly, Karan Sharma, Christian S. Wright, Xin Yi, Perla C. Reyes Fernandez, Aaron T Gegg, Taylor A Gorrell, Megan L. Noonan, A. Baghdady, Jacob A Sieger, Annette C Dolphin, Stuart J Warden, Padmini J. Deosthale, Lilian I Plotkin, Uma Sankar, J. Hum, A. Robling, M. Farach-Carson, William R. Thompson","doi":"10.1093/jbmrpl/ziad008","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad008","url":null,"abstract":"\u0000 Voltage sensitive calcium channels (VSCCs) influence bone structure and function, including anabolic responses to mechanical loading. While the pore-forming (α1) subunit of VSCCs allows Ca2+ influx, auxiliary subunits regulate the biophysical properties of the pore. The α2δ1 subunit influences gating kinetics of the α1 pore and enables mechanically induced signaling in osteocytes; however, the skeletal function of α2δ1 in vivo remains unknown. In this work, we examined the skeletal consequences of deleting Cacna2d1, the gene encoding α2δ1. Dual energy X-ray absorptiometry (DEXA) and microcomputed tomography (μCT) imaging demonstrated that deletion of α2δ1 diminished bone mineral content and density in both male and female C57BL/6 mice. Structural differences manifested in both trabecular and cortical bone for males, while the absence of α2δ1 affected only cortical bone in female mice. Deletion of α2δ1 impaired skeletal mechanical properties in both sexes, as measured by three-point bending to failure. While no changes in osteoblast number or activity were found for either sex, male mice displayed a significant increase in osteoclast number, accompanied by increased eroded bone surface and upregulation of genes that regulate osteoclast differentiation. Deletion of α2δ1 also rendered the skeleton insensitive to exogenous mechanical loading in males. While previous work demonstrates that VSCCs are essential for anabolic responses to mechanical loading, the mechanism by which these channels sense and respond to force remained unclear. Our data demonstrate that the α2δ1 auxiliary VSCC subunit functions to maintain baseline bone mass and strength through regulation of osteoclast activity, and also provides skeletal mechanotransduction in male mice. These data reveal a molecular player in our understanding of the mechanisms by which VSCCs influence skeletal adaptation.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139440525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Connor Devine, Kenna Brown, Kat O Patton, Chelsea M Heveran, Stephen A Martin
Advancing age is the strongest risk factor for osteoporosis and skeletal fragility. Rapamycin is an FDA approved immunosuppressant that inhibits the mechanistic target of rapamycin (mTOR) complex, extends lifespan, and protects against aging-related diseases in multiple species; however, the impact of rapamycin on skeletal tissue is incompletely understood. We evaluated the effects of a short-term, low-dosage, interval rapamycin treatment on bone microarchitecture and strength in young-adult (3-months-old) and aged female (20-months-old) C57BL/6 mice. Rapamycin (2 mg/kg body mass) was administered via intraperitoneal injection 1x/5 days for a duration of 8 weeks; this treatment regimen has been shown to induce geroprotective effects while minimizing the side-effects associated with higher rapamycin dosages and/or more frequent or prolonged delivery schedules. Aged femurs exhibited lower cancellous bone mineral density, volume, trabecular connectivity density and number, higher trabecular thickness and spacing, and lower cortical thickness compared to young-adult mice. Rapamycin had no impact on assessed microCT parameters. Flexural testing of the femur revealed yield strength and ultimate strength were lower in aged mice compared to young-adult mice. There were no effects of rapamycin on these or other measures of bone biomechanics. Age, but not rapamycin, altered local and global measures of bone turnover. These data demonstrate a short-term, low-dosage, interval, rapamycin treatment does not negatively or positively impact the skeleton of young-adult and aged mice.
{"title":"Rapamycin does not alter bone microarchitecture or material properties quality in young-adult and aged female C57BL/6 mice","authors":"Connor Devine, Kenna Brown, Kat O Patton, Chelsea M Heveran, Stephen A Martin","doi":"10.1093/jbmrpl/ziae001","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae001","url":null,"abstract":"\u0000 Advancing age is the strongest risk factor for osteoporosis and skeletal fragility. Rapamycin is an FDA approved immunosuppressant that inhibits the mechanistic target of rapamycin (mTOR) complex, extends lifespan, and protects against aging-related diseases in multiple species; however, the impact of rapamycin on skeletal tissue is incompletely understood. We evaluated the effects of a short-term, low-dosage, interval rapamycin treatment on bone microarchitecture and strength in young-adult (3-months-old) and aged female (20-months-old) C57BL/6 mice. Rapamycin (2 mg/kg body mass) was administered via intraperitoneal injection 1x/5 days for a duration of 8 weeks; this treatment regimen has been shown to induce geroprotective effects while minimizing the side-effects associated with higher rapamycin dosages and/or more frequent or prolonged delivery schedules. Aged femurs exhibited lower cancellous bone mineral density, volume, trabecular connectivity density and number, higher trabecular thickness and spacing, and lower cortical thickness compared to young-adult mice. Rapamycin had no impact on assessed microCT parameters. Flexural testing of the femur revealed yield strength and ultimate strength were lower in aged mice compared to young-adult mice. There were no effects of rapamycin on these or other measures of bone biomechanics. Age, but not rapamycin, altered local and global measures of bone turnover. These data demonstrate a short-term, low-dosage, interval, rapamycin treatment does not negatively or positively impact the skeleton of young-adult and aged mice.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139440288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aliya A Khan, Lisa G Abbott, Intekhab Ahmed, O. Ayodele, Claudia Gagnon, Richard D Finkelman, Emese Mezosi, Lars Rejnmark, Istvan Takacs, Shaoming Yin, Steven W Ing
Hypoparathyroidism is a rare disease, often inadequately controlled by conventional treatment. PARALLAX was a mandatory post-marketing trial assessing pharmacokinetics and pharmacodynamics of different dosing regimens of recombinant human parathyroid hormone 1–84 (rhPTH[1–84]) for treating hypoparathyroidism. The present study (NCT03364738) was a Phase 4, 1-year open-label extension of PARALLAX. Patients received only two doses of rhPTH(1–84) in PARALLAX and were thus considered treatment-naive at the start of the current study. rhPTH(1–84) was initiated at 50 μg once daily, with doses adjusted based on albumin-corrected serum calcium levels. Albumin-corrected serum calcium (primary outcome measure), health-related quality of life (HRQoL), adverse events, and healthcare resource utilization (HCRU) were assessed. The mean age of the 22 patients included was 50.0 years; 81.8% were women, and 90.9% were White. By end of treatment (EOT), 95.5% of patients had albumin-corrected serum calcium values in the protocol-defined primary endpoint range of 1.88 mmol/L to the upper limit of normal. Serum phosphorus was within the healthy range, and albumin-corrected serum calcium-phosphorus product was below the upper healthy limit throughout, while mean 24-hour urine calcium excretion decreased from baseline to EOT. Mean supplemental doses of calcium and active vitamin D were reduced from baseline to EOT (2402–855 mg/day and 0.8–0.2 μg/day, respectively). Mean serum bone turnover markers, bone-specific alkaline phosphatase, osteocalcin, procollagen type I N-terminal propeptide, and type I collagen C-telopeptide increased 2–5 fold from baseline to EOT. HCRU, disease-related symptoms and impact on HRQoL improved numerically between baseline and EOT. Nine patients (40.9%) experienced treatment-related adverse events; no deaths were reported. Treatment with rhPTH(1–84) once daily for 1 year improved HRQoL, maintained eucalcemia in 95% of patients, normalized serum phosphorus, and decreased urine calcium excretion. The effects observed on urine calcium and the safety profile are consistent with previous findings.
{"title":"Open-label extension of a randomized trial investigating safety and efficacy of rhPTH(1–84) in hypoparathyroidism","authors":"Aliya A Khan, Lisa G Abbott, Intekhab Ahmed, O. Ayodele, Claudia Gagnon, Richard D Finkelman, Emese Mezosi, Lars Rejnmark, Istvan Takacs, Shaoming Yin, Steven W Ing","doi":"10.1093/jbmrpl/ziad010","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad010","url":null,"abstract":"\u0000 Hypoparathyroidism is a rare disease, often inadequately controlled by conventional treatment. PARALLAX was a mandatory post-marketing trial assessing pharmacokinetics and pharmacodynamics of different dosing regimens of recombinant human parathyroid hormone 1–84 (rhPTH[1–84]) for treating hypoparathyroidism. The present study (NCT03364738) was a Phase 4, 1-year open-label extension of PARALLAX. Patients received only two doses of rhPTH(1–84) in PARALLAX and were thus considered treatment-naive at the start of the current study. rhPTH(1–84) was initiated at 50 μg once daily, with doses adjusted based on albumin-corrected serum calcium levels. Albumin-corrected serum calcium (primary outcome measure), health-related quality of life (HRQoL), adverse events, and healthcare resource utilization (HCRU) were assessed. The mean age of the 22 patients included was 50.0 years; 81.8% were women, and 90.9% were White. By end of treatment (EOT), 95.5% of patients had albumin-corrected serum calcium values in the protocol-defined primary endpoint range of 1.88 mmol/L to the upper limit of normal. Serum phosphorus was within the healthy range, and albumin-corrected serum calcium-phosphorus product was below the upper healthy limit throughout, while mean 24-hour urine calcium excretion decreased from baseline to EOT. Mean supplemental doses of calcium and active vitamin D were reduced from baseline to EOT (2402–855 mg/day and 0.8–0.2 μg/day, respectively). Mean serum bone turnover markers, bone-specific alkaline phosphatase, osteocalcin, procollagen type I N-terminal propeptide, and type I collagen C-telopeptide increased 2–5 fold from baseline to EOT. HCRU, disease-related symptoms and impact on HRQoL improved numerically between baseline and EOT. Nine patients (40.9%) experienced treatment-related adverse events; no deaths were reported. Treatment with rhPTH(1–84) once daily for 1 year improved HRQoL, maintained eucalcemia in 95% of patients, normalized serum phosphorus, and decreased urine calcium excretion. The effects observed on urine calcium and the safety profile are consistent with previous findings.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139381269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Julia Eazer, Mina‐Michael Barsoum, Cole Smith, Kazuki Hotta, Brad Behnke, Christina Holmes, Jacob Caldwell, Payal Ghosh, Emily Reid‐Foley, Hyerim Park, Michael Delp, Judy Muller-Delp
The magnitude of bone formation and remodeling is linked to both the magnitude of strain placed on the bone and the perfusion of bone. It was previously reported that an increase in bone perfusion and bone density occurs in the femur of old rats with moderate aerobic exercise training. This study determined the acute and chronic effects of static muscle stretching on bone blood flow and remodeling. Old male Fischer 344 rats were randomized to either a naïve or stretch-trained group. Static stretching of ankle flexor muscles was achieved by placement of a dorsiflexion splint on the left ankle for 30 min/day, 5d/wk for 4wks. The opposite hindlimb served as a contralateral control (nonstretched) limb. Bone blood flow was assessed during and after acute stretching in naïve rats, and at rest and during exercise in stretch-trained rats. Vascular reactivity of the nutrient artery of the proximal tibia was also assessed in stretch-trained rats. MicroCT analysis was used to assess bone volume and micro-architecture of the trabecular bone of both tibias near that growth plate. In naïve rats, static stretching increased blood flow to the proximal tibial metaphasis. Blood flow to the proximal tibial metaphysis during treadmill exercise was higher in the stretched limb after 4 weeks of daily stretching. Daily stretching also increased tibial bone weight and increased total volume in both the proximal and distal tibial metaphyses. In the trabecular bone immediately below the proximal tibial growth plate, total volume and bone volume increased, but bone volume/total volume was unchanged and trabecular connectivity decreased. In contrast, intravascular volume increased in this region of the bone. These data suggest that blood flow to the tibia increases during bouts of static stretching of the hindlimb muscles, and that 4 weeks of daily muscle stretching leads to bone remodeling and an increase in intravascular volume of the tibial bone.
{"title":"Adaptations of bone and bone vasculature to muscular stretch training","authors":"Julia Eazer, Mina‐Michael Barsoum, Cole Smith, Kazuki Hotta, Brad Behnke, Christina Holmes, Jacob Caldwell, Payal Ghosh, Emily Reid‐Foley, Hyerim Park, Michael Delp, Judy Muller-Delp","doi":"10.1093/jbmrpl/ziad019","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad019","url":null,"abstract":"\u0000 The magnitude of bone formation and remodeling is linked to both the magnitude of strain placed on the bone and the perfusion of bone. It was previously reported that an increase in bone perfusion and bone density occurs in the femur of old rats with moderate aerobic exercise training. This study determined the acute and chronic effects of static muscle stretching on bone blood flow and remodeling. Old male Fischer 344 rats were randomized to either a naïve or stretch-trained group. Static stretching of ankle flexor muscles was achieved by placement of a dorsiflexion splint on the left ankle for 30 min/day, 5d/wk for 4wks. The opposite hindlimb served as a contralateral control (nonstretched) limb. Bone blood flow was assessed during and after acute stretching in naïve rats, and at rest and during exercise in stretch-trained rats. Vascular reactivity of the nutrient artery of the proximal tibia was also assessed in stretch-trained rats. MicroCT analysis was used to assess bone volume and micro-architecture of the trabecular bone of both tibias near that growth plate. In naïve rats, static stretching increased blood flow to the proximal tibial metaphasis. Blood flow to the proximal tibial metaphysis during treadmill exercise was higher in the stretched limb after 4 weeks of daily stretching. Daily stretching also increased tibial bone weight and increased total volume in both the proximal and distal tibial metaphyses. In the trabecular bone immediately below the proximal tibial growth plate, total volume and bone volume increased, but bone volume/total volume was unchanged and trabecular connectivity decreased. In contrast, intravascular volume increased in this region of the bone. These data suggest that blood flow to the tibia increases during bouts of static stretching of the hindlimb muscles, and that 4 weeks of daily muscle stretching leads to bone remodeling and an increase in intravascular volume of the tibial bone.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139387496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ilka Maus, M. Dreiner, Sebastian Zetzsche, F. Metzen, Bryony C Ross, D. Mählich, M. Koch, Anja Niehoff, Brunhilde Wirth
PLS3 loss-of-function mutations in humans and mice cause X-linked primary osteoporosis. However, it remains largely unknown how PLS3 mutations cause osteoporosis and which function PLS3 plays in bone homeostasis. A recent study showed that the ubiquitous Pls3 KO in mice results in osteoporosis with decreased bone thickness and stiffness. In these mice, mainly osteoclasts were impacted in their function, exhibiting increased resorptive activity and altered podosome formation through a misregulation of the NFκB pathway. Specifically, Pls3 KO caused the decreased nuclear localization of its interaction partner NFκB repressing factor, NKRF, thereby augmenting Nfatc1 transcription. However, it has not been proven if, indeed, the osteoclasts are the major cell type affected and responsible for the osteoporosis development in ubiquitous Pls3 KO mice. Here, we generated osteoclast-specific Pls3 KO female (Pls3fl/fl; LysMCretg/0) and male (Pls3fl;LysMCretg/0) mice and demonstrate specific PLS3 loss in cultured osteoclasts. In addition, we developed a novel polyclonal PLS3 antibody that showed for the first time specific PLS3 loss in immunofluorescence staining of osteoclasts in contrast to previously available antibodies against PLS3 that failed to show PLS3-specificity in mouse cells. Moreover, we demonstrate that the osteoclast-specific Pls3 KO causes a dramatic increase in the resorptive activity of osteoclasts in vitro. Despite this pronounced effect on osteoclast resorption activity, osteoclast-specific Pls3 KO in vivo failed to cause any osteoporotic phenotype in 12-, 24-, and 48-week-old mice as proven by micro-CT and three-point bending test. These results demonstrate that the pathomechanism of PLS3-associated osteoporosis is highly complex and cannot be reproduced in a system singularly focused on one cell type, leading us to conclude that the loss of PLS3 in alternative bone cell types, such as osteoblasts and osteocytes contributes to the osteoporosis phenotype in ubiquitous Pls3 KO mice.
人类和小鼠的 PLS3 功能缺失突变会导致 X 连锁原发性骨质疏松症。然而，人们对 PLS3 突变如何导致骨质疏松症以及 PLS3 在骨稳态中发挥何种功能仍然知之甚少。最近的一项研究表明，小鼠中无处不在的 Pls3 KO 会导致骨质疏松症，骨厚度和硬度下降。在这些小鼠中，主要是破骨细胞的功能受到影响，表现出更强的吸收活性，并通过 NFκB 通路的误调改变了荚膜体的形成。具体来说，Pls3 KO导致其相互作用伙伴NFκB抑制因子NKRF的核定位减少，从而增强了Nfatc1的转录。然而，尚未证实破骨细胞是否是受影响的主要细胞类型，以及是否是导致无处不在的 Pls3 KO 小鼠发生骨质疏松症的原因。在这里，我们产生了破骨细胞特异性 Pls3 KO 雌性（Pls3fl/fl; LysMCretg/0）和雄性（Pls3fl;LysMCretg/0）小鼠，并在培养的破骨细胞中证明了特异性 PLS3 缺失。此外，我们还开发了一种新型多克隆 PLS3 抗体，该抗体首次在破骨细胞的免疫荧光染色中显示出特异性 PLS3 缺失，而之前可用的 PLS3 抗体未能在小鼠细胞中显示出 PLS3 特异性。此外，我们还证明，破骨细胞特异性 Pls3 KO 会导致体外破骨细胞的吸收活性急剧增加。尽管对破骨细胞的吸收活性有明显的影响，但通过显微 CT 和三点弯曲试验证明，体内破骨细胞特异性 Pls3 KO 在 12 周龄、24 周龄和 48 周龄的小鼠中均未导致任何骨质疏松表型。这些结果表明，与 PLS3 相关的骨质疏松症的病理机制非常复杂，无法在一个只关注一种细胞类型的系统中再现，因此我们得出结论，在其他骨细胞类型（如成骨细胞和骨细胞）中 PLS3 的缺失导致了无处不在的 Pls3 KO 小鼠的骨质疏松症表型。
{"title":"Osteoclast-specific Plastin 3 knockout in mice fail to develop osteoporosis despite dramatic increased osteoclast resorption activity","authors":"Ilka Maus, M. Dreiner, Sebastian Zetzsche, F. Metzen, Bryony C Ross, D. Mählich, M. Koch, Anja Niehoff, Brunhilde Wirth","doi":"10.1093/jbmrpl/ziad009","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad009","url":null,"abstract":"\u0000 PLS3 loss-of-function mutations in humans and mice cause X-linked primary osteoporosis. However, it remains largely unknown how PLS3 mutations cause osteoporosis and which function PLS3 plays in bone homeostasis. A recent study showed that the ubiquitous Pls3 KO in mice results in osteoporosis with decreased bone thickness and stiffness. In these mice, mainly osteoclasts were impacted in their function, exhibiting increased resorptive activity and altered podosome formation through a misregulation of the NFκB pathway. Specifically, Pls3 KO caused the decreased nuclear localization of its interaction partner NFκB repressing factor, NKRF, thereby augmenting Nfatc1 transcription. However, it has not been proven if, indeed, the osteoclasts are the major cell type affected and responsible for the osteoporosis development in ubiquitous Pls3 KO mice.\u0000 Here, we generated osteoclast-specific Pls3 KO female (Pls3fl/fl; LysMCretg/0) and male (Pls3fl;LysMCretg/0) mice and demonstrate specific PLS3 loss in cultured osteoclasts. In addition, we developed a novel polyclonal PLS3 antibody that showed for the first time specific PLS3 loss in immunofluorescence staining of osteoclasts in contrast to previously available antibodies against PLS3 that failed to show PLS3-specificity in mouse cells. Moreover, we demonstrate that the osteoclast-specific Pls3 KO causes a dramatic increase in the resorptive activity of osteoclasts in vitro. Despite this pronounced effect on osteoclast resorption activity, osteoclast-specific Pls3 KO in vivo failed to cause any osteoporotic phenotype in 12-, 24-, and 48-week-old mice as proven by micro-CT and three-point bending test. These results demonstrate that the pathomechanism of PLS3-associated osteoporosis is highly complex and cannot be reproduced in a system singularly focused on one cell type, leading us to conclude that the loss of PLS3 in alternative bone cell types, such as osteoblasts and osteocytes contributes to the osteoporosis phenotype in ubiquitous Pls3 KO mice.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139450710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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