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Nirwan N, Jain S, Vohora D. Linagliptin-metformin combination: A novel approach to mitigate 4-vinyl cyclohexene di epoxide and dexamethasone-induced osteoporosis in mice. Bone 2025; 198:117526. [PMID: 40398630 DOI: 10.1016/j.bone.2025.117526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 05/13/2025] [Accepted: 05/15/2025] [Indexed: 05/23/2025]
Abstract
Elevated levels of dipeptidyl-peptidase (DPP-4) enzyme, associated with accelerated bone resorption, are linked to both post-menopausal osteoporosis (PMO) and glucocorticoid-induced osteoporosis (GIO). Consequently, DPP-4 inhibitors, a class of anti-diabetic drugs, emerge as potential candidates for repurposing as anti-osteoporotic agents. In this study, we explored the effect of 4-week treatment with linagliptin (a DPP-4 inhibitor) and its combination with metformin on PMO and GIO in mice. PMO was induced in Balb/c mice by injecting 4-vinyl cyclohexene diepoxide (VCD), 160 mg/kg, ip for 15 days while GIO was induced by administering dexamethasone (DEX) 5 mg/kg, ip for 21 days. A significant improvement in bone architectural parameters and bone mineral density (BMD) was observed following the linagliptin-metformin combination, which was consistent with the altered bone turnover markers i.e., increased ALP, osteocalcin, BMP-2, and reduced serum calcium, TRAP, sclerostin and pro-inflammatory cytokines. Results from bone immunohistochemistry (IHC) demonstrated that the combination led to an increase in immunopositive OPG cells, while RANKL expression was diminished. Linagliptin, however, demonstrated only partial improvement in the PMO model. Conversely, in the GIO model, linagliptin did not show a significant effect except for improved BMD and sclerostin levels. Treatment with metformin did not show significant changes in either model. These findings suggest that the combination of linagliptin with metformin could alleviate the PMO and GIO, possibly through targeting AMPK and Wnt signaling pathway and thereby modulating BMP-2, sclerostin and RANKL/OPG.
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Affiliation(s)
- Nikita Nirwan
- Neurobehavioral Pharmacology Laboratory, Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Shreshta Jain
- Neurobehavioral Pharmacology Laboratory, Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Divya Vohora
- Neurobehavioral Pharmacology Laboratory, Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
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Jakob F, Hennen S, Gautrois M, Khalil F, Lockhart A. Novel selective glucocorticoid receptor modulator GRM-01 demonstrates dissociation of anti-inflammatory effects from adverse effects on glucose and bone metabolism. Front Pharmacol 2025; 16:1542351. [PMID: 40110125 PMCID: PMC11920646 DOI: 10.3389/fphar.2025.1542351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 02/10/2025] [Indexed: 03/22/2025] Open
Abstract
Introduction The development of selective GR agonist and modulators (SEGRAMs) aimed to minimize the adverse effects of chronic glucocorticoid treatment (e.g., hyperglycemia and osteoporosis) by separating the transactivation and transrepression activities of the glucocorticoid receptor (GR). Herein we report the pharmacologic profile of clinical candidate GRM-01, a novel, orally available, non-steroidal SEGRAM. Methods In vitro GR, progesterone receptor (PR), and mineralocorticoid receptor (MR) binding and reporter gene assays were conducted to determine GRM-01 potency and selectivity. Anti-inflammatory effects were investigated in vitro using functional assays in rat and human whole blood, human lung cells, and primary fibroblast-like synoviocytes from human donors with rheumatoid arthritis. In vitro assays measured tyrosine aminotransferase [TAT] activity in human hepatocytes and osteoprotegerin release from human osteoblasts as markers of glucose and bone metabolism, respectively. In vivo studies examined the effect of GRM-01 on biomarkers in a rat model of inflammation and on cortisol levels in Cynomolgus monkeys. Animal pharmacokinetics (PK) for GRM-01 were determined and used to predict its human PK. Results GRM-01 is a potent and selective ligand of human GR versus human PR and MR (inhibition constant = 12 vs. 3,700 and >10,000 nM, respectively). GRM-01 displayed partial induction (transactivation) at the GR (half-maximal effective concentration [EC50] = 60.2 nM, efficacy 31.8%) versus prednisolone (EC50 = 24.3 nM, efficacy 80.5%). GRM-01 demonstrated anti-inflammatory efficacy, inhibiting tumor necrosis factor-α and interferon-γ release in whole blood assays, and interleukin-6 release in cellular assays. GRM-01 weakly increased TAT activity in HepG2 cells (efficacy 14.0% vs. 92.4% with prednisolone) and partially inhibited osteoprotegerin release in MG-63 cells (by 58% vs. 100%). In vivo, GRM-01 dose-dependently reduced rat ankle swelling, had anti-nociceptive effects, and did not increase blood glucose. In Cynomolgus monkeys, GRM-01 dose-dependently reduced plasma cortisol. Animal PK found that GRM-01 had high oral bioavailability, generally low clearance, and good tissue partitioning. The predicted human total plasma clearance of GRM-01 was 0.25 mL/min/kg, volume of distribution 2.124 L/kg, and half-life ∼98 h. Conclusion GRM-01 displays a favorable preclinical pharmacologic profile consistent with a SEGRAM, and based on this is currently in Phase 1 development.
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Affiliation(s)
- Florian Jakob
- Research and Development, Grünenthal GmbH, Aachen, Germany
| | | | | | - Feras Khalil
- Research and Development, Grünenthal GmbH, Aachen, Germany
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Sen P, Uday S. Bone Health in Paediatric Inflammatory Bowel Disease. Diagnostics (Basel) 2025; 15:580. [PMID: 40075827 PMCID: PMC11899547 DOI: 10.3390/diagnostics15050580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 02/17/2025] [Accepted: 02/22/2025] [Indexed: 03/14/2025] Open
Abstract
Paediatric inflammatory bowel disease (IBD) is often complicated by bone loss resulting in an increased risk of fractures and impaired quality of life. Underlying inflammation, nutritional deficiencies and glucocorticoid therapy are some of the factors contributing to secondary osteoporosis in IBD. Optimising nutrition, dietary supplementation and timely screening are essential in preventing bone loss. Bisphosphonate therapy remains the cornerstone of medical management of osteoporosis. This review explores the various mechanisms contributing towards poor bone health in IBD and the recent advances in diagnostic and preventive approaches along with updates in management strategies.
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Affiliation(s)
- Proteek Sen
- Department of Endocrinology and Diabetes, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham B4 6NH, UK;
| | - Suma Uday
- Department of Endocrinology and Diabetes, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham B4 6NH, UK;
- Department of Metabolism and Systems Science, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
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Lee S, Hong N, Cho SJ, Shin S, Rhee Y. Effect of romosozumab on bone mineral density and trabecular bone score in premenopausal women with low bone mass. Osteoporos Int 2025; 36:323-331. [PMID: 39812671 DOI: 10.1007/s00198-024-07336-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 12/03/2024] [Indexed: 01/16/2025]
Abstract
We investigated the efficacy of romosozumab in premenopausal women with low bone mass. Romosozumab substantially increased bone mineral density and trabecular bone score in these women, aligning with its proven therapeutic benefits for postmenopausal osteoporosis. PURPOSE Romosozumab, an anti-sclerostin antibody, is a promising anabolic agent that increases bone formation and decreases bone resorption. However, its efficacy in premenopausal women with low bone mass remains understudied. METHODS We retrospectively reviewed premenopausal women with low bone mass treated with romosozumab (ROMO group) or drug-naïve patients (control group). Patients in the ROMO group were classified into the glucocorticoid-induced osteoporosis (GIOP), idiopathic osteoporosis (IOP), and pregnancy and lactation-induced osteoporosis (PLO) subgroups. Bone mineral density (BMD) and trabecular bone score (TBS) were measured before and after one year of romosozumab treatment. RESULTS Twenty-five patients in the ROMO group and five in the control group were included in the study. Among patients in the ROMO group, 12 were in the GIOP, 9 in the IOP, and 4 in the PLO subgroups. The mean age was 37.0 years [32.0-42.0], and the median body mass index was 18.8 kg/m2 [17.5-21.3]. After romosozumab treatment, lumbar spine (LS), femur neck (FN) BMD, and TBS increased from baseline (LSBMD, 12.8% [8.2-19.3], p < 0.001; FNBMD, 4.6% [- 0.6-10.7], p = 0.016; TBS, 4.1% ± 3.8, p < 0.001) in the ROMO group. Patients in both the GIOP and IOP subgroups showed a significant increase in LSBMD, while those in the IOP subgroup demonstrated significant increases in FNBMD. CONCLUSION We demonstrated romosozumab's efficacy in BMD increment in premenopausal women. Romosozumab may be a potential treatment option for premenopausal women with low bone mass, regardless of etiologies, although further research on fracture risk reduction is warranted.
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Affiliation(s)
- Seunghyun Lee
- Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Namki Hong
- Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Sung Joon Cho
- Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Sungjae Shin
- Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Department of Internal Medicine, Endocrine Research Institute, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea
| | - Yumie Rhee
- Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
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Xie W, Wan WT, Liu SY, Wang JQ, Chen C, Sun X, Liu XY, Yang Q. Causal effects of the RANK-RANKL-OPG system and scoliosis: A bidirectional 2-sample Mendelian randomization study. Medicine (Baltimore) 2024; 103:e40934. [PMID: 39686424 PMCID: PMC11651458 DOI: 10.1097/md.0000000000040934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 11/24/2024] [Indexed: 12/18/2024] Open
Abstract
Epidemiological studies and a recent Mendelian randomization (MR) study have identified an association between low bone mass and an increased risk of scoliosis. Previous research suggests that bone loss in patients with scoliosis may be related to the RANK-RANKL-OPG system. This study is to investigate whether a causal relationship exists between the RANK-RANKL-OPG system and the development of scoliosis. Genome-wide association study (GWAS) data for RANK and RANKL were sourced from the UK Biobank's Pharmaceutical Proteomics Project, while OPG data were derived from 2 independent cohorts, and scoliosis data from the FinnGen R10 database. A bidirectional 2-sample MR framework was applied to investigate causal relationships between OPG, RANK, RANKL, and scoliosis, with inverse variance weighting (IVW) as the main analytical method. Meta-analysis was used to integrate findings across cohorts, and multiple sensitivity analyses were conducted to assess the robustness and reliability of the results. According to the IVW results, there was no significant causal relationship between RANK (OR = 0.973, 95% CI = 0.871-1.087, P = .626) and RANKL (OR = 1.048, 95% CI = 0.938-1.171, P = .411) and scoliosis. OPG is a potential protective factor for scoliosis (Folkersen 2020 OR = 0.739, 95% CI = 0.611-0.893, P = .002; Zhao 2023 OR = 0.833, 95% CI = 0.716-0.968, P = .017).The results of Meta-analysis also showed OPG (P = 1.428e-4) would reduce the risk of scoliosis. Inverse MR analysis showed no statistically significant causal relationship between scoliosis and RANK, RANKL and OPG levels (P > .05). Our study employing MR methodology provides robust evidence supporting a causal relationship between decreased osteoprotegerin (OPG) levels and increased susceptibility to scoliosis. However, no significant relationship was found between scoliosis with the RANK-RANKL-OPG system. This research establishes a basis for further exploration of the pathophysiological mechanisms and potential targeted treatments for scoliosis. Future studies are necessary to understand how OPG influences the development of scoliosis.
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Affiliation(s)
- Wei Xie
- Department of Spine Surgery, Tianjin Hospital, Tianjin University, Tianjin, China
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Sport, Exercise & Health, Tianjin University of Sport, Tianjin, China
| | - Wen-Tao Wan
- Department of Spine Surgery, Tianjin Hospital, Tianjin University, Tianjin, China
- Graduate School, Tianjin Medical University, Tianjin, China
| | - Shuai-Yi Liu
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Sport, Exercise & Health, Tianjin University of Sport, Tianjin, China
| | - Jia-Qi Wang
- The First Clinical Medical College, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China
| | - Chao Chen
- Department of Spine Surgery, Tianjin Hospital, Tianjin University, Tianjin, China
| | - Xun Sun
- Department of Spine Surgery, Tianjin Hospital, Tianjin University, Tianjin, China
| | - Xin-Yu Liu
- Department of Orthopedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopedics, Advanced Medical Research Institute, Jinan, Shandong, China
| | - Qiang Yang
- Department of Spine Surgery, Tianjin Hospital, Tianjin University, Tianjin, China
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Yu T, Chen M, Wen J, Liu J, Li K, Jin L, Yue J, Yang Z, Xi J. The effects of all-trans retinoic acid on prednisolone-induced osteoporosis in zebrafish larvae. Bone 2024; 189:117261. [PMID: 39303930 DOI: 10.1016/j.bone.2024.117261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/15/2024] [Accepted: 09/17/2024] [Indexed: 09/22/2024]
Abstract
Glucocorticoids (GCs) are extensively used as anti-inflammatory and immunosuppressive medications in the long-term treatment of rheumatic disorders, respiratory diseases, renal diseases, and organ transplantation. Prolonged use of GCs can reduce bone mineral density, leading to osteoporosis (Glucocorticoid Induced Osteoporosis, GIOP) and fracture. All-trans retinoic acid (ATRA) is an active vitamin A metabolite that regulates embryonic development and adult organ function. ATRA has been found in studies to enhance osteogenesis. To examine the interventional effects of ATRA on GIOP and the mechanisms of ATRA activities, we first performed bioinformatic analysis to identify potential gene targets of ATRA. Zebrafish larvae were recruited as experimental animals, and the frequently used GC, prednisolone, was administered to larvae to construct a GIOP model. We evaluated the influence of exogenous ATRA on the activities of bone metabolic enzymes, the expression of genes linked to osteoblasts and osteoclasts, and the restoration of bone mineral density and bone mass in GIOP zebrafish larvae. Furthermore, we studied the influence of RBM14, a transcriptional coactivator and negative reciprocal factor of ATRA, on the regulation of osteoblastic gene expression during the anti-GIOP process of ATRA using the morpholino knockdown approach. The findings of bone metabolic enzyme activity (alkaline phosphatase, ALP and tartrate-resistant acid phosphatase, TRAP) and expression assays of osteoblastic marker genes (Runx2a, Runx2b, SP7, Csf1a, RANKL, and CTSK) indicated that ATRA had bidirectional effects on osteogenesis. However, in the GIOP model, ATRA reversed the GIOP-induced osteoporosis phenotype by inhibiting the GIOP-induced suppression of osteoblastic metabolic enzyme (ALP) activities and osteoblastic marker gene expression (Runx2a, Runx2b, and SP7), and this antagonism was concentration-dependent. We also observed that ATRA inhibited RBM14 expression in zebrafish larvae, while ATRA alone and RBM14 knockdown showed a consistent induction of osteoblast marker gene expression, implying that ATRA's inhibitory effect on RBM14 expression may underlie ATRA's osteogenic effects. Based on these data, we postulated that ATRA may ameliorate GIOP by decreasing RBM14 expression, thereby enhancing osteoblastic marker gene expression.
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Affiliation(s)
- Ting Yu
- Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Manci Chen
- Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Jing Wen
- Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Juan Liu
- Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Ke Li
- Demonstration Center for Experimental Basic Medicine Education, Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, Hubei 430071, China
| | - Lei Jin
- Wuhan Wuchang Hospital, Wuhan, Hubei 430063, China
| | - Jiang Yue
- Department of Pharmacology, Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, Hubei 430071, China
| | - Zheqiong Yang
- Demonstration Center for Experimental Basic Medicine Education, Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, Hubei 430071, China.
| | - Jinlei Xi
- Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China.
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Qin Y, Zhao W, Jia Z, Bauman WA, Peng Y, Guo XE, Chen Z, He Z, Cardozo CP, Wang D, Qin W. Neuroprotective macromolecular methylprednisolone prodrug nanomedicine prevents glucocorticoid-induced muscle atrophy and osteoporosis in a rat model of spinal cord injury. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2024; 62:102773. [PMID: 38960364 PMCID: PMC11513243 DOI: 10.1016/j.nano.2024.102773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 06/06/2024] [Accepted: 06/28/2024] [Indexed: 07/05/2024]
Abstract
To address the adverse side effects associated with systemic high-dose methylprednisolone (MP) therapy for acute spinal cord injury (SCI), we have developed a N-2-hydroxypropyl methacrylamide copolymer-based MP prodrug nanomedicine (Nano-MP). Intravenous Nano-MP selectively targeted to the inflamed SCI lesion and significantly improved neuroprotection and functional recovery after acute SCI. In the present study, we comprehensively assessed the potential adverse side effects associated with the treatment in the SCI rat models, including reduced body weight and food intake, impaired glucose metabolism, and reduced musculoskeletal mass and integrity. In contrast to free MP treatment, intravenous Nano-MP after acute SCI not only offered superior neuroprotection and functional recovery but also significantly mitigated or even eliminated the aforementioned adverse side effects. The superior safety features of Nano-MP observed in this study further confirmed the clinical translational potential of Nano-MP as a highly promising drug candidate for better clinical management of patients with acute SCI.
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Affiliation(s)
- Yiwen Qin
- Spinal Cord Damage Research Center, James J. Peters Veteran Affairs Medical Center, Bronx, NY, USA; GCM Grosvenor, New York, USA
| | - Wei Zhao
- Spinal Cord Damage Research Center, James J. Peters Veteran Affairs Medical Center, Bronx, NY, USA; Departments of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Zhenshan Jia
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA
| | - William A Bauman
- Departments of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA; Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yuanzhen Peng
- Spinal Cord Damage Research Center, James J. Peters Veteran Affairs Medical Center, Bronx, NY, USA
| | - X Edward Guo
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Zihao Chen
- Departments of Biotechnology, Brown University, Providence, RI, USA
| | - Zhiming He
- College of Dentistry, New York University, NY, New York, USA
| | - Christopher P Cardozo
- Spinal Cord Damage Research Center, James J. Peters Veteran Affairs Medical Center, Bronx, NY, USA; Departments of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA; Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Dong Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Weiping Qin
- Spinal Cord Damage Research Center, James J. Peters Veteran Affairs Medical Center, Bronx, NY, USA; Departments of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA.
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Zheng X, Ye FC, Sun T, Liu FJ, Wu MJ, Zheng WH, Wu LF. Delay the progression of glucocorticoid-induced osteoporosis: Fraxin targets ferroptosis via the Nrf2/GPX4 pathway. Phytother Res 2024; 38:5203-5224. [PMID: 39192711 DOI: 10.1002/ptr.8310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 07/09/2024] [Accepted: 07/24/2024] [Indexed: 08/29/2024]
Abstract
Glucocorticoid-induced osteoporosis (GIOP) commonly accelerates bone loss, increasing the risk of fractures and osteonecrosis more significantly than traditional menopausal osteoporosis. The extracellular environment influenced by glucocorticoids heightens fracture and osteonecrosis risks. Fraxin (Fra), a key component of the traditional Chinese herbal remedy Cortex Fraxini, is known for its wide-ranging pharmacological effects, but its impact on GIOP remains unexplored. This investigation aims to delineate the effects and underlying mechanisms of Fra in combating dexamethasone (Dex)-induced ferroptosis and GIOP. We established a mouse model of GIOP via intraperitoneal injections of Dex and cultured osteoblasts with Dex treatment for in vitro analysis. We evaluated the impact of Fra on Dex-treated osteoblasts through assays such as C11-BODIPY and FerroOrange staining, mitochondrial functionality tests, and protein expression analyses via Western blot and immunofluorescence. The influence of Fra on bone microarchitecture of GIOP in mice was assessed using microcomputerized tomography, hematoxylin and eosin staining, double-labeling with Calcein-Alizarin Red S, and immunohistochemistry at imaging and histological levels. Based on our data, Fra prevented Dex-induced ferroptosis and bone loss. In vitro, glutathione levels increased and malondialdehyde, lipid peroxidation, and mitochondrial reactive oxygen species decreased. Fra treatment also increases nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and COL1A1 expression and promotes bone formation. To delve deeper into the mechanism, the findings revealed that Fra triggered the activation of Nrf2/GPX4 signaling. Moreover, the use of siRNA-Nrf2 blocked the beneficial effect of Fra in osteoblasts cultivated with Dex. Fra effectively combats GIOP by activating the Nrf2/GPX4 signaling pathway to inhibit ferroptosis.
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Affiliation(s)
- Xiang Zheng
- Department of Orthopedics, Lishui Municipal Central Hospital, Lishui, Zhejiang, China
- Department of Orthopedics, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Fang-Chen Ye
- The First School of Medicine, Nanfang Medical University, Guangzhou, China
| | - Tao Sun
- Department of Orthopedics, Lishui Municipal Central Hospital, Lishui, Zhejiang, China
- Department of Orthopedics, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Fei-Jun Liu
- Department of Orthopedics, Lishui Municipal Central Hospital, Lishui, Zhejiang, China
- Department of Orthopedics, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Ming-Jian Wu
- Department of Orthopedics, Lishui Municipal Central Hospital, Lishui, Zhejiang, China
- Department of Orthopedics, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Wen-Hao Zheng
- Department of Orthopaedic, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ling-Feng Wu
- Department of Orthopedics, Lishui Municipal Central Hospital, Lishui, Zhejiang, China
- Department of Orthopedics, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
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Alasfar S, Me HM, Budhiraja P. Approach to Late Noninfectious Post-Transplant Complications. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:436-449. [PMID: 39232614 DOI: 10.1053/j.akdh.2024.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 05/16/2024] [Accepted: 05/24/2024] [Indexed: 09/06/2024]
Abstract
The management of noninfectious complications in kidney transplant recipients includes a broad spectrum of conditions, including metabolic issues, cardiovascular diseases, and malignancies, each presenting unique challenges for nephrologists managing these patients. Unlike infectious complications, these noninfectious issues require nuanced, multidisciplinary approaches for prevention, diagnosis, and management, emphasizing the need for personalized care plans. Cardiovascular disease is particularly significant, standing as the primary cause of death post-transplantation, with recent data indicating an overtaking of cancer death rates over infections among kidney transplant recipients. The intricacies of managing these patients, influenced by the burden of kidney disease and immunosuppression, highlight the importance of a collaborative care model. Although nephrologists may not directly treat all these conditions, their understanding of the unique aspects of transplant recipients is crucial. They play a pivotal role in coordinating care with specialists such as cardiologists, endocrinologists, hematologists, and oncologists, ensuring comprehensive management that addresses these specific post-transplant complications. This review discusses the epidemiology, underlying mechanisms, clinical manifestations, and management strategies of various noninfectious complications post-kidney transplant, with a focus on cardiovascular, metabolic, oncologic, and hematologic complications.
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Affiliation(s)
- Sami Alasfar
- Mayo Clinic Arizona, Division of Nephrology, Department of Medicine, Phoenix, AZ.
| | - Hay Me Me
- Mayo Clinic Arizona, Division of Nephrology, Department of Medicine, Phoenix, AZ
| | - Pooja Budhiraja
- Mayo Clinic Arizona, Division of Nephrology, Department of Medicine, Phoenix, AZ
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Yang P, Shen F, You C, Lou F, Shi Y. Gli1 + Progenitors Mediate Glucocorticoid-Induced Osteoporosis In Vivo. Int J Mol Sci 2024; 25:4371. [PMID: 38673956 PMCID: PMC11050080 DOI: 10.3390/ijms25084371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/04/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
For a wide range of chronic autoimmune and inflammatory diseases in both adults and children, synthetic glucocorticoids (GCs) are one of the most effective treatments. However, besides other adverse effects, GCs inhibit bone mass at multiple levels, and at different ages, especially in puberty. Although extensive studies have investigated the mechanism of GC-induced osteoporosis, their target cell populations still be obscure. Here, our data show that the osteoblast subpopulation among Gli1+ metaphyseal mesenchymal progenitors (MMPs) is responsive to GCs as indicated by lineage tracing and single-cell RNA sequencing experiments. Furthermore, the proliferation and differentiation of Gli1+ MMPs are both decreased, which may be because GCs impair the oxidative phosphorylation(OXPHOS) and aerobic glycolysis of Gli1+ MMPs. Teriparatide, as one of the potential treatments for GCs in bone mass, is sought to increase bone volume by increasing the proliferation and differentiation of Gli1+ MMPs in vivo. Notably, our data demonstrate teriparatide ameliorates GC-caused bone defects by targeting Gli1+ MMPs. Thus, Gli1+ MMPs will be the potential mesenchymal progenitors in response to diverse pharmaceutical administrations in regulating bone formation.
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Affiliation(s)
- Puying Yang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; (P.Y.); (F.S.); (C.Y.); (F.L.)
| | - Fangyuan Shen
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; (P.Y.); (F.S.); (C.Y.); (F.L.)
| | - Chengjia You
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; (P.Y.); (F.S.); (C.Y.); (F.L.)
| | - Feng Lou
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; (P.Y.); (F.S.); (C.Y.); (F.L.)
- Department of Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Yu Shi
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; (P.Y.); (F.S.); (C.Y.); (F.L.)
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11
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Saad FA, Saad JF, Siciliano G, Merlini L, Angelini C. Duchenne Muscular Dystrophy Gene Therapy. Curr Gene Ther 2024; 24:17-28. [PMID: 36411557 DOI: 10.2174/1566523223666221118160932] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 09/27/2022] [Accepted: 10/11/2022] [Indexed: 11/23/2022]
Abstract
Duchenne and Becker muscular dystrophies are allelic X-linked recessive neuromuscular diseases affecting both skeletal and cardiac muscles. Therefore, owing to their single X chromosome, the affected boys receive pathogenic gene mutations from their unknowing carrier mothers. Current pharmacological drugs are palliative that address the symptoms of the disease rather than the genetic cause imbedded in the Dystrophin gene DNA sequence. Therefore, alternative therapies like gene drugs that could address the genetic cause of the disease at its root are crucial, which include gene transfer/implantation, exon skipping, and gene editing. Presently, it is possible through genetic reprogramming to engineer AAV vectors to deliver certain therapeutic cargos specifically to muscle or other organs regardless of their serotype. Similarly, it is possible to direct the biogenesis of exosomes to carry gene editing constituents or certain therapeutic cargos to specific tissue or cell type like brain and muscle. While autologous exosomes are immunologically inert, it is possible to camouflage AAV capsids, and lipid nanoparticles to evade the immune system recognition. In this review, we highlight current opportunities for Duchenne muscular dystrophy gene therapy, which has been known thus far as an incurable genetic disease. This article is a part of Gene Therapy of Rare Genetic Diseases thematic issue.
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Affiliation(s)
- Fawzy A Saad
- Department of Biology, Padua University School of Medicine, Via Trieste 75, Padova 35121, Italy
- Department of Gene Therapy, Saad Pharmaceuticals, Tornimäe 7-26, Tallinn, 10145, Estonia
| | - Jasen F Saad
- Department of Gene Therapy, Saad Pharmaceuticals, Tornimäe 7-26, Tallinn, 10145, Estonia
| | - Gabriele Siciliano
- Department of Clinical and Experimental Medicine, Pisa University School of Medicine, Pisa, Italy
| | - Luciano Merlini
- Department of Biomedical and Neuromotor Sciences, Bologna University School of Medicine, 40126 Bologna, Italy
| | - Corrado Angelini
- Department Neurosciences, Padova University School of Medicine, Padova, Italy
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12
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Harsløf T, Hikmet R, Ebbehøj E, Langdahl B. Bone turnover decreases and bone structure improves during treatment with weekly high-dose methylprednisolone for 12 weeks in Graves' orbitopathy. Endocrine 2023; 82:664-672. [PMID: 37676399 PMCID: PMC10618317 DOI: 10.1007/s12020-023-03494-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 08/11/2023] [Indexed: 09/08/2023]
Abstract
PURPOSE Weekly treatment with the intravenous glucocorticoid methylprednisolone for 12 weeks is mainstay in the treatment of Graves' orbitopathy but may decrease bone mass and impair bone structure. We therefore investigated bone turnover, -mass and -structure during the treatment cause in these patients. METHODS We included 32 patients with Graves' orbitopathy scheduled for treatment with methylprednisolone. Bone turnover and thyroid function was measured at baseline and after 3, 9, 12, and 24 weeks, bone mineral density (BMD) was measured using dual x-ray absorptiometry at baseline and after 12 and 24 weeks, and bone structure was measured using high-resolution peripheral quantitative computed tomography at baseline and after 12 weeks. RESULTS Bone turnover and tri-iodothyronine decreased throughout the study. Cortical volumetric BMD at both the radius and tibia increased significantly by 0.98 ± 0.38% (p = 0.01) and 1.35 ± 0.50% (p = 0.01), respectively and cortical porosity at both the radius and tibia decreased significantly by -7.67 ± 3.13% (p = 0.04) and -3.30 ± 2.17% (p = 0.04), respectively. Bone mineral density was stable during the first 12 weeks but increased significantly by 2.26 ± 3.61% at the femoral neck (p < 0.01) and by 2.24 ± 4.24% at the total hip towards week 24 (p = 0.02). Stratified analyses suggested that remission of hyperthyroidism was the most important determinant of changes in bone turnover, bone mass and structure. CONCLUSION During a 12-week course of high-dose intravenous methylprednisolone bone turnover and cortical porosity decreased and during 24 weeks follow up bone mineral density increased. In terms of bone, methylprednisolone therefore is a safe treatment for Graves' orbitopathy.
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Affiliation(s)
- Torben Harsløf
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
- Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
| | - Rawan Hikmet
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Eva Ebbehøj
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Bente Langdahl
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
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Pofi R, Caratti G, Ray DW, Tomlinson JW. Treating the Side Effects of Exogenous Glucocorticoids; Can We Separate the Good From the Bad? Endocr Rev 2023; 44:975-1011. [PMID: 37253115 PMCID: PMC10638606 DOI: 10.1210/endrev/bnad016] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/25/2023] [Accepted: 05/26/2023] [Indexed: 06/01/2023]
Abstract
It is estimated that 2% to 3% of the population are currently prescribed systemic or topical glucocorticoid treatment. The potent anti-inflammatory action of glucocorticoids to deliver therapeutic benefit is not in doubt. However, the side effects associated with their use, including central weight gain, hypertension, insulin resistance, type 2 diabetes (T2D), and osteoporosis, often collectively termed iatrogenic Cushing's syndrome, are associated with a significant health and economic burden. The precise cellular mechanisms underpinning the differential action of glucocorticoids to drive the desirable and undesirable effects are still not completely understood. Faced with the unmet clinical need to limit glucocorticoid-induced adverse effects alongside ensuring the preservation of anti-inflammatory actions, several strategies have been pursued. The coprescription of existing licensed drugs to treat incident adverse effects can be effective, but data examining the prevention of adverse effects are limited. Novel selective glucocorticoid receptor agonists and selective glucocorticoid receptor modulators have been designed that aim to specifically and selectively activate anti-inflammatory responses based upon their interaction with the glucocorticoid receptor. Several of these compounds are currently in clinical trials to evaluate their efficacy. More recently, strategies exploiting tissue-specific glucocorticoid metabolism through the isoforms of 11β-hydroxysteroid dehydrogenase has shown early potential, although data from clinical trials are limited. The aim of any treatment is to maximize benefit while minimizing risk, and within this review we define the adverse effect profile associated with glucocorticoid use and evaluate current and developing strategies that aim to limit side effects but preserve desirable therapeutic efficacy.
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Affiliation(s)
- Riccardo Pofi
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK
| | - Giorgio Caratti
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK
| | - David W Ray
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK
- Oxford Kavli Centre for Nanoscience Discovery, University of Oxford, Oxford OX37LE, UK
| | - Jeremy W Tomlinson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK
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Tang IYK, Luk L, Wong V, Pang S, Lao V, So H. Reduced bone mineral density in patients with idiopathic inflammatory myopathies: a case-control study. Ther Adv Musculoskelet Dis 2023; 15:1759720X231181968. [PMID: 37484925 PMCID: PMC10356997 DOI: 10.1177/1759720x231181968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Accepted: 05/30/2023] [Indexed: 07/25/2023] Open
Abstract
Background Patients with idiopathic inflammatory myopathies (IIMs) are at risk of reduced bone mineral density (BMD). Objectives To compare the prevalence of reduced BMD between patients with IIMs and controls and to determine its risk factors. Design This was a single-center case-control study. Methods BMD was assessed by dual-energy X-ray absorptiometry. The prevalence of reduced BMD in IIM patients and age-and sex-matched non-rheumatological controls was compared. The BMD results of female IIM were also compared to age-matched female rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients. Independent factors associated with reduced BMD in IIM patients were identified by multivariate analyses. Results A total of 230 patients (IIM: 65, non-rheumatological controls: 65, RA: 50, SLE: 50) were recruited. The mean age of IIM patients was 58.6 ± 11.0 years and 76.9% were females. Significantly, more IIM patients had reduced BMD (73.8% versus 43.1%, p = 0.043) and osteoporosis (29.2% versus 13.8%, p = 0.033) than non-rheumatological controls. Multivariate analysis confirmed that IIM was independently associated with reduced BMD (OR: 2.12, p = 0.048, 95% CI: 1.01-4.46). The prevalence of reduced BMD was not significantly different between IIM, RA, and SLE patients but the mean hip BMD was the lowest in the IIM group (0.641 ± 0.152 g/cm2versus 0.663 ± 0.102g/cm2 in the RA group versus 0.708 ± 0.132 g/cm2 in the SLE group, p = 0.035). Lower body mass index and more advanced age were independently associated with lower BMD in IIM patients. Conclusion Reduced BMD was more prevalent in IIM patients than in non-rheumatological controls. Hip BMD was lower in patients with IIMs than RA or SLE. Close monitoring and early treatment are encouraged especially in patients with risk factors.
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Affiliation(s)
- Iris Yan Ki Tang
- Division of Rheumatology and Clinical Immunology, Department of Medicine, The University of Hong Kong, Hong Kong
| | - Lucas Luk
- Department of Medicine and Geriatrics, Kwong Wah Hospital, Hong Kong
| | - Victor Wong
- Department of Medicine and Geriatrics, Kwong Wah Hospital, Hong Kong
| | - Steve Pang
- Department of Medicine and Geriatrics, Kwong Wah Hospital, Hong Kong
| | - Virginia Lao
- Department of Medicine and Geriatrics, Kwong Wah Hospital, Hong Kong
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Reyes Fernandez PC, Wright CS, Farach-Carson MC, Thompson WR. Examining Mechanisms for Voltage-Sensitive Calcium Channel-Mediated Secretion Events in Bone Cells. Calcif Tissue Int 2023; 113:126-142. [PMID: 37261463 PMCID: PMC11008533 DOI: 10.1007/s00223-023-01097-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 05/16/2023] [Indexed: 06/02/2023]
Abstract
In addition to their well-described functions in cell excitability, voltage-sensitive calcium channels (VSCCs) serve a critical role in calcium (Ca2+)-mediated secretion of pleiotropic paracrine and endocrine factors, including those produced in bone. Influx of Ca2+ through VSCCs activates intracellular signaling pathways to modulate a variety of cellular processes that include cell proliferation, differentiation, and bone adaptation in response to mechanical stimuli. Less well understood is the role of VSCCs in the control of bone and calcium homeostasis mediated through secreted factors. In this review, we discuss the various functions of VSCCs in skeletal cells as regulators of Ca2+ dynamics and detail how these channels might control the release of bioactive factors from bone cells. Because VSCCs are druggable, a better understanding of the multiple functions of these channels in the skeleton offers the opportunity for developing new therapies to enhance and maintain bone and to improve systemic health.
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Affiliation(s)
- Perla C Reyes Fernandez
- Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN, 46202, USA
- Center for Musculoskeletal Health, Indiana University, Indianapolis, IN, 46202, USA
| | - Christian S Wright
- Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN, 46202, USA
- Center for Musculoskeletal Health, Indiana University, Indianapolis, IN, 46202, USA
| | - Mary C Farach-Carson
- Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX, 77054, USA
- Departments of BioSciences and Bioengineering, Rice University, Houston, TX, 77005, USA
| | - William R Thompson
- Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN, 46202, USA.
- Center for Musculoskeletal Health, Indiana University, Indianapolis, IN, 46202, USA.
- Department of Anatomy, Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, IN, 46202, USA.
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Wei H, Zhao Y, Xiang L. Bone health in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2023; 17:921-935. [PMID: 37589220 DOI: 10.1080/17474124.2023.2248874] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Accepted: 08/14/2023] [Indexed: 08/18/2023]
Abstract
INTRODUCTION Inflammatory bowel disease (IBD) is a chronic disease characterized by the presence of systemic inflammation, manifesting not only as gastrointestinal symptoms but also as extraintestinal bone complications, including osteopenia and osteoporosis. However, the association between IBD and osteoporosis is complex, and the presence of multifactorial participants in the development of osteoporosis is increasingly recognized. Unlike in adults, delayed puberty and growth hormone/insulin-like growth factor-1 axis abnormalities are essential risk factors for osteoporosis in pediatric patients with IBD. AREAS COVERED This article reviews the potential pathophysiological mechanisms contributing to osteoporosis in adult and pediatric patients with IBD and provides evidence for effective prevention and treatment, focusing on pediatric patients with IBD. A search was performed from PubMed and Web of Science inception to February 2023 to identify articles on IBD, osteoporosis, pediatric, and fracture risk. EXPERT OPINION A comprehensive treatment pattern based on individualized principles can be used to manage pediatric IBD-related osteoporosis.
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Affiliation(s)
- Hao Wei
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yihan Zhao
- Department of Cardiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Lisha Xiang
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Chen M, Fu W, Xu H, Liu CJ. Pathogenic mechanisms of glucocorticoid-induced osteoporosis. Cytokine Growth Factor Rev 2023; 70:54-66. [PMID: 36906448 PMCID: PMC10518688 DOI: 10.1016/j.cytogfr.2023.03.002] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/21/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023]
Abstract
Glucocorticoid (GC) is one of the most prescribed medicines to treat various inflammatory and autoimmune diseases. However, high doses and long-term use of GCs lead to multiple adverse effects, particularly glucocorticoid-induced osteoporosis (GIO). Excessive GCs exert detrimental effects on bone cells, including osteoblasts, osteoclasts, and osteocytes, leading to impaired bone formation and resorption. The actions of exogenous GCs are considered to be strongly cell-type and dose dependent. GC excess inhibits the proliferation and differentiation of osteoblasts and enhances the apoptosis of osteoblasts and osteocytes, eventually contributing to reduced bone formation. Effects of GC excess on osteoclasts mainly include enhanced osteoclastogenesis, increased lifespan and number of mature osteoclasts, and diminished osteoclast apoptosis, which result in increased bone resorption. Furthermore, GCs have an impact on the secretion of bone cells, subsequently disturbing the process of osteoblastogenesis and osteoclastogenesis. This review provides timely update and summary of recent discoveries in the field of GIO, with a particular focus on the effects of exogenous GCs on bone cells and the crosstalk among them under GC excess.
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Affiliation(s)
- Meng Chen
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA; School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Wenyu Fu
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA
| | - Huiyun Xu
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.
| | - Chuan-Ju Liu
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA; Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, USA.
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Samsonraj RM, Law SF, Chandra A, Pignolo RJ. An unbiased proteomics approach to identify the senescence-associated secretory phenotype of human bone marrow-derived mesenchymal stem cells. Bone Rep 2023; 18:101674. [PMID: 36994454 PMCID: PMC10041468 DOI: 10.1016/j.bonr.2023.101674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 03/17/2023] [Indexed: 03/28/2023] Open
Abstract
Mesenchymal stem cells (MSCs) derived from bone marrow can support skeletal tissue repair and regeneration owing to their self-renewing capacity, differentiation ability, and trophic functions. Bone marrow-derived MSCs undergo dramatic changes with aging, including the senescence-associated secretory phenotype (SASP) which may largely contribute to age-related changes in bone tissue leading to osteoporosis. A mass spectrometry-based proteomics approach was used to investigate the MSC SASP. Replicative senescence was achieved by exhaustive in vitro sub-cultivation and confirmed by standard proliferation criteria. Conditioned media from non-senescent and senescent MSCs underwent mass spectrometry. Proteomics and bioinformatics analyses enabled the identification of 95 proteins expressed uniquely in senescent MSCs. Protein ontology analysis revealed the enrichment of proteins linked to the extracellular matrix, exosomes, cell adhesion, and calcium ion binding. The proteomic analysis was independently validated by taking ten identified proteins with relevance to bone aging and confirming their increased abundance in conditioned media from replicatively senescent versus non-senescent MSCs (ACTα2, LTF, SOD1, IL-6, LTBP2, PXDN, SERPINE 1, COL1α1, THBS1, OPG). These target proteins were used to further investigate changes in the MSC SASP profile in response to other inducers of senescence, ionizing radiation (IR) and H2O2. Similar secreted protein expression profiles with replicatively senescent cells were seen with H2O2 treatment except for LTF and PXDN, which were increased by IR treatment. With both IR and H2O2 treatment there was a decrease in THBS1. In vivo investigation of these secreted proteins with aging was shown by significant changes in the abundance of OPG, COL1α1, IL-6, ACTα2, SERPINE 1, and THBS1 in the plasma of aged rats. This unbiased, comprehensive analysis of the changes in the MSC secretome with senescence defines the unique protein signature of the SASP in these cells and provides a better understanding of the aging bone microenvironment.
Identified the senescence-associated secretory phenotype of mesenchymal stem cells. Investigated protein expression under different senescence induction conditions. Showed significant changes in in vivo abundance of target proteins in aging rats.
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Affiliation(s)
| | - Susan F. Law
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Abhishek Chandra
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Robert J. Pignolo
- Department of Medicine, Mayo Clinic, Rochester, MN, USA
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
- Corresponding author at: Robert and Arlene Kogod Professor of Geriatric Medicine, Department of Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
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Brent MB. Pharmaceutical treatment of bone loss: From animal models and drug development to future treatment strategies. Pharmacol Ther 2023; 244:108383. [PMID: 36933702 DOI: 10.1016/j.pharmthera.2023.108383] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 02/18/2023] [Accepted: 03/09/2023] [Indexed: 03/17/2023]
Abstract
Animal models are fundamental to advance our knowledge of the underlying pathophysiology of bone loss and to study pharmaceutical countermeasures against it. The animal model of post-menopausal osteoporosis from ovariectomy is the most widely used preclinical approach to study skeletal deterioration. However, several other animal models exist, each with unique characteristics such as bone loss from disuse, lactation, glucocorticoid excess, or exposure to hypobaric hypoxia. The present review aimed to provide a comprehensive overview of these animal models to emphasize the importance and significance of investigating bone loss and pharmaceutical countermeasures from perspectives other than post-menopausal osteoporosis only. Hence, the pathophysiology and underlying cellular mechanisms involved in the various types of bone loss are different, and this might influence which prevention and treatment strategies are the most effective. In addition, the review sought to map the current landscape of pharmaceutical countermeasures against osteoporosis with an emphasis on how drug development has changed from being driven by clinical observations and enhancement or repurposing of existing drugs to today's use of targeted anti-bodies that are the result of advanced insights into the underlying molecular mechanisms of bone formation and resorption. Moreover, new treatment combinations or repurposing opportunities of already approved drugs with a focus on dabigatran, parathyroid hormone and abaloparatide, growth hormone, inhibitors of the activin signaling pathway, acetazolamide, zoledronate, and romosozumab are discussed. Despite the considerable progress in drug development, there is still a clear need to improve treatment strategies and develop new pharmaceuticals against various types of osteoporosis. The review also highlights that new treatment indications should be explored using multiple animal models of bone loss in order to ensure a broad representation of different types of skeletal deterioration instead of mainly focusing on primary osteoporosis from post-menopausal estrogen deficiency.
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Affiliation(s)
- Mikkel Bo Brent
- Department of Biomedicine, Aarhus University, Denmark, Wilhelm Meyers Allé 3, 8000 Aarhus C, Denmark.
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Kobayakawa T, Miyazaki A, Kanayama Y, Hirano Y, Takahashi J, Suzuki T, Nakamura Y. Comparable efficacy of denosumab and romosozumab in patients with rheumatoid arthritis receiving glucocorticoid administration. Mod Rheumatol 2023; 33:96-103. [PMID: 35234889 DOI: 10.1093/mr/roac014] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 11/16/2021] [Accepted: 01/28/2022] [Indexed: 01/05/2023]
Abstract
OBJECTIVES Romosozumab is a newly released and widely known molecular-targeted drug for severe osteoporosis treatment with comparable effectiveness to denosumab. However, there have been no reports discussing the efficacy of those treatments for rheumatoid arthritis (RA) patients, especially those receiving glucocorticoids. This retrospective observational registry study compared the efficacy of 12-month treatment of denosumab and romosozumab in RA patients under the influence of glucocorticoid intake. METHODS Following propensity score matching, 36 patients each in the denosumab and romosozumab groups were analysed in this study. Drug effectiveness was evaluated by measuring bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck at baseline, 6 and 12 months as well as alterations in P1NP, TRACP-5b, and simplified disease activity index (SDAI). The occurrence of adverse events and new fractures was also assessed. RESULTS At 12 months of treatment, BMD at the lumbar spine was increased by 7.5% in the denosumab group and 8.7% in the romosozumab group, which were both significantly and comparably elevated over baseline. At the total hip and femoral neck, romosozumab tended to exhibit favourable efficacy to increase BMD versus denosumab. Both P1NP and TRACP-5b were significantly lower in the denosumab group as compared with the baseline. Conversely in the romosozumab group, P1NP was increased over baseline, while TRACP-5b was decreased. Regarding SDAI alterations, both the romosozumab and denosumab groups exhibited comparable improvements in RA disease activity over time during treatment. Recorded adverse events and new fractures during treatment were few and minor in both groups. CONCLUSIONS Romosozumab exhibited comparable efficacy to denosumab for increasing BMD even under the influence of glucocorticoids for treating RA. Both drugs may be therefore suitable for managing osteoporosis in patients with RA and glucocorticoid intake.
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Affiliation(s)
| | - Akiko Miyazaki
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Yasuhide Kanayama
- Department of Orthopedic Surgery and Rheumatology, Toyota Kosei Hospital, Toyota, Aichi, Japan
| | - Yuji Hirano
- Department of Rheumatology, Toyohashi Municipal Hospital, Toyohashi, Aichi, Japan
| | - Jun Takahashi
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Takako Suzuki
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.,Department of Human Nutrition, Faculty of Human Nutrition, Tokyo Kasei Gakuin University, Tokyo, Japan
| | - Yukio Nakamura
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
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Chekalina NI, Plaksa VM, Kazakov YM, Tribrat TA, Shut SV, Petrov YY, Ivanytska TA. GENDER AND AGE ASPECTS IN THE PATHOGENESIS OF BONE MINERAL DENSITY DISORDERS. POLSKI MERKURIUSZ LEKARSKI : ORGAN POLSKIEGO TOWARZYSTWA LEKARSKIEGO 2023; 51:375-381. [PMID: 37756458 DOI: 10.36740/merkur202304112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/29/2023]
Abstract
OBJECTIVE The aim: To assess the structural and functional state of bone tissue in terms of gender and age. PATIENTS AND METHODS Materials and Methods: 108 people aged 54.7±14.8 years, who were divided into two groups according to gender, participated in the retrospective cohort study. All patients underwent ultrasound densitometry to assess bone mineral density (BMD) on the radial bone with an assessment of T-score, Z-score, and speed of ultrasonic wave propagation (SoS). RESULTS Results: The study found that T-score and Z-score values, which corresponded to osteoporosis, were recorded in the age group > 50 years, regardless of the gender of the subjects. All women older than 35 years had a decrease in BMD below -1.0 SD by T-score. It was determined that osteoporosis criteria clearly prevail in women of the > 50-year-old group. In osteoporosis, the SoS is significantly lower than in individuals with normal indicators of the T-criterion. According to the results of the T-score comparison, BMD disorders were determined in postmenopausal women which emphasize the importance of the level of female sex hormones in the formation of osteopenic syndrome, in contrast to men, in whom no changes in the state of bone tissue were recorded. CONCLUSION Conclusions: The results of the research prove the prevalence of osteopenic syndrome in terms of age and gender, with an emphasis on women aged 50 years and older. Screening for BMD disorders using ultrasound densitometry is appropriate and allows taking measures to prevent the progression of osteoporosis in the early stages.
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Davis CS, Faino AV, Onchiri F, Gibson RL, Merjaneh L, Ramsey BW, Rosenfeld M, Cogen JD. Systemic Corticosteroids in the Management of Pediatric Cystic Fibrosis Pulmonary Exacerbations. Ann Am Thorac Soc 2023; 20:75-82. [PMID: 36044723 PMCID: PMC12039857 DOI: 10.1513/annalsats.202203-201oc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 08/31/2022] [Indexed: 02/05/2023] Open
Abstract
Rationale: Pulmonary exacerbation (PEx) events contribute to lung function decline in people with cystic fibrosis (CF). CF Foundation PEx guidelines note that a short course of systemic corticosteroids may offer benefit without contributing to long-term adverse effects. However, insufficient evidence exists to recommend systemic corticosteroids for PEx treatment. Objectives: To determine if systemic corticosteroids for the treatment of in-hospital pediatric PEx are associated with improved clinical outcomes compared with treatment without systemic corticosteroids. Methods: We conducted a retrospective cohort study using the CF Foundation Patient Registry-Pediatric Health Information System linked database. People with CF were included if hospitalized for a PEx between 2006 and 2018 and were 6-21 years of age. Time to next PEx was assessed by Cox proportional hazards regression. Lung function outcomes were assessed by linear mixed-effect modeling and generalized estimating equations. To address confounding by indication, inverse probability treatment weighting was used. Results: A total of 3,471 people with CF contributed 9,787 PEx for analysis. Systemic corticosteroids were used in 15% of all PEx. In our primary analysis, systemic corticosteroids were not associated with better pre- to post-PEx percent predicted forced expiratory volume in 1 second responses (mean difference, -0.36; 95% confidence interval [CI], -1.14, 0.42; P = 0.4) or a higher odds of returning to lung function baseline (odds ratio, 0.97; 95% CI, 0.84-1.12; P = 0.7) but were associated with a reduced chance of future PEx requiring intravenous antibiotics (hazard ratio, 0.91; 95% CI, 0.85-0.96; P = 0.002). When restricting the analysis to one PEx per person, lung function outcomes remained no different among PEx treated with or without systemic corticosteroids, but, in contrast to our primary analysis, the use of systemic corticosteroids was no longer associated with a reduced chance of having a future PEx requiring intravenous antibiotics (hazard ratio, 0.96; 95% CI, 0.86, 1.07; P = 0.42). Conclusions: Systemic corticosteroid treatment for in-hospital pediatric PEx was not associated with improved lung function outcomes. Prospective trials are needed to better evaluate the risks and benefits of systemic corticosteroid use for PEx treatment in children with CF.
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Affiliation(s)
| | - Anna V Faino
- Core for Biostatistics, Epidemiology, and Analytics in Research, Seattle Children's Research Institute, Seattle, Washington
| | - Frankline Onchiri
- Core for Biostatistics, Epidemiology, and Analytics in Research, Seattle Children's Research Institute, Seattle, Washington
| | | | - Lina Merjaneh
- Division of Endocrinology and Diabetes, Department of Pediatrics, University of Washington, Seattle, Washington; and
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Abstract
Endocrine comorbidities have become increasingly important medical considerations as improving cystic fibrosis (CF) care increases life expectancy. Although the underlying pathophysiology of CF-related diabetes remains elusive, the use of novel technologies and therapeutics seeks to improve both CF-related outcomes and quality of life. Improvements in the overall health of those with CF have tempered concerns about pubertal delay and short stature; however, other comorbidities such as hypogonadism and bone disease are increasingly recognized. Following the introduction of highly effective modulator therapies there are many lessons to be learned about their long-term impact on endocrine comorbidities.
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Affiliation(s)
- Andrea Kelly
- Division of Endocrinology & Diabetes, University of Pennsylvania Perelman School of Medicine, Children's Hospital of Philadelphia, Room 14363, Roberts Building for Pediatric Research, 2716 South Street, Philadelphia, PA 19146, USA
| | - Brynn E Marks
- Division of Endocrinology & Diabetes, Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Children's Hospital of Philadelphia, Room 7547, The Hub for Clinical Collaboration, 3501 Civic Center Blvd, Philadelphia, PA 19104, USA
| | - Michael S Stalvey
- Department of Pediatrics, UAB Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Children's of Alabama, CPPII M30, 1600 7th Avenue South, Birmingham, AL 35233-1711, USA; Department of Medicine, UAB Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Children's of Alabama, CPPII M30, 1600 7th Avenue South, Birmingham, AL 35233-1711, USA.
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24
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Noroozzadeh M, Amiri M, Farhadi-Azar M, Ramezani Tehrani F. Bone Health in Women With Polycystic Ovary Syndrome: A Narrative Review. J Clin Densitom 2022; 25:606-614. [PMID: 35430131 DOI: 10.1016/j.jocd.2022.02.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 02/13/2022] [Accepted: 02/23/2022] [Indexed: 11/19/2022]
Abstract
Bone as an active connective and endocrine tissue is influenced by hormones, physical activity, inflammatory factors, minerals, dietary components, and body weight. Bone fractures are a major cause of decreased quality of life and mortality in humans. Polycystic ovary syndrome (PCOS), is one of the most common endocrine disorders in women of reproductive age worldwide. PCOS is associated with disturbances in androgen and estrogen levels, insulin resistance (IR), obesity, as well as low-grade chronic inflammation, and gut microbiota (GM) dysbiosis, all of which may negatively or positively affect bone metabolism. However, it has not yet been well clarified whether PCOS is bone-protective or bone-destructive. This study aimed to review the association between bone health and PCOS, and summarize its related factors. PubMed, Scopus, and Web of Science databases were searched to retrieve relevant English publications investigating the relationship between bone health and PCOS. Several disorders associated with PCOS can negatively or positively affect bone metabolism. Despite some positive effects of insulin, androgens, estrogens, and obesity on bone, IR, estrogen deficiency, low-grade chronic inflammation, and GM dysbiosis may adversely affect the bone metabolism in PCOS women. Studies comparing bone mineral density or bone metabolism and the risk of bone fractures in women with PCOS have controversial results. Further studies are required to understand the mechanisms underlying bone metabolism in PCOS subjects. Moreover, prospective studies are needed to estimate the risk of bone fractures and osteoporosis in PCOS subjects.
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Affiliation(s)
- Mahsa Noroozzadeh
- Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mina Amiri
- Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahbanoo Farhadi-Azar
- Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fahimeh Ramezani Tehrani
- Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Tocotrienol as a Protecting Agent against Glucocorticoid-Induced Osteoporosis: A Mini Review of Potential Mechanisms. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27185862. [PMID: 36144598 PMCID: PMC9506150 DOI: 10.3390/molecules27185862] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/03/2022] [Accepted: 09/08/2022] [Indexed: 11/18/2022]
Abstract
Glucocorticoid-induced osteogenic dysfunction is the main pathologyical mechanism underlying the development of glucocorticoid-induced osteoporosis. Glucocorticoids promote adipogenic differentiation and osteoblast apoptosis through various pathways. Various ongoing studies are exploring the potential of natural products in preventing glucocorticoid-induced osteoporosis. Preclinical studies have consistently shown the bone protective effects of tocotrienol through its antioxidant and anabolic effects. This review aims to summarise the potential mechanisms of tocotrienol in preventing glucocorticoid-induced osteoporosis based on existing in vivo and in vitro evidence. The current literature showed that tocotrienol prevents oxidative damage on osteoblasts exposed to high levels of glucocorticoids. Tocotrienol reduces lipid peroxidation and increases oxidative stress enzyme activities. The reduction in oxidative stress protects the osteoblasts and preserves the bone microstructure and biomechanical strength of glucocorticoid-treated animals. In other animal models, tocotrienol has been shown to activate the Wnt/β-catenin pathway and lower the RANKL/OPG ratio, which are the targets of glucocorticoids. In conclusion, tocotrienol enhances osteogenic differentiation and bone formation in glucocorticoid-treated osteoblasts while improving structural integrity in glucocorticoid-treated rats. This is achieved by preventing oxidative stress and osteoblast apoptosis. However, these preclinical results should be validated in a randomised controlled trial.
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26
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Löfdahl E, Rådegran G, Fagher K. Bone health and cardiac transplantation. Best Pract Res Clin Rheumatol 2022; 36:101770. [PMID: 36127249 DOI: 10.1016/j.berh.2022.101770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Patients who undergo heart transplantation (HT) have increased loss of bone mineral density (BMD) [g/cm2]. The greatest drop in BMD occurs within the first year after HT with a decrease 3.5-8.5% in the lumbar spine and 5.6-10.5% in the femoral neck. Thereafter, BMD tend to stabilize or even recover to some degree. Accordingly, risk of fracture correlates to BMD evolution, with the highest rate of fractures during the first year, with a cumulative incidence of 12-36%. Fragility fractures contributes to increased morbidity and increased mortality. The pathophysiology behind BMD impairment in HT patients is complex and involves side-effects of the immunosuppressive therapy and of heart failure medications, as well as organ failure. Of the immunosuppressive agents, corticosteroids (CS) exerts the greatest impact on BMD through multiple cellular pathways. Also, calcineurin inhibitors seem have a negative impact on BMD, mainly mediated through enhancement of bone resorption. Additionally, kidney dysfunction has a significant effect on bone homeostasis and is frequently present in HT patients. The optimal timing and type of pharmacological treatment of osteoporosis in HT patients are not yet known. However, bisphosphonates and monoclonal antibody against RANK ligand (Denosumab) may have beneficial effects on bone metabolism in HT patients. However, their efficacy and safety in have not been thoroughly studied in this particular patient population. Therefore, careful individual evaluation of prescription, frequency, and possible treatment options is advisable in this patient population.
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Affiliation(s)
- Eveline Löfdahl
- Department of Clinical Sciences Lund, Lund University, Sweden; The Section for Heart Failure and Valvular Disease, VO. Heart and Lung Medicine, Skåne University Hospital, Lund, Sweden.
| | - Göran Rådegran
- Department of Clinical Sciences Lund, Lund University, Sweden; The Section for Heart Failure and Valvular Disease, VO. Heart and Lung Medicine, Skåne University Hospital, Lund, Sweden
| | - Katarina Fagher
- Department of Clinical Sciences Lund, Lund University, Sweden; Department of Endocrinology, Skåne University Hospital, Sweden
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27
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Abstract
Glucocorticoid use is ubiquitous and is associated with multiple adverse reactions. Among them, osteoporosis and bone fractures are of our concern. In this review, we present current evidence on the effect of glucocorticoids on bone mineral density and the risk of fractures, the mechanisms underlying those effects, and the recommendations for monitoring and treating patients who take them. The bone mineral density of the lumbar spine and total hip is lower, and the risk of fractures is higher in glucocorticoid users than non-users. These effects have a rapid onset, are dose-dependent, and improve soon after discontinuation of glucocorticoids. They also appear to occur even with non-systemic routes of administration and with low doses. Glucocorticoids reduce bone mineral density by increasing osteoclast activity and decreasing osteoblast and osteocyte activity. Calcium metabolism and parathyroid hormone activity are less important than was initially thought. Treatment decisions are on risk stratification using clinical, radiographic, and prediction tools. Our armamentarium for the treatment and prevention of glucocorticoid-induced osteoporosis includes calcium and vitamin D, bisphosphonates, recombinant parathyroid hormone, monoclonal antibodies against receptor activator of nuclear factor kappa-B ligand, and hormone treatments.
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Affiliation(s)
- Mariana Urquiaga
- Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, AL, USA.
| | - Kenneth G Saag
- Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, AL, USA
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28
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Cao J, Chen Y, Wang H. 11β-hydroxysteroid dehydrogenases and biomarkers in fetal development. Toxicology 2022; 479:153316. [PMID: 36096318 DOI: 10.1016/j.tox.2022.153316] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 08/29/2022] [Accepted: 09/07/2022] [Indexed: 11/27/2022]
Abstract
It is known that basal glucocorticoid levels in utero are essential for regulating fetal development and maturation, and determine the fate of later life. Recently, more and more studies suggest that adverse prenatal environments may cause abnormal maternal glucocorticoid levels in utero. 11β-hydroxysteroid dehydrogenases (11β-HSDs) are widely distributed in the target organs of glucocorticoids (GCs) and mineralocorticoids. 11β-HSDs is involved in fetal physiological and pathological development by activating or inactivating GCs. Prenatal adverse environments (including exogenous and maternal environments) can affect the expression and activity of 11β-HSDs in the placenta and fetus via multiple pathways. It induces abnormal local glucocorticoid levels in fetal multiple tissues, fetal developmental programming and homeostasis changes, and the susceptibility to various diseases after birth. We also discuss the interventions of 11β-HSDs inhibitors on fetal developmental programming and susceptibility to multiple diseases. Finally, we propose that 11β-HSD2 can be used as a molecular target for fetal developmental toxicity, while 11β-HSD1 can be regarded as an intervention target to prevent fetal-originated diseases. This review will provide a theoretical basis for the early prevention and treatment of fetal-originated diseases.
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Affiliation(s)
- Jiangang Cao
- Department of Pharmacology, Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan 430071, China
| | - Yawen Chen
- Department of Pharmacology, Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan 430071, China
| | - Hui Wang
- Department of Pharmacology, Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
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29
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Henning P, Conaway HH, Lerner UH. Stimulation of osteoclast formation and bone resorption by glucocorticoids: Synergistic interactions with the calcium regulating hormones parathyroid hormone and 1,25(OH) 2-vitamin D3. VITAMINS AND HORMONES 2022; 120:231-270. [PMID: 35953112 DOI: 10.1016/bs.vh.2022.04.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Osteoporosis is a significant health problem, with skeletal fractures increasing morbidity and mortality. Excess glucocorticoids (GC) represents the leading cause of secondary osteoporosis. The first phase of glucocorticoid-induced osteoporosis is increased bone resorption. In this Chapter, in vitro studies of the direct glucocorticoid receptor (GR) mediated cellular effects of GC on osteoclasts to affect bone resorption and indirect effects on osteoblast lineage cells to increase the RANKL/OPG ratio and stimulate osteoclastogenesis and bone resorption are reviewed in detail, together with detailed descriptions of in vivo effects of GC in different portions of the skeleton in research animals and humans. Brief sections are devoted to contrasting functions of GC in osteonecrosis, vitamin D formation, in vitro and in vivo bone resorptive actions dependent on vitamin D receptor and vitamin D toxicity, as well as the molecular basis of GR action. Included are also more detailed assessments of the interactions of GC with the major calcium regulating hormones, 1,25(OH)2-vitamin D3 and parathyroid hormone, describing the in vitro increases in RANKL/OPG ratios, osteoclastogenesis and synergistic bone resorption that occurs when GC is combined with either 1,25(OH)2-vitamin D3 or parathyroid hormone. Additionally, a molecular basic for the synergistic interaction of GC with 1,25(OH)2-vitamin D3 is provided along with a suggested molecular basic for the interaction between GC and parathyroid hormone.
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Affiliation(s)
- Petra Henning
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - H Herschel Conaway
- Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
| | - Ulf H Lerner
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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30
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Abbas A, Schini M, Ainsworth G, Brown SR, Oughton J, Crowley RK, Cooper MS, Fairclough RJ, Eastell R, Stewart PM. Effect of AZD4017, a Selective 11β-HSD1 Inhibitor, on Bone Turnover Markers in Postmenopausal Osteopenia. J Clin Endocrinol Metab 2022; 107:2026-2035. [PMID: 35275196 PMCID: PMC9202729 DOI: 10.1210/clinem/dgac100] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT The causative link between circulating glucocorticoid excess and osteoporosis is well-established. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which increases local cortisol production, is expressed in human osteoblasts and its activity increases with age. OBJECTIVE We hypothesized that local 11β-HSD1 might mediate an age-related decrease in bone formation and that selective 11β-HSD1 inhibition may enhance bone formation. METHODS A dual-center, phase II, randomized, double-blind, placebo-controlled trial of 90 days' treatment with AZD4017 (a selective 11β-HSD1 inhibitor) was conducted in 55 postmenopausal women with osteopenia. Participants received 400 mg oral AZD4017 twice daily vs matched placebo over 90 days. The primary outcome measure was the impact on the bone formation marker osteocalcin. Secondary objectives included correlation with 11β-HSD1 activity. RESULTS At 90 days, osteocalcin levels did not differ between treatment groups: active (mean 22.3 [SD 8.6] ng/mL, n = 22) and placebo (21.7 [SD 9.2] ng/mL, n = 24), with a baseline-adjusted treatment effect of 0.95 (95% CI: -2.69, 4.60). The results from the urinary [THF + alloTHF]/THE ratio (index of 11β-HSD1 activity) and the urinary cortisol/cortisone ratio (index of 11β-HSD2 activity) confirmed a > 90% inhibition of 11β-HSD1 but no change in activity of 11β-HSD2. CONCLUSION This trial demonstrates that AZD4017 selectively inhibits 11β-HSD1 activity in vivo in a safe and reversible manner. Following 90 days of treatment, there is no effect on bone formation, indicating that the relative impairment of bone mineral density in postmenopausal women is not mediated by local intracellular production of cortisol under normal physiological concentrations.
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Affiliation(s)
- Afroze Abbas
- Faculty of Medicine and Health, University of Leeds, and Leeds Teaching Hospitals NHS Trust, Leeds LS9 7TF, UK
| | - Marian Schini
- Academic Unit of Bone Metabolism, University of Sheffield, Sheffield S5 7AU, UK
| | - Gemma Ainsworth
- Clinical Trials Research Unit, University of Leeds, Leeds LS2 9JT, UK
| | - Sarah R Brown
- Clinical Trials Research Unit, University of Leeds, Leeds LS2 9JT, UK
| | - Jamie Oughton
- Clinical Trials Research Unit, University of Leeds, Leeds LS2 9JT, UK
| | - Rachel K Crowley
- School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
| | - Mark S Cooper
- Concord Clinical School, Faculty of Medicine & Health, University of Sydney, NSW 2139, Australia
| | - Rebecca J Fairclough
- Emerging Innovations Unit, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Richard Eastell
- Academic Unit of Bone Metabolism, University of Sheffield, Sheffield S5 7AU, UK
| | - Paul M Stewart
- Faculty of Medicine and Health, University of Leeds, and Leeds Teaching Hospitals NHS Trust, Leeds LS9 7TF, UK
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31
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Park SS, Uzelac A, Kotsopoulos J. Delineating the role of osteoprotegerin as a marker of breast cancer risk among women with a BRCA1 mutation. Hered Cancer Clin Pract 2022; 20:14. [PMID: 35418083 PMCID: PMC9008947 DOI: 10.1186/s13053-022-00223-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 03/30/2022] [Indexed: 11/26/2022] Open
Abstract
Women with a pathogenic germline mutation in the BRCA1 gene face a very high lifetime risk of developing breast cancer, estimated at 72% by age 80. Prophylactic bilateral mastectomy is the only effective way to lower their risk; however, most women with a mutation opt for intensive screening with annual MRI and mammography. Given that the BRCA1 gene was identified over 20 years ago, there is a need to identify a novel non-surgical approach to hereditary breast cancer prevention. Here, we provide a review of the emerging preclinical and epidemiologic evidence implicating the dysregulation of progesterone-mediated receptor activator of nuclear factor κB (RANK) signaling in the pathogenesis of BRCA1-associated breast cancer. Experimental studies have demonstrated that RANK inhibition suppresses Brca1-mammary tumorigenesis, suggesting a potential target for prevention. Data from studies conducted among women with a BRCA1 mutation further support this pathway in BRCA1-associated breast cancer development. Progesterone-containing (but not estrogen-alone) hormone replacement therapy is associated with an increased risk of breast cancer in women with a BRCA1 mutation. Furthermore, BRCA1 mutation carriers have significantly lower levels of circulating osteoprotegerin (OPG), the decoy receptor for RANK-ligand (RANKL) and thus endogenous inhibitor of RANK signaling. OPG levels may be associated with the risk of disease, suggesting a role of this protein as a potential biomarker of breast cancer risk. This may improve upon current risk prediction models, stratifying women at the highest risk of developing the disease, and further identify those who may be targets for anti-RANKL chemoprevention. Collectively, the evidence supports therapeutic inhibition of the RANK pathway for the primary prevention of BRCA1-associated breast cancer, which may generate unique prevention strategies (without prophylactic surgery) and enhance quality of life.
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Affiliation(s)
- Sarah Sohyun Park
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
- Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada
| | - Aleksandra Uzelac
- Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada
| | - Joanne Kotsopoulos
- Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada.
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
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32
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Herath M, Langdahl B, Ebeling PR, Milat F. Challenges in the diagnosis and management of glucocorticoid-induced osteoporosis in younger and older adults. Clin Endocrinol (Oxf) 2022; 96:460-474. [PMID: 34811782 DOI: 10.1111/cen.14637] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 10/16/2021] [Accepted: 10/26/2021] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Glucocorticoids constitute a considerable risk for developing osteoporosis in both younger and older adults. However, currently available bone imaging modalities and fracture-risk assessment tools do not adequately capture the dramatic changes in bone microarchitecture, heterogeneity of glucocorticoid exposure, the impact of chronic disease and other osteoporosis risk factors on the assessment of osteoporosis in these individuals. DESIGN A narrative review is presented, following a systematic search of the literature from 2000 to 2021. RESULTS Our current appreciation of glucocorticoid-induced osteoporosis (GIO) is focused on older populations, with limited evidence to guide the investigation, risk assessment and treatment in premenopausal women and men less than 50 years. The impact of the underlying chronic disease on secondary osteoporosis in these younger adults is also poorly understood. CONCLUSION Through this narrative review, we provide a comprehensive overview of and recommendations for optimising the management of this common cause of secondary osteoporosis younger and older adults.
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Affiliation(s)
- Madhuni Herath
- Department of Endocrinology, Monash Health, Melbourne, Victoria, Australia
- Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia
- Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Victoria, Australia
| | - Bente Langdahl
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Peter R Ebeling
- Department of Endocrinology, Monash Health, Melbourne, Victoria, Australia
- Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia
| | - Frances Milat
- Department of Endocrinology, Monash Health, Melbourne, Victoria, Australia
- Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia
- Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Victoria, Australia
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Tripathi AK, Rai D, Kothari P, Kushwaha P, Sashidhara KV, Trivedi R. Benzofuran pyran hybrid prevents glucocorticoid induced osteoporosis in mice via modulation of canonical Wnt/β-catenin signaling. Apoptosis 2022; 27:90-111. [PMID: 35107658 PMCID: PMC8808472 DOI: 10.1007/s10495-021-01702-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2021] [Indexed: 11/26/2022]
Abstract
Glucocorticoid induced osteoporosis (GIOP) is the second most leading cause of osteoporosis. We have identified a compound, a benzofuran pyran hybrid compound 4e that has osteogenic potential and we wanted to assess its efficacy in GIOP in male mice. We assessed the effect of dexamethasone and compound 4e on primary osteoblasts using various cell based and immunofluorescence assays. For in vivo studies we administered methylprednisolone and compound 4e as a prophylactic measure in male Balb/c mice for 28 days and then evaluated the effect on bone microarchitecture by microCT, bone formation by histology along with clinically relevant bone markers. Compound 4e preserved osteoblast differentiation as evident by higher ALP positive cells and mineralization in compound treated groups. Compound 4e also increased the expression of osteogenic genes. This compound guarded β-catenin expression both in vitro and in vivo as confirmed by western blot and immunofluorescence assays. This led to the preservation of bone microarchitecture and cortical thickness at 2.5 mg kg−1 and 5 mg kg−1 doses. Further compound 4e enhanced bone formation rate and regulated osteocyte death. The osteogenic potential of compound 4e was reflected by an increased level of serum marker osteocalcin and decreased levels of SOST and CTX-I. Overall, Compound 4e is able to overcome the catabolic effect of dexamethasone on bone by targeting the canonical WNT/β-catenin signaling as evidenced by both in vitro and in vivo studies.
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Affiliation(s)
- Ashish Kumar Tripathi
- Endocrinology Division, CSIR-Central Drug Research Institute, 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, Uttar Pradesh, 226031, India
| | - Divya Rai
- Endocrinology Division, CSIR-Central Drug Research Institute, 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, Uttar Pradesh, 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Priyanka Kothari
- Endocrinology Division, CSIR-Central Drug Research Institute, 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, Uttar Pradesh, 226031, India
| | - Pragati Kushwaha
- Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Koneni V Sashidhara
- Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Ritu Trivedi
- Endocrinology Division, CSIR-Central Drug Research Institute, 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, Uttar Pradesh, 226031, India.
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Eid R, Abdelsalam M, Fathy AA, Abd-El Ghaffar DM, Elmarghany EB, El-Hanafy AA, Mostafa N, Hamdy N, Niazy NA, Hammad A, Abolenein HM. Predictors of decreased bone mineral density in childhood systemic lupus erythematosus: possible role of osteoprotegerin gene polymorphisms. J Pediatr Endocrinol Metab 2022; 35:79-87. [PMID: 34787382 DOI: 10.1515/jpem-2021-0496] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 11/02/2021] [Indexed: 11/15/2022]
Abstract
OBJECTIVES This study aims to explore effects of osteoprotegerin (OPG) gene polymorphisms and other possible factors on bone mineral density (BMD) in children with systemic lupus erythematosus (SLE). METHODS Osteoprotegerin gene rs2073617 and rs3134069 were evaluated in 74 SLE patients and 100 controls then genotypes, alleles and haplotypes' frequencies were compared between cases and controls and between patients with BMD z-scores above and below -2 evaluated by dual energy X-ray absorptiometry (DEXA). Disease activity was evaluated by SLE disease activity index (SLEDAI). RESULTS The patients aged 14.01 ± 2.6 years and included 57 (77%) females and 27 (36%) patients with BMD z-score below -2. Genotypes, alleles, and haplotypes frequencies did not differ between patients and controls (p>0.05 for all). Rs3134069 GG genotype and G allele (p=0.001, 0.002) and rs2073617 TT genotype and T allele (p=0.01, 0.006) were significantly higher in patients with BMD below -2. Cumulative glucocorticoids dose, disease duration, and SLEDAI scores were higher in patients with BMD below -2 (p=0.01, 0.01, <0.001, respectively). Regression analysis showed T allele of rs2073617, duration of illness (above 36 months), and cumulative SLEDAI (above 10) as independent predictors of decreased BMD (p 0.02, 0.003, and 0.002, respectively). CONCLUSIONS This is the first study to demonstrate OPG gene influence on BMD in children with SLE. The studied SNPs are not risk for developing SLE but, rs2073617 T allele is a possible predictor for reduced BMD in SLE. Other predictors include long disease duration and high activity supporting that osteoporosis in SLE is multifactorial.
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Affiliation(s)
- Riham Eid
- Pediatric Nephrology Unit, Department of Pediatrics, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Maha Abdelsalam
- Immunology Unit, Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.,Immunology Department, Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo, Egypt
| | - Aya A Fathy
- Public Health and Community Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Dena M Abd-El Ghaffar
- Rehabilitation and Physical Medicine Department, Rheumatology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Eman B Elmarghany
- Rehabilitation and Physical Medicine Department, Rheumatology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Aya A El-Hanafy
- Medical Biochemistry Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Nora Mostafa
- Medical Biochemistry Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Nashwa Hamdy
- Pediatric Nephrology Unit, Department of Pediatrics, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Nermeen A Niazy
- Public Health and Community Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ayman Hammad
- Pediatric Nephrology Unit, Department of Pediatrics, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Hadil M Abolenein
- Pediatric Endocrinology and Diabetes Unit, Department of Pediatrics, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Gado M, Baschant U, Hofbauer LC, Henneicke H. Bad to the Bone: The Effects of Therapeutic Glucocorticoids on Osteoblasts and Osteocytes. Front Endocrinol (Lausanne) 2022; 13:835720. [PMID: 35432217 PMCID: PMC9008133 DOI: 10.3389/fendo.2022.835720] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 02/10/2022] [Indexed: 02/06/2023] Open
Abstract
Despite the continued development of specialized immunosuppressive therapies in the form of monoclonal antibodies, glucocorticoids remain a mainstay in the treatment of rheumatological and auto-inflammatory disorders. Therapeutic glucocorticoids are unmatched in the breadth of their immunosuppressive properties and deliver their anti-inflammatory effects at unparalleled speed. However, long-term exposure to therapeutic doses of glucocorticoids decreases bone mass and increases the risk of fractures - particularly in the spine - thus limiting their clinical use. Due to the abundant expression of glucocorticoid receptors across all skeletal cell populations and their respective progenitors, therapeutic glucocorticoids affect skeletal quality through a plethora of cellular targets and molecular mechanisms. However, recent evidence from rodent studies, supported by clinical data, highlights the considerable role of cells of the osteoblast lineage in the pathogenesis of glucocorticoid-induced osteoporosis: it is now appreciated that cells of the osteoblast lineage are key targets of therapeutic glucocorticoids and have an outsized role in mediating their undesirable skeletal effects. As part of this article, we review the molecular mechanisms underpinning the detrimental effects of supraphysiological levels of glucocorticoids on cells of the osteoblast lineage including osteocytes and highlight the clinical implications of recent discoveries in the field.
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Affiliation(s)
- Manuel Gado
- Center for Regenerative Therapies TU Dresden, Technische Universität Dresden, Dresden, Germany
| | - Ulrike Baschant
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Center for Healthy Aging, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Lorenz C. Hofbauer
- Center for Regenerative Therapies TU Dresden, Technische Universität Dresden, Dresden, Germany
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Center for Healthy Aging, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Holger Henneicke
- Center for Regenerative Therapies TU Dresden, Technische Universität Dresden, Dresden, Germany
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Center for Healthy Aging, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- *Correspondence: Holger Henneicke,
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36
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Adriaansen BPH, Schröder MAM, Span PN, Sweep FCGJ, van Herwaarden AE, Claahsen-van der Grinten HL. Challenges in treatment of patients with non-classic congenital adrenal hyperplasia. Front Endocrinol (Lausanne) 2022; 13:1064024. [PMID: 36578966 PMCID: PMC9791115 DOI: 10.3389/fendo.2022.1064024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 11/25/2022] [Indexed: 12/14/2022] Open
Abstract
Congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase deficiency (21OHD) or 11β-hydroxylase deficiency (11OHD) are congenital conditions with affected adrenal steroidogenesis. Patients with classic 21OHD and 11OHD have a (nearly) complete enzyme deficiency resulting in impaired cortisol synthesis. Elevated precursor steroids are shunted into the unaffected adrenal androgen synthesis pathway leading to elevated adrenal androgen concentrations in these patients. Classic patients are treated with glucocorticoid substitution to compensate for the low cortisol levels and to decrease elevated adrenal androgens levels via negative feedback on the pituitary gland. On the contrary, non-classic CAH (NCCAH) patients have more residual enzymatic activity and do generally not suffer from clinically relevant glucocorticoid deficiency. However, these patients may develop symptoms due to elevated adrenal androgen levels, which are most often less elevated compared to classic patients. Although glucocorticoid treatment can lower adrenal androgen production, the supraphysiological dosages also may have a negative impact on the cardiovascular system and bone health. Therefore, the benefit of glucocorticoid treatment is questionable. An individualized treatment plan is desirable as patients can present with various symptoms or may be asymptomatic. In this review, we discuss the advantages and disadvantages of different treatment options used in patients with NCCAH due to 21OHD and 11OHD.
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Affiliation(s)
- Bas P. H. Adriaansen
- Radboud Institute of Health Sciences, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands
- Department of Pediatric Endocrinology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, Netherlands
| | - Mariska A. M. Schröder
- Department of Pediatric Endocrinology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, Netherlands
| | - Paul N. Span
- Radiotherapy & OncoImmunology Laboratory, Radboud Institute of Molecular Life Sciences, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Fred C. G. J. Sweep
- Radboud Institute of Health Sciences, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Antonius E. van Herwaarden
- Radboud Institute of Health Sciences, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Hedi L. Claahsen-van der Grinten
- Department of Pediatric Endocrinology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, Netherlands
- *Correspondence: Hedi L. Claahsen-van der Grinten,
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Liu Y, Fu B, Li X, Chen C, Li X, Xu L, Wang B. Bushen huoxue decoction inhibits RANKL-stimulated osteoclastogenesis and glucocorticoid-induced bone loss by modulating the NF-κB, ERK, and JNK signaling pathways. Front Pharmacol 2022; 13:1007839. [PMID: 36467086 PMCID: PMC9716084 DOI: 10.3389/fphar.2022.1007839] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 11/09/2022] [Indexed: 11/19/2022] Open
Abstract
Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis, which is caused by a disorder in bone metabolism due to excessive activation of osteoclasts. Bushen Huoxue decoction (BHD) is an herbal formula with multiple pharmacological effects, including anti-inflammatory, antioxidant activity and stem cell migration promotion. However, the effect of BHD on osteoclastogenesis has not been reported. In this study, we aimed to elucidate the effect of BHD on RANKL-stimulated osteoclastogenesis and explored its underlying mechanisms of action in vitro. Our results show that BHD had no effect on BMMs and RAW264.7 cells viability, but inhibited RANKL-induced osteoclast formation in vitro. Furthermore, BHD attenuated RANKL-induced NF-κB, ERK, and JNK signaling. The attenuation of NF-κB, ERK, and JNK activation were enough to impede downstream expression of c-fos and NFATc1 and related specific genes. Meanwhile, we investigated the therapeutic effect of BHD on glucocorticoid-induced osteoporosis (GIOP) mice. The result indicated that BHD prevents glucocorticoid-induced osteoporosis and preserves bone volume by repressing osteoclast activity. Collectively, BHD shows significant osteoclast inhibition and holds great promise in the treatment of osteoporosis.
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Affiliation(s)
- Yamei Liu
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Binlan Fu
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China.,Laboratory of Orthopedics and Traumatology, Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaoman Li
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China.,Laboratory of Orthopedics and Traumatology, Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chen Chen
- School of Chinese Herbal Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xican Li
- School of Chinese Herbal Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Liangliang Xu
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bin Wang
- Department of Traumatology, The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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Sirufo MM, De Pietro F, Catalogna A, Ginaldi L, De Martinis M. The Microbiota-Bone-Allergy Interplay. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 19:ijerph19010282. [PMID: 35010543 PMCID: PMC8750778 DOI: 10.3390/ijerph19010282] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/22/2021] [Accepted: 12/24/2021] [Indexed: 12/18/2022]
Abstract
Emerging knowledge suggests an increasing importance of gut microbiota in health and disease. Allergy and bone metabolism are closely interconnected, and the possible negative effects of common therapies are not the only aspects of this relationship. The immune system is influenced by the microbiota-host interactions, and several pieces of evidence suggest the existence of an interplay between microbiota, bone metabolism, and allergies. Understanding these inter-relationships is essential for the development of new potential strategies of treatment and prevention targeting microbiota. A wide range of substances and germs, prebiotics and probiotics, are capable of influencing and modifying the microbiota. Prebiotics and probiotics have been shown in several studies to have different actions based on various factors such as sex, hormonal status, and age. In this review, we summarize the latest knowledge on the topic, and we discuss practical implications and the need for further studies.
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Affiliation(s)
- Maria Maddalena Sirufo
- Department of Life, Health and Environmental Sciences, University of L’Aquila, Piazzale Salvatore Tommasi n. 1, 67100 L’Aquila, Italy; (M.M.S.); (F.D.P.); (A.C.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04, 64100 Teramo, Italy
| | - Francesca De Pietro
- Department of Life, Health and Environmental Sciences, University of L’Aquila, Piazzale Salvatore Tommasi n. 1, 67100 L’Aquila, Italy; (M.M.S.); (F.D.P.); (A.C.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04, 64100 Teramo, Italy
| | - Alessandra Catalogna
- Department of Life, Health and Environmental Sciences, University of L’Aquila, Piazzale Salvatore Tommasi n. 1, 67100 L’Aquila, Italy; (M.M.S.); (F.D.P.); (A.C.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04, 64100 Teramo, Italy
| | - Lia Ginaldi
- Department of Life, Health and Environmental Sciences, University of L’Aquila, Piazzale Salvatore Tommasi n. 1, 67100 L’Aquila, Italy; (M.M.S.); (F.D.P.); (A.C.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04, 64100 Teramo, Italy
| | - Massimo De Martinis
- Department of Life, Health and Environmental Sciences, University of L’Aquila, Piazzale Salvatore Tommasi n. 1, 67100 L’Aquila, Italy; (M.M.S.); (F.D.P.); (A.C.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04, 64100 Teramo, Italy
- Correspondence: ; Tel.: +39-0861-429548
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Antihistamines Potentiate Dexamethasone Anti-Inflammatory Effects. Impact on Glucocorticoid Receptor-Mediated Expression of Inflammation-Related Genes. Cells 2021; 10:cells10113026. [PMID: 34831249 PMCID: PMC8617649 DOI: 10.3390/cells10113026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 10/29/2021] [Accepted: 11/02/2021] [Indexed: 12/20/2022] Open
Abstract
Antihistamines and glucocorticoids (GCs) are often used together in the clinic to treat several inflammation-related situations. Although there is no rationale for this association, clinical practice has assumed that, due to their concomitant anti-inflammatory effects, there should be an intrinsic benefit to their co-administration. In this work, we evaluated the effects of the co-treatment of several antihistamines on dexamethasone-induced glucocorticoid receptor transcriptional activity on the expression of various inflammation-related genes in A549 and U937 cell lines. Our results show that all antihistamines potentiate GCs' anti-inflammatory effects, presenting ligand-, cell- and gene-dependent effects. Given that treatment with GCs has strong adverse effects, particularly on bone metabolism, we also examined the impact of antihistamine co-treatment on the expression of bone metabolism markers. Using MC3T3-E1 pre-osteoblastic cells, we observed that, though the antihistamine azelastine reduces the expression of dexamethasone-induced bone loss molecular markers, it potentiates osteoblast apoptosis. Our results suggest that the synergistic effect could contribute to reducing GC clinical doses, ineffective by itself but effective in combination with an antihistamine. This could result in a therapeutic advantage, as the addition of an antihistamine may reinforce the wanted effects of GCs, while related adverse effects could be diminished or at least mitigated. By modulating the patterns of gene activation/repression mediated by GR, antihistamines could enhance only the desired effects of GCs, allowing their effective dose to be reduced. Further research is needed to correctly determine the clinical scope, benefits, and potential risks of this therapeutic strategy.
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40
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The Effects of Osteoporotic and Non-osteoporotic Medications on Fracture Risk and Bone Mineral Density. Drugs 2021; 81:1831-1858. [PMID: 34724173 PMCID: PMC8578161 DOI: 10.1007/s40265-021-01625-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2021] [Indexed: 12/26/2022]
Abstract
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.
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Alrowaili MG, Hussein AM, Eid EA, Serria MS, Abdellatif H, Sakr HF. Effect of Intermittent Fasting on Glucose Homeostasis and Bone Remodeling in Glucocorticoid-Induced Osteoporosis Rat Model. J Bone Metab 2021; 28:307-316. [PMID: 34905677 PMCID: PMC8671024 DOI: 10.11005/jbm.2021.28.4.307] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/19/2021] [Accepted: 09/28/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The present study examined the effect of intermittent fasting (IF) on bone mineral content (BMC) and bone mineral density (BMD) and the markers of bone remodeling in a glucocorticoid-induced osteoporosis (GIO) rat model. METHODS Forty male rats were allocated to 4 groups (N=10 per group): control group of normal rats; control+IF group (normal rats subjected to IF for 16-18 hr daily for 90 days); dexamethasone (DEX) group: (DEX [0.5 mg i.p.] for 90 days); and DEX+IF group (DEX and IF for 90 days). By the end of the experiment, BMD and BMC in the right tibia were measured. Serum levels of the following were measured: glucose; insulin; triglycerides (TGs); total cholesterol; parathyroid hormone (PTH); osteoprotegerin (OPG); receptor activator of nuclear factor-κB (RANK); bone-resorbing cytokines, including bone deoxypyridinoline (DPD), N-terminal telopeptide of collagen type I (NTX-1), and tartrate-resistant acid phosphatase 5b (TRAP-5b); and bone-forming cytokines, including alkaline phosphatase (ALP) and osteocalcin (OC). RESULTS DEX administration for 90 days resulted in significantly increased serum levels of glucose, insulin, TGs, cholesterol, PTH, OPG, DPD, NTX-1, and TRAP-5b and significantly decreased BMD, BMC, and serum levels of RANK, OC, and ALP (all P<0.05). IF for 90 days significantly improved all these parameters (all P<0.05). CONCLUSIONS IF corrected GIO in rats by inhibiting osteoclastogenesis and PTH secretion and stimulating osteoblast activity.
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Affiliation(s)
- Majed G. Alrowaili
- Department of Surgery (Orthopedic Division), Faculty of Medicine, Northern Border University, Arar,
Saudi Arabia
| | - Abdelaziz M. Hussein
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura,
Egypt
| | - Elsayed A. Eid
- Department of Internal Medicine and Endocrinology, Delta University for Science and Technology, Gamasa,
Egypt
| | - Mohamed S. Serria
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura,
Egypt
| | - Hussein Abdellatif
- Department of Human and Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat,
Oman
- Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura,
Egypt
| | - Hussein F Sakr
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura,
Egypt
- Department of Physiology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat,
Oman
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Velentza L, Zaman F, Sävendahl L. Bone health in glucocorticoid-treated childhood acute lymphoblastic leukemia. Crit Rev Oncol Hematol 2021; 168:103492. [PMID: 34655742 DOI: 10.1016/j.critrevonc.2021.103492] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 08/05/2021] [Accepted: 09/08/2021] [Indexed: 12/30/2022] Open
Abstract
Glucocorticoids (GCs) are widely used in the treatment of childhood acute lymphoblastic leukemia (ALL), but their long-term use is also associated with bone-related morbidities. Among others, growth deficit, decreased bone mineral density (BMD) and increased fracture rate are well-documented and severely impact quality of life. Unfortunately, no efficient treatment for the management of bone health impairment in patients and survivors is currently available. The overall goal of this review is to discuss the existing data on how GCs impair bone health in pediatric ALL and attempts made to minimize these side effects.
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Affiliation(s)
- Lilly Velentza
- Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
| | - Farasat Zaman
- Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Lars Sävendahl
- Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Pediatric Endocrinology Unit, Karolinska University Hospital, Stockholm, Sweden
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Saag KG, McDermott MT, Adachi J, Lems W, Lane NE, Geusens P, Kees Stad R, Chen L, Huang S, Dore R, Cohen S. The Effect of Discontinuing Denosumab in Patients With Rheumatoid Arthritis Treated With Glucocorticoids. Arthritis Rheumatol 2021; 74:604-611. [PMID: 34535967 PMCID: PMC9305881 DOI: 10.1002/art.41981] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 08/11/2021] [Accepted: 09/14/2021] [Indexed: 11/23/2022]
Abstract
Objective To evaluate changes in bone turnover and bone mineral density (BMD) in patients with rheumatoid arthritis (RA) receiving glucocorticoids, after discontinuation of denosumab for 12 months. Methods We conducted a randomized, double‐blind, placebo‐controlled, phase II study of RA patients. Patients received placebo, denosumab 60 mg, or denosumab 180 mg every 6 months for 12 months and were followed up for an additional 12 months after discontinuation, during which no bone loss prevention therapy was instituted. Changes from baseline in serum C‐terminal telopeptide of type I collagen (CTX), serum procollagen type I N‐terminal propeptide (PINP), and lumbar spine and total hip BMD were evaluated. Results In this post hoc analysis of patients treated with glucocorticoids at study baseline (n = 82), levels of CTX and PINP decreased significantly from baseline in both denosumab groups. Following denosumab discontinuation, CTX returned to baseline and was not significantly different from the placebo group 6 and 12 months after discontinuation. Median percentage changes from baseline PINP in those treated with denosumab 60 mg were −0.16% and 15.3% at 6 and 12 months, respectively, after discontinuation (P = 0.062 and P = 0.017, versus placebo); corresponding changes with denosumab 180 mg were 9.0% and 75.8%, respectively (P = 0.018 and P = 0.002 versus placebo). Compared to placebo, lumbar spine and total hip BMD increased in patients receiving denosumab and returned to baseline 12 months after discontinuation. No osteoporotic fractures were reported during treatment or in the off‐treatment period. Conclusion In this analysis of short‐term denosumab use in RA patients receiving glucocorticoids, denosumab discontinuation resulted in a gradual increase in bone turnover, which was associated with a return to baseline lumbar spine and total hip BMD.
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Affiliation(s)
| | | | | | - Willem Lems
- Amsterdam Universitair Medische Centra, VU Medisch Centrum, Amsterdam, The Netherlands
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Osteoprotegerin expression and serum values in obese women with type 2 diabetes mellitus. Mol Biol Rep 2021; 48:7095-7104. [PMID: 34487291 PMCID: PMC8419664 DOI: 10.1007/s11033-021-06699-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 08/31/2021] [Indexed: 10/25/2022]
Abstract
BACKGROUND Obesity and diabetes prevalence are increasing worldwide. We aimed to detect the possible association of osteoprotegerin (OPG) gene expression with visceral adiposity indices and cardiometabolic risk factors among obese women. METHODS AND RESULTS The study enrolled 150 controls and 150 obese cases subdivided into two subgroups non-diabetic (n = 70) and 80 patients with type 2 diabetes mellitus (T2DM). Circulating OPG gene expression levels were figured out by real time PCR (Polymerase Chain Reaction). Serum OPG levels were assessed by Enzyme Linked Immunosorbent Assay. Our results explored that OPG serum levels were lower in the obese women compared to control group (p < 0.001) and obese diabetics had higher serum levels of OPG in comparison to obese non-diabetic patients (p < 0.001). Expression levels of OPG were higher in obese women than controls (p < 0.001). Moreover, the blood expression levels of OPG gene were higher in diabetic obese patients than non-diabetics. We found positive correlations between parameters of metabolic syndrome and obesity indices. After adjustment of the traditional risk factors, stepwise linear regression analysis test revealed that OPG expression levels were independently correlated with glycated hemoglobin, high-density lipoprotein-cholesterol, and waist-to-hip ratio. CONCLUSIONS OPG mRNA levels were associated with surrogate markers of insulin resistance in Egyptian obese women.
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Steell L, Gray SR, Russell RK, MacDonald J, Seenan JP, Wong SC, Gaya DR. Pathogenesis of Musculoskeletal Deficits in Children and Adults with Inflammatory Bowel Disease. Nutrients 2021; 13:nu13082899. [PMID: 34445056 PMCID: PMC8398806 DOI: 10.3390/nu13082899] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 08/18/2021] [Accepted: 08/20/2021] [Indexed: 12/11/2022] Open
Abstract
Musculoskeletal deficits are among the most commonly reported extra-intestinal manifestations and complications of inflammatory bowel disease (IBD), especially in those with Crohn’s disease. The adverse effects of IBD on bone and muscle are multifactorial, including the direct effects of underlying inflammatory disease processes, nutritional deficits, and therapeutic effects. These factors also indirectly impact bone and muscle by interfering with regulatory pathways. Resultantly, individuals with IBD are at increased risk of osteoporosis and sarcopenia and associated musculoskeletal morbidity. In paediatric IBD, these factors may contribute to suboptimal bone and muscle accrual. This review evaluates the main pathogenic factors associated with musculoskeletal deficits in children and adults with IBD and summarises the current literature and understanding of the musculoskeletal phenotype in these patients.
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Affiliation(s)
- Lewis Steell
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, UK; (L.S.); (S.R.G.)
| | - Stuart R. Gray
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, UK; (L.S.); (S.R.G.)
| | - Richard K. Russell
- Department of Paediatric Gastroenterology, Royal Hospital for Sick Children, Edinburgh EH16 4TJ, UK;
| | - Jonathan MacDonald
- Department of Gastroenterology, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK; (J.M.); (J.P.S.)
| | - John Paul Seenan
- Department of Gastroenterology, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK; (J.M.); (J.P.S.)
| | - Sze Choong Wong
- Department of Paediatric Endocrinology, Royal Hospital for Children, Glasgow G51 4TF, UK;
| | - Daniel R. Gaya
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow G4 0SF, UK
- Correspondence:
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Peng CH, Lin WY, Yeh KT, Chen IH, Wu WT, Lin MD. The molecular etiology and treatment of glucocorticoid-induced osteoporosis. Tzu Chi Med J 2021; 33:212-223. [PMID: 34386357 PMCID: PMC8323641 DOI: 10.4103/tcmj.tcmj_233_20] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/19/2020] [Accepted: 12/30/2020] [Indexed: 12/30/2022] Open
Abstract
Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis, accounting for 20% of osteoporosis diagnoses. Using glucocorticoids for >6 months leads to osteoporosis in 50% of patients, resulting in an increased risk of fracture and death. Osteoblasts, osteocytes, and osteoclasts work together to maintain bone homeostasis. When bone formation and resorption are out of balance, abnormalities in bone structure or function may occur. Excess glucocorticoids disrupt the bone homeostasis by promoting osteoclast formation and prolonging osteoclasts' lifespan, leading to an increase in bone resorption. On the other hand, glucocorticoids inhibit osteoblasts' formation and facilitate apoptosis of osteoblasts and osteocytes, resulting in a reduction of bone formation. Several signaling pathways, signaling modulators, endocrines, and cytokines are involved in the molecular etiology of GIOP. Clinically, adults ≥40 years of age using glucocorticoids chronically with a high fracture risk are considered to have medical intervention. In addition to vitamin D and calcium tablet supplementations, the major therapeutic options approved for GIOP treatment include antiresorption drug bisphosphonates, parathyroid hormone N-terminal fragment teriparatide, and the monoclonal antibody denosumab. The selective estrogen receptor modulator can only be used under specific condition for postmenopausal women who have GIOP but fail to the regular GIOP treatment or have specific therapeutic contraindications. In this review, we focus on the molecular etiology of GIOP and the molecular pharmacology of the therapeutic drugs used for GIOP treatment.
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Affiliation(s)
- Cheng-Huan Peng
- Department of Orthopedics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.,Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.,School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Wen-Ying Lin
- Department of Orthopedics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Kuang-Ting Yeh
- Department of Orthopedics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.,School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Ing-Ho Chen
- Department of Orthopedics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.,School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Wen-Tien Wu
- Department of Orthopedics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.,Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.,School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Ming-Der Lin
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.,Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan
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Vincze A, Gaál J, Griger Z. Bone Health in Idiopathic Inflammatory Myopathies: Diagnosis and Management. Curr Rheumatol Rep 2021; 23:55. [PMID: 34196873 PMCID: PMC8249248 DOI: 10.1007/s11926-021-01016-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2021] [Indexed: 01/22/2023]
Abstract
PURPOSE OF REVIEW This article provides an update on the most recent advances in epidemiology, pathogenesis, diagnostic procedures, and therapeutic approaches for myositis-associated bone diseases, such as osteoporosis and bone fractures. RECENT FINDINGS In the recent years, several studies showed that osteoporosis and consequent fractures are a common and frequently underestimated complication in patients with idiopathic inflammatory myopathies (IIM). In younger patients, asymptomatic fractures might present in the early phase of the disease which could increase the risk of development of further fractures. High-risk patients could be selected with early application of combined diagnostic procedures, such as fracture risk scores with steroid dose adjustments and imaging. Recent advances might help clinicians from different fields of medicine in the early recognition and management of myositis-associated osteoporosis, which will potentially improve the quality of life of patients with IIM.
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Affiliation(s)
- Anett Vincze
- Division of Clinical Immunology, Faculty of Medicine, University of Debrecen, Móricz Zsigmond út 22, Debrecen, H-4032, Hungary
- Gyula Petrányi Doctoral School of Clinical Immunology and Allergology, University of Debrecen, Debrecen, Hungary
| | - János Gaál
- Division of Clinical Immunology, Faculty of Medicine, University of Debrecen, Móricz Zsigmond út 22, Debrecen, H-4032, Hungary
- Gyula Petrányi Doctoral School of Clinical Immunology and Allergology, University of Debrecen, Debrecen, Hungary
- Department of Medicine, Kenézy Gyula University Hospital, University of Debrecen, Debrecen, Hungary
| | - Zoltán Griger
- Division of Clinical Immunology, Faculty of Medicine, University of Debrecen, Móricz Zsigmond út 22, Debrecen, H-4032, Hungary.
- Gyula Petrányi Doctoral School of Clinical Immunology and Allergology, University of Debrecen, Debrecen, Hungary.
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48
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Rajakumar SA, Papp E, Lee KK, Grandal I, Merico D, Liu CC, Allo B, Zhang L, Grynpas MD, Minden MD, Hitzler JK, Guidos CJ, Danska JS. B cell acute lymphoblastic leukemia cells mediate RANK-RANKL-dependent bone destruction. Sci Transl Med 2021; 12:12/561/eaba5942. [PMID: 32938796 DOI: 10.1126/scitranslmed.aba5942] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 06/05/2020] [Accepted: 07/21/2020] [Indexed: 12/20/2022]
Abstract
Although most children survive B cell acute lymphoblastic leukemia (B-ALL), they frequently experience long-term, treatment-related health problems, including osteopenia and osteonecrosis. Because some children present with fractures at ALL diagnosis, we considered the possibility that leukemic B cells contribute directly to bone pathology. To identify potential mechanisms of B-ALL-driven bone destruction, we examined the p53 -/-; Rag2 -/-; Prkdcscid/scid triple mutant (TM) mice and p53 -/-; Prkdcscid/scid double mutant (DM) mouse models of spontaneous B-ALL. In contrast to DM animals, leukemic TM mice displayed brittle bones, and the TM leukemic cells overexpressed Rankl, encoding receptor activator of nuclear factor κB ligand. RANKL is a key regulator of osteoclast differentiation and bone loss. Transfer of TM leukemic cells into immunodeficient recipient mice caused trabecular bone loss. To determine whether human B-ALL can exert similar effects, we evaluated primary human B-ALL blasts isolated at diagnosis for RANKL expression and their impact on bone pathology after their transplantation into NOD.Prkdcscid/scidIl2rgtm1Wjl /SzJ (NSG) recipient mice. Primary B-ALL cells conferred bone destruction evident in increased multinucleated osteoclasts, trabecular bone loss, destruction of the metaphyseal growth plate, and reduction in adipocyte mass in these patient-derived xenografts (PDXs). Treating PDX mice with the RANKL antagonist recombinant osteoprotegerin-Fc (rOPG-Fc) protected the bone from B-ALL-induced destruction even under conditions of heavy tumor burden. Our data demonstrate a critical role of the RANK-RANKL axis in causing B-ALL-mediated bone pathology and provide preclinical support for RANKL-targeted therapy trials to reduce acute and long-term bone destruction in these patients.
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Affiliation(s)
- Sujeetha A Rajakumar
- Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Eniko Papp
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.,Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
| | - Kathy K Lee
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5T 3H7, Canada.,Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Ildiko Grandal
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
| | - Daniele Merico
- Center for Applied Genomics, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
| | - Careesa C Liu
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5T 3H7, Canada.,Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Bedilu Allo
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5T 3H7, Canada
| | - Lucia Zhang
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5T 3H7, Canada.,Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Marc D Grynpas
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5T 3H7, Canada.,Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Mark D Minden
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.,Princess Margaret Cancer Center, University Health Network, Toronto, Ontario M5G 2M9, Canada
| | - Johann K Hitzler
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.,Department of Pediatrics, Division of Hematology and Oncology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
| | - Cynthia J Guidos
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.,Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Jayne S Danska
- Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada. .,Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.,Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
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49
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Cho SK, Sung YK. Update on Glucocorticoid Induced Osteoporosis. Endocrinol Metab (Seoul) 2021; 36:536-543. [PMID: 34107602 PMCID: PMC8258322 DOI: 10.3803/enm.2021.1021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/17/2021] [Accepted: 04/19/2021] [Indexed: 12/26/2022] Open
Abstract
Glucocorticoids are used to treat many autoimmune and inflammatory diseases. However, an adverse systemic effect is a deleterious effect on bone, which may lead to glucocorticoid-induced osteoporosis, characterized by a rapid and transient increase in bone resorption and fracture risk, which may increase rapidly within 3 months of commencing oral glucocorticoids. Therefore, early risk assessment and intervention are crucial for preventing fractures in patients receiving glucocorticoids. Recent practice guidelines recommend an assessment for fracture risk in patients beginning or receiving glucocorticoids for more than 3 months, and they have suggested fracture risk assessment tool values for identifying patients who need preventive treatment. Bisphosphonates are currently the recommended first-line therapy for the prevention and treatment of glucocorticoid-induced osteoporosis. These have been shown to increase the bone mineral density in the spine and hip and to decrease the incidence of vertebral fractures. Recently, a more potent antiresorptive agent, denosumab, has been shown to increase the bone density in patients receiving glucocorticoids. Teriparatide has been shown to have a preventive effect on vertebral fractures, but not on nonvertebral fractures. In this article we aimed to provide an update on glucocorticoid-induced osteoporosis by focusing on the assessment of its risk and treatment options.
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Affiliation(s)
- Soo-Kyung Cho
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
| | - Yoon-Kyoung Sung
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
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50
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Elango J, Bao B, Wu W. The hidden secrets of soluble RANKL in bone biology. Cytokine 2021; 144:155559. [PMID: 33994070 DOI: 10.1016/j.cyto.2021.155559] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/24/2021] [Accepted: 04/26/2021] [Indexed: 12/25/2022]
Abstract
The discovery of cytokine tumor necrosis factor (TNF) in the 20th century revealed numerous secrets about organ development. In particular, the functions identified for the receptor activator of nuclear factor kappa-β (NF-κβ) ligand (also known as the RANKL/osteoprotegerin ligand (OPGL) or RANK ligand/TNFSF11) in the homeostasis of skeletal structure, function and regulation were not anticipated. Empirical evidence established the receptor-ligand interaction of RANKL with RANK in osteoclast formation. Reverse signaling of RANKL triggers NF-κβ for the degradation of β-catenin to inhibit bone formation. There is also evidence that RANKL modifies the behavior of other cells in the bone microenvironment, including osteoblasts, chondrocytes, endothelial cells and lymphocytes during normal (homeostatic) and diseased (osteoimmune) states. Two forms of RANKL, i.e., soluble and membrane-bound RANKL, are produced by bone cells. Even though soluble RANKL (sRANKL) and membrane-bound RANKL (mRANKL) both stimulate osteoclast formation in vitro, their biological roles are different. mRANKL triggers osteoclastogenesis by binding to RANK through cell-cell interaction; however, sRANKL released from osteogenic cells binds to RANK without cell-cell interaction. This review attempts to hypothesize how sRANKL functions biologically in bone and explore how this hypothesis might influence future research.
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Affiliation(s)
- Jeevithan Elango
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China.
| | - Bin Bao
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Wenhui Wu
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China.
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