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Sakuma H, Kanemaru H, Kurokawa A, Soga M, Yamashita M, Nozawa-Kobayashi M, Niimi K, Kobayashi T. Prevalence of MRONJ in patients treated with antiresorptive agents for glucocorticoid-induced osteoporosis. Oral Maxillofac Surg 2025; 29:84. [PMID: 40237920 DOI: 10.1007/s10006-025-01383-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 04/07/2025] [Indexed: 04/18/2025]
Abstract
PURPOSE In this study, we aimed to investigate the incidence of medication-related osteonecrosis of the jaw (MRONJ) in patients with glucocorticoid-induced osteoporosis (GIOP) and to examine risk factors for MRONJ development, as well as the preventive effect of tooth extraction before antiresorptive agent (ARA) administration. METHODS This retrospective study included patients who received ARA to prevent fragility fractures due to GIOP. The cumulative incidence of MRONJ in patients with GIOP was calculated using the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were used to analyze risk factors for MRONJ occurrence. RESULTS The study included 327 individuals. Six patients developed MRONJ; the crude incidence of MRONJ was 1.8%, and the cumulative incidence at 1, 2, 3, 4, and 5 years was 0.32%, 0.97%, 1.35%, 1.85%, and 2.56%, respectively. In this study, 159 teeth were extracted during dental intervention before ARA administration in 58 patients; however, no MRONJ development was observed at the extraction site. Tooth extraction, diabetes mellitus, and duration of ARA administration were not identified as risk factors in this study. CONCLUSIONS The incidence of MRONJ in patients with GIOP was higher than the previously reported incidence in patients with age-related osteoporosis but lower than the incidence in patients using high-dose ARA. The results support the effectiveness of prophylactic procedures to remove the infected lesions as much as possible from the jawbone and periodontal tissue before ARA administration. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Hidenobu Sakuma
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274, Gakkocho, Niigata City, 951-8514, Japan.
| | - Hiroko Kanemaru
- Oral Management Clinic for Medical Cooperation, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - Akira Kurokawa
- Oral Management Clinic for Medical Cooperation, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - Marie Soga
- Oral Management Clinic for Medical Cooperation, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - Moe Yamashita
- Oral Management Clinic for Medical Cooperation, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - Mai Nozawa-Kobayashi
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274, Gakkocho, Niigata City, 951-8514, Japan
- Minamiuonuma City Yukiguni Yamato Hospital Dentistry/Pediatric Dentistry, Minamiuonuma, Japan
| | - Kanae Niimi
- Patient Support Center, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - Tadaharu Kobayashi
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274, Gakkocho, Niigata City, 951-8514, Japan
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Khanka S, Rastogi SK, Singh KB, Sharma K, Parwez S, Siddiqi MI, Sinha AK, Kumar R, Singh D. Pym-18a, a novel pyrimidine derivative ameliorates glucocorticoid induced osteoblast apoptosis and promotes osteogenesis via autophagy and PINK 1/Parkin mediated mitophagy induction. Biochem Pharmacol 2025; 233:116751. [PMID: 39800267 DOI: 10.1016/j.bcp.2025.116751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 12/11/2024] [Accepted: 01/09/2025] [Indexed: 01/15/2025]
Abstract
Glucocorticoid-induced osteoporosis (GIOP) is the most common type of secondary osteoporosis, marked by reduced bone density and impaired osteoblast function. Current treatments have serious side effects, highlighting the need for new drug candidates. Pyrimidine derivatives have been noted for their potential in suppressing osteoclastogenesis, but their effects on osteogenesis and GIOP remain underexplored. Our recent study identified a novel pyrimidine derivative, Pym-18a, which enhances osteoblast functions. In this study, Pym-18a was found to mitigate the detrimental effects of Dexamethasone (Dex) in osteoblast cells and in GIOP in Balb/C mice. Pretreatment with Pym-18a followed by Dex (100 µM) for 24 h restored osteoblast alkaline phosphatase activity and viability. Pym-18a reduced Dex-induced apoptosis and reactive oxygen species (ROS) generation at cellular and mitochondrial levels and preserved mitochondrial membrane potential. Dex impaired autophagy and mitophagy, however but Pym-18a pretreatment increased expression of autophagy markers (LC3II) and mitophagy markers (PINK1, Parkin, TOM20) while decreasing P62 expression. The osteogenic effects of Pym-18a were diminished in the presence of 3-MA (an autophagy inhibitor). In silico studies showed mTOR inhibition by Pym-18a, corroborated by its suppression of Dex-induced mTOR activation. In vivo, Pym-18a (10 mg/kg) significantly improved bone microarchitecture, trabecular connectivity, and strength, and corrected P1NP and CTX levels altered by Dex. Pym-18a also promoted autophagy, mitophagy, and suppressed mTOR activation in GIOP mice. Overall, Pym-18a mitigates detrimental effect of Dex by modulating autophagy and PINK/Parkin-mediated mitophagy through mTOR inhibition, suggesting it as a potential novel therapeutic option for GIOP.
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Affiliation(s)
- Sonu Khanka
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Sumit K Rastogi
- Division of Medicinal & Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Krishna Bhan Singh
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Kriti Sharma
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Shahid Parwez
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Mohammad Imran Siddiqi
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Arun K Sinha
- Division of Medicinal & Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Ravindra Kumar
- Division of Medicinal & Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Divya Singh
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India.
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Li H, Liu H, Wang B, Liang N, Wu M, Qi X, Lu H. Joint replacement for rheumatoid arthritis: When, why, and how! Insights from an orthopedic surgeon. Best Pract Res Clin Rheumatol 2025; 39:102034. [PMID: 39828465 DOI: 10.1016/j.berh.2025.102034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 12/30/2024] [Accepted: 01/08/2025] [Indexed: 01/22/2025]
Abstract
The past several decades have seen significant advancements in joint replacement surgery for rheumatoid arthritis (RA). Joint replacement procedures have become vital options for patients with severe joint damage and functional impairment. There has been an increased emphasis on personalized surgical strategies that tailor joint replacement decisions based on a patient's unique clinical characteristics and the extent of joint damage. Achieving personalized outcomes requires clearly understanding the patient's baseline joint function and comparative data on different prosthetic designs and techniques. Comprehensive preoperative preparation is fundamental to ensuring surgical success. This includes thoroughly evaluating the patient's medication history, the extent of joint damage, and overall systemic health. Despite careful surgical planning, trade-offs between different replacement options often remain. In this paper, we review the perioperative preparation and surgical techniques in joint replacement surgery for RA. Additionally, we discuss the challenges in optimizing postoperative rehabilitation and preventing complications, which remains a key factor in achieving full recovery and maximizing the benefits of joint replacement surgery for RA patients. The pathological basis of RA is an acute or chronic inflammation of the synovial membrane. As a result, synovial joints throughout the body can be affected, including joints in the upper limbs (shoulders, elbows, wrists, metacarpophalangeal joints, and interphalangeal joints) as well as in the lower limbs (hips, knees, and ankles). If drug treatments fail to control inflammation adequately, recurrent synovitis in the affected joints can lead to swelling, effusion, cartilage erosion, and eventual cartilage loss. Due to decreased weight-bearing, along with the use of various medications-particularly glucocorticoids-widespread subchondral bone osteoporosis, bone marrow edema, and bone destruction may occur, leading to cystic degeneration and even extensive bone defects. In the advanced stages of RA, deformities can develop, such as "boutonniere" and "swan-neck" deformities in the fingers, ulnar deviation of the wrist, "otto pelvic" due to central acetabular erosion and dislocation of the hip, varus or valgus deformities of the knee, flexion contractures, and destruction or fusion of the ankle joint. The foot can also present deformities, such as hallux valgus and overlapping toes. Total joint replacement surgery has become the most effective surgical treatment for severe joint destruction and deformities in late-stage RA. Among all joints, the hip and knee are the most frequently replaced, as their dysfunction severely impacts the patient's ability to walk, leading to disability and loss of mobility. In this review, we provided a comprehensive discussion on the perioperative management of patients with RA, focusing on preoperative preparation, intraoperative planning, and postoperative rehabilitation and assessment. Rheumatology Department Perspective on Preoperative Preparation for RA Joint Replacement Surgery.
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Affiliation(s)
- Hu Li
- Department of Arthritis Clinic and Research Center, Peking University People's Hospital, Beijing, 100044, China
| | - Hao Liu
- Department of Orthopedics, Peking University Third Hospital, Beijing, 100191, China
| | - Boyang Wang
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, 100044, China
| | - Ninggang Liang
- Department of Arthritis Clinic and Research Center, Peking University People's Hospital, Beijing, 100044, China
| | - Moxuan Wu
- Department of Arthritis Clinic and Research Center, Peking University People's Hospital, Beijing, 100044, China
| | - Xuan Qi
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China; Department of Rheumatism and Immunology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Houshan Lu
- Department of Arthritis Clinic and Research Center, Peking University People's Hospital, Beijing, 100044, China.
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Tan L, Tu Y, Miao Z, Zhao Y, Liang Y, Zhong J, Zhong R, Xu N, Chen X, He C. Glycyrol alleviates osteoporosis through dual modulation on osteoclastogenesis and osteogenesis by targeting Syk signaling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 138:156429. [PMID: 39939034 DOI: 10.1016/j.phymed.2025.156429] [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: 06/21/2024] [Revised: 01/14/2025] [Accepted: 01/24/2025] [Indexed: 02/14/2025]
Abstract
BACKGROUND Osteoporosis, characterized by an imbalance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation, has become a serious public health challenge worldwide. Glycyrol (GC) is a representative natural coumestan isolated from licorice that shows multiple pharmacological activities, but its anti-osteoporotic effect and underlying mechanisms remain unclear. RESULTS GC significantly suppressed lipopolysaccharide-induced mouse bone loss and dexamethasone-induced zebrafish bone formation deficiency. Meanwhile, GC exhibited dual effects of inhibiting osteoclast formation and bone resorption, and stimulating osteoblast differentiation and mineralization. By combining kinomic screening assay, bioinformatics analysis and cellular target engagement validation, spleen tyrosine kinase (Syk) was identified as a key kinase target of GC. Subsequently, Syk was determined to play important roles in promoting osteoclast formation and impeding osteoblast differentiation. Interestingly, GC directly bound to the active cavity of Syk through hydrogen bonds and significantly inhibited its activity. Moreover, GC remarkably inhibited RANKL-induced activation of Syk/PLCγ2/Ca2+/NFATc1 and MAPK pathways in macrophages undergoing differentiation into osteoclasts. CONCLUSION These results demonstrated that GC exerted a dual regulation on osteoclastogenesis and osteogenesis and consequently alleviated osteoporosis through targeting Syk and its downstream signaling pathways. In addition, the current study emphasizes the key roles of Syk in bone resorption and formation, suggesting the application potential of Syk inhibitors for the management of bone diseases. Meanwhile, this study provides evidence supporting the development of GC or its derivatives as effective anti-resorptive and bone anabolic agents for the prevention or treatment of osteoporosis and other bone diseases.
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Affiliation(s)
- Lihua Tan
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, 999078, China
| | - Yanbei Tu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, 999078, China; School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Zhimin Miao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, 999078, China
| | - Yuxin Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, 999078, China
| | - Yongkai Liang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, 999078, China
| | - Jinmiao Zhong
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, 999078, China
| | - Ruting Zhong
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, 999078, China
| | - Nan Xu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, 999078, China
| | - Xin Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, 999078, China
| | - Chengwei He
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, 999078, China.
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Xu W, Lu G, Gong L, Tang W, Jiang W. Nitrogen-containing bisphosphonate for vascular calcification: animal experiments, systematic review and meta-analysis. BMC Cardiovasc Disord 2025; 25:66. [PMID: 39891062 PMCID: PMC11783937 DOI: 10.1186/s12872-025-04526-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] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 01/26/2025] [Indexed: 02/03/2025] Open
Abstract
BACKGROUND The purpose of our study was to explore the effect of nitrogen-containing bisphosphonate (N-BP) on vascular calcification (VC) through animal experiments and a meta-analysis. METHODS In our animal experiments, Sprague-Dawley (SD) rats were randomly divided into a control group, a VC group, a low-dose zoledronic acid (ZOL) (20 µg/kg) group and a high-dose ZOL (100 µg/kg) group. The calcification of the aortic arch was observed by alizarin red staining. The calcium content of the aortic arch was measured. In our systematic review and meta-analysis, databases, including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI), and the Wanfang database, were searched from their inception to December 20, 2023. Eligible studies comparing N-BP versus no N-BP in the treatment of VC were included. RESULTS In our animal experiment, the red-stained calcification structure in the low-dose ZOL group was slightly reduced and the red-stained calcification structure in the high-dose ZOL group was significantly reduced compared with that in the VC. The calcium content in the low-dose ZOL group was slightly lower than that in the VC group, but the difference was not significant (P = 0.08). The calcium content in the high-dose ZOL group was significantly lower than that in the VC group (P < 0.0001). Our meta-analysis of human studies revealed that N-BP did not reduce the arterial calcification score (P = 0.46). Our meta-analysis of animal studies revealed that N-BP did not significantly reduce the arterial calcification score (P = 0.09), but N-BP reduced the arterial calcification area (P < 0.00001), arterial calcium content (P = 0.009) and PO4 content (P = 0.0001). CONCLUSIONS Our animal experiment revealed that high-dose ZOL inhibited VC, but low-dose ZOL did not significantly inhibit VC. Our meta-analysis of human studies revealed that N-BP was not effective in the treatment of VC, but our meta-analysis of animal studies suggested a role of N-BP in inhibiting VC.
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Affiliation(s)
- Wei Xu
- Department of Nephrology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, 213000, Jiangsu, China.
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China.
| | - Guoyuan Lu
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China
| | - Lifeng Gong
- Department of Nephrology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, 213000, Jiangsu, China
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Weigang Tang
- Department of Nephrology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, 213000, Jiangsu, China
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Wei Jiang
- Department of Nephrology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, 213000, Jiangsu, China
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
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Wang H, Zhao Y, Liu H, Zhang X, Lv S, Zhou T, Cui H, Zhao J, Li X. Untargeted metabolomics revealed the mechanism of aucubin on glucocorticoid-induced osteoporosis in mice through modulating arachidonic acid metabolism. J Pharm Biomed Anal 2024; 248:116273. [PMID: 38878451 DOI: 10.1016/j.jpba.2024.116273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 05/28/2024] [Accepted: 06/02/2024] [Indexed: 07/20/2024]
Abstract
Glucocorticoid-induced osteoporosis (GIOP) represents the most prevalent form of secondary osteoporosis. Aucubin (AU), a principal active component found in traditional herbal medicines such as Eucommia ulmoides, has been demonstrated to enhance osteoblast differentiation. Nonetheless, the precise therapeutic effects of AU on GIOP and the complex underlying regulatory mechanisms warrant further investigation. We first established a GIOP model in female mice and then assessed the therapeutic effects of AU using micro-CT analysis, biomechanical testing, measurements of serum calcium (Ca) and phosphorus (P) levels, and histological analyses using Hematoxylin and Eosin (HE) and Masson staining. Subsequently, non-targeted metabolomics was employed in order to study the effects of AU on serum metabolites in GIOP mice. The levels of the factors related to these metabolites were quantified using real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blot analyses. Finally, the effects of AU on osteoblastic and osteoclastic differentiation were examined. We found that AU significantly ameliorated bone microarchitecture and strength in GIOP mice. It mitigated pathological damages such as impairment of trabecular bone structure and reduction in collagen fibers, while concurrently elevating serum levels of Ca and P. Non-targeted metabolomics revealed that Arachidonic acid (AA) metabolism serves as a common pathway between the control and GIOP groups, as well as between the high-dose AU (AUH) and GIOP groups. AU notably upregulates prostaglandin-endoperoxide synthase 2 (PTGS2) and microsomal prostaglandin-E synthase 1 (PTGES) expression and downregulates prostaglandin-H2 D-isomerase (PTGDS) expression. Furthermore, AU treatment increased the expression of runt-related transcription factor 2 (Runx2) and transcription factor Sp7 (Osterix), enhanced serum alkaline phosphatase (ALP) activity, and reduced osteoclast expression. These results indicate that AU is a potential drug for treating GIOP, and its mechanism is related to regulating AA metabolism and promoting osteoblast differentiation. However, the key targets of AU in treating GIOP still need further exploration.
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Affiliation(s)
- Hengjun Wang
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province 050091, China; Department of Orthopedics, Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, Hebei Province 061013, China
| | - Yunchao Zhao
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province 050091, China; Department of Orthopedics, Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, Hebei Province 061013, China
| | - Huan Liu
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province 050091, China; Department of Orthopedics, Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, Hebei Province 061013, China
| | - Xuelei Zhang
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province 050091, China; Department of Orthopedics, Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, Hebei Province 061013, China
| | - Shuquan Lv
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province 050091, China; Department of Hebei Key Laboratory of Integrated Traditional Chinese and Western Medicine in Osteoarthrosis Research, Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, Hebei Province 061013, China; Department of Diabetes, Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, Hebei Province 061013, China
| | - Tingting Zhou
- Department of Orthopedics, Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, Hebei Province 061013, China; Department of Hebei Key Laboratory of Integrated Traditional Chinese and Western Medicine in Osteoarthrosis Research, Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, Hebei Province 061013, China; Department of Hebei Province Integrated Traditional Chinese and Western Medicine 3D Printing Technology Innovation Center, Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, Hebei Province 061013, China
| | - Huantian Cui
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, Yunnan Province 650500, China
| | - Jianyong Zhao
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province 050091, China; Department of Orthopedics, Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, Hebei Province 061013, China.
| | - Xiaoming Li
- Department of Orthopedics, Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, Hebei Province 061013, China; Department of Hebei Key Laboratory of Integrated Traditional Chinese and Western Medicine in Osteoarthrosis Research, Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, Hebei Province 061013, China; Department of Hebei Province Integrated Traditional Chinese and Western Medicine 3D Printing Technology Innovation Center, Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou, Hebei Province 061013, China.
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7
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Ding P, Gao C, Zhou J, Mei J, Li G, Liu D, Li H, Liao P, Yao M, Wang B, Lu Y, Peng X, Jiang C, Yin J, Huang Y, Zheng M, Gao Y, Zhang C, Gao J. Mitochondria from osteolineage cells regulate myeloid cell-mediated bone resorption. Nat Commun 2024; 15:5094. [PMID: 38877020 PMCID: PMC11178781 DOI: 10.1038/s41467-024-49159-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 05/24/2024] [Indexed: 06/16/2024] Open
Abstract
Interactions between osteolineage cells and myeloid cells play important roles in maintaining skeletal homeostasis. Herein, we find that osteolineage cells transfer mitochondria to myeloid cells. Impairment of the transfer of mitochondria by deleting MIRO1 in osteolineage cells leads to increased myeloid cell commitment toward osteoclastic lineage cells and promotes bone resorption. In detail, impaired mitochondrial transfer from osteolineage cells alters glutathione metabolism and protects osteoclastic lineage cells from ferroptosis, thus promoting osteoclast activities. Furthermore, mitochondrial transfer from osteolineage cells to myeloid cells is involved in the regulation of glucocorticoid-induced osteoporosis, and glutathione depletion alleviates the progression of glucocorticoid-induced osteoporosis. These findings reveal an unappreciated mechanism underlying the interaction between osteolineage cells and myeloid cells to regulate skeletal metabolic homeostasis and provide insights into glucocorticoid-induced osteoporosis progression.
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Affiliation(s)
- Peng Ding
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
- Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
| | - Chuan Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
- Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
| | - Jian Zhou
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
- Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
| | - Jialun Mei
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
- Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
| | - Gan Li
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
- Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
| | - Delin Liu
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
- Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
| | - Hao Li
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
- Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
| | - Peng Liao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
- Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
| | - Meng Yao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
- Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
| | - Bingqi Wang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
- Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
| | - Yafei Lu
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
- Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
| | - Xiaoyuan Peng
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
| | - Chenyi Jiang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
| | - Jimin Yin
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
| | - Yigang Huang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China
| | - Minghao Zheng
- Centre for Orthopaedic Translational Research, Medical School, University of Western Australia, Nedlands, WA, 6009, Australia
| | - Youshui Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China.
| | - Changqing Zhang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China.
- Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China.
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China.
- Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China.
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8
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Xu W, Lu G, Gong L, Tang W, Liu X, Yang Q, Jiang W, Liu X, Li X. Non-nitrogen-containing bisphosphonates and nitrogen-containing bisphosphonates for the treatment of atherosclerosis and vascular calcification: A meta-analysis. Medicine (Baltimore) 2024; 103:e38404. [PMID: 38847712 PMCID: PMC11155605 DOI: 10.1097/md.0000000000038404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 05/08/2024] [Indexed: 06/10/2024] Open
Abstract
BACKGROUND The role of non-nitrogen-containing bisphosphonates (non-N-BPs) and nitrogen-containing bisphosphonates (N-BPs) in the treatment of atherosclerosis (AS) and vascular calcification (VC) is uncertain. This meta-analysis was conducted to evaluate the efficacy of non-N-BPs and N-BPs in the treatment of AS and VC. METHODS The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases were searched from their inception to July 5th, 2023. Eligible studies comparing bisphosphonates (BPs) versus no BPs in the treatment of AS and VC were included. The data were analyzed using Review Manager Version 5.3. RESULTS Seventeen studies were included in this meta-analysis. Twelve were randomized control trials (RCTs), and 5 were nonrandomized studies. Overall, 813 patients were included in the BPs group, and 821 patients were included in the no BPs group. Compared with no BP treatment, non-N-BP or N-BP treatment did not affect serum calcium (P > .05), phosphorus (P > .05) or parathyroid hormone (PTH) levels (P > .05). Regarding the effect on serum lipids, non-N-BPs decreased the serum total cholesterol (TC) level (P < .05) and increased the serum triglyceride (TG) level (P < .01) but did not affect the serum low-density lipoprotein cholesterol (LDL-C) level (P > .05). N-BPs did not affect serum TC (P > .05), TG (P > .05) or LDL-C levels (P > .05). Regarding the effect on AS, non-N-BPs did not have a beneficial effect (P > .05). N-BPs had a beneficial effect on AS, including reducing the intima-media thickness (IMT) (P < .05) and plaque area (P < .01). For the effect on VC, non-N-BPs had a beneficial effect (P < .01), but N-BPs did not have a beneficial effect (P > .05). CONCLUSION Non-N-BPs and N-BPs did not affect serum calcium, phosphorus or PTH levels. Non-N-BPs decreased serum TC levels and increased serum TG levels. N-BPs did not affect serum lipid levels. Non-N-BPs had a beneficial effect on VC, and N-BPs had a beneficial effect on AS.
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Affiliation(s)
- Wei Xu
- Department of Nephrology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Nephrology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
- Department of Nephrology, People’s Hospital of Hainan Tibetan Autonomous Prefecture, Hainan Tibetan Autonomous Prefecture, Qinghai, China
| | - Guoyuan Lu
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Lifeng Gong
- Department of Nephrology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Nephrology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
| | - Weigang Tang
- Department of Nephrology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Nephrology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
| | - Xiaowu Liu
- Department of Nephrology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Nephrology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
| | - Qichao Yang
- Department of Nephrology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Nephrology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
| | - Wei Jiang
- Department of Nephrology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Nephrology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
- Department of Nephrology, People’s Hospital of Hainan Tibetan Autonomous Prefecture, Hainan Tibetan Autonomous Prefecture, Qinghai, China
| | - Xiaoming Liu
- Department of Nephrology, People’s Hospital of Hainan Tibetan Autonomous Prefecture, Hainan Tibetan Autonomous Prefecture, Qinghai, China
| | - Xianping Li
- Department of Nephrology, People’s Hospital of Hainan Tibetan Autonomous Prefecture, Hainan Tibetan Autonomous Prefecture, Qinghai, China
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9
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van den Bergh JP, Geusens P, Appelman-Dijkstra NM, van den Broek HJG, Elders PJM, de Klerk G, van Oostwaard M, Willems HC, Zillikens MC, Lems WF. The Dutch multidisciplinary guideline osteoporosis and fracture prevention, taking a local guideline to the international arena. Arch Osteoporos 2024; 19:23. [PMID: 38564062 PMCID: PMC10987374 DOI: 10.1007/s11657-024-01378-3] [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: 11/10/2023] [Accepted: 01/26/2024] [Indexed: 04/04/2024]
Abstract
BACKGROUND In 2018, a grant was provided for an evidence-based guideline on osteoporosis and fracture prevention based on 10 clinically relevant questions. METHODS A multidisciplinary working group was formed with delegates from Dutch scientific and professional societies, including representatives from the patient's organization and the Dutch Institute for Medical Knowledge. The purpose was to obtain a broad consensus among all participating societies to facilitate the implementation of the updated guideline. RESULTS Novel recommendations in our guideline are as follows: - In patients with an indication for DXA of the lumbar spine and hips, there is also an indication for VFA. - Directly starting with anabolic drugs (teriparatide or romosozumab) in patients with a very high fracture risk; - Directly starting with zoledronic acid in patients 75 years and over with a hip fracture (independent of DXA); - Directly starting with parenteral drugs (denosumab, teriparatide, zoledronic acid) in glucocorticoid-induced osteoporosis with very high fracture risk; - A lifelong fracture risk management, including lifestyle, is indicated from the start of the first treatment. CONCLUSION In our new multidisciplinary guideline osteoporosis and fracture prevention, we developed 5 "relatively new statements" that are all a crucial step forward in the optimization of diagnosis and treatment for fracture prevention. We also developed 5 flowcharts, and we suppose that this may be helpful for individual doctors and their patients in daily practice and may facilitate implementation.
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Affiliation(s)
- J P van den Bergh
- Department of Internal Medicine, VieCuri Medical Center, Venlo, the Netherlands.
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
| | - P Geusens
- Department of Internal Medicine, Subdivision Rheumatology, Maastricht University Medical Center, Maastricht, the Netherlands
- Department of Medicine and Life Science, Hasselt University, Hasselt, Belgium
| | - N M Appelman-Dijkstra
- Department of Internal Medicine, Division Endocrinology, Leiden University Medical Center, Leiden, the Netherlands
| | | | - P J M Elders
- Department of General Practice, Amsterdam Public Health Institute, Amsterdam UMC, Amsterdam, the Netherlands
| | - G de Klerk
- Department of Surgery, ADRZ, Goes, the Netherlands
| | - M van Oostwaard
- Department of Internal Medicine, VieCuri Medical Center, Venlo, the Netherlands
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands
| | - H C Willems
- Department of Internal Medicine and Geriatrics, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - M C Zillikens
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - W F Lems
- Department of Rheumatology, Amsterdam University Medical Center, Amsterdam, the Netherlands
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10
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Hu SJ, Cheng G, Chen GC, Zhou H, Zhang Q, Zhao QM, Lian CX, Zhao ZH, Zhang QL, Han T, Zhang QY, Qin LP. Cannabinoid receptors type 2: Function and development in agonist discovery from synthetic and natural sources with applications for the therapy of osteoporosis. ARAB J CHEM 2024; 17:105536. [DOI: 10.1016/j.arabjc.2023.105536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025] Open
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11
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Xu N, Cui G, Zhao S, Li Y, Liu Q, Liu X, Zhao C, Feng R, Kuang M, Han S. Therapeutic Effects of Mechanical Stress-Induced C2C12-Derived Exosomes on Glucocorticoid-Induced Osteoporosis Through miR-92a-3p/PTEN/AKT Signaling Pathway. Int J Nanomedicine 2023; 18:7583-7603. [PMID: 38106447 PMCID: PMC10725637 DOI: 10.2147/ijn.s435301] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 12/01/2023] [Indexed: 12/19/2023] Open
Abstract
Introduction Osteoporosis is a common bone disease in which the bone loses density and strength and is prone to fracture. Bone marrow mesenchymal stem cells (BMSCs) are important in bone-related diseases. Exosomes, as mediators of cell communication, have potential in cell processes. Previous studies have focused on muscle factors' regulation of bone remodeling, but research on exosomes is lacking. Methods In order to confirm the therapeutic effect of mechanically stimulated myocytes (C2C12) derived exosomes (Exosome-MS) on the Glucocorticoid-induced osteoporosis(GIOP) compared with unmechanically stimulated myocytes (C2C12) derived exosomes (Exosomes), we established a dexamethasone-induced osteoporosis model in vivo and in vitro. Cell viability and proliferation were assessed using CCK8 and EDU assays. Osteogenic potential was evaluated through Western blotting, real-time PCR, alkaline phosphatase activity assay, and alizarin red staining. Differential expression of miRNAs was determined by high-throughput sequencing. The regulatory mechanism of miR-92a-3p on cell proliferation and osteogenic differentiation via the PTEN/AKT pathway was investigated using real-time PCR, luciferase reporter gene assay, Western blotting, and immunofluorescence. The therapeutic effects of exosomes were evaluated in vivo using microCT, HE staining, Masson staining, and immunohistochemistry. Results In this study, we found that exosomes derived from mechanical stress had a positive impact on the proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs). Importantly, we demonstrated that miR-92a-3p mimics could reverse dexamethasone-induced osteoporosis in vitro and in vivo, indicating that mechanical stress-induced mouse myoblast-derived exosomes could promote osteogenesis and prevent the occurrence and progression of osteoporosis in mice through miR-92a-3p/PTEN/AKT signaling pathway. Conclusion Exosomes derived from mechanical stress-induced myoblasts can promote the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells through miR-92a-3p/PTEN/AKT signaling pathway, and can have a therapeutic effect on glucocorticoid-induced osteoporosis in mice in vivo.
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Affiliation(s)
- Ning Xu
- Department of Orthopedic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, 250014, People’s Republic of China
| | - Guanzheng Cui
- Department of Orthopedic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, 250014, People’s Republic of China
| | - Shengyin Zhao
- Department of Orthopedic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, 250014, People’s Republic of China
| | - Yu Li
- Department of Orthopedic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, 250014, People’s Republic of China
| | - Qian Liu
- Department of Pain, Qilu Hospital of Shandong University, Jinan, 250012, People’s Republic of China
| | - Xuchang Liu
- Department of Orthopedic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, 250014, People’s Republic of China
| | - Chuanliang Zhao
- Department of Orthopedic Surgery, The Affiliated Taian City Central Hospital of Qingdao University, Taian, 271000, People’s Republic of China
| | - Rongjie Feng
- Department of Orthopedic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, 250014, People’s Republic of China
| | - Mingjie Kuang
- Department of Orthopedic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, 250014, People’s Republic of China
| | - Shijie Han
- Department of Orthopedic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, 250014, People’s Republic of China
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Zeng C, Wang S, Gu H, Chen F, Wang Z, Li J, Xie Z, Feng P, Shen H, Wu Y. Galangin mitigates glucocorticoid-induced osteoporosis by activating autophagy of BMSCs via triggering the PKA/CREB signaling pathway. Acta Biochim Biophys Sin (Shanghai) 2023; 55:1275-1287. [PMID: 37365870 PMCID: PMC10448057 DOI: 10.3724/abbs.2023063] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 02/20/2023] [Indexed: 04/05/2023] Open
Abstract
Glucocorticoid-induced osteoporosis (GIOP), one of the most common and serious adverse effects associated with glucocorticoid administration, manifests as decreased bone formation and increased bone resorption, eventually culminating in bone loss. Galangin (GAL) is a flavonoid extracted from the medicinal herbal galangal that possesses a variety of pharmacological activities and can inhibit osteoclastogenesis. However, the effects of GAL on GIOP remain unclear. Our study aims to explore the effects of GAL on GIOP in mice and the underlying mechanism. Our results show that GAL markedly mitigates the severity of dexamethasone (Dex)-induced osteoporosis in mice and potentiates osteogenic differentiation in mouse bone marrow-derived mesenchymal stem cells (BMSCs). Furthermore, GAL also significantly counteracts Dex-mediated suppression of osteogenic differentiation and autophagy in human BMSCs. GAL augments PKA/CREB-mediated autophagic flux in BMSCs and the bones of osteoporotic mice. GAL-mediated osteogenic differentiation in Dex-treated BMSCs is significantly decreased by the PKA inhibitor H89 and autophagy inhibitor 3-methyladenine. Collectively, our data indicate that GAL can ameliorate GIOP, partly by augmenting the mineralization of BMSCs by potentiating PKA/CREB-mediated autophagic flux, highlighting its potential therapeutic use in treating glucocorticoid-related osteoporosis.
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Affiliation(s)
- Chenying Zeng
- Center for BiotherapyEighth Affiliated Hospital of Sun Yat-sen UniversityShenzhen518033China
| | - Shan Wang
- Center for BiotherapyEighth Affiliated Hospital of Sun Yat-sen UniversityShenzhen518033China
| | - Huimin Gu
- Center for BiotherapyEighth Affiliated Hospital of Sun Yat-sen UniversityShenzhen518033China
| | - Fenglei Chen
- Department of OrthopedicsEighth Affiliated Hospital of Sun Yat-sen UniversityShenzhen518033China
| | - Ziming Wang
- Department of OrthopedicsEighth Affiliated Hospital of Sun Yat-sen UniversityShenzhen518033China
| | - Jinteng Li
- Department of OrthopedicsEighth Affiliated Hospital of Sun Yat-sen UniversityShenzhen518033China
| | - Zhongyu Xie
- Department of OrthopedicsEighth Affiliated Hospital of Sun Yat-sen UniversityShenzhen518033China
| | - Pei Feng
- Center for BiotherapyEighth Affiliated Hospital of Sun Yat-sen UniversityShenzhen518033China
| | - Huiyong Shen
- Department of OrthopedicsEighth Affiliated Hospital of Sun Yat-sen UniversityShenzhen518033China
- Department of OrthopedicsSun Yat-sen Memorial Hospital of Sun Yat-sen UniversityGuangzhou510120China
| | - Yanfeng Wu
- Center for BiotherapyEighth Affiliated Hospital of Sun Yat-sen UniversityShenzhen518033China
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13
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Yuan C, Liang Y, Zhu K, Xie W. Clinical efficacy of denosumab, teriparatide, and oral bisphosphonates in the prevention of glucocorticoid-induced osteoporosis: a systematic review and meta-analysis. J Orthop Surg Res 2023; 18:447. [PMID: 37349750 DOI: 10.1186/s13018-023-03920-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 06/08/2023] [Indexed: 06/24/2023] Open
Abstract
BACKGROUND Continuous use of glucocorticoids (GCs) has become the primary cause of secondary osteoporosis. Bisphosphonate drugs were given priority over denosumab and teriparatide in the 2017 American College of Rheumatology (ACR) guidelines but have a series of shortcomings. This study aims to explore the efficacy and safety of teriparatide and denosumab compared with those of oral bisphosphonate drugs. METHODS We systematically searched studies included in the PubMed, Web of Science, Embase, and Cochrane library databases and included randomized controlled trials that compared denosumab or teriparatide with oral bisphosphonates. Risk estimates were pooled using both fixed and random effects models. RESULTS We included 10 studies involving 2923 patients who received GCs for meta-analysis, including two drug base analyses and four sensitivity analyses. Teriparatide and denosumab were superior to bisphosphonates in increasing the bone mineral density (BMD) of the lumbar vertebrae [teriparatide: mean difference [MD] 3.98%, 95% confidence interval [CI] 3.61-4.175%, P = 0.00001; denosumab: MD 2.07%, 95% CI 0.97-3.17%, P = 0.0002]. Teriparatide was superior to bisphosphonates in preventing vertebral fractures and increasing hip BMD [MD 2.39%, 95% CI 1.47-3.32, P < 0.00001]. There was no statistically significant difference between serious adverse events, adverse events, and nonvertebral fracture prevention drugs. CONCLUSIONS Teriparatide and denosumab exhibited similar or even superior characteristics to bisphosphonates in our study, and we believe that they have the potential to become first-line GC-induced osteoporosis treatments, especially for patients who have previously received other anti-osteoporotic drugs with poor efficacy.
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Affiliation(s)
- Chuanjian Yuan
- Shandong University of Traditional Chinese Medicine CN, Jinan, China
| | - Yanchen Liang
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine CN, Jinan, China.
| | - Kai Zhu
- Shandong University of Traditional Chinese Medicine CN, Jinan, China
| | - Wenpeng Xie
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine CN, Jinan, China
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Singh S, Verma SC, Kumar V, Sharma K, Singh D, Khan S, Gupta N, Singh R, Khan F, Chanda D, Mishra DP, Singh D, Roy P, Gupta A. Synthesis of amide derivatives of 3-aryl-3H-benzopyrans as osteogenic agent concomitant with anticancer activity. Bioorg Chem 2023; 133:106380. [PMID: 36731295 DOI: 10.1016/j.bioorg.2023.106380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 12/02/2022] [Accepted: 01/15/2023] [Indexed: 01/22/2023]
Abstract
The present study reports a series of 3-aryl-3H-benzopyran-based amide derivatives as osteogenic agents concomitant with anticancer activity. Six target compounds viz 22e, 22f, 23i, and 24b-d showed good osteogenic activity at 1 pM and 100 pM concentrations. One of the potential molecules, 24b, effectively induced ALP activity and mRNA expression of osteogenic marker genes at 1 pM and bone mineralization at 100 pM concentrations. These molecules also presented significant growth inhibition of osteosarcoma (MG63) and estrogen-dependent and -independent (MCF-7 and MDA-MB-231) breast cancer cells. The most active compound, 24b, inhibited the growth of all the cancer cells within the IC50 10.45-12.66 µM. The mechanistic studies about 24b showed that 24b induced apoptosis via activation of the Caspase-3 enzyme and inhibited cancer cell migration. In silico molecular docking performed for 24b revealed its interaction with estrogen receptor-β (ER-β) preferentially.
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Affiliation(s)
- Sarita Singh
- Phytochemistry Division, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Kukrail Road, Lucknow 226015, India; Academy of Scientific and Innovative Research (AcSIR),Ghaziabad, Uttar Pradesh- 201002, India
| | - Surendra Chandra Verma
- Phytochemistry Division, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Kukrail Road, Lucknow 226015, India
| | - Vinay Kumar
- Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247667, Uttarakhand, India
| | - Kriti Sharma
- Division of Endocrinology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram extension, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR),Ghaziabad, Uttar Pradesh- 201002, India
| | - Diksha Singh
- Bioprospection and Product Development, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Kukrail Road, Lucknow 226015, India
| | - Sana Khan
- Technology Dissemination and Computational Division, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Kukrail Road, Lucknow 226015, India
| | - Neelam Gupta
- Division of Endocrinology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram extension, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR),Ghaziabad, Uttar Pradesh- 201002, India
| | - Romila Singh
- Division of Endocrinology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram extension, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR),Ghaziabad, Uttar Pradesh- 201002, India
| | - Feroz Khan
- Technology Dissemination and Computational Division, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Kukrail Road, Lucknow 226015, India; Academy of Scientific and Innovative Research (AcSIR),Ghaziabad, Uttar Pradesh- 201002, India
| | - Debabrata Chanda
- Bioprospection and Product Development, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Kukrail Road, Lucknow 226015, India; Academy of Scientific and Innovative Research (AcSIR),Ghaziabad, Uttar Pradesh- 201002, India
| | - Durga Prasad Mishra
- Division of Endocrinology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram extension, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR),Ghaziabad, Uttar Pradesh- 201002, India
| | - Divya Singh
- Division of Endocrinology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram extension, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR),Ghaziabad, Uttar Pradesh- 201002, India
| | - Partha Roy
- Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247667, Uttarakhand, India
| | - Atul Gupta
- Phytochemistry Division, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Kukrail Road, Lucknow 226015, India; Academy of Scientific and Innovative Research (AcSIR),Ghaziabad, Uttar Pradesh- 201002, India.
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15
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Li Y, Liu Q, Ma Q, Ma Z, Chen J, Yu A, Ma C, Qiu L, Shi H, Liang H, Hu M. Identification of key variants correlated with susceptibility of primary osteoporosis in the Chinese Han group. Ann Hum Genet 2023; 87:63-74. [PMID: 36479902 DOI: 10.1111/ahg.12490] [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: 04/19/2022] [Revised: 11/12/2022] [Accepted: 11/21/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Primary osteoporosis is a systemic skeletal disease characterized by reduced bone mass and vulnerability to fractures. The genetics of osteoporosis in the Chinese population remain unclear, which hinders the prevention and treatment of osteoporosis in China. This study aimed to explore the susceptibility genes and the roles played by their variants in osteoporosis. METHODS Blood samples were collected from 45 osteoporosis patients and 30 healthy individuals, and genome-wide association study was performed on array data. The expression levels of the candidate gene in different genotypes were further determined by using quantitative real-time PCR. Moreover, the differentiation capacity of bone marrow mesenchymal stem cells under different genotypes from osteoporosis patients was investigated. RESULTS The most significant variant rs1891632 located in the upstream (918 bp) region of CRB2, which could down-regulate the expression levels of CRB2 in genotype-tissue expression database and played an essential role in the regulation of osteoblastic and osteoclastic differentiation during skeletal development. Another significant variant rs1061657 located within the 3'UTR region of TBX3 gene. We found that the mRNA levels of TBX3 decreased in the bMSCs of old osteoporosis patients. Interestingly, osteoblast differentiation capacity and TBX3 mRNA levels were similar between the young healthy individuals carrying derived and ancestral allele of rs1061657, whereas the differentiation capacity and TBX3 mRNA levels dramatically declined in elderly patients with osteoporosis. CONCLUSIONS The variant rs1061657 might affect the osteogenesis of bMSCs in an age-dependent manner and that TBX3 may be a key susceptibility gene for primary osteoporosis. In conclusion, CRB2 and TBX3 may influence the development of osteoporosis; additionally, rs1891632 and rs1061657, as the key variants first reported to be associated with primary osteoporosis, may potentially contribute to predicting the risk of osteoporosis (especially for older individuals) and may serve as therapeutic targets.
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Affiliation(s)
- Yanjiao Li
- Yunnan Key Laboratory for Basic Research on Bone and Joint Diseases & Yunnan Stem Cell Translational Research Center, Kunming University, Kunming, China
| | - Qi Liu
- Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai, China
| | - Qiuye Ma
- Orthopedics, Chongqing Jiulongpo District Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Zhaoxia Ma
- Yunnan Key Laboratory for Basic Research on Bone and Joint Diseases & Yunnan Stem Cell Translational Research Center, Kunming University, Kunming, China
| | - Juan Chen
- Yunnan Key Laboratory for Basic Research on Bone and Joint Diseases & Yunnan Stem Cell Translational Research Center, Kunming University, Kunming, China
| | - An Yu
- Yunnan Key Laboratory for Basic Research on Bone and Joint Diseases & Yunnan Stem Cell Translational Research Center, Kunming University, Kunming, China
| | - Changguo Ma
- Yunnan Key Laboratory for Basic Research on Bone and Joint Diseases & Yunnan Stem Cell Translational Research Center, Kunming University, Kunming, China
| | - Lihua Qiu
- Yunnan Key Laboratory for Basic Research on Bone and Joint Diseases & Yunnan Stem Cell Translational Research Center, Kunming University, Kunming, China
| | - Hong Shi
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China
| | - Hongsuo Liang
- Joint Surgery Department of the Second People's Hospital of Nanning City, Guangxi Zhuang Autonomous Region, Nanning, China
| | - Min Hu
- Yunnan Key Laboratory for Basic Research on Bone and Joint Diseases & Yunnan Stem Cell Translational Research Center, Kunming University, Kunming, China
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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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17
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Rai R, Singh KB, Khanka S, Maurya R, Singh D. Cladrin alleviates dexamethasone-induced apoptosis of osteoblasts and promotes bone formation through autophagy induction via AMPK/mTOR signaling. Free Radic Biol Med 2022; 190:339-350. [PMID: 35998794 DOI: 10.1016/j.freeradbiomed.2022.08.028] [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: 05/25/2022] [Revised: 08/05/2022] [Accepted: 08/16/2022] [Indexed: 12/09/2022]
Abstract
Glucocorticoid-induced osteoporosis (GIOP) is a common clinical consequence that arises due to the extensive usage of glucocorticoids. Cladrin (Clad), a methoxylated isoflavone has been reported to have a bone protecting effect by enhancing osteoblast proliferation and differentiation. However, its consequences on GIOP are not reported yet. This study investigates whether Clad protects against the deleterious effects of Dexamethasone (Dex) on osteoblast and bone. Mice calvarial osteoblasts were treated with Clad and then exposed to Dex to study the effect on osteoblast differentiation, proliferation, and survival. Further, GIOP mice were treated with Clad (5 and 10 mg/kg) doses along with reference standard alendronate (ALN 3 mg/kg) for evaluation of bone protecting effect of Clad. We analyzed bone and vertebral microarchitecture, mechanical strength, and biochemical parameters. We observed that Clad at 10 nM concentration mitigated Dex-induced cytotoxicity and defend osteoblasts against apoptosis. Subsequent results demonstrate that Clad suppressed apoptosis of osteoblast in the presence of Dex by enhancing autophagy in a way that was reliant on the AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathway. Furthermore, micro-CT scanning, eco MRI results, and serum CTX levels revealed that 12 weeks of Clad treatment prevented bone loss and preserved trabecular bone mass in GIOP animals. We also observed that Clad treated osteoblasts had a lower rate of apoptosis and a greater LC3-II/LC3-I ratio than the Dex group. Our findings show that Clad can protect osteoblasts against glucocorticoids by inducing autophagy via the AMPK/mTOR pathway.
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Affiliation(s)
- Reena Rai
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Krishna Bhan Singh
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR) Ghaziabad, Uttar Pradesh, 201002, India
| | - Sonu Khanka
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR) Ghaziabad, Uttar Pradesh, 201002, India
| | - Rakesh Maurya
- Division of Medicinal & Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Divya Singh
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR) Ghaziabad, Uttar Pradesh, 201002, India.
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18
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Öztürk E, Çiğiloğlu A, Çakmak G, Öztürk ZA. An inconvenient status in anti-osteoporotic treatment process: corticosteroid use. REVISTA DA ASSOCIAÇÃO MÉDICA BRASILEIRA 2022; 68:636-640. [DOI: 10.1590/1806-9282.20211368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 02/11/2022] [Indexed: 11/22/2022]
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Luís M, Boers M, Saag K, Buttgereit F, da Silva JAP. The safety of glucocorticoids in the treatment of inflammatory rheumatic disease: new evidence. Curr Opin Rheumatol 2022; 34:179-186. [PMID: 35238807 DOI: 10.1097/bor.0000000000000870] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
PURPOSE OF REVIEW Glucocorticoids justifiably remain a cornerstone in the treatment of many inflammatory rheumatic diseases but many are opposed to their use because of the side effects, most of them known to be dose-dependent. Most concerns regarding glucocorticoids stem from observational studies which are affected by several forms of bias, mainly confounding by indication, that may result in overestimation of harm. Solid evidence regarding the safety of low-dose glucocorticoids remains remarkably scarce. RECENT FINDINGS Several observational studies showed heterogeneous results and two 6-month trials showed no increase of harm. The GLORIA trial of 5 mg/day prednisolone vs. placebo in patients aged 65+ is the first randomized control trial with glucocorticoids safety as coprimary outcome. The benefits of glucocorticoids in terms of symptoms and structural damage were confirmed, but the proportion of patients with at least one adverse event of special interest (serious or glucocorticoids-related) was increased by 24%, mostly due to nonsevere infections. SUMMARY Based on current evidence the benefit-risk balance of low-dose glucocorticoids in rheumatoid arthritis, and probably in other rheumatic diseases is generally favourable. Physicians should be aware of the risks and mitigate them, but avoid the negative effects of unfounded fear.
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Affiliation(s)
- Mariana Luís
- Rheumatology Department, Centra Hospitalar e Universitário de Coimbra
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Maarten Boers
- Department of Epidemiology & Biostatistics, VU University Medical Center, Amsterdam
- Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Ken Saag
- Division of Clinical Immunology and Rheumatology, Center for Education and Research on Therapeutics University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Frank Buttgereit
- Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany
| | - José A P da Silva
- Rheumatology Department, Centra Hospitalar e Universitário de Coimbra
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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20
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Incidence and predictors of fragility fracture in postmenopausal rheumatoid arthritis patients receiving oral bisphosphonates: a longitudinal observational study. BMC Rheumatol 2022; 6:8. [PMID: 35220965 PMCID: PMC8883631 DOI: 10.1186/s41927-021-00243-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: 08/13/2021] [Accepted: 12/03/2021] [Indexed: 11/28/2022] Open
Abstract
Background Although many studies have reported the predictors of fractures in patients with rheumatoid arthritis (RA) who are not receiving anti-osteoporotic treatments or who are receiving unspecified treatments, studies focusing on the predictors of fracture in patients with RA who are currently being treated with oral bisphosphonates (BP) are quite scarce. This study aims to investigate the incidence and predictors of fragility fracture in postmenopausal patients with RA receiving oral BP. Methods This retrospective longitudinal observational study comprised 98 postmenopausal RA patients receiving oral BP for a minimum of 6 months between April 2015 and December 2020. The cumulative incidence of fragility fractures including vertebral and nonvertebral fractures was investigated using the Kaplan–Meier method. Cox proportional hazards analysis was used to analyze baseline predictors of future fragility fractures. To determine a cutoff value of continuous predictors, the receiver-operating characteristic curve was applied. Results Twenty patients developed fractures during the study period, with a cumulative incidence of 6.1% at 12 months, 10.5% at a median follow-up of 28 months, and 14.4% at 36 months. Multivariable Cox hazards analysis showed a history of prior vertebral fracture (hazard ratio [HR] 6.26, 95% confidence interval [CI] 1.99‒19.68, P = 0.001) and dose of methotrexate (HR 0.87, 95% CI 0.76‒0.99, P = 0.041) to be independent predictors. The cutoff value for methotrexate dose was 4 mg/week. Conclusions We found a cumulative incidence of any fractures of 10.5% at 28 months in patients with RA currently being treated with oral BP. A history of prior vertebral fractures and methotrexate dose were positive and negative predictors for fractures, respectively. Practitioners should consider selecting another anti-osteoporotic drug in patients with RA who remain at risk despite receiving oral BP.
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Krüger BT, Steppe L, Vettorazzi S, Haffner-Luntzer M, Lee S, Dorn AK, Ignatius A, Tuckermann J, Ahmad M. Inhibition of Cdk5 Ameliorates Skeletal Bone Loss in Glucocorticoid-Treated Mice. Biomedicines 2022; 10:404. [PMID: 35203613 PMCID: PMC8962259 DOI: 10.3390/biomedicines10020404] [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: 01/14/2022] [Revised: 02/02/2022] [Accepted: 02/05/2022] [Indexed: 11/16/2022] Open
Abstract
Glucocorticoids (GCs) are widely used to treat inflammatory diseases. However, their long-term use leads to glucocorticoid-induced osteoporosis, increasing morbidity and mortality. Both anabolic and anti-resorptive drugs are used to counteract GC-induced bone loss, however, they are expensive and/or have major side effects. Therefore, identifying new targets for cost-effective, small-molecule inhibitors is essential. We recently identified cyclin-dependent kinase 5 (Cdk5) as a suppressor of osteoblast differentiation and showed that its inhibition with roscovitine promoted osteoblastogenesis, thus improving the skeletal bone mass and fracture healing. Here, we assessed whether Cdk5 knockdown or inhibition could also reverse the GC-mediated suppression of osteoblast differentiation, bone loss, and fracture healing. We first demonstrated that Cdk5 silencing abolished the dexamethasone (Dex)-induced downregulation of alkaline phosphatase (Alp) activity, osteoblast-specific marker gene expression (Runx2, Sp7, Alpl, and Bglap), and mineralization. Similarly, Cdk5 inhibition rescued Dex-induced suppression of Alp activity. We further demonstrated that Cdk5 inhibition reversed prednisolone (Pred)-induced bone loss in mice, due to reduced osteoclastogenesis rather than improved osteoblastogenesis. Moreover, we revealed that Cdk5 inhibition failed to improve Pred-mediated impaired fracture healing. Taken together, we demonstrated that Cdk5 inhibition with roscovitine ameliorated GC-mediated bone loss but did not reverse GC-induced compromised fracture healing in mice.
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Affiliation(s)
- Benjamin Thilo Krüger
- Institute of Orthopedic Research and Biomechanics, Ulm University, Helmholtzstrasse 14, 89081 Ulm, Germany; (B.T.K.); (L.S.); (M.H.-L.)
| | - Lena Steppe
- Institute of Orthopedic Research and Biomechanics, Ulm University, Helmholtzstrasse 14, 89081 Ulm, Germany; (B.T.K.); (L.S.); (M.H.-L.)
| | - Sabine Vettorazzi
- Institute of Comparative Molecular Endocrinology (CME), Ulm University, Helmholtzstrasse 8/1, 89081 Ulm, Germany; (S.V.); (S.L.); (A.-K.D.)
| | - Melanie Haffner-Luntzer
- Institute of Orthopedic Research and Biomechanics, Ulm University, Helmholtzstrasse 14, 89081 Ulm, Germany; (B.T.K.); (L.S.); (M.H.-L.)
| | - Sooyeon Lee
- Institute of Comparative Molecular Endocrinology (CME), Ulm University, Helmholtzstrasse 8/1, 89081 Ulm, Germany; (S.V.); (S.L.); (A.-K.D.)
| | - Ann-Kristin Dorn
- Institute of Comparative Molecular Endocrinology (CME), Ulm University, Helmholtzstrasse 8/1, 89081 Ulm, Germany; (S.V.); (S.L.); (A.-K.D.)
| | - Anita Ignatius
- Institute of Orthopedic Research and Biomechanics, Ulm University, Helmholtzstrasse 14, 89081 Ulm, Germany; (B.T.K.); (L.S.); (M.H.-L.)
| | - Jan Tuckermann
- Institute of Comparative Molecular Endocrinology (CME), Ulm University, Helmholtzstrasse 8/1, 89081 Ulm, Germany; (S.V.); (S.L.); (A.-K.D.)
| | - Mubashir Ahmad
- Institute of Orthopedic Research and Biomechanics, Ulm University, Helmholtzstrasse 14, 89081 Ulm, Germany; (B.T.K.); (L.S.); (M.H.-L.)
- Institute of Comparative Molecular Endocrinology (CME), Ulm University, Helmholtzstrasse 8/1, 89081 Ulm, Germany; (S.V.); (S.L.); (A.-K.D.)
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22
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Efficacy of Yigu® versus Aclasta® in Chinese postmenopausal women with osteoporosis: a multicenter prospective study. Arch Osteoporos 2022; 17:14. [PMID: 35020038 PMCID: PMC8755672 DOI: 10.1007/s11657-021-01052-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 12/16/2021] [Indexed: 02/03/2023]
Abstract
Zoledronic acid (ZOL) is a therapy inhibiting bone resorption. In this study, generic ZOL (Yigu®) showed its clinical efficacy consistency with original ZOL (Aclasta®) in Chinese postmenopausal women with osteoporosis. This study provides a practical basis for the application of Yigu® in Chinese population. INTRODUCTION Yigu® has been approved its bioequivalence to Aclasta®. However, the clinical efficacy and safety of Yigu® have not been evaluated yet. Here, we compared the effectiveness and safety between Yigu® and Aclasta® in Chinese postmenopausal women with osteoporosis and assessed the efficacy of intravenous infusion of ZOL. METHODS This was a randomized open-label, active-controlled study in postmenopausal women with osteoporosis of 14 clinical centers in China. Postmenopausal women with osteoporosis were recruited and randomized to receive a single infusion of 5 mg Yigu® or Aclasta®. The primary endpoint was the percentage change in bone mineral density (BMD) at lumbar spine after 12 months of treatment and was assessed for equivalence. The secondary endpoint was the percentage change in BMD at proximal femur after 12 months. Additional secondary endpoints were percentage changes in BMD at the above sites after 6 months of treatment and changes in bone turnover biomarkers during ZOL treatment. Safety was also evaluated and compared between two groups. RESULTS A total of 458 postmenopausal women with osteoporosis were enrolled (n = 227, Yigu®; n = 231, Aclasta®). The mean percentage change in the BMD had no statistical difference at the lumbar spine (5.32% vs 5.18%), total hip (2.72% vs 2.83%), and femoral neck (2.37% vs 2.81%) between Yigu® and Aclasta® groups after 12 months of treatment. The mean difference of BMD change at the lumbar spine after 12 months between two groups was 0.15% (95% CI: - 0.71 to 1.00, equivalence margin: - 1.5%, 1.5%), demonstrating the treatments were equivalent. Meanwhile, the decreases in the P1NP and β-CTX showed no difference between two groups after 14 days and 6 and 12 months of treatment. As regards the whole sample, BMD significantly increased after 12 months of treatment. Also, serum C-terminal telopeptide of type 1 collagen (β-CTX) and procollagen 1 N-terminal peptide (P1NP) significantly decreased at each visit period. The overall adverse events were comparable and quite well between two groups. CONCLUSION Intravenous infusion of zoledronic acid achieved the potent anti-resorptive effects which led to significant increase in BMD of Chinese postmenopausal women with osteoporosis. Yigu® was equivalent to Aclasta® with respect to efficacy and safety.
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Luan Y, Ji W, Zhang J, Hou H, Xue L. Risk of Osteoporotic Fractures Caused by Methylprednisolone and Proton Pump Inhibitors in Chinese Rheumatoid Arthritis Patients. INT J PHARMACOL 2021. [DOI: 10.3923/ijp.2021.408.413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Hoff M, Skovlund E, Meyer HE, Langhammer A, Søgaard AJ, Syversen U, Holvik K, Abrahamsen B, Schei B. Does treatment with bisphosphonates protect against fractures in real life? The HUNT study, Norway. Osteoporos Int 2021; 32:1395-1404. [PMID: 33479844 PMCID: PMC8192327 DOI: 10.1007/s00198-021-05845-2] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 01/11/2021] [Indexed: 12/02/2022]
Abstract
UNLABELLED Bisphosphonates reduce fractures in randomized controlled trials (RCT); however, there is less information from real life. In our population including 14,990 women and 13,239 men, use of bisphosphonates reduced risk of fractures in hip and forearm in women. The magnitude of the effect was comparable to results from RCT. INTRODUCTION The objective was to examine if treatment with bisphosphonates (BPs) was associated with reduced risk of fractures in the hip and forearm in women and men in the general population. METHODS In a cohort study based on data from the third wave of the population-based HUNT Study (HUNT3), the fracture registry in Nord-Trøndelag, and the Norwegian Prescription Database, 14,990 women and 13,239 men 50-85 years were followed from the date of participating in HUNT3 (2006-2008) until the date of first fracture in the hip or forearm, death, or end of study (31 December 2012). Hazard ratios with 95% confidence intervals for hip and forearm fracture according to use of BPs were estimated using Cox proportional hazards models with time-dependent exposure. Adjustment for individual FRAX® fracture risk assessment scores was included. RESULTS BPs, predominantly alendronate, were used by 9.4% of the women and 1.5% of the men. During a median of 5.2 years of follow-up, 265 women and 133 men had a hip fracture, and 662 women and 127 men had a forearm fracture. Compared with non-users of BPs, the hazard ratios with 95% confidence interval for a fracture among users of BPs adjusted for age and FRAX® were 0.67 (0.52-0.86) for women and 1.13 (0.50-2.57) for men. Among users of glucocorticoids, the corresponding figures were 0.35 (0.19-0.66) and 1.16 (0.33-4.09), respectively. CONCLUSIONS Use of BPs was associated with reduced risk of fractures in hip and forearm in women, and the magnitude of effect is comparable to results from RCTs.
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Affiliation(s)
- M Hoff
- Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.
- Department of Public Health and Nursing, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.
- Department of Rheumatology, St. Olavs hospital, Trondheim University Hospital, Trondheim, Norway.
| | - E Skovlund
- Department of Public Health and Nursing, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
- Norwegian Institute of Public Health, Oslo, Norway
| | - H E Meyer
- Norwegian Institute of Public Health, Oslo, Norway
- Department of Community Medicine and Global Health, University of Oslo, Oslo, Norway
| | - A Langhammer
- HUNT Research Centre, Department of Public Health and Nursing, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
- Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
| | - A J Søgaard
- Norwegian Institute of Public Health, Oslo, Norway
| | - U Syversen
- Department of Endocrinology, St. Olavs hospital, Trondheim University Hospital, Trondheim, Norway
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
| | - K Holvik
- Norwegian Institute of Public Health, Oslo, Norway
| | - B Abrahamsen
- Department of Medicine, Holbæk Hospital, Holbæk, Denmark
- Odense Patient Data Explorative Network, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - B Schei
- Department of Public Health and Nursing, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
- Department of Gynecology, St. Olavs hospital, Trondheim University Hospital, Trondheim, Norway
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Hu Z, Zhang L, Lin Z, Zhao C, Xu S, Lin H, Zhang J, Li W, Chu Y. Prevalence and risk factors for bone loss in rheumatoid arthritis patients from South China: modeled by three methods. BMC Musculoskelet Disord 2021; 22:534. [PMID: 34118911 PMCID: PMC8199806 DOI: 10.1186/s12891-021-04403-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 05/21/2021] [Indexed: 11/27/2022] Open
Abstract
Background To explore the prevalence of bone loss among patients with rheumatoid arthritis (RA) and healthy controls (HC) and further explored the risk factors for osteopenia and osteoporosis of RA patients. Methods A cross-sectional survey was undertaken in four hospitals in different districts in South China to reveal the prevalence of bone loss in patients. Case records, laboratory tests, and bone mineral density (BMD) results of patients were collected. Traditional multivariable logistic regression analysis and two machine learning methods, including least absolute shrinkage selection operator (LASSO) and random forest (RF) were for exploring the risk factors for osteopenia or osteoporosis in RA patients. Results Four hundred five patients with RA and 198 HC were included. RA patients had lower BMD in almost BMD measurement sites than healthy controls; the decline of lumbar spine BMD was earlier than HC. RA patients were more likely to comorbid with osteopenia and osteoporosis (p for trend < 0.001) in the lumbar spine than HC. Higher serum 25-hydroxyvitamin D3 level and using tumor necrosis factor inhibitor in the last year were protective factors; aging, lower body mass index, and increased serum uric acid might be risk factors for bone loss. Conclusions RA patients were more prone and earlier to have bone loss than HC. More attention should be paid to measuring BMD in RA patients aging with lower BMI or hyperuricemia. Besides, serum vitamin D and all three measurement sites are recommended to check routinely. TNFi usage in the last year might benefit bone mass. Supplementary Information The online version contains supplementary material available at 10.1186/s12891-021-04403-5.
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Affiliation(s)
- Zhuoran Hu
- Division of Rheumatology, the Third Affiliated Hospital of Sun Yat-sen University, No.600, Tianhe Road, Tianhe District, Guangzhou City, 51000, China
| | - Lei Zhang
- Division of Rheumatology, Zhuhai Hospital of Guangdong Provincial Hospital of Chinese Medicine, No.53, Ji'Da Jingle Road, Xiangzhou District, Zhuhai City, 519015, China
| | - Zhiming Lin
- Division of Rheumatology, the Third Affiliated Hospital of Sun Yat-sen University, No.600, Tianhe Road, Tianhe District, Guangzhou City, 51000, China
| | - Changlin Zhao
- Division of Cardiology, the Third Affiliated Hospital of Sun Yat-sen University, No.600, Tianhe Road, Tianhe District, Guangzhou City, 51000, China
| | - Shuiming Xu
- Division of Rheumatology, Ganzhou Municipal Hospital, No.49, Dagong Road, Ganzhou City, 341000, China
| | - He Lin
- Division of Rheumatology, Fujian Provincial Hospital, No. 134, Dongjie Road, Fuzhou City, 350000, China
| | - Jiejing Zhang
- Division of Rheumatology, Zhuhai Hospital of Guangdong Provincial Hospital of Chinese Medicine, No.53, Ji'Da Jingle Road, Xiangzhou District, Zhuhai City, 519015, China
| | - Wenjie Li
- Division of Rheumatology, Zhuhai Hospital of Guangdong Provincial Hospital of Chinese Medicine, No.53, Ji'Da Jingle Road, Xiangzhou District, Zhuhai City, 519015, China.
| | - Yongliang Chu
- Division of Rheumatology, Zhuhai Hospital of Guangdong Provincial Hospital of Chinese Medicine, No.53, Ji'Da Jingle Road, Xiangzhou District, Zhuhai City, 519015, China.
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Zhang C, Wen T, Li C, Ruan D, He Q. Cluster phenomenon of vertebral refractures after posterior pedicle screw fixation in a patient with glucocorticosteroid-induced Kümmell's disease: a treatment dilemma. Arch Osteoporos 2021; 16:93. [PMID: 34105042 DOI: 10.1007/s11657-021-00941-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 04/07/2021] [Indexed: 02/03/2023]
Abstract
INTRODUCTION Surgical treatments are usually preferred in patients with Kümmell's disease since it represents a failure of conservative treatment for osteoporotic vertebral compression fracture without evidence of spontaneous healing. However, the risk of postoperative refractures is much higher in patients with glucocorticosteroid-induced osteoporosis (GIOP) than in those with primary osteoporosis, possessing a therapeutic challenge and dilemma to orthopaedic surgeons. CASE REPORT We described a rare cluster phenomenon of vertebral refractures in a patient with GIOP subsequent to segmental internal fixation for the initial management of glucocorticosteroid-induced Kümmell's disease, and a review of the literature. CONCLUSION Our patient illustrates that clinicians should be aware of the significant management dilemma and possible disastrous outcome after surgical interventions for glucocorticosteroid-induced Kümmell's disease and, thus, pay much more attention to comprehensive perioperative antiosteoporotic medications for patients with GIOP in current medical treatment.
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Affiliation(s)
- Chao Zhang
- Department of Orthopaedic Surgery, The Sixth Medical Center, General Hospital of PLA, 6# Fucheng Road, Haidian District, Beijing, 100048, China.
| | - Tianyong Wen
- Department of Orthopaedic Surgery, The Sixth Medical Center, General Hospital of PLA, 6# Fucheng Road, Haidian District, Beijing, 100048, China
| | - Chao Li
- Department of Orthopaedic Surgery, The Sixth Medical Center, General Hospital of PLA, 6# Fucheng Road, Haidian District, Beijing, 100048, China
| | - Dike Ruan
- Department of Orthopaedic Surgery, The Sixth Medical Center, General Hospital of PLA, 6# Fucheng Road, Haidian District, Beijing, 100048, China
| | - Qing He
- Department of Orthopaedic Surgery, The Sixth Medical Center, General Hospital of PLA, 6# Fucheng Road, Haidian District, Beijing, 100048, China
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Chen C, Alqwbani M, Zhao J, Yang R, Wang S, Pan X. Effects of Teriparatide versus Salmon Calcitonin Therapy for the Treatment of Osteoporosis in Asia: A Meta-analysis of Randomized Controlled Trials. Endocr Metab Immune Disord Drug Targets 2021; 21:932-942. [PMID: 33109070 DOI: 10.2174/1871530320999200817114817] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 06/21/2020] [Accepted: 06/30/2020] [Indexed: 02/08/2023]
Abstract
Objective:
The objective of this meta-analysis was to compare the efficacy and safety of
teriparatide versus salmon calcitonin for the treatment of osteoporosis in Asian patients and to investigate
whether the results of global studies could be applicable to Asian patients.
Methods:
PubMed, OVID, Cochrane Central Register of Controlled Trials (CENTRAL) and EMBASE
up to December 2018 were searched. Eligible randomized controlled trials (RCTs) that compared teriparatide
versus salmon calcitonin in Asian osteoporosis population were included. Preferred Reporting
Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for data synthesis,
and Cochrane Collaboration software Review Manager 5.3 was used to analyze the pooled data.
Results:
Three RCTs involving 529 patients were included (mean age 68.7 yr; 93.4% females; mean
follow-up 6 months); outcome measures included bone mineral density (BMD) of the femoral neck,
total hip and lumbar spine; bone markers and adverse events. We found that the period of 6-months of
teriparatide treatment was helpful for the improvement of the BMD of lumbar vertebra, however, the
improvement of BMD was not significant in the femoral neck and total hip joint. There was a positive
correlation between bone-specific alkaline phosphatase (BSAP) and osteocalcin (OCN) and the response
of Asian patients to subcutaneous injection of 20 micrograms per day of teriparatide. The proportion
of the occurrence of adverse effects was more obvious in the teriparatide group compared with
salmon calcitonin, but there was no significant difference.
Conclusion:
Results suggested that the use of teriparatide could improve the lumbar BMD by shortterm
(six months) application in Asian osteoporosis patients, which is beneficial to the patients who
cannot tolerate adverse events of long-term treatment. The BSAP and OCN bone markers could be
useful to monitor the responses of Asian osteoporosis patients to teriparatide treatment. Finally, both of
teriparatide and salmon calcitonin were well tolerated by Asian patients.
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Affiliation(s)
- Changjun Chen
- Department of Orthopaedics, Shandong University Qilu Hospital, No.107, Jinan Culture Road, Jinan 250012, China
| | - Mohammed Alqwbani
- Department of Orthopaedics Surgery, West China Hospital, Sichuan University, No. 37 Wainan Guoxue Road, Chengdu, 610041, China
| | - Jie Zhao
- Department of Ophtalmology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
| | - Ruitong Yang
- Department of Orthopaedics, Shandong University Qilu Hospital, No.107, Jinan Culture Road, Jinan 250012, China
| | - Songgang Wang
- Department of Orthopaedics, Shandong University Qilu Hospital, No.107, Jinan Culture Road, Jinan 250012, China
| | - Xin Pan
- Department of Orthopaedics, Shandong University Qilu Hospital, No.107, Jinan Culture Road, Jinan 250012, China
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28
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Review of Current Real-World Experience with Teriparatide as Treatment of Osteoporosis in Different Patient Groups. J Clin Med 2021; 10:jcm10071403. [PMID: 33915736 PMCID: PMC8037129 DOI: 10.3390/jcm10071403] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/14/2021] [Accepted: 03/19/2021] [Indexed: 12/17/2022] Open
Abstract
Teriparatide has proven effective in reducing both vertebral and non-vertebral fractures in clinical trials of post-menopausal and glucocorticoid-induced osteoporosis. Widespread adoption of Teriparatide over the last two decades means that there is now substantial experience of its use in routine clinical practice, which is summarized in this paper. Extensive real-world experience of Teriparatide in post-menopausal osteoporosis confirms the fracture and bone density benefits seen in clinical trials, with similar outcomes identified also in male and glucocorticoid-induced osteoporosis. Conversely, very limited experience has been reported in pre-menopausal osteoporosis or in the use of Teriparatide in combination with other therapies. Surveillance studies have identified no safety signals relating to the possible association of Teriparatide with osteosarcoma. We also review the evidence for predicting response to Teriparatide in order to inform the debate on where best to use Teriparatide in an increasingly crowded therapeutic landscape.
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29
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Messina OD, Vidal LF, Wilman MV, Bultink IEM, Raterman HG, Lems W. Management of glucocorticoid-induced osteoporosis. Aging Clin Exp Res 2021; 33:793-804. [PMID: 33751462 DOI: 10.1007/s40520-021-01823-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 02/19/2021] [Indexed: 12/19/2022]
Abstract
Long-term glucocorticoid (GC) therapy is frequently indicated to treat autoimmune and chronic inflammatory diseases in daily clinical practice. Two of the most devastating untoward effects are bone loss and fractures. Doses as low as 2.5 mg of prednisone for more than 3 months can impair bone integrity. Population at risk is defined based on the dose and duration of GC therapy and should be stratified according to FRAX (Fracture Risk Assessment Tool), major osteoporotic fracture, prior fractures, and bone mineral density values (BMD). General measures include to prescribe the lowest dose of GC to control the underlying disease for the shortest possible time, maintain adequate vitamin D levels and calcium intake, maintain mobility, and prescribe a bone acting agent in patients at high risk of fracture. These agents include oral and intravenous bisphosphonates, denosumab, and teriparatide.
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30
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Strontium gluconate potently promotes osteoblast development and restores bone formation in glucocorticoid-induced osteoporosis rats. Biochem Biophys Res Commun 2021; 554:33-40. [PMID: 33774277 DOI: 10.1016/j.bbrc.2021.02.100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 02/20/2021] [Indexed: 11/23/2022]
Abstract
Glucocorticoid-induced osteoporosis (GIOP) has emerged as a challenge after long-term glucocorticoid administration during the clinical therapy of diverse diseases. Although some candidates for GIOP treatment have been explored, there is still a lack of reliable drugs for GIOP prevention. In this study, rat bone marrow stem cells (rBMSCs) were utilized to investigate the feasibility of applying strontium gluconate (GluSr), which displays mild activity, easy absorption and good biocompatibility, for GIOP prevention. Thirty-two SD rats were divided into 4 groups to explore the effects of GluSr on osteoporosis rescue in vivo. Our results suggested that GluSr markedly alleviated dexamethasone (DEX)-induced apoptosis of osteoblast precursor cells and rBMSCs and enhanced rBMSC osteogenesis differentiation in vitro. GluSr also effectively promoted osteoblast survival, inhibited osteoclast differentiation and restored bone formation in GIOP rat models. Microarray analysis of the femora from GIOP rats treated with GluSr revealed that the signalling pathways of the glucocorticoid receptor (GR), oestrogen receptor gene (ESR) and vitamin D receptor (VDR) were involved in bone restoration by GluSr. In summary, our study proved that GluSr enhanced osteoblast differentiation and suppressed osteoclast activity both in vitro and in vivo. GluSr might function as a novel strontium reagent for GIOP prevention.
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31
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Coffman AA, Basta-Pljakic J, Guerra RM, Ebetino FH, Lundy MW, Majeska RJ, Schaffler MB. A Bisphosphonate With a Low Hydroxyapatite Binding Affinity Prevents Bone Loss in Mice After Ovariectomy and Reverses Rapidly With Treatment Cessation. JBMR Plus 2021; 5:e10476. [PMID: 33869992 PMCID: PMC8046044 DOI: 10.1002/jbm4.10476] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 02/04/2021] [Indexed: 12/30/2022] Open
Abstract
Bisphosphonates (BPs) are a mainstay of osteoporosis treatment; however, concerns about bone health based on oversuppression of remodeling remain. Long‐term bone remodeling suppression adversely affects bone material properties with microdamage accumulation and reduced fracture toughness in animals and increases in matrix mineralization and atypical femur fractures in patients. Although a “drug holiday” from BPs to restore remodeling and improve bone quality seems reasonable, clinical BPs have long functional half‐lives because of their high hydroxyapatite (HAP) binding affinities. This places a practical limit on the reversibility and effectiveness of a drug holiday. BPs with low HAP affinity and strong osteoclast inhibition potentially offer an alternative approach; their antiresorptive effect should reverse rapidly when dosing is discontinued. This study tested this concept using NE‐58025, a BP with low HAP affinity and moderate osteoclast inhibition potential. Young adult female C57Bl/6 mice were ovariectomized (OVX) and treated with NE‐58025, risedronate, or PBS vehicle for 3 months to test effectiveness in preventing long‐term bone loss. Bone microarchitecture, histomorphometry, and whole‐bone mechanical properties were assessed. To test reversibility, OVX mice were similarly treated for 3 months, treatment was stopped, and bone was assessed up to 3 months post‐treatment. NE‐58025 and RIS inhibited long‐term OVX‐induced bone loss, but NE‐58025 antiresorptive effects were more pronounced. Withdrawing NE‐58025 treatment led to the rapid onset of trabecular resorption with a 200% increase in osteoclast surface and bone loss within 1 month. Cessation of risedronate treatment did not lead to increases in resorption indices or bone loss. These results show that NE‐58025 prevents OVX‐induced bone loss, and its effects reverse quickly following cessation treatment in vivo. Low‐HAP affinity BPs may have use as reversible, antiresorptive agents with a rapid on/off profile, which may be useful for maintaining bone health with long‐term BP treatment. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Abigail A Coffman
- Department of Biomedical Engineering The City College of New York New York NY USA
| | - Jelena Basta-Pljakic
- Department of Biomedical Engineering The City College of New York New York NY USA
| | - Rosa M Guerra
- Department of Biomedical Engineering The City College of New York New York NY USA
| | - Frank H Ebetino
- Department of Chemistry University of Rochester Rochester NY USA.,BioVinc, LLC Pasadena CA USA
| | - Mark W Lundy
- BioVinc, LLC Pasadena CA USA.,Department of Anatomy and Cell Biology Indiana University Indianapolis IN USA
| | - Robert J Majeska
- Department of Biomedical Engineering The City College of New York New York NY USA
| | - Mitchell B Schaffler
- Department of Biomedical Engineering The City College of New York New York NY USA
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32
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Frara S, Allora A, di Filippo L, Formenti AM, Loli P, Polizzi E, Tradati D, Ulivieri FM, Giustina A. Osteopathy in mild adrenal Cushing's syndrome and Cushing disease. Best Pract Res Clin Endocrinol Metab 2021; 35:101515. [PMID: 33795196 DOI: 10.1016/j.beem.2021.101515] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Pathophysiology and effects of endogenous glucocorticoid (GC) excess on skeletal endpoints as well as awareness and management of bone fragility are reviewed. Cushing's syndrome (CS) increase the risk of fracture affecting prevalently bone quality. Bone antiresorptive agents (SERMs, bisphosphonates and denosumab) as well as teriparatide increase bone mineral density and in some instances reduce fracture risk. Awareness and management of bone health in CS can be improved.
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Affiliation(s)
- Stefano Frara
- Institute of Endocrine and Metabolic Sciences, Università Vita-Salute San Raffaele, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Agnese Allora
- Institute of Endocrine and Metabolic Sciences, Università Vita-Salute San Raffaele, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Luigi di Filippo
- Institute of Endocrine and Metabolic Sciences, Università Vita-Salute San Raffaele, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Anna Maria Formenti
- Institute of Endocrine and Metabolic Sciences, Università Vita-Salute San Raffaele, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Paola Loli
- Institute of Endocrine and Metabolic Sciences, Università Vita-Salute San Raffaele, IRCCS Ospedale San Raffaele, Milan, Italy
| | | | - Daniele Tradati
- Department of Orthopedics and Traumatology, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Fabio Massimo Ulivieri
- Institute of Endocrine and Metabolic Sciences, Università Vita-Salute San Raffaele, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Andrea Giustina
- Institute of Endocrine and Metabolic Sciences, Università Vita-Salute San Raffaele, IRCCS Ospedale San Raffaele, Milan, Italy.
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33
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Hayes KN, Baschant U, Hauser B, Burden AM, Winter EM. When to Start and Stop Bone-Protecting Medication for Preventing Glucocorticoid-Induced Osteoporosis. Front Endocrinol (Lausanne) 2021; 12:782118. [PMID: 34975756 PMCID: PMC8715727 DOI: 10.3389/fendo.2021.782118] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 11/19/2021] [Indexed: 01/28/2023] Open
Abstract
Glucocorticoid-induced osteoporosis (GIOP) leads to fractures in up to 40% of patients with chronic glucocorticoid (GC) therapy when left untreated. GCs rapidly increase fracture risk, and thus many patients with anticipated chronic GC exposures should start anti-osteoporosis pharmacotherapy to prevent fractures. In addition to low awareness of the need for anti-osteoporosis therapy among clinicians treating patients with GCs, a major barrier to prevention of fractures from GIOP is a lack of clear guideline recommendations on when to start and stop anti-osteoporosis treatment in patients with GC use. The aim of this narrative review is to summarize current evidence and provide considerations for the duration of anti-osteoporosis treatment in patients taking GCs based on pre-clinical, clinical, epidemiologic, and pharmacologic evidence. We review the pathophysiology of GIOP, outline current guideline recommendations on initiating and stopping anti-osteoporosis therapy for GIOP, and present considerations for the duration of anti-osteoporosis treatment based on existing evidence. In each section, we illustrate major points through a patient case example. Finally, we conclude with proposed areas for future research and emerging areas of interest related to GIOP clinical management.
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Affiliation(s)
- Kaleen N. Hayes
- Department of Health Services, Policy, and Practice, Brown University School of Public Health, Providence, RI, United States
| | - Ulrike Baschant
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III and Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
- *Correspondence: Ulrike Baschant,
| | - Barbara Hauser
- Rheumatic Disease Unit, Western General Hospital, National Health Service (NHS) Lothian, Edinburgh, United Kingdom
- Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Andrea M. Burden
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology [Eidgenössische Technische Hochschule (ETH)] Zurich, Zurich, Switzerland
| | - Elizabeth M. Winter
- Center for Bone Quality, Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
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34
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Fratter A, Pellizzato M. Novel micellar system for Vitamin D3 oral delivery: Assessment of enteric absorption through a digestion-like in vitro model. J Drug Deliv Sci Technol 2020. [DOI: 10.1016/j.jddst.2020.101840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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35
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Raterman HG, Bultink IE, Lems WF. Osteoporosis in patients with rheumatoid arthritis: an update in epidemiology, pathogenesis, and fracture prevention. Expert Opin Pharmacother 2020; 21:1725-1737. [PMID: 32605401 DOI: 10.1080/14656566.2020.1787381] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is a chronic disabling disease characterized by a symmetrical articular involvement due to ongoing joint inflammation, if left insufficiently treated. Local and generalized bone loss is one of the main extra-articular complications of RA and leads to an increased risk for fragility fractures, which further impair functional ability, quality of life, and life expectancy. Therefore, there is an urgent need for good fracture risk management in the vulnerable RA patient. AREAS COVERED The authors review: the epidemiology and pathophysiology (i.e. risk factors) of osteoporosis (OP), fracture, and vertebral fracture risk assessment, the effects of anti-rheumatic drugs on bone loss, pharmacological treatment of OP in RA including both bisphosphonates (BP) and newer drugs including anti-resorptives and osteoanabolic treatment options. EXPERT OPINION Patients with active RA have elevated bone resorption and local bone loss. Moreover, these patients are at increased risk for generalized bone loss, vertebral and non-vertebral fractures. Since general risk factors (such as low BMI, fall risk) and RA-related factors play a role, optimal fracture prevention in RA patients is based on optimal diagnostics based on both of these factors, and on the use of adequate non-medical and medical treatment options.
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Affiliation(s)
- Hennie G Raterman
- Department of Rheumatology, North West Clinics , Alkmaar, The Netherlands
| | - Irene Em Bultink
- Department of Rheumatology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Rheumatology and Immunology Center , Amsterdam, The Netherlands
| | - Willem F Lems
- Department of Rheumatology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Rheumatology and Immunology Center , Amsterdam, The Netherlands.,Department of Rheumatology, Amsterdam Rheumatology and Immunology Center , Amsterdam, The Netherlands
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36
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Topliss DJ. Editorial: long-term oral budesonide treatment and risk of osteoporotic fractures in patients with microscopic colitis-not a totally clean bill of health. Aliment Pharmacol Ther 2020; 51:991-992. [PMID: 32338783 DOI: 10.1111/apt.15723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Duncan J Topliss
- Department of Endocrinology & Diabetes, Alfred Hospital, Monash University, Melbourne, Australia
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37
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Chiodini I, Merlotti D, Falchetti A, Gennari L. Treatment options for glucocorticoid-induced osteoporosis. Expert Opin Pharmacother 2020; 21:721-732. [PMID: 32004105 DOI: 10.1080/14656566.2020.1721467] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Glucocorticoid (GC) induced osteoporosis (GIOP) is the most common form of secondary osteoporosis. It develops in a dose and time dependent manner, due to a rapid and transient increase in bone resorption, followed by the inhibition of bone formation. AREAS COVERED In this review, the authors summarize the pathophysiology of GIOP and give discussion to the clinical management of patients taking GCs, focusing on the currently available drugs that have antiresorptive or anabolic activity on bone. EXPERT OPINION Despite the widespread use of GCs and their well-established detrimental skeletal effects, GIOP remains an under-diagnosed and under-treated condition. Indeed, the clinical management of GIOP is still debated, so that the recent guidelines differ in their indications for pharmacological intervention. Either bone mineral density (BMD) or algorithms such as FRAX do not completely account for the remarkable and rapid increase in fracture risk of most GC-treated patients. Moreover, while oral bisphosphonates remain the most used and cost-effective option, the potential increased benefits of more potent antiresorptive agents (e.g. denosumab and zoledronate) or anabolic compounds (e.g. teriparatide) warrant further investigation. Despite the above limitations, the assessment of fracture risk is recommended for all individuals committed to receiving oral GCs for 3 months or longer.
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Affiliation(s)
- Iacopo Chiodini
- Istituto Auxologico Italiano, IRCCS, Unit for Bone Metabolism Diseases and Diabetes & Lab of Endocrine and Metabolic Research , Milan, Italy
| | - Daniela Merlotti
- Department of Medicine, Surgery and Neurosciences, University of Siena , Italy
| | - Alberto Falchetti
- Istituto Auxologico Italiano, IRCCS, Unit for Bone Metabolism Diseases and Diabetes & Lab of Endocrine and Metabolic Research , Milan, Italy
| | - Luigi Gennari
- Department of Medicine, Surgery and Neurosciences, University of Siena , Italy
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38
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" Bridging the Gap" Everything that Could Have Been Avoided If We Had Applied Gender Medicine, Pharmacogenetics and Personalized Medicine in the Gender-Omics and Sex-Omics Era. Int J Mol Sci 2019; 21:ijms21010296. [PMID: 31906252 PMCID: PMC6982247 DOI: 10.3390/ijms21010296] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 12/21/2019] [Accepted: 12/30/2019] [Indexed: 02/06/2023] Open
Abstract
Gender medicine is the first step of personalized medicine and patient-centred care, an essential development to achieve the standard goal of a holistic approach to patients and diseases. By addressing the interrelation and integration of biological markers (i.e., sex) with indicators of psychological/cultural behaviour (i.e., gender), gender medicine represents the crucial assumption for achieving the personalized health-care required in the third millennium. However, ‘sex’ and ‘gender’ are often misused as synonyms, leading to frequent misunderstandings in those who are not deeply involved in the field. Overall, we have to face the evidence that biological, genetic, epigenetic, psycho-social, cultural, and environmental factors mutually interact in defining sex/gender differences, and at the same time in establishing potential unwanted sex/gender disparities. Prioritizing the role of sex/gender in physiological and pathological processes is crucial in terms of efficient prevention, clinical signs’ identification, prognosis definition, and therapy optimization. In this regard, the omics-approach has become a powerful tool to identify sex/gender-specific disease markers, with potential benefits also in terms of socio-psychological wellbeing for each individual, and cost-effectiveness for National Healthcare systems. “Being a male or being a female” is indeed important from a health point of view and it is no longer possible to avoid “sex and gender lens” when approaching patients. Accordingly, personalized healthcare must be based on evidence from targeted research studies aimed at understanding how sex and gender influence health across the entire life span. The rapid development of genetic tools in the molecular medicine approaches and their impact in healthcare is an example of highly specialized applications that have moved from specialists to primary care providers (e.g., pharmacogenetic and pharmacogenomic applications in routine medical practice). Gender medicine needs to follow the same path and become an established medical approach. To face the genetic, molecular and pharmacological bases of the existing sex/gender gap by means of omics approaches will pave the way to the discovery and identification of novel drug-targets/therapeutic protocols, personalized laboratory tests and diagnostic procedures (sex/gender-omics). In this scenario, the aim of the present review is not to simply resume the state-of-the-art in the field, rather an opportunity to gain insights into gender medicine, spanning from molecular up to social and psychological stances. The description and critical discussion of some key selected multidisciplinary topics considered as paradigmatic of sex/gender differences and sex/gender inequalities will allow to draft and design strategies useful to fill the existing gap and move forward.
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39
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Franco-Trepat E, Guillán-Fresco M, Alonso-Pérez A, Jorge-Mora A, Francisco V, Gualillo O, Gómez R. Visfatin Connection: Present and Future in Osteoarthritis and Osteoporosis. J Clin Med 2019; 8:jcm8081178. [PMID: 31394795 PMCID: PMC6723538 DOI: 10.3390/jcm8081178] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 07/29/2019] [Accepted: 08/04/2019] [Indexed: 12/15/2022] Open
Abstract
Musculoskeletal pathologies (MSPs) such as osteoarthritis (OA) and osteoporosis (OP), are a set of disorders that cause severe pain, motion difficulties, and even permanent disability. In developed countries, the current incidence of MSPs reaches about one in four adults and keeps escalating as a consequence of aging and sedentarism. Interestingly, OA and OP have been closely related to similar risk factors, including aging, metabolic alterations, and inflammation. Visfatin, an adipokine with an inflammatory and catabolic profile, has been associated with several OA and OP metabolic risk factors, such as obesity, insulin resistance, and type II diabetes. Furthermore, visfatin has been associated with the innate immune receptor toll-like receptor 4 (TLR4), which plays a key role in cartilage and bone inflammatory and catabolic responses. Moreover, visfatin has been related to several OA and OP pathologic features. The aim of this work is to bring together basic and clinical data regarding the common role of visfatin in these pathologies and their major shared risk factors. Finally, we discuss the pitfalls of visfatin as a potential biomarker and therapeutic target in both pathologies.
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Affiliation(s)
- Eloi Franco-Trepat
- Musculoskeletal Pathology Group, Institute IDIS, Santiago University Clinical Hospital, SERGAS, 15706 Santiago de Compostela, Spain
| | - María Guillán-Fresco
- Musculoskeletal Pathology Group, Institute IDIS, Santiago University Clinical Hospital, SERGAS, 15706 Santiago de Compostela, Spain
| | - Ana Alonso-Pérez
- Musculoskeletal Pathology Group, Institute IDIS, Santiago University Clinical Hospital, SERGAS, 15706 Santiago de Compostela, Spain
| | - Alberto Jorge-Mora
- Musculoskeletal Pathology Group, Institute IDIS, Santiago University Clinical Hospital, SERGAS, 15706 Santiago de Compostela, Spain
| | - Vera Francisco
- Research laboratory 9, Institute IDIS, Santiago University Clinical Hospital, SERGAS, 15706 Santiago de Compostela, Spain
| | - Oreste Gualillo
- Research laboratory 9, Institute IDIS, Santiago University Clinical Hospital, SERGAS, 15706 Santiago de Compostela, Spain
| | - Rodolfo Gómez
- Musculoskeletal Pathology Group, Institute IDIS, Santiago University Clinical Hospital, SERGAS, 15706 Santiago de Compostela, Spain.
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