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Meng L, Sun L, Li M. Research Progress on the Influence of Novel Targeted Drugs for Osteoporosis on Glucose Metabolism. Biomolecules 2025; 15:331. [PMID: 40149867 PMCID: PMC11939858 DOI: 10.3390/biom15030331] [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: 12/20/2024] [Revised: 02/20/2025] [Accepted: 02/21/2025] [Indexed: 03/29/2025] Open
Abstract
Both diabetes and osteoporosis are serious chronic conditions. Evidence is mounting that several bone-derived hormones play a role in glucose metabolism in patients with diabetes. Notably, novel biotargeted anti-osteoporotic agents have been recently found to reduce the risk of diabetes. This review explores the correlation of osteokines, including the receptor activator of nuclear factor-κB ligand (RANKL), sclerostin, and Dickkopf-1 (DKK1) with glycemic indicators in patients with diabetes, as well as the effects of their respective monoclonal antibodies on glucose metabolism and their possible mechanisms. Denosumab, the monoclonal antibody against RANKL, has been shown to reduce glycated hemoglobin (HbA1c) and the risk of diabetes, possibly by enhancing pancreatic β-cell survival and glucagon-like peptide-1 secretion. Sclerostin was positively correlated with HbA1c and may induce insulin resistance via endoplasmic reticulum stress. The association of DKK1 with fasting plasma glucose and HbA1c is still unclear, though decreasing DKK1 levels may correlate with β-cell survival. However, few studies have investigated the effects of antibodies against sclerostin or DKK1 on glucose metabolism. Further research is required to elucidate the influence of novel anti-osteoporotic biotargeted agents on glucose homeostasis in patients with diabetes and their underlying mechanisms.
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Affiliation(s)
| | | | - Mei Li
- Key Laboratory of Endocrinology of National Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China; (L.M.)
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2
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Su ST, Lee YH, Tsai YC, Shih PC. Glycemic Control and Fracture Risk in Patients With Type 2 Diabetes Mellitus. Int J Rheum Dis 2025; 28:e70103. [PMID: 39895462 DOI: 10.1111/1756-185x.70103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 01/14/2025] [Accepted: 01/22/2025] [Indexed: 02/04/2025]
Affiliation(s)
- Shiuan-Tzuen Su
- Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Yung-Heng Lee
- Department of Orthopedics, Feng Yuan Hospital, Ministry of Health and Welfare, Taichung, Taiwan
- Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung, Taiwan
- Department of Senior Services Industry Management, Minghsin University of Science and Technology, Hsinchu, Taiwan
- Department of Recreation and Sport Management, Shu-Te University, Kaohsiung, Taiwan
| | - Yuan-Chih Tsai
- Department of Emergency Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Po-Cheng Shih
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Allergy, Immunology & Rheumatology, Changhua Christian Hospital, Changhua, Taiwan
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ElSayed NA, McCoy RG, Aleppo G, Bajaj M, Balapattabi K, Beverly EA, Briggs Early K, Bruemmer D, Cusi K, Echouffo-Tcheugui JB, Ekhlaspour L, Fleming TK, Garg R, Khunti K, Lal R, Levin SR, Lingvay I, Matfin G, Napoli N, Pandya N, Parish SJ, Pekas EJ, Pilla SJ, Pirih FQ, Polsky S, Segal AR, Jeffrie Seley J, Stanton RC, Verduzco-Gutierrez M, Younossi ZM, Bannuru RR. 4. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Care in Diabetes-2025. Diabetes Care 2025; 48:S59-S85. [PMID: 39651988 PMCID: PMC11635044 DOI: 10.2337/dc25-s004] [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: 12/14/2024]
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Rathmann W, Kostev K. Type 2 diabetes incidence in patients initiating denosumab or alendronate treatment: a primary care cohort study. Osteoporos Int 2024; 35:2099-2106. [PMID: 39046498 DOI: 10.1007/s00198-024-07182-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 07/05/2024] [Indexed: 07/25/2024]
Abstract
Denosumab initiation is related to a lower risk of type 2 diabetes than alendronate in anti-osteoporotic treatment-naïve users in primary care practices. PURPOSE Links have been suggested between bone metabolism and glucose tolerance. Downregulation of the receptor activator of nuclear factor κ B ligand (RANKL) signaling improves glucose metabolism. Denosumab, a human monoclonal antibody against RANKL, may be associated with a lower risk of type 2 diabetes (T2D). The aim was to compare incidence rates of T2DM in primary care patients initiating denosumab or alendronate, which is a first-line therapy of osteoporosis. Alendronate as comparator enhances comparability of the two cohorts. METHOD The IQVIA Disease Analyzer comprises a representative panel of general and specialist practices (Germany). A new-user comparative study was conducted among patients with denosumab or alendronate treatment (2010-2021) without history of diabetes and age ≥ 45 years. Incidence rates (per 1,000 person-years) and Cox proportional hazard ratios (HR; 95%CI) for T2DM were estimated. RESULTS The cohorts consisted of 3,354 denosumab (age: 75 years; women: 87%) and 27,068 alendronate (76 years; 86%) users. Overall, 1,038 persons developed T2D during 54,916 person-years. T2DM incidence rates per 1,000 person-years were 11.9 (9.5-14.4) for denosumab and 20.1 (18.8-21.3) for alendronate users, respectively. Denosumab was associated with a reduced risk of T2DM compared to alendronate, adjusting for age, sex, index year, visits, obesity, comorbidities and statins (HR: 0.73; 0.58-0.89). CONCLUSION In this comparative study of older patients seen in routine practices, denosumab was associated with a lower risk of developing T2DM than alendronate.
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Affiliation(s)
- Wolfgang Rathmann
- Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Auf'm Hennekamp 65, Düsseldorf, 40225, Germany.
- German Center for Diabetes Research, Partner Düsseldorf, Munich-Neuherberg, Germany.
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Smith C, Lin X, Parker L, Yeap BB, Hayes A, Levinger I. The role of bone in energy metabolism: A focus on osteocalcin. Bone 2024; 188:117238. [PMID: 39153587 DOI: 10.1016/j.bone.2024.117238] [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: 04/08/2024] [Revised: 08/06/2024] [Accepted: 08/14/2024] [Indexed: 08/19/2024]
Abstract
Understanding the mechanisms involved in whole body glucose regulation is key for the discovery of new treatments for type 2 diabetes (T2D). Historically, glucose regulation was largely focused on responses to insulin and glucagon. Impacts of incretin-based therapies, and importance of muscle mass, are also highly relevant. Recently, bone was recognized as an endocrine organ, with several bone proteins, known as osteokines, implicated in glucose metabolism through their effects on the liver, skeletal muscle, and adipose tissue. Research efforts mostly focused on osteocalcin (OC) as a leading example. This review will provide an overview on this role of bone by discussing bone turnover markers (BTMs), the receptor activator of nuclear factor kB ligand (RANKL), osteoprotegerin (OPG), sclerostin (SCL) and lipocalin 2 (LCN2), with a focus on OC. Since 2007, some, but not all, research using mostly OC genetically modified animal models suggested undercarboxylated (uc) OC acts as a hormone involved in energy metabolism. Most data generated from in vivo, ex vivo and in vitro models, indicate that exogenous ucOC administration improves whole-body and skeletal muscle glucose metabolism. Although data in humans are generally supportive, findings are often discordant likely due to methodological differences and observational nature of that research. Overall, evidence supports the concept that bone-derived factors are involved in energy metabolism, some having beneficial effects (ucOC, OPG) others negative (RANKL, SCL), with the role of some (LCN2, other BTMs) remaining unclear. Whether the effect of osteokines on glucose regulation is clinically significant and of therapeutic value for people with insulin resistance and T2D remains to be confirmed.
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Affiliation(s)
- Cassandra Smith
- Nutrition & Health Innovation Research Institute, School of Health and Medical Sciences, Edith Cowan University, Perth, Western Australia, Australia; Medical School, The University of Western Australia, Perth, Western Australia, Australia; Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Victoria University and Western Health, St Albans, VIC, Australia
| | - Xuzhu Lin
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Lewan Parker
- Institute for Physical Activity and Nutrition (IPAN), Deakin University, Geelong, VIC, Australia
| | - Bu B Yeap
- Medical School, The University of Western Australia, Perth, Western Australia, Australia; Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Australia
| | - Alan Hayes
- Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Victoria University and Western Health, St Albans, VIC, Australia; Department of Medicine - Western Health, The University of Melbourne, Footscray, VIC, Australia
| | - Itamar Levinger
- Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Victoria University and Western Health, St Albans, VIC, Australia; Department of Medicine - Western Health, The University of Melbourne, Footscray, VIC, Australia.
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6
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Hofbauer LC, Rauner M. Denosumab-Protection for Bone and Beyond? J Clin Endocrinol Metab 2024; 109:e2159-e2160. [PMID: 38551213 DOI: 10.1210/clinem/dgae207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/23/2024] [Accepted: 03/26/2024] [Indexed: 09/17/2024]
Affiliation(s)
- Lorenz C Hofbauer
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III and University Center for Healthy Aging, Medical Faculty and University Hospital Carl Gustav Carus, Dresden University of Technology, 01307 Dresden, Germany
| | - Martina Rauner
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III and University Center for Healthy Aging, Medical Faculty and University Hospital Carl Gustav Carus, Dresden University of Technology, 01307 Dresden, Germany
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Philippoteaux C. Ostéoporose. REVUE DU RHUMATISME 2024; 91:545-548. [DOI: 10.1016/j.rhum.2024.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Ramchand SK, Hoermann R, White S, Yeo B, Francis PA, Xu CLH, Zajac JD, Seeman E, Grossmann M. Cardiometabolic Effects of Denosumab in Premenopausal Women With Breast Cancer Receiving Estradiol Suppression: RCT. J Clin Endocrinol Metab 2024; 109:e1857-e1866. [PMID: 38181438 PMCID: PMC11403315 DOI: 10.1210/clinem/dgae003] [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: 09/22/2023] [Revised: 12/20/2023] [Accepted: 01/04/2024] [Indexed: 01/07/2024]
Abstract
CONTEXT Menopause is associated with changes in musculoskeletal, body composition, and metabolic parameters that may be amplified in premenopausal women receiving estradiol suppression for breast cancer. Denosumab offsets deleterious skeletal effects of estradiol suppression and has been reported to have effects on body composition and metabolic parameters in preclinical and observational studies, but evidence from double-blind randomized controlled trials is limited. OBJECTIVE To assess the effect of denosumab on body composition and metabolic parameters. METHODS In a prespecified secondary analysis of a 12-month randomized, double-blind, placebo-controlled trial, 68 premenopausal women with breast cancer initiating ovarian function suppression and aromatase inhibition were randomized to denosumab 60-mg or placebo administered at baseline and 6 months. Outcome measures were total and regional fat and lean mass (DXA), body mass index (BMI), waist and hip circumference, fasting glucose, HOMA-IR, and lipid profile. Using a mixed model, between-group mean adjusted differences over time are reported. RESULTS Over 12 months, relative to placebo, android and gynoid fat mass decreased in the denosumab group (-266 g [95% CI -453 to -79], P = .02, and -452 g [-783 to -122], P = .03, respectively). Total fat mass and waist circumference were lower in the denosumab group but not significantly (-1792 g [-3346 to -240], P = .08 and (- 3.77 cm [-6.76 to -0.79], P = .06, respectively). No significant treatment effects were detected in lean mass, BMI, hip circumference, fasting glucose, HOMA-IR, or lipid profile. CONCLUSION In premenopausal women receiving estradiol suppression, denosumab decreases some measures of fat mass with no detectable effects on other measures of body composition or metabolic parameters.
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Affiliation(s)
- Sabashini K Ramchand
- Department of Medicine, Austin Health, University of Melbourne, Victoria 3084, Australia
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, MA 02114, USA
| | - Rudolf Hoermann
- Department of Medicine, Austin Health, University of Melbourne, Victoria 3084, Australia
| | - Shane White
- Department of Medicine, Austin Health, University of Melbourne, Victoria 3084, Australia
- Olivia Newton-John Cancer & Wellness Centre, Austin Health, Victoria 3084, Australia
| | - Belinda Yeo
- Department of Medicine, Austin Health, University of Melbourne, Victoria 3084, Australia
- Olivia Newton-John Cancer & Wellness Centre, Austin Health, Victoria 3084, Australia
| | - Prudence A Francis
- Peter MacCallum Cancer Centre, Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3052, Australia
| | - Cecilia L H Xu
- Department of Medicine, Austin Health, University of Melbourne, Victoria 3084, Australia
| | - Jeffrey D Zajac
- Department of Medicine, Austin Health, University of Melbourne, Victoria 3084, Australia
- Department of Endocrinology, Austin Health, Victoria 3084, Australia
| | - Ego Seeman
- Department of Medicine, Austin Health, University of Melbourne, Victoria 3084, Australia
- Department of Endocrinology, Austin Health, Victoria 3084, Australia
| | - Mathis Grossmann
- Department of Medicine, Austin Health, University of Melbourne, Victoria 3084, Australia
- Department of Endocrinology, Austin Health, Victoria 3084, Australia
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Sheu A, White CP, Center JR. Bone metabolism in diabetes: a clinician's guide to understanding the bone-glucose interplay. Diabetologia 2024; 67:1493-1506. [PMID: 38761257 PMCID: PMC11343884 DOI: 10.1007/s00125-024-06172-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 04/10/2024] [Indexed: 05/20/2024]
Abstract
Skeletal fragility is an increasingly recognised, but poorly understood, complication of both type 1 and type 2 diabetes. Fracture risk varies according to skeletal site and diabetes-related characteristics. Post-fracture outcomes, including mortality risk, are worse in those with diabetes, placing these people at significant risk. Each fracture therefore represents a sentinel event that warrants targeted management. However, diabetes is a very heterogeneous condition with complex interactions between multiple co-existing, and highly correlated, factors that preclude a clear assessment of the independent clinical markers and pathophysiological drivers for diabetic osteopathy. Additionally, fracture risk calculators and routinely used clinical bone measurements generally underestimate fracture risk in people with diabetes. In the absence of dedicated prospective studies including detailed bone and metabolic characteristics, optimal management centres around selecting treatments that minimise skeletal and metabolic harm. This review summarises the clinical landscape of diabetic osteopathy and outlines the interplay between metabolic and skeletal health. The underlying pathophysiology of skeletal fragility in diabetes and a rationale for considering a diabetes-based paradigm in assessing and managing diabetic bone disease will be discussed.
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Affiliation(s)
- Angela Sheu
- Skeletal Diseases Program, Garvan Institute of Medical Research, Sydney, Australia.
- Clinical School, St Vincent's Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia.
- Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, Australia.
| | - Christopher P White
- Clinical School, Prince of Wales Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia
- Department of Endocrinology and Metabolism, Prince of Wales Hospital, Sydney, Australia
| | - Jacqueline R Center
- Skeletal Diseases Program, Garvan Institute of Medical Research, Sydney, Australia
- Clinical School, St Vincent's Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia
- Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, Australia
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Zhou M, An YZ, Guo Q, Zhou HY, Luo XH. Energy homeostasis in the bone. Trends Endocrinol Metab 2024; 35:439-451. [PMID: 38242815 DOI: 10.1016/j.tem.2023.12.009] [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: 11/01/2023] [Revised: 12/19/2023] [Accepted: 12/21/2023] [Indexed: 01/21/2024]
Abstract
The bone serves as an energy reservoir and actively engages in whole-body energy metabolism. Numerous studies have determined fuel requirements and bioenergetic properties of bone under physiological conditions as well as the dysregulation of energy metabolism associated with bone metabolic diseases. Here, we review the main sources of energy in bone cells and their regulation, as well as the endocrine role of the bone in systemic energy homeostasis. Moreover, we discuss metabolic changes that occur as a result of osteoporosis. Exploration in this area will contribute to an enhanced comprehension of bone energy metabolism, presenting novel possibilities to address metabolic diseases.
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Affiliation(s)
- Min Zhou
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan 410008, PR China; Key Laboratory of Aging-Related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, PR China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Hunan 410008, PR China
| | - Yu-Ze An
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan 410008, PR China; Key Laboratory of Aging-Related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, PR China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Hunan 410008, PR China
| | - Qi Guo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan 410008, PR China; Key Laboratory of Aging-Related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, PR China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Hunan 410008, PR China
| | - Hai-Yan Zhou
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan 410008, PR China; Key Laboratory of Aging-Related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, PR China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Hunan 410008, PR China.
| | - Xiang-Hang Luo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan 410008, PR China; Key Laboratory of Aging-Related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, PR China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Hunan 410008, PR China.
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Wang Y, Jiang Y, Li J, Lin X, Luo Y, Tan S, Yang H, Gao Z, Cui X, Yin P, Kong D, Gao Y, Cheng Y, Zhang L, Tang P, Lyu H. Effect of denosumab on glucose metabolism in postmenopausal osteoporotic women with prediabetes: a study protocol for a 12-month multicenter, open-label, randomized controlled trial. Trials 2023; 24:812. [PMID: 38111052 PMCID: PMC10726555 DOI: 10.1186/s13063-023-07769-0] [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: 06/07/2023] [Accepted: 11/03/2023] [Indexed: 12/20/2023] Open
Abstract
BACKGROUND Participants with prediabetes are at a high risk of developing type 2 diabetes (T2D). Recent studies have suggested that blocking the receptor activator of nuclear factor-κB ligand (RANKL) may improve glucose metabolism and delay the development of T2D. However, the effect of denosumab, a fully human monoclonal antibody that inhibits RANKL, on glycemic parameters in the prediabetes population is uncertain. We aim to examine the effect of denosumab on glucose metabolism in postmenopausal women with osteoporosis and prediabetes. METHODS This is a 12-month multicenter, open-label, randomized controlled trial involving postmenopausal women who have been diagnosed with both osteoporosis and prediabetes. Osteoporosis is defined by the World Health Organization (WHO) as a bone mineral density T score of ≤ - 2.5, as measured by dual-energy X-ray absorptiometry (DXA). Prediabetes is defined as (i) a fasting plasma glucose level of 100-125 mg/dL, (ii) a 2-hour plasma glucose level of 140-199 mg/dL, or (iii) a glycosylated hemoglobin A1c (HbA1c) level of 5.7-6.4%. A total of 346 eligible subjects will be randomly assigned in a 1:1 ratio to receive either subcutaneous denosumab 60 mg every 6 months or oral alendronate 70 mg every week for 12 months. The primary outcome is the change in HbA1c levels from baseline to 12 months. Secondary outcomes include changes in fasting and 2-hour blood glucose levels, serum insulin levels, C-peptide levels, and insulin sensitivity from baseline to 12 months, and the incidence of T2D at the end of the study. Follow-up visits will be scheduled at 3, 6, 9, and 12 months. DISCUSSION This study aims to provide evidence on the efficacy of denosumab on glucose metabolism in postmenopausal women with osteoporosis and prediabetes. The results derived from this clinical trial may provide insight into the potential of denosumab in preventing T2D in high-risk populations. TRIAL REGISTRATION This study had been registered in the Chinese Clinical Trials Registry. REGISTRATION NUMBER ChiCTR2300070789 on April 23, 2023. https://www.chictr.org.cn .
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Affiliation(s)
- Yilin Wang
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of Orthopedics, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, 100853, People's Republic of China
| | - Yu Jiang
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of Orthopedics, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, 100853, People's Republic of China
| | - Jia Li
- Department of Orthopedics, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, 100853, People's Republic of China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, 100853, China
| | - Xisheng Lin
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of Rehabilitation, the Second Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Yan Luo
- Department of Orthopedics, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, 100853, People's Republic of China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, 100853, China
| | - Shuhuai Tan
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of Orthopedics, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, 100853, People's Republic of China
| | - Haohan Yang
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of Orthopedics, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, 100853, People's Republic of China
| | - Zefu Gao
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of Orthopedics, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, 100853, People's Republic of China
| | - Xiang Cui
- Department of Orthopedics, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, 100853, People's Republic of China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, 100853, China
| | - Pengbin Yin
- Department of Orthopedics, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, 100853, People's Republic of China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, 100853, China
| | - Dan Kong
- Department of Orthopedics, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, 100853, People's Republic of China
| | - Yuan Gao
- Department of Nursing, the First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Yu Cheng
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, 100853, China
| | - Licheng Zhang
- Department of Orthopedics, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, 100853, People's Republic of China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, 100853, China
| | - Peifu Tang
- Department of Orthopedics, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, 100853, People's Republic of China.
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, 100853, China.
| | - Houchen Lyu
- Department of Orthopedics, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, 100853, People's Republic of China.
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, 100853, China.
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Lin SC, Tsou SH, Kuo CY, Chen WL, Wu KW, Lin CL, Huang CN. Denosumab Attenuates Glucolipotoxicity-Induced β-Cell Dysfunction and Apoptosis by Attenuating RANK/RANKL Signals. Int J Mol Sci 2023; 24:10289. [PMID: 37373436 DOI: 10.3390/ijms241210289] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/14/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
Obesity is strongly associated with insulin sensitivity in type 2 diabetes (T2D), mainly because free fatty acids (FFAs) are released from excess fat tissue. Long-term exposure to high levels of FFAs and glucose leads to glucolipotoxicity, causing damage to pancreatic β-cells, thus accelerating the progression of T2D. Therefore, the prevention of β-cell dysfunction and apoptosis is essential to prevent the development of T2D. Unfortunately, there are currently no specific clinical strategies for protecting β-cells, highlighting the need for effective therapies or preventive approaches to improve the survival of β-cells in T2D. Interestingly, recent studies have shown that the monoclonal antibody denosumab (DMB), used in osteoporosis, displays a positive effect on blood glucose regulation in patients with T2D. DMB acts as an osteoprotegerin (OPG) by inhibiting the receptor activator of the NF-κB ligand (RANKL), preventing the maturation and function of osteoclasts. However, the exact mechanism by which the RANK/RANKL signal affects glucose homeostasis has not been fully explained. The present study used human 1.4 × 107 β-cells to simulate the T2D metabolic condition of high glucose and free fatty acids (FFAs), and it investigated the ability of DMB to protect β-cells from glucolipotoxicity. Our results show that DMB effectively attenuated the cell dysfunction and apoptosis caused by high glucose and FFAs in β-cells. This may be caused by blocking the RANK/RANKL pathway that reduced mammalian sterile 20-like kinase 1 (MST1) activation and indirectly increased pancreatic and duodenal homeobox 1 (PDX-1) expression. Furthermore, the increase in inflammatory cytokines and ROS caused by the RANK/RANKL signal also played an important role in glucolipotoxicity-induced cytotoxicity, and DMB can also protect β-cells by reducing the mechanisms mentioned above. These findings provide detailed molecular mechanisms for the future development of DMB as a potential protective agent of β-cells.
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Affiliation(s)
- Sheng-Chieh Lin
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Orthopaedics, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Sing-Hua Tsou
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Chien-Yin Kuo
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Surgery, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Wei-Liang Chen
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Kuan-Wen Wu
- Department of Orthopaedic Surgery, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Chih-Li Lin
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Chien-Ning Huang
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Chung Shan Medical University Hospital, Taichung 402, Taiwan
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Xing B, Yu J, Zhang H, Li Y. RANKL inhibition: a new target of treating diabetes mellitus? Ther Adv Endocrinol Metab 2023; 14:20420188231170754. [PMID: 37223831 PMCID: PMC10201162 DOI: 10.1177/20420188231170754] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 04/03/2023] [Indexed: 05/25/2023] Open
Abstract
Accumulating evidence demonstrates the link between glucose and bone metabolism. The receptor activator of nuclear factor-kB ligand (RANKL)/the receptor activator of NF-κB (RANK)/osteoprotegerin (OPG) axis is an essential signaling axis maintaining the balance between bone resorption and bone formation. In recent years, it has been found that RANKL and RANK are distributed not only in bone but also in the liver, muscle, adipose tissue, pancreas, and other tissues that may influence glucose metabolism. Some scholars have suggested that the blockage of the RANKL signaling may protect islet β-cell function and prevent diabetes; simultaneously, there also exist different views that RANKL can improve insulin resistance through inducing the beige adipocyte differentiation and increase energy expenditure. Currently, the results of the regulatory effect on glucose metabolism of RANKL remain conflicting. Denosumab (Dmab), a fully human monoclonal antibody that can bind to RANKL and prevent osteoclast formation, is a commonly used antiosteoporosis drug. Recent basic studies have found that Dmab seems to regulate glucose homeostasis and β-cell function in humanized mice or in vitro human β-cell models. Besides, some clinical data have also reported the glucometabolic effects of Dmab, however, with limited and inconsistent results. This review mainly describes the impact of the RANKL signaling pathway on glucose metabolism and summarizes clinical evidence that links Dmab and DM to seek a new therapeutic strategy for diabetes.
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Affiliation(s)
- Baodi Xing
- Department of Endocrinology, Key Laboratory of
Endocrinology of National Health Commission, Translation Medicine Center,
Peking Union Medical College Hospital, Chinese Academy of Medical Sciences
and Peking Union Medical College, Beijing, China
| | - Jie Yu
- Department of Endocrinology, Key Laboratory of
Endocrinology of National Health Commission, Translation Medicine Center,
Peking Union Medical College Hospital, Chinese Academy of Medical Sciences
and Peking Union Medical College, Beijing, China
| | - Huabing Zhang
- Department of Endocrinology, NHC Key Laboratory
of Endocrinology, Peking Union Medical College Hospital (Dongdan campus),
Chinese Academy of Medical Sciences and Peking Union Medical College, No.1
Shuaifuyuan, Wangfujing Dongcheng District, Beijing 100730, China
| | - Yuxiu Li
- Department of Endocrinology, NHC Key Laboratory
of Endocrinology, Peking Union Medical College Hospital (Dongdan campus),
Chinese Academy of Medical Sciences and Peking Union Medical College, No.1
Shuaifuyuan, Wangfujing Dongcheng District, Beijing 100730, China
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14
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Lyu H, Zhao SS, Zhang L, Wei J, Li X, Li H, Liu Y, Yin P, Norvang V, Yoshida K, Tedeschi SK, Zeng C, Lei G, Tang P, Solomon DH. Denosumab and incidence of type 2 diabetes among adults with osteoporosis: population based cohort study. BMJ 2023; 381:e073435. [PMID: 37072150 PMCID: PMC10111187 DOI: 10.1136/bmj-2022-073435] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/20/2023]
Abstract
OBJECTIVE To estimate the effect of denosumab compared with oral bisphosphonates on reducing the risk of type 2 diabetes in adults with osteoporosis. DESIGN Population based study involving emulation of a randomized target trial using electronic health records. SETTING IQVIA Medical Research Data primary care database in the United Kingdom, 1995-2021. PARTICIPANTS Adults aged 45 years or older who used denosumab or an oral bisphosphonate for osteoporosis. MAIN OUTCOME MEASURES The primary outcome was incident type 2 diabetes, as defined by diagnostic codes. Cox proportional hazards models were used to estimate adjusted hazard ratios and 95% confidence intervals, comparing denosumab with oral bisphosphonates using an as treated approach. RESULTS 4301 new users of denosumab were matched on propensity score to 21 038 users of an oral bisphosphonate and followed for a mean of 2.2 years. The incidence rate of type 2 diabetes in denosumab users was 5.7 (95% confidence interval 4.3 to 7.3) per 1000 person years and in oral bisphosphonate users was 8.3 (7.4 to 9.2) per 1000 person years. Initiation of denosumab was associated with a reduced risk of type 2 diabetes (hazard ratio 0.68, 95% confidence interval 0.52 to 0.89). Participants with prediabetes appeared to benefit more from denosumab compared with an oral bisphosphonate (hazard ratio 0.54, 0.35 to 0.82), as did those with a body mass index ≥30 (0.65, 0.40 to 1.06). CONCLUSIONS In this population based study, denosumab use was associated with a lower risk of incident type 2 diabetes compared with oral bisphosphonate use in adults with osteoporosis. This study provides evidence at a population level that denosumab may have added benefits for glucose metabolism compared with oral bisphosphonates.
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Affiliation(s)
- Houchen Lyu
- Department of Orthopaedics, The Chinese PLA General Hospital, Beijing 100853, China
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, The Chinese PLA General Hospital, Beijing, China
| | - Sizheng Steven Zhao
- Centre for Epidemiology Versus Arthritis, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UK
| | - Licheng Zhang
- Department of Orthopaedics, The Chinese PLA General Hospital, Beijing 100853, China
- National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, The Chinese PLA General Hospital, Beijing, China
| | - Jie Wei
- Department of epidemiology and health statistics, Xiangya School of Public Health, Central South University, Changsha, China
- Health Management Center, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoxiao Li
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Hui Li
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yi Liu
- Division of Endocrinology, New York Presbyterian Hospital, Weill Cornell Medical College, New York, NY, USA
| | - Pengbin Yin
- Department of Orthopaedics, The Chinese PLA General Hospital, Beijing 100853, China
- National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, The Chinese PLA General Hospital, Beijing, China
| | - Vibeke Norvang
- Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway
| | - Kazuki Yoshida
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Sara K Tedeschi
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Chao Zeng
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
| | - Guanghua Lei
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
| | - Peifu Tang
- Department of Orthopaedics, The Chinese PLA General Hospital, Beijing 100853, China
- National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, The Chinese PLA General Hospital, Beijing, China
| | - Daniel H Solomon
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA 02115, USA
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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15
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Viggers R, Starup-Linde J, Vestergaard P. Discrepancies in type of first major osteoporotic fracture and anti-osteoporotic therapy in elderly people with type 2 diabetes mellitus: A retrospective Danish cohort study. Bone 2023; 171:116745. [PMID: 36965654 DOI: 10.1016/j.bone.2023.116745] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 03/16/2023] [Accepted: 03/20/2023] [Indexed: 03/27/2023]
Abstract
OBJECTIVE Subjects with diabetes mellitus have an increased risk of fractures. We aimed to identify discrepancies in the first type of major osteoporotic fracture (MOF) and anti-osteoporotic therapy between subjects with type 2 diabetes (T2D) and subjects without diabetes. Methods and research design. We conducted a retrospective national cohort study by access to all discharge diagnoses (ICD-10 system) and redeemed drug prescriptions (ATC classification system). We included all subjects alive and Danish citizens in 2010 and identified subjects with T2D diagnosed after the age of 50 between 1998 and 2018. Only subjects with a MOF after the index date were included in the main analysis. The type of MOF was identified by diagnosis codes and categorized into Humerus, Forearm, Spine, and Hip. Multinomial logistic regression modeling was used to assess the predicted probability changes in MOF type between T2D and control subjects. Data on first anti-osteoporotic therapy after the MOF was assessed by redeemed drug prescriptions. Mortality and time to therapy after the MOF were evaluated by cox proportional hazards. RESULT We included 26,588 subjects with T2D and 97,982 subjects without diabetes. The mean age was age 69.33 (±10.34) for T2D and 69.85 (±10.19) for control subjects. The cohort was primarily females (67 %). Subjects with T2D had a higher probability of hip (3.98 % [95 % CI 3.29; 4.67]) and humerus (2.82 % [95 % CI 2.17; 3.46]) fractures as the first MOF compared to control subjects. However, the probability of forearm fractures as the first MOF was 6.77 % (95 % CI 6.08; 7.46) lower among subjects with T2D. The multiple adjusted hazard ratio for anti-osteoporotic treatment after the first MOF was 0.80 (95 % CI 0.77; 0.88) for T2D compared to controls among treatment-naïve subjects. CONCLUSION Forearm fractures were the most frequent type of MOF and were more prevalent in control subjects. Subjects with T2D had a significantly higher probability of hip and humerus fractures as the first MOF but had a 20 % lower chance of anti-osteoporotic treatment afterwards.
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Affiliation(s)
- Rikke Viggers
- Steno Diabetes Center North Denmark, Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
| | - Jakob Starup-Linde
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Peter Vestergaard
- Steno Diabetes Center North Denmark, Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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16
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Kan B, Hou J, Leslie WD, Jiang D, Zhang J, Yang S. Associations of estrogen therapy and non-estrogen anti-resorptive therapy with diabetes mellitus risk: A classical and Bayesian meta-analysis. Bone 2023; 171:116738. [PMID: 36933854 DOI: 10.1016/j.bone.2023.116738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 02/27/2023] [Accepted: 03/13/2023] [Indexed: 03/18/2023]
Abstract
Anti-resorptive therapy (AT) increases insulin resistance and decrease insulin secretion through reduced undercarboxylated osteocalcin in mice. However, there are inconsistent findings regarding the impact of AT use on the risk of diabetes mellitus in humans. We examined the association between AT and incident diabetes mellitus using classical and Bayesian meta-analysis. We searched Pubmed, Medline, Embase, Web of Science, Cochrane, and Google Scholar for studies listed from database inception to 25 February 2022. Randomized controlled trials (RCTs) and cohort studies reporting associations of estrogen therapy (ET) and non-estrogen anti-resorptive therapy (NEAT) with incident diabetes mellitus were included. Two reviewers independently extracted research data such as ET and NEAT, diabetes mellitus, risk ratios (RRs), and 95 % confidence intervals (CIs) for incident diabetes mellitus associated with ET and NEAT from individual studies. This meta-analysis included data from nineteen original studies, consisting of fourteen ET and five NEAT studies. ET was associated with reduced risk of diabetes mellitus in the classical meta-analysis (RR: 0.90; 95 % CI: 0.81-0.99). Slightly stronger results were found in the meta-analysis of RCTs (RR: 0.83; 95 % CI: 0.77-0.89). The probability that RR < 1.0 was 95 % in the overall analysis and 99 % in RCTs under weakly informative prior. Although NEAT was associated with reduced risk of diabetes mellitus overall (RR: 0.80; 95 % CI: 0.67-0.97), this was not found in the RCT meta-analysis (RR: 0.90; 95 % CI: 0.75-1.10). Under weakly informative prior, the probabilities that NEAT reduces diabetes mellitus by >0 % were 99 %, and 73 % in the overall and RCT meta-analysis, respectively. In conclusion, meta-analysis provided consistent evidence against the hypothesis that AT increases diabetes risk. ET may reduce the risk of diabetes mellitus. Whether NEAT reduces the risk of diabetes mellitus is uncertain and requires additional evidence from RCTs.
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Affiliation(s)
- Bo Kan
- Department of Clinical Laboratory, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jiaoyu Hou
- Department of Geriatrics, The First Hospital of Jilin University, Changchun, Jilin, China
| | - William D Leslie
- Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Depeng Jiang
- Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Juan Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin, China
| | - Shuman Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin, China.
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17
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Zawada A, Ratajczak AE, Rychter AM, Szymczak-Tomczak A, Dobrowolska A, Krela-Kaźmierczak I. Treatment of Diabetes and Osteoporosis—A Reciprocal Risk? Biomedicines 2022; 10:biomedicines10092191. [PMID: 36140292 PMCID: PMC9495959 DOI: 10.3390/biomedicines10092191] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 08/29/2022] [Accepted: 08/30/2022] [Indexed: 11/30/2022] Open
Abstract
Diabetes mellitus is a metabolic and systematic disorder that requires individualized therapy. The disease leads to various consequences, resulting in the destruction of tissues and organs. The aforementioned outcomes also include bone mineral disorders, caused by medications as well as diet therapy and physical activity. Some drugs may have a beneficial effect on both bone mineral density and the risk of fractures. Nevertheless, the impact of other medications remains unknown. Focusing on pharmacotherapy in diabetes may prevent bone mineral disorders and influence both the treatment and quality of life in patients suffering from diabetes mellitus. On the other hand, anti-osteoporosis drugs, such as antiresorptive or anabolic drugs, as well as drugs with a mixed mechanism of action, may affect carbohydrate metabolism, particularly in patients with diabetes. Therefore, the treatment of diabetes as well as osteoporosis prevention are vital for this group of patients.
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Affiliation(s)
- Agnieszka Zawada
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, 61-701 Poznn, Poland
- Correspondence: (A.Z.); (A.E.R.); Tel.: +48-667-385-996 or +48-8691-343 (A.E.R.); Fax: +48-8691-686 (A.E.R.)
| | - Alicja Ewa Ratajczak
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, 61-701 Poznn, Poland
- Doctoral School, Poznan University of Medical Sciences, 61-701 Poznan, Poland
- Correspondence: (A.Z.); (A.E.R.); Tel.: +48-667-385-996 or +48-8691-343 (A.E.R.); Fax: +48-8691-686 (A.E.R.)
| | - Anna Maria Rychter
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, 61-701 Poznn, Poland
- Doctoral School, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Aleksandra Szymczak-Tomczak
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, 61-701 Poznn, Poland
| | - Agnieszka Dobrowolska
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, 61-701 Poznn, Poland
| | - Iwona Krela-Kaźmierczak
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, 61-701 Poznn, Poland
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18
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Karsenty G, Khosla S. The crosstalk between bone remodeling and energy metabolism: A translational perspective. Cell Metab 2022; 34:805-817. [PMID: 35545088 PMCID: PMC9535690 DOI: 10.1016/j.cmet.2022.04.010] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/30/2022] [Accepted: 04/20/2022] [Indexed: 12/15/2022]
Abstract
Genetics in model organisms has progressively broken down walls that previously separated different disciplines of biology. One example of this holistic evolution is the recognition of the complex relationship that exists between the control of bone mass (bone remodeling) and energy metabolism in mammals. Numerous hormones orchestrate this crosstalk. In particular, the study of the leptin-mediated regulation of bone mass has not only revealed the existence of a central control of bone mass but has also led to the realization that sympathetic innervation is a major regulator of bone remodeling. This happened at a time when the use of drugs aiming at treating osteoporosis, the most frequent bone disease, has dwindled. This review will highlight the main aspects of the leptin-mediated regulation of bone mass and how this led to the realization that β-blockers, which block the effects of the sympathetic nervous system, may be a viable option to prevent osteoporosis.
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Affiliation(s)
- Gerard Karsenty
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
| | - Sundeep Khosla
- Kogod Center of Aging and Division of Endocrinology and Metabolism, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
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19
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Sheu A, Greenfield JR, White CP, Center JR. Assessment and treatment of osteoporosis and fractures in type 2 diabetes. Trends Endocrinol Metab 2022; 33:333-344. [PMID: 35307247 DOI: 10.1016/j.tem.2022.02.006] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/01/2022] [Accepted: 02/22/2022] [Indexed: 01/10/2023]
Abstract
There is substantial, and growing, evidence that type 2 diabetes (T2D) is associated with skeletal fragility, despite often preserved bone mineral density. As post-fracture outcomes, including mortality, are worse in people with T2D, bone management should be carefully considered in this highly vulnerable group. However, current fracture risk calculators inadequately predict fracture risk in T2D, and dedicated randomised controlled trials identifying optimal management in patients with T2D are lacking, raising questions about the ideal assessment and treatment of bone health in these people. We synthesise the current literature on evaluating bone measurements in T2D and summarise the evidence for safety and efficacy of both T2D and anti-osteoporosis medications in relation to bone health in these patients.
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Affiliation(s)
- Angela Sheu
- Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia; Clinical School, St Vincent's Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia; Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, Australia.
| | - Jerry R Greenfield
- Clinical School, St Vincent's Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia; Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, Australia; Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, Australia
| | - Christopher P White
- Clinical School, Prince of Wales Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia; Department of Endocrinology and Metabolism, Prince of Wales Hospital, Sydney, Australia
| | - Jacqueline R Center
- Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia; Clinical School, St Vincent's Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia; Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, Australia
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20
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Khosla S, Samakkarnthai P, Monroe DG, Farr JN. Update on the pathogenesis and treatment of skeletal fragility in type 2 diabetes mellitus. Nat Rev Endocrinol 2021; 17:685-697. [PMID: 34518671 PMCID: PMC8605611 DOI: 10.1038/s41574-021-00555-5] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/06/2021] [Indexed: 02/08/2023]
Abstract
Fracture risk is increased in patients with type 2 diabetes mellitus (T2DM). In addition, these patients sustain fractures despite having higher levels of areal bone mineral density, as measured by dual-energy X-ray absorptiometry, than individuals without T2DM. Thus, additional factors such as alterations in bone quality could have important roles in mediating skeletal fragility in patients with T2DM. Although the pathogenesis of increased fracture risk in T2DM is multifactorial, impairments in bone material properties and increases in cortical porosity have emerged as two key skeletal abnormalities that contribute to skeletal fragility in patients with T2DM. In addition, indices of bone formation are uniformly reduced in patients with T2DM, with evidence from mouse studies published over the past few years linking this abnormality to accelerated skeletal ageing, specifically cellular senescence. In this Review, we highlight the latest advances in our understanding of the mechanisms of skeletal fragility in patients with T2DM and suggest potential novel therapeutic approaches to address this problem.
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Affiliation(s)
- Sundeep Khosla
- Division of Endocrinology and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
| | - Parinya Samakkarnthai
- Division of Endocrinology and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
- Division of Endocrinology, Phramongkutklao Hospital and College of Medicine, Bangkok, Thailand
| | - David G Monroe
- Division of Endocrinology and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Joshua N Farr
- Division of Endocrinology and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
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21
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Pacheco-Soto BT, Elguezabal-Rodelo RG, Porchia LM, Torres-Rasgado E, Pérez-Fuentes R, Gonzalez-Mejia ME. Denosumab improves glucose parameters in patients with impaired glucose tolerance: a systematic review and meta-analysis. J Drug Assess 2021; 10:97-105. [PMID: 34676131 PMCID: PMC8525927 DOI: 10.1080/21556660.2021.1989194] [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] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Objective Receptor activator of NF-κβ ligand (RANKL) is crucial for the development of hepatic insulin resistance and poor glucose uptake; therefore, inhibiting RANKL with Denosumab could improve fasting plasma glucose (FPG) and insulin (FPI). Methods A systematic review was conducted to evaluate the effects of Denosumab on glycemic parameters. PubMed, SCOPUS, EBSCO, and LILACS databases were searched for studies that investigated the effect of Denosumab on FPG, glycated hemoglobin (HbA1c), FPI, and Homeostatic Model Assessment for Insulin Resistance (HOMA1-IR). The pooled standard difference in means (SDM) and 95% confidence intervals (95%CI) were calculated. The results were stratified into (1) Normal Glucose Tolerance (NGT) and (2) Impaired Glucose Tolerance (IGT). Results Six publications (1203 participants) were included. There was a significant association between Denosumab and FPG (SDM = -0.388, 95%CI: -0.705 to -0.070, p = .017) and with HOMA1-IR (SDM = -0.223, 95%CI: -0.388 to -0.058, p = .008), but not for HbA1c and FPI. When stratified by glucose tolerance, the association between Denosumab and FPG, HbA1c, and HOMA1-IR was present for the IGT group. Lastly, Denosumab had a time-dependent effect on HbA1c (slope = -0.037, 95%CI: -0.059 to -0.015, p < .005). Conclusions Denosumab significantly improved glycemic parameters. This outcome was more prominent for subjects with compromised glucose tolerance, positing that Denosumab can be used as a treatment to improve glucose metabolism for persons with pre-diabetes and diabetes.
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Affiliation(s)
| | | | - Leonardo M Porchia
- Laboratorio de Fisiopatología en Enfermedades Crónicas, Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Delegación Puebla, Puebla, Mexico
| | | | - Ricardo Pérez-Fuentes
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico.,Laboratorio de Fisiopatología en Enfermedades Crónicas, Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Delegación Puebla, Puebla, Mexico
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22
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Chiodini I, Gaudio A, Palermo A, Napoli N, Vescini F, Falchetti A, Merlotti D, Eller-Vainicher C, Carnevale V, Scillitani A, Pugliese G, Rendina D, Salcuni A, Bertoldo F, Gonnelli S, Nuti R, Toscano V, Triggiani V, Cenci S, Gennari L. Management of bone fragility in type 2 diabetes: Perspective from an interdisciplinary expert panel. Nutr Metab Cardiovasc Dis 2021; 31:2210-2233. [PMID: 34059385 DOI: 10.1016/j.numecd.2021.04.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/11/2021] [Accepted: 04/15/2021] [Indexed: 12/22/2022]
Abstract
AIM Bone fragility is increasingly recognized as a relevant complication of type 2 diabetes (T2D) and diabetic patients with fragility fractures have higher mortality rates than non diabetic individuals or diabetic patients without fractures. However, current diagnostic approaches for fracture risk stratification, such as bone mineral density measurement or the use of risk assessment algorithms, largely underestimate fracture risk in T2D patients. A multidisciplinary expert panel was established in order to in order to formulate clinical consensus recommendations on bone health assessment and management of fracture risk in patients with T2D. DATA SYNTHESIS The following key questions were addressed: a) which are the risk factors for bone fragility in T2D?, b) which diagnostic procedures can be currently used to stratify fracture risk in T2D patients?, c) which are the effects of antidiabetic treatments on bone?, and d) how to prevent and treat bone fragility in T2D patients? Based on the available data members of this panel suggest that the stratification of fracture risk in patients with diabetes should firstly rely on the presence of a previous fragility fracture and on the individual risk profile, with the inclusion of T2D-specific risk factors (namely T2D duration above 10 yrs, presence of chronic T2D complications, use of insulin or thiazolidinediones and persistent HbA1c levels above 8% for at least 1 year). Two independent diagnostic approaches were then suggested in the presence or the absence of a prevalent fragility fracture, respectively. CONCLUSIONS Clinical trials in T2D patients at risk for fragility fractures are needed to determine the efficacy and safety of available antiresorptive and anabolic agents in this specific setting.
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Affiliation(s)
- Iacopo Chiodini
- Unit for Bone Metabolism Diseases and Diabetes and Lab of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Medical Science and Community Health, University of Milan, Milan, Italy
| | - Agostino Gaudio
- Department of Clinical and Experimental Medicine, University of Catania, University Hospital "G. Rodolico" Catania, Italy
| | - Andrea Palermo
- Department of Endocrinology and Diabetes, University Campus Bio-Medico, Rome, Italy
| | - Nicola Napoli
- Department of Endocrinology and Diabetes, University Campus Bio-Medico, Rome, Italy
| | - Fabio Vescini
- Endocrinology and Metabolism Unit, University-Hospital S. M. Misericordia of Udine, Italy
| | - Alberto Falchetti
- Unit for Bone Metabolism Diseases and Diabetes and Lab of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy; EndOsMet, Villa Donatello Private Hospital, Florence, Italy
| | - Daniela Merlotti
- Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Siena, Italy; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
| | | | - Vincenzo Carnevale
- Unit of Internal Medicine, "Casa Sollievo della Sofferenza" Hospital, IRCCS, San Giovanni Rotondo, (FG), Italy
| | - Alfredo Scillitani
- Unit of Endocrinology, "Casa Sollievo della Sofferenza" Hospital, IRCCS, San Giovanni Rotondo, (FG), Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, and Diabetes Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Domenico Rendina
- Department of Clinical Medicine and Surgery, "Federico II" University of Naples, Naples, Italy
| | - Antonio Salcuni
- Endocrinology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Francesco Bertoldo
- Department of Medicine, University of Verona, Policlinico GB Rossi, Verona, Italy
| | - Stefano Gonnelli
- Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Siena, Italy
| | - Ranuccio Nuti
- Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Siena, Italy
| | - Vincenzo Toscano
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy
| | - Vincenzo Triggiani
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases. University of Bari "Aldo Moro", Bari, Italy
| | - Simone Cenci
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
| | - Luigi Gennari
- Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Siena, Italy.
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23
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Napoli N, Incalzi RA, De Gennaro G, Marcocci C, Marfella R, Papalia R, Purrello F, Ruggiero C, Tarantino U, Tramontana F, Conte C. Bone fragility in patients with diabetes mellitus: A consensus statement from the working group of the Italian Diabetes Society (SID), Italian Society of Endocrinology (SIE), Italian Society of Gerontology and Geriatrics (SIGG), Italian Society of Orthopaedics and Traumatology (SIOT). Nutr Metab Cardiovasc Dis 2021; 31:1375-1390. [PMID: 33812734 DOI: 10.1016/j.numecd.2021.01.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 01/24/2021] [Accepted: 01/25/2021] [Indexed: 02/08/2023]
Abstract
Bone fragility is one of the possible complications of diabetes, either type 1 (T1D) or type 2 (T2D). Bone fragility can affect patients of different age and with different disease severity depending on type of diabetes, disease duration and the presence of other complications. Fracture risk assessment should be started at different stages in the natural history of the disease depending on the type of diabetes and other risk factors. The risk of fracture in T1D is higher than in T2D, imposing a much earlier screening and therapeutic intervention that should also take into account a patient's life expectancy, diabetes complications etc. The therapeutic armamentarium for T2D has been enriched with drugs that may influence bone metabolism, and clinicians should be aware of these effects. Considering the complexity of diabetes and osteoporosis and the range of variables that influence treatment choices in a given individual, the Working Group on bone fragility in patients with diabetes mellitus has identified and issued recommendations based on the variables that should guide screening of bone fragility and management of diabetes and bone fragility: (A)ge, (B)MD, (C)omplications, (D)uration of disease, & (F)ractures (ABCD&F). Consideration of these parameters may help clinicians identify the best time for screening, the appropriate glycaemic target and anti-osteoporosis drug for patients with diabetes at risk of or with bone fragility.
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Affiliation(s)
- Nicola Napoli
- Unit of Endocrinology and Diabetes, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy; Division of Bone and Mineral Diseases, Washington University in St. Louis, St. Louis, MO, USA.
| | - Raffaele A Incalzi
- Unit of Geriatrics, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy.
| | - Giovanni De Gennaro
- Diabetes Center, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Claudio Marcocci
- Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Rocco Papalia
- Unit of Orthopedic and Trauma Surgery, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Francesco Purrello
- Department of Clinical and Experimental Medicine, University of Catania, 95100 Catania, Italy; Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy
| | - Carmelinda Ruggiero
- Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy
| | - Umberto Tarantino
- Department of Clinical Sciences and Translational Medicine, Faculty of Medicine and Surgery, "Tor Vergata" University of Rome, Rome, Italy; Department of Orthopaedics and Traumatology, "Policlinico Tor Vergata" Foundation, Rome, Italy
| | - Flavia Tramontana
- Unit of Endocrinology and Diabetes, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Caterina Conte
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy; Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Milan, Italy
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24
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Ochoa-Précoma R, Pacheco-Soto BT, Porchia LM, Torres-Rasgado E, Pérez-Fuentes R, Gonzalez-Mejia ME. Association between Osteoprotegerin and Charcot Neuroarthropathy: a systematic review. Acta Diabetol 2021; 58:475-484. [PMID: 33394132 DOI: 10.1007/s00592-020-01638-x] [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: 08/25/2020] [Accepted: 11/08/2020] [Indexed: 11/09/2022]
Abstract
AIMS Osteoprotegerin (OPG) has been associated with Charcot Neuroarthropathy (CN); however, three studied OPG polymorphisms (1181C > G, 245A > C and 950 T > C) have yielded conflicting results. Therefore, this meta-analysis was conducted to determine the difference in serum OPG concentrations between healthy controls and diabetics with and without CN and the effect OPG polymorphisms have on CN development. METHODS PubMed, LILAC, SCOPUS, and EBSCO databases and retrieved publications' bibliographies were searched for studies that examined for OPG and CN. Depending on the heterogeneity, fixed or random effects were used to calculate the pooled odds ratio (OR) or standard difference in means (SDM) with 95% confidence intervals (95%CI) for 5 genetic models (heterozygous, homozygous, dominant, recessive, and allelic) and serum concentrations, respectively. RESULTS Seven publications (12 studies) demonstrated that serum OPG concentrations were more elevated in subjects with CN (SDM = 0.719, 95%CI = 0.555-0.883, p < 0.001). When CN was compared to healthy controls or diabetics, the difference was more prominent for healthy controls (SDM = 1.043, 95%CI = 0.676-1.409, p < 0.001) than diabetics (SDM = 0.639, 95%CI = 0.456-0.821, p < 0.001) and the SDM difference was significant (p = 0.013). Using 6 publications (9 studies), neither the 1181C > G or the 950 T > C polymorphisms showed any significant associations for any genetic model. For the 245A > C polymorphism, only the homozygous genetic model showed a significant association between the polymorphism and CN (OR = 2.850, 95%CI: 1.051-7.729, p = 0.040). CONCLUSIONS Here, we determined a potential correlation between the CN and serum OPG concentrations and that only the CC genotype of the 245A > C polymorphism showed an increased risk of developing CN.
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Affiliation(s)
- Renata Ochoa-Précoma
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, Calle 13 Sur 2901, Colonia Volcanes, 72420, Puebla, México
| | - Blanca T Pacheco-Soto
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, Calle 13 Sur 2901, Colonia Volcanes, 72420, Puebla, México
| | - Leonardo M Porchia
- Laboratorio de Fisiopatología en Enfermedades Crónicas, Centro de Investigación Biomédica de Oriente, IMSS. Delegación Puebla. Carretera Federal Atlixco Metepec Km, 4.5, Colonia Centro, 74360, Atlixco, Puebla, México
| | - Enrique Torres-Rasgado
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, Calle 13 Sur 2901, Colonia Volcanes, 72420, Puebla, México
| | - Ricardo Pérez-Fuentes
- Laboratorio de Fisiopatología en Enfermedades Crónicas, Centro de Investigación Biomédica de Oriente, IMSS. Delegación Puebla. Carretera Federal Atlixco Metepec Km, 4.5, Colonia Centro, 74360, Atlixco, Puebla, México
| | - M Elba Gonzalez-Mejia
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, Calle 13 Sur 2901, Colonia Volcanes, 72420, Puebla, México.
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25
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Anastasilakis AD, Tsourdi E, Tabacco G, Naciu AM, Napoli N, Vescini F, Palermo A. The Impact of Antiosteoporotic Drugs on Glucose Metabolism and Fracture Risk in Diabetes: Good or Bad News? J Clin Med 2021; 10:jcm10050996. [PMID: 33801212 PMCID: PMC7957889 DOI: 10.3390/jcm10050996] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 02/18/2021] [Accepted: 02/22/2021] [Indexed: 12/20/2022] Open
Abstract
Osteoporosis and diabetes mellitus represent global health problems due to their high, and increasing with aging, prevalence in the general population. Osteoporosis can be successfully treated with both antiresorptive and anabolic drugs. While these drugs are clearly effective in reducing the risk of fracture in patients with postmenopausal and male osteoporosis, it is still unclear whether they may have the same efficacy in patients with diabetic osteopathy. Furthermore, as bone-derived cytokines (osteokines) are able to influence glucose metabolism, it is conceivable that antiosteoporotic drugs may have an effect on glycemic control through their modulation of bone turnover that affects the osteokines’ release. These aspects are addressed in this narrative review by means of an unrestricted computerized literature search in the PubMed database. Our findings indicate a balance between good and bad news. Active bone therapies and their modulation of bone turnover do not appear to play a clinically significant role in glucose metabolism in humans. Moreover, there are insufficient data to clarify whether there are any differences in the efficacy of antiosteoporotic drugs on fracture incidence between diabetic and nondiabetic patients with osteoporosis. Although more studies are required for stronger recommendations to be issued, bisphosphonates appear to be the first-line drug for treatment of osteoporosis in diabetic patients, while denosumab seems preferable for older patients, particularly for those with impaired renal function, and osteoanabolic agents should be reserved for patients with more severe forms of osteoporosis.
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Affiliation(s)
| | - Elena Tsourdi
- Department of Medicine (III) &Center for Healthy Aging, Technische Universität Dresden Medical Center, 01307 Dresden, Germany
- Correspondence: ; Tel.: +49-351-458-12933; Fax: +49-351-458-5801
| | - Gaia Tabacco
- Unit of Endocrinology and Diabetes, Campus Bio-Medico University, 00128 Rome, Italy; (G.T.); (A.M.N.); (N.N.); (A.P.)
| | - Anda Mihaela Naciu
- Unit of Endocrinology and Diabetes, Campus Bio-Medico University, 00128 Rome, Italy; (G.T.); (A.M.N.); (N.N.); (A.P.)
| | - Nicola Napoli
- Unit of Endocrinology and Diabetes, Campus Bio-Medico University, 00128 Rome, Italy; (G.T.); (A.M.N.); (N.N.); (A.P.)
| | - Fabio Vescini
- Department of Endocrinology and Diabetes, Santa Maria della Misericordia Hospital, 33100 Udine, Italy;
| | - Andrea Palermo
- Unit of Endocrinology and Diabetes, Campus Bio-Medico University, 00128 Rome, Italy; (G.T.); (A.M.N.); (N.N.); (A.P.)
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26
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Postmenopausal osteoporosis coexisting with other metabolic diseases: Treatment considerations. Maturitas 2021; 147:19-25. [PMID: 33832643 DOI: 10.1016/j.maturitas.2021.02.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/18/2021] [Accepted: 02/27/2021] [Indexed: 12/13/2022]
Abstract
In postmenopausal women, osteoporosis may coexist with other metabolic diseases, including, but not limited to, obesity, diabetes, nonalcoholic fatty liver disease (NAFLD), dyslipidemia and cardiovascular disease (CVD). This association may lie beyond simple coincidence owing to high prevalence of all these diseases, especially in the aging population, as common pathogenetic mechanisms between them and osteoporosis may exist. In this context, anti-osteoporotic medications may affect the pathogenesis of some of these metabolic diseases; this is an important consideration when selecting the most appropriate medication for osteoporotic patients with coexistent metabolic diseases. Conversely, some current or emerging medications for metabolic diseases adversely affect bone metabolism and, if possible, should be avoided in women with postmenopausal osteoporosis. The main aim of this review is to summarize the evidence on anti-osteoporotic treatment in postmenopausal women with concomitant metabolic diseases, i.e. obesity, diabetes, NAFLD, dyslipidemia and CVD. The secondary aim is to present data on the effect of current or emerging medication for metabolic diseases on bone metabolism of postmenopausal women. Deeper understanding of the underlying links between osteoporosis and metabolic diseases may have clinical implications. However, mechanistic studies are needed to elucidate the potential pathophysiological links, as well as clinical trials in women with postmenopausal osteoporosis coexisting with specific metabolic diseases; these may guide clinical practice in the future for the selection of the best anti-osteoporotic medication for each patient with specific metabolic diseases.
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27
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Cipriani C, Piemonte S, Colangelo L, De Martino V, Diacinti D, Ferrone F, Piazzolla V, Fassino V, Nieddu L, Minisola S, Pepe J. Inhibition of the RANKL with denosumab has no effect on circulating markers of atherosclerosis in women with postmenopausal osteoporosis: a pilot study. Endocrine 2021; 71:199-207. [PMID: 32897516 DOI: 10.1007/s12020-020-02483-2] [Citation(s) in RCA: 5] [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: 05/28/2020] [Accepted: 08/26/2020] [Indexed: 12/22/2022]
Abstract
PURPOSE We evaluated the early effect of denosumab on circulating markers of atherosclerosis in women with postmenopausal osteoporosis. METHODS Denosumab (60 mg) was administered subcutaneously every 6 months (m) in 27 women (mean age 75 ± 5 years) with postmenopausal osteoporosis and high cardiovascular risk for a total of 24 m. Zoledronic acid was administered in 6 age-matched women as a single intravenous dose. Serum levels of vascular cell adhesion protein 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E and P selectin, CD-40 ligand (CD40L), interleukin-6 (IL-6), matrix metalloproteinase (MMP) 1 and 9, monocyte chemoattractant protein-1 (MCP-1), fibrinogen (FBG), and high sensitivity C-reactive protein (hs-CRP) were measured at baseline, 15 days (d), 2, 6 and 12 m after dosing. In the denosumab group, observation was extended to 24 m as secondary endpoint. RESULTS Serum ICAM-1 levels showed significant increase in the zoledronic acid group (+18 ± 0.1%; p < 0.01) at 12 m. In the denosumab group, we observed a significant increase in serum CD40L (+2 ± 0.8%; p < 0.001), MMP-1 (+11 ± 0.4%, p < 0.02), and MMP-9 (+39.4 ± 0.8%, p < 0.01) at 24 m. There was a significant increase in serum FBG and hs-CRP in both groups at 12 m (denosumab:+2.2 ± 0.2% and +50.3 ± 1.6%; zoledronic acid: +9.4 ± 0.1 and +81.8 ± 0.8%; p < 0.01). No significant between-group differences were found. CONCLUSIONS 24-m treatment with denosumab has no effect on the circulating markers of atherosclerosis in women with postmenopausal osteoporosis. Fluctuation of serum ICAM-1, CD40L, MMPs, FBG and hs-CRP can be ascribed to perturbation of immunological mechanisms stimulated by denosumab and zoledronic acid.
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Affiliation(s)
- Cristiana Cipriani
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.
| | - Sara Piemonte
- ASL ROMA 1, Distretto 2, via Tagliamento 19, 00198, Rome, Italy
| | - Luciano Colangelo
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - Viviana De Martino
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - Daniele Diacinti
- Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Federica Ferrone
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - Valentina Piazzolla
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - Valeria Fassino
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Luciano Nieddu
- Faculty of Economics, UNINT University, Via Cristoforo Colombo 200, 00147, Rome, Italy
| | - Salvatore Minisola
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - Jessica Pepe
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
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28
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Romero-Díaz C, Duarte-Montero D, Gutiérrez-Romero SA, Mendivil CO. Diabetes and Bone Fragility. Diabetes Ther 2021; 12:71-86. [PMID: 33185853 PMCID: PMC7843783 DOI: 10.1007/s13300-020-00964-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 10/29/2020] [Indexed: 02/08/2023] Open
Abstract
Diabetes is a highly prevalent disease with complications that impact most bodily systems. However, the impact of diabetes on bone health is frequently ignored or underestimated. Both type 1 (T1D) and type 2 diabetes (T2D) are associated with a higher risk of fractures, albeit through different mechanisms. T1D is characterized by near total insulinopenia, which affects the anabolic tone of bone and results in reduced bone mineral density (BMD). Meanwhile, patients with T2D have normal or high BMD, but carry an increased risk of fractures due to alterations of bone microarchitecture and a local humoral environment that stimulates osteoclast activity. Chronic hyperglycemia induces non-enzymatic glycation of collagen in both types of diabetes. Epidemiological evidence confirms a largely increased fracture risk in T1D and T2D, but also that it can be substantially reduced by opportune monitoring of fracture risk and appropriate treatment of both diabetes itself and osteopenia or osteoporosis if they are present. In this review, we summarize the mechanistic, epidemiological, and clinical evidence that links diabetes and bone fragility, and describe the impact of available diabetes treatments on bone health.
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Affiliation(s)
| | | | | | - Carlos O Mendivil
- School of Medicine, Universidad de los Andes, Bogotá, Colombia.
- Department of Internal Medicine, Endocrinology Section, Fundación Santa Fe de Bogotá, Bogotá, Colombia.
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29
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Rossini A, Frigerio S, Dozio E, Trevisan R, Perseghin G, Corbetta S. Effect of Denosumab on Glucose Homeostasis in Postmenopausal Women with Breast Cancer Treated with Aromatase Inhibitors: A Pilot Study. Int J Endocrinol 2020; 2020:1809150. [PMID: 33204260 PMCID: PMC7666635 DOI: 10.1155/2020/1809150] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 07/20/2020] [Accepted: 10/24/2020] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Aromatase inhibitors in women with breast cancer have been associated with cancer treatment-induced bone loss (CTIBL), increased fracture risk, and impairment of glucose metabolism. Denosumab (Dmab), a monoclonal antibody against RANKL, which is a key regulator of the osteoclast activity, is effective as an antiresorptive agent in the treatment of CTIBL. Since RANKL/RANK pathway may contribute to the pathogenesis of glucometabolic disorders, it has been suggested that Dmab may improve glucose homeostasis. Our pilot study evaluated the effect of a single administration of 60 mg Dmab on glucose metabolism in a cohort of women with breast cancer treated with aromatase inhibitors. METHODS Fifteen postmenopausal nondiabetic women were prospectively enrolled. Oral glucose tolerance test (OGTT) and metabolic parameters, including FGF21, were assessed at baseline and one month after Dmab injection. Midterm glucose control was evaluated by measuring glycated haemoglobin (HbA1c) levels 5 months after Dmab. RESULTS Parameters of glucose metabolism were not different one month after Dmab but circulating FGF21 levels significantly decreased (128.5 ± 46.8 versus 100.2 ± 48.8 pg/mL; p=0.016). Considering patients with insulin resistance at baseline (HOMA-IR > 2.5 and Matsuda Index < 2.5; n = 5), reduced mean fasting insulin levels (16.3 ± 4.9 versus 13.5 ± 3.5 mcU/mL; p=0.029) and increased insulin sensitivity index QUICKI (0.317 ± 0.013 versus 0.327 ± 0.009; p=0.025) were found. Nonetheless, HbA1c increased 5 months after Dmab (36.0 ± 2.3 versus 39.6 ± 3.1 mmol/mol; p=0.01). CONCLUSIONS Although RANKL blockade induced a short-term positive effect on insulin sensitivity, particularly in insulin-resistant patients, a benefit on long-term glucose metabolism was not evident. In conclusion, Dmab is safe for glucose metabolism in aromatase inhibitor-treated women with breast cancer.
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Affiliation(s)
- Alessandro Rossini
- Endocrinology and Diabetes Unit, ASST Papa Giovanni XXIII, Bergamo 24127, Italy
| | - Sofia Frigerio
- Endocrinology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan 20122, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan 20122, Italy
| | - Elena Dozio
- Department of Biomedical Sciences for Health, University of Milan, Milan 20122, Italy
| | - Roberto Trevisan
- Endocrinology and Diabetes Unit, ASST Papa Giovanni XXIII, Bergamo 24127, Italy
- Department of Medicine and Surgery, Università Degli Studi di Milano-Bicocca, Monza 20900, Italy
| | - Gianluca Perseghin
- Department of Medicine and Surgery, Università Degli Studi di Milano-Bicocca, Monza 20900, Italy
- Department of Medicine and Rehabilitation, Policlinico Monza, Monza 20900, Italy
| | - Sabrina Corbetta
- Endocrinology and Diabetology Service, IRCCS Istituto Ortopedico Galeazzi, Milan 20161, Italy
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan 20122, Italy
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30
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Sherk VD, Schauer I, Shah VN. Update on the Acute Effects of Glucose, Insulin, and Incretins on Bone Turnover In Vivo. Curr Osteoporos Rep 2020; 18:371-377. [PMID: 32504189 PMCID: PMC8118128 DOI: 10.1007/s11914-020-00598-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE OF REVIEW To provide an update on the acute effects of glucose, insulin, and incretins on markers of bone turnover in those with and without diabetes. RECENT FINDINGS Bone resorption is suppressed acutely in response to glucose and insulin challenges in both healthy subjects and patients with diabetes. The suppression is stronger with oral glucose compared with intravenous delivery. Stronger responses with oral glucose may be related to incretin effects on insulin secretion or from a direct effect on bone turnover. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) infusion acutely suppresses bone resorption without much effect on bone formation. The bone turnover response to a metabolic challenge may be attenuated in type 2 diabetes, but this is an understudied area. A knowledge gap exists regarding bone turnover responses to a metabolic challenge in type 1 diabetes. The gut-pancreas-bone link is potentially an endocrine axis. This linkage is disrupted in diabetes, but the mechanism and progression of this disruption are not understood.
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Affiliation(s)
- Vanessa D Sherk
- Department of Orthopedics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
| | - Irene Schauer
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Rocky Mountain Regional VA Medical Center, Aurora, CO, USA
| | - Viral N Shah
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
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Ferrari S, Eastell R, Napoli N, Schwartz A, Hofbauer LC, Chines A, Wang A, Pannacciulli N, Cummings SR. Denosumab in postmenopausal women with osteoporosis and diabetes: Subgroup analysis of FREEDOM and FREEDOM extension. Bone 2020; 134:115268. [PMID: 32058020 DOI: 10.1016/j.bone.2020.115268] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 01/22/2020] [Accepted: 02/09/2020] [Indexed: 01/06/2023]
Abstract
PURPOSE Diabetes and osteoporosis occur frequently in older adults and are both associated with increased fracture risk. Denosumab treatment reduced new vertebral, nonvertebral, and hip fractures over 3 years, with continued low fracture incidence for up to 10 years in postmenopausal women with osteoporosis. However, its effects in diabetic subjects with osteoporosis have not yet been investigated. METHODS Post hoc analysis of the 3-year, placebo-controlled FREEDOM study and 7-year Extension included postmenopausal women with osteoporosis and diabetes. Effects on BMD, vertebral, and nonvertebral fracture incidence were evaluated. RESULTS Of 7808 subjects in FREEDOM, 508 with diabetes received denosumab (n = 266) or placebo (n = 242). Among those, BMD increased significantly with denosumab versus placebo in FREEDOM, and continued to increase during the Extension in long-term (continuing denosumab) and crossover (placebo to denosumab) denosumab subjects. In FREEDOM, denosumab-treated subjects with diabetes had significantly lower new vertebral fracture rates (1.6%) versus placebo (8.0%) (RR: 0.20 [95% CI 0.07-0.61]; p = .001). Nonvertebral fracture incidence was higher with denosumab (11.7%) versus placebo (5.9%) (HR: 1.94 [95% CI 1.00-3.77]; p = .046), although there were fewer hip fractures with denosumab (World Health Organization, 2017 [1]) than placebo (4; nonsignificant). During the first 3 years in FREEDOM Extension, new vertebral and nonvertebral fracture incidences were low in long-term and crossover denosumab diabetic groups (≤6%), consistent with the overall Extension population; yearly nonvertebral fracture incidence was comparable to the FREEDOM placebo group. CONCLUSION Denosumab significantly increased BMD and decreased vertebral fracture risk in subjects with osteoporosis and diabetes. No reduction in nonvertebral fractures was observed.
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Affiliation(s)
- Serge Ferrari
- Division of Bone Diseases, Geneva University Hospitals, Geneva, Switzerland.
| | - Richard Eastell
- Academic unit of Bone Metabolism, University of Sheffield, Sheffield, UK
| | - Nicola Napoli
- John T. Milliken Department of Medicine, Campus Bio-Medico, University of Rome, Rome, Italy; Ospedale Galeazzi IRCCS, Milan, Italy
| | - Ann Schwartz
- School of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Lorenz C Hofbauer
- Center for Healthy Aging and Division of Endocrinology, Diabetes, and Bone Diseases, Technische Universität Dresden, Dresden, Germany
| | - Arkadi Chines
- Global Development, Amgen Inc., Thousand Oaks, CA, USA
| | - Andrea Wang
- Global Biostatistical Science, Amgen Inc., Thousand Oaks, CA, USA
| | | | - Steven R Cummings
- School of Medicine, University of California San Francisco, San Francisco, CA, USA
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Identification of osteoclast-osteoblast coupling factors in humans reveals links between bone and energy metabolism. Nat Commun 2020; 11:87. [PMID: 31911667 PMCID: PMC6946812 DOI: 10.1038/s41467-019-14003-6] [Citation(s) in RCA: 138] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 12/09/2019] [Indexed: 01/20/2023] Open
Abstract
Bone remodeling consists of resorption by osteoclasts followed by formation by osteoblasts, and osteoclasts are a source of bone formation-stimulating factors. Here we utilize osteoclast ablation by denosumab (DMAb) and RNA-sequencing of bone biopsies from postmenopausal women to identify osteoclast-secreted factors suppressed by DMAb. Based on these analyses, LIF, CREG2, CST3, CCBE1, and DPP4 are likely osteoclast-derived coupling factors in humans. Given the role of Dipeptidyl Peptidase-4 (DPP4) in glucose homeostasis, we further demonstrate that DMAb-treated participants have a significant reduction in circulating DPP4 and increase in Glucagon-like peptide (GLP)-1 levels as compared to the placebo-treated group, and also that type 2 diabetic patients treated with DMAb show significant reductions in HbA1c as compared to patients treated either with bisphosphonates or calcium and vitamin D. Thus, our results identify several coupling factors in humans and uncover osteoclast-derived DPP4 as a potential link between bone remodeling and energy metabolism. Anti-resorptive bone therapies also inhibit bone formation, as osteoclasts secrete factors that stimulate bone formation by osteoblasts. Here, the authors identify osteoclast-secreted factors that couple bone resorption to bone formation in healthy subjects, and show that osteoclast-derived DPP4 may be a factor coupling bone resorption to energy metabolism.
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Cipriani C, Colangelo L, Santori R, Renella M, Mastrantonio M, Minisola S, Pepe J. The Interplay Between Bone and Glucose Metabolism. Front Endocrinol (Lausanne) 2020; 11:122. [PMID: 32265831 PMCID: PMC7105593 DOI: 10.3389/fendo.2020.00122] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 02/24/2020] [Indexed: 12/13/2022] Open
Abstract
The multiple endocrine functions of bone other than those related to mineral metabolism, such as regulation of insulin sensitivity, glucose homeostasis, and energy metabolism, have recently been discovered. In vitro and murine studies investigated the impact of several molecules derived from osteoblasts and osteocytes on glucose metabolism. In addition, the effect of glucose on bone cells suggested a mutual cross-talk between bone and glucose homeostasis. In humans, these mechanisms are the pivotal determinant of the skeletal fragility associated with both type 1 and type 2 diabetes. Metabolic abnormalities associated with diabetes, such as increase in adipose tissue, reduction of lean mass, effects of hyperglycemia per se, production of the advanced glycation end products, diabetes-associated chronic kidney disease, and perturbation of the calcium-PTH-vitamin D metabolism, are the main mechanisms involved. Finally, there have been multiple reports of antidiabetic drugs affecting the skeleton, with differences among basic and clinical research data, as well as of anti-osteoporosis medication influencing glucose metabolism. This review focuses on the aspects linking glucose and bone metabolism by offering insight into the most recent evidence in humans.
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Liu JM, Zhu DL, Mu YM, Xia WB. Management of fracture risk in patients with diabetes-Chinese Expert Consensus. J Diabetes 2019; 11:906-919. [PMID: 31219236 DOI: 10.1111/1753-0407.12962] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 05/20/2019] [Accepted: 06/17/2019] [Indexed: 02/06/2023] Open
Affiliation(s)
- Jian-Min Liu
- Department of Endocrine and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao-tong University School of Medicine, Shanghai, China
| | - Da-Long Zhu
- Department of Endocrinology, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Yi-Ming Mu
- Department of Endocrinology, The General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Wei-Bo Xia
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
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Abe I, Ochi K, Takashi Y, Yamao Y, Ohishi H, Fujii H, Minezaki M, Sugimoto K, Kudo T, Abe M, Ohnishi Y, Mukoubara S, Kobayashi K. Effect of denosumab, a human monoclonal antibody of receptor activator of nuclear factor kappa-B ligand (RANKL), upon glycemic and metabolic parameters: Effect of denosumab on glycemic parameters. Medicine (Baltimore) 2019; 98:e18067. [PMID: 31764838 PMCID: PMC6882599 DOI: 10.1097/md.0000000000018067] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Osteoporosis is a complication of type 2 diabetes mellitus (T2DM). Blockade of receptor activator of nuclear factor kappa-B ligand (RANKL) improves osteoporosis, but might also improve glucose tolerance through reduction of hepatic insulin resistance. However, the effect of denosumab (a human monoclonal antibody of RANKL) upon glycemic and metabolic parameters is controversial. We revealed the effect of denosumab upon glycemic and metabolic parameters for 52 weeks. We evaluated 20 individuals diagnosed with both osteoporosis (male and female: postmenopausal) and T2DM. We measured glycemic and metabolic parameters before and 26/52 weeks after administration of denosumab (60 mg per 26 weeks) without changing any other medication each patient was taking. All patients completed the study without complications and the T-score (lumbar spine and femoral neck) improved significantly from baseline to 52 weeks after denosumab administration (P < .001, .001, respectively). None of the glycemic parameters changed significantly from baseline to 26 weeks after denosumab administration, but levels of glycated hemoglobin and homeostasis model assessment of insulin resistance improved significantly from baseline to 52 weeks after administration (P = .019, .008, respectively). The levels of liver enzymes did not change significantly from baseline to 26 weeks after denosumab administration, but levels of aspartate transaminase and alanine aminotransferase improved significantly from baseline to 52 weeks after administration (P = .014, .004, respectively). None of the markers of lipid metabolism and body mass index changed significantly from baseline to 26/52 weeks after denosumab administration. These data demonstrated that denosumab is useful for T2DM patients with osteoporosis for glycemic control via improvement of insulin resistance. Also, the effect of denosumab might be due to improvement of hepatic function.
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Affiliation(s)
- Ichiro Abe
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka
- Department of Internal Medicine, Nagasaki Prefecture Iki Hospital, Iki, Nagasaki
| | - Kentaro Ochi
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka
- Department of Internal Medicine, Nagasaki Prefecture Iki Hospital, Iki, Nagasaki
| | - Yuichi Takashi
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka
- Department of Internal Medicine, Nagasaki Prefecture Iki Hospital, Iki, Nagasaki
| | - Yuka Yamao
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka
| | - Hanako Ohishi
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka
| | - Hideyuki Fujii
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka
- Department of Internal Medicine, Nagasaki Prefecture Iki Hospital, Iki, Nagasaki
| | - Midori Minezaki
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka
- Department of Internal Medicine, Nagasaki Prefecture Iki Hospital, Iki, Nagasaki
| | - Kaoru Sugimoto
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka
| | - Tadachika Kudo
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka
| | - Makiko Abe
- Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan
| | - Yasushi Ohnishi
- Department of Internal Medicine, Nagasaki Prefecture Iki Hospital, Iki, Nagasaki
| | - Shigeaki Mukoubara
- Department of Internal Medicine, Nagasaki Prefecture Iki Hospital, Iki, Nagasaki
| | - Kunihisa Kobayashi
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka
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Costantini S, Conte C. Bone health in diabetes and prediabetes. World J Diabetes 2019; 10:421-445. [PMID: 31523379 PMCID: PMC6715571 DOI: 10.4239/wjd.v10.i8.421] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 06/03/2019] [Accepted: 07/20/2019] [Indexed: 02/05/2023] Open
Abstract
Bone fragility has been recognized as a complication of diabetes, both type 1 diabetes (T1D) and type 2 diabetes (T2D), whereas the relationship between prediabetes and fracture risk is less clear. Fractures can deeply impact a diabetic patient's quality of life. However, the mechanisms underlying bone fragility in diabetes are complex and have not been fully elucidated. Patients with T1D generally exhibit low bone mineral density (BMD), although the relatively small reduction in BMD does not entirely explain the increase in fracture risk. On the contrary, patients with T2D or prediabetes have normal or even higher BMD as compared with healthy subjects. These observations suggest that factors other than bone mass may influence fracture risk. Some of these factors have been identified, including disease duration, poor glycemic control, presence of diabetes complications, and certain antidiabetic drugs. Nevertheless, currently available tools for the prediction of risk inadequately capture diabetic patients at increased risk of fracture. Aim of this review is to provide a comprehensive overview of bone health and the mechanisms responsible for increased susceptibility to fracture across the spectrum of glycemic status, spanning from insulin resistance to overt forms of diabetes. The management of bone fragility in diabetic patient is also discussed.
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Affiliation(s)
- Silvia Costantini
- Department of Immunology, Transplantation and Infectious Diseases, Vita-Salute San Raffaele University, Milan 20123, Italy
- Epatocentro Ticino, Lugano 6900, Switzerland
| | - Caterina Conte
- Department of Immunology, Transplantation and Infectious Diseases, Vita-Salute San Raffaele University, Milan 20123, Italy
- IRCCS Ospedale San Raffaele, Internal Medicine and Transplantation, Milan 20123, Italy
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Picke AK, Campbell G, Napoli N, Hofbauer LC, Rauner M. Update on the impact of type 2 diabetes mellitus on bone metabolism and material properties. Endocr Connect 2019; 8:R55-R70. [PMID: 30772871 PMCID: PMC6391903 DOI: 10.1530/ec-18-0456] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 01/24/2019] [Indexed: 11/23/2022]
Abstract
The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide, especially as a result of our aging society, high caloric intake and sedentary lifestyle. Besides the well-known complications of T2DM on the cardiovascular system, the eyes, kidneys and nerves, bone strength is also impaired in diabetic patients. Patients with T2DM have a 40-70% increased risk for fractures, despite having a normal to increased bone mineral density, suggesting that other factors besides bone quantity must account for increased bone fragility. This review summarizes the current knowledge on the complex effects of T2DM on bone including effects on bone cells, bone material properties and other endocrine systems that subsequently affect bone, discusses the effects of T2DM medications on bone and concludes with a model identifying factors that may contribute to poor bone quality and increased bone fragility in T2DM.
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Affiliation(s)
- Ann-Kristin Picke
- Institute of Comparative Molecular Endocrinology, Ulm University, Ulm, Germany
| | - Graeme Campbell
- Institute of Biomechanics, TUHH Hamburg University of Technology, Hamburg, Germany
| | - Nicola Napoli
- Diabetes and Bone Network, Department Endocrinology and Diabetes, University Campus Bio-Medico of Rome, Rome, Italy
- Division of Bone and Mineral Diseases, Washington University in St Louis, St Louis, Missouri, USA
| | - Lorenz C Hofbauer
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Martina Rauner
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
- Correspondence should be addressed to M Rauner:
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38
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Liu DM, Mosialou I, Liu JM. Bone: Another potential target to treat, prevent and predict diabetes. Diabetes Obes Metab 2018; 20:1817-1828. [PMID: 29687585 DOI: 10.1111/dom.13330] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 04/16/2018] [Accepted: 04/18/2018] [Indexed: 12/30/2022]
Abstract
Type 2 diabetes mellitus is now a worldwide health problem with increasing prevalence. Mounting efforts have been made to treat, prevent and predict this chronic disease. In recent years, increasing evidence from mice and clinical studies suggests that bone-derived molecules modulate glucose metabolism. This review aims to summarize our current understanding of the interplay between bone and glucose metabolism and to highlight potential new means of therapeutic intervention. The first molecule recognized as a link between bone and glucose metabolism is osteocalcin (OCN), which functions in its active form, that is, undercarboxylated OCN (ucOC). ucOC acts in promoting insulin expression and secretion, facilitating insulin sensitivity, and favouring glucose and fatty acid uptake and utilization. A second bone-derived molecule, lipocalin2, functions in suppressing appetite in mice through its action on the hypothalamus. Osteocytes, the most abundant cells in bone matrix, are suggested to act on the browning of white adipose tissue and energy expenditure through secretion of bone morphogenetic protein 7 and sclerostin. The involvement of bone resorption in glucose homeostasis has also been examined. However, there is evidence indicating the implication of the receptor activator of nuclear factor κ-B ligand, neuropeptide Y, and other known and unidentified bone-derived factors that function in glucose homeostasis. We summarize recent advances and the rationale for treating, preventing and predicting diabetes by skeleton intervention.
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Affiliation(s)
- Dong-Mei Liu
- Department of Rheumatology, ZhongShan Hospital, FuDan University, Shanghai, China
| | - Ioanna Mosialou
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Jian-Min Liu
- Department of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao-tong University School of Medicine, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai, China
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