|
1
|
Lou Y, Chen H, Fei S, Chen X, Guo L, Pan Q. Role of denosumab in lipid metabolism disorders: clinical significance and potential mechanisms. Arch Osteoporos 2025; 20:68. [PMID: 40418391 DOI: 10.1007/s11657-025-01546-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 04/11/2025] [Indexed: 05/27/2025]
Abstract
PURPOSE Lipid metabolism disorders, characterized by abnormal blood lipid levels, are central to the pathogenesis of obesity, nonalcoholic fatty liver disease (NAFLD), and atherosclerosis. These conditions increase the risk of type 2 diabetes, cardiovascular diseases (CVD), and stroke, highlighting the need for novel therapeutic approaches. Emerging evidence suggests a complex interplay between bone and lipid metabolism, with RANKL playing a key role. This review explores the potential of denosumab, a RANKL-targeting monoclonal antibody, in modulating lipid metabolism and its broader metabolic implications. METHODS We conducted a comprehensive literature review to analyze the molecular mechanisms by which denosumab influences lipid metabolism, with a focus on the OPG/RANKL/RANK signaling pathway. Additionally, we examined the roles of immune modulation, bone marrow adipose tissue, and gut microbiota in metabolic diseases. RESULTS Denosumab, primarily known for its anti-resorptive effects in osteoporosis, may also exert beneficial effects on lipid metabolism. Preclinical and clinical studies suggest its potential in ameliorating obesity, NAFLD, and atherosclerosis. The OPG/RANKL/RANK axis appears to mediate crosstalk between bone and metabolic pathways, while immune regulation and gut microbiota may further contribute to these effects. CONCLUSION Denosumab shows promise as a therapeutic agent for lipid metabolism disorders, though long-term metabolic effects remain unclear. Further research is needed to validate its efficacy and elucidate underlying mechanisms, which could pave the way for novel treatments targeting metabolic diseases.
Collapse
Affiliation(s)
- Yuan Lou
- Department of Endocrinology Institute of Geriatric Medicine, Beijing Hospital, National Center of Gerontology, Chinese Academy of Medical Sciences, Beijing, 100000, China
- Chinese Academy of Medical Sciences, Graduate School of Peking Union Medical College, Beijing, 100000, China
| | - Huan Chen
- Department of Endocrinology Institute of Geriatric Medicine, Beijing Hospital, National Center of Gerontology, Chinese Academy of Medical Sciences, Beijing, 100000, China
- Chinese Academy of Medical Sciences, Graduate School of Peking Union Medical College, Beijing, 100000, China
| | - Sijia Fei
- Department of Endocrinology Institute of Geriatric Medicine, Beijing Hospital, National Center of Gerontology, Chinese Academy of Medical Sciences, Beijing, 100000, China
| | - Xinda Chen
- Department of Endocrinology, Institute of Geriatric Medicine, Beijing Hospital, National Center of Gerontology, Beijing, 100000, China
| | - Lixin Guo
- Department of Endocrinology Institute of Geriatric Medicine, Beijing Hospital, National Center of Gerontology, Chinese Academy of Medical Sciences, Beijing, 100000, China.
- Chinese Academy of Medical Sciences, Graduate School of Peking Union Medical College, Beijing, 100000, China.
| | - Qi Pan
- Department of Endocrinology Institute of Geriatric Medicine, Beijing Hospital, National Center of Gerontology, Chinese Academy of Medical Sciences, Beijing, 100000, China.
- Chinese Academy of Medical Sciences, Graduate School of Peking Union Medical College, Beijing, 100000, China.
| |
Collapse
|
|
2
|
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] [Download PDF] [Figures] [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.
Collapse
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.)
| |
Collapse
|
|
3
|
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
| |
Collapse
|
|
4
|
Gostage J, Kostenuik P, Goljanek-Whysall K, Bellantuono I, McCloskey E, Bonnet N. Extra-osseous Roles of the RANK-RANKL-OPG Axis with a Focus on Skeletal Muscle. Curr Osteoporos Rep 2024; 22:632-650. [PMID: 39325366 PMCID: PMC11499344 DOI: 10.1007/s11914-024-00890-2] [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] [Accepted: 09/11/2024] [Indexed: 09/27/2024]
Abstract
PURPOSE OF REVIEW This review aims to consolidate recent observations regarding extra-osseous roles of the RANK-RANKL-OPG axis, primarily within skeletal muscle. RECENT FINDINGS Preclinical efforts to decipher a common signalling pathway that links the synchronous decline in bone and muscle health in ageing and disease disclosed a potential role of the RANK-RANKL-OPG axis in skeletal muscle. Evidence suggests RANKL inhibition benefits skeletal muscle function, mass, fibre-type switching, calcium homeostasis and reduces fall incidence. However, there still exists ambiguity regarding the exact mechanistic actions and subsequent functional improvements. Other potential RANK-RANKL-OPG extra-osseous roles include regulation of neural-inflammation and glucose metabolism. Growing evidence suggests the RANK-RANKL-OPG axis may play a regulatory role in extra-osseous tissues, especially in skeletal muscle. Targeting RANKL may be a novel therapy in ameliorating loss of muscle mass and function. More research is warranted to determine the causality of the RANK-RANKL-OPG axis in extra-osseous tissues, especially those affected by aging.
Collapse
Affiliation(s)
- John Gostage
- The Medical Research Council/Versus Arthritis Centre for Integrated Research Into Musculoskeletal Aging, CIMA, University of Liverpool, Liverpool, UK
- Division of Clinical Medicine, School of Medicine and Population Health, Healthy Lifespan Institute and the Centre for Integrated Research in Musculoskeletal Aging, University of Sheffield, Sheffield, UK
- Discipline of Physiology, School of Medicine, University of Galway, Galway, Ireland
| | - Paul Kostenuik
- School of Dentistry and Phylon Pharma Services, University of Michigan, Thousand Oaks, CA, USA
| | - Katarzyna Goljanek-Whysall
- The Medical Research Council/Versus Arthritis Centre for Integrated Research Into Musculoskeletal Aging, CIMA, University of Liverpool, Liverpool, UK
- Discipline of Physiology, School of Medicine, University of Galway, Galway, Ireland
| | - Ilaria Bellantuono
- The Medical Research Council/Versus Arthritis Centre for Integrated Research Into Musculoskeletal Aging, CIMA, University of Liverpool, Liverpool, UK
- Division of Clinical Medicine, School of Medicine and Population Health, Healthy Lifespan Institute and the Centre for Integrated Research in Musculoskeletal Aging, University of Sheffield, Sheffield, UK
| | - Eugene McCloskey
- The Medical Research Council/Versus Arthritis Centre for Integrated Research Into Musculoskeletal Aging, CIMA, University of Liverpool, Liverpool, UK
- Division of Clinical Medicine, School of Medicine and Population Health, Healthy Lifespan Institute and the Centre for Integrated Research in Musculoskeletal Aging, University of Sheffield, Sheffield, UK
| | - Nicolas Bonnet
- Service of Bone Diseases, Department of Medicine, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland.
| |
Collapse
|
|
5
|
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.
Collapse
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.
| |
Collapse
|
|
6
|
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.
Collapse
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
| |
Collapse
|
|
7
|
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.
Collapse
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
| |
Collapse
|
|
8
|
Forner P, Sheu A. Bone Health in Patients With Type 2 Diabetes. J Endocr Soc 2024; 8:bvae112. [PMID: 38887632 PMCID: PMC11181004 DOI: 10.1210/jendso/bvae112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Indexed: 06/20/2024] Open
Abstract
The association between type 2 diabetes mellitus (T2DM) and skeletal fragility is complex, with effects on bone at the cellular, molecular, and biomechanical levels. As a result, people with T2DM, compared to those without, are at increased risk of fracture, despite often having preserved bone mineral density (BMD) on dual-energy x-ray absorptiometry (DXA). Maladaptive skeletal loading and changes in bone architecture (particularly cortical porosity and low cortical volumes, the hallmark of diabetic osteopathy) are not apparent on routine DXA. Alternative imaging modalities, including quantitative computed tomography and trabecular bone score, allow for noninvasive visualization of cortical and trabecular compartments and may be useful in identifying those at risk for fractures. Current fracture risk calculators underestimate fracture risk in T2DM, partly due to their reliance on BMD. As a result, individuals with T2DM, who are at high risk of fracture, may be overlooked for commencement of osteoporosis therapy. Rather, management of skeletal health in T2DM should include consideration of treatment initiation at lower BMD thresholds, the use of adjusted fracture risk calculators, and consideration of metabolic and nonskeletal risk factors. Antidiabetic medications have differing effects on the skeleton and treatment choice should consider the bone impacts in those at risk for fracture. T2DM poses a unique challenge when it comes to assessing bone health and fracture risk. This article discusses the clinical burden and presentation of skeletal disease in T2DM. Two clinical cases are presented to illustrate a clinical approach in assessing and managing fracture risk in these patients.
Collapse
Affiliation(s)
- Patrice Forner
- Clinical School, Faculty of Medicine, St Vincent's Hospital, University of New South Wales Sydney, Sydney, NSW 2010, Australia
- Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, NSW 2010, Australia
| | - Angela Sheu
- Clinical School, Faculty of Medicine, St Vincent's Hospital, University of New South Wales Sydney, Sydney, NSW 2010, Australia
- Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, NSW 2010, Australia
- Skeletal Diseases Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2035, Australia
| |
Collapse
|
|
9
|
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 .
Collapse
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.
| |
Collapse
|
|
10
|
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: 13] [Impact Index Per Article: 6.5] [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.
Collapse
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
| |
Collapse
|
|
11
|
Vachliotis ID, Polyzos SA. Osteoprotegerin/Receptor Activator of Nuclear Factor-Kappa B Ligand/Receptor Activator of Nuclear Factor-Kappa B Axis in Obesity, Type 2 Diabetes Mellitus, and Nonalcoholic Fatty Liver Disease. Curr Obes Rep 2023:10.1007/s13679-023-00505-4. [PMID: 37208545 DOI: 10.1007/s13679-023-00505-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/29/2023] [Indexed: 05/21/2023]
Abstract
PURPOSE OF REVIEW To summarize evidence on the potential involvement of the osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B (NF-κΒ) ligand (RANKL)/receptor activator of NF-κΒ (RANK) axis in the pathogenesis of metabolic diseases. RECENT FINDINGS The OPG-RANKL-RANK axis, which has been originally involved in bone remodeling and osteoporosis, is now recognized as a potential contributor in the pathogenesis of obesity and its associated comorbidities, i.e., type 2 diabetes mellitus and nonalcoholic fatty liver disease. Besides bone, OPG and RANKL are also produced in adipose tissue and may be involved in the inflammatory process associated with obesity. Metabolically healthy obesity has been associated with lower circulating OPG concentrations, possibly representing a counteracting mechanism, while elevated serum OPG levels may reflect an increased risk of metabolic dysfunction or cardiovascular disease. OPG and RANKL have been also proposed as potential regulators of glucose metabolism and are potentially involved in the pathogenesis of type 2 diabetes mellitus. In clinical terms, type 2 diabetes mellitus has been consistently associated with increased serum OPG concentrations. With regard to nonalcoholic fatty liver disease, experimental data suggest a potential contribution of OPG and RANKL in hepatic steatosis, inflammation, and fibrosis; however, most clinical studies showed reduction in serum concentrations of OPG and RANKL. The emerging contribution of the OPG-RANKL-RANK axis to the pathogenesis of obesity and its associated comorbidities warrants further investigation by mechanistic studies and may have potential diagnostic and therapeutic implications.
Collapse
Affiliation(s)
- Ilias D Vachliotis
- First Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece.
- Second Department of Internal Medicine, 424 General Military Hospital, Thessaloniki, 56429, Greece.
| | - Stergios A Polyzos
- First Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece
| |
Collapse
|
|
12
|
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.
Collapse
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
| |
Collapse
|
|
13
|
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.
Collapse
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
| |
Collapse
|
|
14
|
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: 64] [Impact Index Per Article: 21.3] [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.
Collapse
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
| |
Collapse
|
|
15
|
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.
Collapse
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
| | | |
Collapse
|
|
16
|
Gaudio A, Xourafa A, Rapisarda R, Castellino P. Therapeutic Options in the Management of Aromatase Inhibitor-Associated Bone Loss. Endocr Metab Immune Disord Drug Targets 2021; 22:259-273. [PMID: 34370654 DOI: 10.2174/1871530321666210809153152] [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: 01/19/2021] [Revised: 06/11/2021] [Accepted: 06/11/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Breast cancer is the most commonly occurring cancer in women worldwide. Early breast cancer is a kind of invasive neoplasm that has not proliferated beyond the breast or the axillary lymph nodes. Current therapeutic strategies for breast cancer mainly include local therapies such as surgery or radiotherapy and systemic therapies like chemotherapy, endocrine, and targeted therapy.Nowadays, the adjuvant treatment for hormone receptor-positive early breast cancer in postmenopausal women remains the main effective systemic therapy which can improve disease-free survival and overall survival; it involves several endocrine treatment regimens including selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), or a combination of them. AIs have been shown to be more effective in preventing recurrence in postmenopausal women with early breast cancer when compared with tamoxifen, thus representing the standard of care for adjuvant endocrine therapy. Although AIs are usually well-tolerated, they can have some side effects. Apart from the appearance of arthralgias or myalgias and cardiovascular events, AI therapies, reducing already low endogenous postmenopausal estradiol levels, cause increased bone loss and increase fracture risk in postmenopausal women. OBJECTIVES To evaluate the therapeutic options in the management of aromatase inhibitor-associated bone loss (AIBL). METHODS We reviewed the current literature dealing with different therapeutic options in the treatment of AIBL. RESULTS Clinical practice guidelines recommend a careful evaluation of skeletal health in all women with breast cancer before AI therapy initiation. Adequate calcium and vitamin D intake have also been suggested. Pharmacological attempts to minimize AI-related bone loss have focused on the use of antiresorptive agents, such as bisphosphonates and denosumab, to protect bone integrity and reduce the risk of fractures. Furthermore, clinical trials have shown that by making the bone microenvironment less susceptible to breast cancer metastasis, these drugs are able to increase disease-free survival. CONCLUSIONS AI, thatare the pillar of the systemic treatment for patients with hormone receptor-positive breast cancer, are associated with different side effects, and in particular osteoporosis and fractures. Both bisphosphonates and denosumab are able to prevent this negative effect.
Collapse
Affiliation(s)
- Agostino Gaudio
- Department of Clinical and Experimental Medicine, University of Catania , Italy
| | | | | | - Pietro Castellino
- Department of Clinical and Experimental Medicine, University of Catania , Italy
| |
Collapse
|
|
17
|
Li X, Sun F, Lu J, Zhang J, Wang J, Zhu H, Gu M, Ma J. Osteoclasts May Affect Glucose Uptake-Related Insulin Resistance by Secreting Resistin. Diabetes Metab Syndr Obes 2021; 14:3461-3470. [PMID: 34366677 PMCID: PMC8336992 DOI: 10.2147/dmso.s316964] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/06/2021] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVES Bone may play a role in the modulation of insulin sensitivity. Insulin resistance can be caused by increased resistin. However, whether osteoclasts affect the insulin resistance via resistin remains unclear. In the present study, we show the expression of resistin in osteoclasts and the possible underlying role of resistin on glucose uptake-related insulin resistance in vitro. METHODS Conditioned mediums (CM) were collected from Raw264.7 cells treated without (CCM) or with RANKL (CM3, treated with RANKL for 3 days; CM5, treated with RANKL for 5 days) and transfected with control or resistin siRNA (CMsiRNA). The osteoclast formation was examined by tartrate resistant acid phosphatase (TRAP) staining. C2C12 myoblasts were cultured with the CM or CMsiRNA. Glucose uptake was evaluated by 2-NBDG fluorescence intensity. Resistin expression was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay. Statistical analysis was performed by an independent two sample t-test or one-way ANOVA. RESULTS The 2-NBDG fluorescence intensity was higher in C2C12 cells treated with CCM compared to those that received CM3 and CM5 (p < 0.05). Resistin mRNA and protein expressions were both increased in RAW264.7 cells treated with RANKL for 3 days and 5 days compared with those cells without RANKL administration. The 2-NBDG fluorescence intensities in C2C12 cells treated with CMsiRNA and CM5+Anti-resistin antibody were significantly higher than those cultured with CM5 (p < 0.05). CONCLUSION Osteoclasts may promote glucose uptake-related insulin resistance by secreting resistin.
Collapse
Affiliation(s)
- Xiangqi Li
- Department of Endocrinology, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, 200135, People’s Republic of China
| | - Fei Sun
- Department of Endocrinology, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, 200135, People’s Republic of China
| | - Jiancan Lu
- Department of Endocrinology, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, 200135, People’s Republic of China
| | - Jichen Zhang
- Department of Endocrinology, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, 200135, People’s Republic of China
| | - Jingnan Wang
- Department of Endocrinology, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, 200135, People’s Republic of China
| | - Hongling Zhu
- Department of Endocrinology, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, 200135, People’s Republic of China
| | - Mingjun Gu
- Department of Endocrinology, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, 200135, People’s Republic of China
| | - Junhua Ma
- Department of Endocrinology, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, 200135, People’s Republic of China
| |
Collapse
|
|
18
|
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.
Collapse
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.)
| |
Collapse
|
|
19
|
Cannarella R, Musso N, Condorelli RA, Musmeci M, Stefani S, Aversa A, La Vignera S, Calogero AE. The 2039 A/G FSH receptor gene polymorphism influences glucose metabolism in healthy men. Endocrine 2020; 70:629-634. [PMID: 32681384 PMCID: PMC7674314 DOI: 10.1007/s12020-020-02420-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 07/06/2020] [Indexed: 11/12/2022]
Abstract
OBJECTIVE To assess the role of c. 2039 A/G (p. Asp680Ser) (rs6166) and c. -29 G/A (rs1394205) follicle-stimulating hormone receptor (FSHR) gene single nucleotide polymorphisms (SNPs) in a cohort of healthy men. METHODS One-hundred twenty-seven healthy men underwent evaluation of the anthropometric parameters, assessment of metabolic and lipid profile, measurement FSH serum levels, and genotyping of both the aforementioned FSHR SNPs. Data grouped according to the FSHR rs6166 or rs1394205 genotypes underwent to statistical analysis. MAIN RESULTS The three groups of men for each FSHR SNP did not differ statistically significantly for body mass index and serum FSH levels. As for FSHR rs6166 SNP, glucose levels were significantly lower in men with the GG genotype compared with those with the AA genotype. Men with AG had lower insulin levels and HOMA index values compared with those carrying the genotype AA (p < 0.05). The GG group showed a negative correlation between serum FSH levels and insulin and between serum FSH levels and HOMA index (p < 0.05). In contrast, men grouped according to the FSHR rs1394205 genotype showed no significant difference in blood glucose, serum insulin levels, and HOMA index. The AG group showed a negative correlation between FSH insulin and between serum FSH levels and HOMA index (p < 0.05). CONCLUSIONS Men with the genotype GG of the FSHR rs6166 SNP have lower blood glucose levels than those with the AA genotype. Their FSH levels inversely correlated with insulin and HOMA index. In contrast, the genotype FSHR rs6166 A/G did not reveal any role of FSH on glucose metabolism in healthy men. The inverse relationship between FSH and insulin or HOMA index in the group with the genotype GG of the FSHR rs6166 SNP suggests a possible cross-talk between FSH and insulin.
Collapse
Affiliation(s)
- Rossella Cannarella
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Nicolò Musso
- Bio-nanotech Research and Innovation Tower (BRIT), University of Catania, Catania, Italy
| | - Rosita A Condorelli
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Marco Musmeci
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Stefania Stefani
- Bio-nanotech Research and Innovation Tower (BRIT), University of Catania, Catania, Italy
| | - Antonio Aversa
- Department of Experimental and Clinical Medicine, "Magna Graecia" University, Catanzaro, Italy
| | - Sandro La Vignera
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Aldo E Calogero
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
| |
Collapse
|
|
20
|
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.
Collapse
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
| |
Collapse
|
|
21
|
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.
Collapse
|
|
22
|
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.
Collapse
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
| |
Collapse
|
|
23
|
Juel Mortensen L, Lorenzen M, Jørgensen N, Andersson AM, Nielsen JE, Petersen LI, Lanske B, Juul A, Hansen JB, Blomberg Jensen M. Possible link between FSH and RANKL release from adipocytes in men with impaired gonadal function including Klinefelter syndrome. Bone 2019; 123:103-114. [PMID: 30914274 DOI: 10.1016/j.bone.2019.03.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 02/19/2019] [Accepted: 03/18/2019] [Indexed: 11/21/2022]
Abstract
INTRODUCTION The FSH receptor (FSHR) has been found to be expressed in human bone cells and bone marrow-adipocytes, and highly-debated mouse studies have suggested extra-gonadal effects of gonadotropins on glucose, adipocyte and bone homeostasis. These putative effects could be direct or indirectly mediated by endocrine factors released from bone-cells or adipocytes. Here, we investigated whether gonadotropins are linked with glucose- and lipid-metabolism in hypergonadotropic men. METHODS Single centre, cross-sectional study of 307 men with idiopathic infertility and 28 men with Klinefelter syndrome (KS). OUTCOME associations between serum LH and FSH with soluble-RANKL (sRANKL), osteoprotegerin (OPG), osteocalcin, fasting glucose and insulin, sex steroids, and body composition. Expression of FSHR was studied in human-derived adipocyte-cell-models (hMADS, TERT-hWA) and FSH stimulation of RANKL expression and secretion in hMADS in vitro. RESULTS Serum FSH was not directly linked with glucose- and lipid-metabolism. However, FSH was inversely associated with sRANKL in both infertile men and KS men (p = .023 and p = .012). Infertile men with elevated FSH (>11 U/L) had significantly lower sRANKL (p = .015). sRANKL was positively associated with fat percentage, fasting insulin, and glucose (all p < .05). Men with prediabetes had higher sRANKL (p = .021), but lower testosterone (p < .0001) and Inhibin B (p = .005). The FSHR was expressed in the investigated human derived adipocytes, and 3-6 h treatment with FSH markedly increased RANKL release (p < .05). CONCLUSION KS and infertile men with prediabetes have low Inhibin B, and testosterone but elevated RANKL compared with non-prediabetic men despite comparable levels of serum gonadotropins. Serum FSH and sRANKL was inversely associated in both infertile and KS men, but the increased release of RANKL from FSH treated adipocytes suggest a direct effect of FSH on RANKL production in some tissues. Further studies are required to clarify whether FSH targets RANKL in the skeleton. ClinicalTrial_ID:NCT01304927.
Collapse
Affiliation(s)
- Li Juel Mortensen
- Group of skeletal, mineral and gonadal endocrinology, University Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark; Division of Bone and Mineral Research, HSDM/HMS, Harvard Medical School, Boston, USA
| | - Mette Lorenzen
- Group of skeletal, mineral and gonadal endocrinology, University Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark
| | - Niels Jørgensen
- University Department of Growth and Reproduction and International Center for Research, Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen 2100, Denmark
| | - Anna-Maria Andersson
- University Department of Growth and Reproduction and International Center for Research, Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen 2100, Denmark
| | - John E Nielsen
- University Department of Growth and Reproduction and International Center for Research, Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen 2100, Denmark
| | - Louise I Petersen
- Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Beate Lanske
- Division of Bone and Mineral Research, HSDM/HMS, Harvard Medical School, Boston, USA
| | - Anders Juul
- University Department of Growth and Reproduction and International Center for Research, Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen 2100, Denmark
| | - Jacob B Hansen
- Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Martin Blomberg Jensen
- Group of skeletal, mineral and gonadal endocrinology, University Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark; Division of Bone and Mineral Research, HSDM/HMS, Harvard Medical School, Boston, USA.
| |
Collapse
|
|
24
|
Napoli N, Pannacciulli N, Vittinghoff E, Crittenden D, Yun J, Wang A, Wagman R, Schwartz AV. Effect of denosumab on fasting glucose in women with diabetes or prediabetes from the FREEDOM trial. Diabetes Metab Res Rev 2018; 34:e2991. [PMID: 29430796 DOI: 10.1002/dmrr.2991] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 11/15/2017] [Accepted: 12/03/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND RANKL is a key regulator of bone resorption that may also modulate glucose metabolism. Denosumab (DMAb) is a fully human monoclonal antibody that binds RANKL and was associated with fracture risk reduction in the FREEDOM trial. We hypothesized that DMAb treatment decreased fasting serum glucose (FSG) relative to placebo in women with diabetes or prediabetes enrolled in FREEDOM trial. METHODS Post hoc analysis of FREEDOM, in which 7808 postmenopausal osteoporotic women were randomized to receive DMAb or placebo every 6 months for 36 months. All diabetes group included subjects with a self-report of diabetes, use of antidiabetic medication (ADM), or an FSG ≥ 126 mg/dL at baseline. The diabetes group without prior ADM use included subjects with a self-reported history of diabetes or FSG level ≥ 126 mg/dL at baseline. Prediabetes was defined as an FSG of 100 to 125 mg/dL on no ADM. Average postbaseline FSG across visits was estimated and compared between DMAb and placebo. Main outcome measures are the difference in average postbaseline FSG across follow-up visits between DMAb and placebo. RESULTS Estimated average postbaseline FSG across visits was not different between DMAb and placebo in either all diabetes group (P = .20) or those with prediabetes (P = .42); in diabetic women not on ADM, estimated average postbaseline FSG across visits was lower with DMAb than placebo (-6.8 mg/dL; 95% CI, -12.6 to -1.0; P = .02). CONCLUSIONS DMAb did not affect FSG in postmenopausal osteoporotic women with prediabetes or diabetes. There was evidence of modest FSG lowering with DMAb in those with diabetes who were not on ADM. It remains to be determined whether blockade of RANKL has a clinically important effect on glucose metabolism.
Collapse
Affiliation(s)
- Nicola Napoli
- Division of Endocrinology and Diabetes, University Campus Bio-Medico di Roma, Rome, Italy
- Division of Bone and Mineral Diseases, Washington University in St Louis, St Louis, MO, USA
| | | | - Eric Vittinghoff
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | | | - Jang Yun
- Amgen, Inc, Thousand Oaks, CA, USA
| | | | | | - Ann V Schwartz
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| |
Collapse
|
|
25
|
Ma C, Tonks KT, Center JR, Samocha-Bonet D, Greenfield JR. Complex interplay among adiposity, insulin resistance and bone health. Clin Obes 2018; 8:131-139. [PMID: 29334695 DOI: 10.1111/cob.12240] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2017] [Revised: 10/31/2017] [Accepted: 11/23/2017] [Indexed: 12/28/2022]
Abstract
Obesity and osteoporosis are common public health problems. Paradoxically, while obesity is associated with higher bone density, type 2 diabetic obese individuals have an increased fracture risk. Although obesity and insulin resistance co-exist, some obese individuals remain insulin-sensitive. We suggest that the apparent paradox relating obesity, bone density and fracture risk in type 2 diabetes may be at least partly influenced by differences in bone strength and quality between insulin-resistant and insulin-sensitive obese individuals. In this review, we focus on the complex interplay between, adiposity, insulin resistance and osteoporotic fracture risk and suggest that this is an important area of study that has implications for individually tailored and targeted treatment to prevent osteoporotic fracture in obese type 2 diabetic individuals.
Collapse
Affiliation(s)
- C Ma
- Department of Endocrinology, The First Hospital of Qinhuangdao, Qinhuangdao, China
| | - K T Tonks
- Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, Australia
- Diabetes and Metabolism Program, Garvan Institute of Medical Research, Sydney, Australia
| | - J R Center
- Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, Australia
- Bone Biology Research Program, Garvan Institute of Medical Research, Sydney, Australia
| | - D Samocha-Bonet
- Diabetes and Metabolism Program, Garvan Institute of Medical Research, Sydney, Australia
- Faculty of Medicine, St Vincent's Clinical School, University of New South Wales, Sydney, Australia
| | - J R Greenfield
- Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, Australia
- Diabetes and Metabolism Program, Garvan Institute of Medical Research, Sydney, Australia
- Faculty of Medicine, St Vincent's Clinical School, University of New South Wales, Sydney, Australia
| |
Collapse
|
|
26
|
McGee-Lawrence ME, Pierce JL, Yu K, Culpepper NR, Bradley EW, Westendorf JJ. Loss of Hdac3 in osteoprogenitors increases bone expression of osteoprotegerin, improving systemic insulin sensitivity. J Cell Physiol 2017; 233:2671-2680. [PMID: 28840938 DOI: 10.1002/jcp.26148] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 08/14/2017] [Indexed: 12/22/2022]
Abstract
Type 2 diabetes is an emerging global health epidemic. Foundations for new therapies are arising from understanding interactions between body systems. Bone-derived factors that reduce RANKL (receptor activator of NF-kappa B ligand) signaling in the liver may prevent insulin resistance and the onset of type 2 diabetes. Here we demonstrate that deletion of the epigenetic regulator, Hdac3, in Osx1-expressing osteoprogenitors prevents insulin resistance induced by high fat diet by increasing serum and skeletal gene expression levels of osteoprotegerin (Opg), a natural inhibitor of RANKL signaling. Removal of one Opg allele in mice lacking Hdac3 in Osx1+ osteoprogenitors increases the insulin resistance of the Hdac3-deficient mice on a high fat diet. Thus, Hdac3-depletion in osteoblasts increases expression of Opg, subsequently preserving insulin sensitivity. The Hdac inhibitor vorinostat also increased Opg transcription and histone acetylation of the Opg locus. These results define a new mechanism by which bone regulates systemic insulin sensitivity.
Collapse
Affiliation(s)
- Meghan E McGee-Lawrence
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia.,Department of Orthopaedic Surgery, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Jessica L Pierce
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Kanglun Yu
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Natasha R Culpepper
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia
| | | | - Jennifer J Westendorf
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota.,Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
27
|
Lasco A, Morabito N, Basile G, Atteritano M, Gaudio A, Giorgianni GM, Morini E, Faraci B, Bellone F, Catalano A. Denosumab Inhibition of RANKL and Insulin Resistance in Postmenopausal Women with Osteoporosis. Calcif Tissue Int 2016; 98:123-8. [PMID: 26498169 DOI: 10.1007/s00223-015-0075-5] [Citation(s) in RCA: 33] [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: 08/05/2015] [Accepted: 10/16/2015] [Indexed: 02/06/2023]
Abstract
The tumor necrosis factor-related cytokine receptor activator of nuclear factor kappa B ligand (RANKL) has been proposed as predictor of incident type 2 diabetes mellitus, and experimental blockade of RANKL resulted in a marked improvement of glucose tolerance. Denosumab is a fully human monoclonal antibody that binds to RANKL and prevents osteoclast formation, function and survival, leading to fracture risk reduction. The aim of our study was to investigate glucometabolic parameters, insulin resistance, and lipid profile in non-diabetic women receiving denosumab. Forty-eight women with postmenopausal osteoporosis were enrolled and treated with a subcutaneous dose (60 mg) of denosumab. At baseline and after 4, 12, ad 24 weeks, insulin resistance was computed by homeostasis model assessment of insulin resistance (HOMA-IR) and total cholesterol, triglycerides and HDL cholesterol were also measured. At baseline and after 24 weeks, bone turn-over markers were also evaluated. After denosumab administration, with the exception of a slight reduction of insulin and HOMA-IR values after 4 weeks (p < 0.05), neither fasting plasma glucose nor insulin and insulin resistance were significantly changed. Lipid parameters remained unchanged at each time-points of this study. A reduction of C-telopeptide of type 1 collagen (-63%, p < 0.0001) and osteocalcin (-45%, p < 0.0001), as bone resorption and formation markers, respectively, were observed after 24 weeks. Baseline levels of bone biomarkers were not predictive of HOMA-IR, and changes of osteocalcin were not associated to markers of glucose control. In osteoporotic otherwise healthy postmenopausal women, denosumab was not associated with relevant modification of insulin resistance and lipid profile.
Collapse
Affiliation(s)
- Antonino Lasco
- Department of Clinical and Experimental Medicine, University Hospital of Messina, A.O.U. Policlinico "G. Martino", Via C. Valeria, 98125, Messina, Italy
| | - Nunziata Morabito
- Department of Clinical and Experimental Medicine, University Hospital of Messina, A.O.U. Policlinico "G. Martino", Via C. Valeria, 98125, Messina, Italy
| | - Giorgio Basile
- Department of Clinical and Experimental Medicine, University Hospital of Messina, A.O.U. Policlinico "G. Martino", Via C. Valeria, 98125, Messina, Italy
| | - Marco Atteritano
- Department of Clinical and Experimental Medicine, University Hospital of Messina, A.O.U. Policlinico "G. Martino", Via C. Valeria, 98125, Messina, Italy
| | - Agostino Gaudio
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | | | - Elisabetta Morini
- Department of Clinical and Experimental Medicine, University Hospital of Messina, A.O.U. Policlinico "G. Martino", Via C. Valeria, 98125, Messina, Italy
| | - Bianca Faraci
- Department of Clinical and Experimental Medicine, University Hospital of Messina, A.O.U. Policlinico "G. Martino", Via C. Valeria, 98125, Messina, Italy
| | - Federica Bellone
- Department of Clinical and Experimental Medicine, University Hospital of Messina, A.O.U. Policlinico "G. Martino", Via C. Valeria, 98125, Messina, Italy
| | - Antonino Catalano
- Department of Clinical and Experimental Medicine, University Hospital of Messina, A.O.U. Policlinico "G. Martino", Via C. Valeria, 98125, Messina, Italy.
| |
Collapse
|