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Li W, Wang W, Zhang M, Chen Q, Li F, Li S. The assessment of marrow adiposity in type 1 diabetic rabbits through magnetic resonance spectroscopy is linked to bone resorption. Front Endocrinol (Lausanne) 2025; 15:1518656. [PMID: 39926390 PMCID: PMC11803209 DOI: 10.3389/fendo.2024.1518656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 12/31/2024] [Indexed: 02/11/2025] Open
Abstract
Background Enhanced marrow adiposity is frequently linked with a decline in bone density. The underlying mechanisms responsible for bone loss in diabetes are not well understood. In this investigation, we employed an alloxan-induced diabetes rabbit model to unravel the association between marrow fat content and bone resorption, utilizing magnetic resonance spectroscopy. Methods Forty 4-month-old male New Zealand rabbits were randomly allocated into two groups: a control group and an alloxan-induced diabetic group, each consisting of 20 rabbits. Biochemical analyses covered plasma glucose, enzyme levels, lipid profiles, blood urea nitrogen, creatinine levels, and markers of bone turnover. Quantification of bone marrow adipose tissue utilized both MR spectroscopy and histological examinations. Dual-energy X-ray absorptiometry and microcomputed tomography were employed to determine bone density and trabecular bone microarchitectures. The expression levels of marrow adipocyte markers (peroxisome proliferator-activated receptor-gamma2, CCAAT/enhancer-binding protein-α, and fatty acid binding protein 4) and markers of bone resorption [tartrate-resistant acid phosphatase (TRACP) and cathepsin K] were assessed using RT-PCR. Results Diabetic rabbits exhibited significant increases in marrow fat fraction (MFF) over time (MFF increased by 13.2% at 1.5 months and 24.9% at 3 months relative to baseline conditions, respectively). These changes were accompanied by the deterioration of trabecular microarchitectures. Marrow adipogenesis was evident through a 31.0% increase in adipocyte size, a 60.0% rise in adipocyte number, a 103.3% increase in the percentage of adipocyte area, and elevated mRNA expressions of marrow adipocyte markers. Osteoclast markers (TRACP and cathepsin K RNA and serum TRACP5b levels) were elevated in diabetic rabbits. MFF exhibited a robust correlation with trabecular bone microarchitectures. A significant positive correlation was identified between ΔMFF and serum ΔTRACP5b levels. Moreover, MFF at 3 months showed a strong positive correlation with serum TRACP5b levels (r = 0.763), as well as with the mRNA expression of osteoclast markers, including TRACP (r = 0.784) and cathepsin K (r = 0.659), all with p <0.001. Conclusions Rabbits with type 1 diabetes experience an expansion of marrow adiposity, and this enhanced marrow adiposity is associated with increased osteoclast activity.
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Affiliation(s)
- Wei Li
- Department of Radiology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Wei Wang
- Department of Radiology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Minlan Zhang
- Department of Laboratory Medicine, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Qi Chen
- Department of Radiology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Fengyi Li
- Department of Radiology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Shaojun Li
- Department of Radiology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
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2
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Liu H, Liu L, Rosen CJ. Bone Marrow Adipocytes as Novel Regulators of Metabolic Homeostasis: Clinical Consequences of Bone Marrow Adiposity. Curr Obes Rep 2025; 14:9. [PMID: 39808256 DOI: 10.1007/s13679-024-00594-9] [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: 11/21/2024] [Indexed: 01/16/2025]
Abstract
PURPOSE OF REVIEW Bone marrow adipose tissue is a distinctive fat depot located within the skeleton, with the potential to influence both local and systemic metabolic processes. Although significant strides have been made in understanding bone marrow adipose tissue over the past decade, many questions remain regarding their precise lineage and functional roles. RECENT FINDINGS Recent studies have highlighted bone marrow adipose tissue's involvement in continuous cross-talk with other organs and systems, exerting both endocrine and paracrine functions that play a crucial role in metabolic homeostasis, skeletal remodeling, hematopoiesis, and the progression of bone metastases. The advancement of imaging techniques, particularly cross-sectional imaging, has profoundly expanded our understanding of the complexities beyond the traditional view of bone marrow adipose tissue as an inert depot. Notably, marrow adipocytes are anatomically and functionally distinct from brown, beige, and classic white adipocytes. Emerging evidence suggests that bone marrow adipocytes, bone marrow adipose tissue originate from the differentiation of bone marrow mesenchymal stromal cells; however, they appear to be a heterogeneous population with varying metabolic profiles, lipid compositions, secretory properties, and functional responses depending on their specific location within the bone marrow. This review provides an up-to-date synthesis of current knowledge on bone marrow adipocytes, emphasizing the relationships between bone marrow adipogenesis and factors such as aging, osteoporosis, obesity, and bone marrow tumors or metastases, thereby elucidating the mechanisms underlying musculoskeletal pathophysiology.
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Affiliation(s)
- Hanghang Liu
- State Key Laboratory of Oral Diseases & National Center for Stomatology &, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
- Maine Medical Center Research Institute, Maine Medical Center, 81 Research Drive, Scarborough, ME, 04074, USA
| | - Linyi Liu
- Maine Medical Center Research Institute, Maine Medical Center, 81 Research Drive, Scarborough, ME, 04074, USA
| | - Clifford J Rosen
- Maine Medical Center Research Institute, Maine Medical Center, 81 Research Drive, Scarborough, ME, 04074, USA.
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3
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Wang Z, Zhang M, Jia D. Assessment of fracture risk in diabetic patients. J Diabetes Metab Disord 2024; 23:1653-1663. [PMID: 39610523 PMCID: PMC11599524 DOI: 10.1007/s40200-024-01474-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 07/16/2024] [Indexed: 11/30/2024]
Abstract
Patients with diabetes often experience reduced bone strength, resulting in a higher fracture risk. This decline and increased susceptibility stem from intricate interactions within the bone microstructure. However, current gold standard methods for assessing bone strength, such as bone mineral density, and widely-used fracture risk assessment tools do not accurately predict fracture risk in diabetic patients. Therefore, it is crucial to incorporate additional indicators that evaluate bone quality and specific markers relevant to diabetes to enhance the accuracy of predictive models. Moreover, the selection of appropriate algorithms for model construction is essential. This review aims to introduce indicators from both imaging examinations and laboratory indicators that hold significant value for inclusion in fracture risk prediction models for diabetic patients. Additionally, this study provides an overview of the research progress in fracture risk prediction models for diabetic patients, serving as a valuable reference for clinical practice.
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Affiliation(s)
- Zhenpeng Wang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Mei Zhang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Dan Jia
- Department of Outpatient, West China Hospital, Sichuan University, Chengdu, China
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Zheng Y, Nour MA, Lanovaz J, Johnston JJD, Kontulainen S. Bone and muscle differences in children and adolescents with type 1 diabetes: The mediating role of physical activity. Bone 2024; 187:117206. [PMID: 39029608 DOI: 10.1016/j.bone.2024.117206] [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: 04/07/2024] [Revised: 06/14/2024] [Accepted: 07/16/2024] [Indexed: 07/21/2024]
Abstract
Children with type 1 diabetes (T1D) experience an increased risk of fracture, which may be related to altered bone development. We aimed to assess differences in bone, muscle and physical activity (PA), and explore if better muscle and PA measures would mitigate bone differences between children and adolescents with T1D and typically developing peers (TDP). We matched 56 children and adolescents with T1D (mean age 11.9 yrs) and 56 TDP (11.5 yrs) by sex and maturity from 171 participants with T1D and 66 TDP (6-17 yrs). We assessed the distal radius and tibia with high-resolution peripheral quantitative computed tomography (HR-pQCT), and the radius and tibia shaft bone and muscle with pQCT. We also measured muscle function from force-related measures in neuromuscular performance tests (push-up, grip test, countermovement and long jump). We compared PA based on questionnaire scores and accelerometers between groups. Bone, muscle, and neuromuscular performance measures were compared using MANOVA. We used mediation to explore the role of PA and muscle in bone differences. Children and adolescents with T1D had 6-10 % lower trabecular density, bone volume fraction, thickness and number at both distal radius and tibia, and 11 % higher trabecular separation at the distal radius than TDP. They also had 3-16 % higher cortical and tissue mineral density, and cortical thickness at the distal radius, 5-7 % higher cortical density and 1-3 % higher muscle density at both shaft sites compared to TDP. PA mediated the between-group difference in trabecular number (indirect effect -0.04) at the distal radius. Children and adolescents with T1D had lower trabecular bone density and deficits in trabecular micro-architecture, but higher cortical bone density and thickness at the radius and tibia compared to TDP. They engaged in less PA but had comparable muscle measures to those of TDP. PA participation may assist in mitigating deficit in trabecular number observed in children and adolescents with T1D.
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Affiliation(s)
- Yuwen Zheng
- College of Kinesiology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5B2, Canada
| | - Munier A Nour
- College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
| | - Joel Lanovaz
- College of Kinesiology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5B2, Canada
| | - James J D Johnston
- College of Engineering, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5A9, Canada
| | - Saija Kontulainen
- College of Kinesiology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5B2, Canada.
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5
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Johannesdottir F, Tedtsen T, Cooke LM, Mahar S, Zhang M, Nustad J, Garrahan MA, Gehman SE, Yu EW, Bouxsein ML. Microvascular disease and early diabetes onset are associated with deficits in femoral neck bone density and structure among older adults with longstanding type 1 diabetes. J Bone Miner Res 2024; 39:1454-1463. [PMID: 39151032 PMCID: PMC11425704 DOI: 10.1093/jbmr/zjae134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 07/29/2024] [Accepted: 08/04/2024] [Indexed: 08/18/2024]
Abstract
Adults with type 1 diabetes (T1D) have increased hip fracture risk, yet no studies have assessed volumetric bone density or structure at the hip in older adults with T1D. Here, we used previously collected 3D CT scans of the proximal femur from older adults with longstanding T1D and non-diabetic controls to identify bone deficits that may contribute to hip fracture in T1D. In this retrospective cohort study, we identified 101 adults with T1D and 181 age-, sex-, and race-matched non-diabetic controls (CON) who received abdominal or pelvis CT exams from 2010 to 2020. Among adults with T1D, 33 (33%) had mild-to-moderate nephropathy, 61 (60%) had neuropathy, and 71 (70%) had retinopathy. Within the whole cohort, adults with T1D tended to have lower FN density, though differences did not reach statistical significance. The subset of the T1D group who were diagnosed before age 15 had lower total BMC (-14%, TtBMC), cortical BMC (-19.5%, CtBMC), and smaller Ct cross-sectional area (-12.6, CtCSA) than their matched controls (p<.05 for all). Individuals with T1D who were diagnosed at a later age did not differ from controls in any bone outcome (p>.21). Furthermore, adults with T1D and nephropathy had lower FN aBMD (-10.6%), TtBMC (-17%), CtBMC (-24%), and smaller CtCSA (-15.4%) compared to matched controls (p<.05 for all). Adults with T1D and neuropathy had cortical bone deficits (8.4%-12%, p<.04). In summary, among older adults with T1D, those who were diagnosed before the age of 15 yr, as well as those with nephropathy and neuropathy had unfavorable bone outcomes at the FN, which may contribute to the high risk of hip fractures among patients with T1D. These novel observations highlight the longstanding detrimental impact of T1D when present during bone accrual and skeletal fragility as an additional complication of microvascular disease in individuals with T1D.
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Affiliation(s)
- Fjola Johannesdottir
- Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States
- Harvard Medical School, Boston, MA 02215, United States
| | - Trinity Tedtsen
- Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States
| | - Laura M Cooke
- Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, United States
| | - Sarah Mahar
- Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States
| | - Meng Zhang
- Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States
| | - Jordan Nustad
- Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States
| | - Margaret A Garrahan
- Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, United States
| | - Sarah E Gehman
- Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, United States
| | - Elaine W Yu
- Harvard Medical School, Boston, MA 02215, United States
- Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, United States
| | - Mary L Bouxsein
- Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States
- Harvard Medical School, Boston, MA 02215, United States
- Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, United States
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6
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Paschalis EP, Gamsjaeger S, Graeff-Armas LA, Bare SP, Recker RR, Akhter MP. Enzymatic and Non-enzymatic Collagen Cross-Links and Fracture Occurrence in Type 1 Diabetes Patients. Calcif Tissue Int 2024; 115:328-333. [PMID: 38871838 DOI: 10.1007/s00223-024-01243-y] [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: 12/20/2023] [Accepted: 05/31/2024] [Indexed: 06/15/2024]
Abstract
Increased fracture risk in type 1 diabetes (T1D) patients is not fully captured by bone mineral density (BMD) by DXA. Advanced glycation end-products (AGEs) have been implicated in the increased fracture risk in T1D, yet recent publications question this. To test the hypothesis that enzymatic collagen cross-links rather than AGEs correlate with fracture incidence in T1D, we analyzed iliac crest biopsies from sex-matched, fracturing T1D patients (N = 5; T1DFx), 6 non-fracturing T1D patients (T1DNoFx), and 6 healthy subjects, by Raman microspectroscopy as a function of tissue age (based on double fluorescent labels), in intracortical and trabecular bone, to determine pyridinoline (Pyd), ε-N-Carboxymethyl-L-lysine, and pentosidine (PEN)). There were no differences in the clinical characteristics between the T1DFx and T1DNoFx groups. At trabecular forming surfaces, T1DFx patients had higher PEN and Pyd content compared to T1DNoFx ones. Previous studies have shown that elevated PEN does not necessarily correlate with fracture incidence in postmenopausal, long-term T1D patients. On the other hand, the elevated Pyd content in the T1DFx patients would be consistent with published studies showing a significant correlation between elevated trivalent enzymatic collagen cross-links and fracture occurrence independent of BMD. Collagen fibers with high Pyd content are more brittle. Thus, a plausible suggestion is that it is the enzymatic collagen cross-links that either by themselves or in combination with the adverse effects of increased AGE accumulation that result in fragility fracture in T1D.
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Affiliation(s)
| | | | | | - Sue P Bare
- Osteoporosis Research Center, Creighton University, Omaha, NE, USA
| | - Robert R Recker
- Osteoporosis Research Center, Creighton University, Omaha, NE, USA
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7
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Leungsuwan DS, Chandran M. Bone Fragility in Diabetes and its Management: A Narrative Review. Drugs 2024; 84:1111-1134. [PMID: 39103693 DOI: 10.1007/s40265-024-02078-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2024] [Indexed: 08/07/2024]
Abstract
Bone fragility is a serious yet under-recognised complication of diabetes mellitus (DM) that is associated with significant morbidity and mortality. Multiple complex pathophysiological mechanisms mediating bone fragility amongst DM patients have been proposed and identified. Fracture risk in both type 1 diabetes (T1D) and type 2 diabetes (T2D) continues to be understated and underestimated by conventional risk assessment tools, posing an additional challenge to the identification of at-risk patients who may benefit from earlier intervention or preventive strategies. Over the years, an increasing body of evidence has demonstrated the efficacy of osteo-pharmacological agents in managing skeletal fragility in DM. This review seeks to elaborate on the risk of bone fragility in DM, the underlying pathogenesis and skeletal alterations, the approach to fracture risk assessment in DM, management strategies and therapeutic options.
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Affiliation(s)
| | - Manju Chandran
- Osteoporosis and Bone Metabolism Unit, Department of Endocrinology, Singapore General Hospital, 20 College Road, ACADEMIA, Singapore, 169856, Singapore.
- DUKE NUS Medical School, Singapore, Singapore.
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8
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Kupai K, Kang HL, Pósa A, Csonka Á, Várkonyi T, Valkusz Z. Bone Loss in Diabetes Mellitus: Diaporosis. Int J Mol Sci 2024; 25:7269. [PMID: 39000376 PMCID: PMC11242219 DOI: 10.3390/ijms25137269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 06/21/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
The objective of this review is to examine the connection between osteoporosis and diabetes, compare the underlying causes of osteoporosis in various forms of diabetes, and suggest optimal methods for diagnosing and assessing fracture risk in diabetic patients. This narrative review discusses the key factors contributing to the heightened risk of fractures in individuals with diabetes, as well as the shared elements impacting the treatment of both diabetes mellitus and osteoporosis. Understanding the close link between diabetes and a heightened risk of fractures is crucial in effectively managing both conditions. There are several review articles of meta-analysis regarding diaporosis. Nevertheless, no review articles showed collected and well-organized medications of antidiabetics and made for inconvenient reading for those who were interested in details of drug mechanisms. In this article, we presented collected and comprehensive charts of every antidiabetic medication which was linked to fracture risk and indicated plausible descriptions according to research articles.
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Affiliation(s)
- Krisztina Kupai
- Department of Internal Medicine, Albert Szent-Györgyi Medical School, University of Szeged, 6703 Szeged, Hungary
- Department of Oral Biology and Experimental Dental Research, Faculty of Dentistry, University of Szeged, 6703 Szeged, Hungary
| | - Hsu Lin Kang
- Department of Oral Biology and Experimental Dental Research, Faculty of Dentistry, University of Szeged, 6703 Szeged, Hungary
| | - Anikó Pósa
- Department of Oral Biology and Experimental Dental Research, Faculty of Dentistry, University of Szeged, 6703 Szeged, Hungary
| | - Ákos Csonka
- Department of Traumatology, University of Szeged, 6725 Szeged, Hungary;
| | - Tamás Várkonyi
- Department of Internal Medicine, Albert Szent-Györgyi Medical School, University of Szeged, 6703 Szeged, Hungary
| | - Zsuzsanna Valkusz
- Department of Internal Medicine, Albert Szent-Györgyi Medical School, University of Szeged, 6703 Szeged, Hungary
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9
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Zhang X, Tian L, Majumdar A, Scheller EL. Function and Regulation of Bone Marrow Adipose Tissue in Health and Disease: State of the Field and Clinical Considerations. Compr Physiol 2024; 14:5521-5579. [PMID: 39109972 PMCID: PMC11725182 DOI: 10.1002/cphy.c230016] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2025]
Abstract
Bone marrow adipose tissue (BMAT) is a metabolically and clinically relevant fat depot that exists within bone. Two subtypes of BMAT, regulated and constitutive, reside in hematopoietic-rich red marrow and fatty yellow marrow, respectively, and exhibit distinct characteristics compared to peripheral fat such as white and brown adipose tissues. Bone marrow adipocytes (BMAds) are evolutionally preserved in most vertebrates, start development after birth and expand throughout life, and originate from unique progenitor populations that control bone formation and hematopoiesis. Mature BMAds also interact closely with other cellular components of the bone marrow niche, serving as a nearby energy reservoir to support the skeletal system, a signaling hub that contributes to both local and systemic homeostasis, and a final fuel reserve for survival during starvation. Though BMAT and bone are often inversely correlated, more BMAT does not always mean less bone, and the prevention of BMAT expansion as a strategy to prevent bone loss remains questionable. BMAT adipogenesis and lipid metabolism are regulated by the nervous systems and a variety of circulating hormones. This contributes to the plasticity of BMAT, including BMAT expansion in common physiological or pathological conditions, and BMAT catabolism under certain extreme circumstances, which are often associated with malnutrition and/or systemic inflammation. Altogether, this article provides a comprehensive overview of the local and systemic functions of BMAT and discusses the regulation and plasticity of this unique adipose tissue depot in health and disease. © 2024 American Physiological Society. Compr Physiol 14:5521-5579, 2024.
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Affiliation(s)
- Xiao Zhang
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
| | - Linda Tian
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
| | - Anurag Majumdar
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
| | - Erica L. Scheller
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
- Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri, USA
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Dresner-Pollak R. Skeletal Fragility in Adult People Living With Type 1 Diabetes. Endocr Pract 2024; 30:592-597. [PMID: 38556079 DOI: 10.1016/j.eprac.2024.03.392] [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: 01/16/2024] [Revised: 03/23/2024] [Accepted: 03/27/2024] [Indexed: 04/02/2024]
Abstract
Advances in the management of people with type 1 diabetes (T1D) led to longer life expectancy, but with it an aging population with age-associated conditions. While macrovascular and microvascular complications are widely recognized, bone fragility has received considerably less attention, although fractures lead to high morbidity and mortality. Hip fracture risk is up to sixfold higher in T1D than in nondiabetic controls and significantly higher than in type 2 diabetes. Hip fractures occur at a younger age, and the consequences are worse. The risk of nonvertebral fractures is also significantly increased. Altered bone quality is a major underlying mechanism. Areal BMD measured by DXA underestimates fracture risk. BMD testing is recommended in T1D patients with poor glycemic control and/or microvascular complications. Trabecular bone score is mildly reduced, and its ability to predict fractures in T1D is unknown. Bone turnover markers, particularly procollagen type 1 N-terminal propeptide, are suppressed and do not predict fracture risk in T1D. T1D-related risk factors for fractures include disease onset at age <20 years, longer disease duration, HbA1c ≥8%, hypoglycemic episodes and microvascular complications. Data regarding the efficacy of therapeutic interventions to prevent or treat skeletal fragility in T1D is scant. Adequate calcium and vitamin D intake and fall prevention are recommended. Antiosteoporosis therapies are recommended in T1D patients with previous hip or vertebral fragility fracture, more than 1 other fragility fracture, BMD T-score < -2.5 at the femoral neck or spine, and increased FRAX score. Fracture risk assessment needs to be part of the management of people with T1D.
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Affiliation(s)
- Rivka Dresner-Pollak
- Department of Endocrinology and Metabolism, Division of Medicine, Hadassah Medical Organization, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
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11
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Li W, Wang W, Zhang M, Chen Q, Li S. Associations of marrow fat fraction with MR imaging based trabecular bone microarchitecture in first-time diagnosed type 1 diabetes mellitus. Front Endocrinol (Lausanne) 2024; 15:1287591. [PMID: 38774224 PMCID: PMC11106440 DOI: 10.3389/fendo.2024.1287591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 04/24/2024] [Indexed: 05/24/2024] Open
Abstract
Purpose To determine whether there are alterations in marrow fat content in individuals first-time diagnosed with type 1 diabetes mellitus (T1DM) and to explore the associations between marrow fat fraction and MRI-based findings in trabecular bone microarchitecture. Method A case-control study was conducted, involving adults with first-time diagnosed T1DM (n=35) and age- and sex-matched healthy adults (n=46). Dual-energy X-ray absorptiometry and 3 Tesla-MRI of the proximal tibia were performed to assess trabecular microarchitecture and vertebral marrow fat fraction. Multiple linear regression analysis was used to test the associations of marrow fat fraction with trabecular microarchitecture and bone density while adjusting for potential confounding factors. Results In individuals first-time diagnosed with T1DM, the marrow fat fraction was significantly higher (p < 0.001) compared to healthy controls. T1DM patients also exhibited higher trabecular separation [median (IQR): 2.19 (1.70, 2.68) vs 1.81 (1.62, 2.10), p < 0.001], lower trabecular volume [0.45 (0.30, 0.56) vs 0.53 (0.38, 0.60), p = 0.013], and lower trabecular number [0.37 (0.26, 0.44) vs 0.41 (0.32, 0.47), p = 0.020] compared to controls. However, bone density was similar between the two groups (p = 0.815). In individuals with T1DM, there was an inverse association between marrow fat fraction and trabecular volume (r = -0.69, p < 0.001) as well as trabecular number (r = -0.55, p < 0.001), and a positive association with trabecular separation (r = 0.75, p < 0.001). Marrow fat fraction was independently associated with total trabecular volume (standardized β = -0.21), trabecular number (β = -0.12), and trabecular separation (β = 0.57) of the proximal tibia after adjusting for various factors including age, gender, body mass index, physical activity, smoking status, alcohol consumption, blood glucose, plasma glycated hemoglobin, lipid profile, and bone turnover biomarkers. Conclusions Individuals first-time diagnosed with T1DM experience expansion of marrow adiposity, and elevated marrow fat content is associated with MRI-based trabecular microstructure.
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Affiliation(s)
- Wei Li
- Department of Radiology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Wei Wang
- Department of Radiology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Minlan Zhang
- Department of Laboratory Medicine, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Qi Chen
- Department of Radiology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Shaojun Li
- Department of Radiology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
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12
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Marinelli Busilacchi E, Morsia E, Poloni A. Bone Marrow Adipose Tissue. Cells 2024; 13:724. [PMID: 38727260 PMCID: PMC11083575 DOI: 10.3390/cells13090724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/19/2024] [Accepted: 04/19/2024] [Indexed: 05/13/2024] Open
Abstract
Bone marrow (BM) acts as a dynamic organ within the bone cavity, responsible for hematopoiesis, skeletal remodeling, and immune system control. Bone marrow adipose tissue (BMAT) was long simply considered a filler of space, but now it is known that it instead constitutes an essential element of the BM microenvironment that participates in homeostasis, influences bone health and bone remodeling, alters hematopoietic stem cell functions, contributes to the commitment of mesenchymal stem cells, provides effects to immune homeostasis and defense against infections, and participates in energy metabolism and inflammation. BMAT has emerged as a significant contributor to the development and progression of various diseases, shedding light on its complex relationship with health. Notably, BMAT has been implicated in metabolic disorders, hematological malignancies, and skeletal conditions. BMAT has been shown to support the proliferation of tumor cells in acute myeloid leukemia and niche adipocytes have been found to protect cancer cells against chemotherapy, contributing to treatment resistance. Moreover, BMAT's impact on bone density and remodeling can lead to conditions like osteoporosis, where high levels of BMAT are inversely correlated with bone mineral density, increasing the risk of fractures. BMAT has also been associated with diabetes, obesity, and anorexia nervosa, with varying effects on individuals depending on their weight and health status. Understanding the interaction between adipocytes and different diseases may lead to new therapeutic strategies.
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Affiliation(s)
- Elena Marinelli Busilacchi
- Hematology Laboratory, Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, 60126 Ancona, Italy; (E.M.B.); (E.M.)
| | - Erika Morsia
- Hematology Laboratory, Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, 60126 Ancona, Italy; (E.M.B.); (E.M.)
- Hematology, AOU delle Marche, 60126 Ancona, Italy
| | - Antonella Poloni
- Hematology Laboratory, Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, 60126 Ancona, Italy; (E.M.B.); (E.M.)
- Hematology, AOU delle Marche, 60126 Ancona, Italy
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13
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Walle M, Duseja A, Whittier DE, Vilaca T, Paggiosi M, Eastell R, Müller R, Collins CJ. Bone remodeling and responsiveness to mechanical stimuli in individuals with type 1 diabetes mellitus. J Bone Miner Res 2024; 39:85-94. [PMID: 38477745 PMCID: PMC11340785 DOI: 10.1093/jbmr/zjad014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 11/24/2023] [Accepted: 12/01/2023] [Indexed: 03/14/2024]
Abstract
Type 1 diabetes mellitus (T1DM) has been linked to increased osteocyte apoptosis, local accumulation of mineralized lacunar spaces, and microdamage suggesting an impairment of the mechanoregulation network in affected individuals. Diabetic neuropathy might exacerbate this dysfunction through direct effects on bone turnover, and indirect effects on balance, muscle strength, and gait. However, the in vivo effects of impaired bone mechanoregulation on bone remodeling in humans remain underexplored. This longitudinal cohort study assessed consenting participants with T1DM and varying degree of distal symmetric sensorimotor polyneuropathy (T1DM, n = 20, median age 46.5 yr, eight female) and controls (CTRL; n = 9, median age 59.0 yr, four female) at baseline and 4-yr follow-up. Nerve conduction in participants with T1DM was tested using DPNCheck and bone remodeling was quantified with longitudinal high-resolution peripheral quantitative-computed tomography (HR-pQCT, 82 μm) at the standard distal sites. Local trabecular bone formation (Tb.F) and resorption (Tb.R) sites were captured by implementing 3D rigid image registration of HR-pQCT images, and the mechanical environment across the bone microarchitecture at these sites was simulated using micro-finite element analysis. We calculated odds ratios to determine the likelihood of bone formation (ORF) and resorption (ORR) with increasing/decreasing strain in percent as markers for mechanoregulation. At the distal radius, Tb.F was 47% lower and Tb.R was 59% lower in T1DM participants compared with CTRL (P < .05). Tb.F correlated positively with nerve conduction amplitude (R = 0.69, P < .05) in participants with T1DM and negatively with glycated hemoglobin (HbA1c) (R = -0.45, P < .05). Additionally, ORF was 34% lower and ORR was 18% lower in T1DM compared with CTRL (P < .05). Our findings represent in vivo evidence suggesting that bone remodeling in individuals with T1DM is in a state of low responsiveness to mechanical stimuli, resulting in impaired bone formation and resorption rates; these correlate to the degree of neuropathy and level of diabetes control.
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Affiliation(s)
- Matthias Walle
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Ankita Duseja
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
| | - Danielle E Whittier
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
- Department of Osteoporosis, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Tatiane Vilaca
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
| | - Margaret Paggiosi
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
| | - Richard Eastell
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
| | - Ralph Müller
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Caitlyn J Collins
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
- Department of Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, VA, United States
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14
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Emerzian SR, Johannesdottir F, Yu EW, Bouxsein ML. Use of noninvasive imaging to identify causes of skeletal fragility in adults with diabetes: a review. JBMR Plus 2024; 8:ziae003. [PMID: 38505529 PMCID: PMC10945731 DOI: 10.1093/jbmrpl/ziae003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/21/2023] [Accepted: 01/04/2024] [Indexed: 03/21/2024] Open
Abstract
Diabetes, a disease marked by consistent high blood glucose levels, is associated with various complications such as neuropathy, nephropathy, retinopathy, and cardiovascular disease. Notably, skeletal fragility has emerged as a significant complication in both type 1 (T1D) and type 2 (T2D) diabetic patients. This review examines noninvasive imaging studies that evaluate skeletal outcomes in adults with T1D and T2D, emphasizing distinct skeletal phenotypes linked with each condition and pinpointing gaps in understanding bone health in diabetes. Although traditional DXA-BMD does not fully capture the increased fracture risk in diabetes, recent techniques such as quantitative computed tomography, peripheral quantitative computed tomography, high-resolution quantitative computed tomography, and MRI provide insights into 3D bone density, microstructure, and strength. Notably, existing studies present heterogeneous results possibly due to variations in design, outcome measures, and potential misclassification between T1D and T2D. Thus, the true nature of diabetic skeletal fragility is yet to be fully understood. As T1D and T2D are diverse conditions with heterogeneous subtypes, future research should delve deeper into skeletal fragility by diabetic phenotypes and focus on longitudinal studies in larger, diverse cohorts to elucidate the complex influence of T1D and T2D on bone health and fracture outcomes.
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Affiliation(s)
- Shannon R Emerzian
- Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, United States
| | - Fjola Johannesdottir
- Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, United States
| | - Elaine W Yu
- Department of Medicine, Endocrine Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
| | - Mary L Bouxsein
- Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, United States
- Department of Medicine, Endocrine Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
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15
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Rubin MR, Dhaliwal R. Role of advanced glycation endproducts in bone fragility in type 1 diabetes. Bone 2024; 178:116928. [PMID: 37802378 DOI: 10.1016/j.bone.2023.116928] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 09/28/2023] [Accepted: 10/03/2023] [Indexed: 10/10/2023]
Abstract
The excess fracture risk observed in adults with type 1 diabetes (T1D) is inexplicable in the presence of only modest reductions in areal bone mineral density (BMD). Accumulation of advanced glycation endproducts (AGEs) in bone has been invoked as one explanation for the increased bone fragility in diabetes. The evidence linking AGEs and fractures in individuals with T1D is sparse, although the association has been observed in individuals with type 2 diabetes. Recent data show that in T1D, AGEs as measured by skin intrinsic fluorescence, are a risk factor for lower BMD. Further research in T1D is needed to ascertain whether there is a causal relationship between fractures and AGEs. If confirmed, this would pave the way for finding interventions that can slow AGE accumulation and thus reduce fractures in T1D.
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Affiliation(s)
- Mishaela R Rubin
- Metabolic Bone Disease Unit, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, United States of America
| | - Ruban Dhaliwal
- Division of Endocrinology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, United States of America.
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16
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Bhattacharya S, Nagendra L, Chandran M, Kapoor N, Patil P, Dutta D, Kalra S. Trabecular bone score in adults with type 1 diabetes: a meta-analysis. Osteoporos Int 2024; 35:105-115. [PMID: 37819402 DOI: 10.1007/s00198-023-06935-z] [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: 12/28/2022] [Accepted: 09/29/2023] [Indexed: 10/13/2023]
Abstract
Type 1 diabetes mellitus (T1DM) is associated with a disproportionately high fracture rate despite a minimal decrease in bone mineral density. Though trabecular bone score (TBS), an indirect measure of bone architecture, is lower in adults with T1DM, the modest difference is unlikely to account for the large excess risk and calls for further exploration. INTRODUCTION Fracture rates in type 1 diabetes mellitus (T1DM) are disproportionately high compared to the modestly low bone mineral density (BMD). Distortion of bone microarchitecture compromises bone quality in T1DM and is indirectly measured by trabecular bone score (TBS). TBS could potentially be used as a screening tool for skeletal assessment; however, there are inconsistencies in the studies evaluating TBS in T1DM. We performed this meta-analysis to address this knowledge gap. METHODS An electronic literature search was conducted using PubMed, Scopus, and Web of Science resources (all-year time span) to identify studies relating to TBS in T1DM. Cross-sectional and retrospective studies in adults with T1DM were included. TBS and BMD data were extracted for pooled analysis. Fracture risk could not be analyzed as there were insufficient studies reporting it. RESULT Data from six studies were included (T1DM: n = 378 and controls: n = 286). Pooled analysis showed a significantly lower TBS [standardized mean difference (SMD) = - 0.37, 95% CI - 0.52 to - 0.21; p < 0.00001] in T1DM compared to controls. There was no difference in the lumbar spine BMD (6 studies, SMD - 0.06, 95% CI - 0.22 to 0.09; p = 0.43) and total hip BMD (6 studies, SMD - 0.17, 95% CI - 0.35 to 0.01; p = 0.06) in the case and control groups. CONCLUSIONS Adults with T1DM have a lower TBS but similar total hip and lumbar spine BMD compared to controls. The risk attributable to the significant but limited difference in TBS falls short of explaining the large excess propensity to fragility fracture in adults with T1DM. Further studies on clarification of the mechanism and whether TBS is suited to screen for fracture risk in adults with T1DM are necessary.
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Affiliation(s)
| | - Lakshmi Nagendra
- Department of Endocrinology, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, Karnataka, India.
| | - Manju Chandran
- Osteoporosis and Bone Metabolism Unit, Department of Endocrinology, Singapore General Hospital, Singapore, Singapore
- DUKE NUS Medical School, Singapore, Singapore
| | - Nitin Kapoor
- Department of Endocrinology, Diabetes, and Metabolism, Christian Medical College and Hospital, Vellore, Tamil Nadu, India
- B Non-Communicable Disease Unit, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Prakash Patil
- Central Research Laboratory, K.S Hegde Medical Academy (KSHEMA), NITTE (Deemed to Be University), Mangalore, Karnataka, India
| | - Deep Dutta
- Department of Endocrinology, Centre for Endocrinology, Arthritis, and Rheumatism (CEDAR), Superspeciality Healthcare, Dwarka, New Delhi, India
| | - Sanjay Kalra
- Department of Endocrinology, Bharti Hospital, Karnal, Haryana, India
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17
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Pan R, Zhang Y, Zhao Y. Trabecular bone score in type 1 diabetes: a meta-analysis of cross-sectional studies. J Orthop Surg Res 2023; 18:794. [PMID: 37875949 PMCID: PMC10594696 DOI: 10.1186/s13018-023-04289-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/15/2023] [Indexed: 10/26/2023] Open
Abstract
BACKGROUND Bone fragility is a recognized complication of type 1 diabetes (T1D). Thus, lower trabecular bone score (TBS) measurements in T1D patients can be predicted. However, the results of current studies on TBS in patients with T1D are inconsistent. In this context, the present study aimed to test the hypothesis that T1D is associated with lower TBS through a meta-analysis. METHODS An electronic search of the literature was conducted using PubMed, Embase and Web of science databases to identify studies related to TBS and T1D, supplemented by an additional manual check of the reference list of relevant original and review articles. All data was analyzed using a random effects model. Results were compared using standardized mean differences (SMD) and 95% confidence intervals (CI). P ≤ 0.05 was considered statistically significant. Review Manager 5.4 software and Stata 17.0 software were used for statistical analysis. RESULTS Seven cross-sectional studies involving 848 participants were included. TBS was lower in T1D patients than in healthy controls on random effects analysis, with no heterogeneity (SMD = - 0.39, 95% CI [- 0.53, - 0.24], P < 0.001; I2 = 0%). In addition, by subgroup analysis, T1D patients were strongly associated with reduced TBS in different regions and age groups, and the results were independent of covariate adjustment. CONCLUSION This study showed that TBS was lower in patients with T1D than in healthy individuals with normal blood glucose levels, suggesting that TBS may be a useful measure to assess fracture risk in T1D.
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Affiliation(s)
- Runzhou Pan
- Department of Endocrinology, Cangzhou Central Hospital, Cangzhou, Hebei Province, China
| | - Yan Zhang
- Department of Endocrinology, Cangzhou Central Hospital, Cangzhou, Hebei Province, China
| | - Yongcai Zhao
- Department of Endocrinology, Cangzhou Central Hospital, Cangzhou, Hebei Province, China.
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18
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Draghici AE, Zahedi B, Taylor JA, Bouxsein ML, Yu EW. Vascular deficits contributing to skeletal fragility in type 1 diabetes. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2023; 4:1272804. [PMID: 37867730 PMCID: PMC10587602 DOI: 10.3389/fcdhc.2023.1272804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 09/15/2023] [Indexed: 10/24/2023]
Abstract
Over 1 million Americans are currently living with T1D and improvements in diabetes management have increased the number of adults with T1D living into later decades of life. This growing population of older adults with diabetes is more susceptible to aging comorbidities, including both vascular disease and osteoporosis. Indeed, adults with T1D have a 2- to 3- fold higher risk of any fracture and up to 7-fold higher risk of hip fracture compared to those without diabetes. Recently, diabetes-related vascular deficits have emerged as potential risks factors for impaired bone blood flow and poor bone health and it has been hypothesized that there is a direct pathophysiologic link between vascular disease and skeletal outcomes in T1D. Indeed, microvascular disease (MVD), one of the most serious consequences of diabetes, has been linked to worse bone microarchitecture in older adults with T1D compared to their counterparts without MVD. The association between the presence of microvascular complications and compromised bone microarchitecture indicates the potential direct deleterious effect of vascular compromise, leading to abnormal skeletal blood flow, altered bone remodeling, and deficits in bone structure. In addition, vascular diabetic complications are characterized by increased vascular calcification, decreased arterial distensibility, and vascular remodeling with increased arterial stiffness and thickness of the vessel walls. These extensive alterations in vascular structure lead to impaired myogenic control and reduced nitric-oxide mediated vasodilation, compromising regulation of blood flow across almost all vascular beds and significantly restricting skeletal muscle blood flow seen in those with T1D. Vascular deficits in T1D may very well extend to bone, compromising skeletal blood flow control, and resulting in reduced blood flow to bone, thus negatively impacting bone health. Indeed, several animal and ex vivo human studies report that diabetes induces microvascular damage within bone are strongly correlated with diabetes disease severity and duration. In this review article, we will discuss the contribution of diabetes-induced vascular deficits to bone density, bone microarchitecture, and bone blood flow regulation, and review the potential contribution of vascular disease to skeletal fragility in T1D.
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Affiliation(s)
- Adina E. Draghici
- Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA, United States
- Cardiovascular Research Laboratory, Schoen Adams Research Institute at Spaulding Rehabilitation, Cambridge, MA, United States
| | - Bita Zahedi
- Endocrine Unit, Massachusetts General Hospital, Boston, MA, United States
| | - J. Andrew Taylor
- Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA, United States
- Cardiovascular Research Laboratory, Schoen Adams Research Institute at Spaulding Rehabilitation, Cambridge, MA, United States
| | - Mary L. Bouxsein
- Endocrine Unit, Massachusetts General Hospital, Boston, MA, United States
- Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - Elaine W. Yu
- Endocrine Unit, Massachusetts General Hospital, Boston, MA, United States
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19
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Urbano F, Farella I, Brunetti G, Faienza MF. Pediatric Type 1 Diabetes: Mechanisms and Impact of Technologies on Comorbidities and Life Expectancy. Int J Mol Sci 2023; 24:11980. [PMID: 37569354 PMCID: PMC10418611 DOI: 10.3390/ijms241511980] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/20/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Type 1 diabetes (T1D) is one of the most common chronic diseases in childhood, with a progressively increasing incidence. T1D management requires lifelong insulin treatment and ongoing health care support. The main goal of treatment is to maintain blood glucose levels as close to the physiological range as possible, particularly to avoid blood glucose fluctuations, which have been linked to morbidity and mortality in patients with T1D. Indeed, the guidelines of the International Society for Pediatric and Adolescent Diabetes (ISPAD) recommend a glycated hemoglobin (HbA1c) level < 53 mmol/mol (<7.0%) for young people with T1D to avoid comorbidities. Moreover, diabetic disease strongly influences the quality of life of young patients who must undergo continuous monitoring of glycemic values and the administration of subcutaneous insulin. In recent decades, the development of automated insulin delivery (AID) systems improved the metabolic control and the quality of life of T1D patients. Continuous subcutaneous insulin infusion (CSII) combined with continuous glucose monitoring (CGM) devices connected to smartphones represent a good therapeutic option, especially in young children. In this literature review, we revised the mechanisms of the currently available technologies for T1D in pediatric age and explored their effect on short- and long-term diabetes-related comorbidities, quality of life, and life expectation.
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Affiliation(s)
- Flavia Urbano
- Giovanni XXIII Pediatric Hospital, 70126 Bari, Italy;
| | - Ilaria Farella
- Clinica Medica “A. Murri”, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Giacomina Brunetti
- Department of Biosciences, Biotechnologies, and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy
| | - Maria Felicia Faienza
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy;
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20
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Meier C, Eastell R, Pierroz DD, Lane NE, Al-Daghri N, Suzuki A, Napoli N, Mithal A, Chakhtoura M, Fuleihan GEH, Ferrari S. Biochemical Markers of Bone Fragility in Patients with Diabetes. A Narrative Review by the IOF and the ECTS. J Clin Endocrinol Metab 2023; 108:dgad255. [PMID: 37155585 PMCID: PMC10505554 DOI: 10.1210/clinem/dgad255] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/24/2023] [Accepted: 05/03/2023] [Indexed: 05/10/2023]
Abstract
CONTEXT The risk of fragility fractures is increased in both type 1 and type 2 diabetes. Numerous biochemical markers reflecting bone and/or glucose metabolism have been evaluated in this context. This review summarizes current data on biochemical markers in relation to bone fragility and fracture risk in diabetes. METHODS Literature review by a group of experts from the International Osteoporosis Foundation (IOF) and European Calcified Tissue Society (ECTS) focusing on biochemical markers, diabetes, diabetes treatments and bone in adults. RESULTS Although bone resorption and bone formation markers are low and poorly predictive of fracture risk in diabetes, osteoporosis drugs seem to change bone turnover markers in diabetics similarly to non-diabetics, with similar reductions in fracture risk. Several other biochemical markers related to bone and glucose metabolism have been correlated with BMD and/or fracture risk in diabetes, including osteocyte-related markers such as sclerostin, HbA1c and advanced glycation end products (AGEs), inflammatory markers and adipokines, as well as IGF-1 and calciotropic hormones. CONCLUSION Several biochemical markers and hormonal levels related to bone and/or glucose metabolism have been associated with skeletal parameters in diabetes. Currently, only HbA1c levels seem to provide a reliable estimate of fracture risk, while bone turnover markers could be used to monitor the effects of anti-osteoporosis therapy.
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Affiliation(s)
- Christian Meier
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Basel, 4031 Basel, Switzerland
| | - Richard Eastell
- Academic Unit of Bone Metabolism, Mellanby Centre for Bone Research, University of Sheffield, S57AU Sheffield, UK
| | | | - Nancy E Lane
- Department of Medicine and Rheumatology, Davis School of Medicine, University of California, Sacramento, CA 95817, USA
| | - Nasser Al-Daghri
- Department of Biochemistry, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Atsushi Suzuki
- Department of Endocrinology, Diabetes and Metabolism, Fujita Health University, Toyoake, Aichi 470-1192, Japan
| | - Nicola Napoli
- Unit of Endocrinology and Diabetes, Department of Medicine, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Ambrish Mithal
- Institute of Diabetes and Endocrinology, Max Healthcare, Saket, New Delhi 110017, India
| | - Marlene Chakhtoura
- Department of Internal Medicine, Division of Endocrinology, Calcium Metabolism and Osteoporosis Program, WHO Collaborating Center for Metabolic Bone Disorders, American University of Beirut Medical Center, Riad El Solh, Beirut 6044, Lebanon
| | - Ghada El-Hajj Fuleihan
- Department of Internal Medicine, Division of Endocrinology, Calcium Metabolism and Osteoporosis Program, WHO Collaborating Center for Metabolic Bone Disorders, American University of Beirut Medical Center, Riad El Solh, Beirut 6044, Lebanon
| | - Serge Ferrari
- Service and Laboratory of Bone Diseases, Geneva University Hospital and Faculty of Medicine, 1205 Geneva, Switzerland
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21
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Aleksova J, Ebeling PR, Milat F, Elder GJ. DXA-derived advanced hip analysis and the trabecular bone score in end-stage kidney disease secondary to type 1 diabetes. Eur J Endocrinol 2022; 187:883-892. [PMID: 36315195 DOI: 10.1530/eje-22-0687] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 10/31/2022] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Patients with end-stage kidney disease (ESKD) caused by type 1 diabetes mellitus (T1DM) have a heightened fracture risk. Bone mineral density (BMD) may predict fracture less accurately in ESKD than in patients with chronic kidney disease (CKD) stages 1-3b or the general population. Alternate, readily available imaging modalities are needed to improve ESKD fracture risk assessment. This study aimed to assess dual-energy X-ray absorptiometry (DXA)-derived BMD, the trabecular bone score (TBS) and advanced hip analysis parameters in patients with ESKD due to T1DM and to compare their results with those of patients with ESKD from other causes. METHODS We compared the DXA-derived TBS, hip cortical thickness (CT) and femoral neck (FN) buckling ratio (BR), an index of FN stability, of patients with T1DM and ESKD undergoing simultaneous pancreas kidney transplantation, patients with ESKD from other causes receiving kidney transplants and population reference ranges. RESULTS Of 227 patients with ESKD, 28% had T1DM and 65% were male. Compared with other ESKD patients, patients with T1DM were younger (42 ± 7.7 vs 51 ± 13.8 years), had shorter dialysis duration (24.4 ± 21 vs 42.6 ± 40 months), had higher HbA1c (7.9 ± 1.57% vs 5.4 ± 0.95%) and had lower BMI (25 ± 6 vs 27 ± 5 kg/m2). They had lower spine, hip and UD radius BMD Z-scores (all P ≤ 0.001), TBS (1.33 ± 0.12 vs 1.36 ± 0.12; P = 0.05), CT at the FN (P = 0.03), calcar (P = 0.006) and shaft (P < 0.001) and higher BR (10.1±7.1 vs 7.7±4; P = 0.006). All ESKD parameters were lower than population-based reference ranges (P < 0.001). Adjusting for age, sex, dialysis vintage and weight, prevalent vertebral fractures in patients with T1DM and ESKD were associated with higher BR (odds ratio (OR): 3.27 (95% CI: 1.19-8.92), P = 0.002) and lower FN CT (OR: 3.70 (95% CI: 1.13-12.50)). CONCLUSION Patients with ESKD and T1DM have reduced TBS, reduced CT and increased BR compared with other ESKD patients. Prospective study of these parameters is warranted to determine their utility in fracture risk prediction and management. SIGNIFICANCE STATEMENT Patients with ESKD and T1DM have an elevated fracture risk due to decreased bone strength. As an adjunct to BMD, evaluating dual-energy X-ray absorptiometry parameters that incorporate structural change may have greater value in patients with ESKD and T1DM than in the general population. In this study, patients with ESKD due to T1DM had lower BMD, lower trabecular bone scores, more severe loss of CT and higher BR than other patients with ESKD and people from the general population. Both lower CT and higher BR were associated with prevalent vertebral fractures in patients with T1DM and ESKD. Changes to these parameters should be evaluated for incident fracture prediction.
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Affiliation(s)
- Jasna Aleksova
- Hudson Institute for Medical Research
- Department of Medicine, Monash University
- Department of Endocrinology, Monash Health
| | - Peter R Ebeling
- Department of Medicine, Monash University
- Department of Endocrinology, Monash Health
| | - Frances Milat
- Hudson Institute for Medical Research
- Department of Medicine, Monash University
- Department of Endocrinology, Monash Health
| | - Grahame J Elder
- Department of Renal Medicine, Westmead Hospital
- Skeletal Biology Program, Garvan Institute of Medical Research
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Zheng Y, Rostami Haji Abadi M, Ghafouri Z, Meira Goes S, Johnston JJD, Nour M, Kontulainen S. Bone deficits in children and youth with type 1 diabetes: A systematic review and meta-analysis. Bone 2022; 163:116509. [PMID: 35914713 DOI: 10.1016/j.bone.2022.116509] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 07/13/2022] [Accepted: 07/26/2022] [Indexed: 11/26/2022]
Abstract
Deficits in bone mineral and weaker bone structure in children with type 1 diabetes (T1D) may contribute to a lifelong risk of fracture. However, there is no meta-analysis comparing bone properties beyond density between children with T1D and typically developing children (TDC). This meta-analysis aimed to assess differences and related factors in bone mineral content (BMC), density, area, micro-architecture and estimated strength between children with T1D and TDC. We systematically searched MEDLINE, Embase, CINAHL, Web of Science, Scopus, Cochrane Library databases, and included 36 in the meta-analysis (2222 children and youth with T1D, 2316 TDC; mean age ≤18 yrs., range 1-24). We estimated standardized mean differences (SMD) using random-effects models and explored the role of age, body size, sex ratio, disease duration, hemoglobin A1c in relation to BMC and areal density (aBMD) SMD using meta-regressions. Children and youth with T1D had lower total body BMC (SMD: -0.21, 95% CI: -0.37 to -0.05), aBMD (-0.30, -0.50 to -0.11); lumbar spine BMC (-0.17, -0.28 to -0.06), aBMD (-0.20, -0.32 to -0.08), bone mineral apparent density (-0.30, -0.48 to -0.13); femoral neck aBMD (-0.21, -0.33 to -0.09); distal radius and tibia trabecular density (-0.38, -0.64 to -0.12 and -0.35, -0.51 to -0.18, respectively) and bone volume fraction (-0.33, -0.56 to -0.09 and -0.37, -0.60 to -0.14, respectively); distal tibia trabecular thickness (-0.41, -0.67 to -0.16); and tibia shaft cortical content (-0.33, -0.56 to -0.10). Advanced age was associated with larger SMD in total body BMC (-0.13, -0.21 to -0.04) and aBMD (-0.09; -0.17 to -0.01) and longer disease duration with larger SMD in total body aBMD (-0.14; -0.24 to -0.04). Children and youth with T1D have lower BMC, aBMD and deficits in trabecular density and micro-architecture. Deficits in BMC and aBMD appeared to increase with age and disease duration. Bone deficits may contribute to fracture risk and require attention in diabetes research and care. STUDY REGISTRATION: PROSPERO (CRD42020200819).
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Affiliation(s)
- Yuwen Zheng
- College of Kinesiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5B2
| | | | - Zahra Ghafouri
- College of Kinesiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5B2
| | - Suelen Meira Goes
- College of Kinesiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5B2; College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E5
| | - James J D Johnston
- College of Engineering, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5A9
| | - Munier Nour
- College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E5
| | - Saija Kontulainen
- College of Kinesiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5B2.
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23
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Shu JB, Kim TY. Bone marrow adiposity in diabetes and clinical interventions. Curr Opin Endocrinol Diabetes Obes 2022; 29:303-309. [PMID: 35776685 DOI: 10.1097/med.0000000000000741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE OF REVIEW This study aims to review bone marrow adipose tissue (BMAT) changes in people with diabetes, contributing factors, and interventions. RECENT FINDINGS In type 1 diabetes (T1D), BMAT levels are similar to healthy controls, although few studies have been performed. In type 2 diabetes (T2D), both BMAT content and composition appear altered, and recent bone histomorphometry data suggests increased BMAT is both through adipocyte hyperplasia and hypertrophy. Position emission tomography scanning suggests BMAT is a major source of basal glucose uptake. BMAT is responsive to metabolic interventions. SUMMARY BMAT is a unique fat depot that is influenced by metabolic factors and proposed to negatively affect the skeleton. BMAT alterations are more consistently seen in T2D compared to T1D. Interventions such as thiazolidinedione treatment may increase BMAT, whereas metformin treatment, weight loss, and exercise may decrease BMAT. Further understanding of the role of BMAT will provide insight into the pathogenesis of diabetic bone disease and could lead to targeted preventive and therapeutic strategies.
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Affiliation(s)
- Jessica B Shu
- University of California, San Francisco and the San Francisco VA Health Care System, San Francisco, California, USA
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24
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Abstract
PURPOSE OF REVIEW This review article presents the most recent research on bone fragility in individuals with diabetes from a medical imaging perspective. RECENT FINDINGS The widespread availability of dual-energy X-ray absorptiometry (DXA) and trabecular bone score (TBS) software has led to recent assessments of bone fragility with this texture parameter in several studies of type 2 diabetes mellitus (T2D), but in few of type 1 diabetes mellitus (T1D). Although most studies show a trend of reduced TBS values in T2D independent of areal bone mineral density (aBMD) of the lumbar spine, some studies also show the limitations of TBS in both T2D and T1D. Given the limitations of DXA to assess bone strength and investigate the etiology of bone fragility in diabetes, more investigators are incorporating three-dimensional (3D) medical imaging techniques in their studies. Recent use of 3D medical imaging to assess bone fragility in the setting of diabetes has been mostly limited to a few cross-sectional studies predominantly incorporating high-resolution peripheral quantitative computed tomography (HR-pQCT). Although HR-pQCT studies indicate higher tibial cortical porosity in subjects with T2D, results are inconsistent in T1D due to differences in study designs, sample sizes, and subject characteristics, among other factors. With respect to central CT, recent studies support a previous finding in the literature indicating femoral neck geometrical impairments in subjects with T2D and provide encouraging results for the incorporation of finite element analysis (FEA) to assess bone strength in studies of T2D. In the recent literature, there are no studies assessing bone fragility in T1D with QCT, and only two studies used pQCT reporting tibial and radial impairments in young women and children with T1D, respectively. Magnetic resonance imaging (MRI) has not been recently used in diabetic studies of bone fragility. SUMMARY As bone fragility in diabetes is not explained by DXA-derived aBMD and given the limitations of cross-sectional studies, it is imperative to use 3D imaging techniques for longitudinal assessments of the density, quality, and microenvironment of bone to improve our understanding of the effects of diabetes on bone and reduce the risk of fracture in this large and vulnerable population of subjects with diabetes.
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Affiliation(s)
- Julio Carballido-Gamio
- Department of Radiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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25
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Rubin MR, de Boer IH, Backlund JYC, Arends V, Gubitosi-Klug R, Wallia A, Sinha Gregory N, Barnie A, Burghardt AJ, Lachin JM, Braffett BH, Schwartz AV. Biochemical Markers of Bone Turnover in Older Adults With Type 1 Diabetes. J Clin Endocrinol Metab 2022; 107:e2405-e2416. [PMID: 35188961 PMCID: PMC9113800 DOI: 10.1210/clinem/dgac099] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Type 1 diabetes (T1D) is characterized by high fracture risk, yet little is known regarding diabetes-related mechanisms or risk factors. OBJECTIVE Determine whether glycemic control, advanced glycation end products (AGEs), and microvascular complications are associated with bone turnover markers among older T1D adults. DESIGN Cross-sectional. SETTING Epidemiology of Diabetes Interventions and Complications study (6 of 27 clinical centers). PARTICIPANTS 232 T1D participants followed for >30 years. EXPOSURES Glycemic control ascertained as concurrent and cumulative hemoglobin A1c (HbA1c); kidney function, by estimated glomerular filtration rates (eGFR); and AGEs, by skin intrinsic fluorescence. MAIN OUTCOME MEASURES Serum procollagen 1 intact N-terminal propeptide (PINP), bone-specific alkaline phosphatase (bone ALP), serum C-telopeptide (sCTX), tartrate-resistant acid phosphatase 5b (TRACP5b), and sclerostin. RESULTS Mean age was 59.6 ± 6.8 years, and 48% were female. In models with HbA1c, eGFR, and AGEs, adjusted for age and sex, higher concurrent HbA1c was associated with lower PINP [β -3.4 pg/mL (95% CI -6.1, -0.7), P = 0.015 for each 1% higher HbA1c]. Lower eGFR was associated with higher PINP [6.9 pg/mL (95% CI 3.8, 10.0), P < 0.0001 for each -20 mL/min/1.73 m2 eGFR], bone ALP [1.0 U/L (95% CI 0.2, 1.9), P = 0.011], sCTX [53.6 pg/mL (95% CI 32.6, 74.6), P < 0.0001], and TRACP5b [0.3 U/L (95% CI 0.1, 0.4), P = 0.002]. However, AGEs were not associated with any bone turnover markers in adjusted models. HbA1c, eGFR, and AGEs were not associated with sclerostin levels. CONCLUSIONS Among older adults with T1D, poor glycemic control is a risk factor for reduced bone formation, while reduced kidney function is a risk factor for increased bone resorption and formation.
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Affiliation(s)
| | - Ian H de Boer
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Jye-Yu C Backlund
- The Biostatistics Center, George Washington University, Rockville, MD,USA
| | - Valerie Arends
- Departement of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
| | - Rose Gubitosi-Klug
- Case Western Reserve/Rainbow Babies and Children’s Hospital, Cleveland, OH, USA
| | - Amisha Wallia
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | | | | | - Andrew J Burghardt
- Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA
| | - John M Lachin
- The Biostatistics Center, George Washington University, Rockville, MD,USA
| | - Barbara H Braffett
- The Biostatistics Center, George Washington University, Rockville, MD,USA
| | - Ann V Schwartz
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
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26
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Sewing L, Potasso L, Baumann S, Schenk D, Gazozcu F, Lippuner K, Kraenzlin M, Zysset P, Meier C. Bone Microarchitecture and Strength in Long-Standing Type 1 Diabetes. J Bone Miner Res 2022; 37:837-847. [PMID: 35094426 PMCID: PMC9313576 DOI: 10.1002/jbmr.4517] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 01/09/2022] [Accepted: 01/21/2022] [Indexed: 11/22/2022]
Abstract
Type 1 diabetes (T1DM) is associated with an increased fracture risk, specifically at nonvertebral sites. The influence of glycemic control and microvascular disease on skeletal health in long-standing T1DM remains largely unknown. We aimed to assess areal (aBMD) and volumetric bone mineral density (vBMD), bone microarchitecture, bone turnover, and estimated bone strength in patients with long-standing T1DM, defined as disease duration ≥25 years. We recruited 59 patients with T1DM (disease duration 37.7 ± 9.0 years; age 59.9 ± 9.9 years.; body mass index [BMI] 25.5 ± 3.7 kg/m2 ; 5-year median glycated hemoglobin [HbA1c] 7.1% [IQR 6.82-7.40]) and 77 nondiabetic controls. Dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HRpQCT) at the ultradistal radius and tibia, and biochemical markers of bone turnover were assessed. Group comparisons were performed after adjustment for age, gender, and BMI. Patients with T1DM had lower aBMD at the hip (p < 0.001), distal radius (p = 0.01), lumbar spine (p = 0.04), and femoral neck (p = 0.05) as compared to controls. Cross-linked C-telopeptide (CTX), a marker of bone resorption, was significantly lower in T1DM (p = 0.005). At the distal radius there were no significant differences in vBMD and bone microarchitecture between both groups. In contrast, patients with T1DM had lower cortical thickness (estimate [95% confidence interval]: -0.14 [-0.24, -0.05], p < 0.01) and lower cortical vBMD (-28.66 [-54.38, -2.93], p = 0.03) at the ultradistal tibia. Bone strength and bone stiffness at the tibia, determined by homogenized finite element modeling, were significantly reduced in T1DM compared to controls. Both the altered cortical microarchitecture and decreased bone strength and stiffness were dependent on the presence of diabetic peripheral neuropathy. In addition to a reduced aBMD and decreased bone resorption, long-standing, well-controlled T1DM is associated with a cortical bone deficit at the ultradistal tibia with reduced bone strength and stiffness. Diabetic neuropathy was found to be a determinant of cortical bone structure and bone strength at the tibia, potentially contributing to the increased nonvertebral fracture risk. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Lilian Sewing
- Department of Endocrinology, Diabetology and Metabolism University Hospital Basel, Basel, Switzerland
| | - Laura Potasso
- Department of Endocrinology, Diabetology and Metabolism University Hospital Basel, Basel, Switzerland.,Department of Clinical Research, University of Basel, Basel, Switzerland
| | - Sandra Baumann
- Department of Endocrinology, Diabetology and Metabolism University Hospital Basel, Basel, Switzerland
| | - Denis Schenk
- ARTORG Center, University of Bern, Bern, Switzerland
| | - Furkan Gazozcu
- Department of Osteoporosis, University Hospital Bern, Bern, Switzerland
| | - Kurt Lippuner
- Department of Osteoporosis, University Hospital Bern, Bern, Switzerland
| | | | | | - Christian Meier
- Department of Endocrinology, Diabetology and Metabolism University Hospital Basel, Basel, Switzerland.,Endocrine Clinic and Laboratory, Basel, Switzerland
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27
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Ebeling PR, Nguyen HH, Aleksova J, Vincent AJ, Wong P, Milat F. Secondary Osteoporosis. Endocr Rev 2022; 43:240-313. [PMID: 34476488 DOI: 10.1210/endrev/bnab028] [Citation(s) in RCA: 139] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Indexed: 02/07/2023]
Abstract
Osteoporosis is a global public health problem, with fractures contributing to significant morbidity and mortality. Although postmenopausal osteoporosis is most common, up to 30% of postmenopausal women, > 50% of premenopausal women, and between 50% and 80% of men have secondary osteoporosis. Exclusion of secondary causes is important, as treatment of such patients often commences by treating the underlying condition. These are varied but often neglected, ranging from endocrine to chronic inflammatory and genetic conditions. General screening is recommended for all patients with osteoporosis, with advanced investigations reserved for premenopausal women and men aged < 50 years, for older patients in whom classical risk factors for osteoporosis are absent, and for all patients with the lowest bone mass (Z-score ≤ -2). The response of secondary osteoporosis to conventional anti-osteoporosis therapy may be inadequate if the underlying condition is unrecognized and untreated. Bone densitometry, using dual-energy x-ray absorptiometry, may underestimate fracture risk in some chronic diseases, including glucocorticoid-induced osteoporosis, type 2 diabetes, and obesity, and may overestimate fracture risk in others (eg, Turner syndrome). FRAX and trabecular bone score may provide additional information regarding fracture risk in secondary osteoporosis, but their use is limited to adults aged ≥ 40 years and ≥ 50 years, respectively. In addition, FRAX requires adjustment in some chronic conditions, such as glucocorticoid use, type 2 diabetes, and HIV. In most conditions, evidence for antiresorptive or anabolic therapy is limited to increases in bone mass. Current osteoporosis management guidelines also neglect secondary osteoporosis and these existing evidence gaps are discussed.
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Affiliation(s)
- Peter R Ebeling
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia
| | - Hanh H Nguyen
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Department of Endocrinology and Diabetes, Western Health, Victoria 3011, Australia
| | - Jasna Aleksova
- Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
| | - Amanda J Vincent
- Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Monash Centre for Health Research and Implementation, School of Public Health and Preventative Medicine, Monash University, Clayton, Victoria 3168, Australia
| | - Phillip Wong
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
| | - Frances Milat
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
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28
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Travis C, Srivastava PS, Hawke TJ, Kalaitzoglou E. Diabetic Bone Disease and Diabetic Myopathy: Manifestations of the Impaired Muscle-Bone Unit in Type 1 Diabetes. J Diabetes Res 2022; 2022:2650342. [PMID: 35601019 PMCID: PMC9119786 DOI: 10.1155/2022/2650342] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 01/18/2022] [Accepted: 04/28/2022] [Indexed: 11/25/2022] Open
Abstract
Type 1 diabetes is associated with complications affecting muscle and bone, with diabetic bone disease and diabetic myopathy becoming increasingly reported in the past few decades. This review is aimed at succinctly reviewing the literature on the current knowledge regarding these increasingly identified and possibly interconnected complications on the musculoskeletal system. Furthermore, this review summarizes several nonmechanical factors that could be mediating the development and progression of premature musculoskeletal decline in this population and discusses preventative measures to reduce the burden of diabetes on the musculoskeletal system.
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Affiliation(s)
- Callie Travis
- University of Kentucky College of Medicine, Lexington, KY, USA
| | - Priya S. Srivastava
- Department of Pediatrics, Division of Pediatric Endocrinology, UCSF Benioff Children's Hospital, San Francisco, CA, USA
| | - Thomas J. Hawke
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Evangelia Kalaitzoglou
- University of Kentucky, Barnstable Brown Diabetes Center, Lexington, KY, USA
- Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY 40536, USA
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29
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Palui R, Pramanik S, Mondal S, Ray S. Critical review of bone health, fracture risk and management of bone fragility in diabetes mellitus. World J Diabetes 2021; 12:706-729. [PMID: 34168723 PMCID: PMC8192255 DOI: 10.4239/wjd.v12.i6.706] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/08/2021] [Accepted: 04/29/2021] [Indexed: 02/06/2023] Open
Abstract
The risk of fracture is increased in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). However, in contrast to the former, patients with T2DM usually possess higher bone mineral density. Thus, there is a considerable difference in the pathophysiological basis of poor bone health between the two types of diabetes. Impaired bone strength due to poor bone microarchitecture and low bone turnover along with increased risk of fall are among the major factors behind elevated fracture risk. Moreover, some antidiabetic medications further enhance the fragility of the bone. On the other hand, antiosteoporosis medications can affect the glucose homeostasis in these patients. It is also difficult to predict the fracture risk in these patients because conventional tools such as bone mineral density and Fracture Risk Assessment Tool score assessment can underestimate the risk. Evidence-based recommendations for risk evaluation and management of poor bone health in diabetes are sparse in the literature. With the advancement in imaging technology, newer modalities are available to evaluate the bone quality and risk assessment in patients with diabetes. The purpose of this review is to explore the pathophysiology behind poor bone health in diabetic patients. Approach to the fracture risk evaluation in both T1DM and T2DM as well as the pragmatic use and efficacy of the available treatment options have been discussed in depth.
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Affiliation(s)
- Rajan Palui
- Department of Endocrinology, The Mission Hospital, Durgapur 713212, West Bengal, India
| | - Subhodip Pramanik
- Department of Endocrinology, Neotia Getwel Healthcare Centre, Siliguri 734010, West Bengal, India
| | - Sunetra Mondal
- Department of Endocrinology, Institute of Post Graduate Medical Education and Research (IPGMER), Kolkata 700020, West Bengal, India
| | - Sayantan Ray
- Department of Endocrinology, Medica Superspeciality Hospital and Medica Clinic, Kolkata 700099, West Bengal, India
- Department of Endocrinology, Jagannath Gupta Institute of Medical Sciences and Hospital, Kolkata 700137, West Bengal, India
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30
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Wang HJ, Giambini H, Chen JW, Wang QS, Hou HG, Luo SM, Chen JY, Zhuang TF, Chen YF, Wu TT, Zha ZG, Liu YJ, Zheng XF. Diabetes mellitus accelerates the progression of osteoarthritis in streptozotocin-induced diabetic mice by deteriorating bone microarchitecture, bone mineral composition, and bone strength of subchondral bone. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:768. [PMID: 34268381 PMCID: PMC8246216 DOI: 10.21037/atm-20-6797] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 02/21/2021] [Indexed: 01/11/2023]
Abstract
Background The purpose of this study was to develop an optimal diabetes-osteoarthritis (DM-OA) mouse model to validate that diabetes aggravates osteoarthritis (OA) and to evaluate the microarchitecture, chemical composition, and biomechanical properties of subchondral bone (SB) as a consequence of the DM-OA-induced damage induced. Methods Mice were randomly divided into three groups: DM-OA group, OA group, and sham group. Blood glucose levels, body weight, and food intake of all animals were recorded. Serum calcium (Ca) and osteocalcin (OCN) levels were compared in the three groups. The messenger ribonucleic acid (mRNA) and protein expression of key regulators for bone metabolism were detected. A semi-quantitative grading system [Osteoarthritis Research Society International (OARSI)] was used to evaluate cartilage and SB degeneration. Microspectroscopy, microindentations, micro-computed tomography (CT) imaging, and fracture load of compression testing were also used to evaluate trabecular SB properties. Results Glycemic monitoring and pancreas pathological results indicated stable high blood glucose and massive destruction of pancreas and islet cells in the DM-OA group. Serum levels of bone specific alkaline phosphatase (ALP-B) and tartrate-resistant acid phosphatase 5b (TRACP-5b) in the DM-group were higher than those of the other two groups while levels of serum Ca and OCN were lower. Meanwhile, the protein and mRNA expression of osteoblast-specific biomarkers [osteoprotegerin/receptor activator of nuclear factor kappa-B ligand (OPG/RANKL) ratio, collagen type I (COL-I), Runt-related transcription factor 2 (RUNX-2), OCN] were suppressed, and osteoclast-specific biomarkers [sclerostin (SOST)] was elevated in the DM-OA group. The mineral-to-collagen ratio, microindentation elastic modulus, hardness, micro-architectural parameters, bone mineral density, and fracture load of SB trabecular bone of the DM-OA group joint were lower than those of the other two groups. On the other hand, The OARSI score, trabecular spacing, and structural model index of the DM-OA group joint were higher than those of the other two groups. Conclusions The glycemic and pancreatic pathological results indicated that the DM-OA model was a simple and reliable model induced by streptozotocin (STZ) and surgery. The results revealed the mechanisms through which diabetes accelerates OA; that is, by damaging and deteriorating the functions of SB, including its microarchitecture, chemical composition, and biomechanical properties.
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Affiliation(s)
- Hua-Jun Wang
- The First Clinical College, Jinan University & Department of Orthopedic Surgery and Sports Medicine Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Hugo Giambini
- Department of Biomedical Engineering, The University of Texas at San Antonio, San Antonio, TX, USA
| | - Ji-Wen Chen
- The First Clinical College, Jinan University & Department of Orthopedic Surgery and Sports Medicine Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Qiu-Shi Wang
- The First Clinical College, Jinan University & Department of Orthopedic Surgery and Sports Medicine Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Hui-Ge Hou
- The First Clinical College, Jinan University & Department of Orthopedic Surgery and Sports Medicine Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Si-Min Luo
- The First Clinical College, Jinan University & Department of Orthopedic Surgery and Sports Medicine Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Jun-Yuan Chen
- The First Clinical College, Jinan University & Department of Orthopedic Surgery and Sports Medicine Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Teng-Feng Zhuang
- The First Clinical College, Jinan University & Department of Orthopedic Surgery and Sports Medicine Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Yuan-Feng Chen
- The First Clinical College, Jinan University & Department of Orthopedic Surgery and Sports Medicine Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Ting-Ting Wu
- The First Clinical College, Jinan University & Department of Orthopedic Surgery and Sports Medicine Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Zhen-Gang Zha
- The First Clinical College, Jinan University & Department of Orthopedic Surgery and Sports Medicine Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - You-Jie Liu
- The First Clinical College, Jinan University & Department of Orthopedic Surgery and Sports Medicine Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Xiao-Fei Zheng
- The First Clinical College, Jinan University & Department of Orthopedic Surgery and Sports Medicine Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
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31
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Jørgensen HS, David K, Salam S, Evenepoel P. Traditional and Non-traditional Risk Factors for Osteoporosis in CKD. Calcif Tissue Int 2021; 108:496-511. [PMID: 33586002 DOI: 10.1007/s00223-020-00786-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 12/02/2020] [Indexed: 12/11/2022]
Abstract
Osteoporosis is a state of bone fragility with reduced skeletal resistance to trauma, and consequently increased risk of fracture. A wide range of conditions, including traditional risk factors, lifestyle choices, diseases and their treatments may contribute to bone fragility. It is therefore not surprising that the multi-morbid patient with chronic kidney disease (CKD) is at a particularly high risk. CKD is associated with reduced bone quantity, as well as impaired bone quality. Bone fragility in CKD is a composite of primary osteoporosis, accumulation of traditional and uremia-related risk factors, assaults brought on by systemic disease, and detrimental effects of drugs. Some risk factors are modifiable and represent potential targets for intervention. This review provides an overview of the heterogeneity of bone fragility in CKD.
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Affiliation(s)
- Hanne Skou Jørgensen
- Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Karel David
- Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Syazrah Salam
- Sheffield Kidney Institute, Sheffield Teaching Hospitals National Health Service Foundation Trust, Sheffield, UK
- Academic Unit of Bone Metabolism and 3 Mellanby Centre for Bone Research, Medical School, University of Sheffield, Sheffield, UK
| | - Pieter Evenepoel
- Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
- Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
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Hildebrandt N, Colditz J, Dutra C, Goes P, Salbach-Hirsch J, Thiele S, Hofbauer LC, Rauner M. Role of osteogenic Dickkopf-1 in bone remodeling and bone healing in mice with type I diabetes mellitus. Sci Rep 2021; 11:1920. [PMID: 33479403 PMCID: PMC7820472 DOI: 10.1038/s41598-021-81543-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 01/05/2021] [Indexed: 12/11/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) is associated with low bone mass and a higher risk for fractures. Dickkopf-1 (Dkk1), which inhibits Wnt signaling, osteoblast function, and bone formation, has been found to be increased in the serum of patients with T1DM. Here, we investigated the functional role of Dkk1 in T1DM-induced bone loss in mice. T1DM was induced in 10-week-old male mice with Dkk1-deficiency in late osteoblasts/osteocytes (Dkk1f/f;Dmp1-Cre, cKO) and littermate control mice by 5 subsequent injections of streptozotocin (40 mg/kg). Age-matched, non-diabetic control groups received citrate buffer instead. At week 12, calvarial defects were created in subgroups of each cohort. After a total of 16 weeks, weight, fat, the femoral bone phenotype and the area of the bone defect were analyzed using µCT and dynamic histomorphometry. During the experiment, diabetic WT and cKO mice did not gain body weight compared to control mice. Further they lost their perigonadal and subcutaneous fat pads. Diabetic mice had highly elevated serum glucose levels and impaired glucose tolerance, regardless of their Dkk1 levels. T1DM led to a 36% decrease in trabecular bone volume in Cre− negative control animals, whereas Dkk1 cKO mice only lost 16%. Of note, Dkk1 cKO mice were completely protected from T1DM-induced cortical bone loss. T1DM suppressed the bone formation rate, the number of osteoblasts at trabecular bone, serum levels of P1NP and bone defect healing in both, Dkk1-deficient and sufficient, mice. This may be explained by increased serum sclerostin levels in both genotypes and the strict dependence on bone formation for bone defect healing. In contrast, the number of osteoclasts and TRACP 5b serum levels only increased in diabetic control mice, but not in Dkk1 cKO mice. In summary, Dkk1 derived from osteogenic cells does not influence the development of T1DM but plays a crucial role in T1DM-induced bone loss in male mice by regulating osteoclast numbers.
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Affiliation(s)
- Nick Hildebrandt
- Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Juliane Colditz
- Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.,Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103, Leipzig, Germany
| | - Caio Dutra
- Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.,Post-Graduation Program in Morphological Science, Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Paula Goes
- Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.,Department of Pathology and Legal Medicine, School of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Juliane Salbach-Hirsch
- Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Sylvia Thiele
- Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Lorenz C Hofbauer
- Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Martina Rauner
- Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
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BIOMECHANICAL PROPERTIES AND MACROELEMENT ELEMENT COMPOSITION OF LONG TUBULAR BONE OF RATS UNDER EXPERIMENTAL HYPERGLYCAEMIA. WORLD OF MEDICINE AND BIOLOGY 2021. [DOI: 10.26724/2079-8334-2021-2-76-232-238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Xu L, Yu J, Wang O, Hou Y, Li W, Zhang H, Ping F, Xu Q, Li Y, Xia W. Comparison of differences in bone microarchitecture in adult- versus juvenile-onset type 1 diabetes Asian males versus non-diabetes males: an observational cross-sectional pilot study. Endocrine 2021; 71:87-95. [PMID: 32915436 PMCID: PMC7835289 DOI: 10.1007/s12020-020-02480-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 08/26/2020] [Indexed: 12/16/2022]
Abstract
PURPOSE Evidence about bone microarchitecture in Asian type 1 diabetes (T1D) patients is lacking. We assessed the bone microarchitecture in T1D patients versus controls and compare the differences between juvenile-onset and adult-onset T1D patients. METHODS This cross-sectional study recruited 32 Asian males with T1D and 32 age-, sex-, and body mass index (BMI)-matched controls. Dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) for ultradistal nondominant radius and tibia were performed. The data were analyzed using Student's t test and analysis of covariance. RESULTS Among the patients, 15 had juvenile-onset T1D, with a median disease duration of 11 years, and 17 had adult-onset T1D, with a median disease duration of 7 years. At the radius, adult-onset and juvenile-onset T1D patients had lower total volumetric bone mineral density (vBMD), trabecular vBMD, trabecular bone volume fraction (BV/TV), and trabecular thickness (Tb.Th) (p < 0.05) than the control subjects. After adjusting for BMI, disease duration, and insulin dose, juvenile-onset patients tended to have lower trabecular vBMD, BV/TV, Tb.Th, and intracortical porosity (Ct.Po) than adult-onset patients. At the tibia, adult-onset patients displayed lower total vBMD, lower Ct. vBMD, and higher Ct.Po (p < 0.05), while juvenile-onset patients had lower Tb.Th and standard deviation of trabecular number (1/Tb.N.SD) (p < 0.05) than control subjects. After adjustment for covariates, adult-onset patients tended to have higher cortical pore diameter (Ct.Po.Dm) than juvenile-onset patients. CONCLUSIONS T1D patients were associated with compromised bone microarchitecture, adult-onset and juvenile-onset T1D patients demonstrated some differences in cortical and trabecular microarchitecture.
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Affiliation(s)
- Lingling Xu
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science, 100730, Beijing, China
| | - Jie Yu
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science, 100730, Beijing, China
| | - Ou Wang
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science, 100730, Beijing, China
| | - Yanfang Hou
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science, 100730, Beijing, China
| | - Wei Li
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science, 100730, Beijing, China
| | - Huabing Zhang
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science, 100730, Beijing, China
| | - Fan Ping
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science, 100730, Beijing, China
| | - Qun Xu
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 100005, Beijing, China
| | - Yuxiu Li
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science, 100730, Beijing, China.
| | - Weibo Xia
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science, 100730, Beijing, China.
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Abstract
Many children with chronic disease are now surviving into adulthood. As a result, there is a growing interest in optimizing bone health early in the disease course with the dual goals of improving quality of life during childhood and reducing life-long fracture risk. Risk factors for impaired bone health in these children include immobility, nutritional deficiency, exposure to bone toxic therapies, hormonal deficiencies affecting growth and pubertal development, and chronic inflammation. This review focuses on the chronic diseases of childhood most commonly associated with impaired bone health. Recent research findings and clinical practice recommendations, when available, for specific disorders are summarized.
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Affiliation(s)
- David R Weber
- Department of Pediatrics - Endocrinology, Golisano Children's Hospital, University of Rochester, Rochester, NY, USA.
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Liu Q, Yang Z, Xie C, Ling L, Hu H, Cao Y, Huang Y, Zhu Q, Hua Y. The Hyperglycemia and Hyperketonemia Impaired Bone Microstructures: A Pilot Study in Rats. Front Endocrinol (Lausanne) 2020; 11:590575. [PMID: 33193101 PMCID: PMC7642598 DOI: 10.3389/fendo.2020.590575] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 09/22/2020] [Indexed: 12/14/2022] Open
Abstract
Though diabetes mellitus (DM) is one of the known causes of osteoporosis, it is also realized that ketogenic diet (KD), an effective regimen for epilepsy, impairs bone microstructures. However, the similarities and differences of effects between these two factors are still unknown. The purpose of this study is to identify different effects between hyperglycemia and hyperketonemia, which are manifestations of DM and KD, on bone in rats. Thirty male Sprague-Dawley rats were randomly divided into three groups: the sham, DM, and KD groups. Hyperglycemia was achieved by intravenous injection of streptozotocin in DM group, while hyperketonemia was induced by application of ketogenic diet (carbohydrates-to-fat as 1:3) in KD group. The body weight, blood ketone body, and blood glucose were recorded, and the bone turnover markers, bone length, bone microstructures, bone biomechanics and histomorphology were measured after 12 weeks intervention. Compared with the control and KD groups, a significant body weight loss was found in the DM group, and the bone lengths of tibia and femur of the group were shortened. The blood glucose and blood ketone were noticeably increased in the DM and KD rats, respectively. Microstructures and properties of cancellous bone were significantly deteriorated in both the DM and KD groups compared with the sham group, as the bone volumes were decreased and the bone trabecula structures were disturbed. Meanwhile, the thickness and strength of cortical bone was reduced more in the DM group than those in the sham and KD groups. The HE staining showed that bone trabecula was significantly decreased in both the DM and KD groups, and more adipose tissue was observed in the KD rats. The activity of osteoblasts was decreased more in both the KD and DM groups than that in the sham group, while the activity of osteoclasts of the two groups was remarkably increased. The present study indicates that both hyperglycemia and hyperketonemia have adverse effects on bone. Therefore, it is worth paying more attention to the bone status of patients with hyperglycemia and hyperketonemia in clinic.
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Affiliation(s)
- Qi Liu
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhou Yang
- Department of Orthopaedic Surgery, Southern University of Science and Technology Hospital, Shenzhen, China
| | - Chuhai Xie
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Long Ling
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Hailan Hu
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yanming Cao
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yan Huang
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qingan Zhu
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yue Hua
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
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Thangavelu T, Silverman E, Akhter MP, Lyden E, Recker RR, Graeff-Armas LA. Trabecular bone score and transilial bone trabecular histomorphometry in type 1 diabetes and healthy controls. Bone 2020; 137:115451. [PMID: 32450341 PMCID: PMC7354208 DOI: 10.1016/j.bone.2020.115451] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 04/24/2020] [Accepted: 05/20/2020] [Indexed: 12/11/2022]
Abstract
Patients with type 1 Diabetes Mellitus (T1DM) have an increased risk of fracture. Little is known about the microarchitecture of trabecular bone in T1DM, which may account for some of the increased risk. We report here a secondary analysis comparing Trabecular Bone Score (TBS) derived from DXA to 2-D histomorphometric and 3-D micro-computerized tomography (CT) variables obtained from iliac biopsies in 83 subjects (29 T1DM and 54 controls). The transilial bone biopsy specimens were fixed, embedded and scanned using a desktop micro-CT at 16 μm resolution. They were then sectioned and quantitative histomorphometry was performed. TBS of the anterior/posterior (AP) spine was obtained by re-analysis of AP lumbar spine DXA images. Overall, there were no differences in TBS, histomorphometry or micro-CT measurements between T1DM and controls. There was a significant association between TBS and 2-D BV/TV using multivariable linear regression after adjusting for group, age and gender. For every 1 unit increase in 2-D BV/TV, TBS increases by 0.0036 units after adjusting for group, gender and age. In conclusion, T1DM does not result in abnormal TBS, histomorphometric or micro-CT variables in young T1DM patients in the absence of diabetic complications. TBS is a good surrogate measure for trabecular microarchitecture.
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Affiliation(s)
- Thiyagarajan Thangavelu
- Department of Diabetes, Endocrinology & Metabolism, University of Nebraska Medical Center, United States of America
| | - Emily Silverman
- Department of Diabetes, Endocrinology & Metabolism, University of Nebraska Medical Center, United States of America
| | - Mohammed P Akhter
- Osteoporosis Research Center, Creighton University, United States of America
| | - Elizabeth Lyden
- Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, United States of America
| | - Robert R Recker
- Osteoporosis Research Center, Creighton University, United States of America
| | - Laura A Graeff-Armas
- Department of Diabetes, Endocrinology & Metabolism, University of Nebraska Medical Center, United States of America.
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Mitchell DM, Caksa S, Joseph T, Bouxsein ML, Misra M. Elevated HbA1c Is Associated with Altered Cortical and Trabecular Microarchitecture in Girls with Type 1 Diabetes. J Clin Endocrinol Metab 2020; 105:5639696. [PMID: 31761940 PMCID: PMC7064304 DOI: 10.1210/clinem/dgz221] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 11/22/2019] [Indexed: 12/27/2022]
Abstract
CONTEXT Skeletal fragility is a significant complication of type 1 diabetes (T1D), with an increased risk of fracture observed starting in childhood. Altered bone accrual and microarchitectural development during the critical peripubertal years may contribute to this fragility. OBJECTIVE To evaluate differences in skeletal microarchitecture between girls with T1D and controls and to assess factors associated with these differences. DESIGN Cross-sectional comparison. PARTICIPANTS Girls ages 10-16 years, 62 with T1D and 61 controls. RESULTS Areal bone mineral density (BMD) measured by dual-energy x-ray absorptiometry did not differ between girls with and without T1D. At the distal tibia, trabecular BMD was 7.3 ± 2.9% lower in T1D (P = 0.013), with fewer plate-like and axially-aligned trabeculae. Cortical porosity was 21.5 ± 10.5% higher, while the estimated failure load was 4.7 ± 2.2% lower in T1D (P = 0.043 and P = 0.037, respectively). At the distal radius, BMD and microarchitecture showed similar differences between the groups but did not reach statistical significance. After stratifying by HbA1c, only those girls with T1D and HbA1c > 8.5% differed significantly from controls. P1NP, a marker of bone formation, was lower in T1D while CTX and TRAcP5b, markers of bone resorption and osteoclast number, respectively, did not differ. The insulin-like growth factor 1 (IGF-1) Z-score was lower in T1D, and after adjustment for the IGF-1 Z-score, associations between T1D status and trabecular microarchitecture were largely attenuated. CONCLUSIONS Skeletal microarchitecture is altered in T1D early in the course of disease and among those with higher average glycemia. Suppressed bone formation and lower circulating IGF-1 likely contribute to this phenotype.
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Affiliation(s)
- Deborah M Mitchell
- Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Pediatric Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Correspondence and Reprint Requests: Deborah Mitchell, MD, Endocrine Unit, Massachusetts General Hospital, 50 Blossom St., Boston, MA 02114. Phone: 617-724-2034; Fax: 617-726-1703. E-mail:
| | - Signe Caksa
- Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Taïsha Joseph
- Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Mary L Bouxsein
- Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Center for Advanced Orthopaedic Studies, Beth Israel Deaconness Medical Center and Harvard Medical School, Boston, Massachusetts
| | - Madhusmita Misra
- Pediatric Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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Halper-Stromberg E, Gallo T, Champakanath A, Taki I, Rewers M, Snell-Bergeon J, Frohnert BI, Shah VN. Bone Mineral Density across the Lifespan in Patients with Type 1 Diabetes. J Clin Endocrinol Metab 2020; 105:5611085. [PMID: 31676897 PMCID: PMC7112965 DOI: 10.1210/clinem/dgz153] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 10/29/2019] [Indexed: 01/14/2023]
Abstract
CONTEXT Fracture risk in people with type 1 diabetes (T1D) is higher than their peers without diabetes. OBJECTIVE To compare bone mineral density (BMD) across the lifespan in individuals with T1D and age- and sex-matched healthy controls. DESIGN Cross-sectional. SETTING Subjects (5-71 years) with T1D and matched controls from ongoing research studies at Barbara Davis Center for Diabetes. PATIENTS OR OTHER PARTICIPANTS Participants with lumbar spine BMD by dual X-ray absorptiometry (DXA) were divided into 2 groups: children ≤20 years and adults >20 years. INTERVENTION None. MAIN OUTCOME MEASURES Comparison of BMD by diabetes status across age groups and sex using a linear least squares model adjusted for age and body mass index (body mass index (BMI) for adults; and BMI z-score in children). RESULTS Lumbar spine BMD from 194 patients with T1D and 156 controls were analyzed. There was no difference in age- and BMI-adjusted lumbar spine BMD between patients with T1D and controls: among male children (least squares mean ± standard error of the mean [LSM ± SEM]; 0.80 ± 0.01 vs 0.80 ± 0.02 g/cm2, P = .98) or adults (1.01 ± 0.03 vs 1.01 ± 0.03 g/cm2, P = .95), and female children (0.78 ± 0.02 vs 0.81 ± 0.02 g/cm2, P = .23) or adults (0.98 ± 0.02 vs 1.01 ± 0.02 g/cm2, P = .19). Lumbar spine (0.98 ± 0.02 vs 1.04 ± 0.02 g/cm2, P = .05), femoral neck (0.71 ± 0.02 vs 0.79 ± 0.02 g/cm2, P = .003), and total hip (0.84 ± 0.02 vs 0.91 ± 0.02, P = .005) BMD was lower among postmenopausal women with T1D than postmenopausal women without diabetes. CONCLUSION Across age groups, lumbar spine BMD was similar in patients with T1D compared with age- and sex-matched participants without diabetes, except postmenopausal females with T1D had lower lumbar spine, femoral neck, and total hip BMD.
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Affiliation(s)
- Eitan Halper-Stromberg
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical campus, Aurora, Colorado
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland
| | - Tyler Gallo
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical campus, Aurora, Colorado
- Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Anagha Champakanath
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical campus, Aurora, Colorado
| | - Iman Taki
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical campus, Aurora, Colorado
| | - Marian Rewers
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical campus, Aurora, Colorado
| | - Janet Snell-Bergeon
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical campus, Aurora, Colorado
| | - Brigitte I Frohnert
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical campus, Aurora, Colorado
| | - Viral N Shah
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical campus, Aurora, Colorado
- Correspondence and Reprint Requests: Viral N. Shah, MD, Assistant Professor of Medicine & Pediatrics, Barbara Davis Center for Diabetes, Adult Clinic, School of Medicine, University of Colorado Anschutz Medical Campus, 1775 Aurora Ct, Room M20-1318, Aurora, CO 80045. E-mail:
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Abstract
PURPOSE OF REVIEW The goal of this review is to explore clinical associations between peripheral neuropathy and diabetic bone disease and to discuss how nerve dysfunction may contribute to dysregulation of bone metabolism, reduced bone quality, and fracture risk. RECENT FINDINGS Diabetic neuropathy can decrease peripheral sensation (sensory neuropathy), impair motor coordination (motor neuropathy), and increase postural hypotension (autonomic neuropathy). Together, this can impair overall balance and increase the risk for falls and fractures. In addition, the peripheral nervous system has the potential to regulate bone metabolism directly through the action of local neurotransmitters on bone cells and indirectly through neuroregulation of the skeletal vascular supply. This review critically evaluates existing evidence for diabetic peripheral neuropathy as a risk factor or direct actor on bone disease. In addition, we address therapeutic and experimental considerations to guide patient care and future research evaluating the emerging relationship between diabetic neuropathy and bone health.
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Affiliation(s)
- Alec T Beeve
- Department of Medicine, Division of Bone and Mineral Diseases, Washington University, 660 South Euclid Avenue, Saint Louis, MO, 63110, USA
- Department of Biomedical Engineering, Washington University, 6201 Forsyth Blvd, Saint Louis, MO, 63105, USA
| | - Jennifer M Brazill
- Department of Medicine, Division of Bone and Mineral Diseases, Washington University, 660 South Euclid Avenue, Saint Louis, MO, 63110, USA
| | - Erica L Scheller
- Department of Medicine, Division of Bone and Mineral Diseases, Washington University, 660 South Euclid Avenue, Saint Louis, MO, 63110, USA.
- Department of Biomedical Engineering, Washington University, 6201 Forsyth Blvd, Saint Louis, MO, 63105, USA.
- Department of Cell Biology and Physiology, Washington University, 660 South Euclid Avenue, Saint Louis, MO, 63110, USA.
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Lau S, Lee M. Hyperglycaemia is an under-appreciated but modifiable risk factor in managing people with type 1 diabetes and fragility fractures. Foot (Edinb) 2019; 40:43-45. [PMID: 31082672 DOI: 10.1016/j.foot.2019.04.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 04/09/2019] [Accepted: 04/12/2019] [Indexed: 02/04/2023]
Abstract
There are two major musculoskeletal effects of Type 1 diabetes mellitus (T1DM) - fragility fractures and impaired fracture union. Fractures in these patients are a significant and limb threatening injury. Traditionally, they have been treated with prolonged immobilisation and as rigid as possible internal fixation. Recently, hyperglycaemia has been recognised as the most significant modifiable risk factor in treating patients with T1DM and fractured limbs. This article reviews this association further and outlines the role of orthopaedic surgeons in minimising orthopaedic-related complications.
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Affiliation(s)
- Simon Lau
- Royal Melbourne Hospital, Victoria, Australia.
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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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Chen SC, Shepherd S, McMillan M, McNeilly J, Foster J, Wong SC, Robertson KJ, Ahmed SF. Skeletal Fragility and Its Clinical Determinants in Children With Type 1 Diabetes. J Clin Endocrinol Metab 2019; 104:3585-3594. [PMID: 30848792 DOI: 10.1210/jc.2019-00084] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 03/04/2019] [Indexed: 12/18/2022]
Abstract
CONTEXT Type 1 diabetes (T1D) is associated with an increased fracture risk at all ages. OBJECTIVE To understand the determinants of bone health and fractures in children with T1D. DESIGN Case-control study of children with T1D on bone-turnover markers, dual-energy X-ray absorptiometry, and 3 Tesla-MRI of the proximal tibia to assess bone microarchitecture and vertebral marrow adiposity compared with age- and sex-matched healthy children. RESULTS Thirty-two children with T1D at a median (range) age of 13.7 years (10.4, 16.7) and 26 controls, aged 13.8 years (10.2, 17.8), were recruited. In children with T1D, serum bone-specific alkaline phosphatase (BAP) SD score (SDS), C-terminal telopeptide of type I collagen SDS, and total body (TB) and lumbar spine bone mineral density (BMD) SDS were lower (all P < 0.05). Children with T1D also had lower trabecular volume [0.55 (0.47, 0.63) vs 0.59 (0.47, 0.63); P = 0.024], lower trabecular number [1.67 (1.56, 1.93) vs 1.82 (1.56, 1.99); P = 0.004], and higher trabecular separation [0.27 (0.21, 0.32) vs 0.24 (0.20, 0.33); P = 0.001] than controls. Marrow adiposity was similar in both groups (P = 0.25). Bone formation, as assessed by BAP, was lower in children with poorer glycemic control (P = 0.009) and who were acidotic at initial presentation (P = 0.017) but higher in children on continuous subcutaneous insulin infusion (P = 0.025). Fractures were more likely to be encountered in children with T1D compared with controls (31% vs 19%; P< 0.001). Compared with those without fractures, the T1D children with a fracture history had poorer glycemic control (P = 0.007) and lower TB BMD (P < 0.001) but no differences in bone microarchitecture. CONCLUSION Children with T1D display a low bone-turnover state with reduced bone mineralization and poorer bone microarchitecture.
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Affiliation(s)
- Suet Ching Chen
- Developmental Endocrinology Research Group, School of Medicine, Dentistry & Nursing, University of Glasgow, Glasgow, United Kingdom
- Paediatric Diabetes Service, National Health Service Greater Glasgow and Clyde, Glasgow, United Kingdom
| | - Sheila Shepherd
- Developmental Endocrinology Research Group, School of Medicine, Dentistry & Nursing, University of Glasgow, Glasgow, United Kingdom
| | - Martin McMillan
- Developmental Endocrinology Research Group, School of Medicine, Dentistry & Nursing, University of Glasgow, Glasgow, United Kingdom
| | - Jane McNeilly
- Department of Clinical Biochemistry, Royal Hospital for Children, National Health Service Greater Glasgow and Clyde, Glasgow, United Kingdom
| | - John Foster
- Department of Clinical Physics, National Health Service Greater Glasgow and Clyde, Glasgow, United Kingdom
| | - Sze Choong Wong
- Developmental Endocrinology Research Group, School of Medicine, Dentistry & Nursing, University of Glasgow, Glasgow, United Kingdom
| | - Kenneth J Robertson
- Paediatric Diabetes Service, National Health Service Greater Glasgow and Clyde, Glasgow, United Kingdom
| | - S Faisal Ahmed
- Developmental Endocrinology Research Group, School of Medicine, Dentistry & Nursing, University of Glasgow, Glasgow, United Kingdom
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Carvalho AL, Massaro B, Silva LTPE, Salmon CEG, Fukada SY, Nogueira-Barbosa MH, Elias J, Freitas MCF, Couri CEB, Oliveira MC, Simões BP, Rosen CJ, de Paula FJA. Emerging Aspects of the Body Composition, Bone Marrow Adipose Tissue and Skeletal Phenotypes in Type 1 Diabetes Mellitus. J Clin Densitom 2019; 22:420-428. [PMID: 30100221 DOI: 10.1016/j.jocd.2018.06.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 06/22/2018] [Accepted: 06/26/2018] [Indexed: 12/12/2022]
Abstract
Anthropomorphic measures among type 1 diabetic patients are changing as the obesity epidemic continues. Excess fat mass may impact bone density and ultimately fracture risk. We studied the interaction between bone and adipose tissue in type 1 diabetes subjects submitted to two different clinical managements: (I) conventional insulin therapy or (II) autologous nonmyeloablative hematopoietic stem-cell transplantation (AHST). The study comprised 3 groups matched by age, gender, height and weight: control (C = 24), type 1 diabetes (T1D = 23) and type 1 diabetes treated with AHST (T1D-AHST = 9). Bone mineral density (BMD) and trabecular bone score (TBS) were assessed by dual X-ray absorptiometry (DXA). 1H Magnetic resonance spectroscopy was used to assess bone marrow adipose tissue (BMAT) in the L3 vertebra, and abdominal magnetic resonance imaging was used to assess intrahepatic lipids (IHL), visceral (VAT) and subcutaneous adipose tissue (SAT). Individuals conventionally treated for T1D were more likely to be overweight (C = 23.8 ± 3.7; T1D = 25.3 ± 3.4; T1D-AHST = 22.5 ± 2.2 Kg/m2; p > 0.05), but there was no excessive lipid accumulation in VAT or liver. Areal BMD of the three groups were similar at all sites; lumbar spine TBS (L3) was lower in type 1 diabetes (p < 0.05). Neither SAT nor VAT had any association with bone parameters. Bone marrow adipose tissue (BMAT) lipid profiles were similar among groups. BMAT saturated lipids were associated with cholesterol, whereas unsaturated lipids had an association with IGF1. Overweight and normal weight subjects with type 1 diabetes have normal areal bone density, but lower trabecular bone scores. Adipose distribution is normal and BMAT volume is similar to controls, irrespective of clinical treatment.
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Affiliation(s)
- Adriana L Carvalho
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Bianca Massaro
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Luciana T P E Silva
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Carlos E G Salmon
- Department of Physics, Faculty of Philosophy, Sciences and Arts of Ribeirao Preto, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Sandra Y Fukada
- Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Marcello H Nogueira-Barbosa
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Jorge Elias
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Maria C F Freitas
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Carlos E B Couri
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Maria C Oliveira
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Belinda P Simões
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Clifford J Rosen
- Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, ME, USA
| | - Francisco J A de Paula
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil.
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Bone disorders associated with diabetes mellitus and its treatments. Joint Bone Spine 2019; 86:315-320. [DOI: 10.1016/j.jbspin.2018.08.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/20/2018] [Indexed: 01/02/2023]
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Shen Y, Guo S, Chen G, Ding Y, Wu Y, Tian W. Hyperglycemia Induces Osteoclastogenesis and Bone Destruction Through the Activation of Ca 2+/Calmodulin-Dependent Protein Kinase II. Calcif Tissue Int 2019; 104:390-401. [PMID: 30506439 DOI: 10.1007/s00223-018-0499-9] [Citation(s) in RCA: 8] [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: 07/28/2018] [Accepted: 11/24/2018] [Indexed: 02/07/2023]
Abstract
Hyperglycemia induces osteoclastogenesis and bone resorption through complicated, undefined mechanisms. Ca2+/calmodulin-dependent protein kinase II (CaMKII) promotes osteoclastogenesis, and could be activated by hyperglycemia. Here, we investigated whether CaMKII is involved in hyperglycemia-induced osteoclastogenesis and subsequent bone resorption. Osteoclast formation, bone resorption, CaMKII expression and phosphorylation were measured under high glucose in vitro and in streptozotocin-induced hyperglycemia rats with or without CaMKII inhibitor KN93. The results showed that 25 mmol/L high glucose in vitro promoted cathepsin K and tartrate-resistant acid phosphatase expression (p < 0.05) and osteoclast formation (p < 0.01) associated with enhancing β isoform expression (p < 0.05) and CaMKII phosphorylation (p < 0.001). Hyperglycemia promoted the formation of osteoclasts and resorption of trabecular and alveolar bone, and inhibited sizes of femur and mandible associated with enhanced CaMKII phosphorylation (p < 0.001) in rats. All these changes could be alleviated by KN93. These findings imply that CaMKII participates not only in hyperglycemia-induced osteoclastogenesis and subsequent bone resorption, but also in the hyperglycemia-induced developmental inhibition of bone.
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Affiliation(s)
- Yanxin Shen
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People's Republic of China
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Shujuan Guo
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People's Republic of China
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People's Republic of China
- Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Guoqing Chen
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People's Republic of China
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Yi Ding
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People's Republic of China
- Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Yafei Wu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People's Republic of China.
- Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People's Republic of China.
| | - Weidong Tian
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People's Republic of China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People's Republic of China.
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People's Republic of China.
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Starup-Linde J, Hygum K, Harsløf T, Langdahl B. Type 1 Diabetes and Bone Fragility: Links and Risks. Diabetes Metab Syndr Obes 2019; 12:2539-2547. [PMID: 31819579 PMCID: PMC6899065 DOI: 10.2147/dmso.s191091] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 11/19/2019] [Indexed: 12/21/2022] Open
Abstract
Type 1 diabetes (T1D) is associated with an increased fracture risk, which is present at young and old age. Reductions in bone mineral density do not explain the increased fracture risk. Novel scanning modalities suggest that structural deficits may contribute to the increased fracture risk. Furthermore, T1D may due to insulinopenia be a state of low bone turnover. However, diabetes complications and comorbidities may influence fracture risk. Patients with T1D are fearful of falls. The diabetes related complications, hypoglycemic events, and antihypertensive treatment may all lead to falls. Thus, the increased fracture risk in T1D seems to be multifactorial, and earlier intervention with antiosteoporotic medication and focus on fall prevention is needed. This systematic review addresses the epidemiology of fractures and osteoporosis in patients with T1D and the factors that influence fracture risk.
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Affiliation(s)
- Jakob Starup-Linde
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
- Department of Medicine, Region Hospital Horsens, Aarhus, Denmark
- Correspondence: Jakob Starup-Linde Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, Aarhus NDK-8200, DenmarkTel +45 29926952 Email
| | - Katrine Hygum
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Torben Harsløf
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Bente Langdahl
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
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Dhaliwal R, Foster NC, Boyle C, Al Mukaddam M, Weinstock RS, Rickels MR, Shah VN, DiMeglio LA. Determinants of fracture in adults with type 1 diabetes in the USA: Results from the T1D Exchange Clinic Registry. J Diabetes Complications 2018; 32:1006-1011. [PMID: 30220582 DOI: 10.1016/j.jdiacomp.2018.08.016] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 08/27/2018] [Accepted: 08/29/2018] [Indexed: 02/07/2023]
Abstract
AIMS To examine the prevalence/determinants of fracture in the T1D Exchange Clinic Registry. RESEARCH DESIGN/METHODS Adults (≥18 years) with T1D duration ≥5 years, diagnosed before age 45 years completed a fracture questionnaire. Additional characteristics were collected from registry data. Only fractures reported as occurring after T1D diagnosis were included. Characteristics were compared between those with and without fractures. RESULTS Respondents included 756 adults (mean age 39 ± 16 years, 28% ≥50 years, 63% female, 90% non-Hispanic White, diabetes duration 24 ± 14 years); 48% reported ≥1 fracture since diagnosis. Of the 659 reported fractures, 24% involved metatarsal/toe, 21% metacarpal/fingers, 14% fibula/tibia, 5% hip/pelvis/femur and 3% vertebrae. Those with fracture were more likely to be older (43 ± 16 vs. 36 ± 14 years), have longer T1D duration (28 ± 14 vs. 20 ± 12 years), been diagnosed with T1D before age 20 years (79% vs. 71%) compared to those without fracture (all p-values < 0.01). CONCLUSIONS Data from this national sample suggest fractures in adults with T1D are common at young age and frequently involve peripheral sites. Age, longer diabetes duration, and T1D diagnosis prior to peak bone mass accrual are notable risk factors. Further research is needed to examine the impact of these determinants on fracture risk in T1D.
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Affiliation(s)
- Ruban Dhaliwal
- SUNY Upstate Medical University, Syracuse, NY, United States of America
| | - Nicole C Foster
- Jaeb Center for Health Research, Tampa, FL, United States of America
| | - Claire Boyle
- Jaeb Center for Health Research, Tampa, FL, United States of America.
| | - Mona Al Mukaddam
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States of America
| | - Ruth S Weinstock
- SUNY Upstate Medical University, Syracuse, NY, United States of America
| | - Michael R Rickels
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States of America
| | - Viral N Shah
- Barbara Davis Center for Diabetes, Aurora, CO, United States of America
| | - Linda A DiMeglio
- Indiana University School of Medicine, Indianapolis, IN, United States of America
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Wierzbicka E, Swiercz A, Pludowski P, Jaworski M, Szalecki M. Skeletal Status, Body Composition, and Glycaemic Control in Adolescents with Type 1 Diabetes Mellitus. J Diabetes Res 2018; 2018:8121634. [PMID: 30250851 PMCID: PMC6140037 DOI: 10.1155/2018/8121634] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 07/13/2018] [Accepted: 08/08/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Disturbed bone turnover, osteoporosis, and increased fracture risk are late complications of insulin-dependent diabetes mellitus. Little is known about how far and to what extent can glycaemic control of type 1 diabetes mellitus (T1DM) prevent disturbances of bone health and body composition during the growth and maturation period. OBJECTIVE The aim of this cross-sectional study was to compare the skeletal status outcomes and body composition between patients stratified by glycaemic control (1-year HbA1c levels) into well- and poorly-controlled subgroups in a population of T1DM adolescents, that is, <8% and ≥8%, respectively. SUBJECTS AND METHODS Skeletal status and body composition were evaluated in 60 adolescents with T1DM (53.3% female; mean aged: 15.1 ± 1.9 years; disease duration: 5.1 ± 3.9 years) using dual energy X-ray absorptiometry (GE Prodigy). The results were compared to age- and sex-adjusted reference values for healthy controls. The calculated Z-scores of different metabolic control subgroups were compared. Clinical data was also assessed. RESULTS As evidenced by Z-scores, patients with T1DM revealed a significantly lower TBBMD (total body bone mineral density), TBBMC (total body bone mineral content), S24BMD (bone mineral density of lumbar spine L2-L4), and TBBMC/LBM ratio (total body bone mineral content/lean body mass), but higher FM (fat mass) and FM/LBM ratio (fat mass/lean body mass) values compared to an age- and sex-adjusted general population. The subset (43.3% patients) with poor metabolic control (HbA1c ≥ 8%) had lower TBBMD, TBBMC, and LBM compared to respective values noted in the HbA1c < 8% group, after adjusting for confounders (mean Z-scores: -0.74 vs. -0.10, p = 0.037; -0.67 vs. +0.01, p = 0.026; and -0.45 vs. +0.20, p = 0.043, respectively). Additionally, we found a significant difference in the TBBMC/LBM ratio (relative bone strength index) between the metabolic groups (-0.58 vs. -0.07; p = 0.021). A statistically significant negative correlation between 1-year HbA1c levels and Z-scores of TBBMD, TBBMC, and LBM was also observed. In patients with longer disease duration, a significant negative correlation was established only for TBBMD, after adjusting for confounders. The relationships between densitometric values and age at onset of T1DM and sex were not significant and showed no relation to any of the analysed parameters of the disease course. CONCLUSION Findings from this study of adolescents with T1DM indicate that the lower Z-scores of TBBMD, TBBMC, and LBM as well as the TBBMC/LBM ratio are associated with increased HbA1c levels. Their recognition can be crucial in directing strategies to optimise metabolic control and improve diabetes management for bone development and maintenance in adolescents with T1DM.
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Affiliation(s)
- Elzbieta Wierzbicka
- Department of Human Nutrition, Warsaw University of Life Sciences (SGGW), Warsaw, Poland
| | - Anna Swiercz
- Department of Endocrinology and Diabetology, The Children's Memorial Health Institute, Warsaw, Poland
| | - Pawel Pludowski
- Department of Biochemistry, Radioimmunology, and Experimental Medicine, The Children's Memorial Health Institute, Warsaw, Poland
| | - Maciej Jaworski
- Department of Biochemistry, Radioimmunology, and Experimental Medicine, The Children's Memorial Health Institute, Warsaw, Poland
| | - Mieczyslaw Szalecki
- Department of Endocrinology and Diabetology, The Children's Memorial Health Institute, Warsaw, Poland
- Faculty of Medicine and Health Sciences, Jan Kochanowski University, Kielce, Poland
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Abstract
PURPOSE OF REVIEW This article reviews recent publications on the effect of type 1 diabetes (T1D) on fracture risk, bone mineral density (BMD), bone structure, and bone tissue quality. Possible fracture prevention strategies for patients with T1D have also been reviewed. RECENT FINDINGS T1D is associated with substantially elevated fracture risk and modestly low BMD at the femoral neck. However, BMD alone does not explain higher observed fracture risk in T1D. T1D also affects bone macro- and microstructure, characterized by thinner cortices and trabecular bone changes such as thinner and more widely spaced trabeculae. Structural bone deficit is pronounced in the presence of microvascular complications. Tissue-level changes, such as accumulation of advanced glycation endproducts, detrimental alterations of the mineral phase because of low bone turnover, and occlusion of vascular channels in bone by mineralized tissue, are implicated in pathophysiology of bone fragility in T1D. There are no guidelines on screening and prevention of osteoporotic fractures in T1D. SUMMARY More studies are needed to understand the influence of T1D on structural bone quality and tissue material properties. There is a need for a prospective study to evaluate better screening strategies for diagnosis and treatment of osteoporosis in T1D.
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Affiliation(s)
- Viral N. Shah
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - R. Dana Carpenter
- Department of Mechanical Engineering, University of Colorado Denver, San Francisco, California, USA
| | - Virginia L. Ferguson
- Department of Mechanical Engineering, University of Colorado Boulder, San Francisco, California, USA
| | - Ann V. Schwartz
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA
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