Advanced Glycation End Products, Diabetes, and Bone Strength

Yamamoto, Masahiro; Sugimoto, Toshitsugu

doi:10.1007/s11914-016-0332-1

Cited by 164 publications

(135 citation statements)

References 75 publications

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“…Advanced glycation end products (AGEs) are compounds generated through non‐enzymatic reactions occurring between sugars and amine residues. In diabetes, where glucose levels are elevated, AGEs are deposited in many tissues, including bone . AGEs are associated with increased bone fragility in diabetes; thus, by lowering glucose levels, insulin may help to decrease accumulation of AGEs in bone .…”

Section: Drugs and Bonementioning

confidence: 99%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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Summary Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age‐matched persons without diabetes, attributed to disease‐specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin‐based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall‐related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo‐anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium‐dependent glucose co‐transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes‐related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.

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Section: Drugs and Bonementioning

confidence: 99%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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“…The cross‐sectional design also limits our ability to infer causality, so future prospective studies will help progress this line of questioning. Additionally, we relied on serum pentosidine as a measure of AGEs, but other AGEs such as N‐carboxymethyl‐lysine and endogenous AGE receptors are also relevant to bone health . Noninvasive measures of AGEs such as SAF might be useful in the pediatric setting.…”

Section: Discussionmentioning

confidence: 99%

Pentosidine Is Associated With Cortical Bone Geometry and Insulin Resistance in Otherwise Healthy Children

Kindler

Laing

Liu

et al. 2019

Journal of Bone and Mineral Research

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Pentosidine is an advanced glycation end product (AGE) associated with fracture in adults with diabetes. AGE accumulation in bone collagen contributes to bone fragility but might also adversely influence bone turnover and, consequently, bone geometry. The relationships between AGEs and bone health have yet to be studied in children. Thus, the objective of this study was to assess relationships between pentosidine and cortical bone volumetric density, geometry, and estimated strength in children. Participants were otherwise healthy black and white boys and girls, ages 9 to 13 years, who were at sexual maturation stage 2 or 3 (N = 160). Tibia and radius cortical bone and muscle area (66% site) were assessed via pQCT. In fasting sera, insulin, glucose, and pentosidine were measured. The Quantitative Insulin Sensitivity Check Index (QUICKI), a measure of insulin sensitivity, was calculated. While controlling for race, sex, maturation, and height, pentosidine negatively correlated with QUICKI (P < 0.05). In unadjusted analyses, pentosidine was associated with lower radius and tibia cortical volumetric bone mineral density, bone mineral content (Ct.BMC), area (Ct.Ar), and thickness (Ct.Th); a larger radius endosteal circumference (Endo.Circ); and lower tibia polar strength strain index (all P < 0.05). While controlling for race, sex, maturation, height, and muscle area, pentosidine was negatively associated with tibia Ct.BMC, Ct.Ar, and Ct.Th but positively associated with Endo.Circ (all P < 0.05). Linear regression revealed a significant interaction between pentosidine and QUICKI in relation to tibia Ct.Th (pinteraction = 0.049), indicating that the negative relationship between pentosidine and Ct.Th was stronger in those with lower QUICKI (ie, greater insulin resistance). This is the first study to report evidence of a potentially adverse influence of AGEs on bone strength in otherwise healthy children. This relationship was strongest in children with the greatest insulin resistance, supporting further work in youth with chronic metabolic health conditions. © 2019 American Society for Bone and Mineral Research.

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“…Where the reduction in bone turnover accounts for the increased bone mass in T2DM, hyperglycaemia contributes to the aggregation of advanced glycation end products (AGEs) in bone, compromising bone strength and quality in both T1DM and T2DM. Normally, enzymatic collagen cross‐linking contributes to bone strength and scaffolding via an increase in collagen stiffness . However, it is the undesirable non‐enzymatic cross‐links that result in the modification of the bone's extracellular matrix resulting in bone brittleness .…”

Section: Bone Defects In Diabetic Patientsmentioning

confidence: 99%

“…Two prominent AGEs produced in collagen fibres are pentosidine (PEN) and carboxymethyl lysine, and they have a negative impact on bone health through multiple mechanisms: via modification of the bone matrix, by binding to the receptor for AGE (RAGE) and via the production of reactive oxygen intermediates . Hyperglycaemia and AGEs have been correlated with the suppression of osteoblast differentiation, the induction of osteoblast apoptosis, promoting bone resorption by osteoclast and IL‐6 production . This was evidenced in vitro whereby the addition of AGE in a culture of unfractionated bone cells on dentin slices displayed a significant increase in the number of osteoclast‐generated resorption pits .…”

Section: Bone Defects In Diabetic Patientsmentioning

confidence: 99%

“…In addition, an increase in RAGE numbers was observed in the healing bone tissue of diabetic animals . AGEs are an agonist for RAGE whereby the AGE‐RAGE complex is associated with a reduction in bone turnover and bone deterioration . The endogenous secretory RAGE (esRAGE) is a decoy receptor and functions by binding to AGE and inhibiting intracellular signals via RAGE activation .…”

Section: Bone Defects In Diabetic Patientsmentioning

confidence: 99%

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Weak bones in diabetes mellitus – an update on pharmaceutical treatment options

Lin

Dass

2018

Journal of Pharmacy and Pharmacology

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Objectives Diabetes mellitus is often associated with a number of complications such as nephropathy, neuropathy, retinopathy and foot ulcers. However, weak bone is a diabetic complication that is often overlooked. Although the exact mechanism for weak bones within diabetes mellitus is unclear, studies have shown that the mechanism does differ in both type I (T1DM) and type II diabetes (T2DM). This review, however, investigates the application of mesenchymal stem cells, recombinant human bone morphogenetic protein-2, teriparatide, insulin administration and the effectiveness of a peroxisome proliferator-activated receptor-ϒ modulator, netoglitazone in the context of diabetic weak bones. Key findings In T1DM, weak bones may be the result of defective osteoblast activity, the absence of insulin's anabolic effects on bone, the deregulation of the bone-pancreas negative feedback loop and advanced glycation end product (AGE) aggregation within the bone matrix as a result of hyperglycaemia. Interestingly, T2DM patients placed on insulin administration, thiazolidinediones, SGLT2 inhibitors and sulfonylureas have an associated increased fracture risk. T2DM patients are also observed to have high sclerostin levels that impair osteoblast gene transcription, AGE aggregation within bone, which compromises bone strength and a decrease in esRAGE concentration resulting in a negative association with vertebral fractures. Summary Effective treatment options for weak bones in the context of diabetes are currently lacking. There is certainly scope for discovery and development of novel agents that could alleviate this complication in diabetes patients.

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Advanced Glycation End Products, Diabetes, and Bone Strength

Cited by 164 publications

References 75 publications

Diabetes pharmacotherapy and effects on the musculoskeletal system

Diabetes pharmacotherapy and effects on the musculoskeletal system

Pentosidine Is Associated With Cortical Bone Geometry and Insulin Resistance in Otherwise Healthy Children

Weak bones in diabetes mellitus – an update on pharmaceutical treatment options

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