Advanced glycation endproducts and bone quality: practical implications for people with type 2 diabetes

Abstract

Purpose of review Individuals with type 2 diabetes (T2D) are at increased risk of fracture, often despite normal bone density. This observation suggests deficits in bone quality in the setting of abnormal glucose homeostasis. The goal of this article is to review recent developments in our understanding of how advanced glycation end products (AGEs) are incorporated into the skeleton with resultant deleterious effects on bone health and structural integrity in patients with T2D. Recent findings The adverse effects of skeletal AGE accumulation on bone remodeling and the ability of the bone to deform and absorb energy prior to fracture have been demonstrated both at the bench as well as in small human studies; however, questions remain as to how these findings might be better explored in large, population-based investigations. Summary Hyperglycemia drives systemic, circulating AGE formation with subsequent accumulation in the bone tissue. In those with T2D, studies suggest that AGEs diminish fracture resistance, though larger clinical studies are needed to better define the direct role of longstanding AGE accumulation on bone strength in humans as well as to motivate potential interventions to reverse or disrupt skeletal AGE deposition with the goal of fracture prevention.

Effects of diabetes on osteocytes

“…In addition to directly causing bone damage, AGEs bind their receptor (RAGE) in multiple tissues to over-activate RAGE signaling in several diverse cell types. For example, AGEs can bind to RAGE on the surface of osteoblasts and osteocytes [57], thereby generating inflammation, causing osteocyte dysfunction, and potentially contributing to the development of T2D and its complications [56]. Recently, our group used mass spectrometry to show that Nε-(1-CarboxyMethyl)-L-lysine (CML), one of the most dominant AGEs [58], accumulates excessively in osteocyte-enriched bone samples and serum of young adult obese mice with T2D [53 ▪▪ ].…”

“…Alongside the premature accumulation of senescent cells, metabolic dysfunction with T2D additionally causes AGEs to form in multiple tissues throughout the body via sugar-mediated nonenzymatic glycation of long-lived proteins [57]. Collagen in bone is particularly vulnerable to AGE accumulation, which can alter the biomechanical and material properties of the skeleton [57]. In addition to directly causing bone damage, AGEs bind their receptor (RAGE) in multiple tissues to over-activate RAGE signaling in several diverse cell types.…”

Bone Structure and Turnover in Postmenopausal Women With Long‐Standing Type 1 Diabetes

“…Chronic hyperglycemia and accumulation of advanced glycation end products have been implicated as potential reasons for low bone formation in people with diabetes. (27,28) Most but not all studies using HR-pQCT have reported microstructural deterioration of trabecular bone and reduced cortical thickness at the distal radius among people with T1D (29)(30)(31)(32) and such changes are more pronounced in those who have microvascular disease. (29,31) However, our study and a previous study (14) using gold standard histomorphometry did not demonstrate any differences in bone structure.…”

“…Chronic hyperglycemia and accumulation of advanced glycation end products have been implicated as potential reasons for low bone formation in people with diabetes. ( 27,28 )…”

Skeletal health in diabetes

“…Swanson [8] reviewed recent publications demonstrating that sleep disruptions may be associated with low bone formation and increased fracture risk. In that issue, two reviews were dedicated on highlighting chronic hyperglycemia leading to increased advanced glycation endproducts (AGEs) accumulation and its possible implication on tissue material properties and skeletal fragility in people with diabetes [9,10]. It is also currently debatable whether skeletal fragility should be considered as a complication or comorbidity related to diabetes [11].…”