The complex pathophysiology of bone fragility in obesity and type 2 diabetes mellitus: therapeutic targets to promote osteogenesis

Abstract

Fractures associated with Type2 diabetes (T2DM) are major public health concerns in an increasingly obese and aging population. Patients with obesity or T2DM have normal or better than normal bone mineral density but at an increased risk for fractures. Hence it is crucial to understand the pathophysiology and mechanism of how T2DM and obesity result in altered bone physiology leading to increased fracture risk. Although enhanced osteoclast mediated bone resorption has been reported for these patients, the most notable observation among patients with T2DM is the reduction in bone formation from mostly dysfunction in osteoblast differentiation and survival. Studies have shown that obesity and T2DM are associated with increased adipogenesis which is most likely at the expense of reduced osteogenesis and myogenesis considering that adipocytes, osteoblasts, and myoblasts originate from the same progenitor cells. Furthermore, emerging data point to an inter-relationship between bone and metabolic homeostasis suggesting that these physiologic processes could be under the control of common regulatory pathways. Thus, this review aims to explore the complex mechanisms involved in lineage differentiation and their effect on bone pathophysiology in patients with obesity and T2DM along with an examination of potential novel pharmacological targets or a re-evaluation of existing drugs to improve bone homeostasis.

Links among Obesity, Type 2 Diabetes Mellitus, and Osteoporosis: Bone as a Target

“…Moreover, factors that are secreted by bone marrow adipocytes (e.g., adipokines, pro-inflammatory and immunoregulatory cytokines, and receptor activator of nuclear factor kappa beta ligand (RANKL)) may also contribute to altered skeletal homeostasis after bone marrow adipose tissue expansion [9,45]. In addition, accumulation of senescent cells and elevated levels of oxidative stress in the bone microenvironment in obesity and T2DM are among factors that may participate in bone marrow stromal cell dysfunction and cause a shift in bone marrow stromal cell differentiation phenotype that favors adipogenesis over osteogenesis [2]. The expansion of bone marrow adipose tissue was observed in bone biopsies from obese elderly men [46].…”

“…However, for Asians, obesity is defined as a BMI greater than or equal to 25 kg/m 2 . It is predicted that by 2030, 20% of women, 14% of men, and more than 1 billion people will be living with obesity [1][2][3]. Obesity is the most important risk factor for T2DM, which is characterized by chronic hyperglycemia, insulin resistance, and inefficient insulin secretion and action.…”

“…In general, obesity and T2DM are linked to normal or higher BMD; however, paradoxically, both aforementioned conditions are associated with an elevated risk of fragility fractures at specific sites. In the case of obesity, this phenomenon is denoted by the term "obesity paradox" [1,2]. The aim of this review was to summarize the interactions among obesity, T2DM, and osteoporosis, considering bone as a target organ.…”

Trabecular Bone Score (TBS) in Individuals with Type 2 Diabetes Mellitus: An Updated Review

“…Additionally, we mention further topics to explore such as the results of murine experiments showing linagliptin and metformin protective effects against bone loss [131] (one of the pathogenic traits being metformin-induced down regulation of RAGE-JAK2-STAT1 signal transduction pathway) [132]. Also, the metabolic components other than the anomalies of glucose profile, such as obesity, chronic steatosis, and abnormal lipid status might add a supplementary influence on bone damage that may be additional to insulin resistance, hyperinsulinemia, and increased blood glycemia together with the potential impairment of mineral metabolism [133][134][135].…”

Evaluating the correlation of sclerostin levels with obesity and type 2 diabetes in a multiethnic population living in Kuwait

“…Both obesity and T2DM are complex metabolic disorders of multifaceted etiology accompanied by a series of complications, including macrovascular diseases (hypertension, hyperlipidemia, heart attacks, coronary artery disease, strokes, cerebral vascular disease, and peripheral vascular disease), microvascular diseases (retinopathy, nephropathy, and neuropathy), and cancers ( 6 ). Recently, studies have shown that bone health is also compromised in people with obesity and T2DM ( 7 ).…”