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

Siresha Bathina, Reina Armamento-Villareal, Siresha Bathina, Reina Armamento-Villareal

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.

Keywords: adipogenesis; diabetes; myogenesis; obesity; osteogenesis.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2023 Bathina and Armamento-Villareal.

Figures

Figure 1
Figure 1
Schematic proposal of pathophysiology of bone fragility in Obesity and T2DM. Even though underlying mechanisms are unclear, both T2DM and Obesity causes oxidative stress and inflammation. T2DM causes the accumulation of AGEs with increased oxidative stress leading to osteoblast dysfunction and reduced bone formation (i.e. reduced Runx2 and OCN) followed by increasing bone fragility. On the other hand, obesity is associated with increased pro-inflammatory markers and pro-resorptive factors such as RANKL, TRAP5b. However, whether obesity by itself has any effect on osteoblastic function is unclear. Altogether, the above contribute to simultaneous effect on bone tissue homeostasis leading to bone fragility15-21.
Figure 2
Figure 2
Proposed effect of T therapy in Obesity. Binding of testosterone might initiate the PPARγ-Prdm16-Pgc1a complex with retinoid X receptor (RXR) which not only activates the browning of adipose tissue by re-programming but may also activate the myogenic cascade and runx2 gene involved osteogenesis. Thus, T therapy with its activator Prdm16 might be a novel therapeutic target and research on this transcriptional activator needs to be consider.

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