The Bone Beat

Understanding and Combating Bone Loss in Elderly Men

Bone loss and the weakening of bone structure are serious concerns for elderly men, significantly increasing their risk of fractures and, unfortunately, higher mortality rates. While testosterone (Tes) has long been suspected of playing a protective role in bone health, the precise ways it works have remained a mystery – until now.

Unveiling the Mechanisms of Male Bone Loss

Recent research has shed new light on how bone loss manifests in elderly men and the critical role of testosterone. Bone microarchitectural analysis reveals that older men experience a reduction in both the outer (cortical) and inner (trabecular) bone thickness. Importantly, increased porosity in the cortical bone, particularly in the upper part of the hip near the joint, was also observed.

A comprehensive study of 352 individuals further solidified the link between testosterone and bone health. The findings show that low testosterone levels (below 9.415 nmol·L−1) are associated with a higher risk of bone loss.

The Testosterone-AR-TNC Axis: A Key Discovery

To understand the “how” behind testosterone’s influence, researchers turned to in vivo studies. Mice genetically engineered to lack the osteoblastic androgen receptor (AR) – a protein that testosterone binds to in bone-forming cells – showed similar bone deterioration in their femurs (thigh bones) when subjected to conditions mimicking bone loss (tail-suspension). They exhibited decreased trabecular bone and increased cortical porosity, mirroring the human observations.

This groundbreaking research identified a crucial pathway: Testosterone enhances the differentiation of osteoblasts (bone-forming cells) through an AR-mediated upregulation of a protein called tenascin-C (TNC).

TNC: A Shield Against Bone Breakdown

The study further delved into the mechanism by which TNC protects bone. Molecular modeling suggests that a specific part of TNC, its fibrinogen C-terminal domain, actively inhibits the formation and activity of osteoclasts (bone-resorbing cells). It does this by binding to integrin αV, a protein on osteoclasts, effectively blocking the adhesion of other proteins that would otherwise promote bone breakdown.

To validate this finding, a synthetic peptide (pep2) was created to mimic this protective TNC domain. Remarkably, this peptide was able to preserve bone architecture in the genetically modified mice lacking the androgen receptor and experiencing bone loss, highlighting its therapeutic potential.

A New Biomarker for Bone Loss

The research also identified a promising new biomarker. Elevated levels of serum extracellular vesicle amyloid precursor protein were observed, secondary to the decline in the Tes-AR-TNC pathway and the overactivation of osteoclasts. When combined with low testosterone levels, this protein emerged as a significant indicator of bone loss.

Looking Forward: New Avenues for Intervention

This study marks a significant step forward in our understanding of male bone remodeling. By identifying the Testosterone-AR-TNC axis as a key regulator of bone health in men, it offers invaluable insights for:

• Improved fracture risk assessment: Understanding this pathway can help clinicians better predict who is at higher risk of bone fractures.
• Targeted interventions: This discovery opens new doors for developing therapies that specifically target the Tes-AR-TNC axis to prevent and treat bone destruction in elderly men.

We are excited about the potential of these findings to improve the lives of elderly men by offering new strategies to combat bone loss and maintain strong, healthy bones.

Stay tuned for more updates on advances in bone health research!