Perspective on post-menopausal osteoporosis: establishing an interdisciplinary understanding of the sequence of events from the molecular level to whole bone fractures

Abstract

Current drug treatments for post-menopausal osteoporosis cannot eliminate bone fractures, possibly because the mechanisms responsible for bone loss are not fully understood. Although research within various disciplines has significantly advanced the state of knowledge, fundamental findings are not widely understood between different disciplines. For that reason, this paper presents noteworthy experimental findings from discrete disciplines focusing on post-menopausal osteoporosis. These studies have established that, in addition to bone loss, significant changes in bone micro-architecture, tissue composition and micro-damage occur. Cellular processes and molecular signalling pathways governing pathological bone resorption have been identified to a certain extent. Ongoing studies endeavour to determine how such changes are initiated at the onset of oestrogen deficiency. It emerges that, because of the discrete nature of previous research studies, the sequence of events that lead to bone fracture is not fully understood. In this paper, two sequences of multi-scale changes are proposed and the experimental challenges that need to be overcome to fully define this sequence are outlined. Future studies must comprehensively characterize the time sequence of molecular-, cellular- and tissue-level changes to attain a coherent understanding of the events that ultimately lead to bone fracture and inform the future development of treatments for post-menopausal osteoporosis.

Figure 1.

Contribution of bone mass and bone quality in load bearing in normal bone; bone strength is determined by bone mass, morphology, micro-architecture, tissue composition and micro-damage (micro-damage image courtesy of Professor F. J. O'Brien, Royal College of Surgeons in Ireland).

Figure 2.

(a) Primary sequence of events; molecules governing osteoclast activity are upregulated leading to increased osteoclastogenesis, while molecules inhibiting osteoclasts are downregulated. These events reduce apoptosis and result in excess bone resorption. (b) Secondary responses to bone loss; mechanical loading on the remaining tissue is increased and tissue mineralization is altered to compensate for bone loss. Increased mineralization may dissociate collagen or non-collagenous protein bonds and lead to damage accumulation and ultimately bone fracture. Feedback mechanisms are indicated by dashed lines. Unfilled rectangle, in vitro; filled rectangle, osteoporosis/OVX.

Figure 3.

(a) Primary sequence of events; genetic and molecular regulators of osteoblasts alter their activity to increase the production of proteins that govern osteoblastogenesis, tissue mineralization and collagen synthesis, which subsequently alters tissue stiffness. (b) Secondary responses; as a consequence of increased stiffness the mechanical loading to osteocytes reduces and, in response, osteoclastic resorption occurs to remove excess bone tissue. The changes in collagen cross-linking and damage accumulation ensue as a result of increased mineral and these events culminate and increase the fracture susceptibility of the tissue. Feedback mechanisms are indicated by dashed lines. Unfilled rectangle, in vitro; filled rectangle, osteoporosis/OVX.