Abstract
Bone mass is determined by the relative balance of action between osteoblasts, which deposit bone matrix, and osteoclasts, which resorb bone matrix. Imbalance in these actions leads to conditions of high or low bone mass. Osteoporosis, i.e., low bone mass, is a common medical condition that places individuals at elevated risk of fracture and greater likelihood of disability, loss of independence, and death. Both anti-resorptive and anabolic medications are available and are generally successful at stabilizing and/or promoting gains in bone mass. However, each current medication has significant drawbacks which present considerable challenges for the long-term management of this chronic condition. Unfortunately, there are few new candidate therapies in the drug development pipeline. This underscores a need for identifying new treatment targets for increasing bone mass, particularly for novel pathways lacking a therapeutic modality in development. However, a report from 2018 identified a striking lack of heterogeneity among molecular pathways studied in the bone remodeling field, with just three pathways accounting for more than 50% of publications and 46% of United States National Institutes of Health-funded grants. Here, we update the prior analysis to 2018-2022 to a) examine the heterogeneity of molecular pathways studied in the bone remodeling field in that time and b) determine if new functional evidence has emerged for additional lesser-known pathways which might hold therapeutic potential. Our results reveal a sustained lack of diversity in research that may restrict discovery of novel therapeutic approaches. We call for an expansion into lesser-studied pathways to broaden the collective focus of the field and highlight several pathways for which functional evidence supports a role in the regulation of bone remodeling. Future work is required to determine therapeutic potential and elucidate the mechanism(s) by which these pathways intersect with the complicated signal transduction network underlying bone remodeling.