Advances in the molecular pharmacology of bone and cancer‐related bone diseases

Over recent years, our understanding of the mechanisms that drive bone disorders has dramatically increased, supported by advances in technology that facilitate the dissection of the cellular and molecular crosstalk that underpins disease pathogenesis. This has translated to the clinic, with new treatment modalities emerging, alongside research efforts to optimise existing therapies. This BJP themed issue focussing on the molecular pharmacology of bone and cancerrelated bone diseases arose from a conference held at St Catherine's College in Oxford in 2018 entitled “The 8th International Workshop on Advances in the Molecular Pharmacology and Therapeutics of Bone and Other Musculoskeletal Diseases” and the “Cancer and Bone Society 2018 Meeting. ” The themed issue contains a number of in-depth review articles across a spectrum from basic science through to patient care, all addressing key advances in musculoskeletal research. Osteoporosis is one of the most prevalent diseases in our society, with a worldwide impact on more than 200 million patients, who suffer from reduced bone mass and fractures. Pharmacological approaches target either bone resorption, bone formation, or both. These different mechanisms of action result in different clinical responses. For example, a greater response in bone mineral density (BMD) is observed in patients with severe osteoporosis receiving treatments that stimulate bone formation such as parathyroid hormone or romosozumab (anti-sclerostin antibody) as compared to anti-resorptives, such as bisphosphonates or denosumab (anti-RANKL antibody). The review article by Bente Langdahl (2021) provides a comprehensive overview of the currently available treatments for osteoporosis and discusses unmet medical needs and the move towards a personalised or optimised approach to such treatments to achieve maximum benefit. For patients with skeletal malignancies, cancer-induced bone disease is a major clinical feature, increasing fracture risk and causing severe bone pain in patients with solid tumour metastases, such as in breast and prostate cancer with bone metastases. In the haematological malignancy of multiple myeloma, the osteolytic bone disease is exacerbated by suppression of bone formation. This has a major clinical effect, as the majority of patients present with bone disease, treatment with anti-resorptives can be effective to prevent further bone loss but is unable to repair existing bone loss. As such, an improved understanding and clinical targeting of osteoblast suppression are imperative. This is elegantly discussed by Marino et al. (2021), describing the underlying cellular mechanisms that are dysregulated and current anti-resorptives, followed by a detailed discussion of the potential for bone anabolic agents and novel approaches that are emerging in the preclinical setting and show promise for translation to the clinic. The challenge of repairing existing bone lesions is a key area in the context of cancer-induced bone disease, with the potential to have a huge effect on patient quality of life. One of the key mechanisms driving cancer-induced bone disease is known to be parathyroid hormone-related protein. This protein is expressed by late-stage cancer cells that up-regulate RANKL and drives the osteolytic component of cancer-induced bone disease. Interestingly, more recently, parathyroid hormone-related protein has been found to have multiple roles including a protective effect in early breast cancer and a role in tumour dormancy. Mechanistic studies have identified multiple mechanisms, involving canonical signalling through the parathyroid-1 receptors, and non-canonical, mediated through distinct parathyroid hormone-related protein domains. Martin and Johnson (2021) provide an in-depth review of these distinct mechanisms and roles of parathyroid hormone-related protein at different disease stages, so expanding our traditional way of thinking and opening up new avenues for targeting this molecule. For the majority of patients, bone metastases are ultimately fatal, and so increasing our understanding of the mechanisms underlying this metastatic progression is vital to develop new therapeutic approaches. Non-coding RNAs represent one such approach and, while they were first identified in the 1990s, their importance as biological regulators were not recognised until the early 2000s. There is increasing evidence to demonstrate the importance of non-coding RNAs (including long ncRNAs, microRNAs, and circular RNAs) in bone remodelling and bone metastasis, as detailed by Puppo et al. (2021). Furthermore, they not only represent potential therapeutic targets but also biomarkers. The ability to predict those patients at greatest risk of fatal bone metastases is currently challenging and, as such, the prognostic potential for non-coding RNAs is incredibly exciting. LINKED ARTICLES: This article is part of a themed issue onThe molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley. com/doi/10.1111/bph.v178. 9/issuetoc DOI: 10.1111/bph.15431