Osteoporosis is the most common age-related bone disease which affects hundreds of millions of individuals worldwide. It is estimated that one in three women and one in five men aged over 50 suffer from osteoporotic bone fractures. Osteoporosis is caused by excessive activity of bone resorbing cells, while activity of bone-forming cells is reduced. In healthy individuals, a balanced activity of these two cell types allows constant bone turnover. In osteoporosis, disproportionate bone resorption leads to low bone mineral density and consequently weak and fracture-prone bones. When new bone formation is unable to catch up with bone loss, bone eventually weakens, and becomes more prone to fractures. Most current osteoporosis therapies include the use of bisphosphonates, which block the activity of bone resorbing cells, and thus prevent excessive bone resorption.
However, prolonged treatment with these drugs eliminates the necessary bone turn-over leading to increased fracture risk and other unwanted side effects. Therefore, there is an urgent need to develop new strategies that overcome the limitations of current treatments. There are now new progresses in this area. They have been developed in a cooperation of Professors Christoph Winkler (Department of Biological Sciences, National University of Singapore) and Manfred Schartl (Biocenter, Julius-Maximilians-Universität Würzburg, Germany). Using genetic analysis in a small laboratory fish model, the Japanese medaka (Oryzias latipes), the research team identified a small protein, the chemokine CXCL9, that, under osteoporotic conditions, diffuses towards reservoirs that hold bone resorbing cell precursors. These precursors produce a receptor, CXCR3, on their cell surface.
Upon activation by CXCL9, the precursors are mobilised and migrate long distances in a highly directed fashion towards the bone matrix, where they start resorbing bone. Both CXCL9 and its receptor CXCR3 have long been known to modulate the migration of immune cells to inflammation sites, for example in psoriasis and rheumatoid arthritis. There are several chemical inhibitors blocking CXCR3 activity that have had little success in clinical tests for the treatment of psoriasis. The research team showed that these inhibitors are highly effective in blocking bone resorbing cells’ recruitment and protecting bone from osteoporotic insult. On the other side, a new evidence seems to support the employment of biphosphonates in treating osteoarthritis. Researchers believe bisphosphonates may alter bone marrow lesions, improve pain and halt OA progression.
Alternatively, they could also alter the mechanical properties of bone, thereby potentially contributing to detrimental effects. Using data from the Osteoarthritis Initiative, a longitudinal cohort of people with or at risk for knee OA, the researchers identified women who started bisphosphonates and matched them to women who weren’t on the drug. Measurements in bone marrow lesion volume were taken when they first started on bisphosphonate and then a year later. Changes in bone marrow lesion volume between the two groups were then compared. When researchers looked at those who had bone marrow lesions at baseline, they found that the women who started bisphosphonates had had more bone marrow lesions that decreased in size than the women who did not start bisphosphonates.
These results suggest that bisphosphonates do not appear to be harmful, at least over one year, and perhaps may even help decrease bone marrow lesions in those that have them.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific referencesTutti gli articoli
Phan QT et al. Proc Natl Acad Sci USA 2020 Jul 27:202006093.
Fan G et al. Medicine (Baltimore). 2020 Apr; 99(15):e18964.
Cai G, Aitken D et al. JAMA. 2020 Apr 21; 323(15):1456-1466.
Van Spil WE et al. Biochem Pharmacol. 2019 Jul; 165:41-48.