Targeting age-related multi-morbidities with bisphosphonates
Looking further than just the bones
The UK SPINE funds several flagship projects to accelerate drug discovery for healthy ageing. One of these flagship projects looks at the use of bisphosphonates to treat the multimorbidities of ageing. Dr. James Edwards and Dr. Helen Knowles of the Botnar Research Centre of Oxford University explain why this research is so important for healthy ageing.
Why are Bisphosphonates so interesting to treat the multimorbidities of ageing?
For over 40 years, Bisphosphonates (BPs) have been the leading drugs for the treatment of skeletal disorders characterised by bone loss, ranging from osteoporosis and Paget’s disease (a bone remodelling disease) to secondary cancer spread to bone and myeloma (cancer of the bone marrow).
New clinical evidence suggests that BPs may also have beneficial effects outside of the skeleton in preventing a range of other disorders including: cardiovascular disease, neurodegeneration (such as Alzheimer’s disease), cancer and above all improving overall lifespan. These characteristics could greatly benefit human health as the ageing population increases.
How do Bisphosphanates work?
BPs act by binding strongly to bone mineral and are subsequently taken up by osteoclasts. These bone cells share the same lineage as certain immune cells (Macrophages) and can break down bone (a process called resorption). This process is a normal part of bone maintenance. It only becomes detrimental once the breakdown of bone mass exceeds bone build-up, as seen in osteoporosis. Once BP’s interact with osteoclasts they inhibit their bone-resorbing activity. An image of how these drugs are thought to work can be found on here. In recent years, clinical trials using BPs have to everyone’s surprise observed a reduction in all-cause mortality, several cancers and cardiovascular outcomes in patients receiving BPs. It is now important to ask whether there are plausible and rational explanations for these non-skeletal benefits of BPs on lifespan and other health outcomes.
Laboratory studies on these anti-ageing effects are currently very limited with initial data suggesting that the BP zoledronate might extend the lifespan of mesenchymal stem cells, prevent radiation-induced DNA damage and encourage DNA repair. Other studies showed that combining BPs with other drugs such as statins (which are prescribed to lower blood cholesterol) extends lifespan in animal models of progeria syndromes. These are genetically encoded disorders with symptoms resembling accelerated ageing. This observation is under clinical evaluation in the equivalent human syndromes.
Sarah Geronimo With Progeria Stricken Rochelle Pondare by Tilly Holland / CC BY
What is the UK SPINE BP flagship programme addressing specifically?
There is currently very little knowledge of the cellular and molecular mechanisms driving these effects. However, obtaining this knowledge is vital to enable re-purposing of BPs to maximise the clinical benefit of these well-tolerated, affordable and accessible drugs. The UK SPINE BP project brings together scientists with expertise in ageing mechanisms and BP research at the Botnar Research Centre in the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS) at the University of Oxford and is funded as a Flagship project by UK SPINE.
The aim of our research is to improve our basic understanding of the mechanisms underlying these fascinating effects. This project will screen the cellular responses of different non-skeletal cell types to BPs, as well as studying the extra-skeletal distribution of BPs in lab animals.
Our aim is to provide the evidence and confidence to accelerate the use of these highly accessible BPs toward clinical use as an anti-ageing therapy and have a positive impact on the growing number of older people.