Bisphosphonates Symposium; Bone and Beyond summary

On 27^th and 28^th of September, the titans of bisphosphonates from across the globe assembled in the stunning Sheldonian Theatre in Oxford, for the Bisphosphonates Symposium; Bone and Beyond, to discuss the potential for repurposing bisphosphonates from treatment of bone disorders to treatment of age-related multimorbidities. The symposium was organised by Professor Graham Russell (University of Oxford), Professor Richard Eastell (University of Sheffield) and Dr Harriet Teare (UK SPINE Knowledge Exchange).

The first day featured talks outlining the staggering non-skeletal effects of the bisphosphonate Zoledronate observed in clinical trials and ongoing studies attempting to understand the mechanisms underlying these effects. Professor Russell set the scene, with an overview of the current challenges of Zoledronate treatment, such as the comparatively high cost of intravenous Zoledronate treatment in contrast with the oral formulation of other, less potent bisphosphonates such as Alendronate. Professor Russell also outlined the many proposed mechanisms of action underlying the non-skeletal effects of bisphosphonates. Professor Ian Reid (University of Auckland) then presented on the treatment of Paget’s disease with Zoledronate and the findings of his recent publication on the effect of oral Zoledronate treatment on bone turnover[1]. Professor Ken Lyles (Duke University of Medicine) presented on the findings of clinical trials with Zoledronate from the United States[2], and Professor Rob Coleman closed the morning with a talk on the role of bisphosphonates in the treatment of cancer[3]. With the scene firmly set and the challenges ahead well laid out, the group broke for lunch – hungry for both food and answers.

The afternoon began with Dr. Jim Kirkland (Mayo Clinic) presenting on the mechanisms underlying senolytics[4] and Professor James Edwards (University of Oxford) giving an overview of his cellular, genomic and proteomic studies of the mechanisms underlying Zoledronate treatment. Then I (Medicines Discovery Catapult) gave an overview of my ongoing study using spatial transcriptomic analysis to understand the effects of Zoledronate treatment in different tissues, before Dr. Ghada Alsaleh (University of Oxford) closed the first day with a talk on autophagy, acute phase response, γδ T cells and innate immunity.

The following day focused on the optimal study design and clinical endpoints of trials to treat multimorbidities and the next steps required to begin the process of repurposing Zoledronate. Professor Steve Cummings (University of California, San Francisco) started the morning with a talk on the various endpoints of Zolageing studies, including measures of biological and epigenetic ageing[5]. Professor Duncan Richards (University of Oxford) and Professor Jonathan Cook (University of Oxford) presented on the challenges of studies with multiple endpoints, such as increased type 1 errors leading to incorrect data interpretation, and Professor Richard Eastell (University of Sheffield) gave an overview of the surrogate endpoints and safety of bisphosphonates in osteoporosis trials[6]. The morning ended with a review of the pharmacology of bisphosphonates by Professor Serge Cremers[7] (Columbia University) and a presentation of the regulatory interactions and potential future applications of Orazol from Dr. John Fox (Transcriptogen Ltd).

In the afternoon session, Dr. Marian Schini (University of Sheffield) gave an overview of the next steps in the bisphosphonate repurposing, followed by Professor Daniel Prieto-Alhambra (University of Oxford) who presented the potential benefits of extending the use of bisphosphonates beyond the traditional treatment of bone disorders[8]. The afternoon was rounded off by Professor Nick Harvey (University of Southampton) who gave a talk on the challenges and unmet medical opportunities within sarcopenia[9], before Professor Gary Ford (University of Oxford) gave an overview of the role of the National Institute for Health and Care Research (NIHR)[10].

The symposium closed with a round table discussion, where the attendants discussed the potential routes forward, including the merits of reformulation of Zoledronate compared to the use of existing oral bisphosphonates, the classification and route of administration of the final therapeutic, and potential approaches for increasing the absorbency of oral Zoledronate. The clinical endpoints of future trials were also discussed, including the suggestion to focus only on a single outcome measure such as bone mineral density (BMD), before broadening the application for use into multimorbidity. Some attendees felt that the best route forward would be to repeat Professor Reid’s study with an increased number of patients, primarily focussing on the skeletal effects of bisphosphonates while also investigating the non-skeletal effects. Other attendees questioned whether oral formulation of Zoledronate was indeed the right approach, concerned that it could take years to improve the absorption, and has the potential for increased adverse effects following regular bisphosphonate treatment.

Overall, the symposium not only enabled the attendees to review the current evidence supporting the case for repurposing bisphosphonates such as Zoledronate to treat multimorbidity, but also allowed experts within the field to form or renew connections which can be nurtured into collaborations. Ultimately, it is hoped that the outputs from these collaborations will allow patients to benefit from both the skeletal and non-skeletal benefits of bisphosphonates and help reduce the cost (both physical and financial) of multimorbidity in ageing.