Treatment of OI with Parathyroid hormone and Zoledronic acid

Interview with Prof. Stuart H. Ralston, University of Edinburgh, Western General Hospital, UK

Who are you & what is your relationship to OI?

I am a physician and rheumatologist with a special interest in the treatment of bone diseases. I have been taking care of patients with OI for many years and run a specialist clinic for these patients in Edinburgh at the Western General Hospital where I work.

Can you tell us how the TOPaZ project was initiated?

The TOPaZ project was initiated partly through my own desire to generate a better evidence base for the treatment of OI and also through conversations with OI patients who were surprised to hear that we weren’t sure whether any of the drugs that we use to treat OI are effective at preventing fractures!

This led to discussions with other stakeholders interested in OI. This included Prof Bente Langdahl in Denmark, who also has an interest in OI, and the Brittle Bone Society in the UK. We were all concerned to try and improve outcome and that lead to me writing a grant to evaluate the effects of treatment on bone fractures in adults with OI. The study has been financed by the Efficacy and Mechanisms Evaluation (EME) board in the UK which is supported by the MRC and NIHR. We also received a donation of Teriparatide from Eli Lilly and company who provided the medicine free of charge.

What is the aim of the study?

The aim of the study is to determine if a 2-year course of teriparatide (TPTD) followed by an infusion of zoledronic acid (ZA) is superior to standard care in preventing fractures in adults with OI. We chose to study the effects of treatment on fractures since this is one of the most important complications of OI. It may be surprising to your readers that until TOPAZ, no trial has been designed to assess the effects on fractures. Rather, they have only studied effects on bone density.

To do a fracture prevention trial, quite large numbers of patients are needed. We have calculated that we will need to study 380 people with OI for 5 years to determine if the TPTD/ZA has a significant advantage over standard care. By that I mean that we are hoping TPTD/ZA may reduce fracture numbers by 25% or more than SC. At the moment we have enrolled 247/380 people so we are at 65% of our target. Standard care may consist of calcium and vitamin D supplements and bisphosphonates or denosumab or no treatment. Anything except TPTD. The study commenced in 2018 and has been in progress 2 years. We were hoping to end in 2023 but things have delayed a lot with Covid19 and I suspect it may be 2024 until we get the results. Having said that we are restarting recruitment now in the UK again and hopefully other countries will follow. Countries involved are UK, Republic of Ireland, Netherlands (Amsterdam), France (Paris) and Denmark (Aarhus), where some are in the planning/starting phase of recruitment.

The methods are to invite patients to the study, check a DEXA, spine x-ray (to assess vertebral fractures) and some routine bloods and questionnaires to assess things like pain and quality of life. Patients are also offered genetic testing to define the gene mutation responsible for OI. Following this, participants are randomised to one of the two treatment arms (TPTD/ZA or SC). Those in TPTD/ZA arm have 2 years TPTD then get an infusion of ZA and then are followed up without treatment for 3 years. Follow up in total is about 5 years.

Are you still recruiting?

Yes we are. If someone is interested it is possible to email the Topaz study team (topaz.trial@ed.ac.uk) and we can put you in touch with the closest centre.

Do you have patient involvement?

Yes, we involved patients in the study design right from the start and we have had very good support from the BBS in the UK.

Any messages for the readers of OIFE Magazine?

Yes! This is an important study which could change the treatment approaches in adults with OI. If you are interested in taking part and are based in UK, Ireland, Netherlands, Demark or France please get in touch to register your interest.