Randomised trial of Teriparatide followed by Zoledronic acid versus standard care to prevent fractures in adults with Osteogenesis Imperfecta

Problem to be addressed Osteogenesis imperfecta (OI) is an inherited skeletal disorder characterised by increased risk of fragility fractures. Bisphosphonates are frequently prescribed for adult patients with OI with the aim of preventing fractures but the evidence base for efficacy is poor. Recent evidence suggests that the bone anabolic agent teriparatide (TPTD) increases bone mineral density (BMD) and may have the potential to prevent fractures in OI. Aim of study The primary objective will be to investigate if a two year course of TPTD followed by followed by antiresorptive therapy with a single infusion of zoledronic acid (ZA) in adults with OI reduces the proportion of patients who experience a validated clinical fracture as compared with standard care. Secondary objectives will be to determine if TPTD followed by ZA (TPTD/ZA) reduces the total number of fractures; the risk of vertebral fractures; and to evaluate if TPTD/ZA influences bone pain, quality of life and functional status as compared with standard care. Design Prospective, open label randomised controlled trial with blinded adjudication of the primary endpoint. Adults with OI will be randomised to receive TPTD injections for two years followed by a ZA infusion to maintain the increase in BMD or to standard care consisting of no active treatment or bisphosphonates at the discretion of local investigators. Minimisation will be used to balance the groups for factors known or suspected to influence fracture risk. A mechanistic sub-study will evaluate the clinical and genetic predictors of response to treatment. Sample size and study power A sample size of 350 (175 participants per group) will provide 88 % power to detect a 25% reduction in risk of clinical fractures with TPTD/ZA compared with standard care. This is based on an analysis where the groups are compared using a log-rank test stratified by the minimisation variables, with a 5% two-sided significance level. This assumes that the annual rate of incident clinical fractures will be 16%, and that new vertebral fractures will be detected by the end of study spine radiographs in 15% of participants. The sample size calculation takes into account a possible dropout rate of up to 15% of participants lost to follow up. Recruitment The study will involve 24 referral centres for OI in the UK, one each in the Republic of Ireland, France, the Netherlands & Denmark. A feasibility study suggested that about 51% of adult OI patients may be interested in taking part. Assuming that the actual recruitment rate is about 35% it is estimated that 1085 subjects will need to be screened to reach target. Study duration and timelines The total study duration will be about 102 months, comprising set up and centre initiation over 16 months; recruitment over 58 months; and an average duration of follow up of about 48 months with a range of between 25 and 92 months. Importance to NHS If the study showed that TPTD/ZA substantially reduces fracture risk in adult OI savings would be made in fracture treatment costs, and in improving quality of life for those affected.