Title: Randomised trial of Teriparatide followed by Zoledronic acid versus standard care to prevent fractures in adults with Osteogenesis Imperfecta
Funder: Chief Scientist Office, Scotland

Abstract: 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 The study will be powered to detect a 25% reduction in risk of fracture with TPTD/ZA compared with standard care based on analysis using a log-rank test with a 5% two-sided significance level, assuming that the annual rate of fracture is 16% and that the average duration of follow up is 4 years. A cohort of 352 patients (176 per group) will provide 85% power to detect such an effect. The sample size will be inflated to 190 per group (380 in total) to account for missing data and the possibility that patients may be lost to follow up. Recruitment The study will involving 25 referral centres for OI in the UK and one in the Republic of Ireland. A feasibility study suggests that about 51% of adult OI patients may be interested in taking part. Assuming that the actual recruitment rate is about 35% we need to screen 1085 subjects to reach target. Study duration and timelines The study duration will be 78 months, comprising set up and centre initiation over 16 months; recruitment over 24 months and treatment and follow up of between 36 and 60 months with an average duration of 48 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.

Lay abstract: Osteogenesis Imperfecta (OI) is an inherited disorder known as "brittle bone disease" which is associated with a greatly increased risk of broken bones (fractures). People with OI may suffer tens or hundreds of fractures during their lifetime and often become disabled as a result. There is no effective treatment for OI. Some doctors prescribe drugs called bisphosphonates to try and prevent fractures in OI but it is unclear if they are effective. Most patients with OI receive no treatment for their condition. Teriparatide (TPTD) has been shown to reduce the risk of fractures occurring in osteoporosis (a disease affecting older people cause by thinning of the bones). Recently TPTD has been studied in patients with OI. Although the effects on bone density were encouraging this study was not designed to determine whether TPTD was effective at reducing the risk of fractures which are the most important complication of OI. The aim of the present study is to determine if a two year spell of treatment with TPTD followed by treatment with another drug called zoledronic acid (ZA) to maintain the beneficial effect of TPTD on the skeleton is effective at reducing the risk of fractures in adults with OI. These treatments will be compared with standard care which in the UK most often involves having no active treatment but in about one third of patients involves being prescribed bisphosphonates The proposed clinical trial is the first study to try and assess whether drug treatment can reduce the risk of fractures in OI. The study will be important for patients and for the NHS whatever the results show. If the result is positive it will provide firm evidence that TPTD/ZA can reduce fracture risk in OI and would transform the treatment of this condition. If it is negative it will also be informative in highlighting the need to investigate alternative approaches to reduce fracture burden in the rare but disabling condition.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: CONGENITAL DISORDERS