TOPaZ study
Research type
Research Study
Full title
Treatment of Osteogenesis Imperfecta with Parathyroid hormone and Zoledronic acid
IRAS ID
207747
Contact name
Stuart Ralston
Contact email
Eudract number
2016-003228-22
ISRCTN Number
ISRCTN15313991
Duration of Study in the UK
6 years, 5 months, 4 days
Research summary
Osteogenesis Imperfecta (OI) is an inherited disorder known as "brittle bone disease" which is associated with a greatly increased risk of fractures. People with OI may suffer tens or hundreds of fractures during their lifetime and often become disabled as a result of this. There is no curative treatment for OI. Many doctors treat OI patients with drugs called bisphosphonates which are also used in osteoporosis, but it’s not clear if they are effective at preventing fractures. While clinical trials have been performed with other osteoporosis treatments in OI, no trials have been performed to determine if these treatments reduce the risk of fracture. The aim of the present study is to determine if a two year spell of treatment with a drug called teriparatide (TPTD) followed by treatment with another drug called zoledronic acid to maintain the 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 might consist of no active treatment or bisphosphonates which are prescribed to about 30% of patients with OI in the UK. This is first trial which has been designed to determine if drug treatment can reduce the risk of fractures in OI. If positive, it could be life-changing for those affected. If negative it would signal the need to investigate alternative approaches to reduce fracture burden in the rare but disabling condition.
Lay summary of study results: The aim of the TOPaZ study was to determine whether a new treatment approach using a combination of medicines that increase bone mineral density (BMD) could reduce the number of new fractures experienced by adults with osteogenesis imperfecta (OI), a genetic condition that causes bones to break easily. The study team recruited 350 participants from 27 specialist centres in the UK and Europe and followed them up for an average time of just over five years.
People taking part in the study were randomly allocated to one of two groups. One group received teriparatide (TPTD), a medication that stimulates new bone formation, given as a daily injection for two years, followed by a single infusion of zoledronic acid (ZA), a medicine that prevents bone loss. Both treatments have been shown to be effective in the treatment of osteoporosis, a disease where there is low BMD and an increased risk of fracture. The reason for using ZA following TPTD was to maintain increases in BMD that we thought might occur in OI as the result of TPTD treatment. The other group received standard care (SC), which could include medicines used for the treatment of bone disease or no treatment. In fact, just over half of the participants allocated to SC received no bone targeted treatment and the most common treatment in the SC group was vitamin D supplements which were given to 26% of participants.
The group that were treated with TPTD/ZA had a substantial increase in BMD at both the spine and hip during the study as compared with SC. Biomarkers of new bone formation were also increased following 2 years TPTD and then fell once again following ZA. This demonstrates that people with IO respond in a similar way to these treatments as patients with osteoporosis. Despite this, the combination of TPTD/ZA did not reduce the number of fractures as compared with ZA, even though more fractures occurred during TOPaZ than have been reported occurred in all previous clinical trials of treatments in OI combined.
The number and type of side effects were similar in both treatment groups, and no new safety concerns were identified.
The results of this study are important as it shows conclusively that medicine which increase BMD do not necessarily reduced fracture risk in OI. This suggests that reductions in bone quality or bone strength are the main cause of fractures in OI as opposed to reductions in BMD. The findings reported are likely to change the current treatment approach to people with OI which is based on prescribing medicines that increase BMD.
Additional findings
None
Challenges and Limitations
This study does have some limitations.
Although the TOPaZ study included more people than any previous study in OI, and accumulated more fractures than has occurred in all previous trials of OI combined, the number of participants with a new fracture confirmed by x-ray was lower than was originally expected.
Although TPTD/ZA increased BMD at both the spine and hip it is possible that the change may not have been big enough to prevent fractures. We think this is unlikely as the preliminary results of another trial with a different bone forming agent has just been reported in which substantial increases in BMD occurred but there was also no difference in fracture occurrence.
Another limitation is that participants knew which treatment they were receiving. However, this is very unlikely to have affected the main results about fractures, because all fractures were reviewed by independent experts who did not know which treatment each person had received.
A major strength of the study is the large number of participants and the fact that the entry criteria were broad. This means the results are relevant to most people with a clinical diagnosis of OI.
The study provides for the first time, robust evidence to show that treatments that increase bone density in OI do not necessarily reduce the risk of fractures.REC name
East of Scotland Research Ethics Service REC 2
REC reference
16/ES/0110
Date of REC Opinion
12 Sep 2016
REC opinion
Favourable Opinion