Treatment of Osteogenesis Imperfecta with Parathyroid hormone and Zoledronic acid

Osteogenesis imperfecta (OI) is an inherited skeletal disorder with a
prevalence of about 11/100,000 which is characterised by an increased risk of
fragility fractures (1). It is most commonly caused by mutations of the COLIA1
or COL1A2 genes which result in the production of collagen which is abnormal or
present in reduced amounts although mutations in several other genes have been
identified over recent years which can result in the same clinical phenotype
(2).

The fracture risk in OI is at least an order of magnitude above that in
patients with osteoporosis. Affected individuals are at increased risk of
fragility fractures throughout life but the highest rates of fracture are
during childhood and above the age of 50 years (3). While affected individuals
suffer tens or hundreds of fractures during their lifetime (2-4) there is
relatively little information on fracture rate in prospective studies. A survey
of adult patients with OI recently carried out in collaboration with the
brittle bone society revealed that 79% of subjects had suffered a fracture
during the previous 5 years, equivalent to an annualised fracture rate of about
16%. This is in keeping with data from randomised trials and observational
studies, which on average, have reported an annualised fracture rate of about
17% (4-9).

Bone mineral density (BMD) is variable in patients with OI (10) and the
increased risk of fracture is observed even in patients with normal BMD or
osteopenia (3;4). However, a cohort study in Norway found that patients with
BMD values in the osteoporotic range (T-score <-2.5) had a 3-fold higher rate
of fractures than those with normal BMD or osteopenia (4). This is an important
observation since it provides proof-of-concept that strategies aimed at
increasing bone mass might reduce fracture rate in OI.

Bisphosphonates are frequently prescribed for patients with OI with the aim of
preventing fractures but the evidence base for efficacy is poor. Previous
Cochrane reviews and meta-analysis of trials in OI have concluded that while
bisphosphonates consistently increased BMD in both children and adults the
effects on fracture risk are uncertain (11-13). It remains unclear why the
increase in BMD resulting from bisphosphonate treatment has not been associated
with a consistent reduction in fractures. However one explanation might be that
the increase in BMD that occurs with bisphosphonates is due mainly to increased
mineralisation of bone, rather than an increase in the amount of bone tissue
(14).

Recently a randomised placebo controlled trial with the bone anabolic agent
teriparatide (TPTD) has been conducted in adults with OI with encouraging
results (9). Not only did TPTD increase BMD when compared with placebo but the
odds ratio of fracture was reduced in the active treatment arm, but not
significantly (0.73; 95% CI 0.28-1.90). This study had a short duration of
follow up however, and was not powered to detect a reduction in fracture risk.
Another observational study of TPTD also showed encouraging results in OI
patients previously treated with bisphosphonates but fracture data were not
reported (5).

This study has been transitioned to CTIS with ID 2024-519705-36-00 check the CTIS register for the current data.

The primary objective will be to investigate if a two-year course of TPTD
followed by antiresorptive treatment with a single infusion of ZA in adults
with OI reduces the proportion of patients who experience a fracture as
compared with standard care.

This will be a randomised controlled trial with an open design.
Following informed consent adult patients with a clinical diagnosis of OI will
be randomised in a 1:1 ratio to receive treatment with TPTD for 2 years
followed by an infusion of ZA with follow up for a further 2-3 years to to
receive standard care for the duration of the study. Standard care may consist
of no active treatment or bisphosphonates. The treatment strategy in the
standard care group will be left to the discretion of the patients usual care
provider.

The study will involve four scheduled visits over a 4-5 year period.

The duration of the follow-up will be determined by the rate at which fractures
accumulate across the whole study population. It is expected that the duration
of follow-up for individual patients will vary between 4-5 years.

Baseline: At the baseline/screening visit, patients will be provided with
information about the study and invited to take part by providing written
informed consent. A brief physical examination will be undertaken, along with
medical history and documentation of current drug treatments. They will have
safety bloods taken to ensure there are no contraindications to treatment and
will have other bloods for genetic analysis and assessment of specialised
biochemical markers of bone turnover. Participants will undergo a DEXA (dual
energy x-ray absorptiometry) and spine x-rays and a special x-ray of the wrist
called a high resolution quantitative computed tomography (HRpQCT) scan will be
taken. Questionnaire will be completed by participants to assess bone pain,
quality of life and functional status. Following completion of these tests,
patients will be randomised into one of the treatment groups.

Participants in the TPTD group will be supplied with injection devices
containing the treatment and trained in their use. The participant will
self-inject the treatment on a daily basis for up to two years.

12 month visit
Safety and research bloods will be repeated, along with the participant
questionnaire and a HRpQCT scan.

24 month visit
Safety and research bloods will be repeated, along with the participant
questionnaire and a HRpQCT scan and a DEXA scan.

End of study visit
Safety and research bloods will be repeated, along with the participant
questionnaire and a HRpQCT scan, DEXA scan and spine x-ray. Participants
reaching the end of their 24 month course of TPTD will have a ZA infusion
scheduled.

Every 6 months for the duration of the trial all participants will receive a
phone call from the research team to check for any adverse events and
fractures.

Participants within the active treatment arm will also be asked to attend more
frequently (approximately every 4 months) during the treatment period to pick
up new supplies of TPTD and return used pens.

24 months of teriparatide followed by a single infusion of zoledronic acid.

- 4 participant questionnaires
- 4 sets of blood samples (safety bloods and research bloods)
- 3 DEXA scans
- 2 spine x-rays
- 4 HRpQCT scans
- Daily injections of TPTD for 24 months if randomised to active treatment arm
- Single infusion of zoledronic acid if randomised to active treatment arm
- Daily completion of a pen injection diary 24 months if randomised to active
treatment arm
- Completion of an event diary by all participants for duration of trial