Treatment of Osteogenesis Imperfecta With Parathyroid Hormone and Zoledronic Acid

Incident clinical fractures validated by x-ray or other imaging

Time frame · Through study completion, approximately 5 years

Proportion of participants experiencing a clinical fracture validated by x-ray or other imaging as compared to standard care

Total number of incident vertebral fractures

Time frame · Baseline (0) and Final Trial Visit (5 years after baseline)

Incident vertebral fractures assessed by imaging of the thoracic and lumbar spine and reviewed by an independent masked adjudicator using two spine x-rays collected at the start and end of the trial

Total number of fractures

Time frame · Through study completion, approximately 5 years

Total number of fractures experienced by participant defined as combination of validated clinical fractures, vertebral fractures and fractures reported by participants where imaging was not performed, was not feasible or where results were inconclusive

Pain assessed by the Brief Pain Inventory (BPI) Short Form measure

Time frame · Baseline (0), 12 months, 24 months and Final Trial Visit (5 years after baseline)

Bone pain assessed by the Brief Pain Inventory (BPI) Short Form, a Patient Reported Outcome Measure completed at 4 time-points throughout the trial. The BPI gives two main scores - a pain severity score and a pain interference score. The pain severity score is calculated from the four questions (3-6) about pain intensity. Each item is rated from 0 (no pain) to 10 (pain as bad as you can imagine). The scores from the 4 questions are added together and then divided by 4, giving a severity score out of 10. The pain interference score corresponds to Question 9 responses. The seven sub-items are rated from 0 (does not interfere) to 10 (completely interferes). The scores are added together and divided by 7, giving an interference score out of 10. Question 2 (pain drawing diagram), Question 7 and Question 8 (pain relief treatment or medication) do not contribute to the scoring.

Quality of life assessed by the SF-36 (v1) Quality of Life

Time frame · Baseline, 12 months, 24 months and Final Trial Visit (5 years after baseline

The SF-36 questionnaire consists of 36 generic health questions: 8 health domains of the questionnaire, each of which are summarised (Physical functioning score (10 items), Role-physical score (4 items), Bodily pain (2 items), General health score (5 items), Vitality score (4 items), Social functioning score (2 items), Role-emotional score (3 items), and Mental health score (5 items)). The resulting score for each domain is standardized, to obtain values ranging from 0 to 100, with higher values indicating a better quality of life.Two overall summary measures (physical and mental component scores) are calculated.

Sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI) measure

Time frame · Baseline (0), 12 months, 24 months and Final Trial Visit (5 years after baseline)

Sleep quality as assessed by the Pittsburgh Sleep Quality Index, a Patient Reported Outcome Measure completed at 4 time-points throughout the trial. The Pittsburgh Sleep Quality Index contains 19 self-rated questions. The questions are combined to form seven 'component' scores, each of which has a range of 0-3 points. In all cases, a score of 0 indicates no difficulty while a score of 3 indicates severe difficulty. The seven component scores are added to yield one global score, ranging from 0-21 points, 0 indicating no difficulty and 21 indicating severe difficulties in all areas.

Functional status assessed by the Health Assessment Questionnaire (HAQ) measure

Time frame · Baseline (0), 12 months, 24 months and Final Trial Visit (5 years after baseline)

The HAQ includes 8 blocks of questions covering difficulties performing simple daily activities. There are 20 questions in total. A 4 point grading system is used to denote degree of difficulty (0=none, 1=some difficulty, 2=great difficulty, 3=not able to perform at all). Each item has a companion aids-devices variable used to record types of assistance the subject uses for his/her usual activities. These variables are coded from 0 to 3 (0 = No assistance is needed, 1 = A special device is used by the subject in his/her usual activities, 2 = The subject usually needs help from another person, 3 = The subject usually needs BOTH a special device AND help from another person). The highest score reported for any component question of the 8 categories determines the score for that category. A global score is calculated by summing the scores for each of the categories and dividing by the number of categories answered.

Adverse events

Time frame · Through study completion, approximately 5 years

All adverse events reported throughout the duration of the trial. Summarised by treatment and by severity, causality and seriousness, reporting both the number of events and the number of patients experiencing a given event.

Mechanistic analyses (ITT)

Time frame · Biological samples collected at Baseline (0), 12 months, 24 months and Final Trial Visit (5 years after baseline)

Relationship between gender, clinical OI subtype, lowest Bone Mineral Density T score at spine or hip (≤ -2.5 or \> -2.5)), type of genetic mutation (mutations of COLIA1 or COLIA2 and biochemical markers of bone turnover with fracture occurrence and response to treatment. Descriptive statistics by treatment group for each subgroup will be presented. The primary outcome, defined as the proportion of participants experiencing a clinical fracture validated by x-ray or other imaging, will be analysed for these subgroups. The interaction between subgroup and treatment will be included in the primary and secondary analysis models to determine if the treatment effect differs by subgroup.