Evaluation of Teriparatide and Zoledronic Acid in the Management of Osteogenesis Imperfecta: A Randomized Controlled Trial

The primary objective of this study is to evaluate whether a two-year treatment regimen with **teriparatide** (TPTD), followed by **zoledronic acid** (ZA), reduces the proportion of participants with **osteogenesis imperfecta** experiencing fractures confirmed by imaging, compared to standard care. This is clinically relevant as it aims to improve bone health and reduce fracture risk in patients with this genetic disorder, potentially offering a more effective treatment strategy.

Secondary objectives include comparing the effects of TPTD/ZA and standard care on the total number of fractures, specifically spine fractures, and assessing differences in bone pain using the Brief Pain Inventory (BPI). The study will also evaluate quality of life through the SF36 questionnaire, sleep quality via the Pittsburgh Sleep Quality Index (PSQI), and functional status using the Health Assessment Questionnaire (HAQ) and EuroQol5D (EQ5D) tools. Additionally, the trial will explore the relationship between patient demographics, clinical features of osteogenesis imperfecta, baseline bone density values, type of genetic mutation, biochemical markers of bone turnover, and fracture occurrence, as well as the response to treatment.

The clinical trial involves a total of **303 participants** diagnosed with **osteogenesis imperfecta**. The study population includes both male and female adults aged 18 years and above. Participants were selected based on their clinical diagnosis of osteogenesis imperfecta and their ability to consent and comply with the study protocol. The trial does not specifically target a vulnerable population. Participants' general health status is not detailed, nor are specific lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants are willing and able to adhere to the study requirements, but further demographic or lifestyle information is not provided by the sponsor.

The clinical trial is designed to evaluate the efficacy of a two-year treatment regimen with **teriparatide** followed by **zoledronic acid** in reducing the incidence of fractures in patients with **osteogenesis imperfecta**. This study is a randomized, double-blind, controlled trial, comparing the investigational treatment with standard care, which may include no active treatment or treatment with bisphosphonates, based on patient and provider preference. The trial is event-driven and will conclude once 139 participants have experienced a clinical fracture confirmed by imaging, with an anticipated average follow-up duration of 62 months.

Participants will undergo a series of study visits, beginning with an inclusion visit to assess eligibility based on criteria such as age (18 years and above) and the ability to consent and comply with the study protocol. Follow-up visits will occur at regular intervals to monitor the occurrence of fractures, assess bone pain, quality of life, and functional status using validated tools such as the Brief Pain Inventory (BPI), SF36 questionnaire, Health Assessment Questionnaire (HAQ), and EuroQol5D (EQ5D). The end-of-study visit will coincide with the primary endpoint evaluation, approximately 62 months after the start of the trial.

The expected length of participant involvement is up to 62 months, depending on the occurrence of the primary endpoint. Conditions that may lead to early termination from the study include withdrawal of consent, non-compliance with the study protocol, or the occurrence of adverse events that necessitate discontinuation of the investigational treatment. The trial aims to provide comprehensive data on the effectiveness of the treatment regimen in reducing fracture risk and improving patient outcomes in osteogenesis imperfecta.

The clinical trial involves the administration of several treatments, including both experimental and comparator medications. **Alendronic Acid 70 mg tablets** are administered orally. The pharmaceutical form is a tablet, and the active substance is **alendronate sodium trihydrate**. The maximum total dose is 70 mg, and the treatment period can extend up to 99 weeks. This medication is not specifically licensed for osteogenesis imperfecta but is commonly used for this indication.

**FORSTEO 20 micrograms/80 microliters solution for injection in pre-filled pen** is administered via injection. The active substance is **teriparatide**, and the maximum daily dose is 20 micrograms. The treatment period is limited to 24 months. This medication is sometimes used for osteogenesis imperfecta, although it is not officially licensed for this condition.

**Risedronate Sodium 35 mg Film-coated Tablets** are administered orally. The active substance is **risedronate sodium**, with a maximum total dose of 35 mg. The treatment period can last up to 99 weeks. This medication is not licensed for osteogenesis imperfecta but is widely used for this purpose.

**Zoledronic Acid Seacross 5 mg/100ml solution for infusion** is administered as a solution for infusion. The active substance is **zoledronic acid monohydrate**, with a maximum total dose of 5 mg. The treatment period is limited to a single administration. This medication is sometimes used off-label for osteogenesis imperfecta.

**Fultium-D3 800 IU Capsules** are administered orally. The active substance is **colecalciferol**, with a maximum total dose of 800 IU. The treatment period can extend up to 99 weeks. This medication is often used for osteogenesis imperfecta, although it is not officially licensed for this condition.

**Ibandronic acid Accord 3 mg solution for injection in pre-filled syringe** is administered intravenously. The active substance is **ibandronic acid**, with a maximum total dose of 3 mg. The treatment period can last up to 99 weeks. This medication is not licensed for osteogenesis imperfecta but is widely used for this indication.

**Disodium Pamidronate 15mg/ml Concentrate for Solution for Infusion** is administered as a solution for infusion. The active substance is **pamidronate disodium**, with a maximum total dose of 15 mg. The treatment period can extend up to 99 weeks. This medication is not licensed for osteogenesis imperfecta but is widely used for this purpose.

**Prolia 60 mg solution for injection in pre-filled syringe** is administered subcutaneously. The active substance is **denosumab**, with a maximum total dose of 60 mg. The treatment period can last up to 99 weeks. This medication is not licensed for osteogenesis imperfecta but is widely used for this indication.

**Calcichew-D3 500 mg/200 IU Chewable Tablet** is administered orally. The active substances are **colecalciferol** and **calcium carbonate**, with a maximum total dose of 500 mg. The treatment period can extend up to 99 weeks. This medication is sometimes used for osteogenesis imperfecta, although it is not officially licensed for this condition.

**Ibandronic acid Sandoz 150 mg Film-coated Tablets** are administered orally. The active substance is **sodium ibandronate**, with a maximum total dose of 150 mg. The treatment period can last up to 99 weeks. This medication is not licensed for osteogenesis imperfecta but is widely used for this indication.

**CLASTEON® 400mg capsules** are administered orally. The active substance is **clodronate disodium**, with a maximum total dose of 1600 mg. The treatment period can extend up to 99 weeks. This medication is not licensed for osteogenesis imperfecta but is widely used for this purpose.

Efficacy in this clinical trial will be assessed primarily by evaluating the proportion of participants experiencing a clinical fracture, which will be validated by x-ray or other imaging techniques. This is an event-driven study, and it will conclude when 139 participants have experienced an incident clinical fracture, with an expected average follow-up duration of 62 months. Secondary endpoints include the total number of clinical fractures validated by imaging, the number of incident vertebral fractures assessed by imaging of the thoracic and lumbar spine, and the total number of fractures experienced by participants, including those reported without imaging or with inconclusive imaging results.

Additional secondary endpoints involve assessments of bone pain using the Brief Pain Inventory (BPI), quality of life using the SF36 questionnaire, functional status using the Health Assessment Questionnaire (HAQ) and EuroQol5D (EQ5D) assessment tools, and the recording of adverse events. These parameters will be evaluated at specific time points: bone pain, health-related quality of life, and functional status will be assessed after 12 months, 24 months, and at the end of the study, approximately 62 months. The total number of clinical fractures, incident vertebral fractures, and total number of fractures will be evaluated concurrently with the primary endpoint, on average after 62 months of follow-up.