Romosozumab vs Bisphosphonates for Osteogenesis Imperfecta

Recruiting at 38 trial locations

Overseen By Amgen Call Center

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Amgen

Disqualifiers: Electrophoresis pattern, Gene mutation, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 12 months

106 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. Please consult with the trial coordinators for more details.

What evidence supports the effectiveness of the drug Romosozumab or bisphosphonates for treating osteogenesis imperfecta?

Research shows that bisphosphonates like zoledronic acid and alendronate can increase bone mineral density and improve quality of life in patients with osteogenesis imperfecta, suggesting they are effective in managing this condition. ^{1 2 3 4 5}

What are the safety concerns associated with bisphosphonates and romosozumab?

Bisphosphonates, used for osteoporosis, can cause stomach issues, flu-like symptoms, and rare serious effects like jaw bone problems and unusual thigh bone fractures. Romosozumab has not shown a significant risk for these fractures in current data. ^{6 7 8 9 10}

How does the drug romosozumab differ from bisphosphonates for treating osteogenesis imperfecta?

Romosozumab is unique because it not only helps build new bone but also reduces bone breakdown by targeting a protein called sclerostin, which is different from bisphosphonates that mainly slow down bone loss. This dual action can significantly increase bone density and reduce fracture risk, making it a promising option for patients with osteogenesis imperfecta who have not responded well to other treatments. ^{11 12 13 14 15}

What is the purpose of this trial?

The primary objective of this study is to evaluate the effect of romosozumab treatment for 12-months compared with bisphosphonate(s) on the number of clinical fractures at 12-months; the number of any fractures at 12-months and change in lumbar spine bone mineral density (BMD) Z-score at 6-months.

Research Team

MD

Principal Investigator

Amgen

Eligibility Criteria

This trial is for children and adolescents aged 5 to less than 18 with Osteogenesis Imperfecta (OI), a condition that makes bones fragile. Participants must have had at least three fractures in the past two years or one nonvertebral fracture plus a vertebral fracture, or two vertebral fractures. They need a lumbar spine Z-score of ≤-1.0 and must be able to walk, with assistance if necessary.

Inclusion Criteria

I have had 3 or more fractures in the last 2 years or at least 1 non-spine fracture and 1 spine fracture.

My family's condition is passed down directly from one parent.

Participant has provided informed consent/assent prior to initiation of any study specific activities/procedures

Exclusion Criteria

I have current oral infections that are not treated or healed.

Current hypocalcemia (albumin-adjusted serum calcium <lower limit of normal [LLN]) or hypercalcemia (albumin-adjusted serum calcium > upper limit of normal [ULN] of the laboratory's reference range)

I have a history of long QT syndrome.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either romosozumab once a month or bisphosphonates per local standard of care for 12 months

12 months

Monthly visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

1-2 visits (in-person)

Extension

Participants may continue to be monitored for treatment-emergent adverse events

3 months

Treatment Details

Interventions

• Bisphosphonate
• Romosozumab

Trial Overview The study compares Romosozumab with Bisphosphonates over 12 months to see which treatment better reduces the number of bone fractures in kids with OI. It also looks at changes in bone density after six months. The goal is to find out if Romosozumab can improve bone strength more effectively than current treatments.

Participant Groups

Group I: Romosozumab Experimental Treatment 1 Intervention

Participants will receive romosozumab once a month (QM) for 12 months.

Group II: Standard of Care Bisphosphonate Active Control 1 Intervention

Participants will receive bisphosphonates per local standard of care treatment regimens, as determined by the investigator for 12 months.

Bisphosphonate is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• High calcium levels in cancer patients
• Bone metastases

Approved in United States as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• Glucocorticoid-induced osteoporosis
• High calcium levels in cancer patients
• Bone metastases

Approved in Canada as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• High calcium levels in cancer patients
• Bone metastases

Approved in Japan as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• High calcium levels in cancer patients
• Bone metastases

Approved in China as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• High calcium levels in cancer patients
• Bone metastases

Approved in Switzerland as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• High calcium levels in cancer patients
• Bone metastases

Who Is Running the Clinical Trial?

Amgen

Lead Sponsor

Trials

1,508

Recruited

1,433,000+

Founded

1980

Headquarters

Thousand Oaks, USA

Known For

Human Therapeutics

Top Products

Enbrel, Prolia, Neulasta, Otezla

Robert A. Bradway

Amgen

Chief Executive Officer since 2012

MBA from Harvard Business School

Paul Burton

Amgen

Chief Medical Officer since 2023

MD from University of London, PhD in Molecular and Cellular Biology from Imperial College London

Findings from Research

In a study of 90 adults with osteogenesis imperfecta (OI), bisphosphonate treatment, particularly intravenous pamidronate, significantly increased bone mineral density (BMD) in type I and type III/IV patients over an average treatment duration of 52 months.

While bisphosphonates improved BMD, they did not reduce fracture rates in type I OI patients, and only pamidronate treatment led to a decrease in fracture rates for type III/IV patients, suggesting that bisphosphonate therapy may not be suitable for all OI adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bone mineral density and fracture rate in response to intravenous and oral bisphosphonates in adult osteogenesis imperfecta. Shapiro, JR., Thompson, CB., Wu, Y., et al.[2018]

Intravenous zoledronic acid has been shown to be an effective treatment for children with mild osteogenesis imperfecta (OI), leading to an increase in bone mineral density (BMD) z-scores over 2 years of treatment.

The treatment was associated with some side effects, including transient decreases in serum calcium and phosphate levels, and two cases of symptomatic hypocalcemia, indicating the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zoledronic acid treatment in children with osteogenesis imperfecta. Vuorimies, I., Toiviainen-Salo, S., Hero, M., et al.[2022]

In a study of 161 children and adolescents with osteogenesis imperfecta, both intravenous zoledronic acid (ZOL) and oral alendronate (ALN) were effective in increasing bone mineral density (BMD), with ZOL showing a slightly higher increase in Z-scores.

ZOL was significantly more effective than ALN in reducing the clinical fracture rate, indicating it may provide better long-term safety and efficacy for patients with osteogenesis imperfecta.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ZOLEDRONIC ACID VERSUS ALENDRONATE IN THE TREATMENT OF CHILDREN WITH OSTEOGENESIS IMPERFECTA: A 2-YEAR CLINICAL STUDY. Lv, F., Liu, Y., Xu, X., et al.[2021]

Alendronate treatment over 2 years significantly improved bone mineral density in children with osteogenesis imperfecta (OI), with increases of 47.8% to 106.6% in the lumbar spine and 24% to 51.4% in forearm bones.

The treatment was found to be safe and well-tolerated, with no significant side effects reported, suggesting that alendronate could be a promising oral alternative to pamidronate for increasing bone density in OI patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alendronate treatment in osteogenesis imperfecta. Madenci, E., Yilmaz, K., Yilmaz, M., et al.[2013]

A study involving 20 children with osteogenesis imperfecta (OI) showed that daily alendronate therapy significantly improved vertebral bone mineral density and quality of life markers after one year, with most improvements noted in self-care and well-being scores.

Alendronate was well tolerated with minimal side effects, indicating it is a safe and effective treatment option for enhancing bone health and quality of life in children with OI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of alendronate on quality of life in children with osteogenesis imperfecta. Seikaly, MG., Kopanati, S., Salhab, N., et al.[2019]

Oral bisphosphonates, commonly used for osteoporosis, can cause various adverse events including gastrointestinal issues, musculoskeletal pain, and osteonecrosis of the jaw, while intravenous bisphosphonates are linked to similar issues but with added risks of renal toxicity.

The severity and frequency of adverse events from bisphosphonates are often related to the dosage and potency of the medication, highlighting the need for careful management in their use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bisphosphonate-associated adverse events. Papapetrou, PD.[2022]

Bisphosphonates are generally safe and well-tolerated for treating osteoporosis, with the most common side effects being gastrointestinal discomfort and flu-like symptoms, while serious adverse events are rare.

Skeletal complications like osteonecrosis of the jaw and atypical fragility fractures are infrequent compared to the risk of osteoporotic fractures, suggesting that the benefits of bisphosphonates often outweigh these risks, especially in patients with a similar fracture risk as those in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse effects of bisphosphonates. Abrahamsen, B.[2022]

Aminobisphosphonates have been effectively used for over 20 years to treat osteoporosis, with initial studies showing few adverse events.

Recent pharmacovigilance reports have identified various complications, some serious, particularly with high doses used in oncology and long-term treatment, raising safety concerns for osteoporosis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adverse effects of bisphosphonates]. Arboleya, L., Alperi, M., Alonso, S.[2011]

A study analyzing 1692 reports of atypical femur fractures (AFF) found that several anti-osteoporosis drugs, including alendronate and denosumab, are associated with an increased risk of AFF, with alendronate showing the highest risk signal.

The analysis indicated that while alendronate, denosumab, and other bisphosphonates had significant risk signals for AFF, drugs like raloxifene and romosozumab did not show any association, suggesting varying safety profiles among osteoporosis treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atypical femur fracture associated with common anti-osteoporosis drugs in FDA adverse event reporting system. Xiao, Y., Chen, Y., Huang, Y., et al.[2023]

Bisphosphonates like pamidronate and clodronate are commonly used in cancer treatment, with newer options like ibandronate and zoledronate showing promise for shorter infusion times and potentially better patient compliance.

While intravenous administration is preferred for chemotherapy patients due to its effectiveness, oral bisphosphonates offer outpatient convenience despite lower absorption rates and possible digestive side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dosing regimens and main adverse events of bisphosphonates. Body, JJ.[2019]

Sequential treatment with romosozumab followed by alendronate is a cost-effective option for postmenopausal women with severe osteoporosis, showing an increase of 0.089 quality-adjusted life years (QALYs) at an additional cost of €3002 compared to alendronate alone.

The analysis indicated a 97.9% probability that this sequential treatment is cost-effective, given the Swedish willingness-to-pay threshold of €60,000 per QALY, making it a promising strategy for reducing fracture risk in high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of romosozumab for the treatment of postmenopausal women with severe osteoporosis at high risk of fracture in Sweden. Söreskog, E., Lindberg, I., Kanis, JA., et al.[2021]

Romosozumab is an effective treatment for severe osteoporosis in postmenopausal women, significantly reducing vertebral and clinical fracture risk compared to placebo and oral alendronate in pivotal phase III trials involving monthly doses over 12 months.

The treatment not only increased bone mineral density significantly but also maintained these benefits even after transitioning to other osteoporosis therapies, indicating its potential as a valuable option for women at high risk of fractures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Romosozumab: A Review in Postmenopausal Osteoporosis. Paik, J., Scott, LJ.[2021]

In a case study of a 64-year-old man with osteogenesis imperfecta (OI) and severe osteoporosis, treatment with romosozumab led to significant increases in bone mineral density (BMD) of 22.0% in the lumbar spine and 136.4% in the total hip after 12 months.

Romosozumab treatment was well-tolerated, with no severe adverse effects reported, suggesting it may be a safe and effective option for improving bone health in patients with osteoporosis due to OI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of romosozumab for osteoporosis in a patient with osteogenesis imperfecta: A case report. Uehara, M., Nakamura, Y., Nakano, M., et al.[2022]

In a study of 175 postmenopausal osteoporosis patients over 12 months, romosozumab treatment significantly increased bone mineral density (BMD) similarly in both groups, whether or not they received active vitamin D supplementation.

While both groups showed comparable increases in BMD, the group receiving vitamin D had a smaller increase in a bone formation marker (P1NP) and a larger decrease in a bone resorption marker (TRACP-5b), suggesting that vitamin D may influence bone turnover without affecting overall BMD gains.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of romosozumab with and without active vitamin D analog supplementation for postmenopausal osteoporosis. Kobayakawa, T., Miyazaki, A., Takahashi, J., et al.[2022]

Romosozumab, a newly approved treatment for osteoporosis in Japan, effectively increases bone mineral density and reduces fracture risk by stimulating bone formation and suppressing bone resorption.

The ARCH study showed that romosozumab is more effective than alendronate, but due to its reversible effects, patients will need to follow up with anti-resorptive therapy after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Sequential treatment of osteoporosis with anti-sclerostin.] Inoue, D.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Bone mineral density and fracture rate in response to intravenous and oral bisphosphonates in adult osteogenesis imperfecta. [2018]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Zoledronic acid treatment in children with osteogenesis imperfecta. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

ZOLEDRONIC ACID VERSUS ALENDRONATE IN THE TREATMENT OF CHILDREN WITH OSTEOGENESIS IMPERFECTA: A 2-YEAR CLINICAL STUDY. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Alendronate treatment in osteogenesis imperfecta. [2013]

5. United States pubmed.ncbi.nlm.nih.gov

Impact of alendronate on quality of life in children with osteogenesis imperfecta. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Bisphosphonate-associated adverse events. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Adverse effects of bisphosphonates. [2022]

8. Spain pubmed.ncbi.nlm.nih.gov

[Adverse effects of bisphosphonates]. [2011]

9. England pubmed.ncbi.nlm.nih.gov

Atypical femur fracture associated with common anti-osteoporosis drugs in FDA adverse event reporting system. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Dosing regimens and main adverse events of bisphosphonates. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of romosozumab for the treatment of postmenopausal women with severe osteoporosis at high risk of fracture in Sweden. [2021]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Romosozumab: A Review in Postmenopausal Osteoporosis. [2021]

13. England pubmed.ncbi.nlm.nih.gov

Efficacy of romosozumab for osteoporosis in a patient with osteogenesis imperfecta: A case report. [2022]

14. England pubmed.ncbi.nlm.nih.gov

Effects of romosozumab with and without active vitamin D analog supplementation for postmenopausal osteoporosis. [2022]

15. Japan pubmed.ncbi.nlm.nih.gov

[Sequential treatment of osteoporosis with anti-sclerostin.] [2019]