Denosumab for Fibrous Dysplasia

Overseen By Alison M Boyce, M.D.

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Dental and Craniofacial Research (NIDCR)

Disqualifiers: Pregnancy, Osteomyelitis, Dental surgery, others

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

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 17

Duration: 48 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called denosumab (also known as Prolia or Xgeva) to determine if it can stop the growth of bone lesions in children with fibrous dysplasia, a condition where abnormal bone growth can lead to fractures and deformities. The goal is to assess whether denosumab can effectively manage these bone lesions and improve the quality of life for these children. Children aged 4 to 14 years with fibrous dysplasia who are already in a related study might be suitable candidates. Participants will receive regular injections and undergo tests to monitor their bone health during the trial. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important findings.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you've used another investigational agent within the last 3 months before starting the trial.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are using another investigational drug, you must stop it at least 3 months before starting the trial.

Is there any evidence suggesting that denosumab is likely to be safe for humans?

In earlier studies, denosumab has shown promise in treating fibrous dysplasia (FD), a condition affecting bones. Research shows that denosumab can lower bone turnover markers, substances in the blood indicating the rate of bone breakdown and rebuilding. This suggests the drug might help slow the disease's activity.

Safety remains a major concern, especially for children. Evidence from studies on adults with FD suggests that denosumab is generally well-tolerated. Some patients experienced fewer side effects with moderate doses compared to higher ones. Common side effects in adults include reactions at the injection site and low calcium levels in the blood, which can be managed with proper monitoring and care.

While these findings are promising, the safety of denosumab in children is still under investigation. This trial aims to gather more information to ensure the treatment is safe and effective for younger patients with FD. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for fibrous dysplasia?

Denosumab is unique because it targets a protein called RANKL, which plays a key role in bone remodeling. Unlike traditional treatments for fibrous dysplasia, which often involve managing symptoms with pain relievers or surgical interventions, Denosumab acts directly to inhibit bone resorption. This new approach may offer a more targeted treatment, potentially reducing the bone lesions and weakening associated with fibrous dysplasia. Researchers are excited because Denosumab could provide more effective and less invasive management of the condition.

What evidence suggests that denosumab might be an effective treatment for fibrous dysplasia?

Research shows that denosumab, the treatment under study in this trial, holds promise for treating fibrous dysplasia (FD). Studies have found that it can significantly reduce activity in bone lesions and strengthen affected bones. Patients who took denosumab reported less bone pain and showed decreases in markers indicating bone activity. Overall, denosumab appears well-tolerated and may help manage the symptoms and progression of FD. ^{1 3 4 5 6}

Who Is on the Research Team?

Alison M Boyce, M.D.

Principal Investigator

National Institute of Dental and Craniofacial Research (NIDCR)

Are You a Good Fit for This Trial?

Children aged 4-14 with Fibrous Dysplasia enrolled in a specific NIH study, weighing at least 12 kg. They must have a guardian who can consent to the trial and agree to use effective contraception if of reproductive age. Exclusions include low calcium levels, untreated hypophosphatemia, recent investigational drug use, safety concerns as per investigator's discretion, pregnancy or lactation, allergy to denosumab, jaw bone issues or recent surgeries.

Inclusion Criteria

I am between 4 and 14 years old.

I have been diagnosed with fibrous dysplasia.

Concurrent enrollment in the companion Screening and Natural History protocol 98-D-0145

Exclusion Criteria

My calcium levels are currently low, but I can try to increase them.

I have not had any bone surgery in the 6 weeks before starting denosumab.

Known allergic reactions to denosumab

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person or telehealth)

Treatment

Participants receive denosumab injections every 4 weeks for 48 weeks, with additional tests and evaluations

48 weeks

12 visits (in-person), additional local lab visits every 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

28 weeks

4 overnight stays in hospital, additional follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Denosumab

Trial Overview The trial is testing denosumab injections every four weeks for one year in children with FD. The goal is to see if it stops the growth of weak and potentially harmful bone lesions. Participants will undergo various tests including dental exams and scans during their hospital stays and local lab visits.

How Is the Trial Designed?

Group I: treatment Experimental Treatment 1 Intervention

treatment arm

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

Approved in European Union as Prolia for:

• Osteoporosis in postmenopausal women
• Bone loss associated with hormone ablation therapy for prostate cancer
• Bone loss associated with hormone ablation therapy for breast cancer

Approved in United States as Prolia for:

• Treatment of postmenopausal women with osteoporosis at high risk for fracture
• Treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer
• Treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer

Approved in Canada as Prolia for:

• Treatment of osteoporosis in postmenopausal women at high risk for fracture
• Treatment to increase bone mass in men with osteoporosis at high risk for fracture

Approved in Japan as Prolia for:

• Treatment of osteoporosis in postmenopausal women
• Treatment of bone loss associated with hormone ablation therapy for prostate cancer

Who Is Running the Clinical Trial?

National Institute of Dental and Craniofacial Research (NIDCR)

Lead Sponsor

Trials

312

Recruited

853,000+

Published Research Related to This Trial

The British Society for Rheumatology has created a nationwide register to monitor long-term toxicity and benefits of biologic agents in patients with rheumatological disorders, aiming to provide valuable data on their safety and efficacy.

The study includes a comparison group of patients with active rheumatoid arthritis receiving conventional treatments, allowing for a thorough analysis of the differences in outcomes between biologic and traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The British Society for Rheumatology biologics register. Watson, K., Symmons, D., Griffiths, I., et al.[2018]

The DANBIO database captured 20 times more adverse events related to biological agents than the Danish Medicines Agency, highlighting its effectiveness in monitoring patient safety.

Infections and hypersensitivity reactions were the most common adverse events, with older age, longer disease duration, and a higher number of previous DMARD treatments identified as risk factors for bacterial infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Routine database registration of biological therapy increases the reporting of adverse events twentyfold in clinical practice. First results from the Danish Database (DANBIO). Hetland, ML., Unkerskov, J., Ravn, T., et al.[2019]

Denosumab therapy led to a decrease in the size and activity of fibrous dysplasia lesions in two patients, along with reduced pain and bone turnover markers, which was not achieved with previous bisphosphonate treatments.

These cases suggest that denosumab could be a promising alternative for patients who do not respond to bisphosphonates, and it may also serve as neoadjuvant therapy to enhance surgical outcomes in severe cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regression of fibrous dysplasia in response to denosumab therapy: A report of two cases. Meier, ME., van der Bruggen, W., van de Sande, MAJ., et al.[2021]

Denosumab, a drug used to prevent bone loss, was linked to a non-healing area in the lower jaw after a tooth extraction, highlighting a potential complication associated with its use.

After stopping denosumab, the non-healing area healed successfully, suggesting that discontinuation of the drug may be necessary to allow for healing in similar cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Denosumab: a case of MRONJ with resolution. Lyttle, CV., Patterson, H.[2018]

Denosumab, a monoclonal antibody that inhibits RANKL, shows consistent pharmacokinetics across a large population of 1,076 subjects, including both healthy individuals and cancer patients, indicating its effectiveness in preventing osteoclast activation and survival.

The study found that after administering denosumab, over 95% of patients achieved more than 97% RANKL occupancy, suggesting that dosage adjustments based on body weight, age, race, or tumor type are unnecessary for patients with bone metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic analysis of denosumab in patients with bone metastases from solid tumours. Gibiansky, L., Sutjandra, L., Doshi, S., et al.[2021]

Long-term safety and effectiveness of TNF-alpha inhibitors are being monitored through independent, academia-initiated drug registers in several European countries, which include all licensed biological agents and utilize standardized reporting systems for adverse events.

These registers have identified key safety concerns related to infections, malignancies, cardiovascular events, and pregnancy outcomes, highlighting the importance of ongoing collaboration between regulatory authorities, academia, and pharmaceutical companies for effective pharmacovigilance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European biologicals registers: methodology, selected results and perspectives. Zink, A., Askling, J., Dixon, WG., et al.[2013]

Denosumab, a medication commonly used to treat osteoporosis, has known side effects like atypical femur fractures and osteonecrosis of the jaw, but this case report highlights a potential link to interstitial lung disease (ILD) as well.

While this is the first reported case of ILD possibly related to denosumab, it does not establish a direct cause-and-effect relationship, but it suggests that healthcare providers should consider denosumab exposure in patients presenting with ILD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interstitial Lung Disease in a Patient Treated with Denosumab. Ruiz, AC., Carrascosa, MF., Concha, ST., et al.[2022]

Denosumab is a novel antiresorptive drug approved in the UK for preventing osteoporotic fractures in postmenopausal women and for managing skeletal-related events in patients with bone metastases.

There is a risk of osteonecrosis of the jaw (ARONJ) associated with denosumab, which dental professionals need to consider when advising patients undergoing dental treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Denosumab, an Alternative to Bisphosphonates but also Associated with Osteonecrosis of the Jaw--What is the Risk?. Sidhu, HK.[2018]

In a study of 96 adult patients with fibrous dysplasia/McCune-Albright syndrome, potential biomarkers like RANKL, IL-6, and sclerostin did not correlate with traditional bone turnover markers or pain levels, indicating they may not be useful for assessing disease severity or treatment response.

However, pre-treatment levels of IL-6 and the RANKL/OPG ratio showed some potential in predicting clinical response to denosumab, suggesting that these biomarkers could be further explored in future studies alongside imaging and patient-reported outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical value of RANKL, OPG, IL-6 and sclerostin as biomarkers for fibrous dysplasia/McCune-Albright syndrome. Meier, ME., Hagelstein-Rotman, M., Streefland, TCM., et al.[2023]

Denosumab (XGEVA®) is a monoclonal antibody that effectively inhibits bone resorption by preventing the activation of osteoclasts, making it a targeted treatment for patients with bone metastases.

In Phase 3 clinical studies, denosumab was found to be superior to zoledronic acid in delaying skeletal-related events (SREs) by a median of 8.2 months, suggesting it may be a more effective treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative pharmacology of denosumab in patients with bone metastases from solid tumors. Perez Ruixo, JJ., Doshi, S., Sohn, W., et al.[2015]

A study analyzing 2602 suspected adverse drug reactions (ADRs) from the FDA Adverse Event Reporting System found that biologic drugs for rheumatoid arthritis are associated with significant safety concerns, particularly infections and neoplasms, with infliximab being notably implicated.

The research identified 63 signals of disproportionate reporting related to serious medical events, especially blood disorders linked to rituximab, and highlighted risks such as intestinal perforation and pulmonary fibrosis that warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Biologics Approved for the Treatment of Rheumatoid Arthritis and Other Autoimmune Diseases: A Disproportionality Analysis from the FDA Adverse Event Reporting System (FAERS). Araujo, AGS., Borba, HHL., Tonin, FS., et al.[2019]

Denosumab, a monoclonal antibody targeting RANKL, showed significant efficacy in reducing pain and tumor growth in a 9-year-old boy with severe fibrous dysplasia over 7 months of treatment, indicating its potential as a therapeutic option for this condition.

While denosumab effectively suppressed bone turnover markers and reduced disease symptoms, it also caused notable disturbances in mineral metabolism, including hypophosphatemia and secondary hyperparathyroidism, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Denosumab treatment for fibrous dysplasia. Boyce, AM., Chong, WH., Yao, J., et al.[2021]

Denosumab was administered to two patients with fibrous dysplasia (FD) who had previously been treated with bisphosphonates, but neither patient experienced improvement in bone pain after treatment with denosumab.

Despite the lack of pain relief in these cases, literature suggests that denosumab may reduce bone turnover markers and has shown promise in improving bone pain for other patients with FD, indicating the need for further research on its efficacy and optimal treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Denosumab Use in Adults With Fibrous Dysplasia: Case Reports and Review of the Literature. Hung, C., Shibli-Rahhal, A.[2022]

The study identifies a negative impact on connective tissue associated with a specific drug used to treat a rare disease, highlighting potential safety concerns.

Understanding these adverse effects is crucial for evaluating the overall efficacy and safety profile of the drug in patients with this rare condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cysteamine: Ehlers-Danlos syndrome. [2013]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39673171/

Safety and Efficacy of Moderate-dose Denosumab in ... A phase 2 trial of the RANKL inhibitor denosumab (NCT03571191) reported profound reductions in lesion activity and increased lesional mineralization after 6 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3377825/

Denosumab Treatment for Fibrous Dysplasia - PMC The primary endpoint of denosumab efficacy was the rate of change in tumor volume as measured by CT. Additional efficacy endpoints were bone turnover markers ( ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03571191

NCT03571191 | Denosumab Treatment for Fibrous Dysplasia The primary objective of this study is to evaluate the effect of denosumab on bone turnover in individuals with fibrous dysplasia (FD).

4. academic.oup.com academic.oup.com/jcem/article/104/12/6069/5544499

Denosumab in Patients With Fibrous Dysplasia Previously ... Denosumab 60 mg given subcutaneously every 3 months decreased bone pain and serum markers of bone turnover and was well tolerated in 12 patients with sever.

5. fdmasalliance.org fdmasalliance.org/research/safety-and-efficacy-of-denosumab-for-fibrous-dysplasia-of-bone/

Safety and Efficacy of Denosumab for Fibrous Dysplasia ... In this study involving patients with fibrous dysplasia of bone, denosumab was associated with marked reductions in the serum bone markers and with bony ...

6. nejm.org nejm.org/doi/full/10.1056/NEJMc2214862

Safety and Efficacy of Denosumab for Fibrous Dysplasia ... In this study involving patients with fibrous dysplasia of bone, denosumab was associated with marked reductions in the serum bone markers ...