Denosumab for Fibrous Dysplasia

Age: 18+

Sex: Any

Trial Phase: Phase 2

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

Must be taking: Calcium, Vitamin D

Must not be taking: Bisphosphonates

Disqualifiers: Osteomyelitis, Dental surgery, Pregnancy, 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: Unknown

Duration: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effects of denosumab, a medication, on individuals with fibrous dysplasia, a condition causing abnormal bone growth and pain. The main goal is to determine if denosumab can reduce bone turnover (the process of bone tissue being broken down and replaced) and alleviate bone pain. Researchers will also examine the impact of discontinuing the medication on bone health. Adults with fibrous dysplasia who have experienced related bone pain for at least three months may be suitable candidates for this study. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that you have not used bisphosphonates (a type of medication for bone conditions) within one year before starting the study. Other current medications are not specifically mentioned, so it's best to discuss your medications with the study team.

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

Research has shown that denosumab has been tested for safety in people with fibrous dysplasia (FD). In some studies, denosumab significantly lowered bone markers, substances in the blood that indicate bone health, demonstrating its expected action in the body.

For those considering joining a trial, it's important to know that past studies have shown denosumab to be well-tolerated. While side effects can occur, they are usually manageable. Common side effects might include reactions at the injection site, while serious side effects are rare.

The FDA has approved denosumab for other conditions, such as osteoporosis, so its safety profile is well-established. However, each condition and study is different, so discussing any concerns with a doctor is crucial. ^{1 2 3 4 5}

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

Denosumab is unique because it targets the RANKL pathway, which plays a crucial role in bone remodeling and reabsorption. Unlike traditional treatments for fibrous dysplasia, which often include pain management and surgical interventions, denosumab directly inhibits the cells that break down bone, potentially reducing bone lesions and associated symptoms. Researchers are excited about this treatment as it offers a targeted approach that could provide better control of the disease and improve the quality of life for patients with fibrous dysplasia.

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

Research has shown that denosumab, which participants in this trial will receive, can help reduce bone problems in people with fibrous dysplasia (FD). Studies have found that patients experienced less bone pain, and their bones became stronger and less likely to break. Additionally, the activity of affected bone areas noticeably decreased. Tests measuring bone health in the blood also showed significant improvements. These findings suggest that denosumab could be a promising treatment for managing symptoms of fibrous dysplasia. ^{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?

Adults over 18 with confirmed fibrous dysplasia and chronic bone pain, who have reached skeletal maturity. They must not have used denosumab or bisphosphonates in the past year, be willing to take supplements, use two forms of contraception if applicable, and cannot be pregnant or planning pregnancy within five months post-study.

Inclusion Criteria

I have had bone pain for at least 3 months in an area affected by FD.

Verbal confirmation required for the use of two forms of contraception from study consent through five months after study completion

Serum calcium or albumin-adjusted serum calcium within the normal range for the NIH laboratory

Exclusion Criteria

I have received denosumab in the last year.

I have had jawbone infections or conditions needing oral surgery.

I have had a bone fracture within the last 3 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive denosumab at 120 mg per dose every 4 weeks for six months, with loading doses on days 7 and 14 of month 1

6 months

Observation

Participants are followed for an 8-month observation period after treatment

8 months

Follow-up

A final visit occurs 21 months after denosumab discontinuation to monitor long-term effects

21 months post-treatment

What Are the Treatments Tested in This Trial?

Interventions

• Denosumab

Trial Overview The trial tests Denosumab's effects on bone turnover in fibrous dysplasia patients. It involves monthly doses for six months followed by an eight-month observation period. The study measures changes in bone markers, lesion intensity via PET/CT scans, and FD-related pain levels.

How Is the Trial Designed?

Group I: 1 Experimental Treatment 1 Intervention

Denosumab will be administered at 120 mg per dose every 4 weeks for six months, with loading doses on days 8 and 15 of month 1.

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

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]

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]

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]

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]

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 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 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 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 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 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, 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]

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]

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]

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 ...