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

9 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Denosumab for treating fibrous dysplasia?

Denosumab has shown promise in reducing pain and the size of bone lesions in patients with fibrous dysplasia, as seen in case reports where patients experienced improvements that were not achieved with previous treatments. Additionally, Denosumab is effective in other bone-related conditions, like osteoporosis, by targeting a protein involved in bone breakdown, which may explain its potential benefits in fibrous dysplasia. ^{1 2 3 4 5}

Is Denosumab generally safe for use in humans?

Denosumab, also known as Prolia or Xgeva, is a biologic treatment that has been monitored for safety in various conditions, including rheumatoid arthritis. Safety data from registers in Europe and the UK show that biologic treatments can have adverse effects, such as infections and cardiovascular events, which are closely monitored to ensure patient safety. ^{6 7 8 9 10}

How is the drug denosumab unique for treating fibrous dysplasia?

Denosumab is unique because it is a monoclonal antibody that targets RANKL, a protein involved in bone resorption, which is different from traditional treatments like bisphosphonates. It is administered as a subcutaneous injection, offering an alternative route and mechanism for managing bone-related conditions. ^{5 11 12 13 14}

What is the purpose of this trial?

This trial is testing denosumab, a drug that helps strengthen bones, in adults with fibrous dysplasia, a condition where bones grow abnormally. Denosumab works by stopping the cells that break down bone tissue, aiming to reduce bone pain and improve bone strength.

Research Team

Alison M Boyce, M.D.

Principal Investigator

National Institute of Dental and Craniofacial Research (NIDCR)

Eligibility Criteria

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.

I use two reliable birth control methods if I can have children.

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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, 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]

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]

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 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]

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]

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]

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, 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]

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]

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]

References

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

Denosumab treatment for fibrous dysplasia. [2021]

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

Regression of fibrous dysplasia in response to denosumab therapy: A report of two cases. [2021]

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

Denosumab Use in Adults With Fibrous Dysplasia: Case Reports and Review of the Literature. [2022]

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

Clinical value of RANKL, OPG, IL-6 and sclerostin as biomarkers for fibrous dysplasia/McCune-Albright syndrome. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Denosumab: a case of MRONJ with resolution. [2018]

6. England 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). [2019]

7. New Zealand 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). [2019]

8. France pubmed.ncbi.nlm.nih.gov

Cysteamine: Ehlers-Danlos syndrome. [2013]

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

European biologicals registers: methodology, selected results and perspectives. [2013]

10. England pubmed.ncbi.nlm.nih.gov

The British Society for Rheumatology biologics register. [2018]

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

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

12. Switzerland pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic analysis of denosumab in patients with bone metastases from solid tumours. [2021]

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

Quantitative pharmacology of denosumab in patients with bone metastases from solid tumors. [2015]

14. Italy pubmed.ncbi.nlm.nih.gov

Interstitial Lung Disease in a Patient Treated with Denosumab. [2022]