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

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests an injectable medication in children with fibrous dysplasia. The drug works by preventing excessive bone breakdown, aiming to stop the growth of bone lesions. It has shown promise in treating fibrous dysplasia.

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.

What data supports the idea that Denosumab for Fibrous Dysplasia is an effective drug?

The available research shows that Denosumab can be effective for treating Fibrous Dysplasia. In one case, a 9-year-old boy with severe Fibrous Dysplasia experienced a significant reduction in pain and tumor growth after 7 months of Denosumab treatment. Another report described two patients who saw a decrease in the size and activity of their lesions, along with reduced pain, which was not achieved with previous treatments. These findings suggest that Denosumab may be more effective than traditional treatments like bisphosphonates, especially in severe cases. ^{1 2 3 4 5}

What data supports the effectiveness of the drug denosumab for 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. ^{1 2 3 4 5}

What safety data is available for Denosumab (Prolia, Xgeva)?

The safety data for Denosumab, also known as Prolia or Xgeva, can be inferred from studies on biological therapies used in rheumatology and autoimmune diseases. The Danish Database (DANBIO) and the British Society for Rheumatology biologics register provide insights into adverse events and long-term toxicity associated with biological agents. These registers track adverse events such as infections, malignancies, cardiovascular events, and more, ensuring high-quality data for safety surveillance. Although these studies focus on a range of biologics, they highlight the importance of monitoring adverse drug reactions in clinical practice. ^{6 7 8 9 10}

Is Denosumab 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 important to consider when evaluating their use. ^{6 7 8 9 10}

Is the drug Denosumab a promising treatment for Fibrous Dysplasia?

Denosumab is a promising drug because it helps prevent bone problems in people with certain conditions, like cancer that has spread to the bones. It works by stopping cells that break down bone, which can help keep bones stronger for longer. ^{5 11 12 13 14}

How is the drug denosumab different from other treatments for fibrous dysplasia?

Denosumab is unique because it is a fully human monoclonal antibody that targets RANKL, a protein involved in bone breakdown, which is different from traditional treatments like bisphosphonates. It is administered as a subcutaneous injection, offering an alternative for patients who may not respond well to other therapies. ^{5 11 12 13 14}

Research Team

Alison M Boyce, M.D.

Principal Investigator

National Institute of Dental and Craniofacial Research (NIDCR)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

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]

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]

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]

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]

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 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. 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]

7. England pubmed.ncbi.nlm.nih.gov

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

8. England pubmed.ncbi.nlm.nih.gov

The British Society for Rheumatology biologics register. [2018]

9. 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]

10. France pubmed.ncbi.nlm.nih.gov

Cysteamine: Ehlers-Danlos syndrome. [2013]

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]