Denosumab Switch for Osteoporosis

Overseen By Josh Melnick, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Alabama at Birmingham

Must be taking: Glucocorticoids

Must not be taking: Bisphosphonates, Denosumab

Disqualifiers: Unstable medical condition, Hyperthyroidism, Hypothyroidism, 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: 3

Duration: 6-9 months

45 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Investigators will test the hypothesis that an increase in bone turnover markers (e.g. carboxy-terminal collagen crosslinks (CTX) and P1NP) in patients currently taking chronic glucocorticoids will be attenuated more in those who switch from denosumab to "late" zoledronic acid (9 months after last denosumab dose) compared to participants randomized to "early" zoledronic acid (6 months after last denosumab dose) or weekly alendronate (6 months after last denosumab dose).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does require that you have been on glucocorticoids for at least 3 months and continue them for at least 6 more months. If you are taking bisphosphonates, you must not have used them in the past 2 years.

Is Denosumab safe for humans?

Denosumab, used for treating osteoporosis, has been shown to be generally safe in humans, with common side effects including back pain, pain in the arms or legs, and high cholesterol. Long-term studies have not shown increasing trends in these side effects over time. ^{1 2 3 4 5}

How is the drug Denosumab unique for treating osteoporosis?

Denosumab is unique because it is the first fully human monoclonal antibody that works by blocking a protein called RANK ligand, which prevents the formation and activity of cells that break down bone. It is administered as a subcutaneous injection every six months, offering a convenient dosing schedule compared to other treatments like bisphosphonates, which are often taken more frequently. ^{1 4 6 7 8}

What data supports the effectiveness of the drug Denosumab for osteoporosis?

Denosumab has been shown to significantly increase bone mineral density and reduce the risk of fractures in postmenopausal women with osteoporosis. It is more effective at improving bone density than continuing treatment with bisphosphonates, and it decreases vertebral fractures by 68%, nonvertebral fractures by 19%, and hip fractures by 42% over at least 36 months. ^{1 3 4 9 10}

Are You a Good Fit for This Trial?

This trial is for men and women aged 18 or older who have been using glucocorticoids at a certain dose for over 3 months and will continue for at least another six. They must have osteoporosis as shown by bone density scores, or a history of fractures with less severe bone loss. Exclusions include various other bone diseases, recent cancer, dental issues, malnutrition disorders, pregnancy/breastfeeding without contraception use, and intolerance to study drugs.

Inclusion Criteria

I have been taking a steroid medication equivalent to more than 7.5 mg of prednisone daily for over 3 months and will continue for at least 6 months.

My bone density is low, or I've had a fracture due to weak bones.

Exclusion Criteria

I have been diagnosed with Addison's disease.

Not a good candidate for study participation in opinion of investigator

I cannot take denosumab due to bad reactions or allergies.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

1 visit (in-person)

Treatment

Participants switch from Denosumab to either early or late Zoledronic Acid or Alendronate

6-9 months

Regular visits for treatment administration

Follow-up

Participants are monitored for changes in bone turnover markers and safety

6 months

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Denosumab

Trial Overview The study tests if switching from Denosumab (DMAB) to 'late' zoledronic acid (9 months after last DMAB dose) versus 'early' zoledronic acid (6 months after last DMAB dose) or weekly alendronate affects bone turnover markers in patients on long-term steroids differently.

How Is the Trial Designed?

Group I: DMAB to "Early" Zoledronic Acid (ZA) Active Control 1 Intervention

Switch from Denosumab 60 mg administered subcutaneously (SC) to one "early" zoledronic acid infusion (5 mg; 6 months after last denosumab dose)

Group II: Denosumab (DMAB) to Alendronate (ALN) Active Control 1 Intervention

Switch from Denosumab 60 mg administered subcutaneously (SC) to weekly oral alendronate (70 mg; started 6 months after last denosumab dose)

Group III: DMAB to "Late" ZA Active Control 1 Intervention

Switch from Denosumab 60 mg administered subcutaneously (SC) to one "late" zoledronic acid infusion (5 mg; 9 months after last denosumab dose)

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?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

Vrije Universiteit Brussel

Collaborator

Trials

213

Recruited

272,000+

Maastricht University

Collaborator

Trials

246

Recruited

13,190,000+

Amgen

Industry 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

Published Research Related to This Trial

Denosumab, a monoclonal antibody that inhibits osteoclast activity, has been shown to significantly increase bone mineral density for over 3 years and reduce the risk of fractures, including a 42% decrease in hip fractures.

The safety profile of denosumab is comparable to other osteoporosis treatments, although there are concerns about potential risks such as immunosuppression and cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The clinical use of denosumab for the management of low bone mineral density in postmenopausal women. Harris, KB., Nealy, KL., Jackson, DJ., et al.[2015]

Denosumab, a monoclonal antibody that targets RANKL, significantly reduces the risk of fractures in postmenopausal women with osteoporosis, showing a 68% reduction in new vertebral fractures and a 40% reduction in hip fractures over a 3-year trial.

Long-term treatment with denosumab did not show increasing trends in adverse events, indicating that its safety profile remains stable over 6 years, even when comparing data from initial placebo recipients who later received the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Observations With 3 Years of Denosumab Exposure: Comparison Between Subjects Who Received Denosumab During the Randomized FREEDOM Trial and Subjects Who Crossed Over to Denosumab During the FREEDOM Extension. Watts, NB., Brown, JP., Papapoulos, S., et al.[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]

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]

Citations

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

Denosumab: What's new? [2021]

2. Ireland pubmed.ncbi.nlm.nih.gov

Treatment of osteoporosis with denosumab. [2015]

3. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of denosumab vs. bisphosphonates in postmenopausal women previously treated with oral bisphosphonates. [2021]

4. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Preliminary results of an open-label observational study evaluating the efficacy and safety of Prolia used in women with postmenopausal osteoporosis]. [2015]

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

The clinical use of denosumab for the management of low bone mineral density in postmenopausal women. [2015]

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

Safety Observations With 3 Years of Denosumab Exposure: Comparison Between Subjects Who Received Denosumab During the Randomized FREEDOM Trial and Subjects Who Crossed Over to Denosumab During the FREEDOM Extension. [2018]

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

Denosumab for treatment of postmenopausal osteoporosis. [2019]

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

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

9. Switzerland pubmed.ncbi.nlm.nih.gov

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

10. Switzerland pubmed.ncbi.nlm.nih.gov

[Treatment of osteoporosis with Denosumab]. [2015]