Denosumab for Spinal Cord Injury

Recruiting at 1 trial location

Overseen By William A Bauman, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: James J. Peters Veterans Affairs Medical Center

Must not be taking: Anabolic steroids, Bisphosphonates

Disqualifiers: Post-menopausal, Cancer, Hypocalcemia, others

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: 6

Duration: 6 months

5 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on anabolic or steroid hormonal therapy, bisphosphonates, or high-dose corticosteroids, you may not be eligible to participate.

What data supports the effectiveness of the drug Denosumab for spinal cord injury?

Research shows that Denosumab helps maintain bone density in people with spinal cord injuries, especially around the knee, which is important because these areas are prone to fractures. It has also been shown to increase bone mass in individuals with recent spinal cord injuries, making it a promising option for treating bone loss related to these injuries. ^{1 2 3 4 5}

Is Denosumab generally safe for humans?

Denosumab has been used in humans for conditions like osteoporosis and has shown some common side effects such as back pain and high cholesterol. Rarely, it can cause liver issues, as seen in a few cases. In animal studies, it affected bone development in infants, but these effects were mostly reversible. ^{6 7 8 9 10}

How is the drug denosumab unique for treating spinal cord injury?

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 for spinal cord injury that may not focus on bone health. It is typically used for preventing bone complications in cancer patients, making its application in spinal cord injury novel. ^{9 11 12 13 14}

What is the purpose of this trial?

This trial is testing if the drug denosumab can prevent bone loss in people who have had a recent spinal cord injury. The drug is already used for other bone loss conditions but is experimental for this purpose. It works by stopping the process that breaks down bones, helping to keep them strong.

Research Team

Steven C Kirshblum, M.D.

Principal Investigator

Kessler Institute for Rehabilitation

William A Bauman, M.D.

Principal Investigator

James J. Peters VA Medical Center

Eligibility Criteria

Inclusion Criteria

You have partial paralysis from a spinal cord injury.

Your injury happened less than 6 months ago.

Exclusion Criteria

Pregnancy

You have a serious long-term health condition.

Women who have already gone through menopause.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Denosumab or placebo injections at baseline and 6 months

6 months

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

3 visits (in-person)

Treatment Details

Interventions

• Denosumab

Participant Groups

Group I: Denosumab, AIS Grade D (ambulatory) Experimental Treatment 1 Intervention

8 subjects with AIS grade D will be randomized to receive Denosumab (Prolia 120mg SC) administered at baseline and 6 months.

Group II: Denosumab, AIS Grade C (non-ambulatory) Experimental Treatment 1 Intervention

8 subjects with AIS grade C will be randomized to receive Denosumab (Prolia 120mg SC) administered at baseline and 6 months.

Group III: Placebo, AIS Grade D (ambulatory) Placebo Group 1 Intervention

8 subjects with AIS grade D will be randomized to the placebo group and will receive the identical volume of normal saline at parallel time points.

Group IV: Placebo, AIS Grade C (non-ambulatory) Placebo Group 1 Intervention

8 subjects with AIS grade C will be randomized to the placebo group and will receive the identical volume of normal saline at parallel time points.

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?

James J. Peters Veterans Affairs Medical Center

Lead Sponsor

Trials

59

Recruited

2,900+

Kessler Institute for Rehabilitation

Industry Sponsor

Trials

23

Recruited

1,100+

Findings from Research

Denosumab, a medication used to prevent osteoporosis in patients with low bone mineral density, has been associated with rare cases of hepatotoxicity, including a newly reported case of immune-mediated liver injury in a 43-year-old woman after three years of treatment.

The patient's liver function tests showed significantly elevated levels of liver enzymes, indicating potential drug-induced liver injury, which was confirmed by a liver biopsy revealing chronic inflammation and interface hepatitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Denosumab-Induced Immune Hepatitis. Ostrovsky, V., Malnick, S., Ish-Shalom, S., et al.[2021]

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]

A 72-year-old woman developed severe liver damage (submassive hepatic necrosis) after receiving denosumab, indicating a potential adverse drug reaction linked to immune response and cytokine induction.

The case highlights that RANKL inhibition by denosumab can lead to significant liver injury, as evidenced by elevated liver enzymes and proinflammatory cytokines, suggesting careful monitoring is needed for patients receiving this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe hepatocytotoxicity linked to denosumab. Malnick, S., Maor, Y., Melzer, E., et al.[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 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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Administration of Denosumab Preserves Bone Mineral Density at the Knee in Persons With Subacute Spinal Cord Injury: Findings From a Randomized Clinical Trial. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Denosumab increases sublesional bone mass in osteoporotic individuals with recent spinal cord injury. [2018]

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

Loss of lower extremity bone mineral density 1 year after denosumab is discontinued in persons with subacute spinal cord injury. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Pharmacological approaches for bone health in persons with spinal cord injury. [2021]

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

Neuroprotective effects of raloxifene on experimental spinal cord injury in rats. [2015]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Denosumab-Induced Immune Hepatitis. [2021]

7. 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]

8. Netherlands pubmed.ncbi.nlm.nih.gov

The similarity of pharmacokinetics, pharmacodynamics, safety, and immunogenicity between recombinant fully human anti-RANKL monoclonal antibody injection (MW032) and denosumab (Xgeva®) in healthy Chinese subjects: A single-center, randomized, double-blind, single-dose, parallel-controlled clinical study. [2022]

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

Vertebral compression fractures in patients under treatment with denosumab: a contraindication for percutaneous vertebroplasty? [2018]

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

Reproductive toxicity of denosumab in cynomolgus monkeys. [2015]

11. Italy pubmed.ncbi.nlm.nih.gov

Severe hepatocytotoxicity linked to denosumab. [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

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

14. England pubmed.ncbi.nlm.nih.gov

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