Romosozumab + Denosumab for Spinal Cord Injury

Recruiting at 1 trial location

Overseen By Christopher M Cirnigliaro, M.S.

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: James J. Peters Veterans Affairs Medical Center

Must not be taking: Glucocorticoids, Bisphosphonates, Corticosteroids, others

Disqualifiers: Coronary heart disease, Stroke, Bone cancer, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

39 Participants Needed

Trial Summary

What is the purpose of this trial?

The objective of the proposed work is to determine whether administration for 12 months of romosozumab (evenity) followed by 12 months of denosumab (prolia) will maintain bone mass at the knee in subjects with chronic SCI.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but certain medications like glucocorticoids and bisphosphonates may affect eligibility. It's best to discuss your current medications with the study staff.

What data supports the effectiveness of the drug Romosozumab + Denosumab for Spinal Cord Injury?

Research shows that Romosozumab helps build bone and reduce fractures in osteoporosis, while Denosumab is effective in preventing bone complications in cancer patients. Together, they may help improve bone health and reduce fracture risk, which could be beneficial for spinal cord injury patients. ^{1 2 3 4 5}

Is the combination of Romosozumab and Denosumab safe for humans?

Denosumab has been associated with rare cases of liver injury due to immune reactions and may increase the risk of infections. Romosozumab has been reviewed for safety, but there is potential cardiovascular risk associated with its use. ^{3 6 7 8 9}

How does the drug combination of Romosozumab and Denosumab differ from other treatments for spinal cord injury?

The combination of Romosozumab and Denosumab is unique because Romosozumab increases bone formation and decreases bone breakdown, while Denosumab helps maintain these benefits by further preventing bone loss. This sequential approach is particularly effective in increasing bone density and reducing fracture risk, which is not typically addressed by other treatments for spinal cord injury. ^{1 5 10 11 12}

Research Team

Christopher P Cardozo, M.D.

Principal Investigator

James J Peters VA Medical Center

William A. Bauman, MD

Principal Investigator

James J Peters VA Medical Center

Eligibility Criteria

This trial is for males aged 18-65 and premenopausal females aged 18-55 with chronic spinal cord injury (SCI) of more than 3 years, who are mostly wheelchair-dependent. Participants must have low bone density at the knee and agree to use effective contraception. Exclusions include weakened immune systems, heart disease history, recent heavy anti-inflammatory or bone density medication use, jawbone issues, abnormal calcium levels, cancer within the last five years, certain endocrine disorders, major fractures or surgeries in the past year.

Inclusion Criteria

Agreement to use a highly effective contraceptive method for women of reproductive potential

The bone density in your lower leg is equal to or less than 1.0 grams per square centimeter.

You have had a spinal cord injury for more than 3 years.

Exclusion Criteria

Pregnancy, or plans to become pregnant within 6 months after the end of study treatment

I have bone cancer.

You have a history of drinking too much alcohol for a long time.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive romosozumab monthly for 12 months followed by denosumab at month 12 and 18

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Denosumab
• Romoszumab

Trial Overview The study tests if a year-long treatment with Romosozumab followed by Denosumab can maintain knee bone mass in people with long-term SCI. It compares these drugs against a placebo over a period of two years to see which is better at improving bone health.

Participant Groups

Group I: Romosozumab group Experimental Treatment 2 Interventions

Romosozumab (evenity) administered monthly from baseline to month 11 followed by denosumab (prolia) at month 12 and 18

Group II: Control group Placebo Group 2 Interventions

Placebo administered monthly from baseline to month 11 followed by denosumab (prolia) at month 12 and 18

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

In the FRAME study involving 7180 postmenopausal women with osteoporosis, romosozumab significantly increased bone mineral density (BMD) at the spine and hip by 13% and 7%, respectively, after 12 months, and led to a substantial reduction in vertebral fractures by 81% in the following year.

Most patients treated with romosozumab experienced at least a 3% gain in BMD, with mean T-score increases indicating that the benefits of romosozumab over 2 years were comparable to 7 years of continuous treatment with denosumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FRAME Study: The Foundation Effect of Building Bone With 1 Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab. Cosman, F., Crittenden, DB., Ferrari, S., et al.[2019]

In a study involving 7180 postmenopausal women with osteoporosis, romosozumab significantly reduced the risk of clinical vertebral fractures (VFxs) by 83% compared to placebo over 12 months, with only 3 cases in the romosozumab group versus 17 in the placebo group.

Romosozumab works by inhibiting sclerostin, which increases bone formation and decreases bone resorption, leading to rapid improvements in bone density and strength, thereby reducing fracture risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of 1 Year of Romosozumab on the Incidence of Clinical Vertebral Fractures in Postmenopausal Women With Osteoporosis: Results From the FRAME Study. Geusens, P., Oates, M., Miyauchi, A., et al.[2020]

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]

Romosozumab significantly increases spine bone mineral density (BMD) after 12 months of treatment, with a 10.67% increase observed in a study of 262 patients, indicating its efficacy in treating spine osteoporosis.

The treatment was associated with a low incidence of new fractures (only five cases) and no fatal adverse events, highlighting its safety profile, especially in patients not previously treated with other osteoporosis medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early clinical effects, safety, and predictors of the effects of romosozumab treatment in osteoporosis patients: one-year study. Tominaga, A., Wada, K., Okazaki, K., et al.[2022]

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]

In a review of 33 randomized controlled trials involving 22,253 patients, denosumab treatment was associated with a higher incidence of serious adverse events related to infections, particularly in the ear, nose, throat, and gastrointestinal areas.

Despite the increased risk of serious infections, the overall risk of any infection and infection-related mortality was similar to that of comparator groups, suggesting that while denosumab may pose some infection risks, it does not significantly increase the likelihood of severe outcomes compared to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk for Infections During Treatment With Denosumab for Osteoporosis: A Systematic Review and Meta-analysis. Diker-Cohen, T., Rosenberg, D., Avni, T., et al.[2021]

In a study involving 2825 postmenopausal women at very high fracture risk (VHFR), romosozumab significantly reduced the incidence of new vertebral fractures by 76%, clinical fractures by 60%, and nonvertebral fractures by 54% compared to placebo after the first year.

The fracture risk reduction was sustained into the second year when women transitioned from romosozumab to denosumab, indicating that romosozumab is effective in improving bone health and reducing fracture risk in high-risk populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Romosozumab Efficacy in Postmenopausal Women With No Prior Fracture Who Fulfill Criteria for Very High Fracture Risk. McClung, MR., Betah, D., Deignan, C., et al.[2023]

Romosozumab significantly reduces the incidence of new vertebral fractures in postmenopausal women with osteoporosis after just 12 months of treatment, showing strong efficacy compared to both placebo and active bisphosphonate controls.

However, there is a concerning numerical increase in cardiovascular events associated with romosozumab, suggesting it should be used cautiously, especially in patients with a history of cardiovascular issues or high cardiovascular risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Romosozumab: a Review of Efficacy, Safety, and Cardiovascular Risk. Fixen, C., Tunoa, J.[2021]

Romosozumab, a monoclonal antibody that targets sclerostin, significantly increases bone mineral density and reduces the risk of fragility fractures when administered monthly for one year, especially when followed by denosumab.

Compared to other treatments like alendronate and teriparatide, romosozumab shows superior efficacy in increasing bone mineral density, making it a strong option for patients at high risk of fractures who do not have serious vascular issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Romosozumab : a new treatment for severe osteoporosis]. Uebelhart, B., Ferrari, S.[2021]

Romosozumab effectively increases bone formation and decreases bone resorption by inhibiting sclerostin, leading to significant reductions in fractures, particularly in postmenopausal women with osteoporosis.

In a pivotal study (FRAME) and its extension, 12 months of romosozumab treatment resulted in sustained benefits in fracture reduction and bone mineral density gains when followed by 24 months of denosumab, suggesting a promising treatment sequence for osteoporosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The sequential therapy of romosozumab followed by denosumab for osteoporosis.] Ono, K., Tanaka, S.[2019]

In a phase-2 trial involving 402 patients, romosozumab did not significantly accelerate the healing of tibial fractures compared to placebo, with median healing times being similar across groups.

The safety and tolerability of romosozumab were comparable to placebo, indicating that while it may not enhance healing, it does not pose additional risks in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Romosozumab in Skeletally Mature Adults with a Fresh Unilateral Tibial Diaphyseal Fracture: A Randomized Phase-2 Study. Bhandari, M., Schemitsch, EH., Karachalios, T., et al.[2021]

References

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

FRAME Study: The Foundation Effect of Building Bone With 1 Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab. [2019]

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

The Effect of 1 Year of Romosozumab on the Incidence of Clinical Vertebral Fractures in Postmenopausal Women With Osteoporosis: Results From the FRAME Study. [2020]

3. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

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

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

Early clinical effects, safety, and predictors of the effects of romosozumab treatment in osteoporosis patients: one-year study. [2022]

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

Denosumab-Induced Immune Hepatitis. [2021]

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

Risk for Infections During Treatment With Denosumab for Osteoporosis: A Systematic Review and Meta-analysis. [2021]

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

Romosozumab Efficacy in Postmenopausal Women With No Prior Fracture Who Fulfill Criteria for Very High Fracture Risk. [2023]

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

Romosozumab: a Review of Efficacy, Safety, and Cardiovascular Risk. [2021]

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

[Romosozumab : a new treatment for severe osteoporosis]. [2021]

11. Japan pubmed.ncbi.nlm.nih.gov

[The sequential therapy of romosozumab followed by denosumab for osteoporosis.] [2019]

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

Romosozumab in Skeletally Mature Adults with a Fresh Unilateral Tibial Diaphyseal Fracture: A Randomized Phase-2 Study. [2021]