Romosozumab + Zoledronic Acid for Osteoporosis

(RUBI Trial)

Overseen By Bari M Guzikowski, BA

Age: 65+

Sex: Female

Trial Phase: Phase 4

Sponsor: Susan L. Greenspan

Must not be taking: Bisphosphonates, Denosumab, Teriparatide, Romosozumab

Disqualifiers: Recent CVD, Renal insufficiency, others

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

Compensation: Varies

Number of Visits: 12

Duration: 12 months

200 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out if one year of romosozumab (Evenity®), a monthly injection given in the arm under the skin, prior to an infusion of zoledronic acid Reclast®, works to treat bone loss and prevent it from worsening in older women (ages 65 and older) who have osteoporosis and reside in long-term care (LTC) facilities.

Do I need to stop my current medications for the trial?

You can continue taking medications that affect bone and mineral metabolism, like glucocorticoids and anticonvulsants, and osteoporosis agents like estrogen/progesterone or raloxifene if prescribed by your doctor. However, you cannot participate if you are currently on certain osteoporosis therapies like bisphosphonates, denosumab, teriparatide, abaloparatide, or romosozumab.

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

Research shows that Romosozumab is effective in treating osteoporosis by increasing bone density and reducing the risk of fractures, especially in postmenopausal women. Studies have demonstrated that it works well when used alone or followed by another drug called denosumab, leading to ongoing improvements in bone health. ^{1 2 3 4 5}

Is Romosozumab safe for humans?

Romosozumab has been studied for safety in several clinical trials for osteoporosis, and while it is generally considered safe, there may be potential cardiovascular risks (related to the heart and blood vessels) associated with its use. The FDA's adverse event reporting system is used to monitor any unexpected side effects. ^{2 6 7 8 9}

How does the drug romosozumab differ from other osteoporosis treatments?

Romosozumab is unique because it is a monoclonal antibody that both promotes bone formation and reduces bone breakdown by targeting sclerostin, a protein that regulates bone growth. This dual action leads to rapid and significant increases in bone density, which is more effective than many other treatments like bisphosphonates or parathyroid hormone analogs. It is typically followed by another drug to maintain its benefits. ^{4 10 11 12 13}

Research Team

Susan L Greenspan, MD

Principal Investigator

University of Pittsburgh

Eligibility Criteria

This trial is for women aged 65 or older with osteoporosis, living in long-term care facilities. They must have a bone density score of -2.5 SD or lower, a history of fractures, or meet certain risk criteria. Excluded are non-walkers, those with recent severe heart issues, kidney problems preventing IV treatment, recent stroke or heart attack victims, current users of specific osteoporosis meds and very low vitamin D levels.

Inclusion Criteria

Willing and able to complete the informed consent process or provide consent by proxy

I am a woman aged 65 or older living in a care facility.

I have osteoporosis or had a major bone fracture.

Exclusion Criteria

Your vitamin D levels are lower than 25 ng/mL.

I am currently taking or have recently taken medication for osteoporosis.

I am unable to walk on my own.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive monthly subcutaneous injections of Romosozumab for 12 months, followed by a Zoledronic Acid infusion

12 months

12 visits (in-person) for injections, 1 visit (in-person) for infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Regular monitoring visits

Treatment Details

Interventions

• Romosozumab

Trial Overview The study tests if romosozumab injections followed by zoledronic acid infusion can improve bone health in elderly women with osteoporosis at LTC facilities. It compares the effects to placebo treatments alongside standard calcium and vitamin D supplements.

Participant Groups

Group I: Romosozumab, then Zoledronic Acid Experimental Treatment 3 Interventions

Monthly dose: 210 mg Romosozumab subcutaneous injections; Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplements); all participants will receive 5 mg Zoledronic Acid IV infusion at the Month 12 visit.

Group II: Placebo, then Zoledronic Acid Placebo Group 3 Interventions

Monthly dose: placebo saline subcutaneous injections; Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplements); all participants will receive 5 mg Zoledronic Acid IV infusion at the Month 12 visit.

Who Is Running the Clinical Trial?

Susan L. Greenspan

Lead Sponsor

Trials

6

Recruited

990+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Findings from Research

In a study of 148 postmenopausal osteoporosis patients, those who were treatment-naïve showed the greatest increase in bone mineral density (BMD) after 12 months of romosozumab treatment, with an 18.2% increase in lumbar spine BMD compared to lower increases in patients previously treated with bisphosphonates or other therapies.

The effectiveness of romosozumab in increasing BMD was significantly influenced by the type of prior treatment and early changes in bone turnover markers, indicating that these factors can help predict treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of prior osteoporosis treatment on 12-month treatment response of romosozumab in patients with postmenopausal osteoporosis. Ebina, K., Tsuboi, H., Nagayama, Y., et al.[2021]

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 treatment significantly increased bone mineral density (BMD) in the lumbar spine compared to denosumab, with increases of 4.9% and 5.2% at 3 and 6 months, respectively, versus 2.3% and 3.2% for denosumab.

Despite the improvement in BMD, romosozumab did not significantly affect disease activity in rheumatoid arthritis (RA) patients over the 6-month study period, indicating that while it may help with bone health, it does not impact RA symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of romosozumab or denosumab treatment on the bone mineral density and disease activity for 6 months in patients with rheumatoid arthritis with severe osteoporosis: An open-label, randomized, pilot study. Mochizuki, T., Yano, K., Ikari, K., et al.[2022]

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 study of 130 postmenopausal osteoporosis patients, those who were treatment-naïve showed the greatest increase in lumbar spine bone mineral density (BMD) after six months of romosozumab treatment, with a 13.6% increase compared to lower increases in patients previously treated with bisphosphonates, denosumab, or teriparatide.

The early changes in bone turnover markers, specifically PINP and TRACP-5b, were significant predictors of the increase in lumbar spine BMD, indicating that monitoring these markers could help assess treatment response to romosozumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of prior osteoporosis treatment on early treatment response of romosozumab in patients with postmenopausal osteoporosis. Ebina, K., Hirao, M., Tsuboi, H., et al.[2021]

Romosozumab, a new treatment for osteoporosis, has been associated with several significant adverse events, including injection site pain, cardiac failure, renal impairment, pneumonia, and increased blood alkaline phosphatase levels, based on an analysis of 1,948 reported adverse events from the FDA Adverse Event Reporting System.

The study highlights the importance of monitoring these potential adverse reactions in clinical settings, as the reporting odds ratios indicate a strong association between romosozumab and these adverse events, suggesting that healthcare providers should be cautious when prescribing this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pharmacovigilance analysis of FDA adverse event reporting system events for romosozumab. Chen, Z., Li, M., Li, S., et al.[2023]

Romosozumab significantly increases bone mineral density (BMD) in patients with osteoporosis, showing greater gains at the lumbar spine and hip compared to teriparatide after 12 months, making it an effective treatment option.

While romosozumab reduces fracture risk in high-risk postmenopausal women, it is associated with a higher incidence of serious cardiovascular events, so it should be avoided in patients with recent history of myocardial infarction or stroke.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Romosozumab: A Novel Injectable Sclerostin Inhibitor With Anabolic and Antiresorptive Effects for Osteoporosis. Nealy, KL., Harris, KB.[2021]

Romosozumab significantly improved bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck compared to teriparatide, with notable improvements observed at both 6 and 12 months in a review of 4 studies involving 1304 patients.

Romosozumab had fewer injection-site reactions compared to teriparatide, and there were no significant differences in serious adverse events or mortality, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Romosozumab versus Teriparatide for the Treatment of Postmenopausal Osteoporosis: A Systematic Review and Meta-analysis through a Grade Analysis of Evidence. Tian, A., Jia, H., Zhu, S., et al.[2023]

Romosozumab significantly reduces the risk of fractures in postmenopausal women with osteoporosis, showing a 63% lower risk of new vertebral fractures and a 41% lower risk of hip fractures compared to other therapies, based on data from six randomized controlled trials involving over 5,600 participants.

The treatment also leads to substantial increases in bone mineral density (BMD) at key sites like the lumbar spine and hip, while demonstrating a good safety profile with no significant increase in adverse events compared to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Romosozumab treatment in postmenopausal women with osteoporosis: a meta-analysis of randomized controlled trials. Liu, Y., Cao, Y., Zhang, S., et al.[2019]

Romosozumab is an effective treatment for severe osteoporosis in postmenopausal women, significantly reducing vertebral and clinical fracture risk compared to placebo and oral alendronate in pivotal phase III trials involving monthly doses over 12 months.

The treatment not only increased bone mineral density significantly but also maintained these benefits even after transitioning to other osteoporosis therapies, indicating its potential as a valuable option for women at high risk of fractures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Romosozumab: A Review in Postmenopausal Osteoporosis. Paik, J., Scott, LJ.[2021]

In a study involving 347 postmenopausal women with osteoporosis and knee osteoarthritis, romosozumab did not significantly improve knee pain or function compared to placebo, indicating it may not be effective for this specific condition.

However, romosozumab treatment resulted in significant gains in bone mineral density (BMD), suggesting it may still provide benefits for bone health in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Romosozumab Treatment in Postmenopausal Women With Osteoporosis and Knee Osteoarthritis: Results From a Substudy of a Phase 3 Clinical Trial. Lane, NE., Betah, D., Deignan, C., et al.[2023]

In a study of 175 postmenopausal osteoporosis patients over 12 months, romosozumab treatment significantly increased bone mineral density (BMD) similarly in both groups, whether or not they received active vitamin D supplementation.

While both groups showed comparable increases in BMD, the group receiving vitamin D had a smaller increase in a bone formation marker (P1NP) and a larger decrease in a bone resorption marker (TRACP-5b), suggesting that vitamin D may influence bone turnover without affecting overall BMD gains.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of romosozumab with and without active vitamin D analog supplementation for postmenopausal osteoporosis. Kobayakawa, T., Miyazaki, A., Takahashi, J., et al.[2022]

Romosozumab is a highly effective treatment for osteoporosis, functioning as a monoclonal antibody that inhibits sclerostin, leading to increased bone mineral density (BMD) and superior results compared to traditional treatments like bisphosphonates and PTH analogs.

While romosozumab shows significant benefits in bone density and fracture risk reduction, it carries a black box warning for patients with recent myocardial infarction or stroke, indicating a need for caution and further research on its cardiovascular safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Utility of Romosozumab in the Management of Osteoporosis: Focus on Patient Selection and Perspectives. Lim, SY., Bolster, MB.[2022]

References

1. France pubmed.ncbi.nlm.nih.gov

Effects of prior osteoporosis treatment on 12-month treatment response of romosozumab in patients with postmenopausal osteoporosis. [2021]

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

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

3. Netherlands pubmed.ncbi.nlm.nih.gov

Effects of romosozumab or denosumab treatment on the bone mineral density and disease activity for 6 months in patients with rheumatoid arthritis with severe osteoporosis: An open-label, randomized, pilot study. [2022]

4. Japan pubmed.ncbi.nlm.nih.gov

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

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

Effects of prior osteoporosis treatment on early treatment response of romosozumab in patients with postmenopausal osteoporosis. [2021]

6. England pubmed.ncbi.nlm.nih.gov

A pharmacovigilance analysis of FDA adverse event reporting system events for romosozumab. [2023]

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

Romosozumab: A Novel Injectable Sclerostin Inhibitor With Anabolic and Antiresorptive Effects for Osteoporosis. [2021]

8. Australia pubmed.ncbi.nlm.nih.gov

Romosozumab versus Teriparatide for the Treatment of Postmenopausal Osteoporosis: A Systematic Review and Meta-analysis through a Grade Analysis of Evidence. [2023]

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

Romosozumab treatment in postmenopausal women with osteoporosis: a meta-analysis of randomized controlled trials. [2019]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Romosozumab: A Review in Postmenopausal Osteoporosis. [2021]

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

Effect of Romosozumab Treatment in Postmenopausal Women With Osteoporosis and Knee Osteoarthritis: Results From a Substudy of a Phase 3 Clinical Trial. [2023]

12. England pubmed.ncbi.nlm.nih.gov

Effects of romosozumab with and without active vitamin D analog supplementation for postmenopausal osteoporosis. [2022]

13. New Zealand pubmed.ncbi.nlm.nih.gov

Clinical Utility of Romosozumab in the Management of Osteoporosis: Focus on Patient Selection and Perspectives. [2022]