Romosozumab + Denosumab for Osteoporosis

Overseen By Mafo Kamanda-Kosseh

Age: 18 - 65

Sex: Female

Trial Phase: Phase 2

Sponsor: Columbia University

Must not be taking: Anticoagulants, Anticonvulsants, Glucocorticoids, others

Disqualifiers: Cardiovascular disease, Mineral disorders, Pregnancy, 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

Compensation: Varies

Number of Visits: 16

Duration: 12 months

31 Participants Needed

Trial Summary

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

The trial requires stopping certain medications before joining. If you're on drugs for osteoporosis like raloxifene, bisphosphonates, or denosumab, you must stop them for a specific period before participating. For example, you need to wait 3 months after stopping raloxifene or calcitonin, 12 months after stopping certain bisphosphonates, and 18 months after the last dose of denosumab. Other medications like glucocorticoids, anticonvulsants, and anticoagulants also have specific requirements. Check with the trial team for details on your specific medications.

Will I have to stop taking my current medications?

The trial requires participants to stop certain medications before joining. If you're taking drugs for osteoporosis, you must stop them for a specific period before participating, such as 3 months for raloxifene or calcitonin, and up to 24 months for zoledronate. Check with the trial team to see if your current medications are affected.

What data supports the idea that Romosozumab + Denosumab for Osteoporosis is an effective drug?

The available research shows that using Romosozumab followed by Denosumab significantly improves bone health in people with osteoporosis. In a study called FRAME, postmenopausal women who took Romosozumab for a year had a 13% increase in spine bone density and a 7% increase in hip bone density. They also had fewer fractures compared to those who took a placebo. After switching to Denosumab, these benefits continued, with a significant reduction in fractures over two years. This combination treatment showed similar bone density improvements in two years as seven years of continuous Denosumab alone. ^{1 2 3 4 5}

What data supports the effectiveness of the drug combination Romosozumab and Denosumab for osteoporosis?

Research shows that using Romosozumab for one year followed by Denosumab for another year significantly increases bone density and reduces the risk of fractures in postmenopausal women with osteoporosis. This combination therapy led to a 13% increase in spine bone density and a 7% increase in hip bone density, with a notable reduction in vertebral fractures. ^{1 2 3 4 5}

What safety data is available for Romosozumab and Denosumab in treating osteoporosis?

Romosozumab has been evaluated in several studies, including three phase III clinical trials, which demonstrated its efficacy in increasing bone mineral density and reducing fractures. However, there are safety concerns, particularly regarding cardiovascular risks, as major adverse cardiac events were observed in one clinical trial. Other reported adverse effects include arthralgia, headache, and injection site reactions. Romosozumab is recommended for postmenopausal women at high risk for fractures but should be avoided in those with a history of or at high risk for cardiovascular disease. The FDA Adverse Event Reporting System (FAERS) provides additional data on adverse events associated with Romosozumab. Denosumab, marketed as Prolia and Xgeva, is another treatment for osteoporosis, but specific safety data for its combination with Romosozumab is not detailed in the provided research. ^{6 7 8 9 10}

Is the combination of Romosozumab and Denosumab safe for treating osteoporosis?

Romosozumab has been shown to increase bone density and reduce fractures, but it may cause side effects like joint pain, headaches, and injection site reactions. There is also a potential risk of heart-related issues, so it should not be used by those with a history of heart disease. Denosumab, used after Romosozumab, is generally well-tolerated but can cause low calcium levels and skin infections. ^{1 7 8 9 10}

Is the drug Romosozumab, followed by Denosumab, a promising treatment for osteoporosis?

Yes, Romosozumab followed by Denosumab is promising for osteoporosis because it significantly increases bone density and reduces fractures, offering long-term benefits. ^{1 4 11 12 13}

How is the drug combination of Romosozumab and Denosumab unique for treating osteoporosis?

The combination of Romosozumab and Denosumab is unique because Romosozumab first increases bone formation and decreases bone breakdown, leading to significant bone density gains, and then Denosumab maintains these gains by further preventing bone loss. This sequential approach results in greater bone density improvements and fracture risk reduction compared to other treatments. ^{1 4 11 12 13}

What is the purpose of this trial?

The overarching goal of the research program is to define optimal treatment for premenopausal women with clinically significant fracture syndromes that require medical therapy. The investigators hypothesize that romosozumab will be associated with improvements in bone mass and microarchitecture in premenopausal women, and also that the responses and response rates will exceed those observed in premenopausal women treated with teriparatide. The investigators will test this hypothesis in this phase 2 study of 30 premenopausal women with idiopathic osteoporosis (IOP) who will receive 12M of romosozumab 210 mg monthly followed by 12M of denosumab 60 mg SC q6M. Aim 1 will define the within-group effects of this regimen. Aim 2 will compare results from participants treated with romosozumab-denosumab to the investigator's well-characterized historical controls treated with teriparatide followed by denosumab.

Research Team

Elizabeth Shane, MD

Principal Investigator

Columbia University

Adi Cohen, MD

Principal Investigator

Columbia University

Eligibility Criteria

This trial is for premenopausal women aged 18-48 with idiopathic osteoporosis, regular menstrual cycles, and no secondary cause of bone loss. Participants must have had low-trauma fractures and a T-score or Z-score ≤ -1.5 at certain bone sites. They should agree to highly effective contraception during the study.

Inclusion Criteria

I agree to use highly effective birth control during the study.

I am a woman aged 18-48, premenopausal, with regular periods and no osteoporosis.

I have had fractures from minor falls and my bone density scores are low.

Exclusion Criteria

I have a history of heart disease but my recent ECG is normal or not concerning.

I have a condition affecting my intestines, such as celiac disease or Crohn's.

I have a new, untreated hormone gland disorder.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive romosozumab 210 mg monthly for 12 months

12 months

12 visits (in-person)

Transition

Participants transition from romosozumab to denosumab treatment

0-1 month

Treatment

Participants receive denosumab 60 mg every six months for 12 months

12 months

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

2 visits (in-person)

Treatment Details

Interventions

• Denosumab
• Romosozumab

Trial Overview The study tests if romosozumab improves bone mass in premenopausal women with osteoporosis better than teriparatide does. It involves giving participants romosozumab monthly for a year followed by denosumab every six months for another year, comparing their results to historical controls.

Participant Groups

Group I: Romosozumab followed by denosumab Experimental Treatment 2 Interventions

Romosozumab 210 mg subcutaneous injection, once a month for 12 months followed by denosumab 60 mg subcutaneous injection, once every six months for 12 months.

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?

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

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

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]

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 significantly increased bone mineral density (BMD) at the lumbar spine by 10.2% after 12 months, compared to a 5.0% increase with denosumab, indicating its superior efficacy for this specific area in postmenopausal women with rheumatoid arthritis and severe osteoporosis.

Both treatments showed similar effects on disease activity and joint damage, suggesting that while romosozumab is better for increasing lumbar spine BMD, it does not provide additional benefits in terms of reducing disease activity or joint damage compared to denosumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of romosozumab versus denosumab treatment on bone mineral density after 1 year in rheumatoid arthritis patients with severe osteoporosis: A randomized clinical pilot study. Mochizuki, T., Yano, K., Ikari, K., et al.[2023]

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 monoclonal antibody, effectively increases bone mineral density and reduces fracture risk in postmenopausal women with osteoporosis by promoting bone formation and inhibiting bone resorption through sclerostin inhibition, based on a review of five controlled clinical trials.

While romosozumab shows significant benefits in improving bone health, it is associated with a higher risk of cardiovascular adverse effects compared to other osteoporosis treatments, highlighting the need for careful consideration in its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Romosozumab and Sequential Therapy in Postmenopausal Osteoporosis. Slaton, RM., Boyd, K., Iranikhah, M.[2021]

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 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 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 is an effective treatment for osteoporosis in postmenopausal women, significantly increasing bone mineral density and reducing the risk of vertebral and hip fractures, as shown in Phase III trials.

While romosozumab is the first drug to both inhibit bone resorption and stimulate bone formation, it carries risks of major adverse cardiac events and should be avoided in women with a history of cardiovascular disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Romosozumab: A Novel Agent in the Treatment for Postmenopausal Osteoporosis. Miller, SA., St Onge, EL., Whalen, KL.[2021]

Romosozumab, a newly approved treatment for osteoporosis in Japan, effectively increases bone mineral density and reduces fracture risk by stimulating bone formation and suppressing bone resorption.

The ARCH study showed that romosozumab is more effective than alendronate, but due to its reversible effects, patients will need to follow up with anti-resorptive therapy after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Sequential treatment of osteoporosis with anti-sclerostin.] Inoue, D.[2019]

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 significantly increased bone mineral density (BMD) in postmenopausal women with low BMD over 24 months, with the highest gains observed in those receiving the 210 mg monthly dose (15.1% increase in lumbar spine and 5.4% in total hip).

Transitioning from romosozumab to denosumab continued to enhance BMD, while discontinuation of romosozumab led to a decrease in BMD back toward pretreatment levels, indicating that the effects of romosozumab are reversible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of 24 Months of Treatment With Romosozumab Followed by 12 Months of Denosumab or Placebo in Postmenopausal Women With Low Bone Mineral Density: A Randomized, Double-Blind, Phase 2, Parallel Group Study. McClung, MR., Brown, JP., Diez-Perez, A., et al.[2019]

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. 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]

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

Comparison of romosozumab versus denosumab treatment on bone mineral density after 1 year in rheumatoid arthritis patients with severe osteoporosis: A randomized clinical pilot study. [2023]

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

Romosozumab and Sequential Therapy in Postmenopausal Osteoporosis. [2021]

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

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

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

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

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

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

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

Romosozumab: A Novel Agent in the Treatment for Postmenopausal Osteoporosis. [2021]

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

[Sequential treatment of osteoporosis with anti-sclerostin.] [2019]

12. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Effects of 24 Months of Treatment With Romosozumab Followed by 12 Months of Denosumab or Placebo in Postmenopausal Women With Low Bone Mineral Density: A Randomized, Double-Blind, Phase 2, Parallel Group Study. [2019]