Denosumab for Broken Bones in Dialysis Patients

(PREFERRED-1 Trial)

Recruiting at 5 trial locations

Overseen By Jennifer Arnold

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Western University, Canada

Must not be taking: Osteoporosis medications

Disqualifiers: Kidney recovery, Palliative care, Childbearing, 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: Unknown

Duration: 15 months

60 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

If you are currently taking certain osteoporosis medications, including denosumab, bisphosphonates, or others listed in the trial's exclusion criteria, you will need to stop taking them to participate in this trial. The protocol does not specify a washout period, but you should discuss this with the trial team.

What data supports the effectiveness of the drug denosumab for broken bones in dialysis patients?

Denosumab has been shown to increase bone mineral density (BMD) in male dialysis patients with low BMD, making it an effective treatment for improving bone health in this group. ^{1 2 3 4 5}

Is denosumab safe for dialysis patients?

Denosumab can cause severe hypocalcemia (low calcium levels in the blood) in dialysis patients, which can be dangerous. Patients with advanced kidney disease, especially those on dialysis, should be closely monitored and may need calcium and vitamin D supplements if using this medication. ^{1 4 6 7 8}

How is the drug denosumab unique for treating broken bones in dialysis patients?

Denosumab is unique because it is a monoclonal antibody (a type of protein made in the lab) that targets RANKL, which is involved in bone breakdown, and it is administered as an injection every six months. Unlike other treatments, it has shown effectiveness in increasing bone mineral density in dialysis patients, but it also carries a risk of severe hypocalcemia (low calcium levels in the blood), requiring careful monitoring and supplementation with calcium and vitamin D. ^{1 4 5 6 9}

What is the purpose of this trial?

PREFERRED-1 is a pilot study designed to determine the feasibility of a large randomized, pragmatic, open-label, comparative-effectiveness trial of denosumab for the prevention of fragility fractures in people receiving hemodialysis. The pilot study will enroll at least 60 patients from across at least 6 different hemodialysis centres in Ontario, Canada. Patients on outpatient maintenance hemodialysis at high risk of fragility fracture, will be randomized 1:1 to a denosumab care pathway vs. usual care. Primary outcomes include recruitment feasibility and treatment adherence. Secondary outcomes include safety and participant satisfaction with our protocol and processes.

Research Team

Kristin K Clemens, MD, MSc

Principal Investigator

St. Joseph's Health Care London

Eligibility Criteria

This trial is for adults over 40 on outpatient maintenance hemodialysis with chronic kidney disease at high risk of bone fractures. They must have certain blood calcium, PTH, and ALP levels and be eligible for denosumab through Ontario's drug programs. Exclusions include current use of specific osteoporosis medications or treatments, planned major dental surgery, known allergy to denosumab, or expected changes in dialysis treatment within a year.

Inclusion Criteria

I am at high risk for breaking bones easily due to conditions like osteoporosis.

Your blood tests show high levels of calcium, PTH, or alkaline phosphatase.

I can get denosumab through my provincial drug benefits.

Exclusion Criteria

You are currently taking certain medications for osteoporosis, have certain planned dental surgeries, or have specific allergies or intolerances.

I am currently taking cinacalcet (Sensipar).

I am expected to start IV treatment with drugs like pamidronate or zoledronic acid.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 60 mg of denosumab every 6 months over a 15-month period, with monitoring of serum calcium and phosphate, and administration of vitamin D and calcium as needed.

15 months

In-person visits during regular hemodialysis sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment, including monitoring of serum calcium and parathyroid hormone levels.

4 weeks

Monitoring visits following each denosumab injection

Treatment Details

Interventions

• Denosumab

Trial Overview The PREFERRED-1 study tests whether Denosumab can prevent fractures better than usual care in patients with kidney disease on dialysis. At least 60 participants from various centers will either follow a Denosumab care pathway including calcium and vitamin D supplements plus monitoring or receive the standard fracture prevention treatments.

Participant Groups

Group I: Intervention Experimental Treatment 3 Interventions

60 mg of denosumab (Prolia) will be administered every 6 months over a 15 - month period. Monitoring of serum calcium and phosphate will occur and bloodwork will be drawn for 7 weeks following each denosumab injection. Correction of vitamin D deficiency (if required), the adjustment of calcium dialysate and the provision of intravenous (IV) or oral (po) calcitriol/calcidiol will be administered as needed following each denosumab injection as described in the Beside Protocol. Once the study monitoring period is over, serum calcium monitoring and management will occur as per routine care in the dialysis centre. All intervention activities will occur during regularly scheduled hemodyalisis sessions.

Group II: Usual care Active Control 1 Intervention

Usual care participants will continue to receive the typical standard of care in their dialysis unit which includes their routine dialysis monitoring and bloodwork. They will not receive denosumab, calcium and vitamin prophylaxis. There will be no extra monitoring or bloodwork.

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?

Western University, Canada

Lead Sponsor

Trials

270

Recruited

62,500+

ICES

Collaborator

Trials

4

Recruited

327,000+

Western University

Collaborator

Trials

31

Recruited

129,000+

ICES

Industry Sponsor

Trials

6

Recruited

534,000+

Academic Medical Organization of Southwestern Ontario

Collaborator

Trials

17

Recruited

1,600+

The Kidney Foundation of Canada

Collaborator

Trials

16

Recruited

3,200+

Findings from Research

In a study of 75 patients with osteoporosis and decreased kidney function, treatment with denosumab (Prolia®) over an average of 5.3 years led to significant improvements in bone mineral density, with a 12% increase in the lumbar spine and a 7% increase in the hip T scores.

The treatment was generally well tolerated, although 20% of patients experienced new fractures and 21% had biochemical hypocalcemia, indicating the need for monitoring calcium levels during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of osteoporosis with denosumab in patients with decreased kidney function. Svendsen, OL.[2023]

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

Treatment of osteoporosis with denosumab in patients with decreased kidney function. [2023]

2. Italy pubmed.ncbi.nlm.nih.gov

The effect of previous treatment with bisphosphonate and renal impairment on the response to denosumab in osteoporosis: a 'real-life' study. [2022]

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

Reducing the risk of denosumab-induced hypocalcemia in patients with advanced chronic kidney disease: a quality improvement initiative. [2023]

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

Osteoporosis Drug Increases Hypocalcemia Risk in Dialysis Patients. [2023]

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

Denosumab for Male Hemodialysis Patients with Low Bone Mineral Density: A Case-Control Study. [2020]

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

Severe hypocalcemia following denosumab injection in a hemodialysis patient. [2017]

7. Czech Republic pubmed.ncbi.nlm.nih.gov

Denosumab associated with bone density increase and clinical improvement in a long-term hemodialysis patient. Case report and review of the literature. [2016]

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

Denosumab Safety and Efficacy Among Participants in the FREEDOM Extension Study With Mild to Moderate Chronic Kidney Disease. [2021]

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

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