Romosozumab to Improve Bone Mineral Density and Architecture in Chronic SCI

NCT ID: NCT04232657

Last Updated: 2025-04-01

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 36 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-03-01
• Study Completion Date: 2027-03-01

Brief Summary

Treatment for sublesional bone loss (osteoporosis) in persons with chronic, motor-complete spinal cord injury (SCI) has been limited and unsuccessful to date. Romosozumab, a sclerostin antagonist, has potential to increase bone formation (anabolic) and decrease bone resorption (anti-catabolic) in persons with chronic SCI. Conventional anti-resorptive therapy alone would not be anticipated to reverse sublesional bone loss in a timely manner because the skeleton below the level of lesion in chronic SCI is assumed to be in a low turnover state. However, because there is a high likelihood that the bone accrued while on romosozumab will be lost once discontinued, denosumab, an anti-resorptive agent, will be administered after treatment with romosozumab, to maintain or, possibly, to continue to increase, bone mineral density (BMD).

The purpose of this study is to address the gap in the treatment of osteoporosis in individuals with chronic SCI by partially restoring BMD with romosozumab treatment for 12 months and then to maintain, or further increase, BMD with denosumab treatment for 12 months. A two group, randomized, double-blind, placebo-controlled clinical trial will be conducted in 39 participants who have chronic (>3 years), motor-complete or incomplete SCI and areal BMD (aBMD) values at the distal femur of at the distal femur <1.0 g/cm2 measured by dual photon X-ray absorptiometry (DXA). The intervention group will receive 12 months of romosozumab followed by 12 months of denosumab, and the control group will receive 12 months of placebo followed by 12 months denosumab.

Detailed Description

Persons with chronic spinal cord injury (SCI) have markedly reduced bone mass and the loss of skeletal architectural integrity, which predisposes them to low-impact fractures. Currently, there is no practical treatment to reverse the severe bone loss in persons with chronic SCI. In the proposed study, a dual pharmacological intervention will be tested to improve bone health. Restoration of bone mass below the level of injury would be expected to reduce the morbidity associated with fractures and permit safer participation in upright activities. Quality of life would be substantially improved because of the ability to engage more securely in activities of daily living and to integrate into the community. Despite the depressed skeletal activity below the level of lesion in persons with chronic SCI, net bone loss occurs because resorption exceeds formation, with a difference between these rates in those with SCI being greater than that observed in the able-bodied population. Thus, it would be anticipated to be of value in persons with chronic SCI to increase bone turnover with the objective to increase bone formation over that of bone resorption. In a preclinical study that administered an anti-sclerostin antibody to rats 12 weeks after complete spinal cord transection bone, mineral density (BMD) was almost fully restored at the distal femoral metaphysis, with improved bone structure, and mechanical strength; in contrast, vehicle-treated animals after complete spinal transection had a marked reduction in distal femoral metaphysis BMD and a deterioration in bone structure and mechanical strength. When used to treat postmenopausal osteoporosis, romosozumab, a human monoclonal anti-sclerostin antibody, was more effective to increase bone mineral density (BMD) and to reduce fracture than any other anti-resorptive or bone-anabolic agent, and this effect was also evident for the appendicular skeleton, which is the site in individuals with chronic SCI of greatest bone loss and most frequent fracture. Because of the absence of clinical options available for the treatment of osteoporosis in individuals with chronic paralysis, the investigators have proposed to test an antagonist of sclerostin, which is a potent bone anabolic agent with proven efficacy in treating women with postmenopausal osteoporosis, to improve bone mass and reduce fragility fractures.

Thirty-nine male and female subjects with chronic, motor-complete or incomplete SCI (>3 years post injury, American Spinal Injury Association Impairment Scale A & B) between the ages of 18 and 55 years old (for females) or 65 years old (for males) who have aBMD at the distal femur at the distal femur <1.0 g/cm2 will be recruited for participation in a randomized, double-blind, placebo-controlled, parallel group clinical trial. The outcome measures of the proposed study are bone mineral density (BMD) by peripheral quantitative computed tomography (pQCT) and dual energy x-ray absorptiometry (DXA), and biochemical markers of bone resorption and formation. This prospective, randomized, placebo controlled clinical trial will take place at the James J. Peters VA Medical Center (JJPVAMC) and Kessler Institute for Rehabilitation (KIR) (each facility will perform patient enrollment and study procedures).

Conditions

Spinal Cord Injury (=3 Years); Sublesional Bone Loss Secondary to SCI

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

Romosozumab Treatment (baseline to month 11)

Of the thirty-nine (39) individuals with chronic spinal cord injury (SCI) enrolled in this study, twenty-six (26) participants will be randomly selected to received romosozumab (210mg SQ) once a month for 12 months.

Group Type: EXPERIMENTAL

Romosozumab

Intervention Type: DRUG

39 subjects with chronic SCI will be studied with a 2:1 ratio of randomization of drug to placebo. Romosozumab (210mg SQ) will be administered once a month for 12 months. Participants will arrive at the JJPVAMC or KIR once a month to receive injections of romosozumab or placebo. A designated unblinded healthcare professional will be responsible for administering these injections.

Placebo (baseline to month 12)

Of the thirty-nine (39) individuals with chronic SCI enrolled in this study, thirteen (13) participants will be randomly selected to received placebo injections (NS SQ) once a month for 12 months. They will follow study procedures identical to those performed by individuals in the treatment (romosozumab) group.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Thirteen (13) of the thirty-nine (39) subjects enrolled in this study will be randomly selected to receive placebo (NS SQ) injections for 12 months (baseline - month 11). The placebo injections will be administered by an unblinded healthcare professional (registered nurse / physician). Participants will be blinded to their group assignment (romosozumab treatment or placebo).

Denosumab (month 12 to month 24)

Both groups (treatment and placebo) will receive denosumab (60mg SQ) at months 12 and 18 for maintenance of or to further increase bone mineral density (BMD) at regions of interest (ROI).

Group Type: ACTIVE_COMPARATOR

Denosumab

Intervention Type: DRUG

Because there is a high likelihood that the bone accrued while on romosozumab will be lost once discontinued, denosumab, an anti-resorptive agent, will be administered after treatment with romosozumab, to maintain or, possibly, to continue to increase, bone mineral density. Denosumab will be administered to both groups (treatment and placebo) for an additional 12 months. Participants will be asked to arrive at the JJPVAMC once every 6 months to receive injections of denosumab by a healthcare professional.

Interventions

Romosozumab

39 subjects with chronic SCI will be studied with a 2:1 ratio of randomization of drug to placebo. Romosozumab (210mg SQ) will be administered once a month for 12 months. Participants will arrive at the JJPVAMC or KIR once a month to receive injections of romosozumab or placebo. A designated unblinded healthcare professional will be responsible for administering these injections.

Intervention Type: DRUG

Denosumab

Because there is a high likelihood that the bone accrued while on romosozumab will be lost once discontinued, denosumab, an anti-resorptive agent, will be administered after treatment with romosozumab, to maintain or, possibly, to continue to increase, bone mineral density. Denosumab will be administered to both groups (treatment and placebo) for an additional 12 months. Participants will be asked to arrive at the JJPVAMC once every 6 months to receive injections of denosumab by a healthcare professional.

Intervention Type: DRUG

Placebo

Thirteen (13) of the thirty-nine (39) subjects enrolled in this study will be randomly selected to receive placebo (NS SQ) injections for 12 months (baseline - month 11). The placebo injections will be administered by an unblinded healthcare professional (registered nurse / physician). Participants will be blinded to their group assignment (romosozumab treatment or placebo).

Intervention Type: DRUG

Other Intervention Names

Evenity; Prolia; Normal Saline (NS) injection

Eligibility Criteria

Inclusion Criteria

• Motor-complete or incomplete SCI [all levels of lesion] classified using International Standards for Neurological Classification for Spinal Cord Injury (ISNCSCI) impairment scale] as ISNCSCI score A-C
• Duration of injury >3 years
• Males (18-65 years old) and females (premenopausal, between the ages of 18 and 55 years old).
• aBMD at the distal femur <1.0 g/cm2 (determined at screening)

Exclusion Criteria

• Long-bone fracture of the leg within the past year
• History of prior bone disease (Paget's hyperparathyroidism, etc.)
• Active and/or history of coronary heart disease or stroke within the past year
• Postmenopausal women
• Men with known hypogonadism prior to SCI
• Anabolic therapy longer than six months duration after SCI
• Glucocorticoid administration longer than three months duration within the last year, and/or prescribed moderate or high dose corticosteroids (>40 mg/d prednisone or an equivalent dose of other corticosteroid medication) for longer than one week, not including drug administered to preserve neurological function at the time of acute SCI
• Endocrinopathies (hyperthyroidism, Cushing's disease or syndrome, etc.)
• Severe underlying chronic disease (e.g., COPD, end-stage heart disease, chronic renal failure)
• Heterotopic ossification (HO) of the knee region (the distal femoral epiphysis is the primary endpoint); HO to any other boney region will not prevent study participation as long as contraindicated medications have not been prescribed)
• Chronic alcohol abuse
• Hypocalcemia
• Pregnancy
• Prescribed a bisphosphonate for HO, or prescribed any other agent to treat osteoporosis other than calcium and vitamin D
• Electrical stimulation of the lower extremities
• Current diagnosis of cancer or history of cancer
• Osteosarcoma
• Life expectancy less than 5 years

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Kessler Institute for Rehabilitation

INDUSTRY

Sponsor Role: collaborator

VA Office of Research and Development

FED

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Christopher Cardozo, MD

Role: PRINCIPAL_INVESTIGATOR

James J. Peters Veterans Affairs Medical Center

Locations

Kessler Institute for Rehabilitation

West Orange, New Jersey, United States

James J. Peters VA Medical Center, Bronx, NY

The Bronx, New York, United States

Countries

United States

Provided Documents

Document Type: Informed Consent Form

View Document

Other Identifiers

BAU-19-66

Identifier Type: OTHER

Identifier Source: secondary_id

1600530

Identifier Type: OTHER

Identifier Source: secondary_id

B3415-R

Identifier Type: -

Identifier Source: org_study_id

NCT05180032

Identifier Type: -

Identifier Source: nct_alias