Romosozumab to Improve Bone Mineral Density and Architecture in Chronic SCI

Study Overview
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Brief Summary
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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
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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 post injury, American Spinal Injury Association Impairment Scale A & B) between the ages of 18 and 55 years old 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).

Official Title
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Romosozumab to Improve Bone Mineral Density and Architecture in Chronic SCI

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

Intervention / Treatment
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* Drug: Romosozumab
* Drug: Denosumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Motor-complete or incomplete SCI [C4 and below [upper motor lesions as determined by the International Standards for Neurological Classification for Spinal Cord Injury (ISNCSCI) impairment scale]; ISNCSCI score A-C Duration of injury >3 years Males and females (premenopausal) between the ages of 18 and 55 years old (the upper age limit is to reduce the influence of age on the ability of the skeleton to respond to pharmacologic stimulation) 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, osteoporosis, 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blind, placebo-controlled, parallel group clinical trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Romosozumab Treatment (baseline to month 11)<br>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. | Drug: Romosozumab<br>* 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.<br>* Other names: Evenity;|
| Placebo Comparator: Placebo (baseline to month 12)<br>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. | Drug: Placebo<br>* 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).<br>* Other names: Normal Saline (NS) injection;|
| Active Comparator: Denosumab (month 12 to month 24)<br>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). | Drug: Denosumab<br>* 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.<br>* Other names: Prolia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in vBMD at the Distal Femur, measured by pQCT after 12 months of romosozumab treatment | Percent change of volumetric BMD (vBMD) (mg/cm^3)at the distal femur, measured by peripheral quantitative computed tomography (pQCT) (slice thickness 2.4mm, default voxel size of 0.5mm), with 12 months of romosozumab therapy. vBMD measurements will be taken at baseline, month 6 and month 12. | Baseline (0), Month 6, Month 12 | 
| Change in vBMD at the distal femur after an additional 12 months of denosumab treatment | Percent change of Integral vBMD (mg/cm^3)at the distal femur, measured by pQCT (slice thickness 2.4mm, default voxel size of 0.5mm), after additional 12 months of denosumab therapy. vBMD measurements will be taken by pQCT at months 18 and 24. | Month 18, Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spinal Cord Injury, Veterans Affairs RR&D, Sublesional Bone Loss