Romosozumab to Improve Bone Mineral Density and Architecture in Chronic SCI

  • STATUS
    Recruiting
  • End date
    Aug 1, 2024
  • participants needed
    39
  • sponsor
    VA Office of Research and Development
Updated on 29 April 2022
x-rays
spinal cord
spinal cord disorder

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 SCI and areal BMD (aBMD) values at the distal femur of at the distal femur 0.7 g/cm2 but 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.

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 SCI (>3 post injury, American Spinal Injury Association Impairment Scale A & B) between the ages of 18 and 50 years old who have aBMD at the distal femur at the distal femur 0.7 g/cm2 but 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).

Details
Condition Spinal Cord Injury (=3 Years), Sublesional Bone Loss Secondary to SCI
Treatment Placebo, Denosumab, Romosozumab
Clinical Study IdentifierNCT04232657
SponsorVA Office of Research and Development
Last Modified on29 April 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Traumatic SCI [C4-T10 [upper motor lesions as determined by the International Standards for Neurological Classification for Spinal Cord Injury (ISNCSCI) impairment scale]; ISNCSCI score A & B
Duration of injury 3 years
Males and females (premenopausal) between the ages of 18 and 50 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 0.7 g/cm2 but 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
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