Teriparatide and stress fracture healing in young adults (RETURN - Research on Efficacy of Teriparatide Use in the Return of recruits to Normal duty): study protocol for a randomised controlled trial

Abstract

Background: Stress fractures are a common and potentially debilitating overuse injury to bone and occur frequently among military recruits and athletes. Recovery from a lower body stress fracture typically requires several weeks of physical rehabilitation. Teriparatide, a recombinant form of the bioactive portion of parathyroid hormone (1-34 amino acids), is used to treat osteoporosis, prevent osteoporotic fractures, and enhance fracture healing due to its net anabolic effect on bone. The study aim is to investigate the effect of teriparatide on stress fracture healing in young, otherwise healthy adults undergoing military training.

Methods: In a two-arm, parallel, prospective, randomised controlled, intention-to-treat trial, Army recruits (n = 136 men and women, 18-40 years) with a magnetic resonance imaging (MRI) diagnosed lower body stress fracture (pelvic girdle, sacrum, coccyx, or lower limb) will be randomised to receive either usual Army standard care, or teriparatide and usual Army standard care. Teriparatide will be self-administered by subcutaneous injections (20 μg/day) for 16 weeks, continuing to 24 weeks where a fracture remains unhealed at week 16. The primary outcome will be the improvement in radiological healing by two grades or more, or reduction to grade zero, 8 weeks after randomisation, assessed using Fredericson grading of MRI by radiologists blind to the randomisation. Secondary outcomes will be time to radiological healing, assessed by MRI at 8, 10, 12, 14, 16, 20 and 24 weeks, until healed; time to clinical healing, assessed using a clinical severity score of injury signs and symptoms; time to discharge from Army physical rehabilitation; pain, assessed by visual analogue scale; health-related quality of life, using the Short Form (36) Health Survey; and adverse events. Exploratory outcomes will include blood and urine biochemistry; bone density and morphology assessed using dual-energy X-ray absorptiometry, peripheral quantitative computed tomography (pQCT), and high-resolution pQCT; physical activity measured using accelerometers; and long-term future fracture rate.

Discussion: This study will evaluate whether teriparatide, in addition to standard care, is more effective for stress fracture healing than standard care alone in Army recruits who have sustained a lower body stress fracture.

Trial registration: ClinicalTrials.gov NCT04196855 . Registered on 12 December 2019.

Keywords: Bone; Intention-to-treat; Magnetic resonance imaging; Military; Musculoskeletal injury; Parathyroid hormone; Prospective randomised controlled trial; Rehabilitation; Stress fracture; Teriparatide.

Conflict of interest statement

WDF has received unrestricted research grants, sat on advisory boards, and given lectures on behalf of Eli Lilly, NPS Pharmaceuticals, Shire and Nycomed. JWM has received research grants and consultancy fees from GlaxoSmithKline and GE Healthcare. ATC, KGE, AC, MH, LS, EP, APT, AMS and JPG declare they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1

Overview of the trial design, interventions and assessments. 1Serum 25-hydroxyvitamin D < 30 nmol/L, deficient; ≥30 nmol/L, not deficient; 2Pregnancy test for all at baseline, week 16 and 24, and four-weekly for participants allocated to the intervention arm; 3Weekly visual analogue scale; 4Short Form (36) Health Survey; 5Dual-energy X-ray absorptiometry (DXA) scan of the lumbar spine and hips (baseline and week 16 only); peripheral quantitative computed tomography (pQCT) scan of the diaphyseal tibia; and high-resolution pQCT (HR-pQCT) scan of the metaphyseal tibia and radius; 6Accelerometer worn 24 h/day and replaced four-weekly; 7Columbia-Suicide Severity Rating Scale (C-SSRS) for all at baseline, and four-weekly for participants allocated to the intervention arm; 8Review of Army fitness records; 9Magnetic resonance imaging (MRI) scans to cease when fracture is radiologically healed; 10Clinical assessments twice weekly after fracture is radiologically healed, and to cease when fracture is clinically healed; 11Review of Army medical records

Fig. 2

Schedule of study enrolment, interventions and assessments. 1Intervention and assessments to continue after week 16 only where fractures are unhealed at week 16; 2Serum 25-hydroxyvitamin D < 30 nmol/L, deficient; ≥30 nmol/L, not deficient; 3Daily subcutaneous injection (20 μg/day); 4Magnetic resonance imaging (MRI) scans to cease when fracture is radiologically healed; 5Clinical assessments twice weekly after fracture is radiologically healed, and to cease when fracture is clinically healed; 6Weekly visual analogue scale; 7Short Form (36) Health Survey; 8Adverse events recorded for 4 weeks after participant’s final study visit (i.e. until weeks 20 or 28). 9Safety and research blood biochemistry; 10Safety and research urine biochemistry; 11Dual-energy X-ray absorptiometry (DXA) scan of the lumbar spine and hips (allocation and week 16 only); peripheral quantitative computed tomography (pQCT) scan of the diaphyseal tibia; and high-resolution pQCT (HR-pQCT) scan of the metaphyseal tibia and radius; 12Accelerometer worn 24 h/day and replaced four-weekly; 13Review of Army medical records for 5 years after participant’s final study visit; 14Columbia-Suicide Severity Scale for all at allocation, and four-weekly for participants allocated to the intervention arm; 15Review of Army fitness records; 16Pregnancy test for all at allocation, week 16 and 24, and four-weekly for participants allocated to the intervention arm