Teriparatide for Fracture Repair in Humans (TERAFRAP)

Teriparatide for Fracture Repair in Humans: A Prospective, Randomized, Double-blind Placebo-controlled Pilot Study in Female and Male Patients With Proximal Humerus Fracture: The TERAFRAP Study

This study will test the hypothesis that daily subcuaneous administration of 20µg of teriparatide (TPTD) as compared to daily subcuaneous placebo for twelve weeks accelerates proximal 2-segment humerus fracture healing and improves the three dimensional structural properties of bone as measured via quantitative bone image analysis and finite element modeling assessed by quantitative computed tomography.

Primary objective: The primary objective is the quantitative assessment of fracture healing (2-segment proximal humerus frafcture) in the treatment (daily teriapratide 20µg subcitaneous injection for 12 weeks) and in the placebo group (daily placebo subcutaneous injection for 12 weeks) based on computed tomography data (QCT; baseline and after 12 weeks) and computational analysis of the three simensional bone structure in the fracture zone. Bone structure will be assessed by means of quantized bone texture characteristics (callus formation, improvement of trabecualar and cortical bone structure) in the vicinity of the fracture. Secondary objectives: 2.1.Detection and quantification of changes in bone mineralization at the fracture site between a baseline QCT scan and a follow-up QCT scan (planned interval: 12 weeks) using 3-D texture-based cluster analysis between the two groups. 2.2 Evaluation of bone strength variation in the proximal humerus and the measurement of biomechanical properties (stiffness, strength, damage) based on the Finite Element (FE) technique between the two groups. 2.3.Baseline characterization of osteoporotic study population: age, sex, concomitant diseases, serum markers of bone formation and bone resorption, serum colecalciferol levels. 2.4.Evaluation of fasting bone formation and resorption markers at baseline and after 3 months follow up between the TPDT and the placebo group. 2.5.Assessment of quality of life improvement for TPTD and placebo groups with EQ-5D questionnaire (measurement every 4 weeks). 2.6.Assessment of pain reduction in TPTD and placebo groups by visual analog scale (VAS) during 12 weeks (measurement every 4 weeks). 2.7.Assessment of functional testing after 3 and 6 months (functional testing score (ASES Score: "American Shoulder and Elbow Surgeon Score") 2.8.Dual energy x-ray absorptiometry (DXA) bone mineral density (BMD) measurements of lumbar spine and early changes of geometrical hip parameters (cross sectional area - CSA, cross sectional moment of inertia - CSMI), hip BMD(femoral neck and total hip area) and total body (lean mass, fat mass, total body BMD) 2.9. Number of Participants with Adverse Events as a Measure of Safety and Tolerability

As a basis for change quantification, we will identify 3D micro-architecture patterns that occur in the study CT data. These patterns are either learned based on annotated examples, manual segmentation of specific regions in a number of reference examples, or in a data-driven fashion (computer based identification of pattern classes).

The FEA Method will be a second diagnostic tool in order to evaluate the change in bone strength in the proximal humerus during treatment.

The extent of bridging and callus formation will be quantified, based on the voxel-wise comparison of follow-up data. The accumulated density difference between baseline and follow-up over a region of interest serves as parameter.

Inclusion Criteria: recent proximal 2-segment humerus fracture (0-8 days post fracture) no surgical treatment at fractured site signed informed consent postmenopausal female and male patients aged 60 - 85 years established osteoporosis as defined by BMD measured with DXA-technology (dual energy X-ray absorptiometry) with a T-score ≤ -2.0 spine or hip Exclusion Criteria: Hypersensitivity to the active substance or to any of the excipients. Pre-existing hypercalcemia Severe renal impairment (eGFR< 35ml/min) Metabolic bone diseases (including hyperparathyroidism and Paget's disease of the bone) other than primary osteoporosis or glucorticoid-induced osteoporosis. Unexplained elevations of alkaline phosphatase Prior external beam or implant radiation therapy to the skeleton Patients with skeletal malignancies or bone metastases should be excluded from treatment with teriparatide. any prior antiresorptive therapy (oral/intravenous bisphosphonates, RANKL-antibody, SERMs) any prior strontium ranelate therapy any prior TPTD of PTH 1-84 therapy malignancies ≤ 5 years except basalioma hypo-/hypercalcemia baseline 25-OH vitamin D3 level ≤10 ng/ml prosthesis at fractured and contralateral humerus

Aspenberg P, Johansson T. Teriparatide improves early callus formation in distal radial fractures. Acta Orthop. 2010 Apr;81(2):234-6. doi: 10.3109/17453671003761946. Erratum In: Acta Orthop. 2010 Oct;81(5):647.