Local remodelling and mechanoregulation of bone fracture healing in healthy, aged, and osteoporotic humans

The current knowledge of bone fracture healing is mainly based on the healing in the bone shaft, referred to as cortical bone, even though many age and osteoporosis associated fractures occur at bone endings, referred to as trabecular bone. Little is known about its regulation by mechanical forces and age and osteoporosis might affect fracture healing and are potential causes for delaying healing. We therefore need to better understand the healing process and its mechanoregulation in healthy, aged, and osteoporotic human bone. In addition, to ultimately improve clinical diagnosis and prognosis, we need to develop ways of predicting the progression and success of fracture healing. Both are, however, challenging, as detailed local changes in the bone, referred to as remodelling, need to be observed and quantified in patients. Investigating the mechanoregulation requires the calculation of mechanical loading, which in turn requires the definition of physiological loading conditions, usually not known in patients. In the present project, we aim at (1) investigating local remodelling and (2) local mechanoregulation of trabecular bone fracture healing in healthy, aged, and osteoporotic humans as well as (3) predicting this mechanoregulated fracture healing. To achieve the first aim, we propose to use high-resolution clinical computed tomography (HR-pQCT) to assess the bone microstructure at the distal forearm in patients, and to develop image analysis methods to quantify microstructural differences between images from several time points. Recent attempts in a pilot study showed that it is possible to determine such changes in patients. To achieve the second aim, we propose to use a recently developed biomechanical method and to validate it with a sheep experiment where the mechanical loading is known. To achieve the third aim, we propose to develop a computer model that is capable of simulating trabecular fracture healing and its mechanoregulation as explored in the first two aims. Overall, this project requires an extremely broad range of expertise that will be provided in a Swiss-Austrian-German DACH collaboration combining their strengths. The Medial University Innsbruck with its experience in performing longitudinal clinical studies will be responsible for aim 1, ETH Zurich with its expertise in bone imaging and biomechanical analysis for aim 2, and Ulm University with its expertise in computational modelling of fracture healing for aim 3. The proposed work will elucidate mechanoregulated local trabecular bone fracture healing and help investigating whether age and osteoporosis affect the healing process in humans and if so, indicates which mechanisms might be involved. It will also provide the tools to investigate microstructural bone changes over time and even to predict the healing. This will ultimately allow better monitoring and even simulation of the repair process to improve clinical diagnosis and prognosis in patients with bone fractures.

At the department of Orthopedics and Trauma Surgery of Medical University Innsbruck 106 study participants were recruited during the study period. All patients who presented with distal radius fractures, that could be treated conservatively were screened for inclusion to the study. From initial radiographs of the injured wrists fracture, severity was obtained. Patients were immobilized with a plaster cast for five weeks. Patients information, like demographics, handedness and health status were recorded. Follow-up appointments, including cast changes, radiographic and clinical examinations of both wrists were coordinated by our department and took place in our outpatients clinic. According to our developed examination schedule, check-ups at seven time points for one year (baseline, 1 week, 3 weeks, 5 weeks, 3 months, 6 months, and one year) were done. In addition to objective measurements of function like grip strength and range of motion, subjective parameters like pain assessment and Questionnaires about quality in daily living were obtained. All patients additionally received DXA-Scans to group patients into subgroups according to their bone quality. Furthermore, fasting blood samples were taken. After defining an in vivo HR-pQCT imaging protocol we were able to acquire high-resolution time-lapsed images of both wrists. Different imaging protocols for the fracture and contralateral arm were developed and optimized to improve reproducibility. To increase mobility and decrease swelling a novel exercise protocol including fist closures in the initial healing period and usage of Gripinators after cast removal a novel exercise protocol was implemented and introduced to the participants. All HR-pQCT-images were visually classified into different grades regarding motion artifacts. In all radiographic images joint angles of the distal radius were measured and compared at different follow-up times. We started to evaluate the gained HR-pQCT-images corresponding to the results of clinical parameters during fracture healing and compared them according to patients age, gender, and bone quality. We also correlate imaging data and biomarkers with clinical outcome and bone healing to show the progression of fracture healing in the period of one year.