Intratrabecular bone remodeling - a previously overlooked mode of remodeling hyperactivated by parathyroid hormone

Currently, no consensus exists on either terminology, definition, or the biological significance of the phenomena intratrabecular tunneling. Despite this, observations of intratrabecular tunneling are frequently reported in literature covering diseases or treatments involving parathyroid hormone or kidneys. A few attempts to quantify this phenomena have been made mainly based on bone resorption, despite the concurrent presence of bone formation. This study demonstrates that intratrabecular tunneling is a previously unrecognized physiological mode of intratrabecular bone remodeling occurring across conditions and ages. Similar to intracortical remodeling, it is induced by PTH-treatment and creates an extensive interconnected tunnel-network that hollows out the trabeculae. This study primarily utilizes iliac crest bone biopsies collected from a clinical trial where patients with hypoparathyroidism were randomized to receive daily injections with either 100μg rhPTH(1-84) or placebo as add-on to conventional therapy for 6 months. In addition, further bone biopsies were collected from a 24-month open-label extension study, including patients receiving either only conventional treatment, continued rhPTH-treatment or discontinued rhPTH-treatment. Histomorphometry demonstrated that PTH-treatment induced an 18-fold and 36-fold increase in intratrabecular porosity after 6 and 30 months of treatment, respectively. After 6-months of PTH- versus conventional treatment, a median 7.7% versus 0.0% were eroded pores, 69.1% versus 0.0% were eroded-formative pores, 12.9% versus 0.0% were formative pores and 0.9% versus 81.2% were quiescent pores. PTH-treatment withdrawal normalized the intratrabecular remodeling to levels similar to conventional therapy. The intratrabecular remodeling mainly occurred in plates and junctions of trabeculae, and not in trabecular rods. Intratrabecular remodeling parameters showed a positive correlation with PTH-induced trabecular mineralization and a negative correlation with active vitamin D-supplementary doses. Dynamics of the PTH-induced intratrabecular remodeling could be tracked using time-lapsed synchrotron radiation μCT in a rabbit model and the complexity of the trabecular strain environment was confirmed with micro-finite-element analysis.