P0872EFFECT OF PARATHYROID HORMONE OSCILLATIONS ON BONE HEALTH: FROM OSTEO-ANABOLISM TO CATABOLISM

Abstract

Abstract Background and Aims In patients with chronic kidney disease or primary hyperparathyroidism, chronically elevated parathyroid hormones (PTH) levels exert catabolic effects on the bone. In contrast, PTH oscillations (as seen in healthy subjects) or daily application of teriparatide (a form of PTH consisting of the N-terminal 34 amino acids; it is used to treat osteoporosis) promote bone formation. These differential responses have important clinical and therapeutic implications. Although the anabolic effects of PTH (and teriparatide) cycling are widely accepted, the underlying osteo-anabolic dynamics are not well understood. Method A recently developed mechanistic physiology-based model quantitating the interrelations of osteoclasts, osteoblasts and osteocytes on bone remodeling is used (Cherif et al., ΝΔΤ 2018, 33 (συππλ. 1): 165–166). The model incorporates cell-to-cell signaling pathways (i.e., RANK-RANKL-OPG), intracellular pathways, cytokines (i.e. TGFβ), PTH, sclerostin, and endocrine and paracrine feedbacks. Using the validated model, we explore the effect of altered PTH (teriparatide) administration regimen (e.g., dosing frequency and amplitude) on bone catabolism and anabolism, respectively. Results As in previous studies, the model accurately predicts differential responses of osteo-anabolic and catabolic effects of continuously and intermittently elevated PTH (teriparatide) levels, respectively. In addition, we observe that intermittent administration of PTH with a high frequency and amplitude induces bone catabolism similar to that seen in pathologies with continuously elevated PTH (i.e. primary or secondary hyperparathyroidism). We see a more than 3-fold change from baseline in osteoclastic over osteoblastic activities, resulting in a bone efflux of calcium and phosphate. Low PTH frequency with high dosing amplitude induces both osteoclastic and osteoblastic activities, but the net result is bone anabolism. Further, Fig. 1 shows a nonlinear region where high osteoblastic activities exceed osteoclastic resorption. These findings suggest the existence of optimal PTH (teriparatide) frequency-amplitude combinations that enhance anabolic gains, beyond which there can be a detrimental effect on bone. Conclusion Our results suggest that both frequency and amplitude of PTH (teriparatide) cycling affect the balance of osteo-catabolic and -anabolic effects. Understanding the underlying mechanism of differential osteo-anabolic and -catabolic responses induced by intermittent and continuous levels of PTH, respectively, may provide new therapeutic options for patients and minimize unintended consequences of intervention protocols.