THE SPATIO-TEMPORAL BEHAVIOR OF BASIC MULTICELLULAR UNITS IN A PTH-INDUCED CORTICAL BONE REMODELING RABBIT MODEL

The adult skeleton is continuously renewed by the bone remodeling process, which is carried out by coupled and balanced activities, localized in time and space, via cellular groupings known as basic multicellular units (BMUs). In cortical bone, a BMU is depicted as a cutting cone of osteoclasts in the front resorbing bone, followed by a reversal phase, and then a closing cone lined by osteoblasts behind forming new bone. Any imbalance in this sequence of events can lead to bone diseases such as osteoporosis. Although it is well known that many factors affect BMU activity and contribute to osteoporosis, little is known about BMU dynamic spatio-temporal regulation. The rate of BMU progression, their longitudinal erosion rate (LER) is a key example of where knowledge is lacking. LER has only been inferred by 2D (histological) double-labeling techniques based on remodeling in a steady state where the cutting cone advance is equal to that of the closing cone. If these spatio-temporal relationships are valid and constant, increasing the bone formation rate, as observed with recombinant parathyroid hormone (PTH), an anabolic treatment for osteoporosis, would concomitantly elevate LER. The present study utilizes a new methodology to explore whether the increased cortical remodeling activity induced by PTH, including accelerated bone formation, leads to an elevated LER. BMU progression was manipulated via different dosing regimens: PTH and PTH withdrawal (PTHW). It was hypothesized that LER would be higher during active dosing. After 14 days of PTH dosing, rabbit distal right tibiae were imaged in vivo by synchrotron-based phase-contrast micro-CT. For the following 14 days, the PTH group received the same treatment while the PTHW group was administered saline. At 28 days, the rabbits were then euthanized, and the tibiae were imaged ex vivo by micro-CT. The in vivo and ex vivo right limb data sets were then registered, and LER was measured as the distance traversed by BMU cutting cones divided by 14 days. A total of 638 BMUs were assessed. Counter to the hypothesis, LER was lower in the PTH (34.61 µm/day) compared with the PTHW (39.37 µm/day; p < 0.01) group. Slower BMU progression suggests that PTH has an important role in enhancing coupling both by increasing bone formation and slowing the advance of bone resorption within BMUs. This novel insight into BMU dynamics indicates that further investigation into LER modulation is warranted, with potential implications for combatting remodeling-related disease, improving treatment, and potentially reducing drug side effects