Abstract
ABSTRACTTo test how osteoporosis drugs affect bone matrix maturation during cortical bone remodeling, 72 pregnant rats were switched from a 0.4% to a 0.01% calcium diet at parturition for a 23‐day lactation period. At weaning, eight dams were sacrificed to establish baseline values, while the remaining dams were returned to 0.4% calcium and treated with vehicle (saline), sodium fluoride (NaF), zoledronic acid (ZA), or sclerostin antibody (Scl‐Ab) for either 7 or 28 days (eight animals per group per time point). Femora were examined by μCT, dynamic histomorphometry, Fourier transform infrared imaging, and three‐point bending of notched specimens. Cortical porosity decreased in all groups from baseline to day 28. Intracortical mineralizing surface (MS/BS) and mineral apposition rate (MAR), as well as the mineral‐to‐matrix ratio were unaffected by treatment, but intracortical crystallinity was increased in the ZA group at day 10 compared with vehicle. Cortical area increased in all groups over 28 days mainly because of an addition of bone at the endocortical surface. Endocortical MS/BS did not vary among the groups, but endocortical MAR was suppressed in the NaF group at day 2 and elevated in the Scl‐Ab group at day 4 compared with vehicle. Endocortical mineral‐to‐matrix ratio was increased at days 5 and 10 following NaF treatment and endocortical crystallinity was increased at day 5 following ZA treatment compared with vehicle. Fracture toughness did not differ among the groups. Thus, the treatments affected matrix maturation more strongly at the endocortical then intracortical envelope. In this model of induced remodeling, the bone formation phase is synchronized at multiple sites, facilitating study of the effects of drugs or other bone‐targeting agents on matrix maturation independent of their effects on the initiation of remodeling. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Highlights
Bone remodeling is a complex process that is initiated when osteoclasts resorb bone matrix and is completed only after the deposited collagen matrix is mineralized
Our lab has shown in adult rats that the bone formation phase is synchronized at multiple remodeling sites following a regimen in which a low calcium diet during lactation is followed by return to normal calcium intake upon weaning.[1,2] The model is characterized by normal matrix mineralization kinetics[2] and minimal effects on mineral metabolism during the formation period.[1]
We demonstrate the utility of the lactation/low Ca rat as a preclinical model to study the effects of bone-targeting treatments on matrix maturation independent of their effects on bone remodeling
Summary
Bone remodeling is a complex process that is initiated when osteoclasts resorb bone matrix and is completed only after the deposited collagen matrix is mineralized. One can induce remodeling and synchronize the formation phase making the process of matrix mineralization in the adult skeleton more amenable to study. To this end, our lab has shown in adult rats that the bone formation phase is synchronized at multiple remodeling sites following a regimen in which a low calcium diet during lactation is followed by return to normal calcium intake upon weaning.[1,2] The model is characterized by normal matrix mineralization kinetics[2] and minimal effects on mineral metabolism during the formation period.[1]. Had there been a preclinical model to assess the effect of NaF on maturation, it is likely that these fractures could have been avoided
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