Osteoporosis Treatments Affect Bone Matrix Maturation in a Rat Model of Induced Cortical Remodeling

Abstract

To 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.

The relative contribution of bone microarchitecture and matrix composition to implant fixation strength in rats

“…For example, bisphosphonates are known to have positive effects on early implant fixation clinically, 3 as well as osseointegration 42 . Bisphosphonates have also been shown to alter bone matrix composition including crystallinity 6–8 . Based on our results, it is likely that both changes in the bone structure and composition likely contribute to the increased fixation strength reported in preclinical animal models 24 .…”

“…Bone matrix composition is altered in prevalent diseases relevant to orthopedic surgery such as osteoporosis and type 2 diabetes mellitus (T2DM). While osteoporosis is mainly thought of as a disease of low bone mineral density, both preclinical 5 and clinical observation studies 6–9 have demonstrated that bone matrix composition is also altered by osteoporosis and these alterations contribute to fragility fracture risk 10 . T2DM is another condition known to change bone matrix composition in preclinical 11 and clinical studies, 12,13 which likely contribute to the elevated rates of fragility fracture despite normal bone mineral density 14,15 …”

Zucker Diabetic‐Sprague Dawley Rats Have Impaired Peri‐Implant Bone Formation, Matrix Composition, and Implant Fixation Strength

“…Additional technical limitations include the lack of tissue age–specific measurements of bone matrix composition and the limited number of individual spectra collected for each animal. Although we have used fluorescent labels in the past to make tissue age–specific measurements on rat tissues, ( 68 ) the Raman instrument we used for this analysis was not equipped with fluorescent imaging. The lack of tissue‐age resolution could increase the intra‐specimen variability in the Raman measurements and prevents us from determining whether the measured matrix changes were due to differences in newly formed bone or changes to existing bone matrix.…”