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Sequential High-Impact Loading and Zoledronic Acid Before Hindlimb Unloading Protects Against Decrements in Bone Microarchitecture and Strength

Boudreaux, Ramon D , Perticone, Jacqueline I , Ellman, Rachel , Lenfest, Scott E , Bloomfield, Susan A and Hogan, Harry A (2014) Sequential High-Impact Loading and Zoledronic Acid Before Hindlimb Unloading Protects Against Decrements in Bone Microarchitecture and Strength. Published Thesis:


The purpose of our investigation was to evaluate the efficacy of prophylactic interventions consisting of impact loading (free-fall landing) and/or a bisphosphonate (zoledronic acid), to counter disuse-induced bone loss of adult male rats (6 months old) subjected to 28 days of hindlimb unloading. Furthermore, we aimed to define the effects of these treatments on mechanical strength properties and bone turnover. We hypothesized that monotherapy would mitigate adverse alterations in bone mass, microarchitecture, and strength, while the combined sequential treatment would completely prevent them. Animals were assigned to one of six groups (n=12 each): baseline control (BC, euthanized on study day 0), cage control (CC), hindlimb unloading (HU), zoledronic acid treatment plus hindlimb unloading (ZA+HU), impact loading treatment plus hindlimb unloading (IL+HU), and impact loading and zoledronic acid treatments plus hindlimb unloading (IL+ZA+HU). IL animals were dropped 25 times (five drops from 30 cm followed by 20 drops from 60 cm) three times per week for the first five weeks of the study. ZA (60 μg/kg body weight) was administered on day 36, immediately following IL and just prior to HU. HU began on day 37 and persisted for four weeks.
At the distal femur metaphysis (DFM) and femoral neck (FN), HU caused declines in cancellous bone volume fraction (BV/TV, -25%) and total volumetric bone mineral density (vBMD, -14%), respectively, compared to CC. Mechanical strength and bone turnover were also impaired due to unloading. Individually, IL and ZA attenuated HU-induced changes in mass, microarchitecture, and strength, but when given sequentially, IL+ZA fully rescued them. While HU caused an uncoupling of bone remodeling, ZA treatment successfully reduced bone degradation without affecting bone formation. Treatment with IL followed by ZA resulted in enhanced DFM BV/TV (+20%) and trabecular thickness (Tb.Th, +5%). Also, FN ultimate force was highest with combination treatment. While IL and ZA alone attenuated the deleterious effects of disuse on bone quality, when the two were administered in sequence adult male rats were fully protected against HU-induced alterations in bone mass, microarchitecture, strength, and turnover.

Item Type: Article
Date Deposited: 02 May 2016 23:45
Last Modified: 02 May 2016 23:45


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