Impact of Anti-Resorptive Treatment on Recovery of Bone After Disuse

Bisphosphonates (BP), drugs that inhibit bone resorption, are used to minimize bone loss in long-duration spaceflight, extended bed rest, and acute spinal cord injury; however, the long term impact of BP use on recovery of bone after disuse is not well understood. This experiment tests the hypothesis that the BP zoledronic acid (ZOL) administered 7 days before hindlimb unloading (HU) will protect against loss of bone mass during 28 days of HU by suppressing bone resorption activity while also diminishing the ability of cancellous bone formation rate (BFR) to recover following HU. Male Sprague Dawley rats (6 mo) were assigned to aging control (AC), HU, and HU+ZOL groups and subjected to 28 days of HU, then to 56 days of weight-bearing recovery (REC). One group of rats was given 2 fluorescent labels 7 days apart to measure BFR in the final week of HU and the other group was given the same labels in the final week of REC. Histomorphometric analyses of the proximal tibia and distal femur showed lower osteoclast surface, a measure of bone resorption, 35 days after injection and 119 days after injection (-50% and -75%, respectively, compared to HU). This verified that ZOL successfully suppressed bone resorption. Dynamic histomorphometry revealed that cancellous BFR was lower in ZOL+HU versus AC both immediately after HU (-96.6%) and after the recovery period (-99.9%) (

Exercise training modifies the bone and endocrine response to graded reductions in energy availability in skeletally mature female rodents

IntroductionReductions in energy availability leading to weight loss can induce loss of bone and impact important endocrine regulators of bone integrity. We sought to elucidate whether endurance exercise (EX) can mitigate bone loss observed in sedentary (SED) skeletally mature rodents subjected to graded energy deficits.MethodsFemale virgin rats (n=84, 5-mo-old; 12/group) were randomized to baseline controls and either sedentary (SED) or exercise (EX) conditions, and within each exercise status to adlib-fed (ADLIB), or moderate (MOD) or severe (SEV) energy restriction diets for 12 weeks. Rats assigned to EX groups performed treadmill running to increase weekly energy expenditure by 10%. MOD-ER-SED, SEV-ER-SED, MOD-ER-EX and SEV-ER-EX were fed modified AIN93M diets with 20%, 40% 10%, and 30% less energy content, respectively, with 100% of all other nutrients provided.ResultsEnergy availability (EA) was effectively reduced by ~14% and ~30% in the MOD-ER and SEV-ER groups, respectively. MOD-ER for 12 weeks resulted in few negative impacts on bone and, except for serum leptin in MOD-ER-SED rats, no significant changes in endocrine factors. By contrast, SEV-ER in SED rats resulted in significantly lower total body and femoral neck bone mass, and reduced serum estradiol, IGF-1 and leptin. EX rats experiencing the same reduction in energy availability as SEV-ER-SED exhibited higher total body mass, lean mass, total BMC, and higher serum IGF-1 at the end of 12 weeks. Bone mechanical properties at 3 bone sites (mid-femur, distal femur, femoral neck) were minimally impacted by ER but positively affected by EX.DiscussionThese findings indicate that combining increased EX energy expenditure with smaller reductions in energy intake to achieve a targeted reduction in EA provides some protection against loss of bone mass and lean mass in skeletally mature female rats, likely due to better preservation of circulating IGF-1, and that bone mechanical integrity is not significantly degraded with either moderate or severe reduced EA

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

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