title: Development of a low-dose anti-resorptive drug regimen reveals synergistic suppression of bone formation when coupled with disuse.
abstract: Safe and effective countermeasures to spaceflight-induced osteoporosis are required to mitigate the potential for mission-critical fractures and ensure long-term bone health in astronauts. Two anti-resorptive drugs, the bisphosphonate zoledronic acid (ZOL) and the anti-receptor activator of NF-kappaB ligand protein osteoprotegerin (OPG), were investigated to find the minimum, comparable doses that yield a maximal increase in bone quality, while minimizing deleterious effects on turnover and mineralization. Through a series of five trials in normally loaded female mice (n = 56/trial), analysis of trabecular volume fraction and connectivity using microcomputed tomography, along with biomechanical testing, quantitative histomorphometry, and compositional analysis, was used to select 45 microg/kg ZOL and 500 microg/kg OPG as doses that satisfy these criteria. These doses were then examined for their ability to mitigate bone loss following short-term unloading through hindlimb suspension (HLS). Seventy-two mice were prophylactically administered ZOL, OPG, or PBS and assigned to loaded control or 2-wk HLS groups (n = 12 for each of 6 groups). Both anti-resorptives were able to preserve trabecular microarchitecture and femoral elastic and maximum force in HLS mice (+30-40% ZOL/OPG vs. PBS). In HLS mice, anti-resorptive dosing reduced resorption perimeter at the femoral endocortical surface by 30% vs. PBS. In loaded control mice, anti-resorptives produced no change in bone formation rate; however, reductions in bone formation rate brought about by HLS were exacerbated by anti-resorptive treatment, suggesting synergistic inhibition of osteoblasts during disuse. Refined anti-resorptive dosing will tend to target countermeasures to the period of disuse, resulting in faster recovery and less adverse effects for astronauts.
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Shane A J
authors.initials: SA
authors.lastname: Lloyd
authors.forename: Neil D
authors.initials: ND
authors.lastname: Travis
authors.forename: Teng
authors.initials: T
authors.lastname: Lu
authors.forename: Ted A
authors.initials: TA
authors.lastname: Bateman
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D050071:Bone Density Conservation Agents / Q000008:administration & dosage*; D001862:Bone Resorption / Q000517:prevention & control; D002113:Calcification, Physiologic / Q000187:drug effects*; D004164:Diphosphonates / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology; D019417:Hindlimb Suspension; D007093:Imidazoles / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000000981:diagnostic imaging / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000517:prevention & control*; D053244:Osteoprotegerin / Q000008:administration & dosage*; D013026:Space Flight; D014057:Tomography, X-Ray Computed; D018544:Weightlessness Countermeasures; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D053244:Osteoprotegerin; C506030:TNFRSF11B protein, human; D000077211:Zoledronic Acid