title: Inhibited osteoclastic bone resorption through alendronate treatment in rats reduces severe osteoarthritis progression.
abstract: Osteoarthritis (OA) is a non-rheumatoid joint disease characterized by progressive degeneration of extra-cellular cartilage matrix (ECM), enhanced subchondral bone remodeling, osteophyte formation and synovial thickening. Alendronate (ALN) is a potent inhibitor of osteoclastic bone resorption and results in reduced bone remodeling. This study investigated the effects of pre-emptive use of ALN on OA related osteoclastic subchondral bone resorption in an in vivo rat model for severe OA. Using multi-modality imaging we measured effects of ALN treatment within cartilage and synovium. Severe osteoarthritis was induced in left rat knees using papain injections in combination with a moderate running protocol. Twenty rats were treated with subcutaneous ALN injections and compared to twenty untreated controls. Animals were longitudinally monitored for 12weeks with in vivo μCT to measure subchondral bone changes and SPECT/CT to determine synovial macrophage activation using a folate-based radiotracer. Articular cartilage was analyzed at 6 and 12weeks with ex vivo contrast enhanced μCT and histology to measure sulfated-glycosaminoglycan (sGAG) content and cartilage thickness. ALN treatment successfully inhibited subchondral bone remodeling. As a result we found less subchondral plate porosity and reduced osteophytosis. ALN treatment did not reduce subchondral sclerosis. However, after the OA induction phase, ALN treatment protected cartilage ECM from degradation and reduced synovial macrophage activation. Surprisingly, ALN treatment also improved sGAG content of tibia cartilage in healthy joints. Our data was consistent with the hypothesis that osteoclastic bone resorption might play an important role in OA and may be a driving force for progression of the disease. However, our study suggest that this effect might not solely be effects on osteoclastic activity, since ALN treatment also influenced macrophage functioning. Additionally, ALN treatment and physical activity exercised a positive effect in healthy control joints, which increased cartilage sGAG content. More research on this topic might lead to novel insights as to improve cartilage quality.
authors.affiliation: Department of Orthopaedics, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address: m.siebelt@erasmusmc.nl.
authors.forename: M
authors.initials: M
authors.lastname: Siebelt
authors.affiliation: Department of Orthopaedics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Waarsing
authors.affiliation: Department of Nuclear Medicine, Erasmus University Medical Center, The Netherlands.
authors.forename: H C
authors.initials: HC
authors.lastname: Groen
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, Villigen-PSI, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Müller
authors.affiliation: Department of Nuclear Medicine, Erasmus University Medical Center, The Netherlands.
authors.forename: S J
authors.initials: SJ
authors.lastname: Koelewijn
authors.affiliation: Department of Nuclear Medicine, Erasmus University Medical Center, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: de Blois
authors.affiliation: Department of Orthopaedics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: J A N
authors.initials: JA
authors.lastname: Verhaar
authors.affiliation: Department of Nuclear Medicine, Erasmus University Medical Center, The Netherlands; Department of Radiology, Erasmus University Medical Center, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: de Jong
authors.affiliation: Department of Biomechanical Engineering, Delft University of Technology, Delft, The Netherlands; Dept. Orthopaedics & Dept. Rheumatology, UMC Utrecht, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Weinans
mesh_terms: D019386:Alendronate / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001862:Bone Resorption / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology; D018450:Disease Progression; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D010003:Osteoarthritis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology*; D017208:Rats, Wistar; D013583:Synovial Membrane / Q000187:drug effects / Q000473:pathology; D055114:X-Ray Microtomography
chemical_list: D019386:Alendronate
keywords: Alendronate; Articular cartilage; Exercise; Osteoarthritis; Osteoclast; Subchondral bone