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Shih M.-S.,PharmaLegacy Laboratories
Current Osteoporosis Reports | Year: 2012

Osteoporosis is a clinical manifestation of fracture from weakened bone tissues. Fracture is the result of incompatibility between biomechanical loading forces and material properties of bone tissues. Bone tissues constantly renew themselves and renovate microstructurally in responding to physiopathological changes. This kind of adaptation evolves as human lifestyles progress to modernization and as medicinal therapeutics advance to individualization. Realization of the bone tissues' adaptation broadens the choices for therapeutic approaches and the utilization of combinational treatments for the sake of not only prolonging life span but also improving life quality. © Springer Science+Business Media, LLC 2012.

Pennypacker B.L.,Bone Biology Group | Chen C.M.,Bone Biology Group | Zheng H.,PharmaLegacy Laboratories | Shih M.-S.,PharmaLegacy Laboratories | And 3 more authors.
Journal of Bone and Mineral Research | Year: 2014

Treatment with the cathepsin K (CatK) inhibitor odanacatib (ODN) protects against bone loss and maintains normal biomechanical properties in the spine and hip of ovariectomized (OVX) preclinical models. Here, we characterized the effects of ODN on the dynamics of cortical modeling and remodeling, and dimension and strength of the central femur in adult OVX-rhesus monkeys. Animals were treated with vehicle or ODN (6 or 30mg/kg, once per day [q.d., p.o.]) in prevention mode for 21 months. Calcein and tetracycline double-labeling were given at 12 and 21 months, and the femoral cross-sections were subjected to dynamic histomorphometric and cement line analyses. ODN treatment significantly increased periosteal and endocortical bone formation (BFR/BS), accompanied with an increase in endocortical mineralizing surface (102%, p<0.01) with the 6mg/kg dose. ODN at both doses reduced remodeling hemiosteon numbers by 51% and 66% (p<0.05), respectively, and ODN 30mg/kg numerically reduced activation frequency without affecting wall thickness. On the same endocortical surface, ODN increased all modeling-based parameters, while reducing intracortical remodeling, consistent with the observed no treatment effects on cortical porosity. ODN 30mg/kg markedly increased cortical thickness (CtTh, p<0.001) and reduced marrow area (p<0.01). Lastly, ODN treatment increased femoral structural strength (p<0.001). Peak load was positively correlated with the increases in bone mineral content (BMC) (r2=0.9057, p<0.0001) and CtTh (r2=0.6866, p<0.0001). Taken together, by reducing cortical remodeling-based and stimulating modeling-based bone formation, ODN significantly improved cortical dimension and strength in OVX monkeys. This novel mechanism of CatK inhibition in stimulating cortical formation suggests that ODN represents a novel therapeutic approach for the treatment of osteoporosis. © 2014 American Society for Bone and Mineral Research.

Zheng H.,PharmaLegacy Laboratories | Bai Y.,PharmaLegacy Laboratories | Shih M.-S.,PharmaLegacy Laboratories | Hoffmann C.,Curasan AG | And 3 more authors.
Journal of Biomedical Materials Research - Part B Applied Biomaterials | Year: 2014

In this study, we tested the performance and biocompatibility of a composite of β-tricalcium phosphate (β-TCP) to collagen as a bone void filler (Cerasorb® Ortho Foam) in a rabbit distal femoral condyle model. β-TCP is a completely resorbable synthetic calcium phosphate and the addition of a collagen matrix couples the osteoconductive effects of the two components. Furthermore, the malleable properties of the implant material during surgical applications for shape control will be enhanced. A critical size defect of 6 mm in diameter and 10 mm in depth was drilled into each distal femur of the rabbits. One hole was filled with the test substance and the other was left empty for control. After 1, 3, and 6 months the animals were killed and the degree of bone healing analyzed. In total, 18 animals were investigated. When the β-TCP composite was used, histological, histomorphometric, and biomechanical evaluations revealed significantly better bone healing in terms of quantity and quality of the newly formed bone. Moreover, no signs of inflammation were observed in the animals and no allergic or foreign body reaction was noted. This suggests high biocompatibility and osteoconductivity of the investigated material to a bone void in an immune responsive species. Copyright © 2013 Wiley Periodicals, Inc.

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