title: Effects of large doses of olpadronate (dimethyl-pamidronate) on mineral density, cross-sectional architecture, and mechanical properties of rat femurs.
abstract: As part of a safety-assessment study, doses of 8, 40, and 200 mg/kg per day, 6 days per week, of sodium olpadronate (dimethyl-APD, Me2-APD) were given by gavage to 10-week-old male and female rats during 27 weeks. Only the 200 mg/kg per day dose provoked toxic effects and a meaningful growth depression, regardless of the animal gender. In male animals, doses of 40 or 200 mg/kg per day improved strength, stiffness, and cross-sectional moment of inertia (CSMI) of femur diaphyses despite the toxic effects observed at the highest dose. Changes in bone mechanical properties were a consequence of those induced in CSMI. Regression analyses showed a treatment-induced improvement in bone modeling (as assessed by CSMI) for the same level of bone material stiffness (as expressed by calculated values of elastic modulus). The high dependency of results on body mass bearing suggested that these effects were exerted through an increase in the efficiency of bone mechanostat. Strikingly, they were not evident in female rats. If not related to a lower bone bioavailability of bisphosphonates in female rats as described by others, this phenomenon may have reflected: (1) their a smaller biomass; and/or (2) a less effective mechanostatic regulation of bone architecture derived from a higher bone material stiffness related to male animals. An increase of BMD with a predominance toward the distal region was observed in all femurs studied. This effect, unrelated to the observed changes in mechanical properties, seems to express a lack of remodeling of primary cartilage or bone tissue.
authors.affiliation: Centro de Estudios de Metabolismo Fosfocálcico (CEMFoC), Consejo de Investigaciones (CIUNR), Universidad Nacional de Rosario, Argentina.
authors.forename: J L
authors.initials: JL
authors.lastname: Ferretti
authors.forename: N
authors.initials: N
authors.lastname: Mondelo
authors.forename: R F
authors.initials: RF
authors.lastname: Capozza
authors.forename: G R
authors.initials: GR
authors.lastname: Cointry
authors.forename: J R
authors.initials: JR
authors.lastname: Zanchetta
authors.forename: E
authors.initials: E
authors.lastname: Montuori
mesh_terms: D015502:Absorptiometry, Photon; D000704:Analysis of Variance; D000818:Animals; D001682:Biological Availability; D001696:Biomechanical Phenomena; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects; D004164:Diphosphonates / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005269:Femur / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012044:Regression Analysis; D012737:Sex Factors; D012984:Software
chemical_list: D004164:Diphosphonates; C055774:olpadronic acid