Continuous alendronate treatment throughout growth, maturation, and aging in the rat results in increases in bone mass and mechanical properties

Abstract

Alendronate (4-amino-1-hydroxybutylidene bisphosphonate) is a novel amino bisphosphonate that is being developed for the treatment of osteolytic bone disorders such as osteoporosis. As part of a 2-year carcinogenicity study, we investigated the morphologic and biomechanical effects of long-term alendronate (ALN) therapy, given throughout skeletal growth, maturation, and aging, on rat vertebrae and femora. Three treatment groups, receiving either deionized water, low- (1.00 mg/kg), or high-dose (3.75 mg/kg) ALN, were given daily oral treatment for 105 weeks. Results from mechanical tests indicate that ALN therapy (in males) increased the vertebral ultimate compressive load by 96% in the high- and 51% in the low-dose groups when compared with controls. ALN similarly increased the male ultimate femoral bending load by 59% in the high- and 31% in the low-dose groups. Vertebrae and femora from female rats treated with both high- and low-dose ALN also failed at significantly higher loads than controls, but no differences were seen between low- and high-dose groups. Morphologic analysis of both male and female vertebrae revealed a dose-dependent increase in area fraction of bone. Rats receiving high-dose ALN had a greater area fraction of bone than those receiving low doses. Both groups were greater than controls. Thus, the administration of ALN resulted in increased femoral cortical bending load when compared with control animals, as well as increased vertebral ultimate compressive load commensurate with a dose-related preservation of vertebral bone.(ABSTRACT TRUNCATED AT 250 WORDS)

Density and structural changes in the bone of growing rats after weekly alendronate administration with and without a methotrexate challenge

“…This agrees with findings in mice 7,8,12 and rats. 11 With substantially higher doses of ALN (2.5 mg/kg/wk), however, moderate limb shortening (! 5%) occurred.…”

“…6,7,24,25 The dose was within the range of that found to be safe and effective for increasing bone density in mice (0.125-0.35 mg/kg/ week), whether given weekly or divided into daily portions. 5,7,8,11,12 MTX was administered following a regimen previously used to model high-dose chemotherapy in an adult Sprague-Dawley rat. 21 Briefly, over the first 19 days of the study CTL and MTX groups received intraperitoneal injections of saline or 0.75 mg/kg/day MTX (Ben Venue Laboratories, Bedford, OH), respectively, in a 5 days on/9 days off/5 days on regimen.…”

“…[7][8][9] In rats, some reports showed a reduction, and some did not. 5,6,11 These studies involved continuous (daily) ALN administration, although two recent studies in mice employed intermittent (weekly) dosing with similar findings. 8,12 Despite the fact that current ALN therapy has shifted to intermittent dosing 13,14 and despite indications of its species-specific pharmacokinetics, 15,16 the effect of weekly ALN administration on the density, morphology, and strength of growing bone in rats has apparently not been studied.…”

O alendronato de sódio na prevenção da osteopenia secundária à imobilização gessada, em ratas: avaliação histomorfométrica

“…O alendronato de sódio, ou simplesmente alendronato, é um monossódio 4-amino-1-hidroxibutilidine bifosfonato que tem potência maior e grande seletividade para inibir a reabsorção óssea, sem afetar a for-mação óssea, o que não era observado com os outros compostos (10)(11)(14)(15)17) .…”

“…Foi atribuída a este volume corporal a interferência nos resultados dos ensaios. Além disso, em função da idade dos animais para completar o estudo (105 semanas), ocorreu morte de aproximadamente 80% dos ratos por causas não relacionadas com o tratamento (17) .…”