The Efficacy of the use of Alendronate in the Treatment of OIM/OIM Mice: Effects on Spinal Parameters**

· (a – Merck: Supplied the Drug)

INTRODUCTION: Osteogenesis Imperfecta (OI) is a known type I collagen disorder which manifests itself in patients as increased fragility with subsequent fractures. The oim/oim mouse contains a naturally occurring mutation, which resembles Type III OI, a moderate-to-severe phenotype. This mouse model has previously been used to study the effect of alendronate, a thirdgeneration bisphosphonate, in decreasing the fragility of bones. Earlier work has shown a positive effect on decreasing fracture numbers and tibial bowing, and increasing bone density (1). Although alendronate is now in clinical trials for OI, questions still persist as to how long children should stay on this therapy, and if intermittent dosing would be beneficial as well. Accordingly, this pre-clinical study was undertaken to investigate whether the effect of alendronate therapy is equivalent if given either continuously or intermittently to growing oim/oim mice over a long-term period. Here, we present some preliminary results from this study.

MATERIALS AND METHODS: All animal work was done under an IACUC-approved protocol. To date, there are a total of 55 mice, either wild type (+/+) or oim/oim divided into 2 groups, continuous and intermittent dosing. Group size ranged from 3 to 14 mice per group. Treatment began at age 2 weeks and continued until age 26 weeks at sacrifice. Group I consisted of mice receiving alendronate (generously supplied by Merck & Co., West Point, PA) at a dosage of 31 µg/kg/day or saline intermittently for 6 weeks intervals over a 24 week period. Group II consisted of mice receiving alendronate or saline continuously over the 24 week period. At sacrifice, mice were radiographed by high resolution faxitron in the anteriorposterior (AP) and medial-lateral (ML) planes. The faxitrons were digitized and utilized to calculate the number of fractures in the long bones, tibial length and tibial bowing, kyphosis.The heights and density of the L-2 vertebra were measured on scanned images.

RESULTS: Only the spinal data is reported. There was no change in the kyphosis in any of the groups with treatment. The L-2 density increased in the +/+ with continuous treatment greater than intermittent. The oim/oim trended to increased density in both continuous and intermittent groups, approximating the baseline+/+ density.(Table 1) The vertebral heights trended to a minimal increase in the continuous oim/oim group.The +/+ groups showed a decrease in the height in intermittent and continuous groups.(Table 2)

CONCLUSIONS: The initial conclusions are that density changes in the vertebral column are increased with any regimen of alendronate. However, overall alignment is not changed in the sagital plane.Vertebral heights are minimal affected in the oim/ oim groups and is adversely affected in the normal mice.Further studies are being carried out to increase the population and to study the histology and mineral:matrix composition of the spine in these mice. The goal is to establish clinical guidelines for the effective administration of alendronate to the growing OI patient.

** The FDA has not cleared a drug and/or medical device for the use described in this presentation (i.e., the drug or medical device is being discussed in an “off-label” use).

· If noted, the author indicates something of value received. The codes are identified as: a-research or institutional support; b-miscellaneous funding; c-royalties; d-stock options.