LONG-TERM SAFETY OF THE AMINOBISPHOSPHONATE ALENDRONATE IN ADULT DOGS.1. GENERAL SAFETY AND BIOMECHANICAL PROPERTIES OF BONE

Alendronate (4-amino-1-hydroxybutylidene bisphosphonate, ALN) is an am inobisphosphonate that is being developed for the treatment of disease s characterized by increased bone resorption. The purpose of this stud y was to assess the longterm safety of ALN with special emphasis on bo ne strength and bone morphology. Thirty-two (16 males and 16 females) 83- to 86-week-old beagle dogs were treated p.o. for up to 3 years wit h ALN at 0.00, 0.25, 0.5 or 1.0 mg/kg/day. The following parameters of toxicity were assessed: physical signs, body weight, ophthalmology, r adiographic evaluation of bone, electrocardiography, hematology, clini cal chemistry, urinalysis, necropsy including organ weight assessment, histopathology and biomechanical testing of bone. There were no appar ent compound-related alterations in any of the above mentioned paramet ers except the expected changes (related to the pharmacological activi ty of ALN) in serum phosphorus and Ca concentrations and in the histol ogy of bones with active endochondral bone formation (rib). There were mild transient reductions in the serum phosphorus and Ca concentratio ns at the 1.0 mg/kg/day dose level during the early part of the study. There was a dose-dependent delay in bone remodeling in the ribs of al l dogs treated with ALN. There was no similar change in the tibia. Mos t importantly, there were no spontaneous fractures and there were no c hanges in the structural properties of femoral or vertebral bone. The total ALN content of bone in an average dog (10 kg) after 3 years of t reatment with approximately five items of the intended dose for the tr eatment of osteoporosis was approximately 8 mg, which is only 0.001% o f total bone mass (700 g).