Preclinical Assessment of Gastrooesophageal Tolerance of the New Antiosteoporotic Drug Strontium Ranelate: An Endoscopic Study in Monkeys

Abstract

This study was aimed at evaluating the digestive tolerance of the new antiosteoporotic drug, strontium ranelate, and to compare it to that of another strontium salt, strontium chloride (SrCl 2 ). Strontium ranelate, SrCl 2 , or placebo were administered orally (capsules) to 3 groups of 2 male and 2 female cynomolgus monkeys (Macaca fascicularis) once a day for 7 days at a dose of 2 g/day, which is the recommended therapeutic dose in man. Endoscopic examination of the oesophagus, the stomach and the first part of the duodenum was performed on fasted animals approximately 3 hr after the first (Day 1) and last dosing (Day 7), and, on Day 8 and Day 14 in case of lesions on Day 7. Strontium ranelate did not induce any acute or subchronic toxic effect on the gastric mucosa, the oesophagus and the first part of the duodenum. On the contrary, acute and superficial damages were noted on all animals receiving SrCl 2 such as haemorrhagic and erosive lesions (formation of an ulcer in one male and a marked congestive antritis in one female). These effects were reversible after cessation of treatment. The microscopic examination of biopsies sampled at the site of gastric lesions revealed moderate granulocyte infiltration, indicating a local irritating origin of the lesions. Strontium ranelate by oral route is safe for the gastric mucosa while SrCl 2 induced superficial and reversible lesions.Safety and tolerance are particularly key issues with treatments against post-menopausal osteoporosis, which are mainly administered over a long period of time to elderly people. The currently available antiosteoporotic drugs, such as bisphosphonates, induce gastrointestinal side-effects when given by oral route, from abdominal pain (Maconi & Porro 1995;Sherman & Bini 1999) to gastric ulcer (Graham et al. 1997), which can affect a reliable compliance.Strontium ranelate is composed of two stable strontium atoms and of an organic moiety, ranelic acid. Strontium ranelate has been shown to prevent bone loss by decreasing osteoclast resorption and by inducing osteoblast formation in vivo (Marie et al. 1993) and in vitro (Canalis et al. 1996;Baron & Tsouderos 2002;Takahashi et al. 2003), and has therefore been developed for the treatment of post-menopausal osteoporosis.An endoscopic study was set up to assess in the cynomolgus monkey (Macaca fascicularis) the strontium ranelate tolerance on the gastrooesophageal tract, by comparison with strontium chloride (SrCl 2 ), a common strontium salt.Until now, the gastric tolerability of strontium chloride was not known. However, other chloride-containing chemicals, such as NaCl and KCl, when used as hypertonic solutions, have ulcerogenic activity in animals (Barkin et al.Author for correspondence: Isabelle Dupin-Roger, Servier, 6 place des Pléiades, 92415 Courbevoie Cedex, France (fax π33 1 5572 6436, e-mail philippe.halbout/fr.netgrs.com).1983; Takeuchi et al. 1986). This effect have raised the possibility of gastric intolerance with SrCl 2 .The primate model was described as a good model f...

The effects of strontium chloride on viability of mouse connective tissue fibroblast cells

“…Behaviour, growth, food intake, and the weights and microscopic appearance of the liver and kidney were normal in all groups of young adult rats (130-170g; three of each sex per group) fed strontium chloride hexa-hydrate at up to 3000 mg/kg in the diet for two weeks (about 50-100mg/kg body weight per day as strontium, assuming rats ingest food at the equivalent of 5-10% of their body weight daily). There were no clear effects on haematology, and the bones were not examined in this range-finding study [17].…”