Effective doses for strontium ranelate

Abstract

Dear Editors, I have read with great interest the article entitled “Strontium ranelate does not stimulate bone formation in ovariectomized rats” published online in Osteoporosis International. In this article [1], Drs Fuchs and colleagues from Procter & Gamble Pharmaceuticals conclude that strontium ranelate (SrR) at dosages of 25 and 150 mg/kg/day does not induce an anabolic response in ovariectomized rats. Important concerns can be raised about the study’s methods and data interpretation. It is unfortunate that the authors tested doses of SrR that are clearly too low to be effective. There are major differences in the pharmacokinetics of strontium between rats and humans, and one can only compare effective doses based on circulating Sr concentrations. In clinical studies, the mean serum strontium level in postmenopausal women receiving 2 g/day of SrR was 10,560 ng/ml [2, 3]. In the present study, the mean serum strontium level in ovariectomized rats receiving 150 mg/kg/day of SrR and a normal calcium diet was 1,746 ng/ml, i.e., more than 6 times less than the effective clinical dose. At the dose of 25 mg/kg/day of SrR and a normal calcium diet, the animals were even 37-fold underexposed. Thus, the doses used in this study were far from being relevant to the effective dose in clinical trials. In previous studies, we demonstrated that SrR at clinically relevant doses can prevent bone loss in ovariectomized rats by reducing bone resorption and maintaining bone formation [4], demonstrating the efficacy of SrR at these doses in the prevention of bone loss in estrogen-deficient rats. The authors of this study also tested the effect of SrR at the same low doses in calcium-deficient ovariectomized rats. Again, these conditions are not relevant to effective clinical doses in humans receiving calcium and vitamin D supplementation. Additionally, the interpretation of the data in such ovariectomized rats receiving a low-calcium diet appears unclear given the known impact of calcium deficiency on bone mineralization and bone resorption, which was not assessed in this study due to a lack of corresponding control groups. Overall, the methodological and dosage limitations of this study do not allow conclusions on the efficacy of SrR in this model, since the efficacy of SrR should be based on data obtained in conditions that are relevant to clinical trials.