Microsoft Word - HRE300BF.rtf

We have read with interest the article of Prof. J.-Y. Reginster entitled ‘Treatment of Bone in Elderly Subjects: Calcium, Vitamin D, Fluor, Bisphosphonates, Calcitonin’ [1], recently published in Hormone Research, and have the following comments regarding bisphosphonates, which have been the subject of studies in our laboratory for the last 9 years. We think that it would be more useful to classify bisphosphonates on the basis of their potency and therapeutic ratio (effective dose vs. dose which produces side effects) rather than the time of their discovery (first-generation, second-generation, etc). For example, the least potent bisphosphonate, etidronate, was reported to produce osteomalacia [2] at doses used for the treatment of osteoporosis; while pamidronate, although 100-fold more potent, produced GI side effects at therapeutic doses [3]. Since some side effects, such as osteomalacia, are related to the bisphosphonate moiety, they are less likely to occur with more potent compounds, such as alendronate or risedronate. We noted a significant error in the interpretation of the paper of Apseloff et al. [4] in which tail-suspended rats were treated with alendronate. First of all, the investigators compared tailsuspended treated rats to free-roaming rats, rather than to tail-suspended untreated animals. Furthermore, they compared the 35% increase in bone density in the distal tibia with the 13 % increase in bone strength in the diaphysis (the only place where strength was measured by the three-point bending test) and did not take into account that those are different anatomic locations. The strength in the diaphysis could not and should not be affected by the bone mass increase in the distal part of the long bones. In the diaphysis, the increase in strength was 13%, commensurate with the increase in density, about 13%, as expected for normal bone. Furthermore, alendronate has been shown to increase bone strength in direct proportion to bone mass in a large number of studies in different species and treatment protocols. These include: ovariec-tomized rats treated for 6 months [5]; ovari-ectomized baboons treated for 2 years [6]; normal female and male rats treated for 2 years [7]; normal minipigs treated for 1 year [8], and normal female and male dogs treated for 3 years [in press]. I understand that the findings reported in these papers, which have been mailed to Prof. Reginster, have allayed the author’s concern about the safety of alendronate since they