7% and 55.5%, respectively). Diarrhea, nausea, and headache were more frequently reported. These events occurred mainly during the first 3 months of treatment. Skin and subcutaneous disorders were reported similarly in the three groups (5.5% in the SR/SR group, 7.3% in the SR/placebo group, and 4.3% in the placebo/SR group). Two serious adverse events classified as skin Procaspase activation disorder occurred: one contusion due to a fall in the placebo/SR group and one in the SR/placebo. None was considered as related to the study drug. Serum creatinine kinase

concentrations increased in some HDAC inhibitors in clinical trials patients starting strontium ranelate. High levels (concentration greater than three times the upper value of the normal reference range) were detected in 0.7% of the patients (three patients), but none reached five times the upper value of the normal reference range. Concerning calcium homeostasis, over 4 years, mild decreases in calcium and parathyroid hormone (PTH) serum levels were observed in the strontium ranelate group (from 2.38 ± 0.13 mmol/L at baseline to 2.22 ± 0.10 mmol/L

at end and from 30.98 ± 12.71 pg/mL at baseline to 28.75 ± 11.60 pg/mL at end, respectively), while blood phosphorus concentration slightly increased (from 1.22 ± 0.19 mmol/L at baseline to 1.31 ± 0.17 mmol/L at end). These changes were of too small magnitude to have clinical relevance. During the fifth year, in the group which stopped strontium ranelate, trends to inverse changes were observed; slight increase in serum calcium concentration (from 2.31 ± 0.93 Wnt tumor to 2.36 ± 0.09 mmol/L) and decrease

in blood phosphorus concentration (1.31 ± 0.16 to 1.22 ± 0.14 mmol/L). Discussion The Phosphoglycerate kinase main result of this pre-planned analysis is that long-term treatment (4 years) with strontium ranelate produced a significant 33% reduction in the risk of vertebral fractures. A similar reduction (36%) was seen in the subset of severely affected patients with ≥2 prevalent vertebral fractures at baseline. The reductions in fracture risk were associated with a progressive increase in BMD of the lumbar and hip regions that extended throughout the treatment period. Few studies of anti-osteoporotic drugs using randomized initial treatment periods of duration comparable to the present trial (4 years) and in the same type of patients are published. In patients without prevalent vertebral fracture, alendronate (10 mg/day) reduced by 44% vertebral fractures over 4 years, but no data were available in patients with prevalent vertebral fracture [26]. Raloxifene reduced vertebral fracture by 34% over 4 years in patients with prevalent vertebral fracture [27]. The 33% risk reduction seen over 4 years in this study is of similar magnitude to these results. No data are available for risedronate for initial randomized periods of 4 years or longer, but a reduction in vertebral fractures of 59% was reported from a smaller (265 patients) 2-year extension to a 3-year study [28].