Patients were also excluded if they had taken intravenous bisphosphonates within 12 months prior to the screening visit, or strontium ranelate or fluoride at therapeutic doses (≥20 mg/day) for more than 3 months in the 2 years prior to randomization, SYN-117 or for more than a total of 2 years, or at any dosages within the 6 months prior to randomization. Previous treatment for any duration with calcitonin, oral bisphosphonates, or active vitamin D3 analogues

that had been stopped prior to or at the randomization visit was allowed. All patients provided written informed consent. Biochemical markers of bone turnover Serum concentrations of two BTMs were measured at baseline and at 3, 6 and 18 months of treatment: (1) the bone formation mTOR kinase assay marker PINP and (2) the bone resorption marker C-terminal cross-linked telopeptides of type I collagen

(CTx). Fasting blood samples (10 ml) were collected in the morning, then serum samples were prepared and stored at −20 °C or lower at the study site for up to 4 months before being sent to a central laboratory (Covance, Geneva, Switzerland) for storage at −80 °C and processing. All samples from an individual were assayed in a single analytical batch. Serum intact PINP was measured by the Intact UniQ RIA assay (Orion Diagnostica, Espoo, Finland). This assay is not sensitive to the small molecular weight degradation products of the pro-peptide (cross-reaction only 1.2 %). The inter-assay ADP ribosylation factor (within day) analytical coefficient of variation (CV) was less than 3.1–8.2 % over the reference interval. Serum CTx was measured by the Serum Crosslaps® ELISA (Nordic STI571 concentration Bioscience Diagnostics, Herlev, Denmark). The inter-assay CV was 5.4–11.4 %. High-resolution quantitative CT and FEA CT scans were performed at baseline and at 6 and 18 months of treatment. To optimize image quality

serving as the input data for FE analyses, we used an HRQCT protocol rather than a standard QCT protocol with thicker slices and lower plane resolution. All HRQCT assessments performed in this study have been described elsewhere [30, 37], and are briefly summarized below. A thin-slice spiral CT of the 12th thoracic vertebra (T12) was acquired using a scanner set at 120 kV and 360 mA s. If T12 was fractured, the HRQCT was performed on an intact L1 vertebra. Two images were reconstructed. The first one had a large field of view (FOV), included the patient and calibration phantom, and was used to calibrate the second image on which all analyses were carried out. The second image, with a smaller FOV size of 80 or 96 mm (pixel sizes of 0.156 or 0.188 mm) depending on the scanner type, included only the vertebra. In this latter image, the complete vertebral body was segmented using a semi-automatic algorithm.