Efficacy of combined treatment with alendronate (ALN) and eldecalcitol, a new active vitamin D analog, compared to that of concomitant ALN, vitamin D plus calcium treatment in Japanese patients with primary osteoporosis

The e-ADVANCED (Eldecalcitol; Alendronate plus vitamin D Versus AleNdronate Combined with ElDecalcitol) study was a randomized, unblinded clinical trial carried out to assess the efficacy on BMD, bone turnover markers (BTMs) and safety, of addition of ELD as compared to that of vitamin D plus Ca supplementation in osteoporotic patients receiving weekly ALN treatment (JapicCTI-No.111653). We analyzed the data of 219 subjects, including 214 females and 5 males, ranging in age from 60 to 90 years (yr.) (mean, 71.5 yr.), who had osteoporosis (defined as a low BMD (70 % of the young adult mean (YAM); 0.708 g/cm² by the Hologic QDR series) or osteopenia (80 % of the YAM; 0.809 g/cm² by the Hologic QDR series) with at least one vertebral fracture, according to the criteria of the Japanese Society for Bone and Mineral Research [6]. Prevalent vertebral fractures were assessed by x-ray examination of the vertebrae, and diagnosed according to the criteria of the Japanese Society for Bone and Mineral Research [7]. All the subjects were 60 years old or older, and patients were excluded from the study if they had fractures in any of the lumbar vertebrae L2–L4 or had disorders such as primary hyperparathyroidism, Cushing’s syndrome, gonadal insufficiency, poorly controlled diabetes mellitus, or other causes of secondary osteoporosis, or a history of/suspected active urolithiasis at any time. Subjects were also excluded if they had taken BPs within 48 weeks before entry into this study, taken glucocorticoids, calcitonin, vitamin K, active vitamin D compounds, ipriflavones, selective estrogen receptor modulators, or hormone replacement therapy within 8 weeks prior to entry into this study, or taken PTH, anti-receptor activator of NF-kappaB ligand (RANKL) antibody, cathepsin K inhibitor prior to entry, had serum calcium levels above or below the normal range, serum creatinine levels of over 1.0 mg/dL, any disorder associated with delayed passage of food through the esophagus, received/were scheduled to receive any invasive dental procedures, clinically significant hepatic or cardiac disorders, or active malignant tumor or prior therapy for malignancy within the previous 3 years. The subjects were enrolled at 13 centers in Japan. The study was conducted with the approval of the institutional review board at each center and in accordance with the Declaration of Helsinki and the Japanese of Good Clinical Practice Guidelines. Written informed consent was obtained from each patient prior to any study-related procedure.

Patients were randomly assigned at a 1:1 ratio to receive oral ALN at the dose of 35 mg weekly, the approved dosage in Japan, plus oral ELD at the dose of 0.75 μg daily (ALN + ELD group), or oral ALN at the dose of 35 mg weekly with oral vitamin D 400 IU + Ca 610 mg daily (ALN + VitD group). Randomization was performed by a computerized system. The subjects were stratified into groups on the basis of the L2-4 BMD values (≥70 %YAM/<70 %YAM). The randomization sequence was created by the person responsible for the investigational product randomization. Neither the patients nor the investigators were blinded to the treatment assignment at any time during the study period. Compliance with the study treatment was assessed based on the medication diaries maintained by each subject.

The BMD values at the lumbar spine (L-BMD), femoral neck (FN-BMD) and total hip in the posterior-anterior projections were measured at the baseline and at 24 and 48 weeks by dual-energy x-ray absorptiometry (DXA). The 13 study centers participating in this trial were all equipped with the Hologic QDR series (QDR2000, QDR4500, Explorer, Delphi or Discovery, Hologic, Inc.) for the BMD measurements. A central facility (Department of Radiological Technology, Kawasaki College of Allied Health Professions) performed quality assurance of the longitudinal adjustment. Adjustment for DXA machine differences was made to calibrate each machine with standardized phantoms. All the DXA measurements were analyzed at a central site by a radiologist who was blinded to the treatment group assignment. Radiographs of the thoracic and lumbar spine were taken at the baseline and at 48 weeks to assess the incidence of vertebral fractures. To identify morphometric vertebral fractures, the vertebral bodies in the lateral projections from Th4 to L4 were quantitated using a semi-quantitative (SQ) methodology [8] by a central committee who was also blinded to the treatment assessment. Patients with more than one incident L2–L4 vertebral fracture during the treatment period were excluded from the BMD analysis. Hip BMD images not satisfying the appropriate positioning criteria were also excluded by the central committee.

Serum and postprandial urine samples were collected at the baseline and at 4, 12, 24, and 48 weeks of treatment to evaluate Ca-related parameters such as the serum Ca, serum phosphorus, serum albumin, serum creatinine, and urinary Ca adjusted by mg/dL GF. In addition, routine blood biochemical analyses, including evaluation of the hematological, hepatic, and renal functions were conducted at the baseline and at 24 and 48 weeks. Bone turnover markers, including type I collagen C-telopeptide (sCTX) (β-Crosslaps N, Fujirebio Inc, Tokyo), urinary type I collagen N-telopeptide (uNTX) (Osteomark NTx; Alere, Orlando, FL), tartrate-resistant acid phosphatase 5b (TRACP-5b) (Osteolinks TRAP-5b, DS Pharma Biomedical Co., Ltd, Osaka), serum bone-specific alkaline phosphatase (BAP) (Access Ostase, Beckman Coulter, Inc., Brea, CA), and amino-terminal propeptide of type 1 procollagen (P1NP) (Procollagen Intact P1NP, TFB Inc. Tokyo) were assessed at the baseline and at 12, 24, and 48 weeks. Blood levels of the calcium-regulating hormones such as intact PTH (Intact-PTH, Roche Diagnostics, Hoffmann-La Roche Ltd, Indianapolis, IN), 25(OH) D (CPBA, LSI Medience Corporation, Tokyo), and 1,25(OH)₂D (1,25(OH)2D RIA Kit [TFB], Fujirebio Inc., Tokyo) were also evaluated at the baseline and at 24 and 48 weeks.

All the patients were asked about the occurrence of any adverse events at each visit, and all adverse events were analyzed, regardless of the investigators’ assessments of the causality. The Medical Dictionary for Regulatory Activities (MedDRA, version 16.1) was used to categorize the reported adverse events.

The primary endpoint was the percent change of the lumbar spine BMD (L-BMD) at the patient’s last visit, week 48 from the baseline. Analyses were performed according to the intent-to-treat principle, in which all randomized patients who had taken at least one dose of the study drug and had undergone both a baseline and at least one post-randomization measurement of the BMD, bone markers, and other parameters were included. Missing data were imputed by the last observation carried forward (LOCF) method. ANCOVA adjusted for the baseline data was used between the ALN + ELD and ALN + VitD groups. Significance level is used 5 % for two-sided p value. As exploratory analysis, group means and 95 % confidence intervals are calculated for the percent changes from the baseline in the lumbar, total hip and femoral neck BMD, and were used to assess the changes within each group for each visit. The relationships between the variables were assessed by calculation of the Pearson’s correlation. Multiplicities adjustments are not used for p values of exploratory analysis.