Study Design
This study was a multicenter, open-label, single-arm study conducted in Japan (JapicCTI-132276). The subjects received once-weekly subcutaneous injection of 56.5 μg teriparatide for 24 months (104 weeks) and standard therapy that included daily oral doses of calcium (610 mg), vitamin D (400 IU), and magnesium (30 mg) (New Calcichew D3; Daiichi Sankyo Healthcare Co., Ltd., Tokyo, Japan).
This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice (GCP). Moreover, institutional review board (IRB) approval of the protocol was in place before the study at each of the 25 study sites.
Subjects
The eligibility criteria established for study subjects were as follows: man or woman aged 65 years or older; able to walk independently; diagnosis of primary osteoporosis based on the diagnostic criteria for primary osteoporosis (FY2012 revised version) by the Japanese Society for Bone and Mineral Research [7]; at least one but no more than five prevalent fractures between the fourth thoracic vertebra (Th4) and the fourth lumbar vertebra (L4); and a mean BMD of the second through fourth lumbar vertebrae (L2–L4) of less than 80% of the young adult mean (YAM) at the time of enrollment. Patients diagnosed with secondary osteoporosis, patients with a non-osteoporotic disease that causes decreased bone mass, and patients with any X-ray findings that affect the assessment of lumbar BMD by dual energy X-ray absorptiometry (DXA) were excluded. Also excluded were patients with any of the following conditions and those judged by the investigator as unsuitable for participation in the clinical study: a serum calcium level of 11.0 mg/dl or above; a malignant bone tumor or a metastatic bone tumor; previous radiation therapy affecting the bone or otherwise at high risk of developing osteosarcoma; or a serum alkaline phosphatase (ALP) level more than double the standard level. Patients who had received treatment with teriparatide or an anti-receptor activator of nuclear factor kappa B ligand (RANKL) antibody in the past, bisphosphonate within 52 weeks before treatment commencement, or any other osteoporosis drug within 8 weeks before treatment commencement were also excluded.
Efficacy Endpoints
The primary endpoint selected was the percentage change from baseline in L2–L4 BMD at week 104. The secondary endpoints were the percentage changes in total hip BMD and femoral neck BMD and X-ray-confirmed new vertebral fractures and clinical fractures. Other variables assessed included the time profiles of bone turnover markers (bone formation and bone resorption markers). In addition, radial BMDs (distal 1/3, 1/6, and 1/10 sites of the radius) were measured with peripheral dual-energy X-ray absorptiometry (DXA) at two study sites. The differences in BMD values between Week 72 and Week 104 were also examined.
Efficacy Measures
BMDs of the lumbar spine, femur, and radius were measured by DXA at screening, baseline, and Weeks 24, 48, 72, and 104. The lumbar and femoral BMDs were measured with a Discovery, Explorer, Delphi, or QDR4500 (Hologic, Bedford, MA) device, which was calibrated before each test for precision control with a lumbar spine phantom attached to the device. For external quality control, specialists checked QC sheets from all study sites every month and then maintenance was performed if needed. The radial BMDs were measured at two study sites equipped with a peripheral DXA. Both study sites used a DCS-600EXV (Hitachi Ltd., Tokyo, Japan) to perform the measurements. The lumbar and femoral BMD measurements were centrally analyzed by a BMD analysis institution and then assessed independently by two members of a Bone Mass-assessment Committee (HH, TeS). When the two members differed in their assessments, the Bone Mass-assessment Committee considered the case to render an assessment that was considered final. The radial BMD measurements were centrally analyzed by the BMD analysis institution and then assessed through a consultation in the Bone Mass-assessment Committee by the two members of the committee to make an assessment that was considered final.
To assess morphological vertebral fractures, X-ray images of the lumbar/thoracic vertebrae were taken at screening and baseline and at 24, 48, 72, and 104 weeks after. A Fracture-assessment Committee (TeN, HK, MI, TeS) assessed the vertebrae from Th4 through L4 by a semi-quantitative method (SQ) [8] and a quantitative method (QM) [9, 10]. A new vertebral fracture was defined as an increase of one grade or more of a vertebral body that was normal (SQ grade 0) at baseline combined with a 20% or greater reduction in height at either the anterior edge, center, or posterior edge of the vertebral body. A clinical fracture was defined as a fracture associated with clinically apparent symptoms such as pain that could be confirmed by X-ray imaging or magnetic resonance imaging (MRI). Clinical fractures were confirmed by the investigator at each of the study sites. A fragility fracture was defined as a clinical fracture that the investigator judged was not induced by a large external force.
To measure bone turnover markers, blood and urine samples were collected at baseline and before the study drug was administered at Weeks 4, 12, 24, 48, 72, and 104. Samples were stored either in a refrigerator or a freezer, depending on the type of marker to be measured, before measurement by a validated central laboratory (LSI Medience Corporation, Tokyo, Japan). Serum osteocalcin (OC) was measured by immunoradiometric assay (BGP-IRMA; LSI Medience Corporation, Tokyo, Japan); serum procollagen type I amino-terminal propeptide (P1NP) was measured by radioimmunoassay (Fujirebio Inc., Tokyo, Japan); and urinary cross-linked N-telopeptide of type I collagen (NTX) was measured by enzyme-linked immunoassay (Alere Medical Co., Ltd., Tokyo, Japan).
Adverse Events
Safety was assessed collectively on the basis of adverse events, including serious adverse events, and adverse events leading to study discontinuation. The subjects underwent medical examinations and regular blood tests, blood chemistry tests, urinalyses, and vital sign measurements. The investigators reported adverse events, which were coded to the preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA, version 16.0).
Sample Size
To summarize the percentage change from baseline in lumbar (L2–L4) BMD data using descriptive statistics, it was adequate that the 95% confidence interval in this study was of a similar degree to that in the TOWER trial. On the basis of the sample size and the rate of discontinuations in the population used for lumbar BMD analysis in the TOWER trial, a target sample size of 175 subjects was selected to commence treatment in this study. In the TOWER trial [2], the population in the active drug group analyzed for lumbar BMD included 107 subjects at Week 72. Thus, to ensure a similar degree of 95% confidence interval (12.6–13.4) in this study, approximately 110 subjects were needed at Weeks 72 and 104. Given that, in the TOWER trial, the rate of discontinuations was 20% through Week 24, and 5.5% of the subjects discontinued the study over each 24-week period thereafter, the overall rate of discontinuation in this study was expected to reach 37%. Therefore, it was determined that 175 subjects were needed at the start of treatment to ensure the availability of 110 subjects at week 104.
Statistical Analysis
Efficacy was analyzed using the full analysis set (FAS). The FAS included all subjects who received at least one dose, except those who had any GCP deviation, those confirmed to have no primary osteoporosis, and those for whom no post-treatment efficacy data were available.
Percentage changes from baseline in L2–L4 BMD, the primary endpoint, were summarized over time to determine the 95% confidence interval for the percentage change. The total hip, femoral neck, and radial (distal 1/3, 1/6, and 1/10 sites of the radius) BMDs were also summarized in a similar manner. Cumulative incidences of fractures at each time point were estimated by the Kaplan–Meier method. Percentage changes from baseline in bone turnover markers were summarized over time. A comparison between baseline and each time point or between Week 72 and Week 104 for BMD was performed by the paired t test. A comparison between baseline and each time point for bone turnover markers was performed by the Wilcoxon rank sum test. The relationships between the BMD absolute change category and the incident nonvertebral fracture number were assessed by the Chi square test.
Safety was analyzed using the population that included all subjects who received at least one dose. Incidences of each adverse event were summarized by onset time. Statistical analyses were performed using SAS version 9.1 or 9.4 (SAS Institute, Cary, NC, USA).