Selection of Endpoints. Bone remodeling is a constant process in the adult human skeleton and maintains the integrity of the skeleton through a process of replacing old bone (resorption) with new bone formation (anabolism). Both cortical and trabecular bone are involved in this process which needs to be in balance to maintain normal bone density and strength (20). In childhood, the balance favors bone formation and, with aging, the process favors the resorptive component, causing bone loss. Assessments of this balance of formation and resorption can be performed over the long-term by quantitative imaging of bone density. Consequences of bone loss are commonly observed as fracture in a severe osteoporotic population. An improvement in bone quality and quantity can reduce the risk of existing and incidental fracture. Therefore, while earlier studies have demonstrated the benefit of BA058 for improvement in BMD in postmenopausal women, this study will assess the relative efficacy and safety of BA058 80 µg for prevention of new fractures in the same population but among the cohort of patients with a history of fracture, or those who are at an increased risk of fracture. While all new fractures will be assessed, the relative short duration of treatment anticipated with BA058 is unlikely to yield definitive evidence of fracture prevention benefit at all anatomical sites, therefore the study is designed to identify a statistically significant benefit on vertebral fracture. Non-vertebral fractures will be assessed as a secondary efficacy endpoint as will BMD changes by DXA at spine, hip and femoral neck as additional indices of bone anabolic benefit. In addition to BMD by DXA, bone formation and resorption markers will also be assessed over time (21). The rise in the markers of bone formation indicates restoration of lost bone, in particular the lost microarchitecture that places osteoporotic women at an increased risk for fracture. Increases in the principal markers of bone formation: N-terminal propeptide of type I procollagen (PINP), osteocalcin, and bone-specific alkaline phosphatase (BSAP) are accepted predictors of BMD change (21,22). Serum C-telopeptides (CTX), a marker of bone resorption and collagen breakdown, will also be measured in this study. Markers of anabolic effect and resorptive effect have become valuable tools in the management of osteoporosis since they can provide early information on potential treatment efficacy (23).
Selection of Endpoints. The fracture incidence; either clinically or radiologically determined, based on clinical events or protocol-directed vertebral x-rays at Month 6 of this Extension Study; will be tabulated. In addition, BMD results from the six months of treatment with alendronate will also be tabulated, with additional tabular categories for results from the entire contiguous 24 months from baseline of study BA058-05-003 through the end of Study BA058-05-005, as well as the results during the 18 months of study BA058-05-003, for subjects who eventually enter study BA058-05-005. Bone formation (PINP, osteocalcin, BSAP) and resorption (CTX) markers will also be assessed. Clinical incidence of any fracture and radiologic incidence of vertebral fracture will also be evaluated at Month 24. The End-of-Treatment (Visit 9) evaluations for BMD, vertebral fracture, and non-vertebral fracture assessments from BA058-05-003 will serve as the baseline evaluations in this study. Subjects will be monitored for safety events and will have safety assessments performed at each study visit. At Month 6 and Month 24, BMD by DXA, as well as clinical and radiologic assessment of the spine for assessment of fractures will be performed. Bone formation and resorption markers will also be assessed at Day 1 and Month 6. Further details of these assessments are in Section 7.0, and in Appendix 14.1 and 14.2.
Selection of Endpoints. The fracture incidence; either clinically or radiologically determined, based on clinical events or protocol-directed vertebral x-rays at Month 6 of this Extension Study; will be analyzed. In addition, BMD results from the six months of treatment with alendronate will also be analyzed. Bone formation (PINP, osteocalcin, BSAP) and resorption (CTX) markers will also be assessed. Clinical incidence of any fracture and radiologic incidence of vertebral fracture will also be evaluated at Month 24. The End-of-Treatment (Visit 9) evaluations for BMD, vertebral fracture, and non-vertebral fracture assessments from BA058-05-003 will serve as the baseline evaluations in this study. In addition to the 6-month assessment, clinical and radiologic assessment of the spine for assessment of fractures will be performed at Month 24. At Months 6, 12, 18 and 24, BMD by DXA, as well as clinical assessments of fractures will be performed. Bone formation and resorption markers will also be assessed at Day 1 and Months 6, 12 18 and 24. Further details of these assessments are in Section 7.0, and in Appendix 14.1 and 14.2. Subjects will be monitored for safety events and will have safety assessments performed at each study visit.
