The treatment options for osteoporosis, a major health complication in the aged population, are limited to pharmacologic interventions, the majority of which are antiresorptive. In this revised application, we propose to evaluate the efficacy of a unique, biomechanically based treatment for bone loss;low magnitude mechanical stimulation. This revised application responds to all reviewers concerns. Preliminary data in the animal (mouse, rat, turkey, sheep) and human (women 3-8 years past the menopause, children with disabling conditions, 10-13 year old girls with low bone mineral density (BMD), 16-21 year old girls with a fracture history and low BMD) demonstrate that high frequency, low magnitude mechanical stimulation (LMMS) can preserve BMD against systemic pressures to resorb (e.g., disuse, aging), and can stimulate new bone formation. Histomorphometric evaluation demonstrates that this effect is achieved primarily by enhancing the formative activity of the skeleton, and that it is most efficacious in animals/humans with low BMD. To confirm and extend these observations, we are proposing a two-year, double-blind, randomized, placebo-controlled clinical trial of LMMS in 200 elderly women and men (65 years of age and older), with body mass index <27 kg/m2) and low T-scores from -1 to -2.5) at the hip. A clinical center located in Boston, MA will recruit subjects from six independent living facilities in close geographic proximity serving a population of 2,082 residents, and all data will be handled by a Data Coordinating Center (Maryland Medical Research Institute). Following a two-week run-in with an inactive vibrating platform, participants meeting the inclusion/exclusion criteria will be randomized to either brief daily exposure to LMMS (10 min/d of 0.3g @ 30Hz;1g = Earth's gravitational field = 9.8 m/s2) on a vibrating platform or a placebo platform over two years. All participants will receive 500 mg of elemental calcium and 400 IU of vitamin D per day. The primary endpoints will be changes in volumetric trabecular BMD of the spine and hip by quantitative computed tomography. The secondary outcome will be the change in biochemical markers of bone formation (Procollagen type 1 N-terminal peptide and Bone Specific Alkaline Phosphatase) and resorption (C-terminal Telopeptide of type I collagen). Adverse events will be monitored throughout the study by the investigators and a Data and Safety Monitoring Board. This study is not powered to address fracture. For this study we have assembled a collaboration of internationally known experts in osteoporosis involving older persons, together with a respected and experienced coordinating center. Based on strong preliminary data, this study will provide new and important information about the role of low magnitude high frequency mechanical stimulation on the skeleton.
