Stimulation of osteogenesis by means of sustained delivery of various natural androgenic hormones.

Sex steroids play an essential role in the maintenance of bone health throughout life, and the mechanisms by which these effects are mediated in a subject of much controversy. Osteoblast cells appear to be stimulated by androgens in vitro, however their use in vivo is limited due to the virilizing side effects as well as alterations in the lipoprotein profiles. The use of targeted sustained release of anabolic steroids may stimulate fracture healing without untoward side effects. The specific aims were: (1) to compare fracture healing in a rat femoral defect model using tricalcium phosphate lysine (TCPL) drug delivery systems to deliver T, DHT and AED for long duration; (2) to quantify the level of steroid delivered from the system; and (3) to use bone histomorphometric techniques to analyze new bone formation at the defect site. A total of 125 adult male Sprague Dawley were obtained and acclimatized for two weeks in the animal care prior surgical procedures. All animals were kept on a 12-hour day/night cycle and were fed Purina rodent chow and water ad libitum. The animals were randomly divided into five equal groups (n = 25 per group). Group 1 animals were used as the intact control. Group 2-5 animals were placed under anesthesia and a standard approach was used to create a 6-mm defect using a dental burr in the midshaft of the femur. Group 2 animals were implanted with a sham TCPL delivery system adjacent to the defect. Animals in groups 3, 4, and 5 received a TCPL delivery system loaded with T, DHT, and AED, respectively. Animals were weighed, x-rayed, and blood samples were drawn on a weekly basis. The rats were sacrificed after 3, 6, 9 12 and 15 weeks and reproductive, vital organs, and fracture calluses were collected and analyzed. Morphometric analysis of the femurs revealed that the use of sustained delivery of DHT induced remarkable bone ingrowth compared to the sham and other experimental groups. All treated femurs appeared healthy and normal bone architecture was observed by the end of the 6 week phase. Measurements of the inner perimeter of the bone on the endosteal side showed significant reduction in the androgens treated animals. The quantitative findings confirms our preliminary studies and endorsing the previous data that the sustained delivery of T or its metabolite (DHT) can stimulate the osteoblastic activities in which eventually causes an increase in the cortical bone density.