Cyclosporin A (CsA) administered to actively growing young rats produces a high-turnover osteopenia. We investigated and compared the effect of CsA on the bone mineral metabolism in young rats with that of older rats, which have a lower rate of bone turnover. A group of 24 young (9 weeks) and 24 older (9 months) male Sprague-Dawley rats were orally administered 15 mg/kg of CsA or placebo daily for 24 days. Rats were weighed and serum assayed serially for bone gla protein (BGP), parathyroid hormone, ionized calcium, blood urea nitrogen, creatinine, and 1,25-dihydroxyvitamin D [1,25-(OH)(2)D]. After sacrifice, histomorphometric analysis was performed on undecalcified proximal tibial metaphysis with double-fluorescent labeling. Serum BGP levels were significantly elevated in both young and older rats administered CsA, and 1,25-(OH)(2)D levels were significantly elevated in CsA-treated young rats more than in older rats. Body weight was significantly reduced in CsA-treated older rats. There were mild but significant alterations in renal function in both groups receiving CsA. In the most comprehensive examination to date of the effects of CsA on bone histomorphometry, both young (-44%) and older rats (-20%) lost significant amounts of trabecular bone compared to their respective controls. Bone loss in young rats was mainly due to a reduced number of trabeculae; older rats lost mainly trabecular thickness. Microanatomic nodal studies were consistent with these results. These data demonstrate that although cancellous bone loss induced by CsA is more marked in young Fats, older rats with slower bone turnover are also at risk.

Due to its short half-life, renal toxicity and necessity for daily subcutaneous injections, recombinant human growth hormone (rhGH) would best be administered in a controlled release formulation. One approach to this is the use of biodegradable laminar implants based on poly(lactic/glycolic) acid. Two PLGA laminar implant formulations (10% w/w), F1 and F2, were designed and statistically compared with a conventional commercial injectable (Norditropin®). The following variables were chosen as responses: body weight, organ weights (heart, spleen and thymus), and tibia weights and dimensions. After statistical analysis, the most sensitive responses for detecting differences between formulations were body weight, tibia length and organ weights. Initial in vitro studies of these formulations showed an incomplete gradual release (after 15 days 40% rhGH released from F1 and 60% from F2) and in vivo the best results were obtained with F1. This formulation showed the best growth curve and the highest values of all the above responses. In conclusion, this type of formulation provides a sustained release of rhGH for at least 15 days and a greater efficacy than the frequent administration of the conventional injectable.