Expression analy sis indicates that protection is due to changes Enzastaurin IC50 in multi ple genes belonging to different functional categories. Three of these genes have been validated exemplifying the involved pathways, IL 1b, PTX3 and PROKR2. Bisphosphonates, synthetic analogs of Inhibitors,Modulators,Libraries pyropho sphate, are the most effective inhibitors of bone resorp tion and are currently used in the treatment of several bone diseases. Their mechanism of action has been well described. They bind tightly to bone mineral surface, penetrate into osteoclasts and stimulate their apoptosis through the inhibition of Inhibitors,Modulators,Libraries the mevalonate pathway. Recent findings suggest that bisphosphonates may also indirectly suppress bone resorption through their action on osteoblasts, and osteocytes, which could represent another target for these drugs.

Instead, it is not clear if BPs have also a beneficial influence on the bone formation process. Histomorpho metric analysis in osteoporotic subjects indicates that BPs may increase the mean wall thickness and reduce the imbalance between formation and resorption at the basic multicellular unit, leading to a conti nuing increase in bone mineral density even after a long period of treatment, Inhibitors,Modulators,Libraries as demonstrated in clinical studies. They also control osteoblastic proliferation and differ entiation, modulate osteoblast production of extra cellular matrix proteins, regulate the secretion of several cytokines and growth factors and enhance prolif eration and maturation of bone marrow stromal cells to osteoblastic Inhibitors,Modulators,Libraries lineage. Bisphosphonates are also able to prevent apoptosis of osteoblasts and osteocytes induced by glucocorticoid therapy.

It is well known that osteocytes are well differentiated osteoblasts regu larly spaced throughout the mineralized matrix. They are believed to detect bone microdamage and to trans mit signals leading to its Inhibitors,Modulators,Libraries repair. The disruption of the osteocyte network could com promise this mechanism, leading to accumulated micro damage and increased bone fragility. Such a defect in bone quality could account for the higher incidence of fractures and the disproportion between the significant increase in bone fragility and the relative small decrease of BMD observed, for example, in glucocorticoid induced osteoporosis.

In our previous histomorphometric study on glucocor ticoid induced osteoporosis we found that rats trea ted with risedronate showed increased trabecular number and thickness and decreased trabecular glucose metabolism separa tion not only with respect to glucocorticoid treated rats but also with respect to controls. In addition, increased wall thickness, the end product of osteoblastic activity, was observed. In terms of turnover, rats treated with Ris showed a reduced activation frequency with an increased active Formation Period. All these findings suggest an effect of Ris on osteoblastic lineage and sup port the hypothesis of a neoformative activity of bisphosphonates.