An estimated 10 million Americans over the age of 50 years old suffer from osteoporosis and a further 32.9 million have low bone mass, placing them at an increased risk for developing this condition. Associated with an increased risk of fractures, which are both clinically problematic and costly to healthcare systems. The development of new osteoporosis treatments therefore offers immense opportunities to the pharmaceutical industry. The global osteoporosis therapies market, including estrogen replacement therapy drugs was estimated at $5.5 billion in 2001 and projected to double by 2008 in the face of population aging, decreased bone quality and increased awareness of osteoporosis.

Once dominated by hormone replacement therapies (HRTs), the field of osteoporosis has undergone three major changes since the mid-1990's. First, the bisphosphonate Fosamax was launched in 1995. Since this launch the bisphosphonates have become the most effective means of limiting bone loss. Then, in January 1998 Eli Lilly launched Evista (raloxifene), the first selective estrogen receptor modulator and as a result the concept of combining the beneficial effects of estrogen antagonism (ie anti-cancer activity) and agonism (ie bone health) became a real therapeutic possibility. Most recently the FDA has approved the use of the parathyroid hormone Forteo (teriparatide), the first treatment for osteoporosis with anabolic activity. In a recent DiscoveryDossier we analyze therapeutic and pharmaceutical opportunities in the field of osteoporosis.

Nitric oxide has been shown to play an important role in the regulation of bone resorption. However, the role of endogenous nitric oxide (NO) on osteoclast activity remains controversial. Researchers at the Universite de Picardie-Jules Verne in France have recently demonstrated that rabbit mature osteoclasts express mRNA encoding for neuronal NO synthase (nNOS) suggesting that this enzyme could be involved in basal NO production in these cells. Further study revealed that a NO scavenger inhibited osteoclastic bone resorption in a dose dependent manner and induced osteoclast apoptosis by a mechanism involving caspase 3 activation. These results suggest that basal concentration of endogenous NO may be essential for normal bone resorption by supporting osteoclast survival.

In a further series of experiments the specific non-competitive NMDA receptor antagonists, MK801 and DEP, were shown to strongly inhibit bone resorption. As with the NO scavenger, this was related to osteoclast apoptosis and caspase 3 activation. Since MK801-induced osteoclast apoptosis was partially reversed in the presence of small amount of the NO donor, SNAP, and because the NMDA receptor is involved in NO production in neuronal cells, it is hypothesized that the activation of osteoclast NMDA receptors could have a similar function as those in neuronal cells.

These studies confirm the role of NO in bone resorption and suggest that NO scavengers or preventing the generation of NO by inhibiting nNOS or through the use of NMDA antagonists represents a new approach to the serious problem of osteoporosis.

Entry date Friday, April 11, 2003

Adapted from Mentaverri et al, J Cell Biochem 2003 Apr 15;88(6):1145-1156 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk