Therapeutic & pharmaceutical opportunities for osteoporosis and atherosclerosis

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 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 anticipation of the launch of Forteo, LeadDiscovery in collaboration with field-leader, Cees Vermeer have produced a state of the art report on both the field of osteoprosis in general and also more specifically on the ability of vitamin K mimics to limit both osteoporosis and atherosclerosis, a therapeutic profile that will be of considerable benefit to a large number of patients.

This report reviews the physiology of bone turnover as well as the etiology, epidemiology and treatment options relating to osteoporosis. The dossier continues with a full analysis of vitamin K and how its role in both bone health and cardiovascular function may result in vitamin K mimics contributing to a future breakthrough in osteoporosis therapeutics. Concluding with an in depth account of the osteoporosis market, development activity within this sector and full profiles of companies involved in this development, the report allows a full understanding of the osteoporosis field. This understanding is aimed at helping companies determine the competition or collaborative opportunities to be faced when developing vitamin K mimics or indeed other unrelated therapies.

Osteoporosis therapies act to reduce bone resorption, stimulate bone growth or to improve the mineralization of existing bone. The mode of action of antiresorptive treatments such as the bisphosphonates involves the inhibition of osteoclast activity while that of anabolic treatments involves the stimulation of osteoblast activity. Both increase bone volume and subsequent mineralization results in improved bone strength and resistance to fracture. Density and fracture resistance depend not only on mineralization but also on a well organized microarchitecture of bone minerals. Vitamin K is evolving as a key regulator of bone mineral structure and this vitamin and its mimics are therefore strongly implicated as a therapeutic candidates for the prevention of osteoporosis. Further evidence suggests that vitamin K is also able to inhibit osteoclast function. This combination of mineralization and antiresorptive activity offers significant advantages over existing treatments. Possible additional osteoblastogenic activity may further increase this advantage.

The ability of vitamin K to regulate bone mineralization stems from the role of reduced vitamin K as a coenzyme of gammaglutamyl carboxylase. This enzyme is involved in the carboxylation of glutamate into Gla residues during the post-translational phase of protein biosynthesis. Gla-residues are found on well-defined positions in a restricted number of proteins, where they are essential for calcium-binding. Such proteins include those involved in bone physiology. Given its therapeutic potential, vitamin K is overviewed in detail in this report with especial attention paid to molecular mechanisms of action. In addition to regulating bone mineralization, vitamin K is also able to reduce the calcification of atherosclerotic plaques. The development of cardiovascular disease is a common co-morbidity in osteoporosis patients and indeed Lilly are currently attempting to gain approval to promote Evista as a treatment of heart disease. Approval is expected to greatly boost the market value of this therapy. Vitamin K appears to posses this profile not only as a result of reduced calcification and hence plaque stabilization but also possibly as a result of its ability to reduce hypocholesterolemia, atherosclerosis progression and coagulation.

Vitamin K exists in two forms, K1 and K2. Both vitamins are coenzymes of gammaglutamyl carboxylase and are thus able to regulate mineralization of bone and calcification of blood vessels. Vitamin K2 however is more effective than vitamin K1 with respect to osteoclastogenesis; likewise hypocholesterolemic effects and the ability to slow atherosclerotic progression have only been observed with vitamin K2. This is due in part to the geranylgeranyl side chain of vitamin K2 which inhibits the mevalonate pathway, thus preventing the prenylation of growth factors required for osteoclast activation in much the same way as nitrogen-containing bisphosphonates. This therefore suggests that modelling of vitamin K2 may lead to the development of therapeutic candidates able to reduce resorption, increase bone mineralization and limit atherosclerosis. Furthermore, targeting vitamin K2 over vitamin K1 may be confer beneficial pharmacokinetics given that vitamin K1 concentrates in the liver while vitamin K2 is well distributed to bone and blood vessel walls. Equally, this profile is expected to limit the primary adverse effect associated with vitamin K, negative interactions with coumarin anti-coagulants, since the proteins involved in coagulation are primarily synthesized in the liver.

The osteoporosis field has witnessed a number of breakthroughs in recent years. Paralleling this activity has been an rapid influx of companies with a focus on osteoporosis. Likewise the pipelines of companies with a historic interest in osteoporosis has also changed to adapt to evolving therapeutic patterns. This report therefore offers a full analysis of pharmaceutical activity in the osteoporosis field. This information will be of key importance to companies whether they wish to develop vitamin K related therapies or unrelated candidates. In short this DiscoveryDossier will benefit all involved in developing osteoporosis therapies.