Two of the most predominant skeletal diseases are osteoporosis and arthritis. Osteroporosis affects an estimated 10 million Americans over the age of 50 years old and a further 32.9 million have low bone mass, placing them at an increased risk for developing this condition. Osteoporosis is blamed for more than 1.5 million fractures in the US each year. One in two women and one in eight men over 50 years of age will suffer an osteoporosis-related fracture during their lifetime. The direct medical cost for treating such fractures was estimated at $16.8 billion in 2001, up from around $13.8 billion in 1995. The US osteoporosis therapies market, including estrogen replacement therapy drugs, generated approximately $3.9 billion in 2001; the global market was estimated at $5.5 billion and projected to double by 2008. LeadDiscovery have recently published an analysis of therapeutic and pharmaceutical opportunities surrounding osteoporosis. Rheumatoid arthritis is less common than osteoporosis but is a significant health problem all the same affecting about 1% of all populations, women two to three times more often than men. This translates to a total of 5 million in the major pharmaceutical markets, a figure that is likely to rise to approximately 5.7 million by 2010. The market for agents used to treat rheumatoid arthritis totaled $1.6 billion in 2000. At present, treatments of this disease are based on symptomatic therapies such as NSAIDs (including the new COX-2 inhibitors), gold-containing compounds and corticosteroids. The current trend is to move towards disease-modifying anti-rheumatic drugs (DMARDs). Inhibitors of angiogenesis offer one exciting approach. Other approaches include the use of immunosuppressants. Examples of this therapeutic class include methotrexate, azathioprine and cyclosporine although side effect profiles are driving the industry towards more specific modulators of cytokines. One such example is Toyama’s T-614 (iguratimod). This oral anti-inflammatory agent, suppresses the production of IL-1, IL-6, IL-8 and TNF and is in phase III development for the treatment of rheumatoid arthritis as a result of its ability to slow bone destruction. More recently it has been shown that T-614 also stimulates osteoblastic differentiation of stromal and preosteoblastic cell lines in the presence or absence of recombinant human bone morphogenetic protein-2 (rhBMP-2). This corresponded to a 14-fold increase in the calcium content of stromal but not preosteoblastic cells and also and over-expression of osterix, an essential transcription factor for osteoblastic differentiation in stromal cells. Oral administration of T-614 to mice also promoted rhBMP-2 induced bone formation in vivo. Taken together, these results suggested that T-614 posesses anabolic effects on bone metabolism, in addition to its well-characterized anti-resorptive activity. Since this also represents an attractive profile for osteoporosis treatments and because experimental and clinical studies support a link between post-menopausal changes in cytokine status and bone loss, the investigation of the effect of this therapeutic candidate and other immune modulators on the development of osteoporosis deserves attention

January, 2003

Adapted from Kuriyama et al, Biochem Biophys Res Commun 2002 Dec 20;299(5):903-9