Researchers report the efficacy of the bisphosphonate, YM529 in preclinical rheumatoid arthritis studies

DailyUpdates 25th March 2004: Since their launch the bisphosphonates have become the most effective means of limiting bone loss in osteoporosis. More recently this class of drug has demonstrated potential in the treatment of cancer; now researchers report on the efficacy of a new bisphosphonate, YM529, in an experimental model of rheumatoid arthritis.

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. Since their launch the bisphosphonates have become the most effective means of limiting bone loss.

Many patients with cancer develop metastases to bone, which affects quality of life and contributes to the morbidity of the disease. Following their approval for the treatment of osteoporosis, bisphosphonates were also approved for the treatment and prevention of fractures related to metastatic disease. Clinical trials of zoledronic acid for example have shown that it can reduce markers of bone resorption by 40% to 60% in patients with multiple myeloma and breast, prostate, and lung cancers. More recently researchers have demonstrated that bisphosphonates have direct antitumor effects.

Bisphosphonates inhibit farnesyl diphosphate synthase resulting in reduced isoprenylation of key regulatory proteins and contributing to the inhibition of proliferation and stimulation of apoptosis in cultured human cancer cells. In addition, bisphosphonate treatment interferes with breast cancer cell adhesion to bone matrix, and inhibits cell migration and invasion. More recently researchers at Novartis have demonstrated that zoledronic acid is also a potent inhibitor of angiogenesis.

Bone loss and neo-vascularization are both features of rheumatoid arthritis and the ability of bisposphonates to target both of these phenomenon suggests that this therapeutic class may be of benefit to arthritis patients.

Rheumatoid arthritis is one of the more common autoimmune diseases along with multiple sclerosis, type I diabetes and Crohn’s disease. Approximately one in five people in the western world suffer from autoimmune diseases and some estimates indicate that 75% of these are women. In total it is predicted that the annual value of the market for drugs used to treat autoimmune disease will soon exceed $20 billion. An estimated 5 million individuals suffer from rheumatoid arthritis, a figure which will increase to 5.7 million by 2010.

In a recent study appearing in the journal, Clinical & Experimental Rheumatology Masuda-Aiba et al observed that a new third-generation bisphosphonate, YM529, represents a candidate treatment for rheumatoid arthritis.

The authors report that prophylactic or, more importantly, therapeutic treatment of animals with experimental arthritis with YM529 suppressed the severity of disease and suggest that YM529 may act on arthritic joints locally to prevent inflammation. These data are consistent with previous clinical studies investigating the efficacy of other bisphosphonates in patients with rheumatoid arthritis. Although further experiments are necessary to elucidate the underlying mechanisms, YM529 deserves consideration as a treatment for this disease.

(source DailyUpdates 25th March; for a full abstract of the original paper see Clin Exp Rheumatol. 2004 Jan-Feb;22(1):71-8; for further information see Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates)

In this edition of DailyUpdates, LeadDiscovery also highlights data describing the voltage-gated potassium channel Kv1.3 as a target for diabetes...MEK inhibition as a treatment for influenza B virus infection...non-small cell lung cancer as a target disease for herpes simplex type 1 thymidine kinase-ganciclovir gene therapy...and much more.