Kynurenine pathway metabolism in patients with osteoporosis after 2 years of drug treatment.
1. Metabolism of tryptophan along the oxidative pathway via kynurenine results in the production of quinolinic acid and kynurenic acid, which can act on glutamate receptors in peripheral tissues. We have now measured the concentrations of kynurenine pathway metabolites in the plasma of patients with osteoporosis before treatment with drugs, throughout and after 2 years of treatment with the drugs raloxifene or etidronate. Oxidative stress was assessed by measuring levels of the lipid peroxidation products malondialdehyde and 4-hydroxynonenal. Kynurenines were analysed by HPLC. Bone density was measured using dual-energy X-ray absorptiometry scans. 2. Patients with osteoporosis showed significantly lower baseline levels of 3-hydroxyanthranilic acid compared with healthy controls, but significantly higher levels of anthranilic acid and lipid peroxidation products. After 2 years treatment with etidronate and calcium, we observed significant therapeutic responses quantified by bone densitometric scanning. Significant improvements were not seen in patients treated with raloxifene. 3. In parallel, the levels of 3-hydroxyanthranilic acid, anthranilic acid and lipid peroxidation products were restored to control values by both drug treatments studied and tryptophan levels were increased significantly compared with baseline values. 4. The results suggest that tryptophan metabolism is altered in osteoporosis in a manner that could contribute to the oxidative stress and, thus, to progress of the disease. The oxidative metabolism of tryptophan (the kynurenine pathway) could represent a novel target for the development of new drugs for the treatment of osteoporosis. In addition, we noted that etidronate is a more effective drug than raloxifene, but that the simultaneous use of non-steroidal anti-inflammatory drugs may reduce the efficacy of etidronate.
Forrest
Caroline M
CM
Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK.
Mackay
Gillian M
GM
Oxford
Lynn
L
Stoy
Nicholas
N
Stone
Trevor W
TW
Darlington
L Gail
LG
D015095:3-Hydroxyanthranilic Acid / Q000737:chemistry / Q000378:metabolism; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000627:therapeutic use*; D007736:Kynurenic Acid / Q000737:chemistry / Q000378:metabolism; D007737:Kynurenine / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D015227:Lipid Peroxidation; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D019798:Neopterin / Q000097:blood; D010024:Osteoporosis / Q000188:drug therapy* / Q000378:metabolism*; D012980:Sodium Salicylate / Q000627:therapeutic use*; D014364:Tryptophan / Q000737:chemistry / Q000378:metabolism; D062367:ortho-Aminobenzoates / Q000737:chemistry / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D015095:3-Hydroxyanthranilic Acid; D007737:Kynurenine; D019798:Neopterin; D014364:Tryptophan; D007736:Kynurenic Acid; D012980:Sodium Salicylate; D007213:Indomethacin