acid-phosphatase and beta-Thalassemia

The pathogenesis of bone resorption in β-thalassemia major is multifactorial and our understanding of the underlying molecular and cellular mechanisms remains incomplete. Considering the emerging importance of the endocannabinoid/endovanilloid system in bone metabolism, it may be instructive to examine a potential role for this system in the development of osteoporosis in patients with β-thalassemia major and its relationship with iron overload and iron chelation therapy. This study demonstrates that, in thalassemic-derived osteoclasts, tartrate-resistant acid phosphatase expression inversely correlates with femoral and lumbar bone mineral density, and directly correlates with ferritin levels and liver iron concentration. The vanilloid agonist resiniferatoxin dramatically reduces cathepsin K levels and osteoclast numbers in vitro, without affecting tartrate-resistant acid phosphatase expression. The iron chelators deferoxamine, deferiprone and deferasirox decrease both tartrate-resistant acid phosphatase and cathepsin K expression, as well as osteoclast activity. Taken together, these data show that transient receptor potential vanilloid type 1 activation/desensitization influences tartrate-resistant acid phosphatase expression and activity, and this effect is dependent on iron, suggesting a pivotal role for iron overload in the dysregulation of bone metabolism in patients with thalassemia major. Our applied pharmacology provides evidence for the potential of iron chelators to abrogate these effects by reducing osteoclast activity. Whether iron chelation therapy is capable of restoring bone health in humans requires further study, but the potential to provide dual benefits for patients with β-thalassemia major -preventing iron-overload and alleviating associated osteoporotic changes - is exciting.

Topics: Acid Phosphatase; Adult; beta-Thalassemia; Biomarkers; Blotting, Western; Case-Control Studies; Cathepsin K; Cells, Cultured; Female; Fluorescent Antibody Technique; Follow-Up Studies; Humans; Iron Chelating Agents; Iron Overload; Isoenzymes; Male; Osteoclasts; Osteoporosis; Prognosis; Real-Time Polymerase Chain Reaction; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tartrate-Resistant Acid Phosphatase; TRPV Cation Channels

Osteoporosis in beta-thalassaemia is multifactorial; increased osteoclast function seems to play an important role in its pathogenesis. The aim of this study was to evaluate the effect of pamidronate on the osteoporosis of thalassaemia. To this effect we studied 26 patients who received this drug in doses of 30 or 60 mg i.v. once a month over 12 months. The effects were monitored by measuring bone mineral density (BMD) in association with markers of osteoclast function [soluble receptor activator of nuclear factor-kappa B ligand (sRANKL), osteoprotegerin (OPG)] and of bone remodelling [N-telopeptide of collagen type-I (NTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-5b), bone-alkaline phosphatase (bALP), and osteocalcin (OC)]. Thirty healthy individuals were also studied, as controls. NTX, TRACP-5b, bALP and OC levels were significantly higher in thalassaemic patients compared with controls; in contrast, OPG levels were significantly lower, while the levels of sRANKL varied within normal limits. Administration of pamidronate was followed by a clear decrease of NTX, TRACP-5b, OPG, and OC, and by a significant increase in the BMD of the lumbar spine, which was similar in patients of both treatment groups. These data suggest that pamidronate, at a monthly dose of 30 mg, is an effective treatment for thalassaemic osteoporosis.

Topics: Acid Phosphatase; Adult; Alkaline Phosphatase; Anti-Inflammatory Agents; beta-Thalassemia; Biomarkers; Blood Transfusion; Bone Density; Carrier Proteins; Case-Control Studies; Collagen; Collagen Type I; Diphosphonates; Drug Administration Schedule; Female; Glycoproteins; Humans; Isoenzymes; Lumbar Vertebrae; Male; Membrane Glycoproteins; Middle Aged; Osteocalcin; Osteoporosis; Osteoprotegerin; Pamidronate; Peptides; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Statistics, Nonparametric; Tartrate-Resistant Acid Phosphatase