Disease relevance of C08141

• A 6 month course of oral tiludronate may counteract postmenopausal bone loss for at least a year by decreasing bone resorption [1].
• Prevention of postmenopausal bone loss by tiludronate [1].
• To assess the optimal dosage of oral tiludronate in Paget's disease of bone [2].
• Exhaustive biochemical investigations failed to reveal significant toxicity of tiludronate up to the 800-mg daily dose investigated [2].
• Groups 1 and 2 were given vehicle only (distilled water), and groups 3, 4, and 5 were given tiludronate orally at doses of 25, 50, and 100 mg/kg body weight (BW)/day, respectively, throughout the experimental period [3].

High impact information on C08141

• Bone mineral density of the lumbar spine decreased significantly by 2.1% (SE 0.8%) in the placebo group and did not significantly change in the tiludronate group (+1.33 [0.8]%) [1].
• Treatment with tiludronate was not followed by increased secretion of parathyroid hormone [1].
• CONCLUSION: Serum OPG increases in Paget's disease and decreases after treatment with tiludronate, especially in patients with the highest OPG values [4].
• OPG concentrations decreased significantly after treatment with tiludronate (P < 0.005), whereas no significant changes were observed in serum RANKL values [4].
• Comparative prospective, double-blind, multicenter study of the efficacy of tiludronate and etidronate in the treatment of Paget's disease of bone [5].

Chemical compound and disease context of C08141

• The nitrogen-containing bisphosphonate pamidronate was significantly more toxic on a panel of eight neuroblastoma cell lines than the non-nitrogen-containing bisphosphonates, clodronate and tiludronate [6].

Biological context of C08141

• Tiludronate appears effective in reducing bone resorption without impairing bone formation in a manner that preserved bone mass and bone cell coupling [7].
• Tiludronate also potently inhibited proton transport in yeast microsomal preparations (IC50 = 3.5 microM) and inhibited the activity of purified yeast V-ATPase [8].
• The inhibition was noncompetitive with respect to ATP, and tiludronate did not protect the pump from inactivation by N-ethylmaleimide, strongly suggesting that tiludronate does not bind to the catalytic site of the enzyme [8].
• Human pharmacokinetics of tiludronate [9].
• Bone tolerance studies indicate that tiludronate is a safe compound with an appreciable therapeutic margin since it can effectively inhibit bone resorption without reducing bone mineralization and strength [10].

Anatomical context of C08141

• The bisphosphonate tiludronate is a potent inhibitor of the osteoclast vacuolar H(+)-ATPase [8].
• Effects of tiludronate on bone mass, structure, and turnover at the epiphyseal, primary, and secondary spongiosa in the proximal tibia of growing rats after sciatic neurectomy [3].
• However, the actin rings in OCLs were disrupted by the addition of tiludronate soon after they began to resorb dentine [11].
• The transport of a new bisphosphonate, Tiludronate, was investigated on the human adenocarcinoma cell line, CACO-2 [12].
• Based on these different observations, we could suggest that Tiludronate mainly used the paracellular pathway to cross the intestinal epithelium [12].

Associations of C08141 with other chemical compounds

• Comparative studies have shown that second- and third-generation bisphosphonates, such as tiludronate, alendronate and risedronate, are more effective than etidronate at inhibiting bone turnover in Paget's disease but they have not been found to be significantly more effective in controlling bone pain [13].
• These results strongly suggest that tiludronate but not etidronate suppresses the PGF2alpha-stimulated VEGF synthesis in osteoblasts, and that the effect of tiludronate is exerted at the point between PKC and Raf-1 [14].
• However, the IL-6 secretion induced by PGE1 or (Bu)2cAMP was hardly affected by tiludronate [15].
• However, tiludronate had little effect on the formation of choline induced by TPA, a protein kinase C activator [15].
• Effects of tiludronate and ibandronate on the secretion of proinflammatory cytokines and nitric oxide from macrophages in vitro [16].

Gene context of C08141

• RESULTS: Tiludronate significantly inhibited both MMP-1 and MMP-3 activity in a concentration-dependent manner [17].
• The PGF(2alpha)-stimulated phosphorylation of p44/p42 MAP kinase was suppressed by tiludronate [14].
• However, some agents either lose their efficacy or have no added effects on BMD when they are coadministered (e.g., tiludronate and PTH, calcitonin and PTH, calcitonin and anabolic steroids) [18].
• Although serum osteocalcin levels were decreased in the medium- and high-dose tiludronate groups, both serum PTH and 1,25(OH)2D levels were increased only in the high-dose group [19].
• Tiludronate significantly inhibited the NaF-induced IL-6 secretion in human osteoblastic osteosarcoma Saos-2 cells [15].

Analytical, diagnostic and therapeutic context of C08141

• Effect of ovariectomy on intraosseous vascularization and bone remodelling in rats: action of tiludronate [20].
• Seventy-eight 12-week-old Wistar male rats were assigned to 13 groups: 1 baseline group, and for each time point, 1 control group treated with vehicle and three tail-suspended groups treated with either tiludronate (0.5 or 5 mg/kg) or vehicle, administered s. c. every other day, during the last week before sacrifice [21].
• The methodology of clinical trials of oral tiludronate in Paget's disease of bone [22].
• In a double-blind study, we have had the opportunity to compare the effects of tiludronate and of etidronate (both at a fixed dose of 400 mg/day orally) on the radiological changes of 12 patients suffering from Paget's disease of bone [23].
• Using three-dimensional microtomography, dual X-ray/densitometry, and histomorphometry, we evaluated tiludronate effects in the bone loss model of immobilization in tail-suspended rats after 7, 13, and 23 days [21].

References