A comparison of incidences of vertebral fracture in Japanese patients with involutional osteoporosis treated with risedronate and etidronate: a randomized, double-masked trial

To demonstrate the clinical benefit of risedronate at 2.5mg daily in the treatment of involutional osteoporosis, the effect of risedronate on incidence of vertebral fracture was compared with that of etidronate. A total of 547 patients with one to four vertebral fractures were randomized to receive either treatment with 2.5mg/day of risedronate or intermittent treatment (treatment of 2 weeks and off period of 10 weeks) with 200mg/day of etidronate for 96 weeks in a double-masked fashion. All patients received 200mg calcium supplement daily. Lateral and anteroposterior thoracic and lumbar spine radiographs were obtained at baseline and at 24, 48, 72, and 96 weeks. Cumulative incidence rates of patients who had at least one new or worsening vertebral fracture during the 96-week period were 12.3% for risedronate and 14.2% for etidronate, and it was verified that the fracture prevention effect of risedronate was not inferior to that of etidronate. The incidence rates of fracture during the initial 24-week period were 8.8% for risedronate and 6.0% for etidronate, but the cumulative incidence rate of fracture from 24 to 96 weeks was lower in the risedronate group (3.9%) as compared to the etidronate group (8.7%). Height loss was significantly less in the risedronate group (–0.28cm) than in the etidronate group (–0.70cm) after 96 weeks. Decreases in bone resorption markers including urinary total deoxypyridinoline and NTX were significantly greater in the risedronate group than in the etidronate group throughout the treatment period. An improvement of patient QOL was observed in both groups. No significant difference in the incidence of adverse events was observed between the two treatments. Daily oral risedronate (2.5mg) was shown to provide an effective therapy for involutional osteoporosis in Japanese patients with good tolerability.     

The effects of bone therapy on tibial bone loss in young women with anorexia nervosa

OBJECTIVE: Osteoporosis is recognized as a common medical complication of anorexia nervosa (AN). The purpose of the current study was to investigate the recovery mechanism of osteoporosis in AN and the effect of medical treatment on the skeletal system. METHOD: We conducted a randomized placebo-controlled study of the effects of etidronate and calcium and vitamin D on bone loss in 41 outpatients with the restricting type of AN (AN-R). We measured the tibial speed of sound (SOS) before and after 3 months of treatment. RESULTS: The bone mineral density (BMD) of the tibial SOS change in both the etidronate group and the calcium and vitamin D Group was significantly greater (p < .001) than in the control group. Urine-N-telopeptide cross-links of type I collagen (NTx) before and after treatment decreased significantly (p < .01) in the etidronate group. CONCLUSION: These findings suggest that both etidronate and calcium and vitamin D are equally efficacious for reversing the degree of osteoporosis in patients with AN.     

Synthesis of bisphosphonate derivatives of ATP by T4 DNA ligase, ubiquitin activating enzyme (E1) and other ligases

T4 DNA ligase and the ubiquitin activating enzyme (E1), catalyze the synthesis of ATP beta,gamma-bisphosphonate derivatives. Concerning T4 DNA ligase: (i) etidronate (pC(OH)(CH(3))p) displaced the AMP moiety of the complex E-AMP in a concentration dependent manner; (ii) the K(m) values and the rate of synthesis k(cat) (s(-1)), determined for the following compounds were, respectively: etidronate, 0.73+/-0.09 mM and (70+/-10)x10(-3) s(-1); clodronate (pCCl(2)p), 0.08+/-0.01 mM and (4.1+/-0.3)x10(-3) s(-1); methylenebisphosphonate (pCH(2)p), 0.024+/-0.001 mM and (0.6+/-0.1)x10(-3) s(-1); tripolyphosphate (P(3)) (in the synthesis of adenosine 5'-tetraphosphate, p(4)A), 1.30+/-0.30 mM and (6.2+/-1.1)x10(-3) s(-1); (iii) in the presence of GTP and ATP, inhibition of the synthesis of Ap(4)G was observed with clodronate but not with pamidronate (pC(OH)(CH(2)-CH(2)-NH(3))p). Concerning the ubiquitin activating enzyme (E1): methylenebisphosphonate was the only bisphosphonate, out of the ones tested, that served as substrate for the synthesis of an ATP derivative (K(m)=0.36+/-0.09 mM and k(cat)=0.15+/-0.02 s(-1)). None of the above bisphosphonates were substrates of the reaction catalyzed by luciferase or by acyl-CoA synthetase. The ability of acetyl-CoA synthetase to use methylenebisphosphonate as substrate depended on the commercial source of the enzyme. In our view this report widens our knowledge of the enzymes able to metabolize bisphosphonates, a therapeutic tool widely used in the treatment of osteoporosis.     

The Effect of Heating to Intracanal Temperature on the Stability of Sodium Hypochlorite Admixed with Etidronate or EDTA for Continuous Chelation

Introduction

Tetrasodium etidronate (Na₄ etidronate) and tetrasodium EDTA (Na₄ EDTA) are chelators that can combine with sodium hypochlorite (NaOCl) as a 1-mix endodontic irrigant in a process called continuous chelation. The therapeutic window of these mixtures is determined by the chemical reaction between NaOCl and the chelator. At room temperature, this window is 60 minutes for Na₄ etidronate and 30 minutes for Na₄ EDTA. Because reaction kinetics are influenced by heat, this study assesses the influence of heating to an intracanal temperature of 35°C on the therapeutic window in continuous chelation.

Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo: Role in osteoclast-mediated NK cell activation

The aim of this study is to establish osteoclasts as key immune effectors capable of activating the function of Natural Killer (NK) cells, and expanding their numbers, and to determine in vivo and in vitro effect of bisphosphonates (BPs) during NK cell interaction with osteoclasts and on systemic and local immune function. The profiles of 27 cytokines, chemokines and growth factors released from osteoclasts were found to be different from dendritic cells and M1 macrophages but resembling to untreated monocytes and M2 macrophages. Nitrogen-containing BPs Zoledronate (ZOL) and Alendronate (ALN), but not non-nitrogen-containing BPs Etidronate (ETI), triggered increased release of pro-inflammatory mediators from osteoclasts while all three BPs decreased pit formation by osteoclasts. ZOL and ALN mediated significant release of IL-6, TNF-` and IL-1β, whereas they inhibited IL-10 secretion by osteoclasts. Treatment of osteoclasts with ZOL inhibited NK cell mediated cytotoxicity whereas it induced significant secretion of cytokines and chemokines. NK cells lysed osteoclasts much more than their precursor cells monocytes, and this correlated with the decreased expression of MHC class I expression on osteoclasts. Intravenous injection of ZOL in mice induced pro-inflammatory microenvironment in bone marrow and demonstrated significant immune activation. By contrast, tooth extraction wound of gingival tissues exhibited profound immune suppressive microenvironment associated with dysregulated wound healing due to the effect of ZOL which could potentially be responsible for the pathogenesis of Osteonecrosis of the Jaw (ONJ). Finally, based on the data obtained in this paper we demonstrate that osteoclasts can be used as targets for the expansion of NK cells with superior function for immunotherapy of cancer.     

What Predicts Early Fracture or Bone Loss on Bisphosphonate Therapy?

Factors predicting early fracture or bone loss on bisphosphonate therapy are not well defined. We studied 1588 patients over the age of 50 yr who were started on cyclic etidronate (1119) or alendronate (469) in the CANDOO (Canadian Database for Osteoporosis and Osteopenia Patients) Study. Incident fracture within 2 yr of starting therapy occurred in 31 patients and was independently predicted by a previous history of nonvertebral fracture (odds ratio [OR], 2.98, 95% confidence interval [CI], 1.30, 6.83, p = 0.010). Two hundred and fifty-seven patients lost >/=3% bone mass at the hip or spine (early bone loss) while on bisphosphonate therapy. Protection from early bone loss was most strongly independently predicted by treatment with alendronate with no previous history of etidronate use (OR, 0.29, CI, 0.13, 0.62, p = 0.002). In conclusion, early fracture on bisphosphonate therapy is most strongly predicted by a previous history of fracture and early bone loss is most strongly predicted by the potency of the prescribed bisphosphonate.     

Long‐term results of disodium etidronate treatment in pulmonary alveolar microlithiasis

Pulmonary alveolar microlithiasis (PAM) is a rare disease with alveolar microliths mainly composed of calcium phosphate. The gene responsible for the disease is SLC34A2, which encodes a type‐IIb sodium phosphate cotransporter, has been described recently. Treatment of this disease is not clearly defined. Disodium etidronate is a member of bisphonates and it has been administered in these patients due to its inhibitory effect on the precipitation of hydroxyapatite microcrystals. Here, clinical and radiological improvement of two patients with PAM who were treated with disodium etidronate for 9 and 11 years, respectively, are presented. The pathogenetic mechanism of this treatment on the genetic basis of disease is discussed. Pediatr Pulmonol. 2010; 45:514–517. © 2010 Wiley‐Liss, Inc.     

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.