Disease relevance of MK 217

• BACKGROUND: Alendronate, an aminobisphosphonate and a selective inhibitor of osteoclast-mediated bone resorption, is used to treat osteoporosis in postmenopausal women and Paget's disease of bone [1].
• Alendronate in postmenopausal osteoporosis [2].
• Recommendations to reduce the risk of esophagitis include swallowing alendronate with 180 to 240 ml (6 to 8 oz) of water on arising in the morning, remaining upright for at least 30 minutes after swallowing the tablet and until the first food of the day has been ingested, and discontinuing the drug promptly if esophageal symptoms develop [1].
• CONCLUSIONS: At doses used for the treatment of osteoporosis, risedronate was associated with a significantly lower incidence of gastric ulcers than alendronate [3].
• CONCLUSIONS: Treatment with alendronate, 10 mg daily, significantly increased BMD in patients with Crohn's disease and was safe and well tolerated [4].

Psychiatry related information on MK 217

• In addition, alendronate produced a significant risk reduction of 40% (RR = 0.60; 95% CI = 0.47-0.77; p < 0.01) for the composite event of clinical hip, spine, and wrist fractures [5].
• Chronic alcohol consumption uncouples formation from ongoing resorption, and resorption is inhibited by alendronate [6].
• Letter re: alendronate in anorexia nervosa [7].
• Although alendronate, a bisphosphonate drug, decreased blood calcium, it affected neither locomotor activity nor serum phosphorus level [8].
• Alendronate-induced auditory hallucinations and visual disturbances [9].

High impact information on MK 217

• The increase in bone mineral density in the alendronate group was greater than that in the placebo group at all measurement sites (P<0.001) [10].
• At three years, the mean (+/- SE) differences in bone mineral density between the women receiving 10 mg of alendronate daily and those receiving placebo were 8.8 +/- 0.4 percent in the spine, 5.9 +/- 0.5 percent in the femoral neck, 7.8 +/- 0.6 percent in the trochanter, and 2.5 +/- 0.3 percent in the total body (P < 0.001 for all comparisons) [11].
• Alendronate decreased the risk of radiographic vertebral fractures by 44% overall (relative risk, 0.56; 95% CI, 0.39-0.80; treatment-control difference, 1.7%; NNT, 60) [12].
• Inhibition of bone resorption by administration of the bisphosphonate alendronate led to a decrease of the absolute number of osteoblast progenitors; however, it did not influence the stimulating effect of ovariectomy on osteoblastogenesis or osteoclastogenesis [13].
• The bone-induced H+ extrusion was inhibited by salmon calcitonin (10(-8) M, for 2 h), and was not present after pretreating the bone slices with the aminobisphosphonate alendronate (ALN) [14].

Chemical compound and disease context of MK 217

• Gaucher disease: alendronate disodium improves bone mineral density in adults receiving enzyme therapy [15].
• In the present study, the effects of two clinically used BPs, the amino-BP alendronate and clodronate, on adhesion, invasion, and migration of human PC-3 prostate cancer cells were examined in vitro [16].
• We previously reported that alendronate, a nitrogen-containing bisphosphonate, inhibited ovarian cancer cell migration by attenuating the activation of Rho through inhibiting the mevalonate pathway [17].
• Alendronate inhibits lysophosphatidic acid-induced migration of human ovarian cancer cells by attenuating the activation of rho [18].
• Treatment of ovarian cancer cells with alendronate resulted in inactivation of Rho, changes of cell morphology, loss of stress fiber formation, and focal adhesion assembly, and the suppression of phosphorylation of myosin light chain and tyrosine phosphorylation of focal adhesion proteins, which are essential processes for cell migration [18].

Biological context of MK 217

• CONCLUSIONS: Alendronate increases bone density in patients receiving glucocorticoid therapy [19].
• We investigated the effect of treatment with the bisphosphonate alendronate on bone mass and markers of bone remodeling in patients with Crohn's disease [4].
• Alendronate decreased markers of bone resorption to a new steady state by 3 months and decreased markers of bone formation by 6 to 12 months [20].
• These results suggest that alendronate inhibits Rho activation by preventing geranylgeranylation, which results in inhibition of LPA-induced migration of human ovarian cancer cells [18].
• The results demonstrate that alendronate pretreatment very effectively inhibited in vitro invasion of prostate cancer cells in a dose-dependent manner, with an IC50 as low as approximately 1 pM [16].

Anatomical context of MK 217

• The bone density of the trochanter and total body also increased significantly in the patients treated with alendronate [19].
• Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure [21].
• 6 d later the label was 600-1,000 microns away from the epiphyseal plate and buried inside the bone, indicating normal growth and matrix deposition on top of alendronate-containing bone [21].
• All tested aminobisphosphonates (alendronate, ibandronate, and pamidronate) induced significant expansion of gamma delta T cells (V gamma 9V delta 2++ subset) in peripheral blood mononuclear cell cultures of healthy donors at clinically relevant concentrations (half-maximal activity, 0.9-4 mcmol/L) [22].
• In the treatment model, in which alendronate was given from 10 days after tumor inoculation when macroscopic tumors are already implanted in the peritoneum, the antitumor effect was weaker but still significant [17].

Associations of MK 217 with other chemical compounds

• An increase in bone mineral density at the spine, total hip, and total body has been reported with raloxifene but seems to be less than that seen with estrogen or alendronate therapy [23].
• Furthermore, rabbit osteoclast formation and activity also are inhibited by lovastatin and alendronate [24].
• Together, these findings support the hypothesis that alendronate, acting directly on osteoclasts, inhibits a rate-limiting step in the cholesterol biosynthesis pathway, essential for osteoclast function [24].
• Using T-cell receptor (TCR) transfer studies, we show that recognition of antigenic aminobisphosphonates that are known to stimulate human gammadelta T cells in vitro and in vivo (potency: risedronate > alendronate > pamidronate) requires expression of the Vgamma2Vdelta2 TCR and is thus Vgamma2Vdelta2 TCR-dependent [25].
• To compare the mechanism of action of clodronate and alendronate, effects on protein prenylation in osteoclasts and macrophages in vivo were also assessed [26].

Gene context of MK 217

• The inhibitory effect of 10(-6) M alendronate on PBMC proliferation was reversed by 10 U/ml recombinant rIL-1 beta, whereas other cytokines such as IL-6, TNF-alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF) had no effect [27].
• Alendronate exhibited dose-dependent inhibition of the production of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) by activated monocytes [27].
• Thus, alendronate acts on monocytes to inhibit their antigen-presenting/accessory cell functions through a mechanism that can be overcome by exogenous IL-1 [27].
• Evaluation of bone turnover and osteoclastic cytokines in early rheumatoid arthritis treated with alendronate [28].
• A potent bisphosphonate compound, alendronate, inhibited MMP-2 secretion to block solubilization of collagen 1 [29].

Analytical, diagnostic and therapeutic context of MK 217

• Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group [30].
• Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group [19].
• Meta-analyses of therapies for postmenopausal osteoporosis. II. Meta-analysis of alendronate for the treatment of postmenopausal women [31].
• Mean (SD) increases in bone mass at the hip in women treated with alendronate alone were significantly greater than in those treated with hormone replacement therapy alone (4.2% [3.8] vs 3.0% [4.9]; P<.05, respectively), and alendronate resulted in more responders to therapy [32].
• OBJECTIVE: To determine whether the effect of alendronate is sustained at 4 years of treatment and persists after treatment is discontinued [33].

References