DOI QR코드

DOI QR Code

Effects of D-003 (10 mg/day) on Bone Mineral Density of the Lumbar Spine and Femoral Neck in Postmenopausal Women: A Randomized, Double-Blinded Study

  • Ceballos, Alfredo (Medical Surgical Research Centre) ;
  • Castano, Gladys (Medical Surgical Research Centre) ;
  • Mendoza, Sarahi (Centre of Natural Products, National Centre for Scientific Research) ;
  • Gonzalez, Juan (Medical Surgical Research Centre) ;
  • Mas, Rosa (Centre of Natural Products, National Centre for Scientific Research) ;
  • Fernandez, Lilia (Centre of Natural Products, National Centre for Scientific Research) ;
  • Illnait, Jose (Centre of Natural Products, National Centre for Scientific Research) ;
  • Mesa, Meilis (Medical Surgical Research Centre) ;
  • Gamez, Rafael (Centre of Natural Products, National Centre for Scientific Research) ;
  • Fernandez, Julio Cesar (Centre of Natural Products, National Centre for Scientific Research) ;
  • Telles, Ricardo (Medical Surgical Research Centre) ;
  • Marrero, Duany (Medical Surgical Research Centre) ;
  • Eng, Mainel Gomez (Software and Database Group of the National Centre for Scientific Research) ;
  • Ruiz, Dalmer (Software and Database Group of the National Centre for Scientific Research) ;
  • Jardines, Yunaisi (Software and Database Group of the National Centre for Scientific Research)
  • 발행 : 2011.06.01

초록

Background/Aims: Increased osteoclast activity is a pivotal finding in osteoporosis. This increase is mediated via the mevalonate-to-cholesterol pathway, which is involved in producing the intermediates required for osteoclast activity. D-003, a mixture of high molecular weight sugarcane wax acids, has been shown to inhibit cholesterol synthesis prior to mevalonate production, resulting in a reduction of bone loss and resorption in ovariectomized rats. Moreover, previous studies have demonstrated that short-term D-003 treatment reduces urinary excretion of deoxypyridinoline/creatinine in postmenopausal women. Methods: We performed a double-blinded, placebo-controlled study to investigate the effects of D-003 (10 mg/day) treatment for 3 years on bone mineral density (BMD) in 83 postmenopausal women with low BMD. Results: Over 3 years, D-003 treatment increased lumbar spine BMD (5.1%, p < 0.01) and improved osteoporosis-related quality of life scores as compared with placebo-treated controls. D-003 was also well tolerated; the frequency of adverse events in the bone, joints, or muscle with D-003 treatment (p < 0.05) was lower than in the placebo group. Conclusions: D-003 treatment (10 mg/day) for 3 years increased lumbar spine BMD and produced clinical improvements in postmenopausal women with low BMD. Further studies, however, will be required to confirm these results.

키워드

참고문헌

  1. Delmas PD. Treatment of postmenopausal osteoporosis. Lancet 2002;359:2018-2026. https://doi.org/10.1016/S0140-6736(02)08827-X
  2. Wildner M, Peters A, Raghuvanshi VS, Hohnloser J, Siebert U. Superiority of age and weight as variables in predicting osteoporosis in postmenopausal white women. Osteoporos Int 2003;14:950-956. https://doi.org/10.1007/s00198-003-1487-z
  3. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337-342. https://doi.org/10.1038/nature01658
  4. Coxon FP, Thompson K, Rogers MJ. Recent advances in understanding the mechanism of action of bisphosphonates. Curr Opin Pharmacol 2006;6:307-312. https://doi.org/10.1016/j.coph.2006.03.005
  5. van Beek E, Pieterman E, Cohen L, Lowik C, Papapoulos S. Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem Biophys Res Commun 1999;264:108-111. https://doi.org/10.1006/bbrc.1999.1499
  6. van beek E, Lowik C, van der Pluijm G, Papapoulos S. The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: a clue to the mechanism of action of nitrogen-containing bisphosphonates. J Bone Miner Res 1999;14:722-729. https://doi.org/10.1359/jbmr.1999.14.5.722
  7. Cummings SR, Karpf DB, Harris F, et al. Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med 2002;112:281-289. https://doi.org/10.1016/S0002-9343(01)01124-X
  8. Bone HG, Hosking D, Devogelaer JP, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004;350:1189-1199. https://doi.org/10.1056/NEJMoa030897
  9. Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab 2000;85:4118-4124. https://doi.org/10.1210/jc.85.11.4118
  10. Roux C, Seeman E, Eastell R, et al. Efficacy of risedronate on clinical vertebral fractures within six months. Curr Med Res Opin 2004;20:433-439. https://doi.org/10.1185/030079903125003125
  11. Chesnut III CH, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 2004;19:1241-1249. https://doi.org/10.1359/JBMR.040325
  12. Boonen S, Laan RF, Barton IP, Watts NB. Effect of osteoporosis treatments on risk of non-vertebral fractures: review and meta-analysis of intention-to-treat studies. Osteoporos Int 2005;16:1291-1298. https://doi.org/10.1007/s00198-005-1945-x
  13. Cranney A, Wells G, Willan A, et al. Meta-analyses of therapies for postmenopausal osteoporosis. II. Meta-analysis of alendronate for the treatment of postmenopausal women. Endocr Rev 2002;23:508-516. https://doi.org/10.1210/er.2001-2002
  14. Parhami F, Garfinkel A, Demer LL. Role of lipids in osteoporosis. Arterioscler Thromb Vasc Biol 2000;20:2346-2348. https://doi.org/10.1161/01.ATV.20.11.2346
  15. Bauer DC. HMG CoA reductase inhibitors and the skeleton: a comprehensive review. Osteoporos Int 2003;14:273-282. https://doi.org/10.1007/s00198-002-1323-x
  16. Bauer DC, Mundy GR, Jamal SA, et al. Use of statins and fracture: results of 4 prospective studies and cumulative meta-analysis of observational studies and controlled trials. Arch Intern Med 2004;164:146-152. https://doi.org/10.1001/archinte.164.2.146
  17. Rejnmark L, Buus NH, Vestergaard P, et al. Effects of simvastatin on bone turnover and BMD: a 1-year randomized controlled trial in postmenopausal osteopenic women. J Bone Miner Res 2004;19:737-744. https://doi.org/10.1359/jbmr.040209
  18. Reid IR, Hague W, Emberson J, et al. Effect of pravastatin on frequency of fracture in the LIPID study: secondary analysis of a randomised controlled trial. Long-term Intervention with Pravastatin in Ischaemic Disease. Lancet 2001;357:509-512. https://doi.org/10.1016/S0140-6736(00)04042-3
  19. Mas R. D-003: antiplatelet therapy, treatment of lipoprotein disorders. Drugs Future 2004;29:773-786. https://doi.org/10.1358/dof.2004.029.08.828449
  20. Menendez R, Mas R, Amor AM, Rodeiros I, Gonzalez RM, Alfonso JL. Inhibition of cholesterol biosynthesis in cultured fibroblasts by D003, a mixture of very long chain saturated fatty acids. Pharmacol Res 2001;44:299-304. https://doi.org/10.1006/phrs.2001.0851
  21. Menendez R, Mas R, Perez J, Gonzalez RM, Jimenez S. Oral administration of D-003, a mixture of very long chain fatty acids prevents casein-induced endogenous hypercholesterolemia in rabbits. Can J Physiol Pharmacol 2004;82:22-29. https://doi.org/10.1139/y03-123
  22. Castano G, Menendez R, Mas R, et al. Effects of D-003, a new hypocholesterolaemic and antiplatelet compound, on lipid profile and lipid peroxidation in healthy volunteers. Clin Drug Investig 2003;23:193-203.
  23. Castano G, Mas R, Fernandez L, et al. Effects of D-003 on the lipid profile of patients with type II hypercholesterolaemia: a phase II clinical study. Clin Drug Investig 2003;23:789-802. https://doi.org/10.2165/00044011-200323120-00004
  24. Menendez R, Mas R, Amor AM, et al. Inhibition of rat lipoprotein lipid peroxidation by the oral administration of D003, a mixture of very long-chain saturated fatty acids. Can J Physiol Pharmacol 2002;80:13-21. https://doi.org/10.1139/y01-088
  25. Mendoza S, Noa M, Mas R, Mendoza N. Effects of D-003 (5-200 mg/kg), a mixture of high molecular weight aliphatic acids from sugarcane wax, on bones and bone cell apoptosis in ovariectomized rats. Int J Tissue React 2005;27:213-222.
  26. Mendoza S, Noa M, Mas R, Mendoza N. Comparison of the effects of D-003, a mixture of high-molecular-weight aliphatic acids from sugarcane wax, and pravastatin on bones and osteoclast apoptosis of ovariectomized rats. Drugs Exp Clin Res 2005;31:181-191.
  27. Noa M, Mendoza S, Mas R, Mendoza N, Goicochea E. Long-term effects of D-003, a mixture of high molecular weight acids from sugarcane wax, on bones of ovariectomized rats: a one year study. Pharmazie 2008;63:486-488.
  28. Noa M, Mendoza S, Mas R, Mendoza N, Leon F. Effect of D-003, a mixture of very high molecular weight aliphatic acids, on prednisolone-induced osteoporosis in Sprague-Dawley rats. Drugs R D 2004;5:281-290. https://doi.org/10.2165/00126839-200405050-00004
  29. Ceballos A, Mas R, Castano G, et al. The effect of D-003 (10 mg/day) on biochemical parameters of bone remodelling in postmenopausal women: a randomized, double-blind study. Int J Clin Pharmacol Res 2005;25:175-186.
  30. van Schoor NM, Knol DL, Glas CA, et al. Development of the Qualeffo-31, an osteoporosis-specific quality-of-life questionnaire. Osteoporos Int 2006;17:543-551. https://doi.org/10.1007/s00198-005-0024-7
  31. Seigler L, Wu WT. Separation of serum high-density lipoprotein for cholesterol determination: ultracentrifugation vs precipitation with sodium phosphotungstate and magnesium chloride. Clin Chem 1981;27:838-841.
  32. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502.
  33. O'Brien PC, Shampo MA. Statistical considerations for performing multiple tests in a single experiment. 5. Comparing two therapies with respect to several endpoints. Mayo Clin Proc 1988;63:1140-1143. https://doi.org/10.1016/S0025-6196(12)65511-6
  34. Yang TS, Tsan SH, Chen CR, Chang SP, Yuan CC. Effects of alendronate on bone turnover markers in early postmenopausal women. Zhonghua Yi Xue Za Zhi (Taipei) 1998;61:568-576.
  35. Reid IR, Ames RW, Evans MC, Gamble GD, Sharpe SJ. Long-term effects of calcium supplementation on bone loss and fractures in postmenopausal women: a randomized controlled trial. Am J Med 1995;98:331-335. https://doi.org/10.1016/S0002-9343(99)80310-6
  36. Heaney RP. The bone-remodeling transient: implications for the interpretation of clinical studies of bone mass change. J Bone Miner Res 1994;9:1515-1523.
  37. Bone HG, Downs RW Jr, Tucci JR, et al. Dose-response relationships for alendronate treatment in osteoporotic elderly women: Alendronate Elderly Osteoporosis Study Centers. J Clin Endocrinol Metab 1997;82:265-274. https://doi.org/10.1210/jc.82.1.265
  38. Pols HA, Felsenberg D, Hanley DA, et al. Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: results of the FOSIT study. Fosamax International Trial Study Group. Osteoporos Int 1999;9:461-468. https://doi.org/10.1007/PL00004171
  39. Iwamoto J, Sato Y, Uzawa M, Takeda T, Matsumoto H. Comparison of effects of alendronate and raloxifene on lumbar bone mineral density, bone turnover, and lipid metabolism in elderly women with osteoporosis. Yonsei Med J 2008;49:119-128. https://doi.org/10.3349/ymj.2008.49.1.119
  40. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998;280:2077-2082. https://doi.org/10.1001/jama.280.24.2077