Journal of Bone and Mineral Metabolism

, Volume 29, Issue 1, pp 62–70 | Cite as

Urinary pentosidine and plasma homocysteine levels at baseline predict future fractures in osteoporosis patients under bisphosphonate treatment

  • Masataka Shiraki
  • Tatsuhiko Kuroda
  • Yumiko Shiraki
  • Shiro Tanaka
  • Tsuyoshi Higuchi
  • Mitsuru Saito
Original Article


To clarify what kind of risk factors predict incident fractures in patients treated with bisphosphonates, the authors investigated the relationship between baseline characteristics and incident vertebral fracture in Japanese osteoporosis patients undergoing bisphosphonate treatment. This was a multi-center follow-up study conducted at three centers, in which a total of 251 Japanese patients with osteoporosis (mean age 70.5 years) from the three centers were followed for 3.2 ± 2.0 years. Baseline data, including pre-existing fractures, bone mineral density in the lumbar spine (LBMD), bone metabolic markers, urinary pentosidine, and plasma homocysteine, were evaluated. Changes in LBMD, bone turnover markers, and incident fractures after the treatment were followed. Sixty-one patients developed incident vertebral fractures; this group of patients was older and had lower LBMD, a higher prevalent vertebral fracture number, and higher homocysteine and pentosidine levels than patients who did not develop incident vertebral fractures. Changes in LBMD, urinary N-terminal telopeptides of type I collagen (NTX), and bone-derived alkaline phosphatase showed no significant association with the occurrence of vertebral fractures. Cox’s proportional hazard model demonstrated that age, prevalent fracture, pentosidine, and homocysteine were independent predictors of the incident vertebral fracture rate under bisphosphonate treatment. Higher baseline levels of pentosidine and homocysteine in osteoporosis patients are potential risk factors for incident vertebral fractures when these patients are treated with bisphosphonates. Further clarification is needed to explain why such patients have higher fracture susceptibility.


Pentosidine Homocysteine Bisphosphonates Osteoporosis Fracture 



This work was partly supported by a Grant-in-Aid from the Japan Osteoporosis Foundation.


  1. 1.
    NIH consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy (2001) Osteoporosis prevention, diagnosis and therapy. JAMA 285:785–795CrossRefGoogle Scholar
  2. 2.
    Silverman SL, Minshall ME, Shen W, Harper KD, Xie S (2001) Health-Related Quality of Life Subgroup of the Multiple Outcomes of Raloxifene Evaluation Study. The relationship of health-related quality of life to prevalent and incident vertebral fractures in postmenopausal women with osteoporosis: results from Multiple Outcomes of Raloxifene Evaluation Study. Arthritis Rheum 44:2611–2619CrossRefPubMedGoogle Scholar
  3. 3.
    Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 348:1535–1541CrossRefPubMedGoogle Scholar
  4. 4.
    Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, Palermo L, Prineas R, Rubin SM, Scott JC, Vogt T, Wallace R, Yates AJ, LaCroix AZ (1998) Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 280:2077–2082CrossRefPubMedGoogle Scholar
  5. 5.
    Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut CH 3rd, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD (1999) Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. JAMA 282:1344–1352CrossRefPubMedGoogle Scholar
  6. 6.
    Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Glüer CC, Krueger K, Cohen FJ, Eckert S, Ensrud KE, Avioli LV, Lips P, Cummings SR (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 282:637–645CrossRefPubMedGoogle Scholar
  7. 7.
    Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH (2001) Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434–1441CrossRefPubMedGoogle Scholar
  8. 8.
    Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S (2007) The HORIZON recurrent fracture trial. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 357:1799–1809CrossRefPubMedGoogle Scholar
  9. 9.
    Garnero P, Shih WJ, Gineytes E, Karpf DB, Delmas PD (1994) Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J Clin Endocrinol Metab 79:1693–1700CrossRefPubMedGoogle Scholar
  10. 10.
    Boivin GY, Chavassieux PM, Santora AC, Yates J, Meunier PJ (2000) Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone 27:687–694CrossRefPubMedGoogle Scholar
  11. 11.
    Saito M, Mori S, Mashiba T, Komatsubara S, Marumo K (2008) Collagen maturity, glycation induced-pentosidine, and mineralization are increased following 3-year treatment with incadronate in dogs. Osteoporos Int 19:1343–1354CrossRefPubMedGoogle Scholar
  12. 12.
    Tang SY, Allen MR, Phipps R, Burr DB, Vashishth D (2009) Changes in non-enzymatic glycation and its association with altered mechanical properties following 1-year treatment with risedronate or alendronate. Osteopors Int 20:887–894CrossRefGoogle Scholar
  13. 13.
    Glover SJ, Eastell R, McCloskey EV, Rogers A, Garnero P, Lowery J, Belleli R, Wright TM, John MR (2009) Rapid and robust response of biochemical markers of bone formation to teriparatide therapy. Bone 45:1053–1058CrossRefPubMedGoogle Scholar
  14. 14.
    Saito M, Fujii K, Marumo K (2006) Degree of mineralization-related collagen crosslinking in the femoral neck cancellous bone in cases of hip fracture and controls. Calcif Tissue Int 79:160–168CrossRefPubMedGoogle Scholar
  15. 15.
    Saito M, Marumo K, Soshi S, Kida Y, Ushiku C, Shinohara (2009) Raloxifene ameliorates detrimental enzymatic and non-enzymatic collagen cross-links and bone strength in rabbits with hyperhomocysteinemia. Osteoporos Int 21:655–666CrossRefPubMedGoogle Scholar
  16. 16.
    van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM, van der Klift M, de Jonge R, Lindemans J, de Groot LC, Hofman A, Witteman JC, van Leeuwen JP, Breteler MM, Lips P, Pols HA, Uitterlinden AG (2004) Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med 350:2033–2041CrossRefPubMedGoogle Scholar
  17. 17.
    McLean RR, Jacques PF, Selhub J, Tucker KL, Samelson EJ, Broe KE, Hannan MT, Cupples LA, Kiel DP (2004) Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 350:2042–2049CrossRefPubMedGoogle Scholar
  18. 18.
    Shiraki M, Urano T, Kuroda T, Saito M, Tanaka S, Miyao-Koshizuka M, Inoue S (2008) The synergistic effect of bone mineral density and methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T) on fractures. J Bone Miner Metab 26:595–602CrossRefPubMedGoogle Scholar
  19. 19.
    Shiraki M, Kuroda T, Tanaka S, Saito M, Fukunaga M, Nakamura T (2008) Nonenzymatic collagen cross-links induced by glycation (pentosidine) predicts vertebral fractures. J Bone Miner Metab 26:93–100CrossRefPubMedGoogle Scholar
  20. 20.
    Shiraki M, Shiraki Y, Aoki C, Hosoi T, Inoue S, Kaneki M, Ouchi Y (1997) Association of bone mineral density with apolipoprotein E phenotype. J Bone Miner Res 12:1438–1445CrossRefPubMedGoogle Scholar
  21. 21.
    Genant HK, Jergas M, Palermo L, Nevitt M, Valentin RS, Black D, Cummings SR (1996) Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis. The study of osteoporotic fractures research group. J Bone Miner Res 11:984–996CrossRefPubMedGoogle Scholar
  22. 22.
    Orimo H, Hayashi Y, Fukunaga M, Sone T, Fujiwara S, Shiraki M, Kushida K, Miyamoto S, Soen S, Nishimura J, Oh-hashi Y, Hosoi T, Gorai I, Tanaka H, Igai T, Kishimoto H (2001) Osteoporosis diagnostic criteria for primary osteoporosis: year 2000 revision. J Bone Miner Metab 19:331–337CrossRefPubMedGoogle Scholar
  23. 23.
    Yoshihara K, Nakamura K, Kanai M, Nagayama Y, Takahashi S, Saito N, Nagata M (1998) Determination of urinary and serum pentosidine and its application to elder patients. Biol Pharm Bull 21:1005–1008PubMedGoogle Scholar
  24. 24.
    Vester B, Rasmussen K (1991) High performance liquid chromatography method for rapid and accurate determination of homocysteine in plasma and serum. Eur J Clin Chem Clin Biochem 29:549–554PubMedGoogle Scholar
  25. 25.
    Cummings SR, Karpf DB, Harris F, Genant HK, Ensrud K, LaCroix AZ, Black DM (2002) Improvement in spine bone mineral density and reduction in risk of vertebral fractures during the treatment with antiresorptive drugs. Am J Med 112:281–289CrossRefPubMedGoogle Scholar
  26. 26.
    Delmas PD, Seeman E (2004) Changes in bone mineral density explain little of the reduction in vertebral or nonvertebral fracture risk with anti-resorptive therapy. Bone 34:599–604CrossRefPubMedGoogle Scholar
  27. 27.
    Bell KJL, Hayen A, Macaskill P, Irwing L, Craig JC, Ensrud K, Bauer DC (2009) Value of routine monitoring of bone mineral density after starting bisphosphonate treatment: secondary analysis of trial data. Br Med J338:b2266. doi:10.1136/bjm.b2266
  28. 28.
    Shiraki M, Kuroda T, Nakamura T, Fukunaga M, Hosoi T, Orimo H, Makino K (2006) The sample size required for intervention studies on fracture prevention can be decreased by using a bone resorption marker in the inclusion criteria: prospective study of a subset of the Nagano Cohort, on behalf of the Adequate Treatment of Osteoporosis (A-TOP) Research Group. J Bone Miner Metab 24:219–225CrossRefPubMedGoogle Scholar
  29. 29.
    Eastell R, Barton I, Hannon RA, Chines A, Garnero P, Delmas PD (2003) Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res 18:1051–1056CrossRefPubMedGoogle Scholar
  30. 30.
    Seibel MJ, Naganathan V, Barton I, Grauer A (2004) Relationship between pretreatment bone resorption and vertebral fracture incidence in postmenopausal osteoporotic women treated with risedronate. J Bone Miner Res 19:323–329CrossRefPubMedGoogle Scholar
  31. 31.
    Saito M, Marumo K (2010) Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int 21:195–214CrossRefPubMedGoogle Scholar
  32. 32.
    Schwartz AV, Garnero P, Hillier TA, Sellmeyer DE, Strotmeyer ES, Feingold KR, Resnick HE, Tylavsky FA, Black DM, Cummings SR, Harris TB, Bauer DC, for the Health, Aging, Body Composition study (2009) Pentosidine and increased fracture risk in older adults with type 2 diabetes. J Clin Endocrinol Metab 94:2380–2386CrossRefPubMedGoogle Scholar
  33. 33.
    Yamamoto M, Yamaguchi T, Yamauchi M, Yano S, Sugimoto T (2008) Serum pentosidine levels are positively associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes. J Clin Endocrinol Metab 93:1013–1019CrossRefPubMedGoogle Scholar
  34. 34.
    Vashishth D (2007) The role of the collagen matrix in skeletal fragility. Curr Osteoporos Rep 5:62–66CrossRefPubMedGoogle Scholar
  35. 35.
    Wang X, Shen X, Li X, Agrawal CM (2002) Age-related changes in the collagen network and toughness of bone. Bone 31:1–7CrossRefPubMedGoogle Scholar
  36. 36.
    Garnero P, Borel O, Gineyts E, Duboeuf F, Solberg H, Bouxsein ML, Christiansen C, Delmas PD (2006) Extracellular post-translational modifications of collagen are major determinants of biomechanical properties of fetal bovine cortical bone. Bone 38:300–309CrossRefPubMedGoogle Scholar
  37. 37.
    Saito M, Fujii K, Sohshi S, Tanaka T (2006) Reductions in degree of mineralization and enzymatic collagen cross-links and increases in glycation induced pentosidine in the femoral neck cortex in cases of femoral neck fracture. Osteoporos Int 17:986–995CrossRefPubMedGoogle Scholar
  38. 38.
    Gineyts E, Munoz F, Bertholon C, Sornay-Rendu E, Chapurlat R (2010) Urinary levels of pentosidine and risk of fracture in post menopausal women: the OFELY study. Osteoporos Int 21:243–250CrossRefPubMedGoogle Scholar
  39. 39.
    Odetti P, Rossi S, Monacelli F, Poggi A, Cirnigliaro M, Federici M, Federici A (2005) Advanced glycation end products and bone loss during aging. Ann N Y Acad Sci 1043:710–717CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer 2010

Authors and Affiliations

  • Masataka Shiraki
    • 1
  • Tatsuhiko Kuroda
    • 2
  • Yumiko Shiraki
    • 1
  • Shiro Tanaka
    • 3
  • Tsuyoshi Higuchi
    • 4
  • Mitsuru Saito
    • 5
  1. 1.Research Institute and Practice for Involutional DiseasesNaganoJapan
  2. 2.Public Health Research FoundationTokyoJapan
  3. 3.Division of Clinical Trial, Design and Management, Translational Research CenterKyoto UniversityKyotoJapan
  4. 4.Department of Obstetrics and GynecologyHirosaki University School of MedicineAomoriJapan
  5. 5.Department of Orthopedic SurgeryJikei University School of MedicineTokyoJapan

Personalised recommendations