Calcified Tissue International

, Volume 83, Issue 3, pp 167–175

Short-Term Effects of High-Dose Zoledronic Acid Treatment on Bone Mineralization Density Distribution After Orthotopic Liver Transplantation

  • B. M. Misof
  • M. Bodingbauer
  • P. Roschger
  • T. Wekerle
  • B. Pakrah
  • M. Haas
  • A. Kainz
  • R. Oberbauer
  • F. Mühlbacher
  • K. Klaushofer


Patients with “hepatic” bone disease exhibit increased fracture incidence. The effects on bone material properties, their changes due to orthotopic liver transplantation (OLT), as well as zolendronate (ZOL) treatment have not yet been investigated. We studied bone mineralization density distribution (BMDD) in paired transiliacal biopsies (at and 6 months after OLT) from patients (control CON n = 18, treatment group ZOL n = 21, the latter treated with i.v. ZOL at doses of 4 mg/month) for how bone at the material level was affected by the “hepatic” disease in general, as well as by OLT and ZOL in particular. (1) BMDD parameters at baseline reflected disturbed bone matrix mineralization in “hepatic” bone disease combined with low turnover. Trabecular bone displayed a decrease in mean and most frequent calcium concentration (CaMEAN −2.9% and CaPEAK −2.8%, respectively; both P < 0.001), increased heterogeneity of mineralization (CaWIDTH +12.2%, P = 0.01), and increased percentage of bone areas with low mineralization (CaLOW +32.4%, P = 0.02) compared to normal; however, there were no differences compared to cortical bone. (2) Six months after OLT, ZOL-treated trabecular bone displayed reduced CaLOW (−32.0%, P = 0.047), cortical bone increased CaMEAN (+4.2%, P = 0.009), increased CaPEAK (+3.3%, P = 0.040), and decreased CaLOW (−55.7, P = 0.038) compared to CON and increased CaMEAN compared to baseline (+1.9, P = 0.032) without any signs of hyper- or defective mineralization. These changes as consequence of the antiresorptive action of ZOL visible already after 6 months result in beneficial effects on bone matrix mineralization, likely contributing to the significant decrease in fracture incidence observed in these patients 2 years post transplantation.


Liver transplantation High-dose zoledronic acid Bone mineralization density distribution Quantitative backscattered electron imaging 


  1. 1.
    Crawford BA, Labio ED, Strasser SI, McCaughan GW (2006) Vitamin D replacement for cirrhosis related bone disease. Nat Clin Pract Gastroenterol Hepatol 3:689–699PubMedCrossRefGoogle Scholar
  2. 2.
    Hay JE (2003) Osteoporosis in liver diseases and after liver transplantation. J Hepatol 38:856–865PubMedCrossRefGoogle Scholar
  3. 3.
    Monegal A, Navasa M, Guanabens N, Peris P, Pons F, Martinez de Osaba MJ, Rimola A, Rodes J, Munoz-Gomez J (1997) Osteoporosis and bone mineral metabolism disorders in cirrhotic patients referred for orthotopic liver transplantation. Calcif Tissue Int 60:148–154PubMedCrossRefGoogle Scholar
  4. 4.
    Guichelaar MM, Malinchoc M, Sibonga JD, Clarke BL, Hay JE (2003) Bone histomorphometric changes after liver transplantation for chronic cholestatic liver disease. J Bone Miner Res 18:2190–2199PubMedCrossRefGoogle Scholar
  5. 5.
    Millonig G, Graziadei IW, Eichler D, Pfeiffer KP, Finkenstedt G, Muehllechner P, Koenigsrainer A, Margreiter R, Vogel W (2005) Alendronate in combination with calcium and vitamin D prevents bone loss after orthotopic liver transplantation: a prospective single-center study. Liver Transpl 11:960–966PubMedCrossRefGoogle Scholar
  6. 6.
    Klein GL, Endres DB, Colonna JDII, Berquist WE, Goldstein LI, Busuttil RW, Deftos LJ (1989) Absence of hyperparathyroidism in severe liver disease. Calcif Tissue Int 44:330–334PubMedCrossRefGoogle Scholar
  7. 7.
    Monegal A, Navasa M, Guanabens N, Peris P, Pons F, Martinez de Osaba MJ, Ordi J, Rimola A, Rodes J, Munoz-Gomez J (2001) Bone disease after liver transplantation: a long-term prospective study of bone mass changes, hormonal status and histomorphometric characteristics. Osteoporos Int 12:484–492PubMedCrossRefGoogle Scholar
  8. 8.
    Diamond TH, Stiel D, Lunzer M, McDowall D, Eckstein RP, Posen S (1989) Hepatic osteodystrophy. Static and dynamic bone histomorphometry and serum bone Gla-protein in 80 patients with chronic liver disease. Gastroenterology 96:213–221PubMedGoogle Scholar
  9. 9.
    Guichelaar MM, Malinchoc M, Sibonga J, Clarke BL, Hay JE (2002) Bone metabolism in advanced cholestatic liver disease: analysis by bone histomorphometry. Hepatology 36:895–903PubMedGoogle Scholar
  10. 10.
    Hay JE, Lindor KD, Wiesner RH, Dickson ER, Krom RA, LaRusso NF (1991) The metabolic bone disease of primary sclerosing cholangitis. Hepatology 14:257–261PubMedGoogle Scholar
  11. 11.
    McDonald JA, Dunstan CR, Dilworth P, Sherbon K, Sheil AG, Evans RA, McCaughan GW (1991) Bone loss after liver transplantation. Hepatology 14:613–619PubMedCrossRefGoogle Scholar
  12. 12.
    Guichelaar MJ, Kendall R, Malinchoc M, Hay JE (2006) Bone mineral density before and after OLT: long-term follow-up and predictive factors. Liver Transpl 12:1390–1402PubMedCrossRefGoogle Scholar
  13. 13.
    Cohen A, Sambrook P, Shane E (2004) Management of bone loss after organ transplantation. J Bone Miner Res 19:1919–1932PubMedCrossRefGoogle Scholar
  14. 14.
    Siris E (2000) Alendronate in the treatment of osteoporosis: a review of the clinical trials. J Womens Health Gender-Based Med 9:599–606CrossRefGoogle Scholar
  15. 15.
    Crawford BAL, Kam C, Pavlovic J, Byth K, Handelsman DJ, Angus PW, McCaughan GW (2006) Zoledronic acid prevents bone loss after liver transplantation: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 144:239–248PubMedGoogle Scholar
  16. 16.
    Bodingbauer M, Wekerle T, Pakrah B, Silberhumer G, Roschger P, Peck-Radosavljevic M, Grampp S, Rockenschaub S, Berlakovich G, Steininger R, Klaushofer K, Oberbauer R, Mühlbacher F (2007) Prophylactic bisphosphonate treatment prevents bone fractures after liver transplantation. Am J Transplant 7:1763–1769PubMedCrossRefGoogle Scholar
  17. 17.
    Boivin G, Meunier PJ (2002) Effects of bisphosphonates on matrix mineralization. J Musculoskelet Neuronal Interact 2:538–543PubMedGoogle Scholar
  18. 18.
    Borah B, Dufresne TE, Ritman EL, Jorgensen SM, Liu S, Chmielewski PA, Phipps RJ, Zhou X, Sibonga JD, Turner RT (2006) Long-term risedronate treatment normalizes mineralization and continues to preserve trabecular architecture: sequential triple biopsy studies with micro-computed tomography. Bone 39:345–352PubMedCrossRefGoogle Scholar
  19. 19.
    Boyde A, Jones SJ (1983) Backscattered electron imaging of skeletal tissues. Metab Bone Dis Rel Res 5:145–150CrossRefGoogle Scholar
  20. 20.
    Roschger P, Fratzl P, Eschberger J, Klaushofer K (1998) Validation of quantitative backscattered electron imaging for the measurement of mineral density distribution in human bone biopsies. Bone 23:319–326PubMedCrossRefGoogle Scholar
  21. 21.
    Currey JD (2002) Bones: structure and mechanics. Princeton University Press, Princeton, NJ, p 436Google Scholar
  22. 22.
    Fratzl P, Gupta HS, Roschger P, Klaushofer K (2008) Bone nanostructure and its relevance for mechanical performance, disease and treatment. In: Vogel V (ed) Nanotechnology-nanomedicine and nanobiotechnology, Wiley-VCH, Weinheim, Germany (in press)Google Scholar
  23. 23.
    Roschger P, Gupta HS, Berzlanovich A, Ittner G, Dempster DW, Fratzl P, Cosman F, Parisien M, Lindsay R, Nieves JW, Klaushofer K (2003) Constant mineralization density distribution in cancellous human bone. Bone 32:316–323PubMedCrossRefGoogle Scholar
  24. 24.
    Roschger P, Paschalis EP, Fratzl P, Klaushofer K (2008) Bone mineralization density distribution in health and disease. Bone 42:456–466PubMedCrossRefGoogle Scholar
  25. 25.
    Roschger P, Rinnerthaler S, Yates J, Rodan GA, Fratzl P, Klaushofer K (2001) Alendronate increases degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women. Bone 29:185–191PubMedCrossRefGoogle Scholar
  26. 26.
    Zoehrer R, Roschger P, Paschalis EP, Hofstaetter JG, Durchschlag E, Fratzl P, Phipps R, Klaushofer K (2006) Effects of 3- and 5-year treatment with risedronate on bone mineralization density distribution in triple biopsies of the iliac crest in postmenopausal women. J Bone Miner Res 21:1106–1112PubMedCrossRefGoogle Scholar
  27. 27.
    Haas M, Leko-Mohr Z, Roschger P, Kletzmayr J, Schwarz C, Mitterbauer C, Steininger R, Grampp S, Klaushofer K, Delling G, Oberbauer R (2003) Zoledronic acid to prevent bone loss in the first six months after renal transplantation. Kidney Int 63:1130–1136PubMedCrossRefGoogle Scholar
  28. 28.
    Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ et al (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 2:595–610PubMedCrossRefGoogle Scholar
  29. 29.
    Tovey FI, Stamp TCB (1995) The measurement of metabolic bone disease. Measurements in medicine series, vol 1. Parthenon Publishing Group, Carnforth, UKGoogle Scholar
  30. 30.
    Misof BM, Roschger P, Cosman F, Kurland ES, Tesch W, Messmer P, Dempster DW, Nieves J, Shane E, Fratzl P, Klaushofer K, Bilezikian JP, Lindsay R (2003) Effects of intermittent parathyroid hormone administration on bone mineralization density in iliac crest biopsies from patients with osteoporosis: a paired study before and after treatment. J Clin Endocrinol Metab 88:1150–1156PubMedCrossRefGoogle Scholar
  31. 31.
    Roschger P, Dempster DW, Zhou H, Paschalis EP, Silverberg SJ, Shane E, Bilezikian JP, Klaushofer K (2007) New observations on bone quality in mild hyperparathyroidism as determined by quantitative backscattered electron imaging. J Bone Miner Res 22:717–723PubMedCrossRefGoogle Scholar
  32. 32.
    Fratzl P, Roschger P, Fratzl-Zelman N, Paschalis EP, Phipps R, Klaushofer K (2007) Evidence that treatment with risedronate in women with postmenopausal osteoporosis affects bone mineralization and bone volume. Calcif Tissue Int 81:73–80PubMedCrossRefGoogle Scholar
  33. 33.
    Donovan MA, Dempster D, Zhou H, McMahon DJ, Fleischer J, Shane E (2005) Low bone formation in premenopausal women with idiopathic osteoporosis. J Clin Endocrinol Metab 90:3331–3336PubMedCrossRefGoogle Scholar
  34. 34.
    Roschger P, Manjubala I, Hofstaetter JG, Shane E, Donovan MA, Fleischer J, Dempster D, Fratzl P, Klaushofer K (2005) Reduced mineralization density of bone in premenopausal women with idiopathic osteoporosis. Twenty-seventh annual meeting of the American Society for Bone and Mineral Research, Nashville, TN, September 23–27, 2005 [abstract]Google Scholar
  35. 35.
    Guichelaar MM, Malinchoc M, Sibonga J, Clarke BL, Hay JE (2004) Immunosuppressive and postoperative effects of orthotopic liver transplantation on bone metabolism. Liver Transpl 10:638–647PubMedCrossRefGoogle Scholar
  36. 36.
    Vedi S, Ninkovic M, Garrahan NJ, Alexander GJM, Compston JE (2002) Effects of a single infusion of pamidronate prior to liver transplantation: a bone histomorphometric study. Transpl Int 15:290–295PubMedCrossRefGoogle Scholar
  37. 37.
    Ruffoni D, Fratzl P, Roschger P, Klaushofer K, Weinkamer R (2007) The bone mineralization density distribution as a fingerprint of the mineralization process. Bone 40:1308–1319PubMedCrossRefGoogle Scholar
  38. 38.
    Vedi S, Greer S, Skingle SJ, Garrahan NJ, Ninkovic M, Alexander GA, Compston JE (1999) Mechanism of bone loss after liver transplantation: a histomorphometric analysis. J Bone Miner Res 14:281–287PubMedCrossRefGoogle Scholar
  39. 39.
    Crosbie OM, Freaney R, McKenna MJ, Curry MP, Hegarty JE (1999) Predicting bone loss following orthotopic liver transplantation. Gut 44:430–434PubMedCrossRefGoogle Scholar
  40. 40.
    Ebeling PR, Burr DB (2008) Positive effects of intravenous zoledronic acid on bone remodeling and structure: are different effects on osteoblast activity to other oral bisphosphonates responsible? J Bone Miner Res 23:2–5PubMedCrossRefGoogle Scholar
  41. 41.
    Burr DB, Miller L, Grynpas M, Jiliang L, Boyde A, Mashiba T, Hirano T, Johnston CC (2003) Tissue mineralization is increased following 1-year treatment with high doses of bisphosphonates in dogs. Bone 33:960–969PubMedCrossRefGoogle Scholar
  42. 42.
    Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston CC, Burr DB (2000) Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biocmechanical properties in dog rib. J Bone Miner Res 15:613–620PubMedCrossRefGoogle Scholar
  43. 43.
    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) Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 357:1799–1809PubMedCrossRefGoogle Scholar
  44. 44.
    Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822PubMedCrossRefGoogle Scholar
  45. 45.
    Recker RR, Delmas PD, Halse J, Reid IR, Boonen S, Garcia-Hernandez PA, Supronik J, Lewiecki EM, Ochoa L, Miller P, Hu H, Mesenbrink P, Hartl F, Gasser J, Eriksen EF (2008) Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure. J Bone Miner Res 23:6–16PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • B. M. Misof
    • 1
  • M. Bodingbauer
    • 2
  • P. Roschger
    • 1
  • T. Wekerle
    • 2
  • B. Pakrah
    • 3
  • M. Haas
    • 4
  • A. Kainz
    • 4
    • 5
  • R. Oberbauer
    • 4
    • 5
  • F. Mühlbacher
    • 2
  • K. Klaushofer
    • 1
  1. 1.Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 4th Medical Department at Hanusch HospitalUKH MeidlingViennaAustria
  2. 2.Division of Transplantation, Department of SurgeryMedical University of ViennaViennaAustria
  3. 3.Department of NeurosurgeryKA RudolfstiftungViennaAustria
  4. 4.Department of Internal Medicine III, Division of NephrologyMedical University of ViennaViennaAustria
  5. 5.KH ElisabethinenLinzAustria

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