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Calcified Tissue International

, Volume 96, Issue 6, pp 477–489 | Cite as

Ibandronate Increases Sclerostin Levels and Bone Strength in Male Patients with Idiopathic Osteoporosis

  • Christian MuschitzEmail author
  • Roland Kocijan
  • Dieter Pahr
  • Janina M. Patsch
  • Karin Amrein
  • Barbara M. Misof
  • Alexandra Kaider
  • Heinrich Resch
  • Peter Pietschmann
Original Research

Abstract

The pathomechanism of male idiopathic osteoporosis (MIO) differs from postmenopausal osteoporosis with regard to alterations in osteoblast activity. We evaluated intravenous ibandronate (IBN) in 25 MIO patients with fragility fractures in a prospective, monocentric, single-arm, and open-label study for 24 months. The impact and changes of sclerostin (Scl), Dickkopf-1 (DKK-1), CTX, and PINP were examined. Additionally, volumetric cortical, trabecular and areal bone mineral density (BMD), trabecular bone score (TBS), and finite element analyses (FEA) were evaluated. Compared to baseline, median Scl levels were increased after 1 month (Δ 121 %, p < 0.0001) and remained elevated for 12 months. DKK-1 decreased (p < 0.001) to a lesser extent until month 9 with values comparable to baseline at study endpoint. Early changes (baseline–month 1) of Scl negatively correlated with early changes of DKK-1 (−0.72), CTX (−0.82), and PINP (−0.55; p < 0.005 for all). The overall changes over the 24 months study period of Scl negatively correlated with decreased CTX (−0.32) and DKK-1 levels (−0.57, p < 0.0001 for both); CTX and PINP changes positively correlated at each time point (p < 0.001). Volumetric hip BMD increased by 12 and 18 %, respectively (p < 0.0001 for both). Cross-sectional moment of inertia and section modulus for total hip significantly improved (p < 0.05 for all). Areal BMD at total hip, spine, and TBS increased. FEA displayed an increase in bone strength both in the hip (17 %) and vertebrae (13 %, all p < 0.0001) at anatomical sites susceptible for fragility fracture. IBN increases Scl and improves cortical and trabecular bone strength with early and ongoing vigorous suppression of bone resorption.

Keywords

Antiresorptive agents Ibandronate Male osteoporosis Sclerostin Bone turnover marker Finite element analysis 

Notes

Acknowledgements

The authors cordially thank Dr. Heike von Krempelhuber at Tutzing/Germany for assistance in editing the manuscript, Sabine Klauss and Xenia Steiner at Ulm/Germany for graphic design of the figures. The authors further acknowledge the work of the staff of the central laboratory and of the Department of Diagnostic and Interventional Radiology at St. Vincent Hospital Vienna, Austria. QCT DICOM data were calculated without knowledge of the study protocol by Dr. Wolfram Timm at Kiel/Germany. FEA calculations were performed by Dr. Enrico Dall’Ara at the Institute of Lightweight Design and Structural Biomechanics, University of Technology, Vienna, Austria. TBS scores were calculated without knowledge of the study protocol by Prf. Didier Hans at Lausanne/CH.

Conflict of interest

Christian Muschitz has received speaker honoraria from Amgen, Novartis, Servier, Eli Lilly, Nycomed/Takeda, and has received educational grants/research support from the Austrian Society for Bone and Mineral Research, Roche Austria, Eli Lilly Austria, and Amgen Austria. Heinrich Resch has received speaker honoraria from Amgen, Novartis, Servier, Eli Lilly, Nycomed/Takeda, Merck (MSD), and has received educational grants/research support from Eli Lilly and Roche Austria. Peter Pietschmann has received research support and/or honoraria from Amgen GmbH, Eli Lilly GmbH, Fresenius Kabi Austria GmbH, Merck, Sharp and Dohme GmbH, Novartis Pharma, Nycomed Pharma, Roche Austria, Servier Austria, Sanofi-Austria, and Sinapharm. Karin Amrein reports scientific support from Fresenius Kabi Austria. Dieter Pahr is the owner of a consultancy company for FEA calculations and has received a fee for the QCT segmentation, but not for the FEA calculations in this study. Roland Kocijan, Janina M. Patsch, Barbara M. Misof, and Alexandra Kaider have nothing to disclose.

Human and Animal Rights and Informed Consent

This study was planned and conducted according to the Helsinki Declaration of 2000 and was approved by the Ethics Committee of the Medical University of Vienna/Austria (AUT – 25/2006) and by the Ethics Committee of the St. Vincent Hospital Vienna/Austria (EK-Nr: 2006/12). The study was also registered at EudraCT:2006-006692-20. Informed and written consent was obtained from all patients prior to any study related procedure.

Competing interest

This investigator-initiated study was supported by an independent research grant from Roche Austria. Roche Austria was not involved in the study design or had any admission to patient-related data and findings.

References

  1. 1.
    Orwoll ES, Klein RF (2008) Osteoporosis in men: epidemiology, pathophysiology, and clinical characterization. In: Marcus R, Feldman D, Nelson DA, Rosen CJ (eds) Osteoporosis, vol 2, 3rd edn. Academic Press, New YorkGoogle Scholar
  2. 2.
    Patsch JM, Kohler T, Berzlanovich A, Muschitz C, Bieglmayr C, Roschger P, Resch H, Pietschmann P (2011) Trabecular bone microstructure and local gene expression in iliac crest biopsies of men with idiopathic osteoporosis. J Bone Miner Res 26:1584–1592. doi: 10.1002/jbmr.344 CrossRefPubMedGoogle Scholar
  3. 3.
    Fratzl-Zelman N, Roschger P, Misof BM, Nawrot-Wawrzyniak K, Pötter-Lang S, Muschitz C, Resch H, Klaushofer K, Zwettler E (2011) Fragility fractures in men with idiopathic osteoporosis are associated with undermineralization of the bone matrix without evidence of increased bone turnover. Calcif Tissue Int 88:378–387. doi: 10.1007/s00223-011-9466-4 CrossRefPubMedGoogle Scholar
  4. 4.
    Legrand E, Hedde C, Gallois Y, Degasne I, Boux de Casson F, Mathieu E, Baslé MF, Chappard D, Audran M (2011) Osteoporosis in men: a potential role for the sex hormone binding globulin. Bone 29:90–95CrossRefGoogle Scholar
  5. 5.
    Van Pottelbergh I, Goemaere S, Zmierczak H, Kaufman JM (2004) Perturbed sex steroid status in men with idiopathic osteoporosis and their sons. J Clin Endocrinol Metab 89:4949–4953. doi: 10.1210/jc.2003-032081 CrossRefPubMedGoogle Scholar
  6. 6.
    Johansson AG, Eriksen EF, Lindh E, Langdahl B, Blum WF, Lindahl A, Ljunggren O, Ljunghall S (1997) Reduced serum levels of the growth hormone dependent insulin-like growth factor binding protein and a negative bone balance at the level of individual remodeling units in idiopathic osteoporosis in men. J Clin Endocrinol Metab 82:2795–2798. doi: 10.1210/jcem.82.9.4148 PubMedGoogle Scholar
  7. 7.
    Kurland ES, Rosen CJ, Cosman F, McMahon D, Chan F, Shane E, Lindsay R, Dempster D, Bilezikian JP (1997) Insulin-like growth factor-I in men with idiopathic osteoporosis. J Clin Endocrinol Metab 82:2799–2805. doi: 10.1210/jcem.82.9.4253 PubMedGoogle Scholar
  8. 8.
    Patel MB, Arden NK, Masterson LM, Phillips DI, Swaminathan R, Syddall HE, Byrne CD, Wood PJ, Cooper C, Holt RI et al (2005) Investigating the role of the growth hormone-insulin-like growth factor (GH-IGF) axis as a determinant of male bone mineral density (BMD). Bone 37:833–841. doi: 10.1016/j.bone.2005.06.016 CrossRefPubMedGoogle Scholar
  9. 9.
    Gillberg P, Mallmin H, Petrén-Mallmin M, Ljunghall S, Nilsson AG (2002) Two years of treatment with recombinant human growth hormone increases bone mineral density in men with idiopathic osteoporosis. J Clin Endocrinol Metab 87:4900–4906. doi: 10.1210/jc.2002-020231 CrossRefPubMedGoogle Scholar
  10. 10.
    Föger-Samwald U, Patsch JM, Schamall D, Alaghebandan A, Deutschmann J, Salem S, Mousavi M, Pietschmann P (2014) Molecular evidence of osteoblast dysfunction in elderly men with osteoporotic hip fractures. Exp Gerontol 57:114–121. doi: 10.1016/j.exger.2014.05.014 CrossRefPubMedGoogle Scholar
  11. 11.
    Misof BM, Patsch JM, Roschger P, Muschitz C, Gamsjaeger S, Paschalis EP, Prokop E, Klaushofer K, Zwettler E (2014) Intravenous treatment with ibandronate normalizes bone matrix mineralization and reduces cortical porosity after two years in male osteoporosis: a paired biopsy study. J Bone Miner Res 29:440–449. doi: 10.1002/jbmr.2035 CrossRefPubMedGoogle Scholar
  12. 12.
    Mosekilde L, Vestergaard P, Rejnmark L (2013) The pathogenesis, treatment and prevention of osteoporosis in men. Drugs 73:15–29. doi: 10.1007/s40265-012-0003-1 CrossRefPubMedGoogle Scholar
  13. 13.
    Chapurlat RD, Laroche M, Thomas T, Rouanet S, Delmas PD, de Vernejoul MC (2013) Effect of oral monthly ibandronate on bone microarchitecture in women with osteopenia-a randomized placebo-controlled trial. Osteoporos Int 24:311–320. doi: 10.1007/s00198-012-1947-4 CrossRefPubMedGoogle Scholar
  14. 14.
    Catalano A, Morabito N, Basile G, Brancatelli S, Cucinotta D, Lasco A (2013) Zoledronic acid acutely increases sclerostin serum levels in women with postmenopausal osteoporosis. J Clin Endocrinol Metab 98:1911–1915. doi: 10.1210/jc.2012-4039 CrossRefPubMedGoogle Scholar
  15. 15.
    Anastasilakis AD, Polyzos SA, Gkiomisi A, Bisbinas I, Gerou S, Makras P (2013) Comparative effect of zoledronic acid versus denosumab on serum sclerostin and dickkopf-1 levels of naive postmenopausal women with low bone mass: a randomized, head-to-head clinical trial. J Clin Endocrinol Metab 98:3206–3212. doi: 10.1210/jc.2013-1402 CrossRefPubMedGoogle Scholar
  16. 16.
    Orwoll E, Ettinger M, Weiss S, Miller P, Kendler D, Graham J, Adami S, Weber K, Lorenc R, Pietschmann P, Vandormael K, Lombardi A (2000) Alendronate for the treatment of osteoporosis in men. N Engl J Med 343:604–610. doi: 10.1056/NEJM200008313430902 CrossRefPubMedGoogle Scholar
  17. 17.
    Silva BC, Boutroy S, Zhang C, McMahon DJ, Zhou B, Wang J et al (2013) Trabecular bone score (TBS)—a novel method to evaluate bone microarchitectural texture in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 98:1963–1970. doi: 10.1210/jc.2012-4255 CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Silva BC, Leslie WD, Resch H, Lamy O, Lesnyak O, Binkley N, McCloskey EV, Kanis JA, Bilezikian JP (2014) Trabecular bone score: a noninvasive analytical method based upon the DXA image. J Bone Miner Res 29:518–530. doi: 10.1002/jbmr.2176 CrossRefPubMedGoogle Scholar
  19. 19.
    Dall’Ara E, Schmidt R, Pahr D, Varga P, Chevalier Y, Patsch J, Kainberger F, Zysset P (2010) A nonlinear finite element model validation study based on a novel experimental technique for inducing anterior wedge-shape fractures in human vertebral bodies in vitro. J Biomech 43:2374–2380. doi: 10.1016/j.jbiomech.2010.04.023 CrossRefPubMedGoogle Scholar
  20. 20.
    Dall’Ara E, Luisier B, Schmidt R, Kainberger F, Zysset P, Pahr D (2013) A nonlinear QCT-based finite element model validation study for the human femur tested in two configurations in vitro. Bone 52:27–38. doi: 10.1016/j.bone.2012.09.006 CrossRefPubMedGoogle Scholar
  21. 21.
    Chung YE, Lee SH, Lee SY, Kim SY, Kim HH, Mirza FS, Lee SK, Lorenzo JA, Kim GS, Koh JM (2012) Long-term treatment with raloxifene, but not bisphosphonates, reduces circulating sclerostin levels in postmenopausal women. Osteoporos Int 23:1235–1243. doi: 10.1007/s00198-011-1675-1 CrossRefPubMedGoogle Scholar
  22. 22.
    Polyzos SA, Anastasilakis AD, Bratengeier C, Woloszczuk W, Papatheodorou A, Terpos E (2012) Serum sclerostin levels positively correlate with lumbar spinal bone mineral density in postmenopausal women-the six-month effect of risedronate and teriparatide. Osteoporos Int 23:1171–1176. doi: 10.1007/s00198-010-1525-6 CrossRefPubMedGoogle Scholar
  23. 23.
    Ota K, Quint P, Ruan M, Pederson L, Westendorf JJ, Khosla S, Oursler MJ (2013) Sclerostin is expressed in osteoclasts from aged mice and reduces osteoclast-mediated stimulation of mineralization. J Cell Biochem 114:1901–1907. doi: 10.1002/jcb.24537 CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Russel RG, Watts NB, Ebetino FH, Rogers MJ (2008) Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 19:733–759. doi: 10.1007/s00198-007-0540-8 CrossRefGoogle Scholar
  25. 25.
    Gatti D, Viapiana O, Idolazzi L, Fracassi E, Ionescu C, Dartizio C, Troplini S, Kunnathully V, Adami S, Rossini M (2014) Distinct effect of zoledronate and clodronate on circulating levels of DKK1 and sclerostin in women with postmenopausal osteoporosis. Bone 67:189–192. doi: 10.1016/j.bone.2014.06.037 CrossRefPubMedGoogle Scholar
  26. 26.
    Stains JP, Watkins MP, Grimston SK, Hebert C, Civitelli R (2014) Molecular mechanisms of osteoblast/osteocyte regulation by connexin43. Calcif Tissue Int 94:55–67. doi: 10.1007/s00223-013-9742-6 CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Plotkin LI, Bellido T (2013) Beyond gap junctions: connexin43 and bone cell signaling. Bone 52:157–166. doi: 10.1016/j.bone.2012.09.030 CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Bivi N, Nelson MT, Faillace ME, Li J, Miller LM, Plotkin LI (2012) Deletion of Cx43 from osteocytes results in defective bone material properties but does not decrease extrinsic strength in cortical bone. Calcif Tissue Int 91:215–224. doi: 10.1007/s00223-012-9628-z CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Bellido T, Plotkin LI (2011) Novel actions of bisphosphonates in bone: preservation of osteoblast and osteocyte viability. Bone 49:50–55. doi: 10.1016/j.bone.2010.08.008 CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Maruotti N, Corrado A, Neve A, Cantatore FP (2012) Bisphosphonates: effects on osteoblast. Eur J Clin Pharmacol 68:1013–1018. doi: 10.1007/s00228-012-1216-7 CrossRefPubMedGoogle Scholar
  31. 31.
    Sapir-Koren R, Livshits G (2014) Osteocyte control of bone remodeling: is sclerostin a key molecular coordinator of the balanced bone resorption-formation cycles? Osteoporos Int 25:2685–2700. doi: 10.1007/s00198-014-2808-0 CrossRefPubMedGoogle Scholar
  32. 32.
    Li X, Grisanti M, Fan W, Asuncion FJ, Tan HL, Dwyer D et al (2011) Dickkopf-1 regulates bone formation in young growing rodents and upon traumatic injury. J Bone Miner Res 26:2610–2621. doi: 10.1002/jbmr.472 CrossRefPubMedGoogle Scholar
  33. 33.
    Muschitz C, Kocijan R, Fahrleitner-Pammer A, Pavo I, Haschka J, Schima W, Kapiotis S, Resch H (2014) Overlapping and continued alendronate or raloxifene administration in patients on teriparatide: effects on areal and volumetric bone mineral density—the CONFORS Study. J Bone Miner Res 29:1777–1785. doi: 10.1002/jbmr.2216 CrossRefPubMedGoogle Scholar
  34. 34.
    Genant HK, Lewiecki EM, Fuerst T, Fries M (2012) Effect of monthly ibandronate on hip structural geometry in men with low bone density. Osteoporos Int 23:257–265. doi: 10.1007/s00198-011-1732-9 CrossRefPubMedGoogle Scholar
  35. 35.
    Orwoll ES, Binkley NC, Lewiecki EM, Gruntmanis U, Fries MA, Dasic G (2010) Efficacy and safety of monthly ibandronate in men with low bone density. Bone 46:970–976. doi: 10.1016/j.bone.2009.12.034 CrossRefPubMedGoogle Scholar
  36. 36.
    Fahrleitner-Pammer A, Piswanger-Soelkner JC, Pieber TR, Obermayer-Pietsch BM, Pilz S, Dimai HP, Prenner G, Tscheliessnigg KH, Hauge E, Portugaller RH, Dobnig H (2009) Ibandronate prevents bone loss and reduces vertebral fracture risk in male cardiac transplant patients: a randomized double-blind, placebo-controlled trial. J Bone Miner Res 24(7):1335–1344. doi: 10.1359/jbmr.090216 CrossRefPubMedGoogle Scholar
  37. 37.
    Ringe JD, Faber H, Dorst A (2001) Alendronate treatment of established primary osteoporosis in men: results of a 2-year prospective study. J Clin Endocrinol Metab 86:5252–5255. doi: 10.1210/jcem.86.11.7988 CrossRefPubMedGoogle Scholar
  38. 38.
    Orwoll ES, Miller PD, Adachi JD, Brown J, Adler RA, Kendler D, Bucci-Rechtweg C, Readie A, Mesenbrink P, Weinstein RS (2010) Efficacy and safety of a once-yearly i.v. Infusion of zoledronic acid 5 mg versus a once-weekly 70-mg oral alendronate in the treatment of male osteoporosis: a randomized, multicenter, double-blind, active-controlled study. J Bone Miner Res 25:2239–2250. doi: 10.1002/jbmr.119 CrossRefPubMedGoogle Scholar
  39. 39.
    Keaveny TM, McClung MR, Genant HK, Zanchetta JR, Kendler D, Brown JP et al (2014) Femoral and vertebral strength improvements in postmenopausal women with osteoporosis treated with denosumab. J Bone Miner Res 29:158–165. doi: 10.1002/jbmr.2024 CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    Amrein K, Amrein S, Drexler C, Dimai HP, Dobnig H, Pfeifer K, Fahrleitner-Pammer A (2012) Sclerostin and its association with physical activity, age, gender, body composition, and bone mineral content in healthy adults. J Clin Endocrinol Metab 97:148–154. doi: 10.1210/jc.2011-2152 CrossRefPubMedGoogle Scholar
  41. 41.
    Kocijan R, Muschitz C, Fahrleitner-Pammer A, Amrein K, Pietschmann P, Haschka J, Dinu S, Kapiotis S, Resch H (2014) Serum sclerostin levels are decreased in adult patients with different types of osteogenesis imperfecta. J Clin Endocrinol Metab 99:E311–E319. doi: 10.1210/jc.2013-2244 CrossRefPubMedGoogle Scholar
  42. 42.
    Szulc P, Boutroy S, Vilayphiou N, Schoppet M, Rauner M, Chapurlat R, Hamann C, Hofbauer LC (2013) Correlates of bone microarchitectural parameters and serum sclerostin levels in men: the STRAMBO study. J Bone Miner Res 28(8):1760–1770. doi: 10.1002/jbmr.1888 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Christian Muschitz
    • 1
    Email author
  • Roland Kocijan
    • 1
  • Dieter Pahr
    • 2
  • Janina M. Patsch
    • 3
  • Karin Amrein
    • 4
  • Barbara M. Misof
    • 5
  • Alexandra Kaider
    • 6
  • Heinrich Resch
    • 1
  • Peter Pietschmann
    • 7
  1. 1.Medical Department II, St. Vincent HospitalAcademic Teaching Hospital of the Medical University of ViennaViennaAustria
  2. 2.Institute of Lightweight Design and Structural BiomechanicsUniversity of TechnologyViennaAustria
  3. 3.Department of Diagnostic RadiologyMedical University of ViennaViennaAustria
  4. 4.Division of Endocrinology and Metabolism, Department of Internal MedicineMedical University of GrazGrazAustria
  5. 5.Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Medical DepartmentHanusch HospitalViennaAustria
  6. 6.Center for Medical Statistics, Informatics and Intelligent SystemsMedical University of ViennaViennaAustria
  7. 7.Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and ImmunologyMedical University of ViennaViennaAustria

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