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Bone tissue quality in patients with monoclonal gammopathy of uncertain significance

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Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Introduction

Monoclonal gammopathy of uncertain significance (MGUS) is highly prevalent in older adults and affects bone structure, with osteoporosis and increased risk of fractures in up to 14% of affected patients. Dual-energy X-ray absorptiometry (DXA), the standard technique for diagnosing osteoporosis, is ineffective to reveal microstructure and bone quality in this disease.

Materials and methods

We conducted a cross-sectional study of patients with MGUS, recruited consecutively from the Hematology and Internal Medicine Departments of Hospital del Mar, Barcelona, between January 2011 and January 2018. Medical records, clinical results and spinal X-ray images were collected. Bone mineral density (BMD) at hip and spine was measured by DXA and Bone Material Strength index (BMSi) by impact microindentation on the tibial mid-shaft.

Results

Thirty-nine patients with MGUS and 65 age-matched controls without previous fractures were included. In the MGUS group, 11 (28.2%) patients had prevalent fractures, nearly half of them vertebral (n = 5, 45.45%). Compared to controls, MGUS patients had significantly lower BMSi, a mean (SD) of 70.72 (9.70) vs. 78.29 (8.70), p = 0.001, and lower spinal BMD values (0.900 [0.159] vs. 1.003 [0.168], respectively, p = 0.012), but no significant differences at femoral neck and total hip. No association was observed between BMSi and DXA. Bone remodeling markers (procollagen type-1 N propeptide, bone-alkaline phosphatase and C-terminal telopeptide of type I collagen) did not differ between the two groups.

Conclusions

Spinal BMD and mechanical properties of bone tissue, as measured by impact microindentation, were impaired in patients with MGUS. These changes in bone tissue mechanical resistance were independent of DXA levels.

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References

  1. Therneau TM, Kyle RA, Melton LJ 3rd, Larson DR, Benson JT, Colby CL, Dispenzieri A, Kumar S, Katzmann JA, Cerhan JR, Rajkumar SV (2012) Incidence of monoclonal gammopathy of undetermined significance and estimation of duration before first clinical recognition. Mayo Clin Proc 87:1071–1079

    PubMed  PubMed Central  Google Scholar 

  2. Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, Dispenzieri A, Katzmann JA, Melton LJ 3rd (2006) Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 354:1362–1369

    CAS  Google Scholar 

  3. Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G et al (2014) International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 15:e538–e548

    Google Scholar 

  4. Drake MT (2014) Unveiling skeletal fragility in patients diagnosed with MGUS: no longer a condition of undetermined significance? J Bone Miner Res 29:2529–2533

    PubMed  PubMed Central  Google Scholar 

  5. Golombick T, Diamond T (2008) Prevalence of monoclonal gammopathy of undetermined significance/myeloma in patients with acute osteoporotic vertebral fractures. Acta Haematol 120:87–90

    PubMed  Google Scholar 

  6. Kristinsson SY, Tang M, Pfeiffer RM, Björkholm M, Blimark C, Mellqvist UH, Wahlin A, Turesson I, Landgren O (2010) Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: a population-based study. Blood 116:2651–2655

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Melton Iii LJ, Rajkumar SV, Khosla S, Achenbach SJ, Oberg AL, Kyle RA (2004) Fracture risk in monoclonal gammopathy of undetermined significance. J Bone Min Res 19:25–30

    Google Scholar 

  8. Pepe J, Petrucci MT, Nofroni I, Fassino V, Diacinti D, Romagnoli E, Minisola S (2006) Lumbar bone mineral density as the major factor determining increased prevalence of vertebral fractures in monoclonal gammopathy of undetermined significance. Br J Haematol 134:485–490

    Google Scholar 

  9. Veronese N, Luchini C, Solmi M, Sergi G, Manzato E, Stubbs B (2018) Monoclonal gammopathy of undetermined significance and bone health outcomes: a systematic review and exploratory meta-analysis. J Bone Miner Metab 36:128–132

    PubMed  Google Scholar 

  10. Bataille R, Chappard D, Basle MF (1996) Quantifiable excess of bone resorption in monoclonal gammopathy is an early symptom of malignancy: a prospective study of 87 bone biopsies. Blood 87:4762–4769

    CAS  PubMed  Google Scholar 

  11. Spaan I, Raymakers RA, Stolpe A, Peperzak V (2018) Wnt signaling in multiple myeloma: a central player in disease with therapeutic potential. J Hematol Oncol 11:67

    PubMed  PubMed Central  Google Scholar 

  12. Roussou MT, Dimopoulos A, Kastritis MA, Migkou E, Christoulas M, Gavriatopoulou D, Zagouri F, Matsouka C, Anagnostou D, Terpos E (2009) Increased expression of macrophage inflammatory protein-1α on trephine biopsies correlates with extensive bone disease, increased angiogenesis and advanced stage in newly diagnosed patients with multiple myeloma. Leukemia 23:2177–2181

    CAS  PubMed  Google Scholar 

  13. Ng AC, Khosla S, Charatcharoenwitthaya N, Kumar SK, Achenbach SJ, Holets MF, McCready LK, Melton LJ III, Kyle RA, Rajkumar SV, Drake MT (2011) Bone microstructural changes revealed by HRpQCT imaging and elevated DKK1 and MIP-1α levels in patients with monoclonal gammopathy of undetermined significance. Blood 118:6529–6534

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Beck TJ, Looker AC, Ruff CB, Sievanen H, Wahner HW (2000) Structural trends in the aging femoral neck and proximal shaft: analysis of the third national health and nutrition examination survey dual-energy X-ray absorptiometry data. J Bone Miner Res 15:2297–2304

    CAS  PubMed  Google Scholar 

  15. Stone KL, Seeley DG, Lui LY, Cauley JA, Ensrud K, Browner WS, Nevitt MC, Cummings SR (2003) Osteoporotic Fractures Research Group. BMD at multiple sites and risk of fracture of multiple types: long-term. J Bone Min Res 18:1947–1954

    Google Scholar 

  16. Bolotin HH (2007) DXA in vivo BMD methodology: an erroneous and misleading research and clinical gauge of bone mineral status, bone fragility, and bone remodelling. Bone 41:138–154

    CAS  Google Scholar 

  17. Piot JM, Royer M, Schmidt-Tanguy A, Hoppé E, Gardembas M, Bourrée T, Hunault M, François S, Boyer F, Ifrah N, Renier G, Chevailler A, Audran M, Chappard D, Libouban H, Mabilleau G, Legrand E, Bouvard B (2015) Factors associated with an increased risk of vertebral fracture in monoclonal gammopathies of undetermined significance. Blood Cancer J 5:e345

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Farr JN, Zhang W, Kumar SK, Jacques RM, Ng AC, McCready LK, Rajkumar SV, Drake MT (2014) Altered cortical microarchitecture in patients with monoclonal gammopathy of undetermined significance. Blood 123:647–649

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Stein EM, Dash A, Bucovsky M, Agarwal S, Fu J, Lentzsch S, Shane E (2019) Disrupted radial and tibial microarchitecture in patients with monoclonal gammopathy of undetermined significance. Osteoporos Int 30:629–635

    CAS  PubMed  Google Scholar 

  20. Diez-Perez A, Güerri R, Nogues X, Cáceres E, Peña MJ, Mellibovsky L, Randall C, Bridges D, Weaver JC, Proctor A, Brimer D, Koester KJ, Ritchie RO, Hansma PK (2010) Microindentation for in vivo measurement of bone tissue mechanical properties in humans. J Bone Miner Res 25:1877–1885

    PubMed  PubMed Central  Google Scholar 

  21. Mellibovsky L, Prieto-Alhambra D, Mellibovsky F, Güerri-Fernández R, Nogués X, Randall C, Hansma PK, Díez-Pérez A (2015) Bone tissue properties measurement by reference point indentation in glucocorticoid-induced osteoporosis. J Bone Miner Res 30:1651–1656

    CAS  PubMed  Google Scholar 

  22. Farr JN, Drake MT, Amin S, Melton LJ 3rd, McCready LK, Khosla S (2014) In vivo assessment of bone quality in postmenopausal women with type 2 diabetes. J Bone Miner Res 29:787–795

    PubMed  PubMed Central  Google Scholar 

  23. Herrera S, Pérez-López J, Moltó-Abad M, Güerri-Fernández R, Cabezudo E, Novelli S, Esteve J, Hernández A, Roig I, Solanich X, Prieto-Alhambra D, Nogués X, Díez-Pérez A (2017) Assessment of bone health in patients with type 1 Gaucher disease using impact microindentation. J Bone Miner Res 32:1575–1581

    CAS  PubMed  Google Scholar 

  24. Güerri-Fernández R, Molina D, Villar-García J, Prieto-Alhambra D, Mellibovsky L, Nogués X, González-Mena A, Guelar A, Trenchs-Rodríguez M, Herrera-Fernández S, Horcajada JP, Díez-Pérez A, Knobel H (2016) Brief report: HIV infection is associated with worse bone material properties, independently of bone mineral density. J Acquir Immune Defic Syndr 72:314–318

    PubMed  Google Scholar 

  25. Güerri-Fernández RC, Nogués X, Quesada Gómez JM, Torres Del Pliego E, Puig L, García-Giralt N, Yoskovitz G, Mellibovsky L, Hansma PK, Díez-Pérez A (2013) Microindentation for in vivo measurement of bone tissue material properties in atypical femoral fracture patients and controls. J Bone Miner Res 28:162–168

    PubMed  Google Scholar 

  26. Malgo F, Hamdy NAT, Rabelink TJ, Kroon HM, Claessen KMJA, Pereira AM, Biermasz NR, Appelman-Dijkstra NM (2017) Bone material strength index as measured by impact microindentation is altered in patients with acromegaly. Eur J Endocrinol 176:339–434

    CAS  PubMed  Google Scholar 

  27. Go RS, Rajkumar SV (2018) How I manage monoclonal gammopathy of undetermined significance. Blood 131:163–173

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Diez-Perez A, Bouxsein ML, Eriksen EF, Khosla S, Nyman JS, Papapoulos S, Tang SY (2016) Technical note: Recommendations for a standard procedure to assess cortical bone at the tissue-level in vivo using impact microindentation. Bone Rep 5:181–185

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Rosnow RL, Rosenthal R (1993) Computing contrasts, effect sizes, and counternulls on other people’s published data: general procedures for research consumers. Psychol Methods 1:331–340

    Google Scholar 

  30. Finner H (1993) On a monotonicity problem in step-down multiple test procedures. J Am Stat Assoc 88:920–923

    Google Scholar 

  31. Nyman JS, Granke M, Singleton RC, Pharr GM (2016) Tissue-level mechanical properties of bone contributing to fracture risk. Curr Osteoporos Rep 14:138–150

    PubMed  PubMed Central  Google Scholar 

  32. Uppuganti S, Granke M, Manhard MK, Does MD, Perrien DS, Lee DH, Nyman JS (2017) Differences in sensitivity to microstructure between cyclic- and impact-based microindentation of human cortical bone. J Orthop Res 35:1442–1452

    PubMed  Google Scholar 

  33. Berenson JR, Anderson KC, Audell RA, Boccia RV, Coleman M et al (2010) Monoclonal gammopathy of undetermined significance: a consensus statement: Guideline. Br J of Haematol 150:28–38

    Google Scholar 

  34. Ng AC, Kumar SK, Rajkumar SV, Drake MT (2009) Impact of vitamin D deficiency on the clinical presentation and prognosis of patients with newly diagnosed multiple myelom. Am J Hematol 84:397–400

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Burwick NN (2017) Vitamin D and plasma cell dyscrasias: reviewing the significance. Ann Hematol 96:1271–1277

    CAS  PubMed  Google Scholar 

  36. Vasikaran S, Eastell R, Bruyère O, Foldes AJ, Garnero P, Griesmacher A, McClung M, Morris HA, Silverman S, Trenti T, Wahl DA, Cooper C, Kanis JA (2011) Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int 22:391–420

    CAS  Google Scholar 

  37. Gregersen H, Jensen P, Gislum M, Jørgensen B, Sørensen HT, Nørgaard M (2006) Fracture risk in patients with monoclonal gammopathy of undetermined significance. Br J Haematol 135:62–67

    PubMed  Google Scholar 

  38. Nilsson AG, Sundh D, Johansson L, Nilsson M, Mellström D, Rudäng R, Zoulakis M, Wallander M, Darelid A, Lorentzon M (2017) Type 2 diabetes mellitus is associated with better bone microarchitecture but lower bone material strength and poorer physical function in elderly women: a population-based study. J Bone Miner Res 32:1062–1071

    PubMed  Google Scholar 

  39. Furst JR, Bandeira LC, Fan WW, Agarwal S, Nishiyama KK, McMahon DJ, Dworakowski E, Jiang H, Silverberg SJ, Rubin MR (2016) Advanced glycation end products and bone material strength in type 2 diabetes. J Clin Endocrinol Metab 101:2502–2510

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Popp KL, Caksa S, Martinez-Betancourt A, Yuan A, Tsai J, Yu EW, Bouxsein ML (2019) Cortical bone material strength index and bone microarchitecture in postmenopausal women with atypical femoral fractures. J Bone Miner Res 34:75–82

    CAS  PubMed  Google Scholar 

  41. Lloyd AA, Gludovatz B, Riedel C, Luengo EA, Saiyed R, Marty E, Lorichd DG, Laned JM, Ritchieg RO, Busse B, Donnelly E (2017) Atypical fracture with long-term bisphosphonate therapy is associated with altered cortical composition and reduced fracture resistance. Proc Natl Acad Sci 114:8722–8727

    CAS  PubMed  Google Scholar 

  42. Nogués X, Prieto-Alhambra D, Güerri-Fernández R, Garcia-Giralt N, Rodriguez-Morera J, Cos L, Mellibovsky L, Díez Pérez A (2017) Fracture during oral bisphosphonate therapy is associated with deteriorated bone material strength index. Bone 103:64–69

    PubMed  Google Scholar 

  43. Rozental TD, Walley KC, Demissie S, Caksa S, Martinez-Betancourt A, Parker AM, Tsai JN, Yu EW, Bouxsein ML (2018) Bone material strength index as measured by impact microindentation in postmenopausal women with distal radius and hip fractures. J Bone Miner Res 33:621–626

    PubMed  Google Scholar 

  44. Sosa DD, Eriksen EF (2017) Reduced bone material strength is associated with increased risk and severity of osteoporotic fractures. an impact microindentation study. Calcif Tissue Int 101:34–42

    CAS  PubMed  Google Scholar 

  45. Malgo F, Hamdy NAT, Papapoulos SE, Appelman-Dijkstra NM (2015) Bone material strength as measured by microindentation in vivo is decreased in patients with fragility fractures independently of bone mineral density. J Clin Endocrinol Metab 100:2039–2045

    CAS  PubMed  Google Scholar 

  46. Malgo F, Hamdy NAT, Papapoulos SE, Appelman-Dijkstra NM (2017) Bone material strength index as measured by impact microindentation is low in patients with fractures irrespective of fracture site. Osteoporos Int 28:2433–2437

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Rudäng R, Zoulakis M, Sundh D, Brisby H, Diez-Perez A, Johansson L, Mellström D, Darelid A, Lorentzon M (2016) Bone material strength is associated with areal BMD but not with prevalent fractures in older women. Osteoporos Int 27:1585–1592

    PubMed  Google Scholar 

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Acknowledgements

We would like to thank Natalia Garcia Giralt, MD, PhD, for her valuable help in the laboratory measurements; Elaine Lilly, PhD, and Valentina Ferreira-Orduna for English language revision. The research leading to these results has been sponsored in part by CIBERFES, Instituto Carlos III, Spanish Ministry of Science, Innovation and Universities and FEDER funds.

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Authors and Affiliations

  1. Department of Internal Medicine, Musculoskeletal Research Group, Hospital del Mar-IMIM, Department of Medicine, Autonomous University of Barcelona and CIBERFES, Instituto Carlos III, Barcelona, Spain

    Guillermina Orduna, Leonardo Mellibovsky, Xavier Nogués, Natalia García-Giralt, Marta Pineda-Moncusí, Roberto Güerri-Fernández & Adolfo Díez-Pérez

  2. Department of Hematology, Hospital del Mar, Barcelona, Spain

    Eugenia Abella

  3. Department of Psychobiology and Methodology, Autonomous University of Barcelona, Barcelona, Spain

    Roser Granero

  4. Oxford NIHR Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, United Kingdom, and CIBERFES, Instituto Carlos III, Barcelona, Spain

    Daniel Prieto-Alhambra

Authors
  1. Guillermina Orduna
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  2. Leonardo Mellibovsky
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  3. Eugenia Abella
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  4. Xavier Nogués
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  5. Roser Granero
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  6. Natalia García-Giralt
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  7. Marta Pineda-Moncusí
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  9. Daniel Prieto-Alhambra
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  10. Adolfo Díez-Pérez
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Contributions

Study design: LM and GO. Study contact: GO and XN. Study conduct: GO, LM, XN and ADP. Data collection: EA, LM and GO. Data analysis: RG, MP, DPA, GO and ADP. Data interpretation: ADP, GO, LM and XN. Drafting manuscript: GO, LM, XN and ADP. Revising manuscript content: All authors. Approving final manuscript: All authors.

Corresponding author

Correspondence to Xavier Nogués.

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Conflict of interest

ADP—Board Membership: UCB, Roche, EchoLight. Payment for lectures: Lilly, UCB, Roche, Gilead. Stocks/stock options: Active Life Sci. XN. Advisory board Amgen, Lilly. Educational talks: Amgen, Lilly, Italfarmaco, FAES. DPA—Department has received research grants from Amgen, UCB. Educational grants: J&J. His research group has received payment for speaker and consultancy services from Amgen and UCB.

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Orduna, G., Mellibovsky, L., Abella, E. et al. Bone tissue quality in patients with monoclonal gammopathy of uncertain significance. J Bone Miner Metab 38, 563–569 (2020). https://doi.org/10.1007/s00774-020-01084-3

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  • DOI: https://doi.org/10.1007/s00774-020-01084-3

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