Osteoporosis International

, Volume 30, Issue 3, pp 629–635 | Cite as

Disrupted radial and tibial microarchitecture in patients with monoclonal gammopathy of undetermined significance

  • E.M. SteinEmail author
  • A. Dash
  • M. Bucovsky
  • S. Agarwal
  • J. Fu
  • S. Lentzsch
  • E. Shane
Original Article



Patients with monoclonal gammopathy of undetermined significance (MGUS) had abnormalities in volumetric BMD (vBMD), microarchitecture, and stiffness at both the radius and tibia by high-resolution peripheral quantitative CT compared to matched controls. This is the first report demonstrating that patients with MGUS have microarchitectural deficits at multiple skeletal sites.


Fracture risk is elevated in patients with monoclonal gammopathy of undetermined significance (MGUS). However, the pathogenesis of bone disease in these patients is poorly understood. Prior work using high-resolution peripheral CT (HRpQCT) demonstrated abnormal microarchitecture at the radius, with predominantly cortical abnormalities. We hypothesized that patients with MGUS have abnormal microarchitecture at both radius and tibia compared to controls, reflecting global skeletal effects of the disease.


This case-control study enrolled 36 subjects; patients with MGUS (n = 12) were matched 1:2 by age, sex, and race to controls (n = 24). Areal BMD (aBMD) was measured by DXA, vBMD, and microarchitecture by HRpQCT, and whole bone stiffness by finite element analysis. Serum was drawn for markers of bone metabolism and inflammation.


By DXA, MGUS patients had lower aBMD at the lumbar spine, femoral neck, and 1/3 radius. Markers of bone metabolism and inflammation did not differ. By HRpQCT at the radius, MGUS patients had lower total, trabecular and cortical density, lower trabecular number, and greater trabecular separation and heterogeneity. At the tibia, MGUS patients had lower total and trabecular density, lower trabecular number, greater separation and heterogeneity, and lower whole bone stiffness.


Patients with MGUS had lower vBMD, cortical, and trabecular abnormalities at the radius compared to matched controls. At the tibia, trabecular abnormalities predominated. These results suggest that in addition to previously described cortical deficits, deterioration of trabecular bone may contribute to a generalized skeletal fragility in patients with MGUS.


Bone quality Microarchitecture Monoclonal gammopathy of undetermined significance Osteoporosis 


Funding information

This work was supported by NIH K23 DK084337 (Stein), NIH U01 AR055968 (Shane), and a gift from the Linden Trust.

Compliance with ethical standards

Conflict of interest

Emily Stein, Alexander Dash, Sanchita Agarwal, Mariana Bucovsky, Jing Fu, Elizabeth Lentzsch, and Elizabeth Shane declare that they have no conflict of interest. Dr. Lentzsch is chief scientific advisor and shareholder of Caelum Biosciences and advisor for Janssen, Bayer, and Karyopharm.


  1. 1.
    Melton LJ 3rd, Rajkumar SV, Khosla S, Achenbach SJ, Oberg AL, Kyle RA (2004) Fracture risk in monoclonal gammopathy of undetermined significance. J Bone Miner Res 19(1):25–30. CrossRefGoogle Scholar
  2. 2.
    Gregersen H, Jensen P, Gislum M, Jorgensen B, Sorensen HT, Norgaard M (2006) Fracture risk in patients with monoclonal gammopathy of undetermined significance. Br J Haematol 135(1):62–67. CrossRefGoogle Scholar
  3. 3.
    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(1):128–132. CrossRefGoogle Scholar
  4. 4.
    Berenson JR, Anderson KC, Audell RA, Boccia RV, Coleman M, Dimopoulos MA, Drake MT, Fonseca R, Harousseau JL, Joshua D, Lonial S, Niesvizky R, Palumbo A, Roodman GD, San-Miguel JF, Singhal S, Weber DM, Zangari M, Wirtschafter E, Yellin O, Kyle RA (2010) Monoclonal gammopathy of undetermined significance: a consensus statement. Br J Haematol 150(1):28–38. Google Scholar
  5. 5.
    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(11):1071–1079. CrossRefGoogle Scholar
  6. 6.
    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(13):1362–1369. CrossRefGoogle Scholar
  7. 7.
    Golombick T, Diamond T (2008) Prevalence of monoclonal gammopathy of undetermined significance/myeloma in patients with acute osteoporotic vertebral fractures. Acta Haematol 120(2):87–90. CrossRefGoogle Scholar
  8. 8.
    Bouvard B, Royer M, Chappard D, Audran M, Hoppe E, Legrand E (2010) Monoclonal gammopathy of undetermined significance, multiple myeloma, and osteoporosis. Joint Bone Spine 77(2):120–124. CrossRefGoogle Scholar
  9. 9.
    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(5):647–649. CrossRefGoogle Scholar
  10. 10.
    Ng AC, Khosla S, Charatcharoenwitthaya N, Kumar SK, Achenbach SJ, Holets MF, McCready LK, Melton LJ 3rd, Kyle RA, Rajkumar SV, Drake MT (2011) Bone microstructural changes revealed by high-resolution peripheral quantitative computed tomography imaging and elevated DKK1 and MIP-1alpha levels in patients with MGUS. Blood 118(25):6529–6534. CrossRefGoogle Scholar
  11. 11.
    Stein EM, Liu XS, Nickolas TL, Cohen A, Thomas V, McMahon DJ, Zhang C, Yin PT, Cosman F, Nieves J, Guo XE, Shane E (2010) Abnormal microarchitecture and reduced stiffness at the radius and tibia in postmenopausal women with fractures. J Bone Miner Res 25(12):2572–2581. CrossRefGoogle Scholar
  12. 12.
    Stein EM, Liu XS, Nickolas TL, Cohen A, Thomas V, McMahon DJ, Zhang C, Cosman F, Nieves J, Greisberg J, Guo XE, Shane E (2011) Abnormal microarchitecture and stiffness in postmenopausal women with ankle fractures. J Clin Endocrinol Metab 96(7):2041–2048. CrossRefGoogle Scholar
  13. 13.
    Stein EM, Liu XS, Nickolas TL, Cohen A, McMahon DJ, Zhou B, Zhang C, Kamanda-Kosseh M, Cosman F, Nieves J, Guo XE, Shane E (2012) Microarchitectural abnormalities are more severe in postmenopausal women with vertebral compared to nonvertebral fractures. J Clin Endocrinol Metab 97(10):E1918–E1926. CrossRefGoogle Scholar
  14. 14.
    Stein EM, Silva BC, Boutroy S, Zhou B, Wang J, Udesky J, Zhang C, McMahon DJ, Romano M, Dworakowski E, Costa AG, Cusano N, Irani D, Cremers S, Shane E, Guo XE, Bilezikian JP (2013) Primary hyperparathyroidism is associated with abnormal cortical and trabecular microstructure and reduced bone stiffness in postmenopausal women. J Bone Miner Res 28(5):1029–1040. CrossRefGoogle Scholar
  15. 15.
    Stein EM, Kepley A, Walker M, Nickolas TL, Nishiyama K, Zhou B, Liu XS, McMahon DJ, Zhang C, Boutroy S, Cosman F, Nieves J, Guo XE, Shane E (2014) Skeletal structure in postmenopausal women with osteopenia and fractures is characterized by abnormal trabecular plates and cortical thinning. J Bone Miner Res 29(5):1101–1109CrossRefGoogle Scholar
  16. 16.
    Agarwal S, Rosete F, Zhang C, McMahon DJ, Guo XE, Shane E, Nishiyama KK (2016) In vivo assessment of bone structure and estimated bone strength by first- and second-generation HR-pQCT. Osteoporos Int 27(10):2955–2966. CrossRefGoogle Scholar
  17. 17.
    Drake MT (2014) Unveiling skeletal fragility in patients diagnosed with MGUS: no longer a condition of undetermined significance? J Bone Miner Res 29(12):2529–2533. CrossRefGoogle Scholar
  18. 18.
    Terpos E, Dimopoulos MA (2014) Less strength and more fractures for MGUS bones. Blood 123(5):603–604. CrossRefGoogle Scholar
  19. 19.
    Kristinsson SY, Tang M, Pfeiffer RM, Bjorkholm 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(15):2651–2655. CrossRefGoogle Scholar
  20. 20.
    Pecherstorfer M, Seibel MJ, Woitge HW, Horn E, Schuster J, Neuda J, Sagaster P, Kohn H, Bayer P, Thiebaud D, Ludwig H (1997) Bone resorption in multiple myeloma and in monoclonal gammopathy of undetermined significance: quantification by urinary pyridinium cross-links of collagen. Blood 90(9):3743–3750Google Scholar
  21. 21.
    Pepe J, Petrucci MT, Mascia ML, Piemonte S, Fassino V, Romagnoli E, Minisola S (2008) The effects of alendronate treatment in osteoporotic patients affected by monoclonal gammopathy of undetermined significance. Calcif Tissue Int 82(6):418–426. CrossRefGoogle Scholar
  22. 22.
    Diamond T, Levy S, Smith A, Day P, Manoharan A (2001) Non-invasive markers of bone turnover and plasma cytokines differ in osteoporotic patients with multiple myeloma and monoclonal gammopathies of undetermined significance. Intern Med J 31(5):272–278CrossRefGoogle Scholar
  23. 23.
    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(5):485–490. CrossRefGoogle Scholar
  24. 24.
    Politou M, Terpos E, Anagnostopoulos A, Szydlo R, Laffan M, Layton M, Apperley JF, Dimopoulos MA, Rahemtulla A (2004) Role of receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin and macrophage protein 1-alpha (MIP-1a) in monoclonal gammopathy of undetermined significance (MGUS). Br J Haematol 126(5):686–689. CrossRefGoogle Scholar
  25. 25.
    Lentzsch S, Gries M, Janz M, Bargou R, Dorken B, Mapara MY (2003) Macrophage inflammatory protein 1-alpha (MIP-1 alpha ) triggers migration and signaling cascades mediating survival and proliferation in multiple myeloma (MM) cells. Blood 101(9):3568–3573. CrossRefGoogle Scholar
  26. 26.
    Fu J, Li S, Feng R, Ma H, Sabeh F, Roodman GD, Wang J, Robinson S, Guo XE, Lund T, Normolle D, Mapara MY, Weiss SJ, Lentzsch S (2016) Multiple myeloma-derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease. J Clin Invest 126(5):1759–1772. CrossRefGoogle Scholar
  27. 27.
    Jakob C, Zavrski I, Heider U, Brux B, Eucker J, Langelotz C, Sinha P, Possinger K, Sezer O (2002) Bone resorption parameters [carboxy-terminal telopeptide of type-I collagen (ICTP), amino-terminal collagen type-I telopeptide (NTx), and deoxypyridinoline (Dpd)] in MGUS and multiple myeloma. Eur J Haematol 69(1):37–42CrossRefGoogle Scholar
  28. 28.
    Pecoraro V, Roli L, Germagnoli L, Banfi G (2015) The prognostic role of bone turnover markers in multiple myeloma patients: the impact of their assay. A systematic review and meta-analysis. Crit Rev Oncol Hematol 96(1):54–66. CrossRefGoogle Scholar
  29. 29.
    Fonseca R, Trendle MC, Leong T, Kyle RA, Oken MM, Kay NE, Van Ness B, Greipp PR (2000) Prognostic value of serum markers of bone metabolism in untreated multiple myeloma patients. Br J Haematol 109(1):24–29CrossRefGoogle Scholar
  30. 30.
    Nishi Y, Atley L, Eyre DE, Edelson JG, Superti-Furga A, Yasuda T, Desnick RJ, Gelb BD (1999) Determination of bone markers in pycnodysostosis: effects of cathepsin K deficiency on bone matrix degradation. J Bone Miner Res 14(11):1902–1908. CrossRefGoogle Scholar
  31. 31.
    Delgado-Calle J, Sato AY, Bellido T (2017) Role and mechanism of action of sclerostin in bone. Bone 96:29–37. CrossRefGoogle Scholar
  32. 32.
    Kristensen IB, Christensen JH, Lyng MB, Moller MB, Pedersen L, Rasmussen LM, Ditzel HJ, Abildgaard N (2014) Expression of osteoblast and osteoclast regulatory genes in the bone marrow microenvironment in multiple myeloma: only up-regulation of Wnt inhibitors SFRP3 and DKK1 is associated with lytic bone disease. Leuk Lymphoma 55(4):911–919. CrossRefGoogle Scholar
  33. 33.
    Heider U, Kaiser M, Mieth M, Lamottke B, Rademacher J, Jakob C, Braendle E, Stover D, Sezer O (2009) Serum concentrations of DKK-1 decrease in patients with multiple myeloma responding to anti-myeloma treatment. Eur J Haematol 82(1):31–38. CrossRefGoogle Scholar
  34. 34.
    Kaiser M, Mieth M, Liebisch P, Oberlander R, Rademacher J, Jakob C, Kleeberg L, Fleissner C, Braendle E, Peters M, Stover D, Sezer O, Heider U (2008) Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma. Eur J Haematol 80(6):490–494. CrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2018

Authors and Affiliations

  • E.M. Stein
    • 1
    Email author
  • A. Dash
    • 1
  • M. Bucovsky
    • 2
  • S. Agarwal
    • 2
  • J. Fu
    • 3
  • S. Lentzsch
    • 3
  • E. Shane
    • 2
  1. 1.Endocrinology and Metabolic Bone Disease ServiceHospital for Special SurgeryNew YorkUSA
  2. 2.Division of EndocrinologyColumbia University College of Physicians and SurgeonsNew YorkUSA
  3. 3.Multiple Myeloma and Amyloidosis ServiceColumbia University College of Physicians and SurgeonsNew YorkUSA

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