Thromb Haemost 2022; 122(05): 692-702
DOI: 10.1055/s-0041-1735964
Coagulation and Fibrinolysis

The Bone Microarchitecture Deficit in Patients with Hemophilia Is Influenced by Arthropathy, Hepatitis C Infection, and Physical Activity

Katharina Holstein*
1   Department of Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
Leonora Witt*
1   Department of Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
Anna Matysiak
1   Department of Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
Constantin Schmidt
2   Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
3   Department of Trauma and Orthopaedic Surgery, Division of Orthopaedics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
Florian Barvencik
2   Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
Michael Amling
2   Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
Tim Rolvien*
3   Department of Trauma and Orthopaedic Surgery, Division of Orthopaedics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
Florian Langer*
1   Department of Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
› Institutsangaben

Abstract

Low bone mineral density (BMD) is common in patients with hemophilia (PWHs). The aim of the present study was to describe BMD and microarchitecture in PWHs in Northern Germany and to determine factors contributing to possible skeletal alterations. Demographic characteristics, BMD and microarchitecture, bone metabolism markers, and orthopaedic joint score (OJS) were assessed during routine check-ups. Areal BMD was assessed by dual-energy X-ray absorptiometry (DXA) at the hip and lumbar spine. Volumetric BMD and microarchitecture were quantified by high-resolution peripheral quantitative computed tomography at the distal radius and tibia. Eighty male PWHs (median age, 33 years; range, 18–77) were retrospectively analyzed, of whom 67 (84.0%) and 13 (16.0%) had hemophilia A and B, respectively. Fifty-four (68.0%), six (7.0%), and 20 (25.0%) patients had severe, moderate, or mild hemophilia, and 35 (44.0%) were hepatitis C virus (HCV) positive. DXA analysis revealed low BMD (Z-score ≤ − 2.0) in 27.5% of PWHs, and higher bone turnover values were associated with lower BMD. Bone microarchitecture was dominated by cortical deficits at the radius and trabecular deficits at the tibia. Cortical deficits at the radius were influenced by lower body mass index, low-grade inflammation, and treatment regimen (higher cortical thickness on primary prophylaxis). Trabecular alterations at the tibia were mainly associated with OJS and HCV status. A positive effect of self-reported sportive activity on BMD could be shown. In conclusion, our findings demonstrate that the site-specific microarchitectural deficit observed in PWHs is primarily negatively influenced by poor joint status, inflammation, HCV infection, and high bone turnover.

Author Contributions

K.H., L.W., M.A., F.B., and F.L. designed the study; K.H., L.W., A.M., and C.S. enrolled patients and collected data; K.H., L.W., and T.R. analyzed the data and wrote the first draft of the manuscript; all authors contributed to data interpretation, manuscript writing, and approved the final version of the manuscript.


* These authors contributed equally to this study.


Supplementary Material



Publikationsverlauf

Eingereicht: 22. Dezember 2020

Angenommen: 17. August 2021

Artikel online veröffentlicht:
29. September 2021

© 2021. Thieme. All rights reserved.

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Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Iorio A, Fabbriciani G, Marcucci M, Brozzetti M, Filipponi P. Bone mineral density in haemophilia patients. A meta-analysis. Thromb Haemost 2010; 103 (03) 596-603
  • 2 Paschou SA, Anagnostis P, Karras S. et al. Bone mineral density in men and children with haemophilia A and B: a systematic review and meta-analysis. Osteoporos Int 2014; 25 (10) 2399-2407
  • 3 Kempton CL, Antun A, Antoniucci DM. et al. Bone density in haemophilia: a single institutional cross-sectional study. Haemophilia 2014; 20 (01) 121-128
  • 4 Ulivieri FM, Rebagliati GAA, Piodi LP. et al. Usefulness of bone microarchitectural and geometric DXA-derived parameters in haemophilic patients. Haemophilia 2018; 24 (06) 980-987
  • 5 Ekinci O, Demircioglu S, Dogan A, Merter M, Yildiz S, Demir C. Decreased bone mineral density and associated factors in severe haemophilia A patients: a case-control study. Haemophilia 2019; 25 (05) e315-e321
  • 6 Gamal Andrawes N, Hashem Fayek M, Salah El-Din N, Atef Mostafa R. Effect of low-dose factor VIII prophylaxis therapy on bone mineral density and 25(OH) vitamin D level in children with severe haemophilia A. Haemophilia 2020; 26 (02) 325-332
  • 7 Boutroy S, Bouxsein ML, Munoz F, Delmas PD. In vivo assessment of trabecular bone microarchitecture by high-resolution peripheral quantitative computed tomography. J Clin Endocrinol Metab 2005; 90 (12) 6508-6515
  • 8 Zhou B, Wang J, Yu YE. et al. High-resolution peripheral quantitative computed tomography (HR-pQCT) can assess microstructural and biomechanical properties of both human distal radius and tibia: ex vivo computational and experimental validations. Bone 2016; 86: 58-67
  • 9 Lee A, Boyd SK, Kline G, Poon MC. Premature changes in trabecular and cortical microarchitecture result in decreased bone strength in hemophilia. Blood 2015; 125 (13) 2160-2163
  • 10 Liel MS, Greenberg DL, Recht M, Vanek C, Klein RF, Taylor JA. Decreased bone density and bone strength in a mouse model of severe factor VIII deficiency. Br J Haematol 2012; 158 (01) 140-143
  • 11 Recht M, Liel MS, Turner RT, Klein RF, Taylor JA. The bone disease associated with factor VIII deficiency in mice is secondary to increased bone resorption. Haemophilia 2013; 19 (06) 908-912
  • 12 Taves S, Sun J, Livingston EW. et al. Hemophilia A and B mice, but not VWF-/-mice, display bone defects in congenital development and remodeling after injury. Sci Rep 2019; 9 (01) 14428
  • 13 Mackie EJ, Loh LH, Sivagurunathan S. et al. Protease-activated receptors in the musculoskeletal system. Int J Biochem Cell Biol 2008; 40 (6–7): 1169-1184
  • 14 Baud'huin M, Duplomb L, Téletchéa S. et al. Factor VIII-von Willebrand factor complex inhibits osteoclastogenesis and controls cell survival. J Biol Chem 2009; 284 (46) 31704-31713
  • 15 Larson EA, Taylor JA. Factor VIII plays a direct role in osteoblast development. Blood 2017; 130 (Suppl. 01) 3661-3661
  • 16 Melchiorre D, Linari S, Manetti M. et al. Clinical, instrumental, serological and histological findings suggest that hemophilia B may be less severe than hemophilia A. Haematologica 2016; 101 (02) 219-225
  • 17 Gilbert MS. Prophylaxis: musculoskeletal evaluation. Semin Hematol 1993; 30 (3, Suppl 2): 3-6
  • 18 Hannan MT, Felson DT, Anderson JJ, Naimark A. Habitual physical activity is not associated with knee osteoarthritis: the Framingham Study. J Rheumatol 1993; 20 (04) 704-709
  • 19 Milovanovic P, Adamu U, Simon MJ. et al. Age- and sex-specific bone structure patterns portend bone fragility in radii and tibiae in relation to osteodensitometry: a high-resolution peripheral quantitative computed tomography study in 385 individuals. J Gerontol A Biol Sci Med Sci 2015; 70 (10) 1269-1275
  • 20 Macdonald HM, Nishiyama KK, Kang J, Hanley DA, Boyd SK. Age-related patterns of trabecular and cortical bone loss differ between sexes and skeletal sites: a population-based HR-pQCT study. J Bone Miner Res 2011; 26 (01) 50-62
  • 21 Anagnostis P, Vakalopoulou S, Slavakis A. et al. Reduced bone mineral density in patients with haemophilia A and B in Northern Greece. Thromb Haemost 2012; 107 (03) 545-551
  • 22 Dagli M, Kutlucan A, Abusoglu S. et al. Evaluation of bone mineral density (BMD) and indicators of bone turnover in patients with hemophilia. Bosn J Basic Med Sci 2018; 18 (02) 206-210
  • 23 Culha V, Akpinar Tekgündüz S, Yarali HN, Tunç B, Özbek NY. Impact of prophylaxis on bone mineral metabolism in children with hemophilia. J Pediatr Hematol Oncol 2019; 41 (02) 121-123
  • 24 Boutroy S, Khosla S, Sornay-Rendu E. et al. Microarchitecture and peripheral BMD are impaired in postmenopausal white women with fracture independently of total hip t-score: an international multicenter study. J Bone Miner Res 2016; 31 (06) 1158-1166
  • 25 Ashritha A, Delhi Kumar CG, Sahoo J, Nalini P. Evaluation of bone mineral density in children with hemophilia: an observational case-control study. J Pediatr Hematol Oncol 2019; 41 (07) 511-514
  • 26 Albayrak C, Albayrak D. Vitamin D levels in children with severe hemophilia A: an underappreciated deficiency. Blood Coagul Fibrinolysis 2015; 26 (03) 285-289
  • 27 Gerstner G, Damiano ML, Tom A. et al. Prevalence and risk factors associated with decreased bone mineral density in patients with haemophilia. Haemophilia 2009; 15 (02) 559-565
  • 28 Kiper Unal HD, Comert Ozkan M, Atilla FD. et al. Evaluation of bone mineral density and related parameters in patients with haemophilia: a single center cross-sectional study. Am J Blood Res 2017; 7 (05) 59-66
  • 29 Khawaji M, Akesson K, Berntorp E. Long-term prophylaxis in severe haemophilia seems to preserve bone mineral density. Haemophilia 2009; 15 (01) 261-266
  • 30 Khawaji M, Astermark J, Akesson K, Berntorp E. Physical activity for prevention of osteoporosis in patients with severe haemophilia on long-term prophylaxis. Haemophilia 2010; 16 (03) 495-501
  • 31 El-Shamy S. Effect of whole body vibration training on quadriceps strength, bone mineral density, and functional capacity in children with hemophilia: a randomized clinical trial. J Musculoskelet Neuronal Interact 2017; 17 (02) 19-26
  • 32 Sossa Melo CL, Wandurraga EA, Peña AM. et al. Low bone mineral density and associated factors in patients with haemophilia in Colombia. Haemophilia 2018; 24 (04) e222-e229
  • 33 Rolvien T, Amling M. Disuse osteoporosis: clinical and mechanistic insights. Calcif Tissue Int 2022; 110 (05) 592-604
  • 34 Cervinka T, Rittweger J, Hyttinen J, Felsenberg D, Sievänen H. Anatomical sector analysis of load-bearing tibial bone structure during 90-day bed rest and 1-year recovery. Clin Physiol Funct Imaging 2011; 31 (04) 249-257
  • 35 Haxaire C, Hakobyan N, Pannellini T. et al. Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-α pathway. Blood 2018; 132 (10) 1064-1074
  • 36 Sahin S, Sadri S, Baslar Z, Ar MC. Osteoporosis in patients with hemophilia: single-center results from a middle-income country. Clin Appl Thromb Hemost 2019; 25: 1076029619861689
  • 37 Linari S, Melchiorre D, Pieri L. et al. Low bone mass and hypovitaminosis D in haemophilia: a single-centre study in patients with severe and moderate haemophilia A and B. Haemophilia 2020; 26 (05) 898-906
  • 38 Mansouritorghabeh H, Rezaieyazdi Z, Saadati N, Saghafi M, Mirfeizi Z, Rezai J. Reduced bone density in individuals with severe hemophilia B. Int J Rheum Dis 2009; 12 (02) 125-129
  • 39 Biver E, Calmy A, Rizzoli R. Bone health in HIV and hepatitis B or C infections. Ther Adv Musculoskelet Dis 2017; 9 (01) 22-34
  • 40 Schmidt T, Schmidt C, Schmidt FN. et al. Disease duration and stage influence bone microstructure in patients with primary biliary cholangitis. J Bone Miner Res 2018; 33 (06) 1011-1019
  • 41 Schmidt T, Schwinge D, Rolvien T. et al. Th17 cell frequency is associated with low bone mass in primary sclerosing cholangitis. J Hepatol 2019; 70 (05) 941-953
  • 42 Anagnostis P, Vakalopoulou S, Vyzantiadis TA. et al. The clinical utility of bone turnover markers in the evaluation of bone disease in patients with haemophilia A and B. Haemophilia 2014; 20 (02) 268-275