Blood. 2015 Mar 26;125(13):2160-3. doi: 10.1182/blood-2014-10-602060.
Premature changes in trabecular and cortical microarchitecture result in decreased bone strength in hemophilia.
- 1Department of Medicine, University of Calgary, Calgary, AB, Canada; Southern Alberta Rare Blood and Bleeding Disorders Comprehensive Care Program, Foothills Medical Centre, Calgary, AB, Canada; and.
- 2Department of Radiology, University of Calgary, Calgary, AB, Canada.
- 3Department of Medicine, University of Calgary, Calgary, AB, Canada;
Low bone density is a growing concern in aging men with hemophilia and may result in high-morbidity fragility fractures. Using high-resolution peripheral quantitative computed tomography (HR-pQCT), we demonstrate low trabecular and cortical bone density contributing to lower volumetric bone mineral density (BMD) at both distal radius and tibia in patients with hemophilia compared with age- and sex-matched controls. The low trabecular bone density found in hemophilia is attributed to significantly decreased trabecular number and increased separation; the lower cortical bone density results from thinner cortices, whereas cortical porosity is maintained. Microfinite element analysis from three-dimensional HR-pQCT images demonstrates that these microarchitectural deficits seen in patients with hemophilia translate into significantly lower estimated failure load (biomechanical bone strength) at the distal tibia and radius when compared with controls. In addition, an inverse association of joint score with BMD and failure load suggests the negative role of hemophilic arthropathy in bone density loss.
Low bone mineral density (BMD) is a recognized complication of hemophilia. Multiple cohort studies as well as a recent meta-analysis demonstrates a strong association of decreased bone density in both adult and children with hemophilia.1–3 What is not as well understood is the mechanism for low bone density in individuals with hemophilia and whether or not this lower bone density translates into increased propensity for fragility fractures or decreased bone strength.
Hemophilia A and hemophilia B, due to a deficiency in factor VIII and IX respectively, are coagulation disorders where the ability to form a fibrin clot is impaired. Individuals with severe hemophilia A or B are prone to spontaneous bleeding, especially into their joints and deep muscles.4 This results in debilitating joint disease especially to weight bearing joints such as ankles and knees, which impairs mobility and decreases axial loading. It is generally assumed that decreased activity due to frequent joint bleeds results in the inability to achieve peak bone mass and thus lower bone mineral density. However, published studies have also demonstrated that children who have yet to develop significant hemophilic arthropathy as well as those receiving prophylaxis (regular replacement with factor concentrates) still demonstrate lower bone density than age- and sex-matched controls.5 This suggests a metabolic component affecting the bone loss in hemophilia patients and studies demonstrated increased bone turnover markers in individuals with hemophilia supports this as well.
Our study aimed at describing the microarchitectural changes affecting the bones of hemophilia patients and how the architectural deficits along with decreased bone density may predispose to fracture risk. We utilized novel imaging technology, high resolution peripheral quantitative computed tomography (HR-pQCT) also known as XtremeCT, to determine the volumetric bone mineral density and microarchitecture of both cortical and trabecular bone at the tibia and radius of the dominant limbs in individuals with severe and moderate hemophilia. XtremeCT is a non-invasive imaging method that examines in vivo 3D bone microarchitecture at an isotropic resolution of 82 µm (Figure 1 &2). It has been validated in terms of its reproducibility to detect age and disease-related changes as compared to conventional dual x-ray absorptiometry (DXA). 6,7 XtremeCT has the advantage over DXA to provide volumetric measurement of bone mineral density as well as information on the architecture of the bone such as porosity and relative densities of cortical versus trabecular bone. From these detailed architectural images, finite element analysis is applied to generate an estimate of the force needed to break the bone (i.e. failure load) to give us a measurement of the strength of the bone.
Figure 1: HR-pQCT images
HR-pQCT data from the CaMOS study (a multicentre Canadian osteoporosis study involving healthy volunteers) provided age- and sex-matched control data for comparison.8 This data from the CaMOS study has recently been presented to serve as normative control data for future HR-pQCT studies.
Our study demonstrated that the BMD in both the trabecular and cortical compartments are significantly lower in hemophilia patients compared to controls. Architectural deficits in bone structure included fewer trabeculae, greater space between trabeculae, and thinner cortical bone, which accounts for the lower BMD in the respective compartments. This poor bone stock due to density loss and bone microarchitectureal deficits in individuals with hemophilia results in decreased failure load, in other words weaker bones, compared to controls. In addition, those hemophiliacs with greater arthropathy measured by the World Federation of Hemophilia joint score had lower failure loads (weaker bones) demonstrating a significant correlation.9
The results of our study confirms lower bone density in hemophilia patients in both trabecular and cortical compartments with evidence of microarchitectural bone deficits, and that this contributes to weaker bones, which are worse in individuals with worse arthropathy. However, the question of why this is occurring remains unanswered. It has been presumed that decreased activity due to hemophilic joint disease and immobility during hemarthroses leads to lower peak bone mass. On the other hand, there is emerging evidence, at least in mouse studies, that FVIII deficiency itself leads to abnormal bone metabolism and systemic bone mineral loss.10 Induced joint hemarthrosis in these FVIII knock-out mice also appears to accelerate local bone density loss in the injured limb compared to non-injured. 11
Our current research aims to investigate if patients with mild hemophilia who do not experience spontaneous hemarthoses and severe haemophilic arthropathy, also have lower BMD and failure loads. We are also investigating if specific joints with more severe arthropathy are associated with a localized lower BMD and failure load compared to joints unaffected by arthropathy.
Figure 2: Pictures demonstrating the HR-pQCT imaging process for patients
- Paschou S a, 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):2399–407.
- Iorio A, Fabbriciani G, Marcucci M, Brozzetti M, Filipponi P. Bone mineral density in haemophilia patients. A meta-analysis. Thromb. Haemost. 2010;103(3):596–603.
- 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(2):559–65.
- Srivastava a, Brewer a K, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia. 2013;19(1):e1–47.
- Barnes C, Wong P, Egan B, et al. Reduced bone density among children with severe hemophilia. Pediatrics. 2004;114(2):e177–81.
- Burghardt AJ, Buie HR, Laib A, Majumdar S, Boyd SK. Reproducibility of direct quantitative measures of cortical bone microarchitecture of the distal radius and tibia by HR-pQCT. Bone. 2010;47(3):519–28.
- 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):6508–15.
- Macdonald HM, Nishiyama KK, Kang J, Hanley D a, 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(1):50–62.
- Lee A, Boyd SK, Kline G, Poon M. Premature changes in trabecular and cortical microarchitecture result in decreased bone strength in hemophilia. Blood. 2015;125(13):2160–2164.
- Recht M, Liel MS, Turner RT, Klein RF, Taylor J a. The bone disease associated with factor VIII deficiency in mice is secondary to increased bone resorption. Haemophilia. 2013;19(6):908–12.
- Lau a G, Sun J, Hannah WB, et al. Joint bleeding in factor VIII deficient mice causes an acute loss of trabecular bone and calcification of joint soft tissues which is prevented with aggressive factor replacement. Haemophilia. 2014;20(5):716–22.