Low Bone Mineral Density in Hemophiliacs

Abstract

Objective: To review the current knowledge on bone health in patients with hemophilia A and the underlying pathogenetic mechanisms.

Data sources: Original research articles, meta-analyses, and scientific reviews.

Data synthesis: Already in childhood, patients with hemophilia A are prone to low bone mineral density, leading to osteopenia and/or osteoporosis. Initially associated with the life style of hemophilia, today we are faced with accumulating evidence that coagulation factor VIII is involved directly or indirectly in bone physiology.

Conclusion: Understanding the role of factor VIII and the mechanisms of decreased bone mineral density in hemophilia A is critically important, especially as non-factor replacement therapies are available, and treatment decisions potentially impact bone health.

Keywords: bone mineral density; coagulation; factor VIII; hemophilia A; osteopenia; osteoporosis.

Figure 1

Cell-based model of coagulation. On the surface of tissue factor (TF) -bearing cells, coagulation is initiated by TF, which leads to the generation of a small amount of thrombin (THR) from prothrombin (FII) (initiation phase). Thrombin amplifies the initiation signal by activating platelets via protease-activated receptors (PAR) and cofactors (FV, FVIII) on the platelet surface (amplification or priming phase). Large amounts of thrombin are then generated on the surface of activated platelets (propagation phase). Solid lines indicate proteolytic conversion of an inactive zymogen to its active form, dotted lines indicate activation. Adapted from reference (7).

Figure 2

Signaling mechanisms with balance of bone formation and resorption in bone metabolism. The balance between bone formation and bone resorption is largely regulated by the Wnt/ β catenin pathway and the RANK/RANKL/OPG axis. Wnt protein binds to its co-receptors Frizzled and LRP5/6 on the surface of osteoblasts, which leads to the stabilization and accumulation of β-catenin in the cytoplasm, before it translocates to the nucleus where it regulates target genes and induces bone formation. This pathway can be inhibited by sclerostin and members of the Dkk protein family. RANKL binds to its receptor RANK, which is expressed on pre-osteoclasts. This induces the activation of several transcription factors and in turn osteoclast differentiation and maturation. OPG, which is a soluble decoy receptor and also secreted by osteoblasts, can bind to RANKL and thereby inhibits bone resorption. Under physiological conditions, OPG and RANKL are in equilibrium and preserve bone homeostasis. Several proinflammatory cytokines and growth factors (white boxes) stimulate and upregulate RANKL expression and mediate osteoclast maturation and activation. The metabolic state of the bone is reflected by its biochemical products, which also serve as bone turnover markers for either bone formation or resorption. b-ALP, bone-specific alkaline phosphatase; CTX-1, carboxy-terminal cross-linking telopeptides of type I collagen; Dkk, Dickkopf; IL, interleukin; LRP, low-density lipoprotein receptor-related protein; M-CSF, macrophage colony-stimulating factor; NTX-1, amino-terminal cross-linking telopeptides of type I collagen; OC, osteocalcin; OPG, osteoprotegerin; PICP, procollagen type 1 carboxy-terminal propeptide; PINP, procollagen type 1 amino-terminal propeptide; RANK, receptor activator of nuclear factor-kappa B; RANKL, receptor activator of nuclear factor-kappa B ligand; TGF-β, transforming growth factor β; TNF-α, tumor necrosis factor α; TRACP-5b, tartrate-resistant acid phosphatase 5b; Wnt, wingless related integration site. Adapted from references (61, 62).

Figure 3

The role of coagulation FVIII in bone health. Current knowledge tells us that several modes of action for FVIII impacting bone mineral density are feasible: either FVIII plays a role outside the coagulation system and directly interacts with main players of bone physiology, including the RANK/RANKL/OPG axis and/or the Wnt/β-catenin pathway, as well as pro-inflammatory cytokines, or the effect happens downstream of FVIII and e.g., the missing interaction with vWF or decreased thrombin production is causative. References for original publications and further reading are written in brackets.