The bone disease associated with factor VIII deficiency in mice is secondary to increased bone resorption

Abstract

Osteopenia and osteoporosis have increasingly become a recognized morbidity of factor VIII (FVIII) deficiency. Recently, we demonstrated that FVIII knockout (KO) mice had significantly decreased bone mass and bone strength despite the fact that they did not have haemarthroses. The aim of this study was to explore the mechanism of bone disease associated with FVIII deficiency. We compared biochemical markers of bone formation and osteoclastogenesis, inflammatory cytokines, as well as static and dynamic histomorphometry of genetically engineered FVIII KO male mice to those of wild-type (WT) controls. At 20 weeks of age, FVIII KO mice, as well as WT controls, were sacrificed. Serum and bones were obtained at the time of sacrifice to study biochemical markers of bone formation (osteocalcin) and osteoclastogenesis (receptor activator of nuclear factor kappa-β and osteoprotegerin), levels of inflammatory cytokines (interleukin-1α and interferon-β) and to perform static and dynamic histomorphometry of tibia cancellous bone. There was no difference in the biochemical markers of bone formation or osteoclastogenesis. However, there were differences in the two bone-associated cytokines studied. In addition, histomorphometric examination revealed cancellous osteopenia in FVIII KO mice as evidenced by decreased bone area and trabecular number and increased trabecular separation. Bone formation parameters were normal in FVIII KO mice. In contrast, osteoclast-lined bone perimeter was increased. These data demonstrate that bone disease in FVIII KO mice is due to an increased rate of bone resorption.

Haemophilia and low bone mass. Ok, but what about fracture risk?

“…Thus, a direct role of haemophilia on fracture risk cannot be excluded. This is also supported by data from recent experimental studies, showing that factor VIII knockout mice demonstrate significantly decreased bone mass and bone strength, without the presence of haemarthroses . The mechanism leading to this skeletal impairment is increased rate of bone resorption .…”

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

“…Intriguingly, one group of investigators has recently reported that in the absence of observed haemorrhage, haemophilia A mice have statistically significant diminution of bone density when compared to their haemostatically normal littermates [23,24]. These authors concluded that low bone density is an inherent phenotype that is independently associated with congenital coagulation FVIII deficiency and is the subject of further mechanistic investigation [25].…”

Influence of body weight on bone mass, architecture and turnover

“…Similarly, pathologies such as hemophilia and anemia involving marrow can place demands on the skeleton that can compromise its mechanical function. Specifically, chronic anemia results in reduced BMD and increased fracture risk due to osteoclast-mediated expansion of the bone marrow cavity in response to increased need for hematopoiesis (Almeida and Roberts 2005; Perisano, et al 2012; Recht, et al 2013; Vogiatzi, et al 2005). The high rate of fragility fractures in the aged, with an annual rate of over nine million worldwide, testifies to the inability of the skeleton to always maintain sufficient mechanical competence (Kanis, et al 2012).…”