Pathogenesis and treatment of osteoporosis in patients with hemophilia

Abstract

Introduction Hemophilia is a rare X-linked recessive inherited bleeding disorder caused by mutations of the genes encoding coagulation factor VIII (FVIII) or IX (FIX). Patients with hemophilia (PWH) often have a high risk of osteoporosis and fractures that is usually ignored. Herein, we review the underlying mechanisms of osteoporosis and the increased risk of fractures and their treatment in patients with FVIII or FIX deficiency. Methods The PubMed, Web of Science, Embase, and Cochrane Library databases were searched to identify original research articles, meta-analyses, and scientific reviews on the mechanisms or treatment of osteoporosis in PWH. Results The pathogenic mechanisms of osteoporosis in PWH are multifactorial and remain unclear. The available evidence shows that FVIII and FIX deficiency may directly affect bone metabolism by interfering with the RANK/RANKL/OPG pathway. Other potential mechanisms of osteoporosis in PWH include thrombin deficiency and the unloading and immobilization of bone, which will affect osteoblast and osteoclast activity by changing the cytokine profiles. The treatment of osteoporosis in PWH includes antiresorptive, anabolic, and dual-action drugs; weight-bearing exercise; fall prevention; and prophylactic coagulation factor replacement therapy. However, clinical studies of the efficacy of anti-osteoporotic agents in osteoporosis of PWH are urgently needed. Conclusion This review summarizes recent progress in research on the pathogenesis of osteoporosis in PWH and provides insights into potential treatment for osteoporosis in PWH.

Insights and implications of sexual dimorphism in osteoporosis

“…2 ). 146 Global knockout of the FVIII gene induced trabecular bone accretion in male mice and diminished cortical compartment accretion in female mice. Furthermore, it resulted in repressed bone formation in male mice but increased resorption in female mice.…”

Haemophilia and Fragility Fractures: From Pathogenesis to Multidisciplinary Approach

“…Administration of this amino-bisphosphonate for 12 months to 10 PWH resulted in an increase in lumbar spine BMD of 4.7%, but no significant change in hip or femoral neck BMD [42]. The limited data on the use of denosumab in PWH by Lin et al documented an improved fracture healing in a man whose BMD increased significantly after 4 months of teriparatide followed by 1 year of denosumab treatment [12]. Therefore, regarding teriparatide, an anabolic agent, the effects on bone health of PWH are poorly understood to date [39].…”

“…Furthermore, thrombin inhibits osteoblast apoptosis and osteoclast differentiation and stimulates osteoblastic cell proliferation, thereby improving bone formation and reducing bone resorption [11]. The role of FVIII is not limited to activation of the coagulation pathway; it also appears to be a biological regulator of bone metabolism [12]. FVIII binds to circulating von Willebrand factor (vWF) to prevent its rapid degradation [13].…”

“…As a result, reduced bone mineral density (BMD) and impaired bone microarchitecture lead to an increased risk of fragility fractures in PWH [29]. However, the pathogenesis of osteoporosis in PWH is not yet fully elucidated and includes thrombin deficiency [30], altered osteoblast and osteoclast activity [31] and reduced mobility or prolonged immobilization [12]. Three distinct HA and HB phenotypes can be distinguished based on the reduction in serum FVIII or FIX levels: severe (<1 IU/dL), moderate (1-5 IU/dL) and mild (5-40 IU/dL) [19].…”

“…As a result, reduced bone mineral density (BMD) and impaired bone microarchitecture lead to an increased risk of fragility fractures in PWH [29]. However, the pathogenesis of osteoporosis in PWH is not yet fully elucidated and includes thrombin deficiency [30], altered osteoblast and osteoclast activity [31] and reduced mobility or prolonged immobilization [12].…”