Bone density in hemophiliacs − known and less-known risk factors
Osteopenia or osteoporosis are known comorbidities of hemophilia and concern many of these patients. What all contributes to their development?
The relationship between hemophilia and BMD − questions remain
Hemophilia is an X-linked recessive bleeding disorder leading to reduced or missing function of clotting factor VIII (FVIII). Hemophilia is characterized by trauma-associated or even spontaneous bleeding, especially in severe forms of the disease.
The development of new effective medications has led to a significant improvement in life expectancy, which is comparable to that of the general population. However, alongside the propensity for joint changes associated with bleeding, there is also a discussion about the tendency for lower bone mineral density (BMD − bone mineral density) in hemophilia.
Studies show that up to 70% of hemophiliacs have lower BMD, with a greater portion meeting the criteria for osteopenia and approximately a third meeting the criteria for osteoporosis. Some results also suggest a higher proportion of fractures compared to the general population. Some meta-analyses have even linked hemophilia with secondary osteoporosis. However, all mechanisms associated with the development of lower BMD are not yet fully understood. It also appears that prophylactic administration of factor VIII or IX concentrates from early childhood may help maintain normal BMD. What is still unclear is whether low BMD in hemophilia is directly caused by the coagulation defect or is a secondary comorbidity influenced, for example, by lifestyle.
Known risk factors
In general, risk factors predisposing to BMD reduction include smoking, alcohol consumption, vitamin D deficiency, and certain medications (e.g., glucocorticoids, warfarin). Another cause could be reduced physical activity, which is generally reported in hemophiliacs, for example, due to fear of trauma or pain. Reduced physical activity can negatively affect the development of peak bone mass in childhood and subsequently BMD throughout life.
Less-known risk factors
In recent years, there is also a hypothesis that FVIII deficiency has a direct impact on reducing BMD, independently of the previously mentioned risk factors. Thus, FVIII might play a direct role outside the coagulation system, specifically in bone metabolism. Research data suggest the involvement of FVIII in metabolism related to the nuclear factor kappa-B signaling pathway (RANK/RANKL/OPG pathway), which regulates the formation of osteoclasts. Another important signaling cascade is the Wnt/β-catenin pathway, which governs the differentiation of osteoblasts.
Conclusion
Some of these insights are still not fully explained, but it is certainly worth considering them when examining the influence of individual factors on bone metabolism, as this could also impact therapeutic consideration. Especially in a situation where there are many effective treatment methods available today that might not require the administration of replacement therapy with a missing factor concentrate.
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Source: Gebetsberger J., Schirmer M., Wurzer W. J., Streif W. Low bone mineral density in hemophiliacs. Front Med (Lausanne) 2022 Feb 2; 9: 794456, doi: 10.3389/fmed.2022.794456.
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