Although many national and regional studies have reported the relationship between hemophilia and osteoporosis, there are no studies that report the current status of osteoporosis in hemophilia patients in China. The number of hemophilia patients in China is as high as 140,000[9], and a trial in China is necessary to verify the relationship between hemophilia and osteoporosis. In this study, the BMD of the four sites of the femoral neck, Ward’s triangle, tuberosity, and total hip of hemophilia patients was significantly lower than that of healthy controls, but the difference in the lumbar spine was not significant. This is similar to the conclusions of some previous studies [10–12]. The incidence of osteoporosis in our case group is as high as 41.51%, which may reflect the actual situation of hemophilia patients in China.
Age is a recognized risk factor for osteoporosis. However, there was no significant correlation between age and bone mineral density in our study, which may be associated with the high concentration of age of the participants we included. Therefore, the effect of age was not reflected in the statistical analysis. BMI has been an essential factor in BMD in both healthy people and people with other diseases[13, 14]. High BMI puts a more mechanical load on bones, increasing bone remodeling and thus increasing bone mass to bear greater loads. In our study, the BMI of the case group was significantly lower than that of the healthy control group. The low BMI puts a less mechanical load on hemophilia patients. This partly explains why load-bearing joints (e.g., hip joints) are more common in hemophiliac osteoporosis, while non-load-bearing joints (e.g., lumbar spine) are relatively normal.
We examined bone turnover markers and explored the relationship with BMD. β-CTx is one of the degradation products of collagen type I, which is present in the blood as an intact immunogenic protein, and collagen type I is the most abundant organic substance in the bone matrix. When physiologic or pathological bone resorption is enhanced, the degradation of type I collagen is also increased, and the corresponding decomposition fragment is increased in peripheral blood [15, 16], so the detection of β-CTx can reflect the degree of bone resorption. In our study, the β-CTx in the case group was significantly higher than in the control group (777.15 ng/L vs. 599.60 ng/L), indicating the degree of bone resorption in the case group was much higher than in the control group. In the correlation analysis, β-CTx was significantly negatively correlated with BMD at all sites. This is similar to the conclusion of Katsarou [17] et al. Type I collagen is the most abundant collagen type in the human body, with an extended peptide chain at the amino (N-terminus) and carboxyl (C-terminus) procollagen. These extended peptide chains (properties) are cleaved by specific proteases during the conversion of procollagen to collagen. When mature collagen is formed, it is deposited in the bone matrix. The determination of PINP reflects the deposition of type I collagen so that PINP can be used as a marker of bone formation [18]. In our study, there was no significant difference in P1NP between the case and control groups, and there was no significant correlation between BMD and P1NP in the correlation analysis. This suggests that bone formation activity is similar in hemophilia patients to healthy patients. From this, we speculate that the pathological mechanism of osteoporosis in hemophilia patients may be that osteoclast activity is enhanced, and osteoblastic activity is not enhanced to the same extent. Several studies have reported that vitamin D deficiency is common in hemophiliacs and may be associated with osteoporosis and fragility fractures [11],[8], [19]. Surprisingly, none of the patients in our study had vitamin D deficiency. No correlation between 25(OH)D and BMD was found in the correlation analysis. In addition, there were no significant differences in PTH, BGP, and calcitonin between the case and control groups, and no significant correlation with BMD was found in the correlation analysis.
Osteoporosis is a known complication in patients with chronic liver disease [20], chronic liver disease patients with increased receptor activator ratios of nuclear factor kappa ligands to osteopontin, leading to increased bone resorption and eventual bone loss [21], besides, hyperbilirubinemia due to chronic liver disease may interfere with osteogenic activity [22]. In addition, long-term chronic inflammation may promote the differentiation of osteoclasts and their precursors and downregulate osteoblast activity through pro-inflammatory cytokines such as tumor necrosis factor and interleukin-1, leading to bone metabolism imbalance [23, 24]. We investigated the incidence of HBV and HCV in patients and analyzed the relationship with osteoporosis. The incidence of HBV was high in both the case group (18 cases, 33.96%) and the control group (13 cases, 26.53%). However, there was no significant correlation between HBV and BMD. Anti-HCV positivity was common in the case group (12 cases, 22.64%), while no patients in the control group were anti-HCV positivity. This is attributed to the increased risk of hematogenous infection due to the need for frequent blood transfusions in hemophiliacs. In the correlation analysis, HCV and BMD had a significant negative correlation. We only measured HbsAg and anti-HCV positive, not viral DNA content, so our conclusions only demonstrate a relationship between previous infection history and BMD.
Previous cross-sectional surveys have found osteoporosis is common in AIDS patients [25]. There were 3 (5.66%) HIV-positive patients in the case group and no HIV-positive patients in the control group. There was no significant association between HIV positivity and BMD, which may be associated with fewer cases. Notably, the use of antivirals has an impact on BMD [26]. Overall, short-term BMD is lost by 1 to 2 percent over 2 to 4 years when antiviral therapy is initiated, followed by an increase or long-term stabilization of BMD [25]. None of our patients are on antiviral therapy, and it was found through questioning that none of the previously infected patients were receiving complete standard antiviral therapy. Therefore, we were unable to analyze the effects of antiviral therapy on osteoporosis.
Decreased activity is a known risk factor for osteoporosis, and we used the FISH score to assess functional independence and reflect the amount of daily activity in people with hemophilia. Patients in the case group had a FISH score distribution of 7 to 24 points, and their functional independence was significantly lower than that of healthy people. The FISH score was positively correlated with BMD of the femoral neck, Ward’s triangle, tuberosity, and hip. Because of recurrent bleeding that begins in childhood, hemophiliacs often choose to avoid activities to reduce the occurrence of bleeding, which leads to a decrease in peak bone mass[27]. Joint deformities lead to decreased mobility, which in turn affects BMD. However, whether joint destruction itself affects BMD is unclear. Repeated intra-articular hemorrhage deposits hemosiderosis on the synovial surface, causing hypertrophic synovitis, and further damage to cartilage and subchondral bone[28]. BMD is most likely affected in this pathological process. Khawaja et al. [29]found that the degree of joint destruction was significantly negatively correlated with BMD at bilateral hips, femoral necks, and greater trochanters. Sossa[30]et al. came to similar conclusions. We counted the number of joint deformities per patient. We found that the number of deformed joints was significantly negatively correlated with BMD at the femoral neck, Ward’s triangle, tuberosity, and hip. However, this effect was no longer significant in multivariate regression analysis. Therefore, it can be determined that joint deformities mainly affect BMD by reducing the amount of activity. More research is needed to explore the effects of joint pathological disruption on BMD.
Long-term prophylaxis has been shown to significantly protect BMD in children with hemophilia [29]. However, the role of long-term prophylaxis has not been demonstrated in adult hemophilia patients [31]. Some scholars have found that long-term deficiency of FVIII is an independent risk factor for osteoporosis and proposed that the mechanism may be FVIII:vWF complex inhibits osteoclast production and differentiation through the RANKL-OPG pathway [32]. Based on this theory, preventive treatment should be beneficial for BMD. We investigated the treatment modalities of hemophiliacs, and all but 3 patients received on-demand treatment, and the remaining 50 patients received tertiary prophylaxis. We counted the duration and dose of preventive treatment. However, in the correlation analysis, no benefit of them was found for BMD. This contradicts previous conclusions, which may be that since our patients are on tertiary prophylaxis, Bone damage is well established before prophylactic therapy begins. Short-term preventive treatment cannot improve this bone destruction. More long-term follow-up studies are needed to assess the role of preventive treatment. We are well aware of the tremendous benefits of preventive treatment in improving bone density in hemophiliacs.