Increased Bone Resorption Is Implicated in the Pathogenesis of Bone Loss in Hemophilia Patients: Correlations with Severity of Hemophilic Arthropathy and HIV Infection.

Osteoporosis has been recently recognized as a comorbidity factor, which affects significantly the quality of life in hemophilia patients. Prolonged immobilization and severity of arthropaphy have been considered as the major factors contributing to the pathogenesis of osteoporosis in hemophilia. However, the exact mechanisms of bone loss have not been fully clarified in this disorder. The aim of this study was to evaluate the incidence of osteoporosis in hemophilia patients, and investigate the possible correlations with clinical and laboratory data in an attempt to better understand the pathogenetic mechanisms that are involved in its development. Ninety-three hemophilia patients were evaluated. Their median age was 36 years (range: 24–46 years). Eighty patients (86%) had severe and 13 patients (13%) moderate haemophilia. Fifty-seven patients (61%) were HIV negative and 36 (38%) HIV positive. The severity of hemophilic arthropahty was assessed using WFH clinical score and Petterson radiological score in all patients. Bone mineral density of the lumbar spine(LS) and the femoral neck(FN) was measured using DEXA technique in 78 out of 93 patients. Bone turnover was studied by the measurement of a series of serum indices:

• bone resorption markers [N- and C-telopeptide of type-I collagen (NTX and CTX, respectively), and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)],

• bone formation markers [bone-alkaline phosphatase (bALP), and osteocalcin], and

• osteoclast stimulating factors [receptor activator of nuclear factor-kB ligand (RANKL), osteoprotegerin (OPG), and tumor necrosis factor-alpha].

Osteopenia(−2,5<T-score<−1.5) or osteoporosis (T-score<−2,5) was found in 83.9% and 60% of the patients in the FN and LS respectively. Osteoporosis was more common among HIV positive patients in both FN (65.3%vs.41.6%; p=0.007) and LS (17.86%vs.5.41%, p=0.004).The severity of osteoporosis in the FN correlated with patients’ total clinical and radiological score (p=0.001). Hemophilia patients showed increased serum levels of all markers of bone resorption and bALP compared with 15 controls of similar gender and age (median NTX: 19.4 vs. 17.4 nM BCE, p=0.018; CTX: 0.61 vs. 0.47 ng/mL, p=0.028; TRACP-5b: 2.7 vs. 1.3 U/L, p<0.01; and bALP: 20.0 vs. 16.9 U/L, p=0.048; for patients and controls, respectively). This increased osteoclastic activity was not found to be mediated by RANKL/RANK/OPG system as we observed no difference in terms of sRANKL/OPG ratio between patients and controls. Therefore it seems that other factors are involved in the increased bone resorption observed in hemophiliacs. In multivariate analysis, HIV infection (p=0.05) and total clinical score (p=0.001), were found to be independent prognostic factors for developing osteoporosis. Our study has shown that the incidence of osteoporosis is high among hemophilia patients and is related to the severity of hemophilic arthropathy. We report for the first time that hemophilia patients have high bone turnover, which seems not to be due to an imbalance of the RANKL/OPG system. HIV infection increases the negative effects of hemophilia on bone metabolism and may contribute to the pathogenetic mechanisms involved in osteoporosis development.