PS1102 HEMOPHILIA ASSOCIATED BONE PATHOLOGY IMPACTS QUALITY OF LIFE
Authors: Goldscheitter G. , Lattimore S. , Taylor J.A. 
Published: June 2019

Background:

People with Hemophilia (PwH) have decreased skeletal health resulting in lower bone mineral density (BMD) and greater risk of fracture. We previously identified the cytokines c‐terminal telopeptide (CTX)‐1, receptor activator of nuclear factor kappa‐B ligand (RANKL), and osteopretegerin (OPG) as critical markers for bone metabolism in hemophilia.

Aims:

This study investigates the relationship between hemophilia‐associated bone pathology, factors including cytokines, factor VIII (FVIII) replacement therapy, and quality of life.

Methods:

Twelve participants with severe FVIII‐deficiency were enrolled in the single site IRB‐approved study. After a 72‐hour washout, plasma samples were obtained at 8 time points over the course of five days with FVIII infusions administered on Day 1 (50 units/Kg) and Day 3 (20 units/Kg). All participants had a physical examination and completed questionnaires on Day 1. The EQ‐5D‐3L was used to report participants’ self‐rated health. The Hemophilia Activities List (HAL) self‐reported physical activity. The International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH‐BAT). BMD was measured as Z‐scores via Dual‐Energy X‐ray Absorptiometry (DEXA) Scanning. Joint assessment was performed using the Hemophilia Joint Health Score (HJHS). Plasma cytokine levels were measured using ELISA and magnetic bead multiplex kits.

Results:

Serum OPG concentrations increased throughout the study period (p = 7.26x10–5) while RANKL concentrations did not change (p = 0.19). The OPG:RANKL ratio exhibited a 6.2‐fold increase between Days 1 and 5. CTX‐1 concentrations were lower (p = 0.006) 30 minutes after the 50 U/kg FVIII infusion. CTX‐1 response for each participant was assessed using linear regression throughout the time course. Spine L1‐L4 Z‐score (SZ) and Hip Total Z‐score (HTZ) correlate with CTX‐1 response (p = 3.4x10–4 and 0.014, respectively). The mean age of participants was 25.2 ± 2.1 at time of first study visit. Participants had a mean SZ of −0.74 ± 0.34, HTZ of −0.17 ± 0.32, Hip Neck Z‐score (HNZ) of −0.16 ± 0.35, and HJHS of 20 ± 5. HTZ and HNZ decreased significantly with patient age (p = 0.027 and 0.032) while SZ and HJHS did not (p = 0.18 and 0.16). Consequently, age correction was applied to BMD comparisons. Statistical comparisons between HAL, EQ‐5D‐3L, and BHQ answers, BMD data, and HJHS are shown in Table 1.

Summary/Conclusion:

This prospective study demonstrates a relationship between FVIII deficiency and bone disease in PwH. OPG acts as a decoy ligand to RANKL, inhibiting osteoclastic bone resorption. The observed increase in OPG:RANKL ratio suggests FVIII has a direct impact on this pathway. Decreased CTX‐1 concentrations following factor infusion and correlations between CTX‐1 response and BMD further suggests that FVIII plays a role in moderating bone remodeling. Hemophilia‐associated bone and joint pathology is associated with decreased quality of life. Correlations between BMD and questionnaire responses demonstrate that poor bone and joint health is physically limiting, causes discomfort, and negatively impacts perceptions of personal well‐being. Furthermore, correlations between BMD and HJHS and ISTH‐BAT responses (Table 1) illustrate a relationship between bleeding management and skeletal health. PwH with lower BMD report more nose and gum bleeds, suggesting a link between FVIII replacement and skeletal health. Bleeds in the extremities were not correlated with decreased BMD or increased HJHS, but abdominal (stomach, iliopsoas) and other bleeds were. Analysis of these data is ongoing.

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