Children with Haemophilia A have reduced bone mineral density (BMD) and are at risk for developing osteoporosis and fractures later in life. The pathogenesis of low BMD in haemophilics is multifactorial and includes immobilization as well as haemophilic arthropathy.. Crucial pathways regulating bone turnover are the receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) axis and WNT/β-catenin signalling. The former regulates osteoclast formation and the latter osteoblast differentiation. There are few data about key regulators of bone turnover in Haemophilia. Our aim was to evaluate the serum levels of the WNT signalling inhibitors, sclerostin and DKK1, as well as of RANKL and OPG, and their correlation with bone remodelling markers and dual X-ray absorptiometry parameters.
Forty-four subjects affected with severe Haemophilia A (mean age 10·11 ± 6·1 years) were consecutively enrolled by six Italian Paediatric Units belonging to the National Scientific Society for Paediatric Haematology and Oncology and/or the Italian Haemophilia Centres Association. In addition, 40 age-matched controls, who lived in the same geographic area, referred to hospital for minor surgery or electrocardiographic screening, were recruited on a voluntary basis.
In the present study we demonstrated that haemophilics show high sclerostin serum levels. Previous studies demonstrated that high sclerostin levels are associated with increased fracture risk, particularly when paired with lower BMD. Furthermore, sclerostin levels were significantly correlated with height-SDS. A possible explanation is that the most of our patients were pre-pubertal, and sclerostin levels have been positively correlated with bone age before puberty, but negatively associated with bone age after pubertal onset. After adjustment for age, we found that sclerostin correlated with PTH and LS-BMD Z-scores, confirming previous studies. Consistent with the positive correlation between sclerostin, RANKL and OPG/RANKL ratio, the inhibition of WNT pathway also regulates osteoclast formation and resorption, increasing RANKL expression and decreasing OPG levels in osteoblasts. The degree of osteopenia showed a significant correlation with joint involvement, supporting the importance of weight-bearing activity in maintaining adequate BMD among haemophilics. The inverse correlation between sclerostin and 25(OH)-Vitamin D and osteocalcin confirms that sclerostin increase could be one factor of bone loss in haemophilics. Additionally, the patients with PTH levels above the normal value had also higher levels of RANKL and lower OPG/RANKL ratio than patients with normal PTH levels, in accordance with data on young adult haemophilics that show a significant trend toward osteoclastogenesis.
In conclusion, our results show that sclerostin plays a role in regulating bone mass in Haemophilia. It would seem to be a compensatory increase in the bone formation rate demonstrated by high osteocalcin levels in young haemophilics. Thus, longitudinal studies are needed to evaluate if sclerostin measurements should be introduced into routine clinical evaluation of low bone mass in children with Haemophilia.
- Bone Density
- Bone Morphogenetic Proteins
- Bone mineral density
- Case-Control Studies
- Child, Preschool
- Genetic Markers
- Haemophilia A
- Hemophilia A
- Lumbar Vertebrae
- Receptor activator of nuclear factor-ÎºB ligand