Inflammation, Multiple Blood Transfusions and Osteoclast Activation in Sickle Cell Disease Patients.

Low bone mass density affects more than 65% of adult sickle cell disease patients and correlates with lower hemoglobin and higher ferritin concentrations (1). Increased iron supply promotes osteoclast differentiation and bone resorption (2). Proinflammatory cytokines also promote bone resorption (3). Tartrate resistant acid phosphatase isoform 5b (TRACP-5b) is produced only by activated osteoclasts and therefore serves as a marker of bone resorption (4). Sickle cell disease is a condition of chronic inflammation and patients often suffer from transfusional iron overload as well. In this study we aimed to determine the predictors of bone resorption in patients with sickle cell disease by measuring circulating levels of TRACP-5b.

Fifty-nine adult sickle cell disease patients and 22 apparently healthy controls were recruited at Howard University Hospital. Patients were at steady state with no crisis, hospitalization or blood transfusion in the last 3 weeks. Clinical and laboratory information was collected at the time of recruitment and TRACP-5b was measured in non-fasting serum samples using an enzyme immuno assay kit (Quidel, San Diego, CA). Serum concentrations of inflammatory cytokines and growth factors were measured by Multiplex assay (Bio-Rad, Hercules, CA)..

Sickle cell disease patients had elevated concentrations of TRACP-5b compared to controls (median values of 4.4 vs. 2.4 U/l, P < 0.0001). Among the patients, TRACP-5b concentrations correlated positively with number of blood transfusions (r = 0.19) and serum concentrations of alkaline phosphatase (r=0.46), endothelin-1 (r=0.39), interleukin-8 (r= 0.38), and interleukin-6 (r=0.25). TRACP-5b correlated negatively with RANTES (r = -0.42) and PDGF (r = -0.31). It did not correlate significantly with serum ferritin (r = -0.03), LDH (r = 0.13) or hemoglobin concentration (r = 0.11). Interestingly, TRACP-5b correlated positively with tricuspid regurgitation velocity, which reflects systolic pulmonary artery pressure (r = 0.30).

Sickle cell patients have elevated steady-state osteoclast activity as reflected in serum TRACP-5b concentrations. Multiple blood transfusions and inflammation are associated findings. Among patients, higher TRACP-5b concentrations are associated with lower concentrations of RANTES and PDGF-BB, factors that influence function of osteoblasts. Further studies are needed to investigate whether common pathways may be involved in osteoclast activation and pulmonary changes in sickle cell disease.

Supported by grants number 2 R25 HL003679-08 and 1 R01 HL079912-02 and 1U54HL090508-01 from NHLBI, by Howard University GCRC grant no 2MOI RR10284-10 from NCRR, NIH, Bethesda, MD, and by the intramural research program of the National Institutes of Health.

Gordeuk:Biomarin: Research Funding; TRF Pharma: Research Funding; Merck: Research Funding; Novartis: Speakers Bureau.