Osteoporosis in Sickle Cell/β-Thalassemia Is Primarily Caused by an Imbalance at the RANKL/OPG Pathway.
Authors: Voskaridou Ersi , Papassotiriou Ioannis , Premetis Evangelos , Meletis John , Loukopoulos Dimitris , Terpos Evangelos 
Published: April 2020

Abstract
Bone involvement is the commonest clinical manifestation of sickle cell disease (SCD) including chronic disorders, such as osteopenia/osteoporosis. The aim of the present study is to evaluate the bone mineral density (BMD) of patients with SCD/β-thalassemia (S/β-th) in parallel with markers of bone turnover in an attempt to better understand the pathophysiology of bone loss in these patients. We studied 52 patients with S/β-th (23M/29F; median age 40 y). The BMD of the lumbar spine (L) and femoral neck (F) was evaluated by DEXA. Bone remodeling was assessed using the following serum indices: (a) bone resorption markers [C-telopeptide of type-I collagen (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)], (b) bone formation markers [bone-alkaline phosphatase (bALP), osteocalcin (OC), and C-terminal propeptide of collagen type-I (CICP)], and (c) osteoclast stimulating factors [soluble receptor activator of nuclear factor κB ligand (sRANKL), and osteoprotegerin (OPG)]. Moreover, all patients had a thorough evaluation of their renal function (creatinine clearance, and cystatin-C serum levels), bone marrow expansion (soluble transferin receptors, sTfR), serum erythropoietin (Epo) and parathyroid hormone (PTH) levels. The same biochemical parameters were also determined in 25 age- and gender-matched controls. According to WHO criteria, 17 patients (32.6%; 8M/9F, median age 45 y) had osteopenia or osteoporosis (median L/T-score: −2.26; L/BMD: 0.9 g/cm2; F/T-score: −1.86; F/BMD: 0.68 g/cm2). In contrast, 30 patients (57.6%; 12M/18F, median age 40 y) had osteosclerosis (median L/T-score: +3.15; L/BMD: 1550.5 g/m2; F/T-score: +0.52; F/BMD: 1113.5 g/cm2). Renal function, Epo, Hb and sTfR levels and the number of crises/year were similar between both groups. All patients displayed increased levels of OPG, bALP, and CICP compared with controls (p&lt;0.02). CTX levels in the osteosclerotic patients were significantly lower than those of both controls (p&lt;0.0001) and osteopenic/osteoporotic patients (p&lt;0.003); this finding implies a diminished bone resorption. Moreover, bALP and PTH in the osteopenia/osteoposis group were higher than those of the osteosclerosis group (p&lt;0.01, and &lt;0.03, respectively). BMD of the osteopenic/osteoporotic patients showed a strong correlation with OPG and CTX levels (p=0.01, and 0.008, respectively). This result, in combination with the significant correlations observed between OPG and sRANKL, TRACP-5b, and bALP in these patients suggests that osteopenia/osteoporosis in S/β-th results mainly from an imbalance at the RANKL/OPG axis. Conversely, considering the absence of correlation between BMD and sTfR in the same patient group, the potential contribution of bone marrow expansion in the development of osteopenia appears much weaker. No correlation between BMD and bone indices observed in osteosclerotic group. In conclusion, this study suggests that the development of bone loss in S/β-th patients is mainly due to an imbalance in RANKL/OPG pathway. Novel agents that target this system, as well as bisphosphonates, maybe useful in the management of this common SCD complication.