Introduction While the mechanism of bone disease in thalassemia is multifactorial and still under investigation, the receptor activator of nuclear factor kappa B (RANK), receptor activator of nuclear factor kappa B ligand (RANKL), and osteoprotegerin (OPG) have pivotal roles in regulating bone metabolism. This study aimed to measure RANKL and OPG serum levels, and to detect the incidence of RANKL rs9533156, OPG rs2073618, and OPG rs2073617 genotypes in pediatric β‐thalassemia patients and to assess their relation to bone mineral density. Methods Sixty patients with transfusion‐dependent β‐thalassemia (TBT) patients ages 5 to 14 years were included, and 60 healthy, age‐ and sex‐matched volunteers contributed as a control group. The patients were scanned for bone mineral density. Results The mean of spine dual‐energy X‐ray absorptiometry (DXA) Z‐score in patients was −1.66 ± 1.02 standard deviation (SD). Twenty‐four of them had low spine DXA Z‐scores. The patients showed significantly lower OPG levels and OPG/RANKLs ratios than the control group (3.28 ± 9.11 ng/ml and 11.38 ± 14.93 ng/ml, and 0.01 ± 0.03 and 0.07 ± 0.09, respectively). The RANKL SNP rs9533156 TC heterozygous genotype was detected more with statistical significance in patients than controls. The incidence of OPG rs2073618 and OPG rs2073617 genotypes were 2.3 times and 1.9 times more frequent in patients than controls, respectively. Conclusion The RANK/RANKL/OPG system may have an important role in regulating bone metabolism in TBT patients, although further studies are needed to clarify its role.