Patients with thalassemia have weaker bones relative to body size compared with healthy controls

Abstract Background: Despite optimal transfusion and chelation regimens, up to 60% of adults with thalassemia (Thal) have low bone mass and are at increased fracture risk. Bones fracture, in part, because they are insufficiently strong to support routine activity. Bone strength is a composite of bone mass, density, and architectural properties. There are limited data focused on bone strength in patients with Thal, and on how bone adapts to body size, or bone robusticity (relationship between periosteal expansion relative to longitudinal growth). Our objectives were to assess the elements of bone strength and to determine if patients with Thal have weaker and more slender bones relative to body size compared to healthy controls. Methods: Spine bone mineral density (BMD) and whole body composition were assessed by Dual Energy X-ray Absorptiometry (DXA, Horizon A, Hologic). Bone mass, volumetric bone density (vBMD) and architecture were also assessed using peripheral quantitative computed tomography (pQCT, XCT 2000, Stratec) in the non-dominant lower leg. pQCT Images were obtained at 3% of tibial bone length (primarily trabecular bone) and 38% (primarily cortical bone). Bone strength and robustness were plotted against body size (body weight x tibial length) for both trabecular and cortical regions of the tibia. A partial regression of the residuals explained the relationship between bone strength and robustness after accounting for body size. Based on the regression of the residuals, functionality was determined, and two groups were formed, those considered to have Strong Bones for body size (SB: positive quadrant) and those with Weaker Bones for body size (WB: negative quadrant). Student's t-test determined differences between groups. Results: Forty-Five patients with Thal (20 ± 9 years, 22 Male, 34 B-Thal, 6 E-B Thal and 5 with HbH Constant Spring) were compared with 34 healthy controls (18 ± 6 years, 15 Male). Seventy six percent of Thal were transfusion dependent. Patients with Thal weighed less, were shorter, had less lean mass and more fat mass compared to healthy controls, all p<0.05. Spine bone mineral density (BMD) Z-score by DXA was lower in Thal (-2.3 ± 1.1) compared to controls (-0.1 ± 0.8; p<0.001). Though volumetric cortical vBMD by pQCT was not different between groups, Thal did have reduced cortical bone area (p<0.001), polar moment of inertia (p=0.005) and strength-strain index (p=0.026) compared with controls. After plotting the residuals to determine bone functionality, there were no differences in body weight, tibial length or cortical BMD between SB and WB groups. However, tibias that were robust relative to body size (SB) were 31% stronger in the cortical bone and 34% stronger in the trabecular bone compared to the WB group. Overall, 56% of controls were categorized in the SB group compared to only 27% of Thal (p=0.012). We then limited analyses to just patients with Thal and compared those with strong bones for size (SB) to those with weaker bones for size (WB). Interestingly, there were no significant differences in transfusion dependency, body weight, lean mass, body fat, spine BMD Z-score or tibial cortical BMD between the SB and WB Thal only groups. However, both strength-strain index (p=0.003), a measure of bone strength and moment of inertia (p=0.008), a measure of bone architecture and distribution were lower in the WB compared with SB Thal groups. Conclusions: Despite the similarity in body weight and body composition between groups, 73% of Thal patients had under-adapted bone strength for body size. However, the Thal participants in the SB group did have a greater moment of inertia compared to the WB group despite similar spine BMD Z-scores. Exercise benefits bone strength by expanding the periosteal surface of the bone which increases bone size or moment of inertia, a key component of bone strength. Exercise could be a non-pharmaceutical approach to improving bone strength in patients with Thal. Future studies are needed to better understand bone adaptation in Thal and if exercise may be beneficial at adapting bone to improve strength and reduce fracture risk.