Adverse Fat Depots and Marrow Adiposity Are Associated With Skeletal Deficits and Insulin Resistance in Long-Term Survivors of Pediatric Hematopoietic Stem Cell Transplantation

Abstract

Allogeneic hematopoietic stem-cell transplantation (alloHSCT) survivors treated with total body irradiation (TBI) exhibit bone deficits and excess adiposity, potentially related to altered mesenchymal stem cell differentiation into osteoblasts or adipocytes. We examined associations among fat distribution, bone microarchitecture, and insulin resistance in alloHSCT survivors after TBI. This was a cross-sectional observational study of 25 alloHSCT survivors (aged 12–25 years) a median of 9.7 (4.3–19.3) years after alloHSCT compared to 25 age-, race-, and sex-matched healthy controls. Vertebral MR spectroscopic imaging and tibia micro-MRI were used to quantify marrow adipose tissue (MAT) and trabecular microarchitecture. Additional measures included DXA whole-body fat mass (WB-FM), leg lean mass (Leg-LM), trunk visceral adipose tissue (VAT), and CT calf muscle density. Insulin resistance in alloHSCT survivors was estimated by HOMA-IR. AlloHSCT survivors had lower Leg-LM (p<0.001), and greater VAT (p<0.01), MAT (p<0.001) and fat infiltration of muscle (p=0.04) independent of WB-FM, vs. matched-controls; BMI did not differ. Survivors had lower bone volume fraction and abnormal microarchitecture including greater erosion and more rod-like structure vs. controls (all p=0.04); 14 had vertebral deformities and two had compression fractures. Greater WB-FM, VAT, MAT and muscle fat infiltration were associated with abnormal trabecular microarchitecture (p<0.04 for all). AlloHSCT HOMA-IR was elevated, associated with younger age at transplantation (p<0.01), and positively correlated with WB-FM and VAT (both p<0.01). In conclusion, the markedly increased marrow adiposity, abnormal bone microarchitecture, and abnormal fat distribution highlight the risks of long-term treatment-related morbidity and mortality in alloHSCT recipients after TBI. Trabecular deterioration was associated with marrow and visceral adiposity. Furthermore, long-term survivors demonstrated sarcopenic obesity, insulin resistance, and vertebral deformities. Future studies are needed to identify strategies to prevent and treat metabolic and skeletal complications in this growing population of childhood alloHSCT survivors.

Skeletal outcomes by peripheral quantitative computed tomography and dual-energy X-ray absorptiometry in adolescent girls with anorexia nervosa

“…Calf muscle and fat CSA (mm 2 ) were assessed at the 66 % diaphyseal site. As previously described [20, 21], pQCT measure of muscle density (g/cm 3 ) was also obtained. Scans were analyzed using Stratec software, version 6.20.…”

Endocrine and Metabolic Disturbances in Survivors of Hematopoietic Stem Cell Transplantation in Childhood and Adolescence

“…Importantly, our patients with MetS were not overweight or obese; high BMI is thus not a sensitive trigger for investigation of MetS after HSCT. Mostoufi-Moab et al [44] reported that allogeneic HSCT survivors treated with TBI exhibit markedly increased marrow adiposity and increased visceral adipose tissue with relatively normal BMI. These survivors demonstrated sarcopenic obesity with insulin resistance, a recognized risk factor for MetS in this population.…”

Skeletal Fragility in Children with Chronic Disease

“…There is building evidence of the effects on increased fat on abnormal bone mass, likely to be mediated by adipocytokines like leptin [29]. The association of increased fat in chronic disease and increased marrow adiposity due to a state of GH resistance and reflective of osteoblastogenesis may also be another mechanism in lower bone formation [30]. …”

“…There may be a place to incorporate evaluation with bone histomorphometry as a form of monitoring in those treated with bisphosphonate to guide duration of therapy. Newer modalities of bone imaging including high-resolution pQCT and micro-MRI [30,46] may allow assessment of bone microarchitecture, and these findings may closely correlate with bone biopsy results [47], although such imaging modalities are currently only available as research tools. …”