Faculty Bibliography

This paper summarizes the highlights of the Special Scientific Sessions of the 44th Annual Scientific Meeting of the International Skeletal Society (ISS), which was hosted in New York, NY, in August 2017.

BACKGROUND:Body composition differs between men and women, with women having proportionally more fat mass and men more muscle mass. Although men and women are both susceptible to obesity, health consequences differ between the sexes. The purpose of our study was to assess sex differences in body composition using anatomic and functional imaging techniques, and its relationship to cardiometabolic risk markers in subjects with overweight/obesity. METHODS:). Subjects underwent dual-energy X-ray absorptiometry (DXA) and computed tomography (CT) for fat and muscle mass, proton MR spectroscopy (1H-MRS) for intrahepatic (IHL) and intramyocellular lipids (IMCL), an oral glucose tolerance test, serum insulin, lipids, and inflammatory markers. Men and women were compared by Wilcoxon signed rank test. Linear correlation and multivariate analyses between body composition and cardiometabolic risk markers were performed. RESULTS:Women and men were of similar mean age and BMI (p ≥ 0.2). Women had higher %fat mass, extremity fat, and lower lean mass compared to men (p ≤ 0.0005). However, men had higher visceral adipose tissue (VAT) and IMCL and higher age-and BMI-adjusted IHL (p < 0.05). At similar age and BMI, men had a more detrimental cardiometabolic risk profile compared to women (p < 0.01). However, VAT in women, and IMCL in men, were more strongly associated with cardiometabolic risk markers, while more lower extremity fat was associated with a more favorable cardiometabolic profile in women compared to men (p ≤ 0.03). CONCLUSIONS:Although the male pattern of fat distribution is associated with a more detrimental cardiometabolic risk profile compared to women of similar age and BMI, VAT is more strongly associated with cardiometabolic risk markers in women, while IMCL are more detrimental in men. Lower extremity fat is relatively protective, in women more than in men. This suggests that detailed anatomic and functional imaging, rather than BMI, provides a more complete understanding of metabolic risk associated with sex differences in fat distribution.

OBJECTIVE:Overweight/obesity is characterized by decreased growth hormone (GH) secretion whereas circulating IGF-I levels are less severely reduced. Yet, the activity of the circulating IGF-system appears to be normal in overweight/obese subjects, as estimated by the ability of serum to activate the IGF-I receptor in vitro (bioactive IGF). We hypothesized that preservation of bioactive IGF in overweight/obese women is regulated by an insulin-mediated suppression of IGF-binding protein-1 (IGFBP-1) and IGFBP-2, and by suppression of IGFBP-3, mediated by low GH. We additionally hypothesized that increases in bioactive IGF would drive changes in body composition with low-dose GH administration. DESIGN:Cross-sectional analysis and 3-month interim analysis of a 6-month randomized, placebo-controlled study of GH administration in 50 overweight/obese women without diabetes mellitus. Bioactive IGF (kinase receptor activation assay) and body composition (DXA) were measured. RESULTS:Prior to treatment, IGFBP-3 (r = -0.33, p = 0.02), but neither IGFBP-1 nor IGFBP-2, associated inversely with bioactive IGF. In multivariate analysis, lower IGFBP-3 correlated with lower peak stimulated GH (r = 0.45, p = 0.05) and higher insulin sensitivity (r = -0.74, p = 0.003). GH administration resulted in an increase in mean serum IGF-I concentrations (144 ± 56 to 269 ± 66 μg/L, p < 0.0001) and bioactive IGF (1.29 ± 0.39 to 2.60 ± 1.12 μg/L, p < 0.0001). The treatment-related increase in bioactive IGF, but not total IGF-I concentration, predicted an increase in lean mass (r = 0.31, p = 0.03) and decrease in total adipose tissue/BMI (r = -0.43, p = 0.003). CONCLUSIONS:Our data suggest that in overweight/obesity, insulin sensitivity and GH have opposing effects on IGF bioactivity through effects on IGFBP-3. Furthermore, increases in bioactive IGF, rather than IGF-I concentration, predicted GH administration-related body composition changes. CLINICAL TRIAL REGISTRATION NUMBER:NCT00131378.

OBJECTIVE:To evaluate clinical and radiological features of pathology-proven extraskeletal osteosarcomas. METHODS:This retrospective study was IRB-approved and HIPAA-compliant. Our pathology database was queried for cases of extraskeletal osteosarcoma. Tumor location, size, imaging appearance, presence of metastases, and clinical outcome were documented. RESULTS:Nineteen patients met inclusion criteria (age 59 ± 15 (range 28-85) years; 15 male, 4 female). Tumors occurred in the lower extremities (12 out of 19, 63%), pelvis/gluteal region (3 out of 19, 16%), upper extremity (2 out of 19, 5%), thorax (1 out of 19, 5%), and neck (1 out of 19, 5%). Two out of 19 (11%) patients had undergone radiation to the tumor site previously. According to pathology, 16 out of 19 tumors were high-grade (84%). Tumors presented as soft-tissue masses measuring 9.5 ± 6.8 (2-29) cm. Tumor mineralization was present in 5 out of 19 cases (26%) and local invasion was found in 1 out of 19 cases (6%). On MRI, tumors typically appeared hyperintense on T2-weighted sequences with enhancement in 15 out of 15 (100%) contrast-enhanced studies, and with central necrosis in 10 out of 19 (53%) cases. Low-grade tumors were smaller (<4 cm; 3 out of 3, 100%) and lacked central necrosis (3 out of 3, 100%). 8 out of 19 patients (42%) had metastases, most commonly to the lung (7 out of 19, 37%) and bone (2 out of 19,11%). Two out of 8 patients (25%) with metastases and 8 out of 11 (73%) without metastases achieved recurrence-free survival (mean follow-up 3.8 ± 4.0 [0.2-14.2]) years. No metastases or deaths occurred in patients with low-grade histology. CONCLUSIONS:Extraskeletal osteosarcomas are rare, typically high-grade malignancies that commonly metastasize to lung and bones. Low-grade tumors and those without metastases have a good prognosis. MRI appearance is nonspecific, with T2 hyperintense signal and heterogeneous enhancement. Unlike conventional osteosarcoma, mineralization is rare.

OBJECTIVES:Plexiform neurofibromas (PNs) are complex, histologically benign peripheral nerve sheath tumors that are challenging to measure by simple line measurements. Computer-aided volumetric segmentation of PN has become the recommended method to assess response in clinical trials directed at PN. Different methods for volumetric analysis of PN have been developed. The goal of this study is to test the level of agreement in volume measurements and in interval changes using two separate methods of volumetric magnetic resonance imaging analysis. METHODS:Three independent volume measurements were performed on 15 PN imaged at three time-points using 3DQI software at Massachusetts General Hospital (MGH) and National Cancer Institute (NCI) and MEDx software at NCI. RESULTS:Median volume differences at each time-point comparing MGH-3DQI and NCI-3DQI were -0.5, -4.2, and -19.9 mL; comparing NCI-3DQI and NCI-MEDx were -21.0, -47.0, and -21.0 mL; comparing MGH-3DQI and NCI-MEDx were -10.0, -70.3, and -29.9 mL. Median differences in percentage change over time comparing MGH-3DQI and NCI-3DQI were -1.7, 1.1, and -1.0%; comparing NCI-3DQI and NCI-MEDx were -2.3, 3.3, and -1.1%; comparing MGH-3DQI and NCI-MEDx were -0.4, 2.0, and -1.5%. Volume differences were <20% of the mean of the two measurements in 117 of 135 comparisons (86.7%). Difference in interval change was <20% in 120 of the 135 comparisons (88.9%), while disease status classification was concordant in 115 of 135 comparisons (85.2%). CONCLUSIONS:The volumes, interval changes, and progression status classifications were in good agreement. The comparison of two volumetric analysis methods suggests no systematic differences in tumor assessment. A prospective comparison of the two methods is planned.

OBJECTIVE:To evaluate the significance of biceps tendon (BT) displacement and peri-bicipital hematoma on MRI in subjects with pectoralis major (PM) tears. We hypothesized that these features might be associated with tear severity at surgery. MATERIALS AND METHODS/METHODS:We retrospectively identified MRI cases with PM injury and reviewed clinical, imaging, and surgical records. MR images were reviewed independently by two musculoskeletal radiologists to determine anterior displacement of BT (BT-disp, in mm) and the presence of triangular-shaped peri-bicipital hematoma. Data were compared with an age- and sex-matched control group and correlated with surgical reports grouped by tear severity. RESULTS:We identified 46 subjects with PM injury (43 men, 3 women; mean age 34 ± 9 years), 26 of whom underwent surgical reconstruction, and 20 matched controls (P > 0.2). BT-disp was significantly higher in PM injury vs controls (P = 0.003), and in tendon vs myotendinous (MT) junction PM tears (P < 0.0001); however, MT junction tears vs controls were similar (P = 0.98). Higher BT-disp and presence of peri-bicipital hematoma correlated significantly with surgical reports describing full-thickness complete tears. BT-disp > 4.5 mm had 86% sensitivity and 75% specificity to detect the most severe tears on surgical reports, whereas the presence of peri-bicipital hematoma was the strongest predictor among both parameters. CONCLUSION/CONCLUSIONS:Anterior BT displacement and peri-bicipital hematoma are helpful indicators of full-thickness complete tears at the humeral insertion.

Background Recent studies have suggested that the quantity and quality of adipose tissue and muscle, assessed on non-contrast computed tomography (CT), may serve as imaging biomarkers of survival in patients with and without neoplasms. Purpose To assess body composition measures that could serve as predictors of therapy response in patients with extremity soft tissue sarcomas treated with radiation therapy and surgery. Material and Methods The study was IRB-approved. Sixty patients had a history of extremity soft tissue sarcoma and underwent FDG-PET/CT prior to radiation therapy and surgical resection. Cross-sectional areas and CT attenuation (HU) of abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and psoas muscle were assessed on non-contrast CT. Clinical information on predictors of tumor recurrence and post-surgical wound infections were recorded. Cox proportional hazard models were used to determine longitudinal associations between body composition and tumor recurrence/wound infections. Results Twenty-three tumor recurrences occurred over a follow-up period of 43 ± 35 months. Higher SAT and lower psoas attenuation were associated with tumor recurrence which remained significant after adjustment for covariates ( P ≤ 0.01). There were 13 post-surgical wound infections. Higher VAT and SAT attenuation were associated with post-surgical wound infections ( P < 0.04); however, VAT attenuation lost significance after adjustment for covariates. Conclusion Abdominal adipose tissue and psoas muscle attenuation assessed on non-contrast CT may predict tumor recurrence and post-surgical infections in patients with extremity soft tissue sarcomas.

BACKGROUND:Altered bone microarchitecture and higher marrow adipose tissue (MAT) may reduce bone strength. High resolution pQCT (HRpQCT) allows assessment of volumetric BMD (vBMD), and size and microarchitecture parameters of bone, while 1H-magnetic resonance spectroscopy (1H-MRS) allows MAT evaluation. We have reported impaired microarchitecture at the non-weight bearing radius in adolescents with anorexia nervosa (AN) and that these changes may precede aBMD deficits. Data are lacking regarding effects of AN on microarchitecture and strength at the weight-bearing tibia in adolescents and young adults, and the impact of changes in microarchitecture and MAT on strength estimates. OBJECTIVE:To compare strength estimates at the distal tibia in adolescents/young adults with AN and controls in relation to vBMD, bone size and microarchitecture, and spine MAT. DESIGN AND METHODS/METHODS:This was a cross-sectional study of 47 adolescents/young adults with AN and 55 controls 14-24years old that assessed aBMD and body composition using DXA, and distal tibia vBMD, size, microarchitecture and strength estimates using HRpQCT, extended cortical analysis, individual trabecular segmentation, and finite element analysis. Lumbar spine MAT (1H-MRS) was assessed in a subset of 19 AN and 22 controls. RESULTS:Areal BMD Z-scores were lower in AN than controls. At the tibia, AN had greater cortical porosity, lower total and cortical vBMD, cortical area and thickness, trabecular number, and strength estimates than controls. Within AN, strength estimates were positively associated with lean mass, aBMD, vBMD, bone size and microarchitectural parameters. MAT was higher in AN, and associated inversely with strength estimates. CONCLUSIONS:Adolescents/young adults with AN have impaired microarchitecture at the weight-bearing tibia and higher spine MAT, associated with reduced bone strength.

CONTEXT:Acromegaly is characterized by growth hormone (GH) and insulinlike growth factor-1 (IGF-1) hypersecretion, and GH and IGF-1 play important roles in regulating body composition and glucose homeostasis. OBJECTIVE:The purpose of our study was to investigate body composition including ectopic lipids, measures of glucose homeostasis, and gonadal steroids in patients with active acromegaly compared with age-, body mass index (BMI)-, and sex-matched controls and to determine changes in these parameters after biochemical control of acromegaly. DESIGN:Cross-sectional study of 20 patients with active acromegaly and 20 healthy matched controls. Prospective study of 16 patients before and after biochemical control of acromegaly. MAIN OUTCOME MEASURES:Body composition including ectopic lipids by magnetic resonance imaging/proton magnetic resonance spectroscopy; measures of glucose homeostasis by an oral glucose tolerance test; gonadal steroids. RESULTS:Patients with active acromegaly had lower mean intrahepatic lipid (IHL) and higher mean fasting insulin and insulin area under the curve (AUC) values than controls. Men with acromegaly had lower mean total testosterone, sex hormone-binding globulin, and estradiol values than male controls. After therapy, homeostasis model assessment of insulin resistance, fasting insulin level, and insulin AUC decreased despite an increase in IHL and abdominal and thigh adipose tissues and a decrease in muscle mass. CONCLUSIONS:Patients with acromegaly were characterized by insulin resistance and hyperinsulinemia but lower IHL compared with age-, BMI-, and sex-matched healthy controls. Biochemical control of acromegaly improved insulin resistance but led to a less favorable anthropometric phenotype with increased IHL and abdominal adiposity and decreased muscle mass.