Faculty Bibliography

BACKGROUND:States of chronic overnutrition and undernutrition are both associated with impaired bone health and increased fracture risk but there are no data on bone microarchitecture following short-term controlled nutritional challenges. OBJECTIVE:The purpose of our study was to evaluate the impact of short-term high-caloric feeding and fasting on bone microarchitecture. We hypothesized that both high-caloric feeding and fasting would have negative effects on microarchitecture. MATERIALS AND METHODS:). Subjects underwent an in-patient 10-day high-caloric visit (caloric intake with goal to achieve 7% weight gain), after which they went home to resume a normal diet for 13-18 days (stabilization period), and were then readmitted for a 10-day in-patient fasting stay (no caloric intake). All subjects underwent HRpQCT (XtremeCT, Scanco Medical AG, Brüttisellen, Switzerland) of the distal tibia and distal radius after each visit to assess volumetric bone mineral density (vBMD), trabecular and cortical microarchitecture, and strength estimates. The Wilcoxon signed rank test was used to perform within group comparisons. RESULTS:During the high-caloric period, there was a mean increase in weight by 6.3 + 1.7% (p < 0.0001). There were no significant changes in bone parameters in the distal tibia or distal radius (p > 0.05). During the stabilization period there was a significant reduction in weight by -2.7 + 1.9% (p < 0.0001) but no change in bone parameters (p > 0.05). During the fasting period there was a further reduction in weight by -8.8 + 1.2% (p < 0.0001). In the distal tibia, there was a significant increase in total and cortical vBMD, trabecular and cortical parameters as well as strength estimates (p < 0.05). In the distal radius there was an increase in total and trabecular vBMD (p < 0.05), while there were no changes in other microarchitecture parameters or strengths estimates. CONCLUSION:Short-term fasting after high-caloric feeding improves vBMD, bone microarchitecture and strength estimates of the distal tibia, while short-term high-caloric feeding does not change vBMD or microarchitecture. These results suggest that short-term fasting after high-caloric feeding in healthy individuals improves bone health and that these changes can be detected using HRpQCT in-vivo.

The Harvard Catalyst KL2/CMeRIT program is a 2-year mentored institutional career award that includes KL2 grants funded by National Institutes of Health (NIH) and CMeRIT grants funded by Harvard Catalyst nonfederal funds. The purpose of this study was to compare outcomes for early-stage investigators funded by the KL2/CMeRIT program to a group of applicants who were not chosen for support to assess the potential impact of the program on early career outcomes. Career data, including academic promotions, subsequent grant funding, and publication rates, from both successful and unsuccessful 2008-2018 KL2/CMeRIT applicants were compiled throughout the year 2020. Data were obtained directly through outreach to both groups and through assessment of online resources. The cohort comprised 487 individuals, 109 awardees, and 378 nonawardees. Awardees were more likely to be subsequently involved in clinical and translational research than nonawardees (92% vs 75%, p < 0.001). A higher proportion of awardees also had achieved academic promotion (81% vs 69%, p = 0.016) and subsequent NIH funding (72% vs 58%, p = 0.047), while there was no difference in publication rates (p = 0.555). Participants in the Harvard Catalyst KL2/CMeRIT program demonstrate greater early career success than nonparticipants though the nonparticipants also fared relatively well.

Aneurysmal bone cyst is a benign bone neoplasm that most commonly arises from the metaphyses of long bones in the first and second decades of life. Here, we describe a case of an aneurysmal bone cyst that occurred in the distal tibial diaphysis of a 72-year-old female that was concerning for malignancy on imaging, demonstrating cortical breakthrough and soft tissue extension. Histologically, the tumor showed the characteristic morphologic features of aneurysmal bone cyst. Fluorescence in situ hybridization was positive for USP6 rearrangement, and RNA sequencing revealed a USP6 gene fusion with VDR, a novel partner that encodes the vitamin D receptor and that has not been implicated previously in human neoplasia. This case highlights the diagnostic challenges presented by aneurysmal bone cyst in elderly adults, and it expands the genetic spectrum of USP6 rearrangements.

Anorexia nervosa is complicated by low bone mineral density (BMD) and increased fracture risk associated with low bone formation and high bone resorption. The lumbar spine is most severely affected. Low bone formation is associated with relative insulin-like growth factor 1 (IGF-1) deficiency. Our objective was to determine whether bone anabolic therapy with recombinant human (rh) IGF-1 used off-label followed by antiresorptive therapy with risedronate would increase BMD more than risedronate or placebo in women with anorexia nervosa. We conducted a 12-month, randomized, placebo-controlled study of 90 ambulatory women with anorexia nervosa and low areal BMD (aBMD). Participants were randomized to three groups: 6 months of rhIGF-1 followed by 6 months of risedronate ("rhIGF-1/Risedronate") (n = 33), 12 months of risedronate ("Risedronate") (n = 33), or double placebo ("Placebo") (n = 16). Outcome measures were lumbar spine (1° endpoint: postero-anterior [PA] spine), hip, and radius aBMD by dual-energy X-ray absorptiometry (DXA), and vertebral, tibial, and radial volumetric BMD (vBMD) and estimated strength by high-resolution peripheral quantitative computed tomography (HR-pCT) (for extremity measurements) and multi-detector computed tomography (for vertebral measurements). At baseline, mean age, body mass index (BMI), aBMD, and vBMD were similar among groups. At 12 months, mean PA lumbar spine aBMD was higher in the rhIGF-1/Risedronate (p = 0.03) group and trended toward being higher in the Risedronate group than Placebo. Mean lateral lumbar spine aBMD was higher, in the rhIGF-1/Risedronate than the Risedronate or Placebo groups (p < 0.05). Vertebral vBMD was higher, and estimated strength trended toward being higher, in the rhIGF-1/Risedronate than Placebo group (p < 0.05). Neither hip or radial aBMD or vBMD, nor radial or tibial estimated strength, differed among groups. rhIGF-1 was well tolerated. Therefore, sequential therapy with rhIGF-1 followed by risedronate increased lateral lumbar spine aBMD more than risedronate or placebo. Strategies that are anabolic and antiresorptive to bone may be effective at increasing BMD in women with anorexia nervosa. © 2021 American Society for Bone and Mineral Research (ASBMR).

BACKGROUND:Bone marrow adipose tissue (BMAT) plays a role in systemic energy metabolism and responds to nutritional changes. Chronic starvation as well as visceral adiposity are associated with BMAT accumulation. Two types of BMAT have been described which differ in anatomic location (proximal-regulated-rBMAT vs distal-constitutive-cBMAT) and composition (higher unsaturated lipids of cBMAT compared to rBMAT). OBJECTIVE:To determine the response of BMAT composition to short-term high-caloric feeding and fasting. We hypothesized that high-feeding and caloric restriction would be associated with differences in BMAT composition according to the skeletal site. MATERIALS AND METHODS:) who were admitted for a 10-day high-caloric stay (caloric intake with goal to achieve 7% weight gain) followed by discharge home for 13-18 days to resume normal diet (stabilization period), followed by a 10-day fasting stay (no caloric intake). Subjects underwent single voxel proton MR spectroscopy (1H-MRS) at 3T of the lumbar spine (L4) (rBMAT), the femoral diaphysis and distal tibial metaphysis (cBMAT) to determine BMAT composition (unsaturation index, UI and saturation index, SI). Within group comparisons were performed by the Wilcoxon signed rank test. RESULTS:After the high-calorie visit, SI of L4 increased compared to baseline (0.62 ± 0.27 to 0.70 ± 0.28, p = 0.02), and there was a trend of an increase in femoral SI and UI (p ≥ 0.07), while there was no significant change in tibial BMAT (p ≥ 0.13). During the stabilization period, SI of L4 decreased (0.70 ± 0.28 to 0.57 ± 0.21, p < 0.0001) and SI of the femoral diaphysis decreased (5.37 ± 2.27 to 5.09 ± 2.43, p = 0.03), while there was no significant change in UI or tibial BMAT (p ≥ 0.14). During the fasting period, SI of L4 increased (0.57 ± 0.21 to 0.63 ± 0.30, p = 0.03), while there was no change in UI (p = 0.7). SI and UI of femoral diaphysis decreased (5.09 ± 2.43 to 4.68 ± 2.15, p = 0.03, and 0.62 ± 0.42 to 0.47 ± 0.37, p = 0.02, respectively) and UI of the tibial metaphysis decreased (1.48 ± 0.49 to 1.24 ± 0.57, p = 0.04). CONCLUSION:1H-MRS is able to quantify BMAT composition during short-term nutritional challenges, showing a significant increase in SI of rBMAT during high caloric feeding and a differential response to fasting with an increase in SI of rBMAT and a decrease in SI and UI of femoral cBMAT and decrease in UI of tibial cBMAT.

BACKGROUND/OBJECTIVE:Obesity is a strong risk factor for adverse outcomes in patients hospitalized with COVID-19, however, the distribution of fat and the amount of muscle mass are more accurate risk factors than BMI. The objective of this study was to assess body composition measures obtained on opportunistic abdominal CTs as predictors of outcome in patients hospitalized with COVID-19. We hypothesized that elevated visceral and intermuscular adipose tissue would be associated with adverse outcome. SUBJECTS/METHODS:Our retrospective study was IRB-approved and HIPAA-compliant. The study group comprised 124 patients (median age: 68 years, IQR: 56, 77; 59 weeks, 65 months) who were admitted with COVID-19 to a single hospital and who had undergone abdominal CT for clinical purposes. Visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intermuscular adipose tissue (IMAT), and paraspinal and abdominal muscle cross-sectional areas (CSA) were assessed. Clinical information including prognostic factors, time of admission to the intensive care unit (ICU) and time of death within 28 days were obtained. Multivariate time-to-event competing risk models were fitted to estimate the hazard ratio (HR) for a composite outcome of ICU admission/mortality associated with a one standard deviation increase in each body compositional measure. Each model was adjusted for age, sex, race, BMI, and cardiometabolic comorbidities. RESULTS:There were 50 patients who were admitted to the ICU or deceased over a median time of 1 day [IQR 1, 6] from hospital admission. Higher VAT/SAT ratio (HR of 1.30; 95% CI 1.04-1.62, p = 0.022) and higher IMAT CSA (HR of 1.44; 95% CI 1.10-1.89, p = 0.008) were associated with a reduced time to ICU admission or death in adjusted models. CONCLUSION:VAT/SAT and IMAT are predictors of adverse outcome in patients hospitalized with COVID-19, independent of other established prognostic factors. This suggests that body composition measures may serve as novel biomarkers of outcome in patients with COVID-19.

BACKGROUND:Sleeve gastrectomy (SG) is the most common metabolic and bariatric surgery (MBS) procedure in adolescents and adults. Only few studies have assessed bone outcomes following SG and it is unknown whether skeletal changes differ by age group. Recent studies have identified marrow adipose tissue (MAT) as a novel biomarker for bone quality with studies in adults showing high MAT in those with visceral adiposity and a reciprocal increase in MAT with bone loss. OBJECTIVE:To determine the impact of SG on volumetric BMD (vBMD) and MAT in adolescents and adults with obesity. We hypothesized that SG would lead to a decrease in vBMD and increase in MAT but that these changes would be less pronounced in adolescents compared to adults. MATERIALS AND METHODS:), before and 12 months after SG. At baseline and 12 months, subjects underwent quantitative CT of the lumbar spine (L1-L2) to assess trabecular vBMD, single voxel proton MR spectroscopy at 3 T (PRESS pulse sequence without water suppression) at L1-L2 to quantify MAT, and MRI of the abdomen to assess visceral (VAT) and subcutaneous adipose tissue (SAT). RESULTS:At baseline, adolescents had lower MAT (p = 0.0002) and higher vBMD (p = 0.050) compared to adults. Adolescents and adults lost 27.9 ± 6.5 vs. 25.0 ± 11.2% of body weight (p < 0.0001 for within group change), while there was no significant difference between groups (p = 0.455). There was a significant reduction in vBMD in adults (-3.9 ± 3.9%, p = 0.005) and a trend for a reduction in adolescents (-3.7 ± 7.5%, p = 0.119), with no significant difference between groups (p = 0.944). Lumbar MAT content increased in both adults and adolescents (p ≤ 0.034), while the difference was not significant between groups (p = 0.281). In adolescents and adults, 12-month percent change in weight and BMI was positively associated with % change in MAT (p ≤ 0.042). 12-month percent change in MAT was positively associated with 12-month % change in SAT in adolescents and 12-month percent change in VAT in adults (p ≤ 0.045). CONCLUSION:SG in adolescents and adults with severe obesity is associated with a reduction in lumbar vBMD and an increase in lumbar MAT, although the reduction in adolescents did not reach statistical significance, with no significant differences in these endpoints between groups. Our results suggest detrimental effects of bariatric surgery on bone for patients across the life span.

There is a global increase in the prevalence of severe obesity in females during adolescence, which is a critical period for neurocognitive development. An increasing number of adolescents and young adults are now undergoing weight loss surgery as a treatment strategy for obesity. In addition to metabolic complications, obesity has been linked to neurocognitive comorbidity, and studies exploring cognitive performance in adolescents with severe obesity and the impact of bariatric surgery on cognitive abilities are limited. Verbal memory and executive function were assessed cross-sectionally in 69 females with moderate to severe obesity and 24 females without obesity, 13-24 years old. In an exploratory analysis, cognitive changes were also assessed longitudinally over 12 months in a subset of 35 females with moderate to severe obesity following weight loss surgery (n = 21) or following usual care without surgery (n = 14). In cross-sectional analysis, females with moderate to severe obesity showed lower scores for short-term and long-term recall (verbal memory) and response inhibition and cognitive flexibility (executive function) than the comparison group, when adjusted for age and baseline intelligence. Females with moderate to severe obesity who underwent surgery showed significant weight loss but no improvement in verbal memory and executive function scores over 12 months compared with those who did not have surgery. Females with moderate to severe obesity demonstrate worse performance in tests of verbal memory and executive function than the comparison group without obesity. In addition, exploratory analyses provide no indication that weight loss surgery improves these observed cognitive decrements over a period of 12 months. Further studies are necessary to comprehensively evaluate changes in cognitive function following bariatric surgery.