Alexander P. Taylor

Bone Microarchitecture Is Impaired in Adolescent Amenorrheic Athletes Compared with Eumenorrheic Athletes and Nonathletic Controls

CONTEXT Bone mineral density (BMD) is lower in young amenorrheic athletes (AA) compared to eumenorrheic athletes (EA) and nonathletic controls and may contribute to fracture risk during a critical time of bone accrual. Abnormal bone microarchitecture is an independent determinant of fracture risk and has not been assessed in young athletes and nonathletes. OBJECTIVE We hypothesized that bone microarchitecture is impaired in AA compared to EA and nonathletes despite weight-bearing exercise. DESIGN AND SETTING We conducted this cross-sectional study at the Clinical Research Center of Massachusetts General Hospital. SUBJECTS AND OUTCOME MEASURES We assessed BMD and bone microarchitecture in 50 subjects [16 AA, 18 EA, and 16 nonathletes (15-21 yr old)] using dual-energy x-ray absorptiometry and high-resolution peripheral quantitative computed tomography. RESULTS Groups did not differ for chronological age, bone age, body mass index, or vitamin D levels. Lumbar BMD Z-scores were lower in AA vs. EA and nonathletes; hip and femoral neck BMD Z-scores were highest in EA. At the weight-bearing tibia, athletes had greater total area, trabecular area, and cortical perimeter than nonathletes, whereas cortical area and thickness trended lower in AA. Trabecular number was lower and trabecular separation higher in AA vs. EA and nonathletes. At the non-weight-bearing radius, trabecular density was lower in AA vs. EA and nonathletes. Later menarchal age was an important determinant of impaired microarchitecture. After controlling for covariates, subject grouping accounted for 18-24% of the variability in tibial trabecular number and separation. CONCLUSION In addition to low BMD, AA have impaired bone microarchitecture compared with EA and nonathletes. These are the first data to show abnormal bone microarchitecture in AA.

Adolescent Girls With Anorexia Nervosa Have Impaired Cortical and Trabecular Microarchitecture and Lower Estimated Bone Strength at the Distal Radius

CONTEXT Adolescents with anorexia nervosa (AN) have low areal bone mineral density (aBMD) at both cortical and trabecular sites, and recent data show impaired trabecular microarchitecture independent of aBMD. However, data are lacking regarding both cortical microarchitecture and bone strength assessment by finite element analysis (FEA) in adolescents with AN. Because microarchitectural abnormalities and FEA may predict fracture risk independent of aBMD, these data are important to obtain. OBJECTIVE Our objective was to compare both cortical and trabecular bone microarchitecture and FEA estimates of bone strength in adolescent girls with AN vs normal-weight controls. DESIGN, SETTING, AND SUBJECTS We conducted a cross-sectional study at a clinical research center that included 44 adolescent girls (21 with AN and 23 normal-weight controls) 14 to 22 years old. MAIN OUTCOME MEASURES We evaluated 1) aBMD (dual-energy x-ray absorptiometry) at the distal radius, lumbar spine, and hip, 2) cortical and trabecular microarchitecture at the ultradistal radius (high-resolution peripheral quantitative computed tomography), and 3) FEA-derived estimates of failure load at the ultradistal radius. RESULTS aBMD was lower in girls with AN vs controls at the lumbar spine and hip but not at the distal radius. Girls with AN had lower total (P < .0001) and trabecular volumetric BMD (P = .02) and higher cortical porosity (P = .03) and trabecular separation (P = .04). Despite comparable total cross-sectional area, trabecular area was higher in girls with AN (P = .04), and cortical area and thickness were lower (P = .002 and .02, respectively). FEA-estimated failure load was lower in girls with AN (P = .004), even after controlling for distal radius aBMD. CONCLUSIONS Both cortical and trabecular microarchitecture are altered in adolescent girls with AN. FEA-estimated failure load is decreased, indicative of reduced bone strength. The finding of reduced cortical bone area in girls with AN is consistent with impaired cortical bone formation at the endosteum as a mechanism underlying these findings.

Cortical Microstructure and Estimated Bone Strength in Young Amenorrheic Athletes, Eumenorrheic Athletes and Non-Athletes

CONTEXT Lower bone density in young amenorrheic athletes (AA) compared to eumenorrheic athletes (EA) and non-athletes may increase fracture risk during a critical time of bone accrual. Finite element analysis (FEA) is a unique tool to estimate bone strength in vivo, and the contribution of cortical microstructure to bone strength in young athletes is not well understood. OBJECTIVE We hypothesized that FEA-estimated stiffness and failure load are impaired in AA at the distal radius and tibia compared to EA and non-athletes despite weight-bearing exercise. DESIGN AND SETTING Cross-sectional study; Clinical Research Center SUBJECTS 34 female endurance athletes involved in weight-bearing sports (17 AA, 17 EA) and 16 non-athletes (14-21 years) of comparable age, maturity and BMI OUTCOME MEASURES: We used HR-pQCT images to assess cortical microarchitecture and FEA to estimate bone stiffness and failure load. RESULTS Cortical perimeter, porosity and trabecular area at the weight-bearing tibia were greater in both groups of athletes than non-athletes, whereas the ratio (%) of cortical to total area was lowest in AA. Despite greater cortical porosity in EA, estimated tibial stiffness and failure load was higher than in non-athletes. However, this advantage was lost in AA. At the non-weight-bearing radius, failure load and stiffness were lower in AA than non-athletes. After controlling for lean mass and menarchal age, athletic status accounted for 5-9% of the variability in stiffness and failure load, menarchal age for 8-23%, and lean mass for 12-37%. CONCLUSION AA have lower FEA-estimated bone strength at the distal radius than non-athletes, and lose the advantage of weight-bearing exercise seen in EA at the distal tibia.

Premenopausal women with a distal radial fracture have deteriorated trabecular bone density and morphology compared with controls without a fracture.

BACKGROUND Measurement of bone mineral density by dual x-ray absorptiometry combined with clinical risk factors is currently the gold standard in diagnosing osteoporosis. Advanced imaging has shown that older patients with fragility fractures have poor bone microarchitecture, often independent of low bone mineral density. We hypothesized that premenopausal women with a fracture of the distal end of the radius have similar bone mineral density but altered bone microarchitecture compared with control subjects without a fracture. METHODS Forty premenopausal women with a recent distal radial fracture were prospectively recruited and matched with eighty control subjects without a fracture. Primary outcome variables included trabecular and cortical microarchitecture at the distal end of the radius and tibia by high-resolution peripheral quantitative computed tomography. Bone mineral density at the wrist, hip, and lumbar spine was also measured by dual x-ray absorptiometry. RESULTS The fracture and control groups did not differ with regard to age, race, or body mass index. Bone mineral density was similar at the femoral neck, lumbar spine, and distal one-third of the radius, but tended to be lower in the fracture group at the hip and ultradistal part of the radius (p = 0.06). Trabecular microarchitecture was deteriorated in the fracture group compared with the control group at both the distal end of the radius and distal end of the tibia. At the distal end of the radius, the fracture group had lower total density and lower trabecular density, number, and thickness compared with the control group (-6% to -14%; p < 0.05 for all). At the distal end of the tibia, total density, trabecular density, trabecular thickness, and cortical thickness were lower in the fracture group than in the control group (-7% to -14%; p < 0.01). Conditional logistic regression showed that trabecular density, thickness, separation, and distribution of trabecular separation remained significantly associated with fracture after adjustment for age and ultradistal radial bone mineral density (adjusted odds ratios [OR]: 2.01 to 2.98; p < 0.05). At the tibia, total density, trabecular density, thickness, cortical area, and cortical thickness remained significantly associated with fracture after adjustment for age and femoral neck bone mineral density (adjusted OR:1.62 to 2.40; p < 0.05). CONCLUSIONS Despite similar bone mineral density values by dual x-ray absorptiometry, premenopausal women with a distal radial fracture have significantly poorer bone microarchitecture at the distal end of the radius and tibia compared with control subjects without a fracture. Early identification of women with poor bone health offers opportunities for interventions aimed at preventing further deterioration and reducing fracture risk.

Differences in skeletal microarchitecture and strength in African-American and white women

African‐American women have a lower risk of fracture than white women, and this difference is only partially explained by differences in dual‐energy X‐ray absorptiometry (DXA) areal bone mineral density (aBMD). Little is known about racial differences in skeletal microarchitecture and the consequences for bone strength. To evaluate potential factors underlying this racial difference in fracture rates, we used high‐resolution peripheral quantitative computed tomography (HR‐pQCT) to assess cortical and trabecular bone microarchitecture and estimate bone strength using micro–finite element analysis (µFEA) in African‐American (n = 100) and white (n = 173) women participating in the Study of Womens Health Across the Nation (SWAN). African‐American women had larger and denser bones than whites, with greater total area, aBMD, and total volumetric BMD (vBMD) at the radius and tibia metaphysis (p < 0.05 for all). African‐Americans had greater trabecular vBMD at the radius, but higher cortical vBMD at the tibia. Cortical microarchitecture tended to show the most pronounced racial differences, with higher cortical area, thickness, and volumes in African‐Americans at both skeletal sites (p < 0.05 for all), and lower cortical porosity in African‐Americans at the tibia (p < 0.05). African‐American women also had greater estimated bone stiffness and failure load at both the radius and tibia. Differences in skeletal microarchitecture and estimated stiffness and failure load persisted even after adjustment for DXA aBMD. The densitometric and microarchitectural predictors of failure load at the radius and tibia were the same in African‐American and white women. In conclusion, differences in bone microarchitecture and density contribute to greater estimated bone strength in African‐Americans and probably explain, at least in part, the lower fracture risk of African‐American women.

Gonadal steroid–dependent effects on bone turnover and bone mineral density in men

BACKGROUND Severe gonadal steroid deficiency induces bone loss in adult men; however, the specific roles of androgen and estrogen deficiency in hypogonadal bone loss are unclear. Additionally, the threshold levels of testosterone and estradiol that initiate bone loss are uncertain. METHODS One hundred ninety-eight healthy men, ages 20-50, received goserelin acetate, which suppresses endogenous gonadal steroid production, and were randomized to treatment with 0, 1.25, 2.5, 5, or 10 grams of testosterone gel daily for 16 weeks. An additional cohort of 202 men was randomized to receive these treatments plus anastrozole, which suppresses conversion of androgens to estrogens. Thirty-seven men served as controls and received placebos for goserelin and testosterone. Changes in bone turnover markers, bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA), and BMD by quantitative computed tomography (QCT) were assessed in all men. Bone microarchitecture was assessed in 100 men. RESULTS As testosterone dosage decreased, the percent change in C-telopeptide increased. These increases were considerably greater when aromatization of testosterone to estradiol was also suppressed, suggesting effects of both testosterone and estradiol deficiency. Decreases in DXA BMD were observed when aromatization was suppressed but were modest in most groups. QCT spine BMD fell substantially in all testosterone-dose groups in which aromatization was also suppressed, and this decline was independent of testosterone dose. Estradiol deficiency disrupted cortical microarchitecture at peripheral sites. Estradiol levels above 10 pg/ml and testosterone levels above 200 ng/dl were generally sufficient to prevent increases in bone resorption and decreases in BMD in men. CONCLUSIONS Estrogens primarily regulate bone homeostasis in adult men, and testosterone and estradiol levels must decline substantially to impact the skeleton. TRIAL REGISTRATION ClinicalTrials.gov, NCT00114114. FUNDING AbbVie Inc., AstraZeneca Pharmaceuticals LP, NIH.

Statin Use and Aneurysm Risk in Patients With Bicuspid Aortic Valve Disease

No medical therapy has been proven to prevent the progression of aortic dilatation in bicuspid aortic valve (BAV) disease, and prophylactic aortic surgery remains the mainstay of treatment.

Effects of Testosterone and Estradiol Deficiency on Vasomotor Symptoms in Hypogonadal Men

CONTEXT The hormonal basis of vasomotor symptoms (VMS) in hypogonadal men is incompletely understood. OBJECTIVE To determine the contributions of testosterone and estradiol deficiency to VMS in hypogonadal men. DESIGN Two randomized trials were conducted sequentially between September 2004 and April 2011. Controls were recruited separately. SETTING A single-site academic medical center. PARTICIPANTS Healthy men ages 20-50, with normal serum testosterone levels. INTERVENTION Cohort 1 (n = 198, 81% completion) received goserelin acetate every 4 weeks to suppress gonadal steroids and were randomized to placebo or 1.25, 2.5, 5, or 10 g of testosterone gel daily for 16 weeks. Cohort 2 (n = 202, 78% completion) received the same regimen as cohort 1 plus anastrozole to block aromatization of testosterone. Controls (n = 37, 89% completion) received placebos for goserelin acetate and testosterone. MAIN OUTCOME MEASURES Incidence of visits with VMS. This was a preplanned secondary analysis. RESULTS VMS were reported at 26% of visits in cohort 1, and 35% of visits in cohort 2 (P = .02), demonstrating an effect of estradiol deficiency. When adjacent estradiol level groups in cohort 1 were compared, the largest difference in VMS incidence was observed between the 5-9.9 and 10-14.9 pg/mL groups (38% vs 16%, P < .001). In cohort 2, the 10-g testosterone group differed significantly from placebo (16% vs 43%, P = .048) after adjustment for small differences in estradiol levels, indicating that high testosterone levels may suppress VMS. CONCLUSIONS Estradiol deficiency is the key mediator of VMS in hypogonadal men. At high levels, testosterone may have a suppressive effect.

RISK FACTORS FOR INFECTIVE ENDOCARDITIS IN SURGICAL PATIENTS WITH BICUSPID AORTIC VALVE DISEASE

Bicuspid aortic valve (BAV) disease is associated with an increased risk of infective endocarditis (IE) compared to the general population. Although prior studies have estimated a 10-30% risk of IE in BAV disease, antibiotic prophylaxis for IE is no longer recommended in these patients. Few studies

STATIN USE AND ANEURYSM RISK IN PATIENTS WITH BICUSPID AORTIC VALVE DISEASE

More than 50% of patients with bicuspid aortic valve (BAV) develop aortic dilatation, placing them at an 8-12 fold increased risk of aortic dissection compared to the general population and thereby warranting prophylactic aortic surgery. Previous studies have indicated that statin therapy might be