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1.  Evaluation and Management of the Premenopausal Woman with Low BMD 
Current osteoporosis reports  2013;11(4):276-285.
Interpretation of bone mineral density (BMD) results in premenopausal women is particularly challenging, since the relationship between BMD and fracture risk is not the same as for postmenopausal women. In most cases, Z scores rather than T scores should be used to define “low BMD” in premenopausal women. The finding of low BMD in a premenopausal woman should prompt thorough evaluation for secondary causes of bone loss. If a secondary cause is found, management should focus on treatment of this condition. In a few cases where the secondary cause cannot be eliminated, treatment with a bone active agent to prevent bone loss should be considered. In women with no fractures and no known secondary cause, low BMD is associated with microarchitectural defects similar to young women with fractures; however, no longitudinal data are available to allow use of BMD to predict fracture risk. BMD is likely to be stable in these women with isolated low BMD, and pharmacologic therapy is rarely necessary. Assessment of markers of bone turnover and follow-up bone density measurements can help to identify those with an ongoing process of bone loss that may indicate a higher risk for fracture, and possible need for pharmacologic intervention.
doi:10.1007/s11914-013-0161-4
PMCID: PMC4139032  PMID: 24091896
Premenopausal Osteoporosis; Bisphosphonates; Teriparatide
2.  Chronic kidney disease and bone fracture: a growing concern 
Kidney international  2008;74(6):721-731.
Susceptibility to fracture is increased across the spectrum of chronic kidney disease (CKD). Moreover, fracture in patients with end-stage kidney disease (ESKD) results in significant excess mortality. The incidence and prevalence of CKD and ESKD are predicted to increase markedly over the coming decades in conjunction with the aging of the population. Given the high prevalence of both osteoporosis and CKD in older adults, it is of the utmost public health relevance to be able to assess fracture risk in this population. Dual-energy X-ray absorptiometry (DXA), which provides an areal measurement of bone mineral density (aBMD), is the clinical standard to predict fracture in individuals with postmenopausal or age-related osteoporosis. Unfortunately, DXA does not discriminate fracture status in patients with ESKD. This may be, in part, because excess parathyroid hormone (PTH) secretion may accompany declining kidney function. Chronic exposure to high PTH levels preferentially causes cortical bone loss, which may be partially offset by periosteal expansion. DXA can neither reliably detect changes in bone volume nor distinguish between trabecular and cortical bone. In addition, DXA measurements may be low, normal, or high in each of the major forms of renal osteodystrophy (ROD). Moreover, postmenopausal or age-related osteoporosis may also affect patients with CKD and ESKD. Currently, transiliac crest bone biopsy is the gold standard to diagnose ROD and osteoporosis in patients with significant kidney dysfunction. However, bone biopsy is an invasive procedure that requires time-consuming analyses. Therefore, there is great interest in developing non-invasive high-resolution imaging techniques that can improve fracture risk prediction for patients with CKD. In this paper, we review studies of fracture risk in the setting of ESKD and CKD, the pathophysiology of increased fracture risk in patients with kidney dysfunction, the utility of various imaging modalities in predicting fracture across the spectrum of CKD, and studies evaluating the use of bisphosphonates in patients with CKD.
doi:10.1038/ki.2008.264
PMCID: PMC4139042  PMID: 18563052
chronic kidney disease; renal osteodystrophy; fracture; bone imaging
3.  Premenopausal Bone Health: Osteoporosis in Premenopausal Women 
This article will discuss the diagnosis of osteoporosis in premenopausal women and the evaluation and management of those with low-trauma fractures and/or low bone mineral density. As secondary causes (glucocorticoid excess, anorexia nervosa, premenopausal estrogen deficiency, and celiac disease) are commonly the underlying cause of osteoporosis in this population, treatment of the underlying condition should be the focus of management. Additional management options, generally reserved for those with major or multiple fractures and/or ongoing bone loss, will also be described.
doi:10.1097/GRF.0b013e3182a8ae55
PMCID: PMC4139057  PMID: 24022503
premenopausal women; osteoporosis; bone mineral density; pregnancy-associated osteoporosis; lactation- associated osteoporosis; idiopathic osteoporosis
6.  Clinical Imaging of Bone Microarchitecture with HR-pQCT 
Current osteoporosis reports  2013;11(2):147-155.
Osteoporosis, a disease characterized by loss of bone mass and structural deterioration, is currently diagnosed by dual-energy x-ray absorptiometry (DXA). However, DXA does not provide information about bone microstructure, which is a key determinant of bone strength. Recent advances in imaging permit the assessment of bone microstructure in vivo using high-resolution peripheral quantitative computed tomography (HR-pQCT). From these data, novel image processing techniques can be applied to characterize bone quality and strength. To date, most HR-pQCT studies are cross-sectional comparing subjects with and without fracture. These studies have shown that HR-pQCT is capable of discriminating fracture status independent of DXA. Recent longitudinal studies present new challenges in terms of analyzing the same region of interest and multisite calibrations. Careful application of analysis techniques and educated clinical interpretation of HR-pQCT results have improved our understanding of various bone-related diseases and will no doubt continue to do so in the future.
doi:10.1007/s11914-013-0142-7
PMCID: PMC4102136  PMID: 23504496
High-resolution peripheral quantitative computed tomography; HR-pQCT; Bone microarchitecture; Osteoporosis; Fragility fractures; Finite element analysis; Clinical imaging
7.  Bone Mass and Turnover in Women with Epilepsy on Antiepileptic Drug Monotherapy 
Annals of neurology  2005;57(2):252-257.
Antiepileptic drugs, particularly cytochrome P450 enzyme inducers, are associated with disorders of bone metabolism. We studied premenopausal women with epilepsy receiving antiepileptic drug monotherapy (phenytoin, carbamazepine, valproate, and lamotrigine). Subjects completed exercise and nutrition questionnaires and bone mineral density studies. Serum was analyzed for indices of bone metabolism including calcium, 25-hydroxyvitamin D, parathyroid hormone, insulin growth factor I, insulin binding protein III, and bone formation markers, bone-specific alkaline phosphatase, and osteocalcin. Urine was analyzed for cross-linked N-telopeptide of type I collagen, a bone resorption marker. Calcium concentrations were significantly less in subjects receiving carbamazepine, phenytoin, and valproate than in those receiving lamotrigine (p = 0.008). Insulin growth factor-I was significantly reduced in subjects receiving phenytoin compared with those receiving lamotrigine (p = 0.017). Subjects receiving phenytoin had significantly greater levels of bone-specific alkaline phosphatase (p = 0.007). Our results demonstrate that phenytoin is associated with changes in bone metabolism and increased bone turnover. The lower calcium concentrations in subjects taking carbamazepine or valproate compared with those taking other antiepileptic drugs suggest that these antiepileptic drugs may have long-term effects. Subjects receiving lamotrigine had no significant reductions in calcium or increases in markers of bone turnover, suggesting this agent is less likely to have long-term adverse effects on bone.
doi:10.1002/ana.20378
PMCID: PMC4102137  PMID: 15668966
8.  Trabecular Bone Strength Predictions of HR-pQCT and Individual Trabeculae Segmentation (ITS)-Based Plate and Rod Finite Element Model Discriminate Postmenopausal Vertebral Fractures 
While high-resolution peripheral quantitative computed tomography (HR-pQCT) has advanced clinical assessment of trabecular bone microstructure, nonlinear microstructural finite element (μFE) prediction of yield strength by HR-pQCT voxel model is impractical for clinical use due to its prohibitively high computational costs. The goal of this study was to develop an efficient HR-pQCT-based plate and rod (PR) modeling technique to fill the unmet clinical need for fast bone strength estimation. By using individual trabecula segmentation (ITS) technique to segment the trabecular structure into individual plates and rods, a patient-specific PR model was implemented by modeling each trabecular plate with multiple shell elements and each rod with a beam element. To validate this modeling technique, predictions by HR-pQCT PR model were compared with those of the registered high resolution μCT voxel model of 19 trabecular sub-volumes from human cadaveric tibiae samples. Both Young’s modulus and yield strength of HR-pQCT PR models strongly correlated with those of μCT voxel models (r2=0.91 and 0.86). Notably, the HR-pQCT PR models achieved major reductions in element number (>40-fold) and CPU time (>1,200-fold). Then, we applied PR model μFE analysis to HR-pQCT images of 60 postmenopausal women with (n=30) and without (n=30) a history of vertebral fracture. HR-pQCT PR model revealed significantly lower Young’s modulus and yield strength at the radius and tibia in fracture subjects compared to controls. Moreover, these mechanical measurements remained significantly lower in fracture subjects at both sites after adjustment for aBMD T-score at the ultradistal radius or total hip. In conclusion, we validated a novel HR-pQCT PR model of human trabecular bone against μCT voxel models and demonstrated its ability to discriminate vertebral fracture status in postmenopausal women. This accurate nonlinear μFE prediction of HR-pQCT PR model, which requires only seconds of desktop computer time, has tremendous promise for clinical assessment of bone strength.
doi:10.1002/jbmr.1919
PMCID: PMC3688669  PMID: 23456922
trabecular microarchitecture; trabecular plate and rod; individual trabeculae segmentation; high-resolution peripheral quantitative computed tomography; finite element model
9.  Trabecular and cortical microarchitecture in postmenopausal HIV-infected women 
Calcified tissue international  2013;92(6):557-565.
Objective
To assess the effects of HIV infection and antiretroviral therapy (ART) on trabecular and cortical microarchitecture in postmenopausal minority women.
Methods
A subgroup of 106 (46 HIV-infected, 60 uninfected) postmenopausal Hispanic and African American women from an established cohort had areal bone mineral density (aBMD) measured by dual-energy x-ray absorptiometry, and trabecular and cortical volumetric BMD (vBMD) and microarchitecture measured by high-resolution peripheral quantitative computed tomography (HRpQCT) at the radius and tibia.
Results
HIV-infected women were slightly younger (58±1 versus 61±1 yrs, p=0.08), and had lower body mass index (BMI, 28±1 versus 32±1 kg/m2, p<0.01). BMI-adjusted aBMD Z scores were lower in HIV-infected women at the lumbar spine, total hip and ultradistal radius. Serum N-telopeptide and C-telopeptide levels were also higher in HIV-infected women. Trabecular and cortical vBMD were similar at the radius, but cortical area (105.5±2.4 versus 120.6±2.0mm2, p<0.01) and thickness (956±33 versus 1075±28 m, p<0.01) at the tibia were approximately 11–12% lower in HIV-infected women. Differences remained significant after adjusting for age, BMI and race/ethnicity. In contrast, cortical porosity was similar in both groups.
Conclusion
Although HIV-infected postmenopausal women had lower aBMD at the spine, total hip and ultradistal radius and higher levels of bone resorption markers, the only differences detected by HRpQCT were lower cortical thickness and area at the tibia.
doi:10.1007/s00223-013-9716-8
PMCID: PMC3656136  PMID: 23460340
HIV; microarchitecture; cortical structure; osteoporosis; postmenopausal women
10.  Lower peak bone mass and abnormal trabecular and cortical microarchitecture in young men infected with HIV early in life 
AIDS (London, England)  2014;28(3):345-353.
Introduction
HIV infection and antiretroviral therapy (ART) early in life may interfere with acquisition of peak bone mass, thereby increasing fracture risk in adulthood.
Methods
We conducted a cross-sectional study of dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) in 30 HIV-infected African–American or Hispanic Tanner stage 5 men aged 20–25 on ART (15 perinatally infected and 15 infected during adolescence) and 15 HIV-uninfected controls.
Results
HIV-infected men were similar in age and BMI, but were more likely to be African–American (P = 0.01) than uninfected men. DXA-derived areal bone mineral density (aBMD) Z-scores were 0.4–1.2 lower in HIV-infected men at the spine, hip, and radius (all P < 0.05). At the radius and tibia, total and trabecular volumetric BMD (vBMD), and cortical and trabecular thickness were between 6 and 19% lower in HIV-infected than uninfected men (P <0.05). HIV-infected men had dramatic deficiencies in plate-related parameters by individual trabeculae segmentation (ITS) analyses and 14–17% lower bone stiffness by finite element analysis revealed. Differences in most HR-pQCT parameters remained significant after adjustment for race/ethnicity. No DXA or HR-pQCT parameters differed between men infected perinatally or during adolescence.
Conclusion
At an age by which young men have typically acquired peak bone mass, HIV-infected men on ART have lower BMD, markedly abnormal trabecular plate and cortical microarchitecture, and decreased whole bone stiffness, whether infected perinatally or during adolescence. Reduced bone strength in young adults infected with HIV early in life may place them at higher risk for fractures as they age.
doi:10.1097/QAD.0000000000000070
PMCID: PMC4019223  PMID: 24072196
bone microarchitecture; bone mineral density; bone strength; high-resolution peripheral quantitative computed tomography; peak bone mass; perinatal HIV infection
11.  PTH(1–84) Administration Reverses Abnormal Bone-Remodeling Dynamics and Structure in Hypoparathyroidism 
Hypoparathyroidism is associated with abnormal structural and dynamic skeletal properties. We hypothesized that parathyroid hormone(1–84) [PTH(1–84)] treatment would restore skeletal properties toward normal in hypoparathyroidism. Sixty-four subjects with hypoparathyroidism were treated with PTH(1–84) for 2 years. All subjects underwent histomorphometric assessment with percutaneous iliac crest bone biopsies. Biopsies were performed at baseline and at 1 or 2 years. Another group of subjects had a single biopsy at 3 months, having received tetracycline before beginning PTH(1–84) and prior to the biopsy (quadruple-label protocol). Measurement of biochemical bone turnover markers was performed. Structural changes after PTH(1–84) included reduced trabecular width (144 ± 34 µm to 128 ± 34 µm, p = 0.03) and increases in trabecular number (1.74 ± 0.34/mm to 2.07 ± 0.50/mm, p = 0.02) at 2 years. Cortical porosity increased at 2 years (7.4% ± 3.2% to 9.2% ± 2.4%, p = 0.03). Histomorphometrically measured dynamic parameters, including mineralizing surface, increased significantly at 3 months, peaking at 1 year (0.7% ± 0.6% to 7.1% ± 6.0%, p = 0.001) and persisting at 2 years. Biochemical measurements of bone turnover increased significantly, peaking at 5 to 9 months of therapy and persisting for 24 months. It is concluded that PTH(1–84) treatment of hypoparathyroidism is associated with increases in histomorphometric and biochemical indices of skeletal dynamics. Structural changes are consistent with an increased remodeling rate in both trabecular and cortical compartments with tunneling resorption in the former. These changes suggest that PTH(1–84) improves abnormal skeletal properties in hypoparathyroidism and restores bone metabolism toward normal euparathyroid levels.
doi:10.1002/jbmr.452
PMCID: PMC4019384  PMID: 21735476
Hypoparathyroidism; PTH(1–84); Bone histomorphometry; Bone turnover markers; Remodeling
12.  Primary Hyperparathyroidism is Associated with Abnormal Cortical and Trabecular Microstructure and Reduced Bone Stiffness in Postmenopausal Women 
Typically, in the milder form of primary hyperparathyroidism (PHPT), seen in most countries now, bone density by DXA and detailed analyses of iliac crest bone biopsies by histomorphometry and µCT show detrimental effects in cortical bone, whereas the trabecular site (lumbar spine by DXA) and the trabecular compartment (by bone biopsy) appear to be relatively well preserved. Despite these findings, fracture risk at both vertebral and non-vertebral sites is increased in PHPT. Emerging technologies, such as high-resolution peripheral quantitative computed tomography (HRpQCT), may provide additional insight into microstructural features at sites such as the forearm and tibia that have heretofore not been easily accessible. Using HRpQCT, we determined cortical and trabecular microstructure at the radius and tibia in 51 postmenopausal women with PHPT and 120 controls. Individual trabecula segmentation (ITS) and micro finite element (µFE) analyses of the HRpQCT images were also performed to further understand how the abnormalities seen by HRpQCT might translate into effects on bone strength. Women with PHPT showed, at both sites, decreased volumetric densities at trabecular and cortical compartments, thinner cortices, and more widely spaced and heterogeneously distributed trabeculae. At the radius, trabeculae were thinner and fewer in PHPT. The radius was affected to a greater extent in the trabecular compartment than the tibia. ITS analyses revealed, at both sites, that plate-like trabeculae were depleted, with a resultant reduction in the plate/rod ratio. Microarchitectural abnormalities were evident by decreased plate-rod and plate-plate junctions at the radius and tibia, and rod-rod junctions at the radius. These trabecular and cortical abnormalities resulted in decreased whole bone stiffness and trabecular stiffness. These results provide evidence that in PHPT, microstructural abnormalities are pervasive and not limited to the cortical compartment. They may help to account for increased global fracture risk in PHPT.
doi:10.1002/jbmr.1841
PMCID: PMC3631282  PMID: 23225022
Primary hyperparathyroidism; high-resolution peripheral quantitative computed tomography; individual trabecula segmentation; finite element analysis; fracture risk
13.  CLINICAL ASSESSMENT OF THE 1/3rd RADIUS USING A NEW DESKTOP ULTRASONIC BONE DENSITOMETER 
Ultrasound in medicine & biology  2013;39(3):388-395.
The objectives of this study were to evaluate the capability of a novel ultrasound device to clinically estimate bone mineral density (BMD) at the 1/3rd radius. The device rests on a desktop and is portable, and permits real-time evaluation of the radial BMD. The device measures two (2) net time delay (NTD) parameters, NTDDW and NTDCW. NTDDW is defined as the difference between the transit time of an ultrasound pulse to travel through soft-tissue, cortex and medullary cavity, and the transit time through soft tissue only of equal overall distance. NTDCW is defined as the difference between the transit time of an ultrasound pulse to travel through soft-tissue and cortex only, and the transit time through soft tissue only again of equal overall distance. The square root of the product of these two parameters is a measure of the radial BMD at the 1/3rd location as measured by dual-energy x-ray absorptiometry (DXA). A clinical IRB-approved study measured ultrasonically sixty adults at the 1/3rd radius. BMD was also measured at the same anatomical site and time using DXA. A linear regression using NTD produced a linear correlation coefficient of 0.93 (P<0.001). These results are consistent with previously reported simulation and in vitro studies. In conclusion, although x-ray methods are effective in bone mass assessment, osteoporosis remains one of the largest undiagnosed and under-diagnosed diseases in the world today. The research described here should enable significant expansion of diagnosis and monitoring of osteoporosis through a desktop device that ultrasonically assesses bone mass at the 1/3rd radius.
doi:10.1016/j.ultrasmedbio.2012.09.024
PMCID: PMC3570600  PMID: 23312957
osteoporosis; bone mineral density; ultrasound; net time delay; DXA; radius
14.  MULTI-CENTER PRECISION OF CORTICAL AND TRABECULAR BONE QUALITY MEASURES ASSESSED BY HR-PQCT 
High-resolution peripheral quantitative computed tomography (HR-pQCT) has recently been introduced as a clinical research tool for in vivo assessment of bone quality. The utility of this technique to address important skeletal health questions requires translation to standardized multi-center data pools. Our goal was to evaluate the feasibility of pooling data in multi-center HR-pQCT imaging trials.
Reproducibility imaging experiments were performed using structure and composition-realistic phantoms constructed from cadaveric radii. Single-center precision was determined by repeat scanning over short (<72hrs), intermediate (3–5mo), and long-term intervals (28mo). Multi-center precision was determined by imaging the phantoms at nine different HR-pQCT centers. Least significant change (LSC) and root mean squared coefficient of variation (RMSCV) for each interval and across centers was calculated for bone density, geometry, microstructure, and biomechanical parameters.
Single-center short-term RMSCVs were <1% for all parameters except Ct.Th (1.1%), Ct.Th.SD (2.6%), Tb.Sp.SD (1.8%), and porosity measures (6–8%). Intermediate-term RMSCVs were generally not statistically different from short-term values. Long-term variability was significantly greater for all density measures (0.7–2.0%; p < 0.05 vs. short-term) and several structure measures: Ct.Th (3.4%; p < 0.01 vs. short-term), Ct.Po (15.4%; p < 0.01 vs. short-term), and Tb.Th (2.2%; p < 0.01 vs. short-term). Multi-center RMSCVs were also significantly higher than short-term values: 2–4% for density and µFE measures (p < 0.0001), 2.6–5.3% for morphometric measures (p < 0.001), while Ct.Po was 16.2% (p < 0.001).
In the absence of subject motion, multi-center precision errors for HR-pQCT parameters were generally less than 5%. Phantom-based multi-center precision was comparable to previously reported in vivo single-center precision errors, although this was approximately 2–5 times worse than ex vivo short-term precision. The data generated from this study will contribute to the future design and validation of standardized procedures that are broadly translatable to multi-center study designs.
doi:10.1002/jbmr.1795
PMCID: PMC3577969  PMID: 23074145
HR-pQCT; osteoporosis; precision; bone; microstructure; bone strength; multi-center studies
15.  Dynamics of bone turnover markers in patients with heart failure and following haemodynamic improvement through ventricular assist device implantation 
European Journal of Heart Failure  2012;14(12):1356-1365.
Aims
Abnormal bone metabolism and progressive demineralization have been described in patients with heart failure (HF). We hypothesized that mechanical unloading through implantation of a ventricular assist device (VAD) with subsequent haemodynamic improvement would correct abnormal bone metabolism in patients with advanced HF.
Methods and results
Serum was collected from 14 controls, 20 patients with moderate HF, 34 patients with advanced HF undergoing VAD implantation, and 34 patients at the time of VAD explantation (mean duration: 169 ± 125 days). Bone metabolism markers were measured using enzyme-linked immunosorption assay (ELISA) or chemiluminescence immunoassay (CLIA). Compared with controls, HF patients showed increased parathyroid hormone (PTH: 42 ± 19 vs. 117 ± 117 pg/mL in HF; P < 0.02) with decreased 25-hydroxyvitamin D [25(OH)D: 29 ± 14 vs. 21 ± 11 ng/mL in HF; P = 0.05]. While procollagen-1 N-terminal peptide (P1NP) and osteocalcin were similar, cross-linked C- and N-telopeptides of type I collagen (CTX and NTX) were both higher in HF (NTX: 14 ± 6 vs. 20 ± 11 ng/mL; P < 0.05; CTX: 0.35 ± 0.13 vs. 1.05 ± 0.78 ng/mL; P < 0.01 for controls and HF, respectively). P1NP increased markedly after VAD implantation (49 ± 37 vs. 121 ± 62 ng/mL; P < 0.0001), with a mild decrease in CTX and NTX levels indicating a shift towards anabolic bone formation. Serum PTH correlated with estimated glomerular filtration rate (r = –0.245, P < 0.05).
Conclusion
Patients with advanced HF are characterized by increased levels of biochemical markers of bone resorption potentially as a result of secondary hyperparathyroidism and uncoupling of bone remodelling. Haemodynamic improvement and mechanical unloading after VAD implantation lead to correction of bone metabolism and increased levels of anabolic bone formation markers.
doi:10.1093/eurjhf/hfs138
PMCID: PMC3598377  PMID: 22989867
Heart failure; Bone metabolism; Ventricular assist; Device
16.  Pancreas-kidney transplantation is associated with reduced fracture risk compared to kidney alone transplantation in men with type 1 diabetes 
Kidney international  2013;83(3):471-478.
Both type 1 diabetes mellitus and end stage renal disease are associated with increased fracture risk, likely due to metabolic abnormalities that reduce bone strength. Simultaneous pancreas-kidney transplantation is a treatment of choice for patients with both disorders, yet the effects of simultaneous pancreas-kidney versus kidney transplantation alone on post-transplantation fracture risk are unknown. From the United States Renal Data System we identified 11, 145 adults with type 1 diabetes undergoing transplantation of whom 4,933 had a simultaneous pancreas-kidney while 6, 212 had a kidney alone transplant between 2000 and 2006. Post-transplantation fractures resulting in hospitalization were identified from discharge codes. Time to first fracture was modeled and propensity score adjustment was used to balance covariates between groups. Fractures occurred in significantly fewer (4.7%) of pancreas-kidney compared to kidney-alone transplant (5.9%) cohorts. After gender stratification and adjustment for fracture covariates, pancreas-kidney transplantation was associated with a significant 31% reduction in fracture risk in men (hazard risk 0.69). Older age, white race, prior dialysis and pre transplantation fracture were also associated with increased fracture risk. Prospective studies are needed to determine the gender-specific mechanisms by which pancreas-kidney transplantation reduces fracture risk in men.
doi:10.1038/ki.2012.430
PMCID: PMC3587361  PMID: 23283136
pancreas-kidney transplantation; fracture; kidney; diabetes; renal; gender differences; USRDS
17.  Vitamin D Deficiency Is Prevalent in Morbidly Obese Adolescents Prior to Bariatric Surgery 
ISRN obesity  2013;2013:284516.
Background
Obese adults are frequently vitamin D deficient before bariatric surgery; whether similar abnormalities exist in morbidly obese adolescents is unknown.
Objective
To determine the prevalence of vitamin D deficiency in morbidly obese adolescents.
Methods
Cross-sectional study of preoperative laboratory measures from 236 adolescents evaluated for bariatric surgery.
Results
The group (N = 219 with 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) levels; 76 boys, 143 girls; 15.9 ± 1.2 years; 43% Caucasian, 35% Hispanic, and 15% African American) had mean BMI of 47.6 ± 8.1 kg/m2. 25OHD levels were deficient (<20 ng/mL) in 53%; 8% had severe deficiency (<10 ng/mL); only 18% of patients were replete (>30 ng/mL). 25OHD levels were inversely associated with BMI (r = −0.28, < 0.0001) and PTH levels (r = −0.24, P = 0.0003). Race was the strongest predictor of 25OHD (P < 0.002); 82% of African Americans, 59% of Hispanics, and 37% of Caucasians were deficient. African American race, BMI, and PTH explained 21% of the variance in 25OHD (P < 0.0001).
Conclusions
Most adolescents presenting for bariatric surgery have suboptimal vitamin D levels, with African Americans and those with higher BMIs at greatest risk for vitamin D deficiency. All morbidly obese adolescents should be screened for vitamin D deficiency before bariatric procedures.
doi:10.1155/2013/284516
PMCID: PMC3664934  PMID: 23724340
18.  Vitamin D Deficiency Is Prevalent in Morbidly Obese Adolescents Prior to Bariatric Surgery 
ISRN Obesity  2013;2013:284516.
Background. Obese adults are frequently vitamin D deficient before bariatric surgery; whether similar abnormalities exist in morbidly obese adolescents is unknown. Objective. To determine the prevalence of vitamin D deficiency in morbidly obese adolescents. Methods. Cross-sectional study of preoperative laboratory measures from 236 adolescents evaluated for bariatric surgery. Results. The group (N = 219 with 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) levels; 76 boys, 143 girls; 15.9 ± 1.2 years; 43% Caucasian, 35% Hispanic, and 15% African American) had mean BMI of 47.6 ± 8.1 kg/m2. 25OHD levels were deficient (<20 ng/mL) in 53%; 8% had severe deficiency (<10 ng/mL); only 18% of patients were replete (>30 ng/mL). 25OHD levels were inversely associated with BMI (r = −0.28, P < 0.0001) and PTH levels (r = −0.24, P = 0.0003). Race was the strongest predictor of 25OHD (P < 0.002); 82% of African Americans, 59% of Hispanics, and 37% of Caucasians were deficient. African American race, BMI, and PTH explained 21% of the variance in 25OHD (P < 0.0001). Conclusions. Most adolescents presenting for bariatric surgery have suboptimal vitamin D levels, with African Americans and those with higher BMIs at greatest risk for vitamin D deficiency. All morbidly obese adolescents should be screened for vitamin D deficiency before bariatric procedures.
doi:10.1155/2013/284516
PMCID: PMC3664934  PMID: 23724340
19.  Individual Trabecula Segmentation (ITS)-Based Morphological Analyses and Micro Finite Element Analysis of HR-pQCT Images Discriminate Postmenopausal Fragility Fractures Independent of DXA Measurements 
Osteoporosis is typically diagnosed by dual energy x-ray absorptiometry (DXA) measurements of areal bone mineral density (aBMD). Emerging technologies, such as high-resolution peripheral quantitative computed tomography (HR-pQCT), may increase the diagnostic accuracy of DXA and enhance our mechanistic understanding of decreased bone strength in osteoporosis. Women with (n=68) and without (n=101) a history of postmenopausal fragility fracture had aBMD measured by DXA, trabecular plate and rod microarchitecture measured by HR-pQCT image-based individual trabeculae segmentation (ITS) analysis, and whole bone and trabecular bone stiffness by micro finite element analysis (μFEA) of HR-pQCT images at the radius and tibia. DXA T-scores were similar in women with and without fractures at the spine, hip and 1/3 radius, but lower in fracture subjects at the ultradistal radius. Trabecular microarchitecture of fracture subjects was characterized by preferential reductions in trabecular plate bone volume, number, and connectivity over rod trabecular parameters, loss of axially aligned trabeculae, and a more rod-like trabecular network. In addition, decreased thickness and size of trabecular plates were observed at the tibia. The differences between groups were greater at the radius than the tibia for plate number, rod bone volume fraction and number and plate-rod and rod-rod junction densities. Most differences between groups remained after adjustment for T-score by DXA. At a fixed bone volume fraction, trabecular plate volume, number and connectivity were directly associated with bone stiffness. In contrast, rod volume, number and connectivity were inversely associated with bone stiffness. In summary, HR-pQCT-based ITS and μFEA measurements discriminate fracture status in postmenopausal women independent of DXA measurements. Moreover, these results suggest that preferential loss of plate-like trabeculae contribute to lower trabecular bone and whole bone stiffness in women with fractures. We conclude that HR-pQCT-based ITS and μFEA measurements increase our understanding of the microstructural pathogenesis of fragility fracture in postmenopausal women.
doi:10.1002/jbmr.562
PMCID: PMC3290758  PMID: 22072446
bone micarchitecture; high-resolution peripheral quantitative computed tomography; individual trabecula segmentation; trabecular plate/rod; fragility fractures
20.  Differences in Bone Microarchitecture Between Postmenopausal Chinese-American and White Women 
Chinese-American women have lower rates of hip and forearm fracture than white women despite lower areal bone density (aBMD) by dual X-ray absorptiometry (DXA). We recently reported higher trabecular (Dtrab) and cortical (Dcomp) bone density as well as greater trabecular (Tb.Th) and cortical thickness (C.Th) but smaller bone area (CSA), as measured by high-resolution peripheral quantitative computed tomography (HR-pQCT), in premenopausal Chinese-American compared with white women. These findings may help to account for the lower fracture rate among Chinese-American women but were limited to measurements in premenopausal women. This study was designed to extend these investigations to postmenopausal Chinese-American (n = 29) and white (n = 68) women. Radius CSA was 10% smaller in the Chinese-American versus the white group (p = .008), whereas their C.Th and Dcomp values were 18% and 6% greater (p < .001 for both). Tibial HR-pQCT results for cortical bone were similar to the radius, but Tb.Th was 11% greater in Chinese-American versus white women (p = .007). Tibial trabecular number and spacing were 17% lower and 20% greater, respectively, in Chinese-American women (p < .0001 for both). There were no differences in trabecular or whole-bone stiffness estimated by microstructural finite-element analysis, but Chinese-American women had a greater percentage of load carried by the cortical bone compartment at the distal radius and tibia. There was no difference in load distribution at the proximal radius or tibia. Whole-bone finite-element analysis may indicate that the thicker, more dense cortical bone and thicker trabeculae in postmenopausal Chinese-American women compensate for fewer trabeculae and smaller bone size.
doi:10.1002/jbmr.352
PMCID: PMC3558983  PMID: 21305606
RACE; VOLUMETRIC BONE DENSITY; MICROARCHITECTURE; CHINESE; WHITE; POSTMENOPAUSAL; DXA; HR-PQCT
21.  Leptin Administration Does Not Prevent the Bone Mineral Metabolism Changes Induced by Weight Loss 
Objective
To examine the effects of weight loss and leptin administration following weight loss on calciotropic hormones and bone turnover.
Materials/Methods
This was a prospective, single blinded study of twelve subjects (8 women, 4 men; 2 non-obese, 10 obese; age range 19–46 years) who were studied on an in-patient basis while maintaining their usual weight [Wtinitial], and during maintenance of 10% weight loss while receiving twice daily injections of either a placebo [Wt−10%P] or replacement doses of leptin [Wt−10%L]. The main outcome measures were markers of bone formation (bone alkaline phosphatase and procollagen type 1 amino terminal propeptide), and resorption (N-telopeptide) as well as parathyroid hormone, calcium and 25-hydroxy vitamin D measured from fasting morning serum.
Results
As expected, serum leptin declined with weight loss. Bone alkaline phosphatase decreased by 12.3 ± 3.9% between Wtinitial and Wt−10%P, and remained suppressed after leptin administration (both P<0.01 compared to baseline). N-telopeptides increased by 37.2 ± 11.3% from Wtinitial to Wt−10%L (P<0.01). Procollagen type 1 amino terminal propeptide, parathyroid hormone, calcium and 25-hydroxy vitamin D did not change.
Conclusions
These results suggest that both decreased bone formation and increased bone resorption underlie bone loss associated with weight loss. Leptin administration did not prevent the uncoupling of bone remodeling that accompanies weight loss.
doi:10.1016/j.metabol.2011.02.010
PMCID: PMC3139754  PMID: 21489573
leptin; bone; weight loss
22.  Normal Vitamin D and Low Free Estradiol in Women on Enzyme-Inducing Antiepileptic Drugs 
Epilepsy & behavior : E&B  2011;21(4):453-458.
Relationships between reproductive hormones, bone turnover markers (BTMs), bone mineral density (BMD) and rates of bone loss were evaluated in premenopausal women with epilepsy on enzyme inducing antiepileptic drugs (EIAEDs; phenytoin or carbamazepine) or lamotrigine. Calciotropic and reproductive hormones,, BTMs, and BMD were measured at baseline and one year. BMD did not differ between groups. Serum calcium (p<0.001) and estrone (p<0.001) were lower in the EIAED group. Sex hormone binding globulin (SHBG) was higher (p<0.001) and percent free estradiol was lower (p<0.001) in the EIAED group. We detected no relationship between BMD change and calciotropic hormones or BTMs. Women with higher SHBG and lower free estradiol sustained more bone loss at the total hip (p=0.04 and p=0.02) and a trend toward more bone loss at the lumbar spine (p=0.07 and p=0.08). These findings suggest that lower estrogen levels may contribute to bone loss in premenopausal women with epilepsy.
doi:10.1016/j.yebeh.2011.05.001
PMCID: PMC3156279  PMID: 21704565
Epilepsy; antiepileptic drugs; vitamin D; estradiol
23.  Vitamin D Deficiency Influences Histomorphometric Features of Bone in Primary Hyperparathyroidism 
Bone  2010;48(3):557-561.
Introduction
Vitamin D deficiency is common in patients with primary hyperparathyroidism (PHPT). The presence of low levels of vitamin D may affect the skeletal consequences of PHPT.
Methods
In this cross-sectional study, transiliac crest bone biopsies were performed after double tetracycline labeling in patients with mild PHPT and analyzed according to serum levels of 25 hydroxyvitamin D (25OHD).
Results
We studied 30 patients with mild PHPT (age 53±11 years; 67% women; calcium 11.1±1.0 mg/dl; PTH 149±129 pg/ml). Serum 25OHD levels were low in the majority of subjects (mean 21±11 ng/ml) and inversely associated with PTH (r=-0.69; p<0.01). 25OHD levels were directly associated with cortical width (Ct.Wi; r=0.46, p<0.03) and trabecular separation (Tb.Sp; r=0.41; p<0.04), but inversely associated with cancellous bone volume (BV/TV; r=-0.39, p<0.04). Subjects with 25OHD levels <20 ng/ml (n=14) and ≥20 ng/ml (n=16) were compared. Groups did not differ by age, sex, menopausal status, serum calcium, creatinine, or 1,25(OH)2D. PTH was 1.8-fold higher in subjects with 25OHD <20 (265±166 pg/ml vs. 95±50 pg/ml; p <0.01). On histomorphometric analysis, those with low 25OHD had lower Ct.Wi (541±167 μm vs. 712±200 μm; p<0.03). Conversely, measures of trabecular microarchitecture were better in those with lower 25OHD, with higher BV/TV (26.1±6.1 % vs. 20.4±6.4 %; p<0.03), greater trabecular number (Tb.N: 2.0±0.4 mm -1 vs. 1.8±0.4 mm -1; p<0.04) and lower Tb.Sp (371±90 μm vs. 472±137 μm; p<0.04). There were no differences between the groups in bone remodeling indices.
Conclusions
Low levels of 25OHD in patients with PHPT are associated with higher concentrations of PTH, greater catabolic effects in cortical bone and greater anabolic effects in trabecular bone.
doi:10.1016/j.bone.2010.10.004
PMCID: PMC3039097  PMID: 20950725
Primary hyperparathyroidism; secondary hyperparathyroidism; vitamin D deficiency; histomorphometry; cortical bone
24.  Abnormal Microarchitecture and Reduced Stiffness at the Radius and Tibia in Postmenopausal Women With Fractures 
Journal of Bone and Mineral Research  2010;25(12):2572-2581.
Measurement of areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry (DXA) has been shown to predict fracture risk. High-resolution peripheral quantitative computed tomography (HR-pQCT) yields additional information about volumetric BMD (vBMD), microarchitecture, and strength that may increase understanding of fracture susceptibility. Women with (n = 68) and without (n = 101) a history of postmenopausal fragility fracture had aBMD measured by DXA and trabecular and cortical vBMD and trabecular microarchitecture of the radius and tibia measured by HR-pQCT. Finite-element analysis (FEA) of HR-pQCT scans was performed to estimate bone stiffness. DXA T-scores were similar in women with and without fracture at the spine, hip, and one-third radius but lower in patients with fracture at the ultradistal radius (p < .01). At the radius fracture, patients had lower total density, cortical thickness, trabecular density, number, thickness, higher trabecular separation and network heterogeneity (p < .0001 to .04). At the tibia, total, cortical, and trabecular density and cortical and trabecular thickness were lower in fracture patients (p < .0001 to .03). The differences between groups were greater at the radius than at the tibia for inner trabecular density, number, trabecular separation, and network heterogeneity (p < .01 to .05). Stiffness was reduced in fracture patients, more markedly at the radius (41% to 44%) than at the tibia (15% to 20%). Women with fractures had reduced vBMD, microarchitectural deterioration, and decreased strength. These differences were more prominent at the radius than at the tibia. HR-pQCT and FEA measurements of peripheral sites are associated with fracture prevalence and may increase understanding of the role of microarchitectural deterioration in fracture susceptibility. © 2010 American Society for Bone and Mineral Research.
doi:10.1002/jbmr.152
PMCID: PMC3149820  PMID: 20564238
MICROARCHITECTURE; STIFFNESS; FRACTURE; OSTEOPOROSIS; POSTMENOPAUSAL
25.  Fracture incidence in HIV-infected women: results from the Women’s Interagency HIV Study 
AIDS (London, England)  2010;24(17):2679-2686.
Background
The clinical importance of the association of HIV infection and antiretroviral therapy (ART) with low bone mineral density (BMD) in premenopausal women is uncertain because BMD stabilizes on established ART and fracture data are limited.
Methods
We measured time to first new fracture at any site with median follow-up of 5.4 years in 2391 (1728 HIV-infected, 663 HIV-uninfected) participants in the Women’s Interagency HIV Study (WIHS). Self-report of fracture was recorded at semiannual visits. Proportional hazard models assessed predictors of incident fracture.
Results
At baseline, HIV-infected women were older (40 ± 9 vs. 36 ± 10 years, P <0.0001), more likely to report postmenopausal status and be hepatitis C virus-infected, and weighed less than HIV-uninfected women. Among HIV-infected women, mean CD4+ cell count was 482 cells/μl; 66% were taking ART. Unadjusted incidence of fracture did not differ between HIV-infected and uninfected women (1.8 vs. 1.4/100 person-years, respectively, P = 0.18). In multivariate models, white (vs. African-American) race, hepatitis C virus infection, and higher serum creatinine, but not HIV serostatus, were statistically significant predictors of incident fracture. Among HIV-infected women, older age, white race, current cigarette use, and history of AIDS-defining illness were associated with incidence of new fracture.
Conclusion
Among predominantly premenopausal women, there was little difference in fracture incidence rates by HIV status, rather traditional risk factors were important predictors. Further research is necessary to characterize fracture risk in HIV-infected women during and after the menopausal transition.
doi:10.1097/QAD.0b013e32833f6294
PMCID: PMC3108019  PMID: 20859192
fracture; fragility fracture; HIV-infected women; premenopausal

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