Abnormal Skeletal Strength and Microarchitecture in Women With Celiac Disease.

CONTEXT: Osteoporosis is often a presenting sign of celiac disease (CD). Whether skeletal fragility in CD is associated with microarchitectural abnormalities is not known. OBJECTIVE: The objective of the study was to evaluate microarchitecture and biomechanical properties of bone in CD. DESIGN: This was a case-control study. SETTING: The study was conducted at a university hospital outpatient facility. PATIENTS: Patients included premenopausal women with newly diagnosed CD (n = 33) and healthy controls (n = 33). MAIN OUTCOME MEASURES: Areal bone mineral density by dual-energy x-ray absorptiometry was measured as was trabecular and cortical volumetric bone mineral density (vBMD) and microarchitecture by high-resolution peripheral computed tomography of the distal radius and tibia. Whole-bone stiffness estimated by finite element analysis. PTH, 25-hydroxyvitamin D, and bone turnover markers were also measured. RESULTS: Groups had similar age, race, and body mass index. Both groups had sufficient 25-hydroxyvitamin D and normal calcium and PTH. Areal bone mineral density was lower in CD. By high-resolution peripheral computed tomography, CD had lower trabecular vBMD, fewer, more widely, and irregularly spaced trabeculae at both the radius and tibia (8%-33%). At the tibia, they also had lower total density (8%) and thinner cortices (10%). Whole-bone stiffness and failure load were lower (11%-21%) in CD at both sites. Biomechanical deficits were associated with trabecular abnormalities. CONCLUSIONS: Women with CD had abnormal vBMD and microarchitecture at both the radius and tibia. Trabecular bone was preferentially affected. These deficits were associated with lower estimates of skeletal strength. These findings suggest a potential structural mechanism for skeletal fragility in CD and support further research into the pathogenesis of fracture in this population.

Teriparatide increases strength of the peripheral skeleton in premenopausal women with idiopathic osteoporosis: a pilot HR-pQCT study.

CONTEXT: In premenopausal women with idiopathic osteoporosis (IOP), treatment with teriparatide leads to substantial improvement in bone density and quality at central skeletal sites. The effects of teriparatide may differ on cortical and trabecular bone and also at the central and the peripheral skeleton. OBJECTIVE: The objective of the study was to determine whether teriparatide was associated with improvements in compartmental volumetric bone mineral density (BMD), bone microarchitecture, and estimated bone strength of the distal radius and tibia as assessed by high-resolution peripheral quantitative computed tomography. DESIGN, SETTING, AND PARTICIPANTS: Premenopausal women (n = 20, age 41 ± 5 y) with IOP (low trauma fractures and/or Z-scores ≤ -2.0) were scanned with high-resolution peripheral quantitative computed tomography at baseline and after 18 months of teriparatide treatment. Cortical and trabecular volumetric BMD and microarchitecture were measured by both standard and advanced techniques, including individual trabecula segmentation, and bone strength was estimated by finite element analysis. MAIN OUTCOME MEASURES: The total volumetric BMD and homogeneous bone stiffness were measured. RESULTS: Trabecular volumetric BMD increased significantly by 2.6% (1.8, 6.2) [median (interquartile range)] at the radius and 2.5% (1.1, 3.6) at the tibia. In addition, trabecular plate bone volume fraction increased by 9.1% (2.1, 17.1) at the radius and 7.6% (1.0, 9.7) at the tibia. Cortical thickness and volumetric density did not change; however, cortical porosity increased at the radius but not at the tibia. Despite these changes, whole-bone stiffness and failure load estimated by finite element analysis increased at both the radius and tibia. CONCLUSIONS: In premenopausal women with IOP, 18 months of teriparatide was associated with increases in trabecular volumetric BMD, improved trabecular microarchitecture, and estimated bone strength at both the radius and tibia.

Association between serum 25-hydroxyvitamin D level and subclinical cardiovascular disease in primary hyperparathyroidism.

CONTEXT: Vitamin D (25OHD) deficiency may be a modifiable cardiovascular (CV) risk factor. 25OHD insufficiency (20-29 ng/mL) and deficiency (<20 ng/mL) are common in primary hyperparathyroidism (PHPT), but their association with CV disease in PHPT has not been systematically investigated. OBJECTIVE: This study evaluated whether low 25OHD is associated with subclinical CV disease in PHPT. DESIGN: This is a cross-sectional analysis of PHPT patients with and without low 25OHD. SETTINGS AND PARTICIPANTS: We studied 110 PHPT patients in a university hospital setting. OUTCOME MEASURES: We measured carotid intima-media thickness; carotid plaque presence/thickness; carotid strain and stiffness; left ventricular mass index; cardiac systolic and diastolic function; and mitral annular calcification. RESULTS: Low 25OHD levels (<30 ng/mL) were observed in 28%, but only 9% had 25OHD deficiency (<20 ng/mL). In the whole group, 25OHD levels negatively correlated with body mass index (r = -0.33, P = .0005), PTH (r = -0.30, P = .001), calcium (r = -0.29, P = .002), renal function, and PHPT duration. CV indices were normal except for carotid intima-media thickness, stiffness, and plaque thickness, which were increased, regardless of 25OHD status. Isovolumic relaxation time was the only CV measure associated with 25OHD (r = -0.26, P = .01). Those with 25OHD less than 20 ng/mL had more severe PHPT and a higher rate of nephrolithiasis. Those with 25OHD less than 30 ng/mL were younger, had higher body mass index, had lower serum phosphate, and were more likely to be male, nonwhite, and Hispanic. Other than lower tissue Doppler e' and higher isovolumic relaxation time within normal range in those with 25OHD less than 30 vs greater than 30 ng/mL, there were no differences in CV indices using either 25OHD threshold. CONCLUSIONS: Patients with mild PHPT have subclinical carotid abnormalities, but low 25OHD is not associated with abnormal carotid or cardiac measures. To the extent that PTH levels differentiated those with 25OHD less than 20 but not 30 ng/mL, these data support a 25OHD threshold of 20 ng/mL as clinically relevant in PHPT.

Rates and determinants of ventriculostomy-related infections during a hospital transition to use of antibiotic-coated external ventricular drains.

OBJECT: The authors evaluated the rates of ventriculostomy-related infections (VRIs) after antibiotic-coated extraventricular drains (ac-EVDs) were introduced as the standard of care. METHODS: A retrospective chart review was conducted of adult patients admitted to NewYork-Presbyterian Hospital neurological intensive care unit in whom an EVD was placed between February 2007 and November 2009, excluding individuals receiving EVDs due to an infection of a primary device. Three time periods were defined depending on type of EVD in use: Period 1, conventional EVDs; Period 2, either ac-EVDs or conventional EVDs; and Period 3, ac-EVDs. Definite/probable VRIs that occurred during the 3 periods were evaluated and established as determinants of VRIs by using a Cox proportional hazards model. Prolonged systemic antibiotics were given for the duration of EVD placement in each of the 3 periods per institutional policy. RESULTS: Data from 141 individuals were evaluated; mean patient age was 53.8 ± 17.2 years and 54% were female. There were 2 definite and 19 probable VRIs. The incidence of definite/probable VRI (per 1000 person-catheter days) decreased from Period 1 to 3 (24.5, 16.2, and 4.4 in Periods 1, 2, and 3, respectively; p < 0.0001). Patients with VRIs were more likely to be female than male (23.7% vs 3.1%, p < 0.003) and have had an EVD in place for a longer duration, although there was no significant difference among the 3 periods (7.9 ± 6.7 [Period 1], 8.1 ± 7.1 [Period 2], and 8.6 ± 5.8 [Period 3] mean days; p = 0.87, ANOVA). Analysis of effect modification in a stepwise model showed that period, age, and age and female interaction were significant predictors of VRIs. The period was the strongest predictor of VRI (p = 0.0075). After adjustment for age and age and sex interaction, the survival rate was 53% at the end of Period 2 and 91% at the end of Period 3. CONCLUSIONS: Rates of VRIs have decreased with the addition of ac-EVDs to the routine use of prolonged systemic antibiotics at the authors' institution.

Teriparatide for idiopathic osteoporosis in premenopausal women: a pilot study.

CONTEXT: Premenopausal women with idiopathic osteoporosis (IOP) have abnormal cortical and trabecular bone microarchitecture. OBJECTIVE: The purpose of this study was to test the hypotheses that teriparatide increases bone mineral density (BMD) and bone formation and improves trabecular microarchitecture and stiffness in women with IOP. DESIGN: This was an open-label pilot study. SETTING: The setting was a tertiary care referral center. PATIENTS: Participants were 21 premenopausal women with unexplained fragility fractures or low BMD. INTERVENTION: Teriparatide was administered at 20 µg daily for 18 to 24 months. MAIN OUTCOME MEASURES: The primary endpoint was within-subject percent change in lumbar spine BMD. Secondary endpoints included percent change in hip and forearm BMD, transiliac biopsy parameters (trabecular bone volume, microarchitecture, stiffness, and adipocytes), serum N-terminal propeptide of procollagen type 1 (P1NP), and C-telopeptide. RESULTS: BMD increased at the spine (10.8 ± 8.3% [SD]), total hip (6.2 ± 5.6%), and femoral neck (7.6 ± 3.4%) (all P < .001). Serum P1NP doubled by 1 month, peaked at 6 months, and returned to baseline by 18 to 24 months. Transiliac biopsies demonstrated significant increases in cortical width and porosity and trabecular bone volume and number increased, mirrored by a 71% increase in trabecular bone stiffness (P < .02-.001). Adipocyte area, perimeter, and volume/marrow volume decreased, with no change in adipocyte number. Four women had no increase in BMD and a blunted, delayed increase in serum P1NP. Nonresponders had markedly lower baseline bone formation rate (0.002 ± 0.001 vs 0.011 ± 0.006 mm²/mm/y; P < .001) and higher serum IGF-1 (208 ± 54 vs 157± 44 ng/mL; P = .03). CONCLUSIONS: Teriparatide was associated with increased spine and hip BMD and improved trabecular microarchitecture and stiffness at the iliac crest in the majority of women with IOP.

Abdominal fat is associated with lower bone formation and inferior bone quality in healthy premenopausal women: a transiliac bone biopsy study.

CONTEXT: The conventional view that obesity is beneficial for bone strength has recently been challenged by studies that link obesity, particularly visceral obesity, to low bone mass and fractures. It is controversial whether effects of obesity on bone are mediated by increased bone resorption or decreased bone formation. OBJECTIVE: The objective of the study was to evaluate bone microarchitecture and remodeling in healthy premenopausal women of varying weights. DESIGN: We measured bone density and trunk fat by dual-energy x-ray absorptiometry in 40 women and by computed tomography in a subset. Bone microarchitecture, stiffness, remodeling, and marrow fat were assessed in labeled transiliac bone biopsies. RESULTS: Body mass index (BMI) ranged from 20.1 to 39.2 kg/m(2). Dual-energy x-ray absorptiometry-trunk fat was directly associated with BMI (r = 0.78, P < .001) and visceral fat by computed tomography (r = 0.79, P < .001). Compared with women in the lowest tertile of trunk fat, those in the highest tertile had inferior bone quality: lower trabecular bone volume (20.4 ± 5.8 vs 29.1 ± 6.1%; P = .001) and stiffness (433 ± 264 vs 782 ± 349 MPa; P = .01) and higher cortical porosity (8.8 ± 3.5 vs 6.3 ± 2.4%; P = .049). Bone formation rate (0.004 ± 0.002 vs 0.011 ± 0.008 mm(2)/mm · year; P = .006) was 64% lower in the highest tertile. Trunk fat was inversely associated with trabecular bone volume (r = -0.50; P < .01) and bone formation rate (r = -0.50; P < .001). The relationship between trunk fat and bone volume remained significant after controlling for age and BMI. CONCLUSIONS: At the tissue level, premenopausal women with more central adiposity had inferior bone quality and stiffness and markedly lower bone formation. Given the rising levels of obesity, these observations require further investigation.

Bariatric surgery results in cortical bone loss.

BACKGROUND: Bariatric surgery results in bone loss at weight-bearing sites, the mechanism of which is unknown. METHODS: Twenty-two women (mean body mass index 44 kg/m(2); aged 45 years) who underwent Roux-en-Y gastric bypass (n = 14) and restrictive procedures (n = 8) had measurements of areal bone mineral density by dual-energy x-ray absorptiometry at the lumbar spine, total hip (TH), femoral neck (FN), and one third radius and trabecular and cortical volumetric bone mineral density and microstructure at the distal radius and tibia by high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and 12 months postoperatively. RESULTS: Mean weight loss was 28 ± 3 kg (P < .0001). PTH rose 23% (P < .02) and 25-hydroxyvitamin D was stable. C-telopeptide increased by 144% (P < .001). Bone-specific alkaline phosphatase did not change. Areal bone mineral density declined at TH (-5.2%; P < .005) and FN (-4.5%; P < .005). By HR-pQCT, trabecular parameters were stable, whereas cortical bone deteriorated, particularly at the tibia: cortical area (-2.7%; P < .01); cortical thickness (-2.1%; P < .01); total density (-1.3%; P = .059); cortical density (-1.7%; P < .01). In multivariate regression, bone loss at the TH and FN were predicted by weight loss. In contrast, only PTH increase predicted cortical deterioration at the tibia. Roux-en-Y gastric bypass patients lost more weight, had more bone loss by dual-energy x-ray absorptiometry and HR-pQCT than those with restrictive procedures, and had declines in cortical load share estimated by finite element analysis. CONCLUSIONS: After bariatric surgery, hip bone loss reflects skeletal unloading and cortical bone loss reflects secondary hyperparathyroidism. This study highlights deterioration of cortical bone loss as a novel mechanism for bone loss after bariatric surgery.

Clinical assessment of the 1/3 radius using a new desktop ultrasonic bone densitometer.

The objectives of this study were to evaluate the capability of a novel ultrasound device to clinically estimate bone mineral density (BMD) at the 1/3 radius. The device rests on a desktop and is portable, and permits real-time evaluation of the radial BMD. The device measures two net time delay (NTD) parameters, NTD(DW) and NTD(CW). NTD(DW) 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. NTD(CW) 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 1/3 location as measured by dual-energy X-ray absorptiometry (DXA). A clinical IRB-approved study measured ultrasonically 60 adults at the 1/3 radius. BMD was also measured at the same anatomic 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 1/3 radius.

Zoledronic acid versus alendronate for the prevention of bone loss after heart or liver transplantation.

CONTEXT: The first year after transplantation is characterized by rapid bone loss. OBJECTIVE: The aim of this study was to compare zoledronic acid (zoledronate) and alendronate for prevention of transplantation bone loss. DESIGN AND SETTING: A randomized clinical trial was conducted at a transplantation center. PATIENTS: The study included 84 adults undergoing heart or liver transplantation and a concurrently transplanted, nonrandomized reference group of 27 adults with T scores greater than -1.5. INTERVENTIONS: Alendronate (70 mg weekly for 12 months) or one 5-mg infusion of zoledronate were both initiated 26 ± 8 d after transplantation. MAIN OUTCOME MEASURES: The primary outcome was total hip bone mineral density (BMD) 1 yr after transplantation. Secondary outcomes included femoral neck and lumbar spine BMD and serum C-telopeptide, a bone resorption marker. RESULTS: In the reference group, BMD declined at the spine and hip (P < 0.001). In the randomized groups, hip BMD remained stable. Spine BMD increased in the zoledronate group and did not change in the alendronate group; at 12 months, the 2.2% difference between groups (95% confidence interval, 0.6 to 3.9%; P = 0.009) favored zoledronate. In heart transplant patients, spine BMD declined in the alendronate and increased in the zoledronate group (-3.0 vs. +1.6%, respectively; between-group difference, 4.2%; 95% confidence interval, 2.1 to 6.3%; P < 0.001). In liver transplant patients, spine BMD increased comparably in both groups. Twelve-month C-telopeptide was lower in the zoledronate group than in the alendronate group (79 vs. 49%; P = 0.04). CONCLUSIONS: One 5-mg infusion of zoledronate and weekly alendronate prevent bone loss at the hip and, in liver transplant patients, increase spine BMD. In heart transplant patients, spine bone BMD remained stable with zoledronate but decreased with alendronate.

Central QCT reveals lower volumetric BMD and stiffness in premenopausal women with idiopathic osteoporosis, regardless of fracture history.

CONTEXT: Idiopathic osteoporosis (IOP) affects otherwise healthy young individuals with intact gonadal function and no secondary cause of bone fragility. In premenopausal women with IOP, a low trauma fracture is evidence of impaired bone quality and strength. The extent to which low bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) reflects low volumetric BMD, bone microstructure, and strength is uncertain in the absence of low trauma fracture. OBJECTIVE: The objective of the study was to compare three-dimensional volumetric BMD and bone stiffness in premenopausal women with IOP based on fracture history, those with idiopathic low BMD (Z score ≤ -2.0) and no low trauma fracture, and normal age-matched controls. DESIGN: We measured volumetric BMD and bone geometry by central quantitative computed tomography (cQCT) scans of the spine and hip and estimated bone stiffness by finite element analysis of cQCT data sets in 32 premenopausal women with IOP, 12 with idiopathic low BMD, and 34 controls. RESULTS: Subjects had comparable decreases in total and trabecular volumetric BMD, cortical thickness, and whole-bone stiffness compared with controls, regardless of fracture history. These differences remained significant after controlling for age, body mass index, and bone size. The positive predictive values of a DXA Z score of -2.0 or less for a cQCT volumetric BMD Z score of -2.0 or less were 95% at the lumbar spine, 90% at the total hip, and 86% at the femoral neck. CONCLUSION: Women with idiopathic low BMD alone and those with low trauma fractures had comparable deficits in bone mass, structure, and stiffness. Low areal BMD by DXA is fairly accurate for predicting low volumetric BMD by cQCT. These results are consistent with three-dimensional bone imaging at the iliac crest, radius, and tibia in premenopausal IOP and suggest that the term osteoporosis may be appropriate in women with Z scores below -2.0, whether or not there is a history of fracture.

Increased marrow adiposity in premenopausal women with idiopathic osteoporosis.

CONTEXT: We have previously reported that premenopausal women with idiopathic osteoporosis based on fractures (IOP) or idiopathic low bone mineral density (ILBMD) exhibit markedly reduced bone mass, profoundly abnormal trabecular microstructure, and significant deficits in trabecular bone stiffness. Bone remodeling was heterogeneous. Those with low bone turnover had evidence of osteoblast dysfunction and the most marked deficits in microstructure and stiffness. OBJECTIVE: Because osteoblasts and marrow adipocytes derive from a common mesenchymal precursor and excess marrow fat has been implicated in the pathogenesis of bone fragility in anorexia nervosa, glucocorticoid excess, and thiazolidinedione exposure, we hypothesized that marrow adiposity would be higher in affected women and inversely related to bone mass, microarchitecture, bone formation rate, and osteoblast number. DESIGN: We analyzed tetracycline-labeled transiliac biopsy specimens in 64 premenopausal women with IOP or ILBMD and 40 controls by three-dimensional micro-computed tomography and two-dimensional quantitative histomorphometry to assess marrow adipocyte number, perimeter, and area. RESULTS: IOP and ILBMD subjects did not differ with regard to any adipocyte parameter, and thus results were combined. Subjects had substantially higher adipocyte number (by 22%), size (by 24%), and volume (by 26%) than controls (P < 0.0001 for all). Results remained significant after adjusting for age, body mass index, and bone volume. Controls demonstrated expected direct associations between marrow adiposity and age and inverse relationships between marrow adiposity and bone formation, volume, and microstructure measures. No such relationships were observed in the subjects. CONCLUSIONS: Higher marrow adiposity and the absence of expected relationships between marrow adiposity and bone microstructure and remodeling in women with IOP or ILBMD suggest that the relationships between fat and bone are abnormal; excess marrow fat may not arise from a switch from the osteoblast to the adipocyte lineage in this disorder. Whether excess marrow fat contributes to the pathogenesis of this disorder remains unclear.