The skeletal consequences of epidural steroid injections: a literature review.

This literature review summarized studies that evaluated the effects of epidural steroid injections (ESIs) on skeletal health. While evidence is limited, studies suggest that ESIs may cause bone loss. Better understanding of these skeletal consequences will help foster strategies to prevent bone loss in the growing population of patients receiving ESIs. PURPOSE: Approximately nine million epidural steroid injections (ESIs) are administered annually in the United States to treat radicular back pain. ESIs often provide pain relief and functional improvement. While the overall incidence of adverse events resulting from ESIs is low, their effects on the skeleton are poorly understood. This is an important consideration given the profound skeletal impact of other forms of glucocorticoids. METHODS: Ovid MEDLINE and PubMed search results since 2010, including older, frequently referenced publications were reviewed. RESULTS: Systemic absorption of glucocorticoids occurs after ESI, which can cause hyperglycemia and endogenous cortisol suppression. The majority of studies investigating the skeletal effects of ESIs are retrospective. Several have found a relationship between low areal bone mineral density (BMD) by dual-energy x-ray absorptiometry and ESI exposure, but this finding is not uniform. Recently a dose-response relationship between ESI exposure and low spine volumetric BMD by computed tomography has been reported. Few studies have investigated the relationship between ESI exposure and fracture risk. Results of these studies are conflicting, and most have not been adequately powered to detect fracture outcomes. CONCLUSIONS: While evidence is limited, studies suggest that ESIs may cause bone loss, particularly those investigating volumetric BMD. Larger doses appear to confer greater risk. Further prospective studies are needed to investigate the relationship between ESI and fracture risk. Better understanding of the skeletal consequences of ESIs will help foster strategies to prevent bone loss in the growing population of patients receiving this treatment.

Risk factors for multi-joint disease in patients with glucocorticoid-induced osteonecrosis.

This study investigated risk factors for osteonecrosis involving multiple joints (MJON) among glucocorticoid-treated patients. The best predictor of MJON was cumulative oral glucocorticoid dose. Risk of MJON was 12-fold higher in patients who had a second risk factor for osteonecrosis. Further research is needed into strategies for prevention of MJON. INTRODUCTION: Osteonecrosis (ON) is a debilitating musculoskeletal condition in which bone cell death can lead to mechanical failure. When multiple joints are affected, pain and disability are compounded. Glucocorticoid treatment is one of the most common predisposing factors for ON. This study investigated risk factors for ON involving multiple joints (MJON) among glucocorticoid-treated patients. METHODS: Fifty-five adults with glucocorticoid-induced ON were prospectively enrolled. MJON was defined as ON in ≥ three joints. Route, dose, duration, and timing of glucocorticoid treatment were assessed. RESULTS: Mean age of enrolled subjects was 44 years, 58% were women. Half had underlying conditions associated with increased ON risk: systemic lupus erythematosus (29%), acute lymphoblastic leukemia (11%), HIV (9%), and alcohol use (4%). Mean daily oral dose of glucocorticoids was 29 mg. Average cumulative oral dose was 30 g over 5 years. The best predictor of MJON was cumulative oral glucocorticoid dose. For each increase of 1,000 mg, risk of MJON increased by 3.2% (95% CI 1.03, 1.67). Glucocorticoid exposure in the first 6 months of therapy, peak dose (oral or IV), and mean daily dose did not independently increase risk of MJON. The risk of MJON was 12-fold in patients who had a second risk factor (95% CI 3.2, 44.4). CONCLUSIONS: Among patients with glucocorticoid-induced ON, cumulative oral dose was the best predictor of multi-joint disease; initial doses of IV and oral glucocorticoids did not independently increase risk. Further research is needed to better define optimal strategies for prevention and treatment of MJON.

Low volumetric bone density is a risk factor for early complications after spine fusion surgery.

This study aims to investigate lumbar spine (LS) volumetric bone density (vBMD) as a risk factor for complications (pseudoarthrosis, instrumentation failure, adjacent fractures), re-operation, and time to complication after fusion. INTRODUCTION: Lumbar spine (LS) fusion surgery is increasingly performed worldwide. Complications after fusion result in significant morbidity and healthcare costs. Multiple factors, including osteoporosis, have been suggested to contribute to risk of complications and re-operation. However, most studies have used DXA, which is subject to artifact in patients with spine pathology, and none have investigated the relationship between BMD and timing of post-operative complications. This study aims to investigate LS volumetric bone density (vBMD) as a risk factor for complications (pseudoarthrosis, instrumentation failure, adjacent fractures), re-operation, and time to complication after fusion. METHODS: We evaluated a cohort of 359 patients who had initial LS fusion surgery at our institution, had pre-operative LS CTs and post-operative imaging available for review. Demographic factors, smoking status, vBMD, and details of surgical procedure were related to likelihood and timing of post-operative complications. RESULTS: Mean age was 60 ± 14 years, vBMD 122 ± 37 g/cm3. Median follow-up was 11 months. Skeletal complications occurred in 47 patients (13%); 34 patients (10%) required re-operation. Low vBMD (directly measured and estimated using HU) and smoking were associated with increased risk of skeletal complications. Each increase in baseline vBMD of 10 g/cm3 decreased the complication hazard and increased the complication-free duration in time-to-event analysis (hazard ratio 0.91, 95% CI 0.83-0.98, p < 0.02). CONCLUSIONS: Low vBMD was a significant risk factor for early post-operative complications in patients undergoing LS fusion. Prospective studies are needed to confirm these findings and to elucidate the optimal timing for follow-up and strategies for prevention of post-operative complications in this population.

Disrupted radial and tibial microarchitecture in patients with monoclonal gammopathy of undetermined significance.

Patients with monoclonal gammopathy of undetermined significance (MGUS) had abnormalities in volumetric BMD (vBMD), microarchitecture, and stiffness at both the radius and tibia by high-resolution peripheral quantitative CT compared to matched controls. This is the first report demonstrating that patients with MGUS have microarchitectural deficits at multiple skeletal sites. INTRODUCTION: Fracture risk is elevated in patients with monoclonal gammopathy of undetermined significance (MGUS). However, the pathogenesis of bone disease in these patients is poorly understood. Prior work using high-resolution peripheral CT (HRpQCT) demonstrated abnormal microarchitecture at the radius, with predominantly cortical abnormalities. We hypothesized that patients with MGUS have abnormal microarchitecture at both radius and tibia compared to controls, reflecting global skeletal effects of the disease. METHODS: This case-control study enrolled 36 subjects; patients with MGUS (n = 12) were matched 1:2 by age, sex, and race to controls (n = 24). Areal BMD (aBMD) was measured by DXA, vBMD, and microarchitecture by HRpQCT, and whole bone stiffness by finite element analysis. Serum was drawn for markers of bone metabolism and inflammation. RESULTS: By DXA, MGUS patients had lower aBMD at the lumbar spine, femoral neck, and 1/3 radius. Markers of bone metabolism and inflammation did not differ. By HRpQCT at the radius, MGUS patients had lower total, trabecular and cortical density, lower trabecular number, and greater trabecular separation and heterogeneity. At the tibia, MGUS patients had lower total and trabecular density, lower trabecular number, greater separation and heterogeneity, and lower whole bone stiffness. CONCLUSIONS: Patients with MGUS had lower vBMD, cortical, and trabecular abnormalities at the radius compared to matched controls. At the tibia, trabecular abnormalities predominated. These results suggest that in addition to previously described cortical deficits, deterioration of trabecular bone may contribute to a generalized skeletal fragility in patients with MGUS.

Abnormal microarchitecture and stiffness in postmenopausal women using chronic inhaled glucocorticoids.

Postmenopausal (PM) women using inhaled glucocorticoids (IGCs) had substantial abnormalities in volumetric BMD (vBMD), microarchitecture, and stiffness using high resolution peripheral computed tomography (HRpQCT) compared to age- and race-matched controls. Abnormalities were most severe at the radius. These preliminary results suggest that there may be major, heretofore unrecognized, skeletal deficits in PM women using IGCs. INTRODUCTION: While oral glucocorticoids are well recognized to have destructive skeletal effects, less is known about the effects of IGCs. The detrimental skeletal effects of IGCs may be greatest in PM women, in whom they compound negative effects of estrogen loss and aging. The goal of this study was to evaluate microarchitecture and stiffness in PM women using chronic IGCs. METHODS: This case-control study compared PM women using IGCs for ≥ 6 months (n = 20) and controls matched for age and race/ethnicity (n = 60). Skeletal parameters assessed included areal BMD (aBMD) by DXA, trabecular and cortical vBMD and microarchitecture by HRpQCT of the radius and tibia, and whole bone stiffness by finite element analysis. RESULTS: By DXA, mean values in both groups were in the osteopenic range; hip aBMD was lower in IGC users (P < 0.04). By HRpQCT, IGC users had lower total, cortical, and trabecular vBMD at both radius and tibia (all P < 0.05). IGC users had lower cortical thickness, lower trabecular number, greater trabecular separation and heterogeneity at the radius (all P < 0.03), and greater heterogeneity at the tibia (P < 0.04). Whole bone stiffness was lower in IGC users at radius (P < 0.03) and tended to be lower at the tibia (P = 0.09). CONCLUSIONS: PM women using IGCs had substantial abnormalities in vBMD, microarchitecture, and stiffness compared to controls. These abnormalities were most severe at the radius. These preliminary results suggest that there may be major, heretofore unrecognized, skeletal deficits in PM women using IGCs.

What is the clinical significance of esophagogastric junction outflow obstruction? evaluation of 60 patients at a tertiary referral center.

BACKGROUND: Esophagogastric junction (EGJ) outflow obstruction (EGJOO) is characterized by impaired EGJ relaxation with intact or weak peristalsis. Our aims were to evaluate: (i) prevalence, (ii) yield of fluoroscopy, endoscopy, and endoscopic ultrasound (EUS), (iii) outcomes, and (iv) whether this data differed based on quantitative EGJ relaxation. METHODS: Studies that met criteria for EGJOO were identified. Demographics, encounters, endoscopy, radiology, treatment decisions, and outcomes were extracted. KEY RESULTS: Sixty studies were identified. Dysphagia was the most common symptom. Forty patients underwent barium esophagram (BE): normal (11), hiatal hernia (20), spasm/dysmotility (17), EGJ narrowing (10), compression (2), Schatzki's ring (5), malrotation (1), gastric volvulus (1), mass (1). Esophagogastroduodenoscopy (EGD) was performed in 41 patients: normal (19), hiatal hernia (13), Schatzki's ring (6), esophagitis (3), esophageal candidiasis (3), mass (1). EUS was performed in 20 patients and was frequently normal. Twenty-two patients underwent intervention. While transient improvement was noted in the majority, persistent improvement was seen in only one of nine patients (dilatation), four of six patients (botulinum toxin), and three patients who underwent per-oral endoscopic myotomy. No patients treated with medical therapy alone had improvement in dysphagia. There was no difference in symptoms or outcomes based on quantitative EGJ relaxation. CONCLUSIONS & INFERENCES: The manometric criterion EGJOO defines a heterogeneous clinical group. While BE, EGD, and EUS all provide complementary information, a significant percentage of these studies will be normal. For patients with dysphagia, outcome may depend on EGJ disruption. There were no differences in symptoms our outcomes based on quantitative EGJ relaxation.

Patient-derived xenotransplants can recapitulate the genetic driver landscape of acute leukemias.

Genomic studies have identified recurrent somatic mutations in acute leukemias. However, current murine models do not sufficiently encompass the genomic complexity of human leukemias. To develop preclinical models, we transplanted 160 samples from patients with acute leukemia (acute myeloid leukemia, mixed lineage leukemia, B-cell acute lymphoblastic leukemia, T-cell ALL) into immunodeficient mice. Of these, 119 engrafted with expected immunophenotype. Targeted sequencing of 374 genes and 265 frequently rearranged RNAs detected recurrent and novel genetic lesions in 48 paired primary tumor (PT) and patient-derived xenotransplant (PDX) samples. Overall, the frequencies of 274 somatic variant alleles correlated between PT and PDX samples, although the data were highly variable for variant alleles present at 0-10%. Seventeen percent of variant alleles were detected in either PT or PDX samples only. Based on variant allele frequency changes, 24 PT-PDX pairs were classified as concordant while the other 24 pairs showed various degree of clonal discordance. There was no correlation of clonal concordance with clinical parameters of diseases. Significantly more bone marrow samples than peripheral blood samples engrafted discordantly. These data demonstrate the utility of developing PDX banks for modeling human leukemia, and emphasize the importance of genomic profiling of PDX and patient samples to ensure concordance before performing mechanistic or therapeutic studies.

Gender is a determinative factor in the initial clinical presentation of eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease resulting in symptoms of esophageal dysmotility. Abnormalities include dysphagia, food impaction and reflux. Although men appear to comprise a majority of the EoE population, few studies have directly assessed gender-associated clinical differences. The aim of this study is to identify the effect of gender on the initial clinical presentation of adult-onset EoE patients. We reviewed our electronic medical record database from January 2008 to December 2011 for adults diagnosed with EoE per the 2011 updated consensus guidelines. Patient demographics, presenting symptoms, endoscopy findings and complications were recorded. Proportions were compared using chi-squared analysis, and means were compared using the Student's t-test. A total of 162 patients met the inclusion criteria and 71 (44%) were women. Women were more likely to report chest pain (P = 0.03) and heartburn (P = 0.06), whereas men more commonly reported dysphagia (P = 0.04) and a history of food impaction (P = 0.05). Endoscopic findings were similar between groups. No patients suffered esophageal perforations. These data suggest that men report more fibrostenotic symptoms and women report more inflammatory symptoms at the time of diagnosis. There was no difference in endoscopic findings between genders. This is one of the only reviews comparing differences in clinical presentation, endoscopic findings and complications between gender for EoE. The current recommended guidelines state that any patient with symptoms of esophageal dysfunction should be biopsied for EoE. Our findings support biopsying patients with typical and atypical symptoms of dysmotility including heartburn and chest pain.

Marrow adiposity assessed on transiliac crest biopsy samples correlates with noninvasive measurement of marrow adiposity by proton magnetic resonance spectroscopy ((1)H-MRS) at the spine but not the femur.

UNLABELLED: Measurement of marrow fat (MF) is important to the study of bone fragility. We measured MF on iliac biopsies and by spine/hip magnetic resonance spectroscopy in the same subjects. Noninvasively assessed spine MF and histomorphometrically assessed MF correlated well. MF quantity and relationships with bone volume differed by measurement site. INTRODUCTION: Excess marrow fat has been implicated in the pathogenesis of osteoporosis in several populations. In the bone marrow, adipocytes and osteoblasts share a common precursor and are reciprocally regulated. In addition, adipocytes may secrete toxic fatty acids and adipokines that adversely affect osteoblasts. Measurement of marrow fat is important to the study of mechanisms of bone fragility. Marrow fat can be quantified on bone biopsy samples by histomorphometry and noninvasively by proton magnetic resonance spectroscopy ((1)H-MRS). In this study, we evaluate relationships between marrow fat assessed using both methods in the same subjects for the first time. METHODS: Sixteen premenopausal women, nine with idiopathic osteoporosis and seven normal controls, had marrow fat measured at the iliac crest by bone biopsy and at the lumbar spine (L3) and proximal femur by (1)H-MRS. RESULTS: At L3, fat fraction by (1)H-MRS correlated directly and significantly with marrow fat variables on iliac crest biopsies (r = 0.5-0.8). In contrast, there were no significant correlations between fat fraction at the femur and marrow fat on biopsies. Marrow fat quantity (%) was greater at the femur than at L3 and the iliac crest and correlated inversely with total hip and femoral neck BMD by DXA. CONCLUSIONS: In summary, measurement of marrow fat in transiliac crest biopsies correlates with marrow fat at the spine but not the proximal femur by (1)H-MRS. There were site-specific differences in marrow fat quantity and in the relationships between marrow fat and bone volume.

Novel and emerging drugs for acute myeloid leukemia.

Acute myeloid leukemia (AML) is a challenging disease to treat with the majority of patients dying from their illness. While overall survival has been markedly prolonged in acute promyelocytic leukemia (APL), survival in younger adults with other subtypes of AML has only modestly improved over the last twenty years. Physicians who treat AML eagerly await drugs like Imatinib for chronic myeloid leukemia, Cladribine for hairy cell leukemia, and Rituximab for non-Hodgkin Lymphoma which have had an important impact on improving outcome. Recent research efforts have focused on refining traditional chemotherapeutic agents to make them more active in AML, targeting specific genetic mutations in myeloid leukemia cells, and utilizing novel agents such as Lenalidomide that have shown activity in other hematologic malignancies. Here, we focus on reviewing the recent literature on agents that may assume a role in clinical practice for patients with AML over the next five years.

Premenopausal women with idiopathic low-trauma fractures and/or low bone mineral density.

INTRODUCTION: In men, idiopathic osteoporosis (IOP) is often associated with low serum insulin-like growth factor (IGF-1) and reduced bone formation. The characteristics of premenopausal women with IOP are not well defined. We aimed to define the clinical, reproductive, and biochemical characteristics of premenopausal women with unexplained osteoporosis. METHODS: This is a cross-sectional study of 64 women with unexplained osteoporosis, 45 with fragility fractures, 19 with low bone mineral density (BMD; Z-score less than or equal to -2.0) and 40 normal controls. The following are the main outcome measures: clinical and anthropometric characteristics, reproductive history, BMD, gonadal and calciotropic hormones, IGF-1, and bone turnover markers (BTMs). RESULTS: Subjects had lower BMI and BMD than controls, but serum and urinary calcium, serum estradiol, vitamin D metabolites, IGF-1, and most BTMs were similar. Serum parathyroid hormone (PTH) and the resorption marker, tartrate-resistant acid phosphatase (TRAP5b), were significantly higher in both groups of subjects than controls and directly associated in all groups. Serum IGF-1 and all BTMs were directly associated in controls, but the association was not significant after controlling for age. There was no relationship between serum IGF-1 and BTMs in subjects. There were few differences between women with fractures and low BMD. CONCLUSIONS: Higher serum TRAP5b and PTH suggest that increased bone turnover, possibly related to subclinical secondary hyperparathyroidism could contribute to the pathogenesis of IOP. The absence of differences between women with fractures and those with very low BMD indicates that this distinction may not be clinically useful to categorize young women with osteoporosis.

Vitamin D in organ transplantation.

Vitamin D deficiency is prevalent among patients with end-stage organ failure awaiting transplant. Low serum 25-hydroxyvitamin D (25-OHD) levels in these patients may be related to many disease-specific factors, as well as decreased sunlight exposure and limited intake of foods containing vitamin D. Low serum 25-OHD levels are also extremely common following solid organ transplantation, both during the immediate postoperative period and in long-term graft recipients. Demographic and lifestyle factors are important in determining D status in transplant recipients. Worse vitamin D status is associated with poorer general health, lower albumin, and even decreased survival among these patients. Although several studies have demonstrated that active forms of vitamin D and its analogues prevent bone loss following transplantation, the data do not show consistent benefit. These therapies may have particular utility after renal transplantation. However, given the narrow therapeutic window with respect to hypercalcemia and hypercalciuria, and the demonstrated efficacy of bisphosphonates to prevent post-transplantation bone loss, we regard these agents as adjunctive rather than primary therapy for transplantation osteoporosis. The effects of 1,25(OH)(2)D on the immune system, which are still being elucidated, may have potential for reducing infections and preventing allograft rejection after transplantation.

Vitamin D deficiency in HIV-infected postmenopausal Hispanic and African-American women.

UNLABELLED: We evaluated vitamin D status in HIV+ and HIV- postmenopausal African-American (AA) and Hispanic women. Most women (74-78%) had insufficient 25-hydroxyvitamin D (25OHD) levels, regardless of HIV status. 25OHD was lower in AA women and women lacking supplement use, providing support for screening and supplementation. Among HIV+ women, 25OHD was associated with current CD4 but not type of antiretroviral therapy. INTRODUCTION: To evaluate vitamin D status and factors associated with vitamin D deficiency and insufficiency in HIV-infected (HIV+) postmenopausal minority women. METHODS: In this cross-sectional study, 89 HIV+ and 95 HIV- postmenopausal women (33% AA and 67% Hispanic) underwent assessment of 25OHD, 1,25-dihydroxyvitamin D, parathyroid hormone, markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry. RESULTS: The prevalence of low 25OHD did not differ by HIV status; the majority of both HIV+ and HIV- women (74-78%) had insufficient levels (<30 ng/ml). Regardless of HIV status, 25OHD was significantly lower in AA subjects, and higher in subjects who used both calcium and multivitamins. In HIV+ women on antiretroviral therapy (ART), 25OHD was directly associated with current CD4 count (r=0.32; p<0.01) independent of age, ethnicity, BMI, or history of AIDS-defining illness. No association was observed between 1,25(OH)(2)D and CD4 count or between serum 25OHD, 1,25(OH)(2)D or PTH and type of ART. CONCLUSIONS: In postmenopausal minority women, vitamin D deficiency was highly prevalent and associated with AA race and lack of supplement use, as well as lower current CD4 cell count. These results provide support for screening and repletion of vitamin D in HIV+ patients.

Cardiac structure and diastolic function in mild primary hyperparathyroidism.

CONTEXT: Data on the presence, extent, and reversibility of cardiovascular disease in primary hyperparathyroidism (PHPT) are conflicting. OBJECTIVE: To evaluate the heart in PHPT, we assessed cardiac structure and diastolic function in patients with mild PHPT compared with age- and sex-matched controls. DESIGN: This was a case-control study. SETTINGS: The study was conducted in a university hospital Metabolic Bone Diseases Unit. PARTICIPANTS: Fifty-four men and women with PHPT and 76 controls without PHPT participated in the study. OUTCOME MEASURES: We measured left ventricular mass index (LVMI), the presence of mitral annular calcification, the ratio of early to late diastolic mitral inflow velocities (E/A), and early diastolic velocity of the lateral mitral annulus using Doppler tissue imaging (tissue Doppler e'). RESULTS: Patients had mild disease with mean (+/-sd) serum calcium 10.5 +/- 0.5 mg/dl and PTH 96 +/- 45 pg/ml. LVMI and diastolic function were normal in PHPT. There was no difference in LVMI (98 +/- 23 vs. 96 +/- 24 g/m(2), P = 0.69) or the frequency of mitral annular calcification between PHPT cases and controls. Diastolic function variables (E/A and tissue Doppler e') were higher (better) in cases compared with controls, although both were within the reference range. PHPT patients with low E/A had higher serum PTH (121 +/- 36 vs. 89 +/- 46 pg/ml, P = 0.03) and calcium (10.8 +/- 0.4 vs. 10.5 +/- 0.5 mg/dl, P = 0.05) than those with normal values. Finally, we found LVMI to be inversely associated with serum 25-hydroxyvitamin D in PHPT (r = -0.29, P < 0.05). All findings persisted after adjustment for group differences in cardiovascular risk factors. CONCLUSIONS: Patients with biochemically mild PHPT do not have evidence of increased left ventricular mass, diastolic dysfunction, or increased valvular calcifications. However, the data support an association between low vitamin D levels and the development of left ventricular hypertrophy in this disorder. Finally, the increased serum calcium and PTH levels in those with diastolic dysfunction suggest that disease severity may determine the presence of cardiac manifestations in PHPT.

Vitamin D insufficiency prior to bariatric surgery: risk factors and a pilot treatment study.

OBJECTIVE: To assess vitamin D status and the influences of race, sun exposure and dietary vitamin D intake on vitamin D levels, and to evaluate two vitamin D repletion regimens in extremely obese patients awaiting bariatric surgery. METHODS: A cross-sectional analysis of dietary vitamin D, sun exposure, PTH [intact (iPTH) and PTH(1-84)] and 25-hydroxyvitamin D (25OHD; differentiated 25OHD2 and 25OHD3) in 56 obese [body mass index (BMI) > 35 kg/m(2)] men and women (age 20-64 years). In a pilot clinical trial, 27 subjects with 25OHD levels < 62 nmol/l were randomized to receive ergocalciferol or cholecalciferol for 8 weeks. RESULTS: Serum 25OHD was low (mean 45 +/- 22 nmol/l) and was inversely associated with BMI (r = -0.36, P < 0.01). Each BMI increase of 1 kg/m(2) was associated with a 1.3 nmol/l decrease in 25OHD (P < 0.01). BMI, sun exposure, African American race and PTH predicted 40% of the variance in 25OHD (P < 0.0001). Serum 25OHD significantly increased at 4 and 8 weeks in both treatment groups (P < 0.001), whereas PTH(1-84) declined significantly in subjects treated with cholecalciferol (P < 0.007) and tended to decrease following ergocalciferol (P < 0.09). CONCLUSIONS: In severely obese individuals, those who are African American, have higher BMI and limited sunlight exposure are at greatest risk for vitamin D insufficiency. These demographic factors can help to identify at-risk patients who require vitamin D repletion prior to bariatric surgery. Commonly prescribed doses of ergocalciferol and cholecalciferol are effective in raising 25OHD. Further investigation is needed to evaluate whether these regimens have differential effects on PTH, and to determine the optimal regimen for vitamin D repletion in the extremely obese patient.

The decline in hip bone density after gastric bypass surgery is associated with extent of weight loss.

CONTEXT: Bariatric surgery is common and may be associated with deleterious effects on the skeleton. OBJECTIVE: Our objective was to assess bone metabolism and bone mineral density (BMD) after Roux-en-Y gastric bypass. DESIGN AND SETTING: We conducted a 1-yr prospective longitudinal study at a university hospital bariatric surgery practice and metabolic bone disease unit. PARTICIPANTS: Participants included 23 obese (mean body mass index 47 kg/m(2)) men and women, aged 20-64 yr. MAIN OUTCOME MEASURES: Serum PTH, 25-hydroxyvitamin D, osteocalcin, and urinary N-telopeptide, and BMD were assessed. RESULTS: Patients lost 45 +/- 2 kg 1 yr postoperatively (P < 0.01). PTH increased early (3 months, 43-50 pg/ml; P < 0.001) and urinary calcium dropped (161-92 mg/24 h; P < 0.01), despite doubling of calcium intake (1318-2488 mg/d; P < 0.001). Serum 25-hydroxyvitamin D concentrations were unchanged (23-26 ng/ml), although vitamin D intake increased by 260% (658 IU/d at baseline to 1698 IU/d at 12 months; P < 0.05). Markers of bone remodeling rose (P < 0.01 for both urinary N-telopeptide and osteocalcin), whereas BMD decreased at the femoral neck (9.2%, P < 0.005) and at the total hip (8.0%, P < 0.005). These declines were strongly associated with the extent of weight loss (femoral neck: r = 0.90, P < 0.0001; and total hip: r = 0.65, P = 0.02). Lumbar spine and distal radius sites did not change. CONCLUSIONS: After Roux-en-Y gastric bypass, there was evidence of calcium and vitamin D malabsorption. Bone turnover increased, and hip bone density rapidly declined. The decline in hip BMD was strongly associated with weight loss itself. Vigilance for nutritional deficiencies and bone loss in patients both before and after bariatric surgery is crucial.

Apolipoprotein E genotype affects plasma lipid response to atorvastatin in a gender specific manner.

The response to therapy with hypolipidemic agents shows considerable individual variation. These differences may be due to the interaction of environmental and genetic factors that affect drug bioavailability, receptor function or ligand structure. Our objective was to assess the effect of apolipoprotein (apo) E genotype and gender on lipid-lowering response to the HMG CoA reductase inhibitor, atorvastatin. Genotyping was carried out on DNA from 328 male and female subjects who participated in a multicentric, double-blind clinical trial, and received 10 mg/day of atorvastatin. Our data demonstrate no significant gender differences for LDL cholesterol levels at baseline. Moreover, mean LDL-C lowering was similar in men (-36.2%, range -2.7 to -57.8%) and in women (-38.1%, range -9.5 to -58.5%) as compared to baseline. However, men carrying the epsilon2 allele had a significantly higher mean LDL-C response (-44%) than epsilon3 homozygotes (-37%) and epsilon4 carriers (-34%); P=0.01 for apoE group by treatment interaction. No such gene/treatment interactions were noted in women, with those carrying the epsilon2 allele showing a similar mean response (-34%) as epsilon3 homozygotes (-39%) and epsilon4 carriers (-34%). Mean plasma triglyceride lowering with atorvastatin was 17%. A significant apoE group by treatment interaction (P=0.010) was also observed in men, with epsilon2 carriers being more responsive (-27%) than epsilon3/3 (-13%) and epsilon4 (-22%). This interaction was not observed in women. In summary, atorvastatin treatment had similar effects on plasma lipid levels in both men and women; however, the apoE gene locus was a significant predictor of LDL-C and TG responses to atorvastatin therapy in men, but not in women.

Molecular analysis of the gonadotropin-releasing hormone receptor in patients with polycystic ovary syndrome.

OBJECTIVE: To determine whether a mutation in the GnRH receptor gene is responsible for polycystic ovary syndrome (PCOS). DESIGN: Molecular analysis of human genomic DNA. SETTING: Academic research environment. PATIENT(S): Eighty patients with PCOS. INTERVENTION(S): Extraction and polymerase chain reaction (PCR) analysis of genomic DNA, confirmation of PCR products by ethidium bromide staining of agarose gels after electrophoresis, denaturing gradient gel electrophoresis of PCR products, and photography. MAIN OUTCOME MEASURE(S): Mutations in the GnRH receptor of women with PCOS. RESULT(S): Denaturing gradient gel electrophoresis revealed no mutations in the exonic sequence encoding the open reading frame of the GnRH receptor. CONCLUSION(S): A mutation in the GnRH receptor gene is unlikely to be the underlying cause of PCOS in most patients. The molecular basis of this disorder remains unknown.