Randomized, controlled trial to assess the safety and efficacy of odanacatib in the treatment of men with osteoporosis.

Odanacatib (ODN) was investigated as an osteoporosis treatment in 292 men. Compared with placebo, odanacatib improved bone mineral density and led to sustained bone resorption decreases while producing relatively little bone formation reduction that leveled off with time. However, increased risk of stroke in another study stopped further odanacatib development. INTRODUCTION: ODN, a selective oral cathepsin K inhibitor, was in development for osteoporosis treatment. This phase 3, double-blind, randomized, placebo-controlled, 24-month study investigated ODN safety and efficacy in men with osteoporosis. METHODS: Men with idiopathic osteoporosis or osteoporosis due to hypogonadism and a lumbar spine or hip (total hip [TH], femoral neck [FN], or trochanter) bone mineral density (BMD) T-score of ≤ - 2.5 to ≥ - 4.0 without prior vertebral fracture or ≤ - 1.5 to ≥ - 4.0 with one prior vertebral fracture were randomized (1:1) to once-weekly ODN 50 mg or placebo. All received 5600 IU vitamin D3 weekly and calcium supplementation as needed (≥ 1200 mg daily). The primary efficacy outcome was changed from baseline in lumbar spine BMD versus placebo. RESULTS: Overall, 292 men, mean age 68.8 years, were randomly assigned to ODN or placebo. Versus placebo, ODN increased BMD from baseline at the lumbar spine, TH, FN, and trochanter by 5.6%, 2.0%, 1.7%, and 2.1%, respectively (all p < 0.01), and decreased uNTx/Cr (68%, p < 0.001), sCTx (77%, p < 0.001), sP1NP (16%, p = 0.001), and sBSAP (8%, p = 0.019). The between-group bone formation marker decrease peaked at 3 months, then returned toward baseline. The safety profile, including cardiovascular events, was similar between groups. CONCLUSION: Though a promising osteoporosis therapy for men, ODN development was discontinued due to increased risk of stroke in the LOFT phase 3 trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT01120600 (registered May 11, 2010).

Early changes in bone turnover and bone mineral density after discontinuation of long-term oral bisphosphonates: a post hoc analysis.

This post hoc analysis of a randomized, double-blind study of postmenopausal women with osteoporosis found that there were early increases in bone turnover markers and decreases in bone mineral density after discontinuation of long-term alendronate. These findings might help guide treatment decisions, including monitoring after alendronate withdrawal. INTRODUCTION: The short-term effects of discontinuing long-term bisphosphonates are poorly characterized. This post hoc analysis investigated 1-12-month changes in bone mineral density (BMD) and bone turnover markers (BTM) after alendronate (ALN) discontinuation. METHODS: Data were from a randomized, double-blind trial of MK-5442 (calcium-sensing receptor antagonist) following oral bisphosphonates, with placebo and continued ALN controls ( ClinicalTrials.gov NCT00996801). Postmenopausal women with osteoporosis had received oral bisphosphonate (≥ 3-4 preceding years; ALN for the 12 months pre-screening), continuing on ALN 70 mg/week (n = 87) or placebo (n = 88). RESULTS: At 12 months, least-squares mean percent changes from baseline BMD (placebo vs. ALN) were lumbar spine (LS): - 0.36 vs. 1.29, total hip: - 1.44 vs. 0.46, and femoral neck (FN): - 1.26 vs. - 0.08 (all P < 0.05). BTM levels increased by 1-3 months, to 12 months, with placebo vs. ALN (P < 0.001). FN BMD decline was greater in the placebo subgroup with higher urinary N-terminal cross-linked telopeptides of type I collagen/creatinine [uNTx/Cr] (P < 0.01), and higher serum N-terminal pro-peptide of type 1 collagen [P1NP] levels (P < 0.05), at baseline. There was a trend toward greater FN BMD loss with higher BTM levels at 3 and/or 6 months. Younger age and higher LS BMD at baseline were associated with greater LS BMD loss at 12 months (P = 0.04 and < 0.01, respectively); higher baseline FN BMD predicted greater FN BMD loss (P = 0.04). CONCLUSION: Early changes in BTM levels and BMD were observed after discontinuation of long-term ALN. Further characterization of factors associated with patients' risk of bone loss upon bisphosphonate discontinuation is warranted.

Ramping Dynamics in the Frontal Cortex Unfold Over Multiple Timescales During Motor Planning.

Plans are formulated and refined over the period leading to their execution, ensuring that the appropriate behavior is enacted at just the right time. While existing evidence suggests that memory circuits convey the passage of time through diverse neuronal responses, it remains unclear whether the neural circuits involved in planning behavior exhibit analogous temporal dynamics. Using publicly available data, we analyzed how activity in the frontal motor cortex evolves during motor planning. Individual neurons exhibited diverse ramping activity throughout a delay interval that preceded a planned movement. The collective activity of these neurons was useful for making temporal predictions that became increasingly precise as the movement time approached. This temporal diversity gave rise to a spectrum of encoding patterns, ranging from stable to dynamic representations of the upcoming movement. Our results indicate that neural activity unfolds over multiple timescales during motor planning, suggesting a shared mechanism in the brain for processing temporal information related to both past memories and future plans.

Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma.

BACKGROUND: Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3 + 3 design nonrandomized, dose-escalation, phase I/IIa trial was conducted to determine the safety, pharmacokinetic (PK) and pharmacodynamic parameters, maximum tolerated dose, and antitumor activity of oral ridaforolimus. PATIENTS AND METHODS: Patients with metastatic or unresectable solid tumors refractory to therapy were eligible. Seven different continuous and intermittent dosing regimens were examined. RESULTS: One hundred and forty-seven patients were enrolled in this study among which 85 were patients with sarcoma. Stomatitis was the most common DLT observed. The dosing regimen, 40 mg QD × 5 days/week, provided the best combination of cumulative dose, dose density, and cumulative exposure, and was the recommended dosing regimen for subsequent clinical development. PK was nonlinear, with less than proportional increases in day-1 blood AUC0-∞ and Cmax, particularly with doses >40 mg. The terminal half-life estimate of ridaforolimus (QD × 5 40 mg) was 42.0 h, and the mean half-life ∼30-60 h. The clinical benefit rate, (complete response, partial response, or stable disease for ≥4 months was 24.5% for all patients and 27.1% for patients with sarcoma. CONCLUSION: Oral ridaforolimus had an acceptable safety profile and exhibited antitumor activity in patients with sarcoma and other malignancies. ClinicalTrials.gov Identifier NCT00112372.

Transgenic songbirds offer an opportunity to develop a genetic model for vocal learning.

Zebra finches are widely used for studying the basic biology of vocal learning. The inability to introduce genetic modifications in these animals has substantially limited studies on the molecular biology of this behavior, however. We used an HIV-based lentivirus to produce germline transgenic zebra finches. The lentivirus encoded the GFP regulated by the human ubiquitin-C promoter [Lois C, Hong EJ, Pease S, Brown EJ, Baltimore D (2002) Science 295:868-872], which is active in a wide variety of cells. The virus was injected into the very early embryo (blastodisc stage) to target the primordial germline cells that later give rise to sperm and eggs. A total of 265 fertile eggs were injected with virus, and 35 hatched (13%); 23 of these potential founders (F0) were bred, and three (13%) produced germline transgenic hatchlings that expressed the GFP protein (F1). Two of these three founders (F0) have produced transgenic young at a rate of 12% and the third at a rate of 6%. Furthermore, two of the F1 generation transgenics have since reproduced, one having five offspring (all GFP positive) and the other four offsping (one GFP positive).

Systematic review: the use of serology to exclude or diagnose coeliac disease (a comparison of the endomysial and tissue transglutaminase antibody tests).

BACKGROUND: With the appreciation of the high prevalence of coeliac disease there is increasing use of serology in screening asymptomatic people and testing those with suggestive features. AIM: To compare the sensitivities and specificities of the endomysial antibody and the tissue transglutaminase antibody tests. METHODS: Using electronic databases a search was made for relevant papers using the terms tissue transglutaminase and endomysial antibody. RESULTS: Both the endomysial antibody and tissue transglutaminase antibody have very high sensitivities (93% for both) and specificities (>99% and >98% respectively) for the diagnosis of typical coeliac disease with villous atrophy. Human recombinant tissue transglutaminase performs much better than guinea pig tissue transglutaminase. Review of studies comparing endomysial antibody with human recombinant tissue transglutaminase antibody shows that endomysial antibody more often has a higher specificity and human recombinant tissue transglutaminase antibody more often has a higher sensitivity. CONCLUSION: The human recombinant tissue transglutaminase antibody is the preferred test for screening asymptomatic people and for excluding coeliac disease in symptomatic individuals with a low pretest probability (i.e. <25%) for coeliac disease. Furthermore, it has a number of practical and financial advantages. If the pretest probability is >25%, biopsy is preferred as the post-test probability of coeliac disease with a negative test is still >2%.

A randomized, double-blind, placebo-controlled, sixteen-week study of subcutaneous golimumab in patients with active nonradiographic axial spondyloarthritis.

OBJECTIVE: Axial spondyloarthritis (SpA) is a chronic inflammatory disease characterized by back pain and stiffness. The objective of this study was to determine whether golimumab is superior to placebo in patients with nonradiographic axial SpA. METHODS: This phase III, double-blind, randomized, placebo-controlled trial was performed to evaluate subcutaneous golimumab (50 mg) versus placebo in patients ages ≥18 years to ≤45 years who had active nonradiographic axial SpA according to the Assessment of SpondyloArthritis international Society (ASAS) criteria for ≤5 years since diagnosis, high disease activity, and an inadequate response to or intolerance of nonsteroidal antiinflammatory drugs. Patients were randomized 1:1 to receive golimumab or placebo subcutaneously every 4 weeks. The primary end point was 20% improvement according to the ASAS criteria (ASAS20) at week 16. Key secondary end points were an ASAS40 response, ASAS partial remission, 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and change in the Spondyloarthritis Research Consortium of Canada (SPARCC) magnetic resonance imaging (MRI) index for sacroiliac (SI) joint inflammation (SPARCC score). RESULTS: Of the 198 patients randomized, 197 were treated (97 received golimumab, and 100 received placebo). The mean age of the patients was 31 years, and 57.1% were male. At baseline, the mean ± SD BASDAI was 6.5 ± 1.5, the mean ± SD ASDAS was 3.5 ± 0.9, and the mean ± SD SPARCC score was 11.3 ± 14.0. The primary end point, an ASAS20 response, was achieved by significantly more patients in the golimumab group compared with the placebo group (71.1% versus 40.0%; P < 0.0001). An ASAS40 response was also achieved by significantly more patients in the golimumab group compared with the placebo group (56.7% versus 23.0%; P < 0.0001). The incidence of adverse events did not differ meaningfully between groups. CONCLUSION: Patients with active nonradiographic axial SpA treated with golimumab had significantly greater improvement in symptoms compared with patients treated with placebo. Golimumab was well tolerated and had a favorable risk/benefit profile.

Bismuth-containing single-antibiotic 1-week triple therapy for Helicobacter pylori eradication.

BACKGROUND: Although bismuth was both the first drug shown to alter the natural history of peptic ulcer disease and also a constituent of the first very effective eradication regimens, it has been excluded from the newer regimens, despite its safety and low cost, in favour of two antibiotics. AIM: To asses a novel 1-week regimen consisting of bismuth, clarithromycin and a proton pump inhibitor in routine clinical practice. METHODS: One hundred and three consecutive patients with peptic ulcer disease and antral biopsies containing Helicobacter pylori were given a 7-day course of treatment with bismuth (tripotassium dicitrato bismuthate chelate) 120 mg q.d.s., clarithromycin 500 mg t.d.s. and lansoprazole 30 mg o.d. Completeness of eradication was assessed by a l3C-urea breath test, in all except three patients, at least 4 months later. RESULTS: Of the 100 patients who were assessed in this open treatment study 84 (84%; 95% CI: 77-91%) had a negative breath test. Minor side-effects were reported by 14% and more troublesome side-effects (nausea, vomiting, diarrhoea, hallucinations, nasty taste and body pains) were reported by 10%. CONCLUSIONS: A 1-week course of triple therapy including bismuth, clarithromycin and a proton pump inhibitor is effective in routine clinical practice and is well tolerated.

Review article: monitoring for drug side-effects in inflammatory bowel disease.

The side-effects suitable for monitoring in patients with inflammatory bowel disease being treated with the four main groups of drugs (5-aminosalicylic acid preparations, azathioprine and 6-mercaptopurine, methotrexate, and corticosteroids) are reviewed. On the basis of the reported frequency, severity and timing of side-effects, a practical scheme of monitoring is recommended. This includes a baseline measurement of full blood count, creatinine and liver function tests in all patients. In the absence of worrying symptoms, we recommend the following: (i) no monitoring for sulfasalazine; (ii) for other 5-aminosalicylic acid preparations, the measurement of creatinine at 6 and 12 months and then annually; (iii) for azathioprine/6-mercaptopurine, thiopurine methyltransferase genotype/phenotype determination has no role in treatment monitoring, but a full blood count at 2 weeks, 1 month, 3 months and then every 3 months should be performed; (iv) for methotrexate, a full blood count and liver function tests should be performed every 3 months; (v) for steroids, dual energy X-ray absorptiometry bone scanning should be performed at the start of therapy, every year in which steroids are used if the T score is < 0, and every 3-5 years if the T score is > 0.

A one-week quadruple eradication regimen for Helicobacter pylori in routine clinical practice.

BACKGROUND: The addition of omeprazole to 1 week of standard triple therapy (tripotassium dicitrato bismuthate, tetracycline and metronidazole) has given a 98% eradication rate in 54 patients at 4-6 weeks in a research setting. We report the result of a similar 1-week regimen in 52 patients in routine clinical practice assessed at a mean of 8 months. METHODS: Fifty-two patients with peptic ulcer disease and antral biopsies containing Helicobacter pylori sensitive to metronidazole were given a 7-day course of treatment: omeprazole 20 mg b.d., tetracycline 500 mg q.d.s. and tripotassium dictitrato bismuthate chelate tablets 120 mg q.d.s., with metronidazole 400 mg five times daily for the last 3 days only. Completeness of eradication was assessed by a 13C-urea breath test at 4-26 months (mean 8 months). RESULTS: Forty-eight patients (92%) had a negative breath test. Three patients vomited on the last day of the course, otherwise the treatment was well tolerated with the expected minor side-effects of tongue discoloration, nausea and unpleasant taste. CONCLUSIONS: The efficacy of a modified 1-week standard triple therapy with omeprazole is confirmed and shown to be almost as effective in routine clinical practice as a similar regimen in a research setting.

How effective are the usual treatments for ulcerative colitis?

BACKGROUND: Details of the efficacy of the drugs used in ulcerative colitis are not readily available. METHODS: We have reviewed all placebo-controlled trials of the commonly used drugs for both induction and maintenance of remission to determine the efficacy and to calculate the numbers needed to treat (NNTs) to achieve a specified benefit for each drug. RESULTS: The drug response rates and the NNTs (with 95% CI) are tabulated for each drug. CONCLUSION: Corticosteroids give a remission rate of 68% in mild or moderate disease and an NNT for remission of 2 (95% CI 1.4-5) in mild disease. Intravenous hydrocortisone gives a remission rate of 60-73%. Aminosalicylates are relatively ineffective in inducing remission with an NNT of 10 (95% CI 7-21) improving to 8 (95% CI 5-20) if the dose > or = 3 g daily. They are better at maintenance (NNT = 6; 95% CI 4-8). Intravenous ciclosporin is very effective in achieving remission in severe colitis with an NNT of 1.2 (95% CI 1-2.5). Although there is fairly good evidence that azathioprine is effective in maintaining remission and is used widely, there are no suitable placebo-controlled trials to calculate the NNT.

How effective are the usual treatments for Crohn's disease?

BACKGROUND: Details of the efficacy of the various drugs used in Crohn's disease are not readily available. METHODS: We have reviewed all placebo controlled trials of the commonly used drugs in Crohn's disease for both the induction and maintenance of remission to determine the efficacy and to calculate the numbers needed to treat (NNTs) to achieve a specified benefit for each drug. RESULTS: Both the drug response rates and the NNTs (with 95% confidence intervals) are tabulated for each drug. CONCLUSION: Prednisolone/prednisone is the most effective drug to achieve remission with a remission rate of 60% and an NNT for remission of 3 (95% confidence interval: 2-6). Aminosalicylates are only moderately effective in achieving remission with an overall NNT of 10 (95% confidence interval: 6-75), but more effective in high-dose (e.g. NNT for Pentasa 4 g daily = 4; 95% confidence interval: 2.6-9), and less effective in maintaining remission with an NNT of 14 (95% confidence interval: 9-29). Both azathioprine and infliximab are associated with remission induction and maintenance rates of 40-66% and NNTs of 3-5. Methotrexate intramuscularly has a remission induction rate of 39% and an NNT of 5 (95% confidence interval: 3-25).

Simple objective criteria for diagnosis of causes of acute diarrhoea on rectal biopsy.

AIM: To identify simple, objective, accurate histological criteria for distinguishing acute infective-type colitis, chronic idiopathic inflammatory bowel disease, and irritable bowel syndrome on rectal biopsy in patients with acute onset diarrhoea at first presentation, one to 10 weeks after onset. METHODS: Cell counts and measurements of mucosal architecture were made on initial rectal biopsies from 18 patients with acute infective-type colitis, 17 patients with first acute presentation of chronic idiopathic inflammatory bowel disease, and 23 patients with irritable bowel syndrome. The data were analysed by ANOVA and discriminant analysis. RESULTS: Lamina propria cells were mainly in the upper third in irritable bowel syndrome patients. Increased lamina propria cellularity, mainly in the middle third, and numbers of crypt intraepithelial neutrophils distinguished acute infective-type colitis from irritable bowel syndrome in 93% of cases. Chronic idiopathic inflammatory bowel disease differed from irritable bowel syndrome and acute infective-type colitis in a decreased number of crypts and altered crypt architecture. Chronic idiopathic inflammatory bowel disease showed higher lamina propria cellularity, especially in the basal third, with an increased number of lamina propria neutrophils. On discriminant analysis, crypt numbers distinguished 86% of the cases of chronic idiopathic inflammatory bowel disease from the other groups. CONCLUSION: At one week or more from onset, acute infective-type colitis is characterised by a superficial increase in lamina propria cellularity, with only a slight increase in the number of polymorphs. At this stage, chronic idiopathic inflammatory bowel disease is characterised by a transmucosal increase in cellularity together with crypt loss and architectural abnormality. Thus, measurement of mucosal architecture establishes simple, accurate, objective criteria for routine biopsy diagnosis of chronic idiopathic inflammatory bowel disease from acute infective-type colitis and irritable bowel syndrome at initial presentation, one to 10 weeks after onset.

The Cronkhite-Canada syndrome: an ultrastructural study of pathogenesis.

Electron microscopical and cytochemical studies of intestinal biopsies from a patient with typical features of the Cronkhite-Canada syndrome show that the primary process affects the crypts. This results in cystic dilatation associated with expansion and focal degeneration of the crypt compartment of the intestinal epithelium. The villous epithelium compartment is reduced but ultrastructurally normal. Inflammation and oedema of the lamina propria follows from leakage of mucin through breaks in the abnormal crypts.

What is colitis? Statistical approach to distinguishing clinically important inflammatory change in rectal biopsy specimens.

Measurements of mucosal dimension, architecture, and cell counts in both lamina propria and epithelium were made on rectal biopsy specimens from 20 patients with irritable bowel syndrome ("normal" controls); 54 patients with ulcerative colitis, Crohn's disease, and non-specific proctitis; eight patients with small bowel Crohn's disease; and 34 in whom the rectal biopsy specimen was not diagnostic. Discriminant analysis was applied to multiple variables based on the measurements, and three variables were identified as of high predictive value. The most powerful discriminant was increased lamina propria cellularity in all forms of chronic colitis. The ratios of surface length to mucosal length and of surface epithelial height to crypt epithelial height also emerged as discriminants. Chronic inflammatory bowel disease was distinguished from normal in 95% of cases with a definite pathological diagnosis, and 85% of borderline cases were correctly classified as either normal or inflammatory when judged by the final diagnosis after follow up. This study provides a basis for automated diagnosis of rectal biopsy specimens and provides objectively validated criteria which can also be applied in routine histological diagnosis.

Defining duodenitis: quantitative histological study of mucosal responses and their correlations.

Biopsies from 56 patients with endoscopically normal duodenal bulbs, duodenitis, or duodenal ulceration were studied for counts of plasma cells, polymorphs, and eosinophils and extent of gastric metaplasia, villous atrophy, and mucosal oedema. A correlation matrix showed that the counts of different types of plasma cells were closely correlated with each other and that there was also a close correlation between the presence of intraepithelial polymorphs, villous atrophy, and gastric metaplasia. Cluster and discriminant analysis indicated that the histological changes could be grouped by their statistical association into three simple categories: normal, which includes many cases incorrectly labelled in some classification systems as mild or chronic duodenitis; histologically defined mild duodenitis, characterised by an appreciable plasma cell response and oedema usually with intraepithelial polymorph infiltration and gastric metaplasia; and severe duodenitis, with an appreciable polymorph response and villous atrophy but decreased plasma cells. Decreased plasma cells may be an important indication of peptic ulceration.

The putative 116 kDa osteoclast specific vacuolar proton pump subunit has ubiquitous tissue distribution.

The pharmacological profile of the osteoclast proton pump has been demonstrated to be unique and to be the most active of all acid transport systems thus far studied. The recently reported putative 116 kDa osteoclast specific vacuolar proton pump subunit could possibly explain the unique nature of this proton pump. Here, we demonstrate however, that the osteoclast 116 kDa subunit is not osteoclast specific but has ubiquitous expression in human tissue.

A strategy for osteoporosis in gastroenterology.

Osteoporotic fractures are a major public health problem. Gastroenterologists see many patients at risk of osteoporosis, particularly those with coeliac disease and inflammatory bowel disease. In this paper, the extent of the problem is reviewed and a strategy of investigation and treatment is recommended.

Coeliac disease: the cause of the various associated disorders?

The advent of the endomysial antibody test has allowed the true association between coeliac disease and at least 12 other disorders to be established. There is evidence suggesting that coeliac disease is a cause of these disorders; a mechanism for this is proposed.

The initial investigation of jaundice in a district general hospital: a study of ultrasonography and hepatobiliary scintigraphy.

Twenty-five jaundiced patients presenting to a district general hospital were investigated by both ultrasonography (performed by a medical physicist) and hepatobiliary scintigraphy using 99Tcm-HIDA. Hepatobiliary scintigraphy was completely unable to distinguish medical from surgical jaundice. However, with mild jaundice--bilirubin < 100 mumol/l--the presence or absence of gall-bladder activity fairly accurately predicted the presence or absence of gall-bladder disease. Ultrasonography had three technical failures. Of the remaining 22 patients, medical jaundice was correctly predicted in nine of ten patients and surgical jaundice in eight of 12 patients. Erroneous results were only obtained from patients with mild jaundice, the accuracy being 100% in the 15 patients with serum bilirubin > 60 mumol/l. In a district general hospital ultrasonography is recommended as the investigation of first choice in jaundice, perhaps complemented by hepatobiliary scintigraphy when the jaundice is mild.