Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial.

SUMMARY: Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. INTRODUCTION: Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. METHODS: The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score≤-2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score≤-1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. RESULTS: Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. CONCLUSIONS: This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants.

Disruption of the EF-2 kinase/Hsp90 protein complex: a possible mechanism to inhibit glioblastoma by geldanamycin.

Glioblastoma multiforme is the most treatment-resistant brain tumor. Elongation factor-2 (EF-2) kinase (calmodulin kinase III) is a unique protein kinase that is overexpressed in glioma cell lines and in human surgical specimens. Several mitogens activate this kinase and inhibitors block mitogen activation and produce cell death. Geldanamycin (GA) is a benzoquinone ansamycin antibiotic that disrupts Hsp90-protein interactions. Because EF-2 kinase is chaperoned by Hsp90, we investigated the effects of GA on the viability of glioma cells, the expression of EF-2 kinase protein, and the interaction between Hsp90 and EF-2 kinase. GA was a potent inhibitor of the clonogenicity of four glioma cells lines with IC(50)s ranging from 1 to 3 nM. 17-allylamino-17-demethoxygeldanamycin (17-AAG), a less toxic and less potent derivative of GA, inhibited the clonogenicity of glioma cells with IC(50) values of 13 nM in C6 cells and 35 nM in T98G cells. Treatment of cell lines for 24-48 h of GA or 17-AAG disrupted EF-2-kinase/Hsp90 interactions as measured by coimmunoprecipitation, resulting in a decreased amount of recoverable kinase in cell lysates. The ability of GA to inhibit the growth of glioma cells was abrogated by overexpressing EF-2 kinase. In addition, 17-AAG significantly inhibited the growth of a glioma xenograft in nude mice. These studies demonstrate for the first time the activity of GAs against human gliomas in vitro and in vivo and suggest that destruction of EF-2 kinase may be an important cytotoxic mechanism of this unique class of drug.

Inhibitory effects of orally administered green tea, black tea, and caffeine on skin carcinogenesis in mice previously treated with ultraviolet B light (high-risk mice): relationship to decreased tissue fat.

Treatment of SKH-1 hairless mice with ultraviolet B light (UVB; 30 mJ/cm(2)) twice a week for 22 weeks resulted in tumor-free animals with a high risk of developing malignant and nonmalignant skin tumors during the next several months in the absence of additional UVB treatment (high-risk mice). Oral administration of green tea or black tea (6 mg tea solids/ml) to UVB-pretreated high-risk SKH-1 mice for 23 weeks after stopping UVB treatment decreased the number of tumors/mouse, decreased the size of the parametrial fat pads, and decreased the thickness of the dermal fat layer away from tumors and directly under tumors. Administration of the decaffeinated teas had little or no effect on these parameters, and adding caffeine (equivalent to the amount in the regular teas) to the decaffeinated teas restored their inhibitory effects. Administration of caffeine alone also decreased the number of tumors/mouse, the size of the parametrial fat pads, and the thickness of the dermal fat layer away from tumors and under tumors. Using data from individual mice and linear regression and correlation analysis, we found a highly significant positive correlation between the thickness of the dermal fat layer away from tumors and the number of tumors/mouse (r = 0.34; P = 0.0001), but the correlation between average tumor size/mouse and the thickness of the dermal fat layer away from tumors was weak (r = 0.16; P = 0.034). The results suggested that p.o. administered tea or caffeine may have decreased tumor multiplicity in part by decreasing fat levels in the dermis. Additional analysis revealed that oral administration of caffeinated beverages (green tea, black tea, decaffeinated green tea plus caffeine, decaffeinated black tea plus caffeine, or caffeine alone) decreased the thickness of the dermal fat layer under large tumors to a much greater extent than under small tumors. This is the first demonstration of a close association between inhibition of carcinogenesis and the lowering of tissue fat levels by a chemopreventive agent.

Characterization of high specific activity [16 alpha-123I]Iodo-17 beta-estradiol as an estrogen receptor-specific radioligand capable of imaging estrogen receptor-positive tumors.

16 alpha-[123I]Iodo-17 beta-estradiol (16 alpha-[123I]E2) has been characterized for use as a selective radioligand for estrogen receptor (ERc) that is capable of generating in situ images of ERc-positive tumors. High specific activity 16 alpha-[123I]E2 (7,500-10,000 Ci/mmol) was used in all determinations. Radiochemical purity was determined by thin layer chromatography, and the selectivity of radioligand for ERc was evaluated using size exclusion high performance liquid chromatography on ERc prepared from rodent uteri. Efficiencies of radioidination approaching 100% were achieved, and excellent receptor selectivity was obtained even when the efficiency of radioiodination was as low as 10%. Low radiochemical purity was always associated with poor selectivity for ERc. No new radioligand species was generated during the course of radiodecay; however, reduced binding over time, even when increased activity was used to compensate for radiodecay, indicated that the formation of a radioinert competitor does occur. 16 alpha-[123I]E2 demonstrated stable, high affinity binding to ERc and was concentrated by ERc-positive tissues. After injecting 16 alpha-[123I]E2 in vivo, images of ERc-containing tissues were obtained, including rabbit reproductive tract and dimethylbenzanthracene-induced tumors. The demonstrations of ERc selectivity and image formation both indicate that 16 alpha-[123I]E2 should have promise as a useful new radiopharmaceutical for imaging ERc-positive cancers.

Effect of cholesterol-lowering therapy on coronary endothelial vasomotor function in patients with coronary artery disease.

BACKGROUND: Improved endothelial function may contribute to the beneficial effects of cholesterol-lowering therapy. METHODS AND RESULTS: In this randomized, double-blind study, we compared the effect of 6 months of simvastatin (40 mg/d) treatment with that of placebo on coronary endothelial vasomotor function in 60 patients with coronary artery disease. Simvastatin lowered LDL-cholesterol by 40+/-12% from 130+/-28 mg/dL (P<0.001). Peak intracoronary acetylcholine infusion produced epicardial coronary constriction at baseline in both the simvastatin (-17+/-13%) and placebo (-24+/-16%) groups. After treatment, acetylcholine produced less constriction in both groups (-12+/-19% and -15+/-14%, respectively, P=0.97). The increase in coronary blood flow during infusion of the peak dose of substance P was blunted at baseline in both the simvastatin (42+/-50%) and placebo (55+/-71%) groups, reflecting impaired endothelium-dependent dilation of coronary microvessels. After treatment, the flow increase was 82+/-81% in the simvastatin group and 63+/-53% in the placebo group (P=0.16). CONCLUSIONS: Six months of cholesterol-lowering therapy has no significant effect on coronary endothelial vasomotor function in the study population of patients with coronary artery disease and mildly elevated cholesterol levels. These findings suggest that the effects of cholesterol lowering on endothelial function are more complex than previously thought.

Assessment of left ventricular diastolic function: comparison of Doppler echocardiography and gated blood pool scintigraphy.

Although left ventricular diastolic filling patterns can be examined by both Doppler velocity recordings and gated blood pool scintigraphy, few data exist regarding a comparison of these techniques. Therefore, Doppler echocardiography and scintigraphy were compared in 25 patients. Pulsed Doppler echocardiography was performed using an apical four chamber view with the sample volume at the level of the mitral anulus. Doppler measurements included peak velocity of the early diastolic filling wave, time to peak early diastolic velocity from both end-systole and end-diastole, diastolic time period and diastolic integrated velocity (early, atrial and total). The cross-sectional area of the mitral anulus and the left ventricular end-diastolic volume were estimated from measurements made on the apical four chamber view. Scintigraphic measurements included normalized peak filling rate, time to normalized filling rate from both end-diastole and end-systole, diastolic time period and relative diastolic filling during early and atrial filling. Doppler echocardiography and scintigraphy compared favorably in assessment of fractional filling during early diastole (r = 0.84) and atrial systole (r = 0.85), ratio of early to atrial filling (r = 0.83), diastolic filling period (r = 0.94) and interval from end-diastole to peak early diastolic flow (r = 0.88). Normalized peak filling rate and time to normalized peak filling rate from end-systole did not correlate closely by these two techniques. The differences in normalized peak filling rate may be explained by difficulties in estimating mitral anulus cross-sectional area and left ventricular end-diastolic volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Statistical properties of the traditional algorithm-based designs for phase I cancer clinical trials.

Although there are several new designs for phase I cancer clinical trials including the continual reassessment method and accelerated titration design, the traditional algorithm-based designs, like the '3 + 3' design, are still widely used because of their practical simplicity. In this paper, we study some key statistical properties of the traditional algorithm-based designs in a general framework and derive the exact formulae for the corresponding statistical quantities. These quantities are important for the investigator to gain insights regarding the design of the trial, and are (i) the probability of a dose being chosen as the maximum tolerated dose (MTD); (ii) the expected number of patients treated at each dose level; (iii) target toxicity level (i.e. the expected dose-limiting toxicity (DLT) incidences at the MTD); (iv) expected DLT incidences at each dose level and (v) expected overall DLT incidences in the trial. Real examples of clinical trials are given, and a computer program to do the calculation can be found at the authors' website approximately linyo" locator-type="url">http://www2.umdnj.edu/ approximately linyo.

Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment.

To evaluate the clinical utility of recently developed biochemical markers of bone turnover to monitor the response of osteoporotic patients to antiresorptive therapy, we compared the results of three advanced assays for markers of bone resorption and four of bone formation to high pressure liquid chromatography (HPLC)-fluorometric assays for urinary pyridinoline and deoxypyridinoline. These assays were also used to resolve the uncertainties concerning the rate of bone turnover in late postmenopausal (late-PMP) osteoporotic women. The rate of bone turnover in 85 women (mean +/- SD age, 63 +/- 6 yr) with low bone mass and all more than 5 yr postmenopausal (mean +/- SD yr PMP, 16 +/- 7 yr) was compared to that in 46 premenopausal women (mean +/- SD age, 40 +/- 5 yr) randomly selected from a large cohort and all having a normal spine bone mineral density (BMD). The late-PMP osteoporotic patients were a subset of patients enrolled in a double blind, placebo-controlled, randomized study comparing the effects of several doses of oral alendronate, a potent and specific inhibitor of bone resorption. Periodically during the 2-yr study, the women's spinal BMD and the level of several markers of bone turnover were measured. Serum total and intact osteocalcin, bone-specific alkaline phosphatase, and carboxy-terminal propeptide of type I collagen measured by RIA were used to assess bone formation. To assess bone resorption, we measured the urinary excretion of total pyridinoline (HPLC Pyr) and deoxypyridinoline (HPLC D-Pyr) by HPLC, type I collagen cross-linked N-telopeptide and urinary free PYR (F-Pyr) by enzyme-linked immunosorbent assay, and the serum concentration of type I collagen cross-linked C-telopeptide (ICTP) by RIA. All bone formation markers, except carboxy-terminal propeptide of type I collagen, and all bone resorption markers, except ICTP, were significantly increased above normal (33-171%; P < 0.001) in late-PMP osteoporotic women. The long term within-patient variability assessed over a 15-month period in the placebo group was low and was somewhat lower for serum markers (12.5-17.4%) than for urinary markers (24-29%). Under treatment with alendronate, resorption markers decreased earlier than markers of bone formation, consistent with a direct action of the drug to inhibit osteoclastic bone resorption. With the exception of F-Pyr and ICTP, the levels of bone markers were reduced to the normal premenopausal range, and this steady state was maintained from 6-15 months.(ABSTRACT TRUNCATED AT 400 WORDS)

Indium-113m perfusion study and the nonfunctioning thyroid nodule.

Indium-113m eluate has been used to study the perfusion of 12 patients with solitary thyroid nodules that appeared "cold" in the 131I and 99mTc image studies. Seven patients with colloid nodules showed no perfusion and the remaining five (three adenomas and two carcinomas) showed good perfusion with indium. Histologic confirmation was obtained in all cases. Indium-113m perfusion study may be useful in differentiating colloid nodules from either adenomas or carcinomas.

Radionuclide scintigraphy: a diagnostic aid in delayed traumatic splenic rupture: case report.

The use of 99mTc-sulfur colloid scintigraphy in the diagnosis of a delayed traummatic splenic rupture 10 days after injury is described. Splenic scintigraphy of patients falling in this category may help the clinician in the early detection of splenic rupture.

Reversible hypoperfusion of the cerebral cortex in normal-pressure hydrocephalus on technetium-99m-HMPAO brain SPECT images after shunt operation.

A man with dementia underwent radionuclide cisternography to establish the diagnosis of communicating hydrocephalus. Technetium-99m-HMPAO brain SPECT images showed marked hypoperfusion of both posterior cerebral cortices and three-dimensional displays that demonstrated perfusion defects at both of the posterior parietotemporal regions. A successful ventriculoperitoneal shunt operation was performed. Five and one-half months later, repeat three-dimensional display showed that the perfusion defects had resolved and a repeat brain SPECT image showed marked improvement of the hypoperfusion. This concurred with postoperative clinical improvement. Technetium-99m-HMPAO brain SPECT, which provides objective documentation of clinical recovery after surgery, could be routinely used to evaluate patients with normal-pressure hydrocephalus.

Technetium-99m MIBI uptake in recurrent parathyroid carcinoma and brown tumors.

Demonstrable parathyroid adenoma in delayed (3-hr) 99mTc-MIBI neck imaging and localization of 201Tl-chloride in brown tumors mimicking skeletal metastases have been reported. Technetium-99m-MIBI scintigraphy is currently the imaging modality of choice for localizing parathyroid tumors in patients with recurrent hyperparathyroidism. This report is a good example of the use of 99mTc-MIBI in the diagnostic work-up of a patient with recurrent hyperparathyroidism, which turned out to be due to parathyroid carcinoma rather than the initial histopathologic diagnosis of parathyroid adenoma. Additionally, the patient's total body 99mTc-MIBI and 99mTc-MDP bone images showed multiple focal lesions in the bone-mimicking metastases.

Discordant technetium-99m-MIBI and technetium-99m-HMPAO uptake of recurrent occipital meningioma on brain SPECT images.

Technetium-99m-HMPAO and 99mTc-MIBI brain SPECT, MRI, CT and cerebral angiogram were studied in a patient with recurrent occipital meningioma. MRI and CT of the head showed right cerebral hemispheric tumor masses involving parasagittal, temporal and parietoccipital areas. The angiograms showed an intense vascular tumor blush in recurrent mass lesions supplied by the following arteries: the meningeal branch of the right external carotid artery, the right middle cerebral artery, the right anterior cerebral artery and the right posterior cerebral artery. Although demonstrable 99mTc-MIBI lesions mass exactly corresponded to CT and MRI (T-1) findings, mass lesions exhibited a mismatch between 99mTc-MIBI (increased uptake) and 99mTc-HMPAO (absent uptake) brain SPECT images. Technetium-99m-MIBI images, rather than 99mTc-HMPAO brain SPECT, resulted in the correct pathological diagnosis of recurrent meningioma.

Reversible thallium-201 perfusion defects of the septal and inferoapical segments in a patient with incomplete right bundle branch block and normal coronary angiogram.

Possible causes of reversible perfusion defect in exercise-rest 201Tl myocardial images in a patient with a normal coronary artery angiogram include left bundle branch block, coronary spasm, myocardial bridges, hypertrophic cardiomyopathy, mitral valve prolapse, aortic valve disease and anomalous origin of the left coronary artery arising from the pulmonary artery. This case is a report of a 34-yr-old man with incomplete right bundle branch block and angiographically normal coronary arteries who was found to have reversible defects involving septal and inferoapical walls on stress-rest 201Tl-chloride myocardial imaging.

Opportunistic intracranial infection in AIDS detection by technetium-99m DTPA brain scintigraphy.

Radionuclide brain scintigraphy and computed tomography (CT) demonstrated cerebral lesions in two patients with acquired immunodeficiency disease syndrome (AIDS) complicated by opportunistic infection of the brain. In the detection of these cerebral lesions, [99mTc]DTPA radionuclide scintigraphy was as reliable as CT. Since malignant lymphoma involving the brain has been seen with increasing frequency in patients with AIDS, the positive brain scan alone is nonspecific and should be correlated appropriately with the clinical setting.

Technetium-99m BIDA biliary scintigraphy in the evaluation of the jaundiced patient.

Biliary scintigraphy using 99mTc p-butyl acetanilidiminodiacetic acid (BIDA) was performed as part of the diagnostic evaluation on 96 patients with jaundice (serum bilirubin greater than 2 mg/dl) to assess its value in this group of patients. The results of scintigraphy revealed no obstruction to the flow of the scintigraphic agent into the duodenum in 54 patients, delayed appearance of the agent (normal upper limit 60 min) in the duodenum indicating partial obstruction in 22 patients, and complete obstruction of the duct demonstrated by absence of agent in the duodenum in 20 patients. The findings were correlated with the final diagnosis and the overall results show accuracy of 92.7%, sensitivity of 97.3%, and specificity of 89.8%. Biliary scintigraphy was thus found to be useful in differentiating nonobstructive, partially obstructive, and completely obstructive causes of jaundice.

Bile leak from gallbladder perforation mimicking bowel activity and a false-negative result in a morphine-augmented cholescintigraphy.

Cholescintigraphy of a patient with bile leak demonstrated intra-abdominal activity that mimicked normal bowel activity. Because the gallbladder was not visualized, morphine was injected intravenously. Gallbladder activity after morphine injection was misleading in the finding of chronic cholecystitis. Concurrent abdominal sonography and computerized tomography revealed a thickened gallbladder wall with a gallstone and pericholecystic fluid collection. Exploratory laparotomy confirmed acute and chronic cholecystitis, cholelithiasis, choledocholithiasis, and a pericholecystic abscess. The false-negative conclusion for acute cholecystitis in the patient's morphine-augmented cholescintigraphy resulted from an acceleration of bile leakage due to pre-existing gallbladder perforation.

Radionuclide gastric emptying studies in patients with anorexia nervosa.

To evaluate gastric emptying in anorexia nervosa patients, 26 patients (17 females, two males, ranging in age from 13 to 40 yr) with upper GI symptoms ingested 150-200 microCi [99mTc]triethelenetetraamine polysterene resin in cereal and were imaged in the supine position. Data were accumulated at 5 min intervals to obtain the gastric emptying time (GET). The results of the studies were divided into three categories: prolonged, 13 patients; rapid, 11; and normal 3. Twelve of 13 patients with prolonged GET were given 10 mg metoclopramide i.v. injections; nine of the 12 patients had a good response and three had no response. Five of the nine patients underwent metoclopramide therapy and four of the patients showed benefit from the therapy. One patient discontinued metoclopramide therapy because of somnolence. Although all patients had subjective symptoms of gastric dysfunction, our results indicated only 50% had objectively prolonged GET, and another 50% showed normal or even rapid GET. Therefore, this radionuclide study enables quantitatively objective documentation of gastric emptying, separation of those patients with rapid or normal GET from those with prolonged GET, thereby avoiding the possible side effects from metoclopramide medication, and prediction of effectiveness of metoclopramide therapy in patients with prolonged GET.

Reverse redistribution on dynamic exercise and dipyridamole stress technetium-99m-MIBI myocardial SPECT.

Reverse redistribution on 201TI-chloride stress-redistribution myocardial scintigraphy has been associated with coronary artery stenosis. We report a patient whose two separate 99mTc-MIBI myocardial SPECT stress studies (dynamic exercise and dipyridamole) showed septal reverse redistribution and fixed inferior defect. Echocardiograms showed left ventricular (LV) hypertrophy and diffuse hypokinesis, especially in the inferior wall, and EKG showed LV hypertrophy and strain and inferior infarct. Coronary angiogram confirmed two-vessel disease involving 80%-90% stenosis of the proximal second diagonal branch of the left anterior descending artery and 75%-90% stenosis of the right coronary artery as well as global left ventricular dysfunction. Reverse redistribution on 99mTc-MIBI myocardial SPECT occurring on dynamic or dipyridamole stress may indicate damaged but viable myocardium.