Determination of low levels of protein impurities in phospholipid samples.
Explore the source record for details and available documents.
Calibration↗
Biomedical subjects
C Christiansen
Publications and source records attributed to C Christiansen.
Six and twelve month changes in bone turnover are related to reduction in vertebral fracture risk during 3 years of raloxifene treatment in postmenopausal osteoporosis.
We studied the relationship between change in bone turnover and vertebral fracture risk during raloxifene therapy using 3-year data from the MORE trial, where 2622 of the 7705 randomized women had measurement of bone markers at baseline and after 6 and 12 months participation. Change in bone turnover was significantly related to future risk of vertebral fracture, also after adjusting for baseline vertebral fracture status and BMD. Thus, for a decrease of 9.3 pg/l in serum osteocalcin after 1 year's raloxifene therapy, the odds ratio (OR) for a new vertebral fracture during 3 years was 0.69 (0.54-0.88), p = 0.003. Similarly, for a decrease of 5.91 microg/l in serum bone alkaline phosphatase, OR was 0.75 (0.62-0.92), p = 0.005. The change in BMD over 12 and 24 months was not related to fracture risk in any of the analyses. The strongest predictor for vertebral fracture was prevalent vertebral fracture--even during therapy. The predictive value of baseline BMD was in the same order of magnitude as bone turnover change during raloxifene treatment. In conclusion, the change in bone turnover is related to fracture risk during raloxifene therapy. In contrast the change in BMD is not related to fracture risk. The strongest predictor for vertebral fracture is prevalent vertebral fracture.
Alkaline Phosphatase↗
The effect of fluvastatin on parameters of bone remodeling.
Statins decrease the hepatic biosynthesis of cholesterol, and reduce the incidence of myocardial infarction in women who have already experienced a myocardial infarction. Statins also reduce the risk of atherosclerosis in diabetic patients, but it is unknown whether they influence the glucose tolerance. It has further been suggested that they may influence bone metabolism. Vitamin C is an antioxidant and it decreases serum cholesterol moderately. Antioxidants may also have other metabolic effects, but these are insufficiently studied. The aim of the present study was to investigate the metabolic effects of the cholesterol-lowering agent fluvastatin and the antioxidant vitamin C. Sixty-eight elderly, postmenopausal women with osteoporosis and mild hypercholesterolemia were randomly assigned to 12 weeks open treatment with either fluvastatin (40 mg daily) + 500 mg vitamin C (n = 45) or vitamin C only (n = 23). We measured biochemical markers of bone formation (serum osteocalcin and total alkaline phosphatase) and bone resorption (serum and urinary CTX), parameters related to diabetes and serum lipids and lipoproteins. Fluvastatin in combination with vitamin C had no effect on bone formation markers. We found a weak decrease in parameters of bone resorption, which was significant from baseline, but not different between the two groups. There were no significant effects on any of the other markers of either fluvastatin or vitamin C. The lipid-lowering effect of fluvastatin was confirmed with a decrease of 20% and 30% in serum total cholesterol and LDL-cholesterol, respectively. We conclude that fluvastatin given in clinically relevant doses has no influence on parameters of bone remodeling. Other statins remain to be investigated.
Aged↗
Intermittent cyclic tiludronate in the treatment of osteoporosis.
The objective of the study was to determine the efficacy and safety of tiludronate in the treatment of postmenopausal osteoporosis. Two placebo-controlled, randomized, double-masked, multicenter, cyclical, intermittent, dose-ranging studies including 1805 women with low vertebral bone mineral density and prevalent vertebral fractures and 488 women with low bone mineral density and no prevalent fracture were conducted. Patients were randomized to either tiludronate 50 mg/day, tiludronate 200 mg/day or placebo, given orally for the first 7 days of each month. A supplement of 500 mg elemental calcium was provided daily from day 8 to the end of the month. Both studies demonstrated no statistically or clinically relevant trends in the incidence of adverse effects across the three treatment groups. However, tiludronate administered at these two doses in a cyclic intermittent regimen was not effective in reducing the incidence of vertebral fractures or increasing spinal bone mineral density. Thus, tiludronate, administered at these doses in a cyclic intermittent regimen, cannot be considered an appropriate treatment of postmenopausal osteoporosis, notwithstanding a high safety profile.
Aged↗
Bone resorption in post-menopausal women with normal and low BMD assessed with biochemical markers specific for telopeptide derived degradation products of collagen type I.
Biochemical markers of bone resorption can be used clinically to predict the risk of osteoporosis-related fractures (prognostic tool) and to assess the response of an osteoporotic patient to an antiresorptive therapy (monitoring tool). Our aim was to assess the ability of four currently marketed biochemical markers of bone resorption, based on the measurement of degradation products from collage type I telopeptides to monitor the elevated resorption associated with menopause. Women (846) were stratified for menopause, age, and bone mineral density and the following markers were measured: urinary cross-linked N-telopeptides of type I collagen (NTx), the levels of breakdown products of type I collagen C-telopeptides in serum (S-CTx), and in urine, by ELISA (U-CTx-E), and RIA (U-CTx-R). Furthermore, the ratio (alpha/beta) between the alphaL form of CTx measured in the CTx RIA and the betaL form measured in the ELISA was calculated. The mean difference was calculated for each marker in women with osteopenia (Op) or osteoporosis (PMO) (WHO definition) compared with healthy premenopausal (Pre) women and postmenopausal (N Post) women with normal bone mass. Serum CTx showed the highest elevation in post- compared with premenopausal women. All marker values were significantly higher in Op and PMO subjects compared with both Pre and to N Post women. Compared with premenopausal values, the largest elevation in both Op and PMO women was observed for serum CTx. Compared with N Post, urine NTx showed the highest increase in OP subjects. The alpha/beta CTx ratio was elevated in post- compared with Pre women, but there was no difference in the ratio among N Post, Op, or PMO women. In conclusion, postmenopausal women showed elevated turnover with all bone resorption markers, but with substantial individual variation in resorption levels. Furthermore, the turnover process in postmenopausal women appears to be quantitatively different from the premenopausal stage, apparent as altered alpha/beta CTx ratios.
Adult↗
Raloxifene and estrogen reduces progression of advanced atherosclerosis--a study in ovariectomized, cholesterol-fed rabbits.
The present study investigated the effect of raloxifene, a selective estrogen receptor modulator (SERM), on aortic atherosclerosis in 80 ovariectomized, cholesterol-fed rabbits with pre-induced atherosclerosis. The animals were fed an atherogenic diet containing 240 mg cholesterol/day for 15 weeks, after this period a baseline control group was sacrificed. Thereafter, oral treatment was initiated with either estradiol 4 mg/day (n=20), raloxifene (210 mg/day) or placebo (n=20). In the treatment period of 39 weeks, the dietary cholesterol content was reduced to 80 mg cholesterol/day. Postmortem evaluation showed a significantly increased uterine weight induced by estradiol treatment (10.3+/-1.2 g), whereas raloxifene intervention caused a decreased uterus weight (1.21+/-0.1 g) when compared to placebo (2.48+/-0.47 g). Throughout the study, serum lipids increased in all groups to levels seen in very high risk humans. After 58 weeks the cholesterol content in the aorta was 3.18+/-0.54 micromol/cm(2) (38% reduction) in the estradiol group, 3.66+/-0.52 micromol/cm(2) (29% reduction) in the raloxifene group and 5.12+/-0.60 micromol/cm(2) in the placebo group. Analyses of the aortic cholesterol content corrected for time-averaged serum cholesterol revealed that both estradiol and raloxifene therapy significantly reduced the progression of atherosclerosis (P<0.01 for both) as compared to placebo.
Animals↗
Incorporation and distribution of strontium in bone.
The distribution and incorporation of strontium into bone has been examined in rats, monkeys, and humans after oral administration of strontium (either strontium chloride or strontium ranelate). After repeated administration for a sufficient period of time (at least 4 weeks in rats), strontium incorporation into bone reaches a plateau level. This plateau appears to be lower in females than in males due to a difference in the absorption process. Steady-state plasma strontium levels are reached more rapidly than in bones, and within 10 days in the rat. The strontium levels in bone vary according to the anatomical site. However, strontium levels at different skeletal sites are strongly correlated, and the strontium content of the lumbar vertebra may be estimated from iliac crest bone biopsies in monkeys. The strontium levels in bone also vary according to the bone structure and higher amounts of strontium are found in cancellous bone than in cortical bone. Furthermore, at the crystal level, higher concentrations of strontium are observed in newly formed bone than in old bone. After withdrawal of treatment, the bone strontium content rapidly decreases in monkeys. The relatively high clearance rate of strontium from bone can be explained by the mechanisms of its incorporation. Strontium is mainly incorporated by exchange onto the crystal surface. In new bone, only a few strontium atoms may be incorporated into the crystal by ionic substitution of calcium. After treatment withdrawal, strontium exchanged onto the crystal is rapidly eliminated, which leads to a rapid decrease in total bone strontium levels. In summary, incorporation of strontium into bone, mainly by exchange onto the crystal surface, is dependent on the duration of treatment, dose, gender, and skeletal site. Nevertheless, bone strontium content is highly correlated with plasma strontium levels and, in bone, between the different skeletal sites.
Administration, Oral↗
Investigation of binding of 125I-iodixanol to high molecular weight substances after incubation with rat liver homogenates.
PURPOSE: It has recently been shown that incubation of iodixanol in rat liver homogenates resulted in formation of iodixanol metabolites. The present study was performed to see if this incubation resulted in any binding of iodixanol to high molecular weight substances, as such a high molecular weight conjugate of iodixanol theoretically might cause initiation of an immune response against this contrast agent. MATERIAL AND METHODS: 125I-iodixanol was incubated with rat liver homogenates for 1 h at 37 degrees C and 17 h at 25 degrees C followed by analysis of the supernatant fractions using gel-permeation chromatography with on-line radiochemical detection. RESULTS: No traces of radioactivity could be detected in the chromatograms, except at the retention time of free iodixanol. CONCLUSION: No binding of iodixanol to high molecular weight substances could be demonstrated after incubation of iodixanol with rat liver homogenates.
Animals↗
Efficacy of levormeloxifene in the prevention of postmenopausal bone loss and on the lipid profile compared to low dose hormone replacement therapy.
Three hundred and one healthy women between 45 and 65 yr of age and at least 1 yr postmenopausal were randomly assigned to 12-month double-blind therapy with levormeloxifene [1.25 (n = 51), 5, 10, or 20 mg/day], low dose continuous combined hormone replacement therapy [HRT; 1 mg 17 beta-estradiol and 0.5 mg norethisterone acetate/day], or placebo (all n = 50). All of the women were also given a daily supplement of calcium (500 mg). Serum CrossLaps decreased by about 50% in the levormeloxifene groups, with no dose-response effect. The group receiving HRT decreased more (>60%), and the placebo group (500 mg calcium alone) decreased by about 10%. The pattern was similar for bone alkaline phosphatase, except that the decreases were smaller, about 30% for the levormeloxifene groups and 50% for the HRT group. Serum osteocalcin also showed highly significant decreases, of the same magnitude in the levormeloxifene and HRT groups. Spinal bone mineral density (BMD) decreased by less than 1% in the placebo group and increased by about 2% in the levormeloxifene groups and by almost 5% in the HRT group (P < 0.001 for the difference between levormeloxifene and HRT vs. placebo). BMD of the total hip and total body changed in the same direction, although differences between groups were not as pronounced as those for BMD spine. Total cholesterol decreased by about 13--20% during levormeloxifene therapy, whereas daily doses of 1 mg estradiol and 0.5 mg norethisterone acetate produced a decrease of only about 8%. Levormeloxifene decreased low density lipoprotein cholesterol by about 22-30% compared with about 12% in the low dose HRT group. High density lipoprotein cholesterol was unchanged in all groups. Endometrial thickness increased both clinically and statistically significantly in the levormeloxifene groups independently of the dose; the difference from the placebo and HRT groups was significant (P < 0.001). There was no significant difference between the HRT and placebo groups. Other adverse events of interest include hot flushes, which did not occur more frequently in the levormeloxifene than the placebo groups, but occurred significantly less frequently in the HRT group (P < 0.05). Breast tenderness was much more common in the HRT group (<0.001) than in all other groups. In conclusion, the study shows that levormeloxifene, a new selective estrogen receptor modulator, has positive effects on BMD and bone turnover and apparently strong estrogenic effects on the serum concentrations of different cholesterol subfractions. Levormeloxifene at the doses tested had an estrogen-like effect on endometrium and no effect on hot flushes. The study was unable to differentiate between the effects of the different doses of levormeloxifene.
Bone Density↗
Ibandronate: a comparison of oral daily dosing versus intermittent dosing in postmenopausal osteoporosis.
The objective of this study was to compare efficacy and safety of continuous versus intermittent oral dosing of ibandronate. Two hundred forty women aged 55-75 years with postmenopausal osteoporosis were randomized to active treatment or placebo. Similar total doses of ibandronate were provided by treatment regimens with either continuous 2.5 mg of ibandronate daily (n = 81) or intermittent 20 mg of ibandronate every other day for the first 24 days, followed by 9 weeks without active drug (n = 78). The placebo group (total, n = 81) was crossed over after 12 months to receive either continuous (n = 37) or intermittent ibandronate (n = 35). By 24 months, bone mineral density (BMD) had increased significantly relative to baseline in both active treatment groups. The continuous and intermittent groups showed statistically equivalent increases in lumbar spine BMD of +5.64% (+/-0.53) and +5.54% (+/-0.53) and in total hip of +3.35% (+/-0.40) and +3.41% (+/-0.40), respectively (per protocol population). Biochemical markers of bone turnover decreased significantly in both treatment groups. The level of marker suppression was similar, although the intermittent group displayed, as expected, more fluctuation over the treatment period. The frequency of adverse events was similar in the treatment groups. In conclusion, the intermittent and continuous regimens showed equivalent changes in BMD and bone turnover. These results confirm previous preclinical findings indicating that the efficacy of ibandronate depends on the total oral dose given rather than on the dosing schedule. This supports development of new flexible dosing regimens targeted to minimize the frequency of dosing, which are expected to improve convenience and lead to enhanced long-term patient compliance.
Administration, Oral↗
Dietary phytoestrogens and estrogen inhibit experimental atherosclerosis.
OBJECTIVE: The effect of phytoestrogen intake in combination with estrogen replacement therapy (ERT) on atherogenesis is largely unknown. The aim was thus to study the impact of phytoestrogens alone, or combined with oral estrogen, on experimental atherosclerosis in cholesterol-fed rabbits. METHODS: Two separate studies were performed in ovariectomized, cholesterol-fed female rabbits. In Study A, 45 rabbits were randomized to either a soy-free diet with or without oral 17 beta-estradiol (E2) 4 mg/day, or a soy-rich diet without any hormone for 14 weeks. In Study B, 100 rabbits were randomized into five groups (oral E2 0.5, 1, 2 or 4 mg/day, or no hormone) based on a soy-rich diet for 30 weeks. RESULTS: By the end of treatment in Study A, aortic cholesterol content was twice the amount in the group treated with the soy-free diet compared with the soy-rich group and with the soy-free plus E2 group (p < 0.001). In Study B, aortic cholesterol content showed no significant difference between the groups (ANOVA, p = 0.49), but a tendency towards a lower aortic cholesterol content in the E2-treated animals compared with placebo was observed. CONCLUSION: Dietary phytoestrogens significantly reduce aortic cholesterol content with a potency comparable to that of ERT, and seem to enhance (although mildly) the antiatherogenic effect of E2 in this model.
Animals↗
Influence of female and male sex steroids on body composition in the rabbit model.
OBJECTIVE: To study the influence on body composition of estrogen replacement therapy (ERT) in female rabbits and of replacement therapy with testosterone (TRT) in male rabbits using dual-energy X-ray absorptiometry (DEXA). METHODS: Cholesterol-fed female and male rabbits receiving a weight-restricted diet (100 g/day) were used. Total lean tissue mass (LTM), total body fat tissue mass (FTM) and total tissue mass (TTM) were determined by DEXA at baseline, after which the animals were gonadectomized and treated with sex steroids. Soft body composition was then determined again after 30-31 weeks of treatment. RESULTS: Relative to controls, ERT with estradiol (E2) doses of 2 and 4 mg/day significantly increased LTM (p < 0.001), whereas E2 0.5 and 1 mg/day had a neutral effect on LTM. The change in fat mass, however, was not statistically significant between groups. In male rabbits, compared with castrated control rabbits, LTM decreased in testosterone-treated animals (by 7-12%; p < 0.001) but FTM decreased relatively more (by 66-79%; p < 0.0001). In both genders, body weight correlated with TTM as determined by DEXA (r = 0.89-0.91, p < 0.0001). CONCLUSION: In this in vivo model of growing rabbits, estrogen replacement significantly increased LTM in female animals, whereas testosterone replacement significantly decreased FTM in males, suggesting that soft body composition of both genders is significantly affected by replacement with sex steroids. Until comparable human data are available, it is speculated that similar changes in soft body composition may occur in humans treated with sex steroids.
Absorptiometry, Photon↗
Delayed allergy-like reactions to X-ray contrast media: mechanistic considerations.
Iodinated X-ray contrast media are among the most frequently used pharmaceuticals for intravascular administration. Although the newer low osmolality, nonionic contrast media, are generally well tolerated, it is well known that they, like the ionic contrast media, give rise to immediate or delayed adverse reactions in susceptible individuals. In the present review, the delayed allergy-like reactions, which by definition occur more than 1 h after contrast medium administration, are described, and the possible pathophysiological mechanisms discussed. Delayed allergy-like reactions to contrast media, which have been reported to occur in 0.5-2% of recipients, are mainly mild to moderate skin reactions of the maculopapular exanthematous and urticarial/angioedematous types. Most of the reactions become apparent after a latency of 3 h to 2 days and disappear within 1 week. The incidence of more severe reactions is extremely low. Main risk factors for delayed allergy-like reactions appear to be a previous contrast medium reaction, a history of allergy, IL-2 treatment and being of Japanese descent. At present, the exact pathogenesis of these delayed reactions is still unclear. There is, however, increasing evidence that a significant proportion of the reactions are T-cell mediated.
Contrast Media↗
Early response in biochemical markers predicts long-term response in bone mass during hormone replacement therapy in early postmenopausal women.
Based on data from 153 early postmenopausal women who completed a double-blind, randomized 3 year study of graded hormone replacement therapy (HRT) doses or placebo, we investigated the value of bone markers to predict prevention of bone loss. Absolute values of serum and urinary CrossLaps (S-CTX and U-CTX) after 2 weeks of treatment were significantly correlated to 3 year bone mass response (r = -0. 28/-0.35; p < 0.001). These associations were fully expressed at 6 months (r = -0.61/-0.64; p < 0.001). Receiver operating characteristic analyses revealed that the predictive capacity of one measurement of a resorption marker after 6 months' treatment performed similarly as assessment of hip bone mass over 3 years in predicting preservation of spinal bone mass over 3 years. Comparable results were obtained using percent change from baseline in resorption markers at both 6 and 12 months, whereas for formation markers percent change was superior to absolute value at 6 months but not at 12 months. Values of accuracy for S-CTX for a cutoff of 1881 pmol/L at 6 months were 85.2% (sensitivity), 74.3% (specificity), 90.5% (positive predictive value), and 63.4% (negative predictive value); U-CTX performed similarly, whereas the values for the formation markers were slightly lower. A cutoff for S-CTX of 1245 pmol/L eliminated false-positive individuals (those who had a decrease below the cutoff but lost bone). In the false-negative group, which was composed of individuals whose S-CTX did not decrease below the cutoff but had preserved bone mass, S-CTX was significantly associated with spinal bone mass response (r = -0. 41; p < 0.01), indicating these women had been treated with a dose that was not at its optimum for their individual bone turnover. For this cutoff, the values were 49.5% (sensitivity), 97.1% (specificity), 98% (positive predictive value), and 40% (negative predictive value). In conclusion, early bone marker measurements predict long-term preservation of bone mass during HRT. Resorption markers seem superior to formation markers, which reflects that the primary effect of HRT is on bone resorption. A strategy with two cutoff levels may optimize the use of bone markers to predict bone mass response. Whether resorption markers can be used to guide individualized treatment remains to be investigated.
Biomarkers↗
Raloxifene reduces atherosclerosis: studies of optimized raloxifene doses in ovariectomized, cholesterol-fed rabbits.
OBJECTIVE: We have previously shown that raloxifene, a selective oestrogen receptor modulator, 35 mg/day inhibits atherosclerosis in ovariectomized, cholesterol-fed rabbits. This effect was only partial as compared to 17beta-oestradiol 4 mg/day; however, plasma raloxifene concentrations were low relative to those obtained in raloxifene-treated women. We therefore investigate the effects of raloxifene at higher doses. DESIGN: The study on atherosclerosis in ovariectomized, cholesterol-fed rabbits (n = 80) compared raloxifene 70 mg/day and 210 mg/day to 17beta-oestradiol 4 mg/day and placebo. RESULTS: After 48 weeks of therapy, the aortic cholesterol content in the 70 mg/day and 210 mg/day raloxifene treatment groups were 471 +/- 56 nmol/mg protein and 456 +/- 56 nmol/mg protein, respectively. This was significantly less than in the placebo group (654 +/- 69 nmol/mg protein; P < 0.05). In the oestrogen-treated group, the aortic cholesterol content was 357 +/- 62 nmol/mg protein (P < 0.01 as compared to placebo). Differences in serum lipids between the treatment groups could only partly explain the effect on aortic cholesterol content, indicating that additional anti-atherogenic mechanisms may contribute to the decrease in aortic atherosclerosis. This anti-atherosclerotic activity of raloxifene was observed at plasma concentrations comparable to those in postmenopausal women during raloxifene treatment. CONCLUSIONS: We conclude that clinically relevant raloxifene treatment inhibits aortic atherosclerosis in ovariectomized, cholesterol-fed rabbits.
Analysis of Variance↗
Patient participation in research in the managed care environment: key perceptions of members in an HMO.
This study's objective was to elicit the views of research among enrollees in an HMO. A questionnaire was mailed to 207 adult enrollees, 55% had been exposed to research and 45% had not. Ninety-four percent of respondents supported research within the HMO, and 87% thought using information from medical records for research was acceptable. Sixty-three percent thought participation in research increased patient understanding of health care. Significantly more prior research participants thought that participation in research improves care. More patients would participate if written information were provided (67%), if feedback of results was provided (72%), and if their clinician invited them (67%). Only a modest percentage (20%) of patients would participate in a randomized trial.
Adult↗
Clinical equivalence of intranasal and oral 17beta-estradiol for postmenopausal symptoms.
OBJECTIVE: The aim of this study was to demonstrate clinical equivalence between a novel intranasal estradiol formulation and a reference oral drug. STUDY DESIGN: In this multinational, double-blind, parallel-group study 659 postmenopausal women with moderate to severe postmenopausal symptoms were randomly assigned to receive either 300 microg/d intranasal 17beta-estradiol (S21400) or 2 mg/d oral micronized estradiol, plus the appropriate placebo, for 24 weeks. All patients also received 10 mg/d dydrogesterone for 14 days per 28-day cycle. Adjustment of intranasal dosage was permitted from week 14 on. The primary efficacy criterion was the Kupperman index at week 14, with a predefined limit of equivalence of 4. RESULTS: Kupperman index scores improved similarly in the 2 groups, from 28.4 +/- 6.2 to 10.0 +/- 8.6 (mean +/- SD) for S21400 and from 28.1 +/- 6.0 to 8.9 +/- 8.0 for oral therapy, with a difference between groups at week 14 of 1.1 +/- 0.6 (90% confidence interval, 0. 0 to 2.2). This was below the predefined equivalence limit of +4 for statistical noninferiority (P <.001). The daily number and intensity of hot flushes decreased similarly in the two treatment groups. Withdrawal bleeding was 20% less frequent with intranasal therapy (90% confidence interval, 12.5 to 27.6). Severe mastalgia was less frequent in the S21400 group (1.0%) than in the group with oral therapy (5.2%; P <.01). Triglyceride and angiotensinogen levels increased significantly with oral therapy but not with S21400. The same number of patients required dose adaptation in the 2 groups (approximately 20%). CONCLUSION: Intranasal administration of 300 microg/d estradiol was at least as effective as oral administration of 2 mg/d estradiol in alleviating postmenopausal symptoms, with less frequent mastalgia and uterine bleeding and without the metabolic consequences of the first-pass effect.
Administration, Intranasal↗