Risedronate Reduces the Risk of First Vertebral Fracture in Osteoporotic Women

Risedronate treatment reduces the risk of vertebral fracture in women with existing vertebral fractures, but its efficacy in prevention of the first vertebral fracture in women with osteoporosis but without vertebral fractures has not been determined. We examined the risk of first vertebral fracture in postmenopausal women who were enrolled in four placebo-controlled clinical trials of risedronate and who had low lumbar spine bone mineral density (BMD) (mean T-score =–3.3) and no vertebral fractures at baseline. Subjects received risedronate 5 mg (n= 328) or placebo (n= 312) daily for up to 3 years; all subjects were given calcium (1000 mg daily), as well as vitamin D supplementation (up to 500 IU daily) if baseline serum 25-hydroxyvitamin D levels were low. The incidence of first vertebral fracture was 9.4% in the women treated with placebo and 2.6% in those treated with risedronate 5 mg (risk reduction of 75%, 95% confidence interval 37% to 90%; P= 0.002). The number of patients who would need to be treated to prevent one new vertebral fracture is 15. When subjects were stratified by age, similar significant reductions were observed in patients with a mean age of 64 years (risk reduction of 70%, 95% CI 8% to 90%; P= 0.030) and in those with a mean age of 76 years (risk reduction of 80%, 95% CI 7% to 96%; P= 0.024). Risedronate treatment therefore significantly reduces the risk of first vertebral fracture in postmenopausal women with osteoporosis, with a similar magnitude of effect early and late after the menopause. Received: 12 September 2001 / Accepted: 11 December 2001     

A Method for Determining Skeletal Lengths from DXA Images

Background  

Skeletal ratios and bone lengths are widely used in anthropology and forensic pathology and hip axis length is a useful predictor of fracture. The aim of this study was to show that skeletal ratios, such as length of femur to height, could be accurately measured from a DXA (dual energy X-ray absorptiometry) image.     

The role of thyroid scanning in hyperthyroidism

Radionuclide thyroid imaging was performed in 872 consecutive patients with hyperthyroidism. Of these, 84% were found to have diffuse toxic hyperplasia (Graves' disease), while 12% had autonomously functioning nodules (Plummer's disease), 3% had Graves' disease developing in a multinodular gland, and in the remaining 1%, either a clear diagnosis could not be established or the hyperthyroidism was due to thyroiditis or the Jod-Basedow phenomenon. It was found that a thyroid scan seldom provides additional diagnostic information in patients with Graves' disease when a diffuse goitre is present. However, if patients are to be treated with radioiodine (131I), thyroid imaging with tracer quantitation can replace a 24-h 131I uptake measurement, this having the advantages that the patients are required to attend only once, and that the gland size can be measured. In addition, visual confirmation of tracer uptake by the thyroid is obtained and patients with thyroiditis will not receive inappropriate therapy. When single or multiple thyroid nodules are palpated, a thyroid scan is crucial in establishing an accurate diagnosis, as it is not otherwise possible to differentiate between Plummer's disease and Graves' disease developing in a multinodular gland. Indeed, in 20 of our 63 patients (32%) with single autonomously functioning nodules, the initial clinical assessment had been incorrect.     

Long-term precision of 18F-fluoride PET skeletal kinetic studies in the assessment of bone metabolism.

(18)F-Fluoride PET allows noninvasive evaluation of regional bone metabolism and has the potential to become a useful tool for assessing patients with metabolic bone disease and evaluating novel drugs being developed for these diseases. The main PET parameter of interest, termed K(i), reflects regional bone metabolism. The aim of this study was to compare the long-term precision of (18)F-fluoride PET with that of biochemical markers of bone turnover assessed over 6 mo. METHODS: Sixteen postmenopausal women with osteoporosis or significant osteopenia and a mean age of 64 y underwent (18)F-fluoride PET of the lumbar spine and measurements of biochemical markers of bone formation (bone-specific alkaline phosphatase and osteocalcin) and bone resorption (urinary deoxypyridinoline) at baseline and 6 mo later. Four different methods for analyzing the (18)F-fluoride PET data were compared: a 4k 3-compartmental model using nonlinear regression analysis (K(i-4k)), a 3k 3-compartmental model using nonlinear regression analysis (K(i-3k)), Patlak analysis (K(i-PAT)), and standardized uptake values. RESULTS: With the exception of a small but significant decrease in K(i-3k) at 6 mo, there were no significant differences between the baseline and 6-mo values for the PET parameters or biochemical markers. The long-term precision, expressed as the coefficient of variation (with 95% confidence interval in parentheses), was 12.2% (9%-19%), 13.8% (10%-22%), 14.4% (11%-22%), and 26.6% (19%-40%) for K(i-3k), K(i-PAT), mean standardized uptake value, and K(i-4k), respectively. For comparison, the precision of the biochemical markers was 10% (7%-15%), 18% (13%-27%), and 14% (10%-21%) for bone-specific alkaline phosphatase, osteocalcin, and urinary deoxypyridinoline, respectively. Intraclass correlation between the baseline and 6-mo values ranged from 0.44 for K(i-4k) to 0.85 for K(i-3k). No significant correlation was found between the repeated mean standardized uptake value measurements. CONCLUSION: The precision and intraclass correlation observed for K(i-3k) and K(i-PAT) was equivalent to that observed for biochemical markers. This study provided initial data on the long-term precision of (18)F-fluoride PET measured at the lumbar spine, which will aid in the accurate interpretation of changes in regional bone metabolism in response to treatment.     

Interactions of Treponema pallidum with endothelial cell monolayers

Syphilis is a chronic disease characterized by hematogenous dissemination of Treponema pallidum into tissues such as the cardiovascular and central nervous systems. In order to test whether these aspects of the pathogenesis of syphilis reflect an ability of T. pallidum to invade vascular entothelial surfaces, we explored the association of T. pallidum with human and rabbit endothelial cells in vitro. Using radiolabeled motile organisms, we found that treponemal attachment was two times greater to rabbit aortic endothelial cells and human umbilical endothelial cells than to HeLa cells. Mild trypsinization of attached treponemes resulted in release from cells of all organisms detectable by darkfield microscopy without visible damage to the monolayer. Nevertheless, 25% of the counts representing T. pallidum remained associated with the cell monolayers. Further trypsin treatment to release the monolayer and differential centrifugation showed that 80% of the remaining cell-associated counts were not within the cells. These results suggest that some treponemes had associated with the monolayer in a trypsin resistant niche. Additionally, motile T. pallidum passed through tight functioned endothelial cell monolayers on membrane filters under conditions were heat-killed T. pallidum and the host indigenous nonpathogen. T. phagedenis biotype Reiter failed to do so. Electron micrographs of transverse sections through the monolayers showed many T. pallidum in junctions between endothelial cells. These studies suggest that T. pallidum may leave the circulation by passing between endothelial cells.     

Serum concentrations of alkaline phosphatase isoenzymes and osteocalcin in normal pregnancy

We measured serum alkaline phosphatase isoenzymes and osteocalcin levels in 40 healthy women at 4-week intervals throughout uncomplicated pregnancies and 6 weeks after delivery in 17 women. Serum bone alkaline phosphatase was significantly higher in the third trimester than in early pregnancy (P less than 0.001), and this elevation was still apparent at the end of the puerperium, suggesting increased bone turnover. Serum osteocalcin was not detected (less than 0.2 micrograms/L) after the first trimester in the majority of women, and it reappeared within 48 h after delivery. The disappearance of osteocalcin after the first trimester and its rapid reappearance after delivery suggest placental clearance of this peptide. We conclude that serum osteocalcin measurements cannot be used as a marker of bone metabolism during pregnancy.     

Eyelid movements during blinking in patients with Parkinson's disease.

We examined eyelid movements during spontaneous, voluntary, and trigeminal reflex blinks in 16 patients with mild to moderate Parkinson's disease (PD) off medication and 14 controls. Voluntary and reflex blink amplitudes tended to be smaller than normal for PD patients, whereas eyelid kinematics (amplitude-maximum velocity relationship) for all three blink types were normal. Spontaneous blink rate was less than normal for 10 patients and abnormally high for 6 patients. A significant positive correlation between spontaneous blink amplitude and blink rate was found. These observations suggest that PD modifies the gain of a premotor blink circuit shared by spontaneous, voluntary, and reflex blinks.     

Reappraisal of the baseline bone scan in breast cancer

Baseline staging bone scans in 1,267 consecutive women with breast cancer attending a single clinic between 1980 and 1986 were reviewed. 0.3% of patients with T1, 3% with T2, 8% with T3, 13% with T4 tumors and none of those with Stage 1, 3% with Stage 2, 7% with Stage 3, and 47% with Stage 4 disease had a positive scan due to bone metastases. Two hundred eight-nine (23%) had bone scan abnormalities secondary to radiologically confirmed benign bone disease. In 20 patients, no cause for a bone scan abnormality could be found after a median follow-up of 3.50 yr, a false-positive frequency of 1.6%. The false-negative rate was 0.08%. It is concluded that patients with tumors less than 2 cm are most unlikely to have a positive scan. In this instance, scans are not required routinely. However, we recommend a baseline scan in all patients with Stage 2, 3, or 4 disease.     

The correction of BMD measurements for bone strontium content.

Strontium ranelate (SR) is a new oral treatment for osteoporosis associated with large increases in bone mineral density (BMD) compared with alternative therapies such as bisphosphonates. Much of the BMD increase during SR treatment is a physical effect caused by the increased attenuation of X-rays due to the accumulation of strontium in bone tissue. The aim of this study was to assess the contribution made by bone strontium content (BSC) to the overall BMD increase by evaluating the percentage F of the BMD change explained by the physical presence of strontium in bone. A value of F less than 100% would provide evidence of the anabolic effect of SR as an additional factor contributing to the overall BMD increase. Studies of mixtures of strontium hydroxyapatite (SrHA) and calcium hydroxyapatite (CaHA) scanned on a variety of dual-energy X-ray absorptiometry (DXA) systems show that a 1% molar ratio of SrHA/(CaHA+SrHA) causes a 10% overestimation of BMD. The correction of spine BMD measurements for the physical effects of strontium depends on knowledge of 2 further factors: (1) bone biopsy measurements of iliac crest BSC and (2) the ratio R of BSC at the DXA site to BSC at the iliac crest measured in animal studies. We used clinical trial data and values of R(spine) measured in studies of monkeys and beagle dogs to determine values of F(spine) for 1, 2, and 3 yr treatment with SR. Based on the average value of R(spine) approximately 0.7 for male and female monkeys, we found values for F(spine) approximately 75-80% for 1, 2, and 3 yr of treatment. Using the value of R(spine) approximately 1.0 from the beagle study gave values of F(spine) approximately 100%. Although values of F(spine) as low as 40% are possible, we conclude that the most likely figure is 75% or greater. However, it is apparent that there are large uncertainties in the correction of BMD results for the effect of bone strontium and that the most important of these is the inference of BSC values at DXA scan sites from measurements of iliac crest bone biopsy specimens.