Response rates to oestrogen treatment in perimenopausal women: 5-year data from the Danish Osteoporosis Prevention Study (DOPS).

OBJECTIVE: To characterise women with no response or with a good response to hormone replacement therapy (HRT), evaluated by change in bone mineral density (BMD). DESIGN: Nested case-control study within a comprehensive cohort study. SUBJECTS AND METHODS: In the Danish Osteoporosis Prevention Study (DOPS), perimenopausal women were allocated to either HRT or no HRT. In the present study, we included 466 women who had been treated with HRT for 5 years and 466 untreated women from the same cohort. Non-responders were women in the treatment group, who decreased in BMD more than the mean decrease observed in the untreated group. Good responders were women with a larger increase in BMD than the upper 95% percentile of untreated women. Baseline characteristics were evaluated as predictors of response to HRT. RESULTS: 8.4 and 5.6% were classified as non-responders, whereas 25 and 57% were good responders according to changes in BMD of the femoral neck and lumbar spine, respectively. Combining measuring sites, 2.6% were non-responders and 20% were good responders. Non-responders at the femoral neck were more often smokers and had a lower spine BMD. Good responders were older, had a higher body weight, and higher alcohol consumption. In addition, good responders at both measurements sites had a lower BMD at the total hip. CONCLUSION: A favourable BMD response to HRT can be expected in most post-menopausal women especially if they are non-smokers with a moderate--as opposed to low--alcohol intake, a high body mass and a low initial hip BMD.

When should densitometry be repeated in healthy peri- and postmenopausal women: the Danish osteoporosis prevention study.

Intervention should be considered in postmenopausal women with bone mineral density (BMD) > or = 1 SD below the reference (T or Z score < -1). However, it is unclear when densitometry should be repeated. This study aimed at determining the need for repeat DXA within 5 years in untreated peri-/postmenopausal women to detect declines of T or Z score to below -1 with 85% confidence. A cohort of 925 healthy women (aged 51.2 +/- 2.9 years) were followed within the Danish Osteoporosis Prevention Study (DOPS) for 5 years without hormone-replacement therapy (HRT). DXA of spine, hip, and forearm was done at 0,1, 2, 3, and 5 years (Hologic QDR-1000/2000). The annual loss in SD units was 0.12 +/- 0.10 at the spine (1.3%), 0.10 +/- 0.09 at the femoral neck (1.2%), and 0.07 +/- 0.09 at the ultradistal (UD) forearm (1.0%). Accordingly, T scores below -1 developed earlier at the spine. The need for a future DXA scan to predict declines of T and Z scores below -1 depended strongly on baseline BMD. In subjects with a positive T score, the risk of developing T < -1 remained at <15% for 5 years at all measured sites. A new scan was needed after 1 year if the T score was below -0.5, and after 3 years if the T score was between 0 and -0.5. Slightly longer intervals apply if Z scores are used. Follow-up densitometry in untreated women should be individually targeted from baseline BMD rather than scheduled at fixed time intervals. An algorithm for planning repeat densitometry in perimenopausal women is provided.

Geometric properties of distal radius and pathogenesis of Colles fracture: a peripheral quantitative computed tomography study.

It is well known among clinicians that Colles fracture patients may have normal projected axial bone mineral density and that bone mass is not synonymous with bone strength. The aim of this work was to investigate whether cross-sectional properties of the distal radius in female patients with recent Colles fracture differ from those of a younger group of normal women without fracture. It was hypothesized that patients with Colles fracture had petite distal radii and that cortical thinning and reduced cortical and trabecular volumetric density are dominant features of this fracture type. We used a multilayer high-precision peripheral quantitative computed tomography (pQCT) device with a long-term precision error of 0.1% for a dedicated phantom during the measurement period (152 d). Clinical measurements were made at an ultradistal site rich in trabecular bone and a less ultradistal site rich in cortical bone. The results show that the following pQCT variables were significantly reduced in the nonfractured radius of the Colles fracture cases: mean ultradistal trabecular volumetric density, mean ultradistal and distal cortical volumetric density, mean ultradistal and distal cortical thickness (p < 0.001 for all differences). The outer cortical diameter, cross-sectional bone area, and cortical bending moment of inertia were not statistically different in the two groups. Thus, it would appear that Colles fracture cases did not have petite distal radii. The results suggest that the deforming force of Colles fracture has a transaxial direction (fall on outstretched arm), resulting in a crush fracture, and that it is not a bending force. We suggest that Colles fracture occurs as a result of the combined effect of a fall on the out-stretched arm, low trabecular and cortical volumetric bone density, and reduced cortical thickness.

Discordance between changes in bone mineral density measured at different skeletal sites in perimenopausal women--implications for assessment of bone loss and response to therapy: The Danish Osteoporosis Prevention Study.

Assessing bone loss and gain is important in clinical decision-making, both in evaluating treatment and in following untreated patients. The aim of this study was to correlate changes in bone mineral density (BMD) at different skeletal sites during the first 5 years after menopause and determine if forearm measurements can substitute for dual-energy X-ray absorptiometry (DXA) of the spine and hip. BMD was measured at 0, 1, 2, 3, and 5 years using Hologic 1000/W and 2000 densitometers in 2,016 perimenopausal women participating in a national cohort study. This analysis comprises 1,422 women remaining in the study after 5 years without changes to their initial treatment (hormone-replacement therapy [HRT], n = 497, or none, n = 925). Despite correlated rates of change between forearm and spine (r2 = 0.11; p < 0.01), one-half of those who experienced a significant decrease in spine BMD at 5 years showed no significant fall in forearm BMD (sensitivity, 50%; specificity, 85%; kappa = 0.25). The total hip had significant better agreement with spine (sensitivity, 63%; specificity, 85%; kappa = 0.37; p < 0.01). Analysis of quartiles of change also showed significant better agreement with spine and whole body for the total hip than for the femoral neck or ultradistal (UD) forearm. In a logistic regression analysis for identification of group (HRT or control), the prediction was best for whole body (82.6%) and spine (80.9%), followed by total hip (78.5%) and forearm (74.7%). In conclusion, changes at the commonly measured sites are discordant, and DXA of the forearm is less useful than DXA of the hip or spine in determining the overall skeletal response to therapy or assessing bone loss in untreated women.

Bone density and geometric properties of the distal radius in displaced and undisplaced Colles' fractures: quantitative CT in 70 women.

We examined cortical and trabecular bone density and geometric properties of the unfractured distal radius in 70 women with recent Colles' fractures, using multilayer peripheral quantitative computed tomography (pQCT). We found that cortical volumetric density, cortical area and mean cortical thickness were lower in the displaced than in the undisplaced fractures, suggesting that the cross-sectional volumetric density and geometric properties of cortical bone may be essential in determining the severity of a Colles' fracture. We also compared lumbar spine and femoral neck bone mineral density (BMD) and the occurrence of osteoporosis in the displaced and undisplaced fracture groups and found no significant difference, which suggests that displacement of a Colles' fracture is not associated with general osteoporosis.

Diagnosis of osteoporosis by planar bone densitometry: can body size be disregarded?

Bone densitometry using dual energy X-ray absorptiometry (DXA) is frequently used to diagnose osteoporosis and to identify patients at risk of later fractures. The parameters of interest are bone mineral content (BMC) and bone mineral areal density (BMD). Bone densitometry results have a large overlap between normals and patient with fractures. This would suggest that other factors are important for the development of fractures or that bone densitometry is not used optimally. It is generally believed that the conversion of BMC to BMD by division of the former by the projected bone area is a good normalization procedure. Other normalization procedures have been attempted in the past with little success. We hypothesized that this might be due to a blurring effect of time since menopause, and that body size could be demonstrated to have an effect on measured BMC and BMD, if this time effect could be eliminated. The results of this study, comprising 1625 early post-menopausal women studied at virtually the same time since menopause, confirm that this is the case. Body surface area was the parameter among conventional body size variables showing the highest correlation with BMC and BMD. It was clearly shown that low values of BMD were seen more often in the lowest than in the highest body surface area quartile. The difference between quartiles was statistically significant. Simple division of BMC by actual body surface area or division of BMD by the square root of body surface removed the uneven distribution between the body surface area quartiles for lumbar spine and femoral neck measurements, and reduced it at peripheral measuring sites. It is suggested that BMC and BMD of the lumbar spine and the femoral neck should be normalized as described to avoid overdiagnosis of osteoporosis in persons of petite body stature and underdiagnosis in tall ones.

Linearity and accuracy errors in bone densitometry.

This investigation was undertaken to quantify accuracy errors and identify possible linearity errors in dual energy X-ray absorptiometry (DXA) of bone, based on studies of commercially available bone densitometers for planar densitometry. The following was found in a combination of in vitro phantom studies and in vivo investigations of human volunteers: (1) Pronounced differences between the instruments when measuring vertebral size and contours of the projected bone regions. (2) Falsely low bone mineral content (BMC in terms of g) in cases of low nominal bone mass, due to the fact that edge regions were omitted by the calculation software of some devices. (3) An increase in the projected bone area secondary to an increase in nominal bone mass with some instruments. (4) Clinically and statistically significant errors of accuracy of BMC and to a lesser extent bone mineral density (BMD). (5) Substantial linearity errors with some osteodensitometers for BMC, a phenomenon that reduces the usefulness of this parameter. It is concluded that DXA devices are affected by a combination of accuracy errors and linearity errors, some more than others, and that linearity errors influence their ability to monitor change in BMC and to a lesser extent in BMD, making system intercomparison difficult.

Effects of strontium ions on growth and dissolution of hydroxyapatite and on bone mineral detection.

Preparation and analyses of a series of hydroxyapatites (HA) containing 1-10 mol % of Ca2+ replaced by Sr2+ is reported. The solubility of these apatites is found to increase with increasing content of Sr2+, 10% SrHA dissolves faster than CaHA at given values of Ca2+ and phosphate concentrations, but with a similar rate at the same degree of saturation. Sr2+ is found to inhibit the rates of both dissolution and growth of CaHA and 10% SrHA at pH 7.2, CaHA being more strongly inhibited by Sr2+ than 10% SrHA. The effect of partial substitution of Ca2+ in hydroxyapatite by Sr2+ on bone mineral content (BMC) and bone mineral density (BMD) measured by dual energy X-ray absorptiometry has been studied using three commercial densitometers. Extrapolating the absorption data for up to 10% replacement of Ca2+ by Sr2+ to 100% substitution of Ca2+ by Sr2+ in HA leads to an apparent increase in BMC or BMD of about a factor of 10. This factor is in agreement with theoretical calculations using attenuation coefficients of the atoms concerned. It is concluded that existing BMC scanners register artificially high values of BMC if the bone contains significant amounts of Sr2+ or other metal ions with atomic number larger than calcium.

Ultrasound measurements of the os calcis. Side differences and prediction of bone density in 39 persons.

We measured the ultrasound Stiffness Index (SI) of the os calcis bilaterally with the Achilles Ultrasound Bone Densitometer in 30 women and 9 men, aged 53 (31-76) years. Lumbar spine BMD (percent of mean per age group) was measured with a DXA bone densitometer. Supplementary BMD measurements of the hip and the nondominant radius were made in 29 of the 39 persons; 11 of them had had a unilateral total hip arthroplasty (THA), the rest were healthy control subjects. SI values were in the range of 78-138 percent. Large individual differences between the right and the left os calcis were seen, even in healthy controls (CV 6.3 percent), although no differences between the means of the two sides were found. The prediction of SI of one os calcis from that of the other was inaccurate (SEE 6 percent). The SI of the dominant os calcis correlated significantly to the lumbar spine BMD, to the hip BMD and to the non-dominant radius BMD. In the group with unilateral THA the individual SI side-differences were larger (CV 8 percent; SEE 9 percent), but no systematic difference between the means of the operated and non-operated sides was found. We conclude that there are large random individual differences between the SI of the right and the left os calcis and recommend measurement of both sides for classification of one individual.

Switching from DXA pencil-beam to fan-beam. II: Studies in vivo.

Switching from the Hologic QDR-1000/W to the QDR-2000 DXA densitometer was critically evaluated with regard to cross-calibration and dosimetry. Studies with bone equivalent humanoid spine phantoms and patient studies were done. Fan-beam scanning with the QDR-2000 is problematic because of magnification. Mean phantom bone mineral content (BMC) and bone mineral density (BMD) were moderately but significantly different. Biological variation disguised differences between the two devices in humans, but significant differences were revealed when individual data were analyzed. Longitudinal assessments of BMC and BMD, initiated with QDR-1000/W and continued with the QDR-2000, should employ single-beam mode only and not fan-beam mode--but even if that is done, significant errors can be introduced. The new QDR-2000 should be properly cross-calibrated with the original densitometer, and one should make sure that the same software, phantom, and type of collimator are used. The radiation dose is substantially higher with QDR-2000 (fan-beam and high-resolution array mode) than with QDR-1000/W (pencil-beam mode) and QDR-2000 (pencil-beam mode), and higher than claimed by the manufacturer. The typical radiation dose given by the manufacturer was half the actual radiation dose measured (e.g., for fan-beam scan 62 microSv versus 33 microSv). High-resolution array mode does not improve precision, but augments the radiation dose to the patient.

Switching from DXA pencil-beam to fan-beam. I: Studies in vitro at four centers.

The performance of the Hologic QDR-2000 DXA osteodensitometer was critically evaluated at four centers, using at all four centers one bone equivalent humanoid spine phantom supplied by the manufacturer. Results were compared with results from Hologic QDR-1000/W using that phantom tested at the same centers. It appears that the concept of fan-beam scanning--as used in the QDR-2000: a fan-beam, a linear array detector above the phantom, and an x-ray tube located rather close to the spine below the phantom--creates problems due to the magnification effect of the fan beam. The effect of decreasing the distance between the "vertebrae" of the phantom and the couch are: bone mineral content (BMC) increases by 2.8% per cm, projected area (Area) by 2.8% per cm, and bone mineral density (BMD) is unchanged. When QDR-1000/W is upgraded to QDR-2000, BMD is relatively constant, but there are shifts of BMC and Area which are partly due to the magnification effect of the fan-beam. Replacement of a QDR-1000/W with a QDR-2000 can invalidate longitudinal measurements, even for BMD, unless the proportionality factors of the QDR-2000 are checked and, if necessary, changed. This is true for switching from QDR-1000/W to pencil-beam mode of QDR-2000 or to fan-beam mode of QDR-2000. Even with pencil-beam mode, the long-term precision error with phantoms is higher for QDR-2000 than for QDR-1000/W (for BMD, 0.47% versus 0.35%).

Magnitude and pattern of skeletal response to long term continuous and cyclic sequential oestrogen/progestin treatment.

OBJECTIVE: To investigate the magnitude and pattern of the changes in bone mass during five years of continuous and cyclic sequential oestrogen/progestin treatment. DESIGN: Prospective study of normal, early postmenopausal women, initially a double-blind, placebo controlled trial, subsequently an open, controlled investigation. SETTING: Clinical physiology unit of a general hospital. SUBJECTS: Sixty-eight normal, early postmenopausal women. RESULTS: 1. Continuous treatment resulted in significantly higher lumbar spine bone density than did sequential treatment (P < 0.001). Lumbar spine bone density was 19% and 15%, respectively, above that of untreated women after three years and onwards, and 10% and 6%, respectively, above the initial value; 2. Both regimens induced a more pronounced rise in lumbar spine bone density than in forearm bone mineral content (P < 0.001); 3. The spontaneous decline (without treatment) in lumbar spine bone density and forearm bone mineral content averaged 1.86% and 1.90% per year, respectively. 4. There was a significant bone loss from the lumbar spine during the last year of active treatment (P < 0.001). This would suggest that lumbar spine bone density rises to a certain level and subsequently declines. However, neither data pooled before computation nor data processed individually for each patient over five years allowed for any definite conclusions regarding the pattern of the long term skeletal response to combined oestrogen/progestin treatment. CONCLUSION: Five years treatment with oestradiol/norethisterone resulted in a substantial gain in bone mass. The highest values were found in the axial skeleton with daily administration of 2 mg oestradiol and 1 mg norethisterone. It is likely that bone mass after an absolute rise begins to decline after about four years of treatment.

Interpretation of lumbar spine densitometry in women with fractures.

Identification of postmenopausal women at risk of developing osteoporotic fractures is a major clinical problem. In this study the use of projected planar lumbar bone density values for individual fracture risk assessment was questioned. Osteodensitometry (DXA) results from 415 normal women, 62 women with previous vertebral compressions, and 76 women with previous low-energy fractures were analyzed, together with their body size and lumbar vertebral body size variables. The following were found: (1) Lumbar vertebral projected bone mineral areal density (BMD) and bone mineral content (BMC) of normal women correlated with body size variables (p < 0.001). (2) Lumbar vertebral body size variables also correlated with body size variables (p < 0.001). Logistic regression analysis of measured and derived physical variables from women without and with vertebral compression fractures (n = 477) showed: (3) The best compression fracture discriminator, significantly better than BMD, was BMC divided by (Hmax/165 cm)1.5 x (D/4.35 cm)1.5, where Hmax is the body height (cm) at the menopause, and D the mean lumbar vertebral diameter of the three mid-lumbar vertebral bodies (cm). This parameter was termed BMCcorr.. ROC analysis showed: (4) At a BMCcorr. true positive ratio of 80% the corresponding uncorrected BMC or BMD true positive ratio was only 60%. The corresponding false positive ratio was 6%. Lumbar osteodensitometry could not be used to identify women with a history of peripheral low-energy fractures. (5) BMCcorr. did not, unlike BMC and BMD, correlate with body size and vertebral size variables. (6) Likewise, an observed correlation between BMC and lean body mass in a subpopulation of 116 normal women was abolished when BMCcorr. replaced BMC.(ABSTRACT TRUNCATED AT 250 WORDS)

Faecal blood loss during administration of acetylsalicylic acid, ketoprofen and two new ketoprofen sustained-release compounds.

The influence of one week's treatment with acetylsalicylic acid, ketoprofen, ketoprofen sustained-release capsules (Biovail capsules), and ketoprofen sustained-release tablets (IBP tablet) on gastrointestinal bleeding was investigated in 41 healthy male volunteers by means of a radiochromium assay. The physiological faecal bleeding was 0.10 to 0.90 ml/day (99% confidence limits). It appeared that faecal bleeding during treatment with acetylsalicylic acid medication was greater than bleeding during medication with ketoprofen capsules in equipotent dosage, the latter being in turn causing significantly more bleeding than during medication with the newly developed Biovail capsules. The most modest faecal bleeding (0.8 ml/day) was seen with IBP tablets.

Fractional intestinal absorption and retention of calcium measured by whole-body counting. Application of a power function model.

By application of a power function model, fractional intestinal calcium absorption was investigated with a new technique involving whole-body counting after successive oral and intravenous administration of standard doses of 47Ca. The fractional calcium retention 7 days after the oral load of 47Ca was also measured. Fractional calcium retention averaged 30.3% in normal subjects and 11.5% in 11 patients with intestinal malabsorption. In the same groups fractional calcium absorption averaged 46.6% and 16.4%, respectively. Fractional calcium retention and intestinal calcium absorption were significantly correlated to body surface area, and there was a well-defined relation between fractional retention and absorption of calcium...