Olaf Bärenholdt

Ten‐Year Absolute Risk of Osteoporotic Fractures According to BMD T Score at Menopause: The Danish Osteoporosis Prevention Study

In the non‐HRT arms of the DOPS study, 10‐year fracture risk was higher at each level of T score than predicted by the Kanis algorithm. Under‐reporting of fractures in registers and inclusion of HRT users are probable explanations for inappropriately low fracture risk estimates for younger women.

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.

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 2016 perimenopausal women participating in a national cohort study. This analysis comprises 1422 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%; κ = 0.25). The total hip had significant better agreement with spine (sensitivity, 63%; specificity, 85%; κ = 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.

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.

Effect of long-term treatment with strontium ranelate on bone strontium content

AIM To investigate the kinetics and magnitude of human bone strontium uptake and retention during and after long-time treatment with strontium ranelate (SrR). METHODS Bone strontium was measured by a novel DPA method developed by us. 32 osteoporotic female patients volunteered to participate in a 3 years open study of the effect on bone Sr. The group was treated with 2 g SrR/day, 17 of the group had received active treatment for 4-5 years before the study. DXA BMD measurements and DPA measurements of the relative bone strontium hydroxy apatite termed %Sr (SrHA/(CaHA+SrHA)) were done simultaneously ultra-distally (UD) on the non-dominant radius every six months during the study and three and six months after treatment stop. RESULTS The highest relative Sr content was found in patients who had been treated for 7-8 years. The variability was pronounced; a mean of 1.1 % Sr was measured at the end of treatment. No effect was demonstrated on distal radius relative bone Ca hydroxy apatite. Bone strontium uptake and retention data were compatible with a power function model. Withdrawal of SrR resulted in a decline in bone Sr, but 73 %Sr and 67 %Sr, respectively remained in UD-radius three and six months after drug withdrawal. CONCLUSION The rise in bone Sr content measured by DPA as well as BMD measured by DXA was most marked initially. After the treatment was stopped bone Sr decreased rapidly only during the first months. In UD-radius the apparent BMD corrected for the influence of %Sr measured by DPA showed a slight decline like in an untreated population. Strontium containing drugs may influence DXA bone mineral measurements several years after treatment withdrawal. According to the power function model the skeletal retention three and six months after stopping the treatment would average 66% and 58%, respectively after three years of treatment, and 76% and 70%, respectively after eight years of treatment. However, individual predictions are uncertain due to large inter-individual variations, and the values cannot be extrapolated to other bone sites.

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)15×(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 BMCcoor. 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) BMCcoor. 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. We suggest that vertebral compression fracture risk limits based on BMC, corrected for individual differences in body size and vertebral body size, replace the commonly used BMD fracture risk limits. The discriminatory ability of BMCcorr. for low-energy fractures needs to be tested in a different population.

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) ≥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.

Faecal Blood Loss During Administration of Acetylsalicylic Acid, Ketoprofen and Two New Ketoprofen Sustained-Release Compounds

The influence of one weeks 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.

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.

Noninvasive Measurement of Bone Strontium

The strontium content of bone has hitherto been impossible to measure noninvasively. A novel dual-photon absorptiometry (DPA) method was developed. 241Am (59.5 keV) and 133Ba (356 keV) were used as radiation sources. The linearity of the DPA method was studied in monkey bones ex vivo after treatment over 52 wk with strontium ranelate. The bone strontium expressed in terms of the percentage molar ratio SrHA/(SrHA + CaHA) x 100%, where HA denotes hydroxyapatite, was measured (1) by the DPA method and (2) by inductively coupled plasma-atomic emission spectrophotometry at the same distal site of the femur. The results correlated significantly: y = 0.33%Sr + 1.086x; r = 0.976; standard error of the estimate (SEE) = 0.57%Sr. In order to measure the accuracy error of Sr%, 30 normal volunteers were measured. Their mean values did not differ significantly from zero and the SD was 0.5%. The radiation dose was small, the equivalent whole-body dose to human subjects being 0.005 micro Sv. This novel DPA method is likely to be successful for bone strontium measurement in humans.