Claus C. Glüer

Association of Five Quantitative Ultrasound Devices and Bone Densitometry With Osteoporotic Vertebral Fractures in a Population-Based Sample: The OPUS Study

We compared the performance of five QUS devices with DXA in a population‐based sample of 2837 women. All QUS approaches discriminated women with and without osteoporotic vertebral fractures. QUS of the calcaneus performed as well as central DXA.

Universal Standardization of Bone Density Measurements: A Method with Optimal Properties for Calibration Among Several Instruments

The International Dual‐Photon X‐Ray Absorptiometry (DXA) Standardization Committee (IDSC) conducted a cross‐calibration study among three models of DXA machines from three different manufacturers. In that study, 100 subjects were scanned on all three machines. A set of equations were derived to convert bone mineral density (BMD) on each machine to a “standardized BMD” (sBMD) such that sBMD from the same subject derived from different machines would be approximately the same. In a reanalysis of the cross‐calibration data, we showed that the conversion method used in the IDSC study did not achieve several optimal properties desirable in such conversions. We derived new conversion equations to sBMD based on minimizing differences among sBMD from the three machines. More important is that the new conversions have no residual bias that was present in the IDSC conversions. The performance of the methods were compared on the cross‐calibration data as well as an external data set. We conclude that the IDSC conversions are adequate for clinical use on other machines worldwide, but that researchers should standardize their own machines in a laboratory using the new method.

A meta-analysis of the association of fracture risk and body mass index in women.

Several recent studies suggest that obesity may be a risk factor for fracture. The aim of this study was to investigate the association between body mass index (BMI) and future fracture risk at different skeletal sites. In prospective cohorts from more than 25 countries, baseline data on BMI were available in 398,610 women with an average age of 63 (range, 20–105) years and follow up of 2.2 million person‐years during which 30,280 osteoporotic fractures (6457 hip fractures) occurred. Femoral neck BMD was measured in 108,267 of these women. Obesity (BMI ≥ 30 kg/m2) was present in 22%. A majority of osteoporotic fractures (81%) and hip fractures (87%) arose in non‐obese women. Compared to a BMI of 25 kg/m2, the hazard ratio (HR) for osteoporotic fracture at a BMI of 35 kg/m2 was 0.87 (95% confidence interval [CI], 0.85–0.90). When adjusted for bone mineral density (BMD), however, the same comparison showed that the HR for osteoporotic fracture was increased (HR, 1.16; 95% CI, 1.09–1.23). Low BMI is a risk factor for hip and all osteoporotic fracture, but is a protective factor for lower leg fracture, whereas high BMI is a risk factor for upper arm (humerus and elbow) fracture. When adjusted for BMD, low BMI remained a risk factor for hip fracture but was protective for osteoporotic fracture, tibia and fibula fracture, distal forearm fracture, and upper arm fracture. When adjusted for BMD, high BMI remained a risk factor for upper arm fracture but was also a risk factor for all osteoporotic fractures. The association between BMI and fracture risk is complex, differs across skeletal sites, and is modified by the interaction between BMI and BMD. At a population level, high BMI remains a protective factor for most sites of fragility fracture. The contribution of increasing population rates of obesity to apparent decreases in fracture rates should be explored.

Monitoring Teriparatide-Associated Changes in Vertebral Microstructure by High-Resolution CT In Vivo: Results From the EUROFORS Study†

We introduce a method for microstructural analysis of vertebral trabecular bone in vivo based on HRCT. When applied to monitor teriparatide treatment, changes in structural variables exceeded and were partially independent of changes in volumetric BMD.

Thyroid Function within the Upper Normal Range Is Associated with Reduced Bone Mineral Density and an Increased Risk of Nonvertebral Fractures in Healthy Euthyroid Postmenopausal Women

CONTEXT The relationship between thyroid function and bone mineral density (BMD) is controversial. Existing studies are conflicting and confounded by differences in study design, small patient numbers, and sparse prospective data. OBJECTIVE We hypothesized that variation across the normal range of thyroid status in healthy postmenopausal women is associated with differences in BMD and fracture susceptibility. DESIGN The Osteoporosis and Ultrasound Study (OPUS) is a 6-yr prospective study of fracture-related factors. SETTING We studied a population-based cohort from five European cities. PARTICIPANTS A total of 2374 postmenopausal women participated. Subjects with thyroid disease and nonthyroidal illness and those receiving drugs affecting thyroid status or bone metabolism were excluded, leaving a study population of 1278 healthy euthyroid postmenopausal women. INTERVENTIONS There were no interventions. MAIN OUTCOME MEASURES We measured free T(4) (fT4) (picomoles/liter), free T(3) (fT3) (picomoles/liter), TSH (milliunits/liter), bone turnover markers, BMD, and vertebral, hip, and nonvertebral fractures. RESULTS Higher fT4 (beta = -0.091; P = 0.004) and fT3 (beta = -0.087; P = 0.005) were associated with lower BMD at the hip, and higher fT4 was associated with increasing bone loss at the hip (beta = -0.09; P = 0.015). After adjustment for age, body mass index, and BMD, the risk of nonvertebral fracture was increased by 20% (P = 0.002) and 33% (P = 0.006) in women with higher fT4 or fT3, respectively, whereas higher TSH was protective and the risk was reduced by 35% (P = 0.028). There were independent associations between fT3 and pulse rate (beta = 0.080; P = 0.006), increased grip strength (beta = 0.171; P<0.001), and better balance (beta = 0.099; P < 0.001), indicating that the relationship between thyroid status and fracture risk is complex. CONCLUSIONS Physiological variation in normal thyroid status is related to BMD and nonvertebral fracture.

Impact of Spinal Degenerative Changes on the Evaluation of Bone Mineral Density with Dual Energy X-Ray Absorptiometry (DXA)

Abstract. The purpose of this study is to evaluate degenerative factors in a postmenopausal patient group and differentiate the influence on bone mineral density (BMD) measurements by dual-energy X-ray absorptiometry (DXA). The patients and methods included an investigation of 144 postmenopausal women (mean 63.3 years) with PA-DXA of the spine. Degenerative factors (osteophytes, osteochondrosis, scoliosis, and vascular calcification) were evaluated from plain lumbar radiographs, their estimated probability was analyzed as a function of age, and their influence on BMD measured by PA-DXA was determined. The results of the study revealed osteophytes in 45.8%, vascular calcifications in 24.3%, scoliosis in 22.2%, osteochondrosis in 21.5%. The estimated probability for degenerative factors increased from 35 to 80% in the 55- to 70- year age group. Osteophytes and osteochondrosis were associated with up to a 14% increase in BMD values (P < 0.001). Vascular calcifications showed a positive trend, whereas scoliosis did not show a discernible influence.We concluded that degenerative factors, except for scoliosis, showed an influence on BMD as measured by DXA. Their prevalence increased rapidly between 55 and 70 years of age. Interpretation of PA-DXA spine data for subjects of or above this age range should be complemented by plain film radiographs.

Sequential Treatment of Severe Postmenopausal Osteoporosis After Teriparatide: Final Results of the Randomized, Controlled European Study of Forsteo (EUROFORS)

It is unclear which treatment should be given after stopping teriparatide therapy for severe osteoporosis. In a prospective, randomized, controlled, 2‐yr study, we compared BMD effects and clinical safety of three follow‐up treatments (anabolic with teriparatide, antiresorptive with raloxifene, or no active treatment) after 1 yr of teriparatide. Postmenopausal women with osteoporosis and a recent fragility fracture received open‐label teriparatide (20 μg/d) for 12 mo before they were randomized (3:1:1) to continue teriparatide (n = 305), switch to raloxifene 60 mg/d (n = 100), or receive no active treatment for the second year (n = 102). All patients received calcium and vitamin D supplementation. Changes in areal BMD from baseline to 24 mo were analyzed using mixed‐model repeated measures. Daily teriparatide treatment for 2 yr significantly increased spine BMD by 10.7%. Patients receiving raloxifene in year 2 had no further change in spine BMD from year 1 (change from baseline, 7.9%), whereas patients receiving no active treatment had a BMD decrease of 2.5% in year 2 (change from baseline, +3.8%). At the total hip, BMD increases from baseline at 2 yr were 2.5% with teriparatide, 2.3% with raloxifene, and 0.5% with no active treatment; the respective changes at the femoral neck were 3.5%, 3.1%, and 1.3%. The study had insufficient power to assess antifracture efficacy. In conclusion, BMD increases progressively over 2 yr of teriparatide therapy in women with severe osteoporosis. After discontinuation of teriparatide, raloxifene maintains spine BMD and increases hip BMD.

Improvements in vertebral body strength under teriparatide treatment assessed in vivo by finite element analysis: results from the EUROFORS study.

Monitoring of osteoporosis therapy based solely on DXA is insufficient to assess antifracture efficacy. Estimating bone strength as a variable closely linked to fracture risk is therefore of importance. Finite element (FE) analysis–based strength measures were used to monitor a teriparatide therapy and the associated effects on whole bone and local fracture risk. In 44 postmenopausal women with established osteoporosis participating in the EUROFORS study, FE models based on high‐resolution CT (HRCT) of T12 were evaluated after 0, 6, 12, and 24 mo of teriparatide treatment (20 μg/d). FE‐based strength and stiffness calculations for three different load cases (compression, bending, and combined compression and bending) were compared with volumetric BMD (vBMD) and apparent bone volume fraction (app. BV/TV), as well as DXA‐based areal BMD of the lumbar spine. Local damage of the bone tissue was also modeled. Highly significant improvements in all analyzed variables as early as 6 mo after starting teriparatide were found. After 24 mo, bone strength in compression was increased by 28.1 ± 4.7% (SE), in bending by 28.3 ± 4.9%, whereas app. BV/TV was increased by 54.7 ± 8.8%, vBMD by 19.1 ± 4.0%, and areal BMD of L1–L4 by 10.2 ± 1.2%. When comparing standardized increases, FE changes were significantly larger than those of densitometry and not significantly different from app. BV/TV. The size of regions at high risk for local failure was significantly reduced under teriparatide treatment. Treatment with teriparatide leads to bone strength increases for different loading conditions of close to 30%. FE is a suitable tool for monitoring bone anabolic treatment in groups or individual patients and offers additional information about local failure modes. FE variables showed a higher standardized response to changes than BMD measurements, but further studies are needed to show that the higher response represents a more accurate estimate of treatment‐induced fracture risk reduction.

Quantitative computed tomographic assessment of the effects of 24 months of teriparatide treatment on 3D femoral neck bone distribution, geometry, and bone strength: Results from the EUROFORS study

We studied the changes in bone distribution, geometry, and bone strength based on 3D quantitative computed tomography (QCT) of the femoral neck (FN) in subjects receiving teriparatide (TPTD). Fifty‐two postmenopausal women with severe osteoporosis were analyzed. Patients were divided into three subgroups based on their prior treatment with osteoporosis drugs: treatment‐naive (Tx‐naive; n = 8), pretreated (pre‐Tx; n = 12), and pretreated showing an inadequate response to treatment (inad. pre‐Tx; n = 32). QCT scans were performed at baseline and after 6, 12, and 24 months of treatment and were analyzed with Mindways QCT‐PRO BIT software. Minimum and maximum section modulus, buckling ratio (BR), and cross‐sectional area (CSA) were calculated as measurements of bending strength, risk of buckling, and bone apposition, respectively. After 24 months of TPTD treatment, areal and volumetric FN BMD increased significantly by 4.0% and 3.0%, respectively, compared with baseline. Decreases in cortical volumetric BMD occurred in locations not adversely affecting minimum bending strength indicators. Cortical CSA increased by 4.3%, whereas total CSA remained unchanged over the study duration, indicating that endosteal but no periosteal growth was observed. Strength parameters for buckling did not change at 6 and 12 months but improved significantly at 24 months. Measures of bending strength showed a trend toward improvement. Changes tended to be larger in individuals at higher risk of buckling failure. Prior antiresorptive treatment may delay response to TPTD, but based on the small magnitude of the mostly insignificant changes at 6 months, this does not appear to lead to an interim phase of reduced bone strength. In summary, FN QCT provides a tool for detailed longitudinal investigation of bone strength indices in vivo for different loading modes, yields insight into underlying structural changes, and provides relevant mechanostructural information beyond dual‐energy X‐ray absorptiometry. Continuous TPTD treatment for 24 months improves FN bone strength parameters.

Added value of trabecular bone score to bone mineral density for prediction of osteoporotic fractures in postmenopausal women: the OPUS study.

UNLABELLED The objective of this study was to consider whether trabecular bone score (TBS) improves on areal bone mineral density (aBMD) measurement alone for the prediction of incident fractures in postmenopausal women. PATIENTS AND METHODS The OPUS study was conducted in ambulatory European women aged above 55years, recruited in 5 centers followed over 6years. For the assessment of the performance of TBS, baseline Hologic scans from 3 centers (Kiel, Paris and Sheffield) were available. Follow-up for incident fractures was available for 1007 women (mean age 65.9±6.9years). We compared the performance of TBS, aBMD, and their combination, by using net reclassification improvement (NRI, primary analysis) and receiver operator characteristic (ROC) c-statistical analysis with ORs and areas under the curves (AUCs) (secondary analyses). RESULTS 82 (8.1%) subjects with incident clinical osteoporotic fractures, and 46 (4.6%) with incident radiographic vertebral fractures were recorded over 6years. Performance of TBS was significantly better than lumbar spine (LS) aBMD for the prediction of incident clinical osteoporotic fractures (NRI=16.3%, p=0.007). For radiographic vertebral fractures, TBS and LS aBMD had similar predictive power but the combination of TBS and LS aBMD increased the performance over LS aBMD alone (NRI=8.6%, p=0.046) but the prediction is similar to hip and femoral neck aBMD. In non osteoporotic women, TBS predicted incident fragility fractures similarly to LS aBMD. CONCLUSIONS This prospective study shows that in general population, TBS is a useful tool to improve the performance of lumbar spine aBMD for vertebral osteoporotic fractures.