Thomas Nickelsen

Cognitive function in postmenopausal women treated with raloxifene.

Background In postmenopausal women, estrogen may have a beneficial effect on cognition or reduce the risk of decline in cognitive function. Whether raloxifene, a selective estrogen-receptor modulator, might have similar actions is not known. Methods As part of the Multiple Outcomes of Raloxifene Evaluation trial, we studied 7478 postmenopausal women with osteoporosis (mean age, 66 years), who were enrolled at 178 sites in 25 countries. The women were randomly assigned to receive raloxifene (60 mg or 120 mg) or placebo daily for three years. We compared the mean scores of the groups on six tests of cognitive function, which were administered at base line and at six months and one, two, and three years. Women were classified as having a decline in cognitive function if the change in their scores at three years was in the worst 10 percent. Results The mean cognitive scores in the three groups of women were similar at base line. The scores improved slightly in all three groups during the three-year study peri...

Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial.

Raloxifene is a selective estrogen receptor modulator that in experimental animals acts as an estrogen receptor antagonist in breast and endometrium but as an estrogen receptor agonist in the skeletal and cardiovascular systems. We conducted a 1‐year prospective, randomized, double‐blind trial in 143 postmenopausal osteoporotic women (mean ± SD age, 68.4 ± 5.0 years) with at least one prevalent vertebral fractures and low bone mineral density (BMD), comparing groups receiving raloxifene at 60 mg/day (RLX60) or 120 mg/day (RLX120) and a control group receiving supplements of 750 mg/day of calcium and 400 IU/day of vitamin D. There were no differences among groups in the occurrence of uterine bleeding, thrombophlebitis, breast abnormalities, or increased endometrial thickness (assessed by ultrasonography). As compared with controls, the changes in values over 1 year for RLX60 and RLX120, respectively, were significant for serum bone alkaline phosphatase (−14.9%, −8.87%), serum osteocalcin (−20.7%, −17.0%), and urinary C‐telopeptide fragment of type I collagen/creatinine (−24.9%, −30.8%), markers of bone turnover; for serum total cholesterol (−7.0% for RLX60) and low density lipoprotein cholesterol (LDL) (−11.4% for RLX60) and for the LDL/HDL cholesterol ratio (−13.2%, −8.3%). BMD increased significantly in the total hip (1.66% for RLX60) and ultradistal radius (2.92%, 2.50%). There were nonsignificant trends toward increases over controls in BMD for lumbar spine, total body, and total hip (for RLX120). Using a >15% cutoff definition, raloxifene had no effect on incident fractures, but using a >30% cutoff, there was a dose‐related reduction (p = 0.047). We conclude that raloxifene therapy is well tolerated, reduces serum lipids, and does not stimulate the uterus or breasts. It has beneficial effects on bone, although, under the conditions of this study, these appear to be of a smaller magnitude than have been reported with estrogen therapy.

Effects of two years of daily teriparatide treatment on BMD in postmenopausal women with severe osteoporosis with and without prior antiresorptive treatment

Previous antiresorptive (AR) treatment may influence the response to teriparatide. We examined BMD response and safety in a subgroup of 503 postmenopausal women with osteoporosis who received teriparatide for 24 mo. Patients were divided into three groups based on their prior AR treatment: treatment‐naïve (n = 84); pretreated with no evidence of inadequate treatment response (n = 134); and pretreated showing an inadequate response to AR treatment (n = 285), which was predefined based on the occurrence of fractures, persistent low BMD, and/or significant BMD loss while on therapy. Changes in BMD from baseline were analyzed using mixed model repeated measures. Lumbar spine BMD increased significantly from baseline at 6, 12, 18, and 24 mo in all three groups. The mean gain in spine BMD over 24 mo was greater in the treatment‐naïve group (0.095 g/cm2; 13.1%) than in the AR pretreated (0.074 g/cm2; 10.2%; p < 0.005) and inadequate AR responder (0.071 g/cm2; 9.8%; p < 0.001) groups. The corresponding increases in total hip BMD were 3.8%, 2.3%, and 2.3%, respectively. Early decreases in hip BMD in the inadequate AR responder group were reversed by 18 mo of treatment. Increases in BMD between 18 and 24 mo were highly significant. Nausea (13.3%) and arthralgia (11.7%) were the most commonly reported adverse events. Asymptomatic hypercalcemia was reported in 5.0% of patients. Teriparatide treatment for 24 mo is associated with a significant increase in BMD in patients with and without previous AR use. Prior AR treatment modestly blunted the BMD response to teriparatide. Safety was consistent with current prescribing label information.

Raloxifene hydrochloride, a selective estrogen receptor modulator: safety assessment of effects on cognitive function and mood in postmenopausal women.

Raloxifene hydrochloride (HCl) is a selective estrogen receptor modulator with estrogen agonist effects on bone and lipid metabolism and estrogen antagonist effects on reproductive tissues. Animal studies suggest that raloxifene may affect brain function as well, although the effects of raloxifene on the human brain remain to be established. This paper presents an early safety assessment of raloxifene effects on cognition and mood in postmenopausal women participating in a randomized, double-blind osteoporosis treatment trial. Psychometric test batteries were administered to postmenopausal women at baseline and 1, 6, and 12 months after initiating treatment with raloxifene (60 and 120 mg/day). The Memory Assessment Clinics (MAC) battery and Walter Reed Performance Assessment Battery (PAB) were used to assess multiple and independent aspects of cognitive function, while mood was assessed with the Geriatric Depression Scale (GDS). After 12 months of treatment, there were no significant differences between the raloxifene groups and placebo on performance in either the MAC battery or the PAB. The only significant difference observed was a slight increase in performance favoring the raloxifene 120 mg/day group in an assessment of verbal memory on the MAC battery after 1 month of treatment. Scores on the GDS and the self-reported incidence of mood-related events were not different between treatment groups at any of the assessment periods. These data do not suggest that raloxifene impairs cognition or affects mood in postmenopausal women treated for 1 year. Studies to further assess the safety and potential efficacy of raloxifene with respect to cognitive function are ongoing.

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.

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.

Back pain during different sequential treatment regimens of teriparatide: results from EUROFORS

Abstract Objective: To investigate changes in back pain in postmenopausal women with severe osteoporosis who received teriparatide for 24 months or switched at 12 months to raloxifene or no active treatment. Study design and methods: This prospective, controlled, randomised, open-label, 2-year study enrolled 868 postmenopausal women with osteoporosis and a recent fragility fracture. After 12 months of teriparatide (20 µg/day), 507 patients were randomised to further teriparatide (n = 305), raloxifene 60 mg/day (n = 100), or no active treatment (n = 102) for another 12 months (substudy 1); in substudy 2, 199 patients continued teriparatide. All received calcium and vitamin D supplementation. Back pain was self-assessed by patients using a visual analogue scale (0–100 mm). Changes in back pain were analysed using a mixed model for repeated measures. Results: During year 1, back pain decreased from a mean (SD) of 48.9 mm (24.0) at baseline by 11.5 mm (p < 0.001) in the total study population. In substudy 1, mean change in back pain from month 12 (randomisation) to 24 months was −2.2, −4.4 and +0.7 mm in the teriparatide (p = 0.076), raloxifene (p = 0.041), and no active treatment groups (p = 0.751). There were no between-group differences from randomization to 18 or 24 months. In a sensitivity analysis excluding patients with low baseline back pain (VAS < 30 mm), mean change from randomisation to endpoint was significant for teriparatide (−3.9 mm, p = 0.006) and raloxifene (−6.3 mm, p = 0.018) groups. Subgroup analyses of 503 patients who received teriparatide for up to 2 years showed that patients with a recent vertebral fracture had a greater decrease in back pain than those without (p < 0.05). Those with and without mild back pain (≥30 mm), and those with and without severe back pain (≥60 mm) at baseline all had a statistically significant reduction in back pain after 24 months (p < 0.05). Conclusions: Teriparatide treatment is associated with significant reductions in back pain regardless of the presence of recent vertebral fracture. These results need to be considered with caution due to the open-label design of the study.

Patient compliance with alendronate, risedronate and raloxifene for the treatment of osteoporosis in postmenopausal women

ABSTRACT Objectives: The aim was to investigate patient compliance with different osteoporosis medications commonly prescribed in clinical practice, to determine risk factors associated with discontinuation and to evaluate quality of life changes. Research design and methods: We conducted a 1-year observational study of patients of age ≥ 60 years in a clinical setting at 917 sites in 10 European countries (Germany, Greece, UK, Sweden, Netherlands, Romania, Norway, Finland, Denmark, Estonia), Lebanon and South Africa. Demographic data, concomitant diseases, the reasons for intervention, educational, socio-economical status and disease knowledge were captured at baseline. Self-reported compliance, discontinuation data and health status were collected. Main outcome measures: Out of 5198 patients, 3490 (67.1%) patients received 60 mg daily raloxifene (RAL), 452 (8.7%) 10 mg daily alendronate (AQD), 769 (14.8%) 70 mg once weekly alendronate (AQW) and 487 (9.4%) 5 mg daily risedronate (RIS). Among patients completing the study (4231, 81%), the percentage of patients with high compliance was 80% (RAL), 79% (AQD), 65% (AQW) and 76% (RIS). The discontinuation due to side effects was highest on AQW (7.0%), followed by AQD (6.4%), RAL (3.8%) and RIS (3.4%). The discontinuation-rate was higher for patients with a history of surgical menopause, increased age, lack of knowledge about medical prevention of osteoporosis and thin frame as a reason for intervention. The EQ-5D weighted index showed the highest improvement for RIS (0.13), followed by RAL (0.11), AQD (0.08) and AQW (0.07). Conclusions: Data from this non-interventional observational study indicate moderate overall compliance and discontinuation rate with the prescribed osteoporosis medications.