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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.

Recombinant teriparatide, a bone anabolic agent, is given to treatment-naïve and pre-treated patients with severe osteoporosis, but few data exist comparing the response to teriparatide in these groups. EUROFORS (the EUROpean study of FORSteo‡) enrolled postmenopausal women with established osteoporosis who were either treatment-naïve or had prior antiresorptive (AR) treatment with or without documented inadequate clinical response. The objective of the secondary analysis described here was to evaluate the interim bone mineral density (BMD) response in these groups after one year of open-label teriparatide therapy.Postmenopausal women with established osteoporosis who enrolled in a prospective, randomized, controlled trial received open-label teriparatide 20 µg/day for the first year. With respect to their prior osteoporosis treatment history, they were retrospectively allocated to one of three groups: treatment-naïve (n = 204), prior treatment with an antiresorptive drug (AR-pretreated) (n = 240), or prior antiresorptive treatment with inadequate response (inadequate AR-responders) (n = 421). BMD was measured by dual energy x-ray absorptiometry.Lumbar spine BMD increased from baseline (p0.001) in the three groups (mean, 95% CI); treatment-naïve: 8.4% (7.4%, 9.3%); AR-pretreated: 7.1% (6.3%, 7.9%); inadequate AR-responders: 6.2% (5.6%, 6.9%). Total hip BMD increased from baseline in the treatment-naïve (p0.001): 1.8% (1.1%, 2.5%) but did not change in the AR-pretreated: 0.4% (-0.2%, 1.1%) or inadequate AR-responders: -0.3% (-0.9%, 0.2%). Treatment-emergent adverse events were similar in the three groups.One year of teriparatide significantly (p0.001) increased spine BMD in all groups, and total hip BMD in the treatment-naïve group. Because of the limitations of this interim analysis (most importantly, the short duration of treatment and lack of a control group), further study is needed to determine the optimal treatment duration to reach the potential BMD gains at the proximal femur in patients with prior antiresorptive drug use (mostly bisphosphonates).clinicaltrials.gov, nct00191425.

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.We conducted a 1-year observational study of patients of ageor = 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.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).Data from this non-interventional observational study indicate moderate overall compliance and discontinuation rate with the prescribed osteoporosis medications.

UNLABELLED 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. INTRODUCTION Monitoring of osteoporosis therapy based solely on bone densitometry is insufficient to assess anti-fracture efficacy. Assessing bone microstructure in vivo is therefore of importance. We studied whether it is possible to monitor effects of teriparatide on vertebral trabecular microstructure independent of BMD by high-resolution CT (HRCT). MATERIALS AND METHODS In a subset of 65 postmenopausal women with established osteoporosis who participated in the EUROFORS study, HRCT scans of T(12), quantitative CT of L(1)-L(3), and DXA of L(1)-L(4) were performed after 0, 6, and 12 mo of teriparatide treatment (20 microg/d). We compared BMD and 3D microstructural variables in three groups of women, based on prior antiresorptive treatment: treatment-naive; pretreated; and pretreated women showing inadequate response to treatment. RESULTS We found statistically highly significant increases in most microstructural variables and BMD 6 mo after starting teriparatide. After 12 mo, apparent bone volume fraction (app. BV/TV) increased by 30.6 +/- 4.4% (SE), and apparent trabecular number (app. Tb.N.) increased by 19.0 +/- 3.2% compared with 6.4 +/- 0.7% for areal and 19.3 +/- 2.6% for volumetric BMD. The structural changes were partially independent of BMD as shown by a significantly larger standardized increase and a standardized long-term precision at least as good as DXA. Patients who had shown inadequate response to prior osteoporosis treatment did show improvements in BMD and structural measures comparable to treatment-naive patients. CONCLUSIONS HRCT is a feasible method for longitudinal microstructural analysis of human vertebrae in vivo, offers information beyond BMD, and is sufficiently precise to show profound effects of teriparatide after 12 mo.

Objectives: To review the main findings of the Euralox 1 study – a multicentre, randomised, double-blind study conducted in 1008 healthy postmenopausal women allocated to raloxifene ( n = 495) or continuous combined estrogen–progestin therapy (ccEPT; n = 513) for 6 months – and provide an overview of the risks and benefits of raloxifene and ccEPT. Methods: A review is provided of previously published findings on uterine safety (bleeding rates and changes in endometrial thickness and uterine volume), gynaecological adjudication, cardiovascular risk (lipids, fibrinogen), adverse events, compliance, treatment satisfaction and quality of life. New data on biochemical markers of bone turnover (serum N -telopeptides and C-terminal telopeptides of type I collagen; NTX and CTX) assessed before and after 6 months’ treatment are presented. Results: Raloxifene caused less uterine bleeding than ccEPT and, unlike ccEPT, did not alter endometrial thickness or uterine volume. Serum CTX and NTX levels were reduced in both treatment groups, but the reduction was significantly greater with ccEPT. The two treatments had differential effects on lipids and fibrinogen levels; raloxifene had more favourable effects on serum HDL, the LDL/HDL ratio, and plasma fibrinogen. Raloxifene was associated with fewer adverse events or discontinuations, and this was associated with higher treatment satisfaction and better self-reported compliance. Conclusions: The clinical risk-benefit profile of raloxifene derived from the intermediate endpoints of this study suggests that it may be a better alternative to ccEPT for preventing long-term postmenopausal health risks in healthy postmenopausal women who are not suffering from vasomotor symptoms.

Objective In a previous report, we described the results of a randomized, controlled trial that evaluated the potential of raloxifene to induce or exacerbate hot flushes. Here, we provide additional analyses that were undertaken to identify potential predictors of hot flushes and to assess the clinical usefulness of various therapeutic strategies for the reduction of hot flushes in postmenopausal women who receive raloxifene therapy. Study design In this randomized, double-blind, placebo-controlled study, 487 unselected postmenopausal women were assigned randomly to receive treatment for 8 months with raloxifene, which was administered either at a dose of 60 mg/d every other day for 2 months followed by 60 mg/d (slow-dose escalation) or 60 mg/d throughout (raloxifene), or placebo. Data on the number, duration, intensity, and severity of hot flushes and awakenings because of night sweats were collected. Logistic regression models were used to examine the predictive value of various demographic and menopausal factors on the development or worsening of hot flushes. Results At baseline, 40.4% of all randomly assigned patients had hot flushes. The mean number of hot flushes (3-5 per week) was low. Fewer years postmenopause, surgical menopause, and previous estrogen or estrogen/progestin therapy were significant predictors of hot flushes at baseline but were not predictive of incident hot flushes during treatment with raloxifene. Of the women who received raloxifene therapy who had pre-existing hot flushes at baseline, 36% women had none at the end point. Early postmenopause and surgical menopause were significant predictors of a biologically relevant increase in hot flushes (≥14 flushes/week). Early postmenopause, previous estrogen/progestin therapy, high body mass index, and greater duration of hot flushes at baseline were significant predictors of the need for symptomatic treatment. After 2 months of treatment, women in early postmenopause had significantly more hot flushes with raloxifene therapy than with slow-dose escalation ( P =.042), whereas there was no significant difference between raloxifene therapy and slow-dose escalation among women in later postmenopause. In the 50 patients who requested symptomatic treatment during the study, phytohormones or veralipride did not reduce the number of hot flushes markedly. Conclusion A shorter time since menopause and surgical menopause are important predictors of hot flushes both before and during treatment with raloxifene. Previous estrogen/progestin therapy also increases the risk of hot flushes at baseline. For women in early postmenopause, slow-dose escalation of raloxifene therapy may be a suitable therapeutic strategy for the reduction of the risk of hot flushes.

Raloxifene is approved for the treatment and prevention of postmenopausal osteoporosis. Previous studies have described a raloxifene-associated increase in hot flushes, reported as adverse events. This study was undertaken to provide a detailed evaluation of the potential of raloxifene to induce or exacerbate hot flushes in postmenopausal women.In this double-blind, placebo-controlled, parallel group multicenter study, 487 postmenopausal women were randomized to receive 8 months of treatment with either raloxifene (RLX) at the recommended dose of 60 mg/day, or by slow-dose escalation for the first 2 months, followed by the standard dose for the rest of the study (SDE), or placebo (PL). The frequency, duration, intensity, severity, and impact of hot flushes were measured.With 3-5 hot flushes per week, the mean number at baseline was low. During treatment, it increased by1 hot flush/week in both active treatment groups and decreased by1 hot flush/week with PL. The high proportion ( approximately 60%) of asymptomatic patients at baseline had increased further by the end of treatment in all groups. The proportion of women whose pre-existing hot flushes abated during treatment was significantly greater with SDE (P=.005) and PL (P=.050), but not with RLX, when compared with the proportion with treatment-emergent flushes. There were no statistically significant between-group differences in the distribution of the number of hot flushes after 2 months of treatment. At end point, there were no significant differences between SDE and either RLX or PL, but the difference between RLX and PL was statistically significant (P=.035). There were no significant between-group differences in the hot flush impact scores, in treatment satisfaction, and in the proportion of patients requesting symptomatic treatment to alleviate hot flushes.In a postmenopausal population meeting the criteria for the prescription of RLX, the overall effect of the drug on hot flushes is low. Previous studies using adverse event reports have overestimated the importance of hot flushes in postmenopausal women during treatment with RLX. Slow-dose escalation seems to decrease the number of symptomatic patients further and may be a useful strategy in women reporting flushes when starting RLX.

OBJECTIVE: To compare the incident rate of abnormal endometrial findings in postmenopausal women receiving treatment with either 60 mg of raloxifene or a continuous combined estrogen plus progestin therapy containing 2 mg of 17-estradiol plus 1 mg of norethisterone acetate for a duration of up to 12 months. METHODS: One thousand eight asymptomatic postmenopausal women with osteoporosis or cardiovascular risk factors with an endometrial thickness of less than 5 mm at baseline participated in this prospective, randomized, double-blind trial that lasted 6 months; 347 of these women also participated in a 6-month extension. Women with repeated bleeding or an increase in endometrial thickness to above 5 mm were subjected to saline-infused sonohysterography or hysteroscopy with biopsy. Sonographic, histologic, and clinical findings were adjudicated by a panel of 4 experts blinded with respect to patients’ treatments. All adjudicated patients were grouped into 15 diagnostic categories according to predefined criteria. RESULTS: Three hundred thirty-four women needed adjudication during the core phase, 73 (14.7%) of those taking raloxifene and 261 (50.9%) taking continuous combined estrogen plus progestin therapy (P < .001). Compared with raloxifene, women using continuous combined estrogen plus progestin therapy had significantly higher rates of benign endometrial proliferation (8.8 versus 1.2%, P < .001), endometrial polyps (4.3 versus 2.0%, P .048), and cystic atrophy (5.5 versus 1.2%, P < .001). CONCLUSION: Women using continuous combined estrogen plus progestin therapy more often have benign endometrial pathology and, in our study, more often required the protocol-specific gynecological follow-up assessments for safety reasons, as compared with those using raloxifene. These findings are of clinical relevance when choosing the most appropriate therapy for postmenopausal health risks such as osteoporosis. (Obstet Gynecol 2004;103:881‐91. © 2004 by The American College of Obstetricians and Gynecologists.) LEVEL OF EVIDENCE: I

Zusammenfassung86 wegen Osteoporose oder Osteopenie mit Raloxifen 60 mg behandelte postmenopausale Frauen wurden in einer osteologischen Spezialambulanz über zwei Jahre beobachtet. Insgesamt stieg die Knochenmineraldichte im Mittel um 2,5% in der LWS und um 2,7% in der Hüfte. Drei neue Wirbelkörperfrakturen traten im ersten Jahr auf, im zweiten keine. 7 Patientinnen erlitten je eine extravertebrale Fraktur. Der Anteil von Patientinnen mit Rückenschmerzen ging von 84,9% auf 29,1% zurück. Die mittlere Gesamcholesterinkonzentration im Serum sank um 5,0%, LDL-C um 8,5%. Es traten 23 unerwünschte Ereignisse auf, die – von einigen der Frakturen abgesehen – in keinem Falle schwerwiegend waren. 79 der 86 Frauen nahmen zu Beobachtungsende die Medikation noch immer regelmäßig ein. Die Ergebnisse bestätigen, dass die Resultate vorausgegangener kontrollierter klinischer Studien zu Wirksamkeit und Verträglichkeit von Raloxifen auch unter naturalistischen Praxisbedingungen reproduzierbar sind. Der eindrucksvolle Rückgang der Rückenschmerzen ist hingegen ein neuer Befund, der zwar in einer vorausgehenden Anwendungsbeobachtung schon einmal beschrieben, in kontrollierten Studien aber bisher nicht untersucht wurde.

Objective To compare continuous combined hormone replacement therapy (ccHRT) and raloxifene with respect to compliance and quality of life, which were predefined secondary endpoints of a large, prospective study designed to investigate the uterine effects of both treatments. Design Double-blind, randomised controlled trial of six-month duration. Setting One hundred and twenty-nine gynaecology hospital departments, clinics or practices specialised in women's healthcare, located in Europe, South Africa and Israel. Population Healthy postmenopausal women (n= 1008). Main outcome measures Changes in quality of life using the Women's Health Questionnaire (WHQ) and compliance using a compliance questionnaire and pill count. Adverse event and early discontinuation rates and satisfaction with treatment using a visual analogue scale (VAS). Results Women taking raloxifene reported greater satisfaction with their treatment as assessed on the VAS (P= 0.004),and a lower proportion, as compared with ccHRT, reported being worried by the treatment (9.6%vs 20.2%, P < 0.01). Women taking ccHRT reported greater deterioration in scores from the WHQ for depressed mood and menstrual symptoms than those taking raloxifene (P < 0.01). For memory, vasomotor symptoms and sexual behaviour, the ccHRT group reported significantly greater mean improvements (P < 0.05). Over half (58.8%) of those taking raloxifene noticed no effect, 37.7% felt better and 3.4% felt worse as measured using the compliance questionnaire. Fifty percent of the women taking ccHRT felt better, 37.8% noticed no effect but over 10% felt worse. More women on raloxifene (94.6%) than on ccHRT (85.9%) reported that they were taking their double-blinded medication regularly (P < 0.01). Conclusions A lower rate of adverse event-related discontinuations, the lack of negative effects on quality of life and a smaller proportion of women being worried by the drug treatment were associated with higher treatment satisfaction and better compliance in postmenopausal women taking ccHRT or raloxifene.

The melatonin agonist LY 156735 (LY) is a new investigational drug under development to treat circadian rhythm disorders. The present study assessed the efficacy of LY to alleviate the symptoms of shift lag and to enhance readaptation of desynchronized circadian rhythms to a new time zone.Eight healthy male volunteers of age 25-35 yr participated in three identical trials of 13d duration in a temporal isolation unit separated by washout intervals. A high dose (HD) of 5 mg and a low dose (LD) of 0.5 mg of LY and placebo (PL) were administered double-blinded in a three-period cross-over design. Each trial consisted of an adaptation period, a pre-shift period for baseline measurements, a simulated 9h phase-advance shift, and a post-shift period for follow-up. The time shift was performed at 23:00h of day 6 by advancing the laboratory time to 08:00h of day 7. Double-blind study medication was administered at 14:30h on day 6, and at 22:30h on days 7-10. Subjective ratings of jet lag, alertness, tenseness, and daytime fatigue were assessed using visual analog scales (VAS) and standardized questionnaires. The objective markers of readaptation included core body temperature, wrist actigraphy, cortisol and electrolyte excretion, and a battery of computerized performance tests.HD but not LD enhanced the readaptation speed of all physiological rhythms investigated, as demonstrated by a significantly faster movement of acrophases towards the post-shift target time. HD (p = 0.05) significantly blunted the post-shift deterioration of performance in those tests that were sensitive to shift lag. Parameters of subjective well-being were not significantly affected by either dose.This pilot study demonstrates the chronobiotic efficacy of LY when taken at a dose of 5 mg/d.

Vitamin D deficiency leads to secondary hyperparathyroidism, increased bone turnover, and bone loss and, when severe, to osteomalacia. Vitamin D deficiency is common in elderly people, especially the institutionalized. The definition of vitamin D deficiency is hampered by the fact that large interlaboratory differences exist in assays for serum 25-hydroxyvitamin D (25OHD), the main circulating metabolite. The international Multiple Outcomes of Raloxifene Evaluation study, a large prospective intervention trial in postmenopausal women with osteoporosis, offered the opportunity to compare vitamin D status and parathyroid function throughout many countries over the world. For this study, baseline data were available from 7564 postmenopausal women from 25 countries on 5 continents. All women had osteoporosis, i.e. bone mineral density (BMD) at femoral neck or lumbar spine was lower than t-score -2.5, or they had 2 vertebral fractures. Serum 25OHD was measured by RIA, and serum PTH was measured by immunoradiometric assay. BMD was measured by dual x-ray absorptiometry. The mean (+/-SD) serum 25OHD was 70.8 +/- 30.9 nmol/L. A low serum 25OHD (25 nmol/L) was observed in 4.1% of all women in the Multiple Outcomes of Raloxifene Evaluation study, ranging from 0% in south east Asia (very few patients) to 8.3% in southern Europe. Serum 25OHD was between 25-50 nmol/L in 24.3% of the women. Serum 25OHD showed a significant seasonal relationship, with lower values in all regions in winter. Serum PTH correlated negatively with serum 25OHD (r = -0.25; P0.001). This significant negative correlation was observed in all regions. When serum 25OHD was less than 25, 25-50, or more than 50 nmol/L, respectively, mean serum PTH levels were 4.8, 4.1, and 3.5 pmol/L, respectively (by ANOVA, P0.001). Similarly, mean alkaline phosphatase levels were 83.7, 79.1, and 75.7 U/L (P0.001), respectively, with increasing serum 25OHD. The effect of serum 25OHD on BMD was only significant for the BMD of the trochanter where a serum 25OHD level less than 25 nmol/L was associated with a 4% lower BMD. After 6 months of treatment with vitamin D(3) (400-600 IU/day) and calcium (500 mg/day), serum 25OHD increased from 70.8 +/- 29.8 to 92.3 +/- 28.6 nmol/L. Serum PTH decreased significantly after 6 months of treatment, and this decrease depended on baseline serum 25OHD. When baseline serum 25OHD was less than 25, 25-50, or more than 50 nmol/L, respectively, serum PTH decreased by 0.8, 0.5, or 0.2 pmol/L, respectively (P0.001). In conclusion, serum 25OHD was less than 25 nmol/L in 4% of the women, and this was associated with a 30% higher serum PTH. In 24% of the women serum 25OHD was between 25-50 nmol/L, associated with a 15% higher level of serum PTH compared with women with a serum 25OHD greater than 50 nmol/L. A low serum 25OHD level was also associated with higher serum alkaline phosphatase and lower BMD of the trochanter. Treatment with vitamin D(3) and calcium increased serum 25OHD and decreased serum PTH significantly; the effect was greater for lower baseline serum 25OHD.

Objective To compare the effects of the selective estrogen receptor modulator (SERM) raloxifene (Evista®) and a continuous combined hormone replacement therapy (ccHRT) formulation containing estradiol and norethisterone acetate (Kliogest®) on lipid and fibrinogen levels of postmenopausal women. Methods Euralox 1 was a prospective, randomized, double-blind trial. After a placebo wash-out, healthy postmenopausal women (n = 1008, average age 56.1 ± 4.9 years) with a health risk profile that suggested a potential benefit from either treatment were randomly assigned to either 60 mg raloxifene or ccHRT consisting of 2 mg estradiol and 1 mg norethisterone acetate (NETA) per day for 6 months. Measurements Total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol with its fractions HDL2 and HDL3, the LDL/HDL ratio, triglycerides and fibrinogen were asessed at baseline and after 6 months or on early drop-out. Results Baseline values were comparable between the two grou...

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.

Summary We report the changes in biochemical markers of bone formation during the first 6 months of teriparatide therapy in postmenopausal women with osteoporosis according to previous antiresorptive treatment. Prior therapy does not adversely affect the response to teriparatide treatment. Similar bone markers levels are reached after 6 months of treatment. Introduction The response of biochemical markers of bone turnover with teriparatide therapy in subjects who have previously received osteoporosis drugs is not fully elucidated. We examined biochemical markers of bone formation in women with osteoporosis treated with teriparatide and determined: (1) whether the response is associated with prior osteoporosis therapy, (2) which marker shows the best performance for detecting a response to therapy, and (3) the correlations between early changes in bone markers and subsequent bone mineral density (BMD) changes after 24 months of teriparatide. Methods We conducted a prospective, open-label, 24-month study at 95 centers in 10 countries in 758 postmenopausal women with established osteoporosis (n = 181 treatment-naïve) who had at least one post-baseline bone marker determination. Teriparatide (20 μg/day) was administered for up to 24 months. We measured procollagen type I N-terminal propeptide (PINP), bone-specific alkaline phosphatase (b-ALP), and total alkaline phosphatase (t-ALP) at baseline, 1 and 6 months, and change in BMD at the lumbar spine, total hip and femoral neck from baseline to 24 months. Results Significant increases in formation markers occurred after 1 month of teriparatide regardless of prior osteoporosis therapy. The absolute increase at 1 month was lower in previously treated versus treatment-naïve patients, but after 6 months all groups reached similar levels. PINP showed the best signal-to-noise ratio. Baseline PINP correlated positively and significantly with BMD response at 24 months. Conclusions This study suggests that the long-term responsiveness of bone formation markers to teriparatide is not affected in subjects previously treated with antiresorptive drugs.

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 T(12) were evaluated after 0, 6, 12, and 24 mo of teriparatide treatment (20 microg/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 L(1)-L(4) 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.

International audience; 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 microg/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.

Introduction: EUROFORS was a 2-yr prospective, randomized trial of postmenopausal women with established osteoporosis, designed to investigate various sequential treatments after teriparatide 20 μg/d for 1 yr. The present secondary analysis examined the effects of 2 yr of open-label teriparatide in women previously treated with antiresorptive drugs for at least 1 yr. Methods: A subgroup of 245 women with osteoporosis who had 2 yr of teriparatide treatment were stratified by previous predominant antiresorptive treatment into four groups: alendronate (n = 107), risedronate (n = 59), etidronate (n = 30), and non-bisphosphonate (n = 49). Bone mineral density (BMD) at the lumbar spine and hip was determined after 6, 12, 18, and 24 months, and bone formation markers were measured after 1 and 6 months. Results: Significant increases in bone formation markers occurred in all groups after 1 month of teriparatide treatment. Lumbar spine BMD increased at all visits, whereas a transient decrease in hip BMD, which was subsequently reversed, was observed in all groups. BMD responses were similar in all previous antiresorptive groups. Previous etidronate users showed a higher increase at the spine but not at the hip BMD. Duration of previous antiresorptive therapy and lag time between stopping previous therapy and starting teriparatide did not affect the BMD response at any skeletal site. Treatment-emergent adverse events were similar to those reported in treatment-naive postmenopausal women with osteoporosis treated with teriparatide. Conclusions: Teriparatide induces positive effects on BMD and markers of bone formation in postmenopausal women with established osteoporosis, regardless of previous long-term exposure to antiresorptive therapies.

The Danish Colorectal Cancer Database was established in 1994 with the purpose of monitoring whether diagnostic and surgical principles specified in the evidence-based national guidelines of good clinical practice were followed. Twelve clinical indicators have been listed by the Danish Colorectal Cancer Group, and the performance of each hospital surgical department with respect to these indicators is reported annually. In addition, the register contains a large collection of data that provide valuable information on the influence of comorbidity and lifestyle factors on disease outcome and survival.

Objective To compare the uterine effects of 60 mg of raloxifene with a continuous combined hormone replacement therapy, a preparation of 2 mg 17β-oestradiol (E2) and 1 mg norethisterone acetate for a duration of 12 months. Design A randomised, double-blind trial. Setting Multicentre: Europe, Israel, South Africa. Population Asymptomatic postmenopausal women with risk factors for osteoporosis or cardiovascular disease who had an endometrial thickness of less than 5 mm. One thousand and eight women were randomised for the six month core; of these 420 were invited to continue into a six month extension period. Methods Randomisation to either raloxifene or continuous combined hormone replacement therapy. Patients, recruiters and assessors were blinded to the treatment used. Main outcome measures The frequency of vaginal spotting/bleeding as recorded in a diary, endometrial thickness and uterine volume as measured by transvaginal ultrasonography at baseline and after 6 and 12 months. Results After six months of therapy with raloxifene, the rate of women on raloxifene reporting vaginal bleeding and spotting (6.8%) was similar to the rate in the lead-in phase (8.3%) but increased from 7.0% to 55.1% in the continuous combined hormone replacement therapy group. Raloxifene treatment was not associated with a significant change from baseline to endpoint in mean endometrial thickness (P= 0.11), whereas continuous combined hormone replacement therapy treatment was associated with an increase in this value of mean (SD) of 1.2 (2.2) mm (P < 0.001). Compared with raloxifene, mean endometrial thickness for women on continuous combined hormone replacement therapy was significantly increased at endpoint [4.6 (2.1) mm vs 3.5 (1.7) mm; change from baseline P < 0.001]. In the raloxifene group, there was a trend towards a decrease from baseline in uterine volume [from 31.4 (20.3) to 30.3 (16.2) mm; P= 0.37]; in the continuous combined hormone replacement therapy group, there was a significant increase in uterine volume [from 31.3 (16.3) to 54.0 (36.1) mm; P < 0.001], and the difference in the effect of both compounds on change in uterine volume at endpoint reached statistical significance (P < 0.001). Statistically significant differences between the treatment groups were sustained for all parameters during the extension period. Early discontinuation rates, both overall and due to adverse events, were significantly lower (P < 0.001) in the raloxifene group after 6 and 12 months. Conclusion Compared with continuous combined hormone replacement therapy, 6 and 12 months of raloxifene treatment do not lead to vaginal bleeding/spotting, are not associated with increased endometrial thickness or uterine volume and result in a significantly lower rate of early treatment discontinuations in asymptomatic women receiving treatment to prevent long term postmenopausal health risks.

Raloxifene effectively reduces the incidence of vertebral fractures in patients with postmenopausal osteoporosis. Recent data suggest that low-dose monofluorophosphate (MFP) plus calcium reduces the vertebral fracture rate in postmenopausal women with moderate osteoporosis. The objective of this study was to evaluate the combination of raloxifene and MFP in the treatment of postmenopausal women with osteopenia, osteoporosis and severe osteoporosis. A total of 596 postmenopausal women with osteopenia, osteoporosis and severe osteoporosis (mean femoral neck T-score of –2.87 SD) were randomized to treatment with 60 mg/day raloxifene HCl and 20 mg/day fluoride ions (as MFP) or 20 mg/day fluoride and placebo for 18 months. All patients received calcium (1000 mg/day) and vitamin D (500 IU/day) supplements. Changes in bone mineral density (BMD), as primary endpoint, and the rate of osteoporotic fractures and biochemical markers, as secondary endpoints, were assessed. As compared with MFP, raloxifene plus MFP was associated with significantly greater mean increases in the BMD of the femoral neck (1.37% versus 0.33%; P=0.004), total hip (0.89% versus −0.42%; P

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.

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.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.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 period, with no significant differences among the groups. The risk of decline in the cognitive function, as measured by four of the six tests, did not differ significantly between the two raloxifene groups combined and the placebo group, but there was a trend toward less decline in the combined raloxifene group on the two tests of verbal memory (relative risk, 0.77) and attention, (relative risk, 0.87). Newly reported or worsening hot flashes did not negatively influence test scores or the effect of treatment on test performance.Raloxifene treatment for three years does not affect overall cognitive scores in postmenopausal women with osteoporosis.

ContextRaloxifene hydrochloride is a selective estrogen receptor modulator that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting.ObjectiveTo determine whether women taking raloxifene have a lower risk of invasive breast cancer.Design and SettingThe Multiple Outcomes of Raloxifene Evaluation (MORE), a multicenter, randomized, double-blind trial, in which women taking raloxifene or placebo were followed up for a median of 40 months (SD, 3 years), from 1994 through 1998, at 180 clinical centers composed of community settings and medical practices in 25 countries, mainly in the United States and Europe.ParticipantsA total of 7705 postmenopausal women, younger than 81 (mean age, 66.5) years, with osteoporosis, defined by the presence of vertebral fractures or a femoral neck or spine T-score of at least 2.5 SDs below the mean for young healthy women. Almost all participants (96%) were white. Women who had a history of breast cancer or who were taking estrogen were excluded.InterventionRaloxifene, 60 mg, 2 tablets daily; or raloxifene, 60 mg, 1 tablet daily and 1 placebo tablet; or 2 placebo tablets.Main Outcome MeasuresNew cases of breast cancer, confirmed by histopathology. Transvaginal ultrasonography was used to assess the endometrial effects of raloxifene in 1781 women. Deep vein thrombosis or pulmonary embolism were determined by chart review.ResultsThirteen cases of breast cancer were confirmed among the 5129 women assigned to raloxifene vs 27 among the 2576 women assigned to placebo (relative risk [RR], 0.24; 95% confidence interval [CI], 0.13-0.44; P

Raloxifene is a selective estrogen receptor modulator that has been shown to prevent bone loss in postmenopausal women. Whether it also reduces the risk of fracture remains uncertain, prompting the present trial, the Multiple Outcomes of Raloxifene Evaluation (MORE) study. The randomized, blinded, placebo-controlled trial enlisted 7705 women in 25 countries, ranging in age from 31 to 80 years, who had been postmenopausal for 2 years or longer and met World Health Organization criteria for osteoporosis. Participants were assigned to receive raloxifene in a daily dose of 60 or 120 mg or placebo pills, and, in addition, all of them were given supplemental calcium and cholecalciferol. Follow-up extended for at least 3 years. Baseline and follow-up radiographs were available for 89 percent of women entering the study. One or more new vertebral fractures developed in 7.4 percent of women within 3 years of entry into the study. Those given raloxifene had fewer new fractures, regardless of whether fractures were present at the outset. No overall dose-related difference was found, although women with baseline fractures had fewer new lesions when given the higher dose of raloxifene. The rate of nonvertebral fracture at 3 years was 9.3 percent in the placebo group and 8.5 percent for raloxifene-treated women. Bone mineral density increased by 2 to 3 percent at various sites in the raloxifene group compared with the placebo group. Nearly one fourth of women had serious adverse effects regardless of treatment assignment, but the only ones considered causally related to raloxifene were deep thrombophlebitis and pulmonary embolism. This developed in 1 percent of each dose group and in 0.3 percent of placebo patients. Breast cancer was less frequent in women given raloxifene. Withdrawals due to adverse events were slightly more frequent in the raloxifene group than in the placebo group (10.3 vs. 8.8 percent). Hot flashes were the most common nonserious adverse event. No clinically important renal, hepatic, or hematological abnormalities were noted. These findings indicate that raloxifene treatment over 3 years not only preserves bone mass but also lowers the risk of new vertebral fractures in postmenopausal women with osteoporosis, regardless of whether they have had fractures before starting treatment. J Am Med Assoc 1999;282:637–645

ContextRaloxifene hydrochloride, a selective estrogen receptor modulator, prevents bone loss in postmenopausal women, but whether it reduces fracture risk in these women is not known.ObjectiveTo determine the effect of raloxifene therapy on risk of vertebral and nonvertebral fractures.DesignThe Multiple Outcomes of Raloxifene Evaluation (MORE) study, a multicenter, randomized, blinded, placebo-controlled trial.Setting and ParticipantsA total of 7705 women aged 31 to 80 years in 25 countries who had been postmenopausal for at least 2 years and who met World Health Organization criteria for having osteoporosis. The study began in 1994 and had up to 36 months of follow-up for primary efficacy measurements and nonserious adverse events and up to 40 months of follow-up for serious adverse events.InterventionsParticipants were randomized to 60 mg/d or 120 mg/d of raloxifene or to identically appearing placebo pills; in addition, all women received supplemental calcium and cholecalciferol.Main Outcome MeasuresIncident vertebral fracture was determined radiographically at baseline and at scheduled 24- and 36-month visits. Nonvertebral fracture was ascertained by interview at 6-month-interim visits. Bone mineral density was determined annually by dual-energy x-ray absorptiometry.ResultsAt 36 months of the evaluable radiographs in 6828 women, 503 (7.4%) had at least 1 new vertebral fracture, including 10.1% of women receiving placebo, 6.6% of those receiving 60 mg/d of raloxifene, and 5.4% of those receiving 120 mg/d of raloxifene. Risk of vertebral fracture was reduced in both study groups receiving raloxifene (for 60-mg/d group: relative risk [RR], 0.7; 95% confidence interval [CI], 0.5-0.8; for 120-mg/d group: RR, 0.5; 95% CI, 0.4-0.7). Frequency of vertebral fracture was reduced both in women who did and did not have prevalent fracture. Risk of nonvertebral fracture for raloxifene vs placebo did not differ significantly (RR, 0.9; 95% CI, 0.8-1.1 for both raloxifene groups combined). Compared with placebo, raloxifene increased bone mineral density in the femoral neck by 2.1% (60 mg) and 2.4% (120 mg) and in the spine by 2.6% (60 mg) and 2.7% (120 mg) P

Effective and total left ventricular (LV) stroke volume were assessed in 31 patients with verified aortic or mitral regurgitation, or both, and in 22 patients with normal valvular function using combined first-pass and equilibrium radionuclide ventriculography. The difference between these 2 volumes as a fraction of LV stroke volume was taken as the radionuclide regurgitant fraction. The results were compared with the LV/right ventricular (RV) stroke count ratio and with the angiographic regurgitant fraction according to the method of Sandler and Dodge. Radionuclide regurgitant fraction derived from 2 determinations with a time interval of 1 week showed good reproducibility (n = 15, r = 0.96, SEE = 9.1). Sensitivity was 100% for radionuclide regurgitant fraction and 87% for LV/RV stroke count ratio at equal specificity (100%). Radionuclide regurgitant fraction was more sensitive, especially in severely ill patients, in whom additional RV volume overload led to false-low or false-negative ratios. Angiographic and radionuclide regurgitant fraction showed linear correlation (r = 0.79, p less than 0.001). In contrast, because 5 patients had RV volume overload, only a weak correlation could be noticed between angiography and LV/RV stroke count ratio (r = 0.47, p less than 0.05). Excluding these patients, correlation substantially improved (r = 0.74, p less than 0.001). The combination of first-pass and equilibrium radionuclide ventriculography is a sensitive, specific and well reproducible method for the evaluation of mitral and aortic regurgitation.(ABSTRACT TRUNCATED AT 250 WORDS)