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Early PINP changes correlate with 18-month lumbar spine BMD changes and the correlation was greater with abaloparatide versus teriparatide. The uncoupling index was similar between the two agents.IntroductionWe evaluated the relationship between early PINP changes and subsequent changes in spine BMD following abaloparatide and teriparatide treatments. We also explored the use of an "uncoupling index" (UI), the balance between bone formation and bone resorption, which we hypothesised would be similar in response to these treatment groups.MethodsBlood samples were taken for measurement of bone turnover markers (BTMs) s-PINP and s-CTX at baseline, 1, 3, 6, 12, and 18 months from 189 abaloparatide patients and 227 teriparatide patients randomly selected from all participants who completed the study. BMD was measured by DXA at baseline, 6, 12, and 18 months. Correlations were calculated between log ratio of BTMs from baseline to 3 months and percent change from baseline in BMD at 18 months. A UI was calculated using log transformation and subtraction of the standard deviate for s-CTX from the standard deviate for s-PINP for each patient.ResultsEarly BTM changes were associated with subsequent BMD changes for both treatments. Pearson correlations for the log ratio of PINP over baseline at 3 months and BMD percent change from baseline at 18 months were larger (P

Background: Vertebral fractures increase the risk of new vertebral fractures; however, we are not aware of any study addressing the risk of new vertebral fractures adjacent to existing vertebral fractures. Therefore, we sought to determine the influence of the number and severity of prevalent (preexisting) vertebral fractures on the risk of new adjacent vertebral fractures and to determine whether teriparatide (rhPTH [recombinant human parathyroid hormone] [1-34]) or raloxifene treatment reduces the incidence of adjacent vertebral fractures in postmenopausal women with osteoporosis.Methods: Data from the Fracture Prevention Trial and the Multiple Outcomes of Raloxifene Evaluation trial were analyzed to determine the incidences of new adjacent and new nonadjacent vertebral fractures in the placebo groups and the effect of treatment with raloxifene and teriparatide on the incidence of new adjacent vertebral fractures as compared with that of new nonadjacent vertebral fractures.Results: Of 1226 untreated postmenopausal women with one or more prevalent vertebral fractures at baseline, 196 (16.0%) had a total of 292 new vertebral fractures during the two-year follow-up period, with 108 (8.8%) of the 1226 women having at least one new fracture adjacent to a prevalent fracture. Of the 292 new vertebral fractures, 136 (47%) were adjacent to a previously existing vertebral fracture. The risk of a new adjacent vertebral fracture was 2.5-fold higher than the risk of a new nonadjacent vertebral fracture (4.03% compared with 1.59%). The incidence of new adjacent vertebral fractures increased with both the number and the severity of prevalent vertebral fractures. Teriparatide reduced the risk of any new, new adjacent, and new nonadjacent vertebral fractures by 72%, 75%, and 70%, respectively, compared with the rates in the placebo group. Similarly, compared with the placebo, raloxifene treatment reduced the risk of any new vertebral fracture, new adjacent vertebral fracture, and new nonadjacent vertebral fracture by 54%, 54%, and 53%, respectively.Conclusions: In untreated postmenopausal women with osteoporosis, nearly half of the incident vertebral fractures occur adjacent to an existing vertebral fracture. Both teriparatide and raloxifene can significantly reduce the occurrence of new adjacent and nonadjacent vertebral fractures. [ABSTRACT FROM AUTHOR]

Background: Recombinant human parathyroid hormone (PTH [1-34]; teriparatide) is a new treatment for postmenopausal osteoporosis that can be systemically administered for the primary purpose of increasing bone formation. Because several studies have described the enhancement of fracture-healing and osteointegration in animals after use of PTH, we sought to critically analyze this skeletal effect.Methods: Two hundred and seventy male Sprague-Dawley rats underwent standard, closed femoral fractures and were divided into three groups that were administered daily subcutaneous injections of 5 or 30 mug/kg of PTH (1-34) or vehicle (control). The dosing was administered for up to thirty-five days. Groups were further divided into three subgroups and were killed on day 21, 35, or 84 after the fracture. The bones were subjected to mechanical torsion testing, histomorphometric analysis, or microquantitative computed tomography.Results: By day 21, calluses from the group treated with 30 mug of PTH showed significant increases over the controls with respect to torsional strength, stiffness, bone mineral content, bone mineral density, and cartilage volume. By day 35, both groups treated with PTH showed significant increases in bone mineral content and density and total osseous tissue volume, and they demonstrated significant decreases in void space and cartilage volume (p < 0.05). Torsional strength was significantly increased at this time-point in the group treated with 30 mug of PTH (p < 0.05). While dosing was discontinued on day 35, analyses performed after eighty-four days in the group treated with 30 mug of PTH showed sustained increases over the controls with respect to torsional strength and bone mineral density. No change was noted in osteoclast density at the time-points measured, suggesting that treatment with PTH enhanced bone formation but did not induce bone resorption.Conclusions: These data show that daily systemic administration of PTH (1-34) enhances fracture-healing by increasing bone mineral content and density and strength, and it produces a sustained anabolic effect throughout the remodeling phase of fracture-healing. [ABSTRACT FROM AUTHOR]

Context: Raloxifene hydrochloride, a selective estrogen receptor modulator, prevents bone loss in postmenopausal women, but whether it reduces fracture risk in these women is not known.Objective: To determine the effect of raloxifene therapy on risk of vertebral and nonvertebral fractures.Design: The Multiple Outcomes of Raloxifene Evaluation (MORE) study, a multicenter, randomized, blinded, placebo-controlled trial.Setting and Participants: A 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.Interventions: Participants 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 Measures: Incident 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.Results: At 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<0.001 for all comparisons). Women receiving raloxifene had increased risk of venous thromboembolus vs placebo (RR, 3.1; 95% CI, 1.5-6.2). Raloxifene did not cause vaginal bleeding or breast pain and was associated with a lower incidence of breast cancer.Conclusions: In postmenopausal women with osteoporosis, raloxifene increases bone mineral density in the spine and femoral neck and reduces risk of vertebral fracture. [ABSTRACT FROM AUTHOR]

Anabolic osteoporosis drugs improve bone mineral density by increasing bone formation. The objective of this study was to evaluate the early effects of abaloparatide on indices of bone formation and to assess the effect of abaloparatide on modeling-based formation (MBF), remodeling-based formation (RBF), and overflow MBF (oMBF) in transiliac bone biopsies. In this open-label, single-arm study, 23 postmenopausal women with osteoporosis were treated with 80 μg abaloparatide daily. Subjects received double fluorochrome labels before treatment and before biopsy collection at 3 months. Change in dynamic histomorphometry indices in four bone envelopes were assessed. Median mineralizing surface per unit of bone surface (MS/BS) increased to 24.7%, 48.7%, 21.4%, and 16.3% of total surface after 3 months of abaloparatide treatment, representing 5.5-, 5.2-, 2.8-, and 12.9-fold changes, on cancellous, endocortical, intracortical, and periosteal surfaces (p < .001 versus baseline for all). Mineral apposition rate (MAR) was significantly increased only on intracortical surfaces. Bone formation rate (BFR/BS) was significantly increased on all four bone envelopes. Significant increases versus baseline were observed in MBF on cancellous, endocortical, and periosteal surfaces, for oMBF on cancellous and endocortical surfaces, and for RBF on cancellous, endocortical, and intracortical surfaces. Overall, modeling-based formation (MBF + oMBF) accounted for 37% and 23% of the increase in bone-forming surface on the endocortical and cancellous surfaces, respectively. Changes from baseline in serum biomarkers of bone turnover at either month 1 or month 3 were generally good surrogates for changes in histomorphometric endpoints. In conclusion, treatment with abaloparatide for 3 months stimulated bone formation on cancellous, endocortical, intracortical, and periosteal envelopes in transiliac bone biopsies obtained from postmenopausal women with osteoporosis. These increases reflected stimulation of both remodeling- and modeling-based bone formation, further elucidating the mechanisms by which abaloparatide improves bone mass and lowers fracture risk. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Objective: To evaluate, post hoc, the efficacy and safety of abaloparatide by degree of renal impairment. Methods: ACTIVE was a phase 3, 18-month, randomized, double-blind, active-comparator, placebo-controlled study of postmenopausal women with osteoporosis who received subcutaneous abaloparatide 80 µg, placebo, or open-label teriparatide 20 µg daily. Patients with serum creatinine >2.0 mg/dL or 1.5-2.0 mg/dL with an estimated glomerular filtration rate (eGFR) <37 mL/min, calculated by Cockcroft-Gault formula, were excluded. Results: At baseline, 660 patients had eGFR ≥90 mL/min, 1276 had 60 to ˂90 mL/min, and 527 had <60 mL/min. Older age and lower T-scores were associated with greater renal impairment. Among renal-function subgroups, there were no meaningful changes in bone mineral density, fracture risk reduction, or overall incidence of treatment-emergent adverse events in the active-treatment arms. Anemia, nausea, hypercalcemia, and upper-respiratory-tract infection tended to be more frequent with increasing renal impairment. Hypercalcemia measured by albumin-adjusted serum calcium occurred significantly less frequently with abaloparatide than teriparatide in patients with eGFR <60 mL/min (3.6% versus 10.9%; p  = .008) and in the overall ACTIVE safety population (3.4% versus 6.4%; p  = .006). Computed tomography scans in 376 patients revealed no evidence of increased renal calcification. Conclusion: Increased exposure to abaloparatide and teriparatide in patients with renal impairment led to no meaningful differences in efficacy or safety. These results support the use of abaloparatide without dosage adjustment in patients with renal impairment, provided those with severe renal impairments are monitored for adverse events.

Abaloparatide is a selective activator of the parathyroid hormone type 1 receptor signaling pathway that favors the stimulation of bone formation. Here, we report a prospective, exploratory analysis of bone mineral density (BMD) response rates comparing sequential abaloparatide/alendronate vs placebo/alendronate across the ACTIVE and ACTIVExtend studies. BMD was measured at the lumbar spine, total hip, and femoral neck from the beginning of ACTIVE to the end of ACTIVExtend (18 months of abaloparatide or placebo followed by about 1 month for re-consent, followed by 24 months of alendronate treatment for a total of 43 months). Responders were defined as those patients who had improvements in BMD at 3 anatomic sites-the lumbar spine, total hip, and femoral neck. Three response thresholds, >0%, >3%, and >6%, were evaluated. Five hundred fifty-eight patients in the abaloparatide/alendronate group and 581 patients in the placebo/alendronate group from ACTIVExtend were included in the analysis. At Month 43, a significantly greater proportion of those in the abaloparatide/alendronate group compared with the placebo/alendronate group responded with BMD changes from ACTIVE baseline of >0%, >3%, and >6% at all 3 anatomic sites (p < 0.001 for each comparison). At the>3% threshold, 60.7% (307/506) vs 24.0% (121/505) of patients experienced BMD increases at all 3 sites in the abaloparatide/alendronate vs placebo/alendronate groups, respectively (p < 0.001). A significantly greater proportion of the abaloparatide/alendronate group experienced BMD increases of>0%, >3%, and >6% at each individual anatomic site compared with the placebo/alendronate group at 43 months (p < 0.001). Additionally, at each visit in ACTIVExtend, there was a significantly greater proportion of patients in the abaloparatide/alendronate group above the 3% threshold at each anatomic site compared with the placebo/alendronate group. Results are consistent with the significant BMD response with abaloparatide vs placebo observed in ACTIVE and with the continued fracture risk reduction with sequential abaloparatide/alendronate compared with placebo/alendronate treatment observed in ACTIVE through ACTIVExtend., (© 2019 Published by Elsevier Inc.)

Purpose: Sarcopenia is an age-related muscle condition which is frequently a precursor of frailty, mobility disability and premature death. It has a high prevalence in older populations and presents a considerable social and economic burden. Potential treatments are under development but, as yet, no guidelines support regulatory studies for new drugs to manage sarcopenia. The objective of this position paper is therefore to suggest a set of potential endpoints and target population definitions to stimulate debate and progress within the medico-scientific and regulatory communities., Methods: A multidisciplinary expert working group was hosted by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, which reviewed and discussed the recent literature from a perspective of clinical experience and guideline development. Relevant parallels were drawn from the development of definition of osteoporosis as a disease and clinical assessment of pharmaceutical treatments for that indication., Results: A case-finding decision tree is briefly reviewed with a discussion of recent prevalence estimations of different relevant threshold values. The selection criteria for patients in regulatory studies are discussed according to the aims of the investigation (sarcopenia prevention or treatment) and the stage of project development. The possible endpoints of such studies are reviewed and a plea is made for the establishment of a core outcome set to be used in all clinical trials of sarcopenia., Conclusions: The current lack of guidelines for the assessment of new therapeutic treatments for sarcopenia could potentially hinder the delivery of effective medicines to patients at risk.

Unlabelled: Daily teriparatide injections have been shown to reduce vertebral and non-vertebral fractures. Here, we demonstrate that the magnitude of fracture risk reduction is independent of baseline fracture probability assessed by FRAX., Introduction: Daily administration of 20 or 40 μg teriparatide has been shown to significantly decrease the risk of vertebral and non-vertebral fracture compared with placebo. The aim of the present study was to evaluate fracture risk assessed at baseline using the FRAX® tool and to determine the efficacy of teriparatide as a function of baseline fracture risk., Methods: One thousand six hundred thirty-seven postmenopausal women in the pivotal phase three trial, randomly assigned to receive placebo (n = 544), teriparatide 20 μg per day (n = 541) or teriparatide 40 μg per day (n = 552), were studied. Baseline clinical risk factors were entered into country-specific FRAX models to compute the 10-year probability of major osteoporotic fractures with or without input of femoral neck BMD. Because there was no difference in effect of 20 and 40 μg teriparatide daily on fracture occurrence, the two active groups were merged. The interaction between probability of a major fracture and treatment efficacy was examined by Poisson regression., Results: The 10-year probability of major osteoporotic fractures (with BMD) ranged from 2.2-67.2 %. Treatment with teriparatide was associated with a 37 % decrease in all non-vertebral fractures (95 % CI 10-56 %) and a 56 % decrease in low-energy non-vertebral fractures (95 % CI 24-75 %) compared with placebo. The risk of morphometric vertebral fractures decreased significantly by 66 % (95 % CI 50-77 %). Hazard ratios for the effect of teriparatide on the fracture outcome did not change significantly with increasing fracture probability (p > 0.30). Similar findings were noted for the interaction when BMD was excluded from the FRAX model, or when probability of hip fracture was used as the marker of baseline risk., Conclusion: We conclude that teriparatide significantly decreases the risk of non-vertebral and morphometric vertebral fractures in women by a similar extent, irrespective of baseline fracture probability.

Administration of blosozumab, a humanized monoclonal antibody that binds sclerostin, increases bone formation and bone mineral density (BMD) in postmenopausal women with low BMD. To evaluate the effect of discontinuing blosozumab, we studied women enrolled in a 1-year randomized, placebo-controlled phase 2 trial for an additional year after they completed treatment. Of the 120 women initially enrolled in the study, 106 women completed treatment and continued into follow-up; 88 women completed 1 year of follow-up. At the beginning of follow-up, groups remained balanced for age, race, and body mass index, but lumbar spine and total hip BMD were increased in prior blosozumab groups, reflecting an anabolic treatment effect. At the end of follow-up, 1 year after discontinuing treatment, lumbar spine BMD remained significantly greater than placebo in women initially treated with blosozumab 270 mg every 2 weeks (Q2W) and blosozumab 180 mg Q2W (6.9% and 3.6% above baseline, respectively). Total hip BMD also declined after discontinuation of treatment but at 1 year after treatment remained significantly greater than placebo in women initially treated with blosozumab 270 mg Q2W and blosozumab 180 mg Q2W (3.9% and 2.6% above baseline, respectively). During follow-up, median serum P1NP was not consistently different between the prior blosozumab groups and placebo. A similar pattern was apparent for median serum C-terminal telopeptide of type 1 collagen (CTx) levels, with more variability. Mean serum total sclerostin concentration increased with blosozumab, indicating target engagement, and declined to baseline after discontinuation. There were no adverse events considered related to prior treatment with blosozumab. Anti-drug antibodies generally declined in patients who had detectable levels during prior treatment. These findings support the continued study of blosozumab as an anabolic therapy for treatment of osteoporosis., (© 2015 American Society for Bone and Mineral Research.)

Sclerostin, a SOST protein secreted by osteocytes, negatively regulates formation of mineralized bone matrix and bone mass. We report the results of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin, in postmenopausal women with low bone mineral density (BMD). Postmenopausal women with a lumbar spine T-score -2.0 to -3.5, inclusive, were randomized to subcutaneous blosozumab 180 mg every 4 weeks (Q4W), 180 mg every 2 weeks (Q2W), 270 mg Q2W, or matching placebo for 1 year, with calcium and vitamin D. Serial measurements of spine and hip BMD and biochemical markers of bone turnover were performed. Overall, 120 women were enrolled in the study (mean age 65.8 years, mean lumbar spine T-score -2.8). Blosozumab treatment resulted in statistically significant dose-related increases in spine, femoral neck, and total hip BMD as compared with placebo. In the highest dose group, BMD increases from baseline reached 17.7% at the spine, and 6.2% at the total hip. Biochemical markers of bone formation increased rapidly during blosozumab treatment, and trended toward pretreatment levels by study end. However, bone specific alkaline phosphatase remained higher than placebo at study end in the highest-dose group. CTx, a biochemical marker of bone resorption, decreased early in blosozumab treatment to a concentration less than that of the placebo group by 2 weeks, and remained reduced throughout blosozumab treatment. Mild injection site reactions were reported more frequently with blosozumab than placebo. In conclusion, treatment of postmenopausal women with an antibody targeted against sclerostin resulted in substantial increases in spine and hip BMD. These results support further study of blosozumab as a potential anabolic therapy for osteoporosis., (© 2014 American Society for Bone and Mineral Research.)

The reduced muscle mass and impaired muscle performance that define sarcopenia in older individuals are associated with increased risk of physical limitation and a variety of chronic diseases. They may also contribute to clinical frailty. A gradual erosion of quality of life (QoL) has been evidenced in these individuals, although much of this research has been done using generic QoL instruments, particularly the SF-36, which may not be ideal in older populations with significant comorbidities. This review and report of an expert meeting presents the current definitions of these geriatric syndromes (sarcopenia and frailty). It then briefly summarizes QoL concepts and specificities in older populations and examines the relevant domains of QoL and what is known concerning QoL decline with these conditions. It calls for a clearer definition of the construct of disability, argues that a disease-specific QoL instrument for sarcopenia/frailty would be an asset for future research, and discusses whether there are available and validated components that could be used to this end and whether the psychometric properties of these instruments are sufficiently tested. It calls also for an approach using utility weighting to provide some cost estimates and suggests that a time trade-off study could be appropriate.

Background: Tamoxifen and raloxifene reduce the risk of breast cancer in women at elevated risk of disease, but the duration of the effect is unknown. We assessed the effectiveness of selective oestrogen receptor modulators (SERMs) on breast cancer incidence., Methods: We did a meta-analysis with individual participant data from nine prevention trials comparing four selective oestrogen receptor modulators (SERMs; tamoxifen, raloxifene, arzoxifene, and lasofoxifene) with placebo, or in one study with tamoxifen. Our primary endpoint was incidence of all breast cancer (including ductal carcinoma in situ) during a 10 year follow-up period. Analysis was by intention to treat., Results: We analysed data for 83,399 women with 306,617 women-years of follow-up. Median follow-up was 65 months (IQR 54-93). Overall, we noted a 38% reduction (hazard ratio [HR] 0·62, 95% CI 0·56-0·69) in breast cancer incidence, and 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. The reduction was larger in the first 5 years of follow-up than in years 5-10 (42%, HR 0·58, 0·51-0·66; p<0·0001 vs 25%, 0·75, 0·61-0·93; p=0·007), but we noted no heterogeneity between time periods. Thromboembolic events were significantly increased with all SERMs (odds ratio 1·73, 95% CI 1·47-2·05; p<0·0001). We recorded a significant reduction of 34% in vertebral fractures (0·66, 0·59-0·73), but only a small effect for non-vertebral fractures (0·93, 0·87-0·99)., Interpretation: For all SERMs, incidence of invasive oestrogen (ER)-positive breast cancer was reduced both during treatment and for at least 5 years after completion. Similar to other preventive interventions, careful consideration of risks and benefits is needed to identify women who are most likely to benefit from these drugs., Funding: Cancer Research UK., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Several studies have concluded that diabetes mellitus and heart disease carry similar risk for future cardiovascular disease (CVD). Most of these studies were too small to quantify independent risks specific to women. The purpose of this study was to determine whether diabetes mellitus is a coronary heart disease (CHD) risk equivalent for prediction of future CHD and CVD events in women., Methods and Results: The Raloxifene Use for the Heart (RUTH) trial was an international, multicenter, double-blind, randomized, placebo-controlled trial of raloxifene and CVD outcomes in 10 101 postmenopausal women selected for high CHD risk. Of these, 3672 had a history of diabetes mellitus without known CHD, and 3265 had a history of CHD without known diabetes mellitus. Cox proportional hazard models were used to compare cardiovascular outcomes in these 2 groups. Mean age at baseline was 67.5 years; median follow-up was 5.6 years. There were 725 deaths, including 450 cardiovascular deaths. In age-adjusted analyses, diabetic women had an increased risk of all-cause mortality compared with women with CHD. Although the overall risk of CHD and CVD was lower in diabetic women compared with women with CHD, the risk of fatal CHD, fatal CVD, and all-cause mortality was similar (hazard ratio [95% confidence interval]: 0.85 [0.65-1.12], 0.99 [0.78-1.25], and 1.18 [0.98-1.42], respectively, after adjusting for age, lifestyle factors, CHD risk factors, statin use, and treatment assignment)., Conclusions: In the RUTH trial, diabetes mellitus was a CHD risk equivalent in women for fatal, but not nonfatal, CHD and CVD.

Unlabelled: The effect of teriparatide and risedronate on back pain was tested, and there was no difference in the proportion of patients experiencing a reduction in back pain between groups after 6 or 18 months. Patients receiving teriparatide had greater increases in bone mineral density and had fewer vertebral fractures., Introduction: This study aimed to understand the effect of teriparatide in reducing back pain in patients with prevalent back pain and vertebral fracture compared to risedronate., Methods: In an 18-month randomized, double-blind, double-dummy trial, we investigated the effects of teriparatide (20 μg/day) vs. risedronate (35 mg/week) in postmenopausal women with back pain likely due to vertebral fracture. The primary objective was to compare the proportion of subjects reporting ≥30% reduction in worst back pain severity from baseline to 6 months as assessed by a numeric rating scale in each treatment group. Pre-specified secondary and exploratory outcomes included assessments of average and worst back pain at additional time points, disability and quality of life, bone mineral density, incidence of fractures, and safety., Results: At 6 months, 59% of teriparatide and 57% of risedronate patients reported ≥30% reduction in worst back pain and there were no differences between groups in the proportion of patients experiencing reduction in worst or average back pain at any time point, disability, or quality of life. There was a greater increase from baseline in bone mineral density at the lumbar spine (p = 0.001) and femoral neck (p = 0.02) with teriparatide compared to risedronate and a lower incidence of vertebral fractures at 18 months (4% teriparatide and 9% risedronate; p = 0.01). Vertebral fractures were less severe (p = 0.04) in the teriparatide group. There was no difference in the overall incidence of adverse events., Conclusions: Although there were no differences in back pain-related endpoints, patients receiving teriparatide had greater skeletal benefit than those receiving risedronate.

To gain insight into the clinical effect of teriparatide and alendronate on the hip, we performed non-linear finite element analysis of quantitative computed tomography (QCT) scans from 48 women who had participated in a randomized, double-blind clinical trial comparing the effects of 18-month treatment of teriparatide 20 μg/d or alendronate 10mg/d. The QCT scans, obtained at baseline, 6, and 18 months, were analyzed for volumetric bone mineral density (BMD) of trabecular bone, the peripheral bone (defined as all the cortical bone plus any endosteal trabecular bone within 3 mm of the periosteal surface), and the integral bone (both trabecular and peripheral), and for overall femoral strength in response to a simulated sideways fall. At 18 months, we found in the women treated with teriparatide that trabecular volumetric BMD increased versus baseline (+4.6%, p<0.001), peripheral volumetric BMD decreased (-1.1%, p<0.05), integral volumetric BMD (+1.0%, p=0.38) and femoral strength (+5.4%, p=0.06) did not change significantly, but the ratio of strength to integral volumetric BMD ratio increased (+4.0%, p=0.04). An increase in the ratio of strength to integral volumetric BMD indicates that overall femoral strength, compared to baseline, increased more than did integral density. For the women treated with alendronate, there were small (<1.0%) but non-significant changes compared to baseline in all these parameters. The only significant between-treatment difference was in the change in trabecular volumetric BMD (p<0.005); related, we also found that, for a given change in peripheral volumetric BMD, femoral strength increased more for teriparatide than for alendronate (p=0.02). We conclude that, despite different compartmental volumetric BMD responses for these two treatments, we could not detect any overall difference in change in femoral strength between the two treatments, although femoral strength increased more than integral volumetric BMD after treatment with teriparatide., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Due to the chronic nature of osteoporosis and the risk of invasive breast cancer, raloxifene 60 mg/day (raloxifene) is intended to be used for long-term treatment (treatment >3 years)., Scope: We review available information concerning long-term use of raloxifene, present several new analyses, and report new data from patients who underwent iliac crest bone biopsies after 8 years of raloxifene therapy. The most important studies were the Multiple Outcomes of Raloxifene Evaluation (MORE) followed by the Continued Outcomes of Raloxifene Evaluation (CORE)., Findings: The primary endpoint in MORE was incidence of vertebral fracture, and the difference between the raloxifene and placebo groups for this endpoint widened during 4 years of therapy, with the relative risk reduction during the fourth year of the study being similar to the relative risk reduction during years 0 to 3 of the study. Continued raloxifene treatment is necessary to preserve bone mineral density (BMD). In MORE, raloxifene lowered markers of bone turnover to a premenopausal reference interval. Biopsies from three patients treated with raloxifene for 8 years showed normal bone and bone cells and double label in all specimens. Invasive breast cancer risk is a clinical consideration in postmenopausal women with osteoporosis, and invasive breast cancer risk reduction was the primary endpoint in CORE. In MORE and CORE, the benefit of raloxifene versus placebo in incidence of invasive breast cancer increased with greater duration of therapy up to 8 years., Conclusions: The long-term use of raloxifene has been evaluated through changes in fracture risk reduction, BMD, markers of bone turnover, iliac crest bone biopsies, and invasive breast cancer risk reduction.

Since 2003, the European Medicines Agency (EMA) document, 'Points to consider on clinical investigation of medicinal products other than NSAIDs (nonsteroidal anti-inflammatory drugs) for the treatment of rheumatoid arthritis' has provided guidance for the clinical development of both biologic and non-biologic disease-modifying antirheumatic drugs (DMARDs). In the last few years, several new products have been developed or are in development for the treatment of RA, which offer significant efficacy with regard to disease control, including prevention of structural damage and disability. Concurrently, novel insights have been gained with respect to the assessment of disease activity, joint damage and disability. New treatment strategies have been established which relate to early therapy, tight control and rapid switching of medication. Accordingly, several new EULAR/ACR recommendations have been or are being developed. Several important additions and changes are needed in the 2003 guidance to incorporate the current scientific knowledge into clinical trial design for the development of future products. Under the auspices of the Group for the Respect of Ethics and Excellence in Science (GREES), a group of experts in the field of RA and clinical trial design met to provide a consensus recommendation for an update to the 2003 EMA guidance document.

Objective: Raloxifene, a selective estrogen receptor modulator, reduces osteoporosis and invasive breast cancer risk but increases risk for venous thromboembolism and fatal stroke in women with or at high risk for coronary heart disease. To assess the risk/benefit of raloxifene as a preventative treatment, we analyzed treatment effects on overall and cause-specific mortality., Methods: A pooled analysis of mortality data was performed from large clinical trials of raloxifene (60 mg/day) versus placebo, including the Multiple Outcomes of Raloxifene Evaluation/Continuing Outcomes Relevant to Evista studies (7705 postmenopausal osteoporotic women followed for 4 years and a subset of 4011 participants followed for an additional 4 years; 110 deaths) and the Raloxifene Use for the Heart trial (10,101 postmenopausal women with coronary disease or multiple risk factors for coronary disease followed for 5.6 years; 1149 deaths). Cause of death was assessed by blinded adjudicators. Cox proportional hazards regression models compared mortality by treatment assignment in a pooled analysis of trial data from the Multiple Outcomes of Raloxifene Evaluation/Continuing Outcomes Relevant to Evista and Raloxifene Use for the Heart trials., Results: All-cause mortality was 10% lower among women assigned to raloxifene 60 mg/day versus placebo (relative hazard 0.90; 95% confidence interval, 0.80-1.00; P=.05). Lower overall mortality was primarily due to lower rates of noncardiovascular deaths, especially a lower rate of noncardiovascular, noncancer deaths., Conclusions: All-cause mortality was 10% lower in pooled analyses among older postmenopausal women receiving raloxifene 60 mg/day compared with placebo, due primarily to a reduction in noncardiovascular, noncancer deaths. The mechanism whereby raloxifene might reduce the risk of noncardiovascular death is unclear., (Published by Elsevier Inc.)

Animal experiments show a dramatic improvement in skeletal repair by teriparatide. We tested the hypothesis that recombinant teriparatide, at the 20 microg dose normally used for osteoporosis treatment or higher, would accelerate fracture repair in humans. Postmenopausal women (45 to 85 years of age) who had sustained a dorsally angulated distal radial fracture in need of closed reduction but no surgery were randomly assigned to 8 weeks of once-daily injections of placebo (n = 34) or teriparatide 20 microg (n = 34) or teriparatide 40 microg (n = 34) within 10 days of fracture. Hypotheses were tested sequentially, beginning with the teriparatide 40 microg versus placebo comparison, using a gatekeeping strategy. The estimated median time from fracture to first radiographic evidence of complete cortical bridging in three of four cortices was 9.1, 7.4, and 8.8 weeks for placebo and teriparatide 20 microg and 40 microg, respectively (overall p = .015). There was no significant difference between the teriparatide 40 microg versus placebo groups (p = .523). In post hoc analyses, there was no significant difference between teriparatide 40 microg versus 20 microg (p = .053); however, the time to healing was shorter in teriparatide 20 microg than placebo (p = .006). The primary hypothesis that teriparatide 40 microg would shorten the time to cortical bridging was not supported. The shortened time to healing for teriparatide 20 microg compared with placebo still may suggest that fracture repair can be accelerated by teriparatide, but this result should be interpreted with caution and warrants further study., (Copyright 2010 American Society for Bone and Mineral Research.)

Summary: The utility of vertebral fracture assessment (VFA) by DXA to detect prevalent vertebral fracture in a multicenter setting was investigated by comparison to conventional radiography. While limited by lower image quality, overall performance of VFA was good but had a tendency to miss mild prevalent fractures., Introduction: In osteoporosis clinical trials standardized spine radiographs are used to detect vertebral fractures as a study endpoint. Lateral spine imaging with dual X-ray absorptiometry (DXA) scanners, known as vertebral fracture assessment (VFA) by DXA, presents a potential alternative to conventional radiography with lower radiation dose and greater patient convenience., Methods: We investigated in a multicenter setting the ability of VFA to detect fractures in comparison with conventional radiography. The study examined 203 postmenopausal women who had imaging of the spine by DXA and radiography. Three radiologists experienced in vertebral fracture assessment independently read the VFA scans and radiographs using the Genant semiquantitative method on two occasions., Conclusions: Analyzing the data from all readable vertebrae, the kappa statistic, sensitivity, and specificity ranged from 0.64-0.77, 0.65-0.84, and 0.97-0.98, respectively. Considering only moderate and severe fractures improved the kappa statistic (0.80-0.91) and sensitivity (0.70-0.86). While image quality of VFA is inferior to radiography, the detection of vertebral fractures using visual scoring is feasible. However, VFA underperformed due to unreadable vertebrae and reduced sensitivity for mild fractures. Nevertheless, VFA correctly identified most moderate and severe vertebral fractures. Despite this limitation, VFA by DXA provides an important tool for clinical research.

Background: Policy makers around the world are currently considering the creation of a regulatory pathway for follow-on biologics (FOB), which will have to account for the substantial technical challenges associated with FOB development. These challenges will likely involve more complexity than comparability assessments of process changes made by the same manufacturer. The history of industry-regulator comparability discussions helps explain why the same degree of testing and flexibility now applied to change-control within a manufacturer's own process, at this time, cannot be extrapolated to the observed and possibly unknown differences between two manufacturing processes that are independently developed by different (non-collaborating) parties., Objectives: This commentary provides recommendations on the technical aspects that should be considered in the creation of an approval pathway for FOB products., Conclusions: In the authors' view, analytical methodology in its current state cannot alone provide full assurance that the FOB is sufficiently similar to the innovator product. Moreover, the FOB manufacturer will not have access to the extensive knowledge accumulated by the innovator manufacturer from early development through marketing. Thus, extensive clinical evaluation will likely be necessary to provide assurance that the FOB is safe and efficacious. If such testing demonstrates the FOB is safe and efficacious per existing regulatory standards, the product should receive marketing approval as a 'similar' product. Since 'similarity' is a fundamentally different determination than establishing interchangeability between the two products, an interchangeability determination must be based on additional testing and market experience to ensure patient safety. Post-marketing surveillance of the FOB should be conducted to ensure that the approved molecule has similar clinical safety and efficacy as the innovator product, prior to any consideration of interchangeability.

Pre-clinical studies indicate that pharmacologic agents can augment fracture union. If these pharmacologic approaches could be translated into clinical benefit and offered to patients with osteoporosis or patients with other risks for impaired fracture union (e.g. in subjects with large defects or open fractures with high complication rate), they could provide an important adjunct to the treatment of fractures. However, widely accepted guidelines are important to encourage the conduct of studies to evaluate bioactive substances, drugs, and new agents that may promote fracture union and subsequent return to normal function. A consensus process was initiated to provide recommendations for the clinical evaluation of potential therapies to augment fracture repair in patients with meta- and diaphyseal fractures. Based on the characteristics of fracture healing and fixation, the following study objectives of a clinical study may be appropriate: a) acceleration of fracture union, b) acceleration of return to normal function and c) reduction of fracture healing complications. The intended goal(s) should determine subsequent study methodology. While an acceleration of return to normal function or a reduction of fracture healing complications in and of themselves may be sufficient primary study endpoints for a phase 3 pivotal study, acceleration of fracture union alone is not. Radiographic evaluation may either occur at multiple time points during the healing process with the aim of measuring the time taken to reach a defined status (e.g. cortical bridging of three cortices or disappearance of fracture lines), or could be obtained at a single pre-determined timepoint, were patients are expected to reach a common clinical milestone (i.e. pain free full weight-bearing in weight-bearing fracture cases). Validated Patient Reported Outcomes (PRO's) measures will need to support the return to normal function co-primary endpoints. If reduction of complication rate (e.g. non-union) is the primary objective, the anticipated complications must be defined in the study protocol, along with their possible associations with the specified fracture type and fixation device. The study design should be randomized, parallel, double-blind, and placebo-controlled, and all fracture subjects should receive a standardized method of fracture fixation, defined as Standard of Care.

It is widely accepted that hip and spine fractures are associated with substantial morbidity, but there is growing awareness that other fractures are under-recognized. The incidence of nonspinal, nonhip fractures is higher than for hip fractures because they occur at an earlier age. Furthermore, the incidence of nonspinal, nonhip fractures exceeds that of hip fractures in men and women >80 years old. Nonspinal, nonhip fractures are associated with considerable morbidity. On average, women with humeral, ankle, distal forearm, and foot fractures experience substantial numbers of limited activity days, and nonspinal, nonhip fractures account for almost a third of health care expenditures attributable to osteoporotic fractures. Nonspinal, nonhip fractures are associated with low bone mineral density, thus it may be possible to identify those at risk. Because these fractures also are indicative of increased risk at other sites, those susceptible might benefit from assessments including these other fracture types. It is the clinician's responsibility to attend to and recognize that nonspinal, nonhip fractures are usually associated with osteoporosis and should be treated.

Unlabelled: FE modeling was used to estimate the biomechanical effects of teriparatide and alendronate on lumbar vertebrae. Both treatments enhanced predicted vertebral strength by increasing average density. This effect was more pronounced for teriparatide, which further increased predicted vertebral strength by altering the distribution of density within the vertebra, preferentially increasing the strength of the trabecular compartment., Introduction: Teriparatide 20 microg/day (TPTD) and alendronate 10 mg/day (ALN) increase areal, measured by DXA, and volumetric, measured by QCT, lumbar spine BMD through opposite effects on bone remodeling. Using finite element (FE) modeling of QCT scans, we sought to compare the vertebral strength characteristics in TPTD- and ALN-treated patients., Materials and Methods: A subset of patients (N = 28 TPTD; N = 25 ALN) from the Forteo Alendronate Comparator Trial who had QCT scans of the spine at baseline and postbaseline were analyzed. The QCT scans were analyzed for compressive strength of the L(3) vertebra using FE modeling. In addition, using controlled parameter studies of the FE models, the effects of changes in density, density distribution, and geometry on strength were calculated, a strength:density ratio was determined, and a response to bending was also quantified., Results: Both treatments had positive effects on predicted vertebral strength characteristics. At least 75% of the patients in each treatment group had increased strength of the vertebra at 6 months compared with baseline. Patients in both treatment groups had increased average volumetric density and increased strength in the trabecular bone, but the median percentage increases for these parameters were 5- to 12-fold greater for TPTD. Larger increases in the strength:density ratio were also observed for TPTD, and these were primarily attributed to preferential increases in trabecular strength., Conclusions: These results provide new insight into the effects of these treatments on estimated biomechanical properties of the vertebra. Both treatments positively affected predicted vertebral strength through their effects on average BMD, but the magnitudes of the effects were quite different. Teriparatide also affected vertebral strength by altering the distribution of density within the vertebra, so that overall, teriparatide had a 5-fold greater percentage increase in the strength:density ratio.

Introduction: Teriparatide is a bone formation agent that increases bone turnover and mass, resulting in an increase in bone strength and a decrease in fracture risk., Methods: The primary purpose of this analysis was to evaluate the association between pretreatment bone turnover marker (BTM) concentrations and the absolute and relative fracture risks after adjusting for baseline femoral neck BMD, number of prevalent vertebral fractures, and age. Because femoral neck BMD is commonly attained in the assessment of patients at risk for osteoporosis, we examined the ability of a multivariate assessment including pretreatment BTM concentration and femoral neck BMD to predict future fracture risk after adjusting for the number of prevalent vertebral fractures. We examined data from the Fracture Prevention Trial, a study designed to determine the effect of teriparatide 20 mcg/day and teriparatide 40 mcg/day on vertebral and nonvertebral fracture risk in postmenopausal women with osteoporosis. BTM were analyzed in two subsets of women within the Fracture Prevention Trial, and included serum bone-specific alkaline phosphatase (BSAP), serum carboxy-terminal extension peptide of procollagen type I (PICP), serum amino-terminal extension peptide of procollagen type I (PINP), urinary free deoxypyridinoline (DPD), and urinary N-terminal telopeptide (NTX)., Results: Teriparatide significantly reduced the risk of fracture [four BTM subset (n = 520), placebo = 14.3%, teriparatide = 5.8%, P < 0.05; PINP subset (n = 771), placebo = 17.7%, teriparatide = 5.5%, P < 0.05]. Subjects with the highest pretreatment BTM concentrations had the greatest fracture risk. Teriparatide-mediated absolute risk reduction was greatest for women with high pretreatment bone turnover; however, the relative fracture risk reduction was independent of pretreatment bone turnover. After adjusting for pretreatment BTM and number of prevalent vertebral fractures, baseline femoral neck BMD was not a significant predictor of fracture risk., Conclusion: Teriparatide-mediated relative fracture risk reduction was independent of pretreatment bone turnover, demonstrating that this therapy offers clinical benefit to patients across a range of disease severity.

Introduction: Vertebral fracture is currently underdiagnosed, despite its common severity and its value to predict further osteoporotic fracture. Morphometry using dual X-ray absorptiometry (DXA) [vertebral fracture assessment (VFA)] is a new technique that may facilitate detection of many vertebral fractures, as images are obtained at the same time as bone mineral density (BMD) measurement, and would also allow avoiding spine radiographs., Methods: We conducted a cross-sectional study to assess the diagnostic value of Instant Vertebral Assessment (IVA), which is a morphometry scan using the Hologic Delphi densitometer, to detect prevalent vertebral fracture in postmenopausal women. Interobserver precision was assessed, then IVA scans were compared with lateral spine radiographs, considered the gold standard, to test diagnostic agreement between the two techniques. Sensitivity, specificity and predictive values were calculated, as well as the likelihood ratio of the positive test, using sensitivity and specificity at each vertebral level., Results: Among 85 patients of whom 50% had at least one vertebral fracture identified with radiographs, we found that interobserver precision was moderate, with frequent difficulties in discerning upper thoracic vertebrae. On a per-vertebra basis, sensitivity was around 70% from L4 to T11 and lower above T11 whereas specificity was above 90% for all vertebrae, and the negative predictive value remained above 80% from L4 to T7 and decreased above T7. On a per-patient basis, sensitivity was 0.69, specificity 0.74, positive predictive value equalled 0.72 and negative predictive value 0.71. When only grades 2 and 3 fractures were considered, results were comparable, with slightly improved specificity. Then, with the likelihood ratios calculated in our sample, we obtained posttest probabilities using the prevalence of vertebral fracture at lumbar and thoracic levels in a large sample of postmenopausal women with osteopenia and osteoporosis with and without vertebral fracture [baseline data in women of the Multiple Outcomes on Raloxifene Evaluation (MORE) trial]. At levels where fractures were most common, likelihood ratios of the positive test were good or excellent, associated with sizeable posttest probabilities., Conclusion: IVA allowed diagnosis of vertebral fracture at levels where vertebral fracture were most common, i.e., the lumbar and mid and lower thoracic levels, but its value was weaker at the upper thoracic levels.

Unlabelled: A follow-up in 1262 women was conducted after the discontinuation of teriparatide. The hazard ratio for combined teriparatide group (20 and 40 microg) for the 50-month period after baseline was 0.57 (p = 0.002), suggesting a sustained effect in reducing the risk of nonvertebral fragility fracture., Introduction: Treatment with teriparatide [rhPTH(1-34)] 20 and 40 microg once-daily subcutaneous dosing significantly reduced the risk of nonvertebral fragility fractures over a median exposure of 19 months., Materials and Methods: All participants in the Fracture Prevention Trial were invited to participate in a follow-up study. Prior treatment assignments were revealed, and patients were able to receive osteoporosis treatments without restriction., Results: Approximately 60% of the 1262 patients received an osteoporosis treatment at some time during follow-up, with greater use in the former placebo group than in the combined former teriparatide group (p < 0.05). The hazard ratios for nonvertebral fragility fractures in each teriparatide group relative to placebo were statistically significant for the 50-month period including treatment and follow-up (p < 0.03). In the follow-up period, the hazard ratio was significantly different between the 40 mug and combined groups versus placebo but not for the 20 microg group versus placebo. However, the 20 and 40 microg groups were not different from each other. Kaplan-Meier analysis of time to fracture showed that the fracture incidence in the former placebo and teriparatide groups diverged during the 50-month period including teriparatide treatment and follow-up (p = 0.009). Total hip and femoral neck BMD decreased in teriparatide-treated patients who had no follow-up treatment; BMD remained stable or further increased in patients who received a bisphosphonate after teriparatide treatment., Conclusions: While the study design is observational, the results support a sustained effect of teriparatide in reducing the risk of nonvertebral fragility fractures up to 30 months after discontinuation of treatment.

Objectives: The Group for the Respect and Excellence in Science (GREES) has reviewed and updated their recommendations for clinical trials to evaluate the efficacy and safety of new chemical entities to be used in the treatment and prevention of glucocorticoid-induced osteoporosis (GIOP)., Methods: Consensus discussion of the committee., Results: With the exception of steroid use posttransplantation, there is no need to differentiate between underlying diseases. Prevention and treatment for GIOP are dependent on exposure to glucocorticoids rather than T-scores as in postmenopausal osteoporosis (PMO). If fracture data are obtained for PMO, it need not be repeated for GIOP, relying instead on bone mineral density (BMD) trials of at least 1 year. GREES recommends several changes in the previous guidance for GIOP. The committee saw no need to repeat preclinical studies if those have been previously done to assure bone quality in PMO. Similarly, phase I and phase II trials, if careful dose selection has been done for PMO, should not be repeated. The "prevention" and "treatment" claims should remain. Since the most recent evidence suggests significant increase in fracture risk for daily doses of prednisone of 5 mg/day or equivalent, clinical trials should concentrate on patients receiving at least this daily dosage. The emergence of bisphosphonates as the reference treatment, together with the rapid bone loss and high fracture incidence in glucocorticoid users, necessitates recommending a noninferiority trial design with lumbar spine BMD as the primary endpoint after 1 year., Conclusions: Registration of new chemical entities to be used in the management of GIOP should be granted, based on a 1-year noninferiority trial, using BMD as primary outcome and alendronate or risedronate as comparator. Demonstration of antifracture efficacy should have been previously demonstrated in PMO.

Teriparatide (rhPTH[1-34]), a bone-forming agent for the treatment of osteoporosis, increases bone mineral density in men and women, and reduces the risk of fractures in women with osteoporosis. However, fracture efficacy has not yet been confirmed in men. Further, there is limited information on the effect of withdrawal of teriparatide. The purpose of this manuscript is to report on bone mineral density and vertebral fracture incidence during a 42-month observation period, from the baseline of the previously reported treatment study in men [1] through 30 months of posttreatment follow-up. Three hundred fifty-five men who were treated with once-daily self-injections of either placebo or 20 or 40 microg of teriparatide participated in the follow-up study. Bone mineral density gradually decreased following discontinuation of teriparatide therapy. However, the lumbar spine and total hip values remained significantly higher than baseline after 30 months of follow-up (p< or =0.001). Antiresorptive treatment prevented the decline and tended to further increase bone mineral density. Lateral thoracic lumbar radiographs obtained at baseline and 18 months after discontinuation of teriparatide were available for 279 men. Of these men, 11.7% assigned to placebo, 5.4% treated with teriparatide 20 microg, and 6.0% treated with teriparatide 40 microg had an incident vertebral fracture. In the combined teriparatide treated groups vs placebo, the risk of vertebral fracture was reduced 51% (nonsignificant, p=0.07). The incidence of moderate or severe fractures was significantly reduced by 83% (p=0.01). In conclusion, men who received teriparatide and who may have received follow-up antiresorptive therapy had a decreased risk of moderate and severe vertebral fractures.

Background: Teriparatide (recombinant human parathyroid hormone [1-34]) reduces fracture risk in postmenopausal women with osteoporosis. We assessed the safety and incidence of new vertebral fractures after withdrawal of teriparatide., Methods: This study is a follow-up to the Fracture Prevention Trial (FPT), a randomized, placebo-controlled study of postmenopausal women with osteoporosis treated with teriparatide (20 or 40 microg) once daily for a mean of 18 months. More than 90% of the women remaining at the end of the FPT continued into the follow-up study (n = 1262). Patients and investigators were unblinded to original treatment group assignment. Women were treated according to standard clinical practice, including elective use of osteoporosis drugs. New vertebral fractures were determined by semiquantitative scoring of lateral thoracic lumbar spine radiographs 18 months after the end of the FPT., Results: During the follow-up study, the reduction in fracture risk associated with previous treatment with teriparatide, 20 and 40 microg, was 41% (P = .004) and 45% (P = .001), respectively, vs placebo. The absolute reduction from the FPT baseline to the 18-month follow-up visit was 13% for both doses. Osteoporosis drugs were used by 47% of women during follow-up, with greater use in the former placebo group (P = .04); nevertheless, persistent fracture protection of previous teriparatide therapy was evident. Post hoc analysis also suggests that teriparatide treatment substantially reduced the increased risk of subsequent fracture in women who sustained a fracture during the FPT (P = .05)., Conclusion: Vertebral fracture risk reduction by teriparatide administration persists for at least 18 months after discontinuation of therapy.

Unlabelled: Histomorphometry and microCT of 51 paired iliac crest biopsy specimens from women treated with teriparatide revealed significant increases in cancellous bone volume, cancellous bone connectivity density, cancellous bone plate-like structure, and cortical thickness, and a reduction in marrow star volume., Introduction: We studied the ability of teriparatide (rDNA origin) injection [rhPTH(1-34), TPTD] to improve both cancellous and cortical bone in a subset of women enrolled in the Fracture Prevention Trial of postmenopausal women with osteoporosis after a mean treatment time of 19 months. This is the first report of a biopsy study after treatment with teriparatide having a sufficient number of paired biopsy samples to provide quantitative structural data., Methods: Fifty-one paired iliac crest bone biopsy specimens (placebo [n = 19], 20 microg teriparatide [n = 18], and 40 microg teriparatide [n = 14]) were analyzed using both two-dimensional (2D) histomorphometry and three-dimensional (3D) microcomputed tomography (microCT). Data for both teriparatide treatment groups were pooled for analysis., Results and Conclusions: By 2D histomorphometric analyses, teriparatide significantly increased cancellous bone volume (median percent change: teriparatide, 14%; placebo, -24%; p = 0.001) and reduced marrow star volume (teriparatide, -16%; placebo, 112%; p = 0.004). Teriparatide administration was not associated with osteomalacia or woven bone, and there were no significant changes in mineral appositional rate or wall thickness. By 3D cancellous and cortical bone structural analyses, teriparatide significantly decreased the cancellous structure model index (teriparatide, -12%; placebo, 7%; p = 0.025), increased cancellous connectivity density (teriparatide, 19%; placebo, - 14%; p = 0.034), and increased cortical thickness (teriparatide, 22%; placebo, 3%; p = 0.012). These data show that teriparatide treatment of postmenopausal women with osteoporosis significantly increased cancellous bone volume and connectivity, improved trabecular morphology with a shift toward a more plate-like structure, and increased cortical bone thickness. These changes in cancellous and cortical bone morphology should improve biomechanical competence and are consistent with the substantially reduced incidences of vertebral and nonvertebral fractures during administration of teriparatide.

Recent advances in the use of parathyroid hormone as a therapeutic agent include a controlled trial that assessed vertebral and non-vertebral fracture risk reduction in women, trials in men, and assessment of treatment on cortical and trabecular bone structure. The occurrence of osteosarcoma in long-term toxicology studies in rats is briefly reviewed.

Although low absolute values of bone mineral density (BMD) predict increased fracture risk in osteoporosis, it is not certain how well increases in BMD with antiresorptive therapy predict observed reductions in fracture risk. This work examines the relationships between changes in BMD after 1 year or 3 years of raloxifene or placebo therapy and the risk for new vertebral fractures at 3 years. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis were randomized to placebo or raloxifene 60 mg/day or 120 mg/day. Relationships between baseline BMD and changes in BMD from baseline with the risk of new vertebral fractures were analyzed in this cohort using logistic regression models with the raloxifene doses pooled. As has been observed in other populations, women with the lowest baseline lumbar spine or femoral neck BMD in the MORE cohort had the greatest risk for vertebral fractures. Furthermore, for any percentage change, either increase or decrease in femoral neck or lumbar spine BMD at 1 year or 3 years, raloxifene-treated patients had a statistically significantly lower vertebral fracture risk compared with placebo-treated patients. The decrease in fracture risk with raloxifene was similar across the range of percentage change in femoral neck BMD observed at 3 years; patients receiving raloxifene had a 36% lower risk of vertebral fracture compared with those receiving placebo. At any percentage change in femoral neck and lumbar spine BMD observed at 1 year, raloxifene treatment decreased the risks of new vertebral fractures at 3 years by 38% and 41%, respectively. The logistic regression model showed that the percentage changes in BMD with raloxifene treatment accounted for 4% of the observed vertebral fracture risk reduction, and the other 96% of the risk reduction remains unexplained. The present data show that the measured BMD changes observed with raloxifene therapy are poor predictors of vertebral fracture risk reduction with raloxifene therapy.

Selective estrogen receptor modulators (SERMs) are structurally diverse compounds that bind to estrogen receptors (ER) and elicit agonist or antagonist responses depending on the target tissue and hormonal milieu. They are being evaluated primarily for conditions associated with aging, including hormone-responsive cancer, osteoporosis and cardiovascular disease. Several SERMs are marketed or are in clinical development, including triphenylethylenes (tamoxifen and its derivatives: toremifene, droloxifene and idoxifene), chromans (levormeloxifene), benzothiophenes (raloxifene, LY353381) and naphthalenes (CP336,156). Tamoxifen and toremifene, both used to treat advanced breast cancer, also have beneficial effects on bone mineral density and serum lipids in postmenopausal women. Tamoxifen was recently shown to decrease the risk of invasive breast cancer in women at high risk. Unfortunately, both drugs also have stimulatory effects on the endometrium. Raloxifene, used for prevention of postmenopausal osteoporosis and fragility fractures, also has favourable effects on bone mineral density, serum lipids and the incidence of invasive breast cancer in postmenopausal women but does not stimulate the endometrium. Like replacement estrogens, SERMs increase the risk of venous thromboembolism. SERMs offer post-menopausal women many of the advantages of estrogen replacement while mitigating some of the disadvantages, particularly the concern over breast cancer. Newer SERMs, exemplified by raloxifene, also eliminate the concerns over endometrial stimulation that were not addressed by first generation SERMs. The clinical success of SERMs has set the stage for a variety of drug therapies based on selective modulation of nuclear receptor activity.

Biochemical markers of bone metabolism (bone markers) are used increasingly to monitor response to therapy and may be predictors of bone loss and fractures. The relationship between fracture rates, which differ between countries, and the rate of bone turnover has not been examined. Therefore, we explored the geographic variability of bone turnover in a selected, healthy study population of 619 postmenopausal women, ages 40-61, participating in a clinical trial of raloxifene hydrochloride for osteoporosis prevention. The subjects were distributed among 38 investigative sites in 10 countries (9-211 subjects/country) on four continents (North America, n = 277, Europe, n = 168, Australia, n = 125, and Africa, n = 49). Specimens for serum osteocalcin (OC), bone-specific alkaline phosphatase (BSAP), and urine type I collagen fragment/urinary creatinine ratio (CTX) were handled in a uniform fashion and assayed in a central laboratory. Mean levels of OC (P < 0.001), BSAP (P = 0. 006), and CTX (P < 0.001) varied significantly by country (ANOVA), with the lowest values typically in German and Spanish subjects and the highest in American and Canadian subjects. The consistent pattern and wide ranges of mean bone marker values (OC 1.6-fold, BSAP 1.7-fold, CTX 3.1-fold) between countries suggest clinically significant differences in bone turnover. Geographic differences in bone markers were not explained by the determined potential confounders of age, years posthysterectomy, total serum cholesterol, and serum follicle stimulating hormone (FSH). We conclude that bone marker values vary substantially by country in this selected study population, suggesting systematic geographic differences in bone metabolism that potentially relate to osteoporotic fracture rates.

Background: Long-term estrogen therapy can reduce the risk of osteoporotic fracture and cardiovascular disease in postmenopausal women. At present, however, these beneficial effects are not separable from undesirable stimulation of breast and endometrial tissues., Methods: We studied the effect of raloxifene, a nonsteroidal benzothiophene, on bone mineral density, serum lipid concentrations, and endometrial thickness in 601 postmenopausal women. The women were randomly assigned to receive 30, 60, or 150 mg of raloxifene or placebo daily for 24 months., Results: The women receiving each dose of raloxifene had significant increases from base-line values in bone mineral density of the lumbar spine, hip, and total body, whereas those receiving placebo had decreases in bone mineral density. For example, at 24 months, the mean (+/-SE) difference in the change in bone mineral density between the women receiving 60 mg of raloxifene per day and those receiving placebo was 2.4+/-0.4 percent for the lumbar spine, 2.4+/-0.4 percent for the total hip, and 2.0+/-0.4 percent for the total body (P<0.001 for all comparisons). Serum concentrations of total cholesterol and low-density lipoprotein cholesterol decreased in all the raloxifene groups, whereas serum concentrations of high-density lipoprotein cholesterol and triglycerides did not change. Endometrial thickness was similar in the raloxifene and placebo groups at all times during the study. The proportion of women receiving raloxifene who reported hot flashes or vaginal bleeding was not different from that of the women receiving placebo., Conclusions: Daily therapy with raloxifene increases bone mineral density, lowers serum concentrations of total and low-density lipoprotein cholesterol, and does not stimulate the endometrium.

Selective estrogen receptor modulators (SERMs) comprise a group of structurally diverse compounds which are distinguished from estrogens by their ability to interact with the estrogen receptor but to act as either an estrogen agonist or antagonist depending on the target tissue and hormonal milieu. The mechanisms by which SERMs elicit tissue-specific responses are being intensively investigated, and recently a novel pathway for estrogen receptor-mediated gene activation by the SERM raloxifene has been demonstrated. The tissue-specific activity of SERMs suggests that they may be clinically useful as, for example, potential substitutes for long-term female hormone replacement therapy. Large-scale clinical testing currently in progress for raloxifene, and soon to begin for other SERMs, will evaluate this important potential.

Although daily injections of parathyroid hormone (PTH) can rapidly reverse estrogen-deficiency bone loss in rats, PTH treatment of osteoporotic humans has to date produced more modest increases in bone mass. To explore the reasons for this important difference, we evaluated the dose- and time-dependence of human PTH 1-84 treatment effects on bone mass and biochemical markers of bone metabolism in rats with estrogen-deficiency bone loss. The highest doses of PTH increased spinal, femoral, and total skeletal mass to supra-normal levels and stimulated cortical endosteal bone formation. Spine and whole skeleton mass and density increased rapidly at first, but then increased more slowly; the rate of change decreased significantly (p < 0.01) during continued treatment with the highest doses of PTH. The effects of PTH treatment on biochemical markers also were both dose-dependent and time-dependent. Serum osteocalcin, a marker of osteoblast function, increased with the highest doses of PTH (p < 0.001), but reached an early plateau and later returned toward baseline. Urinary excretion of pyridinolines, a marker of osteoclast function, increased in a time-dependent fashion throughout treatment (p < 0.001). Serum 1,25(OH)2 vitamin D levels increased in a dose-related fashion, but then decreased toward control levels despite continued treatment. We demonstrate that both osteoblast and osteoclast function are increased during daily PTH therapy in the rat. The pattern of response depends on both the dose of PTH and the duration of therapy. These dose- and time-related effects should be taken into account when designing experimental PTH treatments for osteoporosis, and they deserve intensive study.

Platelet-derived growth factor (PDGF), an osteoblast mitogen, has been demonstrated to accelerate fracture healing and periodontal bone repair when applied locally in vivo. To explore whether PDGF could stimulate bone formation in intact bone, we administered it systemically to rats rendered acutely estrogen-deficient. Because PDGF may stimulate bone resorption in vitro, PDGF was administered with and without an antiresorptive agent (alendronate). All treatments were given by intravenous injection 3 times a week for 6 weeks. Spinal bone mineral density (BMD) decreased by 5% in the vehicle-treated ovariectomized (OVX) rats by the end of the study as determined by DXA. Treatment with PDGF prevented this bone loss and significantly (p < 0.05) increased the bone density in the spine (9%) and whole skeleton (5.8%). Combined treatment with PDGF and alendronate resulted in a greater increase at the spine (18%) and whole skeleton (12.8%) than either agent alone. Histomorphometric analysis demonstrated that treatment with PDGF increased the osteoblast number and osteoblast perimeter without consistent changes in osteoclast estimates. Biomechanical testing demonstrated that PDGF administration increased the vertebral body compressive strength and femoral shaft torsional stiffness and resulted in a trend for enhanced femoral head shearing strength. Coadministration of alendronate further increased these indices of bone strength. PDGF administration also caused premature closure of the growth plate, decreased body fat, and resulted in extraskeletal collagen deposition. We therefore demonstrate, for the first time, that systemic administration of PDGF can increase bone density and strength throughout the skeleton.