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Cosman F.,Helen Hayes Hospital | Cosman F.,Columbia University | Eriksen E.F.,University of Oslo | Recknor C.,United Osteoporosis Centers | And 9 more authors.
Journal of Bone and Mineral Research | Year: 2011

Clinical data suggest concomitant therapy with bisphosphonates and parathyroid hormone (PTH) may blunt the anabolic effect of PTH; rodent models suggest that infrequently administered bisphosphonates may interact differently. To evaluate the effects of combination therapy with an intravenous infusion of zoledronic acid 5mg and daily subcutaneous recombinant human (rh)PTH(1-34) (teriparatide) 20μg versus either agent alone on bone mineral density (BMD) and bone turnover markers, we conducted a 1-year multicenter, multinational, randomized, partial double-blinded, controlled trial. 412 postmenopausal women with osteoporosis (mean age 65±9 years) were randomized to a single infusion of zoledronic acid 5mg plus daily subcutaneous teriparatide 20μg (n=137), zoledronic acid alone (n=137), or teriparatide alone (n=138). The primary endpoint was percentage increase in lumbar spine BMD (assessed by dual-energy X-ray absorptiometry [DXA]) at 52 weeks versus baseline. Secondary endpoints included change in BMD at the spine at earlier time points and at the total hip, trochanter, and femoral neck at all time points. At week 52, lumbar spine BMD had increased 7.5%, 7.0%, and 4.4% in the combination, teriparatide, and zoledronic acid groups, respectively (p<.001 for combination and teriparatide versus zoledronic acid). In the combination group, spine BMD increased more rapidly than with either agent alone (p<.001 versus both teriparatide and zoledronic acid at 13 and 26 weeks). Combination therapy increased total-hip BMD more than teriparatide alone at all times (all p<.01) and more than zoledronic acid at 13 weeks (p<.05), with final 52-week increments of 2.3%, 1.1%, and 2.2% in the combination, teriparatide, and zoledronic acid groups, respectively. With combination therapy, bone formation (assessed by serum N-terminal propeptide of type I collagen [PINP]) increased from 0 to 4 weeks, declined minimally from 4 to 8 weeks, and then rose throughout the trial, with levels above baseline from 6 to 12 months. Bone resorption (assessed by serum β-C-telopeptide of type I collagen [β-CTX]) was markedly reduced with combination therapy from 0 to 8 weeks (a reduction of similar magnitude to that seen with zoledronic acid alone), followed by a gradual increase after week 8, with levels remaining above baseline for the latter half of the year. Levels for both markers were significantly lower with combination therapy versus teriparatide alone (p<.002). Limitations of the study included its short duration, lack of endpoints beyond DXA-based BMD (e.g., quantitative computed tomography and finite-element modeling for bone strength), lack of teriparatide placebo, and insufficient power for fracture outcomes. We conclude that while teriparatide increases spine BMD more than zoledronic acid and zoledronic acid increases hip BMD more than teriparatide, combination therapy provides the largest, most rapid increments when both spine and hip sites are considered. © 2011 American Society for Bone and Mineral Research. Copyright © 2011 American Society for Bone and Mineral Research.


MacIntyre N.J.,McMaster University | Recknor C.P.,United Osteoporosis Centers | Grant S.L.,United Osteoporosis Centers | Recknor J.C.,United Osteoporosis Centers
Osteoporosis International | Year: 2014

Summary: The Safe Functional Motion test (SFM) was developed to document movement strategies used to perform everyday activities that may increase the risk for osteoporotic fracture. After adjusting for variables known to predict vertebral compression fracture (VCF), baseline score on the SFM was a significant independent predictor of incident VCF at 1- and 3-year follow-ups. Introduction: Functionalmovementsmay contribute to risk for VCF. We hypothesize that scores on the SFM, a performance-based test of physical function, are associated with incident VCF. Methods: An osteoporosis clinic database was queried formen and women ≥50 years with an initial SFM and corresponding data for prevalent VCF, history of injurious falls, femoral neck bone mineral density (fnBMD), osteoporosis medication use, and incidentmorphometric VCF at 1-year (n=878) and 3-year follow-ups (n=503). Multiple logistic regressions, adjusted for gender, age, injurious fall(s), fnBMD, prevalent VCF at baseline, and osteoporosis medication use, were used to determine whether SFMscore was associated with incident VCF at follow-up visits. Results: Baseline SFM score was a significant independent predictor of incident VCF at 1-year follow-up (adjusted odds ratio (95% confidence intervals (CI))=0.818 (0.707, 0.948); p<0.008) and 3-year follow-up (adjusted odds ratio (95% CI)=0.728 (0.628, 0.844); p<0.0001). Baseline fnBMD and osteoporosis medication use were significant predictors at 1-year (p=0.05 and <0.0001, respectively) and 3-year (p<0.01 and 0.001, respectively) follow-ups. At 3-year follow-up, gender and prevalent VCF were also significant predictors (p=0.003 and 0.007, respectively). Conclusions: For every 10-point increase in SFM score, the odds of future VCF decreases by 18% at 1 year and 27% at 3 years after adjusting for known covariates. The SFM may aid in the identification of modifiable functional risk factors for VCF. © International Osteoporosis Foundation and National Osteoporosis Foundation 2013.


Wark J.D.,Royal Melbourne Hospital | Bensen W.,McMaster University | Recknor C.,United Osteoporosis Centers | Ryabitseva O.,Regional Hospital No 1 | And 3 more authors.
Osteoporosis International | Year: 2012

Summary: Patients treated with intravenous zoledronic acid 5 mg for osteoporosis may experience post-dose influenza-like symptoms. Oral acetaminophen/paracetamol or ibuprofen administered 4 h post-infusion reduced the proportion of patients with increased oral temperature and worsening post-infusion symptom scores vs. placebo, thus providing an effective strategy for the treatment of such symptoms. Introduction: Once-yearly intravenous zoledronic acid 5 mg is a safe and effective treatment for postmenopausal osteoporosis. This study assessed whether transient influenza-like post-dose symptoms associated with intravenous infusion of zoledronic acid can be reduced by post-dose administration of acetaminophen/paracetamol or ibuprofen. Methods: In an international, multicenter, randomized, double-blind, double-dummy parallel-group study, bisphosphonate-naïve postmenopausal women with osteopenia (n = 481) were randomized to receive zoledronic acid 5 mg + acetaminophen/paracetamol (n = 135), ibuprofen (n = 137) or placebo (n = 137), or placebo + placebo (n = 72). Acetaminophen/paracetamol and ibuprofen were administered every 6 h for 3 days beginning 4 h post-infusion. Results: The proportion of patients with increased oral temperature (≥1°C above 37.5°C) and with worsening post-infusion symptom scores over 3 days was significantly lower in patients receiving ibuprofen (36.8% and 48.5%) or acetaminophen/paracetamol (37.3% and 46.3%) vs. those receiving placebo (63.5% and 75.9%, respectively; all p < 0.0001) compared with background rates of 11.1% and 16.7%, respectively, in the absence of any active treatment. Overall incidence of adverse events was comparable for patients receiving acetaminophen/paracetamol or ibuprofen. Conclusion: Oral acetaminophen/ paracetamol or ibuprofen effectively managed the transient influenza-like symptoms associated with zoledronic acid 5 mg. © 2011 International Osteoporosis Foundation and National Osteoporosis Foundation.


Brown J.P.,University of Québec | Roux C.,University of Paris Descartes | Torring O.,Karolinska Institutet | Ho P.-R.,Amgen Inc. | And 7 more authors.
Journal of Bone and Mineral Research | Year: 2013

Osteoporosis is a chronic disease and requires long-term treatment with pharmacologic therapy to ensure sustained antifracture benefit. Denosumab reduced the risk for new vertebral, nonvertebral, and hip fractures over 36 months in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. Whereas discontinuation of denosumab has been associated with transient increases in bone remodeling and declines in bone mineral density (BMD), the effect on fracture risk during treatment cessation is not as well characterized. To understand the fracture incidence between treatment groups after cessation of investigational product, we evaluated subjects in FREEDOM who discontinued treatment after receiving two to five doses of denosumab or placebo, and continued study participation for ≥7 months. The off-treatment observation period for each individual subject began 7 months after the last dose and lasted until the end of the study. This subgroup of 797 subjects (470 placebo, 327 denosumab), who were evaluable during the off-treatment period, showed similar baseline characteristics for age, prevalent fracture, and lumbar spine and total hip BMD T-scores. During treatment, more placebo-treated subjects as compared with denosumab-treated subjects sustained a fracture and had significant decreases in BMD. During the off-treatment period (median 0.8 years per subject), 42% versus 28% of placebo- and denosumab-treated subjects, respectively, initiated other therapy. Following discontinuation, similar percentages of subjects in both groups sustained a new fracture (9% placebo, 7% denosumab), resulting in a fracture rate per 100 subject-years of 13.5 for placebo and 9.7 for denosumab (hazard ratio [HR] 0.82; 95% confidence interval [CI], 0.49-1.38), adjusted for age and total hip BMD T-score at baseline. There was no apparent difference in fracture occurrence pattern between the groups during the off-treatment period. In summary, there does not appear to be an excess in fracture risk after treatment cessation with denosumab compared with placebo during the off-treatment period for up to 24 months. Copyright © 2013 American Society for Bone and Mineral Research.


Recknor C.,United Osteoporosis Centers | Czerwinski E.,Jagiellonian University | Bone H.G.,Jagiellonian University | Bonnick S.L.,Jagiellonian University | And 10 more authors.
Obstetrics and Gynecology | Year: 2013

OBJECTIVE: To compare the efficacy and safety of denosumab to ibandronate in postmenopausal women with low bone mineral density (BMD) previously treated with a bisphosphonate. METHODS: In a randomized, open-label study, postmenopausal women received 60 mg denosumab sub-cutaneously every 6 months (n=417) or 150 mg ibandronate orally every month (n=416) for 12 months. End points included percentage change from baseline in total hip, femoral neck, and lumbar spine BMD at month 12 and percentage change from baseline in serum C-telopeptide at months 1 and 6 in a substudy. RESULTS: At month 12, significantly greater BMD gains from baseline were observed with denosumab compared with ibandronate at the total hip (2.3% compared with 1.1%), femoral neck (1.7% compared with 0.7%), and lumbar spine (4.1% compared with 2.0%; treatment difference P<.001 at all sites). At month 1, median change in serum C-telopeptide from baseline was 281.1% with denosumab and -35.0% with ibandronate (P<.001); the treatment difference remained significant at month 6 (P<.001). Adverse events occurred in 245 (59.6%) denosumab-treated women and 230 (56.1%) ibandronate-treated women (P=.635). The incidence of serious adverse events was 9.5% for denosumab-treated women and 5.4% for ibandronate-treated women (P=.046). No clustering of events in any organ system accounted for the preponderance of these reports. The incidence rates of serious adverse events involving infection and malignancy were similar between treatment groups. CONCLUSION: In postmenopausal women previously treated with a bisphosphonate and low BMD, denosumab treatment resulted in greater BMD increases than ibandronate at all measured sites. No new safety risks with denosumab treatment were identified. © 2013 by The American College of Obstetricians and Gynecologists.


Devogelaer J.-P.,Catholic University of Louvain | Adler R.A.,ire Medical Center | Recknor C.,United Osteoporosis Centers | See K.,Eli Lilly and Company | And 3 more authors.
Journal of Rheumatology | Year: 2010

Objective. This post-hoc analysis studied the effect of baseline glucocorticoid dose on the 18-month bone mineral density (BMD) response to teriparatide 20 μg/day or alendronate 10 mg/day in 387 patients with glucocorticoid-induced osteoporosis (GIO) from a randomized, double-blind trial. Methods. Lumbar spine (LS), femoral neck (FN), and total hip (TH) BMD were measured at baseline and 18 months. Mean baseline glucocorticoid dose was categorized as low (≤ 5 mg/day), medium (> 5 and < 15 mg/day), or high (≥ 15 mg/day). Results. Baseline LS, FN, and TH BMD were similar between groups, and between glucocorticoid dose categories within each group. LS BMD increases at the low, medium, and high glucocorticoid doses were 8.1%, 6.6%, and 4.6%, respectively, with teriparatide, and 3.6%, 2.8%, and 2.3% with alendronate.Analyzed as a continuous variable, higher glucocorticoid doses had a negative, but nonsignificant, effect on the percentage increase in LS BMD in both groups. Glucocorticoid dose did not significantly affect FN or TH BMD increases in either group. Across the 3 glucocorticoid dose categories, the overall LS BMD increases were different for both treatments combined (p = 0.033), but the relative differences between the treatment groups were not different (interaction, p = 0.52). Conclusion. Teriparatide and alendronate increased LS and hip BMD across a range of baseline glucocorticoid doses. LS BMD increases with teriparatide were greater in the low-dose category than in the high-dose category. Overall LS BMD increases were significantly greater with teriparatide compared with alendronate, which may reflect the respective anabolic and antiresorptive mechanisms of action. Clinical Trial Registry Number: NCT00051558. The Journal of Rheumatology Copyright © 2010. All rights reserved.


Recknor C.,United Osteoporosis Centers
Expert Opinion on Pharmacotherapy | Year: 2011

Introduction: Osteoporosis (OP) is associated with a high risk of fracture and disability and with substantial medical costs. This paper is a review of the intravenous (i.v.) bisphosphonate zoledronic acid 5 mg (ZOL), used in the treatment and prevention of OP. Areas covered: This is a review of the scientific literature, between 2003 and 2010, on the use of ZOL in patients with low bone mass or OP. Expert opinion: ZOL, given as a single infusion once yearly, has proven efficacy in reducing risk of vertebral and hip fractures in postmenopausal women with OP. In men and women with a recent hip fracture, ZOL has been shown to reduce the incidence of future clinical fractures. Data also demonstrate an increase in bone mineral density in postmenopausal women with osteopenia, in men with OP, and in patients at risk for glucocorticoid-induced osteoporosis. The ZOL clinical program has shown this agent to be safe and generally well tolerated. Acute flu-like symptoms may occur following the first infusion of ZOL, but these are generally mild and transient, and decrease in frequency with subsequent infusions. Patients must have adequate renal function (creatinine clearance ≥ 35 ml/min) and be adequately hydrated prior to infusion. With orally administered bisphosphonates, patient compliance and persistence with weekly or monthly dosing are frequently suboptimal. The ability to administer i.v. ZOL once yearly over 15 min for the treatment of OP provides the advantage of guaranteeing medication compliance for the duration of the dosing interval. © 2011 Informa UK, Ltd.


Aspenberg P.,Linköping University | Genant H.K.,University of California at San Francisco | Genant H.K.,Synarc Inc. | Johansson T.,Linköping University | And 10 more authors.
Journal of Bone and Mineral Research | Year: 2010

Animal experiments show a dramatic improvement in skeletal repair by teriparatide. We tested the hypothesis that recombinant teriparatide, at the 20 μg 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 μg (n=34) or teriparatide 40 mg (n=34) within 10 days of fracture. Hypotheses were tested sequentially, beginning with the teriparatide 40 μg 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 μg and 40μg, respectively (overall p=.015). There was no significant difference between the teriparatide 40 μg versus placebo groups (p=.523). In post hoc analyses, there was no significant difference between teriparatide 40 μg versus 20 μg (p=.053); however, the time to healing was shorter in teriparatide 20 mg than placebo (p=.006). The primary hypothesis that teriparatide 40 μg would shorten the time to cortical bridging was not supported. The shortened time to healing for teriparatide 20 μg 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. © 2010 American Society for Bone and Mineral Research.


Keaveny T.M.,University of California at Berkeley | McClung M.R.,Oregon Osteoporosis Center | Genant H.K.,University of California at San Francisco | Genant H.K.,Synarc Inc. | And 13 more authors.
Journal of Bone and Mineral Research | Year: 2014

In the randomized, placebo-controlled FREEDOM study of women aged 60 to 90 years with postmenopausal osteoporosis, treatment with denosumab once every 6 months for 36 months significantly reduced hip and new vertebral fracture risk by 40% and 68%, respectively. To gain further insight into this efficacy, we performed a nonlinear finite element analysis (FEA) of hip and spine quantitative computed tomography (QCT) scans to estimate hip and spine strength in a subset of FREEDOM subjects (n = 48 placebo; n = 51 denosumab) at baseline, 12, 24, and 36 months. We found that, compared with baseline, the finite element estimates of hip strength increased from 12 months (5.3%; p < 0.0001) and through 36 months (8.6%; p < 0.0001) in the denosumab group. For the placebo group, hip strength did not change at 12 months and decreased at 36 months (-5.6%; p < 0.0001). Similar changes were observed at the spine: strength increased by 18.2% at 36 months for the denosumab group (p < 0.0001) and decreased by -4.2% for the placebo group (p = 0.002). At 36 months, hip and spine strength increased for the denosumab group compared with the placebo group by 14.3% (p < 0.0001) and 22.4% (p < 0.0001), respectively. Further analysis of the finite element models indicated that strength associated with the trabecular bone was lost at the hip and spine in the placebo group, whereas strength associated with both the trabecular and cortical bone improved in the denosumab group. In conclusion, treatment with denosumab increased hip and spine strength as estimated by FEA of QCT scans compared with both baseline and placebo owing to positive treatment effects in both the trabecular and cortical bone compartments. These findings provide insight into the mechanism by which denosumab reduces fracture risk for postmenopausal women with osteoporosis. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.


Recknor C.P.,United Osteoporosis Centers | Recker R.R.,Creighton University | Benson C.T.,Eli Lilly and Company | Robins D.A.,Eli Lilly and Company | And 9 more authors.
Journal of Bone and Mineral Research | Year: 2015

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.

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