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Benjamin Z Leder - One of the best experts on this subject based on the ideXlab platform.
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comparison of Teriparatide and denosumab in patients switching from long term bisphosphonate use
The Journal of Clinical Endocrinology and Metabolism, 2019Co-Authors: Houchen Lyu, Benjamin Z Leder, Sizheng Steven Zhao, Kazuki Yoshida, Sara K Tedeschi, Sagar U Nigwekar, Daniel H SolomonAbstract:Context Teriparatide and denosumab are effective treatments for osteoporosis and typically reserved as second-line options after patients have used bisphosphonates. However, limited head-to-head comparative effectiveness data exist between Teriparatide and denosumab. Objective We compared changes in bone mineral density (BMD) between groups treated with Teriparatide or denosumab after using bisphosphonates, focusing on the change in BMD while on either drug over 2 years. Design Observational cohort study using electronic medical records from two academic medical centers in the United States. Participants The study population included osteoporotic patients >45 years who received bisphosphonates >1 year before switching to Teriparatide or denosumab. Outcome measures Annualized BMD change from baseline at the lumbar spine, total hip, and femoral neck. Results Patients treated with Teriparatide (n = 110) were compared with those treated with denosumab (n = 105); the mean (SD) age was 70 (10) years and median duration (interquartile range) of bisphosphonate use was 7.0 (5.6 to 9.7) years. Compared with denosumab users, Teriparatide users had higher annualized BMD change at the spine by 1.3% (95% CI 0.02, 2.7%) but lower at the total hip by -2.2% (95% CI -2.9 to -1.5%) and the femoral neck by -1.1% (95% CI -2.1 to -0.1%). Those who switched to Teriparatide had a transient loss of hip BMD for the first year, with no overall increase in the total hip BMD over 2 years. Conclusions Among patients who use long-term bisphosphonates, the decision of switching to Teriparatide should be made with caution, especially for patients at high risk of hip fracture.
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effects of Teriparatide denosumab or both on spine trabecular microarchitecture in data switch a randomized controlled trial
Journal of Clinical Densitometry, 2017Co-Authors: Joy N Tsai, Hang Lee, Linda A Jiang, Didier Hans, Benjamin Z LederAbstract:In postmenopausal women, 2 yr of combined Teriparatide and denosumab increases bone mineral density more than either drug alone, and switching from either combination or Teriparatide to denosumab for an additional 2 yr further increases bone mineral density. Conversely, switching from denosumab to Teriparatide results in transient bone loss. The effects of these interventions on spine microarchitecture are unknown. In the DATA and DATA-Switch studies, 94 postmenopausal osteoporotic women were randomized to receive 24 mo of Teriparatide (20 µg daily), denosumab (60 mg every 6 mo), or both. Then, women originally assigned to 24 mo of Teriparatide received 24 mo of denosumab, whereas subjects originally randomized to 24 mo of denosumab received 24 mo of Teriparatide. Subjects who received both drugs received an additional 24 mo of denosumab alone. Spine trabecular bone score (TBS, a gray-level textural assessment of bone microarchitecture) was measured blinded from treatment groups using images from 2-dimensional dual-energy X-ray absorptiometry spine scans at 0, 12, 24, 30, 36, and 48 mo in 65 women who had posterior-anterior spine dual-energy X-ray absorptiometry images suitable for TBS analysis. After 24 mo, TBS increased by 2.7 ± 4.7% in the Teriparatide group (p = 0.009 vs baseline), by 1.8 ± 5.0% in the denosumab group (p = 0.118 vs baseline), and by 4.5 ± 6.7% in the combination group (p = 0.017 vs baseline), with no significant between-group differences. In the 6 mo after the treatments were switched (months 24-30), TBS continued to increase in the combination-to-denosumab and Teriparatide-to-denosumab groups but decreased by -1.1 ± 4.0% in the denosumab-to-Teriparatide group (p < 0.05 vs other groups). After 48 mo, compared to month 0, TBS increased by 5.1 ± 5.8% in the Teriparatide-to-denosumab group, by 3.6 ± 4.2% in the denosumab-to-Teriparatide group, and by 6.1 ± 4.7% in the combination-to-denosumab group (p < 0.001 vs baseline for all groups, p = not significant for between-group differences). Switching from Teriparatide to denosumab also increased spine TBS. Conversely, switching from denosumab to Teriparatide transiently degraded spine trabecular microarchitecture, the clinical consequences of which require further study.
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effects of denosumab and Teriparatide transitions on bone microarchitecture and estimated strength the data switch hr pqct study
Journal of Bone and Mineral Research, 2017Co-Authors: Joy N Tsai, Hang Lee, Kyle K Nishiyama, David Lin, Amy Yuan, Mary L Bouxsein, Benjamin Z LederAbstract:In postmenopausal osteoporosis, switching from Teriparatide to denosumab results in continued bone mineral density (BMD) gains whereas switching from denosumab to Teriparatide results in BMD loss. To assess the effects of these transitions on bone microarchitecture and strength, we performed high-resolution peripheral QCT (HR-pQCT) at the distal tibia and radius in postmenopausal osteoporotic women who received 24-months of Teriparatide 20-mcg daily followed by 24-months of denosumab 60-mg every 6 months, 24-months of denosumab followed by 24-months of Teriparatide, or 24-months of both medications followed by 24-months of denosumab. This article is protected by copyright. All rights reserved
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Response to Therapy With Teriparatide, Denosumab, or Both in Postmenopausal Women in the DATA (Denosumab and Teriparatide Administration) Study Randomized Controlled Trial
Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry, 2016Co-Authors: Benjamin Z Leder, Joy N Tsai, Alexander V Uihlein, Robert M Neer, Paul M. Wallace, Sherri-ann M. Burnett-bowieAbstract:Both antiresorptive and anabolic osteoporosis medications increase bone mineral density (BMD), but no single agent can restore normal bone strength in most osteoporotic patients. Moreover, the magnitude and consistency of the patient response to each individual agent vary depending on the anatomic site. In the DATA study, we reported that in postmenopausal osteoporotic women, 2 years of combined denosumab and Teriparatide increase mean BMD at the hip and spine more than either drug alone. In the current analysis, we wished to determine if the individual rates of BMD response were also greater among women treated with both drugs. In DATA, 94 postmenopausal osteoporotic women (ages 51–91) were randomized to receive Teriparatide (20 mcg subcutaneously daily), denosumab (60 mg subcutaneously every 6 mo), or both medications for 24 mo. The BMD of the total hip (TH), femoral neck (FN), and lumbar spine (LS) were assessed by dual-energy X-ray absorptiometry. The 82 subjects who completed all 2-yr treatments were analyzed. Responders were defined as experiencing BMD increases of >3%. An “excellent response” was defined as an increase of >6%. Over 24 mo, TH BMD increased by >3% in 36%, 53%, and 92% of women in the Teriparatide, denosumab, and combination groups, respectively, and by >6% in 11%, 17%, and 50% in the Teriparatide, denosumab, and combination groups, respectively (p 3% in 85%, 93%, and 100% of women in the Teriparatide, denosumab, and combination groups, respectively (p = nonsignificant for all comparisons) and by >6% in 63%, 78%, and 100% of women in the Teriparatide, denosumab, and combination groups, respectively (combination vs Teriparatide, p = 0.001; combination vs denosumab, p = 0.016). In summary, more women treated with 24 mo of combined denosumab and Teriparatide achieved a significant response at the TH and FN than those treated with either drug alone. All women treated with both agents together experienced an excellent response at the LS. These results support the continued investigation of combined denosumab and Teriparatide therapy in postmenopausal osteoporotic women utilizing clinical endpoints such as fracture reduction.
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denosumab and Teriparatide transitions in postmenopausal osteoporosis the data switch study extension of a randomised controlled trial
The Lancet, 2015Co-Authors: Benjamin Z Leder, Joy N Tsai, Alexander V Uihlein, Paul Wallace, Hang Lee, Robert M Neer, Sherriann M BurnettbowieAbstract:Summary Background Unlike most chronic diseases, osteoporosis treatments are generally limited to a single drug at a fixed dose and frequency. Nonetheless, no approved therapy is able to restore skeletal integrity in most osteoporotic patients and the long-term use of osteoporosis drugs is controversial. Thus, many patients are treated with the sequential use of two or more therapies. The DATA study showed that combined Teriparatide and denosumab increased bone mineral density more than either drug alone. Discontinuing Teriparatide and denosumab, however, results in rapidly declining bone mineral density. In this DATA-Switch study, we aimed to assess the changes in bone mineral density in postmenopausal osteoporotic women who transitioned between treatments. Methods This randomised controlled trial (DATA-Switch) is a preplanned extension of the denosumab and Teriparatide administration study (DATA), in which 94 postmenopausal osteoporotic women were randomly assigned to receive 24 months of Teriparatide (20 mg daily), denosumab (60 mg every 6 months), or both drugs. In DATA-Switch, women originally assigned to Teriparatide received denosumab (Teriparatide to denosumab group), those originally assigned to denosumab received Teriparatide (denosumab to Teriparatide group), and those originally assigned to both received an additional 24 months of denosumab alone (combination to denosumab group). Bone mineral density at the spine, hip, and wrist were measured 6 months, 12 months, 18 months, and 24 months after the drug transitions as were biochemical markers of bone turnover. The primary endpoint was the percent change in posterior-anterior spine bone mineral density over 4 years. Between-group changes were assessed by one-way analysis of variance in our modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00926380. Findings Between Sept 27, 2011, and Jan 28, 2013, eligible women from the DATA study were enrolled into DATA-Switch. Of 83 potential enrollees from the DATA study, 77 completed at least one post-baseline visit. After 48 months, the primary outcome of mean spine bone mineral density increased by 18·3% (95% CI 14·9–21·8) in 27 women in the Teriparatide to denosumab group, 14·0% (10·9–17·2) in 27 women the denosumab to Teriparatide group, and 16·0% (14·0–18·0) in 23 women in the combination to denosumab group, although this increase did not differ significantly between groups (for between-group comparisons, p=0·13 for the Teriparatide to denosumab group vs the denosumab to Teriparatide group, p=0·30 for the Teriparatide to denosumab group vs the combination to denosumab group, and p=0·41 for the denosumab to Teriparatide group vs the combination to denosumab group). For the bone mineral density secondary outcomes, total hip bone mineral density increased more in the Teriparatide to denosumab group (6·6% [95% CI 5·3–7·9]) than in the denosumab to Teriparatide group (2·8% [1·3–4·2], p=0·0002), but had the greatest increase in the combination to denosumab group (8·6% [7·1–10·0]; p=0·0446 vs the Teriparatide to denosumab group, p vs the denosumab to Teriparatide group). Similarly, femoral neck bone mineral density increased more in the Teriparatide to denosumab group (8·3% [95% CI 6·1–10·5]) and the combination to denosumab group (9·1% [6·1–12·0]) than in the denosumab to Teriparatide group (4·9% [2·2–7·5]; p=0·0447 for Teriparatide to denosumab vs denosumab to Teriparatide, p=0·0336 for combination to denosumab vs denosumab to Teriparatide). Differences between the combination to denosumab group and the Teriparatide to denosumab group did not differ significantly (p=0·67). After 48 months, radius bone mineral density was unchanged in the Teriparatide to denosumab group (0·0% [95% CI −1·3 to 1·4]), whereas it decreased by −1·8% (−5·0 to 1·3) in the denosumab to Teriparatide group, and increased by 2·8% (1·2–4·4) in the combination to denosumab group (p=0·0075 for the Teriparatide to denosumab group vs the combination to denosumab group; p=0·0099 for the denosumab to Teriparatide group vs the combination to denosumab group). One participant in the denosumab to Teriparatide group had nephrolithiasis, classified as being possibly related to treatment. Interpretation In postmenopausal osteoporotic women switching from Teriparatide to denosumab, bone mineral density continued to increase, whereas switching from denosumab to Teriparatide results in progressive or transient bone loss. These results should be considered when choosing the initial and subsequent management of postmenopausal osteoporotic patients. Funding Amgen, Eli Lilly, and National Institutes of Health.
Bruce H Mitlak - One of the best experts on this subject based on the ideXlab platform.
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FRAX and the effect of Teriparatide on vertebral and non-vertebral fracture
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteopor, 2015Co-Authors: Nicholas C Harvey, Bruce H Mitlak, Russel Burge, John A. Kanis, Anders Odén, Helena Johansson, Eugene MccloskeyAbstract: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. 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. 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. 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. 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.
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sustained nonvertebral fragility fracture risk reduction after discontinuation of Teriparatide treatment
Journal of Bone and Mineral Research, 2005Co-Authors: Richard L Prince, Adrien Sipos, Anwar Hossain, Unni Syversen, Sophia Ishshalom, Ewa Marcinowska, Johan Halse, Robert Lindsay, Gail P Dalsky, Bruce H MitlakAbstract:A follow-up in 1262 women was conducted after the discontinuation of Teriparatide. The hazard ratio for combined Teriparatide group (20 and 40 μg) 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 μg 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 μg and combined groups versus placebo but not for the 20 μg group versus placebo. However, the 20 and 40 μg 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.
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Teriparatide effects on vertebral fractures and bone mineral density in men with osteoporosis treatment and discontinuation of therapy
Osteoporosis International, 2005Co-Authors: Jean Kaufman, Robert Lindsay, Gail P Dalsky, Eric S Orwoll, Stefan Goemaere, San J Martin, A Hossain, Bruce H MitlakAbstract: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 µg 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≤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 µg, and 6.0% treated with Teriparatide 40 µg 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.
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sustained vertebral fracture risk reduction after withdrawal of Teriparatide in postmenopausal women with osteoporosis
JAMA Internal Medicine, 2004Co-Authors: Robert Lindsay, Robert M Neer, Stephen L Myers, Wim H Scheele, Gerhardt Pohl, Silvano Adami, C Mautalen, Jeanyves Reginster, Jan J Stepan, Bruce H MitlakAbstract: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 µg) 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 µg, 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.
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recombinant human parathyroid hormone 1 34 Teriparatide improves both cortical and cancellous bone structure
Journal of Bone and Mineral Research, 2003Co-Authors: Yebin Jiang, Bruce H Mitlak, Jenny Zhao, Ouhong Wang, Harry K Genant, E F EriksenAbstract:Histomorphometry and CT 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 g Teriparatide (n 18), and 40 g Teriparatide (n 14)) were analyzed using both two-dimensional (2D) histomorphometry and three-dimensional (3D) microcomputed tomography (CT). 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. J Bone Miner Res 2003;18:1932-1941
Robert M Neer - One of the best experts on this subject based on the ideXlab platform.
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Response to Therapy With Teriparatide, Denosumab, or Both in Postmenopausal Women in the DATA (Denosumab and Teriparatide Administration) Study Randomized Controlled Trial
Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry, 2016Co-Authors: Benjamin Z Leder, Joy N Tsai, Alexander V Uihlein, Robert M Neer, Paul M. Wallace, Sherri-ann M. Burnett-bowieAbstract:Both antiresorptive and anabolic osteoporosis medications increase bone mineral density (BMD), but no single agent can restore normal bone strength in most osteoporotic patients. Moreover, the magnitude and consistency of the patient response to each individual agent vary depending on the anatomic site. In the DATA study, we reported that in postmenopausal osteoporotic women, 2 years of combined denosumab and Teriparatide increase mean BMD at the hip and spine more than either drug alone. In the current analysis, we wished to determine if the individual rates of BMD response were also greater among women treated with both drugs. In DATA, 94 postmenopausal osteoporotic women (ages 51–91) were randomized to receive Teriparatide (20 mcg subcutaneously daily), denosumab (60 mg subcutaneously every 6 mo), or both medications for 24 mo. The BMD of the total hip (TH), femoral neck (FN), and lumbar spine (LS) were assessed by dual-energy X-ray absorptiometry. The 82 subjects who completed all 2-yr treatments were analyzed. Responders were defined as experiencing BMD increases of >3%. An “excellent response” was defined as an increase of >6%. Over 24 mo, TH BMD increased by >3% in 36%, 53%, and 92% of women in the Teriparatide, denosumab, and combination groups, respectively, and by >6% in 11%, 17%, and 50% in the Teriparatide, denosumab, and combination groups, respectively (p 3% in 85%, 93%, and 100% of women in the Teriparatide, denosumab, and combination groups, respectively (p = nonsignificant for all comparisons) and by >6% in 63%, 78%, and 100% of women in the Teriparatide, denosumab, and combination groups, respectively (combination vs Teriparatide, p = 0.001; combination vs denosumab, p = 0.016). In summary, more women treated with 24 mo of combined denosumab and Teriparatide achieved a significant response at the TH and FN than those treated with either drug alone. All women treated with both agents together experienced an excellent response at the LS. These results support the continued investigation of combined denosumab and Teriparatide therapy in postmenopausal osteoporotic women utilizing clinical endpoints such as fracture reduction.
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denosumab and Teriparatide transitions in postmenopausal osteoporosis the data switch study extension of a randomised controlled trial
The Lancet, 2015Co-Authors: Benjamin Z Leder, Joy N Tsai, Alexander V Uihlein, Paul Wallace, Hang Lee, Robert M Neer, Sherriann M BurnettbowieAbstract:Summary Background Unlike most chronic diseases, osteoporosis treatments are generally limited to a single drug at a fixed dose and frequency. Nonetheless, no approved therapy is able to restore skeletal integrity in most osteoporotic patients and the long-term use of osteoporosis drugs is controversial. Thus, many patients are treated with the sequential use of two or more therapies. The DATA study showed that combined Teriparatide and denosumab increased bone mineral density more than either drug alone. Discontinuing Teriparatide and denosumab, however, results in rapidly declining bone mineral density. In this DATA-Switch study, we aimed to assess the changes in bone mineral density in postmenopausal osteoporotic women who transitioned between treatments. Methods This randomised controlled trial (DATA-Switch) is a preplanned extension of the denosumab and Teriparatide administration study (DATA), in which 94 postmenopausal osteoporotic women were randomly assigned to receive 24 months of Teriparatide (20 mg daily), denosumab (60 mg every 6 months), or both drugs. In DATA-Switch, women originally assigned to Teriparatide received denosumab (Teriparatide to denosumab group), those originally assigned to denosumab received Teriparatide (denosumab to Teriparatide group), and those originally assigned to both received an additional 24 months of denosumab alone (combination to denosumab group). Bone mineral density at the spine, hip, and wrist were measured 6 months, 12 months, 18 months, and 24 months after the drug transitions as were biochemical markers of bone turnover. The primary endpoint was the percent change in posterior-anterior spine bone mineral density over 4 years. Between-group changes were assessed by one-way analysis of variance in our modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00926380. Findings Between Sept 27, 2011, and Jan 28, 2013, eligible women from the DATA study were enrolled into DATA-Switch. Of 83 potential enrollees from the DATA study, 77 completed at least one post-baseline visit. After 48 months, the primary outcome of mean spine bone mineral density increased by 18·3% (95% CI 14·9–21·8) in 27 women in the Teriparatide to denosumab group, 14·0% (10·9–17·2) in 27 women the denosumab to Teriparatide group, and 16·0% (14·0–18·0) in 23 women in the combination to denosumab group, although this increase did not differ significantly between groups (for between-group comparisons, p=0·13 for the Teriparatide to denosumab group vs the denosumab to Teriparatide group, p=0·30 for the Teriparatide to denosumab group vs the combination to denosumab group, and p=0·41 for the denosumab to Teriparatide group vs the combination to denosumab group). For the bone mineral density secondary outcomes, total hip bone mineral density increased more in the Teriparatide to denosumab group (6·6% [95% CI 5·3–7·9]) than in the denosumab to Teriparatide group (2·8% [1·3–4·2], p=0·0002), but had the greatest increase in the combination to denosumab group (8·6% [7·1–10·0]; p=0·0446 vs the Teriparatide to denosumab group, p vs the denosumab to Teriparatide group). Similarly, femoral neck bone mineral density increased more in the Teriparatide to denosumab group (8·3% [95% CI 6·1–10·5]) and the combination to denosumab group (9·1% [6·1–12·0]) than in the denosumab to Teriparatide group (4·9% [2·2–7·5]; p=0·0447 for Teriparatide to denosumab vs denosumab to Teriparatide, p=0·0336 for combination to denosumab vs denosumab to Teriparatide). Differences between the combination to denosumab group and the Teriparatide to denosumab group did not differ significantly (p=0·67). After 48 months, radius bone mineral density was unchanged in the Teriparatide to denosumab group (0·0% [95% CI −1·3 to 1·4]), whereas it decreased by −1·8% (−5·0 to 1·3) in the denosumab to Teriparatide group, and increased by 2·8% (1·2–4·4) in the combination to denosumab group (p=0·0075 for the Teriparatide to denosumab group vs the combination to denosumab group; p=0·0099 for the denosumab to Teriparatide group vs the combination to denosumab group). One participant in the denosumab to Teriparatide group had nephrolithiasis, classified as being possibly related to treatment. Interpretation In postmenopausal osteoporotic women switching from Teriparatide to denosumab, bone mineral density continued to increase, whereas switching from denosumab to Teriparatide results in progressive or transient bone loss. These results should be considered when choosing the initial and subsequent management of postmenopausal osteoporotic patients. Funding Amgen, Eli Lilly, and National Institutes of Health.
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Comparative Resistance to Teriparatide-Induced Bone Resorption With Denosumab or Alendronate
The Journal of clinical endocrinology and metabolism, 2015Co-Authors: Joy N Tsai, Hang Lee, Robert M Neer, Sherri-ann M. Burnett-bowie, Yuli Zhu, Katelyn Foley, Benjamin Z LederAbstract:Context: In postmenopausal osteoporotic women, denosumab fully inhibits Teriparatide-induced bone resorption at approved doses. This property of denosumab is distinct from that of alendronate and likely contributes to the efficacy of combination denosumab and Teriparatide therapy. Whether denosumab fully inhibits bone resorption when challenged by a higher dose of Teriparatide is unknown. Objective: We aimed to define the comparative ability of denosumab and alendronate to block the acute proresorptive effects of high-dose Teriparatide. Design, Setting, and Participants: In this randomized controlled trial, bone resorption (serum C-telopeptide [CTX]) was measured in 25 postmenopausal women prior to and 4 hours after a single 40-μg sc Teriparatide injection. Subjects then received either a single injection of denosumab 60 mg or oral alendronate 70 mg weekly for 8 weeks. After 8 weeks, serum CTX was again measured before and 4 hours after a Teriparatide a 40-μg injection. Outcomes: The primary outcome was t...
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comparative effects of Teriparatide denosumab and combination therapy on peripheral compartmental bone density microarchitecture and estimated strength the data hrpqct study
Journal of Bone and Mineral Research, 2015Co-Authors: Joy N Tsai, Alexander V Uihlein, Hang Lee, Robert M Neer, Sherriann M Burnettbowie, Yuli Zhu, Mary L Bouxsein, Nicholas P Derrico, Benjamin Z LederAbstract:Combined Teriparatide and denosumab increases spine and hip bone mineral density more than either drug alone. The effect of this combination on skeletal microstructure and microarchitecture, however, is unknown. Because skeletal microstructure and microarchitecture are important components of skeletal integrity, we performed high-resolution peripheral QCT assessments at the distal tibia and radius in postmenopausal osteoporotic women randomized to receive Teriparatide 20-µg daily (n=31), denosumab 60-mg every 6 months (n=33), or both (n=30) for 12 months. In the Teriparatide group, total volumetric BMD (vBMD) did not change at either anatomic site but increased in both other groups at both sites. The increase in vBMD at the tibia was greater in the combination group (3.1±2.2%) than both the denosumab (2.2±1.9%) and Teriparatide groups (−0.3±1.9%) (p<0.02 for both comparisons). Cortical vBMD decreased by 1.6±1.9% at the tibia and by 0.9±2.8% at the radius in the Teriparatide group whereas it increased in both other groups at both sites. Tibia cortical vBMD increased more in the combination group (1.5±1.5%) than both monotherapy groups (p<0.04 for both comparisons). Cortical thickness did not change in the Teriparatide group, but increased in both other groups. The increase in cortical thickness at the tibia was greater in the combination group (5.4±3.9%) than both monotherapy groups (p<0.01 for both comparisons). In the Teriparatide group, radial cortical porosity increased by 20.9±37.6% and by 5.6±9.9% at the tibia but did not change in the other two groups. Bone stiffness and failure load, as estimated by finite element analysis, did not change in the Teriparatide group but increased in the other two groups at both sites. Together, these findings suggest that the use of denosumab and Teriparatide in combination improves HR-pQCT measures of bone quality more than either drug alone and may be of significant clinical benefit in the treatment of postmenopausal osteoporosis.
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Effects of Teriparatide, Alendronate, or Both in Women with Postmenopausal Osteoporosis
The Journal of clinical endocrinology and metabolism, 2010Co-Authors: Joel S. Finkelstein, Hang Lee, Jason J. Wyland, Robert M NeerAbstract:Context: Teriparatide increases both bone formation and bone resorption. Objective: We sought to determine whether combining Teriparatide with an antiresorptive agent would alter its anabolic action. Design and Setting: This was a randomized controlled trial conducted in a single university hospital. Patients and Intervention: We randomized 93 postmenopausal women with low bone mineral density (BMD) to alendronate 10 mg daily (group 1), Teriparatide 40 μg sc daily (group 2), or both (group 3) for 30 months. Teriparatide was begun at month 6. Main Outcome Measures: BMD of the lumbar spine, proximal femur, proximal radius, and total body was measured by dual-energy x-ray absorptiometry (DXA) every 6 months. Lumbar spine trabecular BMD was measured at baseline and month 30 by quantitative computed tomography. Serum osteocalcin, N-terminal propeptide of type 1 collagen, and N-telopeptide levels were assessed frequently. Women who had at least one repeat DXA scan on therapy were included in the analyses (n = 69). Results: DXA spine BMD increased more in women treated with Teriparatide alone than with alendronate alone (18 ± 11 vs. 7 ± 4%; P < 0.001) or both (18±11 vs. 12 ± 9%; P = 0.045). Similarly, femoral neck BMD increased more in women treated with Teriparatide alone than with alendronate alone (11 ± 5 vs. 4 ± 4%; P < 0.001) or both (11 ± 5 vs. 3 ± 5%; P < 0.001). Quantitative computed tomography spine BMD increased 1 ± 7, 61 ± 31, and 24 ± 24% in groups 1, 2, and 3 (P < 0.001 for all comparisons). Serum osteocalcin, N-terminal propeptide of type 1 collagen, and cross-linked N-telopeptides of type I collagen increased more with Teriparatide alone than with both (P < 0.001 for each marker). Conclusion: Alendronate reduces the ability of Teriparatide to increase BMD and bone turnover in women.
Paul D Miller - One of the best experts on this subject based on the ideXlab platform.
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effects of intravenous zoledronic acid plus subcutaneous Teriparatide rhpth 1 34 in postmenopausal osteoporosis
Journal of Bone and Mineral Research, 2011Co-Authors: Felicia Cosman, E F Eriksen, Paul D Miller, Chris Recknor, Nuria Guanabens, Christian Kasperk, Philemon Papanastasiou, Aimee Readie, Hanumantha Rao, Jurg A GasserAbstract: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 5 mg and daily subcutaneous recombinant human (rh)PTH(1-34) (Teriparatide) 20 µg 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 5 mg plus daily subcutaneous Teriparatide 20 µg (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.
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Pharmacokinetics of Teriparatide (rhPTH[1-34]) and Calcium Pharmacodynamics in Postmenopausal Women with Osteoporosis
Calcified tissue international, 2010Co-Authors: Julie Satterwhite, Emmett V Glass, Paul D Miller, Fernando Marin, Michael Heathman, Harald DobnigAbstract:Teriparatide (rhPTH[1–34]) affects calcium metabolism in a pattern consistent with the known actions of endogenous parathyroid hormone (PTH). This report describes the pharmacokinetics and resulting serum calcium response to Teriparatide in postmenopausal women with osteoporosis. Pharmacokinetic samples for this analysis were obtained from 360 women who participated in the Fracture Prevention Trial. Postmenopausal women with osteoporosis received daily subcutaneous injections of either Teriparatide 20 μg (4.86 μmol) or placebo, median 21 months’ treatment. Serum Teriparatide and calcium concentrations were measured throughout the study. An indirect-response model was developed to describe the pharmacokinetic–pharmacodynamic relationship between Teriparatide concentrations and serum calcium response. The pharmacokinetics of Teriparatide were characterized by rapid absorption (maximum concentration achieved within 30 min) and rapid elimination (half-life of 1 h), resulting in a total duration of exposure to the peptide of approximately 4 h. Teriparatide transiently increased serum calcium, with the maximum effect observed at approximately 4.25 h (median increase 0.4 mg/dl [0.1 mmol/l]). Calcium concentrations returned to predose levels by 16–24 h after each dose. Persistent hypercalcemia was not observed; one Teriparatide 20 μg-treated patient had a predose serum calcium value above the normal range but
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pharmacokinetics of Teriparatide rhpth 1 34 and calcium pharmacodynamics in postmenopausal women with osteoporosis
Calcified Tissue International, 2010Co-Authors: Julie Satterwhite, Emmett V Glass, Paul D Miller, Fernando Marin, Michael Heathman, Harald DobnigAbstract:Teriparatide (rhPTH[1–34]) affects calcium metabolism in a pattern consistent with the known actions of endogenous parathyroid hormone (PTH). This report describes the pharmacokinetics and resulting serum calcium response to Teriparatide in postmenopausal women with osteoporosis. Pharmacokinetic samples for this analysis were obtained from 360 women who participated in the Fracture Prevention Trial. Postmenopausal women with osteoporosis received daily subcutaneous injections of either Teriparatide 20 μg (4.86 μmol) or placebo, median 21 months’ treatment. Serum Teriparatide and calcium concentrations were measured throughout the study. An indirect-response model was developed to describe the pharmacokinetic–pharmacodynamic relationship between Teriparatide concentrations and serum calcium response. The pharmacokinetics of Teriparatide were characterized by rapid absorption (maximum concentration achieved within 30 min) and rapid elimination (half-life of 1 h), resulting in a total duration of exposure to the peptide of approximately 4 h. Teriparatide transiently increased serum calcium, with the maximum effect observed at approximately 4.25 h (median increase 0.4 mg/dl [0.1 mmol/l]). Calcium concentrations returned to predose levels by 16–24 h after each dose. Persistent hypercalcemia was not observed; one Teriparatide 20 μg-treated patient had a predose serum calcium value above the normal range but <11.0 mg/dl (2.75 mmol/l). Following once-daily subcutaneous administration, Teriparatide produces a modest but transient increase in serum calcium, consistent with the known effects of endogenous PTH on mineral metabolism. The excursion in serum calcium is brief, due to the short length of time that Teriparatide concentrations are elevated.
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change in lumbar spine bmd and vertebral fracture risk reduction in Teriparatide treated postmenopausal women with osteoporosis
Journal of Bone and Mineral Research, 2006Co-Authors: Peiqi Chen, Derek A. Misurski, Paul D Miller, Pierre D Delmas, John H KregeAbstract:Increases in lumbar spine BMD account for 30–41% of the vertebral fracture risk reduction with Teriparatide treatment. The remaining fracture risk reduction is caused by improvements in non-BMD determinants of bone strength. Introduction: Changes in BMD account for a small percentage of the fracture risk reduction seen in patients treated with antiresorptive drugs. The relationship between changes in lumbar spine BMD and vertebral fracture risk reduction with Teriparatide treatment has not been assessed. Materials and Methods: The relationship between spine BMD and the risk of new vertebral fractures after Teriparatide treatment was assessed using data from the Fracture Prevention Trial. Postmenopausal women with osteoporosis (n = 1637) were randomized to placebo or Teriparatide 20 or 40 μg/day for a median of 19 months. Spine BMD was assessed at baseline and 18 months. Vertebrae whose fracture status changed during the trial were removed from the calculation of BMD. Baseline and endpoint lateral spine radiographs were assessed using a visual semiquantitative technique. Results: Both the baseline and change in spine BMD were contributors to vertebral fracture risk. The mean spine BMD increase in Teriparatide-treated patients was 0.09 g/cm2 across tertiles of baseline spine BMD. Compared with placebo, Teriparatide significantly reduced the risk of new vertebral fracture for all endpoint BMD values. Teriparatide-mediated increases in spine BMD accounted for 30% (in the low baseline spine BMD tertile) to 41% (in the high baseline spine BMD tertile) of the reduction in vertebral fracture risk. Conclusions: Increases in BMD account for approximately one third of the vertebral fracture risk reduction seen with Teriparatide. The majority of the risk reduction, however, results from improvements in non-BMD determinants of bone strength.
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opposite bone remodeling effects of Teriparatide and alendronate in increasing bone mass
JAMA Internal Medicine, 2005Co-Authors: Michael R Mcclung, Gail P Dalsky, Molly Omizo, Paul D Miller, David W Donley, Javier San Martin, Roberto Civitelli, Francisco Bandeira, E F EriksenAbstract:Background: Antiresorptive agents for the treatment of osteoporosis suppress bone remodeling and reestablish bone turnover at a lower rate to reduce bone loss. Recombinant Teriparatide (human parathyroid hormone 1-34) stimulates bone formation, increases bone mass, and improves bone microarchitecture. We contrasted the effects of once-daily doses of 20 µg of Teriparatide and 10 mg of alendronate sodium on bone mineral density (BMD) and markers of bone turnover. Methods: Markers of bone turnover and areal BMD were assessed in 203 postmenopausal women with osteoporosis in an 18-month randomized parallel double-blind study; volumetric BMD was measured in a subset of women. Results: Teriparatide significantly increased markers of bone turnover that peaked at 6 months (serum procollagen type I N-terminal propeptide, 218%, and urinary N-telopeptide corrected for creatinine, 58%; P.001); alendronate significantly decreased the markers at 6 months (�67% and �72%, respectively; P.001). At 18 months, areal and volumetric spine BMDs were significantly higher with Teriparatide than with alendronate (10.3% vs 5.5% [P.001] and 19.0% vs 3.8% [P.01], respectively). Areal femoral neck BMD was significantly higher than baseline in the Teriparatide and alendronate groups (3.9% and 3.5%, respectively). There were no significant differences in trabecular femoral neck BMD between the Teriparatide and alendronate groups (4.9% and 2.2%, respectively). Cortical volumetric femoral neck BMD was significantly different between the Teriparatide and alendronate groups (–1.2% and 7.7%, respectively;P=.05). Conclusion: Two distinct options for the management of osteoporosis lead to increases in BMD by opposite mechanisms of action on bone remodeling.
E F Eriksen - One of the best experts on this subject based on the ideXlab platform.
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effects of intravenous zoledronic acid plus subcutaneous Teriparatide rhpth 1 34 in postmenopausal osteoporosis
Journal of Bone and Mineral Research, 2011Co-Authors: Felicia Cosman, E F Eriksen, Paul D Miller, Chris Recknor, Nuria Guanabens, Christian Kasperk, Philemon Papanastasiou, Aimee Readie, Hanumantha Rao, Jurg A GasserAbstract: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 5 mg and daily subcutaneous recombinant human (rh)PTH(1-34) (Teriparatide) 20 µg 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 5 mg plus daily subcutaneous Teriparatide 20 µg (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.
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Teriparatide increases bone formation in modeling and remodeling osteons and enhances igf ii immunoreactivity in postmenopausal women with osteoporosis
Journal of Bone and Mineral Research, 2006Co-Authors: Yanfei L, Gail P Dalsky, Qingqiang Zeng, David W Donley, Louis Georges Stemarie, Christopher J Gallagher, Robert Marcus, E F EriksenAbstract:Transiliac bone biopsies were obtained from 55 women treated with Teriparatide or placebo for 12–24 months. We report direct evidence that modeling bone formation at quiescent surfaces was present only in Teriparatide-treated patients and bone formation at remodeling sites was higher with Teriparatide than placebo. Introduction: Recombinant Teriparatide [human PTH(1-34)], a bone formation agent for the treatment of osteoporosis when given once daily subcutaneously, increases biochemical markers of bone turnover and activation frequency in histomorphometry studies. Materials and Methods: We studied the mechanisms underlying this bone-forming action of Teriparatide at the basic multicellular unit by the appearance of cement lines, a method used to directly classify surfaces as modeling or remodeling osteons, and by the immunolocalization of IGF-I and IGF-II. Transiliac bone biopsies were obtained from 55 postmenopausal women treated with Teriparatide 20 or 40 μg or placebo for 12–24 months (median, 19.8 months) in the Fracture Prevention Trial. Results: A dose-dependent relationship was observed in modeling and mixed remodeling/modeling trabecular hemiosteons. Trabecular and endosteal hemiosteon mean wall thicknesses were significantly higher in both Teriparatide groups than in placebo. There was a dose-dependent relationship in IGF-II immunoreactive staining at all bone envelopes studied. The greater local IGF-II presence after treatment with Teriparatide may play a key role in stimulating bone formation. Conclusions: Direct evidence is presented that 12–24 months of Teriparatide treatment induced modeling bone formation at quiescent surfaces and resulted in greater bone formation at remodeling sites, relative to placebo.
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combination Teriparatide and raloxifene therapy for postmenopausal osteoporosis results from a 6 month double blind placebo controlled trial
Journal of Bone and Mineral Research, 2005Co-Authors: Chad L Deal, E F Eriksen, Molly Omizo, Elliott N Schwartz, Per Cantor, Jingyuan Wang, Emmett V Glass, Stephen L Myers, John H KregeAbstract:We compared combination treatment with Teriparatide plus raloxifene with Teriparatide alone in women with postmenopausal osteoporosis in a 6-month double-blind, placebo-controlled trial that measured biochemical markers of bone turnover and BMD. Markers of bone formation and spine BMD increased similarly with Teriparatide alone and combination therapy. However, combination therapy induced a significantly smaller increase in bone resorption versus Teriparatide alone and significantly increased total hip BMD versus baseline. Introduction: The effects of combining two approved treatments for osteoporosis with different modes of action were examined by comparing Teriparatide [rhPTH(1–34)] monotherapy with combination Teriparatide and raloxifene therapy. Materials and Methods: A 6-month randomized, double-blind trial comparing Teriparatide plus raloxifene (n = 69) versus Teriparatide plus placebo (n = 68) was conducted in postmenopausal women with osteoporosis. Results: Bone formation (N-terminal propeptide of type 1 collagen [PINP]) increased similarly in both treatment groups. However, the increase in bone resorption (serum C-terminal telopeptide of type I collagen [CTx]) in the combination group was significantly smaller than in the Teriparatide-alone group (p = 0.015). Lumbar spine BMD significantly increased 5.19 ± 0.67% from baseline in the Teriparatide-alone group. In the combination group, lumbar spine (6.19 ± 0.65%), femoral neck (2.23 ± 0.64%), and total hip (2.31 ± 0.56%) BMD significantly increased from baseline to study endpoint, and the increase in total hip BMD was significantly greater than in the Teriparatide-alone group (p = 0.04). In the Teriparatide-alone group, mean serum calcium levels increased from baseline to endpoint (0.30 ± 0.06 mg/dl, p < 0.001), whereas mean serum phosphate remained unchanged. In the combination group, mean serum calcium was unchanged, and mean serum phosphate decreased (−0.20 ± 0.06 mg/dl, p < 0.001) from baseline to endpoint. Changes in serum calcium (p < 0.001) and phosphate (p < 0.004) were significantly different between treatment groups. The safety profile of combination therapy was similar to Teriparatide alone. Conclusions: Combination therapy increased bone formation to a similar degree as Teriparatide alone. However, the increase in bone resorption was significantly less and total hip BMD significantly increased for combination therapy compared with Teriparatide alone. Combination treatment with raloxifene may thus enhance the bone forming effects of Teriparatide. Further studies over longer treatment duration that include fracture endpoints are necessary to fully ascertain the clinical significance of combination raloxifene plus Teriparatide therapy in postmenopausal osteoporosis.
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opposite bone remodeling effects of Teriparatide and alendronate in increasing bone mass
JAMA Internal Medicine, 2005Co-Authors: Michael R Mcclung, Gail P Dalsky, Molly Omizo, Paul D Miller, David W Donley, Javier San Martin, Roberto Civitelli, Francisco Bandeira, E F EriksenAbstract:Background: Antiresorptive agents for the treatment of osteoporosis suppress bone remodeling and reestablish bone turnover at a lower rate to reduce bone loss. Recombinant Teriparatide (human parathyroid hormone 1-34) stimulates bone formation, increases bone mass, and improves bone microarchitecture. We contrasted the effects of once-daily doses of 20 µg of Teriparatide and 10 mg of alendronate sodium on bone mineral density (BMD) and markers of bone turnover. Methods: Markers of bone turnover and areal BMD were assessed in 203 postmenopausal women with osteoporosis in an 18-month randomized parallel double-blind study; volumetric BMD was measured in a subset of women. Results: Teriparatide significantly increased markers of bone turnover that peaked at 6 months (serum procollagen type I N-terminal propeptide, 218%, and urinary N-telopeptide corrected for creatinine, 58%; P.001); alendronate significantly decreased the markers at 6 months (�67% and �72%, respectively; P.001). At 18 months, areal and volumetric spine BMDs were significantly higher with Teriparatide than with alendronate (10.3% vs 5.5% [P.001] and 19.0% vs 3.8% [P.01], respectively). Areal femoral neck BMD was significantly higher than baseline in the Teriparatide and alendronate groups (3.9% and 3.5%, respectively). There were no significant differences in trabecular femoral neck BMD between the Teriparatide and alendronate groups (4.9% and 2.2%, respectively). Cortical volumetric femoral neck BMD was significantly different between the Teriparatide and alendronate groups (–1.2% and 7.7%, respectively;P=.05). Conclusion: Two distinct options for the management of osteoporosis lead to increases in BMD by opposite mechanisms of action on bone remodeling.
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effects of Teriparatide rhpth 1 34 treatment on structural geometry of the proximal femur in elderly osteoporotic women
Bone, 2005Co-Authors: Kirsti Uusirasi, E F Eriksen, Masahiko Sato, Lisa M Semanick, J R Zanchetta, Cesar E Bogado, Thomas J BeckAbstract:Abstract Introduction: We evaluated effects of Teriparatide (rDNA origin) injection [Teriparatide, rhPTH (1–34), TPTD] on hip structure among a subset 558 postmenopausal women enrolled in the Fracture Prevention Trial. Methods: Patients were randomized to once-daily, self-administered subcutaneous injections of placebo (N = 189), Teriparatide 20 μg (TPTD20; N = 186), or 40 μg (TPTD40; N = 183) for a median of 20 months. Repeated dual energy X-ray absorptiometry (DXA) hip scans were analyzed with the Hip Structure Analysis (HSA) program to derive structural geometry. Results and conclusions: There were no significant differences in age or body size between groups at baseline, 1 year, or study termination. At the femoral neck, Teriparatide increased bone mass and improved bone geometric strength in both treatment groups compared to the placebo group, with the response being dose-related. The mean difference (95% CI) in bone cross-sectional area (CSA) in the TPTD20 was 3.5% (1.8% to 5.3%), and 6.3% (4.5% to 8.2%) in TPTD40 at study termination, compared to placebo controls. Teriparatide treatment increased bending strength, with the mean difference in section modulus being 3.6% (1.4% to 5.8%) and 6.8% (4.6% to 9.1%) greater in the TPTD20 and TPTD40 groups, respectively. Compared to placebo, local cortical instability characterized by the buckling ratio decreased by 5.5% (3.5% to 7.5%) and 8.6% (6.6% to 10.5%) in the TPTD20 and TPTD40 groups, respectively, during the study period. The changes at the intertrochanteric region were comparable to those at the narrow neck although between-group differences were slightly smaller. Except for an inconsequential (1%) improvement in section modulus in TPTD20, Teriparatide effects did not reach significance at the femoral shaft. In conclusion, Teriparatide treatment improved axial and bending strength, and increased cortical thickness and stability at the femoral neck and intertrochanteric region. Teriparatide treatment effects were not apparent at the purely cortical femoral shaft.
