Differential Effects of Teriparatide and Denosumab on Intact PTH and Bone Formation Indices: AVA Osteoporosis Study.
Ontology highlight
ABSTRACT:
SUBMITTER: Dempster DW
PROVIDER: S-EPMC4880160 | biostudies-literature | 2016 Apr
REPOSITORIES: biostudies-literature
Publications
Differential Effects of Teriparatide and Denosumab on Intact PTH and Bone Formation Indices: AVA Osteoporosis Study.
Dempster David W DW Zhou Hua H Recker Robert R RR Brown Jacques P JP Recknor Christopher P CP Lewiecki E Michael EM Miller Paul D PD Rao Sudhaker D SD Kendler David L DL Lindsay Robert R Krege John H JH Alam Jahangir J Taylor Kathleen A KA Janos Boris B Ruff Valerie A VA
The Journal of clinical endocrinology and metabolism 20160209 4
We compared effects of teriparatide and denosumab on PTH, bone turnover markers, and bone histomorphometry in osteoporotic postmenopausal women. The findings were inconsistent with an early indirect anabolic effect of denosumab. ...[more]
Similar Datasets
Project description:IntroductionOsteoporosis is one of the serious adverse effects associated with glucocorticoid therapy. Although bisphosphonates have been used for glucocorticoid-induced osteoporosis (GIO), some patients have shown an inadequate response. In such cases, denosumab or teriparatide are used. However, there is no consensus on which of these two drugs is superior. We prospectively compared denosumab's and teriparatide's effects on the bone mineral density (BMD) in GIO patients with prior bisphosphonate treatment.Materials and methodsAfter receiving oral bisphosphonates for ≥2 years, GIO patients with low T-score BMD (<-2.5) were switched from bisphosphonates to denosumab (n = 20) or daily teriparatide (n = 21). We measured the BMD (lumbar spine, femoral neck, and total hip) in both groups every 6 months for 24 months.ResultsAt 24 months of treatment, the lumbar spine BMD increased significantly from baseline in both the denosumab and teriparatide groups (baseline vs. denosumab and teriparatide; 5.9 ± 5.6%, P < 0.001 and 7.9 ± 5.4%, P < 0.001). A significant increase in femoral neck BMD from baseline occurred only in the teriparatide group (6.6 ± 10.8%, P < 0.05); denosumab (1.5 ± 5.0%). No significant changes occurred in the total hip BMD from baseline in either group (-0.1 ± 5.6% and 3.3 ± 7.5%, respectively). There was no significant difference between the denosumab and teriparatide groups at 24 months in lumbar spine and femoral neck BMD, but was significantly higher in the teriparatide group at 12 months (P < 0.01 and P < 0.05 in the lumbar spine and femoral neck, respectively).ConclusionTeriparatide might have some advantages over denosumab and be a good alternative for treating GIO patients with prior bisphosphonate treatment.
| S-EPMC7352055 | biostudies-literature
Project description:ContextIn 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.ObjectiveWe aimed to define the comparative ability of denosumab and alendronate to block the acute proresorptive effects of high-dose teriparatide.Design, setting, and participantsIn 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.OutcomesThe primary outcome was the between-group difference in the teriparatide-induced change in CTX from baseline to week 8.ResultsAt baseline, 40 μg of teriparatide induced similar 4-hour increases in mean CTX in both groups (alendronate 47% ± 14%, denosumab 46% ± 16%). After 8 weeks, teriparatide was still able to stimulate bone resorption in women treated with alendronate (mean CTX increase of 43% ± 29%) but not in women treated with denosumab (-7% ± 11%; P < .001 for between group comparison).ConclusionsDenosumab, but not alendronate, fully inhibits the ability of high-dose teriparatide to increase bone resorption acutely. These results suggest that combining denosumab with a more potent anabolic stimulus may result in greater separation between bone resorption and formation and hence greater increases in bone mass.
| S-EPMC5393530 | biostudies-literature
Project description:Daily 20-?g and once-weekly 56.5-?g teriparatide (parathyroid hormone 1-34) treatment regimens increase bone mineral density (BMD) and prevent fractures, but changes in bone turnover markers differ between the two regimens. The aim of the present study was to explain changes in bone turnover markers using once-weekly teriparatide with a simulation model. Temporary increases in bone formation markers and subsequent decreases were observed during once-weekly teriparatide treatment for 72 weeks. These observations support the hypothesis that repeated weekly teriparatide administration stimulates bone remodeling, replacing old bone with new bone and leading to a reduction in the active remodeling surface. A simulation model was developed based on the iterative remodeling cycle that occurs on residual old bone. An increase in bone formation and a subsequent decrease were observed in the preliminary simulation. For each fitted time point, the predicted value was compared to the absolute values of the bone formation and resorption markers and lumbar BMD. The simulation model strongly matched actual changes in bone turnover markers and BMD. This simulation model indicates increased bone formation marker levels in the early stage and a subsequent decrease. It is therefore concluded that remodeling-based bone formation persisted during the entire treatment period with once-weekly teriparatide.
| S-EPMC4472137 | biostudies-literature
Project description:ObjectivesIn our previous 24-month study, we observed that teriparatide had some advantages over denosumab for bone mineral density (BMD) in glucocorticoid-induced osteoporosis (GIO) patients with prior bisphosphonate treatment. We conducted this extension study to investigate whether the advantage of teriparatide obtained in the first 2 years would be maintained after the switch to denosumab.Materials and methodsWe switched patients who had completed 24-month daily teriparatide treatment to denosumab (switch group, n=18) and compared their BMD every 6 months up to 48 months with the group who continued to receive denosumab (denosumab group, n=16).ResultsAt 48 months, the lumbar spine BMD was significantly increased from baseline in both groups (denosumab: 10.4 ± 8.7%, p<0.001; switch: 14.2 ± 6.8%, p<0.001). However, a significant increase in femoral neck BMD from baseline occurred only in the switch group (11.2 ± 14.6%, p<0.05); denosumab (4.1 ± 10.8%). The total hip BMD increased significantly from baseline in both groups (denosumab: 4.60 ± 7.4%, p<0.05; switch: 7.2 ± 6.9%, p<0.01). Femoral neck BMD was significantly increased in the switch versus the denosumab group (p<0.05).ConclusionIn GIO patients with prior bisphosphonate treatment, the advantage of teriparatide may be maintained after the treatment period. A continuous increase in BMD can be expected with teriparatide followed by denosumab.
| S-EPMC8503555 | biostudies-literature
Project description:Without antiresorptive therapy, postmenopausal women lose bone mass after teriparatide (TPTD) discontinuation; estrogen treatment prevents bone loss in this setting. It is not known whether premenopausal women with regular menses lose bone mass after teriparatide discontinuation.This study aimed to test the hypothesis that normally menstruating premenopausal women with idiopathic osteoporosis (IOP) will maintain teriparatide-associated bone mineral density (BMD) gains after medication cessation.Twenty-one premenopausal IOP women previously enrolled in an open-label pilot study of teriparatide (20 mcg for 18-24 mo), had substantial BMD increases at the lumbar spine (LS; 10.8 ± 8.3%), total hip (TH; 6.2 ± 5.6%), and femoral neck (7.6 ± 3.4%). For this study, BMD was remeasured 2.0 ± 0.6 years after teriparatide cessation.Fifteen women, who had gained 11.1 ± 7.2% at LS and 6.1 ± 6.5% at TH and were premenopausal at teriparatide completion, were followed without antiresorptive treatment.Two years after completing teriparatide, BMD declined by 4.8 ± 4.3% (P = .0007) at the LS. In contrast, BMD remained stable at the femoral neck (-1.5 ± 4.2%) and TH (-1.1 ± 3.7%). Those who sustained LS bone loss >3% (-7.3 ± 2.9%; n = 10), did not differ from those with stable LS BMD (0.1 ± 1.1%; n=5) with regard to baseline body mass index, BMD at any site, or duration of followup, but were significantly older at re-evaluation (46 ± 3 vs 38 ± 7; P = .046), had larger increases in LS BMD during teriparatide treatment and higher cancellous bone remodeling on transiliac biopsy at baseline and completion of teriparatide treatment. Serum bone turnover markers did not differ at baseline or teriparatide completion, but tended to be higher at the re-evaluation timepoint in those with post-teriparatide bone loss.These findings lead us to conclude that premenopausal women with IOP, particularly those over 40, may require antiresorptive treatment to prevent bone loss after teriparatide.
| S-EPMC4702457 | biostudies-literature
Project description:BACKGROUND:Osteoporosis medications increase bone-mineral density (BMD) and lower but do not eliminate fracture risk. The combining of anabolic agents with bisphosphonates has not improved efficacy. We compared combined teriparatide and denosumab with both agents alone. METHODS:From September, 2009, to January, 2011, we enrolled postmenopausal women with osteoporosis into this randomised, controlled trial. Patients were assigned in a 1:1:1 ratio to receive 20 ?g teriparatide daily, 60 mg denosumab every 6 months, or both. BMD was measured at 0, 3, 6, and 12 months. Women who completed at least one study visit after baseline were assessed in a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00926380. FINDINGS:94 (94%) of 100 eligible women completed at least one study visit after baseline. At 12 months, posterior-anterior lumbar spine BMD increased more in the combination group (9·1%, [SD 3·9]) than in the teriparatide (6·2% [4·6], p=0·0139) or denosumab (5·5% [3·3], p=0·0005) groups. Femoral-neck BMD also increased more in the combination group (4·2% [3·0]) than in the teriparatide (0·8% [4·1], p=0·0007) and denosumab (2·1% [3·8], p=0·0238) groups, as did total-hip BMD (combination, 4·9% [2·9]; teriparatide, 0·7% [2·7], p<0·0001; denosumab 2·5% [2·6], p=0·0011). INTERPRETATION:Combined teriparatide and denosumab increased BMD more than either agent alone and more than has been reported with approved therapies. Combination treatment might, therefore, be useful to treat patients at high risk of fracture. FUNDING:Amgen, Eli Lilly, National Center for Research Resources.
| S-EPMC4083737 | biostudies-literature
Project description:BackgroundA review of data from large clinical trials reported more than 90% of subjects significantly improved their bone mineral density (BMD) at the lumbar spine (LS) with teriparatide (TPTD) (bone 39:1268-1275, 1). However, our clinical experience suggests that many patients may be non-responders, raising questions as to the true efficacy of TPTD in improving BMD in osteoporotic patients.Questions/purposesThe purpose of the study is to determine the rate of improvement in BMD following 18-24 months of teriparatide (TPTD) in patients with osteoporosis within an orthopedic hospital setting.MethodsThis is a retrospective chart review of patients with osteoporosis who completed 18-24 months of TPTD therapy. The primary endpoint was the change in BMD at lumbar spine (LS) and hip-femoral neck (FN) and total hip (TH) following treatment. Secondary endpoints included the effect of prior bisphosphonate therapy, age, body mass index (BMI) and family history of fracture on BMD response, and the changes in bone-specific markers during active treatment.ResultsSeventy-eight women and men with mean T-scores at the LS?=?-2.63 met the inclusion criteria. The overall group showed a 10.7% increase in LS-BMD after 24 months of TPTD. Eighty-three percent were considered responders defined as ?3.0% increase in LS-BMD. Non-responders (16.7%) had mean LS-BMD change?=?-1.41%. No difference in baseline vitamin D, calcium, creatinine, BMI, age, gender, prior fracture history, or bisphosphonate use was observed between responders and non-responders. No consistent pattern of change in measures of bone markers was noted between responders and non-responders.ConclusionEighty-three percent of patients with osteoporosis showed a >3% increase in BMD after TPTD treatment. Baseline parameters, prior bisphosphonate therapy, and the changes in bone markers showed no correlation with final BMD outcome.
| S-EPMC5481259 | biostudies-literature
Project description:BackgroundIn the Denosumab and Teriparatide Administration (DATA) study, we showed that denosumab fully inhibits teriparatide-induced bone resorption while allowing for continued teriparatide-induced bone formation, resulting in larger increases in hip and spine bone mineral density (BMD) than with either drug alone. We aimed to assess whether administration of denosumab with high dose teriparatide would stimulate larger increases in bone mass than those observed in the DATA study.MethodsDATA-HD was an open-label, randomised, controlled phase 4 trial done at Massachusetts General Hospital. Eligible women were postmenopausal women (at least 36 months since last menses or since hysterectomy with a follicle-stimulating hormone concentration of ≥40 U/L) with osteoporosis. Participants were randomly assigned (1:1) to receive teriparatide 20 μg (standard dose) or 40 μg (high dose) daily via subcutaneous injection for 9 months. At 3 months, both groups were started on denosumab 60 mg every 6 months via subcutaneous injection for 12 months. Areal BMD (aBMD) was measured at 0, 3, 9, and 15 months. Treatment was given open label, but outcome assessors were masked. The primary endpoint was percentage change from baseline in spine areal BMD (aBMD) at 15 months. Women who completed at least one study visit after baseline were included in the modified intention-to-treat analysis. Safety was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, number NCT02176382.FindingsBetween Oct 15, 2014, and June 10, 2016, 269 women were assessed for eligibility. 76 participants were randomly assigned to 20 μg teriparatide (n=39) or 40 μg teriparatide (n=37), of whom 69 completed at least one post-baseline visit. At 15 months, mean spine aBMD had increased to a significantly greater extent in the 40 μg group (17·5% [SD 6·0] increase) than the 20 μg group (9·5% [3·2]; difference 8·1%, 95% CI 5·5 to 10·6, p<0·0001). Mean femoral neck aBMD had also increased to a greater extent in the 40 μg group (6·8% [SD 4·1] increase) than the 20 μg group (4·3% [3·7]; difference 2·5%, 0·5 to 4·5, p=0·04), as did mean total hip aBMD (40 μg group, 6·1% [3·4] increase; 20 μg group, 3·9% [2·9] increase; difference 2·2%, 0·6 to 3·8, p<0·0001). 30 (77%) of 39 participants in the 20 μg group and 29 (78%) of 37 participants in the 40 μg group had an adverse event, and seven (18%) and two (5%) patients had serious adverse events. The most frequent adverse events were joint pain (15 [38%]), muscle cramp (15 [38%]), and fatigue (12 [31%]) in the 20 μg group group and fatigue (14 [38%]), nausea (16 [43%]), and joint pain (17 [46%]) in the 40 μg group. No deaths were reported.InterpretationCombined treatment with teriparatide 40 μg and denosumab increases spine and hip BMD more than standard combination therapy. This large and rapid increase in bone mass suggest that this high dose regimen might provide a method of restoring skeletal integrity in patients with osteoporosis.FundingNational Institutes of Health and the Dart Foundation.
| S-EPMC6980341 | biostudies-literature
Project description:Clinical management of critical bone defects remains a major challenge. Despite preclinical work demonstrating teriparatide (PTH(1-34)) effectiveness in small animals, inconclusive data from clinical trials have raised questions of dose and regimen. To address this, we completed a comprehensive study in the murine femoral allograft model, to assess the effects of dose (0.4, 4, and 40?µg/kg/day) and various treatment regimens on radiographic, histologic, and biomechanical healing at 2, 4, and 9 weeks. Only the high dose (40?µg/kg) of PTH(1-34) demonstrated significant effects when given daily over 9 weeks. Remarkably, equivalent biomechanical results were obtained with delayed, short treatment from 2 to 6 weeks that did not induce a significant increase in endochondral bone formation and callus volume. In contrast, PTH(1-34) treatment from 1 to 5 weeks postop demonstrated similar osteogenic effects as immediate daily treatment for 9 weeks, but failed to achieve a significant increase in biomechanics at 9 weeks. MicroCT and histologic analyses demonstrated that the 2-week delay in treatment allowed for timely completion of the endochondral phase, such that the prominent effects of PTH(1-34) were enhanced intramembranous bone formation and remodeling at the graft-host junction. These findings support the potential use of PTH(1-34) as an adjuvant therapy for massive allograft healing, and suggest that there may be an ideal treatment window in which a short course is administered after the endochondral phase to promote osteoblastic bone formation and remodeling to achieve superior union with modest callus formation.
| S-EPMC3253332 | biostudies-other
Project description:Current osteoporosis medications increase bone mineral density (BMD) modestly and reduce, but do not eliminate, fracture risk. Attempts to improve efficacy by administering anabolic agents and bisphosphonates concomitantly have been unsuccessful. Conversely, 12 months of concomitant denosumab and teriparatide therapy increases BMD more than either drug alone.The purpose of this study was to determine whether 24 months of combined denosumab and teriparatide will increase hip and spine BMD more than either individual agent.Preplanned continuation of the Denosumab and Teriparatide Administration (DATA) randomized controlled trial in which postmenopausal osteoporotic women received teriparatide (20 ?g daily), denosumab (60 mg every 6 months), or both medications for 24 months.Participants were 94 postmenopausal women with osteoporosis.Lumbar spine, femoral neck, total hip, and distal radius BMD and serum markers of bone turnover were measured.At 24 months, lumbar spine BMD increased more in the combination group (12.9 ± 5.0%) than in either the teriparatide (9.5 ± 5.9%, P = .01) or denosumab (8.3 ± 3.4%, P = .008) groups. Femoral neck BMD also increased more in the combination group (6.8 ± 3.6%) than in either the teriparatide (2.8 ± 3.9%, P = .003) or denosumab (4.1 ± 3.8%, P = .008) groups. Similarly, total hip BMD increased more in the combination group (6.3 ± 2.6%) than in the teriparatide (2.0 ± 3.0%) or denosumab (3.2 ± 2.5%) groups (P < .001 for both). Although spine and hip BMD continued to increase in the second year in all groups, these year 2 increases did not differ among groups. Serum C-telopeptide and N-terminal propeptide of type 1 procollagen were equally suppressed in the denosumab and combination groups, whereas osteocalcin decreased more in the denosumab group than in the combination group, a difference that persisted, but lessened, in the second year of therapy.Two years of concomitant teriparatide and denosumab therapy increases BMD more than therapy with either medication alone and more than has been reported with any current therapy. The combination of these agents may prove to be an important treatment option in patients at high risk of fracture.
| S-EPMC4010689 | biostudies-literature