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1.
Sci Rep ; 12(1): 13438, 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35927428

RESUMO

Denosumab is a game-changing drug for giant cell tumor of bone (GCTB); however, its clinical biomarker regarding tumor ossification of GCTB has not been elucidated. In this study, we investigated the relationship between Wnt/ß-catenin signaling and the ossification of GCTB and evaluated whether endogenous nuclear ß-catenin expression predicted denosumab-induced bone formation in GCTB. Genuine patient-derived primary GCTB tumor stromal cells exhibited osteoblastic characteristics. Identified osteoblastic markers and nuclear ß-catenin translocation were significantly upregulated via differentiation induction and were inhibited by treating with Wnt signaling inhibitor, GGTI-286, or selective Rac1-LEF inhibitor, NSC23766. Furthermore, we reviewed the endogenous ossification and nuclear ß-catenin translocation of 86 GCTB clinical samples and elucidated that intra-tumoral ossification was significantly associated with the nuclear translocation. Three-dimensional quantitative analyses (n = 13) of tumoral CT images have revealed that the nuclear ß-catenin translocation of naïve GCTB samples was significantly involved with the denosumab-induced tumor ossification. Our findings suggest a close relationship between the nuclear ß-catenin translocation and the osteoblastic differentiation of GCTB. Investigations of the nuclear ß-catenin in naïve GCTB samples may provide a promising biomarker for predicting the ossification of GCTB following denosumab treatment.


Assuntos
Neoplasias Ósseas , Tumor de Células Gigantes do Osso , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Diferenciação Celular , Denosumab/farmacologia , Denosumab/uso terapêutico , Tumor de Células Gigantes do Osso/diagnóstico por imagem , Tumor de Células Gigantes do Osso/tratamento farmacológico , Tumor de Células Gigantes do Osso/metabolismo , Humanos , Osteoblastos/metabolismo , Osteogênese , beta Catenina
2.
Molecules ; 27(12)2022 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-35745051

RESUMO

The dipeptidyl peptidase 3 (Dpp3) is a ubiquitous zinc-dependent aminopeptidase, participating in the activation or degradation of signaling peptides and in the Keap1-Nrf2 antioxidant pathway. The absence of Dpp3 in the Dpp3 knockout mouse model causes increased osteoclast activity, altered osteogenic function, sustained oxidative stress in the bone tissue, and bone loss. We aimed to assess the association of Dpp3 activity with bone fragility in postmenopausal osteoporosis and the impact of denosumab on enzymatic activity. We conducted a two-phase study including 69 postmenopausal women with severe osteoporosis and 36 postmenopausal women without osteometabolic conditions, as controls (cross-sectional phase). Subjects with severe osteoporosis were assessed at baseline and 14 days after the first denosumab administration (prospective phase). The results showed significant reduction in serum Dpp3 activity (expressed as nmoles of formed product/mg proteins/min) in patients vs. controls (0.791 ± 0.232 vs. 1.195 ± 0.338; p < 0.001), and significant association with bone mass at the femoral neck (r = 0.28, p = 0.02) in patients prior to treatment. We found a negative correlation between C-terminal telopeptide (CTX) or N-terminal pro-peptide of type 1 procollagen (P1NP) levels and Dpp3 activity (respectively, r = -0.29, p = 0.012; and r = -0.2572, p = 0.033). Dpp3 activity did not change after denosumab injection. Our findings support a critical role played by Dpp3 in bone homeostasis as a potential bone protective factor. Additional clinical studies in larger cohorts might explore the implementation of Dpp3 assessment as a biomarker of bone health status.


Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Osteoporose , Animais , Biomarcadores , Densidade Óssea , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Estudos Transversais , Denosumab/metabolismo , Denosumab/farmacologia , Denosumab/uso terapêutico , Dipeptidil Peptidases e Tripeptidil Peptidases , Feminino , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/genética , Pós-Menopausa , Estudos Prospectivos
3.
Br J Cancer ; 127(3): 408-421, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35418213

RESUMO

BACKGROUND: Testicular germ cell tumours (TGCTs) have a high sensitivity to chemotherapy and a high cure rate, although with serious adverse effects. In the search for tumour suppressive drugs, the RANKL inhibitor Denosumab, used to treat osteoporosis, came up as a candidate since RANKL signalling was recently identified in the testis. METHODS: Expression of RANKL, RANK and OPG, and the effects of RANKL inhibition were investigated in human TGCTs, TGCT-derived cell-lines, and TGCT-xenograft models. Serum RANKL was measured in TGCT-patients. RESULTS: RANKL, RANK, and OPG were expressed in germ cell neoplasia in situ (GCNIS), TGCTs, and TGCT-derived cell lines. RANKL-inhibition reduced proliferation of seminoma-derived TCam-2 cells, but had no effect on embryonal carcinoma-derived NTera2 cells. Pretreatment with Denosumab did not augment the effect of cisplatin in vitro. However, inhibition of RANKL in vivo reduced tumour growth exclusively in the TCam-2-xenograft model and Denosumab-treatment decreased proliferation in human GCNIS cultures. In TGCT-patients serum RANKL had no prognostic value. CONCLUSIONS: This study shows that the RANKL signalling system is expressed in GCNIS and seminoma where RANKL inhibition suppresses tumour growth in vitro and in vivo. Future studies are needed to determine whether RANKL is important for the malignant transformation or transition from GCNIS to invasive tumours.


Assuntos
Neoplasias Embrionárias de Células Germinativas , Seminoma , Neoplasias Testiculares , Denosumab/farmacologia , Denosumab/uso terapêutico , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Seminoma/tratamento farmacológico , Seminoma/metabolismo , Neoplasias Testiculares/patologia
4.
J Clin Endocrinol Metab ; 107(7): e2690-e2701, 2022 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-35428889

RESUMO

CONTEXT: Premenopausal women with idiopathic osteoporosis (PreMenIOP) have marked deficits in bone density, microstructure, and strength. OBJECTIVE: To define effects of treatment with teriparatide followed by denosumab on lumbar spine (LS) volumetric bone mineral density (vBMD) and stiffness by finite element analysis assessed on central quantitative computed tomography (cQCT) scans. DESIGN, SETTINGS, AND PARTICIPANTS: Ancillary analysis of baseline, post-teriparatide, and post-denosumab cQCT scans from a randomized trial of 41 women allocated to teriparatide (20 mcg daily; n = 28) or placebo (n = 11). After 6 months, those on teriparatide continued for 18 months, and those on placebo switched to teriparatide for 24 months. After completing teriparatide, 33 enrolled in a Phase 2B extension with denosumab (60 mg every 6 months) for 12 months. MAIN OUTCOME MEASURES: Primary outcomes were percentage change from baseline in LS trabecular vBMD and stiffness after teriparatide and between end of teriparatide and completing denosumab. Percentage change from baseline in LS trabecular vBMD and stiffness after sequential teriparatide and denosumab were secondary outcomes. FINDINGS: There were large increases (all Ps < 0.001) in trabecular vBMD (25%), other vBMD parameters, and stiffness (21%) after teriparatide. Statistically significant increases in trabecular vBMD (10%; P < 0.001) and other vBMD parameters (P = 0.03-0.001) were seen after denosumab, while stiffness increased by 7% (P = 0.068). Sequential teriparatide and denosumab led to highly significant (all Ps < 0.001) increases LS trabecular vBMD (43%), other vBMD parameters (15-31%), and stiffness (21%). CONCLUSIONS: The large and statistically significant increases in volumetric density and stiffness after sequential treatment with teriparatide followed by denosumab are encouraging and support use of this regimen in PreMenIOP.


Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Osteoporose , Densidade Óssea , Denosumab/farmacologia , Denosumab/uso terapêutico , Feminino , Humanos , Vértebras Lombares/diagnóstico por imagem , Osteoporose/diagnóstico por imagem , Osteoporose/tratamento farmacológico , Osteoporose Pós-Menopausa/diagnóstico por imagem , Osteoporose Pós-Menopausa/tratamento farmacológico , Teriparatida
5.
J Korean Med Sci ; 37(13): e68, 2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35380023

RESUMO

BACKGROUND: Denosumab (DEN) and zoledronic acid (ZOL) currently represent the most potent antiresorptive agents for the treatment of osteoporosis. Despite similar effects on bone resorption, these agents have distinct mechanisms of action. The objective of this study was to compare the effect of DEN and ZOL after two-year administration on bone mineral density (BMD), trabecular bone score (TBS), bone turnover markers, and persistence. METHODS: A total of 585 postmenopausal women with osteoporosis who did not use osteoporosis medications were retrospectively reviewed. 290 patients were administered 60 mg DEN subcutaneously every 6 months from 2017 to 2018, and 295 patients were treated with 5 mg ZOL intravenously yearly from 2015 to 2017. BMD, TBS, and C-terminal cross-linking telopeptide of type 1 collagen (CTX) measurements were obtained at baseline and two-year after DEN injection or ZOL infusion. RESULTS: After two-year follow-up, 188 patients in the DEN group and 183 patients in the ZOL group were compared. BMD change from baseline at two years was significantly greater in the DEN group compared with the ZOL group (P < 0.001). The changes of TBS in the DEN group were statistically significant compared with baseline (P < 0.001) and the ZOL group (P < 0.001). The DEN group led to significantly greater reduction of CTX compared with ZOL group (P = 0.041). CONCLUSION: In postmenopausal women with osteoporosis, DEN was associated with greater BMD increase at all measured skeletal sites, greater increase of TBS, and greater inhibition of bone remodeling compared with ZOL.


Assuntos
Denosumab , Osteoporose , Densidade Óssea , Osso Esponjoso , Denosumab/farmacologia , Denosumab/uso terapêutico , Feminino , Humanos , Osteoporose/tratamento farmacológico , Pós-Menopausa/fisiologia , Estudos Retrospectivos , Ácido Zoledrônico/farmacologia , Ácido Zoledrônico/uso terapêutico
6.
BMC Oral Health ; 22(1): 129, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35428235

RESUMO

BACKGROUND: External root resorption is an irreversible loss of dental hard tissue as a result of odontoclastic action. Multiple external cervical root resorptions in permanent teeth are rare. The exact cause of external cervical root resorption is unclear. It is currently well established that RANK/RANKL signaling is essential for osteoclastogenesis and osteoclast-mediated bone resorption. Denosumab is an anti-RANKL antibody used for the treatment of postmenopausal osteoporosis. RANK/RANKL pathway suppression by denosumab is expected to suppress the activity of clastic cells responsible for hard tissue resorption involving both osteoclasts and odontoclasts. CASE PRESENTATION: This case report demonstrates aggressive and generalized idiopathic external cervical root resorption that started and advanced during ongoing antiresorptive therapy with the human monoclonal RANKL-blocking antibody denosumab without discontinuation of therapy in a 74-year-old female patient treated for postmenopausal osteoporosis. The extent of resorptive defects was too large and progressively led to fractures of the teeth. The number of teeth involved and the extend of destruction excluded conservative treatment. The affected teeth had to be extracted for functional prosthetic reconstruction. CONCLUSIONS: This finding suggests that treatment with denosumab may be associated with severe and aggressive odontoclastic resorption of multiple dental roots despite an adequate inhibitory effect on osteoclasts in the treatment of osteoporosis. The RANKL-independent pathways of clastic cell formation are likely to be involved in this pathological process.


Assuntos
Osteoporose Pós-Menopausa , Osteoporose , Reabsorção da Raiz , Idoso , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/farmacologia , Denosumab/metabolismo , Denosumab/farmacologia , Denosumab/uso terapêutico , Feminino , Humanos , Osteoclastos , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/patologia , Reabsorção da Raiz/tratamento farmacológico
7.
Endocrinol Metab (Seoul) ; 37(2): 183-194, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35417954

RESUMO

Denosumab, which has been approved for the treatment of osteoporosis since 2010, is a fully humanised monoclonal antibody against a cytokine, receptor activator of nuclear factor kappa B ligand (RANKL), involved in bone resorption. Continued use of denosumab results in a potent and sustained decrease in bone turnover, an increase in bone mineral density (BMD), and a reduction in vertebral and hip fractures. The anti-resorptive effects of denosumab are reversible upon cessation, and this reversal is accompanied by a transient marked increase in bone turnover that is associated with bone loss, and of concern, an increased risk of multiple vertebral fractures. In this review, we outline the effects of denosumab withdrawal on bone turnover markers, BMD, histomorphometry, and fracture risk. We provide an update on recent clinical trials that sought to answer how clinicians can transition away from denosumab safely with follow-on therapy to mitigate bone loss and summarise the recommendations of various international guidelines.


Assuntos
Osteoporose Pós-Menopausa , Osteoporose , Densidade Óssea , Remodelação Óssea , Denosumab/farmacologia , Denosumab/uso terapêutico , Feminino , Humanos , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico , Osteoporose Pós-Menopausa/induzido quimicamente , Osteoporose Pós-Menopausa/tratamento farmacológico
8.
Am J Sports Med ; 50(6): 1550-1563, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35404150

RESUMO

BACKGROUND: Because of poor clinical outcomes, rotator cuff healing in patients with osteoporosis has recently gained attention. Antiresorptive therapy for osteoporosis has been reported to improve healing after repair. However, the comparative effectiveness of anabolic and antiresorptive agents has not been investigated. HYPOTHESIS: Anabolic therapy with abaloparatide (ABL) would outperform antiresorptive therapy with denosumab (Dmab) to improve rotator cuff healing in the osteoporotic status. STUDY DESIGN: Controlled laboratory study. METHODS: A chronic rotator cuff tear model was established in ovariectomy-induced postmenopausal osteoporotic rats. Then, bilateral rotator cuff repairs were conducted in all experimental rats, which were randomly divided into control (CON), Dmab, and ABL groups to receive the corresponding subcutaneous injections. The rats sacrificed at 2 weeks (the early healing period) were used to detect osteoblast and osteoclast activities, related gene expression (osteoclastogenesis, osteogenesis, and chondrogenesis), new bone formation, and mineralization. In the rats sacrificed at 4 and 8 weeks, the bone mineral density and bone architecture at the repaired site were assessed by micro-computed tomography, and rotator cuff healing was evaluated using histological and biomechanical analyses. RESULTS: At 8 weeks, significantly higher failure load and stiffness were observed in the ABL (25.13 ± 3.54 N, P < .001; 21.65 ± 3.08 N/mm, P < .001; respectively), and Dmab (21.21 ± 2.55 N, P < .001; 16.15 ± 2.07 N/mm, P = .008; respectively) groups than in the CON group (13.36 ± 1.70 N; 11.20 ± 2.59 N/mm; respectively), whereas the ABL treatment provided better failure load and stiffness than Dmab (P = .019; P = .003). Although tendon-to-bone healing was improved by Dmab, the most mature tendon insertion at the interface was observed in the ABL group, including a more organized collagen and fibrocartilage and higher bone quality. ABL significantly promoted bone remodeling via coupling between osteoclasts and osteoblasts (osteoblast to osteoclast ratio: 4.80 ± 0.39; P = .022), thereby stimulating more new bone formation and mineralization at the tendon-to-bone healing interface than Dmab (osteoblast to osteoclast ratio: 3.21 ± 0.75) at 2 weeks. Moreover, ABL had significant effects on gene expression [Runt-realted transcription factor 2 (Runx2, collagen type I-alpha 1 (Col1A1]), and sclerostin for osteogenesis; aggrecan and collagen type II (Col2) for chondrogenesis] in mineralized tissues, indicative of enhanced bone and fibrocartilage formation when compared with the CON and Dmab groups. CONCLUSION: ABL promoted rotator cuff healing in osteoporotic rats by significantly increasing the mineralized tissue quality and collagen maturity at the reattachment site, leading to improved biomechanical properties, and was superior to Dmab in both biomechanical and histological analyses. CLINICAL RELEVANCE: Anabolic therapy with ABL may outperform antiresorptive therapy with Dmab in improving outcomes after rotator cuff repair in osteoporotic patients.


Assuntos
Anabolizantes , Osteoporose , Lesões do Manguito Rotador , Anabolizantes/farmacologia , Animais , Fenômenos Biomecânicos , Remodelação Óssea , Colágeno/metabolismo , Denosumab/farmacologia , Feminino , Humanos , Proteína Relacionada ao Hormônio Paratireóideo , Ratos , Manguito Rotador/cirurgia , Lesões do Manguito Rotador/tratamento farmacológico , Lesões do Manguito Rotador/cirurgia , Cicatrização , Microtomografia por Raio-X
9.
J Bone Miner Res ; 37(6): 1136-1146, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35340062

RESUMO

In a randomized clinical trial in patients initiating glucocorticoid therapy (GC-I) or on long-term therapy (GC-C), denosumab every 6 months increased spine and hip bone mineral density at 12 and 24 months significantly more than daily risedronate. The aim of this study was to evaluate the effects of denosumab compared with risedronate on bone strength and microarchitecture measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) in GC-I and GC-C. A subset of 110 patients had high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the distal radius and tibia at baseline and at 12 and 24 months. Cortical and trabecular microarchitecture were assessed with standard analyses and failure load (FL) with micro-finite element analysis. At the radius at 24 months, FL remained unchanged with denosumab and significantly decreased with risedronate in GC-I (-4.1%, 95% confidence interval [CI] -6.4, -1.8) and, in GC-C, it significantly increased with denosumab (4.3%, 95% CI 2.1, 6.4) and remained unchanged with risedronate. Consequently, FL was significantly higher with denosumab than with risedronate in GC-I (5.6%, 95% CI 2.4, 8.7, p < 0.001) and in GC-C (4.1%, 95% CI 1.1, 7.2, p = 0.011). We also found significant differences between denosumab and risedronate in percentage changes in cortical and trabecular microarchitectural parameters in GC-I and GC-C. Similar results were found at the tibia. To conclude, this HR-pQCT study shows that denosumab is superior to risedronate in terms of preventing FL loss at the distal radius and tibia in GC-I and in increasing FL at the radius in GC-C, based on significant differences in changes in the cortical and trabecular bone compartments between treatment groups in GC-I and GC-C. These results suggest that denosumab could be a useful therapeutic option in patients initiating GC therapy or on long-term GC therapy and may contribute to treatment decisions in this patient population. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Denosumab , Glucocorticoides , Densidade Óssea , Osso e Ossos , Denosumab/farmacologia , Denosumab/uso terapêutico , Glucocorticoides/efeitos adversos , Humanos , Rádio (Anatomia) , Ácido Risedrônico/farmacologia , Tíbia/diagnóstico por imagem
10.
Calcif Tissue Int ; 111(1): 47-55, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35226133

RESUMO

Discontinuation of denosumab (DMab) is associated with decline in bone density. Whether raloxifene can be effective to attenuate bone loss after DMab discontinuation in certain conditions when other antiresorptives cannot be used remains unclear. Data on postmenopausal women with osteoporosis who discontinued DMab treatment after short-term use (1-to-4 doses) at Severance Hospital, Seoul, Korea, between 2017 and 2021 were reviewed. Changes in bone mineral density (BMD) at 12 months after DMab discontinuation was compared between sequential raloxifene users (DR) and those without any sequential antiresorptive (DD) after 1:1 propensity score matching. In matched cohort (66 patients; DR n = 33 vs. DD n = 33), mean age (69.3 ± 8.2 years) and T-score (lumbar spine - 2.2 ± 0.7; total hip - 1.6 ± 0.6) did not differ between two groups at the time of DMab discontinuation. Sequential treatment to raloxifene in DR group attenuated the bone loss in lumbar spine after DMab discontinuation compared to DD group (DR vs. DD; - 2.8% vs. - 5.8%, p = 0.013). The effect of raloxifene on lumbar spine BMD changes remained robust (adjusted ß + 2.92 vs. DD, p = 0.009) after adjustment for covariates. BMD loss at femoral neck (- 1.70% vs. - 2.77%, p = 0.673) and total hip (- 1.42% vs. - 1.44%, p = 0.992) did not differ between two groups. Compared to BMD at DMab initiation, DR partially retained BMD gain by DMab treatment in lumbar spine (+ 3.7%, p = 0.003) and femoral neck (+ 2.8%, p = 0.010), whereas DD did not. Raloxifene use after DMab treatment attenuated lumbar spine BMD loss in postmenopausal women with short exposures (< 2 years) to DMab.


Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Idoso , Densidade Óssea , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Denosumab/farmacologia , Denosumab/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/tratamento farmacológico , Cloridrato de Raloxifeno/farmacologia , Cloridrato de Raloxifeno/uso terapêutico
11.
Osteoporos Int ; 33(6): 1243-1256, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35165774

RESUMO

To evaluate whether treatment sequence affects romosozumab response, this analysis reviewed studies where romosozumab was administered before or following an antiresorptive (alendronate or denosumab). Initial treatment with romosozumab followed by an antiresorptive resulted in larger increases in bone mineral density of both hip and spine compared with the reverse sequence. INTRODUCTION: Teriparatide followed by an antiresorptive increases bone mineral density (BMD) more than using an antiresorptive first. To evaluate whether treatment sequence affects romosozumab response, we reviewed randomized clinical trials where romosozumab was administered before (ARCH, FRAME) or following (STRUCTURE, Phase 2 extension) an antiresorptive (alendronate or denosumab, respectively). METHODS: We evaluated BMD percentage change for total hip (TH) and lumbar spine (LS) and response rates (BMD gains ≥ 3% and ≥ 6%) at years 1 and 2 (except STRUCTURE with only 1-year data available). RESULTS: With 1-year romosozumab initial therapy in ARCH and FRAME, TH BMD increased 6.2% and 6.0%, and LS BMD increased 13.7% and 13.1%, respectively. When romosozumab was administered for 1 year after alendronate (STRUCTURE) or denosumab (Phase 2 extension), TH BMD increased 2.9% and 0.9%, respectively, and LS BMD increased 9.8% and 5.3%, respectively. Over 2 years, TH and LS BMD increased 7.1% and 15.2% with romosozumab/alendronate, 8.5% and 16.6% with romosozumab/denosumab, and 3.8% and 11.5% with denosumab/romosozumab, respectively. A greater proportion of patients achieved BMD gains ≥ 6% when romosozumab was used first, particularly for TH, versus the reverse sequence (69% after romosozumab/denosumab; 15% after denosumab/romosozumab). CONCLUSION: In this study, larger mean BMD increases and greater BMD responder rates were achieved when romosozumab was used before, versus after, an antiresorptive agent. Since BMD on treatment is a strong surrogate for bone strength and fracture risk, this analysis supports the thesis that initial treatment with romosozumab followed by an antiresorptive will result in greater efficacy versus the reverse sequence.


Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Alendronato/farmacologia , Alendronato/uso terapêutico , Anticorpos Monoclonais , Densidade Óssea , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Denosumab/farmacologia , Denosumab/uso terapêutico , Feminino , Humanos , Osteoporose Pós-Menopausa/tratamento farmacológico , Teriparatida/farmacologia , Teriparatida/uso terapêutico
12.
Osteoporos Int ; 33(6): 1265-1273, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35059774

RESUMO

The effect of romosozumab is affected by previous osteoporosis treatment. Here we showed that the duration of the previous treatment just before romosozumab affects the therapeutic effect of romosozumab. Using denosumab and oral bisphosphonates for more than 1 year attenuates the effect of romosozumab. INTRODUCTION: As an anti-sclerostin antibody, romosozumab suppresses bone resorption and stimulates bone formation. We investigated whether the effectiveness of 12 months of romosozumab treatment depended on the duration of previous treatment with teriparatide, denosumab, or oral bisphosphonates. METHODS: In total, 259 osteoporosis patients received subcutaneous injections of romosozumab (210 mg) every 4 weeks during 2019 and 2020. This study was designed as a pre-post comparison. The end points were the percent changes of bone mineral density (BMD) after 12 months of romosozumab treatment. The patients were divided into seven groups depending on the type and duration of previous treatment before starting romosozumab as follows: non-previous treatment group, change from teriparatide used for 1 year or less/more than 1 year, change from denosumab used for 1 year or less/more than 1 year, and change from oral bisphosphonates used for 1 year or less/more than 1 year. RESULTS: The effects of previous treatment with teriparatide on the effectiveness of 12-month romosozumab did not clearly depend on the duration of treatment (p > 0.05). In contrast, the effects of previous treatments with denosumab or oral bisphosphonates on the effectiveness of 12-month romosozumab depended on the previous treatment duration, which was reflected by the differences in percent change of the spine BMD (both p < 0.05), however, there were no significant differences in the percent change of the total hip BMD (both p > 0.05). CONCLUSION: The duration of the previous treatment affected the effectiveness of romosozumab. Using denosumab and oral bisphosphonate for more than 1 year attenuated the effect of romosozumab.


Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Osteoporose , Anticorpos Monoclonais , Densidade Óssea , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Denosumab/farmacologia , Denosumab/uso terapêutico , Difosfonatos/uso terapêutico , Feminino , Humanos , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico , Osteoporose Pós-Menopausa/induzido quimicamente , Osteoporose Pós-Menopausa/tratamento farmacológico , Teriparatida/farmacologia , Teriparatida/uso terapêutico
13.
J Clin Endocrinol Metab ; 107(4): e1528-e1540, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-34849989

RESUMO

CONTEXT: We have previously reported that teriparatide is associated with substantial increases in bone mineral density (BMD) at the lumbar spine (LS), total hip (TH), and femoral neck (FN) and small declines at the distal radius in 41 premenopausal women with idiopathic osteoporosis (IOP), all severely affected with low trauma fractures and/or very low BMD. Effects of teriparatide dissipate if not followed by antiresorptives. OBJECTIVE: To assess the effects of 12 and 24 months of denosumab in premenopausal women with IOP completing 24 months of teriparatide. METHODS: This was a preplanned phase 2B extension study. Premenopausal women with IOP who had completed a course of teriparatide received denosumab 60 mg every 6 months over 24 months. The main outcome measure was within-group change in BMD at the LS at 12 months. Secondary outcomes include change in 12-month BMD at other sites, 24-month BMD at all sites, trabecular bone score (TBS), and bone turnover markers (BTMs). RESULTS: After completing teriparatide, 32 participants took denosumab for 12 months and 29 for 24 months, with statistically significant increases in BMD at the LS (5.2 ± 2.6% and 6.9 ± 2.6%), TH (2.9 ± 2.4% and 4.6 ± 2.8%), and FN (3.0 ± 3.8% and 4.7 ± 4.9%). Over the entire 24-month teriparatide and 24-month denosumab treatment period, BMD increased by 21.9 ± 7.8% at the LS, 9.8 ± 4.6% at the TH, and 9.5 ± 4.7% at the FN (all P < .0001). TBS increased by 5.8 ± 5.6% (P < .001). Serum BTM decreased by 75% to 85% by 3 months and remained suppressed through 12 months of denosumab. Denosumab was generally well tolerated. CONCLUSION: These data support the use of sequential teriparatide and denosumab to increase BMD in premenopausal women with severe osteoporosis.


Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Osteoporose , Densidade Óssea , Denosumab/farmacologia , Denosumab/uso terapêutico , Feminino , Humanos , Vértebras Lombares/diagnóstico por imagem , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico , Osteoporose Pós-Menopausa/tratamento farmacológico , Teriparatida
14.
Bone ; 154: 116187, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34530172

RESUMO

BACKGROUND: Age-related trabecular microstructural deterioration and conversion from plate-like trabeculae to rod-like trabeculae occur because of unbalanced rapid remodeling. As denosumab achieves greater remodeling suppression and lower cortical porosity than alendronate, we hypothesized that denosumab might also preserve trabecular plate microstructure, bone stiffness and strength more effectively than alendronate. METHODS: In this post hoc analysis of a phase 2 study, postmenopausal women randomized to placebo (P, n = 74), denosumab (D, n = 72), or alendronate (A, n = 68). HR-pQCT scans of the distal radius and tibia were performed at baseline and Month-12 (M12). Trabecular compartment was subjected to Individual Trabecula Segmentation while finite element analysis was performed to estimate stiffness and strength. Percent change from baseline at M12 of each parameter was compared between patient groups. RESULTS: At the distal tibia, in the placebo group, plate surface area (pTb.S, -1.3%) decreased while rod bone volume fraction (rBV/TV, +4.5%) and number (rTb.N, +2.1%) increased. These changes were prevented by denosumab but persisted despite alendronate therapy (pTb.S: -1.7%; rBV/TV: +6.9%; rTb.N: +3.0%). Both treatments improved whole bone stiffness (D: +3.1%; A: +1.8%) and failure load (D: +3.0%; A: +2.2%); improvements using denosumab was significant compared to placebo (stiffness: p = 0.004; failure load: p = 0.003). At the distal radius, denosumab increased total trabecular bone volume fraction (BV/TV, +3.4%) and whole bone failure load (+4.0%), significantly different from placebo (BV/TV: p = 0.044; failure load: p = 0.046). Significantly different effects of either drug on plate and rod microstructure were not detected. CONCLUSIONS: Denosumab preserved trabecular plate microstructure. Alendronate did not. However, estimated strength did not differ between denosumab and alendronate treated groups.


Assuntos
Alendronato , Denosumab , Alendronato/farmacologia , Alendronato/uso terapêutico , Densidade Óssea , Denosumab/farmacologia , Denosumab/uso terapêutico , Feminino , Humanos , Rádio (Anatomia)/diagnóstico por imagem , Tíbia/diagnóstico por imagem
15.
Bone ; 156: 116301, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34952228

RESUMO

Fibrous dysplasia (FD) is a rare bone disease caused by GNAS mutation in skeletal stem cells, typically originating from and worsening in childhood. Till now, no cure for FD exists despite the well-recognized etiology. Studies have demonstrated that osteoclastogenesis hyperactivity is caused by elevated RANKL expression, making RANKL inhibition a potential therapy. Although a human monoclonal anti-RANKL antibody, denosumab, has been used in FD patients, the effects and mechanisms of RANKL inhibition for FD treatment require assessment. Denosumab is expensive and can only be injected. Therefore, formulating an oral-administered, cost-effective medicine is encouraged. In the current study, we evaluated the effects of a small-molecule RANKL inhibitor, AS2676293, on a transgenic FD mouse model. AS2676293 effectively suppressed osteoclastogenesis and halted FD progression. The pre-existing bone defects were primarily replaced by newly formed mineralized bone after two weeks of AS2676293 administration. The potent RANKL inhibitory effect and easier route of delivery make AS2676293 a promising target therapy of FD. Results from our study suggested that RANKL inhibition is effective in halting FD progression and promoting bone remineralization, which could benefit the patients with early onset of FD.


Assuntos
Denosumab , Displasia Fibrosa Óssea , Animais , Osso e Ossos/patologia , Denosumab/farmacologia , Denosumab/uso terapêutico , Displasia Fibrosa Óssea/tratamento farmacológico , Humanos , Camundongos , Camundongos Transgênicos , Osteogênese
16.
Cancer Lett ; 520: 374-384, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34416336

RESUMO

Normal breast fibroblasts (NBFs) support and maintain the architecture of the organ, and can also suppress tumorigenesis. However, the mechanisms involved are not fully understood. We have shown here that NBFs suppress breast carcinogenesis through secretion of osteoprotegerin (OPG), a soluble decoy receptor for the Receptor Activator of NF-κB ligand (RANKL). Indeed, NBFs and human recombinant OPG (rOPG), suppressed breast cancer cells proliferation and motility through inhibition of the epithelial-to-mesenchymal transition (EMT) process both in vitro and in vivo. Additionally, rOPG inhibited the IL-6/STAT3 and NF-κB pathways as well as the OPG gene, which turned out to be STAT3-regulated. This was confirmed using denosumab, a RANKL-targeted antibody, which also inhibited NF-κB, down-regulated OPG and repressed EMT in breast cancer cells grown in 2D and 3D. Importantly, both rOPG and denosumab targeted cancer stem cells (CSCs). This was mediated through inhibition of the CSC-related pathway ß-catenin. Moreover, rOPG reduced tumor growth and inhibited breast CSC biomarkers in orthotopic humanized breast tumors. Therefore, normal mammary fibroblasts can suppress carcinogenesis through OPG, which constitutes great potential as preventive and/or therapeutic molecule for breast carcinomas.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Osteoprotegerina/genética , Ligante RANK/genética , Proteínas Recombinantes/genética , beta Catenina/genética , Anticorpos/farmacologia , Anticarcinógenos/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinogênese/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Denosumab/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/genética , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Osteoprotegerina/imunologia , Osteoprotegerina/farmacologia , Ligante RANK/antagonistas & inibidores , Proteínas Recombinantes/farmacologia , Fator de Transcrição STAT3/genética
17.
Anticancer Res ; 41(8): 3917-3923, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34281854

RESUMO

BACKGROUND/AIM: Side effects of zolendronic acid (ZA) and RANKL inhibitors (RANKL-I) include impaired wound healing and osteonecrosis of the jaw. Platelet rich fibrin (PRF) enhances wound healing and bone remodelling in vivo and in vitro. However, the topical use PRF in the surgical treatment of patients with medicament-related osteonecrosis of the jaw is relatively new and not thoroughly investigated. Furthermore, the potential attenuation of the PRF effect following antiresorptive treatment remains unclear. Therefore, we investigated the concentration of growth factors within the PRF in healthy volunteers and in patients with antiresorptive treatment. PATIENTS AND METHODS: Blood samples from healthy volunteers and patients were used to produce PRF. The levels of EGF, VEGF, PDGF-BB, TGF-ß1, BMP-2, and CD31 in the PRF was investigated by ELISA. RESULTS: ZA treatment induced a significant decrease in EGF and TGF-ß1 levels, whereas RANKL-I caused lower TGF-ß1 levels. CONCLUSION: Reduced EGF levels in PRF after ZA treatment may explain the delayed wound healing and question the positive effect of PRF in these patients. PRF use in patients undergoing RANKL-I treatment seems to be more justified.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Denosumab/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Fibrina Rica em Plaquetas/efeitos dos fármacos , Ácido Zoledrônico/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/sangue , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Denosumab/uso terapêutico , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Osteólise/sangue , Osteólise/tratamento farmacológico , Contagem de Plaquetas , Neoplasias da Próstata/sangue , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Adulto Jovem , Ácido Zoledrônico/uso terapêutico
18.
Sci Rep ; 11(1): 14821, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285260

RESUMO

Giant cell tumor of bone (GCTB) is an intermediate malignant bone tumor that is locally aggressive and rarely metastasizes. Denosumab, which is a receptor activator of nuclear factor kappa B ligand (RANKL) inhibitor, can be used to treat GCTB. We focused on potential immunotherapy for GCTB and investigated the tumor microenvironment of GCTB. Programmed death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) expression and signal-regulatory protein alpha (SIRPα), forkhead box P3 (FOXP3), and cluster of differentiation 8 (CD8) infiltration were assessed by immunohistochemical studies of 137 tumor tissues from 96 patients. Of the naive primary specimens, 28% exhibited PD-L1 expression and 39% exhibited IDO1 expression. There was significantly more SIRPα+, FOXP3+, and CD8+ cell infiltration in PD-L1- and IDO1-positive tumors than in PD-L1- and IDO1-negative tumors. The frequency of PD-L1 expression and SIRPα+ cell infiltration in recurrent lesions treated with denosumab was significantly higher than in primary lesions and recurrent lesions not treated with denosumab. PD-L1 expression and higher SIRPα+ cell infiltration were significantly correlated with shorter recurrence-free survival. PD-L1 and SIRPα immune checkpoint inhibitors may provide clinical benefit in GCTB patients with recurrent lesions after denosumab therapy.


Assuntos
Antígenos de Diferenciação/metabolismo , Antígeno B7-H1/metabolismo , Neoplasias Ósseas/tratamento farmacológico , Denosumab/administração & dosagem , Tumor de Células Gigantes do Osso/tratamento farmacológico , Receptores Imunológicos/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/metabolismo , Denosumab/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Tumor de Células Gigantes do Osso/metabolismo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Adulto Jovem
19.
Scand J Clin Lab Invest ; 81(6): 425-431, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34120544

RESUMO

Adjuvant treatment for post-menopausal women with early breast cancer (BC) includes aromatase inhibitors (AI), known to decrease bone mineral density (BMD). In this study, we investigate whether denosumab is a valid second option for patients unable to receive standard adjuvant i.v. zoledronic acid (ZA). In total, 212 patients have been evaluated after they did not receive ZA. Of those 194 were included. After evaluation by an endocrinologist, all patients were offered ZA as their first choice and 15% accepted (N = 29). The remaining 85% were offered denosumab (N = 165). All patients were followed prospectively with blood tests up to 24 months. DXA scans were performed at baseline and 24 months. No difference was observed between the two treatment groups at baseline, with regard to anthropometry and standard biochemistry. Markers of bone turnover (p-PINP, p-CTX, p-bone-specific alkaline phosphatase and p-osteocalcin) all showed significant suppression compared to baseline and remained suppressed throughout the 2 years. BMD showed small and significant increases at the spine (0.024 g/cm2) and total hip (0.019 g/cm2) in the denosumab group but no change at the femoral neck(-0.011g/cm2). In the ZA group, we observed no significant change at the spine (0.015 g/cm2) and total hip (-0.001g/cm2) and a small significant decrease at the femoral neck (-0.037 g/cm2). However, when we compared BMD change between the treatment groups, we found no significant difference.Conclusions: Our data indicate that for BC patients in AI treatment who refused or were not able to receive ZA treatment, denosumab might be recommended as a second choice. Regarding markers of bone turnover and BMD denosumab is equal to ZA.Summary: Women with early breast cancer receiving anti-estrogen treatment are at risk of developing osteoporosis.We followed 194 women receiving zoledronic acid (ZA) or denosumab for up to 2 years.We find that with regard to bone protection, denosumab is a viable alternative to ZA and might be recommended as a second choice.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Denosumab/uso terapêutico , Pós-Menopausa/fisiologia , Ácido Zoledrônico/uso terapêutico , Idoso , Biomarcadores/metabolismo , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Neoplasias da Mama/fisiopatologia , Cálcio/metabolismo , Denosumab/farmacologia , Feminino , Homeostase/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Ácido Zoledrônico/farmacologia
20.
Int J Mol Sci ; 22(7)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33806209

RESUMO

Multiple myeloma (MM) is a B-cell neoplasm characterized by clonal plasma-cell proliferation. The survival and prognosis of this condition have been significantly improved by treatment with active anti-MM drugs such as bortezomib or lenalidomide. Further, the discovery of novel agents has recently paved the way for new areas of investigation. However, MM, including myeloma-related bone diseases, remains fatal. Bone disease or bone destruction in MM is a consequence of skeletal involvement with bone pain, spinal cord compression, and bone fracture resulting from osteolytic lesions. These consequences affect disease outcomes, including patients' quality of life and survival. Several studies have sought to better understand MM bone disease (MBD) through the classification of its molecular mechanisms, including osteoclast activation and osteoblast inhibition. Bisphosphonates and the receptor activator of the nuclear factor-kappa B (NF-κB) ligand (RANKL) inhibitor, denosumab, prevent skeletal-related events in MM. In addition, several other bone-targeting agents, including bone-anabolic drugs, are currently used in preclinical and early clinical evaluations. This review summarizes the current knowledge of the pathogenesis of MBD and discusses novel agents that appear very promising and will soon enter clinical development.


Assuntos
Doenças Ósseas/terapia , Mieloma Múltiplo/terapia , Animais , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Conservadores da Densidade Óssea/uso terapêutico , Doenças Ósseas/etiologia , Remodelação Óssea , Osso e Ossos , Bortezomib/farmacologia , Denosumab/farmacologia , Difosfonatos/farmacologia , Humanos , Mieloma Múltiplo/complicações , Subunidade p50 de NF-kappa B/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteólise/complicações , Ligante RANK/metabolismo , Proteínas Wnt/antagonistas & inibidores
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