RESUMO
Osteoporosis is a skeletal disease characterised by reduced bone mass and deterioration of bone microarchitecture, underlying a higher risk of fragility fractures. Several options are available for its treatment, including both anti-resorptive and anabolic agents. The present review discusses and summarises the most recent literature on anabolic treatment, with a focus on abaloparatide, and on the assessment of fragility fracture risk, with a focus on trabecular bone score. Finally, we provide a discussion on the effects of different antiosteoporotic medications in terms of fragility fracture risk reduction.
Assuntos
Anabolizantes , Conservadores da Densidade Óssea , Densidade Óssea , Osteoporose , Fraturas por Osteoporose , Humanos , Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/etiologia , Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Anabolizantes/uso terapêutico , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Fatores de Risco , Medição de Risco , Resultado do TratamentoRESUMO
Osteoanabolic agents are used as a first line treatment in patients at high fracture risk. The PTH receptor 1 (PTH1R) agonists teriparatide (TPTD) and abaloparatide (ABL) increase bone formation, bone mineral density (BMD), and bone strength by activating PTH receptors on osteoblasts. Romosozumab (ROMO), a humanized monoclonal antibody against sclerostin, dramatically but transiently stimulates bone formation and persistently reduces bone resorption. Osteoanabolic agents increase BMD and bone strength while being more effective than antiresorptives in reducing fracture risk in postmenopausal women. However, direct comparisons of the antifracture benefits of osteoanabolic therapies are limited. In a direct comparison of TPTD and ABL, the latter resulted in greater BMD increases at the hip. While no differences in vertebral or non-vertebral fracture risk were observed between the two drugs, ABL led to a greater reduction of major osteoporotic fractures. Adverse event profiles were similar between the two agents except for hypercalcemia, which occurred more often with TPTD. No direct comparisons of fracture risk reduction between ROMO and the PTH1R agonists exist. Individual studies have shown greater increases in BMD and bone strength with ROMO compared with TPTD in treatment-naive women and in women previously treated with bisphosphonates. Some safety aspects, such as a history of tumor precluding the use of PTH1R agonists, and a history of major cardiovascular events precluding the use of ROMO, should also be considered when choosing between these agents. Finally, convenience of administration, reimbursement by national health systems and length of clinical experience may influence patient choice.
Assuntos
Anticorpos Monoclonais , Conservadores da Densidade Óssea , Densidade Óssea , Receptor Tipo 1 de Hormônio Paratireóideo , Teriparatida , Humanos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/farmacologia , Densidade Óssea/efeitos dos fármacos , Teriparatida/uso terapêutico , Receptor Tipo 1 de Hormônio Paratireóideo/agonistas , Feminino , Fraturas por Osteoporose/prevenção & controle , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológicoRESUMO
BACKGROUND: Low hip bone mineral density (BMD) in patients who undergo total hip arthroplasty (THA) increases the risk of periprosthetic fractures, implant instability, and other complications. Recently, emphasis has been placed on bone health optimization: treating low BMD prior to a planned orthopaedic implant procedure in an effort to normalize BMD and reduce the potential risk of future complications. Abaloparatide is a U.S. Food and Drug Administration-approved osteoanabolic agent for men and postmenopausal women with osteoporosis and a candidate drug for bone health optimization that, in addition to benefits at the spine, increases hip BMD and reduces nonvertebral fracture risk. We hypothesized that abaloparatide would improve BMD in proximal femoral regions surrounding a virtual THA stem. METHODS: This post hoc analysis obtained dual x-ray absorptiometry (DXA) hip scans from 500 randomly selected postmenopausal women with osteoporosis from the Phase-3 Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE, NCT01343004) study after 0, 6, and 18 months of abaloparatide (250 patients) or placebo (250 patients). Hip DXA scans underwent 3-dimensional (3D) modeling via 3D-Shaper, followed by virtual resection of the proximal femur and simulated placement of a tapered, flat-wedge hip stem that guided delineation of the Gruen zones that were fully (zones 1 and 7) or largely (zones 2 and 6) captured in the scanning region. Integral, cortical, and trabecular volumetric BMD, cortical thickness, and cortical surface BMD (the product of cortical volumetric BMD and cortical thickness) were determined for each zone. RESULTS: Compared with placebo, the abaloparatide group showed greater increases in integral volumetric BMD in all zones at months 6 and 18; cortical surface BMD in zones 1, 6, and 7 at month 6; cortical thickness, cortical volumetric BMD, and cortical surface BMD in all zones at month 18; and trabecular volumetric BMD in zones 1 and 7 at months 6 and 18. CONCLUSIONS: Abaloparatide increases BMD in proximal femoral regions that interact with and support femoral stems, suggesting that abaloparatide may have value for preoperative or potentially perioperative bone health optimization in patients with osteoporosis undergoing THA. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.
Assuntos
Absorciometria de Fóton , Artroplastia de Quadril , Conservadores da Densidade Óssea , Densidade Óssea , Fêmur , Osteoporose Pós-Menopausa , Proteína Relacionada ao Hormônio Paratireóideo , Humanos , Feminino , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Idoso , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/farmacologia , Osteoporose Pós-Menopausa/tratamento farmacológico , Artroplastia de Quadril/efeitos adversos , Artroplastia de Quadril/métodos , Pessoa de Meia-Idade , Fêmur/efeitos dos fármacos , Fêmur/diagnóstico por imagem , Fêmur/cirurgiaRESUMO
Review of medical records from 173 women with osteoporosis who received abaloparatide treatment revealed that 96.0% had at least one visit for osteoporosis management and 55.5% had medication support group access. The most common reasons for discontinuing treatment were financial (31.2%) and tolerability (22.8%). Most patients (64.8%) completed treatment as prescribed. PURPOSE: Abaloparatide is approved for the treatment of women with postmenopausal osteoporosis at high risk for fracture. This study evaluated real-world treatment patterns for patients new to abaloparatide, regardless of osteoporosis treatment history. METHODS: Data for patients with ≥ 1 prescription for abaloparatide were collected retrospectively from six academic and clinical practice settings across the US. RESULTS: A total of 173 patients were enrolled (mean [SD] age, 69.8 [7.4] years). At the time of abaloparatide treatment initiation, 78.6% had received other osteoporosis medications. Mean (SD) time from discontinuation of osteoporosis medications prior to initiation of abaloparatide was 1.7 (3.2) years. Twenty-four months of follow-up data from the initiation date of abaloparatide was collected from 94.0% of patients and 6.0% of patients had 12-24 months of follow-up. During the follow-up period, 96.0% of patients had at least one visit for osteoporosis management and 55.5% had access to a medication support program. The median duration of therapy was 18.6 months and 105/162 (64.8%) completed abaloparatide treatment as prescribed. The most common reasons for treatment discontinuation were financial (31.2%) and tolerability (22.8%). Following completion of a course of treatment with abaloparatide, 82/162 (50.6%) patients transitioned to another osteoporosis medication. The median time between abaloparatide treatment course completion and the initiation of follow-on medication was 21 days. CONCLUSION: Most patients completed treatment with abaloparatide as prescribed, and over half continued with an antiresorptive agent. This favorable conduct may be the result of regular follow-up visits and accessibility to both medication and patient support services.
Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Proteína Relacionada ao Hormônio Paratireóideo , Humanos , Feminino , Idoso , Osteoporose Pós-Menopausa/tratamento farmacológico , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Pessoa de Meia-Idade , Estudos Retrospectivos , Fraturas por Osteoporose/prevenção & controle , Adesão à Medicação/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Idoso de 80 Anos ou mais , Custos de MedicamentosRESUMO
Previous parathyroid hormone (PTH)-related peptides (PTHrPs) cannot be used to prevent implant loosening in osteoporosis patients due to the catabolic effect of local sustained release. A novel PTHrP (PTHrP-2) that can be used locally to promote osseointegration of macroporous titanium alloy scaffold (mTAS) and counteract implant slippage in osteoporosis patients is designed. In vitro, PTHrP-2 enhances the proliferation, adhesion, and osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) within the mTAS. Further, it promotes proliferation, migration, angiogenesis-related protein expression, and angiogenesis in human umbilical vein endothelial cells (HUVECs). Compared to PTH(1-34), PTHrP-2 can partially weaken the osteoclast differentiation of RAW 264.7 cells. Even in an oxidative stress microenvironment, PTHrP-2 safeguards the proliferation and migration of BMSCs and HUVECs, reduces reactive oxygen species generation and mitochondrial damage, and partially preserves the angiogenesis of HUVECs. In the Sprague-Dawley (SD) rat osteoporosis model, the therapeutic benefits of PTHrP-2-releasing mTAS (mTASP2 ) and ordinary mTAS implanted for 12 weeks via micro-CT, sequential fluorescent labeling, and histology are compared. The results demonstrate that mTASP2 exhibits high bone growth rate, without osteophyte formation. Consequently, PTHrP-2 exhibits unique local synthesis properties and holds the potential for assisting the osseointegration of alloy implants in osteoporosis patients.
Assuntos
Osseointegração , Osteoporose , Ratos , Animais , Humanos , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Titânio/química , Ratos Sprague-Dawley , Osteogênese , Ligas/farmacologia , Células Endoteliais , Osteoporose/tratamento farmacológico , Impressão TridimensionalRESUMO
The local application of drug-loaded bioactive scaffold materials is one of the important directions to solve the clinical problem of osteoporotic (OP) bone defects. This study retains the advantages of drug loading and mechanical properties of natural 3D bioactive scaffolds. The scaffolds are functionally modified through chemical and self-assembly approaches with application of polydopamine (PDA) nanoparticles and parathyroid hormone-related peptide-1 (PTHrP-1) for efficient local drug loading. This study investigates the effects of the novel bioactive scaffolds on ossification, osteoclastogenesis, and macrophage polarization. This work elucidates the effects of the scaffolds in regulating osteoclastic activity and new bone formation in vitro. Further studies on the establishment and repair of OP bone defects in small animals are conducted, and the potential of natural bioactive porous scaffold materials to promote the repair of OP bone defects is initially verified. The preparation of safe and economical anti-OP bone repair material provides a theoretical basis for clinical translational applications.
Assuntos
Osteoporose , Alicerces Teciduais , Animais , Alicerces Teciduais/química , Regeneração Óssea , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Osteogênese , Osteoporose/tratamento farmacológicoRESUMO
INTRODUCTION: Parathyroid hormone (PTH) plays an important role in maintaining mineral homeostasis by regulating calcium and phosphate levels. Clinical trials have shown that peptides of PTH (1-34), PTH-related protein (PTHrP 1-36), and the new peptide modeled on PTHrP, abaloparatide, can have different anabolic effects on osteoporotic subjects, but the underlying mechanisms are still unclear. The prevalence of moderate and major gingival recession has been shown to be higher in postmenopausal women with osteoporosis. In addition, there is a significant association between osteoporosis and tooth loss. METHODS: We investigated the actions of these peptides on the cementoblasts and teeth of mice. The murine cementoblast line, OCCM-30, known to express collagen I (Col1a1), was treated with intermittent PTH (1-34), PTHrP (1-36), or abaloparatide for 6 h/d for 3 days. Microcomputed tomography was performed on the teeth of mice receiving daily injections of phosphate-buffered saline, PTH (1-34), or abaloparatide. Statistical differences were analyzed by a 2-way or 1-way analysis of variance followed by a Tukey's post-hoc test. Results are expressed as mean ± standard deviation, and P <0.05 was considered significant. RESULTS: Gene expression showed regulation of Bsp, Col1a1, Opg, Rankl, and Mmp13 by the 3 peptides in these cells. Western blots revealed that after intermittent treatment for 3 days, PTH (1-34) caused an increase in COL1A1 protein immediately after treatment. In contrast, abaloparatide showed a latent effect in increasing COL1A1 protein 18 hours after treatment. PTHrP had no effect on COL1A1 expression. Immunofluorescence confirmed the same result as the Western blots. Microcomputed tomography of teeth showed PTH (1-34) injections increased molar root mineral density in mice, whereas abaloparatide increased density in roots of incisors and molars. CONCLUSIONS: This study reveals the differential anabolic effects of intermittent PTH (1-34), PTHrP (1-36), and abaloparatide on cementoblasts, as revealed by COL1A1 expression and root mineral density. Abaloparatide may be a potential therapeutic approach for achieving improved cementogenesis.
Assuntos
Anabolizantes , Osteoporose , Feminino , Camundongos , Animais , Hormônio Paratireóideo , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Cemento Dentário , Cadeia alfa 1 do Colágeno Tipo I , Anabolizantes/farmacologia , Anabolizantes/uso terapêutico , Microtomografia por Raio-X , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Colágeno Tipo I , Raiz Dentária , Minerais/farmacologia , Minerais/uso terapêutico , Fosfatos/farmacologia , Fosfatos/uso terapêuticoRESUMO
OBJECTIVE: Teriparatide (TPTD) and abaloparatide (ABL) are two osteoanabolic drugs targeting parathyroid hormone (PTH)1R signalling. This study aimed to investigate the effects of TPTD and ABL on the adolescent mandibular growth. METHOD: In total, 70 4-week-old male Sprague-Dawley rats were randomly divided into 14 groups, treated with intermittent TPDT or ABL at various doses, accompanied by mandibular advancement (MA) or not. 3D printing was used to fabricate an innovative splint for MA. After a 4-week treatment, morphological measurement, histological and immunohistochemical analysis were performed. Mandibular condylar chondrocytes (MCCs) were treated with TPTD or ABL, followed by CCK-8 assay, alcian blue staining, real time-PCR and immunofluorescent staining. RESULT: In vivo, TPTD or ABL alone increased the condylar length and cartilage thickness, with up-regulated SOX9 and COL II, whilst down-regulated COL X; however, when combined with MA, the promotive effects were attenuated. TPTD or ABL alone increased the mandibular body height and mandibular angle width, whilst increased the mandibular body length and alveolar bone width when combined with MA. In vitro, TPTD or ABL enhanced the MCC proliferation, glycosaminoglycan synthesis, COL II and SOX9 expression, whilst down-regulated COL X, Ihh and PTH1R expression. CONCLUSION: Both ABL and TPTD enhance mandibular growth in adolescent rats with site-specific and mechano-related effects, including propelling chondrogenesis at the condylar cartilage and promoting bone apposition at other mechano-responsive sites. They behave as promising drugs for mandibular growth modification, and in general ABL seems more potent than TPTD in this context.
Assuntos
Conservadores da Densidade Óssea , Teriparatida , Ratos , Masculino , Animais , Teriparatida/farmacologia , Teriparatida/uso terapêutico , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Ratos Sprague-Dawley , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêuticoRESUMO
Abaloparatide significantly increased bone mineral density (BMD) in women with postmenopausal osteoporosis and decreased risk of vertebral, nonvertebral, and clinical fractures compared with placebo. The Abaloparatide for the Treatment of Men with Osteoporosis (ATOM; NCT03512262) study evaluated the efficacy and safety of abaloparatide compared with placebo in men. Eligible men aged 40 to 85 years with osteoporosis were randomized 2:1 to daily subcutaneous injections of abaloparatide 80 µg or placebo for 12 months. The primary endpoint was change from baseline in lumbar spine BMD. Key secondary endpoints included BMD change from baseline at the total hip and femoral neck. A total of 228 men were randomized (abaloparatide, n = 149; placebo, n = 79). Baseline characteristics were similar across treatment groups (mean age, 68.3 years; mean lumbar spine BMD T-score, -2.1). At 12 months, BMD gains were greater with abaloparatide compared with placebo at the lumbar spine (least squares mean percentage change [standard error]: 8.48 [0.54] versus 1.17 [0.72]), total hip (2.14 [0.27] versus 0.01 [0.35]), and femoral neck (2.98 [0.34] versus 0.15 [0.45]) (all p < 0.0001). The most common (≥5%) treatment-emergent adverse events were injection site reaction, dizziness, nasopharyngitis, arthralgia, bronchitis, hypertension, and headache. During 12 months of abaloparatide treatment, men with osteoporosis exhibited rapid and significant improvements in BMD with a safety profile consistent with previous studies. These results suggest abaloparatide can be considered as an effective anabolic treatment option for men with osteoporosis. © 2022 Radius Health Inc and 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
Conservadores da Densidade Óssea , Osteoporose , Proteína Relacionada ao Hormônio Paratireóideo , Idoso , Humanos , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Método Duplo-Cego , Colo do Fêmur , Osteoporose/tratamento farmacológico , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , MasculinoRESUMO
STUDY DESIGN: Prospective randomized placebo controlled animal trial. OBJECTIVE: Determine the effect of daily subcutaneous abaloparatide injection on the intervertebral fusion rate in rabbits undergoing posterolateral fusion. STUDY OF BACKGROUND DATA: Despite the wide utilization of spine fusion, pseudarthrosis remains prevalent, and results in increased morbidity. Abaloparatide is a novel analog of parathyroid hormone-related peptide (1-34) and has shown efficacy in a rat posterolateral spine fusion model to increase fusion rates. The effect of abaloparatide on the fusion rate in a larger animal model remains unknown. MATERIALS AND METHODS: A total of 24 skeletally mature New Zealand White male rabbits underwent bilateral posterolateral spine fusion. Following surgery, the rabbits were randomized to receive either saline as control or abaloparatide subcutaneous injection daily. Specimens underwent manual assessment of fusion, radiographic analysis with both x-ray and high-resolution peripheral quantitative computed tomography, and biomechanical assessment. RESULTS: Rabbits that received abaloparatide had a 100% (10/10) fusion rate compared with 45% (5/11) for controls ( P <0.02) as assessed by manual palpation. Radiographic analysis determined an overall mean fusion score of 4.17±1.03 in the abaloparatide group versus 3.39±1.21 for controls ( P <0.001). The abaloparatide group also had a greater volume of bone formed with a bone volume of 1209±543 mm 3 compared with 551±152 mm 3 ( P <0.001) for controls. The abaloparatide group had significantly greater trabecular bone volume fraction and trabecular thickness and lower specific bone surface and connectivity density in the adjacent levels when compared with controls. Abaloparatide treatment did not impact trabecular number or separation. There were no differences in biomechanical testing in flexion, extension, or lateral bending ( P >0.05) between groups. CONCLUSIONS: Abaloparatide significantly increased the fusion rate in a rabbit posterolateral fusion model as assessed by manual palpation. In addition, there were marked increases in the radiographic evaluation of fusion.
Assuntos
Proteína Relacionada ao Hormônio Paratireóideo , Fusão Vertebral , Animais , Masculino , Coelhos , Ratos , Transplante Ósseo/métodos , Vértebras Lombares/cirurgia , Osteogênese , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Estudos Prospectivos , Fusão Vertebral/métodosRESUMO
Cancer-associated hypercalcemia commonly occurs through abnormal secretions of parathyroid hormone-related protein (PTHrP) from cancer cells. Several cases of PTHrP-producing melanoma causing hypercalcemia have been reported; however, effective management of PTHrP-producing BRAF wild-type melanoma causing hypercalcemia after immune checkpoint inhibitor (ICI) failure is unclear. We report a case of PTHrP-producing BRAF wild-type melanoma leading to oncological emergency by hypercalcemia that was successfully treated with dacarbazine after ICI failure. A 65-year-old Japanese woman had advanced BRAF wild-type melanoma that was refractory to ICI, and then led to hypoxia through exacerbated lung metastases and pleural effusion. Moreover, hypercalcemia appeared in parallel with increase of the serum PTHrP level. Dacarbazine was administered, and after the first administration, the pleural effusion was gradually decreased and hypoxia rapidly disappeared, and the serum calcium and PTHrP levels were improved within normal limits. Dacarbazine after ICI failure is potentially a useful option for oncological emergency due to progression of BRAF wild-type melanoma including PTHrP-producing types. Dacarbazine should be reevaluated as a therapeutic option for oncological emergency in patients with BRAF wild-type melanoma after ICI failure.
Assuntos
Hipercalcemia , Melanoma , Derrame Pleural , Idoso , Dacarbazina/uso terapêutico , Feminino , Humanos , Hipercalcemia/tratamento farmacológico , Hipercalcemia/etiologia , Hipóxia/complicações , Hipóxia/tratamento farmacológico , Inibidores de Checkpoint Imunológico , Melanoma/complicações , Melanoma/tratamento farmacológico , Melanoma/patologia , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Proteínas Proto-Oncogênicas B-rafRESUMO
Osteoporosis is a debilitating disease characterized by reduced bone mineral density and an increased risk of fractures. This review aims to provide a comprehensive overview of, and map current knowledge, obtained from preclinical and clinical studies of the osteoanabolic agent abaloparatide. PubMed and Embase were meticulously searched from inception to May 4, 2021.178 titles and abstracts were screened, and 57 full-text articles were assessed for inclusion. A total of 55 articles were included; 5 (9%) in vitro studies, 21 (38%) in vivo studies, and 29 (53%) clinical studies. Preclinical in vitro studies have demonstrated receptor conformation preferability, structural insights into the receptor-agonist complex, and proliferative effects of abaloparatide on osteoblasts. Preclinical studies have shown abaloparatide to be similarly effective to teriparatide using comparable doses in both ambulating mice and rats challenged by disuse. Other animal studies have reported that abaloparatide effectively mitigates or prevents bone loss from ovariectomy, orchiectomy, and glucocorticoids and improves fracture healing. The pivotal clinical study ACTIVE demonstrated 18 months of treatment with abaloparatide substantially increase bone mineral density and reduce fracture risk in post-menopausal women compared with placebo. The extension study ACTIVExtend highlighted that subsequent treatment with alendronate sustained the bone gained by abaloparatide treatment and the reduced fracture risk for up to two years. Post-hoc sub-group analyses have also supported the efficacy and safety of abaloparatide treatment independent of various baseline risk factors. In conclusion, mounting evidence from preclinical and clinical studies has uniformly reported that abaloparatide increases bone mineral density and reduces fracture risk.
Assuntos
Conservadores da Densidade Óssea/farmacologia , Densidade Óssea/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Animais , Conservadores da Densidade Óssea/uso terapêutico , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Osteoporose/complicações , Fraturas por Osteoporose/etiologia , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Resultado do TratamentoAssuntos
Anabolizantes/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Hormônios e Agentes Reguladores de Cálcio/uso terapêutico , Humanos , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Teriparatida/uso terapêuticoRESUMO
BACKGROUND: Chronic kidney disease (CKD) is an independent risk factor for osteoporosis and is more prevalent among people with CKD than among people who do not have CKD. Although several drugs have been used to effectively treat osteoporosis in the general population, it is unclear whether they are also effective and safe for people with CKD, who have altered systemic mineral and bone metabolism. OBJECTIVES: To assess the efficacy and safety of pharmacological interventions for osteoporosis in patients with CKD stages 3-5, and those undergoing dialysis (5D). SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 25 January 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials comparing any anti-osteoporotic drugs with a placebo, no treatment or usual care in patients with osteoporosis and CKD stages 3 to 5D were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed their quality using the risk of bias tool, and extracted data. The main outcomes were the incidence of fracture at any sites; mean change in the bone mineral density (BMD; measured using dual-energy radiographic absorptiometry (DXA)) of the femoral neck, total hip, lumbar spine, and distal radius; death from all causes; incidence of adverse events; and quality of life (QoL). Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Seven studies involving 9164 randomised participants with osteoporosis and CKD stages 3 to 5D met the inclusion criteria; all participants were postmenopausal women. Five studies included patients with CKD stages 3-4, and two studies included patients with CKD stages 5 or 5D. Five pharmacological interventions were identified (abaloparatide, alendronate, denosumab, raloxifene, and teriparatide). All studies were judged to be at an overall high risk of bias. Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture (RR 0.52, 95% CI 0.39 to 0.69; low certainty evidence). Anti-osteoporotic drugs probably makes little or no difference to the risk of clinical fracture (RR 0.91, 95% CI 0.79 to 1.05; moderate certainty evidence) and adverse events (RR 0.99, 95% CI 0.98 to 1.00; moderate certainty evidence). We were unable to incorporate studies into the meta-analyses for BMD at the femoral neck, lumbar spine and total hip as they only reported the percentage change in the BMD in the intervention group. Among patients with severe CKD stages 5 or 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture (RR 0.33, 95% CI 0.01 to 7.87; very low certainty evidence). It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low (MD 0.01, 95% CI 0.00 to 0.02). Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine (MD 0.03, 95% CI 0.03 to 0.04, low certainty evidence). No adverse events were reported in the included studies. It is uncertain whether anti-osteoporotic drug reduces the risk of death (RR 1.00, 95% CI 0.22 to 4.56; very low certainty evidence). AUTHORS' CONCLUSIONS: Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture in low certainty evidence. Anti-osteoporotic drugs make little or no difference to the risk of clinical fracture and adverse events in moderate certainty evidence. Among patients with CKD stages 5 and 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture and death because the certainty of this evidence is very low. Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine in low certainty evidence. It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low. Larger studies including men, paediatric patients or individuals with unstable CKD-mineral and bone disorder are required to assess the effect of each anti-osteoporotic drug at each stage of CKD.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Osteoporose Pós-Menopausa/terapia , Insuficiência Renal Crônica/complicações , Conduta Expectante , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Viés , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/efeitos adversos , Denosumab/efeitos adversos , Denosumab/uso terapêutico , Feminino , Colo do Fêmur/efeitos dos fármacos , Fraturas Espontâneas/epidemiologia , Fraturas Espontâneas/prevenção & controle , Quadril , Humanos , Indóis/efeitos adversos , Indóis/uso terapêutico , Vértebras Lombares/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/mortalidade , Proteína Relacionada ao Hormônio Paratireóideo/efeitos adversos , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Cloridrato de Raloxifeno/efeitos adversos , Cloridrato de Raloxifeno/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Diálise Renal , Insuficiência Renal Crônica/terapia , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/prevenção & controle , Teriparatida/efeitos adversos , Teriparatida/uso terapêutico , Tiofenos/efeitos adversos , Tiofenos/uso terapêuticoRESUMO
OBJECTIVE: Fractures due to osteoporosis represent a serious burden on patients and healthcare systems. The objective of this review is to provide an overview of the anabolic agent abaloparatide (ABL) for the treatment of postmenopausal women with osteoporosis at high risk for fracture. METHODS: A literature review was conducted using PubMed to identify articles focused on ABL published prior to February 10, 2020, using the search term "abaloparatide". RESULTS: ABL, a synthetic analog of human parathyroid hormone-related protein, increased bone mineral density (BMD), improved bone microarchitecture, and increased bone strength in preclinical and clinical studies. The pivotal phase 3 trial ACTIVE and its extension (ACTIVExtend) demonstrated the efficacy of initial treatment with ABL for 18 months followed by sequential treatment with alendronate (ALN) for an additional 24 months to reduce the risk of vertebral, nonvertebral, clinical, and major osteoporotic fractures and to increase BMD in postmenopausal women with osteoporosis. Discontinuations from ACTIVE were slightly more common in ABL-treated patients due to dizziness, palpitations, nausea, and headache. Post hoc analyses of ACTIVE and ACTIVExtend support the efficacy and safety of ABL in relevant subpopulations including postmenopausal women with various baseline risk factors, women ≥80 years, women with type 2 diabetes mellitus, and women with renal impairment. CONCLUSIONS: ABL is an effective and well-tolerated treatment for women with postmenopausal osteoporosis at high risk for fracture. Its therapeutic effects are sustained with subsequent ALN therapy.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Alendronato/uso terapêutico , Animais , Densidade Óssea/efeitos dos fármacos , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Pós-Menopausa , Fatores de RiscoRESUMO
Osteoporosis is a common and debilitating condition characterized by diminished bone mass and architecture leading to bone fragility. Antiresorptive medicines like bisphosphonates (and less commonly denosumab) are the typical first-line agents for the medical treatment of osteoporosis. However, newer anabolic agents have been shown to improve bone mass and architecture, as well as reduce fracture risk, to a greater degree than traditional antiresorptive therapies. Teriparatide (human recombinant parathyroid hormone (PTH) 1-34, Forteo, Ely Lilly, Indianapolis, IN), which was the first in class to be approved in the United States, is the most widely used anabolic osteoporosis medicine and has shown significant benefit over traditional antiresorptive therapies. However, abaloparatide (synthetic parathyroid-related peptide (PTHrP), Tymlos, Radius Health, Waltham, MA), the second drug in this family, has recently become available for use. In this narrative review, we review the mechanism, effects, and benefits of abaloparatide compared to alternative treatments as well as discuss the current literature in regard to its effect on osteoporosis-related complications in the spine.
Assuntos
Anabolizantes/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose/tratamento farmacológico , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Anabolizantes/farmacologia , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/farmacologia , Difosfonatos/uso terapêutico , Humanos , Osteoporose/prevenção & controle , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Coluna Vertebral , Teriparatida/uso terapêuticoRESUMO
CONTEXT: Abaloparatide is a US Food and Drug Administration-approved parathyroid hormone-related peptide analog for treatment of osteoporosis in postmenopausal women at high risk of fracture. OBJECTIVES: We assessed the cardiovascular safety profile of abaloparatide. DESIGN: Review of heart rate (HR), blood pressure (BP), and cardiovascular-related adverse events (AEs), including major adverse cardiovascular events (MACEs) and heart failure (HF) from: (a) ACTIVE (NCT01343004), a phase 3 trial that randomized 2463 postmenopausal women with osteoporosis to abaloparatide, teriparatide, or placebo for 18 months; (b) ACTIVExtend (NCT01657162), where participants from the abaloparatide and placebo arms received alendronate for 2 years; and (c) a pharmacology study in 55 healthy adults. RESULTS: Abaloparatide and teriparatide transiently increased HR relative to placebo. Following first dose, mean (standard deviation [SD]) HR change from pretreatment to 1 hour posttreatment was 7.9 (8.5) beats per minute (bpm) for abaloparatide, 5.3 (7.5) for teriparatide, and 1.2 (7.1) for placebo. A similar pattern was observed over subsequent visits. In healthy volunteers, HR increase resolved within 4 hours. The corresponding change in mean supine systolic and diastolic BP 1 hour posttreatment was -2.7/-3.6 mmHg (abaloparatide), -2.0/-3.6 (teriparatide), and -1.5/-2.3 (placebo). The percentage of participants with serious cardiac AEs was similar among groups (0.9%-1.0%). In a post hoc analysis, time to first incidence of MACEâ +â HF was longer with abaloparatide (Pâ =â 0.02 vs placebo) and teriparatide (Pâ =â 0.04 vs placebo). CONCLUSIONS: Abaloparatide was associated with transient increases in HR and small decreases in BP in postmenopausal women with osteoporosis, with no increase in risk of serious cardiac AEs, MACE, or HF.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Conservadores da Densidade Óssea/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Insuficiência Cardíaca/induzido quimicamente , Frequência Cardíaca/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Proteína Relacionada ao Hormônio Paratireóideo/efeitos adversos , Idoso , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Proteína Relacionada ao Hormônio Paratireóideo/administração & dosagem , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Pós-Menopausa , Teriparatida/administração & dosagem , Teriparatida/efeitos adversos , Teriparatida/uso terapêutico , Resultado do TratamentoRESUMO
Current osteoporosis medications reduce fractures significantly but have rare and serious adverse effects (osteonecrosis of the jaw, atypical femoral fractures) that may limit their safety for long-term use. Insights from basic bone biology and genetic disorders have led to recent advances in therapeutics for osteoporosis. New approaches now in clinical use include the antisclerostin monoclonal antibody romosozumab, as well as the parathyroid hormone-related peptide analog abaloparatide. Clinical trial data show significant antifracture benefits with recently approved romosozumab. Studies using abaloparatide build on our longstanding experience with teriparatide and the importance of consolidating the bone mineral density gains achieved from an anabolic agent by following it with an antiresorptive. Combination and sequential treatments using osteoporosis medications with different mechanisms of action have also been tested with promising results. On the horizon is the potential for cell-based therapies (e.g., mesenchymal stem cells) and drugs that target the elimination of senescent cells in the bone microenvironment.
Assuntos
Absorciometria de Fóton/métodos , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose/diagnóstico por imagem , Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Densidade Óssea/fisiologia , Conservadores da Densidade Óssea/farmacologia , Denosumab/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Prognóstico , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Resultado do TratamentoRESUMO
OBJECTIVE: To systematically evaluate the effects of bone anabolic therapies (BATs) - specifically, drug therapy with teriparatide, abaloparatide or romosozumab - on fractures, bone mineral density (BMD), and bone metabolites in postmenopausal osteoporosis. METHODS: Six computerized engines were searched through to November 2018. We selected randomized controlled trials (RCTs) evaluating the effect of BATs on postmenopausal osteoporosis and with at least 6 months of follow-up. Controls were placebo, no treatment, or bisphosphonates. Primary outcomes were vertebral and non-vertebral fractures. Secondary outcomes were: BMD determined by dual energy X-ray absorptiometry at total hip, lumbar spine, and femoral neck; N-terminal propeptide of type I procollagen (PINP); C-terminal telopeptide of type I collagen (CTX); and severe adverse events (SAE). We followed the PRISMA guidelines for reporting, and used version 2 of the Cochrane risk-of-bias tool. Frequentist network meta-analyses were performed per outcome. Effects for dichotomous and continuous outcomes were expressed as relative risks and mean differences and their 95% confidence intervals. We used p-scores to rank best treatments per outcome. RESULTS: Sixteen RCTs (nâ¯=â¯18,940) were evaluated. Mean ages ranged between 61 and 74 years, and follow-up times between 6 and 30 months. Four RCTs (nâ¯=â¯971) excluded patients with previous fractures. In contrast to placebo/no treatment, all BATs significantly reduced the risk of vertebral fractures, but no intervention significantly reduced the risk of non-vertebral fractures; abaloparatide ranked better than other interventions for both fracture types (p-scores: 0.95, and 0.89, respectively). All BATs significantly increased BMD at all locations in comparison with placebo/no treatment; romosozumab consistently ranked better than other interventions at all BMD locations (p-scores >0.86). Teriparatide ranked better than other interventions for increasing PINP. No differences in SAE were observed among treatments. CONCLUSIONS: Abaloparatide, romosozumab, and teriparatide are the best treatments, respectively, to reduce vertebral/non-vertebral fractures, increase BMD, and increase bone formation.