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1.
Int J Mol Sci ; 22(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206757

RESUMO

Metastatic bone cancer occurs in every type of cancer but is prevalent in lung, breast, and prostate cancers. These metastases can cause extensive morbidity, including a range of skeletal-related events, often painful and linked with substantial hospital resource usage. The treatment used is a combination of chemotherapy and surgery. However, anticancer drugs are still limited due to severe side effects, drug resistance, poor blood supply, and non-specific drug uptake, necessitating high toxic doses. Bisphosphonates are the main class of drugs utilized to inhibit metastatic bone cancer. It is also used for the treatment of osteoporosis and other bone diseases. However, bisphosphonate also suffers from serious side effects. Thus, there is a serious need to develop bisphosphonate conjugates with promising therapeutic outcomes for treating metastatic bone cancer and osteoporosis. This review article focuses on the biological outcomes of designed bisphosphonate-based conjugates for the treatment of metastatic bone cancer and osteoporosis.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Difosfonatos/uso terapêutico , Osteoporose/tratamento farmacológico , Animais , Conservadores da Densidade Óssea/química , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Difosfonatos/química , Humanos
2.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207275

RESUMO

The aim of the study was to quantify the micro-architectural changes of the jaw bone in response to ovariectomy, exposed or not to bisphosphonate treatment. A total of 47 Wistar rats were ovariectomized (OVX) or sham-operated (shOVX) and exposed to osteoporosis preventive treatment for eight weeks either with bisphosphonates (alendronate, ALN; group OVX-ALN) three days/week at a dose of 2 mg/kg or with saline solution (untreated control condition; group OVX). The bone morphometric parameters of the trabecular jaw bone were assessed using ex vivo micro-computed tomography. The regions of interest investigated in the maxilla were the inter-radicular septum of the second molar and the tuber. The regions quantified in the mandible included the three molar regions and the condyle. A one-way analysis of variance followed by pairwise comparison using Tukey's HSD and the Games-Howell test was conducted to explore significant differences between the groups. In the maxilla, OVX decreased the bone volume in the inter-radicular septum of the second molar. Bisphosphonate treatment was able to prevent this deterioration of the jaw bone. The other investigated maxillary regions were not affected by (un)treated ovariectomy. In the mandible, OVX had a significant negative impact on the jaw bone in the buccal region of the first molar and the inter-radicular region of the third molar. Treatment with ALN was able to prevent this jaw bone loss. At the condyle site, OVX significantly deteriorated the trabecular connectivity and shape, whereas preventive bisphosphonate treatment showed a positive effect on this trabecular bone region. No significant results between the groups were observed for the remaining regions of interest. In summary, our results showed that the effects of ovariectomy-induced osteoporosis are manifested at selected jaw bone regions and that bisphosphonate treatment is capable to prevent these oral bone changes.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Mandíbula/ultraestrutura , Maxila/ultraestrutura , Osteoporose Pós-Menopausa/tratamento farmacológico , Animais , Osso Esponjoso/ultraestrutura , Feminino , Humanos , Ratos , Ratos Wistar
3.
Magy Onkol ; 65(2): 103-111, 2021 Jun 03.
Artigo em Húngaro | MEDLINE | ID: mdl-34081758

RESUMO

The therapeutic impact of KRAS mutations remains controversial in bone metastatic lung adenocarcinoma (LADC). Therefore, our aim was to investigate the effects of KRAS mutational status on overall survival (OS) in these patients according to bisphosphonate therapy (BTx) and radiation therapy (RTx). In total, 134 LADC patients diagnosed with simultaneous bone metastasis were included in this study. The results of the univariate (p=0.008) and multivariate (p=0.004) survival analyses indicated that KRAS mutation is a negative prognostic factor. Both BTx and RTx can increase the OS with a pronounced benefit for patients with KRAS wild-type tumors. Importantly, the concomitant use of BTx and RTx might increase the OS irrespective of KRAS status compared to BTx or RTx alone. In summary, our results might contribute to the development of new therapeutic approaches with regards to KRAS mutational status in bone metastatic LADC.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Colorretais , Neoplasias Pulmonares , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Difosfonatos/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas ras/genética
4.
Medicina (Kaunas) ; 57(5)2021 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-34065104

RESUMO

Medication-related osteonecrosis of the jaw (MRONJ) has become a well-known side effect of antiresorptive, and antiangiogenic drugs commonly used in cancer management. Despite a considerable amount of literature addressing MRONJ, it is still widely accepted that the underlying pathomechanism of MRONJ is unclear. However, several clinical and preclinical studies indicate that infection seems to have a major role in the pathogenesis of MRONJ. Although there is no conclusive evidence for the infection hypothesis yet, available data have shown a robust association between local infection and MRONJ development. This observation is very critical in order to implement policies to reduce the risk of MRONJ in patients under antiresorptive drugs. This critical review was conducted to collect the most reliable evidence regarding the link between local infection and MRONJ pathogenesis.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Neoplasias , Inibidores da Angiogênese , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/tratamento farmacológico , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/epidemiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico
5.
BMJ Case Rep ; 14(6)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34083190

RESUMO

Hypercalcaemia due to immobilisation is an uncommon diagnosis and requires extensive evaluation to rule out common causes of hypercalcaemia such as primary hyperparathyroidism and malignancy.We report an unusual case of profound hypercalcaemia due to immobilisation in a young man due to acute spinal cord ischaemia, leading to paraplegia. Other causes of hypercalcaemia were ruled out and elevated bone turnover markers supported our hypothesis. Conventional treatment with intravenous fluids, bisphosphonates and diuretics was insufficient. Subcutaneous calcitonin lowered the plasma calcium acutely and was continued for 8 weeks. Subsequent normocalcaemia was sustained for 2 years.


Assuntos
Conservadores da Densidade Óssea , Hipercalcemia , Traumatismos da Medula Espinal , Conservadores da Densidade Óssea/uso terapêutico , Calcitonina , Cálcio , Difosfonatos/uso terapêutico , Humanos , Hipercalcemia/diagnóstico , Hipercalcemia/etiologia , Masculino , Traumatismos da Medula Espinal/complicações
6.
Nat Commun ; 12(1): 3247, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059688

RESUMO

The Wnt signaling pathway is intricately connected with bone mass regulation in humans and rodent models. We designed an antibody-based platform that generates potent and selective Wnt mimetics. Using this platform, we engineer bi-specific Wnt mimetics that target Frizzled and low-density lipoprotein receptor-related proteins and evaluate their effects on bone accrual in murine models. These synthetic Wnt agonists induce rapid and robust bone building effects, and correct bone mass deficiency and bone defects in various disease models, including osteoporosis, aging, and long bone fracture. Furthermore, when these Wnt agonists are combined with antiresorptive bisphosphonates or anti-sclerostin antibody therapies, additional bone accrual/maintenance effects are observed compared to monotherapy, which could benefit individuals with severe and/or acute bone-building deficiencies. Our data support the continued development of Wnt mimetics for the treatment of diseases of low bone mineral density, including osteoporosis.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Reabsorção Óssea/tratamento farmacológico , Fraturas do Fêmur/tratamento farmacológico , Osteoporose Pós-Menopausa/tratamento farmacológico , Proteínas Wnt/agonistas , Idoso , Envelhecimento/fisiologia , Animais , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/fisiologia , Conservadores da Densidade Óssea/uso terapêutico , Reabsorção Óssea/fisiopatologia , Difosfonatos/farmacologia , Difosfonatos/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Feminino , Fraturas do Fêmur/patologia , Fêmur/efeitos dos fármacos , Fêmur/lesões , Fêmur/patologia , Humanos , Camundongos , Osteoporose Pós-Menopausa/fisiopatologia , Via de Sinalização Wnt/efeitos dos fármacos , Adulto Jovem
7.
BMC Musculoskelet Disord ; 22(1): 412, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947363

RESUMO

BACKGROUND: Lumbar spinal stenosis (LSS) can cause various neurological symptoms and reduce the daily activity of patients. Many studies have shown that free physical activities and exercise can improve bone mineral density (BMD) in patients with osteoporosis. However, the effect of LSS on BMD has not been reported. The purpose of this study was to investigate the effects of LSS on BMD in patients treated with ibandronate for newly diagnosed osteoporosis. METHODS: Group 1 included 83 patients treated for osteoporosis alone, and group 2 included 76 patients treated for both osteoporosis and symptomatic LSS. We confirmed four BMD values presented as T-score at initial, and 1-, 2-, and 3-year follow-ups. Mean BMD and annual changes of BMD for three years were compared between the two groups. Correlations between initial BMD and total change of BMD, and related factors for continuous BMD improvement for three years were also evaluated. RESULTS: Mean annual BMDs were significantly higher in group 1 compared than in group 2 (-3.39 vs. -3.58 at 1-year; -3.27 vs. -3.49 at 2-year; -3.13 vs. -3.45 at 3-year; all p < 0.05). Annual change of BMD at 1-year follow-up (0.32 vs. 0.21, p = 0.036) and total change of BMD for three years (0.57 vs. 0.35, p = 0.002) were significantly higher in group 1. Group 1 had a strong negative correlation (r = -0.511, P = 0.000) between initial BMD and total change of BMD, whereas group 2 showed a weak negative correlation (r = -0.247, p = 0.032). In multivariate analysis, symptomatic LSS was the only independent risk factor for continuous BMD improvement (Odds ratio = 0.316, p = 0.001). CONCLUSIONS: Symptomatic LSS may interfere with BMD improvement in the treatment of osteoporosis with ibandronate. Active treatment for LSS with more potent treatment for osteoporosis should be taken to increase BMD for patients with osteoporosis and LSS.


Assuntos
Conservadores da Densidade Óssea , Osteoporose , Estenose Espinal , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Humanos , Ácido Ibandrônico , Vértebras Lombares/diagnóstico por imagem , Osteoporose/diagnóstico por imagem , Osteoporose/tratamento farmacológico , Osteoporose/epidemiologia , Estenose Espinal/diagnóstico por imagem , Estenose Espinal/tratamento farmacológico , Resultado do Tratamento
8.
Arch Osteoporos ; 16(1): 60, 2021 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-33813663

RESUMO

We analyzed the long-term persistence of treatment in a FLS. During follow-up, 15.2% of patients had a refracture and 23.8% died. At the 5-year checkup, 74% had started treatment (associated with female sex, previous use of bisphosphonate, and referral to an osteoporosis clinic). Persistence at 1 and 5 years was 70.6% and 46.5%, respectively. INTRODUCTION: To analyze the long-term persistence of treatment in a fracture liaison service (FLS). METHODS: Patients ≥ 50 years with a fragility fracture attended between 2012 and 2016 who were recommended for treatment to prevent new fractures were included. Baseline data included demographics, type of fracture, previous treatment, and FRAX® items. Five years later, patient records were reviewed and the following data were collected: [1] survival; [2] refracture; [3] initiation of treatment, persistence, and medication possession ratio (MPR) > 80%. RESULTS: We included 888 patients, mean age 75 years, 83% women, and mean follow-up 56 months. During follow-up, 135 patients (15.2%) had a refracture (109 major fractures, 50 hip refractures) and 212 patients died (23.8%); at the 5-year checkup, 657 patients (74%) had started some type of treatment. Factors associated with the start of treatment were female sex (OR 2.10; 95% CI: 1.42-3.11), previous use of bisphosphonate (OR 3.91; 95% CI: 2.23-6.86), and referral to an osteoporosis clinic (OR 1.46; 95% CI: 1.02-2.07). Persistence decreased from 70.6% at 12 months to 46.5% at 60 months. An MPR > 80% was confirmed in 449 patients, 68.3% of whom were under treatment. A total of 521 and 447 patients received treatment for at least 24 and 36 months, respectively (79.3% and 68.0% of those who started treatment). CONCLUSIONS: Patients with fragility fractures attended at an FLS showed optimal long-term persistence of treatment. These data can help healthcare managers better calculate the cost-effectiveness of implementing the FLS model.


Assuntos
Conservadores da Densidade Óssea , Osteoporose , Fraturas por Osteoporose , Idoso , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Feminino , Humanos , Masculino , Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/prevenção & controle , Prevenção Secundária
9.
J Bone Miner Metab ; 39(4): 712-718, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33821305

RESUMO

INTRODUCTION: Although bisphosphonates are effective for treating osteoporosis, patient adherence is variable. We conducted this study to determine if prior adherence with another medication used to treat chronic asymptomatic conditions predicts adherence with bisphosphonates. MATERIALS AND METHODS: Retrospective cohort study using linked population-level data for the entire Canadian province of Alberta between April 1, 2009 and March 31, 2017. We examined all new users of an oral or parenteral osteoporosis treatment over the age of 20 who had filled at least one statin prescription in the prior 12 months before the start date of the osteoporosis treatment. Adherence was defined based on medication possession ratio (MPR) and > = 80% was deemed good adherence. Persistence was defined as continuous treatment without an interruption of treatment for more than 56 days. RESULTS: Of 20,612 new users of oral bisphosphonates and 1538 new users of parenteral treatments, prior good adherence with statins was independently associated with both short term [adjusted Odds Ratio (aOR) 1.34 (95% CI 1.26-1.42) at 1 year] and long term [aOR 1.35 (1.20-1.51) at 5 years] adherence with oral bisphosphonates. However, there was no association between prior statin adherence and adherence [OR 0.94 (0.74, 1.20)] or persistence [(OR 0.96 (0.76, 1.22)] with parenteral osteoporosis therapies. Other factors associated with oral bisphosphonate adherence at 1 year included older age, history of bone mineral density scan, and history of pap smear. CONCLUSIONS: Prior adherence to statins is a predictor of subsequent short-term and long-term adherence and persistence with oral bisphosphonates but not parenteral osteoporosis therapies.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Adesão à Medicação , Osteoporose/tratamento farmacológico , Nutrição Parenteral , Idoso , Conservadores da Densidade Óssea/uso terapêutico , Estudos de Coortes , Difosfonatos/uso terapêutico , Feminino , Humanos , Masculino , Razão de Chances , Estudos Retrospectivos
10.
J Bone Miner Metab ; 39(4): 693-699, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33825940

RESUMO

INTRODUCTION: Zoledronic acid (ZA) is an intravenous bisphosphonate used to treat pediatric osteoporosis. Adverse events including hypocalcemia and acute phase reaction (APR) are common following first-infusion. The purpose of this report is to describe implementation of a ZA clinical practice guideline and the subsequent process changes to improve adherence to aspects of the protocol related to safety and efficacy. METHODS: Quality assurance was evaluated by chart review over a 5-year period to compare the prevalence of hypocalcemia and APR to published data. A quality improvement (QI) initiative consisting of process changes including the addition of an endocrine RN to coordinate infusions and a shift to patient/family self-scheduling of infusions was conducted. The effect of the interventions on safety (completion of pre- and post-infusion bloodwork) and efficacy (receipt of all prescribed infusions) outcomes was evaluated. RESULTS: Seventy-two patients received 244 infusions over the period. The frequency of hypocalcemia (22%) and APR (31%) was consistent with prior reports. 99% of patients received pre-infusion bloodwork, 78% received post-first-infusion bloodwork, and 47% received all prescribed infusions. QI initiatives increased the percentage of patients receiving post-first-infusion bloodwork from 67 to 79% and those receiving all infusions from 62 to 74%, but fell short of the goal of 90%. CONCLUSIONS: The implementation of a standardized protocol for ZA use in children was successful in confirming patient eligibility with pre-infusion bloodwork but failed to ensure that patients obtained post-first-infusion bloodwork and received all prescribed infusions. Further efforts to systematize the management of children on ZA are needed.


Assuntos
Ácido Zoledrônico/uso terapêutico , Administração Intravenosa , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/uso terapêutico , Criança , Difosfonatos/uso terapêutico , Feminino , Humanos , Infusões Intravenosas , Masculino , Melhoria de Qualidade , Resultado do Tratamento , Ácido Zoledrônico/administração & dosagem
11.
Sr Care Pharm ; 36(3): 152-158, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33662239

RESUMO

OBJECTIVE: To evaluate the prevalence of bisphosphonate use without a drug holiday and to assess the success of an interdisciplinary approach to manage and discontinue bisphosphonate therapy. SETTING: The study was completed at one rural family medicine center. PRACTICE DESCRIPTION: The practice employs two fulltime pharmacists. Clinical pharmacists' responsibilities include chronic care management as well as collaboration with the team during interdisciplinary clinics. Clinical pharmacists frequently collaborate with other professionals on medication evaluations and quality improvement projects. PRACTICE INNOVATION: The pharmacy team and medical resident collaborated to determine appropriateness of bisphosphonate use. This was a two-phase evaluation. In the first phase, therapies were evaluated based on duration and consistency with guideline recommendations based on a retrospective chart review. In the second phase, the pharmacy and medicine team determined if therapy warranted further continuation or if a drug holiday was needed. The team reached out to providers proactively and provided patient and provider education on discontinuing therapy. MAIN OUTCOME MEASUREMENTS: Patient demographics, bisphosphonate regimen and duration of prescription, frequency of drug holidays, and success rate of therapy discontinuation. RESULTS: Bisphosphonates were prescribed for an average of 4.2 years with 56 patients prescribed therapy for >5 years. Twenty-one of the 56 patients had a history of a drug holiday, and 13 of the 35 remaining patients had therapy discontinued or a drug holiday was initiated based on the team's recommendation. Patients were more likely to be prescribed therapy for >5 years if they were older and had more provider appointments.


Assuntos
Difosfonatos , Assistência Farmacêutica , Difosfonatos/uso terapêutico , Medicina de Família e Comunidade , Humanos , Farmacêuticos , Estudos Retrospectivos
12.
Breast Cancer Res Treat ; 187(2): 477-486, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33755864

RESUMO

PURPOSE: Despite the increasing use of adjuvant bone-modifying agents (BMAs) such as zoledronate and clodronate in the treatment of patients with early stage breast cancer (EBC), little is known about real world practice patterns. A physician survey was performed to address this deficit and determine interest in clinical trials of alternative strategies for BMA administration. METHODS: Canadian oncologists treating patients with EBC were surveyed via an anonymized online survey. The survey collected information on: physician demographics, knowledge and interpretation of adjuvant bisphosphonate guidelines, and real world prescribing practices. Questions also determined thoughts around the design of future adjuvant BMA trials. RESULTS: Of 127 surveyed physicians, 53 eligible invitees responded (response rate 42%). The majority of physicians are offering high-risk postmenopausal patients adjuvant BMAs. The most common BMA regimen was adjuvant zoledronate (45/53, 85%) every 6 months for 3 years. Concerns around toxicities and repeated visits to the cancer centre were perceived as the greatest barriers to adjuvant bisphosphonate use. Respondents were interested in future trials of de-escalation of BMAs comparing a single infusion of zoledronate vs. 6-monthly zoledronate for 3 years. The most favoured primary endpoints for such a trial included disease recurrence and fragility fracture rates. CONCLUSION: Questions around optimal use of adjuvant bisphosphonates in patients with EBC still exist. There is interest among physicians in performing trials of de-escalation of these agents. The results of this survey will assist in designing pragmatic clinical trials to address this question.


Assuntos
Conservadores da Densidade Óssea , Neoplasias da Mama , Oncologistas , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Canadá , Difosfonatos/uso terapêutico , Feminino , Humanos , Recidiva Local de Neoplasia , Inquéritos e Questionários
13.
Clin Ther ; 43(4): 711-719, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33752899

RESUMO

PURPOSE: In patients with primary hyperparathyroidism (PHPT) and severe hypercalcemia, parathyroidectomy remains the only curative therapy. During the coronavirus disease 2019 (COVID-19) pandemic, when many hospital visits are suspended and surgeries cannot be performed, the management of these patients represents a challenging clinical situation. This article presents a literature review and discussion of the pharmacologic management of PHPT and severe hypercalcemia, which can be used as a temporary measure during the COVID-19 pandemic until parathyroidectomy can be performed safely. METHODS: This narrative review was conducted by searching literature on the PubMed, Medline, and Google Scholar databases using the terms primary hyperparathyroidism, hypercalcemia, cinacalcet, bisphosphonates, denosumab, vitamin D, raloxifene, hormone replacement therapy, coronavirus, and COVID-19. FINDINGS: Appropriate monitoring and remote medical follow-up of these patients are essential until the resolution of the pandemic. Cinacalcet is the drug of choice for controlling hypercalcemia, whereas bisphosphonate or denosumab is the drug for improving bone mineral density. Combined therapy with cinacalcet and bisphosphonates or cinacalcet and denosumab should be considered when the effects on serum calcium and bone mineral density are simultaneously desired. IMPLICATIONS: Medical management of PHPT and severe hypercalcemia presents a reasonable alternative for parathyroid surgery during the COVID-19 outbreak and should be instituted until the pandemic ends and surgery can be performed safely.


Assuntos
COVID-19 , Hipercalcemia/tratamento farmacológico , Hiperparatireoidismo Primário/tratamento farmacológico , Densidade Óssea/efeitos dos fármacos , Cálcio/sangue , Cinacalcete/administração & dosagem , Difosfonatos/uso terapêutico , Humanos , Pessoa de Meia-Idade , Paratireoidectomia , Cloridrato de Raloxifeno/uso terapêutico , Vitamina D/farmacologia
14.
Bone ; 148: 115914, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33722772

RESUMO

Osteogenesis imperfecta (OI) is a disease characterised by altered bone tissue material properties together with abnormal micro and macro-architecture and thus bone fragility, increased bone turnover and hyperosteocytosis. Increasingly appreciated are the soft tissue changes, sarcopenia in particular. Approaches to treatment are now multidisciplinary, with bisphosphonates having been the primary pharmacological intervention over the last 20 years. Whilst meta-analyses suggest that anti-fracture efficacy across the life course is equivocal, there is good evidence that for children bisphosphonates reduce fracture risk, increase vertebral size and improve vertebral shape, as well as improving motor function and mobility. The genetics of OI continues to provide insights into the molecular pathogenesis of the disease, although the pathophysiology is less clear. The complexity of the multi-scale interactions of bone tissue with cellular function are gradually being disentangled, but the fundamental question of why increased tissue brittleness should be associated with so many other changes is unclear; ER stress, pro-inflammatory cytokines, accelerated senesence and altered matrix component release might all contribute, but a unifying hypothesis remains elusive. New approaches to therapy are focussed on increasing bone mass, following the paradigm established by the treatment of postmenopausal osteoporosis. For adults, this brings the prospect of restoring previously lost bone - for children, particularly at the severe end of the spectrum, the possibility of further reducing fracture frequency and possibly altering growth and long term function are attractive. The alternatives that might affect tissue brittleness are autophagy enhancement (through the removal of abnormal type I collagen aggregates) and stem cell transplantation - both still at the preclinical stage of assessment. Preclinical assessment is not supportive of targeting inflammatory pathways, although understanding why TGFb signalling is increased, and whether that presents a treatment target in OI, remains to be established.


Assuntos
Fraturas Ósseas , Osteogênese Imperfeita , Adulto , Densidade Óssea , Osso e Ossos , Criança , Difosfonatos/uso terapêutico , Humanos , Osteogênese Imperfeita/tratamento farmacológico
15.
J Bone Miner Metab ; 39(4): 668-677, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33738617

RESUMO

INTRODUCTION: To identify predictors for incident fractures in patients on pharmaceutical treatment for osteoporosis by a secondary analysis of the Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04), which was a 2-year, randomized, parallel-group, controlled trial of minodronate and raloxifene in women with primary osteoporosis. MATERIALS AND METHODS: This was a prospective, observational study using JOINT-04 data, in which biomarkers, such as undercarboxylated osteocalcin (ucOC), N-telopeptide of type 1 collagen, tartrate-resistant acid phosphatase 5b (TRACP-5b), bone alkaline phosphatase, homocysteine, and pentosidine in blood, and physical functions, such as the timed up and go test and one-leg standing test with eyes open (OLST), and the fall risk index, were measured. The relationships of incident morphometric vertebral fractures during the treatment period, as well as prevalent vertebral fractures, and baseline data were analyzed. RESULTS: The full analysis set of the JOINT-04 included 3247 patients (1623 in the minodronate group and 1624 in the raloxifene group). The hazard ratio (95% confidence interval) for incident vertebral fractures over 2 years of pharmacotherapy, adjusted for confounders, was 0.93 (0.90-0.96) for ucOC, 1.15 (1.08-1.23) for TRACP-5b, 1.02 (1.01-1.03) for pentosidine, 0.91 (0.88-0.94) for the OLST, and 1.27 (1.01-1.60) for the fall risk index, which were all independent predictors. CONCLUSION: Evaluating fracture risk for patients with osteoporosis considering these potential risk factors for fracture in addition to the established risk factors may be useful when starting pharmaceutical treatment.


Assuntos
Osteoporose/tratamento farmacológico , Acidentes por Quedas , Idoso , Biomarcadores/metabolismo , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Feminino , Humanos , Imidazóis/uso terapêutico , Análise Multivariada , Osteoporose/complicações , Prevalência , Estudos Prospectivos , Cloridrato de Raloxifeno/uso terapêutico , Fatores de Risco , Fraturas da Coluna Vertebral/tratamento farmacológico , Fraturas da Coluna Vertebral/epidemiologia
16.
Bone ; 147: 115907, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676057

RESUMO

The skeleton is the most common site of secondary disease in breast cancer and prostate cancer, with up to 80% of patients with advanced disease developing bone metastases (BM). The proportion is also substantial in advanced lung cancer (20%-40%). Because of the high prevalence of cancers of the breast, prostate and lung, these cancers account for more than 80% of cases of metastatic bone disease occurring in solid tumours. Metastatic bone disease is associated with greatly increased bone resorption by osteoclasts, leading to moderate to severe pain and other skeletal complications, with major impact on quality of life (QoL). Skeletal Related Events (SREs) have been defined as: pathological long bone or vertebral fractures; spinal cord compression; need for radiation for pain relief or to prevent fracture/spinal cord compression, need for surgery to bone and hypercalcaemia. More recently, Symptomatic Skeletal Events (SSEs) have been defined to monitor QoL. Although there are currently no curative treatments for metastatic bone disease, patients with breast or prostate cancer and BM are now surviving for several years and sometimes longer, and prevention of SREs is the key aim to optimization of QoL. Since their discovery 50 years ago and their introduction more than 30 years ago into the field of metastatic bone disease, a range of oral and intravenous bisphosphonate drugs have made a major contribution to prevention of SREs. Large trials have clearly demonstrated the clinical value of different bisphosphonate-based drugs (including the oral drugs ibandronate and clodronate and intravenous agents such as zoledronate and pamidronate), in treatment of hypercalcaemia of malignancy and the reduction of SREs and SSEs in a range of cancers. Despite the success of denosumab in reducing osteolysis, bisphosphonates also remain mainstay drugs for treatment of metastatic bone disease. Recognizing the 50th Anniversary of the discovery of bisphosphonates, this review focuses on their continuing value in BM treatment and their future potential, for example in providing a bone-targeting vehicle for cytotoxic drugs.


Assuntos
Conservadores da Densidade Óssea , Neoplasias Ósseas , Neoplasias da Mama , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/complicações , Neoplasias Ósseas/tratamento farmacológico , Difosfonatos/uso terapêutico , Humanos , Masculino , Qualidade de Vida , Ácido Zoledrônico
17.
J Med Chem ; 64(3): 1260-1282, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33522236

RESUMO

Bisphosphonates, used for a long time in osteoporosis management, are currently the target of intensive research, from pre-formulation studies to more advanced stages of clinical practice. This review presents an overview of the contributions of this family of compounds to human health, starting with the chemistry and clinical uses of bisphosphonates. Following this, their pharmacology is described, highlighting administration-borne handicaps and undesirable effects. The last three sections of the review describe the research efforts that seek to curb delivery-related issues and expand bisphosphonate use. Innovative routes and strategies of administration, such as nano-encapsulation for oral intake or injectable cements for local or in-bone delivery are presented, as well as the latest results of case studies or preclinical studies proposing new therapeutic indications for the clinically approved bisphosphonates. Finally, a selection of anti-infectious bisphosphonate new drug candidates is shown, with focus on the molecules reported in the last two decades.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Doenças Ósseas/tratamento farmacológico , Difosfonatos/farmacologia , Animais , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/uso terapêutico , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Difosfonatos/administração & dosagem , Difosfonatos/química , Difosfonatos/uso terapêutico , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Humanos
18.
Artigo em Inglês | MEDLINE | ID: mdl-33579002

RESUMO

Denosumab is a human monoclonal antibody that neutralizes RANKL, a cytokine able to interact with the RANK receptor on preosteoclasts and osteoclasts, decreasing their recruitment and differentiation, leading to a decreased bone resorption. The aim of this observational real-life study was to analyze adherence to denosumab therapy and assess its efficacy in increasing bone mineral density (BMD) and modulating biochemical skeletal markers following previous treatments with bisphosphonates in a group of post-menopausal women with osteoporosis. Women were recruited in the specialized center from March 2012 to September 2019. Biochemical markers were recorded at baseline and every six months prior to subsequent drug injection. Dual X-ray absorptiometry was requested at baseline and after 18/24 months. Comparing BMD at baseline and after denosumab therapy in naive patients and in those previously treated with bisphosphonates, a positive therapeutic effect was observed in both groups. The results of our real-life study demonstrate, as expected, that BMD values significantly increased upon denosumab treatment. Interestingly, denosumab showed an increased efficacy in patients previously treated with bisphosphonates. Moreover, biochemical markers data indicate that osteoporotic patients, without other concomitant unstable health conditions, could be evaluated once a year, decreasing the number of specialistic center access.


Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Osteoporose , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Estudos de Coortes , Denosumab/uso terapêutico , Difosfonatos/uso terapêutico , Feminino , Humanos , Osteoporose/tratamento farmacológico , Osteoporose Pós-Menopausa/tratamento farmacológico
19.
Medicine (Baltimore) ; 100(7): e24839, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33607854

RESUMO

BACKGROUND: To systematically evaluate the efficacy of teriparatide and bisphosphonates in preventing fractures in postmenopausal women with osteoporosis. MATERIALS AND METHODS: We performed a systematic search of PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) that compared teriparatide and bisphosphonates for osteoporosis treatment. Searches were performed without language restrictions and included studies from beginning of time to March 2019. Two authors independently screened and extracted the selected article. The quality of the included studies was evaluated using the Cochrane system evaluation method. Data were extracted and analysed using RevMan 5.2 software. RESULTS: Nine RCTs were included for a total of 2990 postmenopausal women with osteoporosis. Of these, 1515 patients were treated with teriparatide and 1475 were treated with bisphosphonates. After pooling the data of 9 studies, there were significant differences between teriparatide and bisphosphonates [relative risk (RR): 0.61, 95% confidence interval (CI) (0.51, 0.74)] in the prevention of fractures according to different follow-up durations (P < .05), whatever alendronate [RR: 0.51, 95% CI (0.27, 0.95)] and other bisphosphonates [RR: 0.63, 95% CI (0.51, 0.77)]. In addition, we found significant differences between teriparatide and bisphosphonates in the prevention of vertebral fractures [RR: 0.47, 95% CI (0.35, 0.64)] and non-vertebral fractures [RR: 0.76, 95% CI (0.58,0.99)]. There were no significant differences in adverse effects between teriparatide and bisphosphonates [RR: 0.89, 95% CI (0.76, 1.03)]. CONCLUSIONS: Based on the results of our meta-analysis, teriparatide was better than bisphosphonates in preventing fractures in postmenopausal women with osteoporosis both in the short-term and long-term follow-up periods. Teriparatide was superior to bisphosphonates in preventing vertebral and non-vertebral fractures. These drugs did not differ in terms of their adverse effects. More high-quality studies are needed to compare other factors such as costs and adverse reactions.


Assuntos
Difosfonatos/uso terapêutico , Fraturas Ósseas/prevenção & controle , Osteoporose Pós-Menopausa/tratamento farmacológico , Teriparatida/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Alendronato/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Estudos de Casos e Controles , Difosfonatos/efeitos adversos , Feminino , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Humanos , Incidência , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto , Fraturas da Coluna Vertebral/epidemiologia , Fraturas da Coluna Vertebral/etiologia , Fraturas da Coluna Vertebral/prevenção & controle , Teriparatida/efeitos adversos , Resultado do Tratamento
20.
Osteoporos Int ; 32(6): 1239-1244, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33624138

RESUMO

Osteogenesis imperfecta (OI) is characterized by bone fragility and increased fracture susceptibility. BMP1 variants have been reported in the rare OI type XIII, specifically referred to herein as BMP1-associated autosomal recessive (AR) OI. We report the clinical presentation and diagnostic evaluation of a patient found to have a novel homozygous variant in BMP1. We also provide an overview of reported BMP1 variants to date, with discussion focusing on the use of bisphosphonate therapy in these patients. A 7-year-old male with speech and motor delay sustained five bilateral tibial fractures with minimal trauma since age 2.5 years. At age 6, he developed severe back pain after a fall. Diffuse spinal osteopenia and multiple vertebral compression fractures (VCF) at T9, L1, L3, and L5 were identified. Total hip BMD was generous (adjusted Z-score* = 1.76), and femoral neck BMD was high (adjusted Z-score* = 2.67). VCFs precluded assessment of lumbar spine BMD. Genetic analysis identified a homozygous missense variant in exon 4 of BMP1 (c.C505T; p.Arg169Cys). Unlike most forms of OI, patients with BMP1-associated AR OI may have normal or paradoxically increased BMD, making BMD and fracture risk correlation difficult. While bisphosphonates (BP) may help reduce recurrent fractures and provide symptomatic relief, the broad phenotypic spectrum and underlying bone pathology, often in the setting of increased BMD, complicate management. HR-pQCT assessment of bone microarchitecture and quality may aid in the decision of BP therapy and subsequent monitoring. Evidence is limited with respect to the effectiveness of BP in this rare form of OI. *Z-score was adjusted for height Z-score.


Assuntos
Fraturas Ósseas , Fraturas por Compressão , Osteogênese Imperfeita , Fraturas da Coluna Vertebral , Densidade Óssea/genética , Criança , Pré-Escolar , Difosfonatos/uso terapêutico , Humanos , Masculino , Mutação , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/genética , Fenótipo , Fraturas da Coluna Vertebral/genética
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