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1.
Drug Deliv ; 30(1): 2164094, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36588399

RESUMO

Low bone mass, degeneration of bone tissue, and disruption of bone microarchitecture are all symptoms of the disease osteoporosis, which can decrease bone strength and increase the risk of fractures. The main objective of the current study was to use a phospholipid-based phase separation in-situ gel (PPSG) in combination with an alendronate sodium nanoemulsion (ALS-NE) to help prevent bone resorption in rats. The effect of factors such as concentrations of the ALS aqueous solution, surfactant Plurol Oleique CC 497, and Maisine CC oil on nanoemulsion characteristics such as stability index and globular size was investigated using an l-optimal coordinate exchange statistical design. Injectable PPSG with the best nanoemulsion formulation was tested for viscosity, gel strength, water absorption, and in-vitro ALS release. ALS retention in the rats' muscles was measured after 30 days. The droplet size and stability index of the optimal nanoemulsion were 90 ± 2.0 nm and 85 ± 1.9%, respectively. When mixed with water, the optimal ALS-NE-loaded PPSG became viscous and achieved 36 seconds of gel strength, which was adequate for an injectable in-situ formulation. In comparison with the ALS solution-loaded in-situ gel, the newly created optimal ALS-NE-loaded PPSG produced the sustained and regulated release of ALS; hence, a higher percentage of ALS remained in rats' muscles after 30 days. PPSG that has been loaded with an ALS-NE may therefore be a more auspicious, productive, and effective platform for osteoporosis treatment than conventional oral forms.


Assuntos
Osteoporose , Animais , Ratos , Alendronato , Emulsões , Osteoporose/tratamento farmacológico , Água
2.
Cochrane Database Syst Rev ; 1: CD002010, 2023 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-36625789

RESUMO

BACKGROUND: Osteoporosis is a disorder of bone mineralisation occurring in about one third of adults with cystic fibrosis. Bisphosphonates can increase bone mineral density and decrease the risk of new fractures in post-menopausal women and people receiving long-term oral corticosteroids. This is an updated version of a previous review. OBJECTIVES: To assess the effects of bisphosphonates on the frequency of fractures, bone mineral density, quality of life, adverse events, trial withdrawals, and survival in people with cystic fibrosis. SEARCH METHODS: We searched the Cystic Fibrosis and Genetic Disorders Group's Trials Register of references (identified from electronic database searches and hand searches of journals and abstract books) on 5 May 2022. We performed additional searches of PubMed, clinicaltrials.gov and the WHO ICTRP (International Clinical Trials Registry Platform) on 5 May 2022. SELECTION CRITERIA: Randomised controlled trials of at least six months duration studying bisphosphonates in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Authors independently selected trials, extracted data and assessed risk of bias in included studies. Trial investigators were contacted to obtain missing data. We judged the certainty of the evidence using GRADE. MAIN RESULTS: We included nine trials with a total of 385 participants (272 adults and 113 children (aged five to 18 years)). Trial durations ranged from six months to two years. Only two of the studies were considered to have a low risk of bias for all the domains.  Bisphosphonates compared to control in people with cystic fibrosis who have not had a lung transplant Seven trials included only adult participants without lung transplants, one trial included both adults and children without lung transplantation (total of 238 adults and 113 children). We analysed adults (n = 238) and children (n = 113) separately. Adults Three trials assessed intravenous bisphosphonates (one assessed pamidronate and two assessed zoledronate) and five trials assessed oral bisphosphonates (one assessed risedronate and four assessed alendronate). Bisphosphonates were compared to either placebo or calcium (with or without additional vitamin D). Data showed no difference between treatment or control groups in new vertebral fractures at 12 months (odds ratio (OR) 0.22, 95% confidence interval (CI) 0.02 to 2.09; 5 trials, 142 participants; very low-certainty evidence) and two trials (44 participants) reported no vertebral fractures at 24 months. There was no difference in non-vertebral fractures at 12 months (OR 2.11, 95% CI 0.18 to 25.35; 4 trials, 95 participants; very low-certainty evidence) and again two trials (44 participants) reported no non-vertebral fractures at 24 months. There was no difference in total fractures between groups at 12 months (OR 0.57, 95% CI 0.13 to 2.50; 5 trials, 142 participants) and no fractures were reported in two trials (44 participants) at 24 months. At 12 months, bisphosphonates may increase bone mineral density at the lumbar spine (mean difference (MD) 6.31, 95% CI 5.39 to 7.22; 6 trials, 171 participants; low-certainty evidence) and at the hip or femur (MD 4.41, 95% 3.44 to 5.37; 5 trials, 155 participants; low-certainty evidence). There was no clear difference in quality of life scores at 12 months (1 trial, 47 participants; low-certainty evidence), but bisphosphonates probably led to more adverse events (bone pain) at 12 months (OR 8.49, 95% CI 3.20 to 22.56; 7 trials, 206 participants; moderate-certainty evidence). Children The single trial in 113 children compared oral alendronate to placebo. We graded all evidence as low certainty. At 12 months we found no difference between treatment and placebo in new vertebral fractures (OR 0.32, 95% CI 0.03 to 3.13; 1 trial, 113 participants) and non-vertebral fractures (OR 0.19, 95% CI 0.01 to 4.04; 1 trial, 113 participants). There was also no difference in total fractures (OR 0.18, 95% CI 0.02 to 1.61; 1 trial, 113 participants). Bisphosphonates may increase bone mineral density at the lumbar spine at 12 months (MD 14.50, 95% CI 12.91 to 16.09). There was no difference in bone or muscle pain (MD 3.00, 95% CI 0.12 to 75.22), fever (MD 3.00, 95% CI 0.12 to 75.22) or gastrointestinal adverse events (OR 0.67, 95% CI 0.20 to 2.26). The trial did not measure bone mineral density at the hip/femur or report on quality of life.  Bisphosphonates compared to control in people with cystic fibrosis who have had a lung transplant One trial of 34 adults who had undergone lung transplantation compared intravenous pamidronate to no bisphosphonate treatment. It did not report at 12 months and we report the 24-month data (not assessed by GRADE). There was no difference in the number of fractures, either vertebral or non-vertebral. However, bone mineral density increased with treatment at the lumbar spine (MD 6.20, 95% CI 4.28 to 8.12) and femur (MD 7.90, 95% CI 5.78 to 10.02). No participants in either group reported either bone pain or fever. The trial did not measure quality of life. AUTHORS' CONCLUSIONS: Oral and intravenous bisphosphonates may increase bone mineral density in people with cystic fibrosis, but there are insufficient data to determine whether treatment reduces fractures. Severe bone pain and flu-like symptoms may occur with intravenous bisphosphonates. Before any firm conclusions can be drawn, trials in larger populations, including children, and of longer duration are needed to determine effects on fracture rate and survival. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids can ameliorate or prevent these adverse events. Future trials should also assess gastrointestinal adverse effects associated with oral bisphosphonates.


Assuntos
Conservadores da Densidade Óssea , Fibrose Cística , Fraturas Ósseas , Dor Musculoesquelética , Osteoporose , Fraturas da Coluna Vertebral , Adulto , Criança , Feminino , Humanos , Alendronato/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Difosfonatos/efeitos adversos , Fraturas Ósseas/prevenção & controle , Dor Musculoesquelética/induzido quimicamente , Osteoporose/tratamento farmacológico , Pamidronato/uso terapêutico , Qualidade de Vida , Ácido Zoledrônico/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
Arch Osteoporos ; 18(1): 18, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36624318

RESUMO

This systematic review (SR) assessed the use of denosumab (Prolia®) to treat osteoporosis in cancer patients receiving endocrine therapy. Denosumab was found to prevent vertebral fractures and improve bone mineral density in cancer patients with osteoporosis. This is the first SR to assess treating osteoporotic cancer patients with denosumab. PURPOSE: This study assessed the effectiveness and safety of denosumab (Prolia®) compared to bisphosphonates (alendronate, ibandronate, risedronate, zoledronate), selective estrogen receptor modulators (SERMs) (bazedoxifene, raloxifene) and placebo for the treatment of osteoporosis in hormone-sensitive cancer patients receiving endocrine therapy (men with prostate cancer [MPC] on hormone ablation therapy [HAT], and women with breast cancer [WBC] on adjuvant aromatase inhibitor therapy [AAIT]). METHODS: Systematic literature searches were conducted in three biomedical databases to identify randomized controlled trials (RCTs). Frequentist network meta-analyses and/or pairwise meta-analyses were performed on predetermined outcomes (i.e., vertebral/nonvertebral fractures, bone mineral density [BMD], mortality, treatment-related adverse events [AEs], serious AEs [SAEs], withdrawal due to treatment-related AEs). RESULTS: A total of 14 RCTs (15 publications) were included. Denosumab was found to prevent vertebral fractures in cancer patients receiving endocrine therapy, relative to placebo. Similarly, denosumab, zoledronate, and alendronate improved BMD at the femoral neck (FN) and lumbar spine (LS) in MPC on HAT, relative to placebo. Denosumab, ibandronate and risedronate improved BMD at the LS and total hip (TH) in WBC on AAIT, relative to placebo. Denosumab and risedronate improved trochanteric (TRO) BMD in WBC on AAIT, relative to placebo. Similarly, denosumab improved FN BMD in WBC on AAIT. CONCLUSION: In MPC on HAT, denosumab (relative to placebo) was effective at preventing vertebral fractures and improving BMD at the FN and LS. Moreover, in WBC on AAIT, denosumab (relative to placebo) improved BMD at the FN, LS, TH, and TRO, as well as prevent vertebral fracture.


Assuntos
Conservadores da Densidade Óssea , Denosumab , Neoplasias , Feminino , Humanos , Masculino , Alendronato/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/efeitos adversos , Denosumab/efeitos adversos , Difosfonatos/efeitos adversos , Hormônios , Ácido Ibandrônico/efeitos adversos , Neoplasias/tratamento farmacológico , Metanálise em Rede , Osteoporose/tratamento farmacológico , Ácido Risedrônico/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Fraturas da Coluna Vertebral/prevenção & controle , Resultado do Tratamento , Ácido Zoledrônico/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
Carbohydr Polym ; 303: 120473, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36657863

RESUMO

A combination of hydrogel materials, and therapeutic agents have been actively reported to facilitate bone defect healing. However, conventionally hydrogels using cross-linker would result in low stability of the hydrogel itself, loss of agents during cross-linking, and complexity of use. In this study, alendronate was tethered to an AlA to improve its bone healing and drug-loading stability. AlA was further functionalized with Ca2+ (AlACa). A mixture of AlACa and alginate formed AlAA hydrogel. The gelation time of AlAA was sufficient for injecting into the defect site. The hydrogel stiffness was controlled, while the stress-relaxation time was fixed. In vitro cell tests demonstrated that the AlAA promoted proliferation and differentiation behaviors. In particular, AlAA showed the best mechanical stiffness with appropriate stress-relaxation and cellular behavior, indicating that it would be beneficial as a scaffold in the bone tissue engineering field.


Assuntos
Hidrogéis , Osteogênese , Hidrogéis/farmacologia , Tecidos Suporte , Alendronato/farmacologia , Cálcio , Engenharia Tecidual , Alginatos/farmacologia
5.
Arch Osteoporos ; 18(1): 19, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36629929

RESUMO

Persistence with initial treatment was highest after 1 year, decreasing afterwards. Persistence was highest for denosumab followed by alendronate. We identified several factors associated with treatment persistence, some of which were the same irrespective of OTx agent, which could help target subgroups of patients in terms of social and healthcare support. PURPOSE: To describe patient characteristics, persistence, and factors associated with the persistence of new users of the bisphosphonates (alendronate, risedronate, and ibandronate) and the RANKL inhibitor denosumab in Denmark. METHODS: A population-based cohort study using health registries (2010-2018). We included alendronate (n = 128,590), risedronate (n = 892), ibandronate (n = 5,855), and denosumab (n = 16,469) users, aged ≥ 50 years. RESULTS: The 1-year persistence was 68.2% in the alendronate cohort; 39.3% in the risedronate cohort; 56.3% in the ibandronate cohort; and 84.0% in the denosumab cohort. The 2-year persistence was 58.7% in the alendronate cohort; 28.0% in the risedronate cohort; 42.9% in the ibandronate cohort; and 71.9% in the denosumab cohort. The 4-year persistence was 46.3%, 15.4%, 29.6%, and 56.9%, respectively. Later years of treatment initiation were associated with lower persistence for alendronate (adjusted odds ratio (OR) with 95% CI was 0.86 (0.81-0.91) in 2016 compared to 2010), but not for risedronate (OR was 1.56 (0.60-4.06), ibandronate (OR was 0.92 (0.71-1.19) or denosumab (OR was 1.11 (0.87-1.43). Older age was associated with higher persistence for all medications and the same goes for the female sex except for ibandronate. Dementia was associated with higher persistence for alendronate but not denosumab, whereas prior osteoporosis treatment (OT) was the opposite. Several comorbidities were associated with lower persistence for alendronate, but not denosumab. CONCLUSION: Persistence was highest for denosumab followed by alendronate. We identified several factors associated with treatment persistence, some of which were the same irrespective of OTx agent, which could help target subgroups of patients in terms of social and healthcare support.


Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Humanos , Feminino , Alendronato/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Ácido Risedrônico/uso terapêutico , Ácido Ibandrônico/uso terapêutico , Estudos de Coortes , Difosfonatos/uso terapêutico , Dinamarca/epidemiologia , Osteoporose Pós-Menopausa/tratamento farmacológico
6.
Int J Nanomedicine ; 17: 6065-6094, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36510618

RESUMO

Osteoporosis is defined as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Because of the systemic nature of osteoporosis, the associated escalation in fracture risk affects virtually all skeletal sites. The problem is serious since it is estimated that more than 23 million men and women are at high risk of osteoporotic-like breakages in the European Union. Alendronate (ALN) is the most commonly prescribed oral nitrogen-containing bisphosphonate (BP) for the prevention and the therapy of osteoporosis. This is also one of the most intensely studied drugs in this field. However, ALN is characterized by restricted oral absorption and bioavailability and simultaneously its administration has serious side-effects (jaw osteonecrosis, irritation of the gastrointestinal system, nausea, musculoskeletal pain, and cardiovascular risks). Therefore, delivery systems enabling controlled release and local action of this drug are of great interest, being widely researched and presented in the literature. In this review, we discuss the current trends in the design of various types of alendronate carriers. Our paper is focused on the most recent developments in the field of nano/biomaterials-based systems for ALN delivery, including nano/microformulations, synthetic/natural polymeric and inorganic materials, hydrogel-based materials, scaffolds, coated-like structures, as well as organic-inorganic hybrids. Topics related to the treatment of complex bone diseases including osteoporosis have been covered in several more general reviews; however, the systems for this particular drug have not yet been discussed in detail.


Assuntos
Conservadores da Densidade Óssea , Osteoporose , Masculino , Feminino , Humanos , Alendronato/química , Materiais Biocompatíveis/uso terapêutico , Osteoporose/tratamento farmacológico , Difosfonatos/uso terapêutico , Osso e Ossos
7.
Medicine (Baltimore) ; 101(48): e32090, 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36482548

RESUMO

BACKGROUND: Glucocorticoid-induced osteoporosis is the most common secondary cause of osteoporosis and the resulting fractures cause significant morbidity. Oral bisphosphonates are currently regarded as first line options on the grounds of their low cost. However, teriparatide has been shown to be superior in its effects on bone mineral density and vertebral fracture risk in glucocorticoid-treated individuals with osteoporosis. We conducted a protocol for systematic review and meta-analysis to assess the effectiveness of alendronate and teriparatide in patients with glucocorticoid-induced osteoporosis. METHODS: The study protocol has been registered on international prospective register of systematic review (PROSPERO registration number: CRD42022371561). The procedure of this protocol will be conducted according to the Preferred Reporting Item for Systematic Review and Meta-analysis Protocols guidance. PubMed, EMBASE, MEDLINE, the Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, Wanfang Database, ClinicalTrials.gov trials registry, and Chinese Clinical Trial Registry will be searched from January 1980 to November 2022. Two authors will assess methodological quality of included studies separately by the Cochrane collaboration's risk of bias tool. We will apply RevMan 5.4 software for statistical analysis. RESULTS: This study will provide a high-quality comprehensive evaluation of the efficacy and safety of alendronate and teriparatide for treating patients with glucocorticoid-induced osteoporosis. CONCLUSION: The conclusion of our systematic review will provide evidence to judge whether teriparatide is an effective intervention for patients with glucocorticoid-induced osteoporosis.


Assuntos
Alendronato , Teriparatida , Humanos , Teriparatida/efeitos adversos , Alendronato/efeitos adversos , Glucocorticoides/efeitos adversos , Revisões Sistemáticas como Assunto , Metanálise como Assunto
8.
Arthritis Res Ther ; 24(1): 265, 2022 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-36494860

RESUMO

Loss of bone is a common medical problem and, while it can be treated with available therapies, some of these therapies have critical side effects. We have previously demonstrated that CGS21680, a selective A2A adenosine receptor agonist, prevents bone loss, but its on-target toxicities (hypotension, tachycardia) and frequent dosing requirements make it unusable in the clinic. We therefore generated a novel alendronate-CGS21680 conjugate (MRS7216), to target the agonist to bone where it remains for long periods thereby diminishing the frequency of administration and curtailing side effects. MRS7216 was synthesized from CGS21680 by sequential activation of the carboxylic acid moiety and reacting with an appropriate amino acid (PEG, alendronic acid) under basic conditions. MRS7216 was tested on C57BL/6J (WT) mice with established osteoporosis (OP) and WT or A2A KO mice with wear particle-induced inflammatory osteolysis (OL). Mice were treated weekly with MRS7216 (10mg/kg). Bone formation was studied after in vivo labeling with calcein/Alizarin Red, and µCT and histology analyses were performed. In addition, human primary osteoblasts and osteoclasts were cultured using bone marrow discarded after hip replacement. Receptor binding studies demonstrate that MRS7216 efficiently binds the A2A adenosine receptor. MRS7216-treated OP and OL mice had significant new bone formation and reduced bone loss compared to vehicle or alendronate-treated mice. Histological analysis showed that MRS7216 treatment significantly reduced osteoclast number and increased osteoblast number in murine models. Interestingly, cultured human osteoclast differentiation was inhibited, and osteoblast differentiation was stimulated by the compound indicating that MRS7216 conjugates represent a novel therapeutic approach to treat osteoporosis and osteolysis.


Assuntos
Reabsorção Óssea , Osteólise , Osteoporose Pós-Menopausa , Feminino , Humanos , Camundongos , Animais , Osteogênese , Alendronato/efeitos adversos , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/patologia , Camundongos Endogâmicos C57BL , Reabsorção Óssea/metabolismo , Osteólise/tratamento farmacológico , Osteólise/prevenção & controle , Osteólise/patologia , Osteoclastos/metabolismo , Modelos Animais de Doenças , Ligante RANK/metabolismo
9.
Age Ageing ; 51(11)2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36413592

RESUMO

BACKGROUND: Osteoporosis is common in older adults leading to fragility fractures at enormous individual and economic cost. Improving long-term adherence with bisphosphonate treatments reduces fracture risk, but adherence rates for first-line oral bisphosphonate alendronate remains low. Although alternative treatment regimens, including annual intravenous infusions are available, patient acceptability remains unclear. Therefore, understanding patients' acceptability and engagement in different bisphosphonate regimens is important to ensure optimal treatment benefits. METHODS: Semi-structured interviews were conducted with 78 patients with a mean age of 69.9 years, who had taken or received bisphosphonates for osteoporosis within the last 24 months. Data analysis included iterative categorisation and used the theoretical framework of acceptability (TFA) to compare the acceptability of treatments regimens. RESULTS: Treatment acceptability and engagement were influenced by the extent to which patients understood the prescribed treatment, and evidence of the treatment working. Acceptability and engagement were compromised when treatment was perceived as burdensome, personal costs were incurred, and patients' values were incompatible with the regimen. The balancing of these factors contributed to patients' ability to cope with the treatment and their emotional responses. Intravenous treatment was generally perceived as easier to understand, more effective, less burdensome with fewer opportunity costs, and a preferable regimen compared with oral bisphosphonates. CONCLUSIONS: Annual intravenous zoledronate bisphosphonate treatment was generally more acceptable to patients, perceived as more straightforward to engage in, although a small portion of patients on oral bisphosphonates were satisfied with treatment. Further research is needed to identify how acceptability and engagement can be optimised.


Assuntos
Conservadores da Densidade Óssea , Fraturas Ósseas , Osteoporose Pós-Menopausa , Osteoporose , Feminino , Humanos , Idoso , Conservadores da Densidade Óssea/efeitos adversos , Osteoporose Pós-Menopausa/induzido quimicamente , Osteoporose/tratamento farmacológico , Difosfonatos/efeitos adversos , Alendronato/efeitos adversos
10.
Aging Clin Exp Res ; 34(11): 2625-2634, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36331798

RESUMO

Oral bisphosphonates are a key intervention in the treatment of osteoporosis and in reducing the risk of fragility fractures. Their use is supported by over 3 decades of evidence; however, patient adherence to oral bisphosphonates remains poor in part due to complex dosing instructions and adverse events, including upper gastrointestinal symptoms. This problem has led to the development of novel oral bisphosphonate formulations. Buffered, effervescent alendronate is dissolved in water and so seeks to reduce upper gastro-intestinal adverse events, and gastro-resistant risedronate aims to reduce the complexity of dosing procedure (e.g. fasting prior to consumption) whilst still maintaining the efficacy of fracture risk reduction. Clinical trials and real-world data have been employed to demonstrate some benefits in terms of reduced upper gastro-intestinal adverse events, adherence, persistence and health economic outcomes. This report describes the result of an ESCEO (European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis) expert working group, which explores where oral bisphosphonates sit in current clinical practice guidelines, review their risk-benefit profile and the consequences of poor adherence before exploring novel oral bisphosphonate formulations and their potential clinical and health economic impact. Further research is required but there are signs that these novel, oral bisphosphonate formulations may lead to improved tolerance of oral bisphosphonates and thus, improved adherence and fracture outcomes.


Assuntos
Fraturas Ósseas , Osteoporose , Humanos , Osteoporose/tratamento farmacológico , Difosfonatos/efeitos adversos , Ácido Risedrônico/uso terapêutico , Alendronato/efeitos adversos
11.
Health Technol Assess ; 26(43): 1-58, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36321501

RESUMO

BACKGROUND: People with avascular necrosis of the hip have very limited treatment options currently available to stop the progression of this disease; this often results in the need for a hip replacement. There is some weak evidence that a class of drugs called bisphosphonates may delay the course of the disease, and this trial was commissioned and set up to provide robust evidence regarding the use of bisphosphonates in adults aged ≥ 18 years with this condition. OBJECTIVES: The aim of the Managing Avascular Necrosis Treatments: an Interventional Study ( MANTIS ) trial was to evaluate the clinical effectiveness and cost-effectiveness of a 12-month course of alendronate in the treatment of avascular necrosis. DESIGN: This was a 66-month, definitive, multisite, two-arm, parallel-group, placebo-controlled, double-blind, randomised controlled trial, with an internal pilot phase. SETTING: Eight secondary care NHS hospitals across the UK. PARTICIPANTS: Planned trial size - 280 adult patients with avascular necrosis. INTERVENTION: Participants in the intervention group received 70 mg of alendronate (an oral bisphosphonate) weekly for 12 months. MAIN OUTCOMES: The main outcomes were Oxford Hip Score at 12 months (short-term outcome) and the time to decision that a hip replacement is required at 36 months (long-term outcome). RESULTS: Twenty-one patients were recruited and randomised to receive either the intervention drug, alendronate, or a placebo-matched tablet. LIMITATIONS: This trial was principally limited by low disease prevalence. Other limitations included the late disease stage at which participants were identified and the rapid progression of the disease. FUTURE WORK: This trial was limited by a low recruitment rate. Avascular necrosis of the hip should be treated as a rare disease. Future trials would need to recruit many more sites and recruit over a longer time period, and, for this reason, a registry may provide a more effective means of collecting data pertaining to this disease. CONCLUSIONS: The MANTIS trial was terminated at the end of the pilot phase, because it did not meet its go/no-go criteria. The main issue was a poor recruitment rate, owing to a lower than expected disease prevalence and difficulties in identifying the condition at a sufficiently early stage. Those patients who were identified and screened either were too advanced in their disease progression or were already taking medication. We would not recommend that a short-term interventional study is conducted on this condition until its prevalence, geographic foci and natural history and better understood. The difficulty of acquiring this understanding is likely to be a barrier in most health-care markets. One means of developing this understanding would be the introduction of a database/registry for patients suffering from avascular necrosis of the hip. TRIAL REGISTRATION: The trial is registered as ISRCTN14015902. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 43. See the NIHR Journals Library website for further project information.


WHAT WAS THE QUESTION?: The Managing Avascular Necrosis Treatments: an Interventional Study ( MANTIS ) trial was designed to compare ways of treating patients with avascular necrosis who are seeking to slow down the deterioration of their condition. Alendronate is a drug routinely available across the NHS in both tablet and injection form, and doctors and scientists believe that it might prevent ongoing hip deterioration and result in fewer patients requiring a total hip replacement. WHAT DID WE DO?: This trial attempted to compare alendronate taken as a tablet with an identical-looking tablet that did not contain any of the drug (a placebo) to find out if alendronate reduced the number of patients requiring a hip replacement and having pain (compared with patients who did not get alendronate). WHAT DID WE FIND?: Patients were willing to participate in the trial but we were able to recruit only a small number to the study. The main reason for this was difficulty in identifying potentially suitable patients and approaching them at the right point in their medical care. This was more challenging than anticipated, particularly because the NHS sites and professionals that patients with this condition seek out are extremely variable in the UK. It was also difficult to locate and identify patients with the condition at an early enough stage, and before they had already started taking the drug. WHAT DOES THIS MEAN?: More information on patients with this rare condition, such as NHS referral pathways, and an understanding of how the condition progresses may help to improve our understanding of this patient group. This information could also help us determine whether or not there is scope to carry out the study in a different way that might enable these patients to be more easily identified.


Assuntos
Alendronato , Avaliação da Tecnologia Biomédica , Adulto , Humanos , Análise Custo-Benefício , Resultado do Tratamento , Necrose
12.
Int J Oral Maxillofac Implants ; 37(7): 1151-1159, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36450020

RESUMO

PURPOSE: To evaluate the effects of ultraviolet (UV) treatment and alendronate immersion on the osseointegration of dental implants and mucosal attachment of dental implant abutments using a mongrel dog model. MATERIALS AND METHODS: A total of 48 sandblasted, large-grit, acid-etched (SLA) titanium dental implants and 48 machined surface healing abutments in four male mongrel dogs were prepared. Implants and healing abutments were divided into four groups (n = 12 per group). The control (CON) group did not undergo additional surface treatments. The UV group was treated with UV for 15 minutes, and the alendronate-immersed (AN) group was soaked in 10-3 M alendronate for 24 hours. The UV treatment and alendronate soaking (UVAN) group was treated with alendronate, followed by UV irradiation. All implants were placed in the mandible of mongrel dogs, and the animals were sacrificed at 4 and 8 weeks postoperatively. Bone-to-implant contact (BIC), bone density, and connective tissue attachment were measured. RESULTS: In cortical bone, the UV group exhibited significantly higher BIC compared to the CON and AN groups (P < .05). In contrast, the AN and UVAN groups did not have significantly higher BIC. In the trabecular bone, there was no statistical difference between the groups. No significant increase in bone density and connective tissue attachment was shown in any group. CONCLUSION: UV treatment of SLA surface implants significantly increased osseointegration in cortical bone. The alendronate immersion did not increase osseointegration, and there was no synergic effect with UV treatment. Further, UV treatment and alendronate immersion of machined healing abutments did not significantly increase connective tissue attachment.


Assuntos
Implantes Dentários , Osseointegração , Masculino , Animais , Cães , Alendronato/farmacologia , Imersão , Membrana Mucosa
13.
Eur J Med Res ; 27(1): 267, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36437468

RESUMO

INTRODUCTION: Osteoporosis is characterized by deterioration of bone microarchitecture and reduced bone mass and can increase the risk of fracture. To reduce this risk, the aim of this study was to compare the combination effects of olive oil and Lepidium sativum compared to the conventional drug therapy alendronate. METHODS: Osteoporosed-induced rat model was established by administration of dexamethasone in female adult albino rats. The serum level of Ca2+, P3+, and osteocalcin was assessed. In addition, histopathological changes and immunohistochemical expression of osteopontin within bone specimens were performed. RESULTS: Our results showed that a combination of olive oil and Lepidium sativum had a beneficial therapeutic effect in the treatment of osteoporosis as compared to alendronate therapy. This was demonstrated by increase of serum Ca2+, P3+, and osteocalcin levels in treated compared to control groups. Intriguingly, the highest effect was noticed in rats that received a combination of olive oil and Lepidium sativum compared to the individual treatment. This was reflected by an increase in the cortical bone thickness and a decrease in immunohistochemical expression of osteopontin compared to individual treated groups. CONCLUSION: We concluded that the administration of a combination of olive oil and Lepidium sativum improves bone mineral health and intensity and reduces the risk of osteoporosis in a rat model.


Assuntos
Lepidium sativum , Osteoporose , Animais , Azeite de Oliva/farmacologia , Azeite de Oliva/uso terapêutico , Osteopontina/genética , Osteopontina/uso terapêutico , Alendronato/farmacologia , Alendronato/uso terapêutico , Osteocalcina/uso terapêutico , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico , Dexametasona/uso terapêutico
14.
Int J Mol Sci ; 23(22)2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36430791

RESUMO

Synthetic implants are used to treat large bone defects that are often unable to regenerate, for example those caused by osteoporosis. It is necessary that the materials used to manufacture them are biocompatible and resorbable. Polymer-ceramic composites, such as those based on poly(L-lactide) (PLLA) and calcium phosphate ceramics (Ca-P), are often used for these purposes. In this study, we attempted to investigate an innovative strategy for two-step (dual) modification of composites and their components to improve the compatibility of composite components and the adhesion between PLA and Ca-P whiskers, and to increase the mechanical strength of the composite, as well as improve osteological bioactivity and prevent bone resorption in composites intended for bone regeneration. In the first step, Ca-P whiskers were modified with a saturated fatty acid namely, lauric acid (LA), or a silane coupling agent γ-aminopropyltriethoxysilane (APTES). Then, the composite, characterized by the best mechanical properties, was modified in the second stage of the work with an active chemical compound used in medicine as a first-line drug in osteoporosis-sodium alendronate, belonging to the group of bisphosphonates (BP). As a result of the research covered in this work, the composite modified with APTES and alendronate was found to be a promising candidate for future biomedical engineering applications.


Assuntos
Osteoporose , Silanos , Humanos , Alendronato/farmacologia , Porosidade , Poliésteres/química , Osteoblastos
15.
Nutrients ; 14(20)2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36296984

RESUMO

Chronic glucocorticoid (GC) therapy is the most common cause of iatrogenic osteoporosis and represents an important risk factor for osteoporosis and bone fractures. New therapeutic approaches are required in order to treat osteoporosis and reduce the side effects related to the use of anti-osteoporotic drugs. In this context, previous studies reported the efficacy of some isoflavones and carotenoids, such as lycopene and genistein, on the reduction of the risk of fracture related to osteoporosis. The aim of this study was to investigate the effects of a combined oral treatment, consisting of genistein and lycopene, in an experimental model of glucocorticoid-induced osteoporosis (GIO). GIO was induced by subcutaneous injection of methylprednisolone (MP, 30 mg/kg) for 60 days, whereas the control group (Sham) received saline solution only. Following induction, MP animals randomly were assigned to receive alendronate, genistein, lycopene, or the association of genistein and lycopene or saline solution for additional 60 days together with MP. Femurs obtained from the Sham group were used for osteoblasts extraction; they were then incubated with dexamethasone (DEX) for 24 h to be then treated with lycopene or genistein or the association of lycopene and genistein for an additional 24 h. Treatments with lycopene and genistein restored the impaired mineralization of cells observed following DEX treatment and stimulated osteoblast differentiation by increasing the depressed expression of bALP and RUNX2 (p < 0.0001). Wnt5a, ß-catenin, and Nrf-2 expression were significantly increased following genistein and lycopene treatment (p < 0.0001), thus confirming their antioxidant activity as well as their ability in stimulating osteoblast function, mostly when genistein and lycopene were used in association. The combined treatment of genistein and lycopene improved the bone damage induced by glucocorticoids and significantly restored the normal architecture of bones as well as adequate interconnectivity of bone trabeculae, thus increasing bone mineral density parameters. The obtained data demonstrated that genistein and lycopene but in particular their association might prevent GC's adverse effects, thus stimulating bone formation and reducing bone resorption, improving bone structure and microarchitecture, through different molecular pathways, such as the Wnt/ß-catenin and the Nrf-2 signaling.


Assuntos
Glucocorticoides , Osteoporose , Animais , Alendronato/farmacologia , Antioxidantes/metabolismo , beta Catenina/metabolismo , Densidade Óssea , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Dexametasona/farmacologia , Suplementos Nutricionais , Genisteína/farmacologia , Glucocorticoides/farmacologia , Licopeno/farmacologia , Metilprednisolona/efeitos adversos , Osteoblastos , Osteogênese , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico
16.
Nutrients ; 14(20)2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36297038

RESUMO

Bone is a dynamic tissue that maintains homeostasis with a balance of osteoclasts for bone resorption and osteoblasts for bone formation. Women are deficient in estrogen after menopause, which promotes bone resorption due to excessive activity of osteoclasts, leading to osteoporosis. TH (also known as dandelion) is native to warm regions and has traditionally been used to treat gynecological diseases and inflammation. Menopause is a major cause of osteoporosis as it causes abnormal activity of osteoclasts, and various studies have shown that anti-inflammatory drugs have the potential to treat osteoporosis. We analyzed the effect of TH on osteoclast differentiation and the relevant mechanisms using RANKL. After administration of TH in a menopause-like rat model in which ovariectomy of the was rats carried out, changes in bone microstructure were analyzed via micro-CT, and the antiosteoporosis effect of TH was verified by a histological analysis. In addition, the pharmacological effects of TH in an animal model of osteoporosis were compared and analyzed with osteoporosis medications (17ß-estradiol (E2) and alendronate (ALN)). TH significantly inhibited the initial osteoclast differentiation via the NFATc1/c-Fos mechanism. In addition, bone density in the femur of osteoporotic rats was increased, and the expression of osteoclast-related factors in the serum and tissues was controlled. The results of this study provide objective evidence of the inhibitory effect of TH on osteoclastogenesis and OVX-induced bone loss.


Assuntos
Reabsorção Óssea , Osteoporose , Feminino , Humanos , Ratos , Animais , Osteoclastos , Alendronato/farmacologia , Ligante RANK/metabolismo , Reabsorção Óssea/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Osteoporose/patologia , Ovariectomia/efeitos adversos , Osteogênese , Anti-Inflamatórios/farmacologia , Estrogênios/farmacologia , Estradiol/farmacologia , Diferenciação Celular
17.
J Nanobiotechnology ; 20(1): 220, 2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36310171

RESUMO

BACKGROUND: Glucocorticoids (GCs) overuse is associated with decreased bone mass and osseous vasculature destruction, leading to severe osteoporosis. Platelet lysates (PL) as a pool of growth factors (GFs) were widely used in local bone repair by its potent pro-regeneration and pro-angiogenesis. However, it is still seldom applied for treating systemic osteopathia due to the lack of a suitable delivery strategy. The non-targeted distribution of GFs might cause tumorigenesis in other organs. RESULTS: In this study, PL-derived exosomes (PL-exo) were isolated to enrich the platelet-derived GFs, followed by conjugating with alendronate (ALN) grafted PEGylated phospholipid (DSPE-PEG-ALN) to establish a bone-targeting PL-exo (PL-exo-ALN). The in vitro hydroxyapatite binding affinity and in vivo bone targeting aggregation of PL-exo were significantly enhanced after ALN modification. Besides directly modulating the osteogenic and angiogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and endothelial progenitor cells (EPCs), respectively, PL-exo-ALN also facilitate their coupling under GCs' stimulation. Additionally, intravenous injection of PL-exo-ALN could successfully rescue GCs induced osteoporosis (GIOP) in vivo. CONCLUSIONS: PL-exo-ALN may be utilized as a novel nanoplatform for precise infusion of GFs to bone sites and exerts promising therapeutic potential for GIOP.


Assuntos
Exossomos , Células-Tronco Mesenquimais , Osteoporose , Humanos , Exossomos/metabolismo , Glucocorticoides/metabolismo , Células-Tronco Mesenquimais/metabolismo , Osteogênese , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico , Alendronato/farmacologia
18.
Am J Sports Med ; 50(13): 3649-3659, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36259712

RESUMO

BACKGROUND: Osteoporosis is an independent risk factor for failure after arthroscopic rotator cuff repair. Since rerupture rates after rotator cuff repair are associated with decreased bone mineral density and bone microarchitecture, adaptations of biomechanical properties of the rotator cuff enthesis in patients with osteoporosis remain unclear. Additionally, the effects of osteogenic therapy carrier drugs used for the treatment of osteoporosis on rotator cuff structure and properties have not been previously documented. PURPOSE: To investigate the changes to soft tissue biomechanics and insertional structure secondary to osteoporosis with and without an osteogenic therapy carrier (ie, modified alendronate). STUDY DESIGN: Controlled laboratory study. METHODS: Biomechanical, histopathological, and microcomputed tomography analyses were performed on 20 shoulders obtained from 10 osteoporotic sheep randomly allocated to modified bisphosphonate (ie, alendronate) or control (ie, osteoporotic without treatment) groups; 6 shoulders from healthy sheep were utilized for comparison purposes. RESULTS: Tendons from the control group exhibited a 57% decrease in undeformed Young modulus as compared with the healthy group (P = .010). Tendons from the modified bisphosphonate treatment group exhibited a 229% increase in initial Young modulus as compared with the control group (P = .010). Marked changes within the tendon insertional organization were noted in both the control and the modified bisphosphonate treatment group samples as evidenced by increased interdigitation of the bone-mineralized fibrocartilaginous junction. The control samples exhibited a markedly paucicellular insertion, whereas the modified bisphosphonate treated tendons exhibited a hypercellular insertional region as compared with the healthy group. Both groups exhibited significantly (P < .01) decreased bone quality underlying the infraspinatus insertion, as evidenced by all microcomputed tomography outcome parameters. CONCLUSION: This work illuminates changes to rotator cuff tendon secondary to osteoporosis. Specifically, it revealed decreased tendon modulus and altered insertional structure in the osteoporotic samples. Secondarily, these data revealed increases in tendon modulus accompanied by increased cellularity within the tendon insertion region after systemic modified bisphosphonate injections. CLINICAL RELEVANCE: Bisphosphonate treatment may have a positive effect on the healing of the enthesis after rotator cuff repair.


Assuntos
Osteoporose , Lesões do Manguito Rotador , Animais , Alendronato , Manguito Rotador/cirurgia , Lesões do Manguito Rotador/cirurgia , Ovinos , Microtomografia por Raio-X
19.
Clin Geriatr Med ; 38(4): 715-726, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36210087

RESUMO

In older adults, polypharmacy and osteoporosis frequently occur contemporaneously. Polypharmacy is increasingly recognized as a risk factor for hip and fall-related fractures. Treatments for osteoporosis include antiresorptive (alendronate, risedronate, zoledronic acid, ibandronate, denosumab) and osteoanabolic (teriparatide, abaloparatide, romosozumab) agents. Polypharmacy is associated with worse adherence to pharmacologic therapy. Thus, the selection of osteoporosis treatment should be individualized and based on a variety of factors, including underlying fracture risk (high vs very high risk), medical comorbidities, medication burden, as well as fracture risk reduction profiles, modes of administration, and side effects of treatment options.


Assuntos
Conservadores da Densidade Óssea , Fraturas Ósseas , Osteoporose , Fraturas por Osteoporose , Idoso , Alendronato/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Denosumab/uso terapêutico , Difosfonatos/efeitos adversos , Humanos , Ácido Ibandrônico/uso terapêutico , Osteoporose/tratamento farmacológico , Polimedicação , Ácido Risedrônico/uso terapêutico , Teriparatida/uso terapêutico , Ácido Zoledrônico/uso terapêutico
20.
Clin Nephrol ; 98(5): 219-228, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36200936

RESUMO

67% of CKD5D patients have low bone mass and present with high (HTO) or non-high (N-HTO) bone turnover. HTO has excessive resorption calling for anti-resorbers, while in N-HTO, anabolic therapy appears preferable. There are no data on this tailored approach. Adult CKD5D patients with dual energy X-ray absorptiometry (DXA) t-scores ≤ -1.0 were enrolled into this 12-month randomized controlled trial and stratified as HTO or N-HTO using values of parathyroid hormone (PTH), PTH-ratio, and TRAP5b. HTO patients were randomized into treatment with alendronate or controls, and N-HTO patients into teriparatide or controls. Clinical, lab, DXA, quantitative computed tomography bone mineral density (QCT BMD), and coronary artery calcifications (CAC) and aorta calcifications (AoC) MSQCT data were obtained at 0 and 12 months. Primary outcome was change (Δ) in BMD by QCT, secondary outcomes were changes in CAC (ΔCAC), in AoC (ΔAoC), and death. There were 80 HTO and 61 N-HTO patients. Median HTO baseline PTH was 664 and N-HTO 183. Bone loss improved in treated N-HTO (5.7 g/cm3 vs. -10.7) but not in HTO (0.2 g/cm3 vs. -3.5) patients. There were no differences in ΔAoC or ΔCAC between treatment groups in either arm. Across all patients in the study, ΔAoC was lower in Blacks than Whites. (3.6 vs. 8.8) The HTO ΔAoC was 5 Hounsfield Units higher than N-HTO. In N-HTO, there were 0 deaths, but 20% in HTO (p = 0.005). N-HTO patients (PTH range 138 - 337 pg/mL) had better survival and less ΔAoC than those with HTO. Teriparatide treatment significantly improved low bone mass in N-HTO patients. Blacks had less ΔAoC regardless of turnover or treatment.


Assuntos
Doenças Ósseas Metabólicas , Insuficiência Renal Crônica , Adulto , Humanos , Absorciometria de Fóton , Alendronato/uso terapêutico , Densidade Óssea , Doenças Ósseas Metabólicas/tratamento farmacológico , Doenças Ósseas Metabólicas/etiologia , Remodelação Óssea , Hormônio Paratireóideo , Teriparatida/uso terapêutico , Insuficiência Renal Crônica/complicações
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