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1.
Yakugaku Zasshi ; 140(1): 63-79, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-31902887

RESUMO

Since the first report in 2003, bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been increasing, without effective clinical strategies. Osteoporosis is common in elderly women, and bisphosphonates (BPs) are typical and widely used anti-osteoporotic or anti-bone-resorptive drugs. BRONJ is now a serious concern in dentistry. As BPs are pyrophosphate analogues and bind strongly to bone hydroxyapatite, and the P-C-P structure of BPs is non-hydrolysable, they accumulate in bones upon repeated administration. During bone-resorption, BPs are taken into osteoclasts and exhibit cytotoxicity, producing a long-lasting anti-bone-resorptive effect. BPs are divided into nitrogen-containing BPs (N-BPs) and non-nitrogen-containing BPs (non-N-BPs). N-BPs have far stronger anti-bone-resorptive effects than non-N-BPs, and BRONJ is caused by N-BPs. Our murine experiments have revealed the following. N-BPs, but not non-N-BPs, exhibit direct and potent inflammatory/necrotic effects on soft-tissues. These effects are augmented by lipopolysaccharide (the inflammatory component of bacterial cell-walls) and the accumulation of N-BPs in jawbones is augmented by inflammation. N-BPs are taken into soft-tissue cells via phosphate-transporters, while the non-N-BPs etidronate and clodronate inhibit this transportation. Etidronate, but not clodronate, has the effect of expelling N-BPs that have accumulated in bones. Moreover, etidronate and clodronate each have an analgesic effect, while clodronate has an anti-inflammatory effect via inhibition of phosphate-transporters. These findings suggest that BRONJ may be induced by phosphate-transporter-mediated and infection-promoted mechanisms, and that etidronate and clodronate may be useful for preventing and treating BRONJ. Our clinical trials support etidronate being useful for treating BRONJ, although additional clinical trials of etidronate and clodronate are needed.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/prevenção & controle , Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/tratamento farmacológico , Conservadores da Densidade Óssea/metabolismo , Conservadores da Densidade Óssea/uso terapêutico , Ensaios Clínicos como Assunto , Ácido Clodrônico/química , Ácido Clodrônico/metabolismo , Ácido Clodrônico/farmacologia , Ácido Clodrônico/uso terapêutico , Difosfonatos/química , Difosfonatos/metabolismo , Difosfonatos/uso terapêutico , Ácido Etidrônico/química , Ácido Etidrônico/metabolismo , Ácido Etidrônico/farmacologia , Ácido Etidrônico/uso terapêutico , Humanos , Inflamação , Arcada Osseodentária/metabolismo , Camundongos , Nitrogênio , Proteínas de Transporte de Fosfato/antagonistas & inibidores , Ratos
2.
Biomed Res Int ; 2019: 2594149, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828096

RESUMO

Purpose: To investigate the comparative efficacies of the five most commonly used bisphosphonates for the secondary prevention of osteoporotic fractures in a Bayesian network meta-analysis. Methods: Five databases and the reference lists of all acquired articles from inception to July 2017 were searched. A Bayesian random-effects model was employed, and vertebral, hip and nonvertebral nonhip fractures were assessed by odds ratios (ORs) and 95%credible intervals. Furthermore, with respect to each endpoint, rank probabilities for each bisphosphonate were evaluated using the surface under the cumulative ranking curve (SUCRA) value. Results: Thirteen eligible studies were identified involving 11,822 patients with osteoporotic fractures. Overall in the pairwise meta-analyses, bisphosphonate use significantly reduced the risk of new vertebral, hip, and nonvertebral nonhip fractures, with ORs and 95% confidence intervals of 0.56 (0.49-0.64), 0.69 (0.48-0.98), and 0.82 (0.70-0.97), respectively. In network meta-analyses, significant differences were found between placebo and any one of the five bisphosphonates for new vertebral fractures. The rank probability plot and the SUCRA calculation results suggested that alendronate was the best intervention (14.6%) for secondary prevention of vertebral fractures, followed by zoledronate (15.3%) and etidronate (22.1%). In terms of the incidence of new hip fractures, alendronate was associated with the lowest incidence (18.5%), followed by zoledronate (43.1%) and risedronate (52.5%). However, zoledronate ranked lowest (16.6%) regarding the incidence of new nonvertebral nonhip fractures, followed by risedronate (23.8%) and alendronate (44.1%). Conclusions: Bisphosphonates show significant efficacy for secondary prevention of new vertebral fractures, and alendronate is most likely to be successful at secondary prevention of vertebral and hip fractures compared with the other four bisphosphonates.


Assuntos
Difosfonatos/uso terapêutico , Fraturas por Osteoporose/tratamento farmacológico , Idoso , Alendronato/uso terapêutico , Teorema de Bayes , Conservadores da Densidade Óssea/uso terapêutico , Ácido Etidrônico/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Ácido Risedrônico/uso terapêutico , Prevenção Secundária/métodos , Ácido Zoledrônico/uso terapêutico
3.
Osteoporos Int ; 30(11): 2311-2319, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31317249

RESUMO

Characteristics of patients starting oral bisphosphonate therapy changed over time, reflecting trends in osteoporosis management (e.g., new drugs to market), and general healthcare delivery (e.g., benzodiazepine use declined, statin use increased). When designing studies that examine osteoporosis drug effects, potential time-related biases must be considered. INTRODUCTION: To describe the type of oral bisphosphonate initiated and characteristics of patients starting oral bisphosphonate therapy over time. METHODS: We identified community-dwelling older adults (ages ≥ 66 years) initiating oral bisphosphonate therapy from April 1996 to March 2016 (1996 to 2015 fiscal years) using healthcare administrative data in Ontario. Patients with conditions other than osteoporosis that may impact bisphosphonate prescribing were excluded. The bisphosphonate initiated and patient characteristics were summarized by fiscal year and stratified by sex. RESULTS: We identified 560,817 eligible patients (81% women). Most patients initiated cyclical etidronate from 1996 until 2005, and then weekly regimens became dominant. In 2008, risedronate became the main oral bisphosphonate (46% risedronate, 43% alendronate, 11% etidronate); with its use increasing after availability of monthly and delayed-release risedronate formulations. In 2015, 71% of patients started risedronate, 28% started alendronate, and less than 2% started etidronate. Characteristics of patients changed over time, reflecting changes in osteoporosis management and general healthcare delivery. Over time, a larger proportion of men (9% to 28%) and patients with diabetes (women 10% to 17%, men 14% to 22%) initiated therapy; benzodiazepine (women 22% to 13%, men 20% to 10%) and estrogen-based hormone replacement therapy (12% to 15% of women 1996-2002 to 3% since 2008) decreased, while statin use increased (women 15% to 39%, men 14% to 52%). CONCLUSIONS: The characteristics of patients starting oral bisphosphonate therapy have changed over time. Consideration must be given to these time trends when designing studies that examine osteoporosis drug effects.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Osteoporose/tratamento farmacológico , Osteoporose/epidemiologia , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Alendronato/uso terapêutico , Esquema de Medicação , Ácido Etidrônico/uso terapêutico , Feminino , Humanos , Masculino , Ontário/epidemiologia , Farmacoepidemiologia/tendências , Ácido Risedrônico/uso terapêutico , Fatores Sexuais , Fatores de Tempo
4.
J Bone Miner Metab ; 37(5): 796-804, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30712064

RESUMO

In patients with chronic kidney disease (CKD) or those undergoing hemodialysis, pathological calcific deposition known as ectopic calcification occurs in soft tissue, resulting in a life-threatening disorder. A potent and effective inhibitor of ectopic calcification is eagerly expected. In the current study, the effects of FYB-931, a novel bisphosphonate compound synthesized for the prevention of ectopic calcification, were compared with those of etidronate using both in vitro and in vivo models. In vitro, FYB-931 inhibited calcification of human aortic smooth muscle cells induced by high phosphate medium in a concentration-dependent manner, and the effect was slightly more potent than that of etidronate. In vivo, rats were administered with three subcutaneous injections of vitamin D3 to induce vascular calcification, and were given FYB-931 (1.5, 5, or 10 mg/kg) or etidronate (9, 30, or 60 mg/kg) orally once daily for 14 days. The increased aortic phosphorus content as an index of vascular calcification was inhibited by both FYB-931 and etidronate in a dose-dependent manner; however, FYB-931 was 10 times more potent than etidronate. FYB-931 inhibited serum tartrate-resistant acid phosphatase (TRACP) activity as a bone resorption marker 5.2 times more potently than etidronate. FYB-931, but not etidronate, significantly decreased serum phosphorus levels. The preferential inhibition of aortic calcification by FYB-931 suggested that possible additional effect including a decline in serum phosphorus may lead to an advantage in terms of its efficacy.


Assuntos
Aorta/patologia , Colecalciferol/uso terapêutico , Difosfonatos/uso terapêutico , Calcificação Vascular/tratamento farmacológico , Animais , Biomarcadores/sangue , Reabsorção Óssea/sangue , Reabsorção Óssea/complicações , Reabsorção Óssea/patologia , Células Cultivadas , Colecalciferol/farmacologia , Difosfonatos/química , Difosfonatos/farmacologia , Ácido Etidrônico/farmacologia , Ácido Etidrônico/uso terapêutico , Humanos , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Ratos Wistar , Fosfatase Ácida Resistente a Tartarato/metabolismo , Calcificação Vascular/sangue , Calcificação Vascular/complicações , Calcificação Vascular/patologia
5.
Osteoporos Int ; 30(4): 817-828, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30607457

RESUMO

In this prospective cohort of 6120 participants aged 50+, nitrogen-bisphosphonates but not non-nitrogen bisphosphonates were associated with a significant 34% mortality risk reduction compared to non-treated propensity score matched controls. These findings open new avenues for research into mechanistic pathways. INTRODUCTION: Emerging evidence suggests that bisphosphonates (BP), first-line treatment of osteoporosis, are associated with reduced risks for all-cause mortality. This study aimed to determine the association between different BP types and mortality risk in participants with or without a fracture. METHODS: A prospective cohort study of users of different BPs matched to non-users by propensity score (age, gender, co-morbidities, fragility fracture status) and time to starting the BP medication from the population-based Canadian Multicentre Osteoporosis Study from nine Canadian centres followed from 1995 to 2013. Mortality risk for bisphosphonate users vs matched non-users was assessed using pairwise multivariable Cox proportional hazards models. RESULTS: There were 2048 women and 308 men on BP and 1970 women and 1794 men who did not receive medication for osteoporosis. The relationship between BP and mortality risk was explored in three separate 1:1 propensity score-matched cohorts of BP users and no treatment (etidronate, n = 599, alendronate, n = 498, and risedronate n = 213). Nitrogen BP (n-BP) (alendronate and risedronate) was associated with lower mortality risks [pairwise HR, 0.66 (95% CI, 0.48-0.91)] while the less potent non-n-BP, etidronate, was not [pairwise HR: 0.89 (95% CI, 0.66-1.20)]. A direct comparison between n-BP and etidronate (n = 340 pairs) also suggested a better survival for n-BP [paired HR, 0.47 (95%CI, (95% CI, 031-0.70)] for n-BP vs. etidronate]. CONCLUSION: Compared to no treatment, nitrogen but not non-nitrogen bisphosphonates appear to be associated with better survival.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Idoso , Alendronato/uso terapêutico , Canadá/epidemiologia , Ácido Etidrônico/uso terapêutico , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Osteoporose/mortalidade , Fraturas por Osteoporose/mortalidade , Estudos Prospectivos , Ácido Risedrônico/uso terapêutico , Fatores de Risco , Comportamento de Redução do Risco
6.
Int Endod J ; 52(2): 237-243, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30030844

RESUMO

AIM: To compare solutions of di- and tetrasodium ethylenediaminetetraacetic acid (EDTA) and 1-hydroxyethane-1,1-diphosphonic acid (HEDP) regarding their ability to solubilize calcium from dentine and remove smear layer. METHODOLOGY: Solutions with a molarity corresponding to that of 17% Na2 EDTA (pH adjusted to 8.5) were prepared by dissolving Na2 and Na4 salts of HEDP (etidronate), or Na4 EDTA in deionized water. Standardized root dentine discs covered by a smear layer were prepared from human third molars. These discs (n = 10 per group) were immersed in test solutions or phosphate-buffered saline for 1 min. The dissolved Ca2+ was determined by atomic absorption spectroscopy, apparently opened dentinal tubules by laser scanning microscopy and automated image analysis. Ca2+ values were compared between groups by parametric, tubular areas by nonparametric methods, α = 0.05. RESULTS: Solutions prepared from the tetrasodium salts were alkaline (pH 11.3-11.4), whilst counterparts made from the disodium salts were acidic. The EDTA solutions dissolved more calcium than the HEDP counterparts (P < 0.05); solutions prepared with the disodium salts dissolved more calcium than those made from the tetrasodium salts (P < 0.05). There was a high correlation between dissolved calcium and the apparently opened tubular areas (Spearman's ρ = 0.81). Differences between groups regarding opened tubules were similar to those observed regarding the Ca2+ values, with a slightly reduced discerning power due to high variance. CONCLUSION: Calcium chelation and thus smear layer removal by EDTA and HEDP are influenced by pH.


Assuntos
Dentina/efeitos dos fármacos , Ácido Edético/uso terapêutico , Ácido Etidrônico/uso terapêutico , Camada de Esfregaço/terapia , Cálcio/análise , Quelantes , Dentina/patologia , Humanos , Concentração de Íons de Hidrogênio , Microscopia Confocal , Dente Serotino , Irrigantes do Canal Radicular/uso terapêutico , Raiz Dentária/efeitos dos fármacos
7.
Naunyn Schmiedebergs Arch Pharmacol ; 392(3): 349-357, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30515539

RESUMO

Etidronate is widely used as a therapeutic agent for osteoporosis. We have recently shown that intrathecal administration of etidronate into mice produces an analgesic effect against the capsaicin-induced nociceptive behavior. However, the effect of etidronate on neuropathic pain at the spinal level remains unknown. Therefore, we examined whether etidronate attenuates pain after partial sciatic nerve ligation (PSNL). We evaluated tactile allodynia 7 days after PSNL by measuring paw withdrawal with the von Frey filament test. The mRNA and protein levels of SLC17A9 in the ipsilateral lumbar dorsal spinal cord of PSNL-operated mice were determined using real-time PCR and western blotting, respectively. PSNL-induced tactile allodynia was attenuated by oral and intrathecal administration of etidronate, with maximum efficiency at 90 and 60 min after injection, respectively. The anti-allodynic effect of intrathecally administered etidronate was completely inhibited by an intrathecal administration of adenosine triphosphate (ATP). The solute carrier family, SLC17, mediates the transport of pain transmitters, like ATP and glutamate. Indeed, we detected several members of the SLC17 family in the mouse dorsal lumbar spinal cord. Among the detected mRNAs, only Slc17a9, encoding for neuronal vesicular ATP transporter, was significantly increased upon PSNL. SLC17A9 protein levels were also significantly increased. In mice subjected to PSNL, SLC17A9 was present in neurons and microglia, but not in astrocytes of the lumbar superficial dorsal horn. Collectively, our results suggest that etidronate produces its anti-allodynic effects by inhibiting SLC17A9-dependent exocytotic ATP release from the dorsal horn in mice subjected to PSNL.


Assuntos
Trifosfato de Adenosina/metabolismo , Analgésicos , Ácido Etidrônico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Medula Espinal/efeitos dos fármacos , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Ácido Etidrônico/farmacologia , Ácido Etidrônico/uso terapêutico , Hiperalgesia/metabolismo , Injeções Espinhais , Ligadura , Masculino , Camundongos , Neuralgia/metabolismo , Proteínas de Transporte de Nucleotídeos/genética , Proteínas de Transporte de Nucleotídeos/metabolismo , Estimulação Física , Nervo Isquiático/cirurgia , Medula Espinal/metabolismo
8.
Oncologist ; 24(3): 303-e102, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30413669

RESUMO

LESSONS LEARNED: Results are consistent with MBC-11 targeting and treating cancer-induced bone lesions by concentrating cytarabine and etidronate at the site of disease.MBC-11 was well tolerated, with an maximum tolerated dose of 5 mg/kg per day and myelosuppression as the principal toxicity.Treatment significantly reduced cancer cell activity in over half of bone lesions detected at baseline.MBC-11 pharmacokinetic and pharmacodynamic parameters are consistent with the novel drug design goals, and encouraging results warrant further clinical development. BACKGROUND: MBC-11 is a first-in-class conjugate of the bone-targeting bisphosphonate etidronate covalently linked to the antimetabolite cytarabine (araC). This first-in-human phase I dose escalation study assessed safety, tolerability, maximum tolerated dose (MTD), plasma pharmacokinetics, bone turnover, tumor biomarkers, and bone lesion activity by fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) imaging. METHODS: Fifteen patients with advanced solid cancers and cancer-induced bone disease (CIBD) were treated with 0.5-10 mg/kg per day of MBC-11 administered daily for 5 days of every 4 weeks for up to four cycles. RESULTS: Grade 1-2 myelosuppression, involving all lineages, was the principal toxicity. Two of three patients treated with 10 mg/kg experienced dose-limiting grade 4 neutropenia and thrombocytopenia (adverse event [AE] duration ≤5 days); the MTD was 5 mg/kg. Four of five patients with pretreatment elevations of the bone resorption marker TRAP5b (tartrate resistant acid phosphatase-5b) had persistent decrements. Six of 13 patients who reported baseline pain noted a reduction after MBC-11. 18F-FDG-PET/CT imaging demonstrated partial metabolic responses in three patients and stable metabolic responses in three other patients. SUVmax (standard unit of emission normalized to total uptake) was reduced by at least 25% in 110 (52%) of 211 bone lesions. Significant activity was noted across all doses, and myelosuppression increased with dose. CONCLUSION: At MBC-11 doses that were well tolerated, substantial reductions in metabolic activity of bone-associated cancer cells provide a foundation for further disease-directed efficacy studies.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Citarabina/uso terapêutico , Ácido Etidrônico/uso terapêutico , Antineoplásicos/farmacologia , Neoplasias Ósseas/secundário , Estudos de Coortes , Citarabina/farmacologia , Ácido Etidrônico/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
Int Endod J ; 51(9): 1030-1036, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29505173

RESUMO

AIM: To evaluate the effectiveness of NaOCl, NaOCl-EDTA and NaOCl + HEBP activated by ultrasonics and XP-endo Finisher on organic tissue removal from simulated internal root resorption cavities. METHODOLOGY: The root canals of 144 single-rooted teeth were instrumented. The teeth were split longitudinally, and semicircular cavities were prepared in the canal walls on each half of the roots. Samples obtained from ground bovine muscle tissue were weighed and adapted into the semicircular cavities. The root fragments were reassembled and cemented to create a circular simulated resorption cavity within the canal. Teeth were divided into twelve groups (n = 12) according to the irrigation protocols: group 1: NaOCl, no activation; group 2: NaOCl, passive ultrasonic irrigation (PUI); group 3: NaOCl, XP-endo Finisher; group 4: NaOCl-EDTA, no activation; group 5: NaOCl-EDTA, PUI; group 6: NaOCl-EDTA, XP-endo Finisher; group 7: NaOCl + HEBP, no activation; group 8: NaOCl + HEBP, PUI; group 9: NaOCl + HEBP, XP-endo Finisher; group 10: distilled water, no activation; group 11: distilled water, PUI; and group 12: distilled water, XP-endo Finisher. The teeth were disassembled, and the tissue remaining inside the resorption cavities were weighed. The data were analysed statistically using two-way anova and Fisher's LSD tests with a significance level of 0.05. RESULTS: The use of XP-endo Finisher with the experimental solutions resulted in the greatest tissue weight loss compared to the other activation protocols (P < 0.001). There was no significant difference between NaOCl and NaOCl + HEBP in terms of tissue removal. CONCLUSION: The use of a NaOCl + HEBP mixture activated with XP-endo Finisher was an effective irrigation regimen for removing simulated organic tissues from artificial internal root resorption cavities in the straight root canals of single-rooted teeth.


Assuntos
Obturação do Canal Radicular/métodos , Reabsorção da Raiz/cirurgia , Ácido Edético/uso terapêutico , Ácido Etidrônico/uso terapêutico , Humanos , Irrigantes do Canal Radicular/uso terapêutico , Obturação do Canal Radicular/instrumentação , Hipoclorito de Sódio/uso terapêutico , Irrigação Terapêutica , Ultrassom/métodos
10.
Cochrane Database Syst Rev ; 12: CD003188, 2017 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-29253322

RESUMO

BACKGROUND: Bisphosphonates are specific inhibitors of osteoclastic activity and are used in the treatment of patients with multiple myeloma (MM). While bisphosphonates are shown to be effective in reducing vertebral fractures and pain, their role in improving overall survival (OS) remains unclear. This is an update of a Cochrane review first published in 2002 and previously updated in 2010 and 2012. OBJECTIVES: To assess the evidence related to benefits and harms associated with use of various types of bisphosphonates (aminobisphosphonates versus non-aminobisphosphonates) in the management of patients with MM. Our primary objective was to determine whether adding bisphosphonates to standard therapy in MM improves OS and progression-free survival (PFS), and decreases skeletal-related morbidity. Our secondary objectives were to determine the effects of bisphosphonates on pain, quality of life, incidence of hypercalcemia, incidence of bisphosphonate-related gastrointestinal toxicities, osteonecrosis of jaw (ONJ) and hypocalcemia. SEARCH METHODS: We searched MEDLINE, Embase (September 2011 to July 2017) and the CENTRAL (2017, Issue 7) to identify all randomized controlled trial (RCT) in MM up to July 2017 using a combination of text and MeSH terms. SELECTION CRITERIA: Any randomized controlled trial (RCT) comparing bisphosphonates versus placebo/no treatment/bisphosphonates and observational studies or case reports examining bisphosphonate-related ONJ in patients with MM were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors extracted the data. Data were pooled and reported as hazard ratio (HR) or risk ratio (RR) using a random-effects model. We used meta-regression to explore statistical heterogeneity. Network meta-analysis using Bayesian approach was conducted. MAIN RESULTS: In this update, we included four new studies (601 participants), resulting in a total of 24 included studies.Twenty RCTs compared bisphosphonates with either placebo or no treatment and four RCTs involved another bisphosphonate as a comparator. The 24 included RCTs enrolled 7293 participants. Pooled results showed that there was moderate-quality evidence of a reduction in mortality with on OS from 41% to 31%, but the confidence interval is consistent with a larger reduction and small increase in mortality compared with placebo or no treatment (HR 0.90, 95% CI 0.76 to 1.07; 14 studies; 2706 participants). There was substantial heterogeneity among the included RCTs (I2 = 65%) for OS. To explain this heterogeneity we performed a meta-regression assessing the relationship between bisphosphonate potency and improvement in OS, which found an OS benefit with zoledronate but limited evidence of an effect on PFS. This provided a further rationale for performing a network meta-analyses of the various types of bisphosphonates that were not compared head-to-head in RCTs. Results from network meta-analyses showed evidence of a benefit for OS with zoledronate compared with etidronate (HR 0.56, 95% CI 0.29 to 0.87) and placebo (HR 0.67, 95% CI 0.46 to 0.91). However, there was no evidence for a difference between zoledronate and other bisphosphonates.The effect of bisphosphonates on disease progression (PFS) is uncertain. Based on the HR of 0.75 (95% CI 0.57 to 1.00; seven studies; 908 participants), 47% participants would experience disease progression without treatment compared with between 30% and 47% with bisphosphonates (low-quality evidence). There is probably a similar risk of non-vertebral fractures between treatment groups (RR 1.03, 95% CI 0.68 to 1.56; six studies; 1389 participants; moderate-quality evidence). Pooled analysis demonstrated evidence for a difference favoring bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; seven studies; 1116 participants; moderate-quality evidence) and skeletal-related events (SREs) (RR 0.74, 95% CI 0.63 to 0.88; 10 studies; 2141 participants; moderate-quality evidence). The evidence for less pain with bisphosphonates was of very low quality (RR 0.75, 95% CI 0.60 to 0.95; eight studies; 1281 participants).Bisphosphonates may increase ONJ compared with placebo but the confidence interval is very wide (RR 4.61, 95% CI 0.99 to 21.35; P = 0.05; six studies; 1284 participants; low-quality evidence). The results from the network meta-analysis did not show any evidence for a difference in the incidence of ONJ (eight RCTs, 3746 participants) between bisphosphonates. Data from nine observational studies (1400 participants) reported an incidence of 5% to 51% with combination of pamidronate and zoledronate, 3% to 11% with zoledronate alone, and 0% to 18% with pamidronate alone.The pooled results showed no evidence for a difference in increase in frequency of gastrointestinal symptoms with the use of bisphosphonates compared with placebo or no treatment (RR 1.23, 95% CI 0.95 to 1.59; seven studies; 1829 participants; low-quality evidence).The pooled results showed no evidence for a difference in increase in frequency of hypocalcemia with the use of bisphosphonates compared with placebo or no treatment (RR 2.19, 95% CI 0.49 to 9.74; three studies; 1090 participants; low-quality evidence). The results from network meta-analysis did not show any evidence for differences in the incidence of hypocalcemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used. AUTHORS' CONCLUSIONS: Use of bisphosphonates in participants with MM reduces pathological vertebral fractures, SREs and pain. Bisphosphonates were associated with an increased risk of developing ONJ. For every 1000 participants treated with bisphosphonates, about one patient will suffer from the ONJ. We found no evidence of superiority of any specific aminobisphosphonate (zoledronate, pamidronate or ibandronate) or non-aminobisphosphonate (etidronate or clodronate) for any outcome. However, zoledronate was found to be better than placebo and first-generation bisposphonate (etidronate) in pooled direct and indirect analyses for improving OS and other outcomes such as vertebral fractures. Direct head-to-head trials of the second-generation bisphosphonates are needed to settle the issue if zoledronate is truly the most efficacious bisphosphonate currently used in practice.


Assuntos
Antineoplásicos/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Doenças Ósseas/tratamento farmacológico , Difosfonatos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Doenças Ósseas/mortalidade , Ácido Clodrônico/uso terapêutico , Intervalo Livre de Doença , Ácido Etidrônico/uso terapêutico , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/prevenção & controle , Humanos , Imidazóis/uso terapêutico , Mieloma Múltiplo/complicações , Mieloma Múltiplo/mortalidade , Pamidronato , Ensaios Clínicos Controlados Aleatórios como Assunto , Fraturas da Coluna Vertebral/epidemiologia , Fraturas da Coluna Vertebral/prevenção & controle , Ácido Zoledrônico
11.
Arch Osteoporos ; 12(1): 81, 2017 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-28936581

RESUMO

Using Swedish and Dutch registry data for women initiating bisphosphonates, we evaluated two methods of comparing the real-world effectiveness of osteoporosis treatments that attempt to adjust for differences in patient baseline characteristics. Each method has advantages and disadvantages; both are potential complements to clinical trial analyses. PURPOSE: We evaluated methods of comparing the real-world effectiveness of osteoporosis treatments that attempt to adjust for both observed and unobserved confounding. METHODS: Swedish and Dutch registry data for women initiating zoledronate or oral bisphosphonates (OBPs; alendronate/risedronate) were used; the primary outcome was fracture. In adjusted direct comparisons (ADCs), regression and matching techniques were used to account for baseline differences in known risk factors for fracture (e.g., age, previous fracture, comorbidities). In an own-control analysis (OCA), for each treatment, fracture incidence in the first 90 days following treatment initiation (the baseline risk period) was compared with fracture incidence in the 1-year period starting 91 days after treatment initiation (the treatment exposure period). RESULTS: In total, 1196 and 149 women initiating zoledronate and 14,764 and 25,058 initiating OBPs were eligible in the Swedish and Dutch registries, respectively. Owing to the small Dutch zoledronate sample, only the Swedish data were used to compare fracture incidences between treatment groups. ADCs showed a numerically higher fracture incidence in the zoledronate than in the OBPs group (hazard ratio 1.09-1.21; not statistically significant, p > 0.05). For both treatment groups, OCA showed a higher fracture incidence in the baseline risk period than in the treatment exposure period, indicating a treatment effect. OCA showed a similar or greater effect in the zoledronate group compared with the OBPs group. CONCLUSIONS: ADC and OCA each possesses advantages and disadvantages. Combining both methods may provide an estimate of real-world treatment efficacy that could potentially complement clinical trial findings.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Imidazóis/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Idoso , Alendronato/uso terapêutico , Estudos de Casos e Controles , Ácido Etidrônico/uso terapêutico , Feminino , Fraturas Ósseas/prevenção & controle , Humanos , Incidência , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Osteoporose Pós-Menopausa/epidemiologia , Fraturas por Osteoporose/prevenção & controle , Sistema de Registros , Ácido Risedrônico/uso terapêutico , Fatores de Risco , Suécia/epidemiologia , Resultado do Tratamento , Ácido Zoledrônico
12.
Pharmacoepidemiol Drug Saf ; 26(10): 1286-1295, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28857419

RESUMO

PURPOSE: To summarize current evidence of the association of bisphosphonate use with breast cancer risk, we used a systematic review and meta-analysis of observational studies to explore this issue. METHODS: A comprehensive search was conducted on PubMed, EMBASE, and the Cochrane Library. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using the random effects model. RESULTS: Bisphosphonate use was associated with a 16% lower breast cancer risk (pool RR0.84, 95%CI 0.77-0.90, n = 8). A protective effect of bisphosphonate was found in cohort studies (RR 0.85, 95%CI 0.80-0.90, n = 4) and case-control studies (RR 0.78, 95%CI 0.64-0.96, n = 4).We also found that the use of bisphosphonate resulted in a statistically significant reduction in all breast cancer risk (RR 0.87, 95%CI 0.81-0.93) and greater reduction in invasive breast cancer risk (RR 0.78, 95%CI 0.68-0.91) and contralateral breast cancer risk (RR, 0.41; 95% CI, 0.20-0.84).With respect to the type of bisphosphonate, we found that alendronate and etidronate resulted significant reduction in breast cancer risk. The short-term use of bisphosphonate (<1 y) led to nonsignificant change (RR 0.93, 95%CI 0.86-1.00), but a significant 26% reduction of breast cancer risk was noted with long-term use (>1 y) (RR 0.74, 95%CI 0.66-0.83). CONCLUSIONS: Our results supported bisphosphonate as being effective in preventing breast cancer, including invasive and contralateral breast cancer. Furthermore, the long-term use (>1 y) of bisphosphonate was more significant in lowering breast cancer risk.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Neoplasias da Mama/epidemiologia , Difosfonatos/uso terapêutico , Administração Oral , Alendronato/uso terapêutico , Neoplasias da Mama/prevenção & controle , Ácido Etidrônico/uso terapêutico , Feminino , Humanos , Medição de Risco , Comportamento de Redução do Risco , Fatores de Tempo , Resultado do Tratamento
13.
Appl Radiat Isot ; 129: 108-116, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28843158

RESUMO

In this study labeling EDTMP (ethylenediamine tetra(methylene phosphonic acid)) and HEDP (Hydroxyethylidene-1, 1-Diphosphonic Acid) as the carrier ligands with Scandium-47 were investigated. The biokinetics of the bone seeking of labeled ligands with Scandium-47 were assessed by measuring the skeletal absorbed dose and then the mice data extrapolated to human absorbed dose and compared with the 186/188Rhenium-HEDP, 153Samarium-EDTMP dosimetry data estimated by other researchers. Because the availability of 47Sc was limited we performed some preliminary studies using 46Sc.


Assuntos
Osso e Ossos/metabolismo , Osso e Ossos/efeitos da radiação , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Escândio/uso terapêutico , Animais , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Estabilidade de Medicamentos , Ácido Etidrônico/química , Ácido Etidrônico/farmacocinética , Ácido Etidrônico/uso terapêutico , Humanos , Técnicas In Vitro , Ligantes , Camundongos , Compostos Organometálicos/química , Compostos Organometálicos/farmacocinética , Compostos Organometálicos/uso terapêutico , Compostos Organofosforados/química , Doses de Radiação , Radioisótopos/química , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Escândio/química , Escândio/farmacocinética , Distribuição Tecidual
14.
Cancer Biother Radiopharm ; 32(5): 184-191, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28598690

RESUMO

Skeletal metastasis is common in advanced stages of various cancers, particularly of the prostate and breast carcinoma. 188Re-HEDP (1-hydroxyethane 1, 1-diphosphonic acid) is a clinically established radiopharmaceutical for bone pain palliation of osseous metastasis, and it takes advantage of high bone affinity. The present work aims at elucidating the possible mechanisms of cell killing by 188Re-HEDP in osteosarcoma cells and biodistribution studies in mice.188Re-HEDP complex was prepared by using lyophilized HEDP kits prepared in-house. In vitro cellular uptake in mineralized bone matrix was found to be 13.41% ± 0.46% (at 2 hours), which was reduced to 2.44% ± 0.12% in the presence of excess amounts of unlabeled HEDP ligand. Uptake of 188Re-HEDP in bones of normal Swiss mice in vivo and mineralized bone in vitro indicated its affinity toward the bone matrix. The study also revealed that cellular toxicity and G2/M cell cycle arrest were dose dependent. At higher doses, G2/M cell cycle arrest was observed, which might be the major cause of cell death and a possible mechanism of bone pain relief.


Assuntos
Neoplasias Ósseas/complicações , Ácido Etidrônico/uso terapêutico , Compostos Organometálicos/uso terapêutico , Dor/etiologia , Compostos Radiofarmacêuticos/uso terapêutico , Técnicas de Cultura de Células , Feminino , Humanos , Masculino
15.
Am J Pathol ; 187(6): 1258-1272, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28416300

RESUMO

Soft tissue calcification occurs in several common acquired pathologies, such as diabetes and hypercholesterolemia, or can result from genetic disorders. ABCC6, a transmembrane transporter primarily expressed in liver and kidneys, initiates a molecular pathway inhibiting ectopic calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into pyrophosphate (PPi), a major calcification inhibitor. Heritable mutations in ABCC6 underlie the incurable calcification disorder pseudoxanthoma elasticum and some cases of generalized arterial calcification of infancy. Herein, we determined that the administration of PPi and the bisphosphonate etidronate to Abcc6-/- mice fully inhibited the acute dystrophic cardiac calcification phenotype, whereas alendronate had no significant effect. We also found that daily injection of PPi to Abcc6-/- mice over several months prevented the development of pseudoxanthoma elasticum-like spontaneous calcification, but failed to reverse already established lesions. Furthermore, we found that the expression of low amounts of the human ABCC6 in liver of transgenic Abcc6-/- mice, resulting in only a 27% increase in plasma PPi levels, led to a major reduction in acute and chronic calcification phenotypes. This proof-of-concept study shows that the development of both acute and chronic calcification associated with ABCC6 deficiency can be prevented by compensating PPi deficits, even partially. Our work indicates that PPi substitution represents a promising strategy to treat ABCC6-dependent calcification disorders.


Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Calcinose/prevenção & controle , Difosfatos/uso terapêutico , Pseudoxantoma Elástico/prevenção & controle , Transportadores de Cassetes de Ligação de ATP/deficiência , Transportadores de Cassetes de Ligação de ATP/genética , Doença Aguda , Animais , Calcinose/metabolismo , Calcinose/patologia , Doença Crônica , Difosfatos/administração & dosagem , Difosfatos/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Ácido Etidrônico/uso terapêutico , Feminino , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Fenótipo , Pseudoxantoma Elástico/metabolismo , Pseudoxantoma Elástico/patologia , Transgenes
16.
Eur J Nucl Med Mol Imaging ; 44(8): 1319-1327, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28421240

RESUMO

BACKGROUND: Rhenium-188-HEDP is a beta-emitting radiopharmaceutical used for palliation of metastatic bone pain. We investigated whether the addition of rhenium-188-HEDP to docetaxel/prednisone improved efficacy of chemotherapy in patients with CRPC. METHODS: Patients with progressive CRPC and osteoblastic bone metastases were randomised for first-line docetaxel 75 mg/m2 3-weekly plus prednisone with or without 2 injections of rhenium-188-HEDP after the third (40 MBq/kg) and after the sixth (20 MBq/kg) cycle of docetaxel. Primary endpoint was progression-free survival (PFS), defined as either PSA, radiographic or clinical progression. Patients were stratified by extent of bone metastases and hospital. RESULTS: Forty-two patients were randomised for standard treatment and 46 patients for combination therapy. Median number of cycles of docetaxel was 9 in the control group and 8 in the experimental group. Median follow-up was 18.4 months. Two patients from the experimental group did not start treatment after randomisation. In the intention to treat analysis no differences in PFS, survival and PSA became apparent between the two groups. In an exploratory per-protocol analysis median overall survival was significantly longer in the experimental group (33.8 months (95%CI 31.75-35.85)) than in the control group (21.0 months (95%CI 13.61-28.39); p 0.012). Also median PFS in patients with a baseline phosphatase >220U/L was significantly better with combination treatment (9.0 months (95%CI 3.92-14.08) versus 6.2 months (95%CI 3.08-9.32); log rank p 0.005). As expected, thrombocytopenia (grade I/II) was reported more frequently in the experimental group (25% versus 0%). CONCLUSION: Combined treatment with rhenium-188-HEDP and docetaxel did not prolong PFS in patients with CRPC. The observed survival benefit in the per-protocol analysis warrants further studies in the combined treatment of chemotherapy and radiopharmaceuticals.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/secundário , Ácido Etidrônico/uso terapêutico , Compostos Organometálicos/uso terapêutico , Prednisona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Taxoides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Docetaxel , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade
17.
Clin Nucl Med ; 42(6): 415-420, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28263212

RESUMO

PURPOSE: In patients with metastatic castration-resistant prostate cancer (mCRPC), bone-seeking radiopharmaceuticals, such as Re-hydroxyethylidene diphosphonate (HEDP), are effective for pain palliation and have a marked antitumor effect. Cabazitaxel is the standard second-line chemotherapy for mCRPC patients. We performed a phase 1 study investigating the safety and feasibility of the combined treatment with Re-HEDP and cabazitaxel in mCRPC patients. METHODS: Patients with mCRPC and documented disease progression on or after docetaxel were eligible for inclusion. In both dose levels, cabazitaxel (4 cycles of cabazitaxel 25 mg/m + 2 cycles of cabazitaxel 20 mg/m in level 1, and 6 cycles of cabazitaxel 25 mg/m in level 2) were combined with 2 cycles of Re-HEDP 40 MBq/kg (1.1 mCi/kg) (after the second and fourth cabazitaxel cycles). Three patients were planned for each dose level, expanding to 6 patients in case of a dose-limiting toxicity (DLT). A DLT is defined as any grade 4 toxicity, or grade 3 toxicity delaying the next treatment cycle. RESULTS: Twelve patients were included, of whom 3 had progressive disease before the third cycle of cabazitaxel. In total, 1 DLT occurred (dose level 1) after treatment cycle 6 (Re-HEDP) (thrombopenia grade 3 delaying the next treatment cycle). The cohort was expanded to 6 patients, with no further DLTs. No DLT occurred in dose level 2. The most important adverse events were of hematologic origin, followed by mild fatigue and diarrhea. CONCLUSIONS: Combination therapy with cabazitaxel and Re-HEDP is feasible and generally well tolerated with similar hematologic toxicity compared with cabazitaxel monotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Ácido Etidrônico/uso terapêutico , Compostos Organometálicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapia , Taxoides/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Progressão da Doença , Docetaxel , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/radioterapia , Taxoides/efeitos adversos , Resultado do Tratamento
18.
J Invest Dermatol ; 137(4): 790-795, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28340679

RESUMO

Pseudoxanthoma elasticum is a prototype of heritable ectopic mineralization disorders, with phenotypic overlap with generalized arterial calcification of infancy and arterial calcification due to CD73 deficiency. Recent observations have suggested that the reduced inorganic pyrophosphate/phosphate ratio is the cause of soft connective tissue mineralization in these disorders. PXE International, a patient advocacy organization, supports research in part by sponsoring biennial research symposia on these disorders; the latest meeting was held in September 2016 at Thomas Jefferson University, Philadelphia. This report summarizes the progress in pseudoxanthoma elasticum and other ectopic mineralization disorders, as presented in the symposium, with focus on translational aspects of precision medicine toward improved diagnostics and treatment development for these currently intractable disorders.


Assuntos
Difosfatos/metabolismo , Ácido Etidrônico/farmacologia , Predisposição Genética para Doença , Pseudoxantoma Elástico/genética , Calcificação Vascular/genética , 5'-Nucleotidase/efeitos dos fármacos , 5'-Nucleotidase/genética , Fosfatase Alcalina/efeitos dos fármacos , Fosfatase Alcalina/genética , Animais , Biópsia por Agulha , Ensaios Clínicos como Assunto , Congressos como Assunto , Modelos Animais de Doenças , Ácido Etidrônico/uso terapêutico , Proteínas Ligadas por GPI/efeitos dos fármacos , Proteínas Ligadas por GPI/genética , Humanos , Imuno-Histoquímica , Internacionalidade , Camundongos , Mutação , Diester Fosfórico Hidrolases/efeitos dos fármacos , Diester Fosfórico Hidrolases/genética , Pseudoxantoma Elástico/patologia , Pirofosfatases/efeitos dos fármacos , Pirofosfatases/genética , Doenças Raras , Calcificação Vascular/fisiopatologia
19.
Cancer Biother Radiopharm ; 32(1): 16-23, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28118029

RESUMO

OBJECTIVE: Rhenium-188-HEDP is an effective radiopharmaceutical for the treatment of painful bone metastases from prostate cancer. The effectiveness of the ß-radiation emitted by 188Re might be enhanced by combination with chemotherapy, using the radiosensitization concept. Therefore, the authors investigated the combined treatment of the taxanes, docetaxel and cabazitaxel, with 188Re in prostate carcinoma cell lines. MATERIALS AND METHODS: The cytotoxic effects of single and combined treatment with taxanes and 188Re were investigated in three human prostate carcinoma cell lines (PC-3, DU 145, and LNCaP), using the colony-forming assay. The half maximal effective concentration (EC50) of all individual agents was determined. The combined treatment was studied at 0.25, 0.5, 1, 2, and 4 times the EC50 of each agent. The interaction was investigated with a regression model. RESULTS: The survival curves showed dose-dependent cell growth inhibition for both the taxanes and 188Re. The regression model showed a good capability of explaining the data. It proved additivity in all combination experiments and confirmed a general trend to a slight subadditive effect. CONCLUSIONS: This proof-of-mechanism study exploring radiosensitization by combining 188Re and taxanes showed no synergism, but significant additivity. This encourages the design of in vivo studies. Future research should explore the potential added value of concomitant treatment of bone metastases with chemotherapy and 188Re-HEDP.


Assuntos
Antineoplásicos/uso terapêutico , Quimiorradioterapia/métodos , Ácido Etidrônico/uso terapêutico , Compostos Organometálicos/uso terapêutico , Neoplasias da Próstata/terapia , Radiossensibilizantes/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Taxoides/uso terapêutico , Neoplasias Ósseas/secundário , Neoplasias Ósseas/terapia , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/efeitos da radiação , Docetaxel , Relação Dose-Resposta a Droga , Humanos , Masculino , Neoplasias da Próstata/patologia
20.
Eur J Nucl Med Mol Imaging ; 44(4): 620-629, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27770145

RESUMO

PURPOSE: To investigate the role of patient-specific dosimetry as a predictive marker of survival and as a potential tool for individualised molecular radiotherapy treatment planning of bone metastases from castration-resistant prostate cancer, and to assess whether higher administered levels of activity are associated with a survival benefit. METHODS: Clinical data from 57 patients who received 2.5-5.1 GBq of 186Re-HEDP as part of NIH-funded phase I/II clinical trials were analysed. Whole-body and SPECT-based absorbed doses to the whole body and bone lesions were calculated for 22 patients receiving 5 GBq. The patient mean absorbed dose was defined as the mean of all bone lesion-absorbed doses in any given patient. Kaplan-Meier curves, log-rank tests, Cox's proportional hazards model and Pearson's correlation coefficients were used for overall survival (OS) and correlation analyses. RESULTS: A statistically significantly longer OS was associated with administered activities above 3.5 GBq in the 57 patients (20.1 vs 7.1 months, hazard ratio: 0.39, 95 % CI: 0.10-0.58, P = 0.002). A total of 379 bone lesions were identified in 22 patients. The mean of the patient mean absorbed dose was 19 (±6) Gy and the mean of the whole-body absorbed dose was 0.33 (±0.11) Gy for the 22 patients. The patient mean absorbed dose (r = 0.65, P = 0.001) and the whole-body absorbed dose (r = 0.63, P = 0.002) showed a positive correlation with disease volume. Significant differences in OS were observed for the univariate group analyses according to disease volume as measured from SPECT imaging of 186Re-HEDP (P = 0.03) and patient mean absorbed dose (P = 0.01), whilst only the disease volume remained significant in a multivariable analysis (P = 0.004). CONCLUSION: This study demonstrated that higher administered activities led to prolonged survival and that for a fixed administered activity, the whole-body and patient mean absorbed doses correlated with the extent of disease, which, in turn, correlated with survival. This study shows the importance of patient stratification to establish absorbed dose-response correlations and indicates the potential to individualise treatment of bone metastases with radiopharmaceuticals according to patient-specific imaging and dosimetry.


Assuntos
Ácido Etidrônico/administração & dosagem , Compostos Organometálicos/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/radioterapia , Doses de Radiação , Compostos Radiofarmacêuticos/administração & dosagem , Planejamento da Radioterapia Assistida por Computador , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/secundário , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ácido Etidrônico/uso terapêutico , Humanos , Masculino , Compostos Organometálicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/patologia , Compostos Radiofarmacêuticos/uso terapêutico , Dosagem Radioterapêutica , Análise de Sobrevida , Tomografia Computadorizada de Emissão de Fóton Único
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