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The Cochrane Database of Systematic... Oct 2017Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse reaction experienced by some individuals to certain medicines commonly used in the treatment of... (Review)
Review
BACKGROUND
Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse reaction experienced by some individuals to certain medicines commonly used in the treatment of cancer and osteoporosis (e.g. bisphosphonates, denosumab and antiangiogenic agents) and involves the progressive destruction of bone in the mandible or maxilla. Depending on the drug, its dosage, and the duration of exposure, the occurrence of this adverse drug reaction may be rare (e.g. following the oral administration of bisphosphonate or denosumab treatments for osteoporosis, or antiangiogenic agent-targeted cancer treatment) or common (e.g. following intravenous bisphosphonate for cancer treatment). MRONJ is associated with significant morbidity, adversely affects quality of life (QoL), and is challenging to treat.
OBJECTIVES
To assess the effects of interventions versus no treatment, placebo, or an active control for the prophylaxis of MRONJ in people exposed to antiresorptive or antiangiogenic drugs.To assess the effects of non-surgical or surgical interventions (either singly or in combination) versus no treatment, placebo, or an active control for the treatment of people with manifest MRONJ.
SEARCH METHODS
Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 23 November 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 10), MEDLINE Ovid (1946 to 23 November 2016), and Embase Ovid (23 May 2016 to 23 November 2016). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on language or publication status when searching the electronic databases; however, the search of Embase was restricted to the last six months due to the Cochrane Embase Project to identify all clinical trials and add them to CENTRAL.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) comparing one modality of intervention with another for the prevention or treatment of MRONJ. For 'prophylaxis of MRONJ', the primary outcome of interest was the incidence of MRONJ; secondary outcomes were QoL, time-to-event, and rate of complications and side effects of the intervention. For 'treatment of established MRONJ', the primary outcome of interest was healing of MRONJ; secondary outcomes were QoL, recurrence, and rate of complications and side effects of the intervention.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the search results, extracted the data, and assessed the risk of bias in the included studies. For dichotomous outcomes, we reported the risk ratio (RR) (or rate ratio) and 95% confidence intervals (CI).
MAIN RESULTS
We included five RCTs (1218 participants) in the review. Three trials focused on the prophylaxis of MRONJ. Two trials investigated options for the treatment of established MRONJ. The RCTs included only participants treated with bisphosphonates and, thus, did not cover the entire spectrum of medications associated with MRONJ. Prophylaxis of MRONJOne trial compared standard care with regular dental examinations in three-month intervals and preventive treatments (including antibiotics before dental extractions and the use of techniques for wound closure that avoid exposure and contamination of bone) in men with metastatic prostate cancer treated with zoledronic acid. The intervention seemed to lower the risk of MRONJ: RR 0.10; 95% CI 0.02 to 0.39 (253 participants; low-quality evidence). Secondary outcomes were not evaluated.As dentoalveolar surgery is considered a common predisposing event for developing MRONJ, one trial investigated the effect of plasma rich in growth factors (PRGF) for preventing MRONJ in people with cancer undergoing dental extractions. There was insufficient evidence to support or refute a benefit of PRGF on MRONJ incidence when compared with standard treatment (RR 0.08, 95% CI 0.00 to 1.51; 176 participants; very low-quality evidence). Secondary outcomes were not reported. In another trial comparing wound closure by primary intention with wound closure by secondary intention after dental extractions in people treated with oral bisphosphonates (700 participants), no cases of intraoperative complications or postoperative MRONJ were observed. QoL was not investigated. Treatment of MRONJOne trial analysed hyperbaric oxygen (HBO) treatment used in addition to standard care (antiseptic rinses, antibiotics, and surgery) compared with standard care alone. HBO in addition to standard care did not significantly improve healing from MRONJ compared with standard care alone (at last follow-up: RR 1.56; 95% CI 0.77 to 3.18; 46 participants included in the analysis; very low-quality evidence). QoL data were presented qualitatively as intragroup comparisons; hence, an effect estimate of treatment on QoL was not possible. Other secondary outcomes were not reported.The other RCT found no significant difference between autofluorescence- and tetracycline fluorescence-guided sequestrectomy for the surgical treatment of MRONJ at any timepoint (at one-year follow-up: RR 1.05; 95% CI 0.86 to 1.30; 34 participants included in the analysis; very low-quality evidence). Secondary outcomes were not reported.
AUTHORS' CONCLUSIONS
Prophylaxis of MRONJOne open-label RCT provided some evidence that dental examinations in three-month intervals and preventive treatments may be more effective than standard care for reducing the incidence of MRONJ in individuals taking intravenous bisphosphonates for advanced cancer. We assessed the certainty of the evidence to be low.There is insufficient evidence to either claim or refute a benefit of either of the interventions tested for prophylaxis of MRONJ (i.e. PRGF inserted into the postextraction alveolus during dental extractions, and wound closure by primary or secondary intention after dental extractions). Treatment of MRONJAvailable evidence is insufficient to either claim or refute a benefit for hyperbaric oxygen therapy as an adjunct to conventional therapy. There is also insufficient evidence to draw conclusions about autofluorescence-guided versus tetracycline fluorescence-guided bone surgery.
Topics: Angiogenesis Inhibitors; Anti-Bacterial Agents; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Denosumab; Dental Care; Diphosphonates; Female; Humans; Hyperbaric Oxygenation; Imidazoles; Intercellular Signaling Peptides and Proteins; Jaw Diseases; Male; Oral Health; Osteonecrosis; Postoperative Complications; Prostatic Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Time Factors; Tooth Extraction; Zoledronic Acid
PubMed: 28983908
DOI: 10.1002/14651858.CD012432.pub2 -
Clinical Oral Implants Research Oct 2018his review evaluated implant survival in geriatric patients (≥75 years) and/or the impact of systemic medical conditions. (Meta-Analysis)
Meta-Analysis
OBJECTIVES
his review evaluated implant survival in geriatric patients (≥75 years) and/or the impact of systemic medical conditions.
MATERIALS AND METHODS
Systematic literature searches were performed to identify studies reporting on geriatric subjects with dental implants and on implant patients who had any of the seven most common systematic conditions among geriatric patients. Meta-analyses were performed on the postloading implant survival rates. The impact of systemic medical conditions and their respective treatment was qualitatively analyzed.
RESULTS
A total of 6,893 studies were identified; of those, 60 studies were included. The fixed-effects model revealed an overall implant survival of 97.3% (95% CI: 94.3, 98.7; studies = 7) and 96.1% (95% CI: 87.3, 98.9; studies = 3), for 1 and 5 years, respectively. In patients with cardiovascular disease, implant survival may be similar or higher compared to healthy patients. High implant survival rates were reported for patients with Parkinson's disease or diabetes mellitus type II. In patients with cancer, implant survival is negatively affected, namely by radiotherapy. Patients with bone metastases receiving high-dose antiresorptive therapy (ART) carry a high risk for complications after implant surgery. Implant survival was reported to be high in patients receiving low-dose ART for treatment of osteoporosis. No evidence was found on implant survival in patients with dementia, respiratory diseases, liver cirrhosis, or osteoarthritis.
CONCLUSIONS
Implant prostheses in geriatric subjects are a predictable treatment option with a very high rate of implant survival. The functional and psychosocial benefits of such intervention should outweigh the associated risks to common medical conditions.
Topics: Age Factors; Aged; Aged, 80 and over; Alveolar Bone Loss; Bone Density Conservation Agents; Cardiovascular Diseases; Dementia; Dental Implantation, Endosseous; Dental Implants; Dental Restoration Failure; Diabetes Complications; Diabetes Mellitus, Type 2; Humans; Lung Diseases; Neoplasm Metastasis; Neoplasms; Osteoporosis; Parkinson Disease; Radiotherapy; Risk Factors; Survival Analysis; Xerostomia
PubMed: 30328186
DOI: 10.1111/clr.13288 -
Medicina Oral, Patologia Oral Y Cirugia... May 2020The aim of the present study was to analyse the incidence, risk ratio (RR) and prognoses of two types of medication-related osteonecrosis of the jaws (MRONJ):... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The aim of the present study was to analyse the incidence, risk ratio (RR) and prognoses of two types of medication-related osteonecrosis of the jaws (MRONJ): denosumab-related osteonecrosis of the jaws (DRONJ) and Bisphosphonate-Related Osteonecrosis of the Jaws (BRONJ) in cancer patients under treatment with denosumab or zoledronic acid (ZA).
MATERIAL AND METHODS
An electronic and manual search was conducted for randomized controlled trials (RCTs) until May 2019. Assessment of the identified studies, risk of bias and data extraction were performed independently by two reviewers. The incidence of DRONJ and BRONJ and the RR to develop MRONJ were calculated at 1 year, 2 years and 3 years of exposure. It was also calculated the odds ratio (OR) of their respective prognoses. They were calculated normalizing the values of the individual studies to 1 year, 2 years or 3 years when necessary through robust regression models using a statistical program.
RESULTS
From 1.277 references identified, 8 RCTs were included, which comprised a total of 13.857 patients with a variety of neoplasms. The incidence of DRONJ in cancer patients under treatment with denosumab ranged from 0.5 to 2.1% after 1 year, 1.1 to 3.0% after 2 years, and 1.3 to 3.2% after 3 years of exposure. The incidence of BRONJ in cancer patients under treatment with ZA ranged from 0.4 to 1.6% after 1 year of exposure, 0.8 to 2.1% after 2 years, and 1.0 to 2.3% after 3 years of exposure. Statistically significant differences were found between denosumab and ZA in the risk of developing MRONJ after 1, 2 and 3 years of exposure. Nevertheless, there were no significant differences in terms of patient prognosis.
CONCLUSIONS
Denosumab is associated with a significantly higher risk of developing MRONJ compared to ZA. Nevertheless, no differences were found in its prognoses.
Topics: Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Denosumab; Diphosphonates; Humans; Neoplasms; Zoledronic Acid
PubMed: 32271321
DOI: 10.4317/medoral.23324 -
Journal of Otolaryngology - Head & Neck... Mar 2021Neck dissection has a central role in the management of head and neck cancers. This systematic review aimed to compare the intraoperative and postoperative parameters... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Neck dissection has a central role in the management of head and neck cancers. This systematic review aimed to compare the intraoperative and postoperative parameters between conventional and LigaSure Small Jaw (LSJ)-assisted neck dissection.
METHODS
PubMed (MEDLINE), Embase, and the Cochrane Library were searched. independently by two authors for relevant articles comparing the outcomes of conventional and LSJ-assisted neck dissection. Data from each study were extracted, and a random-effects model was used in the pooled analysis.
RESULTS
Compared with conventional techniques, LSJ-assisted neck dissection was associated with a significantly reduced operative time. The rates of postoperative hematoma, infection, amount of intraoperative blood loss, the length of hospital stay and the drainage amount showed no significant intergroup differences.
CONCLUSIONS
The meta-analysis provides evidence that properly using LSJ may reduce the operative time compared with that of conventional techniques. Surgeons may consider using LSJ in neck dissection according to personal experiences.
Topics: Equipment Design; Head and Neck Neoplasms; Hemostasis, Surgical; Humans; Ligation; Neck Dissection; Operative Time; Postoperative Complications
PubMed: 33781344
DOI: 10.1186/s40463-021-00504-2 -
Clinical and Experimental Dental... Feb 2023Antiresorptive medication has been reported to be associated with medication-related osteonecrosis of the jaw (MRONJ). This systematic review aims at investigating the... (Review)
Review
OBJECTIVES
Antiresorptive medication has been reported to be associated with medication-related osteonecrosis of the jaw (MRONJ). This systematic review aims at investigating the incidence of and risk factors for MRONJ after tooth extractions in cancer patients treated with high-dose bisphosphonate and denosumab (BP and DS). MATERIAL AND METHODS: The protocol followed the PRISMA statement list and was registered in PROSPERO. Searches were performed for literature published up to April 2021 in the electronic databases PubMed, Embase, Web of Science, and CINAHL and then supplemented by manual research.
RESULTS
The search process resulted in 771 identified articles, of which seven studies fitted the population, intervention, comparison, and outcome framework. All were observational studies and four had control groups. A total of 550 patients treated with BP and DS were identified of whom 271 had received tooth extractions after medication onset. Due to significant heterogenicity in the collected data, only a qualitative analysis was performed. The MRONJ incidence after tooth extractions varied between 11% and 50% at the patient level. MRONJ occurred up to 3 years after the tooth extraction. Teeth affected by inflammation before the extraction and additional osteotomy during the surgical procedure were identified as risk factors.
CONCLUSIONS
Reliable methods of diagnosing MRONJ and adequate follow-up periods are important factors in obtaining the actual incidence of MRONJ after tooth extractions in patients treated with high-dose BP and DS.
Topics: Humans; Bisphosphonate-Associated Osteonecrosis of the Jaw; Incidence; Diphosphonates; Tooth Extraction; Risk Factors; Neoplasms
PubMed: 36464958
DOI: 10.1002/cre2.698 -
The Cochrane Database of Systematic... Dec 2017The prevalence and incidence of pain and skeletal complications of metastatic bone disease such as pathologic fractures, spinal cord compression and hypercalcemia is... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The prevalence and incidence of pain and skeletal complications of metastatic bone disease such as pathologic fractures, spinal cord compression and hypercalcemia is high and an important contributor to morbidity, poor performance status and decreased quality of life. Moreover, pathologic fractures are associated with increased risk of death in people with disseminated malignancies. Therefore, prevention of pain and fractures are important goals in men with prostate cancer at risk for skeletal complications.
OBJECTIVES
To assess the effects of bisphosphonates in men with bone metastases from prostate cancer.
SEARCH METHODS
We identified studies by electronic search of bibliographic databases including the Cochrane Controlled Trials Register and MEDLINE on 13 July 2017 and trial registries. We handsearched the Proceedings of American Society of Clinical Oncology (to July 2017) and reference lists of all eligible trials identified. This is an update of a review last published in 2006.
SELECTION CRITERIA
We included randomized controlled studies comparing the effectiveness of bisphosphonates in men with bone metastases from prostate cancer.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and assessed the quality of trials. We defined the proportion of participants with pain response as the primary end point; secondary outcomes were skeletal-related events, mortality, quality of life, adverse events, analgesic consumption and disease progression. We assessed the quality of the evidence for the main outcomes using the GRADE approach.
MAIN RESULTS
We included 18 trials reporting on 4843 participants comparing the effect of bisphosphonate administration to control regimens.
PRIMARY OUTCOME
there was no clear difference in the proportion of participants with pain response (RR 1.15, 95% CI 0.93 to 1.43; P = 0.20; I = 0%; 3 trials; 876 participants; low quality evidence). In absolute terms, bisphosphonates resulted in a pain response in 40 more participants per 1000 (19 fewer to 114 more).
SECONDARY OUTCOMES
bisphosphonates probably reduced the incidence of skeletal-related events in participants with prostate cancer metastatic to bone (RR 0.87, 95% CI 0.81 to 0.94; P = 0.27; I = 19%; 9 trials; 3153 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in 58 fewer SREs per 1000 (85 fewer to 27 fewer).We found no clinically relevant differences in mortality (RR 0.97, 95% CI 0.91 to 1.04; P = 0.43; I = 1%; 9 trials; 2450 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in 16 fewer deaths per 1000 (47 fewer to 21 more).Outcome definition of quality of life and the measurement tools varied greatly across trials and we were unable to extract any quantitative data for meta-analysis.Bisphosphonates probably increased the number of participants affected by nausea (RR 1.19, 95% CI 1.00 to 1.41; P = 0.05; I = 0%; 9 trials; 3008 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in seven more cases of nausea per 1000 (0 fewer to 14 more). Bisphosphonates probably increased the number of renal adverse events (RR 1.65, 95% CI 1.11 to 2.46; P = 0.01; I = 0%; 7 trials; 1794 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in 22 more renal adverse events per 1000 (4 more to 50 more). We found no clear difference in the number of participants with osteonecrosis of the jaw between groups (RR 1.92, 95% CI 0.75 to 4.90; P = 0.17; I = 0%; 5 trials; 1626 participants; very low quality evidence). In absolute terms, bisphosphonates resulted in seven more cases with osteonecrosis of the jaw per 1000 (2 fewer to 29 more). We observed no clinically relevant difference in the proportion of participants with decreased analgesic consumption (RR 1.19, 95% CI 0.87 to 1.63; P = 0.28; I = 37%; 4 trials; 416 participants). Statistical analysis revealed that bisphosphonates probably reduced the number of participants with disease progression (RR 0.94, 95% CI 0.90 to 0.98; P = 0.006; I = 0%; 7 trials; 2115 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in 36 fewer cases of disease progression per 1000 (71 fewer to 7 fewer).Findings of our predefined subgroup and sensitivity analyses were no different from those of the primary analyses.
AUTHORS' CONCLUSIONS
Based on low quality evidence, there may be no clinically relevant difference in the proportion of men with pain response between bisphosphonates and control regimens in men with bone metastases from prostate cancer. Bisphosphonates probably decrease the number of skeletal-related events and disease progression. These benefits need to be weighed against the increased risk of renal impairment and nausea in men receiving bisphosphonates. Future studies should explicitly evaluate patient important outcomes such as quality of life and pain by using standardized and comparable assessment tools.
Topics: Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Bone Neoplasms; Diphosphonates; Humans; Kidney; Male; Nausea; Pain; Prostatic Neoplasms; Randomized Controlled Trials as Topic
PubMed: 29278410
DOI: 10.1002/14651858.CD006250.pub2 -
Medicina Oral, Patologia Oral Y Cirugia... May 2023Osteoradionecrosis of the jaws (ORNJ) is a severe and challenging complication of head and neck radiation therapy. Despite its aggressiveness and controversy respect to...
BACKGROUND
Osteoradionecrosis of the jaws (ORNJ) is a severe and challenging complication of head and neck radiation therapy. Despite its aggressiveness and controversy respect to its efficacy, surgical intervention remains the main treatment modality. Nevertheless, due to advances in the understanding of ORNJ physiopathology, new treatment alternatives such as the combination of pentoxifylline with tocopherol (PENTO) have emerged. The aim of this systematic review was to assess the reported efficacy of PENTO for the treatment of ORNJ. Material and Methods: Studies were search using Pubmed, The Cochrane Library, Scopus, and Web of Science data bases following the PRISMA guidelines. Inclusion criteria were cohort, case series, randomized or non-randomized clinical studies published in English including human subjects who received PENTO as treatment for ORN of the jaws. Results: Eleven articles met the inclusion criteria and were included for data analysis. All studies reported patients with complete mucosal coverage with no exposed bone (considered healthy) after PENTO treatment, ranging from 16.6% to 100% of the patients, depending on the study. Clinical improvement or disease stabilization was reported between 7.6% and 66.6% of studied individuals, while disease progression was seen in only 5 studies involving 7.6 - 32% of patients.
CONCLUSIONS
PENTO treatment achieved a complete disease control in a significant number of patients in all studies. However, there is no standardized protocol for administering the therapy. It is necessary to determine the pharmacological doses and to evaluate the benefits of adding antibiotics and clodronate. Good quality clinical trials are needed to develop a successful algorithm for the management of ORN of the jaws.
Topics: Humans; Tocopherols; Pentoxifylline; Osteoradionecrosis; Head and Neck Neoplasms; Jaw
PubMed: 36641743
DOI: 10.4317/medoral.25729 -
Head and Neck Pathology Jun 2021Primary intraosseous oral squamous cell carcinoma (PIOSCC) is a rare malignant neoplasm that affects the jaws. Despite its aggressive biological behavior, there are no...
Primary intraosseous oral squamous cell carcinoma (PIOSCC) is a rare malignant neoplasm that affects the jaws. Despite its aggressive biological behavior, there are no studies that evaluated the clinicopathological features of this tumor and parameters associated with its prognosis. The objective of the present study was to conduct a systematic review of the available data on oral and maxillofacial PIOSCC in order to determine its clinicopathological characteristics and biological behavior. We conducted a systematic review in May 2020 in multiple databases using a specific search strategy. Cases diagnosed as PIOSCC in the oral cavity and maxillofacial complex that had sufficient histopathological data, absence of ulceration in the oral mucosa, a negative result for a distant primary tumor, and radiographic evidence of an osteolytic lesion that was entirely or mostly surrounded by the jaw bones were included. A total of 109 published articles were included in our systematic review, corresponding to 257 cases. PIOSCC showed a male predilection (69.3%) and a preference for the mandible (7:1), with the posterior region being the most commonly affected site. The mean age at diagnosis was 57.3 years. Cortical expansion, pain, and lip/facial paresthesia were the most common clinical features. Regarding histopathological features, most PIOSCC were well-differentiated and the solid subtype was the most common. Statistical analysis showed that PIOSCC located in the mandible (p = 0.03) and recurrence (p < 0.01) were significantly associated with a higher mortality rate. PIOSCC has a poor prognosis, with high rates of mortality.
Topics: Female; Humans; Jaw Neoplasms; Male; Middle Aged; Squamous Cell Carcinoma of Head and Neck
PubMed: 33044723
DOI: 10.1007/s12105-020-01234-z -
Journal of Clinical and Experimental... May 2019Ameloblastic fibroma (AF) and ameloblastic fibro-odontoma (AFO) are uncommon benign mixed odontogenic neoplasms. Although unusual microscopic changes including hybrid... (Review)
Review
BACKGROUND
Ameloblastic fibroma (AF) and ameloblastic fibro-odontoma (AFO) are uncommon benign mixed odontogenic neoplasms. Although unusual microscopic changes including hybrid tumors have been documented in publications, their clinical outcome prediction and treatment modality selection are still challenging due to scarcity. Objective: Analysis of AF/AFO's unusual microscopic variants in order to improve histopathologic diagnosis and to help clinicians in making informed treatment choices.
MATERIAL AND METHODS
An electronic search was performed in PubMed's database using keywords: "ameloblastic fibroma", "ameloblastic fibroodontoma", "ameloblastic fibro-odontoma". The search scheme was limited to articles in English, dated 'January 1998' to 'October 2018', with full texts (case reports and series) and human studies. Eligibility criteria included publications having enough clinical, radiological, and histological data to confirm their diagnosis. Age, sex, lesions' location, radiologic features, signs, symptoms, treatment approaches, and recurrences were recorded and analyzed.
RESULTS
In this systematic review, 11 articles (reporting 14 cases) were selected. Patients' mean age was 13.75 years (male/female = 1.8). The posterior region of the mandible was the lesions' commonest location (57.14%). Swelling was reported in 78.57% of the cases, pain in 28.57% but 21.42% were asymptomatic. Radiolucent unilocular appearance was the commonest radiographic feature, but 28.57% of the cases showed a mixed radiolucent-radiopaque appearance. Other reported radiographic findings were impacted tooth (78.57%), root resorption (28.57%), tooth mobility (35.71%), and cortical perforation (14.28%). No recurrences were reported. Calcifying odontogenic cyst (COC) was the commonest lesion associated with AF/AFO (53.33%). Unicystic ameloblastoma and cystic changes without prominent epithelial lining were other reported hybrid lesions. Reported microscopic variations were pigmentation and ghost cell differentiation.
CONCLUSIONS
COC was the commonest lesion associated with AF/AFO. Although COC commonly occurs in the jaws' anterior region, hybrid cases were more common in the posterior area. No malignant transformations were reported. The treatment modality is mostly chosen based on the lesion's most aggressive part. Ameloblastic fibroma, Ameloblastic fibro-odontoma, Odontogenic tumor, Jaw.
PubMed: 31275522
DOI: 10.4317/jced.55460 -
The Cochrane Database of Systematic... Oct 2017Bone is the most common site of metastatic disease associated with breast cancer (BC). Bisphosphonates inhibit osteoclast-mediated bone resorption, and novel targeted... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Bone is the most common site of metastatic disease associated with breast cancer (BC). Bisphosphonates inhibit osteoclast-mediated bone resorption, and novel targeted therapies such as denosumab inhibit other key bone metabolism pathways. We have studied these agents in both early breast cancer and advanced breast cancer settings. This is an update of the review originally published in 2002 and subsequently updated in 2005 and 2012.
OBJECTIVES
To assess the effects of bisphosphonates and other bone agents in addition to anti-cancer treatment: (i) in women with early breast cancer (EBC); (ii) in women with advanced breast cancer without bone metastases (ABC); and (iii) in women with metastatic breast cancer and bone metastases (BCBM).
SEARCH METHODS
In this review update, we searched Cochrane Breast Cancer's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov on 19 September 2016.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) comparing: (a) one treatment with a bisphosphonate/bone-acting agent with the same treatment without a bisphosphonate/bone-acting agent; (b) treatment with one bisphosphonate versus treatment with a different bisphosphonate; (c) treatment with a bisphosphonate versus another bone-acting agent of a different mechanism of action (e.g. denosumab); and (d) immediate treatment with a bisphosphonate/bone-acting agent versus delayed treatment of the same bisphosphonate/bone-acting agent.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data, and assessed risk of bias and quality of the evidence. The primary outcome measure was bone metastases for EBC and ABC, and a skeletal-related event (SRE) for BCBM. We derived risk ratios (RRs) for dichotomous outcomes and the meta-analyses used random-effects models. Secondary outcomes included overall survival and disease-free survival for EBC; we derived hazard ratios (HRs) for these time-to-event outcomes where possible. We collected toxicity and quality-of-life information. GRADE was used to assess the quality of evidence for the most important outcomes in each treatment setting.
MAIN RESULTS
We included 44 RCTs involving 37,302 women.In women with EBC, bisphosphonates were associated with a reduced risk of bone metastases compared to placebo/no bisphosphonate (RR 0.86, 95% confidence interval (CI) 0.75 to 0.99; P = 0.03, 11 studies; 15,005 women; moderate-quality evidence with no significant heterogeneity). Bisphosphonates provided an overall survival benefit with time-to-event data (HR 0.91, 95% CI 0.83 to 0.99; P = 0.04; 9 studies; 13,949 women; high-quality evidence with evidence of heterogeneity). Subgroup analysis by menopausal status showed a survival benefit from bisphosphonates in postmenopausal women (HR 0.77, 95% CI 0.66 to 0.90; P = 0.001; 4 studies; 6048 women; high-quality evidence with no evidence of heterogeneity) but no survival benefit for premenopausal women (HR 1.03, 95% CI 0.86 to 1.22; P = 0.78; 2 studies; 3501 women; high-quality evidence with no heterogeneity). There was evidence of no effect of bisphosphonates on disease-free survival (HR 0.94, 95% 0.87 to 1.02; P = 0.13; 7 studies; 12,578 women; high-quality evidence with significant heterogeneity present) however subgroup analyses showed a disease-free survival benefit from bisphosphonates in postmenopausal women only (HR 0.82, 95% CI 0.74 to 0.91; P < 0.001; 7 studies; 8314 women; high-quality evidence with no heterogeneity). Bisphosphonates did not significantly reduce the incidence of fractures when compared to placebo/no bisphosphonates (RR 0.77, 95% CI 0.54 to 1.08, P = 0.13, 6 studies, 7602 women; moderate-quality evidence due to wide confidence intervals). We await mature overall survival and disease-free survival results for denosumab trials.In women with ABC without clinically evident bone metastases, there was no evidence of an effect of bisphosphonates on bone metastases (RR 0.96, 95% CI 0.65 to 1.43; P = 0.86; 3 studies; 330 women; moderate-quality evidence with no heterogeneity) or overall survival (RR 0.89, 95% CI 0.73 to 1.09; P = 0.28; 3 studies; 330 women; high-quality evidence with no heterogeneity) compared to placebo/no bisphosphonates however the confidence intervals were wide. One study reported a trend towards an extended period of time without a SRE with bisphosphonate compared to placebo (low-quality evidence). One study reported quality of life and there was no apparent difference in scores between bisphosphonate and placebo (moderate-quality evidence).In women with BCBM, bisphosphonates reduced the SRE risk by 14% (RR 0.86, 95% CI 0.78 to 0.95; P = 0.003; 9 studies; 2810 women; high-quality evidence with evidence of heterogeneity) compared with placebo/no bisphosphonates. This benefit persisted when administering either intravenous or oral bisphosphonates versus placebo. Bisphosphonates delayed the median time to a SRE with a median ratio of 1.43 (95% CI 1.29 to 1.58; P < 0.00001; 9 studies; 2891 women; high-quality evidence with no heterogeneity) and reduced bone pain (in 6 out of 11 studies; moderate-quality evidence) compared to placebo/no bisphosphonate. Treatment with bisphosphonates did not appear to affect overall survival (RR 1.01, 95% CI 0.91 to 1.11; P = 0.85; 7 studies; 1935 women; moderate-quality evidence with significant heterogeneity). Quality-of-life scores were slightly better with bisphosphonates than placebo at comparable time points (in three out of five studies; moderate-quality evidence) however scores decreased during the course of the studies. Denosumab reduced the risk of developing a SRE compared with bisphosphonates by 22% (RR 0.78, 0.72 to 0.85; P < 0.001; 3 studies, 2345 women). One study reported data on overall survival and observed no difference in survival between denosumab and bisphosphonate.Reported toxicities across all settings were generally mild. Osteonecrosis of the jaw was rare, occurring less than 0.5% in the adjuvant setting (high-quality evidence).
AUTHORS' CONCLUSIONS
For women with EBC, bisphosphonates reduce the risk of bone metastases and provide an overall survival benefit compared to placebo or no bisphosphonates. There is preliminary evidence suggestive that bisphosphonates provide an overall survival and disease-free survival benefit in postmenopausal women only when compared to placebo or no bisphosphonate. This was not a planned subgroup for these early trials, and we await the completion of new large clinical trials assessing benefit for postmenopausal women. For women with BCBM, bisphosphonates reduce the risk of developing SREs, delay the median time to an SRE, and appear to reduce bone pain compared to placebo or no bisphosphonate.
Topics: Administration, Oral; Bone Density Conservation Agents; Bone Neoplasms; Breast Neoplasms; Clodronic Acid; Denosumab; Diphosphonates; Female; Humans; Imidazoles; Injections, Intravenous; Randomized Controlled Trials as Topic; Zoledronic Acid
PubMed: 29082518
DOI: 10.1002/14651858.CD003474.pub4