-
Rheumatology (Oxford, England) Feb 2023Chronic nonbacterial osteomyelitis (CNO) is a rare inflammatory bone disease. The distinct CNO subtype that affects the anterior chest wall is descriptively named... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Chronic nonbacterial osteomyelitis (CNO) is a rare inflammatory bone disease. The distinct CNO subtype that affects the anterior chest wall is descriptively named sternocostoclavicular hyperostosis (SCCH) and mainly occurs in adults. Literature on CNO/SCCH is scattered and lacks diagnostic and therapeutic consensus.
METHODS
Systematic review and meta-analysis aiming to characterize clinical presentation and therapeutic modalities applied in adult CNO/SCCH patients. Untransformed numerical data and double-arcsine transformed proportional data were pooled in a random effects model in R-4.0.5; proportions were reported with 95% CI.
RESULTS
Forty studies were included, containing data on 2030 and 642 patients for aim 1 and 2, respectively. A female predisposition (67%, 95% CI 60, 73) and major diagnostic delay (5 years 95% CI 3, 7) were noted. Clinical presentation included chest pain (89%, 95% CI 79, 96) and swelling (79%, 95% CI 62, 91). Patients suffered from pustulosis palmoplantaris (53%, 95% CI 37, 68), arthritis (24%, 95% CI 11, 39) and acne (8%, 95% CI 4, 13). Inflammatory markers were inconsistently elevated. Autoantibody and HLA-B27 prevalence was normal, and histopathology unspecific. Increased isotope uptake (99%, 95% CI 96, 100) was a consistent imaging finding. Among manifold treatments, pamidronate and biologicals yielded good response in 83%, 95% CI 60, 98 and 56%, 95% CI 26, 85, respectively.
CONCLUSION
CNO/SCCH literature proves heterogeneous regarding diagnostics and treatment. Timely diagnosis is challenging and mainly follows from increased isotope uptake on nuclear examination. Biopsies, autoantibodies and HLA status are non-contributory, and biochemical inflammation only variably detected. Based on reported data, bisphosphonates and biologicals seem reasonably effective, but due to limitations in design and heterogeneity between studies the precise magnitude of their effect is uncertain. Fundamentally, international consensus seems imperative to advance clinical care for CNO/SCCH.
Topics: Adult; Humans; Female; Acquired Hyperostosis Syndrome; Delayed Diagnosis; Osteomyelitis; Psoriasis
PubMed: 35961032
DOI: 10.1093/rheumatology/keac443 -
The Cochrane Database of Systematic... Feb 2012Bone 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 key pathways in the vicious cycle of bone metastases.
OBJECTIVES
To assess the effect of bisphosphonates on skeletal-related events (SREs), bone pain, quality of life (QoL), recurrence and survival in women with breast cancer with bone metastases (BCBM), advanced breast cancer (ABC) without clinical evidence of bone metastases and early breast cancer (EBC).To assess the effect of denosumab on SREs, bone pain and (QoL) in women with (BCBM).
SEARCH METHODS
We searched the Specialised Register maintained by the Cochrane Breast Cancer Group (CBCGSR), MEDLINE, EMBASE and the WHO International Cancer Trials Registry Platform (WHO ICTRP) on 30 April 2011. We conducted additional handsearching of journals and proceedings of key meetings.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) comparing: (a) bisphosphonates and control, or different bisphosphonates in women with BCBM; (b) denosumab and bisphosphonates in women with BCBM; (c) bisphosphonates and control in women with ABC; (d) bisphosphonates and control in women with EBC; and (e) early versus delayed bisphosphonate treatment in women with EBC.
DATA COLLECTION AND ANALYSIS
Two review authors (MW and NP) independently assessed the trials and extracted the data. We collected toxicity information from the trials.
MAIN RESULTS
We included thirty-four RCTs. In nine studies (2806 patients with BCBM), comparing bisphosphonates with placebo or no bisphosphonates, bisphosphonates reduced the SRE risk by 15% (risk ratio (RR) 0.85; 95% confidence interval (CI) 0.77 to 0.94; P = 0.001). This benefit was most certain with intravenous (i.v.) zoledronic acid (4 mg) (RR 0.59; 95% CI 0.42 to 0.82); i.v. pamidronate (90 mg) (RR 0.77; 95% CI 0.69 to 0.87); and i.v. ibandronate (RR 0.80; 95% CI 0.67 to 0.96). A direct comparison of i.v. zoledronic acid and i.v. pamidronate confirmed at least equivalent efficacy in a single large study. In three studies (3405 patients with BCBM), compared with bisphosphonates, subcutaneous (s.c.) denosumab was more effective in reducing the risk of SREs (RR 0.78; 95% CI 0.72 to 0.85; P < 0.00001).Bisphosphonates reduced the SRE rate in 12 studies (median reduction 28%, range 14% to 48%), with statistically significant reductions reported in 10 studies. Women with BCBM treated with bisphosphonates showed significant delays in the median time to SREs. Compared with placebo or no bisphosphonates, treatment with bisphosphonates significantly improved bone pain in six out of eleven studies. Improvements in global QoL with bisphosphonates compared to placebo were reported in two out of five studies (both ibandronate studies). Treatment with bisphosphonates did not appear to affect survival in women with BCBM. Compared to i.v. zoledronic acid, denosumab also significantly reduced the SRE rate, delayed the time to SREs and prolonged the time in developing pain for patients with no or mild pain at baseline; but there was no difference in survival between patients treated with denosumab and zoledronic acid.Bisphosphonates in women with ABC without clinically evident bone metastases did not reduce the incidence of bone metastases, or improve survival in three studies (320 patients).In seven studies (7847 patients with EBC), currently there is no evidence supporting bisphosphonates in reducing the incidence of bone metastases compared to no bisphosphonates (RR 0.94; 95% CI 0.82 to 1.07; P = 0.36). In three studies (2190 patients with EBC), early bisphosphonate treatment also did not significantly reduce the incidence of bone metastases compared to delayed bisphosphonate treatment (RR 0.73; 95% CI 0.40 to 1.33; P = 0.31). Currently, there is insufficient evidence to make a conclusion about the role of adjuvant bisphosphonates in reducing visceral metastases, locoregional recurrence and total recurrence, or improving survival. There was strong heterogeneity in EBC studies examining the outcomes of total recurrence and survival.Reported toxicity was generally mild. Renal toxicity and osteonecrosis of the jaw (ONJ) have been identified as potential problems with bisphosphonate use. ONJ was reported at similar rates for patients on denosumab compared to zoledronic acid. This highlighted a need for maintaining good oral care, prior to and during treatment, for patients who received long-term bone agents.
AUTHORS' CONCLUSIONS
In women with clinically evident BCBM, bisphosphonates (oral and i.v.) and denosumab (s.c.) reduced the risk of developing SREs, as well as delaying the time to SREs. Some bisphosphonates may also reduce bone pain and may improve QoL. The optimal timing and duration of treatment for patients with BCBM remains uncertain. There is currently insufficient evidence to support the routine use of bisphosphonates as adjuvant treatment for patients with EBC. However, a number of large clinical trials investigating bisphosphonates in EBC have completed accrual and are awaiting results.
Topics: Administration, Oral; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bone Density Conservation Agents; Bone Neoplasms; Breast Neoplasms; Denosumab; Diphosphonates; Female; Humans; Injections, Intravenous; Randomized Controlled Trials as Topic
PubMed: 22336790
DOI: 10.1002/14651858.CD003474.pub3 -
Annals of Oncology : Official Journal... Nov 2015De-escalation of bone-targeted agents, such as bisphosphonates and denosumab, from 4- to 12-weekly dosing is an increasingly used strategy in patients with bone... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
De-escalation of bone-targeted agents, such as bisphosphonates and denosumab, from 4- to 12-weekly dosing is an increasingly used strategy in patients with bone metastases from breast cancer. It is unclear whether there is sufficient evidence to support de-escalation as a standard of care.
METHODS
A systematic review of randomized trials comparing standard 4-weekly administration of bone-targeted agents with de-escalated (Q12-weekly) dosing in breast cancer patients was carried out. Medline, PubMed and the Cochrane Register of Controlled Trials were searched from inception until November 2014 for relevant studies. Outcomes of interest included skeletal-related event (SRE) rates, bone pain, adverse events (AEs) and bone turnover biomarkers. Random-effects meta-analyses were carried out.
RESULTS
A total of nine citations representing seven unique studies were eligible. One study is ongoing with no reported data. Six studies reported data for at least one outcome of interest. Data were available comparing standard versus de-escalated therapy for pamidronate (1 study, 38 patients), zoledronate (3 studies, 1117 patients) and denosumab (2 studies, 284 patients). Meta-analysis of five trials reporting data for on-study SRE rates between standard (61/443 patients) and de-escalated (49/392 patients) arms produced a summary risk ratio of 0.90 (95% confidence interval 0.63-1.29). Meta-analyses of data for AEs and bone turnover biomarkers also showed no statistically significant differences between standard and de-escalated arms, though only limited numbers of patients and events were present for most analyses.
CONCLUSION
In this systematic review of studies of bisphosphonates and denosumab, there appears to be no difference in SREs or pain with de-escalated therapy. While a large, hopefully definitive study is ongoing, the data presented so far are consistent with de-escalation of bone-targeting agents becoming a standard of care for patients with bone metastases from breast cancer.
Topics: Bone Density Conservation Agents; Bone Neoplasms; Breast Neoplasms; Clinical Trials as Topic; Drug Administration Schedule; Female; Humans; Standard of Care
PubMed: 26122727
DOI: 10.1093/annonc/mdv284 -
PloS One 2021Bisphosphonate drugs can be used to improve the outcomes of women with breast cancer. Whilst many meta-analyses have quantified their potential benefits for patients,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Bisphosphonate drugs can be used to improve the outcomes of women with breast cancer. Whilst many meta-analyses have quantified their potential benefits for patients, attempts at comprehensive quantification of potential adverse effects have been limited. We undertook a meta-analysis with novel methodology to identify and quantify these adverse effects.
METHODS
We systematically reviewed randomised controlled trials in breast cancer where at least one of the treatments was a bisphosphonate (zoledronic acid, ibandronate, pamidronate, alendronate or clodronate). Neoadjuvant, adjuvant and metastatic settings were examined. Primary outcomes were adverse events of any type or severity (excluding death). We carried out pairwise and network meta-analyses to estimate the size of any adverse effects potentially related to bisphosphonates. In order to ascertain whether adverse effects differed by individual factors such as age, or interacted with other common adjuvant breast cancer treatments, we examined individual-level patient data for one large trial, AZURE.
FINDINGS
We identified 56 trials that reported adverse data, which included a total of 29,248 patients (18,301 receiving bisphosphonate drugs versus 10,947 not). 24 out of the 103 different adverse outcomes analysed showed a statistically and practically significant increase in patients receiving a bisphosphonate drug compared with those not (2 additional outcomes that appeared statistically significant came only from small studies with low event counts and no clinical suspicion so are likely artifacts). Most of these 24 are already clinically recognised: 'flu-like symptoms, fever, headache and chills; increased bone pain, arthralgia, myalgia, back pain; cardiac events, thromboembolic events; hypocalcaemia and osteonecrosis of the jaw; as well as possibly stiffness and nausea. Oral clodronate appeared to increase the risk of vomiting and diarrhoea (which may also be increased by other bisphosphonates), and there may be some hepatotoxicity. Four additional potential adverse effects emerged for bisphosphonate drugs in this analysis which have not classically be recognised: fatigue, neurosensory problems, hypertonia/muscle spasms and possibly dysgeusia. Several symptoms previously reported as potential side effects in the literature were not significantly increased in this analysis: constipation, insomnia, respiratory problems, oedema or thirst/dry mouth. Individual patient-level data and subgroup analysis revealed little variation in side effects between women of different ages or menopausal status, those with metastatic versus non-metastatic cancer, or between women receiving different concurrent breast cancer therapies.
CONCLUSIONS
This meta-analysis has produced estimates for the absolute frequencies of a range of side effects significantly associated with bisphosphonate drugs when used by breast cancer patients. These results show good agreement with previous literature on the subject but are the first systematic quantification of side effects and their severities. However, the analysis is limited by the availability and quality of data on adverse events, and the potential for bias introduced by a lack of standards for reporting of such events. We therefore present a table of adverse effects for bisphosphonates, identified and quantified to the best of our ability from a large number of trials, which we hope can be used to improve the communication of the potential harms of these drugs to patients and their healthcare providers.
Topics: Adult; Aged; Aged, 80 and over; Bone Density Conservation Agents; Breast Neoplasms; Diphosphonates; Female; Humans; Middle Aged; Network Meta-Analysis; Randomized Controlled Trials as Topic; Young Adult
PubMed: 33544765
DOI: 10.1371/journal.pone.0246441 -
The Cochrane Database of Systematic... 2002Bisphosphonates form part of standard therapy for hypercalcemia and the prevention of skeletal events in some cancers. However, the role of bisphosphonates in pain... (Review)
Review
BACKGROUND
Bisphosphonates form part of standard therapy for hypercalcemia and the prevention of skeletal events in some cancers. However, the role of bisphosphonates in pain relief for bony metastases remains uncertain.
OBJECTIVES
To determine the effectiveness of bisphosphonates for the relief of pain from bone metastases.
SEARCH STRATEGY
MEDLINE (1966-1999), EMBASE (1980-1999), CancerLit (1966-1999), the Cochrane library (Issue 1, 2000) and the Oxford Pain Database were searched using the strategy devised by the Cochrane Pain, Palliative and Supportive Care Group with additional terms 'diphosphonate', 'bisphosphonate', 'multiple myeloma' and 'bone neoplasms'. (Last search: January 2000).
SELECTION CRITERIA
Randomized trials of bisphosphonates compared with open, blinded, or different doses/types of bisphosphonates in cancer patients were included where pain and/or analgesic consumption were outcome measures. Studies where pain was reported only by observers were excluded.
DATA COLLECTION AND ANALYSIS
Article eligibility, quality assessment and data extraction were undertaken by both reviewers. The proportions of patients with pain relief at 4, 8 and 12 weeks were assessed. The proportion of patients with analgesic reduction, the mean pain score, mean analgesic consumption, adverse drug reactions, and quality of life data were compared as secondary outcomes.
MAIN RESULTS
Thirty randomized controlled studies (21 blinded, four open and five active control) with a total of 3682 subjects were included. For each outcome, there were few studies with available data. For the proportion of patients with pain relief (eight studies) pooled data showed benefits for the treatment group, with an NNT at 4 weeks of 11[95% CI 6-36] and at 12 weeks of 7 [95% CI 5-12]. In terms of adverse drug reactions, the NNH was 16 [95% CI 12-27] for discontinuation of therapy. Nausea and vomiting were reported in 24 studies with a non-significant trend for greater risk in the treatment group. One study showed a small improvement in quality of life for the treatment group at 4 weeks. The small number of studies in each subgroup with relevant data limited our ability to explore the most effective bisphosphonates and their relative effectiveness for different primary neoplasms.
REVIEWER'S CONCLUSIONS
There is evidence to support the effectiveness of bisphosphonates in providing some pain relief for bone metastases. There is insufficient evidence to recommend bisphosphonates for immediate effect; as first line therapy; to define the most effective bisphosphonates or their relative effectiveness for different primary neoplasms. Bisphosphonates should be considered where analgesics and/or radiotherapy are inadequate for the management of painful bone metastases.
Topics: Analgesics, Non-Narcotic; Antineoplastic Agents; Bone Neoplasms; Clodronic Acid; Diphosphonates; Etidronic Acid; Humans; Pain; Pamidronate; Randomized Controlled Trials as Topic
PubMed: 12076438
DOI: 10.1002/14651858.CD002068 -
PloS One 2013The role of bisphosphonates (BP) in early breast cancer (BC) has been considered controversial. We performed a meta-analysis of all randomized controlled trials (RCTs)... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The role of bisphosphonates (BP) in early breast cancer (BC) has been considered controversial. We performed a meta-analysis of all randomized controlled trials (RCTs) that appraised the effects of BP on survival in early BC.
METHODS
RCTs were identified by searching the Cochrane Library, MEDLINE databases and conference proceedings. Hazard ratios (HRs) of overall survival (OS), disease-free survival (DFS) and relative risks of adverse events were estimated and pooled.
RESULTS
Thirteen trials met the inclusion criteria, evaluating a total of 15,762 patients. Meta-analysis of ten trials which reported OS revealed no statistically significant benefit in OS for BP (HR 0.89, 95% CI = 0.79 to 1.01). Meta-analysis of nine trials which reported the DFS revealed no benefit in DFS (HR 0.95 (0.81-1.12)). Meta-analysis upon menopausal status showed a statistically significant better DFS in the BP-treated patients (HR 0.81(0.69-0.95)). In meta-regression, chemotherapy was negatively associated with HR of survival.
CONCLUSIONS
Our meta-analysis indicates a positive effect for adjuvant BP on survival only in postmenopausal patients. Meta-regression demonstrated a negative association between chemotherapy use BP effect on survival. Further large scale RCTs are warranted to unravel the specific subgroups that would benefit from the addition of BP in the adjuvant setting.
Topics: Antineoplastic Agents; Bone Density Conservation Agents; Breast Neoplasms; Chemotherapy, Adjuvant; Clodronic Acid; Diphosphonates; Disease-Free Survival; Etidronic Acid; Female; Humans; Ibandronic Acid; Pamidronate; Proportional Hazards Models; Randomized Controlled Trials as Topic; Research Design; Risedronic Acid; Risk; Treatment Outcome
PubMed: 23990894
DOI: 10.1371/journal.pone.0070044 -
The Cochrane Database of Systematic... 2002Bone is the most common site of metastatic disease associated with breast cancer, and affects more than half of women during the course of their disease. Bone metastases... (Review)
Review
BACKGROUND
Bone is the most common site of metastatic disease associated with breast cancer, and affects more than half of women during the course of their disease. Bone metastases are a significant cause of morbidity due to pain, pathological fractures, hypercalcaemia and spinal cord compression, and contribute to mortality. Bisphosphonates, which inhibit osteoclast-mediated bone resorption, are standard care for tumour-associated hypercalcaemia, and have been shown to reduce bone pain, improve quality of life, and to delay skeletal events and reduce their number in patients with multiple myeloma. Several randomized controlled trials have evaluated the role of bisphosphonates in breast cancer.
OBJECTIVES
The aim of this systematic review was to identify, describe and summarize high-quality evidence regarding the effect of bisphosphonates on skeletal events, bone pain, quality of life and survival in women with early and advanced breast cancer.
SEARCH STRATEGY
Randomized controlled trials were identified in the specialized register maintained by the secretariat of the Cochrane Breast Cancer Group (the search was applied to the databases Medline, Central/CCTR, Embase, CancerLit, and included handsearches from a number of other relevant sources). See: Cochrane Collaboration Collaborative Review Group in Breast Cancer search strategy.
SELECTION CRITERIA
Randomized controlled trials evaluating skeletal events in women with metastatic breast cancer and in women with early breast cancer comparing: 1. treatment with a bisphosphonate with the same treatment without a bisphosphonate 2. treatment with one bisphosphonate with treatment with a different bisphosphonate.
DATA COLLECTION AND ANALYSIS
Studies were selected by two independent reviewers. Studies fulfilling the eligibility criteria were evaluated for quality, particularly concealment of allocation to randomized groups. Data were extracted from the published papers or abstracts independently by the two primary reviewers for each of the specified endpoints (skeletal events, bone pain, quality of life and survival). Data on skeletal events and survival were presented as numbers of events, risk ratios and ratios of event rates. Meta-analyses were based on the fixed-effects model (Mantel-Haenszel). Subjective qualitative ratings were used to summarize the quality of life and pain data.
MAIN RESULTS
From 37 reports considered in detail after screening of the 117 reports identified by our search, 19 randomized studies were included. In eight studies that included 1962 women with advanced breast cancer and existing bone metastases, bisphosphonates reduced the risk of developing a skeletal event by 14% (RR 0.86; 95% confidence interval (CI) 0.80-0.91; P < 0.00001). This effect was more modest, but still highly significant if episodes of hypercalcaemia were excluded (6 studies, 1553 women, RR 0.88; 95% CI 0.81-0.96; P = 0.004). For intravenous pamidronate the reduction in the risk of skeletal event was greatest with a dosage of 90 mg (RR 0.77; 95% CI 0.69-0.87). Oral bisphosphonates reduced the risk of a skeletal event by 17% (pooled RR 0.83; 95% CI 0.73-0.94, P = 0.004). Oral clodronate reduced the risk of a skeletal event by 16% in women with advanced breast cancer and clinically evident bone metastases (pooled RR 0.84; 95% CI 0.72-0.98; P = 0.03). Compared with placebo or no bisphosphonate, with bisphosphonates the skeletal event rate was lower in all of eight studies (median reduction of 30%, range 20-48%); statistically significant reductions were reported in six trials (three intravenous pamidronate, two oral clodronate and one intravenous ibandronate). All studies of intravenous pamidronate and oral clodronate in women with advanced breast cancer and clinically evident bone metastases showed significant delays in the median time to a skeletal event. Event-free survival was reported to be longer in women receiving 6 mg of ibandronate compared with control women. Compared with placebo or no bisphosphonate, with bisphosphonates significant improvements in pain were reported in four studies, and improvements in quality of life were reported in two studies. Treatment with bisphosphonates does not appear to affect survival in women with advanced breast cancer. Intravenous zolendronate (4 mg) appeared to have equivalent efficacy when compared with intravenous pamidronate in a single randomized double-blind study. In the three studies of bisphosphonates in 320 women with advanced breast cancer without clinically evident bone metastases, there was no significant reduction in the incidence of skeletal events (RR 0.99; 95% CI 0.67-1.47; P > 0.9). In three studies of oral clodronate that included 1680 women with early breast cancer, there was borderline evidence of a reduction in the risk of developing skeletal metastases (RR 0.73; 95% CI 0.55-0.98; P = 0.04), but there was significant heterogeneity among these studies (P = 0.035). Toxicity or adverse events were described in 14 of the 19 studies. In general, few adverse events were reported.
REVIEWER'S CONCLUSIONS
In women with advanced breast cancer and clinically evident bone metastases, the use of bisphosphonates (oral or intravenous) in addition to hormone therapy or chemotherapy, when compared with placebo or no bisphosphonates, reduces the risk of developing a skeletal event and the skeletal event rate, as well as increasing the time toskeletal event. Bisphosphonates may also reduce bone pain in women with advanced breast cancer and clinically evident bone metastases. In women with early breast cancer the effectiveness of oral clodronate in reducing the incidence of bone metastases remains an open question for research.
Topics: Administration, Oral; Antineoplastic Agents; Bone Neoplasms; Breast Neoplasms; Diphosphonates; Female; Humans; Injections, Intravenous; Randomized Controlled Trials as Topic
PubMed: 11869664
DOI: 10.1002/14651858.CD003474 -
Health Technology Assessment... 2004To identify evidence for the role of bisphosphonates in malignancy for the treatment of hypercalcaemia, prevention of skeletal morbidity and use in the adjuvant setting.... (Review)
Review
OBJECTIVES
To identify evidence for the role of bisphosphonates in malignancy for the treatment of hypercalcaemia, prevention of skeletal morbidity and use in the adjuvant setting. To perform an economic review of current literature and model the cost effectiveness of bisphosphonates in the treatment of hypercalcaemia and prevention of skeletal morbidity.
DATA SOURCES
Electronic databases (1966-June 2001). Cochrane register. Pharmaceutical companies. Experts in the field. Handsearching of abstracts and leading oncology journals (1999-2001).
REVIEW METHODS
Two independent reviewers assessed studies for inclusion, according to predetermined criteria, and extracted relevant data. Overall event rates were pooled in a meta-analysis, odds ratios (OR) were given with 95% confidence intervals (CI). Where data could not be combined, studies were reported individually and proportions compared using chi-squared analysis. Cost and cost-effectiveness were assessed by a decision analytic model comparing different bisphosphonate regimens for the treatment of hypercalcaemia; Markov models were employed to evaluate the use of bisphosphonates to prevent skeletal-related events (SRE) in patients with breast cancer and multiple myeloma.
RESULTS
For acute hypercalcaemia of malignancy, bisphosphonates normalised serum calcium in >70% of patients within 2-6 days. Pamidronate was more effective than control, etidronate, mithramycin and low-dose clodronate, but equal to high dose clodronate, in achieving normocalcaemia. Pamidronate prolongs (doubles) the median time to relapse compared with clodronate or etidronate. For prevention of skeletal morbidity, bisphosphonates compared with placebo, significantly reduced the OR for fractures (OR [95% CI], vertebral, 0.69 [0.57-0.84], non-vertebral, 0.65 [0.54-0.79], combined, 0.65 [0.55-0.78]) radiotherapy 0.67 [0.57-0.79] and hypercalcaemia 0.54 [0.36-0.81] but not orthopaedic surgery 0.70 [0.46-1.05] or spinal cord compression 0.71 [0.47-1.08]. However, reduction in orthopaedic surgery was significant in studies that lasted over a year 0.59 [0.39-0.88]. Bisphosphonates significantly increased the time to first SRE but did not affect survival. Subanalyses were performed for disease groups, drugs and route of administration. Most evidence supports the use of intravenous aminobisphosphonates. For adjuvant use of bisphosphonates, Clodronate, given to patients with primary operable breast cancer and no metastatic disease, significantly reduced the number of patients developing bone metastases. This benefit was not maintained once regular administration had been discontinued. Two trials reported significant survival advantages in the treated groups. Bisphosphonates reduce the number of bone metastases in patients with both early and advanced breast cancer. Bisphosphonates are well tolerated with a low incidence of side-effects. Economic modelling showed that for acute hypercalcaemia, drugs with the longest cumulative duration of normocalcaemia were most cost-effective. Zoledronate 4 mg was the most costly, but most cost-effective treatment. For skeletal morbidity, Markov models estimated that the overall cost of bisphosphonate therapy to prevent an SRE was GBP250 and GBP1500 per event for patients with breast cancer and multiple myeloma, respectively. Bisphosphonate treatment is sometimes cost-saving in breast cancer patients where fractures are prevented.
CONCLUSIONS
High dose aminobisphosphonates are most effective for the treatment of acute hypercalcaemia and delay time to relapse. Bisphosphonates significantly reduce SREs and delay the time to first SRE in patients with bony metastatic disease but do not affect survival. Benefit is demonstrated after administration for at least 6-12 months. The greatest body of evidence supports the use of intravenous aminobisphosphonates. Further evidence is required to support use in the adjuvant setting.
Topics: Bone Neoplasms; Cost-Benefit Analysis; Diphosphonates; Evidence-Based Medicine; Humans; Hypercalcemia; Hyperparathyroidism; State Medicine; United Kingdom
PubMed: 14960258
DOI: 10.3310/hta8040 -
The Cochrane Database of Systematic... Jul 2005Bone is the most common site of metastatic disease associated with breast cancer affecting more than half of women during the course of their disease. Bone metastases... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Bone is the most common site of metastatic disease associated with breast cancer affecting more than half of women during the course of their disease. Bone metastases are a significant cause of morbidity due to pain, pathological fractures, hypercalcaemia and spinal cord compression, and contribute to mortality. Bisphosphonates, which inhibit osteoclast-mediated bone resorption, are standard care for tumour-associated hypercalcaemia, and have been shown to reduce bone pain, improve quality of life, and to delay skeletal events and reduce their number in patients with multiple myeloma. Several randomized controlled trials have evaluated the role of bisphosphonates in breast cancer.
OBJECTIVES
To assess the effect of bisphosphonates on skeletal events, bone pain, quality of life and survival in women with early and advanced breast cancer.
SEARCH STRATEGY
Randomized controlled trials were identified using the specialized register maintained by the Cochrane Breast Cancer Group (the search was applied to the databases Medline, Central/CCTR, Embase, CancerLit, and included handsearches from a number of other relevant sources). See: Cochrane Collaboration Collaborative Review Group in Breast Cancer search strategy.
SELECTION CRITERIA
Randomized controlled trials evaluating skeletal events in women with metastatic breast cancer and early breast cancer comparing: 1. treatment with a bisphosphonate with the same treatment without a bisphosphonate 2. treatment with one bisphosphonate with treatment with a different bisphosphonate.
DATA COLLECTION AND ANALYSIS
Studies were selected by two independent reviewers. Studies fulfilling the eligibility criteria were evaluated for quality, particularly concealment of allocation to randomized groups. Data were extracted from the published papers or abstracts independently by the two primary reviewers for each of the specified endpoints (skeletal events, bone pain, quality of life and survival). Data on skeletal events and survival were presented as numbers of events, risk ratios and ratios of event rates. Meta-analyses were based on the fixed-effects model (Mantel-Haenszel). Subjective qualitative ratings were used to summarize the quality of life and pain data.
MAIN RESULTS
Twenty one randomized studies were included. All studies in advanced breast cancer included women with clinically evident bone metastases (osteolytic and/or mixed osteolytic/osteoblastic) by plain xray and/or radionucleotide bone scans. In nine studies that included 2189 women with advanced breast cancer and existing bone metastases, bisphosphonates reduced the risk of developing a skeletal event by 17% (RR 0.83; 95% confidence interval (CI) 0.78-0.89; P < 0.00001). This effect was more modest, but still highly significant if episodes of hypercalcaemia were excluded (10 studies, 2656 women, RR 0.85; 95% CI 0.79-0.91 P = 0.0001). Overall, intravenous bisphosphonates reduce the risk of developing a skeletal event by 17 % (95% CI 0.78-0.89) compared with oral bisphosphonates, which reduce the risk of developing a skeletal event by 16 % (95% CI 0.76-0.93). Of the currently available bisphosphonates, 4 mg IV zolendronate reduces the risk of developing a skeletal event by 41% (RR 0.59, 95% CI 0.42-0.82), compared with 33 % by 90 mg IV pamdronate (RR 0.77, 95% CI 0.69-0.87), 18 % by 6 mg IV ibandronate (RR 0.82, 95% CI 0.67-1.00), 14 % by 50mg oral ibandronate (RR 0.86, 95% CI 0.73-1.02) and 16 % by 1600 mg oral clodronate (RR 0.84, 95% CI 0.72-0.98). Compared with placebo or no bisphosphonate, with bisphosphonates the skeletal event rate was lower in all of 12 studies in women with clinically evident bone metastases (median reduction of 29%, range 14-48%); statistically significant reductions were reported in 10 trials (four intravenous pamidronate, two oral clodronate, one intravenous ibandronate and two oral ibandronate, a single intravenous zolendronate study). Studies of intravenous zolendronate, pamidronate and oral clodronate in women with advanced breast cancer and clinically evident bone metastases showed significant delays in the median time to a skeletal event. Event-free survival was also reported to be longer in women receiving 6 mg of ibandronate compared with controls. Compared with placebo or no bisphosphonate, with bisphosphonates significant improvements in bone pain were reported in seven studies (90 mg iv pamidronate, 4 mg iv zolendronate, 6 mg iv ibandronate, 1600 mg oral clodronate and 50 mg oral ibandronate). Eight studies tested the effect of bisphosphonates compared with placebo on patient-rated quality of life using a referenced scale. Improvements in global quality of life were reported in only the three studies of iv and oral ibandronate. Treatment with bisphosphonates does not appear to affect survival in women with advanced breast cancer. Intravenous zolendronate (4 mg) appeared to be as effective as pamidronate (90mg) when directly compared in a single randomized double-blind study, based on the risk of developing a skeletal related event, the median time to first skeletal event and skeletal morbidity rate (events per year). Updated re-evaluation of the primary data in the overall population, by multiple event analysis using the method of Anderson-Gill, showed a reduction in the risk of developing any skeletal complication (including hypercalcamia) of 20 % (zolendronate 4 mg compared with pamidronate 90 mg, RR = 0.80, 95% CI 0.66 - 0.97, p = 0.025), suggesting a possible advantage of zolendronate 4 mg compared with pamidronate 90 mg. In the three studies of bisphosphonates in 320 women with advanced breast cancer without clinically evident bone metastases, there was no significant reduction in the incidence of skeletal events (RR 0.99; 95% CI 0.67-1.47; P = 0.97). In the three studies of oral clodronate that included 1653 women with early breast cancer, there was no statistically significant evidence of reduction in the risk of developing skeletal metastases (RR 0.82; 95% CI 0.66-1.01; P = 0.07), or of visceral metastases (RR 0.95; 95% CI 0.80-1.12, p = 0.53). However there was evidence of improved survival (RR 0.82; 95% CI 0.69-0.97, p = 0.02). However there was statistically significant heterogeneity among these studies and a random effects meta-analysis emphasizes the uncertainty of this finding (RR 0.75; 95% CI 0.45 - 1.25; p = 0.19). Toxicity or adverse events were described in 18 of the 21 studies. In general, few serious adverse events were reported. Toxicity associated with bisphosphonates is generally mild and infrequent. Renal toxicity is the main issue with intravenous zolendronate and is dose (8 mg) and infusion time related (< 15 minutes). With daily oral calcium (500 mg) and vitamin D (300-400IU) no significant renal impairment or hypocalcamia was observed with a 15 minute infusion of 4 mg IV zolendronate compared with 90 mg pamidronate. Monitoring of renal function with every cycle of zolendronate was undertaken in all studies and is recommended in practice. No significant renal toxicity was observed with intravenous pamidronate or ibandronate. Mild gastrointestinal toxicity is the main toxicity with oral clodronate and oral ibandronate.
AUTHORS' CONCLUSIONS
In women with advanced breast cancer and clinically evident bone metastases, the use of bisphosphonates (oral or intravenous) in addition to hormone therapy or chemotherapy, when compared with placebo or no bisphosphonates, reduces the risk of developing a skeletal event and the skeletal event rate, as well as increasing the time to skeletal event. Some bisphosphonates may also reduce bone pain in women with advanced breast cancer and clinically evident bone metastases and may improve global quality of life. The optimal timing of initiation of bisphosphonate therapy and duration of treatment is uncertain. In women with early breast cancer the effectiveness of bisphosphonates remains an open question for research.
Topics: Administration, Oral; Antineoplastic Agents; Bone Density Conservation Agents; Bone Neoplasms; Breast Neoplasms; Diphosphonates; Female; Humans; Injections, Intravenous; Randomized Controlled Trials as Topic
PubMed: 16034900
DOI: 10.1002/14651858.CD003474.pub2 -
International Journal of Rheumatic... Mar 2015The aim of this systematic review was to evaluate, critically, the treatment options used in the management of bone loss associated with glucocorticoid (GC) use among... (Review)
Review
AIMS
The aim of this systematic review was to evaluate, critically, the treatment options used in the management of bone loss associated with glucocorticoid (GC) use among children.
METHODS
We performed a systematic search using PubMed, Cochrane clinical trial registry, Clinicaltiral.gov and Ovid databases (1 March, 2013). The search resulted in 34 eligible retrievals. Of them, seven clinical trials that fulfilled the inclusion and exclusion criteria were selected by two authors.
RESULTS
Four studies have compared the effectiveness of bisphosphonates in the treatment of GC-induced low bone mineral density (BMD) in children. Remaining studies were on menatretenone + alfacacidol versus alfacalcidol alone, calcium + vitamin D versus placebo and alfacalcidol versus menatetrenone. In the four studies, bisphosphonates have shown the ability either to improve BMD or prevent bone loss associated with GC use in children. However, alendronate either in oral or intravenous routes and oral pamidronate were the only bisphosphnates that have been studied in children. Vitamin K2 (menatetrenone) combined with alfacalcidol has also preserved BMD in children on long-term GC therapy. Calcium combined with alfacalcidol has also prevented bone loss, greater than menatetrenone. Calcitriol together with Calcium in conventional doses has retarded bone loss, although the combination could not completely prevent the process.
CONCLUSIONS
Vitamin D derivatives such as calcitriol or alfacalcidol together with adequate calcium can be considered suitable treatment options to be started simultaneously when long-term GC therapy is needed in children. For children who have been on GCs or have already lost BMD, either oral pamidronate or alendronate in oral/intravenous routes can be considered based on the availability.
Topics: Administration, Intravenous; Administration, Oral; Adolescent; Age Factors; Bone Density; Bone Density Conservation Agents; Calcium; Child; Dietary Supplements; Diphosphonates; Drug Therapy, Combination; Glucocorticoids; Humans; Osteoporosis; Risk Factors; Treatment Outcome; Vitamin D
PubMed: 25923606
DOI: 10.1111/1756-185X.12560