Comparison of the clinical effectiveness of treatments for aromatase inhibitor-induced arthralgia in breast cancer patients: A systematic review with network meta-analysis.

Aromatase inhibitor-induced arthralgia (AIA) contributes to poor adherence of aromatase inhibitor therapies in patients with breast cancer. A systematic review using network meta-analysis (NMA) was conducted to examine the clinical effectiveness of multiple therapies and rank probabilities for the management of AIA. Randomized controlled trials (RCTs) assessing treatments for AIA in postmenopausal women with stage 0-III hormone receptor-positive breast cancer were searched from inception to October 2021. The main NMA involved 1516 participants from 17 RCTs. Acupuncture was the highest ranked intervention to improve pain intensity followed by sham acupuncture, multicomponent herbal medicine, exercise, duloxetine, vitamin D, omega-3 fatty acids, physical therapy, testosterone, and inactive controls. Single natural products were inferior to controls. The current review provides new insights into the management of AIA in breast cancer survivors for increased survival and can be utilized to make evidence-based decisions regarding treatment.

Use of an alfa-lipoic, Methylsulfonylmethane, Boswellia serrata and Bromelain dietary supplement (OPERA®) for aromatase inhibitors-related arthralgia management (AIA): a prospective phase II trial (NCT04161833).

Aromatase Inhibitors (AIs) are recommended for the adjuvant treatment of hormone receptor positive breast cancer in both high-risk pre-menopausal and post-menopausal population; arthralgia is the main cause of discontinuation of therapy and affects up to 25% of population on AI treatment. The objective of the study was to prospectively evaluate OPERA® (GAMFARMA srl, Milan, Italy), a new dietary supplement where α-Lipoic acid, Boswellia serrata, Methylsulfonylmethane and Bromelain are combined in a single hard-gelatin capsule to be taken once a day. Fifty-three patients with arthralgia (NCI-CTCAE v4.0 grade ≥ 1) occurring during AI therapy were enrolled. All patients received OPERA® from enrollment (T0) up to sixth months (T3). Patients' AI-related arthralgia was evaluated every two months with VAS Scale, PRAI questionnaire, and CTCAE scale. Primary endpoint was the number of patients with symptom resolution (G0) at T3 if compared to T0, according to CTCAE and VAS scale. Secondary endpoints were decrease in arthralgia intensity measured with PRAI score at T3 compared to baseline, safety of OPERA® and rate of AI interruption. Treatment with OPERA® supplement was overall well tolerated; no relevant toxicities related to OPERA® intake were reported. Seven subjects (13.2%) were not included in the final analysis because of consent withdrawal. 46 participants were eligible for final analysis. According to CTCAE scale, 10 out of 46 patients reported symptoms resolution at 6-month follow-up from the time of enrollment T0 (p = 0.0009). According to VAS score, 5 patients reported complete resolution of symptoms at T3 if compared to baseline starting situation T0 (p = 0.0222). Analysis of PRAI score showed a significant reduction in arthralgia-related pain perceived (p = 0.0001). OPERA® was able to reduce the intensity of arthralgia related to AI therapy. Randomized, double-blind studies are warranted to confirm the effectiveness of this dietary supplement.

Yoga versus massage in the treatment of aromatase inhibitor-associated knee joint pain in breast cancer survivors: a randomized controlled trial.

Aromatase inhibitors (AIs) are standard adjuvant therapy for postmenopausal women with oestrogen receptor-positive, early-stage, and metastatic breast cancer. Although effective, the risk of falls due to AI-associated knee joint pain significantly increased. The aim of this study was to evaluate the therapeutic effects of yoga and massage on AI-associated knee joint pain. Breast cancer survivors were randomly assigned to a 6-week yoga intervention-2-week rest-6-week massage exposure (Yoga first, n = 30) or a 6-week massage intervention-2-week rest-6-week yoga exposure (Massage first, n = 30). Evaluations of the treatment efficacy were made at baseline, post-intervention, and post-exposure using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scale, plasma cytokine levels, and changes in meridian energy. The results showed that yoga, superior to massage intervention, significantly reduced AI-associated knee joint pain, as demonstrated by the WOMAC pain score. The yoga intervention improvements were also associated with changes in plasma cytokine levels and meridian energy changes. In conclusion, this study provides scientific evidence that yoga was more effective than massage for reducing AI-associated knee joint pain. Meridian energy changes may provide another scientific, objective, non-invasive way to monitor the therapeutic effects of yoga and investigate another alternative, complementary medicine.

Losartan protects endothelium-dependent relaxation in vivo in a murine model of rheumatoid arthritis.

Angiotensin II-type 1 receptor stimulation is recognised to promote inflammation, a state central to the development and maintenance of rheumatoid arthritis. Herein we examined the use of losartan, an angiotensin II-type 1 receptor antagonist, on vascular reactivity, knee joint diameter and behavioural assessment of pain in a Freund's complete adjuvant (FCA) mouse model of joint inflammation. Monoarthritis was induced via FCA in the presence or absence of losartan with naive mice serving as controls. Knee joint swelling, joint pain (assessed by dynamic weight bearing of limb use), knee joint artery reactivity (assessed ex vivo) and blood perfusion of the knee joint (assessed in vivo) were determined. FCA mediated a significant increase in knee joint diameter and reduced weight-bearing (a surrogate for pain sensation) of the affected limb. Notably, these phenomena were substantially reduced when mice were prophylactically treated with losartan. Assessment of arterial relaxation and blood perfusion with acetylcholine stimulation revealed that FCA resulted in significant vascular dysfunction, which was resolved to naïve levels with losartan treatment. Through the actions of losartan, these findings indicate that the angiotensin II-type 1 receptor is a likely therapeutic target of importance in the development of the physical changes, pain sensation and vascular dysfunction found in inflammatory arthritis.

Acupuncture for Arthralgia Induced by Aromatase Inhibitors in Patients with Breast Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Aromatase inhibitor-induced arthralgia (AIA) is the most common side effect of aromatase inhibitors (AIs) used in breast cancer patients and is related to the rate of adherence to AIs. The clinical effects of acupuncture on AIA have been assessed by some randomized controlled trials (RCTs). However, some studies reported that acupuncture was effective, while others claimed that it was ineffective. To clarify the clinical and placebo effects of acupuncture in treating AIA, we conducted this meta-analysis. METHODS: Two reviewers (XL and GW) independently searched for RCTs in 5 English databases (PubMed, Web of Science, Embase, Springer, Cochrane Library) and 4 Chinese databases (China National Knowledge Infrastructure Database (CNKI), SinoMed, VIP and Wanfang Database) from their inception to 30 November 2019. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, this meta-analysis was performed by fixed or random-effects models, and data were pooled with mean differences (MDs). RESULTS: Seven trials involving 603 patients were reviewed. The primary outcome, the Brief Pain Inventory (BPI) score, significantly differed between the acupuncture and control groups [pain-related interference: MD = -1.89, 95% confidence interval (CI) [-2.99, -0.79], Z = 3.36 (P = .008 < .05), pain severity: MD = -1.57, 95% CI [-2.46, -0.68], Z = 3.45 (P = .0006 < .05), worst pain: MD = -2.31, 95% CI [-3.15, -1.48], Z = 5.47 (P < .0001 < .05)]. No severe adverse events were reported in any study. CONCLUSION: This meta-analysis showed that acupuncture is a safe and effective treatment for breast cancer patients with AIA. Additional research with improved blinding methods is warranted to further explore the nature of non-specific and placebo effects in true and sham acupuncture.

Analgesic and anti-inflammatory articular effects of essential oil and camphor isolated from Ocimum kilimandscharicum Gürke leaves.

ETHNOPHARMACOLOGICAL RELEVANCE: Leaves from Ocimum kilimandscharicum Gürke (Lamiaceae) are popularly used against articular pain. AIM OF STUDY: The aim of this study was to test the anti-inflammatory and anti-hyperalgesic (analgesic) properties of the essential oil and camphor isolated from O. Kilimandscharicum leaves (EOOK) in 4 models including zymosan induced-articular inflammation model in mice. MATERIAL AND METHODS: For in vivo models, EOOK was tested in carrageenan-induced paw edema model with oral doses of 30, 100, and 300 mg/kg (oral administration = p.o.) and in zymosan-induced articular inflammation (including knee edema, leukocyte infiltration, mechanical hyperalgesia and nitric oxide), EOOK (100 mg/kg, p. o.) and camphor (30 mg/kg, p. o.) were tested. EOOK (100 mg/kg, p. o.) was tested in the rolling and also in the adhesion of leukocytes to the mesenteric microcirculation in situ model of carrageenan induced inflammation and EOOK (1, 3, 10, 30, and 60 µg/mL) was tested in vitro against neutrophils chemotaxis induced by N-formyl methionyl leucyl phenylalanine (fMLP). RESULTS: The treatment with EOOK significantly inhibited the carrageenan-induced edema, mechanical and cold hyperalgesia. Both, EOOK and camphor inhibited all articular parameters induced by zymosan. In situ intravitral microscopy analysis, EOOK significantly inhibited carrageenan-induced leukocyte rolling and adhesion. In vitro neutrophils chemotaxis, EOOK inhibited the leukocyte chemotaxis induced by fMLP. CONCLUSIONS: The present study showed that EOOK inhibited pain and inflammatory parameters contributing, at least in part, to explain the popular use of this plant as analgesic natural agent. This study also demonstrates that camphor and some known anti-inflammatory compounds present in EOOK could contribute for analgesic and anti-inflammatory articular properties.

The maintenance effect of acupuncture on the side effects of breast cancer endocrine therapy: A protocol for systematic review and meta analysis.

BACKGROUND: Breast cancer is common among women throughout the world and endocrine therapy is an established part of its treatment. But, unfortunately, this has also resulted in intolerable side effects affecting the quality of life. Acupuncture has been widely used to treat endocrine-related side effects in patients with breast cancer, but how long its effect can be maintained has not been published. The systematic review is designed to evaluate the maintenance efficacy of acupuncture for related side effects after breast cancer endocrine therapy. METHODS AND ANALYSIS: We will search for the following databases: PubMed, Embase, Cochrane Library, Web of Science, including China National Knowledge Infrastructure (CNKI), WanFang Data, Technology Periodical Database (VIP), and China Biology Medicine (CBM) from inception to May 2020. Two reviewers will search these databases, collect all articles, and assess the quality of studies separately, and there will be no limitations on language. The primary outcomes will be assessed using acupuncture for endocrine-related hot flashes and joint pain duration (1 month, 3 months, 6 months). Measurement tools include the Kupperman index, Brief Pain Inventory Short Form (BPI-SF), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Brief Pain Inventory-Short (BPI-SF). We will use RevMan V.5.3 for meta-analysis and employ the Grading of Recommendations Assessment, Development and Evaluation System to assess the quality of evidence. RESULTS: This systematic review will evaluate the maintenance efficacy of acupuncture on the side effects of breast cancer endocrine therapy. CONCLUSION: This study will provide high-quality current evidence of how long its effect can be maintained after acupuncture for related side effects after breast cancer endocrine therapy. ETHICS AND DISSEMINATION: Ethical committee approval is not required for this systematic review as patient data will not be collected. This study will help to inform doctors and researchers on the duration of acupuncture treatment for endocrine-related hot flashes and joint pain. The results will be published in a peer-reviewed journal and will be disseminated in relevant conferences. INPLASY REGISTRATION NUMBER: INPLASY202040024.

Oral treatments with a flavonoid-enriched fraction from Cecropia hololeuca and with rutin reduce articular pain and inflammation in murine zymosan-induced arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Cecropia Loefl. species (Urticaceae) are widely spread across the rainforest in tropical and subtropical regions of Central and South America. Inhabitants of different regions of Brazil employ leaves, fruits and sprouts of Cecropia hololeuca Miq. mainly as anti-inflammatory, anti-asthmatic, expectorant, fever suppressant, and against cough. AIM OF THE STUDY: To evaluate the antinociceptive and anti-inflammatory activities of an aqueous leaf extract of C. hololeuca in a murine model of zymosan-induced arthritis (ZIA) and characterize compounds contributing to these effects. MATERIALS AND METHODS: The crude aqueous extract of C. hololeuca (CAE) was obtained by infusion, screened for antinociceptive and anti-inflammatory activities, and fractionated (solvent partition; RP-2 and Sephadex G-25 column chromatography), yielding fractions that were chemically and pharmacologically investigated. TLC, HPLC-DAD, HPLC-DAD-ESI-MS/MS and NMR analyses were peformed. The antinociceptive activity was assessed by means of acetic acid-induced writhing, hot-plate and rota-rod tests. ZIA was used to evaluate the anti-arthritic activity of oral treatment with CAE, butanolic (BF) and aqueous fraction (AF), as well as the fractions obtained from BF (F2, F2-A and F2-B). Rutin, a flavonoid found in C. hololeuca, was also tested. Mechanical hypernociception, joint edema, local neutrophil recruitment and articular TNF-α quantification were performed to measure the severity of arthritis and identify the anti-inflammatory potential of C. hololeuca. RESULTS: CAE (0.03-1 g/kg, p.o.) showed a dose-related inhibitory effect on acetic acid-induced writhing test, but did not change the pain latency in the hotplate test, nor the first fall time on the rota-rod test. In addition, CAE (1 g/kg, p.o.) inhibited by 65% the mechanical hypernociception, 46% the joint edema, 54% the neutrophil recruitment and 53% the articular TNF-α concentration levels in ZIA. BF (0.4 g/kg, p.o.), AF (0.6 g/kg), F2 (0.1 g/kg) and F2-A (0.045 g/kg), but not F2-B (0.055 g/kg), inhibited the mechanical hypernociception, joint edema and neutrophil recruitment in ZIA. Rutin (0.001-0.03 g/kg, p.o.) produced dose-related inhibitory effects in the mechanical hypernociception, joint edema and neutrophil recruitment, and at 0.03 g/kg also inhibited articular TNF-α synthesis after intra-articular zymosan injection. Isoorientin, isovitexin, rutin and isoquercitrin were identified in the most active fraction (F2-A), along with luteolin and apigenin derivatives, tentatively identified as isoorientin-2″-O-glucoside and isovitexin-2″-O-glucoside. CONCLUSION: This study corroborates the popular use by oral route of aqueous preparations of C. hololeuca against joint inflammatory disorders, such as rheumatoid arthritis. Our results demonstrated for the first time that oral administration of rutin shows antinociceptive and anti-inflammatory effects in ZIA, indicating that this flavonoid is one of the immunomodulatory compounds involved in the anti-arthritic activity of C. hololeuca.

Complementary and alternative medicine and musculoskeletal pain in the first year of adjuvant aromatase inhibitor treatment in early breast cancer patients.

BACKGROUND: Patients with breast cancer (BC) show strong interest in complementary and alternative medicine (CAM), particularly for adverse effects of adjuvant endocrine treatment - e.g., with letrozole. Letrozole often induces myalgia/limb pain and arthralgia, with potential noncompliance and treatment termination. This analysis investigated whether CAM before aromatase inhibitor (AI) therapy is associated with pain development and the intensity of AI-induced musculoskeletal syndrome (AIMSS) during the first year of treatment. PATIENTS AND METHODS: The multicenter phase IV PreFace study evaluated letrozole therapy in postmenopausal, hormone receptor-positive patients with early BC. Patients were asked about CAM use before, 6 months after, and 12 months after treatment started. They recorded pain every month for 1 year in a diary including questions about pain and numeric pain rating scales. Data were analyzed for patients who provided pain information for all time points. RESULTS: Of 1396 patients included, 901 (64.5%) had used CAM before AI treatment. Throughout the observation period, patients with CAM before AI treatment had higher pain values, for both myalgia/limb pain and arthralgia, than non-users. Pain increased significantly in both groups over time, with the largest increase during the first 6 months. No significant difference of pain increase was noted regarding CAM use. CONCLUSIONS: CAM use does not prevent or improve the development of AIMSS. Pain intensity was generally greater in the CAM group. Therefore, because of the risk of non-compliance and treatment discontinuation due to the development of higher pain levels, special attention must be paid to patient education and aftercare in these patients.

Effectiveness, safety, and economic evaluation of adjuvant moxibustion therapy for aromatase inhibitor-induced arthralgia of postmenopausal breast cancer stage I to III patients: Study protocol for a prospective, randomized, assessor-blind, usual-care controlled, parallel-group, pilot clinical trial.

INTRODUCTION: This study is a prospective, assessor-blinded, parallel-group, randomized controlled pilot trial to explore the effectiveness of 12-week adjuvant moxibustion therapy for arthralgia in menopausal females at stage I to III breast cancer on aromatase inhibitor (AI) administration, compared with those receiving usual care. METHODS/DESIGN: Forty-six menopausal female patients with breast cancer who completed cancer therapy will be randomly allocated to either adjuvant moxibustion or usual care groups with a 1:1 allocation ratio. The intervention group will undergo 24 sessions of adjuvant moxibustion therapy with usual care for 12 weeks, whereas the control group will receive only usual care during the same period. The usual care consists of acetaminophen administration on demand and self-directed exercise education to manage AI-related joint pain. The primary outcome is the mean change of the worst pain level according to the Brief Pain Inventory-Short Form between the initial visit and the endpoint. The mean changes in depression, fatigue, and quality of life will also be compared between groups. Safety and pharmacoeconomic evaluations will also be included. DISCUSSION: Continuous variables will be compared by an independent t test or Wilcoxon rank-sum test between the adjuvant moxibustion and usual care groups. Adverse events will be analyzed using the chi-square or Fisher exact test. The statistical analysis will be performed by a 2-tailed test at a significance level of .05.

Acupuncture and Vitamin D for the Management of Aromatase Inhibitor-Induced Arthralgia.

PURPOSE OF REVIEW: Aromatase inhibitor-induced arthralgia (AIA) is a very common syndrome which significantly affects breast cancer survivors' quality of life, and it often leads to non-compliance with aromatase inhibitor (AI) therapy. However, the treatment of AIA remains a clinical challenge. Here, we will review the current data for acupuncture and vitamin D in the management of AIA. RECENT FINDINGS: Acupuncture has been shown to improve AIA symptoms, but it has not consistently been proven to offer significantly more clinical benefit than sham acupuncture. Similarly, while some vitamin D trials have shown benefit, the studies have not consistently shown improvement in AIA symptoms. Neither acupuncture nor vitamin D can be touted as standard treatments for AIA. However, many patients do experience subjective improvement of their symptoms with these therapies. When other treatments, such as exercise and duloxetine, are not feasible or not effective, it is reasonable to offer a trial of acupuncture or vitamin D to patients who are suffering from AIA, as the potential harms are very few, and they do offer possible relief from AIA symptoms.

Therapeutic options for aromatase inhibitor-associated arthralgia in breast cancer survivors: A systematic review of systematic reviews, evidence mapping, and network meta-analysis.

Aromatase inhibitor-associated arthralgia (AIA) is a common problem in breast cancer survivors and is associated with noncompliance with aromatase inhibitor therapy. The aim of this research was to assess the current evidence for the various therapeutic options available for AIA. We searched the PubMed, EMBASE, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects for systematic reviews of trials investigating treatments for AIA to June 2018. Eligible systematic reviews were subjected to evidence mapping and the randomized controlled trials included in the systematic reviews were hand-searched for a network meta-analysis. Six systematic reviews were included in the evidence mapping. Acupuncture was the most common treatment modality studied (four randomized controlled trials), and pharmacological interventions, aerobic exercise, Nordic walking, omega-3 fatty acids, and vitamin D were assessed less frequently. In view of the limitations in the overall confidence level for each review, the evidence for acupuncture as an effective treatment for AIA was considered low. Second, data from 6 randomized controlled trials were included in the network meta-analysis. When compared with a waiting list control, acupuncture (mean difference [MD] -2.00, 95% confidence interval [CI] -3.16, -0.84), aerobic exercise (MD -0.80, 95% CI -1.33, -0.016), and omega-3 fatty acids (MD -2.10, 95% CI -3.23, -0.97) significantly improved pain severity scores. Network meta-analysis of adverse events was not possible because of poor reporting. Acupuncture is presently the most widely investigated intervention but is recommended for AIA with low overall confidence based on the current evidence.

Omega-3 fatty acid use for obese breast cancer patients with aromatase inhibitor-related arthralgia (SWOG S0927).

PURPOSE: Although aromatase inhibitors (AIs) prolong survival in post-menopausal breast cancer (BC) patients, AI-associated arthralgia can lead to discontinuation. Obese patients have higher rates of AI arthralgia than non-obese patients, but treatment options are limited. Omega-3 fatty acid (O3-FA) treatment for AI arthralgia has produced mixed results. METHODS: We performed an exploratory analysis of SWOG S0927, a multicenter randomized placebo-controlled trial of O3-FA use for AI arthralgia. Post-menopausal women with stage I-III BC taking an AI were randomized to 24 weeks of O3-FAs or placebo. Brief Pain Inventory (BPI) questionnaires and fasting serum were collected at baseline, 12, and 24 weeks. The BPI assessment included worst pain, average pain, and pain interference scores (range 0-10). RESULTS: Among the 249 participants, 139 had BMI < 30 kg/m2 (56%) and 110 had BMI ≥ 30 kg/m2 (44%). Among obese patients, O3-FA use was associated with significantly lower BPI worst pain scores at 24 weeks compared with placebo (4.36 vs. 5.70, p = 0.02), whereas among non-obese patients, there was no significant difference in scores between treatment arms (5.27 vs. 4.58, p = 0.28; interaction p = 0.05). Similarly, O3-FA use was associated with lower BPI average pain and pain interference scores at 24 weeks compared with placebo among obese patients, but no significant difference between treatment arms in non-obese patients (interaction p = 0.005 and p = 0.01, respectively). CONCLUSIONS: In obese BC patients, O3-FA use was associated with significantly reduced AI arthralgia compared to placebo.

Effect of Acupuncture vs Sham Acupuncture or Waitlist Control on Joint Pain Related to Aromatase Inhibitors Among Women With Early-Stage Breast Cancer: A Randomized Clinical Trial.

Importance: Musculoskeletal symptoms are the most common adverse effects of aromatase inhibitors and often result in therapy discontinuation. Small studies suggest that acupuncture may decrease aromatase inhibitor-related joint symptoms. Objective: To determine the effect of acupuncture in reducing aromatase inhibitor-related joint pain. Design, Setting, and Patients: Randomized clinical trial conducted at 11 academic centers and clinical sites in the United States from March 2012 to February 2017 (final date of follow-up, September 5, 2017). Eligible patients were postmenopausal women with early-stage breast cancer who were taking an aromatase inhibitor and scored at least 3 on the Brief Pain Inventory Worst Pain (BPI-WP) item (score range, 0-10; higher scores indicate greater pain). Interventions: Patients were randomized 2:1:1 to the true acupuncture (n = 110), sham acupuncture (n = 59), or waitlist control (n = 57) group. True acupuncture and sham acupuncture protocols consisted of 12 acupuncture sessions over 6 weeks (2 sessions per week), followed by 1 session per week for 6 weeks. The waitlist control group did not receive any intervention. All participants were offered 10 acupuncture sessions to be used between weeks 24 and 52. Main Outcomes and Measures: The primary end point was the 6-week BPI-WP score. Mean 6-week BPI-WP scores were compared by study group using linear regression, adjusted for baseline pain and stratification factors (clinically meaningful difference specified as 2 points). Results: Among 226 randomized patients (mean [SD] age, 60.7 [8.6] years; 88% white; mean [SD] baseline BPI-WP score, 6.6 [1.5]), 206 (91.1%) completed the trial. From baseline to 6 weeks, the mean observed BPI-WP score decreased by 2.05 points (reduced pain) in the true acupuncture group, by 1.07 points in the sham acupuncture group, and by 0.99 points in the waitlist control group. The adjusted difference for true acupuncture vs sham acupuncture was 0.92 points (95% CI, 0.20-1.65; P = .01) and for true acupuncture vs waitlist control was 0.96 points (95% CI, 0.24-1.67; P = .01). Patients in the true acupuncture group experienced more grade 1 bruising compared with patients in the sham acupuncture group (47% vs 25%; P = .01). Conclusions and Relevance: Among postmenopausal women with early-stage breast cancer and aromatase inhibitor-related arthralgias, true acupuncture compared with sham acupuncture or with waitlist control resulted in a statistically significant reduction in joint pain at 6 weeks, although the observed improvement was of uncertain clinical importance. Trial Registration: ClinicalTrials.gov Identifier: NCT01535066.

Vitamin D Levels, Vitamin D Receptor Polymorphisms, and Inflammatory Cytokines in Aromatase Inhibitor-Induced Arthralgias: An Analysis of CCTG MA.27.

BACKGROUND: Approximately half of women taking aromatase inhibitor (AI) therapy develop AI-induced arthralgia (AIA), and many might discontinue AI therapy because of the pain. Using plasma samples from the MA.27 study, we assessed several factors potentially associated with AIA. PATIENTS AND METHODS: MA.27 is a phase III adjuvant trial comparing 2 AIs, exemestane versus anastrozole. Within an 893-participant nested case-control AIA genome-wide association study, we nested a 72 AIA case-144 control assessment of vitamin D plasma concentrations, corrected for seasonal and geographic variation. We also examined 9 baseline inflammatory cytokines: interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, interferon (IFN)γ, IL-10, IL-12p70, IL-17, IL-23, and chemokine ligand (CCL)-20. Finally, we analyzed the multivariate effects of baseline factors: vitamin D level, previously identified musculoskeletal single nucleotide polymorphisms, age, body mass index, and vitamin D receptor (VDR) Fok-I variant genotype on AIA development. RESULTS: Changes in vitamin D from baseline to 6 months were not significantly different between cases and controls. Elevated inflammatory cytokine levels were not associated with development of AIA. The multivariate model included no clinical factors associated with AIA. However, women with the VDR Fok-I variant genotype were more likely to have a lower IL-1ß level (P = .0091) and less likely to develop AIA after 6 months of AI compared with those with the wild type VDR (P < .0001). CONCLUSION: In this nested case-control correlative study, vitamin D levels were not significantly associated with development of AIA; however, patients with the Fok-I VDR variant genotype were more likely to have a significant reduction in IL-1ß level, and less likely to develop AIA.

Randomized clinical trial comparing efficacy and safety of brand versus generic alendronate (Bonmax®) for osteoporosis treatment.

INTRODUCTION: Although the same efficacy and tolerability are anticipated due to both drugs containing the same active ingredients, comparative studies between brand and generic alendronate are limited. Accordingly, the objective of this study was to compare efficacy and safety between brand alendronate and a recently introduced generic alendronate drug. METHODS: A total of 140 postmenopausal women or men aged older than 50 years who met the indications for osteoporosis treatment were randomized to receive either generic (Bonmax®) or brand alendronate (Fosamax®) 70 mg/week over a 12-month period during the May 2014 to June 2015 study period. Endpoints included bone mineral density (BMD) changes at the lumbar spine, total hip, and femoral neck; percentage of patients with predefined levels of change in total hip and lumbar spine BMD at 12 months; and, changes in biochemical bone markers at 3, 6, and 12 months. Tolerability was evaluated by patient self-reporting of adverse experiences. RESULTS: At 12 months post-treatment, BMD significantly increased at all sites in both groups. There were no differences in BMD percentage changes or the number of patients with stable or increased BMD after 1 year between groups. No significant differences in the amount of biochemical bone marker reduction or incidence of adverse events were observed between groups. CONCLUSIONS: Generic and brand alendronate produced similar gains in BMD and reduction in bone turnover markers. Both medicadoitions were also equally well-tolerated. Based on these findings, generic alendronate (Bonmax®) is a viable alternative to the original brand of alendronate. TRIAL REGISTRATION: ClinicalTrials.gov NCT02371252.

Auricular Point Acupressure to Manage Aromatase Inhibitor-Induced Arthralgia in Postmenopausal Breast Cancer Survivors: A Pilot Study.

PURPOSE/OBJECTIVES: To assess the feasibility of auricular point acupressure to manage aromatase inhibitor-induced arthralgia.
. DESIGN: Wait list control design.
. SETTING: Outpatient clinics and oncology center.
. SAMPLE: 20 women with aromatase inhibitor-induced arthralgia.
. METHODS: After baseline data were collected, participants waited one month before they received acupressure once per week for four weeks at a convenient time. The baseline data served as the control comparison. Self-reported measures and blood samples were obtained at baseline, at preintervention, weekly during the intervention, and at post-intervention.
. MAIN RESEARCH VARIABLES: The primary outcomes included pain intensity, pain interference, stiffness, and physical function. Inflammatory cytokines and chemokines were tested.
. FINDINGS: After the four-week intervention, participants reported decreases in worst pain and pain interference, and improvements in physical function, cancer-related symptom severity, and interference. The proinflammatory cytokines and chemokines displayed a trend of a mean percentage reduction. The anti-inflammatory cytokine interleukin-13 increased from pre- to postintervention.
. CONCLUSIONS: Auricular point acupressure is feasible and may be effective in managing arthralgia in breast cancer survivors.
. IMPLICATIONS FOR NURSING: Nurses can administer acupressure in clinical settings, which could enhance the management of aromatase inhibitor-induced arthralgia and contribute to a shift from traditional disease-based biomedical models to a broader, integrative, medical paradigm for managing aromatase inhibitor-induced arthralgia.

Effect of acupuncture on aromatase inhibitor-induced arthralgia in patients with breast cancer: A meta-analysis of randomized controlled trials.

PURPOSE: Aromatase inhibitor (AI)-induced arthralgia (AIA) is a common side effect that may lead to premature discontinuation of effective hormonal therapy in patients with breast cancer. Acupuncture may relieve joint pain in patients with AIA. We conducted a meta-analysis of randomized controlled trials (RCTs) to evaluate the effectiveness of acupuncture in pain relief in AIA. METHODS: The PubMed, Embase, Cochrane Library, and Scopus databases and the ClinicalTrials.gov registry were searched for studies published before February 2017. Individual effect sizes were standardized, and a meta-analysis was conducted to calculate the pooled effect size by using a random effect model. Pain was assessed using the Brief Pain Inventory (BPI) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 3-4, 6-8, and 12 weeks. Secondary outcomes included disability level, upper extremity function, physical performance, and quality of life. RESULTS: Five trials involving 181 patients were reviewed. Significant pain reduction was observed after 6-8 weeks of acupuncture treatment. Patients receiving acupuncture showed a significant decrease in the BPI worst pain score (weighted mean difference [WMD]: -3.81, 95% confidence interval [CI]: -5.15 to -2.47) and the WOMAC pain score (WMD: -130.77, 95% CI: -230.31 to -31.22) after 6-8 weeks of treatment. One of the 4 trials reported 18 minor adverse events in 8 patients during 398 intervention episodes. CONCLUSION: Acupuncture is a safe and viable nonpharmacologic treatment that may relieve joint pain in patients with AIA. Additional studies involving a higher number of RCTs are warranted.

Anti-arthritic property of crude extracts of Piptadeniastrum africanum (Mimosaceae) in complete Freund's adjuvant-induced arthritis in rats.

BACKGROUND: Rheumatoid arthritis, disease of unknown causes is a rheumatic and autoimmune pathology, recognised for its increasing frequency and its adverse consequences. It is a disease that occurs in most cases between 50 and 60 years and women are more affected than men. This study aimed at evaluating immunomodulatory and anti-arthritis capacity of aqueous and methanol extracts of stem bark of Piptadeniastrum africanum (Mimosaceae). METHODS: ROS production from phagocytes, proliferation of T-cells, TNF-α and IL-1ß production and cytotoxicity were performed by using chemiluminescence technique, liquid scintillation counter, ELISA and MTT assay, respectively. Anti-arthritic activity was evaluated using a model of adjuvant induced arthritis. RESULTS: Methanol and aqueous extracts of Piptadeniastrum africanum significantly (P < 0.001) inhibited extracellular and intracellular ROS production. These extracts also possess significant (P < 0.001) inhibitory activity on T-cell proliferation other than reduced TNF-α and IL-1ß production. Piptadeniastrum africanum also significantly exhibited antiarthritic activity in complete Freund's adjuvant induced arthritis in rat associated with a significant anti-inflammatory and anti-hyperalgesia activity. CONCLUSIONS: Immunomodulatory, anti-inflammatory, antihyperalgesia and anti-arthritis potential revealed in this study approve that, Piptadeniastrum africanum is a plant rich in compounds with anti-arthritic properties.