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`Predictors of Responsiveness to Bisphosphonate
`Treatment in Patients with Complex Regional Pain
`Syndrome Type I: A Retrospective Chart Analysis 
`Massimo Varenna, PhD  , Maria Manara, MD, Francesca Rovelli, MD,
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`Francesca Zucchi, MD, Luigi Sinigaglia, MD
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`Pain Medicine, Volume 18, Issue 6, 1 June 2017, Pages 1131–1138,
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`https://doi.org/10.1093/pm/pnw207
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`Published: 20 September 2016
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`Abstract
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`Objective. The aim of this study was to assess whether the effectiveness of
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`bisphosphonate infusion in patients with complex regional pain syndrome type
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`I (CRPS-I) is influenced by variables related to patient and/or disease
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`characteristics.
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`Methods. This is a retrospective analysis of patients referred in the last five
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`years to our rheumatologic tertiary care center, all fulfilling the Budapest
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`CRPS-I diagnostic criteria and treated with three different bisphosphonate
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`schedules (clodronate, pamidronate, and neridronate). For every subject,
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`demographic and clinical variables were retrieved and retrospectively analyzed.
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`https://academic.oup.com/painmedicine/article/18/6/1131/2924769
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`8/20/2018
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`Grun. Exh. 1035
`PGR for U.S. Patent No. 9,820,999
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`We identified variables that independently influenced the therapeutic outcome
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`of patients by a logistic regression analysis. For exploratory purposes, the
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`effectiveness of the different bisphosphonate treatments employed was
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`compared.
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`Results. Among the 194 patients included in the analysis, the overall
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`therapeutic response rate was 71.6%. Logistic regression analysis showed that
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`the independent predictive variables for therapeutic effectiveness were disease
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`duration (odds ratio [OR] = 0.83, 95% confidence interval [CI] = 0.72–0.96 for a
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`one-month increment), fracture as a predisposing event (OR = 3.23, 95% CI =
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`1.29–8.03), and “warm” disease subtype (OR = 4.88, 95% CI = 1.57–15.20).
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`These variables were found to influence the odds of responsiveness when
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`analyzed together with age at onset, gender, and disease localization. No
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`significant difference in therapeutic effectiveness was found by comparing the
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`three different bisphosphonate schedules employed.
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`Conclusion. Early disease, fracture as a predisposing event, and “warm”
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`disease subtype are predictors of responsiveness to bisphosphonate treatment
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`in patients with CRPS-I.
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`Keywords: CRPS, Reflex Sympathetic Dystrophy, Treatment, Bisphosphonate,
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`Outcome
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`Topic: bisphosphonates, fractures, complex regional pain syndromes, demogra-
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`phy, reflex sympathetic dystrophy, diagnosis, gender, pamidronate, clodronate,
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`illness length, infusion procedures
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`Issue Section: Original Research Article
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`Introduction
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`Complex regional pain syndrome type I (CRPS-I) is a severe disabling disease in
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`which long-lasting pain is the cardinal feature, together with other hallmarks of this
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`disease including swelling, vasomotor instability, and abnormal sensory findings.
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`The rate of patients showing a progression over time toward a permanent functional
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`impairment rather than those who spontaneously resolve remains an issue still
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`debated [1]. In recent years, although the understanding of the different pathogenic
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`mechanisms of CRPS-I has improved and a multitude of interventions have been
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`proposed and are in use, there has been limited evidence for the effectiveness of any
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`therapeutic modality, no strong consensus exists regarding the optimal
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`management of the syndrome, and a shared therapeutic algorithm has yet to be
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`established. Current treatment interventions include analgesics and anti-
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`inflammatory drugs, opioids, calcitonin, anticonvulsants, antidepressants, local and
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`intravenous (i.v.) anesthetics, transcutaneous electrical nerve stimulation (TENS),
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`occupational therapy, physiotherapy, rehabilitation medicine, and psychological
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`therapies. Several guidelines for the management of CRPS have been published [2
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`–5], but the critical lack of high-quality evidence for the effectiveness of most
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`therapies for CRPS limits the development of an evidence-based approach in
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`managing the condition [2].
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`Over the past two decades, bisphosphonate administration appears to be a
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`therapeutic strategy that has collected convincing evidence, with five randomized
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`controlled trials (RCTs) all showing good results in controlling pain, local
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`inflammation, and functional disability [6–10], improving the quality of life of
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`patients with CRPS-I. Nevertheless, as reported in some meta-analyses, reviews,
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`and institutional guidelines, there are still concerns about widespread use of these
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`drugs, partly justified by some issues that remain unresolved. For example, these
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`trials employed four different drugs (alendronate, clodronate, pamidronate, and
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`neridronate) using two different routes of administration (oral or i.v.); all but one
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`included only patients with early disease and bone involvement, such as a local
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`osteoporosis demonstrated by x-rays or an increased uptake showed by bone scan
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`[6,7,9,10]. Also, the fear of adverse events associated with bisphosphonate
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`administration (e.g., osteonecrosis of the jaw, atypical fractures) possibly
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`contributes to their underuse.
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`Thus, even if combining the results of these studies suggests good evidence for the
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`efficacy of bisphosphonates in CRPS-I, some questions remain. For example,
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`whether there are subgroups of patients who may better respond to bisphosphonate
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`treatment has yet to be established.
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`As a contribution toward answering these questions, we retrospectively collected
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`and analyzed the data of patients with CRPS-I treated with i.v. infusions of various
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`bisphosphonates during the last five years at a tertiary rheumatology care center in
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`order to evaluate if variables related to patient and/or disease and the type of drug
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`employed can influence the treatment outcome.
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`Methods
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`StudyDesign
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`We performed a retrospective data analysis of patients with a diagnosis of CRPS-I
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`referred to our unit in the last five years for treatment with bisphosphonate
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`infusions.
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`Patients
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`All patients referred to the day hospital of our institute for treatment with a course
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`of bisphosphonate infusion from January 2009 to December 2013 were identified
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`from the hospital database that collects administrative information. The results
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`were matched with diagnostic code or free-text data indicating a potential diagnosis
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`of CRPS-I, and medical records of the patients were retrieved. All patients came from
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`the orthopedic and rheumatology outpatient services and the emergency department
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`of our hospital, a tertiary care center devoted to bone and joint diseases.
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`All medical records of patients were reviewed by two of the authors (MM and FR),
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`who had not been involved in the clinical management of the patients, and data were
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`extracted following a predefined data extraction form. The first step (Figure 1) was to
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`exclude patients with diseases that were possibly not CRPS-I, such as regional
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`migratory osteoporosis, post-traumatic bone marrow edema, postarthroscopic bone
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`marrow edema, etc. Among the remaining subjects, patients were included in this
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`study only if: 1) their medical records confirmed that all symptoms and signs
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`included in the Budapest 2007 criteria (now also known as the new International
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`Association for the Study of Pain [IASP] criteria for CRPS) [11] had been assessed and
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`checked before and after treatment; 2) no treatments for CRPS-I, other than anti-
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`inflammatory, or analgesic drugs were administered; 3) other clinical variables
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`included in the data extraction form were available (i.e., precipitating event, pain
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`duration, subtype of disease). The final sample included only patients in whom at the
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`first observation the IASP criteria for research purpose were fulfilled (four
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`symptoms and two or more signs), as confirmed by data reported in clinical records.
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`No patients involved in previous RCT studies were included in this sample.
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`Figure 1
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`View large
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`Download slide
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`Flowchart illustrating the disposition of patients.
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`Treatments
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`All patients were treated with an i.v. infusion of a bisphosphonate. From January
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`2009 to April 2010, patients followed a clodronate infusion course according to an
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`already published schedule (300 mg every day for 10 consecutive days) [7]. In an
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`attempt to shorten the therapeutic course, from May 2010 to August 2011, patients
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`were treated with pamidronate 60 mg infusions given four times every third day, in
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`agreement with some open studies [12,13], and an RCT [8], all showing good results
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`in the treatment of CRPS-I. From September 2011 to December 2013, patients were
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`treated with neridronate 100 mg every third day for four occasions [10]. After the
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`bisphosphonate infusions, all patients underwent physiotherapeutic treatment to
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`improve the functional restoration of the affected limb. Before the treatment, an
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`extensive laboratory assessment was performed in all patients to exclude diseases or
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`other conditions that would otherwise account for the degree of pain and clinical
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`signs. Women of childbearing potential were asked to have a negative pregnancy test
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`before the treatment. Informed consent to be treated with bisphosphonate infusions
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`was obtained from each patient.
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`DataCollection
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`Demographic data were collected for every patient, together with some disease-
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`related variables such as disease duration, localization of the CRPS-I, potential
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`precipitating events, and previous occurrence of CRPS-I.
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`At the day of the first infusion and at the following clinical evaluation, scheduled 40
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`days after the last infusion (day 36–54), all symptoms and signs included in the
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`Budapest 2007 criteria were checked. Allodynia was defined as pain evoked by a light
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`stroking with a small brush and hyperalgesia as pain evoked by a pinprick at the
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`affected site but not at the unaffected site. Clinical subtype, i.e., a “warm” or “cold”
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`phase of the disease, was defined at baseline by assessing the difference in
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`temperature between the involved limb and the contralateral one.
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`OutcomeAssessment
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`At the following clinical evaluation, patients were asked to report the overall efficacy
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`of the treatment in descriptive terms by a four-point verbal score for pain relief
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`(efficacy verbal score [EVS]), already employed in a previous study [7], scored as 0 =
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`no improvement/worsening; 1 = slight/minor improvement of pain; 2 = significant
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`improvement of pain; 3 = excellent improvement/no pain. When evaluated at the last
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`visit, a patient was defined as a “responder” if all the following criteria were
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`simultaneously met: 1) CRPS-I could no longer be diagnosed accordingly with the
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`Budapest 2007 criteria for clinical purpose (three symptoms and two signs); 2) the
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`EVS was rated ≥ 2; and 3) the patient had stopped taking analgesics or other drugs for
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`controlling pain.
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`StatisticalAnalysis
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`Baseline variables were tested for normality of the distribution with Shapiro-Wilks
`
`test. Data are reported as means ± standard deviation (SD) in the case of a normal
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`distribution or medians and interquartile range (IQR) in the case of a non-normal
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`distribution. Comparisons were performed by Student’s t-test for unpaired data for
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`variables normally distributed, and Mann-Whitney tests were performed when non-
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`normally distributed variables were analyzed. The Fisher’s exact test was applied to
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`analyze categorical variables with the Bonferroni correction when more than two
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`variables were analyzed.
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`To investigate the effect of each assessed variable on the therapeutic effectiveness of
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`bisphosphonates treatment, a logistic regression analysis was performed. All the
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`variables that were statistically significant in univariate analysis (P < 0.05) by
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`comparing responder with nonresponder patients, together with other variables not
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`showing a significant difference but deemed of clinical relevance as possible
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`determinants of therapeutic response (age, gender, site of disease), were entered in
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`the model. To explore the effectiveness of the three therapeutic schedules employed,
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`in a further logistic regression model, the different treatments were entered
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`together with all the variables included in the first model using as reference the
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`treatment with the lowest percentage of patients who were responsive, that is,
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`clodronate.
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`All the statistical tests were two-sided at the 5% level and performed using SPSS
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`software (v. 17.0, SPSS, Inc., Chicago, IL, USA).
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`Results
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`The flow chart illustrating the disposition of patients is depicted in Figure 1, and the
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`baseline values of demographic and clinical variables of 194 patients representing
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`the study sample are displayed in Table 1. The mean age at CRPS-I diagnosis was 57.1
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`± 12.9 years, with a greater number of females (122, 62.9%) and a mean age at
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`diagnosis that did not differ between males and females (P = 0.28). The disease
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`duration showed a median value of four months (IQR= 2–6). Lower extremity (foot)
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`was more often affected than upper limb (hand), with 119 patients showing a foot
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`disease (61.3%) and 75 patients showing a hand disease (38.7%). Thirteen patients
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`(6.7%) reported a previous diagnosis of CRPS-I that more often had involved
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`another site (10 cases).
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`Table 1
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`Demographic and baseline clinical findings in patients with CRPS-I treated with bisphosphonates
`
`Parameter 
`
`Patients (N = 194) 
`
`Baseline characteristics 
`
`Age, y, mean ± SD 
`
`57.1 ± 12.9 
`
`Sex, male/female, N (%) 
`
`72 (37.1)/122 (62. 9) 
`
`Disease duration, mo, median, IQR 
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`4 (2–6) 
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`Previous CRPS-I, N (%) 
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`13 (6.7) 
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`Disease subtype, warm/cold/NA, N (%) 
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`142 (73.2)/31 (16.0)/ 21 (10.8) 
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`Localization, N (%) 
`
`Upper limb 
`
`Lower limb 
`
`Predisposing event, N (%) 
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`75 (38.7) 
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`119 (61.3) 
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`Fracture 
`
`83 (42.8) 
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`Parameter 
`
`Patients (N = 194) 
`
`Baseline characteristics 
`
`Trauma 
`
`Surgery 
`
`Others 
`
`Unknown 
`
`43 (22.1) 
`
`28 (14.4) 
`
`11 (5.7) 
`
`29 (14.9) 
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`CRPS-I = complex regional pain syndrome type I; IQR = interquartile range; NA = not applicable
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`(swinging form or not reported).
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`The most common precipitating event was a fracture, reported by 83 patients
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`(42.8%), followed by a trauma without fracture (contusion/sprain), which was
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`identified as the triggering event by 43 patients (22.1%). Twenty-eight patients
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`(14.4%) developed the disease following surgery. For 11 patients (5.7%), the medical
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`record reported several events possibly recognized as a predisposing event
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`(myocardial infarction, hemiparesis, herpes zoster, electrocution, etc.). Finally, in
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`29 cases (14.9%), no precipitating event was identified. In 142 patients (73.2%),
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`CRPS-I was assessed by a physician as “warm,” whereas in 31 cases (16.0%) the
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`disease was described as “cold.” In 21 patients (10.8%), this classification was not
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`applicable because of a swing between a warm to cold type, and this feature was not
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`reported in the medical records. No difference was found between the two disease
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`subtypes (age, gender, predisposing event), but the disease duration was longer in
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`the cold subtype (median = 5, interquartile range [IQR] = 4–8; vs median = 3, IQR = 2
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`–5; P = 0.001).
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`The total sample was treated with one of three different bisphosphonate regimens:
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`clodronate in 42 patients (21.6%), pamidronate in 45 patients (23.2%), and
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`neridronate in 107 patients (55.2%). Overall, 139 patients (71.6%) were considered
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`“responders,” while 55 patients (28.4%) were defined as “nonresponders.” The
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`percentage of responders was, respectively, 64% (27 patients) for clodronate, 71%
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`(32 patients) for pamidronate, and 75% (80 patients) for neridronate (Figure 2). The
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`comparison among the three different treatments (Chi-squared test, adjusting the P
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`values with Bonferroni’s correction) did not show significant differences in
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`responsiveness among the three treatment regimens (P = 0.27).
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`Figure 2
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`View large
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`Download slide
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`Responder rates of CRPS-I patients treated with different bisphosphonate schedules. No significant
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`difference was found among the treatments.
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`The comparisons of clinical variables between responder and nonresponder patients
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`are given in Table 2. No difference was found in age at diagnosis, gender, or disease
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`localization. Instead, responder patients showed a disease duration significantly
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`shorter in comparison with nonresponders (median = 3 months, IQR = 2–5; vs
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`median = 5 months, IQR = 3–8; P = 0.0001). In the responder group, a warm disease
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`subtype was more frequent (79.8%) relative to nonresponders (56.4%, P = 0.0001);
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`conversely, a cold disease was more frequently observed in nonresponder patients
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`(32.7%) than in responder patients (9.3%, P < 0.05). By considering the predisposing
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`event, the greatest percentage of responders was found in patients who developed a
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`CRPS-I following a fracture (69 out of 83, 83.1%). This result was significantly
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`greater in comparison with the responder percentage observed in patients in whom
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`the disease was triggered by all other predisposing events (P = 0.005) and with the
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`responder percentages observed in CRPS-I following a trauma without fracture (P =
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`0.01) or following surgery (P = 0.008).
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`Table 2
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`Comparisons of demographic and clinical variables between 194 patients with CRPS-I
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`responding/not responding to bisphosphonate treatment
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`Responders (N =
`139) 
`
`Nonresponders (N
`= 55) 
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`Responder,
`% 
`
`Characteristics 
`
`Age, y, mean ± SD 
`
`57.3 ± 12.3 
`
`56.5 ± 14.3 
`
`Sex, male/female, N Disease
`duration, mo, median (IQR) 
`
`Disease localization, lower
`limb/upper limb, N 
`
`50/89 
`
`22/33 
`
`3 (2–5) 
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`5 (3–8)*
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`83/56 
`
`36/19 
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`Subtype, warm/cold/NA, N 
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`111/13/15 
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`31/18/6*
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`Predisposing event, N 
`
`Fracture 
`
`Trauma 
`
`Surgery 
`
`Others 
`
`Unknown 
`
`* P = 0.0001 vs responders.
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`69 
`
`27 
`
`16 
`
`7 
`
`20 
`
`14 
`
`16 
`
`12 
`
`4 
`
`9 
`
`†
`83.1
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`‡
`62.8
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`§
`57.1
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`63.6 
`
`69.0 
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`† P = 0.005 for fracture vs all other predisposing events.
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`‡ P = 0.01 for fracture vs trauma.
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`§ P = 0.008 for fracture vs surgery.
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`CRPS-I = complex regional pain syndrome type I; IQR = interquartile range; NA = not applicable
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`(swinging form and not reported).
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`In Table 3, results from the logistic analyses are reported; in these models, the
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`outcome variable was the therapeutic responsiveness (responder vs nonresponder).
`
`The disease duration, a warm disease subtype, and fracture as a predisposing event
`
`were significant predictors of responsiveness to bisphosphonate treatment, while
`
`age, sex, and disease localization did not influence the outcome. When the different
`
`drugs were examined together with the variables included in the first analysis
`
`(Model 2), no significant odds ratio for responsiveness was found for a specific
`
`treatment. Consistent with the results of the previous model, the variables predictive
`
`of a positive outcome were the same, with little difference in the estimated odds.
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`Table 3
`
`Logistic regression analyses of recorded variables for treatment responsiveness to
`
`bisphosphonate in patients with CRPS-I
`
`OR 
`
`95% CI 
`
`P
`
`
`
`Model 1 
`
`Age, 1-y increment 
`
`0.99 
`
`0.96–1.03 
`
`0.6 
`
`Sex, female vs male 
`
`1.27 
`
`0.58–2.79 
`
`0.5 
`
`Disease duration, 1-mo increment 
`
`0.83 
`
`0.72–0.96 
`
`0.01 
`
`Disease localization, lower vs upper limb 
`
`1.22 
`
`0.52–2.86 
`
`0.6 
`
`Subtype, warm vs cold 
`
`4.88 
`
`1.57–15.20 
`
`0.006 
`
`Fracture vs other predisposing event 
`
`3.23 
`
`1.29–8.03 
`
`0.01 
`
`Model 2* 
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`OR 
`
`95% CI 
`
`P
`
`Age, 1-y increment 
`
`0.99 
`
`0.96–1.04 
`
`0.6 
`
`Sex, female vs male 
`
`1.11 
`
`0.51–2.44 
`
`0.7 
`
`Disease duration, 1-mo increment 
`
`0.84 
`
`0.72–0.98 
`
`0.02 
`
`Disease localization, lower vs upper limb 
`
`1.71 
`
`0.67–4.36 
`
`0.2 
`
`Subtype, warm vs cold 
`
`5.07 
`
`1.59–16.15 
`
`0.006 
`
`Fracture vs other predisposing event 
`
`3.24 
`
`1.29–8.11 
`
`0.01 
`
`Clodronate 
`
`Pamidronate 
`
`Neridronate 
`
`1 
`
`2.02 
`
`0.63–6.44 
`
`0.2 
`
`2.15 
`
`0.87–5.33 
`
`* Model 2 includes variables from Model 1 together with treatments clodronate (reference),
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`pamidronate, and neridronate.
`
`CI = confidence interval; CRPS-I = complex regional pain syndrome type I; OR = odds ratio.
`
`No patients complained of serious drug-related adverse events (osteonecrosis of the
`
`jaw or atypical fractures). Six patients treated with clodronate showed only a
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`moderate hypocalcemia (serum calcium lower than 8.8 mg/dl) without clinical
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`symptoms and not requiring treatment. As expected, the most common side effect in
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`patients treated with an aminobisphosphonate (pamidronate and neridronate) was
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`an acute phase reaction (polyarthralgia and/or fever). This adverse event was
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`reported in 16 patients treated with pamidronate (35.5%) and in 32 patients treated
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`with neridronate (29.9%). These symptoms disappeared in two days after the first
`
`infusion, but in 11 patients required acetaminophen treatment 1g t.i.d. for one day.
`
`One patient treated with neridronate developed an acute anterior uveitis after the
`
`fourth infusion that required topical treatment with steroid and atropine; remission
`
`was complete without sequelae.
`
`Discussion
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`The results of this study suggest that patients affected by CRPS-I with an early
`
`disease, a warm disease subtype, and fracture as a predisposing event could be more
`
`responsive to intravenous bisphosphonate treatment, regardless of the age, gender,
`
`and site of disease.
`
`With the exclusion of the localization of disease (a more frequent lower limb
`
`involvement), the sample investigated in this study showed an age distribution, a
`
`male-to-female ratio, and types and prevalence of precipitating events similar to
`
`those reported in the largest-to-date epidemiological study carried out in the
`
`Netherlands [14], suggesting that our sample is quite similar to that observed in a
`
`population-based study. The short disease duration (median = 4 months, IQR = 2–6
`
`months) is probably explained by the operating conditions of our department,
`
`located in the same hospital in which many orthopedic departments manage
`
`patients referred for trauma or fracture and where elective hand and foot surgery is
`
`performed daily.
`
`Although the methodological approach in recruiting and evaluating the final sample
`
`led to the exclusion of a large number of cases, this strategy was chosen in the
`
`attempt to ensure the highest level of diagnostic specificity of the included patients,
`
`that is, 0.79 [11], and the highest level of sensitivity on residual signs and symptoms
`
`when patients were evaluated at the end of the study with the aim to identify those
`
`with a true disease remission (0.99) [11]. In this regard, we used a four-point verbal
`
`score for pain relief that, although being a less sensitive tool than absolute pain
`
`values assessed by a numerical rating scale, is more focused on pain changes before
`
`and after the treatment.
`
`To date, the role of bisphosphonates in the treatment of CRPS-I is still debated, as
`
`shown by a number of meta-analyses, reviews, and guidelines published so far.
`
`While some of these identify bisphosphonates as the therapeutic choice that shows
`
`the clearest evidence of efficacy in comparison with all other interventions tested to
`
`date [15,16], others suggest a possible role, if any, only for patients who show overt
`
`bone involvement, despite bone changes not being included in the diagnostic criteria
`
`currently used to support a diagnosis of CRPS [2,17].
`
`A clear bone involvement (a positive bone scan and/or a patchy or diffuse
`
`osteoporosis on x-ray examination and/or a bone edema showed by MRI) was
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`historically the rationale for the use of bisphosphonates in CRPS-I patients. In our
`
`study, this finding was not explored before the treatment in all patients with a bone
`
`scan or x-ray examination, even if, in addition to the patients who developed a
`
`CRPS-I after a fracture, the short disease duration seemed to correlate with a real
`
`bone involvement [18] that so far remains an unexplored issue [19].
`
`The results of this study suggest that bisphosphonates seem to be more effective
`
`when an acute disease is treated, such as when inflammatory features are associated
`
`with a raised concentration of proinflammatory neuropeptides and mediators [20
`
`–22]. As demonstrated by the regional radiotracer uptake that reflects the local drug
`
`accumulation [23], in this stage of the disease, bisphosphonates can achieve a high
`
`local concentration, for which they could possibly exert a local cytotoxic effect on
`
`inflammatory cells [24,25], with a consequent reduction of the neuropeptide release
`
`(calcitonin gene-related peptide and substance P) [26] and the local expression of
`
`nerve growth factor by macrophages [27].
`
`No significant difference of effectiveness among the three different therapeutic
`
`schedules employed has been found, even if the percentage of responders was higher
`
`for neridronate and lower for clodronate. In this regard, and by considering all RCTs
`
`and open studies published, some speculations can be made. After adjusting for the
`
`relative potency ratio in terms of bio-equivalent doses of the different molecules and
`
`the route of administration, all bisphosphonates seem to be effective, provided they
`
`are administered with a dosage large enough to reach the therapeutic goal. This
`
`inference is drawn mostly from the published results on pamidronate, the
`
`bisphosphonate more frequently employed and for which the therapeutic effect was
`
`greater the higher the dose administered [8,12,13]. Consistently, multiple lines of
`
`evidence showed a dose-dependent antinociceptive effect on bone, inflammatory,
`
`and neuropathic pain exerted by different bisphosphonates, both in animal models
`
`and in clinical studies [28]. In this regard, the ongoing RCT (ClinicalTrials.gov
`
`identifier: NCT02402530) that investigates the efficacy of a low-dosage neridronate
`
`schedule runs a risk of not replicating the results of the already published RCT [10].
`
`Even if the results we observed are consistent with the responder rates observed in
`
`RCTs [7,10], the retrospective, observational design of this study without a
`
`nontreated control group suggests that caution must be exercised in the
`
`interpretation of this result. The short disease duration does not exclude that a
`
`positive outcome in bisphosphonate-treated patients could be influenced by a
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`benign natural course of the disease observed in some cases, and a generalized
`
`feature of CRPS-I management seems to be that the shorter the disease duration the
`
`better the treatment outcome, irrespective of the therapeutic choice [29]. The
`
`natural outcome of the disease toward a full recovery instead of long-lasting pain
`
`and disability [1], as well as prognostic factors influencing the course of CRPS [30], is
`
`an issue inadequately explored in the literature so far. By comparing available data
`
`with our results, a warm disease subtype seems to resolve more likely than cold
`
`CRPS [31], as we found after bisphosphonate treatment. Conversely, in the study of
`
`Beerthuizen et al., none of the 596 patients who developed the disease after a
`
`fracture were healed after 12 months [32], whereas, in our sample, these patients
`
`seemed to recover more often. Also, the lack of an appropriate length of follow-up
`
`does not exclude a number of cases with a transient remission and a new disease
`
`recurrence. However, the permanent remission observed in the RCTs on clodronate
`
`and neridronate (after 12 and 13 months, respectively) could suggest a definitive
`
`healing. It is possible that the physiotherapeutic treatment could have contributed to
`
`the clinical improvement. Finally, only a randomized double-blind trial will be able
`
`to find a real difference of effectiveness among the different bisphosphonates.
`
`In conclusion, this study suggests that patients with CRPS-I with an early disease, a
`
`fracture as a triggering event, and a warm disease subtype are more likely to respond
`
`to treatment with bisphosphonates. The differences in effectiveness observed
`
`between the different regimens are small and likely to be related to the need for
`
`these drugs to be used at the appropriate dosage.
`
`Acknowledgments
`
`We thank Gayle Robins, an independent medical writer, who provided English
`
`language editing and journal styling prior to submission. This assistance was funded
`
`by Abiogen Pharma.
`
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