Pain Medicine 2017; 18: 1131–1138
`doi: 10.1093/pm/pnw207
`
`NEUROPATHIC PAIN SECTION
`
`Original Research Article
`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,* Francesca Zucchi, MD,*
`and Luigi Sinigaglia, MD*
`
`analysis. For exploratory purposes, the effective-
`ness of the different bisphosphonate treatments
`employed was compared.
`
`*Department of Rheumatology, Gaetano Pini Institute,
`Milan, Italy
`
`Correspondence to: Massimo Varenna, MD, PhD, Day
`Hospital di Reumatologia, Istituto Gaetano Pini, Via
`Pini, 9, 20122 Milan, Italy. Tel: þ39-0258-296897; Fax:
`þ39-0258-296495; E-mail: varenna@gpini.it.
`
`Funding sources: No specific funding was received
`from any funding bodies in the public, commercial, or
`not-for-profit sectors to carry out the work described
`in this article.
`
`Disclosure and conflicts of interest: Massimo Varenna
`has received honoraria as a consultant for Abiogen
`Pharma. The other authors have no conflicts of
`interest to report.
`
`Abstract
`
`Objective. The aim of this study was to assess
`whether the effectiveness of bisphosphonate infu-
`sion in patients with complex regional pain syn-
`drome type I (CRPS-I) is influenced by variables
`related to patient and/or disease characteristics.
`
`Methods. This is a retrospective analysis of patients
`referred in the last five years to our rheumatologic
`tertiary care center, all
`fulfilling the Budapest
`CRPS-I diagnostic criteria and treated with three dif-
`ferent bisphosphonate
`schedules
`(clodronate,
`pamidronate, and neridronate). For every subject,
`demographic and clinical variables were retrieved
`and retrospectively analyzed. We identified vari-
`ables that independently influenced the therapeutic
`outcome of patients by a logistic regression
`
`Results. Among the 194 patients included in the
`analysis, the overall therapeutic response rate was
`71.6%. Logistic regression analysis showed that the
`independent predictive variables for therapeutic ef-
`fectiveness were disease duration (odds ratio [OR]
`5 0.83, 95% confidence interval [CI] 5 0.72–0.96 for
`a one-month increment), fracture as a predisposing
`event (OR 5 3.23, 95% CI 5 1.29–8.03), and “warm”
`disease subtype (OR 5 4.88, 95% CI 5 1.57–15.20).
`These variables were found to influence the odds of
`responsiveness when analyzed together with age at
`onset, gender, and disease localization. No signifi-
`cant difference in therapeutic effectiveness was
`found by comparing the three different bisphospho-
`nate schedules employed.
`
`Conclusion. Early disease, fracture as a predispos-
`ing event, and “warm” disease subtype are pre-
`dictors of
`responsiveness to bisphosphonate
`treatment in patients with CRPS-I.
`
`Key Words. CRPS; Reflex Sympathetic Dystrophy;
`Treatment; Bisphosphonate; Outcome
`
`Introduction
`
`Complex regional pain syndrome type I (CRPS-I) is a se-
`vere disabling disease in which long-lasting pain is the
`cardinal
`feature, together with other hallmarks of this
`disease including swelling, vasomotor instability, and ab-
`normal sensory findings. The rate of patients showing a
`progression over time toward a permanent
`functional
`impairment rather than those who spontaneously re-
`solve remains an issue still debated [1]. In recent years,
`although the understanding of the different pathogenic
`mechanisms of CRPS-I has improved and a multitude
`of
`interventions have been proposed and are in use,
`
`VC 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
`
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`Grun. Exh. 1015
`PGR for U.S. Patent No. 9,707,245
`
`

`

`Patients
`
`All patients referred to the day hospital of our institute
`for treatment with a course of bisphosphonate infusion
`from January 2009 to December 2013 were identified
`from the hospital database that collects administrative
`information. The results were matched with diagnostic
`code or free-text data indicating a potential diagnosis of
`CRPS-I, and medical
`records of
`the patients were
`retrieved. All patients came from the orthopedic and
`rheumatology outpatient services and the emergency
`department of our hospital, a tertiary care center
`devoted to bone and joint diseases.
`
`All medical records of patients were reviewed by two of
`the authors (MM and FR), who had not been involved in
`the clinical management of the patients, and data were
`extracted following a predefined data extraction form.
`The first step (Figure 1) was to exclude patients with
`diseases that were possibly not CRPS-I, such as re-
`gional migratory osteoporosis, post-traumatic bone mar-
`row edema, postarthroscopic bone marrow edema, etc.
`Among the remaining subjects, patients were included
`in this study only if: 1) their medical records confirmed
`that all symptoms and signs included in the Budapest
`2007 criteria (now also known as the new International
`Association for
`the Study of Pain [IASP] criteria for
`CRPS)
`[11] had been assessed and checked before
`
`Varenna et al.
`
`there has been limited evidence for the effectiveness of
`any therapeutic modality, no strong consensus exists
`regarding the optimal management of
`the syndrome,
`and a shared therapeutic algorithm has yet to be estab-
`lished. Current
`treatment
`interventions include anal-
`gesics and anti-inflammatory drugs, opioids, calcitonin,
`anticonvulsants, antidepressants, local and intravenous
`(i.v.) anesthetics, transcutaneous electrical nerve stimu-
`lation (TENS), occupational therapy, physiotherapy, re-
`habilitation medicine, and psychological
`therapies.
`Several guidelines for the management of CRPS have
`been published [2–5], but the critical lack of high-quality
`evidence for
`the effectiveness of most
`therapies for
`CRPS limits the development of an evidence-based ap-
`proach in managing the condition [2].
`
`Over the past two decades, bisphosphonate administra-
`tion appears to be a therapeutic strategy that has col-
`lected convincing evidence, with five randomized
`controlled trials (RCTs) all showing good results in con-
`trolling pain, local
`inflammation, and functional disability
`[6–10],
`improving the quality of
`life of patients with
`CRPS-I. Nevertheless, as reported in some meta-
`analyses, reviews, and institutional guidelines, there are
`still concerns about widespread use of
`these drugs,
`partly justified by some issues that remain unresolved.
`For example, these trials employed four different drugs
`(alendronate, clodronate, pamidronate, and neridronate)
`using two different routes of administration (oral or i.v.);
`all but one included only patients with early disease and
`bone involvement, such as a local osteoporosis demon-
`strated by x-rays or an increased uptake showed by
`bone scan [6,7,9,10]. Also, the fear of adverse events
`associated with bisphosphonate administration (e.g.,
`osteonecrosis of
`the jaw, atypical
`fractures) possibly
`contributes to their underuse.
`
`these studies
`Thus, even if combining the results of
`suggests good evidence for the efficacy of bisphospho-
`nates in CRPS-I, some questions remain. For example,
`whether there are subgroups of patients who may better
`respond to bisphosphonate treatment has yet
`to be
`established.
`
`As a contribution toward answering these questions, we
`retrospectively collected and analyzed the data of pa-
`tients with CRPS-I treated with i.v. infusions of various
`bisphosphonates during the last five years at a tertiary
`rheumatology care center in order to evaluate if vari-
`ables related to patient and/or disease and the type of
`drug employed can influence the treatment outcome.
`
`Methods
`
`Study Design
`
`We performed a retrospective data analysis of patients
`with a diagnosis of CRPS-I referred to our unit in the
`last
`five years for
`treatment with bisphosphonate
`infusions.
`
`Figure 1 Flowchart
`patients.
`
`illustrating the disposition of
`
`1132
`
`

`

`and after treatment; 2) no treatments for CRPS-I, other
`than anti-inflammatory, or analgesic drugs were admin-
`istered; 3) other clinical variables included in the data
`extraction form were available (i.e., precipitating event,
`pain duration, subtype of disease). The final sample
`included only patients in whom at the first observation
`the IASP criteria for research purpose were fulfilled (four
`symptoms and two or more signs), as confirmed by
`data reported in clinical records. No patients involved in
`previous RCT studies were included in this sample.
`
`Treatments
`
`infusion of a
`All patients were treated with an i.v.
`bisphosphonate. From January 2009 to April 2010, pa-
`tients followed a clodronate infusion course according
`to an already published schedule (300 mg every day for
`10 consecutive days) [7]. In an attempt to shorten the
`therapeutic course, from May 2010 to August 2011, pa-
`tients were treated with pamidronate 60 mg infusions
`given four
`times every third day,
`in agreement with
`some open studies [12,13], and an RCT [8], all showing
`good results
`in the treatment of CRPS-I. From
`September 2011 to December 2013, patients were
`treated with neridronate 100 mg every third day for four
`occasions [10]. After the bisphosphonate infusions, all
`patients underwent physiotherapeutic treatment to im-
`prove the functional
`restoration of
`the affected limb.
`Before the treatment, an extensive laboratory assess-
`ment was performed in all patients to exclude diseases
`or other conditions that would otherwise account for the
`degree of pain and clinical signs. Women of childbear-
`ing potential were asked to have a negative pregnancy
`test before the treatment.
`Informed consent
`to be
`treated with bisphosphonate infusions was obtained
`from each patient.
`
`Data Collection
`
`Demographic data were collected for every patient, to-
`gether with some disease-related variables such as dis-
`ease duration,
`localization of
`the CRPS-I, potential
`precipitating events, and previous occurrence of CRPS-
`I.
`
`At the day of the first infusion and at the following clin-
`ical evaluation, scheduled 40 days after the last infusion
`(day 36–54), all symptoms and signs included in the
`Budapest 2007 criteria were checked. Allodynia was
`defined as pain evoked by a light stroking with a small
`brush and hyperalgesia as pain evoked by a pinprick at
`the affected site but not at the unaffected site. Clinical
`subtype, i.e., a “warm” or “cold” phase of the disease,
`was defined at baseline by assessing the difference in
`temperature between the involved limb and the contra-
`lateral one.
`
`Outcome Assessment
`
`At the following clinical evaluation, patients were asked
`to report
`the overall efficacy of
`the treatment
`in
`
`CRPS Treatment with Bisphosphonates
`
`descriptive terms by a four-point verbal score for pain
`relief (efficacy verbal score [EVS]), already employed in a
`previous study [7], scored as 0¼ no improvement/wor-
`sening; 1¼ slight/minor improvement of pain; 2¼ signifi-
`cant improvement of pain; 3¼ excellent improvement/no
`pain. When evaluated at the last visit, a patient was
`defined as a “responder” if all the following criteria were
`simultaneously met: 1) CRPS-I could no longer be diag-
`nosed accordingly with the Budapest 2007 criteria for
`clinical purpose (three symptoms and two signs); 2) the
`EVS was rated 2; and 3) the patient had stopped tak-
`ing analgesics or other drugs for controlling pain.
`
`Statistical Analysis
`
`Baseline variables were tested for normality of the distri-
`bution with Shapiro-Wilks test. Data are reported as
`means 6 standard deviation (SD) in the case of a nor-
`mal distribution or medians and interquartile range (IQR)
`in the case of a non-normal distribution. Comparisons
`were performed by Student’s t-test for unpaired data for
`variables normally distributed, and Mann-Whitney tests
`were performed when non-normally distributed variables
`were analyzed. The Fisher’s exact test was applied to
`analyze categorical variables with the Bonferroni correc-
`tion when more than two variables were analyzed.
`
`To investigate the effect of each assessed variable on
`the therapeutic effectiveness of bisphosphonates treat-
`ment, a logistic regression analysis was performed. All
`the variables that were statistically significant in univari-
`ate analysis (P < 0.05) by comparing responder with
`nonresponder patients, together with other variables not
`showing a significant difference but deemed of clinical
`relevance as possible determinants of therapeutic re-
`sponse (age, gender, site of disease), were entered in
`the model. To explore the effectiveness of
`the three
`therapeutic schedules employed, in a further logistic re-
`gression model, the different treatments were entered
`together with all the variables included in the first model
`using as reference the treatment with the lowest per-
`centage of patients who were responsive,
`that
`is,
`clodronate.
`
`All the statistical tests were two-sided at the 5% level
`and performed using SPSS software (v. 17.0, SPSS,
`Inc., Chicago, IL, USA).
`
`Results
`
`The flow chart illustrating the disposition of patients is
`depicted in Figure 1, and the baseline values of demo-
`graphic and clinical variables of 194 patients represent-
`ing the study sample are displayed in Table 1. The
`mean age at CRPS-I diagnosis was 57.1 6 12.9 years,
`with a greater number of females (122, 62.9%) and a
`mean age at diagnosis that did not differ between males
`and females (P¼ 0.28). The disease duration showed a
`median value of four months (IQR¼ 2–6). Lower extrem-
`ity (foot) was more often affected than upper
`limb
`(hand), with 119 patients showing a foot disease
`
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`

`Varenna et al.
`
`Table 1 Demographic and baseline clinical
`findings in patients with CRPS-I treated with
`bisphosphonates
`
`Parameter
`Baseline characteristics
`
`Age, y, mean 6 SD
`Sex, male/female, N (%)
`Disease duration, mo, median, IQR
`Previous CRPS-I, N (%)
`Disease subtype,
`warm/cold/NA, N (%)
`Localization, N (%)
`Upper limb
`Lower limb
`Predisposing event, N (%)
`Fracture
`Trauma
`Surgery
`Others
`Unknown
`
`Patients (N¼ 194)
`
`57.1 6 12.9
`72 (37.1)/122 (62. 9)
`4 (2–6)
`13 (6.7)
`142 (73.2)/31 (16.0)/
`21 (10.8)
`
`75 (38.7)
`119 (61.3)
`
`83 (42.8)
`43 (22.1)
`28 (14.4)
`11 (5.7)
`29 (14.9)
`
`CRPS-I¼ complex
`regional
`pain
`syndrome
`type
`I;
`IQR¼ interquartile range; NA¼ not applicable (swinging form
`or not reported).
`
`(61.3%) and 75 patients showing a hand disease
`(38.7%). Thirteen patients (6.7%) reported a previous
`diagnosis of CRPS-I that more often had involved an-
`other site (10 cases).
`
`The most common precipitating event was a fracture,
`reported by 83 patients (42.8%), followed by a trauma
`without fracture (contusion/sprain), which was identified
`as the triggering event by 43 patients (22.1%). Twenty-
`eight patients (14.4%) developed the disease following
`surgery. For 11 patients (5.7%), the medical record re-
`ported several events possibly recognized as a predis-
`posing event (myocardial infarction, hemiparesis, herpes
`zoster, electrocution, etc.). Finally, in 29 cases (14.9%),
`no precipitating event was identified.
`In 142 patients
`(73.2%), CRPS-I was assessed by a physician as
`“warm,” whereas in 31 cases (16.0%) the disease was
`described as “cold.” In 21 patients (10.8%), this classifi-
`cation was not applicable because of a swing between
`a warm to cold type, and this feature was not reported
`in the medical records. No difference was found be-
`tween the two disease subtypes (age, gender, predis-
`posing event), but the disease duration was longer in
`the cold subtype (median ¼ 5, interquartile range [IQR]
`¼ 4–8; vs median ¼ 3, IQR ¼ 2–5; P¼ 0.001).
`
`Figure 2 Responder rates of CRPS-I patients treated
`with different bisphosphonate schedules. No significant
`difference was found among the treatments.
`
`patients (28.4%) were defined as “nonresponders.” The
`percentage of responders was, respectively, 64% (27
`patients) for clodronate, 71% (32 patients) for pamidro-
`nate, and 75% (80 patients) for neridronate (Figure 2).
`The comparison among the three different treatments
`(Chi-squared test,
`adjusting
`the P values with
`Bonferroni’s correction) did not show significant differ-
`ences in responsiveness among the three treatment
`regimens (P¼ 0.27).
`
`The comparisons of clinical variables between responder
`and nonresponder patients are given in Table 2. No dif-
`ference was found in age at diagnosis, gender, or dis-
`ease localization. Instead, responder patients showed a
`disease duration significantly shorter in comparison with
`nonresponders (median ¼ 3 months, IQR ¼ 2–5; vs me-
`dian ¼ 5 months, IQR ¼ 3–8; P¼ 0.0001). In the re-
`sponder group, a warm disease subtype was more
`frequent
`(79.8%)
`relative to nonresponders (56.4%,
`P¼ 0.0001); conversely, a cold disease was more fre-
`quently observed in nonresponder patients (32.7%) than
`in responder patients (9.3%, P < 0.05). By considering
`the predisposing event, the greatest percentage of re-
`sponders was found in patients who developed a CRPS-
`I following a fracture (69 out of 83, 83.1%). This result
`was significantly greater
`in comparison with the re-
`sponder percentage observed in patients in whom the
`disease was triggered by all other predisposing events
`(P¼ 0.005)
`and with
`the
`responder percentages
`observed in CRPS-I following a trauma without fracture
`(P¼ 0.01) or following surgery (P¼ 0.008).
`
`The total sample was treated with one of three different
`bisphosphonate regimens: clodronate in 42 patients
`(21.6%), pamidronate in 45 patients (23.2%), and neridr-
`onate in 107 patients (55.2%). Overall, 139 patients
`(71.6%) were considered “responders,” while 55
`
`In Table 3, results from the logistic analyses are re-
`ported; in these models, the outcome variable was the
`therapeutic
`responsiveness
`(responder
`vs
`nonre-
`sponder). The disease duration, a warm disease sub-
`type, and fracture as a predisposing event were
`
`1134
`
`

`

`Table 2
`Comparisons of demographic and clinical variables between 194 patients with CRPS-I
`responding/not responding to bisphosphonate treatment
`
`CRPS Treatment with Bisphosphonates
`
`Responders
`(N¼ 139)
`
`Nonresponders
`(N¼ 55)
`
`Responder,
`%
`
`Characteristics
`Age, y, mean 6 SD
`Sex, male/female, N
`Disease duration, mo, median (IQR)
`Disease localization, lower limb/upper limb, N
`Subtype, warm/cold/NA, N
`Predisposing event, N
`Fracture
`Trauma
`Surgery
`Others
`Unknown
`
`57.3 6 12.3
`50/89
`3 (2–5)
`83/56
`111/13/15
`
`56.5 6 14.3
`22/33
`5 (3–8)*
`36/19
`31/18/6*
`
`69
`27
`16
`7
`20
`
`14
`16
`12
`4
`9
`
`83.1†
`62.8‡
`57.1§
`63.6
`69.0
`
`†
`
`‡
`
`*P¼ 0.0001 vs responders.
`P¼ 0.005 for fracture vs all other predisposing events.
`P¼ 0.01 for fracture vs trauma.
`§P¼ 0.008 for fracture vs surgery.
`CRPS-I¼ complex regional pain syndrome type I;
`reported).
`
`IQR¼ interquartile range; NA¼ not applicable (swinging form and not
`
`significant predictors of responsiveness to bisphospho-
`nate 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.
`
`No patients complained of serious drug-related adverse
`events (osteonecrosis of the jaw or atypical fractures).
`Six patients treated with clodronate showed only a
`moderate hypocalcemia (serum calcium lower
`than
`8.8 mg/dl) without clinical symptoms and not requiring
`treatment. As expected, the most common side effect
`in patients
`treated with an aminobisphosphonate
`(pamidronate and neridronate) was an acute phase re-
`action (polyarthralgia and/or fever). This adverse event
`was reported in 16 patients treated with pamidronate
`(35.5%) and in 32 patients treated with neridronate
`(29.9%). These symptoms disappeared in two days after
`the first infusion, but in 11 patients required acetamino-
`phen 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 with-
`out sequelae.
`
`Discussion
`
`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 treat-
`ment,
`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 epi-
`demiological 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 ¼ 4 months, IQR ¼ 2–6 months)
`is
`probably explained by the operating conditions of our de-
`partment, located in the same hospital
`in which many
`orthopedic departments manage patients referred for
`trauma or fracture and where elective hand and foot sur-
`gery 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 specifi-
`city of the included patients, that is, 0.79 [11], and the
`highest level of sensitivity on residual signs and symp-
`toms 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.
`
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`

`Varenna et al.
`
`Table 3
`Logistic regression analyses of
`recorded variables for treatment responsiveness to
`bisphosphonate in patients with CRPS-I
`
`Model 1
`Age, 1-y increment
`Sex, female vs male
`Disease duration, 1-mo
`increment
`Disease localization, lower
`vs upper limb
`Subtype, warm vs cold
`Fracture vs other
`predisposing event
`Model 2*
`Age, 1-y increment
`Sex, female vs male
`Disease duration, 1-mo
`increment
`Disease localization, lower
`vs upper limb
`Subtype, warm vs cold
`Fracture vs other
`predisposing event
`Clodronate
`Pamidronate
`Neridronate
`
`OR
`
`95% CI
`
`P
`
`0.99
`1.27
`0.83
`
`0.96–1.03
`0.58–2.79
`0.72–0.96
`
`0.6
`0.5
`0.01
`
`1.22
`
`0.52–2.86
`
`0.6
`
`4.88
`3.23
`
`1.57–15.20
`1.29–8.03
`
`0.006
`0.01
`
`0.99
`1.11
`0.84
`
`0.96–1.04
`0.51–2.44
`0.72–0.98
`
`0.6
`0.7
`0.02
`
`1.71
`
`0.67–4.36
`
`0.2
`
`5.07
`3.24
`
`1.59–16.15
`1.29–8.11
`
`0.006
`0.01
`
`1
`2.02
`2.15
`
`0.63–6.44
`0.87–5.33
`
`0.2
`
`*Model 2 includes variables from Model 1 together with treat-
`ments clodronate (reference), pamidronate, and neridronate.
`CI¼ confidence interval; CRPS-I¼ complex regional pain syn-
`drome type I; OR ¼ odds ratio.
`
`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 thera-
`peutic choice that shows the clearest evidence of effi-
`cacy 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 crite-
`ria 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 historically
`the rationale for the use of bisphosphonates in CRPS-I
`patients. In our study, this finding was not explored be-
`fore 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 involve-
`ment [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
`
`1136
`
`treated, such as when inflammatory features are associ-
`ated 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 concentra-
`tion, 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 ex-
`pression 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 ad-
`justing 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 infer-
`ence is drawn mostly from the published results on
`pamidronate, the bisphosphonate more frequently em-
`ployed 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 bisphospho-
`nates, both in animal models and in clinical studies [28].
`In this regard, the ongoing RCT (ClinicalTrials.gov identi-
`fier: NCT02402530) that investigates the efficacy of a
`low-dosage neridronate schedule runs a risk of not rep-
`licating 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 retro-
`spective, 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 out-
`come in bisphosphonate-treated patients could be influ-
`enced by a 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, irre-
`spective of the therapeutic choice [29]. The natural out-
`come 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 com-
`paring 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 clodro-
`nate and neridronate (after 12 and 13 months, respect-
`ively) could suggest a definitive healing. It is possible
`that the physiotherapeutic treatment could have contrib-
`uted to the clinical improvement. Finally, only a random-
`ized double-blind trial will be able to find a real
`difference
`of
`effectiveness
`among
`the
`different
`bisphosphonates.
`
`this study suggests that patients with
`In conclusion,
`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 differ-
`ences 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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