ARTHRITIS & RHEUMATISM
`Vol. 50, No. 11, November 2004, pp 3690–3697
`DOI 10.1002/art.20591
`© 2004, American College of Rheumatology
`
`Role of Alendronate in Therapy for
`Posttraumatic Complex Regional Pain Syndrome Type I
`of the Lower Extremity
`
`Daniel-Henri Manicourt, Jean-Pierre Brasseur, Yves Boutsen,
`Genevie`ve Depreseux, and Jean-Pierre Devogelaer
`
`Objective. To evaluate the effects of the antire-
`sorptive agent alendronate at a daily oral dose of 40 mg
`in patients with posttraumatic complex regional pain
`syndrome type I (CRPS I) of the lower extremity.
`Methods. Forty patients were enrolled in this
`8-week randomized, double-blind, placebo-controlled
`study of alendronate therapy for CRPS I, a condition
`associated with regional osteoclastic overactivity. An
`optional 8-week open extension of alendronate therapy
`(weeks 12–20) was available after a 4-week period
`without therapy. Clinical assessments included joint
`mobility, edema of the lower extremity, tolerance to
`pressure in the lower extremity, and levels of spontane-
`ous pain. Urinary levels of type I collagen N-telopeptide
`(NTX) were assessed by enzyme-linked immunosorbent
`assay. Patients were examined at weeks 4, 8, 12, 16, 20,
`and 24. Statistical analysis included two-way factorial
`analysis of variance.
`Results. In contrast to placebo-treated patients
`(n ⴝ 20), all of the alendronate-treated patients (n ⴝ
`19) exhibited a marked and sustained improvement in
`levels of spontaneous pain, pressure tolerance, and joint
`mobility, as well as a significant reduction in urinary
`levels of NTX at weeks 4 and 8. The improvement was
`maintained at week 12. Twelve patients from each
`
`Supported by an institutional grant from Merck Sharp and
`Dohme, Whitehouse Station, NJ. Merck Sharp and Dohme also
`provided the 40-mg alendronate and placebo tablets used in this study.
`Daniel-Henri Manicourt, MD, PhD, Jean-Pierre Brasseur,
`MD, Yves Boutsen, MD, Genevie`ve Depreseux, MS, Jean-Pierre
`Devogelaer, MD: St. Luc University Hospital, Universite´ Catholique
`de Louvain, Brussels, Belgium.
`Address correspondence and reprint requests to Daniel-
`Henri Manicourt, MD, PhD, Department of Rheumatology, Univer-
`site´ Catholique de Louvain 5390, Avenue Mounier, 1200 Brussels,
`Belgium. E-mail: manicourt@bchm.ucl.ac.be.
`Submitted for publication March 7, 2004; accepted in revised
`form July 19, 2004.
`
`treatment group volunteered for the 8-week open trial,
`and all of them had a positive response to alendronate.
`Conclusion. Our findings support the use of oral
`alendronate in posttraumatic CRPS I. By reducing local
`acceleration of bone remodeling, alendronate might
`relieve pain by effects on nociceptive primary afferents
`in bone, pain-associated changes in the spinal cord, and
`possibly also through a central mechanism.
`
`Reflex sympathetic dystrophy, which is now
`called complex regional pain syndrome type I (CRPS I)
`according to criteria of the International Association
`for the Study of Pain (IASP), is a clinical syndrome
`characterized by pain, allodynia, hyperalgesia, edema,
`abnormal vasomotor and sudomotor activity, movement
`disorders, joint stiffness, regional osteopenia, and dys-
`trophic changes in soft tissue (1–7). For many patients,
`the pain and ensuing loss of function lead to permanent
`disability. The nature of the inciting event may be quite
`variable, including visceral lesions, but trauma of an
`extremity accounts for more than 50% of the cases
`(2–5,8). It is now believed that this syndrome is, at least
`in part, a disease of both the central and peripheral
`nervous systems (6,7). There is indeed experimental
`evidence that a sustained peripheral injury may change
`the expression of genes in dorsal root ganglia and central
`pain-projecting neurons of the dorsal horn, and it is
`thought that the resulting change in phenotype estab-
`lishes and maintains sensitization (hyperalgesia and al-
`lodynia), neurogenic inflammation, and autonomic dys-
`regulation (9,10). There is also clinical evidence of
`changes in the central representation of the somatosen-
`sory, sympathetic, and somatomotor systems (7).
`The natural history of CRPS I usually varies with
`its location. CRPS I of the upper extremity is reportedly
`associated with a relatively short-term morbidity. Yet, at
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`Grun. Exh. 1009
`PGR for U.S. Patent No. 9,820,999
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`ORAL ALENDRONATE IN CRPS I
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`3691
`
`1 year after Colles’ fracture, joint stiffness is still appar-
`ent in 50% of cases, whereas up to 20% of patients
`continue to experience pain, tenderness, vascular insta-
`bility, and swelling (8), an observation that may account
`for the 1–2% incidence of CRPS I that has been
`reported in retrospective studies of Colles’ fracture (11).
`With the exception of the hip, however, CRPS I of the
`lower extremity has a protracted course that may persist
`for several years, and chronic sequelae, such as func-
`tional impairment and/or debilitating pain, may occur in
`20–40% of patients (2).
`CRPS I is difficult to treat. It is generally believed
`that physical therapy and related techniques aimed at
`restoring function are a prerequisite for improving pain,
`although too aggressive joint mobilization or invasive
`physical therapy approaches may worsen the underlying
`disease process (12,13). However, in practice, the en-
`deavor is often frustrated by the pain itself, and to
`alleviate this frustration, the therapeutic use of various
`drugs as well as physical and psychological approaches
`have been advocated (12–14). In an exhaustive review of
`the management of CRPS I (15), Forouzanfar et al
`concluded that there is no convincing evidence for the
`efficacy of sympathetic nerve blocks, scavenging of rad-
`icals, prednisolone administration, manual lymph drain-
`age, and acupuncture. On the other hand, since the
`disease process involves enhanced bone resorption and
`turnover, several investigators have examined the effect
`of osteoclast-blocking agents. Salmon calcitonin has
`been reported to be effective in some studies and useless
`in others (5), whereas intravenous administration of
`bisphosphonates (pamidronate, clodronate, or alendro-
`nate) usually results in a significant reduction in pain
`(16–20).
`We therefore decided to conduct a double-blind
`randomized study to assess the efficacy of oral alendro-
`nate versus placebo in patients with posttraumatic CRPS
`I of the lower extremity. In comparison with intravenous
`therapy, oral therapy is less expensive and is associated
`with a placebo effect that is usually less strong. Our study
`has at least 2 important advantages over previous stud-
`ies. First, since the etiology was similar in all study
`patients, we were dealing with a somewhat homoge-
`neous patient group. Second, since the rate of resolution
`of symptoms in CRPS I of the lower extremity is rather
`slow, the placebo-treated patients are likely to represent
`adequate controls.
`
`PATIENTS AND METHODS
`Patients. The results of a preliminary study evaluating
`the effect of placebo (n ⫽ 10 patients) and alendronate (n ⫽ 10
`
`patients) treatment on pressure tolerance scores, a well-
`validated test in CRPS I of the upper extremity (8), indicated
`that the inclusion of 20 patients in each group would be
`sufficient to attain 95% power to detect a 50% increase in the
`pressure tolerance score from a baseline value of 0.2 with a
`significance level of 1% (2-tailed). Accordingly, the present
`study included 40 other patients who had CRPS I of the lower
`extremity. Their CRPS I was secondary to a traumatic event,
`and none had any other condition that would otherwise
`account for the degree of pain and dysfunction.
`All patients included in the present study fulfilled the
`consensus-based diagnostic criteria published by the IASP (1)
`as well as the revised diagnostic research criteria proposed by
`Harden et al (21). They had the following clinical characteris-
`tics: 1) symptoms developed after a traumatic event that was
`not associated with apparent nerve damage; 2) pain was not
`limited to the distribution of a single peripheral nerve; 3)
`spontaneous pain was estimated to be ⬎40 mm on a 0–100-mm
`visual analog scale (VAS); 4) allodynia and hyperalgesia were
`present in the diseased area; 5) besides joint stiffness, the
`affected extremity was swollen, and the skin appeared “glassy”;
`6) a red-bluish skin discoloration was observed and/or exacer-
`bated by dependency (sitting with the legs hanging down); 7) in
`all patients, plain radiographs revealed regional osteoporosis
`(patchy appearance in 17 patients and diffuse in the other 23);
`and 8) during the 3-phase bone scintigram (22,23), the early
`static and late images both revealed high uptake of the
`bone-seeking agent in all patients, but the hemovelocity and
`blood pool were normal in 35 patients and slightly reduced in
`5. No patient had previously received bisphosphonate therapy
`or sympathetic nerve blocks.
`Exclusion criteria included CRPS I of nontraumatic
`origin, calcitonin therapy (if inefficacious) within 1 week prior
`to study entry, gastroduodenal ulcers, diabetes mellitus, hyper-
`thyroidism, renal and liver dysfunction, cardiovascular dis-
`eases, and overt alcohol addiction. Pregnant and/or lactating
`women were also excluded.
`All patients gave written informed consent to partici-
`pate in the study. The study was performed in accordance with
`the amended Declaration of Helsinki and was approved by the
`appropriate local ethics and drug committees.
`Study design. This was an 8-week, randomized,
`double-blind, placebo-controlled study followed by an 8-week
`open study after a 4-week nontherapeutic period. At screening,
`patients who presented with CRPS I of a lower extremity and
`who were candidates for the study completed informed con-
`sent and medical history forms and underwent a physical
`examination, plain radiography, and a 3-phase bone scintigra-
`phy. Blood and urine samples were collected for analysis.
`During the randomization visit, patients who met all entry
`criteria were assigned to either the alendronate group or the
`placebo group, based on a computer-generated blinded ran-
`domization schedule. To preserve the double-blind condition
`of the study, tablets containing 40 mg of alendronate and those
`containing placebo were identical in appearance. As strongly
`recommended by the manufacturer (Merck Sharp and Dohme,
`Whitehouse Station, NJ), the tablets were taken with a full
`glass of water upon arising for the day (after an overnight fast),
`and patients were instructed to remain in an upright position
`for 30 minutes prior to consuming the first food or beverage of
`the day.
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`3692
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`MANICOURT ET AL
`
`(lower score denotes a more tender leg). With examiner
`training, the coefficient of variation of this procedure was
`⬍8%, and the normal range was 0.9–1.1.
`Edema was assessed by measuring the circumference
`of the knee (midpatellar region), ankle, and foot (midtarsal
`region) of both legs. The results are expressed as the ratio of
`the value in the affected joint to the corresponding value in the
`unaffected contralateral joint. The coefficient of variation was
`⬍3%, and the normal range was 0.96–1.04.
`Using a goniometer, mobility of the knee, foot, and
`ankle was assessed. For each movement of flexion and exten-
`sion of the knee, the angle value obtained for the affected knee
`was divided by that obtained for the contralateral knee to give
`the relative test value. Relative test values obtained for flexion
`and extension were then averaged to give the index of knee
`mobility. The coefficient of variation was ⬍3%, and the
`normal range was 0.95–1.05.
`For the foot and ankle, dorsal flexion and plantar
`extension of the ankle as well as subtalar inversion and
`eversion were measured. For each movement, the angle value
`obtained for the affected limb was divided by that obtained for
`the contralateral limb to give the relative test value. Relative
`test values obtained for each of the 4 movements were then
`averaged to give the index of foot and ankle mobility. The
`coefficient of variation was 5%, and the normal range was
`0.94–1.06.
`Urine samples (second void of the morning; fasting
`state) were collected at the time of randomization and at week
`8. Specimens were immediately frozen at –20°C until analyzed
`for levels of type I collagen N-telopeptide (NTX) by use of a
`commercially available enzyme-linked immunosorbent assay
`(Osteomark; Ostex, Seattle, WA). Results were corrected for
`urine dilution by urinary creatinine analysis and expressed in
`nanomoles of bone collagen equivalents (BCE) per liter per
`millimole of creatinine per liter (ratio reported as nM
`BCE/mM creatinine).
`Statistical analysis. After entering all measured data
`into a computer database (SigmaStat; Jandel, San Rafael, CA),
`the treatment randomization was disclosed to allow compari-
`son of the data obtained in the 2 groups of patients. Statistical
`analysis was performed with analysis of variance (ANOVA):
`two-way ANOVA with repeated measurements, the indepen-
`dent criteria being treatment and the correlated criteria being
`time. When needed, Tukey’s test was used for multiple com-
`parisons. P values less than 0.05 were considered statistically
`significant.
`
`RESULTS
`Demographics and baseline characteristics. The
`2 treatment groups were similar with regard to demo-
`graphics and baseline characteristics of the study pa-
`tients (Table 1). In both groups, CRPS I of the ankle and
`foot was more frequent, and the relative percentages of
`the nature of the initiating traumatic events were similar.
`In all cases of postsurgical CRPS I of the knee, the
`nature of the precipitating factor was arthroscopy for
`meniscal problems.
`
`Figure 1. Study protocol. This randomized, double-blind, placebo-
`controlled study was conducted for 8 weeks, and after a washout period
`of 4 weeks, the 8-week open-label phase began. Twenty patients with
`posttraumatic complex regional pain syndrome type I affecting the
`lower extremity were initially enrolled in each treatment group. Twelve
`patients from each treatment group elected to receive alendronate for
`a period of 8 weeks in the open-label phase (weeks 12–20). Arrows
`across the top indicate the followup visits.
`
`After the first 8-week therapeutic period and a 4-week
`nontherapeutic period, patients in both treatment groups who
`wanted to do so received a daily tablet containing 40 mg of
`alendronate for 8 weeks (i.e., from week 12 to week 20).
`Compliance with treatment was estimated by counting
`the number of tablets used from the pack that was given to the
`patient at the baseline visit. A value outside the range of
`80–100% of the original number was considered a protocol
`violation.
`During the entire study period, patients were encour-
`aged to continue their physical therapy and rehabilitation
`program on a regular basis.
`Schedule of visits and assessments. The visit schedule
`is illustrated in Figure 1. Besides the randomization visit (week
`0), patients enrolled in the double-blind, placebo-controlled
`study were seen at week 4, week 8, and week 12. Patients
`included in the open study were seen at week 16, week 20, and
`week 24. Care was taken to examine each patient between the
`hours of 9:00 AM and 11:00 AM, the patient having arisen from
`bed for more than 2 hours at the time of the medical
`appointment.
`At each visit, a 100-mm VAS was used to assess the
`patient’s level of spontaneous pain. As described below, values
`obtained for tenderness, edema, and joint mobility in the
`affected limb were divided by the values obtained for the
`corresponding parameters in the contralateral limb. Although
`CRPS I might also affect the contralateral limb (6,7), there was
`no obvious clinical evidence of spreading of the disease process
`to the contralateral side in our patients.
`Tenderness or pressure tolerance threshold was mea-
`sured with a dolorimeter (8). Using the 1-cm2 applicator tip,
`pressure was applied perpendicular to the skin’s surface at a
`gradual rate of 1 kg/second. For CRPS I of the knee, measure-
`ments were made over the dorsal aspect of the midpatellar and
`midtibial areas of both legs. For CRPS I of the ankle and foot,
`measurements were made over the dorsal aspect of
`the
`midtibial and midtarsal areas of both legs. For each location,
`measurements were made in triplicate, and the mean value was
`recorded as the test value. For each of the 2 areas measured,
`the test value for the affected limb was then divided by the
`corresponding test value for the unaffected limb, and the 2
`ratios were averaged to give the pressure tolerance score
`
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`ORAL ALENDRONATE IN CRPS I
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`Table 1. Demographics and baseline characteristics of patients with
`complex regional pain syndrome type I of the lower limb treated with
`alendronate or placebo*
`
`Parameter
`
`Age, mean ⫾ SD years
`No. of men/women
`Height, mean ⫾ SD cm
`Body mass index, mean ⫾ SD kg/m2
`Disease duration, mean ⫾ SD months
`Disease site
`Knee
`Foot and ankle
`Inciting injury
`Sprain/strain
`Postsurgery
`Fracture
`Contusion
`
`Alendronate
`group
`(n ⫽ 20)
`
`44.6 ⫾ 12.3
`11/9
`169 ⫾ 10
`26 ⫾ 6
`7 ⫾ 2
`
`Placebo
`group
`(n ⫽ 20)
`
`45.2 ⫾ 12.5
`8/12
`168 ⫾ 11
`27 ⫾ 6
`8 ⫾ 3
`
`2
`18
`
`10
`4
`3
`3
`
`8
`12
`
`11
`3
`4
`2
`
`* None of the between-group differences were statistically significant.
`
`Before entry into the study, all patients had
`received various analgesics and nonsteroidal antiinflam-
`matory drugs. Fourteen had received salmon calcitonin.
`Because of this large variety of medications that had
`been taken, no attempt was made to correlate the drug
`treatment with the clinical parameters of disease activity
`at the baseline visit.
`in the
`Tolerability and safety. One patient
`alendronate-treated group dropped out after a thera-
`peutic period of 2 weeks because of upper gastrointes-
`tinal intolerance. One patient in the placebo-treated
`group experienced headache, nausea, and heartburn for
`about 1 hour after ingesting the tablet, but he neverthe-
`less completed the study.
`Efficacy during the initial 12-week study period.
`Obviously, despite various analgesic and antiinflamma-
`tory drug regimens that had been administered for an
`average of 7–8 months, patients included in the study all
`were severely impaired, as evidenced by their pressure
`tolerance scores, spontaneous levels of pain, degree of
`swelling of the affected leg, and levels of joint mobility
`(Figure 2). ANOVA disclosed that over time, treatment
`had a statistically significant effect (variation ⫽ time ⫻
`treatment) on the VAS values (F ⫽ 136, P ⬍ 0.001),
`edema in the affected leg (F ⫽ 5, P ⫽ 0.003), pressure
`tolerance scores (F ⫽ 63, P ⬍ 0.001), and levels of joint
`mobility (F ⫽ 28, P ⬍ 0.001).
`At study entry, the placebo-treated group and the
`alendronate-treated group had similar mean VAS scores
`(Figure 2). In the placebo-treated group, a small, but
`statistically significant, reduction in the mean VAS score
`was detected only at week 12 (P ⬍ 0.05), whereas in the
`
`alendronate-treated group, the mean VAS score was
`already significantly reduced at week 4. A further signif-
`icant drop in the score was noted at week 8 and was
`sustained at week 12. In comparison with the placebo-
`treated group, patients in the alendronate-treated group
`exhibited a significant decrease in their mean VAS
`scores at weeks 4, 8, and 12 (P ⬍ 0.05). It is noteworthy
`that at week 12, the mean VAS score in the alendronate-
`treated group was 33% of that in the placebo-treated
`group.
`
`Before therapy, the 2 groups exhibited a similar
`mean score for pressure tolerance (Figure 2). Alendro-
`nate caused a sharp increase in the mean pressure
`tolerance score at week 4 (P ⬍ 0.05). Although a further
`significant increase in this score was noted at week 8
`(P ⬍ 0.05) and was sustained at week 12, the score
`remained below the normal range of values. In contrast,
`in the placebo-treated group, the mean score remained
`unaffected for up to week 12, and was thus significantly
`lower (P ⬍ 0.05) than that seen in the alendronate-
`treated group at the 3 time points.
`In both groups, the mean score for edema de-
`creased with time (Figure 2). A statistically significant
`decrease was seen at week 4 in the alendronate-treated
`group (P ⬍ 0.05) and only at week 8 in the placebo-
`treated group (P ⬍ 0.05). At week 12, the mean edema
`
`Figure 2. Distribution of visual analog scale (VAS; 0–100-mm scale),
`pressure tolerance, edema, and mobility scores measured in patients
`with posttraumatic complex regional pain syndrome type I affecting
`the lower extremity who were treated with either placebo (n ⫽ 20) or
`alendronate (n ⫽ 19) for up to 8 weeks. Data are shown as box plots.
`The box extends from the 25th percentile to the 75th percentile, with
`a horizontal line at the median (50th percentile). Whiskers extend
`down to the lowest value and up to the highest value. ⴱ ⫽ P ⬍ 0.05 for
`the difference between time periods within each group; ⫹ ⫽P ⬍ 0.05
`for the difference between groups at a given time point.
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`trial of alendronate at a daily oral dose of 40 mg for a
`period of 8 weeks.
`As expected, at week 16, which constituted a
`period of only 4 weeks of alendronate therapy, patients
`that had previously taken a placebo exhibited a dramatic
`improvement (P ⬍ 0.05) in their mean VAS scores for
`spontaneous pain, their mean pressure tolerance scores,
`and their mean joint mobility scores (Figure 4). These
`mean scores showed further improvement at week 20
`(P ⬍ 0.05) and remained unchanged at week 24 (i.e., 4
`weeks after stopping alendronate therapy).
`In patients that had previously taken alendronate
`(Figure 4), continued administration of the bisphospho-
`nate during the 8-week therapeutic period was associ-
`ated with new progressive improvement in the mean
`scores for spontaneous pain, pressure tolerance, and
`
`Figure 4. Distribution of visual analog scale (VAS; 0–100-mm scale),
`pressure tolerance, and mobility scores measured in patients who
`elected to receive alendronate during the 8-week open-label extension
`study. After a nontherapeutic period of 4 weeks, 12 patients from the
`initial placebo group (left panels) and 12 patients from the initial
`alendronate group (right panels) received alendronate at a daily oral
`dose of 40 mg for 8 weeks (week 12 to week 20). Data are shown as box
`plots. The box extends from the 25th percentile to the 75th percentile,
`with a horizontal line at the median (50th percentile). Whiskers extend
`down to the lowest value and up to the highest value. ⴱ ⫽ P ⬍ 0.05 for
`the difference between time periods within each group; ⫹ ⫽P ⬍ 0.05
`for the difference between groups at a given time point.
`
`Figure 3. Changes in urinary levels of cross-linked N-telopeptide of
`type I collagen (NTX) at study entry and at the end of the 8-week
`therapeutic period in the placebo-treated group and the alendronate-
`treated group. Data are shown as box plots, where each box represents
`the 25th to 75th percentiles, whiskers represent the 10th and the 90th
`percentiles, and lines inside the boxes represent the mean. Values are
`expressed as bone collagen equivalents (BCE) (see Patients and
`Methods for derivation). ⴱ ⫽ P ⬍ 0.001 versus week 0 in alendronate-
`treated patients.
`
`score was similar in the 2 groups and remained above the
`normal range of values.
`Before therapy, the 2 groups had a similar mean
`score for joint mobility (Figure 2). In the alendronate-
`treated group, the mean score was markedly enhanced
`(P ⬍ 0.05) as early as at week 4, increased further at
`week 8 (P ⬍ 0.05), and was sustained at week 12. This
`evolution contrasted sharply with that seen in the
`placebo-treated group, where the mean score remained
`unchanged for up to week 8, and increased modestly, but
`significantly (P ⬍ 0.05), at week 12. The mean score for
`joint mobility in the alendronate-treated group was
`significantly higher (P ⬍ 0.05) than that in the placebo-
`treated group at the 3 time points.
`As illustrated in Figure 3, after a therapeutic
`period of 8 weeks, urinary levels of NTX were signifi-
`cantly reduced in the alendronate-treated group (P ⬍
`0.001), but not in the placebo-treated group.
`Efficacy during the 8-week open-label extension
`study. At week 12 of the double-blind study, 8 of the
`placebo-treated patients did not want to continue the
`oral therapy, 4 alendronate-treated patients were unable
`to pursue the study because of logistical reasons, and 4
`other alendronate-treated patients stated that they were
`sufficiently improved that they did not want to take the
`oral medication for a longer time period. Therefore,
`only 12 patients in each group volunteered for the open
`
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`ORAL ALENDRONATE IN CRPS I
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`3695
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`joint mobility (P ⬍ 0.05). This suggests that the previous
`positive effect of alendronate had not reached a plateau
`and was not declining after the first 8-week therapeutic
`period. Furthermore, and as observed after the first
`therapeutic period, this new improvement was sustained
`for at least 4 weeks after stopping the drug. Although
`pressure tolerance scores remained below the normal
`range at week 20, it is worth noting that at that time, the
`mobility scores had reached the normal range in half of
`the patients in this group.
`Treatment outcomes could not be associated with
`the hemovelocity and blood pool values obtained during
`the 3-phase bone scanning, as assessed at study entry, or
`with the diffuse or patchy appearance of regional osteo-
`porosis. However, 3 months after the end of the study
`(week 36), 3 patients in the initial placebo-treated group
`and 2 patients in the initial alendronate-treated group
`experienced a relapse. Further followup studies are
`ongoing.
`
`DISCUSSION
`The consensus-based criteria published by the
`IAPS (1) are adequately sensitive but are not very
`specific. The inclusion of motor and trophic signs and
`symptoms in the modified research criteria (21) has
`improved the specificity without losing much sensitivity.
`However, there is no clear consensus on how to assess
`these criteria in daily clinical practice. Patients included
`in the present study all exhibited the cardinal features of
`CRPS I that have been clearly formulated by several
`authors (4,5,8). The semiquantitative approach we used
`to assess the clinical signs has been well validated in
`CRPS I of the upper extremity (8,24). Furthermore, the
`regional osteoporosis seen in disuse conditions can be
`accurately differentiated from that seen in CRPS I by
`using the pressure tolerance test (8,24).
`Obviously, at a daily dose that corresponds to
`that recommended for Paget’s disease of bone, which
`amounts to 4 times the daily dose recommended for the
`treatment of postmenopausal osteoporosis, oral alen-
`dronate was very efficacious in the treatment of post-
`traumatic CRPS I. Although the positive effect of oral
`alendronate was detected as early as 4 weeks after
`initiation of treatment, the optimal therapeutic time
`period remains to be established, since after 16 weeks of
`alendronate therapy,
`joint mobility had returned to
`values within the normal range in half of the patients,
`whereas tenderness was markedly improved, but still
`remained below the normal range of values in all
`patients. In contrast, alendronate apparently had no
`
`effect on edema, since at week 12, both groups exhibited
`a similar mean score for edema. It is unlikely that the
`reduction in edema was related to the increase in joint
`mobility, since this reduction occurred when joint mo-
`bility was markedly enhanced in the alendronate-treated
`group but hardly improved in the placebo-treated group.
`Our data help to put into perspective the results
`of previous studies that have shown a positive effect of
`intravenous bisphosphonate therapy in patients with
`CRPS I (16–20). Although the majority of those studies
`lacked a placebo control group, the drug was shown to
`relieve pain and enhance the range of motion, and as
`observed in the present study, the beneficial response to
`bisphosphonate therapy was rapid and persisted for
`some time after the end of the therapeutic period.
`Furthermore, these previous studies have shown that
`patients with posttraumatic CRPS I responded better
`than patients with CRPS I associated with other condi-
`tions.
`
`The rationale for using bisphosphonates in the
`treatment of CRPS I relies upon the capacity of the drug
`to inactivate osteoclasts and to antagonize osteoclasto-
`genesis (25). Indeed, it has been suggested that high
`levels of markers of bone resorption at baseline have a
`positive predictive value for bisphosphonate therapy
`(18). The osteoclastic overactivity and bone marrow
`edema seen in CRPS I (2,4,5,26) might contribute to the
`generation and maintenance of chronic pain, since each
`neuron in the nociceptive pathway has the capacity to
`change phenotype in the presence of a sustained peri-
`pheral
`injury (6,7,9,10). This contention is further
`strengthened by the observation that osteoprotegerin
`(OPG), a potent inhibitor of osteoclast-mediated bone
`resorption (27), not only halts bone destruction, but also
`markedly reduces markers of both peripheral and cen-
`tral sensitization in a mouse model of pain associated
`with cancer of the bone (28,29). Therefore, the possible
`effect of OPG in CRPS is worth investigating, and
`alendronate, another potent antiresorptive drug, might
`have alleviated the pain and tenderness in our study
`patients by its effects on primary afferent nociceptors in
`bone and pain-associated changes in the spinal cord.
`Furthermore, since it has been suggested that, upon
`stimulation by substance P that is liberated by the
`activated and sensitized afferent nerve fibers, macro-
`phages start to release proinflammatory cytokines, such
`as tumor necrosis factor ␣ (TNF␣), which in turn,
`further activate afferent fibers by enhancing sodium
`influx into the cells (30), it is also tempting to speculate
`that TNF␣ inhibitors such as etanercept and infliximab
`might have therapeutic effects in CRPS.
`
`6
`
`

`

`3696
`
`MANICOURT ET AL
`
`It is naive, however, to reduce CRPS I to osteo-
`clastic overactivity. The traumatic event
`triggering
`CRPS I in our patients might have damaged C fibers
`and/or A-delta mechanical fibers in soft tissue and
`nerve, another type of injury believed to establish and
`maintain central sensitization (6). Obviously, bisphos-
`phonates exhibit antinociceptive properties in a variety
`of bone and joint disorders (31,32), as well as in other
`painful situations unrelated to bone and joint diseases
`(33). Their pain relief properties might be related to
`their ability to inhibit the production of either proin-
`flammatory cytokines, prostaglandins, lactic acid, and/or
`various neuropeptides and neuromodulators, all of
`which are possibly involved in the sensitization of affer-
`ent nerve fibers and pain modulation (33,34). The highly
`water-soluble bisphosphonates might also have a central
`antinociceptive action, possibly through mechanisms in-
`volving ionized calcium (35). Indeed, ionized calcium-
`channel blockers display antinociceptive properties by
`inhibiting the influx of calcium that is crucial for the
`release of neurotransmitters and other substances impli-
`cated in nociception and inflammation (36,37). In con-
`trast, liposome-encapsulated bisphosphonates, but not
`free bisphosphonates, are able to deplete macrophages
`from an injured nerve and,
`in so doing, to reduce
`neuropathic hyperalgesia and Wallerian degeneration
`(38). This might explain why alendronate was unable to
`restore the pressure tolerance scores to a normal range.
`In conclusion,
`in this randomized placebo-
`controlled trial, we observed that oral alendronate taken
`at a daily dose of 40 mg was well tolerated and appeared
`to be a very effective tool in the management of CRPS
`I, a painful and potentially disabling condition.
`
`ACKNOWLEDGMENTS
`The authors thank the Merck Sharp and Dohme
`Company and, more particularly, Dr. A. J. Yates for providing
`the placebo and 40-mg alendronate tablets, as well as an
`institutional grant for this study.
`
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