Downloaded from
`
`http://ard.bmj.com/
`
`
`
`group.bmj.com on December 14, 2016 - Published by
`
`Annals of the Rheumatic Diseases 1997;56:201–204
`
`201
`
`Bisphosphonate therapy of reflex sympathetic
`dystrophy syndrome
`
`S Adami, V Fossaluzza, D Gatti, E Fracassi, V Braga
`
`Abstract
`Objective—The reflex sympathetic dys-
`trophy syndrome (RSDS) is a painful limb
`disorder, for which a consistently eVective
`treatment has not yet been identified. The
`disease is associated with increased bone
`resorption and patchy osteoporosis, which
`might benefit
`from treatment with
`bisphosphonates, powerful
`inhibitors of
`bone resorption.
`Methods—Twenty patients with RSDS of
`foot and hand, were randomly assigned to
`blind administration of either alendronate
`intravenously (Istituto Gentili, Pisa, Italy)
`7.5 mg dissolved in 250 ml saline solution
`or placebo saline infusions daily for three
`days. Two weeks later all patients had an
`identical
`treatment course with open
`labelled alendronate (7.5 mg/day for three
`days), independent from the results of the
`first blind treatment.
`Results—In the patients treated with blind
`alendronate the diminution in spontane-
`ous
`pain,
`tenderness,
`and
`swelling
`(circumference of the aVected limb) and
`the
`improvement
`in motion were
`significantly
`diVerent
`from baseline
`(p<0.001), from those observed within the
`first
`two weeks in the control group
`(p<0.01), and from week 2 to week 4
`(p<0.01).
`In the patients given blind
`placebo infusions no relevant sympto-
`matic changes were observed after the
`first two weeks of follow up, but they
`responded to
`the
`open alendronate
`therapy given afterwards. In 12 patients
`with RSDS of the hand the ultradistal
`bone mineral content
`(BMC) of
`the
`aVected arm was considerably lower than
`that of the controlateral arm (mean (SD))
`(426(82) mg/cm versus 688(49)). Six weeks
`after the beginning of the trial BMC rose
`by 77(12) mg/cm (p<0.001) in the aVected
`arm, but it did not change in the controla-
`teral.
`Conclusions—These results indicate that
`bisphosphonates should be considered for
`the
`treatment
`of RSDS, producing
`consistent and rapid remission of the dis-
`ease.
`
`(Ann Rheum Dis 1997;56:201–204)
`
`The reflex sympathetic dystrophy syndrome
`(RSDS) is a painful limb disorder character-
`ised by swelling, autonomic dysfunction,
`patchy osteoporosis and, later, contracture for-
`mation. Some of the symptoms might not be
`present or a particular
`feature is more
`
`apparent; this has been responsible for the
`myriad of terms applied to partial descriptions
`and designations of RSDS.1
`Various methods of treatment have been
`tried,
`including physiotherapy,
`calcitonin,
`corticosteroids, sympathetic blockade, non-
`steroidal anti-inflammatory drugs. The results
`of these attempts are inconsistent2–4 and they
`produce slow improvements that cannot be
`easily distinguished from spontaneous remis-
`sion.
`characterised by
`is
`The bone disease
`increased bone
`resorption,5 which might
`benefit from treatment with bisphosphonates,
`powerful inhibitors of bone resorption.6 In pre-
`liminary studies we observed rapid and persist-
`ent remission of
`the symptoms in several
`patients treated with intravenous clodronate or
`alendronate. Our preliminary results together
`with other positive uncontrolled findings with
`intravenous pamidronate7 8 prompted us to
`undertake a double blind study in patients with
`RSDS with
`intravenous
`alendronate,
`a
`powerful bisphosphonate, which was exten-
`sively investigated in our unit
`for several
`years.9 10
`
`Patients and methods
`The study includes 20 patients recruited over a
`period of seven years who were diagnosed as
`having definite RSDS2 on the basis of typical
`clinical symptoms and roentgenographic signs.
`All patients complained of pain, cold sweating
`and tenderness in an extremity associated with
`swelling and signs of vasomotor instability
`(alternate pallor, cyanosis, and redness).
`Radiographic diVuse or patchy osteopenia, or
`both was confirmed in all patients by compar-
`ing the aVected with the controlateral limb and
`by densitometry (see below) in a proportion of
`the patients. The patients in whom all the
`above described RSDS features were not fully
`expressed (that is, the patients classified as
`belonging to group 2 to 52 4 11) were not
`included in this study. The disease could be
`related to previous trauma or fracture in 16, to
`neurological diseases in one, and to unknown
`causes in three subjects, two of whom had type
`2 diabetes (table 1). The aVected sites were the
`hand in 12 and the foot in eight patients. The
`duration of the disease ranged from five to 34
`weeks. Ten patients were referred to us after
`treatment with nasal spray calcitonin (five
`patients),
`or
`continuous
`analgesics
`(six
`patients), which had been proved ineVective.
`All patients had received some physical
`treatment: the compliance to it was variable
`and could be assessed precisely, but it was inef-
`fective in all of them.
`
`COC di Valeggio,
`University of Verona,
`Valeggio, Verona, Italy
`S Adami
`D Gatti
`E Fracassi
`V Braga
`
`Ospedale di Udine,
`Italy
`
`Correspondence to:
`Professor S Adami, Ospedale
`di Valeggio,37067 Valeggio
`s/M, Verona, Italy.
`
`Dr Veceslao Fossaluzza died
`in a car accident in 1994.
`
`Accepted for publication
`27 November 1996
`
`Grun. Exh. 1019
`PGR for U.S. Patent No. 9,408,862
`
`

`

`Downloaded from
`
`http://ard.bmj.com/
`
`
`
`group.bmj.com on December 14, 2016 - Published by
`
`202
`
`Adami, Fossaluzza, Gatti, Fracassi, Braga
`
`Table 1 Clinical characteristics of the two groups of patients
`
`Group
`
`Alendronate blind +
`alendronate open
`Placebo blind + alendronate
`open
`
`No of
`patients
`
`Sex
`F/M
`
`Age
`range
`
`Disease duration
`(weeks, mean
`(SD))
`
`Possible aetiological fasctors (no)
`
`Trauma
`
`Fracture
`
`Neurological Unknown
`
`10
`
`10
`
`7/3
`
`5/5
`
`39-79
`
`16 (17)
`
`48-80
`
`19 (19)
`
`1
`
`2
`
`6
`
`7
`
`1
`
`0
`
`2
`
`1
`
`assessed by physician. The circumference of
`the aVected joints was measured with a tape
`proximally of the first carpo-metacarpal joint
`for the hand and around the ankle for the foot,
`bilaterally; skin labelling was used to improve
`the reproducibility of the measurements.
`In the patients with aVected hands the bone
`mineral content (BMC) of
`the ultradistal
`radius was measured by a DXA instrument
`(Osteoscan, NIM, Verona, Italy) with a CV%
`lower than 1.12
`Informed consent was obtained from all
`patients and this study protocol was approved
`by a local ethical committee.
`Statistical
`significance was assessed by
`Wilcoxon signed rank test and paired Student t
`test, preceded by ANOVA when appropriate
`(Statgraphics, STSC, USA).
`
`Results
`The two groups of patients were comparable
`for most clinical features (table 1) and for the
`duration of the disease.
`blind-
`treated with
`In
`the
`patients
`alendronate the diminution in spontaneous
`pain, tenderness and swelling (circumference
`of the aVected limb) and the improvement in
`motion were
`significantly diVerent
`from
`baseline (p<0.001), from those seen within the
`first two weeks in the control group (p<0.01),
`and from week 2 to week 4 (p<0.01). In the
`patients given blind placebo infusions no
`relevant symptomatic changes were observed
`after the first two weeks of follow up, but they
`responded to the open alendronate therapy
`given afterwards (table 2 and fig 1). At the end
`of
`the fourth week spontaneous pain and
`tenderness were more suppressed in the group
`of patients who had a double course of intrave-
`nous alendronate (−62% versus −48% and
`−53% versus −46%, respectively) but
`this
`diVerence was not
`statistically significant
`(p<0.2). Pooling all patients at the end of the
`controlled and blind observation, spontaneous
`pain decreased by over 75% in five patients and
`over 50% in eight further patients. In three
`patients the changes fell within the 90% confi-
`dence intervals (> −30%) as found in the pla-
`cebo group, after
`the first
`two weeks of
`observation. The seven patients in whom the
`symptoms did not decrease by more than 50%,
`were somewhat younger (mean (SD) 58(12)
`versus 64(13)) and in six of them RSDS was
`related to previous fracture. At the completion
`of the study observation joint rehabilitation
`exercises were necessary in most patients to
`improve motion range. Four patients were lost
`to follow up, being unable to attend regularly
`our outpatient clinic. At the twelfth month of
`follow up, nine patients were considered in
`
`After observation before treatment for two to
`four days, and when no spontaneous modifica-
`tion of the symptoms occurred, the patients
`were randomised to receive, in a double blind
`way, by intravenous infusion either alendronate
`(Istituto Gentili SpA, Pisa, Italy) 7.5 mg or
`placebo, dissolved in 250 ml saline solution
`daily for three days. The two groups were com-
`parable for sex, age range, site (six hands in
`both groups), duration of the symptoms (3-34
`and 6-30 weeks) and possible aetiological
`factor (table 1). The placebo vials had an iden-
`tical appearance to those of alendronate and
`the randomisation was carried out by our
`pharmacist. Clinical assessment was obtained
`twice before treatment and weekly thereafter.
`At day 14 all patients had an identical
`treatment course with open labelled alendro-
`nate (7.5 mg intravenously daily for three
`days), independent from the results of the first
`blind treatment. Treatment
`codes were
`unblinded a few days after the treatment
`courses in two patients and at the completion
`of the study in all the others.
`The eYcacy was assessed by visual analogue
`scale (VSA, from 0 = no pain to 10 = worst
`possible pain)
`for
`spontaneous pain and
`tenderness and by an arbitrary score (from 0 =
`normal to 4 = worst finding) of motion as
`
`Placebo Alendronate
`
`Alendronate
`
`Alendronate
`
`23.8(5.8) 23.8(5.2) 21.5(5.6)
`
`22.9(7.1) 21.3(6.7) 20.4(6.2)
`
`Before
`
`2 wks
`
`4 wks
`
`Before
`
`2 wks
`
`4 wks
`
`40
`
`30
`
`20
`
`10
`
`Circumference (cm)
`
`Figure 1 Changes in the circumference of the aVected limbs (together with mean and
`standard deviation) two and four weeks after the beginning of the trial in the patients
`randomly assigned to either alendronate (right panel) or placebo (left panel) at the
`beginning of the study. At week 2 both groups of patients had a treatment course with
`intravenous alendronate.
`
`

`

`Downloaded from
`
`http://ard.bmj.com/
`
`
`
`group.bmj.com on December 14, 2016 - Published by
`
`Bisphosphonate therapy of reflex sympathetic dystrophy syndrome
`
`203
`
`Table 2 Baseline score and per cent changes in spontaneous pain, tenderness and motion two weeks (2 wks) after the blind treatment with either
`alendronate or placebo. The patients were reassessed on week 4, that is, two weeks after a treatment course with intravenous alendronate given to both
`groups of patients. The score range was 0 to 10 for pain and 0 to 4 for motion score (0 = normal motility)
`
`Spontaneous pain % decrease (percentiles)
`
`Tenderness % decrease (percentiles)
`
`Motion score % decrease (percentiles)
`
`Group
`
`Alendronate blind +
`alendronate open
`Placebo blind +
`alendronate open
`
`Range
`baseline
`
`3-8
`
`3-8
`
`2 wks
`
`4 wks
`
`10th
`
`90th
`
`10th
`
`90th
`
`Range
`baseline
`
`2 wks
`
`4 wks
`
`10th
`
`90th
`
`10th
`
`90th
`
`−90% −37%
`
`−90% −34%
`
`3-9
`
`−72% −21%
`
`−71% −33%
`
`−31% +12%
`
`−71% −12%
`
`3-10
`
`−33% +8%
`
`−64% −17%
`
`Range
`baseline
`
`2-4
`
`2-4
`
`2 wks
`
`4 wks
`
`10th
`
`90th
`
`10th
`
`90th
`
`−50% 0%
`
`−71% −17%
`
`−33% 0%
`
`−67% −12%
`
`considerably lower than of the controlateral
`arm (426 (82) mg/cm versus 688 (49)). Six
`weeks after the beginning of the trial (that is,
`six and four weeks after the first alendronate
`treatment course in the alendronate and in the
`control group respectively) BMC rose by
`77(12) mg/cm (p<0.001) in the aVected arm,
`but it did not change in the controlateral arm
`(fig 2). The BMC of the aVected arm rose also
`in one of the patients in whom the disease
`relapsed and the relapse was accompanied by a
`persistent abnormal local bone uptake at bone
`scan examination.
`The treatments were well tolerated but three
`patients experienced moderate fever (up to
`37.8(cid:176)C) the day after the first
`intravenous
`injection of alendronate, reproducing the typical
`acute phase response occasionally observed after
`administration of amino-bisphosphonates.13
`
`Discussion
`Bisphosphonates are nowadays regarded as
`first choice treatment for malignant hypercal-
`caemia and Paget’s disease of bone,6 and a use-
`ful therapeutic tool for osteoporosis.14–16 The
`results of this study in conjunction with two
`other preliminary reports using intravenous
`pamidronate7 8 show that bisphosphonates may
`be a promising therapeutic approach for
`RSDS.
`condition
`this
`The pathophysiology of
`remains obscure, but the observed prompt
`relief of most symptoms after alendronate
`administration might indicate that these are, at
`least in part, related to increased bone resorp-
`tion, which was undoubtedly blocked by the
`high doses of alendronate used in this study. It
`is thought that in the RSDS the vasodilatation
`precedes bone loss, but the results of this study
`may indicate that the opposite is also true, with
`secondary generation of a vicious circle. The
`interruption of this vicious circle by blocking
`bone resorption may lead to the complete
`remission of
`the disease if
`the primary
`unknown
`causes
`of
`the
`disease
`had
`disappeared. This apparently did not occur in a
`proportion of our patients, in whom the disease
`relapsed. In these latter patients and in a few
`others seen by us outside the present clinical
`trial, the symptoms were relieved and they
`recurred several times after treatment courses
`with either clodronate (300 mg , intravenously
`for 1-5 days) or
`alendronate
`(7.5 mg,
`intravenously once). In RSDS the osteoclasts
`are probably activated by local unidentified
`factors associated with the disease. Bisphos-
`phonates definitely counteract this activation
`
`remission, whereas a relapse of the symptoms
`occurred in four patients who did not obtain a
`clinically significant remission after alendro-
`nate therapy and in three patients who had a
`good response. Four of seven patients who
`relapsed had received only one course of intra-
`venous alendronate, whereas seven of nine
`patients with long term remission had received
`the double alendronate treatment course.
`Bone scans were performed one to six weeks
`before treatment
`in 13 patients and they
`showed increased activity and uptake of the
`periarticular regions of aVected limbs. The
`examinations, for radioprotective reasons, were
`repeated 8-10 weeks after treatment only in
`four patients in whom the disease relapsed. In
`these cases the local bone uptake remained
`abnormally increased and apparently un-
`changed.
`In the 12 patients with RSDS of the hand the
`ultradistal BMC of
`the aVected arm was
`
`900
`
`700
`
`500
`
`Bone mineral content (mg/cm)
`
`300
`
`Before
`After
`Affected wrist
`
`Before
`After
`Unaffected wrist
`
`Figure 2 Changes in the bone mineral content of the wrist six weeks after the beginning of
`the trial in the RSDS aVected and unaVected hand.
`
`

`

`Downloaded from
`
`http://ard.bmj.com/
`
`
`
`group.bmj.com on December 14, 2016 - Published by
`
`204
`
`Adami, Fossaluzza, Gatti, Fracassi, Braga
`
`but, in addition, they might interfere with the
`local production of cytokines. It has been sug-
`gested that bisphosphonates acutely increase
`the release of interleukin 1, interleukin 6, and
`tumour necrosis factor13 17; these findings are
`intriguing even though any relation with our
`findings remains obscure. In our opinion, it is
`more likely that bisphosphonates act at the
`osteoclastic level, the overactivity of which is
`one of the relevant consequences of a cascade
`of events initiated possibly by a nerve injury. A
`controlled study specifically designed to evalu-
`ate the duration of the bisphosphonate eVect
`might contribute to the understanding of this
`specific issue.
`Despite these uncertainties related mostly to
`the pathophysiology of the disease, our results
`indicate that intravenous bisphosphonates are
`an eVective therapeutic approach in most
`patients with RSDS. The eYcacy and the opti-
`mal dose of oral bisphosphonates as well as the
`predictability of
`the therapeutic response
`remain to be established.
`
`1 Kozin F, McCarty DJ, Sims J, Genant H. The reflex sympa-
`thetic dystrophy syndrome. I. Clinical and histological
`studies: Evidence for bilaterality, response to corticoster-
`oids and articular involvement. Am J Med 1976;60:
`321-31.
`2 Kozin F, Ryan LM, Carrera GF, Soin JS, Wortmann RL.
`The reflex sympathetic distrophy syndrome. III Scinti-
`graphic studies . Further evidence for the therapeutic eY-
`cacy of systemic steroids and proposed diagnostic criteria.
`Am J Med 1981;70:23-30.
`3 Doury P, Dirheimer Y, Pattin S. Algodystrophy: Diagnosis and
`therapy of a frequent disease of the locomotor aparatus.New
`York: Springer Verlag, 1981.
`
`4 Doury P. Algodystrophy. Reflex sympathetic dystrophy syn-
`drome. Clin Rheumatol 1988;7:173-80.
`5 Lenggenhager K. Sudeck’s osteodystrphy: its pathogenesis,
`prophylaxis and therapy. Minn Med 1971;54:967-77.
`6 Fleisch H. Bisphosphonates in bone disease. From the laboratory
`to the patient. Berne:H Fleisch, 1993.
`7 Rehman MT, Clayson AD, Marsh D, Adams J, Cantrill JA,
`Anderson DC. Treatment of reflex sympathetic dystrophy
`with intravenous pamidronate. Bone 1992;13:116-8.
`8 Selby PL, Young MJ, Boulton AJM. Bisphosphonates: a new
`treatment for diabetic Charcot neuroarthropathy? Dia-
`betic Medicine 1994;11:28-31.
`9 Adami S, Salvagno G, Guerrera G, Montesanti F, Garavelli
`S, Rosini S, et al. Treatment of Paget’s disease of bone with
`intravenous
`4-amino-1-hydroxybuthylidene-1,1-bisph-
`sphonate. Calcif Tissue Int 1986;39:226-9.
`10 Adami S, Bolzicco GB, Rizzo A, Salvagno G, Bertoldo F,
`Rossini M, et al.The use of dichloromethylene bisphos-
`phonate and aminobutane-bisphosphonate in hypercal-
`cemia of malignancy. Bone Mineral 1987;2:395-404.
`11 Tepperman PS, Grayson ND, Helbert L,
`Jimenez J,
`Williams JI. Reflex sympathetic dystrophy in hemiplegia.
`Arch Phys Med Rehabil 1984;65:442-7.
`12 Adami S, Zamberlan N, Gatti D, Braga V, Broggini M,
`Rossini M,et al. Computed radiographic absortiometry
`and morphometry in the assessment of postmenopausal
`bone loss. Osteoporosis Int 1996;6:8-13.
`13 Adami S, Bhalla AK, Dorizzi R, Montesanti F, Rosini S,
`Salvagno G, et al. The acute-phase response after bisphos-
`phonate administration. Calcif Tissue Int 1987;41:
`326-31.
`14 Watts NB, Harris ST, Genant HK, Wasnich RD, Miller PD,
`Jackson RD, et al. Intermittent cyclical etidronate treat-
`ment of postmenopausal osteoporosis. N Engl J Med
`1990;323:73-9.
`15 Adami S, Passeri M, Ortolani S, Broggini M, Carratelli L,
`Caruso I, et al. EVects of oral alendronate and intranasal
`salmon calcitonin on bone mass and biochemical markers
`of bone turnover in postmenopausal women with oste-
`oporosis. Bone 1995;17:383-90.
`16 Liberman UA, Weiss SR, Bröll J, Minne HW, Quan H, Bell
`NH, et al. EVect of oral alendronate on bone mineral den-
`sity and the incidence of fractures in postmenopausal oste-
`oporosis. N Engl J Med 1995;333:1437-43.
`17 Sauty A, Pecherstorfer M, Zimmer-Roth I, Fioroni L, Markert
`M, Ludwig H, et al. Interleukin-6 and tumor necrosis factor
`levels after bisphosphonates treatment in vitro and in
`patients with malignancy. Bone 1996;18:133-9.
`
`(cid:181)
`

`

`Downloaded from
`
`http://ard.bmj.com/
`
`
`
`group.bmj.com on December 14, 2016 - Published by
`
`Bisphosphonate therapy of reflex sympathetic
`dystrophy syndrome
`
`S Adami, V Fossaluzza, D Gatti, E Fracassi and V Braga
`
`Ann Rheum Dis 
`1997 56: 201-204
`doi: 10.1136/ard.56.3.201
`
`Updated information and services can be found at:
`
` http://ard.bmj.com/content/56/3/201
`
`These include:
`
`References
`
`This article cites 15 articles, 0 of which you can access for free at:
`
`#BIBLhttp://ard.bmj.com/content/56/3/201
`
`
`Email alerting
`service
`
`Receive free email alerts when new articles cite this article. Sign up in the
`box at the top right corner of the online article.
`
`Articles on similar topics can be found in the following collections
`
` (725)Calcium and bone
`
` (4951)Musculoskeletal syndromes
`
` (137)Osteoporosis
`
` (883)
`Pain (neurology)
`
`Topic
`Collections
`
`Notes
`
`To request permissions go to:
`http://group.bmj.com/group/rights-licensing/permissions
`
`To order reprints go to:
`http://journals.bmj.com/cgi/reprintform
`
`To subscribe to BMJ go to:
`http://group.bmj.com/subscribe/
`
`