Abe et al. Journal of Medical Case Reports 2011, 5:349
`http://www.jmedicalcasereports.com/content/5/1/349
`
`JOURNAL OF MEDICAL
`CASE REPORTS
`
`CA S E R EP O R T
`Open Access
`Improvement of pain and regional osteoporotic
`changes in the foot and ankle by low-dose
`bisphosphonate therapy for complex regional
`pain syndrome type I: a case series
`Yasuhisa Abe1, Kousuke Iba1*, Junichi Takada2, Takuro Wada1 and Toshihiko Yamashita1
`
`Abstract
`
`Introduction: Complex regional pain syndrome is characterized by pain, allodynia, hyperalgesia, edema, signs of
`vasomotor instability, movement disorders, joint stiffness, and regional osteopenia. It is recognized to be difficult to
`treat, despite various methods of treatment, including physiotherapy, calcitonin, corticosteroids, sympathetic
`blockade, and nonsteroidal anti-inflammatory drugs. Pathophysiologically, complex regional pain syndrome reveals
`enhanced regional bone resorption and high bone turnover, and so bisphosphonates, which have a potent
`inhibitory effect on bone resorption, were proposed for the treatment of complex regional pain syndrome.
`Case presentation: A 48-year-old Japanese man with complex regional pain syndrome type I had severe right
`ankle pain with a visual analog scale score of 59 out of 100 regardless of treatment with physiotherapy and
`nonsteroidal anti-inflammatory drugs for five months. Radiographs showed marked regional osteoporotic changes
`and bone scintigraphy revealed a marked increase in radioactivity in his ankle. One month after the start of oral
`administration of risedronate (2.5 mg per day), his bone pain had fallen from a VAS score of 59 out of 100 to 18
`out of 100. Bone scintigraphy at 12 months showed a marked reduction in radioactivity to a level comparable to
`that in his normal, left ankle. On the basis of these results, the treatment was discontinued at 15 months. At 32
`months, our patient had almost no pain and radiographic findings revealed that the regional osteoporotic change
`had returned to normal.
`A second 48-year-old Japanese man with complex regional pain syndrome type I had severe right foot pain with a
`visual analog scale score of 83 out of 100 regardless of treatment with physiotherapy and nonsteroidal anti-
`inflammatory drugs for nine months. Radiographs showed regional osteoporotic change in his phalanges,
`metatarsals, and tarsals, and bone scintigraphy revealed a marked increase in radioactivity in his foot. One month
`after the start of oral administration of alendronate (35 mg per week), his bone pain had fallen from a visual
`analog scale score of 83 out of 100 to 30 out of 100 and, at nine months, was further reduced to 3 out of 100.
`The treatment was discontinued at 15 months because of successful pain reduction. At 30 months, our patient had
`no pain and the radiographic findings revealed marked improvement in regional osteoporotic changes.
`Conclusions: We believe low-dose oral administration of bisphosphonate is worth considering for the treatment of
`idiopathic complex regional pain syndrome type I accompanied by regional osteoporotic change.
`
`* Correspondence: iba@sapmed.ac.jp
`1Department of Orthopedic Surgery, Sapporo Medical University School of
`Medicine, Sapporo 060-8543, Japan
`Full list of author information is available at the end of the article
`
`© 2011 Abe et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
`Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
`any medium, provided the original work is properly cited.
`
`Grun. Exh. 1023
`PGR for U.S. Patent No. 9,707,245
`
`

`

`Abe et al. Journal of Medical Case Reports 2011, 5:349
`http://www.jmedicalcasereports.com/content/5/1/349
`
`Page 2 of 6
`
`Introduction
`Complex regional pain syndrome (CRPS) is character-
`ized by pain, allodynia, hyperalgesia, edema, signs of
`vasomotor instability, movement disorders, joint stiff-
`ness, and regional osteopenia [1,2]. Various methods of
`treatment - including physiotherapy, calcitonin, corticos-
`teroids, sympathetic blockade, and nonsteroidal anti-
`inflammatory drugs (NSAIDs) - have been tried [3-5].
`However, in many cases, pain and the ensuing loss of
`function are permanent despite treatment [2,6]. On the
`other hand, previous studies reported that accelerated
`and enhanced bone resorption and turnover play a cen-
`tral pathophysiological role in CRPS [6,7]. Accordingly,
`bisphosphonates, which have a potent inhibitory effect
`on bone resorption, were proposed for the treatment of
`CRPS. In fact, several studies indicated that the intrave-
`nous or high-dose oral administration of bisphosphonate
`improved pain and reduced bone turnover in CRPS
`cases [8-11]. In this report, we present two cases of
`CRPS in which a low dose of oral risedronate (2.5 mg
`per day) or alendronate (35 mg per week) markedly
`decreased pain and regional osteoporotic findings in the
`foot or ankle. Also, since the discontinuation of the
`bisphosphonate treatment, our patients have not com-
`plained of bone pain, and normal bone turnover has
`been observed for more than one year of follow-up
`without additional treatment.
`
`Case presentation
`A 48-year-old Japanese man with CRPS was referred to
`our institute for the treatment of severe right ankle pain
`with a visual analog scale (VAS) [12] score of 59 out of
`100. About five months earlier, he began to feel severe
`right ankle pain without any trigger events. Although
`treatment, including physiotherapy and NSAID adminis-
`tration, was initiated in another clinic, the pain in his
`ankle progressively worsened and he demonstrated gait
`disturbance. A physical examination revealed redness,
`swelling, and remarkable tenderness around his ankle.
`Severe pain and hyperalgesia also resulted in the distur-
`bance of ankle motion and weight-bearing. Radiographs
`showed marked regional osteoporotic changes in the
`distal tibia and fibula at his right ankle compared with
`his left ankle (Figure 1A). Bone scintigraphy with 99
`mTc-methylene diphosphonate revealed a marked
`increase in radioactivity in the bones around his ankle
`(Figure 1B). These clinical findings were consistent with
`CRPS type I (CRPS I) according to criteria of the Inter-
`national Association for the Study of Pain [2]. His lum-
`bar bone mineral density was 0.904 g/cm2, which is
`more than 80% of the Japanese young adult mean
`(YAM). Laboratory tests showed urinary crosslinked N-
`telopeptides of type I collagen (NTX), a bone resorption
`marker, to be 37.6 nmol bone collagen equivalent/
`
`Figure 1 Radiographs (A) and scintigraphs (B) of the both
`ankles before treatment. The radiograph of the right ankle
`showed regional osteoporotic findings at the distal tibia and fibula
`(white arrow) (A). Bone scintigraphy with 99 mTc-methylene
`diphosphonate showed a marked increase in radioactivity around
`the ankle (black arrow) (B).
`
`mmol·Cr (nMBCE/mM·CR) (normal range, 9.3 to 54.3)
`and an alkaline phosphatase (ALP) level of 215 U/L
`(normal range, 110 to 370). Serum calcium (9.1 mg/dL;
`normal range 8.4 to 10.4), serum phosphate (2.9 mg/dL;
`normal range, 2.5 to 4.5), white blood cell count (5600/
`μL; normal range, 3900 to 9800), and C-reactive protein
`(< 0.1 mg/dL; normal range, < 0.3) were all at normal
`levels.
`In accordance with the diagnosis of CRPS I accompa-
`nied by marked regional osteoporotic changes, oral
`administration of risedronate at 2.5 mg per day, the
`same dose used for the treatment of osteoporosis in
`Japan, was initiated to reduce the high bone turnover
`and ankle pain (VAS score of 59 out of 100). One
`month after the start of risedronate treatment, bone
`pain had fallen from a VAS score of 59 out of 100 to 18
`out of 100, and we temporarily discontinued treatment
`at
`five months because of successful ankle pain
`
`

`

`Abe et al. Journal of Medical Case Reports 2011, 5:349
`http://www.jmedicalcasereports.com/content/5/1/349
`
`Page 3 of 6
`
`reduction and the presence of epigastric pain. After nine
`months (four months after the discontinuation of treat-
`ment), we resumed bisphosphonate treatment with oral
`alendronate at 35 mg per week and the ankle pain
`decreased from a VAS score of 18 out of 100 to 10 out
`of 100 at 15 months (Figure 2). Bone scintigraphy at 12
`months showed a marked reduction in radioactivity to a
`level comparable to that in the normal, left ankle (Fig-
`ure 3). In addition, the effect of bisphosphonate on bone
`pain relief correlated with a reduction in NTX level,
`from 37.6 to 12.9 at eight months. On the basis of these
`results, treatment was discontinued at 15 months, and
`ankle pain relief lasted for 32 months (Figure 2). At the
`latest examination at 32 months, our patient had almost
`no pain (VAS score of 9 out of 100) and radiographic
`findings revealed that the regional osteoporotic change
`in his ankle had returned to normal, and findings were
`equivalent to those for his left ankle (Figure 4).
`A second 48-year-old Japanese man with CRPS was
`referred to our institute for treatment of severe right
`foot pain with a VAS score of 83 out of 100. About
`nine months earlier, he began to feel severe right foot
`pain without any trigger events. Although treatment,
`including physiotherapy and NSAID administration, was
`initiated in another clinic, the pain and swelling of his
`right foot progressively worsened, and he demonstrated
`gait disturbance. A physical examination revealed red-
`ness, swelling, and remarkable tenderness of his foot.
`Severe pain and hyperalgesia also resulted in the distur-
`bance of weight-bearing. Radiographs showed regional
`osteoporotic changes in the phalanges, metatarsals, and
`tarsals of his right foot compared with his normal, left
`foot (Figure 5A). Reconstitution computed tomography
`also exhibited the extensive osteoporotic changes in his
`
`Figure 3 Bone scintigraphs of the both ankles after treatment.
`The previously increased radioactivity (Figure 1B) in the right ankle
`was markedly reduced, and findings were comparable to those of
`the normal, left ankle at 12 months after the start of
`bisphosphonate treatment.
`
`foot and ankle (Figure 5B). Bone scintigraphy with 99
`mTc-methylene diphosphonate revealed a marked
`increase in radioactivity in the bones of his foot (Figure
`5C). These clinical findings were consistent with CRPS I
`according to the criteria [2] described for our first
`patient. Lumbar bone mineral density was 0.838 g/cm2,
`which is more than 80% of the YAM. Laboratory tests
`showed an NTX of 48.6 nMBCE/mM·CR and normal
`values of ALP (242 U/L), serum calcium (9.6 mg/dL),
`serum phosphate (3.1 mg/dL), white blood cell count
`(7100/μL), and C-reactive protein (< 0.1 mg/dL).
`
`Figure 2 Change in bone pain (visual analog scale, or VAS). The
`reduction in VAS score after the oral administration of low doses of
`bisphosphonate. Aln, duration of treatment with alendronate at 35
`mg per week; Ris, duration of treatment with risedronate at 2.5 mg
`per day; VAS, visual analog scale (/100 mm).
`
`Figure 4 Radiographs of the both ankles after treatment. The
`regional osteoporotic change in the right ankle (Figure 1A)
`completely returned to normal, and findings were comparable to
`those of the left ankle at 32 months after the start of
`bisphosphonate treatment.
`
`

`

`Abe et al. Journal of Medical Case Reports 2011, 5:349
`http://www.jmedicalcasereports.com/content/5/1/349
`
`Page 4 of 6
`
`In accordance with the diagnosis of CRPS I accompa-
`nied by marked regional osteoporotic findings together
`with the successful treatment of our first patient, weekly
`oral administration of alendronate at 35 mg per week,
`the same dose used for the treatment of osteoporosis in
`Japan, was initiated to reduce the high bone turnover
`and foot pain (VAS score of 83 out of 100). One month
`after the start of alendronate treatment, bone pain had
`fallen from a VAS score of 83 out of 100 to 30 out of
`100 and was further reduced to 18 out of 100 at three
`months and 3 out of 100 at nine months. The treatment
`was discontinued at 15 months because of successful
`pain reduction, and the pain relief lasted for 30 months
`without further alendoronate administration (Figure 6).
`The bone pain relief correlated with a decrease in NTX
`values: 12.0 at 15 months and 14.0 at 24 months. Our
`patient rejected follow-up bone scintigraphy because he
`experienced no symptoms. At the latest examination at
`30 months, he had no pain (VAS score of 0 out of 100)
`and the radiographic findings revealed marked improve-
`ment in regional osteoporotic changes (Figure 7).
`
`Discussion
`CRPS I is difficult to treat, despite the various methods
`that have been tried [3-5], and the therapeutic use of
`various drugs has been reported to be effective in some
`studies and useless in others [3,4,7]. Pathophysiologically,
`CRPS reveals enhanced regional bone resorption and
`high bone turnover, and so several reports have indicated
`that administration of bisphosphonate results in a signifi-
`cant reduction in pain [8-11,13,14]. However, in these
`studies, the method of administration was intravenous or
`in high oral doses (alendronate, 40 mg per day). Recent
`studies have shown that intravenous or high-dose
`bisphosphonate therapy increases the incidence of severe
`side effects, such as bisphosphonate-related osteonecrosis
`
`Figure 5 Radiograph (A), reconstitution computed tomography
`(CT) image (B), and scintigraph (C) of the both feet before
`treatment. The radiograph shows regional osteoporotic changes in
`the phalanges, metatarsals, and tarsals of the right foot compared
`with the normal, left foot (white arrow) (A). Reconstitution CT image
`exhibits the extensive osteoporotic changes in the foot and ankle
`(white arrow) (B). Bone scintigraphy with 99 mTc-methylene
`diphosphonate shows a marked increase in radioactivity in the right
`foot (black arrow) (C).
`
`Figure 6 Changes in bone pain (visual analog scale, or VAS).
`The reduction in VAS score after the oral administration of low
`doses of bisphosphonate. Aln, duration of treatment with
`alendronate at 35 mg per week; VAS, visual analog scale (/100 mm).
`
`

`

`Abe et al. Journal of Medical Case Reports 2011, 5:349
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`Page 5 of 6
`
`CRPS I presented here, bisphosphonate treatment mark-
`edly and rapidly improved the severe bone pain and
`afforded a concomitant reduction in bone turnover in
`the foot and ankle. It was previously recognized that
`bone disorders with increased osteoclastic bone resorp-
`tion, such as Paget disease, are associated with bone
`pain [20], and the osteoclastic bone resorption was sug-
`gested to be critical to the pain, and the inflammation
`occurred adjacent to bone through an activation of the
`acid-sensing receptors through creation of acidosis by
`the osteoclasts [21]. In these cases, bisphosphonates,
`inhibitors of osteoclast activity, were shown to reduce
`bone pain. Thus, in our idiopathic cases, accelerated and
`enhanced bone resorption and turnover in the foot or
`ankle might have played a dominant pathophysiological
`role in the development of CRPS I rather than periph-
`eral nerve disorder as a post-traumatic injury.
`This report has a limitation. We cannot deny the pos-
`sibility that the observed improvement of pain and
`osteoporotic changes was a consequence of spontaneous
`amelioration of the disease. However, in regard to the
`immediate improvement of pain and regional osteoporo-
`sis change after the initiation of bisphosphonate treat-
`ment and the ineffectiveness of the previous treatment
`(including physiotherapy and NSAID administration for
`about six months), the improvement could be consid-
`ered the effect of bisphosphonate. Thus, we believe that
`low-dose oral administration of bisphosphonate is worth
`considering for the treatment of idiopathic CRPS I
`accompanied by high regional bone turnover.
`
`Conclusions
`In two patients with CRPS I, the oral administration of
`low-dose bisphosphonate resulted in an improvement in
`severe pain and regional osteoporotic findings in the
`foot or ankle. We speculate that a low dose of oral
`bisphosphonate might also be effective for the reduction
`in pain in cases of idiopathic CRPS I, particularly when
`accompanied by regional osteoporotic changes.
`
`Consent
`Written informed consent was obtained from the patients
`for publication of this case report and any accompanying
`images. A copy of the written consent is available for
`review by the Editor-in-Chief of this journal.
`
`Abbreviations
`ALP: alkaline phosphatase; CRPS: complex regional pain syndrome; CRPS I:
`complex regional pain syndrome type I; NSAID: nonsteroidal anti-
`inflammatory drug; NTX: N-telopeptides of type I collagen; VAS: visual analog
`scale; YAM: young adult mean.
`
`Author details
`1Department of Orthopedic Surgery, Sapporo Medical University School of
`Medicine, Sapporo 060-8543, Japan. 2Kitago Orthopedic Clinic, Sapporo,
`Japan.
`
`Figure 7 Radiographs of the both feet after treatment. The
`regional osteoporotic changes in the right foot (Figure 5A) were
`markedly improved at 32 months after the start of bisphosphonate
`treatment.
`
`of the jaw [15] or severely suppressed bone turnover
`[16,17]. It was, therefore, considered ideal if low-dose
`bisphosphonate treatment could result
`in similar
`improvements in CRPS symptoms. In this report, we pre-
`sented two patients who had CRPS I and who demon-
`strated marked pain relief and improvements in regional
`osteoporotic change in the foot or ankle as a result of the
`low-dose oral administration of bisphosphonate (risedro-
`nate at 2.5 mg per day or alendronate at 35 mg per
`week) at doses equivalent to those used for the treatment
`of osteoporosis in Japan. Also, in both cases, the ameli-
`orative effects have lasted more than one year, even after
`the administration of bisphosphonate was discontinued.
`We administered the bisphosphonate as a daily risedro-
`nate or weekly alendronate dose, depending on epigastric
`symptoms and patient preference. To the best of our
`knowledge, few reports have indicated that a low dose of
`oral bisphosphonate has any efficacy in the treatment of
`CRPS I, particularly if the follow-up period after the dis-
`continuation of treatment was more than one year.
`The etiology of CRPS I varies, and several studies have
`indicated that most cases of CRPS I are caused by sec-
`ondary etiologies such as trauma and diabetes [10,11].
`Manicourt and colleagues [11] showed that traumatic
`events triggered CRPS I in most of their cases and that
`the pain associated with the disease was due not only to
`enhanced bone turnover but also to the production of
`proinflammatory cytokines and various neuropeptides
`from sustained peripheral nerve injury as a post-trau-
`matic event [11,18,19]. The value of bisphosphonates in
`the treatment of CRPS I disease did not, therefore, seem
`great. However, in regard to the idiopathic cases of
`
`

`

`Abe et al. Journal of Medical Case Reports 2011, 5:349
`http://www.jmedicalcasereports.com/content/5/1/349
`
`Page 6 of 6
`
`Authors’ contributions
`YA, JT, and TW performed the bisphosphonate treatment and several
`examinations of the patients and carried out the follow-up of the patients
`for more than 30 months. KI performed the bisphosphonate treatment and
`several examinations of the patients, carried out the follow-up of the
`patients for more than 30 months, conceived of the study, participated in its
`design and coordination, and helped to draft the manuscript. TY conceived
`of the study, participated in its design and coordination, and helped to draft
`the manuscript. All authors read and approved the final manuscript.
`
`Competing interests
`The authors declare that they have no competing interests.
`
`Received: 17 February 2011 Accepted: 4 August 2011
`Published: 4 August 2011
`
`20.
`
`Siris ES, Lyles KW, Singer FR, Meunier PJ: Medical management of Paget’s
`disease of bone: indications for treatment and review of current
`therapies. J Bone Miner Res 2006, 21:94-98.
`21. Nagae M, Hiraga T, Wakabayashi H, Wang L, Iwata K, Yoneda T: Osteoclasts
`play a part in pain due to the inflammation adjacent to bone. Bone
`2006, 39:1107-1115.
`
`doi:10.1186/1752-1947-5-349
`Cite this article as: Abe et al.: Improvement of pain and regional
`osteoporotic changes in the foot and ankle by low-dose
`bisphosphonate therapy for complex regional pain syndrome type I: a
`case series. Journal of Medical Case Reports 2011 5:349.
`
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