Rheumatology 2004;43:1246–1251 doi:10.

1093/rheumatology/keh295
Advance Access publication 6 July 2004

Pamidronate in the treatment of childhood SAPHO

syndrome
C. Kerrison, J. E. Davidson, A. G. Cleary and M. W. Beresford

Background. SAPHO syndrome is increasingly recognized within the paediatric population. Conventional therapeutic
approaches have often not been effective. Pamidronate is a second-generation bisphosphonate that affects bone turnover and
demonstrates anti-inflammatory properties. In small case series it has given symptomatic relief to adults with this condition.
Objectives. To report the clinical experience with pamidronate in childhood SAPHO syndrome.
Methods. A retrospective observational study of all children with SAPHO syndrome treated with pamidronate between 1996
and 2003 at a tertiary rheumatology centre. The standard dosing regime for pamidronate was 1 mg/kg to a maximum of 30 mg,
administered daily for three consecutive days, repeated 3-monthly as required. Response to treatment was determined by
clinical observation, patient subjective response and reduction in other treatments
Results. Seven girls were treated, with a median (range) age at diagnosis of 11 yr (9–15 yr). All patients demonstrated a
beneficial clinical response, with relief of pain, increased activity and improved well-being. Subsequent courses of pamidronate
were used in all patients. Other medications including corticosteroids and methotrexate could subsequently be stopped.
Transient symptoms were associated with the initial course of pamidronate in some patients. No serious adverse events were
reported.
Conclusions. Pamidronate was associated with a marked improvement in function and well-being, and a reduction of pain and
use of other medications in all patients, with no significant adverse effects. This study represents preliminary clinical data. A
prospective multicentre study is necessary to assess the role and long-term safety of pamidronate in the management of
childhood SAPHO syndrome
KEY WORDS: SAPHO, CRMO, Pamidronate, Childhood.

The association between sterile inflammatory bony lesions and
dermatological eruptions has long been observed, and many
descriptive terms have been used to describe this spectrum of
clinical and radiographic presentation [1]. The term SAPHO syn-
drome has been adopted as an umbrella term to describe these
conditions [2, 3] and stands for Synovitis, Acne, Pustulosis,
Hyperostosis and Osteitis.
In adults, the diagnosis of SAPHO syndrome is made clinically
on the basis of one or more of the following presentations [2]:
chronic, recurrent, multifocal osteomyelitis (CRMO); acute, sub-
acute or chronic arthritis with any of the following—palmoplantar
pustulosis, pustular psoriasis or severe acne; and any severe osteitis
(involvement of a single site is sufficient, including spondylo-
discitis) with any of the following—palmoplantar pustulosis, pus-
tular psoriasis or severe acne. CRMO is a self-limiting, relapsing,
non-infectious, inflammatory condition of bone that may involve
the spine [2, 4].
The most important hallmarks of the SAPHO syndrome are
hyperostosis and osteitis [1, 5]. ‘Hyperostosis’ appears radiologi-
cally as osteosclerosis, with thickening of trabeculae and cortices,
narrowing of the medullary canal, and the external surface of the
bone appearing expanded, indistinct and irregular. ‘Osteitis’ refers
to inflammation of the bone that appears histopathologically
as a sterile inflammatory infiltrate. These lesions usually affect
the anterior thoracic cage and axial skeleton, but can also involve
vertebral, mandibular, pelvic or peripheral long bones as well as
articular surfaces [6–8]. The distribution of bony lesions is very
variable.
SAPHO syndrome is well recognized in the paediatric popula-
tion. Children present with symptoms consistent with CRMO or
localized osteitis, and/or skin manifestations [9–12]. However, it is
recognized that some children may have partial or incomplete
features, and dermatological features are not necessary in making
the diagnosis. Bony lesions present clinically as severe, recurrent,
debilitating pain and tenderness, particularly at night. It has a
significant deleterious effect on general well-being and can there-
fore have a major impact on the whole family.
There is no specific treatment that can cure SAPHO syndrome
[2]. The focus for therapy is therefore symptomatic relief. This has
traditionally taken place using analgesics and non-steroidal anti-
inflammatory drugs (NSAIDs) [2, 8, 13–15]. Other agents have also
been used, including methotrexate (MTX), oral corticosteroids,
colchicine, sulphasalazine and infliximab [2, 8, 13–15]. These have
worked with varying degrees of success and toxicity. However,
no single therapeutic modality has been shown to be consistently
effective [8].
Bisphosphonates are stable analogues of pyrophosphate. They
have a long half-life when incorporated into bone, and have
multiple effects, predominantly inhibition of bone resorption and
turnover [16, 17] as well as a pain-modifying effect [8, 15, 17–19]

Royal Liverpool Children’s NHS Trust, Eaton Road, Liverpool L12 2AP, UK.

Submitted 22 March 2004; revised version accepted 4 June 2004.

Correspondence to: M. W. Beresford, Department of Rheumatology, Royal Liverpool Children’s NHS Trust, Eaton Road, Liverpool L12 2AP, UK.
E-mail: m_beresford@yahoo.com
1246
Rheumatology Vol. 43 No. 10 ß British Society for Rheumatology 2004; all rights reserved
 Pamidronate in childhood SAPHO syndrome 1247

and a significant anti-inflammatory action [20–22]. This makes
them excellent candidates for use in SAPHO syndrome where
hyperostosis, osteitis and bone pain are major features.
Bisphosphonates are becoming established treatments in pae-
diatric practice in the management of osteogenesis imperfecta [17,
23–25], juvenile and glucocorticoid induced osteoporosis [26–29]
and fibrous dysplasia [30, 31], as well as other conditions including
hyperphosphatasia and Gaucher’s disease [16]. A number of adult
case reports have been published in which intravenous pamidro-
nate has been used in cases of SAPHO syndrome refractory to
conventional therapy [8, 13–15, 32]. Although involving small
numbers, a significant clinical response was noted in all reports
with some patients going into complete remission. However, no
randomized controlled trials of bisphosphonates in adult SAPHO
syndrome have been published.
To date there are no published data on the use of bisphos-
phonates in the management of childhood-onset SAPHO syn-
drome. The aim of this study is to present our clinical experience of
using pamidronate in seven children with this diagnosis.
Methods
All patients diagnosed with ‘SAPHO syndrome’, manifesting all
or some of its features [2] and treated at the Royal Liverpool
Children’s NHS Trust between January 1996 and December 2003
were eligible for inclusion in this study. Patients studied had
symptoms refractory to conventional therapy (analgesics and
NSAIDs, with or without the use of corticosteroids or metho-
trexate), and had gone on to receive open-label treatment with
pamidronate. A retrospective review of case notes subsequently
took place for all children meeting these criteria.
Determining the presence of osteitis or hyperostosis was based
on clinical assessment, radiographs, computed tomography (CT)/
magnetic resonance (MRI) scan, increased uptake on bone
scintigraphy (bone scan) and bone biopsy where available.
The treatment regimen for pamidronate was as follows: 1 mg/kg
pamidronate up to a maximum of 30 mg, given as an infusion, once
daily for three consecutive days [19]. The first of the three infusions
was administered over 6 h, and subsequent doses over 4 h, patients
being monitored closely for vital signs and adverse effects. Clinical
improvement was noted and defined by the patients as a decrease in
the intensity or duration of pain, or a decrease in the frequency
of relapses. In addition, clinical observation and reduction in
other treatments were documented. The minimum time period
between courses of pamidronate was 3 months, but the interval
was extended if the patient was entirely asymptomatic.
The case notes of these patients were reviewed for the following
parameters: age at diagnosis, symptoms at presentation, baseline
investigations, diagnostic features, previous medications, time
between diagnosis and treatment with pamidronate, number of
pamidronate courses, impact of treatment on patients’ symptom-
atology, subsequent symptom control and treatment pattern and
any side-effects. A standardized pro forma was used to collect data.
Ethical approval was not required for this study. All parents/
patients gave consent to treatment with pamidronate.
Results
Eight patients were identified during the study period as having
significant on-going symptoms despite conventional therapy and
were therefore offered pamidronate. One of these declined intra-
venous medication due to a needle phobia. Seven patients were
therefore included in this case series.
All seven patients were female. The median (range) age at initial
presentation was 8 yr (7–15 yr) and their median (range) age at
diagnosis of SAPHO syndrome was 11 yr (9–15 yr). Median
(range) duration of follow up after the first course of pamidronate
was 20 months (9–31 months). All patients were treated with anal-
gesics (e.g. paracetamol, codeine) and NSAIDs (e.g. ibuprofen,
diclofenac, naproxen) prior to starting pamidronate.
Table 1 summarizes the patient characteristics, including age
at diagnosis, duration after diagnosis until pamidronate was
commenced, baseline investigations carried out, other medications,
the effect of pamidronate on symptoms, the number of courses
of pamidronate and any side effects noted.
Case 1
This 15-yr-old presented aged 10 with a 4-month history of
swelling and tenderness in the right clavicle, preventing

TABLE 1. Clinical details of patients

Age at Time to Baseline Number Side-effects

Patient diagnosis pamidronatea investigations Medication Effect of pamidronate of courses noted
1 11 5 yr CT, bone biopsy NSAIDs Significant reduced pain and swelling. 2 Flu like symptoms
Reduced NSAIDs. 1st course
Greatly increased activity
2 11 5 yr CT scan, MRI, NSAIDs, pred., Dramatic improvement: Pain and 6 Marked flu like
bone scan, mepred., sulph., well being. symptoms 1st dose
bone biopsy MTX Discontinued MTX and steroids.
No disease flare for 18 months
3 10 4 yr Bone scan NSAIDs, MTX Immediate resolution of pain and 6 (4 at 60 mg)
swelling after 1st dose; recurred
after 3 months, subsequently
longer to improvement
4 12 3 yr CT scan, MRI, NSAIDs, pred. Pain free after 1 month, stopped 3
bone scan, steroids at 2 months, complete
bone biopsy remission after 2.5 yr with annual
treatments
5 15 18 months MRI, bone scan NSAIDs Pain free and normal activity after 4 Transient headache
first infusion; complete remission 1st course
maintained
6 15 1 month MRI, bone scan, NSAIDs Symptoms improved after 1 month, 4
bone biopsy begin to return after 3 months
7 9 4 months MRI, bone scan NSAIDs Pain and mobility improved after 2 Temperature rise
1st course, recurred after 5 months 1st dose

Abbreviations: pred., oral prednisolone; mepred., IV methylprednisolone; sulph., sulphasalazine; MTX, oral and subcutaneous methotrexate.
a
Time period from diagnosis of SAPHO syndrome to trial of pamidronate.
1248 C. Kerrison et al.
participation in sports and social activities. She had acne and a
family history of psoriasis. Plain X-ray and CT revealed a dense
right clavicle with extensive periosteal reaction. Bone scan revealed
a single hot-spot in this area. Bone biopsy was consistent with
chronic osteomyelitis but with no evidence of infection. Long-term
use of analgesics and NSAIDs were unhelpful. The initial dose
of pamidronate was associated with transient flu like symptoms.
There was an associated rapid reduction in pain and swelling, as
well as a marked reduction in her need for NSAID medication.
Despite intermittent symptoms, she was able to take up contact
sports including kickboxing. To date she has required only one
further course of pamidronate.
Case 2
This 11-yr-old girl with pustular psoriasis and a father with
psoriatic arthritis had complained of a painful right hip and a
tender swelling of her right sternoclavicular joint and rib from
the age of 8. A biopsy of her clavicle showed necrotic and lytic
degeneration and a chronic inflammatory response. There was no
evidence of infection or malignancy. A bone scan, CT and MRI
showed increased signal in the right hip, medial aspect of the right
clavicle, left seventh rib, and T12/L1 vertebrae. Despite prolonged
physiotherapy, analgesia, NSAIDs, oral prednisolone, intravenous
methylprednisolone, sulphasalazine, amitriptyline and both oral
and subcutaneous MTX, she still had significant nocturnal, dis-
tressing bone pain, coupled with drug toxicity.
The first dose of pamidronate was associated with flu-like
symptoms, but after the initial course she had a dramatic reduction
in her pain as well as sternoclavicular swelling. Three-monthly
pamidronate was associated with complete remission of her symp-
toms for 18 months, allowing discontinuation of corticosteroids
and MTX.
Case 3
For 2 yr, this 10-yr-old had complained of painful hips, knees and
ankles. She now presented with constant pain and swelling of the
right clavicle. A bone scan showed increased uptake in the right
clavicle, as well as both sacro-iliac joints and the inferior part of
the left humerus. There was no satisfactory relief from a range of
NSAIDs and oral prednisolone was associated with on-going pain
and unacceptable weight gain. After a single dose of pamidronate,
there was an immediate reduction in pain and swelling, and after
the first course, complete resolution of pain and swelling. Symp-
toms recurred after 3 months but a second course was associated
with further improvement. Further relapses were associated with
increasing intensity of symptoms and resulted in a higher dose
of pamidronate (60 mg) being used, each course resulting in
symptom improvement.
Case 4
Aged 8, this child had experienced intermittent pain in her left
thigh. Presenting at the age of 12, she had increasing pain in her
thigh and a painful swelling of her left clavicle. She had no skin
lesions but a family history of psoriasis. A bone scan showed
increased uptake in the left clavicle, left hip and right knee. A CT
scan showed expansion of the left clavicle with sclerosis and an
MRI revealed an inflammatory lesion of the left acetabulum. A
bone biopsy showed no evidence of malignancy. Treatment with
analgesics, ibuprofen and diclofenac had a minimal response. Oral
prednisolone gave a very transient response, but she had repeated
flares despite this. Following her initial course of pamidronate
she was pain-free within 24 h of treatment, and she was weaned
off steroids. She was pain-free for a month after the first course of
pamidronate. Symptoms gradually returned. Following her second
course there was incomplete resolution of symptoms but they were
easily controlled on regular NSAIDs, and she had a good response
to her third course.
Case 5
From the age of 7, this 15-yr-old presented with worsening back
pain and was noted to have pustules on her scalp. The pain became
so severe she was unable to attend school. A plain X-ray of her
spine was normal, but a bone scan and MRI showed increased
signal with compression of T6 vertebra. A repeat bone scan 6
months later showed generalized increased uptake in the thoracic
spine and sacroiliac joints. Treatment with analgesics and NSAIDs
was unsuccessful. She became pain-free with normal activity after
the first pamidronate course, and remained asymptomatic 18
months later following 3-monthly courses.
Case 6
This 15-yr-old girl with psoriasis presented with recurrent pain and
swelling in the left proximal tibia, and went on to develop swelling
and tenderness in her manubrium sternum. MRI and bone scan
revealed chronic active inflammation in the left proximal tibia,
and a bone biopsy was sterile. Initial treatment with analgesics,
NSAIDs and physiotherapy was unhelpful. One month after the
first course of pamidronate there was a decrease in the frequency of
painful episodes, as well as decreased swelling. After subsequent
courses, it also took 1 month to note a similar improvement, which
lasted 3 months.
Case 7
An 8-yr-old girl presented with interscapular pain, particularly
at night time. Aged 9 she had worsening pain spreading to her
legs and she was struggling to walk. Her family also noted she
experienced pain on jumping and when going over bumps in the
car. A spinal X-ray revealed an abnormal T4 vertebra, confirmed
on MRI and bone scan, although there was an abnormal signal
in several adjoining vertebrae. A subsequent bone scan showed
an additional acetabular lesion. Treatment with NSAIDs was
unhelpful, and as parents refused treatment with corticosteroids
and methotrexate, she was commenced on pamidronate. She had
low-grade pyrexia with the first dose of pamidronate only. After
the first course, her pain and mobility improved, and she remained
symptom free for 5 months. A second course was associated with
remission of symptoms.
Discussion
We have presented the first case series of the use of pamidronate in
the management of childhood-onset SAPHO syndrome. A marked
clinical improvement was noted in all seven children treated, and
there were no significant adverse effects. This series of patients
reinforces the growing experience of the use of pamidronate in
ameliorating symptoms associated with SAPHO syndrome, with-
out significant side-effects [8, 13–15]. However, this evidence is
anecdotal, and randomized trials are now needed, both in adults
and children, to assess the efficacy and safety of this treatment.
For consistency of nomenclature, we have used the same term
‘SAPHO syndrome’, proposed for adult patients [2, 3], to describe
the spectrum of presentations and identify our patients. Therefore,
under the diagnosis of SAPHO syndrome we have included CRMO,
and acute, subacute or chronic arthritis and severe osteitis, with
any of the following—palmoplantar pustulosis, pustular psoriasis
 Pamidronate in childhood SAPHO syndrome
or severe acne [2]. Not all our patients had skin manifestations.
As with adult-onset disease, variation in terminology may hamper
understanding of this intriguing disorder [12, 33, 34]. While
recognized in childhood [9–11], the experience of SAPHO
syndrome within a paediatric population is limited. As with adult
disease [35], it may go unrecognized. It is acknowledged that
the term SAPHO syndrome is pertinent to children presenting
with CRMO [11]. As noted in our cohort, dermatological and
bone manifestations may present at different stages in the natural
history of the disease [11, 33]. However, little is known about
the prevalence and characteristics of presentations in children.
Prospective longitudinal data are required to improve character-
ization of this disease in children. The fundamental component
of the disease spectrum is a non-infective inflammatory osteitis
[5]. Dermatological manifestations may or may not be present in
the paediatric cohort [5]. In view of this, in agreement with other
authors, we would propose the use of the term ‘SAPHO spectrum’
to describe the range of conditions which appear to share similar
clinical, radiographic and pathological characteristics [1, 5, 6].
The dosing and scheduling regime for pamidronate was
adopted empirically from the schedule used in treating osteogen-
esis imperfecta [19]. There is wide variation in the paediatric
literature on the dosing schedule of pamidronate between condi-
tions [16] and for a given diagnosis such as osteogenesis imperfecta
[17, 23–25], juvenile osteoporosis [26–29] or polyostotic fibrous
dysplasia [30]. Scheduling varies with administration daily for
between 1 and 18 days, repeated every 3 to 6 months, in doses
ranging from 0.2 to 1.0 mg/kg [16]. None of these paediatric
schedules has been subject to randomized controlled trials.
There have been concerns expressed over the safety of using
1249
symptoms related to inflammatory bony lesions and general sense
of well-being. Bisphosphonates are potent inhibitors of osteoclastic
bone resorption [16]. They act by decreasing the development of
osteoclast progenitor and osteoclast recruitment, and promoting
apoptosis of mature osteoclasts [40] as well as reacting with the
mevalonate pathway, preventing formation of the ruffle border
necessary for bone resorption [13]. As a result, they are important
therapeutic agents in the management of Paget’s disease, multiple
myeloma, malignancy-associated hypercalcaemia, bone metastases
and osteoporosis [8, 11, 16]. It is therefore understandable that
they may have an important role in a condition where excessive
osteogenesis is pathognomic [1].
It is evident that nitrogen-containing bisphosphonates, such
as pamidronate, also have important regulatory effects on the
inflammatory cytokines, although as yet this role is only partially
elucidated [21] and the data are at times contradictory [41, 42].
It can be demonstrated that the production of interleukin (IL)-1,
IL-6 and tumour necrosis factor (TNF)- may be suppressed by
bisphosphonates in vitro [20, 22]. At the same time, administration
of pamidronate to patients with malignancy has been associated
with both a fall in serum IL-6 concentration [41] and a rise in serum
IL-6 and TNF- concentration [42]. An acute phase response
(which might be associated with a rise in serum IL-6 concentration)
is usually only observed following the first intravenous infusion
of pamidronate and is usually not seen subsequently [21, 42].
This might explain the discrepancy between studies. Pamidronate
has been shown in vitro to be able to suppress cell growth and
proliferation, cell migration, the co-stimulatory activity of T cells
and to inhibit the stimulated secretion of the pro-inflammatory
bisphosphonates in children [16, 36, 37]. At the same time, the
benefits of using pamidronate in terms of symptom control and
reduction in the use of other medications with proven adverse
effects must be considered. Original fears of potential damage to
the growing skeleton by preventing normal remodelling have
not proven a significant problem [16]. In our patients, other than
transient side-effects such as low-grade temperature and flu like
symptoms [16, 26], the infusions were well tolerated [17, 25, 27, 28].
There are very limited paediatric long-term data on the efficacy
and side-effects of pamidronate in any condition, and all of these
are anecdotal [16]. Follow-up case series of children treated with
pamidronate for between 2 to 9 yr [17, 23, 25] indicate that it is
well tolerated. In particular, although subject to a variety of dosing
schedules, the longitudinal data that do exist have shown no
evidence of growth impairment [23, 25, 28, 38] and even catch-up
growth in pre-pubertal patients has been demonstrated, with no
excessive suppression of bone remodelling when assessed bio-
chemically [27]. Pamidronate has been shown to cause a marked
improvement in bone mineral density [25, 27–29]. At the same
time, isolated case reports have questioned the long-term safety of
pamidronate, including a case of bisphosphonate-induced osteo-
petrosis, although doses used were much higher than in our regime
[37]. Although most of the medical literature on bisphosphonates is
almost uniformly positive [18], there is a concern that prolonged
administration may increase the risk that bones will become brittle
rather than stronger [36]. The debate underlines the urgent need
for robust data to endorse the efficacy and safety of the off-license
use of this product. This retrospective review noted the impact
of treatment as defined by the patients, in keeping with the most
recently published adult series of 10 patients treated with pamid-
ronate [8], and other case reports [13, 14]. As part of a controlled
trial, robust assessment would need to take place of pain, function,
quality of life and adverse effects. In this case series, the diagnosis
of SAPHO syndrome was often delayed, and pamidronate was
used only when other options were no longer acceptable. With
increasing familiarity of the condition and the use of pamidronate,
earlier intervention and resolution of symptoms may be noted.
It is apparent from adult series [8, 13–15, 39], and from our
own data, that pamidronate has a marked positive impact on the
cytokines IL-1 and TNF- [21, 22]. The anti-inflammatory role
of pamidronate and other bisphosphonates needs to be explored
further, but it is probable that it provides an important element
towards understanding the rapid improvement in symptoms noted
when treating patients with osteitis.
The pain-modifying action of pamidronate noted in osteogen-
esis imperfecta [17–19], non-infective inflammatory bony lesions
[8, 15, 43] and hypertrophic osteoarthropathy [44, 45] was an
important factor in its clinical efficacy in treating the patients
in this study with SAPHO syndrome. It is also notable that pam-
idronate improves patients’ functional ability and well-being, as
well as reducing bone pain, in spondyloarthropathies refractory to
NSAIDs [46, 47], important in view of the clinical overlap that may
exist between SAPHO syndrome, psoriatic arthritis and the
spondyloarthropathies [2, 48].
In conclusion, this is the first description of the use of
pamidronate in childhood-onset SAPHO syndrome. A marked
clinical improvement was noted in all seven children treated, and
there were no significant adverse effects. A controlled clinical trial
is now warranted to assess the efficacy and safety of this treatment
in children.
Key messages
 SAPHO syndrome describes the heter-
ogeneous presentation of inflammatory
Rheumatology
bony lesions recognized in the paedia-
tric population.
 Severe, recurrent, debilitating pain and
tenderness can be effectively controlled
with intravenous pamidronate therapy
with an associated improvement in
general well-being.
 Prospective studies are needed to deter-
mine optimum dosing regimes and long-
term outcomes.
1250 C. Kerrison et al.
Acknowledgements
We acknowledge the work of Dr J. A. Sills, Consultant
Paediatric Rheumatologist, Royal Liverpool Children’s NHS
Trust, and Dr Cronin, Consultant Paediatrician, Bangor Hospital,
for their clinical management of three and one of the patients
respectively included in this study. We acknowledge Professor
H. Carty, Royal Liverpool Children’s NHS Trust for her
radiographic expertise and experience.
None of the authors have any conflict of interest in this case
series.
References
1. Boutin RD, Resnick D. The SAPHO Syndrome: an evolving concept
for unifying several idiopathic disorders of bone and skin. Am J
Roentgenol 1998;170:585–91.
2. Kahn MF, Khan MA. The SAPHO syndrome. Baillieres Clin
Rheumatol 1994;8:333–62.
3. Kahn MF. Why the ‘SAPHO’ syndrome. J Rheumatol 1995;
22:2017–19.
4. Giedion A, Holthusen W, Masel LF, Vischer D. Subacute and chronic
‘symmetrical’ osteomyelitis. Ann Radiol 1972;15:329–42.
5. Earwaker JWS, Cotten A. SAPHO: syndrome or concept? Imaging
findings. Skeletal Radiol 2003;32:311–27.
6. Sugimoto H, Tamura K, Fujii T. The SAPHO syndrome: defining
the radiological spectrum of diseases comprising the syndrome. Eur
Radiol 1998;8:800–6.
7. Suei Y, Taguchi A, Tanimoto K. Diagnostic points and possible
origin of osteomyelitis in synovitis, acne, pustulosis, hyperostosis and
osteitis (SAPHO) syndrome: a radiographic study of 77 mandibular
osteomyelitis cases. Rheumatology 2003;42:1398–403.
8. Amital H, Applbaum YH, Aamar S, Daniel N, Rubinow A. SAPHO
syndrome treated with pamidronate: an open-label study of 10
patients. Rheumatology 2004;43:658–61.
9. Kahn MF. Psoriatic arthritis and synovitis, acne, pustulosis,
hyperostosis, and osteitis syndrome. Curr Opin Rheumatol
1993;5:428–35.
10. Girschick HJ, Huppertz HI, Harmsen D, Krauspe R, Muller-
Hermelink HK, Papadopoulos T. Chronic recurrent multifocal
osteomyelitis in children: diagnostic value of histopathology and
microbial testing. Hum Pathol 1999;30:59–65.
11. Beretta-Piccoli BC, Sauvain MJ, Gal I et al. Synovitis, acne,
pustulosis, hyperostosis, osteitis (SAPHO) syndrome in childhood:
a report of ten cases and review of the literature. Eur J Pediatr
2000;159:594–601.
12. Azouz EM, Jurik AG, Bernard C. Sternocostoclavicular hyper-
ostosis in children: a report of eight cases. Am J Roentgenol 1998;
171:461–6.
13. Courtney PA, Hosking DJ, Fairburn KJ, Deighton CM. Treatment of
SAPHO with pamidronate. Rheumatology 2002;41:1196–8.
14. Marshall H, Bromilow J, Thomas AL, Arden NK. Pamidronate:
a novel treatment for the SAPHO syndrome? Rheumatology 2002;
41:231–3.
15. Guignard S, Bob-Deslandre C, Sayag-Boukris V, Kahan A.
Pamidronate treatment in SAPHO syndrome. Joint Bone Spine
2002;69:392–6.
16. Allgrove J. Biphosphonates. Arch Dis Child 1997;76:73–5.
17. Åström E, Söderhäll S. Beneficial effect of long term intravenous
bisphosphonate treatment in osteogenesis imperfecta. Arch Dis Child
2002;86:356–64.
18. Batch JA, Couper JJ, Rodda C, Cowell CT, Zacharin M. Use of
bisphosphonate therapy for osteoporosis in childhood and adoles-
cence. J Paediatr Child Health 2003;39:88–92.
19. Banerjee I, Shortland GJ, Evans WD. Osteogenesis imperfecta
and intravenous pamidronate. Arch Dis Child 2002;87:562–3.
20. Pennanen N, Lapinjoki S, Urtti A, Monkkonen J. Effect of liposomal
and free bisphosphonates on the IL-1, IL-6 and TNF- secretion from
RAW 264 cells in vitro. Pharm Res 1995;12:916–22.
21. Maksymowych WP. Bisphosphonates for arthritis—a confusing
rationale. J Rheumatol 2003;30:430–4.
22. Huk OL, Zukor DJ, Antoniou J, Petit A. Effect of pamidronate on the
stimulation of macrophage TNF- release by ultra-high-molecular-
weight polyethylene particles: a role for apoptosis. J Orthop Res
1003;21:81–7.
23. Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R.
Cyclical administration of pamidronate in children with severe
osteogenesis imperfecta. N Engl J Med 1998;339:947–52.
24. Devogelaer JP. Uses of bisphosphonates: osteogenesis imperfecta.
Curr Opin Pharmacol 2002;2:748–53.
25. Bembi B, Parma A, Bottega M et al. Intravenous pamidronate
treatment in osteogenesis imperfecta. J Pediatr 1997;131:622–5.
26. Noguera A, Ros JB, Pavia C et al. Bisphosphonates, a new
treatment for glucocorticoid-induced osteoporosis in children.
J Pediatr Endocrinol Metab 2003;16:529–36.
27. Brumsen C, Hamdy NA, Papapoulos SE. Long-term effects
of bisphosphonates on the growing skeleton. Studies of young
patients with severe osteoporosis. Medicine (Baltimore) 1997;76:
266–83.
28. Steelman J, Zeitler P. Treatment of symptomatic pediatric osteoporo-
sis with cyclic single-day intravenous pamidronate infusions. J Pediatr
2003;142:417–23.
29. Shaw NJ, Boivin CM, Crabtree NJ. Intravenous pamidronate in
juvenile osteoporosis. Arch Dis Child 2000;83:143–5.
30. Plotkin H, Rauch F, Zeitlin L, Munns C, Travers R, Glorieux
FH. Effect of pamidronate treatment in children with polyostotic
fibrous dysplasia of bone. J Clin Endocrinol Metab 2003;88:
4569–75.
31. Chapurlat RD, Delmas PD, Liens D, Meunier PJ. Long-term effects
of intravenous pamidronate in fibrous dysplasia of bone. J Bone
Miner Res 1997;12:1746–52.
32. Watts RA, Crisp AJ, Hazleman BL, Daunt SO, Jenner JR. Arthro-
osteitis—a clinical spectrum. Br J Rheumatol 1993;32:403–7.
33. Job-Deslandre C, Krebs S, Khan A. Chronic recurrent multifocal
osteomyelitis: five-year outcomes in 14 pediatric cases. Joint Bone
Spine 2001;68:245–51.
34. Schuster T, Bielek J, Dietz HG, Belohradsky BH. Chronic
recurrent multifocal osteomyelitis (CRMO). Eur J Pediatr Surg
1996;6:45–51.
35. van Doornum S, Barraclough D, McColl G, Wicks I. SAPHO: rare
or just not recognised? Semin Arthritis Rheum 2000;30:70–7.
36. Marini JC. Do bisphosphonates make children’s bones better or
brittle? N Engl J Med 2003;349:423–6.
37. Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S.
Bisphosphonate-induced osteopetrosis. N Engl J Med 2003;349:
457–63.
38. Zeitlin L, Rauch F, Plotkin H, Glorieux FH. Height and weight
development during four years of therapy with cyclical intravenous
pamidronate in children and adolescents with osteogenesis imperfecta
types I, III, and IV. Pediatrics 2003;111:1030–6.
39. Crisp AJ. Pamidronate for SAPHO syndrome. Rheumatology
2003;42:491.
40. Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas
SC, Bellido T. Prevention of osteocyte and osteoblast apoptosis
by bisphosphonates and calcitonin. J Clin Invest 1999;104:
1363–74.
41. Lissoni P, Cazzaniga M, Barni S et al. Acute effects on pamidronate
administration on serum levels of interleukin-6 in advanced solid
tumour patients with bone metastases and their possible implications
in the immunotherapy of cancer with interleukin-2. Eur J Cancer
1997;33:304–6.
42. Sauty A, Pecherstorfer M, Zimmer-Roth I et al. Interleukin-6 and
tumor necrosis factor  levels after bisphosphonates treatment in vitro
and in patients with malignancy. Bone 1996;18:133–9.
 Pamidronate in childhood SAPHO syndrome
43. Maksymowych WP, Aaron SL, Russell AS. Treatment of refractory
symphysitis pubis with intravenous pamidronate. J Rheumatol
2001;28:2754–7.
44. Speden D, Nicklason F, Francis H, Ward J. The use of pamidronate
in hypertrophic pulmonary osteoarthropathy (HPOA). Aust NZ J
Med 1997;27:307–10.
45. Garske LA Bell SC. Pamidronate results in symptom control of
hypertrophic pulmonary osteoarthropathy in cystic fibrosis. Chest
2002;121:1363–4.
1251
46. Maksymowych WP, Lambert R, Jhangri GS et al. Clinical and
radiological amelioration of refractory peripheral spondyloarthritis
by pulse intravenous pamidronate therapy. J Rheumatol 2001;28:
144–55.
47. Dougados M. Disease controlling antirheumatic therapy in spondy-
loarthropathy. J Rheumatol 2001;28(Suppl):16–20.
48. Winchester R. Psoriatic arthritis and the spectrum of syndromes
related to SAPHO (synovitis, acne, pustulosis, hyperostosis, and
osteitis) syndrome. Curr Opin Rheumatol 1999;11:251–6.