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Use of zoledronic acid in pelvic and sacral chronic
recurrent multifocal osteomyelitis (CRMO): a case report
Mohammed S. Alisi, MDab
, Yazan Hammad, MDa
, Hani Al-Ali, MDc
and Freih Abu Hassan, FRCS (Tr & Orth)a
a
Division of Orthopaedics, Department of Special Surgery, School of Medicine, The University of Jordan, Amman, Jordan
b
Faculty of Medicine, Islamic University of Gaza, Gaza, Palestine
c
Ray One Radiology and Diagnostic Imaging Center, Amman, Jordan
INTRODUCTION
C
hronic recurrent multifocal osteomyelitis (CRMO) is
an idiopathic autoinflammatory nonbacterial skel-
etal disease affecting children and adults.1
It is a
systemic disease that presents with recurrent bone pain and
tenderness, mainly in the metaphysis of long bones and
pelvis, or as spondylitis. It may be associated with palmo-
plantar pustulosis, psoriasis, Crohn’s disease, and acne.2
CRMO diagnosis remains a challenge for physicians. It
appears like osteomyelitis on the radiographic views, but
with negative cultures and unresponsiveness to the anti-
biotics. These factors may delay their treatment and expose
patients to multiple unnecessary surgical interventions.3
The CRMO diagnosis is usually confirmed by MRI, which
reflects its extension and soft-tissue or bone edema, and it
helps to exclude bacterial osteomyelitis. A 99mTc bone scan
can also be used to locate other involved sites, but it cannot
differentiate CRMO from neoplasia.4
Despite considering CRMO as a benign disease, it can lead
to persistent bone deformity, pain, and growth retardation.5
Nonsteroidal antiinflammatory drugs (NSAIDs), corticoste-
roids, bisphosphonates, and antitumor necrosis factor-alpha
(TNF-α) are among the treatment options. However, there
is no consensus on the preferred treatment protocol
for CRMO.
Pamidronate is the most widely reported bisphosphonate
to be used in the treatment of CRMO. However, the newer
generation, more potent bisphosphonate, zoledronic acid
(ZA), is rarely reported for the same disease. The authors
present a case of CRMO with pelvic and sacral lesions that
was successfully treated with ZA. Informed consent was
obtained from the patient and his family that data and
images concerning the case would be submitted for
publication.
CASE REPORT
A previously healthy 8-year-old boy presented with a history of
recurrent gluteal pain for 9 mo. The pain was insidious in onset
and gradually progressive. He quantified the pain as 9 out of 10 in
severity during the attack, which had mildly improved with
NSAIDs over the previous months. The pain was interfering with
the patient’s ability to sleep. Eventually, he had difficulty walking.
There were no fever, chills, or any other joint complaints.
Upon examination, he had antalgic gait and tenderness on
deep palpation of the gluteal and sacral areas. However, no
signs of gluteal swelling were present. The patient had signs
of generalized ligamentous laxity but intact sensory and
motor functions of the lower limbs.
His initial laboratory tests (complete blood count [CBC],
erythrocyte sedimentation rate [ESR], C-reactive protein [CRP],
blood film, and kidney function tests) were within normal ranges.
The radiographs of the pelvis and sacrum revealed sclerotic
changes in the body of the right pubis and the medial side of
superior and inferior pubic rami associated with smooth
periosteal reaction. The sclerotic changes also involved the
medial aspect of both iliac bones adjacent to the sacroiliac
joints and in the greater trochanter of the left proximal
femur (Figure 1).
FIGURE 1. The initial pelvic radiograph with multiple sclerotic changes
appeared in the right pubic and both iliac bones.
Financial Disclosure: The authors report no conflicts of
interest.
Correspondence to Mohammed S. Alisi, MD, The University of Jordan,
School of Medicine, Queen Rania Al Abdullah St 266 Al Jubaiha, Amman,
Jordan 11942
Tel: +962790983284; fax: +9625300820;
e-mail: m.elessi2007@hotmail.com.
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C A S E R E P O R T
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2. A three-phase Technetium-99m hydroxydiphosphonate
(99m
Tc-HDP) whole-body bone scan showed a hyperactive
bone pathology with osteoblastic changes involving multiple
areas in the pelvic bones. However, normal vascularity was
noticed in the early flow and blood pool phases. There was an
intense increase in the radiotracer uptake over the superior
and inferior rami of the right pubic bone, irregular increase in
uptake in both iliac wings near the sacroiliac joint areas, and
less intense irregular uptake over the right side of the sacral
bone. There was some asymmetry in the uptake of the
intertrochanteric areas of both femurs (more prominent on
the left side) (Figure 2).
The MRI showed multiple T1 isointense and T2 hyper-
intense bone lesions in the right sacral ala, left greater
trochanter, S1 vertebra, both iliac bones, and right pubic
bone (Figure 3). This was associated with edematous changes
in the surrounding soft-tissue planes and postcontrast
enhancement. The features in both iliac bones are associated
with irregular shaped new bone formation, but without bone
destruction.
At this point, the diagnosis of CMRO was considered, and
the patient was started on ZA. Our protocol included
measuring the serum levels of calcium, phosphorus, urea,
and creatinine and giving an oral 500-mg calcium tablet
every 8 hr, in addition to 1000 IU vitamin D daily for 72 hr
before and after the course. We ensured intravenous hydra-
tion by giving 500 mL glucose/saline (G/S) 0.45% fluid over
3 hr before the treatment.
The dose was 4 mg of ZA with 200 mL G/S 0.45% over 3 hr.
The patient then was discharged home on simple analgesics
(paracetamol) after 4 hr of observation with instructions
regarding home hydration and bed rest for 24 hr.
The courses of ZA were given according to the patient’s
recurrence of symptoms. The second, third, and last doses
FIGURE 2. The three-phase technetium-99m hydroxydiphosphonate (99m
Tc-HDP) whole-body bone scan with evidence of hyperactive bone pathology
involving multiple areas in the pelvic bones.
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3. were 6, 15, and 26 mo after the initial dose, respectively. The
authors reported the severity of the pain score before each
course. The pain score was 9/10, 6/10, 4/10, and 3/10,
respectively.
After the first dose of ZA, the patient experienced
generalized tiredness, bone and muscle pain, and docu-
mented fever of 38.1°C during the 24-hour observation
following the dose. These signs and symptoms completely
resolved the next day, and he noticed significant pain
improvement that progressed to complete relief on the third
day. He resumed his original activity and the hobby of horse
riding after the first dose for the first time in 9 mo.
The follow-up MRI after 21 mo (before the fourth dose)
showed that most of the previous multifocal bone that was
hyperintense on the fluid-sensitive sequence showed signifi-
cant regression. This includes the lesions in the S1 vertebra
and iliac bones.
Of note, very small new lesions were noticed on the left sacral
ala, left ischial bone, left pubic bone, and right greater trochanter
of the proximal femur. The patient received the fourth dose of
ZA at the time of these findings. The previously noted soft-tissue
reactive changes that were surrounding the iliac and right pubic
bones lesions had significantly regressed (Figure 4).
DISCUSSION
CRMO diagnosis is based on clinical, laboratory, and radio-
graphic guidelines that should be followed in clinical
practice, and their application in typical cases can prevent
or minimize the need for bone biopsy.6
CRMO might be suspected in case of bone pain with or
without swelling and without significant features of infec-
tion, with typical radiographic findings (lytic areas, sclerosis,
and new bone formation) and bone biopsy that shows
inflammatory changes with no bacterial growth while not on
antibiotic therapy. The CRP could be within the normal
range if the disease is multifocal; however, it could be
elevated (greater than 30 g/L) if the disease affects one bone.6
Initial imaging with plain radiographs should be performed.
MRI and bone scintigraphy are useful adjuncts to aid in the
early diagnosis of CRMO to avoid unnecessary invasive
diagnostic tests or aggressive therapy.7
In the early stage of the disease, the plain radiograph may
be normal. Once the disease is well established, the osteolytic
and sclerotic lesions will be apparent. The identification of
the multifocal configuration of the disease process by two-
phase (soft-tissue and delayed) whole-body bone scintigra-
phy results in appropriate diagnosis by determining the
presence of abnormality and the extent of disease of CRMO.4
As the patient in this case report presented late, the plain
radiograph revealed sclerotic changes in the body of the right
pubis with a smooth periosteal reaction. This led the authors to
choose whole-body bone scintigraphy to explore other lesions
inthepelvisandotherpartsofthebodyforfurtherinvestigation,
which explored more lesions in the pelvis and sacrum and
clarified the absence of other lesions in the skeleton.
Short Tau inversion recovery (STIR) MRI is useful to
identify bone lesions and tissue edema; they appear hypo-
intense in T1-weighted and hyperintense in T2-weighted
images.8
The MRI in this case showed multiple bone lesions
in the right sacral ala and left greater trochanter, S1 vertebra,
both iliac bones, and right pubic bone associated with tissue
edema, new bone formation but without bone destruction.
Follow-up MRI showed significant regression of the lesions
and disappearance of soft-tissue edema.
Histologic features are not specific; some authors suggest
that biopsy could be avoided if a child has classical
radiographic findings of CRMO, and others have suggested
diagnostic criteria and clinical scores to facilitate CRMO
diagnosis and to reduce the numbers of bone biopsies.6,9
Differential diagnosis includes infection, malignancies,
benign bone tumors, metabolic disorders, and other auto-
inflammatory disorders. Biopsy of the bone lesion is not
required often but could be necessary in unclear cases,
especially for differentiation from bone neoplasia.10
There is no consensus on the preferred treatment protocol,
so the treatment is still empiric. NSAIDs remain the first line
of treatment for pain relief and preventing bone damage. If
no response, it is wise to switch to corticosteroids or
bisphosphonates as a second-line treatment. Other medica-
tions (e.g., methotrexate, sulfasalazine) have an effective role,
and they usually are used in patients with associated
inflammatory bowel disease.10
FIGURE 3. Hyperintense bone lesions in the S1vertebra and both iliac
bones on the initial T2 MRI.
FIGURE 4. The follow-up MRI showing significant regression of soft-tissue
reactive changes that were surrounding the iliac and right pubic bone
lesions.
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4. In multiple lesions, bisphosphonate is described as a
second line of treatment for CRMO; if failed, TNF-α
inhibitors are indicated.6,10
Bisphosphonates have replaced
corticosteroids as a second-line treatment because of the side
effects of corticosteroids.
Pamidronate is the most common bisphosphonate reported
to be used in the treatment of CRMO. Two studies reported the
usage of the newer, more potent, and the later generation of
bisphosphonate ZA in the treatment of CRMO.11,12
ZA is a highly potent intravenous bisphosphonate that has
been increasingly used in children with primary and
secondary osteoporosis because it has the convenience of
shorter infusion time and less frequent dosing compared
with pamidronate.13
It inhibits osteoclast activity and
increases bone mineral density.
The family of this patient did not want to proceed with
oral medication treatment because of unsuccessful experi-
ence with that treatment in the previous 9 mo. The authors
presented ZA as an intravenous treatment option, and the
family agreed.
Acute adverse events related to ZA infusion occur princi-
pally after the first infusion. These include fever, hypocalce-
mia, decreased intake, bone pain, myalgia, and influenza-like
symptoms. The patient experienced generalized tiredness,
bone and muscle pain, and documented fever of 38.1°C after
the first dose. These adverse effects completely resolved the
next day with the use of antipyretics, bed rest, and good oral
fluid intake. These were brief and, for the most part, could be
managed easily at home.
Bisphosphonate-related osteonecrosis of the jaw has been
described in adult patients; however, no cases of osteonec-
rosis have been identified in pediatric patients.14
Bisphosph-
onates are thought to have an antiinflammatory effect by
altering the inflammatory cascade. It induces the release of
interleukin 6 (IL-6) and TNF-α from T-lymphocyte which
explains the zoledronic acid-induced transient fever.15
In this patient, the authors noticed fast and complete pain
relief after the first dose of ZA and complete resolution of the
soft-tissue inflammatory changes over the follow-up period.
This suggested the effectiveness of ZA in CRMO treatment.
These findings can reassure clinicians and patients that the
use of ZA in the pediatric population is relatively safe in the
short term.12
All patients starting on ZA infusion must be given
continuous prophylaxis of calcium, antipyretics, and anal-
gesia to reduce the risk of adverse effects. The patient in this
report was given all the prophylactic measures as a
precaution for the common mild adverse effects of ZA and
was well hydrated to prevent kidney injury.
The authors suggest long-term studies to discuss the effect
of bisphosphonates on patients with CRMO. Also, compara-
tive studies should be implemented to investigate the best
choice of bisphosphonates therapy.
CONCLUSION
CRMO is an uncommon painful bony disorder whose
treatment is focused on improving the quality of life by the
elimination of pain. The authors believe that ZA therapy can
be of benefit in treating patients with CRMO. It is an effective
treatment option for the resolution of pain, modification of
the inflammatory process, and resolving the radiographic
findings caused by CRMO. Further studies are needed for
evaluation of the effectiveness of ZA in CRMO.
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