Non-weight-bearing, pre- and postsurgical immobilization, neoadjuvant and adjuvant chemotherapy are known to act on bone turnover, causing osteoporosis over short and long time periods. Treatment of fracture insurgence is very difficult because it really depends on being able to choose the right time (i.e., when immunodeficiency is less important). We report a case of spontaneous neck femur fracture during adjuvant chemotherapy in a young girl treated with resection and prosthesis reconstruction for distal femur osteosarcoma. Possible prevention and the correct approach and surgical timing are emphasized considering immunodeficiency following chemotherapy

Ferraresi, Virginia

Prencipe, Umberto

Salducca, Nicola

Zoccali, Carmine

Journal of Orthopaedics and Traumatology

English

PubMed

Carmine Zoccali

Umberto Prencipe

Virginia Ferraresi

Nicola Salducca

Springer - Publisher Connector

An osteoporotic hip fracture in a 14-year-old girl undergoing chemotherapy and operated for knee osteosarcoma

CASE REPORT
An osteoporotic hip fracture in a 14-year-old girl undergoing
chemotherapy and operated for knee osteosarcoma
Carmine Zoccali Æ Umberto Prencipe Æ
Virginia Ferraresi Æ Nicola Salducca
Received: 15 May 2008 / Accepted: 11 July 2009 / Published online: 31 July 2009
 Springer-Verlag 2009
Abstract Non-weight-bearing, pre- and postsurgical
immobilization, neoadjuvant and adjuvant chemotherapy
are known to act on bone turnover, causing osteoporosis
over short and long time periods. Treatment of fracture
insurgence is very difficult because it really depends on
being able to choose the right time (i.e., when immuno-
deficiency is less important). We report a case of sponta-
neous neck femur fracture during adjuvant chemotherapy
in a young girl treated with resection and prosthesis
reconstruction for distal femur osteosarcoma. Possible
prevention and the correct approach and surgical timing are
emphasized considering immunodeficiency following
chemotherapy.
Keywords Chemotherapy osteoporosis 
Juvenile osteoporosis  Osteoporosis fracture children 
Methotrexate complications
Introduction
Non-use osteoporosis is well known in the literature; it is
caused by a decrease in osteoblastic activity arising from
an absence of weight bearing and motion. Chemotherapy in
patients who have undergone bone tumor surgery causes
osteoblast inhibition and consequently a decrease in bone
apposition and body mass density [1–6]. Methotrexate
directly locks onto osteoblastic proliferation in the epiph-
yseal plate, inducing apoptosis and a drop off in type-II
collagen synthesis; in spongy bone, it appears to act
directly on osteoclast cell differentiation; osteoporotic
fracture is a possible complication [7].
The other three drugs used in our therapeutic protocols,
are doxorubicin, cisplatin and ifosfamide, and they can also
diminish bone apposition; their effects on bone resistance
become more evident with advanced age [8]. Osteoporotic
fractures are common complications in patients who have
undergone chemotherapy [9, 10].
Case report
A 14-year-old Caucasian girl showed up at our department
for the onset of a tumefaction located in the posteromedial
aspect of the distal right femur. Examination showed a
mass seven centimeters in apparent size that was painful,
hard, mobile on the overlying layers and fixed in the
underlying layers.
Distal femur X-rays indicated an osteolytic lesion with
cortical erosion and minimal periosteal reaction (Codman’s
triangle). Imaging was suggestive of a high-grade osseous
sarcoma (Fig. 1a).
MRI (Fig. 1b) showed neoformation with various
aspects that was more evident on STIR-weighted images
C. Zoccali (&)  U. Prencipe
Oncological Orthopaedics Department,
Muscular-Skeletal Tissue Bank,
IFO, Regina Elena Institute,
Via Elio Chianesi 53, Rome, Italy
e-mail: carminezoccali@libero.it
U. Prencipe
e-mail: prencipe@ifo.it
V. Ferraresi
Oncological Department ‘‘A’’, IFO, IRE, Rome, Italy
e-mail: ferraresi@ifo.it
N. Salducca
Oncological Orthopaedics Department, IFO, IRE, Rome, Italy
e-mail: salducca@ifo.it
123
J Orthopaed Traumatol (2009) 10:151–154
DOI 10.1007/s10195-009-0059-1
and hypointense on T1-weighted images. It extended
throughout the whole distal femur eroding medial cortex
and periosteum without exceeding the epiphyseal plate;
this condition was confirmed by TC (Fig. 1c). Bone scans
revealed intense local uptake and no bone metastasis; this
condition was also evident in total-body TC.
A needle biopsy was performed by medial access and
following histopathology-documented osteosarcoma. The
patient was placed in an oncology ward for neoadjuvant
chemotherapy with methotrexate, cisplatin, adriamycin and
ifosfamide (Italian Sarcoma Group Protocol) [11, 12].
The surgical operation was performed seven days
after the last chemotherapy cycle. A tumor resection and
reconstruction with global modular replacement system
arthroplasty (GMRS, Stryker) was performed (Fig. 1d).
Postoperative days were normal, and when the wound had
healed completely the patient was treated with adjuvant
chemotherapy.
Seven months after the surgery, a nondisplaced asymp-
tomatic neck fracture of the right femur was diagnosed by
routine X-ray and CT scans (Fig. 2a, b). The patient related no
trauma but suffered sudden pain after twisting her right leg.
MRI with contrast clearly showed that it was not a metastasis,
so biopsy was considered unhelpful (Fig. 2c) [13]. A percu-
taneous fixation with cannulated screws was performed in the
period between the last chemotherapy and the next, when
immunodeficiency was less important.
Postoperative days were normal, and weight-bearing was
not allowed for 40 days. X-rays taken 60 days after surgery
showed the healing process (Fig. 3). The fracture had healed
at one year of follow up (Fig. 4). The patient and her parents
gave their consent to the publication of the clinical case.
Fig. 1 a–c Preoperative images
showing a mass in the medial
aspect of the distal femur.
d Postoperative X-rays showing
the prosthesis at the site
152 J Orthopaed Traumatol (2009) 10:151–154
123
Discussion
Neoadjuvant and adjuvant chemotherapy caused a revolu-
tion in the treatment of musculoskeletal sarcoma, increas-
ing the percentage of treatment success. The most popular
treatment protocol is based on the administration of four
chemotherapy drugs: methotrexate, cisplatin, adriamycin,
and ifosfamide. Above all, methotrexate is known to be
related to a drop in bone mass density, a decrease in
osteoblastic activity, and a stimulation of osteoclast cell
differentiation over the short term, as well as a decrease in
peak adolescent bone mass and a facilitation of future
osteoporosis over the long term [14–16]; moreover,
Fig. 2 a X-rays showing a
nondisplaced fracture; b CT
scan showing correct fragment
apposition; c T1-weighted MRI
image showing no metastasis on
the proximal right femur
Fig. 3 Postoperative check showing that the fracture had been
stabilized by cannulated screws
Fig. 4 X-rays showing that the fracture had healed at one year of
follow up
J Orthopaed Traumatol (2009) 10:151–154 153
123
methotrexate osteopathy, characterized by osteoporosis and
joint pain, has been described [17].
Toxic effects of ifosfamide on bone were recently
reported [18]. Pre- and postsurgery immobilization and a
decline in normal activity are other important causes of
worsening osteoporosis. Osteopenia was first described in
long-term survivors of osteosarcoma in 1988, and remains
evident many years after chemotherapy [19].
Although osteoporosis is well known in patients
undergoing chemotherapy for osteosarcoma, there are no
cases of spontaneous fracture in adolescents and pread-
olescents. In our case, the therapeutic issue was whether
to perform a surgical operation or use conservative
management. The fracture occurred about 20 days before,
and in a healthy young girl this is a sufficient length of
time for the fracture to heal. However, in these patients,
chemotherapy retards the healing process, so this fracture
was probably destined to evolve into a pseudarthrosis.
The other problem was to choose the best time for the
operation, because chemotherapy causes immunodefi-
ciency, which can increase the risk of infections and
wound closure problems. The patient had been adminis-
tered high-dose ifosfamide, and growth factors were
administered to decrease the risk of myelotoxicity,
meaning that surgery was possible about one week after
chemotherapy without the need to postdate the next cycle
[20]. Prevention may be a valid approach for patients that
have undergone chemotherapy. Bisphosphonates derive
from the union of two phosphonic acids joined to one
carbon atom; particular formulations are able to interfere
with osteoclast precursor activation, preventing bone
linkage and slowing bone resorption [21]. As it is already
done for osteoporosis associated with other pathologies
(like lymphoblastic leukemia) [22], their assumed use is
rational, but new clinical trials are needed to evaluate a
possible decrease in bone growth and retarded prosthesis
integration.
Conflict of interest statement The authors declare that they have
no conflict of interest related to the publication of this manuscript.
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Alterations of bone turnover and impaired development of bone mineral density in newly diagnosed children with cancer: a 1-year prospective study.

Bisphosphonate therapy for reduced bone mineral density during treatment of acute lymphoblastic leukemia in childhood and adolescence: a report of preliminary experience.

Bisphosphonates: mechanisms of action.

Bone and soft tissue tumors, 2nd edn.

Bone density in survivors of childhood malignancies.

Bone metabolism and mineralisation after cytotoxic chemotherapy including ifosfamide.

Bone mineral density in long-term survivors of highly malignant osteosarcoma.

Bone mineral density in young adult survivors of childhood cancer.

Care and treatment of long-term survivors of childhood cancer.

Cellular mechanisms for methotrexate chemotherapy-induced bone growth defects.

Cross-sectional study of bone mineral density in adult survivors of solid pediatric cancers.

Effect of high and low doses of methotrexate (MTX) on bone mass in subjects treated for osteosarcoma of the limb.

Ifosfamide and mesna: response and toxicity at standard-and high-dose schedules.

Italian Sarcoma Group/Scandinavian Sarcoma Group

Longitudinal evaluation of bone mineral density in children receiving chemotherapy.

Methotrexate osteopathy in patients with osteosarcoma.

Methotrexate osteopathy.

Neoadjuvant chemotherapy with high-dose ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups.

Osteopenia in young adult survivors of childhood cancer.

Osteoporosis due to cancer treatment: pathogenesis and management.

The effect of a doxorubicin, cisplatin and ifosfamide combination chemotherapy on bone turnover.

The effects of methotrexate (MTX) on bone: a densitometric study conducted on 59 patients with MTX administered at different doses.

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An osteoporotic hip fracture in a 14-year-old girl undergoing chemotherapy and operated for knee osteosarcoma

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