Current Molecular Medicine 2011, 11,

1566-5240/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.
Pathobiology and Prevention of Cancer Chemotherapy-Induced
Bone Growth Arrest, Bone Loss, and Osteonecrosis
C. Fan1,2,3, B.K. Foster2,3, W.H. Wallace4 and C.J. Xian*,1,2,3
1Sansom Institute for Health Research, and School of Pharmacy and Medical Sciences, University of South
Australia, Adelaide 5001, Australia
2Discipline of Paediatrics, University of Adelaide, Adelaide 5005, Australia
3Department of Orthopaedic Surgery, Women’s and Children’s Hospital, North Adelaide 5006, Australia
4Royal Hospital for Sick Children, Department of paediatric Haematology and Oncology, Edinburgh, Scotland,
UK
Abstract: Cancer chemotherapy has been recognized as one severe risk factor that influences bone growth
and bone mass accumulation during childhood and adolescence. This article reviews on the importance of this
clinical issue, current understanding of the underlying mechanisms for the skeletal defects and potential
preventative strategies. Both clinical and basic studies that appeared from 1990 to 2010 were reviewed for
bone defects (growth arrest, bone loss, osteonecrosis, and/or fractures) caused by paediatric cancer
chemotherapy. As chemotherapy has become more intensive and achieved greater success in treating
paediatric malignancies, skeletal complications such as bone growth arrest, low bone mass, osteonecrosis,
and fractures during and/or after chemotherapy have become a problem for some cancer patients and
survivors particularly those that have received high dose glucocorticoids and methotrexate. While
chemotherapy-induced skeletal defects are likely multi-factorial, recent studies suggest that different
chemotherapeutic agents can directly impair the activity of the growth plate and metaphysis (the two major
components of the bone growth unit) through different mechanisms, and can alter bone modeling/remodeling
processes via their actions on bone formation cells (osteoblasts), bone resorption cells (osteoclasts) and bone
“maintenance” cells (osteocytes). Intensive use of multi-agent chemotherapy can cause growth arrest, low
bone mass, fractures, and/or osteonecrosis in some paediatric patients. While there are currently no specific
strategies for protecting bone growth during childhood cancer chemotherapy, regular BMD monitoring and
exercise are have been recommended, and possible adjuvant treatments could include calcium/vitamin D,
antioxidants, bisphosphonates, resveratrol, and/or folinic acid.
Keywords: Chemotherapy, childhood cancers, growth plate, bone mass, chondrocytes, osteoblasts, adipocytes,
osteocytes, osteoclasts, bone marrow progenitor cells, methotrexate, glucocorticoids, growth defects, osteoporosis,
osteopenia, osteonecrosis, bone loss, fractures, oxidative stress, prevention, bisphosphonates, calcium, vitamin D,
folinic acid, antioxidants.
INTRODUCTION
One in 600 children will develop cancer in the first
15 years of life. Unlike the majority of adult cancers,
most pediatric cancers are curable using multi-agent
chemotherapy in combination with surgery and
radiotherapy. Currently 80% of patients are alive at five
years from diagnosis and 70% will become long-term
survivors. The intensified use of chemotherapy,
particularly for childhood acute lymphoblastic
leukaemia (ALL), has led to the emergence of a
significant number of cancer survivors facing long-term
skeletal problems including growth arrest, low bone
mass, fractures, osteonecrosis and bone pain. Many
previous clinical studies have already highlighted these
problems, but not until recently have the underlying
mechanisms been investigated via experimental


*Address correspondence to this author at the Sansom Institute for
Health Research, University of South Australia, City East Campus,
GPO, Box 2471, Adelaide 5001, Australia; Tel: (618) 8302 1944;
Fax: (618) 8302 1087; E-mail: cory.xian@unisa.edu.au
studies. Since skeletal health is a major determinant of
quality of life, significance of this clinical issue has been
increasingly important. This review summarises the
clinical studies which have examined skeletal
risks/defects in paediatric cancer patients and survivors
during and after chemotherapy, recent animal studies
investigating the underlying mechanisms, and possible
adjuvant treatments or recommendations for managing
these complications.
BONE GROWTH MECHANISMS AND REGULA-
TION
During bone growth, the growth plate produces
calcified cartilage which serves as a template for the
formation of primary trabecular bone in a process
known as “endochondral ossification” [1] (Fig. 1). This
process involves chondrocyte activation, proliferation,
maturation, hypertrophy, calcification and apoptosis in
the growth plate. Metaphyseal bone formation begins
as blood vessels invade the mineralised cartilage,
bringing in bone-forming cells “osteoblasts” and
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2 Current Molecular Medicine, 2011, Vol. 11, No. 2 Fan et al.
calcified tissue-resorptive cells “osteoclasts”. While
osteoclasts resorb the calcified cartilage, osteoblasts
penetrate the invaded cartilage and replace it with
spongy bone (primary spongiosa). The 3rd type of bone
cells, osteocytes embedded within bone matrix, are
now known to be important in regulating bone
remodeling during growth [2] and for maintaining
homeostasis [3-4]. The coordinated action of
osteoblasts, osteoclasts and osteocytes models and
remodels the mineralized cartilage firstly into woven
primary spongiosa and then further into structurally and
mechanically more mature laminar trabecular bone
(secondary spongiosa) [1].
Osteoblasts bone lining cells synthesizing bone
matrix; they are derived from mesenchymal stem cells
(MSC) along osteoprogenitor cells, preosteoblast and
osteoblast differentiation and maturation pathway.
Osteoclasts are calcified tissue-resorptive cells;
they are produced from monocyte-lineage
haematopoietic cells under the influence of M-CSF
(macrophage colony-stimulating factor), RANKL
(receptor activator for nuclear factor
-B ligand), and
other inflammatory cytokines.
Osteocytes are terminally differentiated osteoblasts
residing in the lacuna/canalicular system within bone
matrix with extensive dendritic cell processes; they are
important in regulating mineralization, mediating
mechanotransduction and in coordinating bone
remodeling during growth and for maintaining
homeostasis.
Many genetic factors are involved in regulating bone
growth and bone mass accumulation, including growth
hormone, sex steroids, growth factors such as IGF-I,
and cytokines, all of which are important in regulating




























Fig. (1). Growth plate, primary spongiosa and secondary spongiosa in endochondral bone formation and as potential targets of
action for commonly used chemotherapeutic agents that cause bone growth arrest and bone loss.
Please add "are" after Osteoblasts, 4th last line above.