Impact of oncopediatric dosing regimen of zoledronic acid on bone growth: Preclinical studies and case report of an osteosarcoma pediatric patient

Abstract

Osteosarcoma and Ewing sarcoma represent the two most frequent primary bone tumors that arise in the pediatric population. Despite recent improvement in their therapeutic management, no improvement in survival rate has been achieved since early 1980 s. Among new therapeutic approaches, bisphosphonates are promising candidates as potent inhibitors of bone resorption. However, their effects on bone growth must be studied at dosing regimen corresponding to pediatric protocols. To this aim, several protocols using zoledronic acid (ZOL) were developed in growing mice (50 mg/kg every 2 days  10). Parameters of bone remodeling and bone growth were investigated by radiography, micro-computed tomography, histology, and biologic analyses. Extramedullar hematopoiesis was searched for in spleen tissue. A transient inhibitory effect of ZOL was observed on bone length, with a bone-growth arrest during treatment owing to an impressive increase in bone formation at the growth plate level (8-to 10-fold increase in BV/TV). This sclerotic band then shifted into the diaphysis as soon as endochondral bone formation started again after the end of ZOL treatment, revealing that osteoclasts and osteoblasts are still active at the growth plate. In conclusion, endochondral bone growth is transiently disturbed by high doses of ZOL corresponding to the pediatric treatment of primary bone tumors. These preclinical observations were confirmed by a case report in a pediatric patient treated in the French OS2006 protocol over 10 months who showed a growth arrest during the ZOL treatment period with normal gain in size after the end of treatment. ß

Preclinical evidence of potential craniofacial adverse effect of zoledronic acid in pediatric patients with bone malignancies

“…The principal objectives of high doses zoledronic acid protocol were not only to protect bone from the tumor-induced osteolysis but also to target tumor cells [27], ZOL being a powerful inhibitor of the mevalonate pathway [28]. Our previous studies have evidenced that high doses of ZOL in mouse, similar to the human pediatric treatment, induced a transient arrest of the axial and appendicular skeleton growth of long bones [20]. These Fig.…”

“…*:p b 0.05; ***:p b 0.001. treatments (day 21, Figs. 1B and C) as it has been previously reported [20]. This phenomenon was due to a huge bone formation observed at the growth plate that can be quantified as a significant augmentation of the specific bone volume (Figs.…”

“…This structure appeared to increase in size from one to three months and was associated with perforation and finally destruction of the mandibular bone (arrows). observations were further supported by clinical data [20], but currently not sufficient to restrict the use of high doses of ZOL to adult patients. However, the impact of elevated cumulative doses of ZOL on craniofacial skeleton growth has never been fully documented and is necessary in the context of onco-pediatric treatment.…”

“…Such inhibition of mineralization has been observed for various BPs using calvaria osteoblast culture [19]. According to the fact that cumulative doses of ZOL used in pediatric cancer protocols are 5 times higher (50 μg/kg every 4 weeks, 10 times: 500 μg/kg/year) than those given for other pediatric bone disorders (same dose, once/6 months: 100 μg/kg/year), we propose to investigate the impact of high doses of ZOL on the peculiar craniofacial skeleton growth, knowing that such doses induce transitory arrest of axial and appendicular skeleton long bone growth as demonstrated in our previous works [20]. Craniofacial skeleton growth is a complex process requiring a harmonious and timely controlled growth of the diverse skeleton entities (bones, teeth…) and fusions of some of them, for instance flat bones of skull.…”

Bone Sarcomas: From Biology to Targeted Therapies

“…The use of zoledronic acid in combination with 1st-line chemotherapy is being addressed for localised EW in Europe, in randomised phase III trials (the current Ewing 2008 and future Euro-EWING2012). In juvenile models, zoledronic acid decreases enchondral bone growth in a reversible manner [154]. …”