Pathobiology and Prevention of Cancer ... - Ingenta Connect

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Current Molecular Medicine 2011, 11, 140-151

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 1

Sansom Institute for Health Research, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide 5001, Australia 2

Discipline of Paediatrics, University of Adelaide, Adelaide 5005, Australia

3

Department of Orthopaedic Surgery, Women’s and Children’s Hospital, North Adelaide 5006, Australia

4

Royal 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: [email protected] 1566-5240/11 $58.00+.00

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 REGULATION 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 © 2011 Bentham Science Publishers Ltd.

Chemotherapy-Induced Bone Growth Defects

Current Molecular Medicine, 2011, Vol. 11, No. 2

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Cellular targets of chemotherapeutic agents in growth plate and metaphysis

Metaphysis bone

Growth plate

Resting zone

Proliferative zone

Hypertrophic zone

Primary spongiosa

Secondary spongiosa

Doxorubicin: Reduces chondrocyte proliferation and collagen‐2 synthesis. Cisplatin: Reduces chondrocyte proliferation and collagen‐2 synthesis. Cyclophosphamide: Induces chondrocyte apoptosis. Etoposide: Suppresses chondrocyte proliferation. Dexamethesone & Prednisolone: Reduce chondrocyte proliferation. 5‐fluorouracil: Induces chondrocyte apoptosis & suppresses chondrocyte proliferation. Methotrexate: Induces chondrocyte apoptosis & reduces chondrocyte proliferation; suppresses collagen II expression Doxorubicin: Reduces bone formation and induces fat formation, resulting in reduction of bone volume. Cisplatin: Decreases activity of both osteoblasts and osteoclasts. Cyclophosphamide: Induces osteoblastic cell apoptosis and reduces cell number. Etoposide: Suppresses osteoblastic cell proliferation; induces osteoblast apoptosis. Dexamethesone & Prednisolone: Increase osteoclast formation and increase osteoblastic and osteocytic cell apoptosis. 5‐fluorouracil: Reduces proliferation and inducse apoptosis in osteoblasts, resulting in reduction of primary spongiosa height and reduction of bone volume. Methotrexate: Induces osteocyte apoptosis & osteoclast formation, decreases stromal progenitor cell and osteoblast proliferation, and increases adipocyte formation; reduces primary spongiosa height & reduces bone volume

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.

calcified tissue-resorptive cells “osteoclasts”. While osteoclasts resorb the calcified cartilage, osteoblasts penetrate the invaded cartilage and replace it with rd spongy bone (primary spongiosa). The 3 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 are 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

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skeletal cell number, function and bone formation/remodeling [1,5]. In addition, many lifestyle and environmental factors such as nutrition and physical activities are also capable of influencing bone growth and bone mass. Recently, chemotherapy in paediatric oncology patients has been recognised as one of the most important risk factors that interfere with bone growth.

CANCER CHEMOTHERAPY-INDUCED BONE GROWTH ARREST, BONE LOSS, AND OSTEONECROSIS Any disturbance to the intricately coordinated bone growth and modeling/remodeling processes may result in growth defects. Intensive chemotherapy is increasingly successful in the treatment of pediatric cancers, and has become an important risk factor for bone defects in paediatric cancer patients and/or survivors. Among the common paediatric cancers including ALL, brain tumors, non-Hodgkin’s lymphoma (NHL) and Hodgkin’s lymphoma, ALL is the most common malignancy, which now has an over 80% of survival rate [6]. Due to intensifying use of chemotherapy and the improved patient survival, bone defects (growth arrest, osteonecrosis, low bone mineral density or BMD, and/or fractures) are becoming important clinical problems in paediatric cancer patients and/or survivors [7,13]. Chemotherapy-Induced Growth Arrest, Bone Loss and Recovery Potential Treatment protocols for ALL involve intensive use of methotrexate (MTX) and glucocorticoids for several years. Children with ALL have low bone turnover and are in a growth hormone resistant state at diagnosis [14]. Glucocorticoid therapy has been shown to lower leg growth [14-15]. During intensive chemotherapy for ALL, children show marked growth deceleration or a significant decrease in height velocity [16,17]. Children with solid tumours have also been demonstrated to grow slowly during treatment with cytotoxic agents [18]. Many studies examined BMD status (represented by Z-scores instead of T-scores for postmenopausal women and in men age 50 and older according to ISCD guidelines) [19-21] in children with ALL or survivors, and reported a reduction in BMD particularly during cancer treatments [14,15,18]. Generally, compared to patients who received chemotherapy alone, patients receiving cranial irradiation in addition to chemotherapy showed a bigger reduction in BMD long after chemotherapy [11]. Some studies examining effects of chemotherapy alone on survivors of childhood malignancies reported either an unaffected [22] or a reduced BMD depending on dosing regimens [9]. However, higher doses of glucocorticoids 2 2 (>9000mg/m prednisolone) and MTX (>40,000 mg/m ) are associated with more severe bone loss in children with ALL which fails to recover after chemotherapy completion [11]. During chemotherapy-maintained

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remission, reduction in bone mineral content occurred in 64% of children with ALL, a condition shown to increase fracture risks with a fracture incidence of 39% during treatment [23]. Similarly, in long-term survivors (average 31 years of age at 16 years of follow up) of malignant osteosarcoma, in which patients had been treated with intensive chemotherapy with doxorubicin, high dose MTX, cyclophosphamide (CTX) and other agents, the BMD was significantly reduced, with 20.8% being osteoporotic and 43.7% osteopenic [24]. It has been shown that adolescents who fail to achieve the peak bone mass have a reduced BMD and possible increased fracture risks later in life [25,26]. Bone recovery after chemotherapy also seems to be both dose and time dependent, and higher fracture risks have been reported during or shortly after completion of treatment [13]. Although most paediatric cancer patients show a recovery of BMD with an increasing time period off chemotherapy, some survivors show a significant low bone mass years later, and fail to reach their potential peak bone mass [16,24,27]. Although discontinuation of MTX showed improvement in skeletal toxicity, higher doses of MTX 2 2 (>50,000mg/m ) and glucocorticoids (>9,080mg/m ) over 3 years were found to be associated with a high risk of bone loss and failure of BMD recovery after discontinuation [8,28]. Patterns of growth after chemotherapy cessation also vary with treatment intensity and length, with some studies reporting a permanent deficit [29], whereas others revealing partial catch-up growth [30]. MTX Osteopathy MTX is the most commonly used anti-folate antimetabolite in paediatric oncology. It is used at high 2 doses (1000-12,000mg/m ) particularly for ALL and osteosarcoma. Clinically, osteopathy in children treated with MTX is characterized by a reduced BMD, dense zones of provisional calcification, transverse metaphyseal bands, multiple fractures and bone pain [31]. MTX osteopathy has been reported in children and adult survivors for treatments of ALL [8], osteosarcoma [31], and even when used at low doses for rheumatoid arthritis [32]. High dose MTX as central nervous system treatment has been shown to reduce bone formation and enhance bone resorption [1415,33]. Glucocorticoid-Induced Bone Loss and Osteonecrosis Glucocorticoids such as dexamethasone and prednisolone are commonly used for treating ALL, and have been reported to affect childhood bone health. Long-term high dose glucocorticoids significantly reduce BMD, increase fracture risks in children, and induce secondary osteoporosis in adults [34, 35]. In children with ALL treated with dexamethasone-based chemotherapy, total body BMD was reduced during the first 32 weeks of intense chemotherapy, with a 6-times


higher fracture rate [27]. Short-term prednisolone therapy in children also showed some bone loss after 4 weeks with a significant reduction in bone formation [36]. Osteonecrosis (ON) is being reported increasingly among young survivors of ALL and NHL as a result of cumulative glucocorticoid treatment. ON caused by high dose glucocorticoids may affect up to 1/3 of ALL and NHL survivors, which is characterised by progressive damage to weight-bearing joints, leading to temporary or permanent loss of blood supply to bones [37]. Clinical manifestations of ON are variable; apart from weight bearing joints (hips and knees), ankles, shoulders, elbows, wrists and spine have also been shown affected [38]. A recent comparison report confirmed that children with a history of ALL and sarcoma are at a higher risk of developing ON [39]; and paediatric patients with a history of stem-cell transplantation [40], glucocorticoid and radiation therapy [41] are at greater risk for developing ON. Furthermore, patients receiving glucocorticoid therapy involving dexamethasone were shown more likely to develop ON than patients receiving prednisolone alone [42]. The pathogenesis of ON appears to be complex. It has been reported that maturing bone during adolescence is generally at a greater risk of developing ON than in adults [43]. Glucocorticoids can induce marrow adipocyte hypertrophy which in turn elevates intraosseous pressure, leading to a reduction of blood flow and impairment of blood perfusion, marrow ischemia and ultimately necrosis [44]. In addition, evidence suggests that suppressed bone formation also contributes to ON [37].

PATHOBIOLOGY FOR INDUCED BONE DAMAGE

CHEMOTHERAPY-

Various studies have suggested that different chemotherapeutic agents may affect the growth plate and/or bone through different mechanisms (Fig. 1). Direct effects on Growth Plate Chondrocytes and Function The chondrocyte number and growth plate thickness positively correlate with the bone growth rate. Various studies have demonstrated that chemotherapy may damage growth plate structure and function directly. In rat long bones, doxorubicin and cisplatin have profound suppressive effects on growth plate thickness and chondrocyte columnar arrangement [25]. CTX (used commonly for NHL, neuroblastoma and sarcoma) and etoposide (for neuroblastoma, Ewing’s sarcoma and retinoblastoma therapy) also have damaging effects on the growth plate proliferative zone [45]. Similarly, anti-metabolite 5-FU (used for paediatric adenocarcinoma) suppresses chondrocyte proliferation, reduces growth plate thickness [46], and induces bone loss in cancer patients [47]. High dose MTX damages growth plate directly by reducing


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proliferation and inducing apoptosis, reducing production of cartilage protein collagen-II and growth plate thickness [48,49]. Damaging effect of MTX on growth plate is dose-dependent, as MTX administered at lower doses or less frequently in rats (at a similar dosage and schedule used for rheumatoid arthritis) did not seem to cause growth plate structural changes [25,50]. Long-term treatment with high dose glucocorticoids also causes growth retardation in children due to their inhibitory action on IGF-I production and sensitivity in the growth plate, suppressing chondrocyte proliferation [51], differentiation [52], matrix synthesis and hypertrophy [53]. Damaging Effects on Osteoprogenitors/Osteoblasts and Bone Formation Earlier in vitro studies demonstrated that human bone marrow mesenchymal stem cells (MSCs), osteoprogenitor and osteoblastic cells can be damaged after exposure to paclitaxel, etoposide and cytarabine, which was due to apoptosis or growth suppression [54,55]. In rats, CTX and etoposide cause apoptosis and decrease density of osteoblasts and preosteoblasts on bone surface [45]. Similarly, MTX reduces proliferation of osteoblasts, pre-osteoblasts [49] and marrow stromal cells in young rats [48]. Consistently, a clinical study showed that toxicity to MSCs caused by high dose combination chemotherapy (5-FU, epidoxorubicin and CTX) is dose-dependent, and there is an irreversible depletion of the stromal progenitor population in patients after high dose treatments [56]. These studies indicate that various chemotherapy drugs can directly damage osteoprogenitor and osteoblastic cells, reducing potential for osteoblast formation and deposition. Studies in patients receiving long-term glucocorticoid treatment show reduced numbers of osteoblasts on cancellous bone [57]. Glucocorticoids reduce osteoblast differentiation, recruitment and activity and induce their apoptosis [58]. Interestingly, dexamethasone suppresses osteoblast formation but stimulates adipocyte differentiation from bone marrow stromal cells, resulting in a decrease in cellularity and fat accumulation in the marrow [59]. Furthermore, glucocorticoids decrease IGF-I production, leading to decreased estrogen secretion [60], which in turn contribute to decreased osteoblast proliferation and anabolic functions [35]. Thus, by altering levels of sex hormones, reducing circulating calcium concentration and enhancing parathyroid hormone (PTH) secretion, glucocorticoids can indirectly reduce bone formation and cause osteoporosis [61] (Fig. 2). Increased Osteoclast Resorption

Formation

and

Bone

In addition to the damage to chondrocytes, osteoblasts, and marrow stromal progenitor cells which results in reduced endochondral ossification and bone

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Pituitary gonadotrophins Suppress

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Calcium loss Calcium absorption

Hyperparathyroidism( PTH)

Testosterone Estrogen

Fig. (2). Direct and indirect effects of glucocorticoid use in causing bone loss. Glucocorticoids can reduce numbers of osteoblasts and osteocytes that result in reduced bone formation and increased osteoclastic bone loss, respectively. Glucocorticoids can indirectly cause an overall reduction in circulating calcium levels through increased renal calcium loss and suppressed intestinal calcium absorption. This triggers parathyroid glands to secrete more parathyroid hormone (PTH), which leads to reduced osteoblastic bone formation and increased osteoclastic bone resorption, and ultimately, bone loss. Glucocorticoid-induced bone loss can also be mediated indirectly via the suppression of pituitary gonadotrophins, which results in decreased production of sex hormones (testosterone and estrogen) and further contributes to bone loss.

formation, chemotherapy also causes increased formation of osteoclasts leading to aggravated bone resorption. In rats, MTX chemotherapy caused an increase in osteoclast precursor pool and osteoclast formation in the marrow, an elevated osteoclast density on bone surface, and loss of trabecular bone [50]. During intensive chemotherapy for ALL, children show increased osteoclastic bone resorption [14,15]. Although the underlying mechanism for chemotherapyinduced osteoclast formation requires further investigation, a higher serum level of pro-inflammatory and osteoclastogenic cytokine TNF- has been found in patients undergoing chemotherapy [62]. Glucocorticoids can enhance osteoclast formation through increasing RANKL and decreasing osteoclastogenesis inhibitory factor osteoprotegerin (OPG) production in osteoblasts [35], resulting in increased osteoclasts precursor recruitment. Interestingly, paclitaxel or anthracycline-based chemotherapy has been shown to elevate serum inflammatory cytokines in breast cancer patients [63,64]. Further studies are required to address whether this pro-inflammatory or pro-osteoclastic state

may be associated with increased osteoclast formation and bone loss in cancer patients on chemotherapy. Osteocyte Apoptosis and Increased Local Bone Resorption Previously, apoptosis of osteocytes has been suggested to at least partially mediate glucocorticoidinduced osteoclastic bone loss [65] and aging-related osteoporosis [66,67]. Recently, MTX has been found to induce apoptosis of osteocytes in rats [48-49]. Since osteocyte apoptosis can disrupt the mechanosensory function of the osteocyte network and causing osteoclast recruitment [68], osteocyte apoptosis may contribute to the chemotherapy-induced development of ON and bone loss. Further studies are required to address potential roles of osteocyte apoptosis in chemotherapy-induced bone loss. Oxidative Stress and Bone Loss Many chemotherapeutic agents target cancer cells by causing oxidative stress, producing reactive oxygen


species (ROS) at a rate exceeding their removal and therefore causing their cell cycle arrest and death [69]. Unfortunately, by causing a marked reduction in levels of vitamin C, vitamin E, -carotene and tissue glutathione [70], chemotherapeutic agents (including anthrycyclines, alkylating agents, platinum based complexes and epipodophyllotoxins) can generate high levels of ROS and oxidative stress in normal tissues, a state which interferes with critical cellular activities and causes adverse effects [69]. Clinically, oxidative stress has been shown to be involved in bone loss [71], and ROS generated are potent inducers for TNF- [72] and other cytokines, which contribute to osteoclast formation and bone loss [73]. Animal studies showed that oxidative stress contributes to osteoporosis through impacting on osteoclast functions [74]. In vitro studies have also provided evidence that oxidative stress inhibits osteogenesis [75], suggesting that oxidative stress causes bone loss also by inhibiting bone formation. Further studies are required to study the effects and underlying mechanisms of chemotherapy-induced oxidative stress and bone loss in the paediatric setting. Other Factors Contributing to Cancer-Related Bone Damage Mechanisms for cancer therapy-induced bone damage are multi-factorial. Apart from chemotherapy or irradiation-induced direct skeletal damage, physical inactivity, the disease itself and malnutrition can also contribute to skeletal defects [22]. Chemotherapy can exert indirect effects on bone growth via malnutrition, due to its adverse effects on gastrointestinal integrity and function [33,76]. Malnutrition during chemotherapy can cause a reduced growth hormone production due to anterior pituitary gland atrophy [33], diminishing levels of IGF-I, which in turn may suppress growth plate function and osteogenesis. In addition, prolonged hospitalization of 3-6 months reduced BMD in young patients due to decreased physical activity [77]. Since most patients with ALL receive chemotherapy for several years, and some survivors show significant reduction in lumbar and femoral BMD [11], it remains unknown how much hospitalisation immobilization contributes to the overall bone loss.

CURRENT INVESTIGATIONS FOR PREVENTION OF CHEMOTHERAPY BONE DAMAGE Due to the significant impacts of chemotherapy on skeletal tissues, it is increasingly important to develop potential strategies to protect bone and ensure bone health in paediatric cancer patients. As there are often no symptoms of bone loss until a fracture occurs, appropriate monitoring of BMD during and after chemotherapy is essential for children receiving chemotherapy [78], and it is important that cancer patients optimize skeletal health during treatment. While recommendations or therapeutic options for minimising childhood bone loss during chemotherapy


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are limited, there have been some considerations or investigations of potential treatments or strategies (Table 1). Calcium/Vitamin D Supplements, Nutrition, and Exercises Since specific therapeutic options for childhood cancer treatment-induced bone defects are not available, simple measures such as adequate calcium/vitamin D intakes and lifestyle changes are important for all children [19]. While the efficacy of calcium absorption is dependent on an adequate level of vitamin D, calcium absorption has been found decreased with a presence of vitamin D deficiency as a result of liver or renal disease during chemotherapy [79]. Thus, adequate daily calcium and vitamin D intakes have been suggested as an important strategy to increase BMD and prevent chemotherapy-induced bone loss [12,78]. In addition, adequate nutritional intake is essential for optimal skeletal growth in children, as dietary intake can directly or indirectly influence bone structure and metabolism [80]. Furthermore, adequate physical exercises are important for supporting bone growth, bone mass accumulation and bone strength [81]. Hence, healthy nutrient intakes and a routine exercise program may provide benefits in improving bone health and overall quality of life for paediatric chemotherapy patients and survivors. Antioxidants Antioxidants have been used in combination with chemotherapy to reduce or prevent ROS-induced toxicities [82]. Commonly used antioxidants include vitamin E, vitamin C, Coenzyme Q10, -carotene, glutathione and soy isoflavones [83]. Animal studies have shown potential benefits of antioxidants in protecting bone against oxidative stress. Apart from being able to reverse lipid peroxidation inhibitory effects and protect against cardiotoxicity, vitamin E was able to preserve the growth plate thickness and sustain normal bone growth [82]. Further studies are required to investigate potential beneficial effects of antioxidants in preserving bone growth and preventing bone loss in paediatric oncology patients. Bisphosphonates Clinical use of bisphosphonates has increased in the past 30 years due to their ability to inhibit osteoclast formation/function and bone loss [78]. Bisphosphonates can also enhance bone formation by promoting osteoblast differentiation, proliferation and maturation [84]. Bisphosphonates, commonly used to reduce bone loss in a variety of clinical conditions in adult patients [85], are now accepted practice for the management of children with osteogenesis imperfecta and juvenile osteoporosis [19]. However, very few studies have investigated use of bisphosphonates in children with cancers. Goldbloom et al. showed that

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Table 1.

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Potential Supplementary Treatments for Preventing Bone Defects During Childhood Cancer Chemotherapy

Agents

Rationale supporting the use

Data supporting the use

Rationale against the use

Calcium & vitamin D

In paediatric cancer patients, vitamin D and calcium deficiency may occur due to malabsorption, malnutrition and lack of sun exposure [79].

During chemotherapy, daily supplementation of 500mg calcium and 400 IU vitamin D are important for preventing childhood bone loss [79].

Vitamin D overdose may cause the increase of intestinal calcium absorption and a high level of blood calcium, leading to calcium deposition in soft tissues (kidney & lungs) and reduce their ability to function [114].

Bisphosphonates

Inducing apoptosis of osteoclasts and preventing bone loss [115], and enhancing bone formation by promoting osteogenic differentiation [116].

Both intravenous infusion of pamidronate and oral administration of alendronate have been shown to improve BMD in paediatric patients undergoing chemotherapy for ALL and NHS [117,118].

Intravenous infusion can cause acute reactions after dosing, such as musculoskeletal pain, vomiting, hyperpyrexia and hypocalcemia [118]. Long-term usage can potentially impair bone remodeling [89].

Folinic acid

Folate deficiency has been reported in paediatric cancer patients receiving MTX (anti-folate drug) [119]. Folate deficiency has also been reported in cancer patients due to poor dietary intake and increased metabolic needs imposed by malignancy.

Folinic acid is clinically used to reduce toxicities in soft tissues caused by high dose MTX chemotherapy. Animal trials showed efficacy of folinic acid supplementation during MTX treatment in preserving growth plate function and bone growth, stromal progenitor cells and overall bone volume [48].

Excess folate or folinic acid supplementation may cause “over rescue” and reduce MTX chemotherapy efficiency [98].

Antioxidants

Anti-cancer drugs have been shown to cause oxidative stress, which can significantly damage normal tissues [69].

Both vitamin E and vitamin C can stimulate bone formation in vivo.

Genistein overdose may potentially influence sexual maturation in children [120].

Resveratrol

Resveratrol possesses an antiinflammatory property as it inhibits NF-B activity and expression of TNF and IL-1 [103], suggesting its potential role in inhibition of osteoclast formation.

Resveratrol has been shown clinically to potentiate the effects of cancer therapy [101]. It can also inhibit free-radical formation and reduces oxidative stress [99].

Currently no studies have been found arguing against the use of resveratrol.

adjuvant pamidronate can successfully relieve bone pain and improve BMD and treat vertebral fractures in children with ALL [86,87]. One recent study even showed that bisphosphonates may be able to treat osteonecrosis in childhood ALL [88]. Despite the improvement of bone quality reported in these limited studies, the impact of potential interaction between bisphosphonates and chemotherapy remains unknown. Since bisphosphonates are known to have a long halflife once incorporated into bone, their long-term use may have detrimental skeletal effects on children’s bone remodeling [89]. However, given their potential benefits on bone health, further studies are required to examine the benefits and safety of long-term use of bisphosphonates in preventing bone loss or fractures in paediatric patients during chemotherapy. Amifostine Amifostine is a cytoprotective agent which can selectively protect normal tissue from cytotoxic effects of cancer treatments, and is the first drug approved for clinical protection against damaging effects of both radiation and chemotherapy [90]. The mechanism for Amifostine as a radioprotectant involves free radical scavenging and hydrogen donation to repair damaged

DNA [91]. Animal studies have shown that pretreatment with Amifostine can prevent radiationinduced bone growth arrest [92]. While fewer studies were found on use of Amifostine in children, one study reported that Amifostine was tolerable with minormoderate acute side effects in paediatric patients [93]. However, several studies also reported that Amifostine failed to reduce ototoxicity, renal and bone marrow toxicity in paediatric patients receiving cisplatin-based chemotherapy [94,95]. Folinic Acid Folinic acid (or Leucovorin) can be converted into active forms of folate in human body, which are important for DNA and RNA synthesis. Folinic acid supplementation has been effective clinically in reducing MTX toxicity (due to an effective folate deficiency) in soft tissues [96]. Animal experiments also showed efficacy of folinic acid in protecting bone growth during MTX chemotherapy. In young rats, folinic acid was able to preserve proliferation and reduce apoptosis in the growth plate, and preserved stromal progenitor cells in the bone marrow [48,50]. While folinic acid rescue is used clinically to reduce toxicity in soft tissues following treatment with high dose MTX,


whether its administration contributes to preserve bone growth in treated children remains to be investigated. In addition, there have been some uncertainties (due to variations in dosing and scheduling) over the potential risk of reducing MTX treatment efficacy or “overrescue”. A study revealed that pretreatment of folate affected peak plasma MTX concentrations in children with ALL/NHL treated with MTX, providing support for the potential “folate over-rescue” concept [97]. Consistently, a recent study suggested that high dose folinic acid may increase relapse risks in children [98]. Paediatric oncology is now divided, using either repeated lower doses of MTX without folinic acid rescue, or high MTX doses with folinic acid rescue [97]. While folinic acid dosage should be reduced as much as possible without intolerable MTX acute toxicities, it has been suggested that MTX/folinic acid dosage ratio at a 1:1 for treatments of ALL is generally without the risk of over rescuing [98]. Further clinical studies are needed to determine the optimal dosing and scheduling of folinic acid administration with MTX. Resveratrol Resveratrol is a natural occurring phytoalexin produced by several plants such as red grapes, berries and peanuts. It has been considered as a potential chemo-preventive agent due to its ability to promote apoptosis and suppress tumor cell proliferation [99, 100], and potentiate the effects of chemotherapeutic agents and radiation therapy [101]. Resveratrol has been shown to inhibit free-radical formation and reduce oxidative stress [99]. Furthermore, resveratrol possesses an anti-inflammatory property as it inhibits NF-B activity and expression of inflammation genes such as TNF-, IL-1, and IL-6 [102,103], suggesting its potential role in inhibiting osteoclast formation and bone resorption. While resveratrol does not affect bone development [104], in vitro studies have shown its potential in bone health by promoting osteoblast formation and inhibiting adipogenesis [105]. Due to these properties, resveratrol may be considered for investigation for its potential use during chemotherapy to potentiate cancer chemotherapeutic efficacy and to limit chemotherapy-associated bone defects. Several pre-clinical and clinical studies have demonstrated that resveratrol is well-tolerated and pharmacologically safe [106,107].

MANAGEMENT OF CHEMOTHERAPY-INDUCED OSTEONECROSIS (ON) As ON is often painless at first, it is crucial to monitor glucocorticoid therapy to minimize and ameliorate long-term toxicities. Proposed strategies for monitoring ON include early MRI diagnosis, frequent follow-up assessments and clear description of therapeutic interventions [38]. These require commonly agreed establishment for both definitions of diagnostic criteria and staging of ON for paediatric cancer patients. Treatment options for ON include both surgical and non-surgical interventions. Surgical


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procedures such as core decompression, bone grafting and joint replacement have been used to slow or stop ON progression [43], with results generally being better in patients with early stage of ON. However, since there are concerns with performing these procedures in growing subjects with open growth plates, they may not be attractive options for children. Non-surgical interventions such as “extracorporeal shock waves” external electrical stimulation have been shown to be more effective in relieving pain for patients affected by early stage of ON than surgical interventions after short-term treatment [108]. Apart from the benefits in ameliorating low bone mass in children with ALL or NHL [109], some studies also reported further advantage of bisphosphonate usage in preventing glucocorticoid-induced ON in children [88].

CONCLUSIONS The established role of intensive chemotherapy in the management of pediatric malignancy has resulted in a growing population of young cancer survivors who are at increased risks of low bone mass in young adult life. Chemotherapy-only regimens during childhood may predispose the child to poor growth, a lower bone mass and a higher fracture risk during the period of chemotherapy and shortly afterwards, and cumulative glucocorticoid treatment can cause osteonecrosis. Recent mechanistic investigation has suggested that chemotherapy can directly suppress endochondral bone formation by suppressing growth plate activity, decreasing osteoblastic density and activity, inducing osteocyte apoptosis, increasing osteoclastic bone resorption, and through oxidative stress. Although there are no specific treatment strategies currently available to protect bone during childhood chemotherapy, therapeutic interventions should include strategies for preserving growth plate integrity, osteoblastic bone formation, and minimizing chemotherapy-induced osteoclastic bone resorption. It has been suggested paediatric patients should be instructed to optimize calcium and vitamin D intakes and exercise regularly during and after chemotherapy. Other recommendations include regular BMD monitoring for early detection of fracture risks, and potential controlled use of bisphosphonates, antioxidants, and/or folinic acid to optimize skeletal health during paediatric cancer treatment. Furthermore, osteonecrosis is currently managed by surgical and/or potentially non-surgical interventions such as external electrical stimulation and controlled bisphosphonate usage.

FUTURE PERSPECTIVES Since high dose glucocorticoids, MTX and other cytotoxic drugs significantly suppress growth plate activity, the judicious use of these drugs while ensuring effectiveness of cancer treatment remains a challenge. On the other hand, it is also important to develop adjuvant treatments that can reduce chemotherapy toxicity in growth plate chondrocytes. While folinic acid

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could be considered to counter MTX toxicity in the growth plate as discussed above, effective agents for reducing glucocorticoid adverse effects in the growth plate remain to be identified. Since glucocorticoids reduce bone lengthening mainly through reducing IGF-I levels and thus growth plate activity locally [13,35], it is unclear whether acute treatment with IGF-I peptide can promote growth plate activity and thus bone lengthening during and/or after chemotherapy. However, due to the limited ability of endocrine IGF-I to restore normal growth and the potential risks reported for administering IGF-I peptide in children (lymphoid hyperplasic induction, endogenous growth hormone suppression), use of recombinant IGF-I should be limited [110]. While PTH has been the only agent approved so far as an anabolic protein (promoting osteoblast action) used to treat adult osteoporosis, an antibody targeting sclerostin (the key negative regulator of bone formation) is currently being optimised in clinical studies and has already shown potency in promoting bone formation, bone mass and strength, and prevent osteoporosis [111]. However, it remains to be investigated whether these agents can promote or maintain bone formation during cancer chemotherapy. As for agents that can minimise bone resorption during and after chemotherapy in paediatric settings, bisphosphonates could hold some promises to reduce the incidence of skeletal defects and improve patients' quality of life. As a potential new anti-osteoclastic drug for treating osteoporosis, Denosumab, a monoclonal antibody against RANKL, has been shown to significantly reduce fracture risks in postmenopausal women [112]. Due to the significantly enhanced osteoclastic activity after chemotherapy, Denosumab could be a good candidate to be studied for its potential for preventing chemotherapy-induced bone loss. Future studies are required for searching for specific, effective and safe strategies for preserving bone growth and preventing bone loss during chemotherapy. Furthermore, new chemotherapy strategies need to be developed which can increase cure rates, reduce relapse incidence, minimise the acute and long-term side effects (including the skeletal defects) and improve the quality of life in the patients and survivors [113].

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[3] [4] [5]

[6]

[7]

[8]

[9]

[10]

[11]

[12] [13]

[14]

[15]

[16]

[17]

[18]

RESEARCH SUPPORT The authors wish to thank Bone Growth Foundation, National Health and Medical Research Council of Australia, Women’s and Children’s Hospital Foundation, and Channel-7 Children’s Research Foundation (South Australia) for funding some of our own research work discussed.

[19] [20]

[21]

[22]

REFERENCES [1]

Xian CJ. Roles of epidermal growth factor family in the regulation of postnatal somatic growth. Endocr Rev 2007; 28: 284-296.

[23]

Stevens HY, Reeve J, Noble BS. Bcl-2, tissue transglutaminase and p53 protein expression in the apoptotic cascade in ribs of premature infants. J Anat 2000; 196 ( Pt 2): 181-191. Noble BS. The osteocyte lineage. Arch Biochem Biophys 2008; 473: 106-111. Bonewald LF, Johnson ML. Osteocytes, mechanosensing and Wnt signaling. Bone 2008; 42: 606-615. van der Eerden BCJ, Karperien M, Wit JM. Systemic and local regulation of the growth plate. Endocr Rev 2003; 24: 782-801. Mitchell C, Payne J, Wade R, et al. The impact of risk stratification by early bone-marrow response in childhood lymphoblastic leukaemia: results from the United Kingdom Medical Research Council trial ALL97 and ALL97/99. Br J Haematol 2009; 146: 424-436. Siebler T, Shalet SM, Robson H. Effects of chemotherapy on bone metabolism and skeletal growth. Horm Res 2002; 58 Suppl 1: 80-85. Mandel K, Atkinson S, Barr RD, Pencharz P. Skeletal morbidity in childhood acute lymphoblastic leukemia. J Clin Oncol 2004; 22: 1215-1221. Thomas IH, Donohue JE, Ness KK, et al. Bone mineral density in young adult survivors of acute lymphoblastic leukemia. Cancer 2008; 113: 3248-3256. Niinimaki RA, Harila-Saari AH, Jartti AE, et al. Osteonecrosis in children treated for lymphoma or solid tumors. J Pediatr Hematol Oncol 2008; 30: 798-802. Wasilewski-Masker K, Kaste SC, Hudson MM, et al. Bone mineral density deficits in survivors of childhood cancer: long-term follow-up guidelines and review of the literature. Pediatrics 2008; 121: e705-713. Ahmed SF, Elmantaser M. Secondary osteoporosis. Endocr Dev 2009; 16: 170-190. Gunes AM, Can E, Saglam H, Ilcol YO, Baytan B. Assessment of bone mineral density and risk factors in children completing treatment for acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2010; 32: e102-107. Crofton PM, Ahmed SF, Wade JC, et al. Effects of intensive chemotherapy on bone and collagen turnover and the growth hormone axis in children with acute lymphoblastic leukemia. J Clin Endocrinol Metab 1998; 83: 3121-3129. Crofton PM, Ahmed SF, Wade JC, et al. Effects of a third intensification block of chemotherapy on bone and collagen turnover, insulin-like growth factor I, its binding proteins and short-term growth in children with acute lymphoblastic leukaemia. Eur J Cancer 1999; 35: 960-967. Halton JM, Atkinson SA, Barr RD. Growth and body composition in response to chemotherapy in children with acute lymphoblastic leukemia. Int J Cancer Suppl 1998; 11: 81-84. Viana MB, Vilela MI. Height deficit during and many years after treatment for acute lymphoblastic leukemia in children: a review. Pediatr Blood Cancer 2008; 50: 509-516; discussion 517. Bath LF, Crofton PM, Evans AE, et al. Bone turnover and growth during and after chemotherapy in children with solid tumors. Pediatr Res 2004; 55: 224-230. Bianchi ML. How to manage osteoporosis in children. Best Pract Res Clin Rheumatol 2005; 19: 991-1005. Kovacs CS. Hemophilia, low bone mass, and osteopenia/osteoporosis. Transfus Apher Sci 2008; 38: 3340. Baim S, Binkley N, Bilezikian JP, et al. Official Positions of the International Society for Clinical Densitometry and executive summary of the 2007 ISCD Position Development Conference. J Clin Densitom 2008; 11: 75-91. van der Sluis IM, van den Heuvel-Eibrink MM, Hahlen K, Krenning EP, de Muinck Keizer-Schrama SM. Bone mineral density, body composition, and height in long-term survivors of acute lymphoblastic leukemia in childhood. Med Pediatr Oncol 2000; 35: 415-420. Atkinson SA, Halton JM, Bradley C, Wu B, Barr RD. Bone and mineral abnormalities in childhood acute lymphoblastic


[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35] [36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

leukemia: influence of disease, drugs and nutrition. Int J Cancer Suppl 1998; 11: 35-39. Holzer G, Krepler P, Koschat MA, et al. Bone mineral density in long-term survivors of highly malignant osteosarcoma. J Bone Joint Surg Br 2003; 85: 231-237. van Leeuwen BL, Hartel RM, Jansen HW, Kamps WA, Hoekstra HJ. The effect of chemotherapy on the morphology of the growth plate and metaphysis of the growing skeleton. Eur J Surg Oncol 2003; 29: 49-58. Haddy TB, Mosher RB, Reaman GH. Late effects in longterm survivors after treatment for childhood acute leukemia. Clin Pediatr (Phila) 2009; 48: 601-608. van der Sluis IM, van den Heuvel-Eibrink MM, Hahlen K, Krenning EP, de Muinck Keizer-Schrama SM. Altered bone mineral density and body composition, and increased fracture risk in childhood acute lymphoblastic leukemia. J Pediatr 2002; 141: 204-210. Kaste SC, Jones-Wallace D, Rose SR, et al. Bone mineral decrements in survivors of childhood acute lymphoblastic leukemia: frequency of occurrence and risk factors for their development. Leukemia 2001; 15: 728-734. Caruso-Nicoletti M, Mancuso M, Spadaro G, et al. Growth and growth hormone in children during and after therapy for acute lymphoblastic leukaemia. Eur J Pediatr 1993; 152: 730-733. Ahmed SF, Wallace WH, Crofton PM, et al. Short-term changes in lower leg length in children treated for acute lymphoblastic leukaemia. J Pediatr Endocrinol Metab 1999; 12: 75-80. Ecklund K, Laor T, Goorin AM, Connolly LP, Jaramillo D. Methotrexate osteopathy in patients with osteosarcoma. Radiology 1997; 202: 543-547. Elliot KJ, Millward-Sadler SJ, Wright MO, et al. Effects of methotrexate on human bone cell responses to mechanical stimulation. Rheumatology (Oxford) 2004; 43: 1226-1231. Crofton PM, Ahmed SF, Wade JC, et al. Bone turnover and growth during and after continuing chemotherapy in children with acute lymphoblastic leukemia. Pediatr Res 2000; 48: 490-496. Leonard MB. Glucocorticoid-induced osteoporosis in children: impact of the underlying disease. Pediatrics 2007; 119 Suppl 2: S166-174. Olney RC. Mechanisms of impaired growth: effect of steroids on bone and cartilage. Horm Res 2009; 72 Suppl 1: 30-35. Yonemura K, Fukasawa H, Fujigaki Y, Hishida A. Skeletal effects of short-term prednisolone therapy in children with steroid-responsive nephrotic syndrome. Clin Exp Nephrol 2001; 5: 40-43. Sala A, Mattano LA, Jr., Barr RD. Osteonecrosis in children and adolescents with cancer - an adverse effect of systemic therapy. Eur J Cancer 2007; 43: 683-689. Kaste SC. Skeletal toxicities of treatment in children with cancer. Pediatr Blood Cancer 2008; 50: 469-473; discussion 486. Kadan-Lottick NS, Dinu I, Wasilewski-Masker K, et al. Osteonecrosis in adult survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol 2008; 26: 3038-3045. Faraci M, Calevo MG, Lanino E, et al. Osteonecrosis after allogeneic stem cell transplantation in childhood. A casecontrol study in Italy. Haematologica 2006; 91: 1096-1099. Bluemke DA, Fishman EK, Scott WW, Jr. Skeletal complications of radiation therapy. Radiographics 1994; 14: 111-121. Arico M, Boccalatte MF, Silvestri D, et al. Osteonecrosis: An emerging complication of intensive chemotherapy for childhood acute lymphoblastic leukemia. Haematologica 2003; 88: 747-753. Barr RD, Sala A. Osteonecrosis in children and adolescents with cancer. Pediatr Blood Cancer 2008; 50: 483-485; discussion 486. Mattano LA, Sather HN, Trigg ME, Nachman JB. Osteonecrosis as a Complication of Treating Acute


[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57] [58]

[59]

[60]

[61]

[62]

[63]

[64]

149

Lymphoblastic Leukemia in Children: A Report From the Children’s Cancer Group. Clin Oncol 2000; 18: 3262-3272. Xian CJ, Cool JC, van Gangelen J, Foster BK, Howarth GS. Effects of etoposide and cyclophosphamide acute chemotherapy on growth plate and metaphyseal bone in rats. Cancer Biol Ther 2007; 6: 170-177. Xian CJ, Cool JC, Pyragius T, Foster BK. Damage and recovery of the bone growth mechanism in young rats following 5-fluorouracil acute chemotherapy. J Cell Biochem 2006; 99: 1688-1704. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003; 3: 330-338. Xian CJ, Cool JC, Scherer MA, Fan C, Foster BK. Folinic acid attenuates methotrexate chemotherapy-induced damages on bone growth mechanisms and pools of bone marrow stromal cells. J Cell Physiol 2008; 214: 777-785. Xian CJ, Cool JC, Scherer MA, et al. Cellular mechanisms for methotrexate chemotherapy-induced bone growth defects. Bone 2007; 41: 842-850. Fan C, Cool JC, Scherer MA, et al. Damaging effects of chronic low-dose methotrexate usage on primary bone formation in young rats and potential protective effects of folinic acid supplementary treatment. Bone 2009; 44: 61-70. Owen HC, Miner JN, Ahmed SF, Farquharson C. The growth plate sparing effects of the selective glucocorticoid receptor modulator, AL-438. Mol Cell Endocrinol 2007; 264: 164-170. Fujita T, Fukuyama R, Enomoto H, Komori T. Dexamethasone inhibits insulin-induced chondrogenesis of ATDC5 cells by preventing PI3K-Akt signaling and DNA binding of Runx2. J Cell Biochem 2004; 93: 374-383. Chrysis D, Zaman F, Chagin AS, Takigawa M, Savendahl L. Dexamethasone induces apoptosis in proliferative chondrocytes through activation of caspases and suppression of the Akt-phosphatidylinositol 3'-kinase signaling pathway. Endocrinology 2005; 146: 1391-1397. Davies JH, Evans BA, Jenney ME, Gregory JW. In vitro effects of combination chemotherapy on osteoblasts: implications for osteopenia in childhood malignancy. Bone 2002; 31: 319-326. Li J, Law HK, Lau YL, Chan GC. Differential damage and recovery of human mesenchymal stem cells after exposure to chemotherapeutic agents. Br J Haematol 2004; 127: 326334. Banfi A, Podestà M, Fazzuoli L, Sertoli MR, Venturini M, Santini G, Cancedda R, Quarto R. High-dose chemotherapy shows a dose-dependent toxicity to bone marrow osteoprogenitors: a mechanism for post-bone marrow transplantation osteopenia. Cancer 2001; 92: 2419-2428. Weinstein RS. Glucocorticoid-induced osteoporosis. Rev Endocr Metab Disord 2001; 2: 65-73. Liu Y, Porta A, Peng X, et al. Prevention of glucocorticoidinduced apoptosis in osteocytes and osteoblasts by calbindin-D28k. J Bone Miner Res 2004; 19: 479-490. Yin L, Li YB, Wang YS. Dexamethasone-induced adipogenesis in primary marrow stromal cell cultures: mechanism of steroid-induced osteonecrosis. Chin Med J (Engl) 2006; 119: 581-588. Gore AC, Attardi B, DeFranco DB. Glucocorticoid repression of the reproductive axis: effects on GnRH and gonadotropin subunit mRNA levels. Mol Cell Endocrinol 2006; 256: 40-48. Yeap SS, Hosking DJ. Management of corticosteroidinduced osteoporosis. Rheumatology (Oxford) 2002; 41: 1088-1094. Darst M, Al-Hassani M, Li T, et al. Augmentation of chemotherapy-induced cytokine production by expression of the platelet-activating factor receptor in a human epithelial carcinoma cell line. J Immunol 2004; 172: 6330-6335. Pusztai L, Mendoza TR, Reuben JM, et al. Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy. Cytokine 2004; 25: 94-102. Mills PJ, Ancoli-Israel S, Parker B, et al. Predictors of inflammation in response to anthracycline-based

150

[65]

[66]

[67] [68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

[77]

[78] [79]

[80] [81]

[82]

[83]

[84]

[85] [86]

[87]

Current Molecular Medicine, 2011, Vol. 11, No. 2 chemotherapy for breast cancer. Brain Behav Immun 2008; 22: 98-104. Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int 2007; 18: 1319-1328. van Essen HW, Holzmann PJ, Blankenstein MA, Lips P, Bravenboer N. Effect of raloxifene treatment on osteocyte apoptosis in postmenopausal women. Calcif Tissue Int 2007; 81: 183-190. Seeman E. Osteocytes--martyrs for integrity of bone strength. Osteoporos Int 2006; 17: 1443-1448. Kogianni G, Mann V, Noble BS. Apoptotic bodies convey activity capable of initiating osteoclastogenesis and localized bone destruction. J Bone Miner Res 2008; 23: 915-927. Conklin KA. Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness. Integr Cancer Ther 2004; 3: 294-300. Babiak RM, Campello AP, Carnieri EG, Oliveira MB. Methotrexate: pentose cycle and oxidative stress. Cell Biochem Funct 1998; 16: 283-293. Basu S MK, Olofsson H, Johansson S, Melhus H. Association between oxidative stress and bone mineral density. Biochem Biophys Res Commun 2001; 288: 275-279. Sener G, Eksioglu-Demiralp E, Cetiner M, et al. L-Carnitine ameliorates methotrexate-induced oxidative organ injury and inhibits leukocyte death. Cell Biol Toxicol 2006; 22: 47-60. Banfi G, Iorio EL, Corsi MM. Oxidative stress, free radicals and bone remodeling. Clin Chem Lab Med 2008; 46: 15501555. Lean JM, Davies JT, Fuller K, et al. A crucial role for thiol antioxidants in estrogen-deficiency bone loss. J Clin Invest 2003; 112: 915-923. Bai XC, Lu D, Bai J, et al. Oxidative stress inhibits osteoblastic differentiation of bone cells by ERK and NFkappaB. Biochem Biophys Res Commun 2004; 314: 197207. Xian CJ. Roles of growth factors in chemotherapy-induced intestinal mucosal damage repair. Curr Pharm Biotechnol 2003; 4: 260-269. Arikoski P, Komulainen J, Riikonen P, et al. Alterations in bone turnover and impaired development of bone mineral density in newly diagnosed children with cancer: a 1-year prospective study. J Clin Endocrinol Metab 1999; 84: 31743181. Michaud LB, Goodin S. Cancer-treatment-induced bone loss, part 2. Am J Health Syst Pharm 2006; 63: 534-546. van der Sluis IM, van den Heuvel-Eibrink MM. Osteoporosis in children with cancer. Pediatr Blood Cancer 2008; 50: 474478; discussion 486. Rizzoli R. Nutrition: its role in bone health. Best Pract Res Clin Endocrinol Metab 2008; 22: 813-829. Macdonald HM, Kontulainen SA, Khan KM, McKay HA. Is a school-based physical activity intervention effective for increasing tibial bone strength in boys and girls? J Bone Miner Res 2007; 22: 434-446. Conklin KA. Dietary antioxidants during cancer chemotherapy: impact on chemotherapeutic effectiveness and development of side effects. Nutr Cancer 2000; 37: 1-18. Block KI, Koch AC, Mead MN, et al. Impact of antioxidant supplementation on chemotherapeutic toxicity: a systematic review of the evidence from randomized controlled trials. Int J Cancer 2008; 123: 1227-1239. von Knoch F, Jaquiery C, Kowalsky M, et al. Effects of bisphosphonates on proliferation and osteoblast differentiation of human bone marrow stromal cells. Biomaterials 2005; 26: 6941-6949. Coleman RE. Risks and benefits of bisphosphonates. Br J Cancer 2008; 98: 1736-1740. Goldbloom EB, Cummings EA, Yhap M. Osteoporosis at presentation of childhood ALL. Pediat Hematol-Oncol 2005; 22: 543-550. Wiernikowski JT, Barr RD, Webber C, et al. Alendronate for steroid-induced osteopenia in children with acute

Fan et al.

[88]

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

[100]

[101] [102]

[103]

[104] [105]

[106]

[107]

lymphoblastic leukaemia or non-Hodgkin's lymphoma: results of a pilot study. J Oncol Pharm Pract 2005; 11: 51-56. Kotecha RS, Powers N, Lee SJ, et al. Use of bisphosphonates for the treatment of osteonecrosis as a complication of therapy for childhood acute lymphoblastic leukaemia (ALL). Pediatr Blood Cancer 2010; 54: 934-940. Rauch F, Munns C, Land C, Glorieux FH. Pamidronate in children and adolescents with osteogenesis imperfecta: effect of treatment discontinuation. J Clin Endocrinol Metab 2006; 91: 1268-1274. Damron TA, Spadaro JA, Margulies B, Damron LA. Dose response of amifostine in protection of growth plate function from irradiation effects. Int J Cancer 2000; 90: 73-79. van der Vijgh WJ, Peters GJ. Protection of normal tissues from the cytotoxic effects of chemotherapy and radiation by amifostine (Ethyol): preclinical aspects. Semin Oncol 1994; 21: 2-7. Damron TA, Margulies B, Biskup D, Spadaro JA. Amifostine before fractionated irradiation protects bone growth in rats better than fractionation alone. Int J Radiat Oncol Biol Phys 2001; 50: 479-483. Phan C, Paris K, Jose B, et al. Tolerance and practicality of amifostine during radiation of pediatric patients to reduce long term side effects and second malignancies. Radiother Oncol 2004; 73: S385. Fisher MJ, Lange BJ, Needle MN, et al. Amifostine for children with medulloblastoma treated with cisplatin-based chemotherapy. Pediatr Blood Cancer 2004; 43: 780-784. Katzenstein HM, Chang KW, Krailo M, et al. Amifostine does not prevent platinum-induced hearing loss associated with the treatment of children with hepatoblastoma: a report of the Intergroup Hepatoblastoma Study P9645 as a part of the Children's Oncology Group. Cancer 2009; 115: 5828-5835. Peters GJ, van der Wilt CL, van Moorsel CJA, et al. Basis for effective combination cancer chemotherapy with antimetabolites. Pharmacol Ther 2000; 87: 227-253. Sterba J, Dusek L, Demlova R, Valik D. Pretreatment plasma folate modulates the pharmacodynamic effect of high-dose methotrexate in children with acute lymphoblastic leukemia and non-Hodgkin lymphoma: "folate overrescue" concept revisited. Clin Chem 2006; 52: 692-700. Skarby TV, Anderson H, Heldrup J, et al. High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia. Leukemia 2006; 20: 1955-1962. Aggarwal BB, Bhardwaj A, Aggarwal RS, et al. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res 2004; 24: 2783-2840. Cecchinato V, Chiaramonte R, Nizzardo M, et al. Resveratrol-induced apoptosis in human T-cell acute lymphoblastic leukaemia MOLT-4 cells. Biochem Pharmacol 2007; 74: 1568-1574. Cucciolla V, Borriello A, Oliva A, et al. Resveratrol: from basic science to the clinic. Cell Cycle 2007; 6: 2495-2510. Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol 2000; 164: 6509-6519. Kang OH, Jang HJ, Chae HS, et al. Anti-inflammatory mechanisms of resveratrol in activated HMC-1 cells: pivotal roles of NF-kappaB and MAPK. Pharmacol Res 2009; 59: 330-337. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 2006; 5: 493-506. Backesjo CM, Li Y, Lindgren U, Haldosen LA. Activation of Sirt1 decreases adipocyte formation during osteoblast differentiation of mesenchymal stem cells. J Bone Miner Res 2006; 21: 993-1002. Bishayee A, Politis T, Darvesh AS. Resveratrol in the chemoprevention and treatment of hepatocellular carcinoma. Cancer Treat Rev; 36: 43-53. Williams LD, Burdock GA, Edwards JA, Beck M, Bausch J. Safety studies conducted on high-purity trans-resveratrol in


[108]

[109]

[110]

[111]

[112]

[113]

[114]

experimental animals. Food Chem Toxicol 2009; 47: 21702182. Wang CJ, Wang FS, Huang CC, et al. Treatment for osteonecrosis of the femoral head: comparison of extracorporeal shock waves with core decompression and bone-grafting. J Bone Joint Surg Am 2005; 87: 2380-2387. Nishii T, Sugano N, Miki H, Hashimoto J, Yoshikawa H. Does aledronate prevent collapse in osteonrcrosis of the femoral head? Clin Orthop Relat Res 2006; 443: 273-279. Rosenbloom AL. Recombinant human insulin-like growth factor I (rhIGF-I) and rhIGF-I/rhIGF-binding-protein-3: new growth treatment options? J Pediatr 2007; 150: 7-11. Ominsky MS, Vlasseros F, Jolette J, et al. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J Bone Miner Res 2010; 25: 948-959. Silverman SL. New therapies for osteoporosis: zoledronic acid, bazedoxifene, and denosumab. Curr Osteoporos Rep 2009; 7: 91-95. Arya LS, Kotikanyadanam SP, Bhargava M, et al. Pattern of relapse in childhood ALL: challenges and lessons from a uniform treatment protocol. J Pediatr Hematol Oncol 2010. Garland CF, Garland FC, Gorham ED, et al. The role of vitamin D in cancer prevention. Am J Public Health 2006; 96: 252-261.

Received: October 20, 2010


Revised: January 03, 2011

Accepted: January 27, 2011

[115]

[116]

[117]

[118]

[119]

[120]

151

Rogers MJ, Gordon S, Benford HL, et al. Cellular and molecular mechanisms of action of bisphosphonates. Cancer 2000; 88: 2961-2978. Knocha FV, Jaquieryb C, Kowalskya M, et al. Effects of bisphosphonates on proliferation and osteoblast differentiation of human bone marrow stromal cells Biomaterials 2005; 26: 6941-6949. Lethaby C, Wiernikowski J, Sala A, et al. Bisphosphonate therapy for reduced bone mineral density during treatment of acute lymphoblastic leukemia in childhood and adolescence: a report of preliminary experience. J Pediatr Hematol Oncol 2007; 29: 613-616. Barr RD, Guo CY, Wiernikowski J, et al. Osteopenia in children with acute lymphoblastic leukemia: a pilot study of amelioration with Pamidronate. Med Pediatr Oncol 2002; 39: 44-46. Ulrich CM, Potter JD. Folate supplementation: too much of a good thing? Cancer Epidemiol Biomarkers Prev 2006; 15: 189-193. Cassidy A, Bingham S, Setchell KD. Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women. Am J Clin Nutr 1994; 60: 333340.