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Bone Mineral Density Deficits in Survivors of Childhood Cancer: Long-term Follow-up Guidelines and Review of the Literature

^a Division of Pediatric Hematology Oncology, Department of Pediatrics
^e Department of Radiation Oncology
^g Division of Endocrinology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
^b Radiological Sciences
^d Hematology Oncology, St Jude Children's Research Hospital, Memphis, Tennessee
^c Department of Radiology, University of Tennessee School of Health Sciences, Memphis, Tennessee
^f Division of Hematology Oncology, Department of Pediatrics, Michigan State University/Kalamazoo Center for Medical Studies, Kalamazoo, Michigan

	ABSTRACT

TOP ABSTRACT DEFINITIONS OF BMD DEFICITS METHODS OF BMD ASSESSMENT METHODS RESULTS CONCLUSIONS COG LATE EFFECTS COMMITTEE... APPENDIX Risk Factors for... REFERENCES

 
The development of curative therapy for most pediatric malignancies has produced a growing population of childhood cancer survivors who are at increased risk for a variety of health problems resulting from their cancer or its treatment. Because of the fact that many treatment-related sequelae may not become clinically apparent until the survivor attains maturity or begins to age, the ability of primary care providers to anticipate late effects of treatment is essential for providing timely interventions that prevent or correct these sequelae and their adverse effects on quality of life. Altered bone metabolism during treatment for childhood cancer may interfere with attainment of peak bone mass, potentially predisposing to premature onset of and more severe complications related to osteopenia and osteoporosis. Bone mineral deficits have been reported after treatment for a variety of pediatric malignancies and represent morbidity that can be reduced or prevented through lifestyle changes and attention to other common cancer-related sequelae such as hypogonadism. The Children's Oncology Group long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers provide risk-based surveillance recommendations that are based on expert opinion and review of the scientific literature for potential late effects of pediatric cancer therapy including osteopenia. This review summarizes the existing literature that has defined characteristics of cancer survivors at risk for bone mineral deficits and contributed to the surveillance and counseling recommendations outlined in the Children's Oncology group long-term follow-up guidelines.

Key Words: osteopenia • bone mineral density • cancer • pediatrics • survivors

Abbreviations: GHD—growth hormone deficiency • BMD—bone mineral density • COG—Children's Oncology Group • LTFU—long-term follow-up • DXA—dual-radiograph absorptiometry • QCT—quantitative computed tomography • ALL—acute lymphoblastic leukemia • HCT—hematopoietic cell transplant • TBI—total body irradiation

The development of curative therapy for most pediatric malignancies has produced a growing population of childhood cancer survivors at increased risk for a variety of health problems resulting from their cancer or its treatment.¹ Because of the fact that many treatment-related sequelae may not become clinically apparent until the survivor gets older, the ability of primary care providers to anticipate late effects is essential for providing timely interventions that prevent or correct these sequelae and their effects on quality of life. Risk-based care, defined as a systematic plan for lifelong screening, surveillance, and prevention that incorporates risks based on the previous cancer, cancer therapy, genetic predispositions, lifestyle behaviors, and comorbid health conditions, is recommended for all survivors.² Knowledge about cancer-related effects permits clinicians to implement risk-based care that includes appropriate health surveillance for medically vulnerable groups.

Cancer treatment can produce occult or subclinical effects that may become clinically significant with aging. One such effect is altered bone metabolism that may interfere with attainment of peak bone mass, potentially predisposing to premature onset of and more severe complications related to osteoporosis. Bone mineral deficits have been reported after treatment for a variety of pediatric malignancies and represent morbidity that can be reduced or prevented through lifestyle changes and attention to cancer-related sequelae such as hypogonadism and growth hormone deficiency (GHD).^3–8 Prednisone and methotrexate, agents that are commonly used in the treatment of childhood leukemia, reduce bone mineral accretion during therapy.^9–12 GHD associated with radiation-induced hypothalamic-pituitary injury may contribute to bone mineral density (BMD) deficits by impairing bone growth and mineral acquisition.¹³ Radiation to reproductive organs and alkylating agent chemotherapy can cause dose-related gonadal injury, and the resultant deficiencies of estrogen or testosterone can result in decreased BMD.^4,8 Timely diagnosis and initiation of appropriate hormonal therapy aid in the correction of bone mineral deficits that may become more clinically important in aging childhood cancer survivors.

The goal of this review is to familiarize primary care physicians and subspecialists who care for cancer survivors with the 2006 Children's Oncology Group (COG) long-term follow-up (LTFU) guidelines for survivors of childhood, adolescent, and young adult cancers surveillance and counseling recommendations for bone mineral deficits and to summarize the existing literature that has defined characteristics of cancer survivors at risk for bone mineral deficits and contributed to the recommendations outlined in the COG LTFU guidelines.

	DEFINITIONS OF BMD DEFICITS

TOP ABSTRACT DEFINITIONS OF BMD DEFICITS METHODS OF BMD ASSESSMENT METHODS RESULTS CONCLUSIONS COG LATE EFFECTS COMMITTEE... APPENDIX Risk Factors for... REFERENCES

 
Clinicians are often familiar with the terms "osteopenia," decreased BMD, and "osteoporosis," a more severe loss of BMD in which the structural integrity of the bone is disturbed and fracture risk is increased.^3,12 However, the International Society of Clinical Densitometry and other groups have recommended that these terms not be used to describe low BMD in children and adolescents.¹⁴ This recommendation was made because the World Health Organization criteria for osteoporosis were based on the T score, an SD score in which BMD is compared with the standard peak density of a healthy young adult woman. Using these criteria, osteoporosis is defined as a BMD of >2.5 SD below the mean BMD of young adult women (BMD T score of <–2.5) and osteopenia as a BMD value between 1.0 and 2.5 SD below the mean BMD of young adult women (–2.5 BMD T score less than –1).¹² The T score and World Health Organization definitions of "osteopenia" and "osteoporosis" apply only to postmenopausal women and not to children and adolescents who have not acquired peak bone mass.¹⁴ The z score, also an SD measurement that compares the BMD to age- and gender-matched normal values, is a more appropriate measurement for children and adolescents.¹⁵

	METHODS OF BMD ASSESSMENT

TOP ABSTRACT DEFINITIONS OF BMD DEFICITS METHODS OF BMD ASSESSMENT METHODS RESULTS CONCLUSIONS COG LATE EFFECTS COMMITTEE... APPENDIX Risk Factors for... REFERENCES

 
Measuring BMD in children and adolescents has its challenges. Dual-radiograph absorptiometry (DXA) has traditionally been used to determine BMD, although there are limitations to its use in young people. Calculation of a z score is performed with software based on published age- and gender-matched normative data sets. However, BMD also varies on the basis of height and stage of puberty, which may not correlate with age in a chronically ill population, and is not incorporated into most software calculations.¹⁵ Density is defined as mass per unit of volume; DXA calculations are based on an areal measurement (g/cm²) that does not take into account the thickness of the bone as a volumetric measurement (g/cm³) does.¹⁵ Therefore, for children with short stature, DXA underestimates BMD. Height age (the age at which 50% of normal children would be the patient's current height) is sometimes used in place of chronologic age in interpretation of BMD; however, this method has also been criticized, because shorter patients are compared with younger, healthier controls. Methods have been developed to calculate an estimated volume from DXA measurements. Fracture risk in healthy children has been found to be associated with volumetric BMD calculated from DXA, and this approach should be considered when interpreting pediatric DXA results.¹⁶ Quantitative computed tomography (QCT) provides a direct and more accurate volumetric measurement of BMD, which eliminates problems with interpretation in short-for-age children.^12,15 This technique also assesses trabecular bone (the metabolically more active compartment) separate from cortical bone, thus providing a sensitive measure of change in bone mineral accretion without confounding by less active cortical bone. This may become the preferred modality in the future; however, it is not currently universally available and involves increased radiation doses compared with DXA, but they are comparable with that of a chest radiograph.^12,15 Peripheral QCT is a newer technique directed at peripheral anatomic sites that involves a fraction of the radiation exposure of QCT; however, this technique has yet to be validated and standardized in the pediatric population. There has been little experience with the use of quantitative ultrasound and MRI in children to assess BMD, but these may be promising, radiation-sparing options as well.³

	METHODS

TOP ABSTRACT DEFINITIONS OF BMD DEFICITS METHODS OF BMD ASSESSMENT METHODS RESULTS CONCLUSIONS COG LATE EFFECTS COMMITTEE... APPENDIX Risk Factors for... REFERENCES

 
In 2003, the COG released the LTFU guidelines for survivors of childhood, adolescent, and young adult cancers to serve as a resource to familiarize health care professionals with the potential late effects of cancer therapy and provide evidence-based surveillance recommendations for risk-based follow-up care.² By facilitating risk-based care, the COG LTFU guidelines aim to improve the quality of life of survivors by promoting early identification and intervention. The surveillance recommendations are appropriate for asymptomatic survivors 2 or more years after completing therapy for a childhood, adolescent, or young adult cancer. Patient education materials called "health links" complement the COG LTFU guidelines. Both can be downloaded from www.survivorshipguidelines.org.

To ensure that the 2006 update of the COG LTFU guidelines reflects the most current evidence-based recommendations, multidisciplinary task forces have been organized within the COG Late Effects Committee to monitor the literature and recommend changes to the guidelines as new information becomes available. The 9-member Guideline Task Force on Skeletal Toxicities consists of 6 physicians who represent expertise in pediatric oncology, radiation oncology, pediatric endocrinology, diagnostic imaging, and internal medicine, a nurse, a physical therapist, and a patient advocate (see "COG Late Effects Committee Guideline Task Force On Skeletal Toxicities Members"). As part of this process, the task force performed an extensive review of literature via Medline (National Library of Medicine, Bethesda, MD) that encompassed the years 1950–2005. Key words included osteopenia, osteoporosis, BMD, pediatric, cancer, methotrexate, steroids, prednisone, ifosfamide, bone marrow transplant, radiation, cranial radiation, and total body irradiation.

	RESULTS

TOP ABSTRACT DEFINITIONS OF BMD DEFICITS METHODS OF BMD ASSESSMENT METHODS RESULTS CONCLUSIONS COG LATE EFFECTS COMMITTEE... APPENDIX Risk Factors for... REFERENCES

 
The Skeletal Toxicities Task Force reviewed 61 articles including 13 meta-analyses, 15 reviews, 3 non–randomized, controlled trials, 8 cohort studies, 15 cross-sectional studies, 6 case-control studies, 1 case report, and 1 expert opinion. Results were derived largely from observational studies that were limited by their relatively small sample sizes, use of convenience samples, heterogeneity of cancer-treatment exposures, variation in time off therapy, differences in diagnostic methodologies for BMD assessment, and retrospective clinical data abstraction. There has been a notable lack of randomized, controlled intervention studies. Key findings from the review are summarized in the Appendix and are discussed further in the subsequent sections.

Clinical Mechanisms of BMD Deficits
The etiology of BMD deficits in childhood cancer patients is multifactorial and includes both direct and indirect effects of cancer and its treatment resulting in bone loss, diminished bone growth, and decreased mineral accrual. Malignant infiltration and certain chemotherapy agents (glucocorticoids, methotrexate) may directly interfere with bone metabolism.^8–12,17 Suboptimal nutrition and decreased physical activity can result from cancer or cancer therapy. In addition, secondary effects of treatment such as hypothalamic pituitary endocrinopathies and primary hypogonadism can lead to BMD deficits.

The greatest amount of literature exists on decreased BMD in patients with acute lymphoblastic leukemia (ALL). Decreased BMD and reduced markers of bone formation have been demonstrated in patients with pediatric ALL at diagnosis.^17,18 Leukemic infiltration has been hypothesized to have a direct effect on vitamin D metabolism.^9,17 Treatment potentially encompasses many of the risk factors for BMD deficits such as high cumulative doses of steroids, methotrexate and the potential use of hematopoietic cell transplant (HCT), cranial radiation, and testicular radiation.^{6,7,11,19–24} Patients with brain tumors often develop multiple endocrinopathies secondary to radiation and surgery that are associated with reduced BMD.²⁵ Osteosarcoma treatment may include high doses of methotrexate, well in excess of the 40000 mg/m² that is associated with a higher risk of BMD deficits.^11,26

Some treatment protocols have been associated with an increased fracture risk during or shortly after therapy. In this regard, Strauss et al²⁷ reported a 5-year cumulative incidence of fractures of 28% among pediatric patients with ALL (median follow-up: 7.6 years since diagnosis). Halton et al²⁸ followed 40 children with ALL, and 39% developed fractures during treatment, with decreased bone mineral content predicting development of fractures. Less is known about the risk of fractures as childhood cancer survivors grow old. Although most survivors will recover bone mass with increasing time off therapy, a portion will demonstrate significant bone density deficits (z scores of >2.5 SD below the mean) years after therapy.^22,29,30 These survivors may not achieve their potential peak bone mass and, thus, will be at increased risk for fracture as adults. According to the National Institutes of Health Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, "[t]he bone mass attained early in life is perhaps the most important determinant of lifelong skeletal health."³ For this reason, early surveillance and intervention are imperative.

Effect of Cancer Treatment on Bone Metabolism
Chemotherapeutic agents with well-established adverse effects on BMD include corticosteroids and methotrexate. Alkylating agent chemotherapy can contribute to BMD deficits secondarily through impairment of gonadal function.¹² Similarly, radiation can result in osteopenia by causing a hypothalamic-pituitary endocrinopathy or gonadal dysfunction. Finally, bone mineral deficits in survivors who are treated with HCT may result from the agents/modalities previously noted, total body irradiation (TBI), supportive care medications used to maintain engraftment and treat complications of HCT such as graft-versus-host disease, or treatment-related endocrinopathies.^31–35 The evidence regarding BMD deficits related to these exposures and conditions are elaborated further below.

Chemotherapy Effects on BMD
Corticosteroids
Steroids exert their effect on bone through a number of pathways including decreased osteoblast activity, increased bone resorption, interference with the growth hormone/insulin-like growth factor 1 axis, reduced muscle strength, and disturbance of calcium balance at the level of the gut and kidney.^10,12,15 Children and adolescents who are exposed to higher doses of steroids, specifically doses >9000 mg/m² of prednisone equivalents (as in some protocols for childhood leukemia), are more likely to develop reduced bone density and not recover to a normal BMD after treatment.¹¹ In addition, the use of the more potent glucocorticoid dexamethasone has been associated with a higher incidence of BMD deficits and fractures than observed after prednisone.²⁷

Methotrexate
Methotrexate's cytotoxic effect on osteoblasts results in reduced bone volume and formation of new bone.³⁶ It is unclear if there is a synergistic effect when methotrexate and steroids are used together as in the treatment of ALL.³⁰ Higher cumulative doses of methotrexate have been associated with a greater incidence of osteopenia.^11,26 In one study, total doses of >40000 mg/m² were associated with the highest risk of osteopenia and failure to recover to a normal BMD after completion of therapy.¹¹

Other Chemotherapeutic Agents
Alkylating agents confer a dose-related risk of gonadal dysfunction that can impact BMD when deficiencies of ovarian or testicular hormones develop. Estrogens play a crucial role in achieving and maintaining peak bone mass by preventing bone resorption and stimulating growth factors necessary for bone growth.³⁷ Androgens seem to have an important role in periosteal apposition, adding to the biochemical strength of the bone.^37,38 The risk of hypogonadism after alkylating agent chemotherapy is related to cumulative dose, age, and gender. Higher cumulative doses, as used in transplant-conditioning regimens, typically produce gonadal damage in males and females. The risk for both genders may be exacerbated by combination therapy with alkylators and radiation therapy, which affect hormone production.³⁹

Radiation
Radiation to the neuroendocrine axis after cranial, orbital/eye, ear/infratemporal, nasopharyngeal, and TBI fields can lead to GHD and central hypogonadism, which are both associated with deficits in BMD. Pelvic and testicular radiation in males and pelvic, whole-abdomen, and lumbar/sacral spine radiation in females can also lead to primary hypogonadism.

GHD is associated with cranial radiation, with the highest risk having been observed in those who received doses of 18 Gy.^12,40,41 Fractionated TBI doses of >12 Gy for transplant conditioning may also result in GHD.^39,41 Growth hormone directly causes bone formation and resorption, which results in a net accumulation of bone mass. It may indirectly influence bone mass through its effects on vitamin D.⁴² Children with GHD should be screened for BMD deficits; however, z scores from DXA may be affected by short stature.¹⁵

Gonadotropin deficiency that leads to secondary deficits in estrogen and testosterone occurs with high-dose radiation (40 Gy) to the neuroendocrine axis.⁴¹ Hypogonadism caused by gonadal radiation occurs at much lower radiation doses, and as with alkylator therapy, the risk varies with gender and pubertal status.³⁹ Ovarian dysfunction and premature menopause are associated with radiation doses of 10 Gy to the ovaries in prepubertal females and 5 Gy in pubertal females.^39,41 In males, although small doses (1–6 Gy) of radiation to the testes are associated with germ-cell failure, higher doses (20 Gy) are required to cause Leydig cell dysfunction with associated androgen insufficiency.^39,41

The thyroid is exquisitely sensitive to radiation injury; thyroid abnormalities most commonly reported after radiation include hypothyroidism, nodules, or thyroid cancer.⁴⁰ Hyperthyroidism, although uncommon, has been associated with local radiation doses of 40 Gy.^40,43 Excess thyroid hormones, both endogenous and exogenous, can lead to increased bone resorption and bone loss.¹²

The data that implicate radiation of the skeleton as a primary risk factor for osteopenia are conflicting. The results of some investigations suggest that local radiation and TBI may directly affect BMD by damaging the bone marrow stroma.^44,45 However, other studies have failed to detect a strong association between TBI and BMD deficits in survivors who were treated with TBI for transplant conditioning.^31,33,44 Radiation-induced fractures have been described for survivors treated with radiation doses of 40 Gy, as used in local control of sarcomas; however, this is a local effect and is not associated with systemic reduced BMD.^46,47

Hematopoietic Cell Transplant
Patients undergoing HCT often receive multiple agents associated with altered bone metabolism as part of their treatment including methotrexate, steroids, TBI, and high-dose alkylating agents.^{32,34,35,48,49} It is unclear if there is additional risk from the transplant itself. Adult transplant studies have shown a 2% to 10% loss of BMD significantly increases the risk of fracture.⁴⁹ Because patients who have had an HCT tend to have more severe acute and chronic therapy-related complications, they are more likely to have additional risk factors such as poor nutrition, decreased physical activity, and less exposure to sunshine.

Other Factors That Contribute to BMD
Genetic/Familial
Genetic and ethnic factors are the main influences in the potential accumulation of skeletal mass.³ It is well established that blacks have a higher BMD than whites. In the adult population, women obtain a lower peak bone mass than men and experience more rapid bone loss that results in an increased incidence of osteoporosis; however, in secondary osteoporosis (osteoporosis that results from a medical disorder), both genders are affected, with some reports of male cancer survivors being disproportionately affected.^{3,6,19,22,50,51} Additional research on the influence of these factors specifically in childhood and adolescent cancer survivors is needed.

Lifestyle Factors
Because genetics, ethnicity, and gender do not change, nutritional status and weight-bearing activity are the most important factors in the prevention of osteoporosis.^5,51,52 Decreased activity has a deleterious affect on BMD.^5,51,52 This is of particular concern for survivors with impaired mobility caused by past surgical interventions. The body must also have a positive calcium balance to build bone and attain peak bone mass. Most children do not regularly consume the recommended daily allowance of calcium and vitamin D and, therefore, may benefit from supplementation to increase BMD.^31,45,51 Smoking and alcohol and caffeine consumption also negatively impact BMD accretion.⁴¹ Consequently, diet, exercise, and lifestyle histories are essential components of the yearly LTFU visit.

Recommendations for Periodic Evaluation
Collectively, the frequency and severity of bone mineral deficits reported for childhood cancer survivors suggest that specific diagnostic and treatment groups may benefit from surveillance and intervention during childhood. However, BMD assessment in children is challenging because of methodologic issues related to normative control data and conflicting opinions regarding the optimal surveillance modality. The 2004 COG LTFU guidelines recommended a more conservative approach, with a baseline BMD evaluation at age 18 that could be assessed by using more robust normative data. However, studies have demonstrated that childhood cancer patients are at highest risk for bony morbidity closer to the time of therapy.^8,53 Intervention is likely to have the greatest impact during puberty, when 40% of bone mass is obtained. By the end of puberty, >90% of total adult bone mass has already been acquired.⁵² Additional bone growth continues through the second decade, at which point bone loss starts; this time course suggests that the window for optimal intervention is relatively small.

Consequently, the 2006 COG LTFU guidelines recommend a baseline evaluation of BMD by DXA or QCT at entry into LTFU, which typically occurs 2 years after completion of cancer therapy, for survivors treated with agents/modalities that predispose to BMD deficits (see Table 1), including any survivor with previous exposure to methotrexate, corticosteroids, or HCT. In addition, BMD evaluation should be considered for survivors with medical conditions associated with BMD deficits such as GHD, hypogonadism, delayed puberty, or hyperthyroidism. Ideally, these studies should be performed at centers that are familiar with interpretation of pediatric scans to avoid such errors as use of T scores and ignoring the effects of delayed growth or maturity on interpretation of the BMD. Results from the baseline evaluation should then inform the frequency of future follow-up. In most studies, BMD in survivors improves with increasing time off therapy; therefore, repeat measurements on patients with normal study results (BMD z score of greater than –1) should not be required. If there is concern about a significant bone mineral deficit (BMD z score of less than –2.5), recurrent fractures, or underlying medical risk factors for decreased BMD, endocrinology consultation should be considered.

Bone loading by way of moderate weight-bearing activity, such as running or jumping, has been proven in multiple studies to positively affect BMD.^5,8 Supplementation with vitamin D, which increases intestinal calcium absorption, and increased calcium intake have been proven to enhance peak bone mass in healthy children.^3,52 In older adults with osteoporosis, calcium and vitamin D intake has also been shown to decrease the number of fractures.³ Total intake of 1000 to 1500 mg of calcium per day with at least the recommended daily allowance of vitamin D (200 IU) through diet or supplementation are recommended for all patients, with diet being the preferred source, according to the COG LTFU guidelines. Clinicians should be aware of the fact that most American children and adolescents are not receiving the recommended dietary intake of calcium.⁵⁴ Although a history of urinary tract calculi should be considered before starting calcium supplementation, more recent data suggest that high calcium intake is not a major risk factor in the development of kidney stones and may, in fact, be protective.^54–56 Ensuring adequate fluid intake and avoiding oxalate-rich foods (eg, black tea, spinach, rhubarb) are reasonable precautions against hypercalciuria.⁵⁶

Cancer survivors with significantly decreased BMD (defined as a BMD z score of >2.5 SD below the mean) may benefit from endocrinology consultation for consideration of potential contributing factors and treatment in appropriate cases. Treatment options such as calcitonin and bisphosphonates are currently reserved for patients with recurrent fractures or those who are on clinical trials. There has been limited research on the use of bisphosphonates in pediatric patients, although these agents have demonstrated benefit in children with skeletal diseases such as osteogenesis imperfecta.^12,57

	CONCLUSIONS

TOP ABSTRACT DEFINITIONS OF BMD DEFICITS METHODS OF BMD ASSESSMENT METHODS RESULTS CONCLUSIONS COG LATE EFFECTS COMMITTEE... APPENDIX Risk Factors for... REFERENCES

 
Survivors of pediatric and adolescent cancers are at risk for low bone mass after completion of therapy. Treatment with corticosteroids, methotrexate, and HCT is associated with an increased risk of BMD deficits. Radiation and alkylating chemotherapy increase the risk of endocrinopathies and gonadal dysfunction that predisposes to reduced BMD. Lifestyle and genetic predisposition may also confer additional risks for BMD deficits. The COG LTFU guidelines are expert opinion and evidence-based surveillance recommendations to guide physicians, so that patients at risk for BMD deficits can receive early intervention. The COG LTFU guidelines and associated patient education materials (called "health links") are available at www.survivorshipguidelines.org.

	COG LATE EFFECTS COMMITTEE GUIDELINE TASK FORCE ON SKELETAL TOXICITIES MEMBERS

TOP ABSTRACT DEFINITIONS OF BMD DEFICITS METHODS OF BMD ASSESSMENT METHODS RESULTS CONCLUSIONS COG LATE EFFECTS COMMITTEE... APPENDIX Risk Factors for... REFERENCES

 
The COG Late Effects Committee Guideline Task Force on Skeletal Toxicities included Arlina Ahluwalia (primary care, Stanford University Medical Center), Natia Esiashvili (radiation oncology, Emory University), Sue Kaste (diagnostic imaging, St Jude Children's Research Hospital), Missy Layfield (patient advocacy, Children's Oncology Group), Victoria Marchese (physical therapy, St Jude Children's Research Hospital), Leonard A. Mattano (co-chair, pediatric oncology, Kalamazoo Center for Medical Sciences), Lillian R. Meacham (co-chair, pediatric endocrinology, Children's Healthcare of Atlanta/Emory University), Susan Shannon Miller (pediatric oncology nursing, Children's Hospital/Harbor-UCLA), and Karen Wasilewski-Masker (pediatric oncology, Children's Healthcare of Atlanta/Emory University).

	APPENDIX Risk Factors for Bone Mineral Deficits

TOP ABSTRACT DEFINITIONS OF BMD DEFICITS METHODS OF BMD ASSESSMENT METHODS RESULTS CONCLUSIONS COG LATE EFFECTS COMMITTEE... APPENDIX Risk Factors for... REFERENCES

 

	FOOTNOTES

 
Accepted Aug 15, 2007.

Address correspondence to Karen Wasilewski-Masker, MD, MSc, Aflac Cancer Center, 5455 Meridian Mark Rd, Suite 400, Atlanta, GA 30342. E-mail: karen.wasilewski{at}choa.org

The authors have indicated they have no financial relationships relevant to this article to disclose.

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TOP ABSTRACT DEFINITIONS OF BMD DEFICITS METHODS OF BMD ASSESSMENT METHODS RESULTS CONCLUSIONS COG LATE EFFECTS COMMITTEE... APPENDIX Risk Factors for... REFERENCES

 

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