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Bone health in cancer survivors
S14
ABSTRACTS / Bone 40 (2007) S8–S21
FGF23 mutations, which all affect conserved serine residues that may undergo O-glycosylation by GALNT3; these mutations also lead to an abnormal processing of FGF23 resulting in increased secretion of C-terminal fragments. Despite these advances, it remains largely unknown how most of the different proteins mentioned above contribute to the regulation of phosphate homeostasis and it is almost certain that additional proteins are involved in this process. Furthermore, it remains to be determined whether the dramatically elevated FGF23 levels in patients with different stages of chronic kidney disease affect bone metabolism, particularly the mineralization of newly formed osteoid. doi:10.1016/j.bone.2007.04.148
Genetic study of children’s bone health and its therapeutic application G. Karsenty Genetics and Development, Columbia University, New York, NY Children’s bone health is a rapidly evolving field of medicine in large part because the last fifteen years have been a period of almost unforeseeable progress in our understanding of skeletal biology. This tremendous growth in knowledge is, in great part, due to the molecular elucidation of human genetic diseases combined with mouse genetics approach to gene functions and molecular studies identifying signaling pathway and target genes. A combination of these three approaches has identified for instance the genes responsible for deidocranial dysplasia, saethre-chotzen syndrome, Coffin-Lowry syndrome, as well as for the skeletal manifestations of neurofibromatosis and of lipodystophy. We should underscore that the same combination of experimental approaches has also contributed to the elucidation of the mode of action of many of these genes. Altogether we have now a fairly sophisticated knowledge of the genetic pathways involved in patterning of the skeleton, in cell differentiation in the skeleton and in bone metabolism. Moreover, a picture is slowly emerging of the genes that are mutated in frequent or rare skeletal dysplasia. This begins to have a significant therapeutic impact for many children. Using this knowledge we have been able, as will be presented at the meeting, to define therapeutic strategies for two of these diseases and to demonstrate the efficiency of these strategies in mice. doi:10.1016/j.bone.2007.04.149
Bone health in cancer survivors Sue C. Kaste, DO Radiological Sciences, St. Jude ChildrenTs Research Hospital, Memphis, TN The population of childhood cancer survivors is currently estimated at one in 570 young adults aged 20 to 34 years. This
rapidly growing cohort underscores the importance of studying long-term complications of cancer therapy. As one example, among cancer cases diagnosed in the U.S. before age 15, acute lymphoblastic leukemia accounts for approximately one fourth; more than 2000 new cases occur annually. Long-term event free survival rates for acute lymphoblastic leukemia now approximate 85% and are expected to climb to 90% in the near future. While childhood cancer patients are returning to the mainstream of life, they carry with them toxicities from prior therapy that may compound or potentiate changes typically seen with the normal aging process. Skeletal toxicities such as scoliosis, craniofacial dysplasia, and limb-length discrepancy are visibly apparent. These physical sequelae, resulting from the primary cancer and its therapy (e.g., surgery and radiation therapy) may present functional limitations and psychosocial challenges, and require extensive surgical interventions. However, skeletal toxicities such as osteonecrosis and deficits in bone mineral density are typically silent until they reach advanced stages when attempts at amelioration may be unsuccessful. These two sequelae result from multifactorial interactions including genetic predisposition, disease, therapy (chemotherapy and radiation therapy) and physical activity. As both bone mineral density deficits and osteonecrosis may occur in a single patient, therapeutic interventions may be complex and standard treatment practices for one toxicity may exacerbate the other toxicity (e.g. in a patient with both osteonecrosis and bone mineral density deficits, encouraging weight-bearing exercise to improve bone mineral density may aggravate osteonecrosis). This presentation comprises an overview of skeletal toxicities in survivors of childhood cancer. It will focus on bone mineral density deficits which may predispose childhood cancer survivors to earlier onset and more severe osteopenia and osteoporosis than the normal population. Also detailed, will be osteonecrosis which may predispose survivors to earlier onset and more severe impairment of joint function. Therapeutic interventions for osteonecrosis are currently limited and, often, ultimately lead to joint resurfacing or replacement at a young age. doi:10.1016/j.bone.2007.04.150
Determinants of skeletal loss and recovery in anorexia nervosa Anne Klibanski Neuroendocrine, Harvard Medical School, Boston, MA Anorexia nervosa (AN) is an increasingly recognized disorder affecting approximately 0.5 to 1% of college age women. We have previously found that in an outpatient study of 130 young women with this disorder, bone mass was reduced at all sites and BMD was reduced by at least 1 SD in 92% of patients and by at least 2.5 SD in 38%. Weight, but not estrogen use was a significant predictor of BMD at all sites. Despite recovery, bone density may remain low. Because the age of onset of the disease is decreasing, the disorder may occur during the peri-pubertal period when accretion of bone mass is maximum and peak bone formation occurs. Therefore, early onset
ABSTRACTS / Bone 40 (2007) S8–S21
FGF23 mutations, which all affect conserved serine residues that may undergo O-glycosylation by GALNT3; these mutations also lead to an abnormal processing of FGF23 resulting in increased secretion of C-terminal fragments. Despite these advances, it remains largely unknown how most of the different proteins mentioned above contribute to the regulation of phosphate homeostasis and it is almost certain that additional proteins are involved in this process. Furthermore, it remains to be determined whether the dramatically elevated FGF23 levels in patients with different stages of chronic kidney disease affect bone metabolism, particularly the mineralization of newly formed osteoid. doi:10.1016/j.bone.2007.04.148
Genetic study of children’s bone health and its therapeutic application G. Karsenty Genetics and Development, Columbia University, New York, NY Children’s bone health is a rapidly evolving field of medicine in large part because the last fifteen years have been a period of almost unforeseeable progress in our understanding of skeletal biology. This tremendous growth in knowledge is, in great part, due to the molecular elucidation of human genetic diseases combined with mouse genetics approach to gene functions and molecular studies identifying signaling pathway and target genes. A combination of these three approaches has identified for instance the genes responsible for deidocranial dysplasia, saethre-chotzen syndrome, Coffin-Lowry syndrome, as well as for the skeletal manifestations of neurofibromatosis and of lipodystophy. We should underscore that the same combination of experimental approaches has also contributed to the elucidation of the mode of action of many of these genes. Altogether we have now a fairly sophisticated knowledge of the genetic pathways involved in patterning of the skeleton, in cell differentiation in the skeleton and in bone metabolism. Moreover, a picture is slowly emerging of the genes that are mutated in frequent or rare skeletal dysplasia. This begins to have a significant therapeutic impact for many children. Using this knowledge we have been able, as will be presented at the meeting, to define therapeutic strategies for two of these diseases and to demonstrate the efficiency of these strategies in mice. doi:10.1016/j.bone.2007.04.149
Bone health in cancer survivors Sue C. Kaste, DO Radiological Sciences, St. Jude ChildrenTs Research Hospital, Memphis, TN The population of childhood cancer survivors is currently estimated at one in 570 young adults aged 20 to 34 years. This
rapidly growing cohort underscores the importance of studying long-term complications of cancer therapy. As one example, among cancer cases diagnosed in the U.S. before age 15, acute lymphoblastic leukemia accounts for approximately one fourth; more than 2000 new cases occur annually. Long-term event free survival rates for acute lymphoblastic leukemia now approximate 85% and are expected to climb to 90% in the near future. While childhood cancer patients are returning to the mainstream of life, they carry with them toxicities from prior therapy that may compound or potentiate changes typically seen with the normal aging process. Skeletal toxicities such as scoliosis, craniofacial dysplasia, and limb-length discrepancy are visibly apparent. These physical sequelae, resulting from the primary cancer and its therapy (e.g., surgery and radiation therapy) may present functional limitations and psychosocial challenges, and require extensive surgical interventions. However, skeletal toxicities such as osteonecrosis and deficits in bone mineral density are typically silent until they reach advanced stages when attempts at amelioration may be unsuccessful. These two sequelae result from multifactorial interactions including genetic predisposition, disease, therapy (chemotherapy and radiation therapy) and physical activity. As both bone mineral density deficits and osteonecrosis may occur in a single patient, therapeutic interventions may be complex and standard treatment practices for one toxicity may exacerbate the other toxicity (e.g. in a patient with both osteonecrosis and bone mineral density deficits, encouraging weight-bearing exercise to improve bone mineral density may aggravate osteonecrosis). This presentation comprises an overview of skeletal toxicities in survivors of childhood cancer. It will focus on bone mineral density deficits which may predispose childhood cancer survivors to earlier onset and more severe osteopenia and osteoporosis than the normal population. Also detailed, will be osteonecrosis which may predispose survivors to earlier onset and more severe impairment of joint function. Therapeutic interventions for osteonecrosis are currently limited and, often, ultimately lead to joint resurfacing or replacement at a young age. doi:10.1016/j.bone.2007.04.150
Determinants of skeletal loss and recovery in anorexia nervosa Anne Klibanski Neuroendocrine, Harvard Medical School, Boston, MA Anorexia nervosa (AN) is an increasingly recognized disorder affecting approximately 0.5 to 1% of college age women. We have previously found that in an outpatient study of 130 young women with this disorder, bone mass was reduced at all sites and BMD was reduced by at least 1 SD in 92% of patients and by at least 2.5 SD in 38%. Weight, but not estrogen use was a significant predictor of BMD at all sites. Despite recovery, bone density may remain low. Because the age of onset of the disease is decreasing, the disorder may occur during the peri-pubertal period when accretion of bone mass is maximum and peak bone formation occurs. Therefore, early onset