Child-Survivors of Acute Lymphoblastic Leukemia: Can the Development of Osteoporosis be Delayed or Avoided Through Physical Activity?

Acute Lymphoblastic Leukemia (ALL), a hematological cancer most-commonly diagnosed in children and young adults, is characterized by uncontrolled proliferation and maturation arrest of the lymphoid progenitor cells found in bone marrow (resulting in an excess of malignant cells). ALL is the most frequent childhood malignancy, with 2000-2500 new cases diagnosed in the United States each year and representing almost one-third of all pediatric cancers. Its peak-incidence is found in patients 2-5 years old. The cause of ALL is still unknown, although there are a small number of cases associated with inherited genetic syndromes (eMedicine 2003). Several specialists have studied the possible connection between ALL and development of osteopenia and osteoporosis later in life, and have concluded that while there appears to be a connection between the two, more research must be done to identify precise mechanisms, and also to determine whether or not this is truly a long-term concern or merely one which disappears once the patient has recovered.
Leukemia, meaning “white blood”, is a disease marked by an increased number of circulating white blood cells (Snively & Beshear 1972). Acute leukemias are classified according to the patient and which cell types are involved. Most pediatric leukemias are lymphoblastic and begin in clusters of lymphocytes within bone marrow, stem cells or other lymphoid tissues (Robbins & Angell 1976). The etiology of leukemia remains unidentified, however, some have postulated that it may be the result of a virus. Due to an overall cure-rate of almost 80%, it has become increasingly important to examine the consequences of the disease and its treatments in its survivors.
Symptoms of ALL comprise fatigue, due largely to anemia; fever, as a secondary infection to neutropenia; and bleeding due to thrombocytopenia, including petechiae, ecchymoses, epistaxis and gingival bleeding. In certain cases, secondary complications may include lymphadenopathy, splenomegaly, hepatomegaly and kidney enlargement. There is also a relatively high risk of bone infiltration, marrow expansion, subperiosteal infiltration and bone necrosis; important factors to consider when theorizing a connection between ALL and higher risk of osteoporosis (Beck 1973). Decreased bone mineral density (BMD) may result from the leukemic process itself, ectopic production of parathyroid hormone, paracrine secretion of lymphokines and decreased physical activity. Treatment of ALL largely includes corticosteroids, methotrexate and radiotherapy (cranial irradiation), and many have hypothesized that alterations in bone mass density may be linked to these methods; it has been widely speculated that treatment of ALL can have negative effects on bone formation and remodeling. Children, the most common patients with ALL, are especially at risk of developing osteoporosis and growth retardation because they may be subject to alterations in bone development during the precise time when building is at its peak (van der Sluis ).
Bone metabolism is a continuous process of modeling and remodeling, with a yearly replacement rate of 10% (Haddy et al. 2001). Osteoporosis is a metabolic disease of the bones, characterized by structural degeneration of bone tissue and steady decrease in bone mass, which causes bones to become weak and more susceptible to fractures; “osteo” translates to bone and “porosis” means porous (Leroux 2001). Osteoporosis is a major health threat for over 44 million people in the U.S., 68% of whom are women; 10 million of these individuals actually have the disease (80% afflicted are women) and 34 million have low bone mass (National Institutes of Health, 2002), a condition known as osteopenia. Osteoporosis is responsible for more than 1.5 million fractures each year in the U.S. and the most common sites of fracture are hip, spine, wrist and ribs. Similar statistics are found in Canada, where 1.4 million people are affected by osteoporosis (350 000 of those reside in Quebec) (Leroux 2001). Although more research is required to determine the precise relationship between ALL and osteopenia, the precursor of osteoporosis (Haddy et al. 2001), the mechanisms can be theorized and the next portion of this paper will examine this possible connection.
Children and adolescents are especially vulnerable to alterations in BMD since this is the time when peak bone mass is built (Haddy et. al. 2001), and since 90% of peak bone density is achieved by the age of 30, it is believed that increased physical activity levels for young people could help prevent bone disorders such as osteopenia and osteoporosis (Eliakim & Beyth 2003). Musculoskeletal disorders are common complications of ALL and its treatment, and children diagnosed with ALL have already been found to have decreased BMD at the time of diagnosis.
A number of research groups have examined the possible connection between ALL and development of osteoporosis and, although some studies have shown these effects to be temporary, there seems to be a positive correlation between ALL and decreased BMD. While no clear resolution has been reached as to whether or not these effects endure long-term (post-remission), all seem to agree that the suspected physiological mechanisms make sense. Bone metabolism is a constant cycle and consists of 80% cortical bone (the dense outer protective portion) and 20% cancellous or trabecular bone (the spongy inner portion). As mentioned, ALL patients are especially susceptible to hampered bone formation due to the disease itself (because of leukemic invasion) and to its treatment, which includes corticosteroids, methotrexate therapy, local and cranial irradiation, and deficiency of various hormones. These individuals also tend to have limited exercise capacity, and tend to inactivity; these limitations are likely due to cancer-related fatigue, and some suffer from nutritional deficiencies including: calcium, vitamin D and magnesium metabolism (Haddy et al. 2001). Limited research has been performed regarding long-term effects of radiotherapy, but a clear correlation appears to exist between reductions in BMD and increased fragility, and dose-level of radiotherapy (Hopewell, 2003).

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