Factors Related to Decreased Bone Mineral Density in Childhood Cancer Survivors

The bone mass attained early in life is known to be the most important determinant of lifelong skeletal health (1). In adults and children a reduction of one standard deviation in bone mineral density (BMD) is associated with a doubling of the fracture risk (2). Decreased BMD can lead to fractures, deformity, pain, and considerable financial burden (3). Childhood cancer treatment is a potential etiologic factor for low BMD among children who survive cancer management (4). For example, fracture risk was 6 times higher in children with acute lymphoblastic leukemia (ALL) compared with healthy controls (5).

Multiple possible etiologic factors for decreased BMD in these patients have been proposed: the disease itself, growth hormone (GH) and/or sex hormone deficiency, intensive chemotherapy, low calcium and vitamin D intake, and reduced physical activity (4). Chemotherapy (especially glucocorticoid [GC] and methotrexate) can affect bone formation by altering osteoblastic activity and proliferation. High-dose GC and intrathecal methotrexate, included in nearly all ALL treatment regimens, can affect bone formation, by altering osteoblastic activity and proliferation (6). Radiation-associated damage to the hypothalamic-pituitary axis can result in growth hormone deficiency and hypogonadism, which impair bone growth and mineral acquisition. The suboptimal activity and nutrition during the treatment course reduce bone formation during developmentally critical time periods (7).

The purpose of this study was to evaluate patterns of BMD after cancer treatment and to identify factors related to the decreased BMD in childhood cancer survivors.

In this study of childhood cancer survivors, we found that 25.7% of subjects had LBMD SDS lower than -2. The age at cancer diagnosis was 9.1 ± 3.5 yr in patients with BMD SDS lower than -2, and 6.9 ± 3.9 yr in patients with BMD SDS greater than -2. The characteristics of patients with LBMD SDS lower than -2 were that they had longer duration of GC treatment and lower BMI SDS. In adult cancer survivors, approximately 50% of the patients have osteopenia or osteoporosis (10). Similar to childhood cancer survivors, the risk of osteoporosis and fractures increases with increased GC dose and duration and low body weight in adult cancer survivors (11).

In our study, the risk of low BMD was higher in patients treated with GC. GCs affect bone directly, but also indirectly by altering hormonal axes, intestinal calcium absorption, and renal excretion of calcium (12). GCs decrease bone formation by promotion of apoptosis of osteocytes and osteoblasts, inhibiting osteoblast bone matrix synthesis, and decreasing proliferation and differentiation of periosteal precursor cells (13). GCs have a greater effect on trabecular bone than on cortical bone. Trabecular bone is more metabolically active and has a more rapid rate of turnover than cortical bone: and, thus may be more susceptible to the effects of cytotoxic agents (14). As such, the bone loss is faster, and fractures develop mainly in bones composed of trabecular bone, like vertebrae, ribs, and the ends of long bones. Young people who have a high rate of bone turnover are very susceptible to GC-mediated bone loss. Longitudinal studies have shown that the most rapid rate of bone loss occurs in the first six months of GC treatment and is similar in both the lumbar spine and the femoral neck (15). Furthermore the degree of GC-induced bone loss is related to average GC dose and to the duration of treatment (16). Longer duration of GC use was related to increased risk of fracture (17).

In our analysis, the patients treated with HSCT had a higher risk of having low BMD SDS. BMD is decreased after HSCT from the direct toxic effects of radiation therapy, chemotherapy as conditioning regimen, and gonadal and pituitary hormone secretion (18). While being treated with HSCT, the differentiation of bone marrow stromal cells into osteoblasts is impaired (19), and there is an increase in bone marrow interleukin-6, which is a bone resorption marker (20). After treatment with high-dose chemotherapy and radiation therapy, ovarian insufficiency can occur. Teinturier et al. (21) demonstrated that the high-dose busulfan seemed to be a major cause of ovarian failure even when given in the prepubertal period. High-dose cyclophosphamide shows a dose-dependent toxicity to bone marrow stromal osteoprogenitors and can cause osteopenia by directly damaging the osteoblastic compartment (19). Also, HSCT results in prolonged hospital stay, low activity, and GH deficiency after cranial radiation therapy (22).

Radiation therapy (RT) has important negative effects on skeletal growth in children and adolescents. RT on the central nerve system (CNS) or administered as part of total body irradiation (TBI) before HSCT may result in pituitary hormone deficiencies (23). Decreased growth hormone (GH) of the pituitary hormone leads to a decrease in the IGF-1/IGFBP-3 ratio. These effects of TBI on the somatotrope axis are harmful for bony growth, as the GH/IGF-1 system induces the proliferation of the epiphyseal growth plate until sex hormone-mediated epiphyseal closure occurs (24). The severity of the growth hormone deficiencies are related to the total radiation dose, the number of fractions, the time period of the radiation treatment, and whether the treatment was at early puberty (23). Consequently it is necessary to measure BMD when radiation is given for a longer duration and larger dose, or when treatment is given at early puberty, or rapidly progressing puberty.

Interestingly, in the patients having BMD SDS lower than -2 SD, the age at diagnosis with cancer (9.1 ± 3.5 yr) was close to the age of pubertal onset. Meanwhile, the patients having BMD SDS greater than -2 SD showed significantly younger age at diagnosis (6.9 ± 3.9 yr). BMD shows a rapid increase in adolescents and during puberty; and if bone growth is affected at this age, BMD is reduced rapidly. Also the gonads are more tolerant to chemotherapy and radiation in early childhood. If treated before puberty, the probability of osteoporosis is reduced due to the diminished risk for hypogonadism (25). Estrogen also plays a vital role in achieving maximal bone mass during puberty. If gonadal dysfunction occurs during puberty, the pubertal growth spurt fails to occur, and peak bone mass is reduced (26).

Nevertheless, the patients having hypogonadism did not show significantly low LBMD SDS (-1.15 ± 1.55 vs -0.18 ± 1.35, P = 0.359). It is unclear why BMD is less affected in patients with hypogonadism. As most of our patients with hypogonadism had undergone hormone therapy, the study did not reflect the impact of hypogonadism accurately (data not shown).

In our study, the duration of GC treatment before HSCT in ALL patients was longer than that for other diseases, but there was no difference in the duration of the GC treatment after HSCT among disease groups. In addition, there was no difference in BMD SDS among disease groups, and the disease category did not have a significant effect on decreased BMD SDS in multivariate logistic regression analysis. Therefore, decreased BMD SDS after HSCT was not affected by the duration of GC use before HSCT but rather affected by long-term treatment of GC for GVHD.

Positive correlation between BMD and body weight has been shown in different age groups (27). Likewise in our study, lower BMI SDS was associated with decreased LBMD SDS. It is well known low body weight increases the risk of low-energy fracture. Potentially beneficial effects of increased body weight may result from the increased mechanical load exerted on bone, which stimulates osteogenesis (28). Thus, the patients with lower BMI are more susceptible to osteopenia.

Although the effects of lean mass on bone included a strong positive effect on BMD, fat mass had a negative effect or did not affect BMD (29). Childhood obesity can cause various complications including psychosocial problems, hyperlipidemia, hepatic steatosis, and carbohydrate metabolism abnormality (25). As such, it is essential to maintain appropriate body weight and increase lean mass by physical activity and exercise.

Many cancer survivors have the additional risk factors of nutritional deficiency and side effects of treatment that result in altered calcium, 1, 25-dihydroxyvitamin D, and magnesium metabolism, as well as prolonged periods of hospitalization and immobilization (12). Survivors of ALL are less active physically than healthy controls, and lower activity correlates with lower lumbar BMD (4).

Sufficient dietary calcium intake and physical activity are essential to promote bone mineralization (10). Treatments of calcium, vitamin D, and exercise have been shown to have varying degrees of effectiveness. Likewise in our study, the patients treated for hypogonadism with hormone therapy or treated with calcium and vitamin D had less of a decrease in BMD SDS (data not shown). As such, patients with risk factors such as prolonged GC use, HSCT, treatment at puberty and lower BMI SDS should be considered for preventive strategies such as adequate calcium, vitamin D intake and increased weight bearing exercise as tolerated (12). In addition, bisphosphonate therapy has been used in the treatment and prevention of diminished BMD in adults undergoing BMT (10). In a study on children on chronic GC therapy with pathological fractures, pamidronate increased BMD, and decreased skeletal pain (30). Side effects of musculoskeletal pain, vomiting, esophagitis, and severe hypocalcemia must be considered in the use of bisphosphonates. Long-term controlled studies are needed to evaluate the risks and benefits of bisphosphonate treatment in children with osteoporosis (12).

There are some limitations to this study. BMD should be included at the time of initial hematologic diagnosis to see the impact of cancer therapy. Because leukemic cell invasion of bone may destroy the spongiosa (12), BMD at the initial diagnosis is also likely to be lower. Furthermore, in addition to measuring BMD, it is necessary to measure other bone turnover markers, such as type I procollagencarboxyterminal (PICP), aminoterminalpropeptide (PINP), and carboxy-terminal telopeptide of type 1 collagen (β-CTX), in order to observe the precise changes of bone metabolism. Thus, further study which includes BMD at initial diagnosis and evaluation of additional bone turnover markers is necessary.

In conclusion, prolonged GC use and reduction in BMI are risk factors for decreased BMD in childhood cancer survivors. Anticipatory follow-up and appropriate treatment are necessary, especially for the patients with risk factors. Early detection of patients at risk will allow early application of adequate preventive and therapeutic measures which may decrease morbidity.