As the number of childhood cancer survivors increases, concerns are increasing regarding the long-term complications and quality of life. In Korea, the current 5-year survival rate for childhood cancer patients under 14 years of age has significantly improved from the pre-1995 rate of 55% to the current rate of nearly 72% [1]. However, the late sequelae associated with childhood cancer and the required treatments are important concerns [2].

A decrease in bone mineral density (BMD) is a common consequence of treatments for cancers in children and adolescents [3]. The pathogenesis of decreased BMD in childhood cancer is multifactorial. Chemotherapy including glucocorticoids, methotrexate, and ifosfamide can affect bone formation. In addition, cancer therapies (e.g., irradiation and alkylating agents) that induce hypogonadism and growth hormone deficiencies can decrease the BMD. Decreased outdoor activity levels might induce decreased muscle mass and vitamin D deficiency as well as decreased BMD [4]. As a result of these multiple factors, many young cancer survivors have reduced BMD. This condition can lead to fractures, deformities, pain, and substantial financial burdens to both the patients' families and society.

Reduced BMD is a well-known treatment-associated complication in children with acute lymphoblastic leukemia (ALL) [3]. ALL and non-Hodgkin lymphoma (NHL) are treated according to similar protocols. Reduced BMD is also frequent in adult NHL survivors, who receive different chemotherapy combinations [5]. Corticosteroids and methotrexate are important therapeutic components of treatment for ALL and NHL, and these agents have been shown to play an important role in the development of reduced BMD in ALL and NHL patients [3, 4].

Bisphosphonate compounds are potent bone resorption inhibitors that have been used to treat primary and secondary osteoporosis. Pamidronate, a second-generation agent of this pharmaceutical family, is the most widely used bisphosphonate in children and adolescents [6]. Pamidronate is reported to have beneficial effects in children with osteogenesis imperfecta [7, 8], fibrous bone dysplasia [9], cerebral palsy [10], and chronic nephropathy [11]. The beneficial effects of pamidronate on osteoporosis or osteopenia in children with ALL have been recently reported for cases, in which pamidronate was administered concurrently with chemotherapy [12, 13].

This study was performed to evaluate the safety and efficacy of pamidronate for BMD deficits in children that resulted from ALL and NHL treatment.

Hogler et al. [15] reported that the 5-year incidence of skeletal complications during and after ALL treatment was 32.7% and that the relative risk of fractures, adjusted for age and gender, was 2.03 when compared to reference data from the UK General Practice Research Database. Survivors of childhood cancers are especially vulnerable to skeletal complications because they are affected during the period when peak bone mass should be achieved. Early treatments for bone loss is very beneficial in these children, since peak bone mass is attained during the adolescent years and provides a basis for bone strength and integrity in later life [11, 16].

Cyclic infusions of pamidronate are widely used as therapy for children with osteogenesis imperfecta [8] and secondary osteoporosis [6, 11]. Infusions of pamidronate at doses of 1-3 mg/kg every 1-4 months is a widely used therapy regimen for patients with osteogenesis imperfecta [7, 8, 17]. However, only a few available publications have reported the use of bisphosphonates in children with cancer.

In this study, children with low BMDs who received IV infusions of pamidronate during and after chemotherapy had increases in both lumbar spine BMDs and BMD Z-scores as well as decreases in bone pain. The results of this study are comparable to those of the pilot study by Barr et al. [12]. In that study, 10 children with ALL were treated with IV infusions of pamidronate, beginning on the first day of a maintenance chemotherapy cycle. The whole body bone mineral contents and lumbar spine BMDs of these patients were increased by 5-10% over the course of a 6-month study period. Goldbloom et al. [13] reported the use of pamidronate in 2 children with vertebral compression fractures at the time of ALL diagnosis; these patients received monthly 1 mg/kg pamidronate doses in addition to standard chemotherapy. Both patients experienced rapid pain relief and gradual improvements in BMD Z-scores. In clinical trials of osteosarcoma patients at the Memorial Sloan-Kettering Cancer Center, IV pamidronate was safely incorporated with chemotherapy and did not impair the efficacy of chemotherapy [18].

Bisphosphonate inhibits osteoclast-mediated bone resorption in various ways, including the prevention of osteoclast formation, differentiation, and apoptosis induction [19]. Bisphosphonate may also prevent steroid-induced osteoporosis by protecting osteocytes and osteoblasts from corticosteroid-induced apoptosis [20]. Accordingly, pamidronate treatment during and after ALL maintenance chemotherapy might prevent steroid-induced osteoporosis.

Among patients who receive ALL therapy, AON is a well-recognized complication in the midst of childhood. Administration of corticosteroids, especially dexamethasone, has been the main etiologic factor for AON. Risk factors include an older age at diagnosis and radiation therapy [21]. There are few reports on the use of bisphosphonates for the treatment of AON in childhood hematologic malignancies. Pamidronate treatment seems to improve pain, musculoskeletal function, and daily activity. However, the objective radiologic benefit of pamidronate treatment is controversial [22, 23]. Four adolescent patients in this study had AON of the long bones (femurs and tibia). Three of the patients had ALL and 1 had NHL and received HSCT. These patients had slower increases in the monthly Z-scores than did non-AON patients (0.000±0.118 vs. 0.246±0.195, respectively; P=0.007). All 4 AON patients showed improvement in pain within 6 months and increases in BMDs after pamidronate treatment, but 2 of them showed decreased BMD Z-scores.

Serum ALP levels decreased during pamidronate treatment. ALP, a plasma membrane enzyme, has been used as a marker of bone formation [24]. In metabolic bone diseases such as Paget's disease, osteomalacia, and renal osteodystrophy, total serum ALP levels have been used to monitor disease activity [25]. Decreased serum ALP levels indicate decreased bone turnover during pamidronate treatment. Therefore, ALP can be a useful marker for monitoring responses to pamidronate treatment. Osteocalcin is produced by osteoblasts and is a sensitive marker of bone formation as ALP. Increased osteocalcin levels reflect increased bone turnover [24]. In this study, the mean osteocalcin levels decreased during pamidronate treatment; however, this change was not statistically significant.

PTH secretion is sensitive to serum calcium levels, and decreased serum ionized calcium levels lead to increased PTH levels. The dose-response curve is sigmoid shaped. PTH secretion dramatically increases when serum calcium levels decrease below 9 mg/dL. The plasma calcium PTH secretion system is designed to respond more dramatically to hypocalcemia than to hypercalcemia [26]. It is assumed that because of these 2 reasons, the degree of PTH increase is higher than that of calcium decrease. Serum ICTP is a marker of bone resorption, reflects the degradation of collagen type I in various bone pathologies, and is inversely correlated with BMD [24]. The high serum ICTP levels did not change during pamidronate treatment. It can be assumed that increased bone turnover is sustained during pamidronate treatment.

Cyclic pamidronate treatment was well tolerated. Seven episodes of flu-like symptoms occurred during the patients' first exposures; these episodes were resolved with acetaminophen. One episode of mild symptomatic hypocalcemia with a tingling sensation in the hand was resolved with calcium supplements. These episodes did not prohibit further dosing.

There were no serious complications, such as osteonecrosis of the jaw (ONJ), in this study. In adults, ONJ is a well-recognized and potentially serious complication of bisphosphonate therapy [27]. Several risk factors for ONJ development have been identified, including periodontal disease, prior history of a dental procedure, exposure duration, bisphosphonate type, and older age [28]. However, there have been no reported cases of ONJ in children. A safe duration of pamidronate therapy has not yet been established for children. However, many studies of pamidronate treatment in children with osteogenesis imperfecta showed that long exposure to bisphosphonate, even exceeding 10 years, was considered safe.

In a recent report, oral alendronate was tolerated in pediatric patients and was suggested to have a positive effect on secondary osteoporosis [29]. However, there are practical limitations in small children; these include the need to administer alendronate after an overnight fast, at least 60 minutes before breakfast, and with at least 100 cc of water, and the requirement that the patient sit or stand for 30 minutes after swallowing alendronate to prevent esophagitis. This makes parenteral pamidronate infusion a preferred therapy over oral alendronate. Zoledronate is a newer and more potent bisphosphonate than pamidronate. In large clinical trials of zoledronate in adult cancer patients, this drug was more effective than pamidronate in reducing the risk of skeletal complication development, and the 2 drugs were associated with similar adverse events [30]. However, there are limited data on the use of zoledronate for secondary osteoporosis in children.

The long-term effects of pamidronate on the growing bones of cancer patients are unknown. The limitations of this study are that it was not a randomized trial and that the follow-up duration was short. In addition, the etiologies of BMD deficits in patients with childhood cancer other than the administration of steroids such as methotrexate, cranial irradiation, and hormonal dysfunction were not analyzed in depth because of the limited number of patients.

In conclusion, cyclic pamidronate therapy for low BMD during and after chemotherapy in children with ALL and NHL appears to be safe and effective. Further studies on a larger population are needed to establish the long-term effects and safety.

(A) Changes in the bone mineral density (BMD) Z-scores. Graph shows the BMD Z-scores for each patient in the control and pamidronate groups at baseline and after follow-up. Eight of the 10 control group patients had decreased BMD Z-scores, and 22 of the 24 pamidronate group patients had increased BMD Z-scores. (B) Changes in BMD (mg/cm²). Graph shows the BMD for each patient in the control and pamidronate groups at baseline and after follow-up. The BMDs of all pamidronate group patients increased after pamidronate therapy; however, the BMDs of 8 control group patients (N=10) decreased.

(A) The monthly BMD Z-score increases in the control and pamidronate groups were -0.024±0.097 and +0.193±0.201, respectively (P<0.001). The median, 25^th and 75^th percentiles (box), and ranges of BMD changes (whiskers) are shown. (B) Changes in the BMD per month (mg/cm²/month) in the control and pamidronate groups were -0.29±4.31 and +11.92±6.98, respectively (P<0.001). The median, 25^th and 75^th percentiles (box), and ranges of the BMD changes (whiskers) are shown.

Table 1 Patient characteristics.

Table 2 Pamidronate therapy outcomes.

Table 3 Factors that affect bone mineral density and pamidronate treatment outcomes.

Table 4 Changes in biochemical values after pamidronate treatment.