Bisphosphonate Induces Remission of Refractory Osteolysis in Langerhans Cell Histiocytosis

Abstract

LANGERHANS CELL histiocytosis (LCH) is a monoclonal proliferation of activated Langerhans-like cells in conjunction with T cells, macrophages, eosinophils, and multinucleated giant cells. The clinical symptoms vary from isolated osteolytic bone lesions to disseminated multiorgan involvement. Osteolytic lesions occur in 85–90% of children with LCH, most of whom are unresponsive to chemotherapies that often cause a decreased quality of life.1 One of the problems in the treatment of LCH is care for the patient who has recurrences of multiple osteolytic bone lesions. Optimal treatment remains unclear and alternative treatments such as irradiation, local injection of corticosteroid, and surgery are not very effective for refractory osteolysis of LCH.1, 2 In 1989, Elomaa et al. reported that clodronate was useful to relieve pain with multifocal eosinophilic granuloma shown in LCH.3 Recently, bisphosphonates, as a potent inhibitor of the osteoclast function, are widely used for the treatment of osteoporosis and neoplastic bone lesions such as multiple myeloma.4 Long-term pamidronate therapy is a safe and effective treatment for children with fibrous dysplasia or osteogenesis imperfecta. According to the same principle, we administered bisphosphonates to two infants with LCH that was refractory to various chemotherapeutic agents. A 12-month-old girl (case 1) and a 10-month-old girl (case 2) were admitted to the University of Occupational and Environmental Health, Japan, because of intractable systemic skin eruptions, cervical lymphadenopathies, and multiple osteolytic lesions of the skull. The two infants' bad moods were probably caused by osteolysis. A skin biopsy revealed the infiltration of dendric cells expressing CD1a and S-100 protein antigens and carrying Birbeck granules on electron microscopy. The diagnosis of LCH was made. These two girls represented very similar clinical courses. The skin eruptions and lymphadenopathies regressed rapidly in response to the remission induction therapy with the combination of vincristine (VCR), cytarabine (Ara C), and prednisolone (PSL). However, severe multiple osteolytic lesions in the two infants were unresponsive to the repeated chemotherapies mentioned previously, and additional therapies including Adriamycin, cyclophosphamide, VCR, and PSL (ACOP) and others, and distressed the two infants. Thus, bisphosphonate therapy was chosen. Etidronate was used because it was the only permitted bisphosphonate at that time in Japan. Because it has been reported that for adults 200–400 mg/day of oral etidronate should be administered and for babies 5–10 mg/kg per day, it was decided to administer 200 mg/m2 per day of oral etidronate to the infants for 14 consecutive days out of every 3 months without any supplement chemotherapies. Informed consent was obtained from their parents. Although calcium and vitamin D were not coadministered, hypocalcemia was not seen during the whole period of the treatment. Figure 1 summarizes the serial three-dimensional computed tomographies (3D-CT) of the skull (case 1) and bone X-ray of the clavicle (case 2) during the course of bisphosphonate therapy. The skull lesions showed a marked response to etidronate. Fig. 1A depicts the skull lesion before etidronate therapy (case 1). The skull lesions showed marked responses to etidronate and the parietal lesions were undetectable by 3D-CT after two courses of treatment (Fig. 1B). It is noteworthy that the girls' occipital bone defects were ameliorated by 90% after six courses of the treatment (Fig. 1C). In case 2, severe osteolysis in the clavicle was observed by bone X-ray before the treatment (Fig. 1D), whereas the osteolytic lesion became undetectable after the treatment (Fig. 1E). Furthermore, their urinary levels of N-terminal telopeptide cross-linked type 1 collagen, a bone resorption marker, was decreased from 1350.2 to 233.6 nmol BCE/mmol Cre (case 1) and from 1973.6 to 310.4 nmol BCE/mmol Cre (case 2) after the treatment. The change might be caused by the natural course of the condition in the two cases. However, the treatments also resulted in an improvement in their moods. The effect of etidronate on an osteolytic lesion on serial 3D-CT (A-C) in the skull of case 1 and (D and E) in the clavicle of case 2 is shown. The skull (A) before etidronate treatment, (B) after three courses of etidronate treatment, (C) after six courses of etidronate treatment is shown. The clavicle (D) before etidronate treatment and (E) after six courses of etidronate treatment is shown. Regarding the long-term effects of bisphosphonate on growing bone, it has been reported that remodeling and growth of bones generally are normal,5 except for one report that stated that mineralization and widening of the growth plates were impaired in a 13-year-old boy.6 Fortunately, during the etidronate therapy of the two infants that we treated, no adverse effects were detected and there were no signs of de novo infiltration of LCH cells, including extra osseous tissues. Bergstrom et al. reported that inhibition of the mevalonate pathway and reduction in geranylgeranyl-diphosphate differ between nitrogen-containing bisphosphonates and nonnitrogen-containing bisphosphonates, and that the first generation of bisphosphonates is, thereby, less potent than the second and the third one.7 Although oral administration is less potent than an intravenous one, oral administration of bisphosphonates administered is easier in the case of a child, and, theoretically, there is less risk to skeletal growth and mineralization.5 However, despite widespread use in adults, the pediatric experience with bisphosphonates is fairly limited. Thus, it is important that physicians share data to permit a better study of the safety and efficacy of these bisphosphonates. In bone lesions, proliferating LCH cells are juxtaposed to activated T cells, macrophages, and eosinophils, which could result in cytokine amplification in an autocrine and/or paracrine stimulation manner. Such a cytokine storm is considered to be linked directly to the recruitment, maturation, and proliferation of LCH cells and osteoclast precursor cells, leading to multifocal bone involvement.8 The growth-inhibitory and cytotoxic effects of nonaminobisphosphonates such as etidronate and clodronate on macrophages and other cells, including osteoclasts, are the results of the cytoplasmic accumulation of the metabolites.9 Because pathological LCH cells arise from the same mononuclear cell lineage as macrophages, they are likely affected in a similar manner. Therefore, bisphosphonates that decrease cytokines and prostaglandins should cause lesion regression by decreasing both monoclonal LCH cell proliferation and osteoclast activity. These two cases suggest that the bisphosphonates therapy is noninvasive and highly effective for refractory bone involvement in LCH and that osteoclastic bone resorption could be involved in the pathological processes of osteolysis of LCH. Furthermore, Farran et al.10 and Arzoo et al.11 recently reported that intravenous treatment of pamidronate was very effective for decreasing severe bone pain in LCH. Large-scale studies comparing bisphosphonate therapy with the currently accepted invasive treatments such as antitumor chemotherapy, irradiation, and surgery in osteolytic lesions of LCH would be very useful.