High-dose chemotherapy shows a dose-dependent toxicity to bone marrow osteoprogenitors: A mechanism for post-bone marrow transplantation osteopenia

BACKGROUND. Osteoporosis is a sequela of hemopoietic cell transplantation with a complex multifactorial pathogenesis in which the relative role of chemotherapy and irradiation is not completely understood. Therefore, the authors investigated the toxicity of chemotherapy-only conditioning regimens on bone homeostasis and bone marrow osteoprogenitors, its dose dependency, and the mechanism of chemotherapy-induced osteopenia. METHODS. Fifty-one patients with high-grade non-Hodgkin lymphoma or breast carcinoma who had been treated previously with high-dose + peripheral blood progenitor cell or conventional chemotherapy or who had not received any treatment (prechemotherapy) were enrolled. The authors measured the bone marrow colony-forming unit fibroblast (CFU-f) and long-term culture-initiating cell frequency, forearm bone mineral density, serum osteotropic hormones and metabolic markers of bone formation (plasma osteocalcin), and resorption (urinary collagen I C-crosslinks). RESULTS. Both high-dose chemotherapy regimens caused a 50% reduction in CFU-f frequency, independently of gonadal function status, whereas conventional chemotherapy and prechemotherapy groups were unaffected. Bone mineral density was measured in 26 non-Hodgkin lymphoma patients and again only high-dose chemotherapy caused a 10% loss in cortical bone and 20% in trabecular bone. No endocrine abnormality was found except for the secondary amenorrhea uniformly induced in the high-dose chemotherapy group. In these patients, plasma osteocalcin unexpectedly failed to increase in response to the menopausal increase in bone resorption rate, showing a selective impairment of the osteoblast compartment to cope with increased functional demand. CONCLUSIONS. Chemotherapy without irradiation shows a dose-dependent toxicity to bone marrow stromal osteoprogenitors and can cause osteopenia by direct damage of the osteoblastic compartment, as a mechanism distinct from and summable to hypogonadism.