Aminoalkylbisphosphonates, potent inhibitors of bone resorption, induce a prolonged stimulation of histamine synthesis and increase macrophages, granulocytes, and osteoclasts in vivo.
Aminoalkyl derivatives of bisphosphonates are potent inhibitors of bone resorption. A single I.P. injection of 4-amino-1-hydroxybutylidene-1,1-bis-phosphonate (AHBuBP) induced a prolonged enhancement of histidine decarboxylase (HDC) activity in the bone marrow, spleen, lung, and liver of mice and resulted in an increase in histamine. The induction of HDC by the agent was dose dependent (16-80 mumol/kg) and peaked 3-4 days after its injection (40 mumol/kg). Repeated S.C. injections of smaller doses of AHBuBP (0.32 or 1.6 mumol/kg/day) for 4 days also enhanced HDC activity. However, the minimum dose capable of inhibiting bone resorption (0.064 mumol/kg/day) was lower than that inducing HDC. Unexpectedly, AHBuBP, at the doses inducing HDC, increased macrophages, granulocytes, and even osteoclasts. The size of osteoclasts was also enlarged by the agent. Another aminobisphosphonate, 3-amino-1-hydroxypropylidene-1,1-bisphosphonate, but none of non-amino derivatives, also exhibited essentially the same effects as those of AHBuBP. These results indicate that in spite of increase in osteoclasts and their enlargement, bone resorption is still inhibited by amino bisphosphonates. As granulocyte and granulocyte-macrophage colony-stimulating factors and interleukin-3 induce HDC in hematopoietic organs, and histamine has a hematopoietic activity, the HDC induction by aminobisphosphonates may be relevant to the proliferation of progenitor cells of macrophages, granulocytes, and osteoclasts.
Endo
Y
Y
Department of Pharmacology, School of Dentistry, Tohoku University, Sendai, Japan.
Nakamura
M
M
Kikuchi
T
T
Shinoda
H
H
Takeda
Y
Y
Nitta
Y
Y
Kumagai
K
K
D019386:Alendronate; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D001862:Bone Resorption / Q000188:drug therapy*; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D002452:Cell Count / Q000187:drug effects; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D004790:Enzyme Induction; D006098:Granulocytes / Q000187:drug effects*; D006632:Histamine / Q000096:biosynthesis*; D006640:Histidine Decarboxylase / Q000096:biosynthesis; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D010529:Peritoneal Cavity / Q000166:cytology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000201:enzymology
D004164:Diphosphonates; D006632:Histamine; D006640:Histidine Decarboxylase; D019386:Alendronate