Improved Bone Delivery of Osteoprotegerin by Bisphosphonate ...
Aminohydroxypropylidene bisphosphonate (AHPrBP) but not dichloromethylene bisphosphonate (Cl2MDP)...
1
312 Abstracts of the Bone and Tooth Society Meeting (OH&) and creatinine (Cr). The patients’ symptoms were scored before and after treatment. P raised the plasma progesterone from 0.5 nmolil to 24.0 nmol/l (p < 0.01). There was no significant fall in plasma FSH, although the symptom score improved from 12.6 to 7.4 (p < 0.01). There was no change in AP and urinary Ca/Cr or OHP/Cr excretion. MPA produced a fall in symptom score from 10.7 to 7.1 @I < 0.05) which was not accompanied by any change in plasma FSH. There was no change in AP or uri- nary Ca/Cr or OHPr/Cr excretion. We conclude that neither P nor MPa has the same effect as either E or NE on post- menopausal bone loss and that this limits their usefulness for postmenopausal hormone replacement. DO ALL DIPHOSPHONATES HAVE HYPERPHOSPHATEMIC EFFECTS IN MAN? A.J.P. Yates, E.V. McCloskey, and J.A. Kanis Department of Himan Metabolism and Clinical Biochemistry, University of Sheffield Medical School, Sheffield, UK. The diphosphonate, etidronate, induces hyperphospha- temia in man by increasing renal tubular reabsorption of phosphate. In contrast, clinical studies with other diphos- phonates have generally shown decreased renal tubular reabsorption of phosphate, perhaps due to secondary hy- perparathyroidism. We have observed, however, small but significant increases in serum phosphate and TmP/GFR following intravenous infusions with clodronate and amino- hexane diphosphonate (AHDP) for 5 days in Pagetic pa- tients. Unlike etidronate (300-700 mg/day) infusion, which induced marked increases in TmP/GFR sustained for 1 month, effects after clodronate (300 mg/day) or AHDP (50 mg/day) were transient and followed by significant de- creases. In addition, clodronate and AHDP, but not eti- dronate, induced hypocalcemia and secondary hyper- parathyroidism, which might have offset a hyperphospha- temic effect. In order to determine whether secondary hyperparathyroidism might mask a hyperphosphatemic effect of other diphosphonates, we examined their effects on phosphate transport in 4 hypoparathyroid subjects. In- travenous clodronate or AHDP induced marked increases in serum phosphate and TmP/GFR of comparable degree to, but shorter duration than, those seen following eti- dronate treatment. These data suggest that all three intra- venous diphosphonates induce hyperphosphatemia. However, this response in Paget’s disease may be offset by the secondary hyperparathyroidism that occurs with the newer diphosphonates. DISTRIBUTION OF AN EXTRACELLULAR MATRIX ANTIGEN RECOGNIZED BY MONOCLONAL ANTIBODY CS-GCB, IN BONE, CARTILAGE, BONE TUMORS, AND SOFT TISSUE C.E. Sheard,’ J.P. Dillon,’ N. Billingham,’ L. Bobrow,’ J.A.S. Pringle,3 and J.A. Gallagher’ Departments of Anatomy and Embryology’ and Histopatholgy,* University College, London, and Department of Morbid Anatomy,3 Institute of Orthopaedics, RNOH, Stanmore, UK. CS-GC3 is a monoclonal antibody secreted by a mouse hybridoma prepared after immunization of a Balb/C mouse with cultured human bone cells. Using immunofluores- cence and the indirect immunoperoxidase technique, we have established that the antibody reacts with an antigen that has a widespread distribution in the extracellular ma- trix of nonskeletal tissue. In cultured human bone cells the antigen is located in intracellular vesicles but not in the pericellular space or adhering to the cell membranes. In frozen sections of bone, an intense reaction is observed in the periosteum, but no staining is observed in calcified bone matrix apart from the perilacunar matrix of osteo- cytes and the superficial layer of forming surfaces. Os- teoblasts are strongly positive, but reactivity is only occa- sionally observed in osteocytes, perhaps reflecting re- sidual synthetic activity. The antigen is present in articular cartilage but only in the perilacunar matrix close to the ar- titular surface and near blood vessels. Staining diminishes in a gradient away from the articular surface and is absent from the matrix of the central zone. Stromal tissue in giant cell lesions is strongly positive, but no staining is observed in giant cells. The distribution suggests that the antibody may be against a minor collagen of a noncollagenous ma- trix protein, or that the antigen is masked or lost from mln- eralized bone matrix. The zonal distribution in cartilage has interesting potential. AMINOHYDROXYPROPYLIDENE BISPHOSPHONATE (AHPrBP) BUT NOT DICHLOROMETHYLENE BISPHOSPHONATE (CI,MDP) EXERTS BIPHASIC EFFECTS ON THE PRODUCTION OF IL-l-LIKE ACTIVITY BY PERIPHERAL BLOOD MONOCYTES D.E. Hughes, A. Crawford, H. Skjodt, and R.G.G. Russell Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School, Sheffield, UK. The bisphosphonates AHPrBP and Cl, MBP are potent in- hibitors of bone resorption in vitro and bone turnover in vivo. Bijvoet et al. (1980) have suggested that AHPrBP may act on cells of the monocyte/macrophage lineage, and since cells of this series are putative osteoclast pre- cursors, the effects of AHPrBP on these cells may be of relevance to the mechanism of its action on bone. AHPrBP enhances lectin-induced macrophage-dependent lym- phocyte proliferation in vitro and induces an acute phase response in vivo. These responses may possibly be me- diated by interleukin 1 (IL-l), which is also a potent stimu- lator of bone resorption in vitro. The effect of these bis- phosphonates on the production of IL-l-like activity by II- popolysaccaride-stimulated human peripheral blood monocytes was assessed by measuring the effect of monocyte-conditioned media on the production of neutral metalloproteinase (measured by caseinase activity) by cultured human articular chondrocytes. The effect of AHPrBP was biphasic, enhancement of the production of IL-l-like activity was observed at 10-7-10-5M AHPrBP, whereas 10-4M AHPrBP inhibited this response without toxicity. Similar concentrations of CI,MDP had no effect. Both bisphosphonates inhibited IL-l-stimulated bone re- sorption in neonatal mouse calvaria at concentrations greater than IO-‘M. These results suggest that some of the observed effects of AHPrBP in vitro and in vivo, may be mediated by its modulation of IL-1 production by mononu- clear phagocytes.
Transcript of Aminohydroxypropylidene bisphosphonate (AHPrBP) but not dichloromethylene bisphosphonate (Cl2MDP)...
312 Abstracts of the Bone and Tooth Society Meeting
(OH&) and creatinine (Cr). The patients’ symptoms were scored before and after treatment. P raised the plasma progesterone from 0.5 nmolil to 24.0 nmol/l (p < 0.01). There was no significant fall in plasma FSH, although the symptom score improved from 12.6 to 7.4 (p < 0.01). There was no change in AP and urinary Ca/Cr or OHP/Cr excretion. MPA produced a fall in symptom score from 10.7 to 7.1 @I < 0.05) which was not accompanied by any change in plasma FSH. There was no change in AP or uri- nary Ca/Cr or OHPr/Cr excretion. We conclude that neither P nor MPa has the same effect as either E or NE on post- menopausal bone loss and that this limits their usefulness for postmenopausal hormone replacement.
DO ALL DIPHOSPHONATES HAVE HYPERPHOSPHATEMIC EFFECTS IN MAN?
A.J.P. Yates, E.V. McCloskey, and J.A. Kanis
Department of Himan Metabolism and Clinical Biochemistry, University of Sheffield Medical School, Sheffield, UK.
The diphosphonate, etidronate, induces hyperphospha- temia in man by increasing renal tubular reabsorption of phosphate. In contrast, clinical studies with other diphos- phonates have generally shown decreased renal tubular reabsorption of phosphate, perhaps due to secondary hy- perparathyroidism. We have observed, however, small but significant increases in serum phosphate and TmP/GFR following intravenous infusions with clodronate and amino- hexane diphosphonate (AHDP) for 5 days in Pagetic pa- tients. Unlike etidronate (300-700 mg/day) infusion, which induced marked increases in TmP/GFR sustained for 1 month, effects after clodronate (300 mg/day) or AHDP (50 mg/day) were transient and followed by significant de- creases. In addition, clodronate and AHDP, but not eti- dronate, induced hypocalcemia and secondary hyper- parathyroidism, which might have offset a hyperphospha- temic effect. In order to determine whether secondary hyperparathyroidism might mask a hyperphosphatemic effect of other diphosphonates, we examined their effects on phosphate transport in 4 hypoparathyroid subjects. In- travenous clodronate or AHDP induced marked increases in serum phosphate and TmP/GFR of comparable degree to, but shorter duration than, those seen following eti- dronate treatment. These data suggest that all three intra- venous diphosphonates induce hyperphosphatemia. However, this response in Paget’s disease may be offset by the secondary hyperparathyroidism that occurs with the newer diphosphonates.
DISTRIBUTION OF AN EXTRACELLULAR MATRIX ANTIGEN RECOGNIZED BY MONOCLONAL ANTIBODY CS-GCB, IN BONE, CARTILAGE, BONE TUMORS, AND SOFT TISSUE
C.E. Sheard,’ J.P. Dillon,’ N. Billingham,’ L. Bobrow,’ J.A.S. Pringle,3 and J.A. Gallagher’
Departments of Anatomy and Embryology’ and Histopatholgy,* University College, London, and Department of Morbid Anatomy,3 Institute of Orthopaedics, RNOH, Stanmore, UK.
CS-GC3 is a monoclonal antibody secreted by a mouse hybridoma prepared after immunization of a Balb/C mouse
with cultured human bone cells. Using immunofluores- cence and the indirect immunoperoxidase technique, we have established that the antibody reacts with an antigen that has a widespread distribution in the extracellular ma- trix of nonskeletal tissue. In cultured human bone cells the antigen is located in intracellular vesicles but not in the pericellular space or adhering to the cell membranes. In frozen sections of bone, an intense reaction is observed in the periosteum, but no staining is observed in calcified bone matrix apart from the perilacunar matrix of osteo- cytes and the superficial layer of forming surfaces. Os- teoblasts are strongly positive, but reactivity is only occa- sionally observed in osteocytes, perhaps reflecting re- sidual synthetic activity. The antigen is present in articular cartilage but only in the perilacunar matrix close to the ar- titular surface and near blood vessels. Staining diminishes in a gradient away from the articular surface and is absent from the matrix of the central zone. Stromal tissue in giant cell lesions is strongly positive, but no staining is observed in giant cells. The distribution suggests that the antibody may be against a minor collagen of a noncollagenous ma- trix protein, or that the antigen is masked or lost from mln- eralized bone matrix. The zonal distribution in cartilage has interesting potential.
AMINOHYDROXYPROPYLIDENE BISPHOSPHONATE (AHPrBP) BUT NOT DICHLOROMETHYLENE BISPHOSPHONATE (CI,MDP) EXERTS BIPHASIC EFFECTS ON THE PRODUCTION OF IL-l-LIKE ACTIVITY BY PERIPHERAL BLOOD MONOCYTES
D.E. Hughes, A. Crawford, H. Skjodt, and R.G.G. Russell
Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School, Sheffield, UK.
The bisphosphonates AHPrBP and Cl, MBP are potent in- hibitors of bone resorption in vitro and bone turnover in vivo. Bijvoet et al. (1980) have suggested that AHPrBP may act on cells of the monocyte/macrophage lineage, and since cells of this series are putative osteoclast pre- cursors, the effects of AHPrBP on these cells may be of relevance to the mechanism of its action on bone. AHPrBP enhances lectin-induced macrophage-dependent lym- phocyte proliferation in vitro and induces an acute phase response in vivo. These responses may possibly be me- diated by interleukin 1 (IL-l), which is also a potent stimu- lator of bone resorption in vitro. The effect of these bis- phosphonates on the production of IL-l-like activity by II- popolysaccaride-stimulated human peripheral blood monocytes was assessed by measuring the effect of monocyte-conditioned media on the production of neutral metalloproteinase (measured by caseinase activity) by cultured human articular chondrocytes. The effect of AHPrBP was biphasic, enhancement of the production of IL-l-like activity was observed at 10-7-10-5M AHPrBP, whereas 10-4M AHPrBP inhibited this response without toxicity. Similar concentrations of CI,MDP had no effect. Both bisphosphonates inhibited IL-l-stimulated bone re- sorption in neonatal mouse calvaria at concentrations greater than IO-‘M. These results suggest that some of the observed effects of AHPrBP in vitro and in vivo, may be mediated by its modulation of IL-1 production by mononu- clear phagocytes.
