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T.j. Hall - One of the best experts on this subject based on the ideXlab platform.
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Phenothiazines are potent inhibitors of osteoclastic Bone resorption
General Pharmacology: The Vascular System, 1996Co-Authors: T.j. Hall, Hong Nyugen, Michelle Schaeublin, Marek Michalsky, Martin MissbachAbstract:1. 1. We have previously shown that promethazine inhibits osteoclastic Bone resorption in the in vitro Bone Slice assay (IC50=0.8 μM), but the mechanism(s) involved are unclear. 2. 2. We have now tested the effects on osteoclast activity of five other structurally related compounds. Phenothiazine, chlorpromazine, amitriptyline, phenazine, and phenoxazine had IC50 values of 0.8, 0.9, 6, 7, and > 10 μM, respectively, in the Bone Slice assay, indicating that the basic phenothiazine structural element itself is important for osteoclast inhibitory activity. 3. 3. The results are discussed in terms of the known effects of phenothiazines on plasma membrane fluidity, blocking of ion channels, and inhibition of calmodulin.
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Gold salts inhibit osteoclastic Bone resorption in vitro.
Inflammation Research, 1996Co-Authors: T.j. Hall, H. Jeker, H. Nyugen, M. SchaeublinAbstract:Loss of Bone mass is commonly associated with rheumatoid arthritis (RA) and is increasingly considered to be due to the increased activity of Bone-resorbing osteoclasts. Gold salts such as auranofin (AF), aurothioglucose (ATG) and aurothiomalate (ATM) have beneficial therapeutic effects in RA, but their mechanisms(s) of action is not well understood. In the present study we have examined the effects of these 3 gold salts on osteoclastic Bone resorption in vitro, using the Bone Slice assay where bovine cortical Bone Slices are resorbed by osteoclasts disaggregated from the long Bones of neonatal rats. All 3 gold salts inhibited osteoclastic Bone resorption with IC50 values of AF=0.1 μg/ml, ATG and ATM=1 μg/ml. All 3 compounds caused a decreased survival of osteoclasts on Bone Slices at high concentrations indicating a cytotoxic effect that was also observed in a cytotoxicity assay with osteoblast-like UMR-106 cells. Preincubation of Bone Slices with various concentrations of AF followed by extensive washing prior to use in the Bone Slice assay also resulted in an inhibition of Bone resorption (IC50=4 μg/ml) and osteoclast survival on the Bone Slices preincubated with high concentrations of AF was decreased. Since these effects were obtained with therapeutic concentrations of gold salts, these results indicate that inhibition of osteoclastic Bone resorption by gold salts may, at least in part, account for their beneficial effects in RA.
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TAXOL INHIBITS OSTEOCLASTIC Bone RESORPTION
Calcified Tissue International, 1995Co-Authors: T.j. Hall, H. Jeker, M. SchaueblinAbstract:We have examined the effect of the anti-tumor compound taxol, on osteoclastic Bone resorption. In the Bone Slice assay, taxol (0.1–0.001 μM) dose-dependently inhibited Bone resorption with an IC50 of 0.08 μM. Osteoclast survival on Bone Slices was unaffected by 0.01–1 μM taxol, but 10 μ M was cytotoxic. Taxol (1 μM) also ihibited osteoclast spreading (45%) on fibronectin-coated slides. The antiproliterative effects of taxol are due to its unique ability to stabilize microtubules. Primary osteoclasts are nonproliferating end cells, so taxol probably inhibits Bone resorption by intertering with other microtubule-dependent functions such as cell polarization, motility or vesicle exocytosis. Since these inhibitory effects on osteoclasts in vitro are seen with therapeutically relevant concentrations, taxol therapy may have beneficial side-effects e.g. inhibition of hyperealcemia and Bone metastases.
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The role of reactive oxygen intermediates in osteoclastic Bone resorption.
Biochemical and Biophysical Research Communications, 1995Co-Authors: T.j. Hall, H. Jeker, M. Schaeublin, K Fuller, Timothy J ChambersAbstract:Abstract Osteoclasts have been shown to produce reactive oxygen intermediates (ROI) and it has been suggested that ROI are involved in the process of Bone resorption. ROI have also been shown to play a central role in the activation of the multisubunit transcription factor NF-κB that enhances the transcription of genes encoding defence and signaling proteins. Therefore, we have assessed the effect of pyrrolidine dithiocarbamate (PDTC), an oxygen-radical scavenger and metal chelator that is a selective and potent inhibitor of NF-κB activation, on osteoclastic Bone resorption in the Bone Slice assay. PDTC (0.001 - 0.1 mM) dose-dependently and non-cytotoxically inhibited osteoclast activity with an IC 50 of 0.01 mM. PDTC (0.01 mM) caused no change in the ratio of resorption pit area to resorption pit depth as measured by Lasertec confocal microscopy, indicating that ROI are not involved in the resorptive process per se . This view is supported by time-course studies showing that addition of PDTC or N-acetyl cysteine (NAG; an ROI scavenger, but not metal chelator), 6 hr after the start of the assay had no significant effect on subsequent Bone resorption. Desferal (100 μM), a chelator of iron and other metal ions, had no significant effect on Bone resorption, indicating (along with the results with NAG) that ROI-scavenging rather than metal chelation is responsible for inhibition of osteoclastic Bone resorption by PDTC. Taken together these results indicate that ROI produced by osteoclasts in the Bone Slice assay are not involved in the process of Bone resorption, but are important during osteoclast activation for Bone resorption, possibly being involved in activation of the transcription factor NF-κB.
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Wortmannin, a potent inhibitor of phosphatidylinositol 3-kinase, inhibits osteoclastic Bone resorption in vitro
Calcified Tissue International, 1995Co-Authors: T.j. Hall, H. Jeker, M. SchaueblinAbstract:Phosphatidylinositol 3-kinase (Pl3-k) is involved in cellular signaling via the phosphoinositol pathway leading to mitogenesis in response to growth factors in proliferating cells, as well as cytoskeletal changes and secretory responses in terminally differentiated cells. The fungal metabolite, wortmannin, is a potent and selective inhibitor of Pl3-k at nanomolar concentrations. We show that wortmannin dose-dependently (0.001 – 1 μM) inhibits Bone resorption by isolated rat osteoclasts in the Bone Slice pit assay with an IC50 of-5 nM. Wortmannin was not cytotoxic since osteoclast morphology and survival on Bone Slices was unaffected by concentrations up to 1 μM. Since primary osteoclasts are terminally differentiated cells and osteoclast cytoplasmic spreading and morphology was unaffected by wortmannin, we suggest that Pl3-k signaling is involved in vesicle exocytosis and ruffled border membrane formation that are required for osteoclastic Bone resorption to take place.
Liang Shan - One of the best experts on this subject based on the ideXlab platform.
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Comparative analysis of effects of reconstruction and radical treatment of the posterior ear canal wall using periosteal osteocomma and mastoid antrum ventilation.
Indian journal of otolaryngology and head and neck surgery : official publication of the Association of Otolaryngologists of India, 2013Co-Authors: Jun Tong, Wenwen Chen, Yaxin Deng, Xunhua Cai, Liang ShanAbstract:To analyze the results of repair defect of the ear canal with autologous Bone containing periosteum and hearing reconstruction and postoperative inflation. Retrospective analysis of the 40 cases of surgeries conducted by senior surgeon. All cases received full open surgeries. Preoperative air conduction (AC) was 67.47 ± 14.32 dBHL, and GAP was 45.95 ± 12.63 dBHL. These cases were divided into two groups: the first 20 ears received repair surgery for radical mastoid cavity with Bone Slice containing periosteum combined with ear ossicle remodeling, namely the Bone Slice group. For another 20 ears, inflator was additionally used and the mastoid antrum cavity was inflated twice a day, namely the inflation group. 9-60 months (median follow-up of 26 months). U test was adopted. All ear canal showed a smooth appearance. Eight cases received CT scans and presenting re-gasification of attic and/or mastoid cavity. Hearing: AC of 47.32 ± 15.63 dBHL, and GAP of 18.28 ± 15.28 dBHL, both P values were <0.01 as compared with that before operation, and the difference was highly significant. 23 cases showed GAP <20 dB, and one case showed GAP >20 at follow-up, but narrowing was >30 dB, and these 24 cases were successful case, with a success rate = 60 %. 16 cases with GAP <10 dB, although 4 cases with GAP >10 dB, narrowing was >30 dB, thus the 20 cases were markedly effective, and with ratio = 50 %. The gap of 30 cases was narrowed more than 15 dB, although two cases showed gap narrowing less than 15 dB, postoperative GAP was less than 10 dB, both were valid, with an efficacy of 32/40 = 80 %, 18 cases (45 %) with AC <40 dBHL. Sub-group analysis: age: group P < 0.05 when the two groups were compared, difference in ages of the two groups were significant, and the age of the inflation group was older. Both GAP and AC of the two groups showed no significant difference before and after the surgery. One case in the Bone Slice group showed poor postoperative hearing, adhesion was found between the mesotympanum and attic in reoperation, and best result of GAP Close to less than 10 dB was obtained using the decomposition method after inflation. Bone Slice containing periosteum can be used for reconstruct the normal ear canal. Auxiliary inflation of middle ear can even promote the tympanic re-gasification and hearing recovery.
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Comparative Analysis of Effects of Reconstruction and Radical Treatment of the Posterior Ear Canal Wall Using Periosteal Osteocomma and Mastoid Antrum Ventilation
Indian Journal of Otolaryngology and Head & Neck Surgery, 2013Co-Authors: Jun Tong, Wenwen Chen, Yaxin Deng, Xunhua Cai, Liang ShanAbstract:To analyze the results of repair defect of the ear canal with autologous Bone containing periosteum and hearing reconstruction and postoperative inflation. Retrospective analysis of the 40 cases of surgeries conducted by senior surgeon. All cases received full open surgeries. Preoperative air conduction (AC) was 67.47 ± 14.32 dBHL, and GAP was 45.95 ± 12.63 dBHL. These cases were divided into two groups: the first 20 ears received repair surgery for radical mastoid cavity with Bone Slice containing periosteum combined with ear ossicle remodeling, namely the Bone Slice group. For another 20 ears, inflator was additionally used and the mastoid antrum cavity was inflated twice a day, namely the inflation group. Follow-up: 9–60 months (median follow-up of 26 months). Statistical analysis: U test was adopted. All ear canal showed a smooth appearance. Eight cases received CT scans and presenting re-gasification of attic and/or mastoid cavity. Hearing: AC of 47.32 ± 15.63 dBHL, and GAP of 18.28 ± 15.28 dBHL, both P values were 20 at follow-up, but narrowing was >30 dB, and these 24 cases were successful case, with a success rate = 60 %. 16 cases with GAP 10 dB, narrowing was >30 dB, thus the 20 cases were markedly effective, and with ratio = 50 %. The gap of 30 cases was narrowed more than 15 dB, although two cases showed gap narrowing less than 15 dB, postoperative GAP was less than 10 dB, both were valid, with an efficacy of 32/40 = 80 %, 18 cases (45 %) with AC
M. Schaueblin - One of the best experts on this subject based on the ideXlab platform.
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TAXOL INHIBITS OSTEOCLASTIC Bone RESORPTION
Calcified Tissue International, 1995Co-Authors: T.j. Hall, H. Jeker, M. SchaueblinAbstract:We have examined the effect of the anti-tumor compound taxol, on osteoclastic Bone resorption. In the Bone Slice assay, taxol (0.1–0.001 μM) dose-dependently inhibited Bone resorption with an IC50 of 0.08 μM. Osteoclast survival on Bone Slices was unaffected by 0.01–1 μM taxol, but 10 μ M was cytotoxic. Taxol (1 μM) also ihibited osteoclast spreading (45%) on fibronectin-coated slides. The antiproliterative effects of taxol are due to its unique ability to stabilize microtubules. Primary osteoclasts are nonproliferating end cells, so taxol probably inhibits Bone resorption by intertering with other microtubule-dependent functions such as cell polarization, motility or vesicle exocytosis. Since these inhibitory effects on osteoclasts in vitro are seen with therapeutically relevant concentrations, taxol therapy may have beneficial side-effects e.g. inhibition of hyperealcemia and Bone metastases.
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Wortmannin, a potent inhibitor of phosphatidylinositol 3-kinase, inhibits osteoclastic Bone resorption in vitro
Calcified Tissue International, 1995Co-Authors: T.j. Hall, H. Jeker, M. SchaueblinAbstract:Phosphatidylinositol 3-kinase (Pl3-k) is involved in cellular signaling via the phosphoinositol pathway leading to mitogenesis in response to growth factors in proliferating cells, as well as cytoskeletal changes and secretory responses in terminally differentiated cells. The fungal metabolite, wortmannin, is a potent and selective inhibitor of Pl3-k at nanomolar concentrations. We show that wortmannin dose-dependently (0.001 – 1 μM) inhibits Bone resorption by isolated rat osteoclasts in the Bone Slice pit assay with an IC50 of-5 nM. Wortmannin was not cytotoxic since osteoclast morphology and survival on Bone Slices was unaffected by concentrations up to 1 μM. Since primary osteoclasts are terminally differentiated cells and osteoclast cytoplasmic spreading and morphology was unaffected by wortmannin, we suggest that Pl3-k signaling is involved in vesicle exocytosis and ruffled border membrane formation that are required for osteoclastic Bone resorption to take place.
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Hydrochlorothiazide inhibits osteoclastic Bone resorption In vitro
Calcified Tissue International, 1994Co-Authors: T.j. Hall, M. SchaueblinAbstract:Long-term thiazide diuretic use is associated with higher Bone mineral density and reduced hip fracture rates, which are attributed to increased serum calcium levels and decreased parathyroid activity that lead to decreased Bone resorption. The present study shows that 1–100 μM hydro-chlorothiazide (HCTZ) dose dependently inhibits Bone resorption by isolated rat osteoclasts in the Bone Slice assay with an IC_50 of ∼20 μM. At these concentrations, HCTZ did not affect osteoclast survival on Bone Slices and had no effect on the proliferation of UMR-106 rat osteoblasts, indicating that the compound is not cytotoxic. However, such concentrations of HCTZ are unlikely to be achieved in man where therapeutic doses are usually 12.5–100 mg/day. That the in vitro effect of HCTZ on Bone resorption may be due to inhibition of osteoclast carbonic anhydrase is discussed.
Jun Tong - One of the best experts on this subject based on the ideXlab platform.
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Comparative analysis of effects of reconstruction and radical treatment of the posterior ear canal wall using periosteal osteocomma and mastoid antrum ventilation.
Indian journal of otolaryngology and head and neck surgery : official publication of the Association of Otolaryngologists of India, 2013Co-Authors: Jun Tong, Wenwen Chen, Yaxin Deng, Xunhua Cai, Liang ShanAbstract:To analyze the results of repair defect of the ear canal with autologous Bone containing periosteum and hearing reconstruction and postoperative inflation. Retrospective analysis of the 40 cases of surgeries conducted by senior surgeon. All cases received full open surgeries. Preoperative air conduction (AC) was 67.47 ± 14.32 dBHL, and GAP was 45.95 ± 12.63 dBHL. These cases were divided into two groups: the first 20 ears received repair surgery for radical mastoid cavity with Bone Slice containing periosteum combined with ear ossicle remodeling, namely the Bone Slice group. For another 20 ears, inflator was additionally used and the mastoid antrum cavity was inflated twice a day, namely the inflation group. 9-60 months (median follow-up of 26 months). U test was adopted. All ear canal showed a smooth appearance. Eight cases received CT scans and presenting re-gasification of attic and/or mastoid cavity. Hearing: AC of 47.32 ± 15.63 dBHL, and GAP of 18.28 ± 15.28 dBHL, both P values were <0.01 as compared with that before operation, and the difference was highly significant. 23 cases showed GAP <20 dB, and one case showed GAP >20 at follow-up, but narrowing was >30 dB, and these 24 cases were successful case, with a success rate = 60 %. 16 cases with GAP <10 dB, although 4 cases with GAP >10 dB, narrowing was >30 dB, thus the 20 cases were markedly effective, and with ratio = 50 %. The gap of 30 cases was narrowed more than 15 dB, although two cases showed gap narrowing less than 15 dB, postoperative GAP was less than 10 dB, both were valid, with an efficacy of 32/40 = 80 %, 18 cases (45 %) with AC <40 dBHL. Sub-group analysis: age: group P < 0.05 when the two groups were compared, difference in ages of the two groups were significant, and the age of the inflation group was older. Both GAP and AC of the two groups showed no significant difference before and after the surgery. One case in the Bone Slice group showed poor postoperative hearing, adhesion was found between the mesotympanum and attic in reoperation, and best result of GAP Close to less than 10 dB was obtained using the decomposition method after inflation. Bone Slice containing periosteum can be used for reconstruct the normal ear canal. Auxiliary inflation of middle ear can even promote the tympanic re-gasification and hearing recovery.
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Comparative Analysis of Effects of Reconstruction and Radical Treatment of the Posterior Ear Canal Wall Using Periosteal Osteocomma and Mastoid Antrum Ventilation
Indian Journal of Otolaryngology and Head & Neck Surgery, 2013Co-Authors: Jun Tong, Wenwen Chen, Yaxin Deng, Xunhua Cai, Liang ShanAbstract:To analyze the results of repair defect of the ear canal with autologous Bone containing periosteum and hearing reconstruction and postoperative inflation. Retrospective analysis of the 40 cases of surgeries conducted by senior surgeon. All cases received full open surgeries. Preoperative air conduction (AC) was 67.47 ± 14.32 dBHL, and GAP was 45.95 ± 12.63 dBHL. These cases were divided into two groups: the first 20 ears received repair surgery for radical mastoid cavity with Bone Slice containing periosteum combined with ear ossicle remodeling, namely the Bone Slice group. For another 20 ears, inflator was additionally used and the mastoid antrum cavity was inflated twice a day, namely the inflation group. Follow-up: 9–60 months (median follow-up of 26 months). Statistical analysis: U test was adopted. All ear canal showed a smooth appearance. Eight cases received CT scans and presenting re-gasification of attic and/or mastoid cavity. Hearing: AC of 47.32 ± 15.63 dBHL, and GAP of 18.28 ± 15.28 dBHL, both P values were 20 at follow-up, but narrowing was >30 dB, and these 24 cases were successful case, with a success rate = 60 %. 16 cases with GAP 10 dB, narrowing was >30 dB, thus the 20 cases were markedly effective, and with ratio = 50 %. The gap of 30 cases was narrowed more than 15 dB, although two cases showed gap narrowing less than 15 dB, postoperative GAP was less than 10 dB, both were valid, with an efficacy of 32/40 = 80 %, 18 cases (45 %) with AC
David W. Dempster - One of the best experts on this subject based on the ideXlab platform.
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Increased resorptive activity and accompanying morphological alterations in osteoclasts derived from the oim/oim mouse model of osteogenesis imperfecta.
Journal of Cellular Biochemistry, 2007Co-Authors: Hao Zhang, David W. Dempster, Stephen B. Doty, Christine Hughes, Nancy P. CamachoAbstract:The current study addresses whether alterations in osteoclasts (OCs) derived from oim/oim mice, an established model of moderate-to-severe OI, are present. Bone marrow cells from oim/oim and wildtype (+/+) mice were cultured on Bone Slices in the presence of MCSF and RANKL and evaluated at days 0, 1, 2, 4, and 7. OCs were identified by tartrate-resistant acid phosphatase (TRAP) staining, and Bone Slice resorption pits were analyzed by reflection microscopy. Flow cytometry was used to examine CD51 (integrin alphaV) and CD61 (integrin beta3) markers. Confocal microscopy was used to assess changes in OC morphology and resorption. There was no difference between the OC precursors of the two genotypes in expression of CD51 and CD61 markers. At day 2, the Bone Slices seeded with oim/oim cells had a greater percentage of mononuclear cells associated with resorption pits compared to +/+ Bone Slices. At day 4, the diameter and area of oim/oim OCs were larger compared to the +/+ OCs, and the number of nuclei per OC was also greater for the oim/oim group. At day 7, the oim/oim OCs contained more F-actin rings compared to the +/+ OCs, and the number of OCs in the oim/oim group was greater compared to the +/+ group. The resorbed area of Bone Slices for the oim/oim group was also greater compared to the +/+ group at day 7. In conclusion, oim/oim mononuclear resorbing cells and OCs showed cellular changes and greater resorptive activity compared to +/+ cells, features that likely contribute to dysregulated Bone remodeling in OI.
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Human osteoclast formation and activity in vitro : Effects of alendronate
Journal of Bone and Mineral Research, 1998Co-Authors: V. Breuil, L. S. Stein, Felicia Cosman, W. Horbert, Jeri W. Nieves, V. Shen, Robert Lindsay, David W. DempsterAbstract:Recent advances in technique have made it possible to study human osteoclast (OC) formation and activity in vitro. The object of the present study was to determine the effects of alendronate (ALN) on human OCs generated from precursors obtained from standard peripheral blood samples. Peripheral blood mononuclear cells from 14 postmenopausal women were cocultured with ST2 stromal cells on Bone Slices in the presence of 10(-7) M 1,25-dihydroxyvitamin D3, 10(-8) M dexamethasone, and 25 ng/ml human macrophage colony-stimulating factor. After 21 days, the cultures contained numerous OCs, which were characterized by multinuclearity, the presence of tartrate-resistant acid phosphatase, calcitonin and vitronectin receptors, and the ability to resorb substantial amounts of Bone, which was inhibited by calcitonin. The percentage area of Bone resorbed per Slice was highly correlated (r = 0.89, p < 0.001) with the concentration of Type I collagen cross-linked C-telopeptides (CTx) released into the culture medium. When added to the medium, ALN inhibited Bone resorption at concentrations < or =10(-7) M. At 10(-7) M, inhibition was achieved primarily by a reduction in OC activity without a marked effect on OC number. At the highest concentration studied (10(-5) M), both OC number and resorption were profoundly decreased. Overnight preincubation of Bone Slices in ALN, without further exposure to ALN, resulted in an inhibition of resorption that was similar to that seen when ALN was present in the medium throughout the entire culture period. We conclude that, except at very high concentrations, the predominant mechanism of action of ALN is to inhibit the activity of differentiated human OCs with little or no effect on recruitment. Interaction between the OC and ALN on the Bone surface is an important component of the inhibitory mechanism. Measurement of CTx in tissue culture medium is a convenient method for assessment of Bone resorption in human OC cultures and offers a number of advantages over morphometric analysis of the Bone Slice.
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The effects of parathyroid hormone (PTH) and PTH-related peptide on osteoclast resorption of Bone Slices in vitro: an analysis of pit size and the resorption focus.
Endocrinology, 1990Co-Authors: Richard J. Murrills, L. S. Stein, C. P. Fey, David W. DempsterAbstract:The mechanism whereby PTH, a potent stimulator of Bone resorption, may under certain circumstances exert anabolic effects on Bone is not known, but it is possible that it involves reduction of the size of osteoclast resorption lacunae. We have therefore made a detailed in vitro study of the effects of PTH and PTH-related peptide (PTHrP) on resorption by neonatal rat osteoclasts paying particular attention to the plan area of resorption pits. In order to distinguish between increased resorption at a particular site and increased numbers of sites, we have used an eyepiece graticule to define a focus of resorption, namely an area occupying l/116th of the Bone Slice, which may contain either one or several pits. In addition we have studied the relationship between the number of pits in a resorption focus and the total area of Bone resorbed at the focus. We found that PTH and PTHrP, at doses between 2 x 10-10 M and 2 x 10-8 M, while exerting significant stimulatory effects on Bone resorption, caused a reductio...