- Email: [email protected]
Bone-site specific phenotypes in VDR transgenic mice
26S
Abstracts
0 53 BONE-SITE SPECIFIC PHETqOTYPES IN VDR TRANSGENIC MICE GP Thomas, S Baker, PA Baldock, JA Eisman and EM Crardiner Bone and Mineral Program, Gatvan Institute ofMedica/Research, Sydney, NSW 2010 1,25-Dihydroxyvitamin Ds (I,25-(OFI)2Ds) stimtdates both bone resorption and formation. We hypothesised that specificallyincreasing the sensitivity of bone forming cells to 1,25-(OH~D3 would enhance bone formation without a corresponding increase in bone resorption. Vitamin D receptor expression was elevated in mature cells of the osteoblastic lineage in OSVDR transgenic mice. Bones from OSVDR mice (OSV3) have been shown to be wider and stronger than those of wild-type FVB/N mice, associated with increased cortical periosteal nfineral apposition. They also had increased trabecular thickness in caudal vertebrae, associated with decreased osteoclast surface but not increased bone formation. The mechanisms underlying these in vivo differences were explored. Bone resorption was similar in FVB/N and OSV3 neonate calvatia organ cultures. However, the resorptive response to 1,25-(OH)2Ds treatment was enhanced in OSV3 calvarial cultures (4.8-fold) compared to FVB/N 0.7-fold) after 5 and 7 days in culture (p<0.001). No differences in basal or 1,25(OI-~D3stimulated resorption was observed in either fetal or neonatal long bones. Consistent with the calvarial findings, mature mineralising OSV3 osteoblastic cultures expressed higher levels of RANK-L (19-fold, p<0.05) and lower levels of OPG (0.5-fold, p<0.05) than FVB/N cultures by semiquantitative RT-PCK Thus, the RANK-L/OPG ratio, an index of osteoclast activation, was 3-fold higher in OSV3 than FVB/N cultures. The increased resorptive response in the calvaria was consistent with the RANK-L/OPG change However, these data are not consistent with in vitro long bone studies or the in vivo findings in vertebral bodies. These inconsistencies, which may relate to bone type and origin, strongly support bone-site spe6fic differences in homeostatic mechanisms.
0 55 P A R A T H Y R O I D E C T O M Y W I T H MINIMAL MORBIDITY C. J. Magarey, T. H. Diamond and P. R. Rohl - Departments o f Endocrine Surgery and Endocrinology, St George Hospital, Sydney. We have investigated a minimally invasive approach to parathyroid surgery to see i f the morbidity can be reduced while maintaining the high (95%) success rate and low (5%) complication rate achieved by the standard four gland exploration. We have also assessed the accuracy of Tc-sestamibi scan localisation preoperatively and its usefulness intraoperatively with a hand held gamma probe. Forty four consecutive patients having surgery for primary hyperparathyroidism (30 with osteoporosis) were included. The 33 in whom a preoperative sestamibi scan indicated a localised, abnormal parathyroid (positive) had an exploration o f that side o f the neck through a 2.5 cm incision. In 25 (57%) the minimal operation was concluded when an adenoma was removed and a normal gland was found on that side. In the other 8, no enlarged gland or more than one was found, and the operation was extended to a standard four gland exploration through a 6cm incision. The 11 with negative sestamibi scans underwent a standard four gland exploration. Two patients refused Tc-sestamibi scans, and the 9 negatives included 4 with hyperplasia and 5 (16%) false negatives with adenomas. Two adenomas were not found at operation through the minimal incision and 6 (18%) were false positive sestamibi scans, including 2 on the wrong side and 4 with hyperplasia. In all but one case surgical exploration was more useful in locating an adenoma than was the intraoperative Tc-sestamibi gamma probe. All 25 minimal operation patients became normocalcaemic, with no postoperative complications, and all had solitary adenomas on histopathology. Fifteen of them went home the following morning. Parathyroidectomy can be achieved successfully with minimal surgery and morbidity in over 50% of cases, when adequate allowance is made for false localisations by Tc-sestamibi.
Bone Vol. 27, No. 4, Supplement October 2000:1S 54S
0 54 Linkage Analysis of Four Candidate Genes Using Osteoporosis Affected Sib Pairs. Scott G. Wilson~, Tim Spector2,/Ulgie L. Taylort, Robert W. Retallack~, Kathryl Henderson3, Joachim Hallrnayer4 and Richard L. Pmlc¢ "5 lEndocrinoloo' & Diabetes, Sir Charles Gairdner Hospital,Nedlands, Australia;2Twin Research Unit, St Thomas's Hospital, Londco, UK; 3School of Physiotherapy, Curtin ~Jniversity of Tectmology, Bentley, Auslaalia; 4Centre for Clinical Research in Nearopsyehialry, Universityof Western Australia, Shenton Park, Australia; ~Dept of Medicine,Universityof WesternAustralia.Nedlmlds, Australia. Low bone mineral deusity (BMD) is the strongest predictor of osteoporotic fracture currently "known. Studies in twins and farmlies have demonstrated that BMD has a large genetic component. However, the genetic control of BMD is muhifactorial, having complex multiple gene and environment interactions. Consequ~fly, many association studies such as those of VDR or ER pol)~alotphismswhich have attempted to examine the role of candidate genes in controllingthis phenotype, have yieldedvariable or conflictingresults. Using a more maditionalapproach, Johnson et al. (1997) defured 11q 1213 as a region strongly linked to high BMD in an extended pedigree. Studies by Koller et al.(1998), further demonstrated linkage of femoral neck BMD as a qtmnlit~tivetrait to the same region. In this study, one hundred and eighty four Caucasian families, conte&fing at least one pair of sisters with low BMD, were used to test hi~kageat four candidate loci. Probands had a spine L1-4, total hip or femoral neck BMD Z<-1.5 (Hologic DEXA: bottom 6.7% of the population). Sisters of probunds had spine L1-4, total hip or femoral neck BMD Z<-I.0 (bottom 15.9%). Caucasian women (109) with BMD -0.5
0 56 PRECLINICAL P H A R M A C O L O G Y OF STRONTIUM RANELATE. PJ Marie 1, P Amman 2, G Boivin 3, C Rey 4, and Y Tsouderos 5 ~INSERM U349, Lariboisiere Hospital, Paris, 2 Division of Bone Diseases, Cantonal Hospital, Geneva, 3 INSERM U403, Lyon, 4ENSC, 1NP, Toulouse, 51RIS, Institut de Recherches Internationales Servier, Courbevoie, France, France. The available pharmacological studies indicate that strontium ranelate (S12911), a divalent strontium salt, may have beneficial effects on bone resorption, bone formation and bone mass. In vitro studies showed that strontium ranelate stimulates the replication of pre-osteoblastic cells and collagen synthesis in rat organ culture and calvaria cells. Strontium ranelate was also found to inhibit the bone resorbing activity of isolated mouse osteoclasts, as well as osteoclast differentiation in chicken bone marrow cultures. In vivo studies showed that strontium raoelate increases the number of trabeculae, femoral bone mineral content and bone mechanical properties in normal rats In normal adult monkeys, strontium ranelate was shown to decrease bone resorption and to increase b o n e volume at the lilac crest level In ovariectomized rats, strontium ranelate inhibited bone resorption whereas bone formation was maintained, which led to prevent trabecular bone loss induced by estrogen deficiency. Curative treatmenl with strontium ranelate also partially restored bone mineral content in ovariectomized rats. Finally, strontium ranelate was found to reduce bone resorption and to partially prevent the long bone loss induced by short-term hind limb immobilization in rats. These data indicate that strontium ranelate can stimulate bone formation and inhibit bone resorption, and increase bone mass in normal or osteopenic animals without having deleterious effects on bone mineralization, indicating that strontium ranelate may be of potential therapeutic value in the prevention or treatment of osteoporosis.
Abstracts
0 53 BONE-SITE SPECIFIC PHETqOTYPES IN VDR TRANSGENIC MICE GP Thomas, S Baker, PA Baldock, JA Eisman and EM Crardiner Bone and Mineral Program, Gatvan Institute ofMedica/Research, Sydney, NSW 2010 1,25-Dihydroxyvitamin Ds (I,25-(OFI)2Ds) stimtdates both bone resorption and formation. We hypothesised that specificallyincreasing the sensitivity of bone forming cells to 1,25-(OH~D3 would enhance bone formation without a corresponding increase in bone resorption. Vitamin D receptor expression was elevated in mature cells of the osteoblastic lineage in OSVDR transgenic mice. Bones from OSVDR mice (OSV3) have been shown to be wider and stronger than those of wild-type FVB/N mice, associated with increased cortical periosteal nfineral apposition. They also had increased trabecular thickness in caudal vertebrae, associated with decreased osteoclast surface but not increased bone formation. The mechanisms underlying these in vivo differences were explored. Bone resorption was similar in FVB/N and OSV3 neonate calvatia organ cultures. However, the resorptive response to 1,25-(OH)2Ds treatment was enhanced in OSV3 calvarial cultures (4.8-fold) compared to FVB/N 0.7-fold) after 5 and 7 days in culture (p<0.001). No differences in basal or 1,25(OI-~D3stimulated resorption was observed in either fetal or neonatal long bones. Consistent with the calvarial findings, mature mineralising OSV3 osteoblastic cultures expressed higher levels of RANK-L (19-fold, p<0.05) and lower levels of OPG (0.5-fold, p<0.05) than FVB/N cultures by semiquantitative RT-PCK Thus, the RANK-L/OPG ratio, an index of osteoclast activation, was 3-fold higher in OSV3 than FVB/N cultures. The increased resorptive response in the calvaria was consistent with the RANK-L/OPG change However, these data are not consistent with in vitro long bone studies or the in vivo findings in vertebral bodies. These inconsistencies, which may relate to bone type and origin, strongly support bone-site spe6fic differences in homeostatic mechanisms.
0 55 P A R A T H Y R O I D E C T O M Y W I T H MINIMAL MORBIDITY C. J. Magarey, T. H. Diamond and P. R. Rohl - Departments o f Endocrine Surgery and Endocrinology, St George Hospital, Sydney. We have investigated a minimally invasive approach to parathyroid surgery to see i f the morbidity can be reduced while maintaining the high (95%) success rate and low (5%) complication rate achieved by the standard four gland exploration. We have also assessed the accuracy of Tc-sestamibi scan localisation preoperatively and its usefulness intraoperatively with a hand held gamma probe. Forty four consecutive patients having surgery for primary hyperparathyroidism (30 with osteoporosis) were included. The 33 in whom a preoperative sestamibi scan indicated a localised, abnormal parathyroid (positive) had an exploration o f that side o f the neck through a 2.5 cm incision. In 25 (57%) the minimal operation was concluded when an adenoma was removed and a normal gland was found on that side. In the other 8, no enlarged gland or more than one was found, and the operation was extended to a standard four gland exploration through a 6cm incision. The 11 with negative sestamibi scans underwent a standard four gland exploration. Two patients refused Tc-sestamibi scans, and the 9 negatives included 4 with hyperplasia and 5 (16%) false negatives with adenomas. Two adenomas were not found at operation through the minimal incision and 6 (18%) were false positive sestamibi scans, including 2 on the wrong side and 4 with hyperplasia. In all but one case surgical exploration was more useful in locating an adenoma than was the intraoperative Tc-sestamibi gamma probe. All 25 minimal operation patients became normocalcaemic, with no postoperative complications, and all had solitary adenomas on histopathology. Fifteen of them went home the following morning. Parathyroidectomy can be achieved successfully with minimal surgery and morbidity in over 50% of cases, when adequate allowance is made for false localisations by Tc-sestamibi.
Bone Vol. 27, No. 4, Supplement October 2000:1S 54S
0 54 Linkage Analysis of Four Candidate Genes Using Osteoporosis Affected Sib Pairs. Scott G. Wilson~, Tim Spector2,/Ulgie L. Taylort, Robert W. Retallack~, Kathryl Henderson3, Joachim Hallrnayer4 and Richard L. Pmlc¢ "5 lEndocrinoloo' & Diabetes, Sir Charles Gairdner Hospital,Nedlands, Australia;2Twin Research Unit, St Thomas's Hospital, Londco, UK; 3School of Physiotherapy, Curtin ~Jniversity of Tectmology, Bentley, Auslaalia; 4Centre for Clinical Research in Nearopsyehialry, Universityof Western Australia, Shenton Park, Australia; ~Dept of Medicine,Universityof WesternAustralia.Nedlmlds, Australia. Low bone mineral deusity (BMD) is the strongest predictor of osteoporotic fracture currently "known. Studies in twins and farmlies have demonstrated that BMD has a large genetic component. However, the genetic control of BMD is muhifactorial, having complex multiple gene and environment interactions. Consequ~fly, many association studies such as those of VDR or ER pol)~alotphismswhich have attempted to examine the role of candidate genes in controllingthis phenotype, have yieldedvariable or conflictingresults. Using a more maditionalapproach, Johnson et al. (1997) defured 11q 1213 as a region strongly linked to high BMD in an extended pedigree. Studies by Koller et al.(1998), further demonstrated linkage of femoral neck BMD as a qtmnlit~tivetrait to the same region. In this study, one hundred and eighty four Caucasian families, conte&fing at least one pair of sisters with low BMD, were used to test hi~kageat four candidate loci. Probands had a spine L1-4, total hip or femoral neck BMD Z<-1.5 (Hologic DEXA: bottom 6.7% of the population). Sisters of probunds had spine L1-4, total hip or femoral neck BMD Z<-I.0 (bottom 15.9%). Caucasian women (109) with BMD -0.5
0 56 PRECLINICAL P H A R M A C O L O G Y OF STRONTIUM RANELATE. PJ Marie 1, P Amman 2, G Boivin 3, C Rey 4, and Y Tsouderos 5 ~INSERM U349, Lariboisiere Hospital, Paris, 2 Division of Bone Diseases, Cantonal Hospital, Geneva, 3 INSERM U403, Lyon, 4ENSC, 1NP, Toulouse, 51RIS, Institut de Recherches Internationales Servier, Courbevoie, France, France. The available pharmacological studies indicate that strontium ranelate (S12911), a divalent strontium salt, may have beneficial effects on bone resorption, bone formation and bone mass. In vitro studies showed that strontium ranelate stimulates the replication of pre-osteoblastic cells and collagen synthesis in rat organ culture and calvaria cells. Strontium ranelate was also found to inhibit the bone resorbing activity of isolated mouse osteoclasts, as well as osteoclast differentiation in chicken bone marrow cultures. In vivo studies showed that strontium raoelate increases the number of trabeculae, femoral bone mineral content and bone mechanical properties in normal rats In normal adult monkeys, strontium ranelate was shown to decrease bone resorption and to increase b o n e volume at the lilac crest level In ovariectomized rats, strontium ranelate inhibited bone resorption whereas bone formation was maintained, which led to prevent trabecular bone loss induced by estrogen deficiency. Curative treatmenl with strontium ranelate also partially restored bone mineral content in ovariectomized rats. Finally, strontium ranelate was found to reduce bone resorption and to partially prevent the long bone loss induced by short-term hind limb immobilization in rats. These data indicate that strontium ranelate can stimulate bone formation and inhibit bone resorption, and increase bone mass in normal or osteopenic animals without having deleterious effects on bone mineralization, indicating that strontium ranelate may be of potential therapeutic value in the prevention or treatment of osteoporosis.