Abstracts / Bone 47 (2010) S72–S241
K200G mutant. The F239A replacement led to a decrease in inhibition but an increase in Ki for RIS (from Ki = 0.34 to Ki = 65.5 nM), IBA (Ki = 15 nM), ALN (from Ki = 56.9 to Ki = 75.4 nM) and PAM (Ki = 945.7 nM), possibly attributable to the inability of the FPPS to switch conformation upon binding of N-BP and IPP. In contrast, initial competitive inhibition for GPP was increased for all N-BPs employed in the study, resulting in reduction of isomerisation constants interpreted as the inability of the FPPS to maintain the isomerised state. These results demonstrate the subtle differences among BPs in their interactions with the K200 and F239 FPPS residues and their potential impact on the pharmacology of N-BPs. Disclosure of Interest: M. Tsoumpra: None declared, B. Barnett: None declared, R. Walters Employee of Shamrock structures Ld, A. Kwaasi: None declared, F. Ebetino Employee of Warner Chilcott Ltd, U. Oppermann: None declared, R. Russell Grant / Research support from P&G Ltd, J. Dunford Grant / Research support from P&G Ltd Keywords: bisphosphonates, FPP synthase, inhibition doi:10.1016/j.bone.2010.04.524
PP389 Can a bisphosphonate-calcium phosphate combination device improve an osteoporotic micro-architecture? O. Gauthier1, P. Janvier2, B. Bujoli3, J. Guicheux4, J.-M. Bouler4, E. Verron4,⁎ 1 National veterinary school, Nantes, France 2 CEISAM, UMR CNRS 6513, Nantes, France 3 UMR CNRS 6513, Nantes, France 4 Laboratory of Tissue Engineering, INSERM U791, Nantes, France Introduction: Resorbable calcium phosphate (CaP) biomaterials have proved a noticeable efficacy in bone reconstruction surgery. Furthermore bisphosphonates (BPs) are well known antiresorptive agents largely used in systemic clinical treatments of osteoporosis. An injectable BP-combined CaP matrix has been developed in order to reinforce locally osteoporotic bone by increasing bone mineral density and improving bone micro architecture. The purpose of this study was to implant such a combined device in the proximal femurs of ovariectomized ewes and to quantify bone structure modifications by three-dimensional microtomography (3D-μCT). Materials and Methods: Calcium deficient apatite was loaded with BP and mixed with a sterile cellulosic-derived hydrogel that made it injectable.: Eight ewes were ovariectomized in order to induce osteoporosis. Biomaterial were implanted for 12 weeks in proximal femur of osteoporotic ewes. 3D-μCT analysis was conducted on all implanted and control femurs. Bone volume density (BV/TV), trabecular thickness (TbTh), space between trabeculae (TbSp) and number of trabeculae (TbN) were measured. Results: Osteoporosis induction is confirmed by a 40.0% decrease of BV/TV (iliac crest). After 12 weeks of implantation most of BP-loaded CDA particles have been resorbed and significant modifications of the bone density and micro architecture are observed in all the treated proximal femurs. Comparing treated versus control femurs, 3D-μCT measurements show significant increases (p < 0.05) for BV/TV (+32,3%), TbTh (+15,8%) and TbN (+16,8%) and a significant decrease for TbSp (12,8%). These modifications were confirmed by histological and SEM observations which revealed CaP granules resorption and new bone trabeculae formation. Discussion: A local combined effect of calcium phosphate particles and BP is evidenced on ewes osteoporotic proximal femurs. Those preliminary results can be considered as a first step for a local approach that aims in delaying or even preventing osteoporotic fractures. In fact, we could expect to reinforce specific bone sites like proximal femurs, vertebral bodies or wrists by implanting calcium phosphate materials that can promote bone ingrowth and release controlled quantities of BP.
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Disclosure of Interest: None declared Keywords: bisphosphonate, calcium phosphate, osteoporotic fractures doi:10.1016/j.bone.2010.04.525
PP390 Patients with surgically cured primary hyperparathyroidism have reduced quality of life compared to healthy age - and sex matched controls A.K. Amstrup1,⁎, L. Rejnmark1, L. Mosekilde1 1 Dept. of Endocrinology and Metabolism C, Aarhus University Holsptal, Aarhus, Denmark Background: Primary hyperparathyroidism (PHPT) is associated with subjective feelings of fatigue and depressions as well as limitation to physical and mental functioning. These quality of life features improve after parathyroidectomy. However, whether former patients regain full quality of life compared to healthy controls has yet to be investigated. Methods: Between February and Marts 2009, 51 former PHPT patients (mean age 61(36-77), 6 male and 45 female) successfully treated by surgery (mean time since operation 7.4 years (range 5-15)), and 51 sex- and age matched healthy controls, filled out the 36-item Short-Form Health Survey version 2(SF36v2). The survey included questions regarding physical and mental health, functioning and limitation in daily life activities. Results: Former patients scored significantly lower compared to controls in physical functioning (p = 0.01), emotional role of limitation (p = 0.01), vitality (p < 0.001) and general health (p = 0.01). Furthermore, summary of physical components (PCS) as well as mental components (MCS) were lower in cases (p = 0.03, p = 0.04, respectively). There was no correlation between time since operation and PCS or MCS. Cases had higher BMI compared to controls (28.8 ± 6.0 vs. 26.0 ± 4.7 kg/m2, p < 0.001). Both groups showed a significant inverse correlation between BMI and PCS (r = -0.41, p < 0.001) and when adjusting for BMI, PCS was no longer significant (p = 0.60). MSC, however did not correlate to BMI and was still lower in cases after adjusting for BMI (p = 0.04). Conclusion: Even though quality of life may improve substantially after operation in former PHPT patients, it is still reduced compared to healthy controls. This might be due partly to increased BMI. Disclosure of Interest: None declared Keywords: parathyroidectomy, primary hyperparathyroidism, quality of life, SF36v2 doi:10.1016/j.bone.2010.04.526
PP391 Vitamin-D status in relation to bone health in healthy Saudi women M.H. Qari1, A.A. Rouzi2, A.A. Maimani3, R.M. Raddadi4, M.-S. Ardawi5,⁎ 1 Department ofHaematology, Faculty of Medicine, Center of Excellence for Osteoporosis Research, King Abdulaziz University, Jeddah, Saudi Arabia 2 Department of Obstetrics & Gynecology, Faculty of Medicine, Center of Excellence for Osteoporosis Research, King Abdulaziz University, Jeddah, Saudi Arabia 3 Department ofDiagnostic Radiology, Faculty of Medicine, Center of Excellence for Osteoporosis Research, Knig Abdulaziz University, Jeddah, Saudi Arabia 4 Department of Clinical Biochemistry, Faculty of Medicine, Center of Excellence for Osteoporosis Research, King Abdulaziz University, Jeddah, Saudi Arabia
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5 Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Center of Excellence for Osteoporosis Research, King Abdulaziz University, Jeddah, Saudi Arabia
Ardawi, MSM1,2; Qari, MH1,2; Rouzi AA1,2 ;Maimani AA1,2; Raddadi RM1. Center of Excellence for Osteoporosis Research1 and Faculty of Medicine2, King Abdulaziz University , Jeddah, Saudi Arabia Background: Few studies exist on the various factors that may contribute to vitamin-D status in relation to bone health among Saudi women. Aims : To determine the factors influencing vitamin-D status in relation to serum 25(OH)D, intact-PTH, bone turnover markers (BTMs), bone mineral density (BMD) and vitamin-D receptor genotype (VDR) among healthy Saudi pre- and postmenopausal women. Subjects and Methods : A total number of 1172 healthy Saudi women living in the Jeddah area were randomly selected and studied. Anthropometric parameters, socioeconomic status, sun exposure index together with serum levels of 25(OH)D, calcitriol, intact-PTH, Ca, PO4, Mg, creatinine, albumin and biochemical BTMs were measured. BMD was measured by a dual energy X-ray absorptiometry and VDR genotypes were also determined. Results: About 10.5% of all women exhibited severe vitamin-D deficiency (serum 25(OH)D <12.5 nmol/L) and 80.0% of exhibited mild vitamin-D deficiency (serum 25(OH)D <50.0 nmol/L) with only 11.8% of all women were considered with adequate vitamin D status (serum 25(OH)D > 75 nmol/L). Increased serum intact-PTH (> 7.0 pmol/L) were evident in 18.5% and 24.6% in pre- and postmenopausal women with serum 25(OH)D < 50 nmol/L. Serum 25(OH)D was lower (P < 0.001) and intact-PTH higher (P < 0.001) in the upper quintiles of BMI and WHR. Multiple linear regression analysis showed that BMI, sun exposure index <0.63, poor dietary vitamin-D supplementation, high WHR and age were independent positive predictors of serum 25(OH)D values (R2 = 0.26). The frequencies of VDR genotypes were 32% GG, 45.2% AG and 22.8% AA respectively. There was no significant contribution of VDR genotypes to BMD or BTMs. Conclusions: Vitamin-D deficiency is highly prevalent among healthy Saudi preand postmenopausal women and largely attributed to obesity, poor exposure to sunlight, poor dietary vitamin-D supplementation and age. Disclosure of Interest: None declared Keywords: bone mineral density, deficiency, Vitamin D doi:10.1016/j.bone.2010.04.527
PP392 Evolution of the radiographic appearance of the metaphyses over the first year of life in type V osteogenesis imperfecta: clues to pathogenesis P. Arundel1,2,⁎, A. Sprigg3, N. Bishop1,2 1 Department of Metabolic Bone Disease, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom 2 Academic Unit of Child Health, University of Sheffield, Sheffield, United Kingdom 3 Department of Radiology, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom Type V osteogenesis imperfecta (OI) is characterized by increased bone fragility, low bone mass, skeletal deformities, a predisposition to hypertrophic callus formation after fracture and calcification of the interosseous membrane of the forearm. Histologically, there is irregular and mesh-like bone lamellation. The condition is inherited in an autosomal dominant pattern but no mutations related to type 1 collagen have been found and the underlying defect remains unknown. We present the case of a Caucasian infant with type V OI and report for the first time the evolution of characteristic radiological appearances of the long bones over the first year of life. The mother was known to have the same condition and antenatal
scanning revealed multiple fractures in the infant. We observed abnormalities of the metaphyses that were present from birth and which evolved from an almost rachitic appearance to the hyperdense metaphyseal bands typical of this condition. Our findings suggest that the underlying defect in type V OI may be an abnormality of a molecule common to both bone and cartilage that is involved with the regulation of growth plate development in early life. Disclosure of Interest: None declared Keywords: osteogenesis imperfecta, pediatrics, radiology doi:10.1016/j.bone.2010.04.528
PP393 Gastrointestinal calcium absorption after ingestion of non calcium containing phosphate binders G.J. Behets1,⁎, P.C. D'Haese1, M.E. De Broe1 1 Laboratory of Pathophysiology, University of Antwerp, Antwerp (Wilrijk), Belgium It is well established that both calcium containing and noncalcium containing phosphate binders (PB) increase gastrointestinal absorption of Ca, leading to increased serum calcium levels, low bone formation rate and increased risk for vascular calcifications, particularly in combination with vitamin D therapy. Due to the high serum calcium levels, renal clearance increases, leading to increased calciuria. Previously, we observed that administration of La2(CO3)3 to rats with renal failure does not induce this increased calciuria. Additionally, in dialysis patients, La2(CO3)3 treatment has been associated with a less pronounced decrease in serum PTH compared to patients treated with other PBs. Since La is a powerful Ca channel blocker at 0.5 mM concentration in vitro, a concentration which can be expected in the gut during treatment, we hypothesized that La2 (CO3)3 treatment results in a smaller increase of gastrointestinal Ca absorption than other PBs. Male Wistar rats (normal renal function and chronic renal failure (CRF)) received a diet supplemented with La2(CO3)3, sevelamer, CaCO3 or cellulose (2% of each) during an 8-day treatment period, followed by a 6-day washout period, during which non supplemented diets were used. Serum ionized calcium was measured daily. Animals with normal renal function show a statistically significant (p < 0.05) increase in serum ionized calcium levels, starting after 2 days of treatment in the sevelamer group, which returned to normal within one day of washout. CaCO3 treated animals showed a smaller increase which was only statistically significant after 2 and 3 days of treatment. La2(CO3)3 treated animals did not show differences vs controls. In the CRF animals, no statistically significant differences were found between the sevelamer, calcium and control groups. Animals treated with La2(CO3)3 however, showed statistically significant lower serum ionized calcium levels, when compared to either of the other treatment groups within 2 days of treatment. During washout, levels returned to normal within 24 hours. Two non calcium containing phosphate binding agents, lanthanum carbonate and sevelamer, show a differential effect on serum ionized calcium levels, both in animals with normal renal function and chronic renal failure. Our findings may be of particular interest for treatment of hypercalcemic patients and/or patients with low bone turnover requiring phosphate control and may facilitate combination treatment with vitamin D. Disclosure of Interest: G. Behets: None declared, P. D'Haese Grant/ Research support from Shire Pharmaceuticals, M. De Broe: None declared Keywords: calcium, phosphate binder doi:10.1016/j.bone.2010.04.529