fumarates and Osteoporosis

The skeletal renin-angiotensin system contributes to the development of osteoporosis. The renin inhibitor aliskiren exhibited beneficial effects on trabecular bone of osteoporotic mice, and this action might be mediated through angiotensin and bradykinin receptor pathways. This study implies the potential application of renin inhibitor in the management for postmenopausal osteoporosis.. The skeletal renin-angiotensin system plays key role in the pathological process of osteoporosis. The present study is designed to elucidate the effect of renin inhibitor aliskiren on trabecular bone and its potential action mechanism in ovariectomized (OVX) mice.. The OVX mice were treated with low dose (5 mg/kg) or high dose (25 mg/kg) of aliskiren or its vehicle for 8 weeks. The bone turnover markers were measured by ELISA. The structural parameters of trabecular bone at lumbar vertebra (LV) and distal femoral metaphysis were measured by micro-CT. The expression of messenger RNA (mRNA) and protein was studied by RT-PCR and immunoblotting, respectively.. Aliskiren treatment reduced urinary excretion of calcium and serum level of tartrate-resistant acid phosphatase in OVX mice. The treatment with aliskiren significantly increased bone volume (BV/TV) and connectivity density (Conn.D) of trabecular bone at LV-2 and LV-5 as well as dramatically enhanced BV/TV, Conn.D, bone mineral density (BMD/BV) and decreased bone surface (BS/BV) at the distal femoral end. Aliskiren significantly down-regulated the expression of angiotensinogen, angiotensin II (Ang II), Ang II type 1 receptor, bradykinin receptor (BR)-1, and osteocytic-specific gene sclerostin as well as the osteoclast-specific genes, including carbonic anhydrase II, matrix metalloproteinase-9, and cathepsin K.. This study revealed that renin inhibitor aliskiren exhibited the beneficial effects on trabecular bone of ovariectomy-induced osteoporotic mice, and the underlying mechanism for this action might be mediated through Ang II and BR signaling pathways in bone.

Topics: Amides; Animals; Biomarkers; Blood Pressure; Bone Density; Bone Density Conservation Agents; Cancellous Bone; Drug Evaluation, Preclinical; Female; Femur; Fumarates; Gene Expression Regulation; Humans; Kallikrein-Kinin System; Lumbar Vertebrae; Mice, Inbred C57BL; Osteoclasts; Osteoporosis; Ovariectomy; Proteins; Renin; Renin-Angiotensin System; RNA, Messenger; X-Ray Microtomography

The skeletal renin–angiotensin system (RAS) is involved in the progression of osteoporosis and the active peptide within the RAS, angiotensin II (ANG II), has deleterious effects on bones. This study was performed to investigate whether suppression of the rate-limiting step of the RAS cascade by the renin inhibitor aliskiren has a benefit on trabecular bone in osteoporotic mice. A postmenopausal osteoporosis model was induced by bilateral ovariectomy. The ovariectomized (OVX) mice were treated with a low (5 mg/kg) or high (25 mg/kg) dose of aliskiren for 6 weeks. Micro-computed tomography was performed to detect trabecular bone parameters of lumbar vertebra and to obtain 3-dimensional (3D) images. Treatment with aliskiren markedly increased bone volume over total volume (p<0.05), trabecular bone number (p<0.05), connectivity density (p<0.05), and bone mineral density (p<0.05) and reduced trabecular bone separation (p<0.05) compared to vehicle-treated OVX mice. Similarly, the 3D images were consistent with the quantitative data that showed aliskiren could markedly reverse the ovariectomy-induced pathological changes of trabecular bone. Thus, this study indicated that the treatment of estrogen-deficient mice with aliskiren could markedly increase bone mass and improve trabecular bone structure, suggesting its potential application in treating postmenopausal osteoporosis.

Topics: Amides; Animals; Antihypertensive Agents; Female; Fumarates; Lumbar Vertebrae; Mice; Osteoporosis; Ovariectomy; Renin; Renin-Angiotensin System; X-Ray Microtomography

Anabolic skeletal agents have recently broadened the therapeutic options for osteoporosis by directly stimulating bone formation and improving bone turnover, bone density, bone size, and bone microarchitecture. We recently demonstrated that two new L: -carnitine derivatives, L: -carnitine fumarate (LC) and isovaleryl-L: -carnitine fumarate (Iso-V-LC), stimulated osteoblast proliferation and differentiation. We here investigated, by histomorphometry in a mouse model of osteoporosis, the impact of these compounds on the repair of trabecular bone and the osteoblast involvement in this process. Fifty-nine inbred adult female CD1 mice in pregnancy were assigned to four treatment groups: (1) controls, mice fed a standard normocalcemic pre- and postpartal diet; (2) Hypo, mice fed a low-calcium isocaloric prepartal diet and a standard postpartal diet; (3) LC, mice fed a group 2-type diet supplemented post-partum with LC; (4) Iso-V-LC, mice fed a group 2-type diet supplemented post-partum with Iso-V-LC. Bone volume/total volume ratio (BV/TV), bone perimeter, osteoblast surface/bone surface, and osteoblast number/bone surface were measured from sections of L3 and L4 vertebral bodies obtained from animals killed on the day of delivery (controls and Hypo) and on days 7, 14, and 21 after delivery (all groups). BV/TV and all osteoblast-based indexes were significantly higher in LC and Iso-V-LC than in Hypo mice at each time point, and Iso-V-LC at the end of the treatment attained levels observed in controls. In conclusion, Iso-V-LC and, to a lesser extent, LC accelerated the recovery of normal BV/TV level after a hypocalcemic diet.

Topics: Animals; Calcification, Physiologic; Calcium; Calcium, Dietary; Carnitine; Cell Count; Cell Proliferation; Disease Models, Animal; Drug Therapy, Combination; Female; Fumarates; Lumbar Vertebrae; Mice; Mice, Inbred Strains; Osteoblasts; Osteoporosis; Pregnancy

Vertebral compression fractures cause pain, deformity, and disability. Polypropylene fumarate (PPF) has shown promise as an injectable cement for bone defects but little is known about its performance for kyphoplasty. The purpose of this study was to evaluate the biomechanical performance of PPF for kyphoplasty in simulated anterior compression fractures in cadaveric vertebral bodies. Thirty-one vertebral bodies (T9 to L4) from osteoporotic cadaveric spines were disarticulated, stripped of soft tissue and compressed on a materials testing machine to determine pretreatment strength and stiffness. All fractures were repaired with inflatable balloon tamps and either polymethylmethacrylate or PPF-30 (containing 30% barium sulfate by dry weight) cement and then retested. Strength restoration with PMMA and PPF-30 were 120% and 104%, respectively, of the pretreatment strengths. For stiffness, PMMA and PPF-30 restored vertebral bodies to 69% and 53%, respectively, of the initial values. There was no significant difference in treatment with either PMMA or PPF-30. The biopolymer PPF-30 exhibits mechanical properties similar to PMMA in a cadaveric kyphoplasty model. PPF biopolymer may be a suitable alternative for kyphoplasty.

Topics: Aged; Aged, 80 and over; Biomechanical Phenomena; Bone Cements; Cadaver; Female; Fractures, Compression; Fumarates; Humans; Lumbar Vertebrae; Male; Osteoporosis; Polypropylenes; Spinal Fractures; Thoracic Vertebrae; Treatment Outcome

The dynamics of total calcium concentration in blood of rat females with osteoporosis caused experimentally after applying it in the form of fumarate was determined. The fumarate was applied in just one dose by the means of stomach tube at the dose of teoporoz_ 4.28 mg of calcium/100 g of body mass. The total calcium concentration in blood was determined: 0; 1; 2; 3; 5 i 7 h after application. It was observed that one hour after application calcium concentration in control group increased by 19.3%, and in the group of animals after ovariectomy it decreased by 6.7% (P < 0.001). After 2 h calcium concentration in both groups returned to its initial state, and after 3 hours three next decrease in relation to initial time by 10% occurred in the control group and by 4% in the group after ovariectomy. Between 4 h and 7 h after administration calcium concentration in both groups of animals was even and it was maintaining at the constant level in the range 2.248-2.172 mM/l.

Topics: Animals; Calcium; Female; Fumarates; Osteoporosis; Rats; Rats, Wistar