| Osteoporosis(OP)is a common disease which characterize with the loss of bone mass,the deterioration of bone microstructure and increased fragility in elder people,and it can be classified as primary and secondary osteoporosis fracture.Primary OP is a common clinical injury especially in menopause women and elder people,and the rate is higher as continual increase in the average life span of people.Secondary osteoporosis contains endocrine disease,induced by drug such as glucocorticoid and heparin,Huppert’s disease.OP may result in the fracture with a relative weak strength of bone.Rapid turnover of bone and un-bearing of fracture after OP may result in non-union before bone bridging especially where osseous callus is scarce in the fracture site.Non-union of the osteoporosis fracture is a most common seen complication.It may decrease even loss the labor capacity and make a heavy burden to family,and high death rate may occur for elder’ weak physical status.The treatment of osteoporosis fracture is difficult to deal due to weak mechanical character.To minimize the negative result,it is essential to take active prevention and treatment to it.Current therapies for non-union contain surgical treatments or drug.Surgical treatments can be conducted with iliac autografts,prosthesis or allografts,with or without anabolic or catabolic reagents such as bone morphogenetic proteins(BMPs)and so on.Current therapies for drug comprise bisphosphonates,calcitonin,parathyroid hormone and calcium production.Bisphosphonates(BPs)are compounds with analogical inorganic pyrophosphate,and can regulate bone mineralization.Bisphosphonates are classified as two categories(the non-nitrogen and nitrogen BPs)and act mainly through inhibiting the osteoclast attachment to bone matrix and inducing apoptosis action to remodel the balance between osteoclast formation and bone resorption in the early stage of fracture healing,and affecting fibroblasts,vein endothelial cells and osteoblasts’ viability and the migration ability.Ibandronate(IB)was the third generation nitrogen-containing BPs(Alendronate sodium or Risedronate sodium),they are generated from the second generation BPs(Pamidronate sodium)through replacing the hydrogen in amino group with saturated hydrocarbon or imidazole ring.It is also used in the treatment of maligment tumor,skeletal metabolic disorders(Paget’disease),osteoporosis or osteoporosis relative disease(lumbar intervertebral disc degeneration)and hypercalcemia of malignancy.Oral or intravenous(IV),intermittent administered ibandronate,are common used methods for the treatment of osteoporosis.However,musculoskeletal pain,gastrointestinal complications and osteonecrosis of the jaw and atypical fragility fractures associated with bisphosphonates are reported in system administration of bisphosphonates.Collagen is comprised of three polypeptide chains intertwined to a typical right-handed triple-helix with a pitch of approximately 8.6 nm,with non-helical regions it becomes a major structural protein responsible for the bone’s most biomechanical properties.It is distributed in many organ and tissues especially in connective tissues.90% extracellular protein of the tendon and more than 50% in the skin is also consisted of collagen.Local application of ibandronate is recognized as promising way for the therapy of osteoporosis and has gained attention in recent years.Collagen is a biodegradable,biocompatible and nontoxic material,it can promote the proliferation of cell and accelerate the cohesion of platelet.Because of its property,biosynthetic collagen has been provided as the basis of biomaterials,and used in various medical areas such as orthopedic and cardiac surgery.Although there have been researches using local application of BPs,only few studies have investigated collagen as a carrier and their effect on implant-bone integration.The aim of the current study was to investigate the hypothesis that local application of IB when combined with collagen as delivery system(CS)can improve the skeletal healing,mechanical stability compared with those in systemic administration in ovariectomized rats.And the result can guide the treatment of osteoporotic fracture in clinics.Part one the establishment of osteoporotic model in ratsObjective: To investigate the successful establishment of osteoporotic model in rat,and prove the feasible plan for mimic the status of women patients after menopause.Method: 12 3-month-old female SD rats(260-300 mg)were used in this experiment.All of them were randomly divided into two groups.All rats were operated after one-week acclimation period.6 of them were ovariectomized with a single longitudinal skin incision on the ventral midline above the level of symphysis pubis with 1-1.5 cm.All animals were housed under controlled standard ambient temperature throughout 3 months.Weight changes,bone mineral density(BMD)and histology were conducted to assure the model to be success.The BMDs of the distal left femurs were measured using QCT and expressed as the observed mean(g/cm3)± standard deviation(SD)of the whole group,based on equipped with appropriate software for bone density assessments.All rats were placed in the same direction.Results: The histology demonstrated that the formation of corpus luteum follicular in ovaries.The body weights of the OVX rats were significantly increased after surgery compared with the sham group(P < 0.05)at 12 weeks.In the OVX group,there was a significant reduction in the distal femoral BMD compared with the sham group at 12 weeks(P < 0.05).Part two the establishment of osteoporotic model in ratsObjective: To investigate the effect on tibial periosteum response with different concentration of ibandronate loaded by collagen spongeMethod: Female Sprague–Dawley rats(3 months’ old)were randomly divided into five treatment groups(n = 12)and assigned to the sham-operated control group(Sham),empty collagen sponge(CS),rats with small dose group(SIB+CS),medium dose group(MIB+CS)and large dose group(LIB+CS).After scraping the tibial periosteum with surgical blades,the collagen combined with or without ibandronate was implanted in,the response of tibial periosteum was observed.Radiograph and Trap staining were used to compare the differences among five groups.Results: Apophysis and thickening of cortical bone was exhibited in the location of implantation in IB treatment group especially in large dosing group.The inhibition of osteoclast was obvious in medium dosing group with the Trap staining.There was a significant difference about the number of osteoclast in five regions of scans.In next step,medium dose will be used for local delivery in part 3.Part three local delivery of ibandronate on the femur fracture healing in aosteoporotic ratsObjective: Focus on local delivery,this part aims to investigate the effect of ibandronate combined with collagen sponge on callus properties and remodeling in an osteoporotic rat model of fracture healing.Method: Normal and ovariectomized(OVX)rats were randomly divided into five treatment groups(n = 24 per group): Sham group;saline control(Control);Collagen sponge group(CS);systemic ibandronate injected groups(150μg/kg;CS+IB),administered at the day of femur fracture;and one local delivery group(CS/IB).Rats were killed at either 4 or 12 weeks postoperatively.Postmortem analyses included radiography,biomechanical tests,Micro-CT analysis,histology,and Serum biochemical analysis for bone turnover with ELISA kits.Results: OVX had a negative effect on the progression of endochondral ossification at 4 weeks.Collgen sponge and ibandronate can improve the callus formation at early stage.Treatment with ibandronate led to a significant increase in trabecular bone volume within the callus,as well as in callus resistance,compared to those in Control and CS rats;Local delivery administration(CS/IB)reduced intrinsic material properties such as elastic modulus,but microarchitecture parameters,including bone volume/total volume(BV/TV),trabecular thickness(Tb.Th),and connectivity density(Conn.D)increased compared with CS+IB group at 12 weeks after surgery.Local ibandronate administration may bind more to callus than that of systemic ones and minimize the lost of circulation,and thus the subsequent callus formation and endochondral ossification were increased significantly,while local administration(CS/IB)mildly suppresses bony callus remodeling which was comparable with systemic administrations.The CTX levels were significantly decreased with local IB treatments.Most importantly,the PINP levels in the OVX rats were significantly higher than those in the Sham rats.Conclusion:1 The ovariectomized rats are able to simulate the high turnover of menopause women after three months feeding normally.2 Medium dose of ibandronate has the most promoted effect for tibial periosteum response,and can accelerate the union of fracture maximally3 Local implantation of ibandronate combined with collagen improves the osteoporotic fracture healing in rats,The bone loss induced by OVX was also noticeably inhibited which exhibited thicker and more intact trabecular bone and the un-union was prevented effectively.It makes it’s the uses in clinics possible. |
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