CN1370071A - Drug for treating fractures - Google Patents
Drug for treating fractures Download PDFInfo
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- CN1370071A CN1370071A CN00811765A CN00811765A CN1370071A CN 1370071 A CN1370071 A CN 1370071A CN 00811765 A CN00811765 A CN 00811765A CN 00811765 A CN00811765 A CN 00811765A CN 1370071 A CN1370071 A CN 1370071A
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- bone
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- fracture
- diphosphonate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
- A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
- A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- Bioinformatics & Cheminformatics (AREA)
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- Gastroenterology & Hepatology (AREA)
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Abstract
A drug selected from a group consisting of bisphosphonates for promoting bone growth and for the treatment of a fracture.
Description
Invention field
The present invention relates to the new indication of a certain class medicine.More particularly, the present invention relates to the purposes that diphosphonate is used for promote osteogenesis and treatment fracture.In diphosphonate, have been found that assistant sharp phosphonate (Zoledronate) and pamldronate (Pamidronate) are effective especially when being used for so a kind of purpose.
Background technology
Diphosphonate is a feature with the P-C-P key, and it has intensive affinity to bone mineral.They are analog of pyrophosphate, contain carbon atom and have replaced oxygen atom.This makes the decomposition that tolerates enzyme in their bodies fully.
According to the configuration of side chain, the effect and the effectiveness of diphosphonate have nothing in common with each other.Diphosphonate suppresses bone resorption by the direct effect to the osteoclast function, also suppresses osteoclast to osteoblastic recruitment.Because these factors, calcium is retained in the skeleton, parathyroid hormone (PTH) and 1 subsequently, 25-(OH)
2Vitamin D increases, and causes that the intestinal calcium absorption increases.In the rat that is growing, this causes bone mass to increase (Licata " diphosphonate therapy " " U.S.'s medical science magazine " 1997, January; 313 (1): 17-22).Under very high dosage, in fact diphosphonate can suppress osteogenesis and function of osteoblast.In fact, be prevention spinal cord injury or arthroplasty of hip ectopic ossification afterwards by one of abundant disclosed diphosphonate indication of document in the past.(Stover etc. " the ossified postoperative recurrence of etidronic acid disodium prevention spinal cord injury ectopic endometrium " " U.S.'s osteoarthrosis surgical magazine " 1976,58 (5): 683-8; Finerman and Stover " hip reset or spinal cord injury after ectopic ossification: two clinical researches carrying out with EHDP " " metabolic bone disease correlation research " 1981,3:337-42; Banovac and Gonzalez " evaluation and conditioning that the spinal cord injury ectopic endometrium is ossified " " spinal cord " 1997,35:158-62.)
Etidronic acid diphosphonate (bispho sphonate etidronate) is at first being tried out very many years ago in the treatment primary osteoporosis.The result is presented at bone density improving and may controls and obtains certain success (Licata, ibid) on the fracture rates.
Hereafter, the purposes of diphosphonate in osteoporosis therapy and prevention is known.They are valuable especially in the conditioning of postmenopausal osteoporosis, but also known at the indication that other influence the purposes in the treatment of obstacle of bone about these medicines.
Because diphosphonate can suppress bone resorption, so they are used as effective therapeutic agent in some diseases that increase to feature with bone turnover rate, comprise Paget, malignant hypercalcemia and operation osteodiastasis osteopathia (metastatic bone disease) (Lombardi " clinic trial diphosphonate " " Italian Medicine Research Inst. yearbook " 1992, the 7-9 month, 7 (supplementary issues 3): 158S-165S).They also are fit to treatment multiple myeloma, mammary cancer surgery osteodiastasis and osteogenesis imperfecta.
In the course of disease of a lot of these obstacles, often fracture.Even but avoided fracture, because the existence of this class obstacle, the danger of its generation also greatly increases.So a lot of ongoing researchs at the purposes of diphosphonate in these obstacles of treatment have concentrated in the safety that is appearing this class treatment of fracture back continuation.A lot of these researchs have been found that, diphosphonate does not all have adverse effect (for example referring to " diphosphonate (pamldronate) is regulated the purposes of Os Caprae seu Ovis fracture repair " " oncology's yearbook " 1994,5 supplementary issue 7:S53-5 such as Goodship to the mechanical integrity recovery of the back long bone of fracturing or to union of fracture; Other sees " diphosphonate (Incadronate) is to the influence of long bones of rats union of fracture " " bone mineral research magazines " 1999,6,14 (6) such as Li: 969-79).
Although the purposes of diphosphonate in above-mentioned and other obstacles is fully open by document, " their model of action still remains to be illustrated.Consequently, recognize their whole treatment potentiality gradually " (referring to summary, Russell etc. " diphosphonate: from laboratory to the clinical laboratory that returns " " bone " 1999,7:25 (1): 97-106).
The invention provides a considerable amount of about the novelty of diphosphonate administration and important indication.
The description of invention
A first aspect of the present invention is to be used for the medicine of promote osteogenesis, is selected from the group of being made up of at least a diphosphonate.
Preferably, promote the osteogenesis of fracture site.In addition, conceivable is the osteogenesis that promotes between bone and prosthese, bone anchoring device or any other bone or the dental implant.
A second aspect of the present invention is to be used for the treatment of the medicine of fracture, is selected from the group of being made up of at least a diphosphonate.
In preferred embodiment, first or second aspect in medicine be that diphosphonate is helped sharp phosphonate.
In further preferred embodiment, first or second aspect in medicine be the diphosphonate pamldronate.
In another embodiment, this medicine can another kind of be selected from the combination of medicine or two or more diphosphonates of the group of being made up of diphosphonate.
A third aspect of the present invention is that medicine is used for the purposes that medicament is made, and this medicine is selected from the group of being made up of at least a diphosphonate, and this medicament is used for promote osteogenesis.
In a kind of preferred implementation of the third aspect, this medicine promotes the osteogenesis of fracture site.
In further embodiment, this medicine promotes the osteogenesis between bone and the prosthese.
A fourth aspect of the present invention is that medicine is used for the purposes that medicament is made, and this medicine is selected from the group of being made up of at least a diphosphonate, and this medicament is used for the treatment of the bone of fracture.
A fifth aspect of the present invention is to be used for the treatment of the method for the bone of fracture, this method comprise will the treatment effective dose medicine to the fracture patient administration, this medicine is selected from the group of being made up of at least a diphosphonate.
Preferably, this medicine by single dose to patient's administration.Further preferably the medicine of single dose is the bone-specific drug early stage administration in fracture.
A sixth aspect of the present invention is to be used for the treatment of the method for fracture, and this method comprises the following steps:
(a) medicine that will treat effective dose is to the fracture patient administration, and this medicine is selected from the group of being made up of at least a diphosphonate; With
(b) bone to fracture provides vibratory stimulation.
Preferred embodiment disclose the purposes of bisphosphonates in promote osteogenesis or treatment fracture and can be used for all clinical measures, be used to nurse one's health the bone of fracture; The most suitable such conditioning of a lot of fracture is only used plaster model to the position that fracture takes place, and fixedly makes knitting with clamping plate by this way; Some fracture only requires the patient to have a rest; Some fracture may require the surgical intervention of certain limit; Other fracture are fit to be nursed one's health with the combination of back two kinds of measures.In addition, select as an alternative or as addition thereto, as disclosed above, providing vibratory stimulation to the bone of fracture also may be desirable in some cases.No matter selecting these still is the bone that other clinical measures are used to nurse one's health fracture, and the present invention discloses at least a bisphosphonates to patient's administration.
In treatment of fractures, use at least a bisphosphonates that some advantages can be arranged.Much all be disclosed in hereinafter in detail.However, for reason clearly, merit attention some more generally advantage from the beginning.They include but not limited to as follows: diphosphonate can be bred by stimulating osteoblast, increases callus and generates; They still are effective osteoclast bone resorption inhibitor; They help prevention of osteoporosis, therefore reduce the disuse osteoporosis relevant with damage; They can also significantly shorten the time of union of fracture.
According to the present invention, diphosphonate can be used for the fracturing situation of conditioning is able to abundant realization.Preferred embodiment disclose diphosphonate really and be applicable to that the situation of fracture nursing comprises at least: (i) increased the new osteogenesis in the operation osteodiastasis skeletonization (distraction osteogenesis):
(a) bone prolongs
(b) bone transhipment (ii) increase with the new osteogenesis in the fracture of open reduction (open reduction) treatment (iii) increase new osteogenesis in the fracture for the treatment of with the medullary cavity internal fixation (iv) increase new osteogenesis in the fracture for the treatment of with expopexy (v) healing delay (vi) improve the skeletonization potentiality of bone graft (graft)---autograft, alloplast or
Synthetic bone graft succedaneum (vii) improves bone in the individual or local osteoporosis bone segment of osteoporosis and supports inner fixing device
Ability (wherein there is potential obstruction in viii) treatment fracture to uncomplicated healing, for example:
(a) senile fracture comprises: neck of femur; Femur on the condyle; Tibia; Ankle; Humerus;
And distal radius (notices that this enumerating only supplies illustration, according to diphosphonate of the present invention
In any case purposes be not limited to only treat these fracture, perhaps with regard to the people of institute's has age
Any other fracture)
(b) pubic branch fatigue fracture
(c) pathologisch Bruch
(d) navicular bone folding
(e) open fracture
(f), when treating, require to prolong to fix, for example: Fracture of femur with non-operative treatment with the disruptive fracture of periosteum (ix) treatment fracture;
Fracture of tibia; With fracture (x) the avascular necrosis patient's of foot and ankle treatment, to strengthen new osteogenesis, the treatment of prevention collapse (xi) congenital pseudarthrosis of tibia and relevant disease.
Further preferred embodiment also discloses in a large number about use the other indication of diphosphonate in the anaplasty operation.These comprise grows to increase bone the diphosphonate administration in the joint replacement prosthese; Be coated with articular prosthesis with the diphosphonate bag, to strengthen the latter's inwardly growth under more partial level.Such therapy also should reduce the influence of Periprosthetic stress shielding.Select as an alternative or addition thereto, can be coated with material package with hydroxyapatite (hydroxyapatite) or other osteoinductives and be coated with prothesis implant body.
In addition, diphosphonate can be used in the arthrodesis, and the fusion in joint just is to increase fusion rate.
A kind ofly disclose preferred embodiment that to be used to implement the medicine that is selected from bisphosphonates of the present invention be pamldronate.It is the sharp phosphonate of assistant that another preferred embodiment discloses the medicine that is selected from this group.But, in further preferred embodiment, except pamldronate or help the sharp phosphonate, can be in addition or select to use other diphosphonates (only otherwise can cause disadvantageous interaction) as an alternative.Other diphosphonate example includes but not limited to fosamax (A1endronate), Tiludronate (Tiludronate), Risedronate (Risedronate), Ibandronate and Incadronate (Incadronate).
In further preferred embodiment, medicine by single dose to patient's administration.In this embodiment, preferably the administration of medicine occur in during the bone process of treatment fracture early stage because diphosphonate in early days administration osteoblastic stimulation and propagation are had positive impact.
In further embodiment, subsequently can be with other dosage to patient's administration.In this embodiment, conceivable is the reaction of assessing before other dosed administration first dosage.
In further preferred embodiment, administering mode can be perioperative intravenous infusion, oral, transdermal or other approach.Perhaps, can adopt the process of oral diphosphonate.All preferably are suitable for the present invention at present and following available drug administration mode with alternate embodiment.Such administering mode must be certainly rationally, convenient feasible, for the patient provides effective dose on the therapeutics, the symphysis that is used for the treatment of and/or promotes to fracture.
The invention also discloses in some embodiment, preferably the bone to fracture applies the vibratility stimulation in addition.Vibratility stimulates can be provided by ultrasound stimulation and vibratory stimulation, and perhaps any other can provide machinery and/or device that vibratility stimulates.In some embodiment, can be applied to the vibratility that is regarded as effective optional frequency in the bone-specific drug of fracture stimulates.But in preferred embodiment, the step that provides vibratility to stimulate comprises that the vibratility that the bone resonant frequency regularly is provided stimulates, and described resonant frequency calculates as the function of bone to the vibration reaction of vibratory stimulation.For this reason, this step can be divided into following part:
(a) bone to fracture provides vibratility to stimulate;
(b) detect the vibratility reaction of bone to vibratory stimulation;
(c) produce the signal that the representative vibration is reacted;
(d) handle this signal, to differentiate at least a resonant frequency of bone; With
(e) provide a kind of signal, stimulate with the vibratility of adjusting bone, so that it is or approximately is at least a resonant frequency of bone.
The step that no matter whether adopts the bone to fracture to provide vibratility to stimulate, preferred embodiment all disclose should be at therapeutic process in early days with at least a diphosphonate to patient's administration.In this, different bone and dissimilar fracture are pressed the different rates healing.Therefore, the commitment of process depends on these variablees.
Diphosphonate has positive impact in a kind of like this commitment administration to osteoblastic stimulation and propagation.Under the situation that adopts vibratility to stimulate, preferably provide such stimulation, the maturation of fracture because mechanical stimulus will help to heal in the therapeutic process later stage.But another preferred embodiment in, the administration of diphosphonate and vibratility stimulate provides that can to occur in therapeutic process early stage.In the embodiment of selecting as an alternative, they can be opposite in time, and they can be alternative, and perhaps they can be in the administration of treatment later stage, and this is considered to be optimal.
Brief description of drawings
With preferred implementation of the present invention is example, described with reference to accompanying drawing, wherein:
Fig. 1 shows the general formula of diphosphonate;
Fig. 2 is the figure of embodiment 1, sets forth lower limb and prolongs matched group and lower limb and do not prolong between the matched group bone mineral density (BMD) difference at regeneration site and regeneration site near-end and far-end (do not provide certainly lower limb do not prolong organize regeneration site BMD value);
Fig. 3 is the figure of embodiment 1, sets forth with the lower limb prolongation group of pamidronic acid salts for treating with the lower limb of pamidronic acid salts for treating not prolong between the group BMD difference at regeneration site and regeneration site near-end and far-end (do not provide certainly lower limb do not prolong organize regeneration site BMD value);
Fig. 4 is the figure of embodiment 1, set forth lower limb prolong matched group and with between the lower limb prolongation group of pamidronic acid salts for treating in the BMD difference of regeneration site and regeneration site near-end and far-end;
The histopathology difference of one of Fig. 5 illustrated embodiments 1 matched group and pamidronic acid salts for treating group sample;
Fig. 6 is the figure of embodiment 2, sets forth the non-operation and back pamidronic acid salts for treating group and the non-operation peak load difference with operation back matched group of performing the operation; With
Fig. 7 is the figure of embodiment 2, sets forth the non-operation and back pamidronic acid salts for treating group and the non-operation Young's modulus difference (1% stain (strain)) with operation back matched group of performing the operation.
Fig. 8 A, 8B and 8C are the figure of embodiment 3, set forth the bone mineral content in tibia operation back 2,4 and 6 all near-ends, regeneration and the distal segment respectively.
Fig. 9 is the figure of embodiment 3, sets forth the natural increase of the bone mineral content (BMC) in the regeneration site.
Figure 10 is the figure of embodiment 3, sets forth the final BMC that six all backs are measured with QCT.
Figure 11 A, 11B and 11C are the figure of embodiment 3, set forth the BMD in tibia operation back 2,4 and 6 all near-ends, regeneration and the distal segment respectively.
Figure 12 is the figure of embodiment 3, sets forth the final BMD that six all backs are measured with QCT.
Figure 13 is the figure of embodiment 3, sets forth the final area of section that six all backs are measured with QCT.
Figure 14 describes the QCT scanning of regeneration site in the embodiment 3 tibias operation rabbit, and they are medians of every group of area of section.
Figure 15 is the figure of embodiment 3, sets forth the final the moment of inertia (momentof inertia) that six all backs are measured with QCT.
Figure 16 is the device reduced graph that the bone of fracture is applied the vibratility stimulation.
The optimal way that carries out an invention
In preferred embodiment, help the manufacturing that sharp phosphonate or pamldronate and/or another kind of bisphosphonates are used for medicament, this medicament is used for the bone of promote osteogenesis or treatment fracture.
Suitably prepare the sharp phosphonate of this medicament or independent assistant or pamldronate and/or the effective dose of another kind of diphosphonate on therapeutics then, via intravenous route to patient's administration.
Preferred embodiment further disclose during the bone process that a kind of like this drug administration occurs in treatment fracture early stage.Diphosphonate has positive impact in a kind of like this commitment administration to osteoblastic stimulation and propagation.Can not need further diphosphonate administration, if can administration after the estimation patient is to the reaction of first dosage but desirable.
In addition, can specify the process of oral diphosphonate, wherein oral diphosphonate in the junior three of union of fracture month for the patient.In another embodiment, can give the process of oral diphosphonate, generate with the callus in the slow increase knitting in the fracture healing process later stage.
The invention also discloses in some embodiment, preferably the bone to fracture applies the vibratility stimulation in addition, as described in international application No.PCT/AU99/00974, quotes at this as a reference.Vibratility stimulates can be provided by ultrasound stimulation and vibratory stimulation, and perhaps any other can provide machinery and/or device that vibratility stimulates.This class preferred embodiment in, the step that provides vibratility to stimulate comprises that the vibratility that the bone resonant frequency regularly is provided stimulates, described resonant frequency calculates as the function of the vibration reaction that bone stimulates vibratility.
With reference to Figure 16, fetal stimulaator 10 is applicable to the specific resonant frequency of measuring bone 11, makes bone 11 be subjected to the stimulation of the specific resonant frequency of bone 11, maintaining stimulus a period of time under this frequency then.This has guaranteed best stimulation, thereby has guaranteed that the best of bone mass promotes, meanwhile, has avoided overstimulation or overload hazard, thereby has avoided fracture.
Install 10 involving vibrations stimulators 12, it at certain frequency scope internal stimulus bone 11, causes the vibration of bone 11 when being activated.Stimulator 12 is subjected to the driving of the signal generator in the computer 14.Signal generator can cause stimulator 12 in the internal vibration of certain frequency scope when being activated at first.Signal generator for example can scan this frequency range.
Detect vibration with detector 13.Detector 13 can comprise an accelerometer or one group of accelerometer.Detector 13 transmits signal and gives computer 14, and the signal from analog form is converted into digital form there, handles then, to measure the frequency domain character of vibration reaction.Computer 14 can be combined with automatic analytical tool, measures the peak acceleration/speed/operation osteodiastasis of bone, thereby measures the resonant frequency of bone.In another embodiment, computer can show the measurement characteristics of vibration reaction with numeral and/or graphics mode, so that device users or attending doctor's labor measurement resonant frequency.Device 10 can comprise artificial stimulation frequency controller 15.Preferably, computer 14 identifies one of resonant frequency of bone 11 from the signal that is received, and transmits signal and gives stimulator 12, stimulates bone 11 down at or about this resonant frequency.
Device can be combined with intervalometer, so that preset the working time of stimulator 12 before activating.A kind of like this time may be to be provided with like this, and suitably login operates in the software program on the computer 14.Preferably, can carry out like this adjustment of vibratory stimulation amplitude, suitably login operates in the software on the computer 14.
Although Figure 16 has simply described device, wherein vibratory stimulation device 12 and detector 13 act on bone via external frame 16, but conceivable is that they will act on the pathological changes limb skin, wherein the stimulation of bone can be a transdermal administration,, definitely be plaster model perhaps via framework or other similar devices around these limbs.
Further conceivable is that this Therapeutic Method is used to promote the osseous tissue growth and keeps bone mass in the treatment of some bone disorders.Example comprises the healing of fracture site, causes that wherein bone vibration causes small movements, bending of fracture site or reverses, and then the promotion knitting.Stimulation also causes small movements, the bending of bone intact part or reverses, and then promotes the osteogenesis of complete bone, prevention of osteoporosis.Equate with the resonant frequency of bone or approximately equate that the facilitation of osseous tissue growth is optimized owing to be adjusted to, and the speed that takes place is faster than the bone that only stimulates under the frequency that the resonant frequency with bone has nothing to do by device 10 stimulus frequency that given.
What imagine easily similarly is that device 10 can be by the setting tool percutaneous effects in bone, the medullaty nailing that the bone section is combined.In this manner, stimulate bone and setting tool down, can increase the osteogenesis between the bone section by resonant frequency at or about bone.
What can also imagine is that device 10 can conveniently transport, and therefore can use in patient family.In this manner, will be to installing 10 pre-set programs, so that the patient will be that vibratory stimulation device 12 and vibrating detector 13 are connected on pathological changes limbs or other body parts active device 10 for what use that this device will do.
Under the situation that adopts vibratility to stimulate, preferably provide such stimulation, the maturation of fracture because mechanical stimulus helps to heal in the therapeutic process later stage.But another preferred embodiment in, it is early stage that the providing of the administration of diphosphonate and vibratory stimulation can occur in therapeutic process.But as disclosed above, they can be opposite in time, and they can be alternative, and perhaps they can be at the treatment later stage, and this is considered to be optimal.
Above-mentioned disclosure will provide more detailed analysis to the effect that treatment had of the bone of agglutination and fracture to drug administration according to the preferred embodiment of the present invention.
Following each embodiment relates to diphosphonate administration in operation osteodiastasis skeletonization.One of purpose of operation osteodiastasis skeletonization (distraction osteogenesis) is to prolong the limbs of operating.Operation osteodiastasis skeletonization that fracture is become is essential.After placing external frame on the limbs, the cutting bone.Between healing stage, along with slow operation osteodiastasis framework, new osteogenesis.
Exactly because bone is fractured during operation, so the result of study of relevant operation osteodiastasis skeletonization is suitable for setting forth the pamldronate administration to effect that bone had.
Embodiment 1: pamldronate (dosage 3mg/kg) method in the operation osteodiastasis skeletonization:
Experimental design
20 eight age in week male NZW rabbit experience tibia lengthening.The existing report of similar rabbit model.After ketamine (ketamine) 15mg/kg and xylazine (xylazine) 4mg/kg IM premedication, with halothane 2% and oxygen 11/min anesthesia.Every rabbit is carried out open meta tibia boring sacrotomy, 0rthofix M-100 holder is installed, use four Orthofix3mm half plug pins (Orthofix, Bussolengo, Italy).After hiding 24 hours, make tibia prolong 0.375mm in per 12 hours and reach 15 days, produce 11.25mm operation osteodiastasis.Then the holder original position was kept somewhere 27 days, regeneration site is merged.The 30mg/100ml pamldronate is pressed 3.0mg/kg to 10 rabbit administrations, and administering mode is the interior infusion of single art two hours; To 10 control animal infusion of saline.When operation finishes and postoperative 12 hours buprenorphine (Buprenorphine) is pressed the 0.05mg/kg administration.But animal ad libitum access feedstuff and drinking-water.After 42 days, put to death rabbit with IV Lethobarb150mg/kg.
Radiography and bone mineral density analysis
From knee two hind legs are carried out disarticulation, keep soft tissue complete.By standard A P orientation, use digital luminous magazine to take lateral projection and plane radiograph limbs, irradiation voltage 50kV, electric current 4mA, 1.1 meters of test tube and film distances by Siemens Multix H/UPH configuration.Measure every part of distance between the plug pin position of dissecting sample, so that every radiograph can both suitably be proofreaied and correct again according to the measurement result of regeneration length.
Use whole dual energy sources X-gamma ray density meter carry out bone mineral density (BMD) measure (LUNARDPX, Radiation Corps, Madison, Wisconsin).Used DXA in the former report background, with carrying out BMD scanning and lateral projection by the directed tibia of anterior-posterior (AP), use aims at software (the LUNAR DPX that measures toy and design, Small Animal Software, 1.0cLUNAR, Radiation Corps, Madison, Wisconsin).Use " HiRes＜0.5kgSlow " scan pattern (" meticulous " collimates, and sample size is 0.6 * 1.2mm, and sample interval is 1/16 second).For the CV of computing machine, research the duration to the rabbit forelimb carry out 30 times scanning.Three boxes are settled in each scanning, and the CV of measured BMD is respectively 3.6%, 4.5% and 5.7% (from the near-end to the far-end).
" interesting areas (ROI) " placed 9.6mm eminence on the scanned picture, obtain regional BMD measurement result.About every tibia that has prolonged, a ROI is placed in regeneration site, and one at its near-end, and one at its far-end.In nonoperative tibia, place two ROI, so that the far-end and near-end ROI (just the distance with the bone end equates) of the tibia that they have been equivalent to prolong.Thereby concerning each projection, produce about every tibia that has prolonged and to amount to three measurement results, produce measurement result twice about every nonoperative tibia.The BMD value is with g/cm
2Expression, and the average and standard deviation of report group data.Utilize paired t check relatively to prolong and nonoperative tibia sample; Check is not used for the comparable group differences in pairs.
Histologic analysis
Carry out the histologic analysis of double blinding mode by two pathologists, they also are the observers.To excise under five pairs of medial tibial periosteal from pamldronate group and five contrasts, in stuck-at-0% formalin buffer.With every bone crosscut is near-end, regeneration site and distal bone sections, decalcification 48 hours in standard EDTA solution then.With each sections longitudinal section, half is embedded in the paraffin storing solution then, and every rabbit has six parts of storing solutions.The microscopy that cutting is 5 microns is with section, with hematoxylin and eosin dyeing.Two pathologists check all sections, and consistent the assessment carried out in the osteogenesis around new osteogenesis, skin thickness, reconstruction degree and the plug pin position.Because the skin thickness expection will be because of slice plane changes, so do not do accurate measurement.Osteoclast activity in the regeneration site is with the quantitaes (Olympus, BH2,40x object lens) of every high power field.Also assessed the degree at osteoblast formation edge.The result:
The eliminating situation
There are 3 kinds of post-operative complication from DXA analyzes, to get rid of: a fracture of tibia (pamldronate group) was arranged near far-end plug pin position at the 1st day; There was a Fracture of femur to require peaceful and comfortable art (pamldronate group) at the 23rd day; A total fibular nerve paralysis (contrast).
The contrast rabbit model
Osteogenesis reliably occurs in the operation osteodiastasis gap.With clinical and radiography inspection, all tibias all engaged at the 42nd day.AP scanning prolongs and does not prolong limbs gained BMD value as shown in Figure 2.Compare with the corresponding site in the non-operation limbs, BMD has remarkable reduction (p＜0.02) in near-end around the extension site and the distal segment.Also there is similar significant difference in side scanning.
The pamldronate group
The BMD that does not find near-end and distal segment in the pamldronate group reduces, and does not have significant difference (p=0.332 near-end, p=0.256 far-end) (Fig. 3) through the BMD between operation and the nonoperative bones of extremities after six weeks.In side scanning, also see same effect.
Fig. 4 has compared the rabbit operation back limbs AP scanning gained BMD and the contrast of giving pamldronate.The BMD of near-end and distal bone has on average increased by 40% and 39% (p＜0.01) respectively around the regeneration site.The BMD of regeneration site compares average 43% (p=0.017) that increased with contrast rabbit tibia.Above-mentioned significant difference has also been confirmed in side scanning.
The BMD and the pamldronate group of nonoperative limbs contrast do not have significant difference.Table I has compared these results.The average regeneration area of pamldronate group increases by 22% (p＜0.05).
The histology
In ten collected duplicate samples, carry out histological examination to nine parts.Also be not included in this analysis the 23rd day disallowable rabbit.The decalcification time comparison of the pamldronate group tibia long 24-48 of product hour in the same old way.The pamldronate group proves that regeneration site generates to be increased, and osteoblast obviously forms the edge, and amount of osteoclast minimizing (2.4/HPF v3.4/HPF contrast), because the lack of evidence of bony remodeling (Fig. 5).Also existing bone within bone to generate in the Cortex Lycii layer of contiguous regeneration site increases, and causes that skin thickness increases (Fig. 5).Osteogenesis in the pamldronate group around the plug pin position also has remarkable increase.There is variability to a certain degree in these factors in the pamldronate group, are reflected on the variability of BMD value.Discuss:
In this experiment, when prolonging beginning with the administration of 3mg/kg pamidronic acid salt pair rabbit, to reduce negative influence to bony remodeling.This strategy has been eliminated the osteoporosis that arrives seen in matched group, activity of the osteoblast in the regeneration site and bone mineral are increased the long-pending remarkable active influence that has.Amount of osteoclast and activity remained minimizing at the 42nd day.Because pamldronate administration when operation, regeneration site generates and the remarkable increase of mineral nitrogenization is the most interesting.No matter pamldronate is attracted to regenerated bone with the performance local action from bone on every side, and still regenerated increase all is owing to PTH and 1,25-(OH)
2Vitamin D changes the anabolic action of secondary.Require further study for estimating these hypothesis.
Suppose that when consistent pulsed predose scheme will be desirable with surgical intervention.Because pamidronic acid salt pair bone mineral has intensive affinity, might make skeleton load pulses dosage reach three to six months, to bring into play positive impact (Glorieux etc. " the serious osteogenesis imperfecta child of pamidronic acid salt pair circulate administration " " New England Journal of Medicine " 1998,339:947-52).Li etc. (ibid) plan to determine whether the patient who accepts successive diphosphonate therapy should cancel this treatment when the contingency fracture.They show with the callus generation in the pretreated rat femur fracture of Incadronate increases.Therapy continued for 16 weeks even further increases callus to generate after fracture, but new bone does not resemble to rebuild the pretreated group and becomes the cortex shell.They reach a conclusion, and should stop this therapy, so that rebuild, but need more research.
Except to the negative influence of rebuilding, in operation osteodiastasis skeletonization, also may be worthless with the diphosphonate successive administration, because longitudinal growth is had adverse effect.In the research of subcutaneous fosamax administration every day, mice in the normal development shows that leg length reduces, and the ductility after the treatment reduces (Raggio etc. " fosamax just reduces in the fracture of developmental mice osteogenesis imperfecta model and do not increase bone length " " North America department of pediatrics shaping association collected works " 1999,5).In this experiment, notice that leg length does not have significant change, the Growth Inhibition hint---nonoperative matched group limbs are than pamldronate group leader 1.4mm although exist.When operation, do not carry out limbs and measure, so this species diversity can not be blood sure owing to the growth inhibited effect.But, the growth inhibited effect can be minimized by a kind of dosage fully.Longitudinal growth is not commented in the research of Li etc. (ibid), but the rat femur that contrasts radiograph explanation continued treatment is shorter than pretreated group and matched group.
Histology in the research has found to point out osteogenesis increase and the bone resorption after the pamldronate administration to reduce.The bone inner region and the regeneration site of this bone around in the extension site are particularly evident, and be more obvious in the operation back leg.Other researchs are pointed out recently, diphosphonate influences the cell of osteoblast system, its mode is different from their inhibitory action (Giuliani etc. " generation of diphosphonate stimulated in vitro Mus and people's bone marrow culture osteoblast precursor and mineralising brief summary; promote mice cub and the early stage osteoblast of mouse aging to generate in the body " " bones " 1998 to osteoclast, 5,22 (5): 455-61).
Because pamldronate increases the osteogenesis ability of regeneration site, its use might increase the precocious danger that merges.The regeneration length decreased average 0.8mm (8%) of the rabbit of pamldronate administration.Although quantity is few not at all surprising, but difference does not reach the significant level on the statistics, if clinical use pamldronate requires to observe carefully this probability.
There are the rabbit operation back limbs of a pamldronate administration still to be continuously Fracture of femur at the 23rd day.This may be random event, but also might be that pamldronate has become fragile bone.
Diphosphonate still remains fully to be estimated to child's toxicological effect.The dosage of this experimental selection 3mg/kg is because this is the general dose (Glorieux etc., ibid) to osteogenesis imperfecta child administration.
After the administration of single dose pamldronate in the whole limbs that prolonged of gained the huge increase of BMD may have the positive therapeutic effect to the child who experiences limb lengthening.Pamldronate increases the prospect likely that this fact of regeneration quantity that is generated provides worth continuation to estimate.Engineering properties, the improvement of dosage and the possible toxicological effect inspection of the bone after requiring further to study the pamidronic acid salts for treating before the clinic trial.
Table I
The summary of finding:
| Average data between pamldronate group and the matched group standard deviation relatively, in the bracket be about 95% cofidence limit | |||||
| Variable | Pamldronate | Contrast | Difference | 95％CI | The p value |
| The limbs length (mm) that has prolonged | 106.0(3.4) | 107.6(4.5) | -1.57 | (-5.76. 2.63) | 0.44 |
| Nonoperative limbs length (mm) | 97.4(2.0) | 98.8(2.2) | -1.45 | (-3.59. 0.74) | 0.18 |
| The tibia weight (g) that has prolonged | 10.9(0.6) | 8.7(0.9) | 2.2 | (1.37.3.03) | ＜0.001 |
| Nonoperative tibia weight (g) | 9.3(0.5) | 8.1(0.4) | 1.19 | (0.71.1.67) | ＜0.001 |
| Regeneration length (mm) | 9.6(0.6) | 10.4(0.7) | -0.75 | (-1.45.- 0.04) | 0.04 |
| Regeneration area (cm 2) | 0.83(0.09) | 0.68(0.13) | 0.15 | (0.03.0.27) | 0.017 |
| AP BMD (the g/cm of regeneration site near-end 2) | 0.51(0.07) | 0.36(0.09) | 0.14 | (0.06.0.23) | 0.004 |
| AP BMD (the g/cm of regeneration site 2) | 0.47(0.11) | 0.33(0.11) | 0.14 | (0.03.0.25) | 0.017 |
| AP BMD (the g/cm of regeneration site far-end 2) | 0.48(0.10) | 0.34(0.08) | 0.14 | (0.04.0.23) | 0.007 |
| AP BMD (the g/cm of the non-operation limbs of near-end 2) | 0.48(0.05) | 0.44(0.03) | 0.04 | (0.00.0.09) | 0.053 |
| AP BMD (the g/cm of the non-operation limbs of far-end 2) | 0.44(0.04) | 0.42(0.02) | 0.02 | (-0.02. 0.05) | 0.31 |
Operation osteodiastasis the immaturity rabbit becomes to have checked the influence of 3mg/kg single dose pamldronate (Novartis) to bone mineral density (BMD) in the bone model.
Check 17 rabbits (9 contrasts, 8 administration pamldronates with two X-ray absorptiometric analysis methods (DXA).Compared with the control, the BMD of pamldronate group has remarkable increase.Compared with the control, the centre plane BMD (g/cm in regeneration proximal bone and the distal bone
2) increased by 40% and 39% (p＜0.05) respectively.Compared with the control, the BMD of bone growth promoting has on average increased by 43% (p＜0.05) again.The average regeneration area that is generated in the pamldronate group also has 22% to increase (p＜0.05).
The histologic analysis of nine rabbits (5 contrasts, 4 pamldronates) has disclosed osteoblast formation edge and the increase of regeneration site mineral nitrogen in the pamldronate rabbit tibia.Give in the rabbit of pamldronate, the Cortex Lycii layer width of osteogenesis around the plug pin position and contiguous regeneration site also has increase.
Pamldronate has remarkable active influence in this limb lengthening model.It has not only reduced under normal circumstances and has prolonged relevant disuse osteoporosis with utilizing external fixator, and has increased the quantity and the density of bone growth promoting again.Require to do further research, to check the engineering properties of regeneration site after the pamldronate administration.
Embodiment 2: the pamldronate (dosage 1mg/kg) in the operation osteodiastasis skeletonization
20 eight age in week male NZW rabbit experience tibia lengthening.After ketamine 15mg/kg and xylazine 4mg/kg IM premedication, with halothane 2% and oxygen 11/min anesthesia.Every rabbit is carried out open meta tibia boring sacrotomy, Orthofix M-100 holder is installed, use four Orthofix3mm half plug pins (Orthofix, Bussolengo, Italy).After hiding 24 hours, make tibia prolong 0.375mm in per 12 hours and reach 15 days, produce 11.25mm operation osteodiastasis.Then the holder original position was kept somewhere 27 days, regeneration site is merged.The 30mg/100ml pamldronate is pressed 1.0mg/kg to 10 rabbit administrations, and administering mode is the interior infusion of single art two hours; To 10 control animal infusion of saline.When operation finishes and postoperative 12 hours buprenorphine is pressed the 0.05mg/kg administration.But animal ad libitum access feedstuff and drinking-water.After 42 days, put to death rabbit with IV Lethobarb150mg/kg.
Radiography and bone mineral density analysis
From knee two hind legs are carried out disarticulation, keep soft tissue complete.By standard A P orientation, use digital luminous magazine to take lateral projection and plane radiograph limbs, irradiation voltage 50kV, electric current 4mA, 1.1 meters of test tube and film distances by Siemens Multix H/UPH configuration.Measure every part of distance between the plug pin position of dissecting sample, so that every radiograph can both suitably be proofreaied and correct again according to the measurement result of regeneration length.
The bone of joint dialysis is peeled off all soft tissues, and (Stratec Medizintechnik Gmbh, Pforzheim Germany) analyzes to utilize Stratec XCT-960A pQCT scanner and analysis software.Obtain two millimeters section, right side (prolongation) tibia has 15 sections, and nonoperative tibia has 10 sections.Obtain five sections separately at regeneration, near-end and distal bone and the corresponding near-end of non-operation limbs and distal bone.Quantitatively CT is a noninvasive method, and the mechanical strength of newborn skeletonization is had the strongest prophecy (Harp etc., 1994).Software can be analyzed and generate about bone mineral density (mg/cm
3), bone mineral content (mg) and area of section (mm
2) data.The data that are used for mechanical analysis have also been generated, just the moment of inertia (mm
4) and maximum y coordinate (to the planar vertical dimension of natural torsion, mm).
Calculate the tension force of every duplicate samples with formula 1:
The D=idol is changeed
Y=is to the vertical dimension of barycenter
L=span length
Press the stress of 2mm interval calculation sample with formula 2 along core:
M=x place moment
Y=is to the vertical dimension of barycenter
I=second the moment of inertia
X=from roll left the axle along the bone distance
The Young's modulus of calculating elastic, it is the straight line portion slope of every " section " or 2mm stress/strain curve at interval.
Utilize azygous couple of tail t check relatively about contrast and treatment group center " section " locate with regenerating section center 1cm in the average Young's modulus value of average data.
Calculate the stress/strain area under curve at matched group and pamldronate group operation osteodiastasis tibia center " section ".Compare them with azygous pair of tail t check once more.The result:
Osteogenesis reliably occurs in the operation osteodiastasis gap.With clinical and radiography inspection, all tibias all engaged at the 42nd day.The bone mineral density of pamldronate group regeneration site near-end and far-end all has remarkable increase (Table II).Bone mineral content also has remarkable increase.Surface of bone is long-pending to have 13% to increase, but this is not statistics significant (p=0.2).
The peak load of the tibia that the pamldronate group has prolonged has strengthened 32% (p=0.004) (Fig. 6).The peak load of the tibia that the pamldronate group has prolonged equates with nonoperative contrast tibia.Young's modulus does not have significant difference between the operation group, be reduced to only to be about 30% (Fig. 7) of complete tibia.Discuss:
In this experiment, when prolonging beginning with the 1.0mg/kg single dose to the rabbit administration, the peak load of measuring after six weeks by four-point bending significantly improves.As our previous experiments, reduced extension site osteoporosis on every side.Although be not that statistics is significant, but bony callus area increased, and is remarkable not resembling in the 3.0mg/kg pamidronic acid salts for treating group sample that occurs in previous experiments.
The peak load increase is likely because the regeneration volume after six weeks increases and content of mineral substances increases.Pamldronate group coefficient of elasticity this statement of facts bone that remains unchanged may not have matched group so ripe.Diphosphonate can confirm it is useful in conjunction with mechanical stimulus: suppose that diphosphonate will increase early stage osteoblastic proliferation, increase bone mineral content, and mechanical stimulus will speed up the maturation of callus.
Table II
| Data between matched group and the pamldronate group relatively | ||||||
| Contrast | Pamldronate | |||||
| On average | ????SD | On average | ????SD | % increases | The P value | |
| Near-end TOT BMC | ????27.98 | ????6.68 | ????34.52 | ????6.27 | ????23％ | 0.03 |
| Regeneration TOT BMC | ????26.13 | ????10.70 | ????30.47 | ????6.67 | ????17％ | NS |
| Far-end TOT BMC | ????28.04 | ????4.65 | ????34.47 | ????4.34 | ????23％ | 0.004 |
| The total BMD of near-end | ????585.53 | ????69.61 | ????650.73 | ????47.06 | ????11％ | 0.03 |
| Total BMD regenerates | ????530.06 | ????77.61 | ????575.03 | ????62.12 | ????8％ | NS |
| The total BMD of far-end | ????650.40 | ????79.40 | ????739.37 | ????56.48 | ????14％ | 0.01 |
| The near-end area | ????52.97 | ????7.94 | ????48.26 | ????7.41 | ????10％ | NS |
| The regeneration area | ????53.13 | ????9.71 | ????46.90 | ????11.91 | ????13％ | NS |
| The far-end area | ????46.85 | ????5.73 | ????43.37 | ????6.54 | ????8％ | NS |
Embodiment 3: sharp phosphonate (dosage 0.1mg/kg) method of assistant in the operation osteodiastasis skeletonization:
Experimental design
24 eight age in week male NZW rabbit experience tibia lengthening.Similarly rabbit model is existing reports.After ketamine 15mg/kg and xylazine 4mg/kg IM premedication, with halothane 2% and oxygen 11/min anesthesia.After being ready to right lower extremity, we carry out open meta tibia boring sacrotomy, and Orthofix M-100 holder is installed, use four Orthofix3mm half plug pins (Orthofix, Bussolengo, Italy).Left lower extremity keeps remaining untouched.After hiding 24 hours, make tibia prolong 0.375mm in per 12 hours and reach 14 days, produce and amount to 10.5mm operation osteodiastasis.Then the holder original position was kept somewhere 28 days, regeneration site is merged.
With the animal random packet, eight animal vias are crossed operation, infusion of saline (contrast) only, eight animals are given 0.1mg/kg and help sharp phosphonate 20 minutes (single dose is helped sharp phosphonate) when operation, and eight animals were given second dose of sharp phosphonate of assistant (the sharp phosphonate of the assistant of repeat administration) at the 14th day in addition.
When operation finishes and postoperative 12 hours buprenorphine is pressed the 0.05mg/kg administration to all animals.But animal ad libitum access feedstuff and drinking-water.After 42 days, put to death rabbit with IV Lethobarb 150mg/kg.
Radiography and bone mineral density analysis
Use whole dual energy sources X-gamma ray density meter two weeks, all around and carry out after six weeks bone mineral content (BMC) and bone mineral density (BMD) measure (LUNAR DPX, Radiation Corps, Madison, Wisconsin).Carry out DXA scanning with being oriented in tibia in anterior-posterior (AP) the projection anchor clamps, use aim at the software measuring toy and design (LUNAR DPX, Small AnimalSoftware, 1.0c LUNAR, Radiation Corps, Madison, Wisconsin).Use " HiRes＜0.5kg Slow " scan pattern (" meticulous " collimates, and sample size is 0.6 * 1.2mm, and sample interval is 1/16 second).
" interesting areas (ROI) " placed 9.6mm eminence on the scanned picture, obtain regional BMC and BMD measurement result.About every tibia that has prolonged, a ROI is placed in regeneration site, and one at its near-end, and one at its far-end.In nonoperative tibia, place two ROI, so that the far-end and near-end ROI (just the distance with the bone end equates) of the tibia that they have been equivalent to prolong.Thereby concerning each projection, produce about every tibia that has prolonged and to amount to three measurement results, produce measurement result twice about every nonoperative tibia.The BMC value is with gram (g) expression, and the BMD value is with g/cm
2Expression, and average, the standard deviation of report group data and 95% confidence interval.
After the rejecting, two hind legs are carried out disarticulation, keep soft tissue complete from knee.By standard A P orientation, use digital luminous magazine to take lateral projection and plane radiograph limbs, irradiation voltage 50kV, electric current 4mA, 1.1 meters of test tube and film distances by Siemens Multix H/UPH configuration.Collimating marks on the film can realize that image suitably proofreaies and correct again according to the measurement result of length millimeter (mm).
For at six week back deployment analysis, then the bone of joint dialysis is peeled off all soft tissues, utilize Stratec XCT-960A pQCT scanner and analysis software analyze (StratecMedizintechnik Gmbh, Pforzheim, Germany).Obtain two millimeters section, right side (prolongation) tibia has 15 sections, and nonoperative tibia has 10 sections.Obtain five sections separately at regeneration, near-end and distal bone and the corresponding near-end of non-operation limbs and distal bone.Software can be analyzed and generate about bone mineral density (mg/cm
3), bone mineral content (g) and area of section (mm
2) data.The data that are used for mechanical analysis have also been generated, just the moment of inertia (mm
4) and maximum y coordinate (to the planar vertical dimension of natural torsion, mm).The result:
The eliminating situation
Single dose is helped sharp phosphonate group has a rabbit to die from gastrointestinal disease on the 9th day suddenly after operation.The repeat administration group has a rabbit operation osteodiastasis and precocious the merging to fail, and gets rid of it.Eight rabbits of remaining matched group and each seven rabbit of Zuo Li phosphonate group.
Bone mineral content (BMC)
The BMC that measures with DXA after two weeks is similar (Fig. 8) in all groups.In the animal of the sharp phosphonate of assistant treatment, between around second week and the, all trizonal mineralizations of limbs all increase sharply after the operation.The treatment group all significantly is different from contrast at All Ranges, except the distal segment of single dose animal (t checks p＜0.01).The BMC of All Ranges is having decline around the and between the 6th week.This is the most tangible in control animal, the single dose group greatly reduce with the dose double group in minimum so that the BMC of two treatment groups compare photograph remarkable increase is arranged after six weeks.After six weeks, the BMC difference between single dose and the repeat administration animal is significant in near-end and distal segment, but in regeneration site not significantly (p＜0.01).
Bone mineral natural rate of growth in the animal regeneration site of process treatment is between the 2nd week and the 4th week significantly higher (Fig. 9, p＜0.01).Between the 4th week and the 6th week, all organize some bone minerals that all scatter and disappear, and the sharp phosphonate group of the assistant of repeat administration is scattered and disappeared minimum (p＜0.05v contrast NS v single dose).
The BMC that helps sharp phosphonate treatment animal All Ranges measures significantly increase (p＜0.01, ANOVA) (Figure 10) with QCT after six weeks.This effect has the enhancing of the relevant mode of dosage in the dose double group.After this t check discloses between single dose and the contrast and the difference between dose double and the single dose all is significant (p＜0.05).The BMC of non-operation tibia does not have significant change.
Bone mineral density
The BMD of matched group regeneration site measures increase to some extent with DXA between the 2nd week and the 4th week, but drops to the value (Figure 11) in the 2nd week once more.The BMD of near-end and remote area descends gradually, and this is the Expected Results (Figure 11) of stress shielding.Completely contradict with it, the BMD that helps sharp phosphonate treatment animal regeneration site increases rapidlyer, and keeps more than half.Help sharp phosphonate and play the effect of protecting near-end and remote area to avoid the stress shielding influence, so that the BMD after six weeks remains on second all levels.The face BMD value of two sharp phosphonate treatment groups of assistant all significantly is different from contrast with the DXA measurement after 4 weeks and 6 weeks, but the single-dose group is never significantly different about face BMD each other with the repeat administration group.
The BMD that helps sharp phosphonate treatment animal All Ranges measures significantly increase (p＜0.01, ANOVA) (Figure 12) with QCT after six weeks.After this t check discloses between single dose and the contrast variant (p＜0.01), but does not have difference (p＞0.05) between repeat administration and the single dose.The BMD of non-operation tibia does not have significant change.Help sharp phosphonate treatment animal and all keep and the similar BMD of nonoperative contrast tibia, and contrast operation osteodiastasis tibia all shows the osteoporosis of significance degree at All Ranges at All Ranges.
Linear measure longimetry after six weeks
There is dosage correlation difference in the length of the non-operation tibia of rabbit, so that single dose is helped the average tibia length comparison of sharp phosphonate group according to reducing 3%, repeat administration group minimizing 7% (ANOVA p＜0.01, Table III).The right tibia in the assistant of repeat administration sharp phosphonate group operation back is also significantly shorter, but the length of regenerating does not have difference between each group.These Notes of Key Datas are helped sharp phosphonate longitudinal growth are had small and definite dosage correlation negative influence at medically (at the physis).
Area of section after six weeks is measured
The area of section of helping sharp phosphonate treatment animal All Ranges with QCT measurements have significant dose dependent increase (p＜0.01, ANOVA).Area of section to non-operation tibia does not have effect (Figure 13) at all.See obvious effects in regeneration site, the single dose group increases by 56%, and the dose double group increases by 105%, but also see area of section at adjacent area considerable increase is arranged, from 29% to 72%.Meta QCT to every group of area of section scans as shown in figure 14.
The moment of inertia even higher increase is arranged is because it is and r
4Proportional (Figure 14).The moment of inertia of regeneration site thereby increase by 111% in the single dose group, increase by 213% in the dose double group (p=0.02, ANOVA).Single dose help between sharp phosphonate and the contrast difference with after this in pairs t check (post-hoc unpaired t test) be (p=0.02) significantly.The further rising of repeated doses group the moment of inertia does not reach significant level, because variability higher (p=0.3).The moment of inertia of peripheral region increases by 57% to 180%.
Engineering properties for regeneration site after the sharp phosphonate administration of inspection assistant still requires to do further to study.Discuss
Although only be the IV infusion, but the remarkable beneficial effect of the sharp phosphonate administration of assistant of this institute record is target organ specific (Figure 10,12,13,14).Not only in regeneration site, and at adjacent area, osteogenesis amount and mineral nitrogen thereof turn into all having and roll up.Simultaneously seldom or do not have an effect to non-operation tibia.Some possible hypothesis can be explained this point.Although the most direct relevant approach even cell line still remain clearly, as if make bone can not feel its mechanical environment but help sharp phosphonate.The BMD of contrast tibia descends gradually, and different with it is that the bone mineral of the bone around sacrotomy and operation osteodiastasis does not does not scatter and disappear.The new bone comparison that is generated simultaneously also is like this according to stronger even bone is strictly controlled in the holder.
Another kind of probability is that the osteoclast inhibitory action has delayed reconstruction, until the callus that generates more than constant.Also having a kind of probability is that diphosphonate directly acts on osteoblast, perhaps by basic fibroblast growth factor (bFGF).Which, still require to do further to study by attempting and accurately illustrating somatomedin and stimulated by the diphosphonate administration or suppresses.
Important observed result is, BMD returns to the value of non-operating comparison limbs, and the increase of BMC is because the new bone quantity of normal density increases mostly.If only be that density increases on the normal level and the quantity of the bone that is generated does not increase, bone will be osteosclerotic so, and will be just brittle, and intensity does not improve.
When the conditioning skeleton trauma, the IV single dose administration during operation is very suitable for clinical scenarios.Helping sharp phosphonate has by abundant disclosed safety profile (the Major P of document the cancer patient who accepts multiple dose administration, Lortholary, Hon J etc. " help sharp phosphonic acids and be better than pamldronate in the hypercalcemia treatments of tumor inducing: combined analysis " Proc ASCO New Orleans, 2000,5,19:209 (summary 814).Abundant hydration trauma patient is the single dose of tolerate surgery front and back fully, if be concerned about hydration, can postpone treatment, until suitable degree.This will reduce the theoretic probability of nephrotoxicity or nephrocalcinosis.
In the selectivity situation, the sharp phosphonate IV of perioperatively high-ranking officer infusion 5-20 minute should be to realize easily and safety.Still require to do further research.
If the attending doctor considers the reaction to perioperatively suboptimum single dose, perhaps prolonged unusually the course of treatment, the further dosage of the strong suggestion of this research will be given other benefit.But increase more than 50% owing to single dose in this model provides new osteogenesis, further dosage can not be customary necessary.In pediatric population, must give with due regard to equally about the negative influence of diphosphonate administration to longitudinal growth.Originally studies show that has the dosage correlation negative influence to longitudinal growth, although single dose only is 3%, only is 7% in the animal of repeat administration, but this still points out in the child who is growing and to prolong the sharp phosphonate administration of assistant and may owe careful.
The area of section increase is a significant benefits very.Regeneration failure appearance on the books main is crooked, and the long bone fracture failure occurs crooked or reverses.Crooked and reverse in the moment of inertia and r
4Or area of section square all is proportional.The regeneration site area of section increases by 56% thereby be equivalent to the moment of inertia and increase by 111%.The repeat administration group increases by 105% and is equal to the moment of inertia increase by 213%.The regeneration intensity index also increases (Table IV) pro rata with area of section.
Seen in this experiment to effect be consistent with the above-mentioned discovery that relates to the pamldronate administration.
Because present animal model only continued for six weeks, can not draw the conclusion that the relevant new bone that is generated is rebuild.Intuition be that area of section will reduce along with bony remodeling.Produce so a large amount of callus and can before rebuilding generation, remove holder.This strategy will allow to rebuild and occur under the environment of physiology load, and the latter is the result that diphosphonate disappears in time, rather than occurs under the stress shielding environment of holder.Be conceived to remove holder bone behavior afterwards and still require to do further research.
The tibia of the sharp phosphonate group of assistant of Table III contrast, the sharp phosphonate of assistant and repeat administration and green strength again
The average 98.00 95.14* 91.14* of sharp phosphonate 1 sharp phosphonate 2 quantity 877 left tibias of assistant of contrast assistant
Average 107.75 107.43 101.57* of SD 1.41 2.48 2.79 right tibias
SD 2.12 4.08 3.21 regeneration site average 10.38 11.29 10.57
SD???????????1.30?????????1.50??????????1.90
* expression has significant difference with ANOVA and after this not paired t check
The regeneration intensity index of the sharp phosphonate group of assistant of Table IV contrast, the sharp phosphonate of assistant and repeat administration
The sharp phosphonate 2RSI 2.09 3.26 4.49 of sharp phosphonate 1 assistant of contrast assistant surpasses the % 56% 114% of contrast
Those skilled in the art will recognize that, can change in a large number and/or revise, shown in the specific embodiment, and do not deviate from the broad spirit or the scope of invention invention.Therefore these embodiments only are regarded as for exemplifying and unrestricted.
Claims (28)
1, the medicine that is used for promote osteogenesis is selected from the group of being made up of at least a diphosphonate.
2, the medicine of claim 1, it is used to promote the fracture site osteogenesis.
3, the medicine of claim 1 or claim 2, it is used to promote bone and prosthese, bone anchoring device or the osteogenesis between other bones or the dental implant arbitrarily.
4, the medicine that is used for the treatment of fracture is selected from the group of being made up of at least a diphosphonate.
5, the medicine of one of any aforementioned claim, wherein this diphosphonate is the sharp phosphonate of assistant.
6, the medicine of one of any claim 1 to 4, wherein this diphosphonate is a pamldronate.
7, the medicine of one of any claim 1 to 4, wherein this medicine is the combination of two or more diphosphonates.
8, medicine is used for the purposes that medicament is made, and this medicine is selected from the group of being made up of at least a diphosphonate, and this medicament is used for promote osteogenesis.
9, the purposes of the medicine of claim 8 is used to promote the osteogenesis of fracture site.
10, the purposes of the medicine of claim 8 is used to promote the osteogenesis between bone and the prosthese.
11, medicine is used for the purposes that medicament is made, and this medicine is selected from the group of being made up of at least a diphosphonate, and this medicament is used for the treatment of the bone of fracture.
12, the purposes of one of any claim 8 to 11, wherein this medicine is the sharp phosphonate of assistant.
13, the purposes of one of any claim 8 to 11, wherein this medicine is a pamldronate.
14, the purposes of one of any claim 8 to 11, wherein this medicine is the combination of two or more diphosphonates.
The method of the bone of 15, treatment fracture, this method comprise the medicine of will treat effective dose to the fracture patient administration, and this medicine is selected from the group of being made up of at least a diphosphonate.
16, the method for claim 15, wherein this medicine with single dose to patient's administration.
17, the method for claim 16, wherein this single dose of drug is the early stage administration of bone-specific drug in fracture.
18, the method for claim 15, administering mode wherein are perioperative intravenous infusions.
19, the method for claim 15, administering mode wherein is oral.
20, the method for claim 15, administering mode wherein is a transdermal.
The method of the bone of 21, treatment fracture, this method comprises the following steps:
(a) medicine that will treat effective dose is to the fracture patient administration, and this medicine is selected from the group of being made up of at least a diphosphonate; With
(b) bone to fracture provides vibratility to stimulate.
22, the method for claim 21, wherein this vibratility stimulates is provided by ultrasound stimulation or vibratory stimulation.
23, the method for claim 21 or claim 22, wherein this vibratility stimulates the vibratility that comprises the resonant frequency that bone regularly is provided to stimulate.
24, the method for claim 23, wherein this resonant frequency calculates as the function of bone to the vibration reaction of vibratility stimulation.
25, the method for one of any claim 21 to 24, wherein this vibratility stimulation is to provide late period at the bone-specific drug of fracturing.
26, the method for one of any claim 21 to 24 wherein provides vibratility step that stimulates and the step for the treatment of the effective dose drug administration to walk abreast.
27, the method for claim 26, wherein the bone-specific drug in fracture provides this vibratility to stimulate in early days, and will treat the drug administration of effective dose.
28, the method for claim 24, wherein the bone-specific drug in fracture provides this vibratility to stimulate late period, and will treat at least a bisphosphonates administration of effective dose.
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| DE60143964D1 (en) | 2001-02-06 | 2011-03-10 | Sydney Children S Hospitals Network Randwick And Westmead Incorporating The Royal Alexandra Hospital | DRUGS TO TREAT OSTEONE COSMETICS AND TO SUPPLY PATIENTS WITH RISK TO OSTEONE CRYOSIS |
| WO2002080933A1 (en) * | 2001-04-03 | 2002-10-17 | The Royal Alexandra Hospital For Children | A drug for use in bone grafting |
| AUPR553701A0 (en) * | 2001-06-07 | 2001-07-12 | Royal Alexandra Hospital For Children, The | A device for the delivery of a drug to a fractured bone |
| EP1508343B1 (en) * | 2003-08-21 | 2015-11-04 | AddBIO AB | Bisphosponate coated implant device and method therefor |
| EP1667691A1 (en) * | 2003-09-19 | 2006-06-14 | Pfizer Products Inc. | Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin d derivatives and a bisphosphonate |
| ITMI20040218A1 (en) * | 2004-02-10 | 2004-05-10 | Abiogen Pharma Spa | USE OF SODIUM NERHYDRONATE TO PROMOTE BONE NEOFORMATION |
| ITMI20040641A1 (en) * | 2004-03-31 | 2004-06-30 | Tb Technology S R L | BIFUNCTIONAL BIOADHESIVE COMPOSITIONS FOR ORAL IMPLANTOLOGY |
| AR048742A1 (en) * | 2004-12-22 | 2006-05-24 | Gador Sa | INTRA-ORAL MEDICINES APPLICATION SYSTEM |
| JP5426168B2 (en) | 2005-10-27 | 2014-02-26 | トーメン メディカル アーゲー | Dental implant and manufacturing method thereof |
| US8882740B2 (en) | 2009-12-23 | 2014-11-11 | Stryker Trauma Gmbh | Method of delivering a biphosphonate and/or strontium ranelate below the surface of a bone |
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| BR8107560A (en) * | 1981-11-19 | 1983-07-05 | Luiz Romariz Duarte | ULTRASONIC STIMULATION OF BONE FRACTURE CONSOLIDATION |
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| AU670337B2 (en) * | 1992-11-30 | 1996-07-11 | Novartis Ag | Use of certain methanebisphosphonic acid derivatives in fracture healing |
| EP0600834A1 (en) * | 1992-11-30 | 1994-06-08 | Ciba-Geigy Ag | Use of methanebisphosphonic acid derivatives for the manufacture of a medicament for fracture healing |
| AU5953894A (en) * | 1992-12-23 | 1994-07-19 | Merck & Co., Inc. | Bisphosphonate/estrogen therapy for treating and preventing bone loss |
| US5403829A (en) * | 1993-03-24 | 1995-04-04 | Leiras Oy | Use of bisphosphonates in endo-osteal bone surgery |
| US5646134A (en) * | 1994-04-21 | 1997-07-08 | Merck & Co., Inc. | Alendronate therapy to prevent loosening of, or pain associated with, orthopedic implant devices |
| GB9408775D0 (en) * | 1994-05-04 | 1994-06-22 | Ciba Geigy Ag | Use of certain methanebisphosphonic acid derivatives to prevent prothesis loosening and prothesis migration |
| CA2221416A1 (en) * | 1995-06-06 | 1996-12-12 | Merck & Co., Inc. | Bisphosphonate therapy for bone loss associated with rheumatoid arthritis |
| US5616571A (en) * | 1995-06-06 | 1997-04-01 | Merck & Co., Inc. | Bisphosphonates prevent bone loss associated with immunosuppressive therapy |
| US5853759A (en) * | 1996-05-17 | 1998-12-29 | Merck & Co.. Inc. | Effervescent alendronate formulation |
| GB9613722D0 (en) * | 1996-06-28 | 1996-08-28 | Univ Liverpool | Chemical compounds |
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1999
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2000
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- 2000-08-17 KR KR1020027002160A patent/KR20020027562A/en not_active Application Discontinuation
- 2000-08-17 EP EP00952791A patent/EP1214079A4/en not_active Withdrawn
- 2000-08-17 BR BR0013416-3A patent/BR0013416A/en not_active Application Discontinuation
- 2000-08-17 JP JP2001518059A patent/JP2003507426A/en active Pending
- 2000-08-17 SK SK238-2002A patent/SK2382002A3/en not_active Application Discontinuation
- 2000-08-17 HU HU0202396A patent/HUP0202396A3/en unknown
- 2000-08-17 CA CA002381302A patent/CA2381302A1/en not_active Abandoned
- 2000-08-17 NZ NZ517538A patent/NZ517538A/en unknown
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- 2000-08-17 WO PCT/AU2000/000982 patent/WO2001013922A1/en active IP Right Grant
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2002
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114532937A (en) * | 2020-11-18 | 2022-05-27 | 中国人民解放军海军军医大学第一附属医院 | Enteroscope auxiliary device |
Also Published As
| Publication number | Publication date |
|---|---|
| NO20020784L (en) | 2002-02-18 |
| PL353485A1 (en) | 2003-11-17 |
| IL148166A0 (en) | 2002-09-12 |
| EP1214079A1 (en) | 2002-06-19 |
| WO2001013922A1 (en) | 2001-03-01 |
| JP2003507426A (en) | 2003-02-25 |
| AUPQ232599A0 (en) | 1999-09-09 |
| NO20020784D0 (en) | 2002-02-18 |
| SK2382002A3 (en) | 2002-09-10 |
| NZ517538A (en) | 2003-07-25 |
| CN100345548C (en) | 2007-10-31 |
| ZA200202160B (en) | 2003-08-27 |
| HK1048441B (en) | 2008-02-22 |
| BR0013416A (en) | 2002-04-30 |
| KR20020027562A (en) | 2002-04-13 |
| HUP0202396A3 (en) | 2005-02-28 |
| CA2381302A1 (en) | 2001-03-01 |
| HUP0202396A2 (en) | 2002-11-28 |
| HK1048441A1 (en) | 2003-04-04 |
| EP1214079A4 (en) | 2004-03-24 |
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