in the kinetics of 99mTc@phosphate uptake. It has beensuggested that circulating 99mTc..MDP is adsorbed selectively onto the mineral phase of forming bone (via hydroxyapatite crystals). This is based on studies carried outin vivo, in which the use of autoradiographic techniqueslocalized the 99mTc to mineralized tissue and not to theunmineralized osteoid or bone cells (13,14). In vitro studies using calcifying solutions support this finding in thatthey indicate that the 99mTc is adsorbed onto the hydroxyapatite nuclei that are being formed (15,16).

It hasalsobeensuggestedthat the collagenmatrix ofbone is the target for 99mTc(12,1 7). This is based on theobservation of its increased uptake by bones in osteomalacia, Paget's disease and hyperparathyroidism when administered as 99mTc@pyrophosphate. These diseases arecharacterized by the accumulation of large quantities ofimmature collagen. Phosphate-containing enzymes whichare present in large quantities in bone (e.g. alkaline phosphatase) have also been suggested to be the binding sitesfor 99mTc(11).

A major role in the kinetics of 99mTc@phosphateuptakein bone is played by its local vascularity, with localizationof 99mTcphosphatase being marked at highly vascularizedbone surfaces (19). An example for this mechanism is thehigh uptake of the radionuclide in the cartilage bars associated with the vascular loops of the growth plate (20). Inaddition, autoradiographic studies demonstrate that thedistribution of pyrophosphate in bone reflects the distribution ofthe blood supply (1,21,22).

There is still a debate in the literature as to whether thisradiopharmaceutical is transported to the bone intact, orwhether it is hydrolysed during its transport to the bone.Most investigators believe that the injected radiolabeledcomplex is transported to the bone where it is deposited(3,5,18,26).

A number ofarticles have indicated that the radiolabeledcomplex is hydrolyzed into its components and that theindividual components are taken up by the bone (27—29).

It has been demonstrated that osteogenesis after injuryto the rat tibial bone could serve as a model for investigating the uptake mechanism of labeled 99mTc@phosphates(30). This is a highly reproducible model of bone healing,which is triggered by ablation of the tibial bone marrowand whose stages of healing are clearly definable (31,32).

The present study was earned out in order to test the hypothesis that intravenously injected Tc-MDP separates intoits technetium and methylene diphosphonate components inthe bone, and that the technetium is preferentially taken-upby the newly-formed osteoid, while the methylene diphosphonate is taken up by the forming mineral. Uptake of Tc-MDPwas studied in a rat model of primary bone formation followingtibial bone marrow ablation. Eachoffive radiopharmaceuticals(°@Tco4, @Tc-MDP,Tc-MD@P,°@Tc-MD@Por MD@P)wasinjected and their uptake was followed in the whole bone aswell as in the organic and inorganic phases of the bone.Irrespective of the radionuclides injected, °@“Tcwas alwaystaken-up preferentially by the organic phase, while the @Pwas preferentiallytaken-up by the inorganicphase. When@°“TcO4was injected,it was not taken up by the boneat all.

These results indicate that the increased incorporation of@°“Tc,when administered as °@“Tc-MDPduring bone healing,

reflectsanenhancementintheformationof theorganicmatrixand not of the calcification process. The study also suggeststhat the @“Tc-MDPdissociates into its technetium and methylene diphosphonate moieties, which are then adsorbed ontothe organicand inorganicphasesrespectively.

JNucIMed 1993;34:104—108

echnetium-99m-labeled phosphates have served asbone scanning agents for the diagnosis ofa broad spectrumof pathological conditions affecting the skeleton, with99mTcmethylene diphosphonate (@mTc@MDP) being themost widely used today (1—8).A comprehensive reviewon technetium chemistry and technetium-based radiopharmaceuticals has been published by Deligny et al. (1)and Deutsh et al. (9).

The theoretical basis for the use of @mTc@labeledphosphates in the diagnosis of bone pathology is based on thehigh affinity of the phosphates for hydroxyapatite (10),enzymes (11) and immature collagen (12). Various authors have stressed the role of one or more ofthese factors

Received Apr. 1, 1992; revision accepted Aug. 24, 1992.Forcorrespondenceand repñntscontact: Dr.ZviSchwartz,Departmentof

Petiodontics,School of Dental Medicine,P.O. Box 1172, Jerusalem 91010,Israel.

104 The Journal of Nuclear Medicine •Vol. 34 •No. 1 •January1993

Uptake and Biodistribution of Technetium-99m-MD32PDuring Rat Tibia! Bone RepairZvi Schwartz, Jashovam Shani, W. Aubrey Soskolne, Haifa Touma, David Amir and Jona Sela

Departments ofPeriodontics, Pharmacology, Oral Pathology and Orthopedic Surgery, The Hebrew University-HadassahFaculties ofDental Medicine and Medicine, Jerusalem, Israel

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In a previous study from this laboratory using this model,the incorporation of three different 99mTc@labeledphosphates was studied and correlated with the incorporationof 47Ca and H332P04. The results suggest that @mTccouldserve as a specific marker of the anabolic phase of remodeling and that it is incorporated into the organic matrix

rather than into the mineral phase (33). The purpose ofthe present study was to confirm the hypothesis that thetechnetium is deposited in the organic matrix and themethylene diphosphonate is deposited in the mineralphase of the bone, as two separate entities.

MATERIALSAND METHODS

AnimalModelA total number of 180 albino rats of the Hebrew University

“Sabra―strain were used in two separate experiments. The ratsweighed between 350—400g and obtained free supply offood andwater. The bone marrow injury was carried out under Ketamine(Ketalar, Parke Davis, Detroit, MI) anesthesia (33 mg/kg bodyweight i.p.). The proximo-medial aspect of the right tibial bonewas exposed 3 mm distal to the knee joint, and a dental burr(size 5/0) rotating at 5000 RPM was used to penetrate throughthe cortical bone into the marrow cavity. Bone marrow wasevacuated by repeated washing with saline, introduced into theintrabony space by a cannula. The skin wounds were then sutured. In sham-operated rats, tibial exposure was performedwithout bone penetration.

ExperimentalDesignIn each of the two experiments, 90 rats were used. In each

experiment, three groups of 30 rats were injured 14 days, 6 daysand 3 days before radionuclide administration. Each group wasdivided into five sub-groups of six animals each. All six animalsin each sub-group were injected with one of the following radioactive compounds, 99mTc04, 99mTc@MDP, Tc-MD32P, 99mTc@

MD32P,or MD32P 18 hr prior to death.

RadiochemicalTechnetium-99m-pertechnitate was eluted from a molybde

num generator manufactured by Soreq Nuclear Research Center,Yavne, Israel. Phosphorus-32-methylene-diphosphonate(MD32P)was synthesized at the Radiochemistry Department of the Nuclear Research Center-Negev, Beer-Sheva, Israel by isotopic exchange of 32Pduring the reaction of tnisopropyl phosphate withmethylene-dibromide, in the presence of H332P04. This was followed by hydrolysis of the tetraalkyl ester formed with HCI, asdescribed by Moedritzer et al. (34). The purity of MD32P wasestablished by running it on precoated silica-gel TLC plates (GoF254: Merck, Darmstadt, Germany), in a solvent consisting of a

mixture of isopropanol:H20:TCA:25% NH4OH (70 mI:50 ml:5gr:0.5 ml). The R1of the MD32Pobtained was0.3—0.35,whichwas in the range ofthe MDP standard used. The specific activityused in this study was 1.2 mCi/mg MDP. The “cold―MDP kitwas reconstituted with 99mTcO4 and saline, according to themanufacturer's instructions, and 0.05 mCi/rat was injected subcutaneously. Technetium-99m-pertechnitate was injected subcutaneously at a dose of 0.05 mCi/rat. Phosphorus-32-methylenediphosphonate was mixed with cold methylene diphosphonate toyield a final concentration identical to the commercial kit.

RadionuclidicStudiesThe radionuclides were administered subcutaneously in a vol

ume of 0.3 ml, and the rats were killed 18 hr later. Tibial boneswere removed, cleaned, weighed and immediately counted for99mTc All bones were then demneralized in 10% trichloroacetic

acid (TCA) for 6 hr, in a shaker at 60 RPM. Samples ofthe TCAextracts (inorganic phase) were counted, as well as the demineralized bones (organic phase). In order to confirm that demineralization with TCA removed all the calcium and phosphate thatwere not part of the organic matrix, a parallel experiment wascarried out in which bones were ached before and after demineralization. No significant differences were found between thetwo methods. In order to count the 32P,bones were dissolved in2 ml tissue solubilizer (Soluene 350, Packard), bleached with 0.2ml of 30% H202 and diluted 1 + 49 with Lumax: Toluene = 1:3,before counting. All samples were counted for 1 mm. Decaycalculations were not necessary, as results were expressed asCPM/mg of injured over noninjured tibiae. Counting was performed using an autogamma scintillation spectrometer (Packered) and a liquid scintillation counter (Betamatic, Kontron).

Statistical EvaluationRadionuclide uptake was assessed by calculating the ratio of

the uptake of radionuclide by treated over untreated tibia foreach rat. Mean treatment/control ratio and standard error of themean (s.e.m.) were calculated for each treatment sub-group, andthe differences between groups were examined using the Wilcoxon-matched paired test. A level of p < 0.05 was consideredsignificant.

RESULTS

Bones from 99mTcO4injected animals did not show anysignificant uptake of the radionuclide above backgroundlevels, in either treated or control legs. After injection of99mTCMDp a significant increase in 99mTc uptake (ex

pressed as a TIC ratio of 2.04) from whole bones wasobserved on the 6th day after injury. At this time pointthere was also a significant increase in the TIC ratio in theorganic phase ( 1.6), however no significant change in theT/C ratio was observed for the inorganic phase (1.03) (Fig.1). When 99mTcMD32p was injected into the animals and

the uptake of 99mTcfollowed (Fig. 2A) a similar pattern ofdistribution ofthe 99mTcwas observed. Uptake of32P, afterinjecting the various labeled phosphates showed that afterinjection of MD32P a significant increase in the TIC ratiowas observed on the sixth and fourteenth day in the wholebone, as well as in the inorganic phase, where the TICvalues ranged between 1. 17—1.20. However the TIC ratiosfrom the organic phase were significantly reduced to 0.78and 0.72 on the sixth and fourteenth days respectively(Fig. 3). The injection of Tc-MD32P showed a similardistribution of the isotope in the whole bone and in the

inorganic phase. However the decrease in the isotopeuptake in the organic phase was more marked (TIC = 0.69and 0.57 on the sixth and fourteenth day respectively) (Fig.4). When 99mTcMD32P was injected, a significant increasein the TIC ratios for the whole bone and the inorganicphase (1.33 and 1.37 respectively) were found for 32P,only

105MDP Biodistribution in Bone Healing •Schwartz et al.

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FIGURE1. Uptakeof @“Tcafterinjectionof @“Tc-MDPat3,6 and 14 days of thial bone healing.The data are expressedasmean ±s.e.m. of the treatment-to-controlratio. *Significantdifferencebetweenthe treatedandcontrol legsusingthe Wilcoxenmatchedpairedtest (p < 0.05).

on the sixth day of healing, while the TIC ratio in theorganic phase was 0.68 (Fig. 2B).

DISCUSSION

The results of this study indicate that while the compound Tc-MDP has the ability to be incorporated intobone, the 99mTcfragment is not adsorbed by it. Injectionof@mTc@MDPleads to a significant increase in the uptakeofthe label by the whole bone on the sixth day after injury.At this time period, primary bone formation is the dominating process at the site of injury and no resorption isobserved (35). This finding is in agreement with previousobservations from our laboratory (33), and suggests that99mTcMDP can provide a measure of net bone formationduring healing (33,36) and during other pathological processes.

Our previous findings show preferential incorporationof99mTcinto the organic phase ofthe injured leg, not intothe inorganic phase, suggesting that there is a separationof the 99mTcMDP into its @mTcand MDP componentsprior to incorporation of the phosphate into the mineralphase. To provide further support for this hypothesis, wetraced the incorporation into the bone of 32Pinjected intorats as MD32P and @mTc@MIY2P.In both situations the32p was preferentially incorporated into the inorganicphase of the injured bone, because it was the nucleus ofthe phosphate component. On the other hand, incorporation of 32Pinto the organic phase of the injured bone wassignificantly less than in the control leg. These resultsindicate that MDP is adsorbed preferentially onto themineral phase ofbone hydroxyapatite, a phenomenon thathas been shown to occur in vitro (15,16).

The finding that 99mTcand 32Pare found in the organicand inorganic phases respectively when @mTc@MD32Pisinjected, indicates that Tc-MDP is hydrolyzed into itstechnetium and phosphate components. The results of this

FIGURE2. (A)Uptakeof @“Tcafterinjectionof @“Tc-MD@Pat 3, 6 and 14 days of tibialbone healing. The data are expressedas mean ±s.e.m. of the treatment-to-controlratio. *5@gnifj@n@differencebetweenthe treatedandcontrollegsusingthe Wilcoxen matchedpairedtest (p < 0.05).(B) Uptakeof MD@Pafterinjectionof@―Tc-MD@Pat 3, 6 and 14 daysof tibialbonehealing.The data are expressedas mean ±s.e.m. of the treatment-tocontrol ratio. *Significant difference between the treated andcontrol legs using the Wilcoxen-matched paired test (p < 0.05).

study support the hypothesis that when 99mTc@labeledphosphate compounds are used as a tracer of bone pathology in clinical nuclear medicine, it is specific for boneosteoid formation (12,1 7,22,37). This hypothesis explainsthe increased uptake found in osteomalacia, Paget's diseaseof bone and hyperparathyroidism, diseases characterizedby the accumulation of large quantities of osteoid.

The in vivo and in vitro studies suggesting that 99mTc@MDP is a marker of mineralization (13—16)are open tocriticism. The in vivo (13,14) studies are based on autoradiography in which the differentiation between the morphologically superimposed organic and inorganic phasesof the bone is difficult. In the in vitro studies (15,16),hydrolysis ofthe 99mTCMDp into its components can notoccur because of lack of any enzymatic activity, andtherefore the technetium must follow the MDP absorptiononto the hydroxyapatite.

The higher specificity of 99mTclabeled MDP comparedto 32Plabeled MDP as a tracer ofbone pathology is obviousfrom the quantitative difference noted in this study between the uptake ratio of@mTc@MDP(1.60—2.04)and Tc

106 The Journal of Nuclear Medicine •Vol. 34 •No. 1 •January1993

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for the label to be detected in it. Hygeian et al. (37) havefurther suggested that hydrolysis of Tc-MDP in blood andinterstitial fluid can only be minor, based on the transitiontime of Tc-MDP in these tissues (38) and therefore it ismost likely that the hydrolysis occurs in the bone tissue.

Although increased ‘2Puptake is specific to the inorganic phase of the healing leg, its uptake into the organicphase is lower in the healing leg than in the control one,as reflected by a TIC ratio significantly less than one. Thiscould be explained by reutilization of ‘2P-labeledmolecules that, after their initial incorporation, are releasedfrom the inorganic phase and are reutilized preferentiallyby the actively calcifying site, thus resulting in its redistri

bution. This does not occur with the @mTcmoiety. Inconclusion, these studies support the hypothesis that theincrease of 99mTc uptake at sites of bone remodeling isassociated with bone matrix formation and not with calcification. It also suggests that the use of dual-labeled99mTcMD)2P may be used to study the regulation ofosteoid formation and calcification simultaneously.

ACKNOWLEDGMENTSThis study was partly supported by a grant from The Israeli

Ministry of Health. The authors gratefully acknowledge the helpof the Radiopharmacy Department of the Soreq Nuclear Research Center in performing the various chromatographies of thelabeled-MDP.

REFERENCES

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14. Einhorn TA, Vigorita VJ, Aaron Z. Localization of @mTc@MDPin bone

0L.

C

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E0a,1@

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Days

FIGURE3. Uptakeof MD32Pafterinjectionof MD@Pat 3, 6and 14 days of tibial bone healing.The data are expressedasmean ±s.e.m. of the treatment-to-controlratio. 4Significantdifferencebetweenthe treatedandcontrol legsusingthe Wilcoxenmatchedpairedtest (p < 0.05).

MD32P (1.17%—1.20%). Both ‘2P-labeledmethylene diphosphonate and 99mTc..MDP show significantly higheruptake by healing bones as compared to the controls at 6and 14 days post-injury. This period is the most activebone-forming period. However, there is a differential uptake between 99mTclabeled MDP and 32P-labeled MDP:99m'f cuptake is significant only on the sixth day, while 32P

provides significant label on both 6 and 14 days post

injury. This difference may reflect the time differentialbetween matrix production which proceeds mineralizationduring bone forming.

An interesting question that arises from the study is thesite at which the hydrolysis of Tc-MDP occurs. The factthat 99mTcO alone is not taken up by bone indicates thatthe 99mTc@MDPmust arrive at the bone site intact in order

Days

FIGURE4. UptakeofMD32PafterinjectionofTc-MD@Pat3,6 and 14 days of tibial bone healing. The data are expressed asmean ±s.e.m.of the treatment-to-controlratio. *Signiflcantdifferencebetweenthe treatedandcontrol legsusingthe Wilcoxenmatchedpairedtest (p < 0.05).

01@

.4-,

C004.,

Ca,

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F-

107MDP Biodistribution in Bone Healing •Schwartz et al.

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22. Guillemart A, 12 Pape A, Galy G, Bensnard JC. Bone kinetics of45Ca and@Tc-PYP:an autoradiographic evaluation. J NuclMed l980;2l:466—470.

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26. Savelkoul TJF, OldenburgSi, Oort WJ, Van Duursma SA. Electrolyticallylabeled 99mTCMDp: chromatographic pattern, stability and biodistributionin rats. In! JAppi Radial Isot 1984;35:709—713.

27.BillinghurstMW,JetteD,AreenbergD.Determinationofoptimalconcentrations of stannous pyrophosphate for in vivo red blood cell labeling withtechnetium. mt J App! Radiat Isot 1980:31:499—504.

28. Claessens RAMJ. PhD thesis, Catholic University, Nijmegen, The Netherlands, 1982.

29. Van LangeveldeA, DriessenOMJ, PauwelsEKJ, Thesingh CW. Aspectsof@@mTcbinding from@ complexto bone. Eur J Nuc! Med 1977:2:47—51.

30. Chisin R, Gazit D, Ulmansky M, Laron A, Allan H, Sela J. Technetium99m-MDP uptake and histological changes during bone marrow regeneration. NudMed Biol l988;1 5:469—476.

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Haematol1975;3:I35—148.33. Shani J, Amir D, Soskolne WA, Schwartz z, Chisin R, Sela J. Correlations

between uptake oftechnetium, calcium, phosphate, and mineralization inrat tibialbone repair.JNuclMed 1990;3l:20l1—2014.

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108 The Journal of Nuclear Medicine •Vol. 34 •No. 1 •January 1993

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1993;34:104-108.J Nucl Med.   Zvi Schwartz, Jashovam Shani, W. Aubrey Soskolne, Haifa Touma, David Amir and Jona Sela 

P During Rat Tibial Bone Repair32Uptake and Biodistribution of Technetium-99m-MD

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