Technetlum-99m--Sn-Pyrophosphate Pharmaco Kinetics and Bone Image Changes In Parathyrold Disease

G. T. Krishnamurthy,A. S. Brickman,and W. H. Blahd

Veterans Administration Wadsworth Hospital Center and UCLA School of Medicine, Los Angeles, California

Skdetal abnormalities in 12 patients with primary , five patients with , and three patients with hypo parathyroidism were studied to compare the diagnostic sensitivity of bone radiologic examination to that of radionuclide studies using tamTc-Sn.pyro. phosphate (P9mTc-PP@) a skeletal-seeking radiopharmaceutical. The results were compared with bone mineral content as measured by the Norland Cameron densitometer. Kinetic data of the blood disappearance and plasma clearance of ssmTcpp. were obtained and compared with data of control subjects without evidence of parathyroid disease. Bone imaging with 99mTc PIJ@ may be more sensitive than routine skeletal radiographs and bone mineral analysis for the evaluation of skeletal abnormalities in patients with parathyroid disfunction. The enhancedpiasma clearance of the tracer observed in patients with primary hyperparathyroidism may reflect the direct effect of excessive on the renal handling of PsmTc-Sn@pyrophosphate. J Nuci Med 18: 236—242,1977

Bone imaging with 99'@Tc-labeled phosphate corn In the present studies scintillation imaging was per pounds has been employed most extensively for the formed with aamTc@Sn@pyrophosphate(oamTc@PPi). detection of metastatic bone lesions, primary bone Urinary excretion of unlabeled pyrophosphate has tumors, infections, Paget's disease, and other benign been reported to be increased in patients with pri lesions of bone (1—5). Application of these imaging mary hyperparathyroidism (7). Contradictory re techniques for the evaluation, diagnosis, and study sults, however, have been reported by others (8). of metabolic bone disease has been limited. The Thus, knowledge concerning the blood disappear present studies were undertaken to establish the role ance and renal clearance of 9omTc@PPj may be of of bone imaging in determining bone abnormalities diagnostic value. in patients with primary hyperparathyroidism, hypo parathyroidism, and pseudohypoparathyroidisrn. In MATERIALS AND METHODS a large series of patients, skeletal radiographs in dicated that focal skeletal lesions (e.g., Brown The specific parathyroid disorder in each patient was established by clinical, biochemical, and radio tumors, cysts, cortical or subperiosteal resorption) occur in approximately 10% of patients with pri logic evaluation, including RIA determination of mary hyperparathyroidism whereas less specific ab serum parathormone levels. Twelve patients with normalities such as generalized demineralization may be found in 30% (6) . A comparison of the rela tive sensitivity of bone roentgenography to that of Received June 21, 1976; revision accepted Nov. 24, 1976. bone imaging in the study of metabolic bone disease For reprints contact: G. T. Krishnamurthy, Nuclear Mcdi cine Service (691/172A), Veterans Administration Wads may provide additional information. worth Hospital Center, Los Angeles, CA 90073.

236 JOURNAL OF NUCLEAR MEDICINE DIAGNOSTIC NUCLEAR MEDICINE primary hyperparathyroidism were studied. Seven Blood and urine samples were collected as de of these were confirmed by histologic examination of scribed elsewhere (10—12). Plasma clearance of the lesion and the remaining five patients by gener 99@'Tc-PP1was calculated by means of the standard ally accepted criteria for the diagnosis of primary clearance formula. Urine was collected hourly for hyperparathyroidism (including hypercalcemia, ele 4 hr. For calculationof clearanceduringthe first vated parathyroid hormone levels, abnormal re hour, the plasma count at 30 mm was used. For cal sponses to oral orthophosphate loading, and histo culation of clearance at the end of the 2nd, 3rd, and logic evidence of hyperparathyroidism from iliac 4th hours, the mean plasma counts at the beginning crest bone biopsy) . Three patients had developed and end of the hour were used. following surgery for either thy Bone roentgenograms and scintillation camera im roid or parathyroid disease (Table I ) . The duration ages were interpreted independently by the radiolo of hypoparathyroidism in these patients ranged from gists and the authors; the readers were informed of 7 to I 1 years. Each was maintained in a normocal the possible clinical diagnosis of metabolic bone dis cemic state with regular doses of 100,000—200,000 ease. Such specific skeletal abnormalities as cyst units of vitamin D2 and oral calcium supplements, and sub-periosteal resorption and such nonspecific but all had been off treatment for 1—3months at the changes as diffuse demineralization were sought for time of bone imaging and kinetics studies. In five (Table 1) . The control group consisted of six pa patients with pseudohypoparathyroidism (Table 1), tients with histologically proven malignant soft-tissue the diagnosis had been confirmed by clinical features tumors and with normal serum levels of calcium, (hypocalcemia, elevated serum PTH levels, brachy phosphorus, and alkaline phosphatase. The serum dactyly) or the failure to enhance urinary excretion parathormone levels were not measured in these of 3',S'-cyclic adenosine monophosphate during an patients, but there was no clinical or biochemical infusion of parathyroid extract. None of these pa evidence to suspect any parathyroid disease. All had tients was under vitamin D therapy at the time of normal renal function bone images, and there was these studies. no uptake of O9mTcpp1 by the primary tumor. The Bone mineral content was evaluated by means of blood disappearance and urinary excretion of aamTc@ the Norland—Cameron bone mineral analyzer. lo PP1 were also compared with four other patients, dine-125 (400 mCi) was used as the external radia who resembled the control group of patients in every tion source. Radiation, collimated to 3 mm, was respect but who in addition had metastatic lesions passed through the radius of the nondominant arm in the bone. Blood and urine clearance values were and detected on the other side of the radius with the tested by Student's t-test for statistical significance. scintillation detector. The selected arm was reposi tioned, studied two or three times, and a mean value RESULTS was calculated. Bone mineral content (gm/cm) and The clinical, biochemical, radiologic, and histo bone width (cm) were measured and their ratio logic findings in each patient are shown in Table 1. (gm/cm2) used for analysis. These results were com Eleven of 12 patients with primary hyperparathy pared with the normal values for age- and sex roidism had hypercalcemia and most of them had matched American Caucasians and considered abnor hypophosphatemia with an elevation of serum PTH. mal if a measurement fell below the 95 % confidence Of the seven patients who underwent parathyroid limit (9). surgery, four had single adenomas and three had Bone roentgenograms were obtained in all pa parathyroid hyperplasia. Five of the patients had tients. Whole-body bone images were obtained with definite elevations of alkaline phosphatase and two a scintillation camera fitted with a Div/Con collima were at the upper limits of normal. Five patients tor, with the diverging side towards the patient, 2—3 showed generalized demineralization of bone, one hr after intravenous injection of I 5 mCi of aOmTc.. patient had subperiosteal resorption in the metacar PP1. Anterior and lateral views of the skull and pals, while the remaining six patients had normal mandible, and anterior views of the feet and hands bone radiologic studies. In seven patients, focal bone were obtained; 300,000 counts were accumulated for lesions were shown by the scintillation camera im each view. The bone images were subjectively ages, and five of these patients had no corresponding graded: 1+ being equal to normal uptake; 2+, lesions by radiographic studies. The majority of le slightly increased; and 3+, markedly increased in sions were confined to distal parts of the extremities, comparison with the normal adjacent bone or the skull, and jaw bones (Table 1). contralateral normal site. A grade of zero indicated In five of 11 hyperparathyroid patients, bone mm decreased uptake. Bone uptake intensity was visually eral content in the distal third of the radius was re compared to the kidney intensity. duced compared with age- and sex-matched controls.

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TABLE 1. BIOCHEMICAL, RADIOLOGIC, HISTOLOGIC, BONE MINERAL, AND BONE IMAGE CHANGES IN PARATHYROID DISEASE

phorus line calcium (mg/dl) (mg/dl) PTH phos (distal Pt. Sex/ (8.8— (3.0— (<0.3 phatase TRP radius) No.Age/ RaceCalcium10.5)Phos 5.0)Alkang/ml)findingsPRIMARYHYPERPARAThYROIDISMHyperplasia,(30—85)Bone(>75%) (gm/cm5) RadiographsRadionuclideimagesSurgical

1 53/M/C 11.60 2.0 135 180 65 0.75(N) Subperiosteal Abnormal Z. E. resorption- hands++ Deminerol izatlon 2 55/M/C 11.80 2.5 0.83 85 55 0.70(L) Normal Abnormal Adenoma hands ++ 3 51/F/C 12.50 2.6 0.40 70 67 — Demineral- Abnormal, left Adenoma, Ca ization radius +++ maxillary sinus M-P joint of rt thumb ++ 4 47/M/C 11.90 4.0 076 70 86 0.89(N) Demineral Abnormal man- Refusedsurgery ization dible -f--j--j 5 58/M/C 10.80 3.4 0.62 58 88 0J8(L) Demineral Normal Surgery pending ization 6 34/M/C 1070 3.6 0.35 80 80 0.85(N) Normal Abnormal man- Furtherfollowup dible -j--j--j maxilla ++ 7 25/M/C 10.00 2.7 0.70 65 84 0.85(N) Normal Normal Furtherfollowup 8 69/M/B 10.70 3.6 0.86 90 82 0.72(N) Normal Abnormal basal Hyperplasia skull ++ Pseudogout hands ++ 9 43/M/C 11.50 2.0 0.60 95 — 077(N) Normal Normal Hyperplasia, Z. E. 10 47/F/B 12.40 3.0 — 105 54 0.54(L) Normal Normal Further followup 11 52/F/C 11.20 2.9 0.70 120 — 0.55(N) Normal Abnormal Adenoma hands++ 12 61/F/C 11.40 3.0 0.42 85 74 0.45(L) Demineral Normal Adenoma Ization PSEUDOHYPOPARAThYROIDISM

135/M/C6.04.50.95160 91 0.82(N) ShortAbnormalcarpalhandsmeta +++bonesfeet ++234/F/C7.9400.5570 92 0.73(N) Demineral izationNormal327/F/C8.54.20.4570 89 0.71(N) NormalAbnormal ++436/F/C7.95.00.63105 hands 87 0.58(L) Short meta ++516/F/C9.04.50.4155 carpal hands bonesAbnormal 93 0.53(L) Short meta. ++HYPOPARAThYROIDISM145/M/B6.55.1Undetectable40 carpal hands bonesAbnormal

91 0.52(L) NormalNormalParathyroid adenoma Postsurgicalhypo parathyroidism255/F/B7.58.4Undetectable35 87 0.40(L) NormalAbnormal man dible ++ Postsurgicalhypo parathyroidism351 (L)thumb +++ (1)big toeThyroidectomy /M/C6.04.9Undetectable55 90 0.69(N) NormalNormalThyroidectomy Postsurgicalhypo parathyroidism

C = Caucasian TRP= Tubular reabsorptionof phosphorus B = Black L = Low PTH parathormone N Normal bone mineral for age- and sex-matchedcontrols S Serum PTH levels were measured through the courtesy of W. Fred Singer, The University of Southern California School of Medicine.

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The plasma clearance of a9mTc@PP1was relatively increased in patients with primary hyperparathyroid ism in comparison with the control patients. The difference was more obvious during the first hour: 54.7 ±11.6 mi/mm in primary hyperparathyroidism versus 38.6 ±9.6 ml/min in control subjects. The differences between the two groups, however, were not statistically significant (Table 2).

DISCUSSION The original description of primary hyperparathy roidism emphasized the presence of skeletal abnor malities. With the recognition of the broad clinical spectrum of this disorder, the incidence of roentgeno graphically recognizable bone disease associated with the biochemical manifestations of hyperparathyroid HOURS P0ST-lNJECT@N ism has diminished. This has been, in large part, related to the insensitivity of the techniques em FIG.1. Blooddisappearanceof @Tc-Sn-pyrophosphatein pa ployed to evaluate bony abnormalities. Thus, in three tientswith parathyrolddisease.Bloodlevelsare identicalfor all series of patients with primary hyperparathyroid groups of patients. (Number of patients in each group indicated within parenthesis.) ism, the incidence of x-ray abnormalities attnbuta ble to hyperparathyroidism ranged from 10 to 33% All five patients with pseudohypoparathyroidism had (6,13,14). The significance of the finding of osteo elevated PTH levels, and four had hypocalcemia. penia in patients with primary hyperparathyroidism The fifth patient was normocalcemic but had an ab is even less clear. Other workers have emphasized the normal response to parathyroid extract. In two of these patients, alkaline phosphatase levels were ele vated. Two patients had radiologic evidence of brachydactyly and one had generalized demineraliza HYPO-P (3) tion. Bone image abnormalities in four of five pa PSEUDOHYPO•-P (5) tients were found mainly in the hands at the pen PRIMARYHVPER-P(9) CONTROL(6) articular regions. 0 40 METASTATICBONEDISEASE(4) w The three patients with hypoparathynoidism had I- Id hypocalcemia at the time of the study. Bone radio 0 x logic studies were normal and only one patient Id showed bone image abnormalities. The lesions were confined primarily to the mandible and the periar 8 I- z ticulan regions of the big toe and thumb. Id 0 Blood radioactivity disappearance curves follow Id ing intravenous injection of D9mTc_PP1were similar A. for all groups of patients (Fig. I ). The urinary ex 2 cretion of OQmTc..pp1,however, was relatively in HOURS POST-INJECTION creased in those patients with primary hyperparathy FIG.2. Urinaryexcretionof‘mTc.Sn-pyrophosphatein patients roidism and pseudohypoparathyroidism compared with parathyroid disease. Relatively increased urinary excretion in patientswith primaryhyperparathyroidismand pseudohypopara with the controls (normal bone) (Fig. 2), and it was thyroidism is statistically significant (p < 0.05) in comparison to significantly increased compared to the four patients patients with metastafic bone disease who had normal serum cal cium. (Number of patients in each group indicated within paren with metastatic bone disease (p < 0.05). thesis.)

PLASMAGroupTimeTABLE 2. TECHNETIUM-99 CLEARANCE(mI/mm) FR AFTERm-PYROPHOSPHATEA SINGLEINJECTION(mean ± s.c.m.)OM

inlection0-.lhr1—2hr2—3hr3-.4hrPrimary after

hyperparathyrodism(n 9)54.7 ±11.6 ±5.1 ±3.2 ±6.1 Control(n 5)= 38.6 ± 9.640.9 313 ±3.526.1 25.3 ±3.623.2 28.4 ±42

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subjective nature of this radiologic finding (14). More recently, the use of bone mineral analysis em ploying photon densitornetry has revealed varying degrees of skeletal mineral abnormality in patients with primary hyperparathyroidism. One study re vealed an incidence of 50% ( 14 ) , while in our small series four of eleven patients ( 36% ) had low bone mineral. Finally, the incidence of histologic abnor malities on bone biopsy which is considered con sistent with excess parathyroid hormone activity is much greater than the bone lesions detected by roentgenography, or than the measurement of serum alkaline phosphatase. In more than 90% of patients B with proven or suspected hyperparathyroidism, ab normal findings have been reported by several in vestigators employing a combination of qualitative techniques or quantitative histologic methods (13, 15—17). In the present studies, only one of 12 patients with @ primary hyperparathyroidism had evidence of in :IF@ creased subperiorsteal resorption by routine radio graphs. This patient had the highest alkaline phos phatase value of the group. In contrast, seven of the FIG. 3. (A) Wristand handradiographsof patientwith para remaining patients had distinctly abnormal findings thyroid adenoma shows normal bone architecture (Patient 3 in on bone imaging with [email protected] of these pa Table 1). (B) Bone image study showstwo focal areas of increased uptake, over distal end of left radius (marked increase, 3+) and tients had alkaline phosphatase values in the normal over proximal end of metacarpal bone of right thumb (slight in range, and four had normal values for bone mineral crease, 2+). content. In the entire group of 12 patients, I 0 had evidence of skeletal disease by radiologic examina by two other groups of investigators (18,19) . The tion, bone densitometry, or skeletal imaging. The skeletal distribution pattern of lesions in parathyroid latter technique appeared to be the most sensitive disorders differs from that of metastatic bone disease for this group of patients. Figure 3A shows a nor where the lesions are more often found in the axial mal radiograph of the wrist and hand of a patient skeleton, especially the vertebral bodies, pelvis, and with primary hyperparathyroidism : Fig. 3B showed the proximal bones of the upper and lower extremi focal lesions in the radionuclide image of the left ties. The peripheral distribution of bone lesions in radius and the right metacarpal bones of the same parathyroid disorders also differs from the distribu patient. tion of lesions in patients with rheumatoid, psoriatic, Four of the five patients with pseudohypopara and gouty arthritis in that it is focal and asymmetric thyroidism and one of the three patients with hypo (20) . In arthritis the concentrationof radioactive parathyroidism showed skeletal abnormalities by tracer is due mainly to the inflamed synovial mem radionuclide imaging. Only two patients with pseu brane in the involved joints (21 ) . Some patients with dohypoparathyroidism, however, and no patients parathyroid disease, however, may show periarticular with hypoparathyroidism had roentgenographically uptake resembling the changes seen in arthritis (Fig. demonstrable lesions. The bone mineral content was 4) . Generalized increased uptake is often observed reduced in three of five patients with pseudohypo in patients with secondary hyperparathyroidism, but parathyroidism and one of three patients with hy this feature was not commonly seen in our patients poparathyroidism. Even in this small group of pa with primary hyperparathyroidism. Focal abnormal tients bone imaging detected more lesions than the ity was the predominant feature. other two diagnostic tests. Technetium-99m-pyrophosphate is avidly taken Most of the skeletal abnormalities detected in the up by both organic and mineral bone matrix, espe radionuclide studies in these patients with parathy cially by the immature collagen of the organic phase roid disorders were located in the peripheral parts during bone formation (21 ) . Local vascularity also of the body: the distal areas of both the lower and plays a significant role. Parathormone has varied upper extremities, mandible, and the bones of the biologic effects on bone in man: increasing activa skull. Similar patterns of distribution were reported tion of osteoprogenator cells; inhibiting modulation

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tients, the increased plasma clearance can be attrib L R uted to increased urine excretion (Fig. 2 ) . This may be appreciated better by comparing the kinetic data of the hyperparathyroid patients with the patients who had metastases. The increased urinary excretion in patients with hyperparathyroidism can be attrib uted primarily to increased parathormone levels, in the metastatic group of patients there was no reason to suspect an abnormal parathormone levels. The increased urinary excretion of 99@'Tc-PP1found in patients with pseudohypoparathyroidism is diffi cult to interpret. Plasma clearance was not measured FIG.4. Imagesofpatientwithpseudohypoparathyroidismshow in these patients. Classically, these patients are typical brachydactily of metacarpal bone. Note also increased pen known to have end organ resistance to PTH and articulan uptake over many metacarpophalangial and interphalangial joints. one would anticipate a normal or decreased urinary excretion of phosphates to PTH infusion. The addi tion of tin to the pyrophosphate complex may have of osteoclasts to osteoblasts; increasing the activity played a role in altering the excretion pattern of the of pre-existing osteoclasts; and inhibiting pre-existing aAmTc..Sn..pyrophosphate. The excretion of 99mTc.. osteoblastic activity. PP1in patients with hypoparathyroidism and controls After a prolonged continuous increase in serum was similar. One may infer therefore that the elevated parathormone a secondary rise in the osteoblast pool serum parathormone will increase urinary excretion often occurs (22 ) . This secondary rise in the osteo of 9amTc@PP1. blast pooi, however, usually fails to maintain normal mineral balance and the skeleton enters into a nega ACKNOWLEDGMENT tive balance. As reflected by increased urinary ex This study was supported in part by VA Research Project cretion of hydroxyproline (21 ), both animals and 5052-06. humans with hyperparathyroidism, rickets, osteo malacia, and Paget's disease have increased collagen REFERENCES turnover. This new collagen has a special affinity for 1. SUBRAMANIAN0, MCAFEE JG : A new complex @@mTc 9AmTc.pp1,which results in “hot―spots in bone im for skeletal imaging. Radiology 99: 192—196,1971 aging studies. The appearance of “hot―spots in one 2. SUBRAMANIANG, MCAFEE JG, BELL EG, et al. : mmTc@ of the three patients with hypoparathyroidism was an labelled polyphosphate as a skeletal imaging agent. Radi ology102:701—704,1972 unexpected result. The overall rate of skeletal re 3. SUBRAMANIANG, MCAFEE JG, BLAIRRJ, et al. : @mTc modeling is very much decreased in hypoparathyroid EHDP: A potential radiopharmaceutical for skeletal imag ism. Untreated chronic hypoparathyroidism patients ing.JNuclMed 13:947—950,1972 manifest a small net increase in bone formation over 4. CASTRONOVOFP, CALLAHANRJ: New bone scanning bone resorption at the endosteal surface due to mod agent: mmTc-labeled1-hydroxy-ethylidene-1,1-disodium phos phonate.JNuclMed 13:823—827,1972 ulation of osteoclasts to osteoblasts (22 ). This slight 5. PEREZR, COHENY, HENRYR, et al.: A new radio increase in osteoblastic activity may explain the in pharmaceutical for “mTcbone scanning. J Nuci Med 13: creased radioactive tracer uptake noted in the pa 788—789,1972 tient with hypoparathyroidism (Table 1). 6. KEATINGFR: Diagnosis of primary hyperparathyroid Blood disappearance curves following injection of ism.JAMA 178:547—555,1961 7. AvIOLI LV, MCDONALD JE, SINGER RA: Excretion OOmTc..pp1were similar for all groups of patients of pyrophosphate in disorders of bone metabolism. I Clin (Fig. 1) . A tendency towards increased urinary ex EndocrinolMetab 25:912—915,1965 cretion of 99@'Tc-PP1,however, was seen in patients 8. RUSSELLROG, HODOKINSONA : The urinary excre with primary hyperparathyroidism and pseudohypo tion of inorganic pyrophosphate in hyperparathyroidism, parathyroidism, all of whom had raised levels of hyperthyroidism, Paget's disease and other disorders of bone metabolism. Clin Sci 36: 435—443,1969 serum parathormone (Fig. 2). 9. MAZESSRB, CAMERONJR: Bone mineral content in The plasma clearance rate of 99mTc_PP1was rela normal U.S. whites. In International Conference on Bone tively increased during the first 2 hr after intrave Mineral Measurement, Mazess RB, ed, Chicago, Oct. 12—13, nous administration in patients with primary hyper 1973. National Institute of Arthritic, Metabolic, and Diges parathyroidism in comparison to the controls. The tive Diseases, 1975, pp 230—237 difference was most apparent during the first hour 10. KRISHNAMURTHYGT, THOMASPB, TuBis M, et al.: Comparison of mmTc-polyphosphate and “F.I. Kinetics. (Table 2) . Since blood radioactivity levels were iden I Nuci Med 15: 832—836,1974 tical for primary hyperparathyroid and control pa II. KRISHNAMURTHYGT, TUBIS M, ENDow iS, et al.:

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Clinical comparison of the kinetics of @mTc-labeledpoly 16. BYERSPD, SMITh R: Quantitative histology and bone phosphate and disphosphonate. I Nuci Med 15: 848-855, in hyperparathyroidism. Q I Med 40: 471—486, 1971 1974 17. BECKERFO, EISENSTEINRE, SCHWARTZTB, et al.: 12. KRISHNAMURT}IYGT, HUEBOTrERRi, WALSHCF, et Needle bone biopsy in primary hyperparathyroidism. Arch al. : Kinetics of mmTc-labeled pyrophosphate and polyphos InternMed 131:650-656,1973 phate in man. I Nuci Med 16: 109—115,1975 18. ROSENThALL, KAYE M: Technetium-99m-pyrophos phate kinetics and imaging in metabolic bone disease. I Nuci 13. GORDONGS, EISENBERGE, LOKEN HF, et a1.: Clini Med 16:33—39,1975 cal endocrinology of parathyroid hormone excess. Recent 19. SY WM: Bone scan in primary hyperparathyroidism. ProgHorm Res 18:297—336,1962 INuciMed 15:1080—1091,1974 14. GENANTHK, HECK LL, LANZI LH, et al. : Primary 20. DESAULNIERSM, Fuics A, HAwKINS D, et al. : Radio hyperparathyroidism. A comprehensive study of clinical, technetium polyphosphate joint imaging. I Nuci Med 15: biochemical and radiotope manifestations. Radiology 109: 417—423, 1974 513—524,1973 21. KAYE M, SILVERSTONS, ROSENTHALLL: Technetium 15. JOWSEYJ: Bone in parathyroid disorders in man. In 99m-pyrophosphate: Studies in vivo and in vitro. I Nuci Talmage RV, Belander LF, eds, Parathyroid Hormone and Med 16: 40—45,1975 Thyrocakitonin. Proceedings of the Third Parathyroid Con 22. RASMUSSENH, BORDIERP: The cellular basisof ference. Excerpta Medica, p 137—151, 1968 metabolic bone disease. N Engi I Med 289: 25—32, 1973

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