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STRONTIUM AND CALCIUM METABOLISM INMETABOLIC BONE DISEASES

Elias C. Dow, John B. Stanbury

J Clin Invest. 1960;39(6):885-903. https://doi.org/10.1172/JCI104109.

Research Article

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STRONTIUMAND CALCIUM METABOLISMIN METABOLICBONEDISEASES*

By ELIAS C. DOWAND JOHN B. STANBURY

(From the Medical Services of the Massachusetts General Hospital and the Department ofMedicine of the Harvard Medical School, Boston, Mass.)

(Submitted for publication September 9, 1959; accepted February 19, 1960)

Skeletal and systemic disease may be reflectedin profound alterations of the metabolism of thebone salts. In human skeletal disease attentionhas focused, for the most part, on the altered me-tabolism of calcium. Several studies indicatethat strontium may have a metabolic pathway sim-ilar to that of calcium and that radiostrontium,because of its ease of measurement, might be aconvenient indicator for observing the transferof calcium through the calcium-containing com-partments of the body.

The investigations to be reported here are con-cerned with the comparative distribution and fateof calcium and strontium in subjects with alteredbone metabolism. Patients with thyroid andparathyroid disease, osteoporosis, and Paget'sdisease were studied after simultaneous intrave-nous administration of strontium85 and calcium45.The results indicate that Sr85 closely parallelsCa45 as an index of skeletal function.

MATERIALS AND METHODS

All patients (Table I) were on the Metabolic Re-search Ward, were ambulatory throughout the study,and spent a few hours out of doors each day with a nursein attendance. Each received a constant neutral ashdiet containing 88 to 206 mg of calcium per day (TableII). The calculated daily magnesium intake did notexceed 200 mg. Fluid intake was kept between 2,000and 2,500 ml per day. After a minimum of 7 days onthe fixed diet, a 3-day control collection of urine andfeces was obtained before administration of the labeledisotopes.

The dose of labeled calcium and strontium was pre-pared from hydrochloric acid stock solutions of Ca"C121of high specific activity, and from carrier-free Sr5'Cl,.2

* This work was done under Atomic Energy Commis-sion Contract AT(30-1)-1755.

1 Obtained from Oak Ridge. Cae emits only betarays of 0.100 Mev average energy and has a half-lifeof 163 days.

2 Produced by Nuclear Science and Engineering Corp.,Pittsburgh, Pa. Sr8' is a pure gamma emitter of 0.513Mev and has a half-life of 65 days.

Predetermined amounts of each isotope were measuredinto separate bottles and saline added so that concen-trations of 1 Ac Cae per ml and 2.5 juc Sr' per ml wereobtained. Equal volumes of each of these solutionswere combined to give a final solution containing 0.5

TABLE I

Clinical data

Name Age Sex Diagnosis

J.H.J-C. (I)J.C. (II)

L.L. (I)

L.L. (I I)

A.J. (I)

A.J. (I I)

A.J. (III)

42 F65 M65 M

Hyperthyroid (diffuse goiter)(Thyrotox.*)

Myxedema (Myx.)Myxedema (Myx.)Euthyroid (4 months on thy-

roid 120-150 mg q.d.) (Nor-mal after Rx)

59 F Follicular adenocarcinoma ofthyroid, metastatic to lungsand left pelvic bones andhip (Met. thyroid Ca)

38 F 3 Years after hemithyroidec-tomy for nontoxic nodulargoiter (Euthyroid)

72 M Hyperparathyroid; diabetesmellitus; myocardial infarct;pyelitis and ? renal stone(Hyperparathyr.)

31 M Progressive idiopathic osteo-porosis (parathyroid ex-ploration negative) (Osteo-porosis)

77 F Chronic osteoporosis (2 yearson estrogen therapy) (Osteo-porosis on Rx)

77 F Chronic osteoporosis (4 monthsoff therapy) (Osteoporosisoff Rx)

67 F Osteitis deformans involving(by X-ray) skull, pelvis andthoracic spine (Paget's)

64 M Osteitis deformans, exten-sive, involving skull, spine,pelvis and lower extremities(Paget's)

64 M Osteitis deformans, on cor-tisone acetate 300 mg q.d.(Paget's on cortisone)

65 M Osteitis deformans, on no ther-apy for 5 months (Paget's)

* Abbreviations are those used in subsequent tables.

ELIAS C. DOWAND JOHN B. STANBURY

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STRONTIUMAND CALCIUM METABOLISMIN BONEDISEASES

/Ac of Ca" and 1.25 ,uc Sr' per ml. Thus, the adminis-tered 10 ml dose delivered a total of 5 ,uc Cae and 12.5,uc Sr'5. Patients for whom only one study was in-tended were given double these amounts in the samevolume. The stable calcium (Ca) in each dose variedfrom 1 to 4 mg.

The prescribed dose was injected from a calibratedsyringe into an antecubital vein 2 hours before break-fast. Blood samples were obtained by venipuncturefrom the opposite arm at 5 and 30 minutes, 1, 2, 4, 6, 8,12, 16 and 32 hours, and daily thereafter. Urine col-lections were made at 0 to 2, 2 to 4 and 4 to 8 hours, andat 8-hour intervals thereafter until the third day, when24-hour collections were begun. Stool collections weremade without a marker in 3-day periods. Except asindicated, each patient was studied for a minimum of 21days.

Metabolic balances for stable calcium, phosphorus andnitrogen were measured according to methods previ-ously described (1). All determinations for calciumwere performed in duplicate on 2 different aliquots ofeach specimen.

Isotopic measurements. Since all samples containedboth Cae and Sr' in varying quantities, the following

method was employed to determine the amount of eachisotope in each specimen.

Sr"5 was measured directly in a well-type scintillationcounter equipped with a pulse-height analyzer. Thisapparatus had a background of 8 cpm, a counting effi-ciency of 16.4 per cent for Sr' (sensitivity = 360,000cpm per mc), and completely excluded radiation fromCa45. Duplicate samples of 2 ml of serum, acidifiedurine, and redissolved stool ash were measured for 10minutes and compared with standards made up from thesame Sr'5 solution as that used for the administereddose. There was a statistical counting error of 2 percent, except for specimens from the latter phases ofeach study, when the probable error of measurement ofSr'5 was as high as 6 per cent.

Specimens for the determination of Ca" were pre-pared by a modification of the method of Maletskos (1).It was repeatedly found that the Sr'5 present, as wellas the Ca', was completely recovered on the planchets.These planchets, containing both Ca" and Sr'5, werecounted in a gas-flow counter (SC-50 Tracerlab) whichhad an efficiency of 20.9 per cent (sensitivity=460,000cpm per mc) for Ca45 and only 1.46 per cent for Sr'5(sensitivity= 32,000 cpm per mc). Duplicate planchets

M.S. P 38 yrs. E THYYROID

CURVEANALYSIS

SERUMSr85 *SPECIFIC ACTIVITY"

K3 = .116 .017

A3 = 20.72 ± 2.59

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.5+K1a I11.91 _ 1.30

Al =43.2± l7.'

1 1 1~~~

1 2 3 4 .083 167 .250 .333

TIME (DA YS)

FIG. 1. ILLUSTRATION OF THE LINE REGRESSIONMETHODOF ANALYSIS APPLIED TO CA" AND SR'5 URINE AND SERUM

SPECIFIC ACTIVITY CURVESOF ALL SUBJECTS STUDIED. The solid lines were fitted to the data by method of least squares,

have a slope, k, and when extrapolated to zero time yield the respective coefficients, A. Note the different time scalefor III, II and I. Since the rate constants represent negative slopes, the value of k is negative.

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ELIAS C. DOWAND JOHN B. STANBURY

of each specimen were measured for a total of 4,000counts each three times over. Each run also includedstandards of Ca4", Sr"5, and a standard of Ca45 and Sr85made up directly from the administered dose.

When both labeled isotopes were measured in the gas-

flow counter, it was necessary to apply a correction forthe Sr85 in order to obtain a true value for Ca45. Fromthe total Sr85 counts per specimen in the -well counter andfrom the counting efficiency of the gas-flow counter forSr85, the counts from the gas-flow counter due to Sr85

alone could be calculated. A decay factor was employedwhen samples of the same specimens were counted inthe respective machines on different days. Subtractingthe Sr85 counts from the total counts of each sampleprovided the counts due to Ca45. A control on thismethod was made with every set of experimental samples.Predicted values of Sr85 standards varied less than 5 per

cent from the observed counts in the gas-flow counter.Likewise, the calculated radioactivity due to Ca45 instandards containing both isotopes was within 3 per

cent of the measured radioactivity of standards contain-ing Ca45 alone.

Concentrations of each labeled isotope were expressedas per cent administered dose per unit volume. Specificactivity was expressed as per cent administered dose per

gram of calcium. Since there were only trace amountsof strontium in the specimens analyzed, stable strontiumwas not determined. The "specific activity" of Sr' was

calculated as per cent administered dose of Sr'" per gram

of calcium.

Methods of analysis

In each case study, Ca45 and Sr85 data were analyzedseparately. Urine and serum specific activities were

plotted semilogarithmically against time. Inspection ofthese curves suggested resolution into at least 3 expo-

nential functions, each function possibly related to a dis-crete calcium compartment within the body. The term"compartment" is used to indicate a functional unit, butnot necessarily an anatomical one. The method of curve

analysis has been described elsewhere (1). The line re-

gression method of Snedecor (2) was used and is illus-trated in Figure 1. Each curve was analyzed in the form:

specific activity = Ale-kt + A2e-k2t + A3e-kst.

In an analysis of a theoretical multicompartmentedsystem the coefficient of each term, A, is a compositeof the compartment size of each component of the sys-

tem. Similarly the rate constant, k, is a composite term.If the assumption is made that compartment sizes andturnover times increase sequentially by an order ofmagnitude, then the coefficients and rate constants ap-

proximate those which actually obtain. Thus, the con-

stants shown in the equation above hold as approxima-tions, and rate constants and compartment sizes (I, II,and III) can be calculated (1).

Calcium "pool." The "pool" of calcium is defined as:

per cent isotope retained in the body at time, tspecific activity at time, t

DAYSOF 21 21 21 21 8 21 18 21 21 21 21 2118 1845

got FECES}C45~~~~~~~~~~~~~~~~URINEj

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EXCRETION 70 URINE

%ADMIN. DOSEOF ISOTOPE 60_

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THYROTOX. ' MYXEDEMA- ' MET EUTHY. HYPER- '-OSTEOPOROS.-' '-PAGET'S DISEASE.-'THYR. PARA-

CA. THYROID

FIG. 2. DIAGRAMMATICPLOT OF TOTAL CA45 AND SR85 EXCRETED AT TIMES INDICATED. Whole body retention in

each case can be easily judged by subtracting the total excretion of each isotope from 100 per cent, the administered

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When calculated for specific times the resulting curverepresents the ratio between the curve of isotope retentionand the specific activity curve. The dimension of thepool is in grams.

The calcium "pool" is a quantitative approximation ofthe amount of body calcium that has mixed with the ad-ministered labeled isotope at a specific time, and pro-vides a value for comparison of patients with differentbone diseases. Since the skeleton contains 99 per centof the total body calcium, calcium "pools"-especially atlater times-are related to the mass of bone that hasmixed. For each isotope, "pool" sizes based on urineand serum specific activities were determined at 3-dayintervals.

RESULTS

Isotopic excretion data. In all disease states andat all times, the patient retained more Ca45 thanSr85; the ratio of retention of Ca45 to that of Sr85varied from 1.1 to 5.7. Figure 2 and Tables IIIand IV show that 1.9 to 8.1 times more Sr85 thanCa45 appeared in the urine.

While renal excretion was the major route of

\ 30.0

Sr85 elimination, fecal loss of Sr85 was substantial.As much as 30 per cent of the administered dosewas lost by this route within the first 21 days. Onthe other hand, fecal losses of each isotope wereequal.

There was no correlation between the total la-beled calcium or strontium and the total stablecalcium excreted.

Specific activities. Urine and serum specific ac-tivity curves of characteristic form are illustratedin Figures 3 through 6. Initially, Sr85 "specificactivity" in the urine was three to eight timeslarger than that of Ca45. As each study pro-gressed, the difference between the two values de-creased so that the respective urine specific ac-tivity curves converged and in some cases inter-sected (Figure 5).

The serum specific activities for each labeledisotope were initially the same and fell close to-gether for at least the first 24 hours and in somecases for the next six days (Figure 4). There-

2 4 6 8 10 12 14TIME (DArYS

16 18 20 22

FIG. 3. CA' AND SR" URINE SPECIFIC ACTIVITIES PLOTTED SEMILOGARITHMICALLYAGAINST TIME FROMDATA OF SUBJECT E.S. WITH PAGET'S DISEASE OF BONE. It isevident that urine values of Sr" are distinctly higher than are Ca" values through-out the period of study.

E.S 6YRS. MGH*590546

PAGET'S DISEASE

URINE SPECIFIC ACTIVITIES°o C45

o° o Sr8500

0_. 0 0 00

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0 ~~~~~~~~~~~~~0- @0

- .~00 @ 0@ *

0 @ 0 0 00 0

2 4 6 8 10 12 14

T/ME (DAYS)

16 18 20 22

FIG. 4. CA"5 AND SR85 SERUM SPECIFIC ACTIVITIES PLOTTED SEMILOGARITHMICALLY AGAINST

TIME FROMDATA OF SUBJECT E.S. WITH PAGET'S DISEASE OF BONE. In contrast to urine curves,the curves here are very approximate, indicating that both isotopes were cleared from the se-

rum at similar rates.

after Sr85 values were increasingly lower so thatthe two curves diverged.

In all patients, Ca45 specific activities in the se-

rum were consistently greater than those in theurine at corresponding times (Table V). Theratio of serum to urine values differed in the vari-ous disease states. For euthyroid subjects, theratio was of the order of 1.30; in thyrotoxicosis,1.54; in myxedema, 1.18; and in the two patientswith Paget's disease, ratios of 1.77 and 3.86 were

found. In the patient with idiopathic progressiveosteoporosis, the ratio was 1.39; and in PatientL.L., who had osteoporosis of the "postmeno-pausal" type, a ratio of 1.80 (while receiving es-

trogen) fell to 1.49 after therapy was omitted.Rate constants, coefficients and compartment

sizes. There was no difference between the rateconstants for Ca45 and Sr85, either in first or sec-

ond exponential components of the serum or inurine curves (Table VI). In the third compo-

nent of the respective curves, Sr85 rate constantswere suggestively larger than Ca45 values.

Coefficients and compartment sizes varied sig-nificantly in the different disease states. The dif-ferences were largest in the third compartment.Third compartment data based on urine meas-

urements showed that Sr85 values paralleled thoseof Ca45 (Table VII). Compartment sizes basedon the serum curves were essentially the same foreach isotope in each individual case (Table VIII).

Calcium "pools." Expressing the data in termsof sequential pool sizes indicated the rapidity andextent to which either isotope entered the bodycalcium spaces. When the Ca45 data from urinemeasurements were employed, the "pool" sizes at

three-day intervals (Figure 7) were in goodagreement with those found in similar patientspreviously reported from this laboratory (1).Table IX demonstrates that the "pool sizes"based on serum specific activities were similar for

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PAGET'S DISEASE

SERUMSPECIFIC ACTIVITIESB * Ca 45

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both Ca45 and Sr85 in each patient. At specifictimes the pool sizes by either isotope varied sig-nificantly among the different disease states.

Paget's disease. The largest retention of eitherisotope was seen in the patients with Paget's dis-ease. Even at the end of 45 days, Patient A.J.(III) had excreted only 18.1 per cent of the ad-ministered Sr85. Furthermore, in Paget's diseasethe body retention curves of both isotopes werequite similar. The ratio of Ca45 to Sr85 retentionnever exceeded 1.1: 1. Specific activities of se-rum, urine and feces were lowest, and compart-ment sizes and calcium "pools" were the largestobserved among the patients studied.

A three-week Ca45 study was performed before(A.J. I) and ten days after institution of corti-sone (A.J. II). While cortisone did not sig-nificantly alter the serum chemical determinationsas shown in Table II, or detectably alter thyroidfunction, after eight days on therapy the cardiac

2 4 6 8 10 12 14

TIME (DAYS)

index 3 fell from a control value of 9.9 to 4.6,and daily urinary calcium excretion was reduced30 per cent. Cortisone caused no dramatic changein Ca45 kinetics. Although the drug seemed tocause a moderate reduction in urine Ca45, com-partment sizes and calcium "pools," all of theseparameters remained decidedly abnormal.

Thyroid and parathyroid disorders. Skeletalkinetics as measured by either isotope proved sen-sitive to the level of thyroid function (Tables VII,VIII, IX). Large compartment sizes and cal-cium "pools" were found in thyrotoxicosis, andlow values in myxedema. The expected changein these parameters (based on Sr85 data) was notfound when Patient J.C. was restudied after treat-

3 The cardiac index is the cardiac output in liters perminute per square meter of body surface by the dye dilu-tion technique. We are indebted to Dr. Lewis Dexter,of the Peter Bent Brigham Hospital, and his laboratorystaff for doing these procedures.

16 18 20 22

FIG. 5. CA' AND SR' URINE SPECIFIC ACTIVITIES PLOTTED SEMILOGARITHMICALLY AGAINST

TIME FROMDATA OF SUBJECTJ.H. WITH MYXEDEMA. Due to differences in rates of excretion ofthe two isotopes, the curves intersect at the end of the study.

J.H. 42 YRS. MGH*993043

MYXEDEMA

o0 URINE SPECIFIC ACTIVITIES00

C 450 0 *Co4a

- 0 o Sr85_ 0

0 0F 0

*0 0.00 0 0.@0.0 000 000@0.0

0 000 0 0@0 0 0*

0"" " o O o o

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SERUMSPECIFIC* Co45o Sr85

MGH*993043

ACTIVITIES

0 0 0.0

1 1 1 12 4 6 8 1O 12 14

TIME (DAYS)16 18 20 22

FIG. 6. CA" AND SR' SPECIFIC ACTIVITIES PLOTTED SEMILOGARITHMICALLY AGAINST TIME FROM

DATA OF SUBJECT J.H. WITH MYXEDEMA. Early divergence of the two curves indicates thatSr' is more rapidly cleared from the serum. Contrast with Paget's disease, Figure 4.

ment for his myxedema. Simple gross isotopicretention values did not discriminate between thy-rotoxicosis and myxedema. Each isotope was re-

tained to about the same degree in both diseasestates.

Patient E.H., with thyroid cancer metastaticto several bone areas, showed no evidence of in-creased calcium turnover by any of the criteriaemployed. Also, the data obtained in J.W., whohad hyperparathyroidism but no clinical evidenceof bone disease, appeared normal. In both ofthese cases serum alkaline phosphatase concen-

trations were repeatedly normal.Osteoporosis. The two patients with osteoporo-

sis showed no unusual pattern of excretion ofstable or labeled calcium or strontium. AlthoughPatient L.L., a postmenopausal female with clini-cally static disease, had lower compartment sizesand calcium "pools," Patient A.L., with progres-

sive active osteoporosis, displayed values similarto those of the euthyroid controls.

Patient L.L. was restudied four months aftercessation of estrogen therapy. Despite a definiteincrease in the output of stable and labeled cal-cium in the urine, specific activity curves retainedthe same appearance, compartment sizes were un-

changed, and the calcium "pool" curves were prac-

tically superimposable on those obtained when thepatient was receiving therapy.

DISCUSSION

Interest in the physiological similarity of stron-tium to calcium began in 1870 when Papillon (3)reported that a "certain amount" of this elementcould be substituted for the calcium normallypresent in bone. A few years later Konig (4)found that ingested strontium was deposited inbone. In 1883, Ringer and Sainsbury (5) dem-onstrated that strontium was similar to calciumion in its action on the contractility of the ven-

tricle of the frog's heart. Subsequently it hasbeen found that strontium prevents and con-

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trols parathyroid tetany (6), stimulates activity ofthe uterus (7) and is effective in blood clotting (8).

Although the human skeleton contains onlytraces of strontium (9, 10), under suitable cir-cumstances it can store appreciable amounts ofthis element (11, 12). As with calcium, virtuallyall deposition takes place in bone. Furthermore,the movement of strontium in and out of the skel-eton parallels that of calcium under the influenceof such agents as parathyroid hormone and vita-min D (13-15). Strontium, a divalent ion ofsimilar ionic radius (1.13 A compared with0.99 A for calcium ion), exchanges heterionicallywith calcium on an equimolar basis and is in-corporated into the crystals of bone (16). Aswith calcium, strontium deposition is not uniform

but varies in different bones and in differentparts of the same bone, the greatest concentrationbeing invariably in areas of active growth and re-

cent mineralization (17-19).Despite these similarities strontium cannot

serve the purpose of lime salt in bone. Shipley andPark, extending Lehnerdt's earlier work (20),showed that when strontium completely replacescalcium in an otherwise adequate diet, "stron-tium" rickets develops (21). Von Hodel's findingthat strontium is preferentially excreted by thekidney has been confirmed many times (22).Gastrointestinal absorption seems to favor calciumover strontium by a factor of about 2 (23).Nevertheless, by eliminating the kidneys andminimizing the role of the gastrointestinal system

TABLE V

Ca4" serum to urine specific activity ratios*

Ca45 specific activity, Ca45 specific activity, RatioPatient serum urine Serum/urine

W.B. 1.99 A 0.14 1.29 41 0.03 1.54 41 0.11(Thyrotox.)

J.H. 15.53 41 0.28 13.18 14 0.22 1.18 := 0.03(Myx.)J.C. (I) 8.09 4 0.32 6.24 1 0.27 1.30 :1: 0.07(Myx.)J.C. (II) 8.89 :1 0.33 3.93 41 0.09 2.26 1= 0.10(Normal after Rx)

E.H. 7.35 4 0.23 5.77 i4 0.14 1.27 :1 0.05(Met. thyroid Ca)

M.S. 9.44 4= 0.16 7.76 :1= 0.54 1.22 4 0.09(Euthyroid)

J.W. 4.72 J= 0.21 3.16 ± 0.05 1.49 :1: 0.07(Hyperparathyr.)

A.L. 4.58 i 0.30 3.29 0.06 1.39 -1 0.09(Osteoporosis)

L.L. (I) 11.30 1 0.29 6.29 4= 0.20 1.80 :1: 0.07(Osteoporosis on Rx)

L.L. (II) 10.21 4 0.30 6.83 i= 0.21 1.49 41= 0.06(Osteoporosis off Rx)

E.S. 0.993 :1 0.01 0.562 1= 0.03 1.77 a= 0.10(Paget's)

A.J. (I) 1.66 4 0.16 0.430 41 0.01 3.86 4= 0.38(Paget's)

A.J. (I I) 2.12 4= 0.39 0.624 4= 0.05 3.40 4 0.70(Paget's on cortisone)

* The Ca45 serum and urine specific activity values are determined at Day 13 which represents the average time (t)of the period corresponding to the third phase of the individual curves (Days 5 to 21). The differences between serumand urine values in each case are significant (p < 0.01).

896 ELIAS C. DOWAND JOHN B. STANBURY

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in experimental animals, MacDonald, Noyes andLarick were able to show that the skeleton per se

was not able to discriminate between trace amountsof calcium and strontium (24).

Present considerations. The present studieswere designed with the above considerations inmind. The use of Sr85 and Ca45 of high specificactivity eliminated distortions due to unphysio-logical amounts of test material. Selecting the in-travenous route for administration minimized therole of the gastrointestinal system, and adminis-tration of both isotopes simultaneously permittedcomparative study of each in the same patient atthe same time.

The findings reported here are not in fullagreement with those of McCance and Widdow-

son (25), nor with those of Harrison, Raymondand Tretheway (26). Those studies, based on

administration of larger amounts of stable stron-tium, showed fecal excretion of strontium to beminimal. Although fecal excretion of Ca45 andSr85 did not vary greatly among the patients stud-ied here, except in those with Paget's disease, theamounts of each labeled isotope eliminated by thisroute were sizable and could neither be ignorednor considered constant. The renal excretion dataare in good agreement with the many animal andhuman studies already reported (23, 24, 27-29)and indicate that the ratio of renal clearance ofstrontium to calcium is about 5.

Whole body retention values of either Sr85 or

Ca45 did not provide a suitable index of skeletal

TABLE VII

Compartment size (grams) based on urine coefficientsI~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

I II III

Patient Ca Sr Ca Sr Ca Sr

W.B. 2.74 0.571 5.45 1.14 22.42 5.07(Thyrotox.)

J.H. 1.32 0.281 2.42 0.383 3.53 0.980(Myx.)J.C. (I) 1.49 0.515 3.09 1.11 6.64 2.39(Myx.)

J.C. (II) 2.64 0.339 4.60 0.536 10.82 1.98(Normal after Rx)

E.H. 1.49 3.12 4.78(Met. thyroid Ca)

M.S. 1.63 0.249 4.32 0.398 4.66 0.556(Euthyroid)

J.W. 2.24 0.683 5.19 1.03 13.07 3.94(Hyperparathyr.)

A.L. 3.13 0.638 6.56 0.960 12.11 3.38(Osteoporosis)

L.L. (I) 1.98 0.227 3.66 0.459 7.49 1.54(Osteoporosis on Rx)

L.L. (II) 1.59 0.262 2.59 0.694 5.59 1.37(Osteoporosis off Rx)

E.S. 4.55 0.756 29.06 2.37 123.30 15.80(Paget's)

A.J. (I) 7.13 44.76 174.2(Paget's)

A.J. (II) 8.65 30.56 131.23(Paget's on cortisone)

A.J. (III) 1.31 6.41 44.25(Paget's)

TABLE VIII

Compartment size (grams) based on serum coefficients

I II III

Patient Ca Sr Ca Sr Ca Sr

W.B. 1.51 1.39 4.48 3.36 16.18 17.57(Thyrotox.)

J.H. 1.11 1.00 2.47 1.75 3.36 3.55(Myx.)

J-C. (I) 1.13 1.17 2.95 2.42 5.05 7.19(Myx.)J.C. (II) 1.31 1.15 2.73 2.58 5.05 6.25(Normal after Rx)

E.H. 0.969 1.78 3.05(Met. thyroid Ca)

M.S. 1.55 1.116 2.89 2.32 4.41 4.83(Euthyroid)

J.W. 2.59 2.57 6.55 5.23 12.27 13.00(Hyperparathyr.)

A.L. 2.45 1.56 5.20 4.24 10.57 14.84(Osteoporosis)

L.L. (I) 0.928 1.11 2.38 2.76 5.49 5.96(Osteoporosis on Rx)

L.L. (II) 0.712 0.945 2.27 2.91 4.50 6.94(Osteoporosis off Rx)

E.S. 2.46 2.64 9.43 13.50 64.52 91.74(Paget's)

A.J. (I) 2.82 22.17 44.44(Paget's)

A.J. (II) 2.35 14.62 26.32(Paget's on cortisone)

A.J. (III) 3.43 22.57 156.01(Paget's)

function, except in Paget's disease. Retention ofthese two elements is a resultant of three mainprocesses, viz., skeletal uptake, renal excretionand fecal elimination. In Paget's disease, skeletaluptake is exaggerated to the extent that relativelylittle of either labeled isotope is available for ex-

cretion. The kidneys compete more successfullywith the skeleton in thyrotoxic patients thanin the normal subjects, in clearing calcium andstrontium from the serum. The result is a nor-

mal or low body retention. In myxedema, re-

duced skeletal uptake permits the excretory mech-anisms more opportunity to clear the serum and,therefore, as in thyrotoxicosis but for differentreasons, the body retention values are similarlylow.

Spencer, Laszlo and Brothers found the plasmalevel of Ca45 higher than that of Sr85 throughouta 12-day study in a patient to whom both iso-topes were administered orally. Blood data forthe first 24 hours were not presented in their re-port (23). Norris and Kisielski, on the otherhand, found that the blood concentrations of Sr89remained above those of Ca45 in mice receivingtracers intravenously (30).

In all of the present studies the concentrationsof Sr"5 and Ca45 in the serum were equal for atleast the first 24 hours. In Paget's disease, whereboth isotopes were cleared from the serum pri-marily by exaggerated skeletal uptake, the serumvalues of each isotope remained equal for at leastsix days and differed only slightly thereafter

IOOO.0

CALCIUM"POOL" CURVESUSING Ca45BASED ON URINE SPECIFIC ACTIVITIES

300.0_A.J. I PAGET'SE.S. PAGET'SA.J. X PAGET'S ON

CORTISONE

i 100.0 W.B. THYROTOXICOSIS

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4 L.L. I OSTEOPOR.ON 1RsL.LO . ONFZ

10.0 J.C. I MYXEDEMA

J.H. MYXEDEMA

1.03 6 9 12 15 18 21

TIME (DA YS)

FIG7CALCIUM "POOL" IN GRAMS. Per cent Ca4" remaining in body at time tCae urine specific activity at time t 'p

logarithmically against time. To preserve clarity the individual values are not plotted.

(Figure 4). The earliest diversion of Sr85 and skeleton itself does not discriminate between theCa45 serum values was seen in myxedema (Fig- two isotopes.ure 6) where skeletal activity is much reduced. Model compartment systems. Various investi-These findings provide indirect evidence that the gators have proposed model compartment systems

TABLE IX

"Pool sizes" (grams) based on serum specific activities

J.c. (II) J.w.W. B. (Thyrotox.) J.H. (Myx.) J.C. (I) (Myx.) (Normal after Rx) M.S. (Euthyroid) (Hyperparathyroid)

Timein days Calcium Strontium Calcium Strontium Calcium Strontium Calcium Strontium Calcium Strontium Calcium Strontium

3 9.69 6.66 3.15 3.03 4.21 5.16 4.54 4.28 3.99 4.48 10.80 9.666 17.55 10.03 3.81 3.79 5.40 6.78 5.88 5.35 5.25 5.63 13.49 13.779 25.22 12.30 3.96 3.97 7.10 8.08 6.60 6.81 6.59 7.10 15.26 16.82

12 33.22 14.65 4.30 4.66 7.37 8.49 7.65 8.39 7.98 8.47 16.90 20.2115 40.81 17.84 4.75 5.61 7.98 8.50 8.63 10.29 9.29 11.09 18.73 24.5218 48.34 22.98 5.09 6.31 9.36 10.01 10.00 13.53 10.92 14.31 20.98 30.2221 56.83 29.49 5.66 8.15 10.34 11.28 11.76 17.20 13.24 19.34

L. L. (I) L. L. (II) A. J. (I) A. J. (III)* A. J. (II)A. L. (Osteoporosis) (Osteoporosis on Rx) (Osteoporosis off Rx) E. S. (Paget's) (Paget's) (Paget's on cortisone)

3 8.82 7.65 4.24 4.56 4.42 4.88 44.82 43.30 40.41 64.23 25.066 10.70 11.41 5.66 6.09 5.62 6.23 73.77 76.85 49.05 116.74 30.999 13.01 15.77 6.59 7.11 6.75 8.10 85.77 101.82 53.12 169.10 35.75

12 15.06 20.60 7.25 8.19 7.79 9.24 94.73 110.30 56.73 184.40 38.9015 16.91 26.06 7.84 9.43 9.00 10.94 104.63 117.94 60.88 195.80 43.1218 19.14 33.75 8.59 10.68 10.52 13.24 115.61 125.25 64.84 208.40 47.7521 22.21 46.21 9.34 12.56 12.32 15.96 127.43 133.58 69.27 227.40

* Sr85 study done 8 months after Ca45 study.

in attempts to quantitate calcium kinetics in theliving organism. The application of these systemsto data from experiments of diversified designaccounts for the lack of uniformity in the pub-lished reports (1, 26, 28, 31, 32). All of the curveanalyses reported here were based on an arbitrarythree-compartment system. No assumption wasmade that the values recorded were physiologi-cally real. Rather, these analyses provided in-formation for two considerations; first, they al-lowed for quantitative comparison of Sr55 and Ca45kinetics in the same patient and secondly, theyindicated that both labeled isotopes were simi-larly affected by specific bone disorders.

Cortisone and Paget's disease. The findings inPaget's disease corroborate those of Albright andHenneman (33) in that cortisone suppressed theactivity of the disease. The effect, while definite,was far from complete in restoring calcium ex-change to normal.

Osteoporosis. Two patients with differenttypes of osteoporosis were available for study.A.L., a young male, had active progressive idio-pathic osteoporosis, and L.L. had chronic dis-ease of the postmenopausal type. In neither wasthe body retention of either labeled isotope par-ticularly low. This is in accord with the findingsby Heaney and Whedon (32) and of Nordin (34)that calcium "accretion" rates are normal inosteoporosis. Although Patient A.L. was in defi-nite negative calcium and phosphorus balance(nitrogen balance being maintained), compart-ment sizes and "calcium pools" were normal.

The value of estrogen therapy in "postmeno-pausal" osteoporosis is difficult to assess. Ani-mal experimentation has not been helpful, becausethe effect of this steroid varies in different species(35-37). Radiography is technically inadequateto evaluate changes in bone density. Human bal-ance data are scarce and are primarily those ofAlbright, Bloomberg and Smith (38) and Reifen-stein and Albright (39).

Patient L.L. was first studied at a time whenshe had been receiving 1.25 mg of estrone sul-fate 4 daily for a prolonged period. The controlstudy (L.L. II) was performed after estrogentherapy had been omitted for four months, a suffi-

4 Conjugated equine estrogens (Premarin).

cient period of timie to insure waning of any es-trogenic effect (33). The difference betweenthe means of the calcium balance during the con-trol and the treatment periods was significant(p < 0.05). The balance data for calcium andphosphorus are in good agreement with those ofReifenstein and Albright and demonstrated di-minished calciuria and phosphaturia during es-trogen therapy. However, the fact that Ca45 andSr85 data showed no differences in skeletal kineticsbetween the control and estrogen therapy studiessuggests that the effects of estrogen are extra-osseous.

Ca45 serum and urine specific activities. SerumCa45 specific activities consistently higher thancorresponding urine values were observed in allcases (Table V). This finding was unexpectedand is not in accord with those of others. Mostinvestigators have reported that Ca45 specificactivities in urine and serum are similar (32, 40).In most of these studies both serum and urine de-terminations are reported only for the first severaldays, when both values are changing rapidly.Since serum sampling is essentially instantaneous,urine specific activities determined on collectionsmade over fixed periods of time, and plotted atthe midpoint of the period, are erroneously ele-vated. This is especially true when the urinevalues are changing rapidly. Bronner, Benda,Harris and Kreplick, in a report of a case ofgargoylism noted that "the corresponding valuesfor urine tend, perhaps, to be lower than those forthe serum" (41). A review of Baker's Ca45studies in patients with neoplastic disease dis-closed that patients with hypercalcemia associatedwith metastatic calcification, with multiple mye-loma, or with carcinoma metastatic to soft tissuesand bone from breast and kidney, had identicalCa45 specific activity curves in serum and urine.5Patients with metastatic breast carcinoma, butwith normocalcemia, had serum to urine specificactivity ratios of over 2. The most striking dis-sociation of serum and urine values occurred in apatient with carcinoma of the prostate, widespreadbone metastases, and low to normal serum cal-cium concentrations. Ca45 specific activities in

5 Weare indebted to Dr. William Baker for permittingus to examine his unpublished data.

the serum were consistently five times higherthan those in the urine during a nine-day study.In our own studies the ratios varied in differentdisease states and were highest in Paget's diseaseand thyrotoxicosis, "normal" in untreated osteo-porosis and lowest (1.18) in myxedema. Thepatient with osteoporosis who received estrogentherapy was found to have a serum to urine Ca45specific activity ratio of 1.80, compared with acontrol value of 1.49.

Nevertheless, the possibility remains that theobserved discrepancy between Ca45 specific ac-tivities of blood and urine represents a systematicbut undisclosed analytical error. In serum analy-sis, a positive error in Ca45 counts or a negativeerror in Ca40 measurement, or both, would resultin a higher serum specific activity. Similarly,lowering of urine specific activities would resultfrom a systematic negative error in Ca45 measure-ments or a positive error in Ca40 determinations,or both. A search for such a source of error hasnot been fruitful. Recovery measurements forCa40 in serum and urine gave excellent valida-tion of the methods used. The fact that the high-est ratios of serum to urine specific activity ap-peared at lowest values for urine specific activitysuggests a systematic error in radioactive isotopicdeterminations when these are present in lowconcentration, but recovery experiments with iso-topic mixtures failed to disclose such an error.The discrepancy would not appear to be attribut-able to renal delay, because it was present longafter administration of the labeled Ca45, when se-rum concentrations were changing very slowlyfrom day to day. An alternative but seeminglyless probable source of the discrepancy is thatCa40 and Ca45 are bound with different affinities toplasma protein, or are differentially excreted bythe kidney, or are differentiated in some other wayto account for the departure of the specific activityratio from unity.

SUMMARYAND CONCLUSIONS

1. The distribution and excretion of Sr85 andCa45 administered simultaneously and intrave-nously were studied in patients with thyroid andparathyroid disorders, osteoporosis, and Paget'sdisease. In all cases and at all times the body

retention of Ca45 was more than Sr85 retention bya factor of 1.1 to 5.7.

2. Differential renal clearance of the two iso-topes accounted for 1.9 to 8.1 times more Sr85than Ca45 in the urine.

3. The amounts of each isotope in the feces weresizable, generally equal, and varied little in thedifferent diseases studied, except in Paget's dis-ease.

4. Calcium "pools" and compartment sizes asdetermined by either isotope proved to be sensi-tive indices of skeletal function. The largest val-ues were found in Paget's disease and thyrotoxi-cosis and the lowest in myxedema.

5. One patient with thyroid cancer metastaticto bone showed no evidence of increased calciumturnover by any of the criteria employed.

6. A patient with hyperparathyroidism but noclinical evidence of bone disease showed no evi-dence of abnormal calcium or strontium dynamics.

7. In one patient with Paget's disease cortisonefailed to suppress completely the activity of thedisease as measured by Ca45 dynamics.

8. There was no unusual pattern of labeled iso-tope excretion in patients with osfeoporosis. Pro-longed estrogen therapy in one patient with osteo-porosis of the postmenopausal type effected nochange in skeletal kinetics as measured by themetabolism of Ca45 or Sr85 but did effect a changein the serum to urine Ca45 specific activity ratio.

9. The observation that Ca45 specific activitieswere consistently greater in serum than in urineand the variation of serum to urine ratios in dif-ferent disease states is discussed as representingeither a true phenomenon or a systematic ana-lytical error.

10. Sr85 qualitatively parallels Ca45 as an indexof skeletal function in metabolic bone diseases.

ACKNOWLEDGMENTS

The authors wish to express their gratitude to Drs.Stephen M. Krane and Gordon L. Brownell for theirinterest and advice, and to Helen J. Corrigan who con-tributed invaluable technical assistance.

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