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1984,

  Th e

  British Journal

  of

  Radiology,

  57 ,

  677-680

AUGUST 1984

Chromium 51 EDTA/technetium 99m MDP plasma ratio to

measure total skeletal function

By A. Patric Nisbet, M.Sc, M.R.C.P.; Susan Edwards, B.Sc, Colin R. Lazarus, B. Pharm., Ph.D.

M.P.S., Julia Malamitsi, M.Sc, Michael N. Maisey, M.D., F.R.C.R., F.R.C.P., Gail D. Mashiter

and Patricia J. Winn

Departments of Nuclear Medicine, Radiology, and Clinical Physics and Bioengineering, Guy s Hospital,

London

  Received November

  1983 and in

  revised form February

  1984)

ABSTRACT

A

  method

  is

  described

  for the

  quantitation

  of

  total skeletal

activity during bone

  scans. The

  method requires

  a

  single

plasma sample only, taken

  at the

  time

  of imaging. The

  ratio

  of

%  injected dose  of

  5 1

C r  EDTA  to  that  o f T c

m

  MDP is

calculated from this sample following combined injection  of

the two radiopharmaceuticals . The

  5 1

C r

  EDTA level corrects

for the

  glomerular filtration

  of T c

m

  M D P .

  Using this

method, which only requires  a  gamma counter, significant

differences from normal controls have been shown  in  patients

with osteomalacia, renal osteodystrophy, Paget's disease  an d

hypercalcaemia.

  The

  method provides routine quantitative

data  to add to the  imaging information  in the  bone scan.

The measurement of total tracer uptake by the skeleton

is now an established method of investigation in the

management of metabolic bone disease. The whole-

body retention of diphosph onate s at 24 h has been

shown to be a sensitive means of identifying patients

with increased bone turnover (Fogelman et al, 1978).

The whole-body retention (WBR) method uses a

whole-body counter and requires two separate visits by

the patient. A method which could be used as an

adjunct to the routine bone scan to provide a

quantitative index of total skeletal function would be of

benefit in the determination of metabolic bone

disorders, identification of the superscan and possibly

for sequential measurements of activity of metastases

and Pagetic lesions.

The  WBR   is evalu ated at 24 h so tha t (w ith the

exception of renal failure) renal excretion of diphos-

phonates can be assumed to be no longer significant.

Any method for evaluation of total skeletal activity

(using blood clearance or whole body retention) at the

time (3-4 h after injection) of the normal bone scan will

require correction for renal handling of diphosphonate.

Diphosphonates are filtered by the human kidney

without significant secretion or absorption, the filtration

fraction being similar to DTPA and EDTA (McAfee

et al, 1981). In rats there is evidence of some secretion

by the tubule (Troehler et al, 1975), but this is also true

Address

  for reprints:

  Susan

  Edwards ,

  Dept.

  of

  Clinical Physics

&

 Bioengineering, Guy's

  Hospital, St. Thomas'

  Street, London,

SE1 9RT,

  England.

of EDTA, and diphosphonates can be treated as

glomerular filtration agents. If diphosphonates and

EDTA are injected simultaneously any difference in

plasma levels of the two tracers will represent

preferential diphosphonate uptake into bone and soft

tissue.

The WBR of diphosphonate in soft tissue has been

shown to be a constant fraction of the administered

dose (Smith et al, 1982) over a w ide ra nge of

conditions. Hence relative differences in EDTA and

diphosphonate plasma levels can be assumed to reflect

diphosphonate uptake into bone.

The purpose of the present study was to investigate

the possibility of a simple test for routine use, based on

the plasma level of T c

m

  M D P at 4 h with the

  5 1

C r

EDTA plasma level, providing a correction for renal

function.

PATIENTS

Eight normal patients, (aged  20 -61 ,  mean age 38)

and 20 patients with carcinoma of the breast, without

metastases and on no therapy (aged 39-80, mean 52),

were taken as the normal control group. The disease

groups comprised:

11 patients with chronic renal failure (aged   22-61 ,

mean 46); 10 patients with Paget's disease (aged

48-75 ,  mean 53); 7 patients with osteomalacia (aged

32-84, mean 53); 20 patients with hypercalcaemia,

predominantly primary hyperparathyroidism, with-

out signs of bone disease, but including three with a

primary neoplasm, without bone secondaries, having

humoral hypercalcaemia of malignancy (aged

  22-11,

mean 51).

METHOD AND RESULTS

To study the clearance of T c

m

  MDP  and

  5 1

C r

EDTA  in vivo,  34 patients had plasma samples taken

over a 7-hour period, following simultaneous injections

of the two agents (Nisbet, 1982; Nisbet et al, 1983).

Typical results are shown in Figs. 1-4. In each figure

the three curves show percentage administered

dose/litre plasma for

  5 1

Cr EDTA and T c

m

  MDP and

the ratio of these two as a function of time to about 400

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V O L .

  57, No. 680

A.

  Patric Nisbet et al

15

F I G .  1.

Clearance and ratio curves for normal subject. The two

clearance curves (open triangles:

  5 1

Cr EDTA; closed triangles:

  T c

m

  MDP) show percentage injected dose per litre of plasma

for the two agents as a function of time. The third curve (open

squares) shows the ratio of these two concentrations as a

function of time. In normals the ratio is almost constant over

the seven hours of the study.

min after injection. In normals the plasma curves are

parallel for MDP and EDTA, with a constant rat io of

% administered

  5 1

Cr dose/litre to % administered

  T c

m

  dose/litre of around 1.2.

In Paget's disease, there is early separation of the

curves, with subsequent approxim ation. The

  5 1

C r / T c

m

ratio rises early with a later plateau.

In osteomalacia, the curves separate early and remain

widely separated over the seven hours of the study. The

5 1

C r / T c

m

  ratio rises steeply throughout.

In hyperparathyroidism, there is a small but

15

10

Cr51EDTA

Tc99m M DP

 

Ratio Cr/Tc

100

20 0

FI G.  2.

3 0 0 4 0 0

minutes

Clearance and ratio curves for patient with Paget 's disease

(see text).

Clearance and ratio curves for patient with osteomalacia

(see text).

15

10

 O51EDTA

•Tc99mMDP

-Ratio Cr/Tc

100

200

FI G.  4.

3 0 0 4 0 0

minutes

Clearance and ratio curves for patient with hypercalcaemia

(see text).

significant separation in the majority of patients,

though a minority have normal curves.

The ratio of

  5 1

C r E D T A / T c

m

  MDP % adminis-

tered dose was measured during routine bone scans

using the following method.

A

  5 1

Cr EDTA* and T c

m

  MDP* mixture was made,

in the ratio of app roxima tely 3 MB q (100 /iCi)

  5 1

C r

EDT A to 550 MB q (15 mCi) T c

m

  MDP. The mixture

was then injected into the patient. Blood samples were

taken at 10, 30, 60 and 240 min (heparinised bottles

10 ml). The residue in the vial was used as a stand ard,

and the samples were counted on a two-channel

automatic gamma counter for

  5 1

Cr and T c

m

  activity

at 24 h (3 ml plasm a, stand ard diluted 1/10000). A

repeat count was performed after five days, when the

*Amersham International pic

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AUGUST  1984

51

Cr EDTAj

99

Tc

m

  ratio for total skeletal function

  T c

m

  activity had decayed to background level,

(standard dilution  1/250).

Following correction for background and crosstalk

from

  51

Cr in the Tc

m

  channel, the ratio of %

administered dose/1 of plasma for

  51

Cr/ Tc

m

  was

calculated. Since only the ratio was used, knowledge of

volumes and activities injected was not necessary.

Chromatography studies showed the Tc

m

  MDP/

51

Cr

EDTA mixture to be stable for more than three hours.

The maximum ratio of the four samples was taken for

each patient. In practice this was the 4 h sample, except

for one patient with Paget's disease. Values of

maximum ratio in the five groups of patients are shown

in Fig. 5.

In the normal control group the ratios ranged from

0.80 to 1.4, with a mean of 1.19 and a standard

deviation of 0.12. The upper limit of normal was set at

1.43 (mean +2 SD). Values of range, mean and SD for

the different disease groups are given in Table I.

Statistical analysis used the non-parametric Mann-

Whitney Rank Sum Test to determine the probabilities

of occurrence on the null hypothesis of the ratios

observed in the pathological groups compared to that in

the 28 normal control group. Probability levels (one-

tailed) were < 0.001 for the osteomalacia, renal

osteodystrophy and Paget's disease groups. For the

hypercalcaemia group the level was < 0.01.

DISCUSSION

The results show clear differences between normal

controls and patients with renal osteodystrophy,

osteomalacia, and Paget's disease. The hypercalcaemic

group showed a less marked but still significant

difference. Patients with active Paget's disease showed

Maximum ratio

7

1 2  4 5

Group number

FI G.  5.

Values of maximum ratio found in different disease groups.

Group 1: Normal controls; Group 2: Renal osteodystrophy;

Group 3: Paget's disease; Group 4: Osteomalacia; Group 5:

Hypercalcaemia.

The horizontal line shows the upper limit of normal

(Mean + 2  SD).

TABLE I

RANGES

  AND

  STANDAR D DEVIATIONS

  FOR

  MAXIMUM RATIO

  IN

VARIOUS PATIENT GROUPS

Group

Normal

Renal osteodystrophy

Paget's disease

Osteomalacia

Hypercalcaemia

Min

0.8

1.5

1.3

1.7

1.1

Maximum Ratio

Max

1.4

4.7

4.0

6.3

2.8

Mean

1.19

2.8

2.5

3.1

1.7

SD

0.12

0.8

0.9

1.4

0.5

elevation of the ratio; patients in whom Paget's disease

had been treated successfully, as shown by return of

alkaline phosphatase to normal values and pain  relief,

showed normal ratio values.The hypercalcaemic group

was an unselected group of undiagnosed hyper-

calcaemic patients still under investigation; 13 had

hyperparathyroidism without elevation of alkaline

phosphatase or radiological bone abnormality, three

had proven malignancy and the rest did not have a firm

diagnosis at the time of writing. There was no sign of

bone disease in any of the hyperparathyroid group,

apart from probable high uptake on the bone scan in

eight patients. The quantitation may assist in the

detection of bone disease in this group.

The finding that the highest ratio of the four occurs

between 3 and 4 h in the vast majority of patients

means that a single blood sample taken at the usual

time for bone scanning will provide quantitative

assessment of the total skeletal activity to add to the

qualitative information from the scan images. This

value appears to have highly significant discriminatory

ability in the detection of renal osteodystrophy,

osteomalacia and Paget's disease, though these con-

ditions cannot be separated from each other by ratio

alone. It may provide valuable information as to the

extent of bone activity in hypercalcaemic bone

disorders. Single plasma values should be acceptably

sensitive for general patient screening, with several

samples providing further information in known cases

of metabolic bone disease. Early sampling may be of

value in disorders with high bone blood flow such as

Paget's disease, where the ratio may peak early after

injection.

CONCLUSION

A single plasma sample technique, applicable to any

routine bone scan, has been shown to demonstrate

skeletal activity in metabolic bone disorders. The

technique may be instituted in any department,

requiring only a well counter; and sampling of all

patients having bone scans does not make much more

work for staff nor increase waiting time for patients.

ACKNOWLEDGMENTS

A.P.N. gratefully acknowledges the support of Guy's Special

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VOL.

  57, No. 680

l

Cr EDTAI T<T ratio for  total skeletal function

Trustees.  We  wish  to  thank Miss  S. V.  Ellam, Miss  N .

Solaiman and Mrs F.  Bradley  for their invaluab le ass istance.

R E F E R E N C E S

FOGELMAN,

  I. ,

  BESSENT,

  R. G. ,

  TURNER,

  J. G.,

  ClTRIN,

  D. L. ,

BOYLE,  I. T. &  G R E I G ,  W. R., 1978. The use of the Who le

Body Retention

  of

 Tc99m d iphosphonate

  in the

 diagnosis

 of

metabolic bone disease.  Journal  of  Nuclear Medicine,  19 ,

270-275.

M C A F E E ,  J. G.,  GROSSMAN,  Z. D.,  G A G N E ,  G. ,  Z E N S ,  A. L.,

SUBRAMANIAN,  G . ,  THOMAS,  F . D . ,  FERNANDEZ,  P . &

ROSKOPF,  M. L.,  1981.  Comparison  of  renal extractio n

efficiencies  for  radioactive agents in

 the

  normal

  dog.  Journal

of Nuclear Medicine,

  22,

 333-338.

NISBET,  A. P., 1982. The  quantitat ion  of Tc99m  MD P  uptake

in bone, using  the relative clearances  of Tc99m  MDP  and

Cr51 EDTA from  the blood . Thesis  for

 MSc

  in  Nuclear

Medicine, University  of London .

NISBET,  A. P.,  E D W A R D S ,  S.,  MASHITER,  G. ,  W I N N ,  P. ,  H ILSO N ,

A.

 J.

 W.

  &

  MAISEY,

  M. N. , 1983.

  Quantitation

  of

  Tc99m

MDP retention during routine bone scanning.  Nuclear

Medicine Communications,  4, 67- 71 .

SMITH,  M. L.,  M A R T I N ,  W.,  FOGELMAN,  I. &  BESSENT,  R. G.,

1982.  Relative distribution  of diphos phon ate between bone

and soft tissue  at 4 and 24 hours: concise comm unication.

Journal  of Nuclear Medicine,

  24, 208-211.

TROEHLER,  U. ,  BONJOUR,  J. P. &  FLEISH,  H., 1975. Renal

secretion

  of

 diphosphonates

  in

 rats.

  Kidney International, 8,

6-13.

Book review

Radiology

  of

 Skeletal Trauma.  (2 vols). By Lee F . Rogers,  pp.

xxviii + 920,  1982 (Churchil l Livingstone, Ed inburgh ), £110.00.

ISBN 0-443-080380

This 900-page treatise  is in two  volumes with  1700

illustrations  and,  apart from  one  chapter  on  imaging

techniques  by Dr. Ronald Hendrix,  is the work  of one man.

One cannot

  but

  marvel  at

 Dr.

  Rogers' industry,  not simply in

writing  an authoritative

  and

  lucid text  but in assembling such

an enormous collection

  of

  illustrations

  on

  such

  a

  difficult

subject  as traum a w here radiographic quali ty  is not  always the

greatest .

The first  160 pages  ar e  devoted  to  chapters  on  general

anatomy, skeletal biomechanics,  and the epidemiology  and

classification  of  fractures,  as  well  as  fracture-healing  and

complications which

  are

  clearly explained

  an d

  illustrated.

Special attention

  is

 also paid  to children, n otably  in relation to

non-accidental trauma  an d epiphyseal injuries.  In the  latter

respect  it was  refreshing  to see an American auth or give  due

acknowledgment  to the work  of  British pioneers  in identifying

these injuries.  The  triangular metaphyseal fragment  is

known  in the US as  Thu rston Holland's corner sign -a

classic example  of the  prophet without h onou r  in his own

country.

Subsequent chapters deal with injury  on a  regional basis.

Abou t

  200

 pages each

  are

 devoted

  to the

  limbs,

 50 to the

 pelvis

an d  66 to the spine,  an d proport ional amounts  to  skull, face

and thorax.  I think it is remarkable that  the coverage of spinal

injuries  is so  com plete within  the  space available  and the

author

  is

 able

 to

  include reference

  to

 such subjects

 as

  injury

 to

the spondylitic spine as well as fractures  of

 the

  larynx.

The chapter on  available imaging techniques by Dr. Hendrix

covers such subjects  as macro-rad iography, bone-scanning and

CT,  although reference

  to

 these techn iques

  is

 also ma de, w here

appropria te ,  in

 the

  general text.

Criticisms are minor  and  mainly syntactical  and  must  not be

allowed

  to

 detract from this tour-de -force.

  Dr.

  Rogers

 is to be

congratulated

  on

  producing what

  is

  obviously going to become

a classic work which will  be essential  in all radiological and

orthopaedic l ibraries.

J. T.  PATTON

680