European Journal of

Nuclear Medicine Short communication

The diphosphonate space: a useful quantitative index of disease activity in patients undergoing hexamethylene diphosphonate (HMDP) bone imaging for Paget's disease A n d r e w Evans ~, A lan Perk ins 2, Mar t in Wastie ~'2, Mike Stone 3, and David Hosk ing 3

Departments of 1 Radiology, = Medical Physics and 3 Metabol ic Unit, University Hospital, Queen's Medical Centre, Nottingham NG7 2UH, UK

Received 3 April 1991

Abstract. Comparison between the plasma levels of in- travenously injected technetium 99m hexamethylene di- phosphonate (99mTc-HMDP) and chromium 5~ ethylene diamine tetra-acetic acid (51Cr-EDTA) reflects the up- take of diphosphonate into bone (the diphosphonate space). This can be used as an index of skeletal function in metabolic bone disease. In a series of 49 patients with Paget's disease the diphosphonate space (DPS) correlat- ed well with other indicators of disease activity such as alkaline phosphatase and urinary hydroxyproline lev- els. The DPS is a good predictor of the volume of skele- tal involvement as estimated from bone images. The DPS also provides a sensitive indicator of response to treatment with intravenously administered bisphosphon- ate. The DPS is simple to perform and is a useful adjunct to routine bone imaging.

Key words: Paget's disease - Hexamethylene diphospho- hate (HMDP) bone imaging - Chromium 51 ethylene diamine tetra-acetic acid (51Cr-EDTA)

Eur J Nucl Med (1991) 18:757-759

Introduction

Radiolabelled diphosphonates such as technetium 99m hexamethylene diphosphonate (99mTc-HMDP), used as bone scanning agents, are extracted by the kidney as well as taken up into bone and soft tissue. The total skeletal uptake of the scanning agent offers the potential for use in the assessment of skeletal function in patients with metabolic bone disease. However, any quantitative measure of skeletal uptake needs to be corrected for renal excretion. Since chromium 51 ethylene diamine tetra-acetic acid (51Cr-EDTA) is handled by the kidney

Offprint requests to: A. Evans

in the same way as 99mTc-HMDP and assuming that the uptake of diphosphonate into soft tissues is a con- stant fraction of the injected dose, the ratio of the two tracers in plasma following combined injection can be used as an index of uptake of diphosphonate into bone. This ratio, the diphosphonate space (DPS), is raised in Paget's disease, osteomalacia, renal osteodystrophy and hypercalcaemia (Nisbet et al. 1984).

The purpose of the present study was to evaluate the DPS in Paget's disease, in relation to disease parame- ters such as volume of bone involved, serum alkaline phosphatase, urinary hydroxyproline excretion and re- sponse to treatment.

Patients and methods

A total of 79 DPS estimations were made in 49 patients undergoing routine bone imaging for Paget's disease. These patients were either untreated or had received bisphosphonate more than 12 months previously. In all, 600 MBq of 99mTc-HMDP and 2.8 MBq of 51Cr- EDTA were injected simultaneously. The DPS was obtained by measuring the count rates of 51Cr-EDTA and 99mTc-HMDP by the temporal decay method in 2-hourly plasma samples between 2 and 8 h post-injection. Appropriate corrections were made for decay and background activity. The ratio is calculated as follows:

DPS - Sample count for 51Cr Standard count for 99mTc × X

Sample count for 99mTC Standard count for SlCr

Dilution of standard for 99mTc Dilution of standard for 51Cr

Bone images of the whole skeleton were obtained using either a GE 400 T or a GE 400 AC-T/Starport gamma-camera. The vol- ume of skeletal involvement was derived by measuring the area of the individual bones showing increased uptake and calculating their volume from previously published data (Howarth 1953).

Plasma alkaline phosphatase was estimated using a Technicon auto analyser (normal range 100 280 IU). Fasting urinary hydrox- yproline to creatinine ratios were obtained using the Hyprognosti-

© Springer-Verlag 1991

758

0

[3_ o9

$ c © r Q - c o O r -

2 ~

m

Before treatment

. "

~ O O •

1 •

I i i i I I

0 8 16 24 32 40

Volume of bone involved (%)

Fig. 1. Relationship between volume of bone involved and peak diphosphonate space in untreated patients (n=39). r=0.75; P<0.001

After treatment

o 4

0 ~ z

8 ..c 2

m I

l e o • . ' .

• O O

I I i i i I

0 8 16 24 32 40

Volume of bone invotved (%)

Fig. 2. Relationship between volume of bone involved and peak diphosphonate space following treatment with 3-aminohydroxy- propylidine-1,1-biphosphonate (APD) (n = 36). r = 0.80; P < 0.001

con kit method (Organon: normal range 10-30 gmol/mmol creati- nine). Paired pre- and post-treatment evaluations of the DPS were made in 17 patients. Treatment consisted of varying doses (15, 30 or 45 mg) of 3-aminohydroxypropylidine-l,l-biphosphonate (APD) infused intravenously at 6-weekly intervals. Post-treatment measurements were performed 6 months after the first injection of APD.

Results

Peak DPS values (the highest figure of the 2, 4, 6 and 8 h values) are presented as they had better correlations with other disease parameters compared with 2, 4, 6 and 8 h values. The peak value was always either the 2 or 4 h value and ranged from 1.0 to 4.5 (median 1.9).

A statistically significant correlation between volume of bone involved and the DPS was found both before (Fig. 1) and after (Fig. 2) treatment ( r - 0 . 7 5 and 0.80, respectively; P = < 0.001).

A statistically significant correlation was found be- tween the pre-treatment DPS and serum alkaline phos- phatase (r = 0.78; P < 0.001) and urinary hydroxyproline (r = 0.75; P < 0.001) levels (Fig. 3).

In patients undergoing treatment with APD the DPS fell in 16 of 17 patients (Wilcoxson signed rank test: P = <0.001). One patient showed no change with treat- ment. The median fall in DPS with treatment was 0.9 (range 0-1.8) (Fig. 4).

Discussion

The DPS is a simple method for quantifying the uptake of diphosphonate into bone. It's excellent correlation

- - . .

0

% .< °

10000

1000

100

10

z~

n i i n n n i

0 1 2 3 4 5 6

Peak diphosphonate space

-d E

lOOO E

v

c

100 b

x £ R

10 :I2

Fig. 3. Relationship between alkaline phosphatase and urinary hyd- roxyproline levels and peak diphosphonate space before treatment (n=30). • r=0.78; P<0.001. zx r=0.75; P 0.001

with the volume of involved bone in Paget's disease avoids the need for a more tedious method of quantifica- tion. Among the methods used to measure total skeletal uptake are those described by Vellenga and Fogelman; none of these methods are, however, in use in routine practice. The method described by Vellenga relied on selecting areas of interest by computer and comparing their average count rates with contralateral normal bone or, if this was not possible, then with a normal reference bone such as the tibia, making a correction for differ- ences in morphology. Using tables of relative bone vol- umes, a scintigraphic index was then calculated which reflected total skeletal activity (Vellenga et al. ]985). The method described by Fogelman, the 24-h whole-body

759

O

0~

O

n

8 x z O.

q:3

09 n

Before After treatment treatment

Fig. 4. Peak diphosphonate space before and after treatment with APD (n = 17)

retention (WBR) of diphosphonate, involves the injec- tion of technetium 99m disphosphonate intravenously with measurement at 5 rain and 24 h of whole-body count rates using a standard shadow shield whole-body monitor (Fogelman 1987). The DPS has the dual advan- tages of being easier and quicker to perform without the need for specialised equipment such as whole-body monitors as well as forming a component of routine bone imaging. Moreover, since the DPS does not rely on subjective mapping of areas of interest, it is likely to be more accurate than the scintigraphic index.

A statistically significant correlation was found be- tween the volume of involved bone and the DPS both before and after treatment. In patients with very active disease, the increased metabolic activity of the affected bone is probably the main determinant of uptake (Har- ink et al. 1987). In patients with less active disease, in- creased vascularity and the persistence of woven bone with its increased surface to volume ratio are likely to be the most important variables determining the increase in DPS (Galasko 1975; Singer et al. 1978). Serum alka- line phosphatase and urinary hydroxyproline are ac- cepted indicators of osteoblastic and osteoclastic activi- ty, respectively (Kanis and Gray 1987).

Whole-body retention of diphosphonate (Smith et al. 1984) shows a similar good correlation with these bio- chemical parameters of disease activity, but as a tech- nique it is limited by access to appropriate equipment.

The DPS is a useful and rapid index of the extent of skeletal involvement, which obviates the need to cal- culate separately the degree of abnormality of each af- fected bone. The reduction with treatment shows that the DPS is a sensitive indicator of response also. It has been questioned whether technetium 99m diphospho- hate is a valid method of assessing response to diphos- phonate treatment on the grounds that skeletal affinity

might be blocked by drug therapy (Fogelman 1987). However, paired lSF- and 99mTc-diphosphonate studies in 15 patients with diphosphonate-treated Paget's dis- ease showed no qualitative difference between the tracer uptakes (Wellman et al. 1977). It was suggested that de- spite the therapeutic diphosphonate load, potential bind- ing sites in the skeleton were so numerous that this had no effect on the affinity for bone scanning agents.

Conclusion

The DPS is an easy quantitative measure of skeletal ac- tivity in patients undergoing routine bone scanning for Paget's disease. We have demonstrated a correlation be- tween the DPS and important disease parameters such as the volume of bone involved, the plasma alkaline phosphatase and urinary hydroxyproline excretion. In addition to providing a useful measure of the extent of skeletal involvement, the DPS also reflects metabolic activity and structural change. The DPS provides a sen- sitive indicator of the response of treatment and can be performed routinely without the need for sophisticat- ed equipment and is neither time-consuming nor expen- sive.

Acknowledgements. We would like to thank Mrs. LC McGurk for typing the manuscript and the Nuclear Medicine Technicians at the Queen's Medical Centre, Nottingham.

References

Fogelman I (1987) Bone scanning in clinical practice. Springer, Berlin Heidelberg New York

Galasko CSB (1975) The pathological basis for skeletal scintigra- phy. J Bone Joint Surg 57:353-359

Harink HI J, Bijvoet OLM, Blanksma H J, Dahlinghaus-Neinhuys PJ (1987) Management with aminobiphosphonate (APD) in Pa- get's disease. Clin Orthop 217:79-97

Howarth S (1953) Cardiac output in osteitis deformans. Clin Sci 12:271-275

Kanis JA, Gray RES (1987) Long term follow-up observations on treatment in Paget's disease of bone. Clin Orthop 217:99- 125

Nisbet AP, Edwards S, Lazarus CR, Malamitsi J, Masey MN, Mashiter GD, Winn PJ (1984) Chromium 51 EDTA/Techne- tium 99M HMDP plasma ratio to measure total skeletal func- tion. Br J Radiol 57 : 677-680

Singer FR, Rude RK, Millis BG (1978) Paget's disease of bone. In: Avioli LV, Krane SM (eds) Metabolic bone disease. Aca- demic Press, New York, pp 489-575

Smith ML, Fogelman I, Ralston S, Boyce BF, Boyle IT (1984) Correlation of skeletal uptake of 99mTc-disphosphonate and alkaline phosphatase before and after oral disphosphonate ther- apy in Paget's disease. Metab Bone Dis Rel Res 5:167-170

Vellenga CJLR, Pauwels EKJ, Bijvoet OLM, Harink HIJ, Frijink WB (1985) Quantitative bone scintigraphy in Paget's disease treated with APD. Br J Radiol 58 : 1165-1172

Wellman HN, Schauwecker D, Robb JA, Khairi MR, Johnston CC (1977) Skeletal scintimaging and radiology in the diagnosis and management of Paget's disease. Clin Orthop 127:55 62