Bone, 6, 29-31 (1985)

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0 1985 Pergamon Press Ltd.

Reduction of Skeletal Blood Flow in Pagets Disease with Disodium

Etidronate Therapy
K.R. WALTON, J.R. GREEN, J. REEVE, and R. WOOTTON

Divisions of Radioisotopes,
UK.
Address for correspondence
Middlesex, HA1 3UJ. UK

Inherited Metabolic Diseases, and Comparative Medicine, M. R. C. Clinical Research Centre. Harrow, Middlesex,

and reprints:

Dr. J. Reeve, Division of Radioisotopes, M.R.C. Clinical Research Centre, Watford Road, Harm,

Abstract

Patients and Methods

Fourteen patients with Pagets disease of bone were treated

with disodium etidronate in doses of 5 to 7 mglkg per day.
Skeletal blood flow (SBF), was measured by the modified
F clearance technique of Wootton et al. (1976) before
treatment and again during treatment. In 10 patients
restudied 3-4 months after the start of therapy, SBF had
fallen by a mean of 21% of the initial value, and the individual differences correlated well with the individual reductions in serum alkaline phosphatase (r = 0.77, P < 0.01).
The results were similar to those seen in an earlier study in
patients treated with calcitonin. However, no early reduction in SBF was seen in six repeat studies performed at the
end of the second week of treatment, in contrast with our
previous findings with calcitonin.

Fourteen patients with Pagets disease of bone and no other demonstrable bone pathology were studied. None had received specific
therapy within the previous year (other than anti-inflammatory and
nonopiate analgesics), and all gave informed consent in accordance
with hospital ethical committee procedures prior to treatment. Measurements of serum alkaline phosphatase (normal range 80-280 IU)
and skeletal blood flow (SBF) (normal range 4-6% blood volume/min),
as described by Wootton et al. (1976), were performed before
treatment.
The technique for measuring SBF has been described in detail
previcusly. In brief, it depends on the rapid uptake of *F into bone.
Since F immediately begins to return to blood after its uptake by bone
(Costeas et al., 1970), the original clearance method proposed by Van
Dyke et al. (1971) underestimates true flow. To correct for tracer reflux,
a modified clearance technique based on deconvolution analysis was
introduced by Wootton et al. (1976). In this method, *F (300 pa),
obtained from the MRC Cyclotron Unit, Hammersmith Hospital, UK,
and a second tracer, 0-EDTA
(50 pCi) obtained from Amersham
International (Code No. CJ. 13P) used as an extracellular fluid tracer,
were given simultaneously by IV injection. Recoveriesof both tracers in
the urine were monitored by sequential urine collections, the patient
being maintained in a hydrated state with a fluid intake of 300 ml/h.
Blood tracer concentrations were measured in sequential vencus
blood samples. The results were used to derive curves describing the
fractions of each tracer dose in the bloodstream and extravascular
001s including bone) with time follawing injection. As tracers, OFand
Cr-EDTA are believed to behave similarly, except that F is taken UD
by bone and has a lower renal clearance.-By de&nvolving the bloob
from the tissues curve for each tracer, a third function describing the
instantanecus uptake and subsequent release of traCer from bone +
not bone is obtained in the units: fraction of the blood volume cleared
per minute. Subtraction of these two impulse response functions gives
the uptake and release curve for a cohort of F ions taken up at a
particular time into the skeleton, stripped of its soft tissue component.
Back extrapolation to zero time gives the estimated effective bone
blood flow.
Disodium etidronate (Didronel) therapy was started on the following
day at a dose of 5 to 7 mglkg per day (usually 400 mg/day), and in five
patients (one of whom was studied twice during two separate ccurses
of treatment) the alkaline phosphatase and SBF measurements were
repeated at 14 days after the start of treatment. In two of these patients

Key Words:

Pagets
Disease
of Bone-Disodium
Etidronate-Skeletal (Bone) Blood Flow-Calcitonin.

Introduction
It is generally accepted that bone blood flow may be considerably elevated in Pagets disease, as Paget himself suggested
(Paget, 1877). It was of interest to know to what extent treatment
of the disease restores bone blood flow to normal. We previously demonstrated that calcitonin therapy significantly reduced bone blood flow when given for a mean duration of 3
months (Wootton et al., 1978, 1981). The recent availability of
the effective oral therapy, disodium etidronate (EHDP), made it
desirable to compare the effectiveness of these two agents in
reducing bone blood flow toward normal.
29

K. R. Walton et al.: Skeletal blood flow in Pagets disease

30

and eight additional patients, the measurements were repeated at 3-4

months. In one case the follow-up study was delayed to the fifth month
of treatment. A single further patient was treated at a dose of 10 mgikg
per day with measurements of SBF before and at 8 weeks of therapy.

Results
The results are summarized in Figure 1. There was no consistent fall in SBF at the 2-week stage, whereas we had previously
observed a fall in SBF after 1 week of calcitonin therapy
(Wootton et al., 1978). However, at 3-4 months, the fall in SBF
was very similar to that seen in response to calcitonin therapy,
occurring at a similar mean rate of 0.17% blood volume per
minute per week of treatment. In the long-term group of 11
patients the mean fall in SBF was 2.2% blood volume per
minute, or 21% of the initial value of SBF. Plasma alkaline
phosphatase fell by a mean of 424 IU, or 36% of its initial value.
Changes in SBF correlated with those in alkaline phosphatase
(r = 0.77, P < 0.01). The 2 patients whose indices failed to
respond affirmed that they had taken the medication.

therapeutic
effect on bone blood
disodium
etidronate
is therefore

has a clinical reputation for rapid relief of bone pain and improvement in the thermographic response (Ring et al., 1977)
that has not been explained by equally rapid changes in biochemical indices, such as plasma alkaline phosphatase or
urinary hydroxyproline excretion. Quantitative scanning techniques may be applied to the measurement of regional skeletal
blood flow (Crawley et al., 1977), using a similar mathematical
analysis to calculate local tracer extraction rates. This would
enable investigators to study the relationship between changes
in bone pain and changes in local skeletal blood flow and
thereby to test the hypothesis that calcitonin achieves its analgesic effect in Pagets disease through a reduction in bone
blood flow rather than through central or peripheral
neuromodulation of painful stimuli, as proposed by Pecile
(1983).
Over 3 months, disodium etidronate was as effective in
reducing skeletal blood flow as calcitonin. These results, therefore, confirm the comparable efficacies of these two treatments
for Pagets disease of bone. For many patients not in an osteoelastic phase in whom a rapid response is not required, disodium etidronate will be the treatment of first choice because of
its greater
effects.

Discussion
In most of these patients with Pagets disease, disodium
etidronate, like calcitonin injections, proved effective in reducing bone blood flow toward normal, although only three entered
the normal range for skeletal blood flow and two regained
normal concentrations of serum alkaline phosphatase.
Our studies to date suggest that bone blood flow can be
higher in Pagets disease than in osteomalacia, another painful
metabolic bone disease (Tellez et al., 1983). The relationship
between bone blood flow and bone pain has been the subject
of some speculation (Arnoldi et al., 1971). Ring has observed
an association between the degree of pain relief and the reduction of the thermographic index over the affected bone (Ring et
al., 1977). The apparent difference in the time of onset of the
long term

Short term

16 -I

-I

flow between calcitonin and

interesting,
since calcitonin

convenience

and

freedom

from

systemic

Achnowledgement:
We are grateful to the MRC Cyclotron
Hammersmith Hospital, for supplles of F.

side

Unit,

References
Arnoldi C.C.. Lemperg R.K. and Llnderholm H.: lmmedlate effect of osteotomy
on the lntramedullary pressure of the femoral head and neck I patients with
degenerative osteoarthritis. Acta Orthopaed. Stand. 4225-33. 1971.
Costeas A., Woodard H.Q. and Laughlin J.S.: Depletion of sF from blood flowing
through bone Journal of Nuclear Medicine 11:43-45.1970.
Crawley J.C.W., GibbsG.P, Reeve J., Veal1N. and Wootton R.: Clinical appllcations of the hybnd scanner with special reference to bone studies. In: MedIcal
Applicabons of Cyclotrons. Turun Yliopisto. Finland, 1977, pp. 141-143.
Paget J.: On a form of chronic lnflammatlon of bones (osteltis deformans).
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Pectle A: Calcitonln and pain reld. Eangle 22,147-l 55, 1983.

Ring E.F.J., Davies J. and Barker J.R Thermcgraphlc assessment of calcltonin
therapy in Pagets disease. In: Bone Disease and Calotonm. J.A Kanis. ed.
Armour Pharmaceuticals, Eastbourne. 1977. pp. 39-48.
Tellez M., Wootton R and Reeve J.: Skeletal blood flow measured with 18F in
patients with osteomalacia and hyperparathyroidism. Eur. J. Nucl. Med.
8299-302, 1983.
Van Dyke D , Anger H.0, Parker H , McRae J., Dobson E.L., YanoY., Naets J.P.
and Linfoot J.: Markedly Increased bone blood flow in myelofibrosis. J. Nucl
Med. 12:506-512, 1971.
Wootton R., Reeve J and Veal1N.. The clinical measurement of skeletal blood

0-d
0

1000

zoo0

3G00 0

low

2000

3cQo

Plasma alkaline phosphatase flu/l)

Fig. 1. Changes in skeletal blood flow and plasma alkaline phosphatase after 2 weeks (left) and 8-20 weeks treatment (right). Each arrow
indicates movement from initial values (circle) to subsequent value
(point of arrow). One patient in the short term group was studied on two
successive courses of treatment (open circles, left). On the right, the
open circle signifies

the patient treated with 10 mglkg

ranges are indicated by the stippled areas.

per day. Normal

flow. Clan. Sci. MO/. Med. 50:261-268. 1976.

Wootton R.. Reeve J., Spellacy E. and Tellez-Yudllevich M.: Skeletal blood flow in
Pagets disease of bore and its response to calcitonln therap+ C/in. SC! MO/.
Med. 54:69-74. 1978.
Wootton R., Tellez M., Green J.R. and Reeve J.: Skeletal blood flow in Pagets
disease of bone Metab. Bone Dis. Rel. ffes. 3:263-270. 1981.

Received: November 8, 1983

Revised: March 19, 1984
Acceoted: Aoril3. 1984

K. R. Walton et al.: Skeletal blood flow in Pagets disease

31

14 pagetiques ont Bte halt&s avec de IQldronate dlsodlque, ir des doses variant de 5 B 7 mglkgljour. Le flux sanguin osseux (FSO), mesure par la
technique modlflee de Woonon et cog. (1976), basee sur la clearance du F, a Btd 6value avant, puis pendant fe traltement. Chez 10 malades
reexamines 3 s 4 mois apres ls debut du traltement fs FSO a chute en moyenne de 21% de 88 valeur lnltlale, et les dlff&ences lndlvlduelles correlent
blen avec les reductlons indlviduelles de8 phosphatases alcallnes drlques (r : 0,77; p < 0.01). Ces resultats sont ldentlques s ceux observes lors
dune etude anterleure chez de8 malades tralt6s par la calcltonlne. Aucune reduction precoce du FSO na et& observee cependant lors de la repetition
de8 rnesures effectuee dans 6 cas ir la fln de la deuxleme semsine de traltement, contralrement s ce que nws avtons constate anterleurement sous
calcltonlne.