Effects of Calcium Infusions in Patients with Postmenopausal Osteoporosis

Joseph Walton, Manuel Dominguez, and Frederic C. Bartter

From earlier studies, it appeared that port- good therapeutic response as iudged by menopausal women with osteoporosis sustained decrease in bone pain and im- may not be so responsive to therapeutic provement in calcium balance. It is con- calcium infusions as younger men. A study eluded that a series of calcium infusions is of seven women with postmenopausal unlikely to be therapeutically useful in osteoporosis revealed that only one had a postmenopausal osteoporosis.

S INCE 1969, several reports from this laboratory have documented the re- sults of using a series of calcium infusions in the treatment of osteoporo-

sis.lm4 Of the 12 patients reported,4 approximately half showed a therapeutic response as measured by subjective sustained decrease in pain, improvement in calcium balance, and increase in gastointestinal absorption of calcium. Ten

of these patients had estimates of bone resorption and formation area before and after a series of infusions. Of these, nine patients showed a decrease in bone resorption area and eight an increase in bone formation area.3

Since postmenopausal osteoporosis is a common illness, it is of interest that only three of the original 12 patients were postmenopausal women. It is of further interest that none of the three had a good response to calcium infusions. One patient failed to respond to all criteria evaluated (she refused bone biop- sies). A second patient had a decrease in bone resorption as her only indication of response. The third postmenopausal patient failed to experience the relief of bone pain so characteristic of the other “responders,” but appeared to respond by the other criteria. Because of these findings, we have evaluated the effects of calcium infusions in seven additional women with postmenopausal osteo- porosis. The results are presented herein.

MATERIALS AND METHODS

Each patient was accepted on referral by her private physician and admitted to the Clinical Center, National Institutes of Health. The clinical characteristics of each are presented in Table 1. All patients had radiolucent thoracic and lumbar vertebrae, and all but two had compression fractures. There was no radiographic evidence of osteomalacia or metastatic bone disease in any

patient. Serum calcium, phosphorus, and alkaline phosphatase were normal in all patients. In

live patients in whom serum immunoreactive parathyroid hormone was measured by the method

of Blair et al.’ the results were normal.

Following evaluation adequate to establish the diagnosis of postmenopausal osteoporosis, each

patient was fed a constant metabolic diet for at least 40 days. Daily dietary calcium and phos- phorus among the patients ranged from 0.54 to 0.85 g and from 0.63 to 1.20 g, respectively. After 2 4 days of equilibration on her diet, each patient underwent a 36-day balance study. The first 12 days served as a control period. During the second 12-day period, I5 mg/kg of Ca++ as calcium

From the Hypertension-Endocrine Branch, National Heart and Lung Institute, National Institutes of Health. Bethesda, Md.

Received for publicarion January 21. 1975.

‘c! 1975 bv Grune & Stratton. Inc.

Metabolism, Vol. 24, No. 7 (July), 1975 049

8

Tab

le 1

. C

linic

al C

hara

cter

isti

cs

Pat

ien

t

A.C

.

A.D

.

G.T

.

E.

P.

J.G

.

N.F

.

R.M

.

Ag

e

61

58

A8

64

75

56

A7

Du

rati

on

S

ince

MW

lOp

aUS

e

(Yd

11

23

30

24

30

14 8

Du

rati

on

o

f S

ymp

tom

s

of

Ost

eop

oro

sis

(Y0 2

28

23

21 6 6 6

Dia

gn

ost

ic

Cri

teri

a

Rad

iolu

ce

nc

y,

tho

rac

ic

an

d

lum

ba

r

vert

eb

ral

fra

ctu

res

Rad

iolu

ce

nc

y o

f lu

mb

ar

an

d

tho

rac

ic

spin

e

Rad

iolu

ce

nc

y,

lum

ba

r a

nd

th

ora

cic

vert

eb

ral

fra

ctu

res

Rad

iolu

ce

nc

y,

lum

ba

r a

nd

th

ora

cic

vert

eb

ral

fra

ctu

res

Rad

iolu

ce

nc

y o

f lu

mb

ar,

th

ora

cic

,

an

d

ce

rvic

al

spin

e

Rad

iolu

ce

nc

y,

lum

ba

r a

nd

th

ora

cic

vert

eb

ral

fra

ctu

res

Rad

iolu

ce

nc

y,

tho

rac

ic

vert

eb

ral

fra

ctu

res

Pre

vio

us

Tre

atm

ent*

Ca

lciu

m

infu

sio

ns

by

p

riva

te

ph

ysi

cia

n

Estr

og

en

s,

an

dro

ge

ns

No

ne

Estr

og

en

s,

an

dro

ge

ns,

o

ral

ca

lciu

m

sup

ple

me

nts

, a

na

lge

sic

s

Ora

l c

alc

ium

su

pp

lem

en

ts,

vita

min

D

Estr

og

en

s,

fluo

ride

, vi

tam

in

D,

ca

l-

ciu

m

infu

sio

ns

by

p

riva

te

ph

ysi

cia

n

Est

rog

ens,

a

na

lge

sic

s

*Pa

tien

t R

.M.

ha

d

be

en

re

ce

ivin

g

rep

lac

em

en

t e

stro

ge

n

for

som

e

yea

rs

wh

en

fir

st

see

n

by

u

s.

This

w

as

co

ntin

ue

d

thro

ug

ho

ut

the

st

ud

ies.

N

on

e

of

the

o

the

r p

atie

nts

w

ere

B

rec

eiv

ing

th

e

me

dic

atio

ns

at

the

tim

e

of

stu

dy

. 5 z .N

CALCIUM INFUSIONS 851

gluceptate in 500 cc normal saline was administered intravenously daily over 4 hr from 9 a.m. to

I p.m. The final I2 days served as a postinfusion period.

During the entire balance study, blood was collected 3 mornings per week and the serum ana-

lyzed for calcium, phosphorus, albumin, creatinine, alkaline phosphatase, sodium, potassium,

bicarbonate, and chloride. These measurements were done by standard automated techniques in

the clinical chemistry laboratory. Urine was collected in 24-hr pools daily, and aliquots were

assayed for calcium by atomic-flame spectrometry and for phosphorus by the method of Fiske and

SubbaRow.6 Stools were collected in 4-day pools, ashed, and assayed for calcium and phosphorus

by the same methods. Carmine red was used as a stool marker.

Five of the seven patients returned after 5-12 mo for follow-up. Each had an interview regard-

ing current pain, radiographs of thoracic and lumbar vertebrae, and a 12-day balance study identi-

cal to the postinfusion balance period.

RESULTS

No patient suffered demonstrable ill effects from the infusions except for mild lethargy. Specifically, there was no instance of hypertension during these infu- sions, and creatinine clearance, monitored daily throughout the balance studies, was unaltered by the infusions.

Fig. 1. Effect of calcium infusion on serum calcium and phosphorus concentration and on cal- cium and phosphorus balance in a patient with postmenopausal osteoporosis. Calcium and phosphorus intake are plotted downward from the zero line. Urinary calcium and phosphorus are represented by the hatched areas above the intake line; fecal calcium and phosphorus are represented by the shaded areas above the urinary calcium and phosphorus.

Patie

nt

Pre

infu

sio

n

Tab

le 2

. R

espo

nse

to C

alci

um I

nfus

ions

Ne

t C

alc

ium

B

ala

nc

e

(mg

/da

y)

Imm

ed

iate

ly

Late

Port

infu

sio

n

Port

infu

sio

n

(4

Ra

dio

gra

ph

ic

Imp

rove

me

nt

Ch

an

ge

s in

Pa

in

AC

.

AD

.

G.T

.

E.P.

J.G

.

N.F

.

R.M

.

-27

+83

+18

3 (6

) N

O

Ye

s

+12

5 -1

16

+93

(6

) N

O

NO

+18

3 +

185

+9

(6)

NO

N

o

+81

+

91

- N

o

No

+15

+

84

- N

o

No

+63

+

57

+45

(‘

2)

No

Tr

an

sie

nt

+57

+

12

+99

(5

) N

o

No

Eac

h d

atu

m i

s a

n a

vera

ge

fo

r 12

da

ys o

f u

rine

co

llec

tion

an

d t

hre

e 4

-da

y s

too

l p

erio

ds.

CALCIUM INFUSIONS 853

The balance study of a typical patient is depicted in Fig. 1. No improvement in calcium balance is seen following the infusions.

The therapeutic benefit of the calcium infusions, as monitored by improve- ment in calcium balance, radiographic bone changes, and subjective improve- ment in pain, is shown in Table 2. In no patient was there decreased radio- lucency of bone. In only one of the seven patients (A.C.) was there a sustained decrease in bone pain. This was also the only patient showing a substantial improvement in calcium balance.

DISCUSSION

Several previous communications from this laboratory have documented a rather dramatic decrease in bone pain in approximately half of the patients with idiopathic osteoporosis treated with calcium infusions.‘-4 This subjective improvement was accompanied in each case by improvement in calcium bal- ance, decrease in bone resorption, and increase in bone formation. In no case of an adult with idiopathic osteoporosis have we been able to detect radio- graphic evidence of increased bone density. This is not surprising since it is estimated that bone density must change by 20’4-40% to be detectable on standard radiographs.7

The absence of subjective improvement among the three postmenopausal women in the original series prompted a more complete study of this subgroup of patients. Presented herein are results indicating a complete failure of six of seven postmenopausal women with osteoporosis to respond therapeutically to a series of calcium infusions.

Dud1 and his colleagues* have recently reported the results of a careful study utilizing a series of calcium infusions in five women. Of these, four were post- menopausal and one was in the same age group but premenopausal. These investigators found no evidence of therapeutic benefit in these five patients.

The reasons for this apparent difference in therapeutic response between postmenopausal women and young to middle-aged men is unclear. While osteo- porosis can represent the result of a number of diseases, no clear differences have been established in idiopathic osteoporosis among the various adult age groups or between the sexes. For whatever reasons, we feel that women with postmenopausal osteoporosis are unlikely to achieve therapeutic benefit from a series of intravenous calcium infusions.

REFERENCES

1. Pak CYC, Zisman E, Evans R, Jowsey J.

Delea ES, Bartter FC: The treatment of osteo-

porosis with calcium’ infusions. Clinical studies.

Am J Med 47~7. 1969

2. Bartter FC: Treatment of osteoporosis by

calcium infisions. Proc R Sot Med 63:339,

1970

3. Jowsey J, Hoye RC, Pak CYC, Bartter FC: The treatment of osteoporosis with calcium

infusions. Evaluation of bone biopsies. Am J

Med 41: 17. 1969

4. Pak CYC, Bartter FC: Progress in the

study and treatment of osteoporosis, in Tal-

mage RV, Munson PL (eds): Calcium, Para-

thyroid Hormone, and the Calcitonins. Pro-

ceedings of the Fourth Parathyroid Conference.

Amsterdam, Excerpta Medica, 1972, p 7 I 5. Blair AJ Jr. Hawker CD, Utiger RD:

854 WALTON, DOMINGUEZ, AND BARTTER

Ectopic hyperparathyroidism in a patient with 7. Lachmann E, Whelan M: Roentgen diag-

metastatic hypernephroma. Metabolism 22: 147, nosis of osteoporosis and its limitations. Radiol-

1973 ogy 26:165, 1936

6. Fiske CH, SubbaRow Y: The calorimetric 8. Dud1 RJ, Ensinck JW, Baylink D, et al:

determination of phosphorus. J Biol Chem 66: Evaluation of intravenous calcium as therapy

375, 1925 for osteoporosis. Am J Med 55:631, 1973