HORMONES IN OSTEOPOROSIS THE METABOLIC EFFECTS OF STEROID · hormones (8); and (8) the...

THE METABOLIC EFFECTS OF STEROIDHORMONES IN OSTEOPOROSIS

Edward C. Reifenstein Jr., Fuller Albright

J Clin Invest. 1947;26(1):24-56. https://doi.org/10.1172/JCI101787.

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THE METABOLIC EFFECTS OF STEROID HORMONESIN OSTEOPOROSIS

BY EDWARDC. REIFENSTEIN, JR., AND FULLER ALBRIGHT1, 2, 8

(From the Medical Service of the Massachusetts General Hospital and the Department ofMedicine of 'the Harvard Medical School, Boston)

(Received for publication May 7, 1946)

In a previous communication from this clinic(1), three metabolic studies on the effect of es-tradiol benzoate on the calcium and phosphorusmetabolisms of patients with post-menopausalosteoporosis were published in abstract form.The first objective of the present paper is to re-port these studies in detail, supplemented by 2 ad-ditional studies: one in which testosterone pro-pionate by itself, and in combination with estradiolbenzoate, was used; and another in which di-ethylstilbestrol by itself, and in combination withprogesterone, was employed. The subject of the

1 The expense of these studies was defrayed by grantsfrom the Josiah Macy, Jr. Foundation, from the Rocke-feller Foundation, and from the National Research Coun-cil (Committee for Research in the Problems of Sex).A bed supported by the Mallinckrodt Chemical Companyon the Metabolic Ward was used for part of these studies.

2 Presented in part at the twenty-sixth annual meetingof the Association for the Study of Internal Secretions,Atlantic City, New Jersey, June 8, 1942, in connectionwith a symposium on "Relation of Endocrines to SkeletalDevelopment"; an outline of this presentation may befound in: Reifenstein, E. C., Jr.; Albright, F.; Parson,W.; and Bloomberg, E.: The effect of estradiol benzoateand of testosterone propionate and of combinations ofboth on post-menopausal osteoporosis and senile osteo-porosis, Endocrinology, 30: S1024 (1942). Also pre-sented in part at the first annual meeting of the AmnericanFederation for Clinical Research, Minneapolis, Minn.,April 20, 1942. Preliminary reports of part of these datamay be found in: Albright, F.; Reifenstein, E. C., Jr.;and Forbes, A. P.: Conferences on the Metabolic Aspectsof Convalescence (Including Bone and Wound Healing),Transactions of the, First Meeting, Sept. 11-12, 1942,IXges 5-7, 37-38; Transactions of the Second Meeting,December 11-12, 1942, pages 69, 96-98; Transactions ofthe Third Meeting, March 12-13, 1943, pages 63-65; andTransactions of the Fourth Meeting, June 11-12, 1943,pages 77-85. Transactions distributed by the JosiahMacy, Jr. Foundation, New York, N. Y.

8 The work described in this paper was done in partunder a contract, recommended by the Committee onMedical Research, between the Office of Scientific Re-search and Development and the Massachusetts GeneralHospital.

last investigation had, in addition to post-meno-pausal osteoporosis, Paget's disease.

The second objective is to publish metabolicstudies on the effect of testosterone propionatealone and in combination with estradiol benzoatein a male patient with senile osteoporosis.

The third objective is to present studies on 3 pa-tients with the acute osteoporotic process whichfollows orthopedic operations, and the effect ofestradiol benzoate on this process in 2 of thesesubjects.

In another previous communication from thisclinic (2), metabolic studies of the effect of es-tradiol benzoate, testosterone propionate, andprogesterone on 3 patients with Cushing's syn-drome were reported. The fourth objective is topresent these data more completely in graphicform, and especially to rectify an unwarrantedconclusion as to the effect of estrogen on the cal-cium balance.

DEFINITION OF OSTEOPOROSIS

Osteoporosis is not synonymous with demineral-ization of bone; it is that category of too-little-bone where the primary disturbance is lack of bonematrix formation. It is not to be confused withosteomalacia, where the primary disturbance isfailure of mineralization of bone, or with osteitisfibrosa generalisata, where the primary disturb-ance is increased bone destruction. For furtherdiscussion, see (1, 3, 4).

CONDITIONS ASSOCIATEDWITH OSTEOPOROSIS

In clinical medicine one encounters the followingconditions associated with osteoporosis: (1) dis-use atrophy, where the normal stimulus to osteo-blastic activity is absent (4, 5); (2) old age, wherethe bone tissue like other tissue (cf. hair, skin,muscles) atrophies; (3) malnutrition, where theprotein requirements are not fulfilled, and thebone matrix, like other tissues, is depleted; (4)

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FIG. 1. CASE 1 (F. F., M.G.H. 156453) : EFFECT OF ESTRADIOL BEN-ZOATE ON NITROGEN, PHOSPHORUS,AND CALCIUM BALANCES, ON SERUM

26

METABOLIC EFFECTS OF STEROID HORMONESIN OSTEOPOROSIS

Cushing's syndrome where, we believe, an excessof the adrenal cortical "sugar" or "S" hormoneinhibits anabolism of protoplasm including bonematrix (2, 6); (5) adaptation syndrome of Selye(7), where, we believe, the pathological physi-ology is the same as in Cushing's syndrome; (6)idiopathic osteoporosis, where the cause of thecondition remains obscure; (7) acromegaly,where the cause may be the increase of pituitaryhormone(s), or the secondary lack of gonadalhormones (8); and (8) the post-menopausalstate, the commonest of all forms, where the diffi-culty is a deficiency in estrogen to stimulate theosteoblasts. Frequently 2 or more factors com-bine in one individual; thus, after an orthopedicoperation (see Cases 7, 8, and 9, below) factors(1) and (5) probably both play a part.

METABOLIC STUDIES

For the methods employed in the accumulation, inter-pretation and presentation of these data, see (9). Casehistories are abstracted in the appendix.

A. Post-menopausal osteoporosisCase 1. Post-Menopausal Osteoporosis; Artificial

Menopause; Estradiol Benzoate Therapy.The metabolic data of Case 1 are shown in Figure 1

and Table I. The first part of the study, conducted in5-day periods, consisted of: (1) three contr'ol periods;(2) five periods with estradiol benzoate 1.66 mgm. intra-muscularly every 3 days; (3) twenty-three days with thesame therapy at home; (1) two periods with the sametherapy; (5) two periods with progesterone 10 mgm. in-tramuscularly daily in addition to the estradiol; and (6)twelve periods after the cessation of both medications.The patient was then discharged on estrogen therapywhich was given continuously in varied dosage duringthe next 3 years; during this interval she was broughtback to the metabolic ward for study (1 to 3 five-dayperiods) on 3 occasions.

The data (Figure 1) are self-explanatory. Attentionshould be called to: (1) nitrogen, phosphorus, and cal-cium equilibria during the control periods (1 to 3); (2)the high serum phosphorus level which tended to fall

under estrogen therapy (less marked in this case than inthe others [vide infra]); (3) the slight improvement innitrogen balance under estrogen therapy; (4) the strik-ing and growing decrease in calcium excretion, both fecaland urinary, with estrogen treatment and the gradualreturn (40 days) in calcium excretion to pre-treatmentlevels following cessation of estrogen therapy; (5) a de-crease with estrogen treatment in the phosphorus excre-tion almost entirely confined to the urinary component,and reasonably proportional to the changes in the calciumand nitrogen metabolisms (see "Theoretical NitrogenBalance"); (6) failure of the serum phosphatase level,the index of osteoblastic activity, to rise under estrogentherapy; (7) an increase in nitrogen, but not in calciumand phosphorus, excretions in periods 11 and 12 with pro-gesterone therapy; and (8) the tendency to retain extra-cellular fluids with estradiol therapy, as suggested by theincrease in the actual weight above the theoretical weight.

The apparent discrepancy in the effect of estrogen onthe calcium and phosphorus balancys during periods 26and 27 is probably to be explained by erroneously highfecal excretions resulting from too short a period ofobservation (9).

Case 2. Post-Menopausal Osteoporosis; PhysiologicalMenopause; Question of Superimposed Atrophy of Dis-use; Estradiol Benzoate Therapy.

The metabolic data of Case 2 are shown in Figure 2and Table II. The study, conducted in 5-day periods,consisted of: (1) five control periods; (2) thirteen pe-riods during which the patient received estradiol benzoate3.32 mgm. intramuscularly every other day. In addition,during the 3 periods 14, 15, and 16, testosterone propionate25 mgm. were administered intramuscularly every otherday.

The data in Case 2 confirm the main observations madeon Case 1. The fall in the serum phosphorus level afterestradiol medication was more pronounced than in Case1, and in addition there was a fall in the serum calciumlevel. Again the serum phosphatase level failed to risewith the improvement in the calcium balance. The dura-tion of the testosterone propionate therapy was too shortto judge its effect on the calcium balance; it broughtabout the expected increase in the nitrogen retention andrise in the urinary 17-ketosteroid excretion. The theo-retical nitrogen balance based on the phosphorus balanceafter it had been corrected for the calcium balance agreesquite well with the measured nitrogen balance.

CALCIUM, PHOSPHORUS,AND ALKALINE PHOSPHATASELEvELS, AND ONBODY WEIGHT IN A FEMALE PATIENT WITH POST-MENOPAUSALOSTEO-POROSIS

For discussion, see text.The dotted line in the nitrogen metabolism data represents the "theoretical

nitrogen balance." The fecal nitrogen was estimated as 10 per cent of theintake. The fecal calciuni and phosphorus values as charted are averagesof 1, 2, 3, or 4 five-day periods as follows: 1 through 3, 4 through 5, 6through 8, 9 through 10, 11 through 12, 13 through 16, 17 through 20, 21through 24, 25, 26 through 27, 28 through 30; the individual values aregiven in Table I.

27


FIG. 2. CASE 2 (E. P., M.G.H. 203540): EFFECT OFESTRADIOL BENZOATEAND TESTOSTERONEPROPIONATEON

Case 3. Post-Menopausal Osteoporosis; ArtificialMenopause; Estradiol Benzoate Therapy.

The metabolic data of Case 3 are shown in Figure 3and Table III. The study, conducted in 5-day periods,consisted of: (1) four control periods; (2) nine periodsin which 1.66 mgm. of estradiol benzoate were admin-istered intramuscularly every 3 days; (3) ninety-threedays at home on the same medication; (4) five periodson the same medication; (5) seven periods during whichthe estradiol dosage was doubled; and (6) five controlperiods of medication. During period 10 the patient wasgiven in addition 10 mgm. of progesterone intramuscularlyeach day.

It will be noted in Figure 3 that the improvement inthe calcium balance in this case following estradiol ther-apy was almost entirely due to the fall in the urinarycalcium excretion. It is further suggested that the posi-tive calcium balance tends to diminish with time (compareperiods 14 to 18 with periods 11 to 13). Note, further-more, that the calcium balance was not improved, andpossibly reduced, when estradiol therapy was doubled inperiods 19 through 25. The fall in the serum phosphoruslevel with medication was especially striking in this case.The actual weight was greater than the theoretical weightduring the therapy, which suggests retention of extra-cellular fluids.

Case 4. Post-Menopausal Osteoporosis; ArtificialMenopause; Methyl Testosterone, Estradiol Benzoateand Pregnenolone Therapy.

The metabolic data of Case 4 are given in Figure 4and Table IV. The study, conducted in 6-day periods,consisted of: (1) four control periods; (2) four periodson methyl testosterone, 40 mgm. by mouth daily; (3) fiveperiods in which 1.66 mgm. of estradiol benzoate daily byinjection were added to the methyl testosterone therapy;(4) five periods back on the methyl testosterone therapyalone; (5) four more control periods off medication;(6) three periods on pregnenolone, 30 mgm. intramuscu-larly daily; (7) four more control periods off medicatiob;(8) five periods back on methyl testosterone, 40 mgm. bymouth daily with a change in the nitrogen and phos-phorus intakes during the -last 3 of these; and (9) one finalperiod where the methyl testosterone therapy was increasedto 100 mgm. by mouth daily. The urinary determina-tions were made on 3-day periods throughout.

In Figure 4 it should be noted first that the theo-retical nitrogen balance is consistently less than the actual

NITROGEN, PHOSPHORUS,AND CALCIUM BALANCES, ONSERUM CALCIUM, PHOSPHORUS,AND ALKALINE PHOS-PHATASE LEVELS, ON BODY WEIGHT AND ON URINARY17-KETOSTEROID EXCRETION

For discussion, see text.The fecal nitrogen was estimated as 10 per cent of the

intake. The fecal phosphorus and calcium values as

charted are averages of 2, 3, 4, or 5 five-day periods as

follows: 1 through 5, 6 through 9, 10 through 13, 14through 16, 17 through 18; the individual values are

given in Table II.

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FIG. 3. CASE 3 (A. M. R., M.G.H. 29358): EFFECT OF ESTRADIOLBENZOATEON NITROGEN, PHOSPHORUS,AND CALCIUM BALANCES, ON

SERUMCALCIUM, PHOSPHORUS,ANDALKALINE PHOSPHATASELEvELS,AND ON BODY WEIGHT IN A FEMALE PATIENT WITH POST-MENO-PAUSAL OSTEOPOROSIS

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FIG. 4. CASE 4 (R. W., M.G.H. 319940): EFFECT OF METHYLTESTOSTERONEALONE AND IN COMBINA-TION WITH ESTRADIOL BENZOATE, AND OF PREGNENOLONEON NITROGEN, PHOSPHORUS,AND CALCIUM BAL-ANCES, ON SERUMCALCIUM, PHOSPHORUS,AND ALKALINE PHOSPHATASELEVELS, ON BODY WEIGHT, AND

ON URINARY 17-KETOSTEROID EXCRETION IN A FEMALE PATIENT WITH POST-MENOPAUSALOSTEOPOROSISFor discussion, see text.

nitrogen balance, which indicates that there is some con-

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analyzed twice with the following results: analysis Oc-tober 1941: calcium 71 mgm., phosphorus 584 mgm., andnitrogen 9.31 grams; analysis February 2, 1944: calcium64 mgm., phosphorus 611 mgm., and nitrogen 8.40 grams.Figure 4 was constructed from the analysis of 1941; hadit been constructed from the analysis of 1944, the dis-crepancy would have been almost eliminated. Thus, ifone recalculates on the basis of the 1944 analysis thetheoretical nitrogen balance of period 4b, and in additionuses the value of 1.283 grams for the fecal nitrogen in-stead of 10 per cent of the intake, one obtains the values+ 0.65 and + 0.45 grams for the theoretical and actualnitrogen balances, respectively, in contrast to the valuesof + 0.18 and + 1.71 grams. Since the above discrepancyis fairly constant, it does not affect the trends inducedby treatment.

Figure 4 is self-explanatory. To be noted are: (1) thedecrease in the nitrogen, phosphorus, and calcium ex-cretions with methyl testosterone therapy, and the re-bound of nitrogen and phosphorus excretions on cessa-tion of therapy; (2) the fact that the fecal, as well as theurinary, excretions of both calcium and phosphorus werereduced under methyl testosterone therapy; (3) the factthat there was not an immediate rebound of the calciumexcretion following cessation of methyl testosteronetherapy; (4) the further improvement in the calciumbalance, but not in the nitrogen balance, when estradiolbenzoate therapy was added to the methyl testosteronetherapy (periods 9 to 13); (5) the fall in serum phos-phorus level with methyl testosterone and especially withestradiol benzoate therapy; (6) the definite tendency ofthe serum calcium level to parallel the serum phosphoruslevel (see also Figure 2); and (7) the failure of theserum phosphatase level to show a significant change.The effect of the pregnenolone therapy is inconclusive;it did not significantly affect the very low 17-ketos-teroid excretion. No explanation is forthcoming in pe-riods 29 and 30 for the low fecal calcium excretions notassociated with low nitrogen and phosphorus excretions;as a result, the data during periods 30 through 36 aredifficult to interpret. The actual and theoretical weightcurves suggest that there was retention of extracellularfluid with methyl testosterone therapy which was aug-mented when estradiol benzoate therapy was added.Pregnenolone therapy had a minimal effect on extracel-lular fluid retention.

Case 5. Post-Menopausal Osteoporosis; Artificial Men-opause; Paget's Disease; Diethylstilbestrol and Proges-terone Therapy.

The metabolic data of Case 5 are given in Figure 5and Table V. The study, conducted in 6-day periods,consisted of: (1) three control periods; (2) five periodson 1 mgm. of diethylstilbestrol by mouth daily; (3) sevenperiods on 15 mgm. of diethylstilbestrol by mouth daily,with an increase in the diet in the last 3 of these; (4)six periods with the same dosage of diethylstilbestrol inwhich progesterone by injection was given in addition (25mgm. daily for the first 4 of these periods, and 100 mgm.

daily for the last 2); and (5) three periods on 15 mgm.of diethylstilbestrol daily alone.

This patient was selected for the study not only be-cause she had marked osteoporosis from an artificialmenopause 30 years before, but because she had, in ad-dition, Paget's disease. The primary pathologic processof the Paget's disease, bone destruction, was not beingresponded to with the usual amount of increased boneformation because of the menopause (4). Therefore, itwas thought that any action of estrogen to stimulate boneformation would be magnified in this patient.

Figure 5 is self-explanatory. To be noted are: (1) themarkedly negative calcium and phosphorus balances dur-ing the control periods; (2) the marked improvement ofthese balances with 1 mgm. of diethylstilbestrol daily; (3)the further improvement with 15 mgm. of diethylstilbestroldaily;' (4) the lack of effect of progesterone on the cal-cium and phosphorus balances; (5) the high serum phos-phorus before treatment; (6) the tendency of the serumphosphorus to fall during treatment; (7) the failure ofthe serum phosphatase to rise with improvement of thecalcium balance; (8) the tendency of the 17-ketosteroidexcretion to rise with progesterone; (9) the failure of the"11-oxysteroid" excretion 4 to fluctuate outside of thenormal range with therapy; (10) the striking fall 6 inthe urinary follicle-stimulating hormone (FSH) excre-tion with diethylstilbestrol therapy; and (11) the subse-quent rise in the FSH excretion when progesteronetherapy was superimposed on the diethylstilbestrol therapy.The increase in the positive nitrogen balance and the in-crease in weight during periods 22 to 24 may be indi-cations that progesterone was acting unfavorably on thenitrogen balance (12). Not explained is the rise inFSH excretion in periods 23 and 24.

B. Senile osteoporosisCase 6. Senile Osteoporosis in a Male of 72; Testos-

terone Propionate and Estradiol Benzoate Therapy.The metabolic data of Case 6, which comprise studies

done on 290 of 530 consecutive days, are shown in Figure6 and Table VI. The study, conducted in 5-day periods,consisted of: (1) five control periods; (2) five periodson testosterone propionate, 25 mgm. by injection daily;(3) five periods in which estradiol benzoate 1.66 mgm.by injection on alternate days was added to the testos-terone propionate therapy; (4) five periods back ontestosterone propionate alone; (5) seven control periodsoff all medication; (6) five periods on estradiol benzoate1.66 mgm. by injection twice daily; (7) ten days withoutcollections on the same medication; (8) two more pe-riods on the same medication; (9) ninety-three days athome on estradiol benzoate 3.32 mgm. by injection 3 times

4These observations were carried out by Dr. NathanB. Talbot with his method (10). The normal range is0.10 to 0.35 mgm. per 24 hours.

5 The level fell from 200-300 units per day to less than6 units per day. Normal range of FSH excretion is 6 to50 mouse units per day (11).

35

L7 I

FIG. 5. CASE 5 (S. B., M.G.H. 430664): EFFECT OF DIETHYLSTILBESTROL ALONEAND IN COMBINATIONWITH PROGESTERONEON NITROGEN, PHOSPHORUS,AND CAL-CIUM BALANCES, ON SERUMCALCIUM, PHOSPHORUS,ANDALKALINE PHOSPHATASELEVELS, ON BODY WEIGHT, AND ON URINARY 17-KETOSTEROID, "11-OXYSTEROID,"AND FOLLICLE-STIMULATING HORMONEEXCRETION IN A FEMALE PATIENT WITHPOST-MENOPAUSALOSTEOPOROSISAND PAGET'S DISEASE

For discussion, see text.36

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FIG. 6. CASE 6 (M. H., M.G.H. 278511): EFFECT OF TESTOSTERONEPROPIONATEALONE AND IN

COMBINATION WITH ESTRADIOL BENZOATE AND VICE VERSA ON NITROGEN, PHOSPHORUS,AND CAL-CIUM BALANCES, ON SERUMCALCIUM, PHOSPHORUS,ANDALKALINE PHOSPHATASELEVELS, ON BODYWEIGHT, AND ON URINARY 17-KETOSTEROID EXCRETION IN A MALE PATIENT WITH SENILE OSTEO-POROSIS


40

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a week; (10) five periods on the same therapy; (11)nine periods in which testosterone propionate 25 mgm. in-tramuscularly daily was added to the estradiol benzoatetherapy, during the last 3 of which periods the intakes ofnitrogen and phosphorus were markedly increased; (12)three periods on the same diet and the same estradiolbenzoate therapy but off testosterone propionate therapy;(13) ninety-one days at home on the same estradiolbenzoate therapy; (14) three periods on the original dietwithout change in the estradiol therapy; (15) forty-threedays at home off all medication; and finally (16) fourcontrol periods on the original diet without medication.

Figure 6 is self-explanatory. The observations as awhole confirm those noted in Cases 1 to 4 with post-menopausal osteoporosis.

Again, as in Case 4, the theoretical nitrogen balanceas charted is consistently less positive than the actual ni-trogen balance which suggests some constant error.This discrepancy is probably to be attributed to errorsin the intakes and to estimation of the fecal nitrogen as10 per cent of the nitrogen intake (see discussion underCase 4). Case 6 received the same diet as Case 4; thisdiet was analyzed twice with the results given in thediscussion under Case 4. Figure 6 was constructed fromthe analysis of 1941; had it been constructed from theanalysis of 1944, as is Table V, the discrepancy wouldhave been almost eliminated. Thus, if one recalculates onthe basis of the 1944 analysis, the theoretical nitrogen bal-ance of period 5, and in addition uses the value of 1.283grams for the fecal nitrogen instead of 10 per cent ofthe intake, one obtains the values + 0.87 and + 1.30 gramsfor the theoretical and actual nitrogen balances, re-spectively, in contrast to the values of + 0.41 and + 2.21grams. As was pointed out in connection with Case 4,since the above discrepancy is fairly constant, it does notaffect the trends induced by treatment.

To be noted especially in Figure 6 are: (1) the markedreduction in nitrogen, phosphorus, and calcium excretionswith testosterone therapy; (2) the lack of rebound inthe calcium excretion as opposed to nitrogen and phos-phorus following cessation of testosterone therapy; (3)the further reduction in the phosphorus and especially inthe calcium excretion, but not in the nitrogen excretion,when estradiol benzoate therapy was added to testosteronepropionate therapy (periods 16 to 20); (4) the improve-ment in all 3 balances when testosterone propionate wasadded to estradiol benzoate therapy (periods 40 to 45);(5) reduction in the fecal as well as the urinary calciumand phosphorus excretions by both testosterone propionateand estradiol benzoate therapy; (6) the effect of bothtestosterone propionate and estradiol benzoate therapy inlowering the serum phosphorus level; (7) the failure ofmarked increases in the nitrogen and phosphorus bal-

J CC Q & X XX CIUM, PHOSPHORUS,AND ALKALINE PHOSPHATASELEV-a I aI i 1ut I I 1 4 aI IU6 I* pI *I I 11I to 1 1314 ELS; WEIGHT; ANDURINARY17-KETOSTEROIDEXcRETION

"DO IN A FEMALE PATIENT WITH OSTEOPOROTICPROCESSIN-FIG. 7. CASE 7 (E. S., M.G.H. 360207): NITROGEN, DUCEDBY OPERATION AND IMMOBILIZATION

PHOSPHORUS,AND CALCIUM BALANCES; SERUM CAL- For discussion, see text.

41


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ances by increased diet to affect the calcium balance (pe-riods 46, 47, 48); (8) the absence of any significantchange in the serum phosphatase and calcium levels; (9)

THEORETICAL NITROGEN the fall in the urinary 17-ketosteroid level with estradiol*

^ssZea@" (benzoate therapy; and (10) the tendency to accumulate ex-

tracellular fluid during both testosterone propionate andestradiol benzoate therapy as suggested by the theoretical

+

URINARY weight curves, with a prompt loss following the cessationl ggjw M of therapy.

C. Osteoporosis resulting from disuse and/or' T'n-'-1'1"'T adaptation syndromeCase 7. "Normal" Female; Effect of Orthopedic Op-o ^ t/ m S 5 > ' - // L eration; No Specific Therapy.

The metabolic data of Case 7 are shown in Figure 7,URINARYP"OSPNORU

and Table VII. Throughout the entire experiment thepatient was on a constant, neutral-ash, low calcium diet,except for the immediate post-operative period. She was

FFCAL PNOSPU up and active during the pre-operative period, and im-mobilized in a cast from the foot to the hip after operation.She underwent an arthrodesis of the right foot on the sec-ond day of period 5; there were no analyses for metabolic

loo CC. data during periods 5 and 6, but the 17-ketosteroid ex-ffi4o

* *_. cretion was followed.

§Jgas . During the 4 control periods the patient was in nega-iJ} t \ *tteW'tive calcium and phosphorus balance; the former was of30_ o_o_O

the order of magnitude one would expect with patients on

this diet (13). As expected, there was a marked increasein the calcium excretion after the operation, which per-

0 sisted unabated to the end of the investigation (58 daysOLMZw after the operation) (14). The increase in calcium ex-cretion was not en,tirely in the urine. The 17-ketosteroid-

Cexcretion was normal pre-operatively, which confirms thecontention that she was not debilitated; it rose immedi-

* ately after operation, and then fell decidedly below thepreoperative level for about 20 days. The pattern of re-sponse was thus similar to that encountered following any_

< / \traumatizing event (15). The marked elevation in 17-ketosteroid excretion in period 11 coincided with the pa-

*4.& ? / tient being allowed up in a wheel chair (16).Periods 7 through 14 in this untreated case serve as as- *z;;aa_a_ _*_*_ **_*

control for similar studies in Cases 8 and 9, who receivedestradiol therapy during the post-operative period (Figure

bcn4e 10).

as Case 8. Multiple Traumatic Fractures with Operativeto 3 3 Reduction of One in a Previously "Normal" Male; Ef-30 9 o fect of Estradiol Benzoate Therapy.* S 9The metabolic data of Case 8 are shown in Figure 8

and Table VIII. The study, conducted in 3-day periods,consisted of; (1) six control periods; (2) six periods

4 in which 1.66 mgm. of estradiol benzoate was given

CALcIuM BALANCES; ON SERUMCALCIUM, PHOSPHORUS,O * _ ; ^ ^ x ÂND ALKALINE PHOSPHATASELEVELS; AND ON URINARY

1213141516171.3I,nlOlaIIISII.lIslIela?IIsI 17-KEToSTEROID EXCRETION IN A MALE PATIENT WITH3-OAY Maoos OSTEOPOROTICPROCESSINDUCED BY MULTIPLE FRAcrUREs,

FIG. 8. CASE 8 (H. D., M.G.H. 382395): EFFEcr OF OPERATION, AND IMMOBILIZATIONESTRADIOL BENZOATE ON NITROGEN, PHOSPHORUS,AND For discussion, see text.

43


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daily by injection; and (3) six post-treatment controlperiods. The stool periods were analyzed 2 at a time.

Figure 8 is self-explanatory. The most important ob-flt <TRCA servations concern the calcium metabolism; these are

RETAMM Mi _ _ better shown in Figure 10 and will be discussed below.Again, there was a fall in the serum phosphorus, and, ifanything, a fall in the serum phosphatase. Of interestis the fall in 17-ketosteroids in period 13, followed by therise in urinary nitrogen, phosphorus, and calcium in pe-riod 14; we believe these to be connected though unex-

+10 ~~~~~~~~~~plained phenomena.Case 9. Bone Grafting Operation in an Ununited Fe-

mur of an Otherwise "Normal" Male; Effect of Es-tradiol Benzoate Therapy.

UMNAM ~~~~~~~Themetabolic data of Case 9 are shown in Figure 940.5- and Table IX. The study, conducted in 3-day periods,

consisted of: (1) six control periods; (2) six periodsin which 1.66 mgm. of estradiol benzoate was given dailyby injection; and (3) six post-treatment control periods.

41.0_ The stool periods were analyzed 2 at a time., OM

Figure 9 is self-explanatory. The theoretical nitrogenbalance shows a constant deviation from the measured ni-

"814 < / 1-> N°7 | trogen balance which suggests some constant errorisb ~~ b ;;;;r ~1--\---<--(videsupra). The calcium data, as in Case 8, are better

shown in Figure 10, and will be discussed below. It shouldbe noted that the serum phosphorus in this case, as op-posed to all of the other cases, did not fall during estradiol

OL 24M̂M ! therapy. The 17-ketosteroid excretion showed a ten--0l ; dency to fall during the estradiol benzoate therapy, which=3] is also somewhat suggested in Figure 7.

+0.33-Further analysis of calcium data of Cases 7,8, and 9

In Figure 10 the calcium data of Cases 8 and 9 with. \ s / \ estradiol benzoate therapy are compared with those of

4. \> \ / \^ Case 7 without such therapy. It is quite clear that es-tradiol benzoate therapy resulted in a decrease in theurinary calcium excretion, but had little effect on the

21 fecal calcium excretion during the 18 days of adminis-tration. However, the tendency for the fecal calcium to

M&n4tMR.decrease in Case 9 after the therapy was stopped may well12- 15t G have been a delayed response to the therapy. The urinary,0 S _ = Z citric acid values carried out and interpreted by Dr.

Ephraim Shorr confirm his finding (17) of a rise duiring8 ~~~~~~~~~~~estrogen therapy.

. I7-SETOSSTKI0 D. Osteoporosis of Cushing's syndrome2 Case 10. Cushing's Syndrome; Nephrolithiasis; Es-0 tradiol Benzoate and Testosterone Propionate Therapy.A4>CTUAL HTn* The metabolic data of Case 10 are shown in graphic

5S ° ^ i\ form in Figure 11. For data in tabular form for periods

M | CALCIUM BALANCES; ON SERUMCALCIUM, PHOSPHORUS,5.1 AND ALKALINE PHOSPHATASELEVELS; ON URiNARY 17-

II 12 131415161?ISI 10191O11111tsS4i5ir7161111 KETOSTEROID ExCRETION AND ON WEIGHT IN A MALE3-053 PWO0S PATIENT WITH OSTEOPOROTCPROCESSINDUCED BY OP-

FIG. 9. CASE 9 (C. M., M.G.H. 348774): EFFECT OF ERATION AND IMMOBILIZATIONESTRADIOL BENZOATE ON NITROGEN, PHOSPHORUS,AND For discussion, see text.

45

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46 EDWARDC. REIFENSTEIN, JR., AND FULLER ALBRIGHT

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FIG. 10. METABoLIc DATA FOR CALCIUM OF CASEs 7, 8, AND 9. 'EFFECTOFESTRADIOLBENZOATEAS COMPAREDWITH No THERAPYONq THE CALCIUMBALANCES IN PATIENTS WITH OSTEOPOROTICPROCESS DUE TO OPERATIONAND IMMOBILIZATION


47

48

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FIG. 11. CASE 10 (B. V., M.G.H. 74372): EFFECr OF ESTRADIOL BENZOATEAND TESTOSTERONEPROPIONATEON NITRO-GEN, PHOSPHORUS,AND CALCIUM BALANCES, AND ON SERUMCALCIUM, PHOSPHORUSAND ALKALINE PHOSPHATASEIN AFEMALE PATIENT WITH OSTEOPOROSIS DUE TO CUSHING'S SYNDROME

For discussion, see text.At the bottom of the chart, the urinary calcium is shown separately on an enlarged scale.

1 through 33, see (2). The study covers 37 five-dayperiods obtained on 4 hospital admissions. Two dietswere used: one for periods 1 through 14, and a second forperiods 15 through 37. The nitrogen intake shown inFigure 11 for periods 17 through 33 is an analyzed value,and differs from that previously published which wastaken from a table. The data in Figure 11 are self-ex-planatory. It should first be noted that the phosphorusbalance corresponds reasonably well with the sum of thenitrogen and calcium balances during the last 23 pe-riods, but not the first 14. This suggests some constant

error in the first 14 periods, probably the value for thenitrogen intake. A more detailed analysis to emphasizethe close agreement between the nitrogen, potassium,phosphorus, and sulphur balances of periods 15 through33 has already been published (9). Although Albrightet al (2) concluded from these studies that estrogen waswithout beneficial effect, this was true with respect tothe nitrogen balance but not altogether true with respect tothe calcium balance. Thus, with the larger dose of es-tradiol benzoate in periods 13 to 14 there is an increase,probably significant, in the calcium balance. Further-


more, when estradiol benzoate was added to testosteronepropionate therapy in periods 30 through 33, there wasa further fall in the urinary calcium excretion and an in-crease in the positive calcium balance. Other observationsto be underlined in Figure 11 are: (1) the marked de-crease in the urinary nitrogen, phosphorus, and calciumexcretions with testosterone propionate therapy; (2) themarked rise in the serum phosphatase level when the in-crease in calcium balance became appreciable (see pe-riods 30 through 33). Whereas Figure 11 suggested thatinsulin had a marked effect on calcium balance (see pe-riods 28 and 29) the authors are inclined to discount thisbecause of the essentially negative result in a second pa-tient with Cushing's syndrome so treated (18).

Case 11. Cushing's Syndrome with Osteoporosis; Es-tradiol Benzoate, Testosterone Propionate, and MethylTestosterone Therapy.

The metabolic data on Case 11 are shown in graphicform in Figure 12. For data in tabular form for periods1 through 36, see (2). The study covers 55 five-dayperiods obtained on 6 hospital admissions. The data inFigure 12 are self-explanatory. It should first be notedthat the phosphorus balance corresponds reasonably wellwith the sum of the nitrogen and calcium balancesthroughout. As in Case 10, one cannot conclude, as didAlbright, et al (2), that estrogen therapy is withoutbeneficial effect. It was started before the metabolicstudy was initiated; so its initial effect is hard to evaluate(see periods 1 through 7); however, further studiesundertaken 35 days after omitting estrogen show that thecalcium balance has changed from positive to negative(compare periods 8 and 9 with 6). Other points to benoted in Figure 12 are: (1) the loweiing of the urinarynitrogen, phosphorus, and calcium excretions with testo-sterone propionate therapy (periods 10 through 18, and23 through 36) and with methyl testosterone therapy(periods 50 through 55); (2) the fact that the fecalphosphorus and calcium excretions were also lowered withthese 2 testosterone compounds; (3) the quick reboundin the nitrogen and phosphorus and not the calcium metab-olisms on cessation of testosterone propionate therapy (seeperiods 19 through 22); (4) the steady improvement incalcium metabolism with continued administration oftestosterone propionate therapy; (5) the elevation of theserum phosphatase with improvement in the calciumbalance; and (6) the rise in the serum phosphorus levelfollowing omission of estradiol benzoate therapy in pe-riod 6. The marked improvement in calcium balancein periods 29 through 36 is probably to be attributed tocontinued testosterone propionate therapy, but the initia-tion of vitamin D therapy in period 29 makes the exactinterpretation difficult. Dehydroisoandrosterone acetatein periods 42 to 46 did not prevent the rebound in nitro-gen and phosphorus metabolisms from omission of testos-terone propionate therapy.

Case 12. Cushing's Syndrome with Osteoporosis;Progesterone and Testosterone Propionate Therapy.

The metabolic data of Case 12 are shown in graphicform in Figure 13. For data in tabular form, see (2).

The study, conducted in 5-day periods, consisted of: (1)five control periods; (2) seven periods on progesteronetherapy, 25 mgm. per day; and (3) four periods on testos-terone propionate therapy, 25 mgm. intramuscularly perday.

The data in Figure 13 are self-explanatory. As pointedout by Albright, et al (2), the progesterone therapy, ifanything, had a slightly beneficial effect on nitrogen,phosphorus, and calcium. The effect was not nearly somarked as that obtained in periods 13 to 16 with testos-terone propionate therapy. Of interest is the rise in thealkaline phosphatase level in period 16, when the calciumbalance became appreciable. It should be noted that the17-ketosteroid excretion was not lowered by progesteroneor elevated by testosterone propionate; the latter findingis surprising, and not in agreement with other studies.

CERTAIN THERAPEUTICASPECTSCONCERNINGPOST-MENOPAUSALOSTEOPOROSIS

A large number of cases, many complicated byfractures, have been treated with estrogens aloneand in combination with testosterone compoundsduring the past 5 years. As a group, these pa-tients have responded very satisfactorily. Withinweeks to months, the pain in the spine and otherbones usually has been considerably or completelyeliminated. There has frequently been an in-crease in weight, apparently an increase in thethickness of the skin and an improvement in thegeneral well-being Whereas the study is impos-sible to control, we have the impression that frac-tures, especially of the hip, in old ladies have re-sponded better than they would have otherwise.However, in spite of these favorable clinical mani-festations, it has been difficult to produce un-disputed evidence that the bones (excluding frac-ture-sites) as visualized by x-ray have becomemore calcified than before the therapy was in-stituted. Nevertheless, the recent films of severalof the longest-treated cases are fairly convincing.

Dosages have ranged as follows: diethylstil-bestrol 0.5 to 1 mgm. daily p.o., estrone sulfate 62.50 to 3.75 mgm. daily p.o., estradiol benzoate1.66 to 3.32 mgm. 3 times a week i.m., and es-tradiol dipropionate 5 mgm. weekly i.m. A fewpatients have been treated by implantation of pel-lets. Excessive estrogenic effect on the endo-metrium has been controlled whenever a respon-sive uterus was present, by interrupting the es-trogenic therapy periodically (every 4 to 6 weeks

6 Conjugated equine estrogens (Premarin [Ayerst, Mc-Kenna and Harrison]).

49


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FIG. 12. CASE 11 (R. B., M.G.H. 3397): EFFEcT OF ESTRADIOL BENZOATE, TESTOSTERONEPROPIONATEAND METHYLTESTOSTERONEON NITROGEN, PHOSPHORUS,AND CALCIUM BALANCES; AND ON SERUMCALCIUM,PHOSPHORUS,AND ALKALINE PHOSPHATASEIN A FEMALE PATIENT WITH OSTEOPOROSISDUE TO CUSHING'SSYNDROME


for 1 to 2 weeks), or by administering at regularintervals (every 4 to 6 weeks) a course of proges-

terone (5 mgm. daily i.m. for 5 days) or of an-

hydro-hydroxyprogesterone (40 to 60 mgm. dailyp.o. for 5 days). Testosterone compounds can-

not be given in most patients with the impunitysuggested from Case 4; she was remarkably freefrom the masculinizing effect of such medication.Most women will not tolerate more than 300 mgm.

per month of androgen. Wehave given methyl

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FIG. 13. CAsE 12 (B. A., M.G.H. 234190): EFFECT OF PROGESTERONEAND TESTOSTERONE

PROPIONATE. ON NITROGEN, P,HOSPHORUS, AND CALcium BALANCES; ON SERUMCALCIUM,

PHOSPHORUS,AND ALKALINE PHOSPHATASE;AND ON URINARY 17-KEToSTEROID EXCRETION

IN A FEmALE PATIENT WITH OSTEOPOROSISDUE Tro CUSIHING'S SYNDROME


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testosterone 10 to 20 mgm. daily p.o., and testo-sterone propionate 10 to 20 or 25 mgm. a week i.m.One of the most successful methods of administer-ing testosterone compounds to these patients is toimplant one or two pellets of testosterone (75mgm. each [Schering]) every 3 to 4 months. Weusually give some form of testosterone at least forthe first 6 to 12 weeks.

Since many of the steroids cause sodium reten-tion, the above endocrine therapy may causeedema in certain elderly patients, especially ifthey have low serum protein levels. If this isnot controlled by a low sodium chloride diet, and/or ammonium chloride, the steroid therapy mayhave to be modified.

Because of the possible danger that continuedestrogenic medication may lead to cancer, it hasbeen our practice to interrupt the medication for7 to 14 days every 4 to 6 weeks, even though theuterus is out. An examination of the vaginalsmear every 6 months provides a further safe-guard (19). If the uterus is in, a record shouldbe kept of the vaginal bleeding; any bleeding notaccording to plan (that is, not following estrogenor progesterone withdrawal) should promptly beinvestigated further.

Since osteoporosis is a deficiency in bone matrixprotoplasm, a high protein diet is probably indi-cated; since it is not a disease of calcium andphosphorus metabolism, excessively high intakesof these minerals and of vitamin D are probablynot indicated. Prolonged immobilization should,of course, be avoided if possible, because of thedanger of superimposed atrophy of disuse.

SUMMARY

1. Osteoporosis is defined as that form of under-mineralization of bone in which the primary de-fect is a hypofunction of the osteoblasts in layingdown bone matrix; eight etiological subgroups arelisted.

2. The effect of certain steroid hormones (no-tably estrogens, androgens, and progesterone) hasbeen studied in 11 cases of osteoporosis: 5 casesof the post-menopausal type, 1 case of the seniletype, 2 cases of the type seen following orthopedicoperations (atrophy of disuse), and 3 cases ofthe Cushing's syndrome type.

3. Estrogens in the 2 forms used (estradiol ben-

zoate and diethylstilbestrol) decreased the calciumand phosphorus excretions in the 4 types ofosteoporosis studied. Additional observations onestrogen therapy follow.

a. The fecal as well as the urinary calcium andphosphorus excretions were decreased inmost instances.

b. The effects were usually manifested within 6days; did not reach a maximum until after 30days; and persisted for 30 to 50 cays aftercessation of therapy.

c. The synthetic estrogen, diethylstilbestrol,appeared to be as effective as the naturally-occurring estrogen, estradiol.

d. The ranges of dosages employed were forestradiol benzoate 3.32 mgm. daily to 1.66mgm. every 3 days intramuscularly, and fordiethylstilbestrol 1 to 15 mgm. daily bymouth. There was no convincing evidencethat the larger doses of estradiol benzoatewere more effective than the smaller; in oneinstance (Figure 3) 3.32 mgm. seemed lesseffective than 1.66 mgm. every third day.In the one case studied, 15 mgm. of diethyl-stilbestrol daily was probably more effectivethan 1 mgm. daily.

e. The serum phosphorus levels, which tend tobe high in the post-menopausal group, fellin almost all instances.

f. The serum alkaline phosphatase levels, con-trary to expectations, did not rise.

g. The urinary nitrogen excretion showed apoorly-sustained decrease.

h. The urinary 17-ketosteroid excretion showeda moderate decrease with estradiol.

4. Androgens in the 2 forms used (testosteronepropionate and methyl testosterone) likewise de-creased the calcium and phosphorus excretions inthe 3 types of osteoporosis (post-menopausal,senile, and Cushing's syndrome) studied. Addi-tional observations on androgen therapy follow.

a. As in the case of estrogens, the fecal as wellas the urinary calcium and phosphorus ex-cretions were decreased; the effect of thetherapy on the calcium metabolism was slowin reaching its maximum, and persisted fora long time after cessation of therapy; theserum phosphorus levels tended to fall; the

52


serum alkaline phosphatase levels failed torise except in the three cases of Cushing'ssyndrome.

b. In contrast to estrogens, the decrease in theurinary nitrogen excretion was marked andprolonged.

c. The ranges of dosages employed were fortestosterone propionate 25 to 50 mgm. dailyintramuscularly, and for methyl testosterone40 to 100 mgm. daily by mouth.

d. Methyl testosterone appeared to be as effec-tive as testosterone propionate.

5. Progesterone, in the dosages of 10, 25, and100 mgm. daily, had no definite effect whethergiven alone or in combination with estrogen.

6. The effect on the calcum metabolism of es-trogen and androgen in combination was greaterthan that of either alone in the post-menopausaland senile groups.

7. In Cushing's syndrome estrogen probablydoes have a beneficial effect on the calcium balance,previous statements to the contrary from this clinicnotwithstanding! However, testosterone com-pounds have a much more striking effect in thiscondition, as opposed to other types of osteo-porosis.

8. The data contain observations on the effectof pregnenolone and dehydroisoandrosterone ace-tate.

9. A short discussion of certain therapeuticaspects of post-menopausal osteoporosis is in-cluded.

The authors are grateful to Drs. Max Gilbert andErwin Schwenk of the Schering Corporation, Bloomfield,New Jersey, for generous supplies of estradiol benzoate(Progynon-B), estradiol dipropionate (Progynon-DP),testosterone propionate (Oreton), methyl testosterone(Oreton-M), progesterone (Proluton), anhydro-hydroxy-progesterone (Pranone), dehydroisoandrosterone acetate,pregnenolone, and other steroids.

The authors are indebted to Drs. Charles H. Burnett,Russell W. Fraser, Anne Pappinheimer Forbes, LaurenceW. Kinsell, Harry F. Klinefelter, Jr., William Parson,Patricia H. Smith, and Hirsh W. Sulkowitch for pro-fessional assistance; and to Esther Bloomberg, DorothyF. Bryant, Evelyn Caroll, Lowell D. Cox, Eleanor F.Dempsey, Elizabeth C. Donaldson, Grace C. Griswold,Marion MacAulay, Robin M. Suby, Shirley L. Wells,and Priscilla White for technical assistance.

APPENDIX

Case historiesCase 1. F. F. (M.G.H. 156453), a 42-year-old woman,

had a bilateral oophorectomy at the age of 41 for endo-metriosis; following the operation she had "nocturnalseizures," the exact nature of which was not determined.During the following year there was a gradual onset ofback pain with increasing dorsal kyphosis and a loss ofenergy. On admission one year after operation, thepatient was in good physical condition except for thedeformities of her spine; her blood pressure was 130/80.X-rays revealed typical codfish deformity of many of thedorsal and lumbar vertebrae, a collapse of some vertebrae,and anterior wedging of others. Laboratory studies:serum calcium 10.5 mgm. per cent, serum phosphorus4.2 mgm. per cent, serum alkaline phosphatase 3.6 Bo-dansky units, serum total protein 7.3 grams per cent,normal glucose tolerance test, some hypoglycemia un-responsiveness in an insulin tolerance test, basal meta-bolic rate of minus 6, follicle-stimulating hormone testpositive for 25 mouse units per 100 ml., and 17-keto-steroid excretion of 4.3 mgm. per 24 hours. This casewas mentioned in previous communications (1 [Case 1],3 [Case 37], 20 [Case 82], 21).

Case 2. E. P. (M.G.H. 203540), a 60-year-old patient,had a physiological menopause at 53. Thirteen monthsbefore admission she fell down 6 steps and fractured herfirst lumbar vertebra; she was kept in bed 5 months forthis injury, and then allowed up with a brace. Eightmonths before admission the 9th dorsal vertebra col-lapsed. Except for back and chest pain, the patient hadno complaints, and was in good general health upon ad-mission. Her blood pressure was 120/90. X-ray exam-ination revealed the fractures of the first lumbar and the9th dorsal vertebrae, marked osteoporosis of the spine andpelvis, but not of the skull, and gall stones. Laboratorystudies: serum calcium 10.1 mgm. per cent; serum phos-phorus 3.5 mgm. per cent; serum alkaline phosphatase 3.7Bodansky units; serum total protein 7.6 grams per cent;no Bence-Jones protein in the urine. This case wasmentioned in previous communications (1 [Case 2],3 [Case 13], 20 [Case 85], 21).

Case 3. A. M. R. (M.G.H. 29358), a 60-year-old phy-sician, developed menopause at 45 following radium treat-ment of submucous fibroids. Four years before admissionshe experienced pain in the back while trying to raise awindow, and in the ensuing 4 years developed severalfractures of vertebrae and progressive deformity of thespine. Physical examination on admission revealed thedeformity of the spine and otherwise no abnormalities.Her blood pressure was 148/90. X-ray examinationshowed deformities of several thoracic and the first lum-bar vertebrae, and osteoporosis of the bones of the spineand pelvis but not of the skull. Laboratory studies:serum calcium 10.1 mgm. per cent; serum phosphorus3.0 mgm. per cent; serum phosphatase 3.7 Bodanskyunits; serum total protein 6.3 grams per cent. This casehas been mentioned in previous communications (1 [Case3], 3 [Case 32], 20 [Case 84], 21).

53


Case 4. R. W. (M.G.H. 319940), a 56-year-old woman,

had a cholecystectomy at 26, and thyroidectomy for thyro-toxicosis at 46. At 48, an artificial menopause was in-duced with radium forf metropathia hemorrhagica. Threeyears before admission the patient strained her back open-

ing a heavy window, and thereafter had several episodesof sharp pain in the back when lifting. Physical examina-tion showed a nervous woman with a tremor of her head,and considerable deformity of her back. Her blood pres-

sure was 115/75. X-ray examination revealed extensiveosteoporosis with multiple fractured vertebrae; bones ofskull were approximately normal in density. Laboratorystudies: no abnormalities of the urine, stools, or bloodcells; urine calcium 2 to 4 plus by the Sulkowitch test;serum calcium 10.6 mgm. per cent; serum phosphorus 3.1mgm. per cent; serum alkaline phosphatase 3.7 Bodanskyunits; serum chloride 93.2 m.eq. per 1.; serum carbondioxide combining power 28.1 m.eq. per 1.; non-proteinnitrogen level 26 mgm. per cent; and total protein 7.8grams per cent with an albumin/globulin ratio of 1.7.Electrocardiographic tracing was normal; follicle-stimu-lating hormone excretion in the urine was high (consistentwith the menopause). This case has been mentioned ina previous communication (21).

Case 5. S. B. (M.G.H. 430664), a 58-year-old woman,

had at the age of 28 a bilateral oophorectomy with a

hysterectomy for pelvic lacerations following childbirth.For some years she had occasional hot flashes and attacksof palpitation and nervousness. At the age of 50 she be-gan to notice weakness and the gradual onset of skeletaldeformities involving the skull, shoulder girdle, lowerribs, pelvis, and bones of the legs. At 54 she had acutetonsillitis, and then a tonsillectomy. At 57 she had pneu-

monia, and after 3 weeks in bed, increased weakness andpain in her tibiae. About this time she used braces on herlegs because of difficulty in walking. Shortly afterwardshe developed low-back pain on weight-bearing.

On admission, the patient was undernourished and de-formed with atrophic skin and muscles, dorsal kyphosisand right cervical-dorsal scoliosis, enlarged parietal bosses,bowing of the femora and tibiae, and collapse of the lumbarspine so that the ribs touched the wings of the iliae. Thechest was distorted; veins of the neck were distended; cor

pulmonale was present; blood pressure was 156/80.X-rays of the skull, shoulder girdle, lower ribs, pelvis,

femora, tibiae, and entire thoracic and lumbar spine ex-

cept for the upper three dorsal vertebrae showed Paget'sdisease; in addition there were marked generalized de-creased density of bones and typical codfish deformity ofmany vertebrae. There were pulmonary fibrosis, cardiacenlargement and displacement, and tortuosity of theaorta. Laboratory studies: serum calcium 10.5 mgm. percent, serum phosphorus 4.2 mgm. per cent, serum alkalinephosphatase 34.3 Bodansky units, serum total protein 7.3grams per cent, serum non-protein nitrogen 31 mgm. percent, serum sodium 140.0 m.eq. per 1., serum potassium4.7 m.eq. per 1., serum chloride 101 m.eq. per 1., serum

carbon dioxide content 34.2 m.eq. per 1., follicle-stimulat-ing hormone test positive for 192 mouse units per 24hours, and 17-ketosteroid excretion of 2.6 mgm. per 24

hours. The venous pressure was 65 mm. of water; thevital capacity was 1,200 ml.

Case 6. M. H. (M.G.H. 278511), a male of 72 years,developed pain in the back after a minor. injury 1 yearbefore admission (1-141). The symptoms persisted inspite of local therapy, and he was referred to the hospital.The only abnormal findings on physical examination werea thin skin and deformities of the spine; his blood pres-sure was 140/80. X-ray examination of the spine showedmarked decrease in density of the vertebrae with a cod-fish deformity of some, and wedging or collapse of others.Laboratory studies: serum calcium 10.0 mgm. per cent;serum phosphorus 3.1 mgm. per cent; serum alkalinephosphatase 4.2 Bodansky units; serum total protein 7.0grams per cent; non-protein nitrogen 18 mgm. per cent;urinary 17-ketosteroid excretion 7.2 and 6.9 mgm. per 24hours; follicle-stimulating hormone excretion in the urinenormal; gastric acidity normal. The normal level of thefollicle-stimulating hormone excretion is evidence againstthe idea of the osteoporosis having been due to the "malemenopause." This case has been mentioned in previouscommunications (6, 9, 21).

Case 7. E. S. (M.G.H. 360207), a female of 35 years,had poliomyelitis at the age of 9 involving the left legalone, and since the age of 14 had worn a 6-pound braceon the left leg. She had always been very active. Forthe 10 years prior to study she had had metatarsal painin the right foot, and for 3 years had turned her rightankle frequently. She was admitted for a triple arthro-desis and muscle transplant to strengthen the right ankde.The menstrual history was normal. From the point ofview of the experiment the patient can be considered anormal adult female in every respect, except for the resi-duals of the poliomyelitis of the left leg; her blood pres-sure was 120/80. Laboratory studies: serum calcium 9.8mgm. per cent; serum phosphorus 3.5 mgm. per cent;serum alkaline phosphatase 2.4 Bodansky units; andserum total protein 4.7 grams per cent; urinary 17-ketos-teroid excretion 7.6 mgm. per 24 hours. This case hasbeen mentioned briefly elsewhere (22).

Case 8. H. D. (M.G.H. 382395), a male fireman of 50years, fell 3 stories and suffered fractures of ribs, pelvis,right tibia and right fibula, and multiple contusions andabrasions. The patient was in shock on admission, butresponded promptly to a blood transfusion. On physicalexamination he was found to be a well-preserved manwithout organic disease; blood pressure was 110/60. AKirschner wire was inserted through the os calcis anda Zimmer bow applied. During the next 2 weeks the frac-tures were reduced by traction and by several manipula-tions under anesthesia. The patient was transferred tothe metabolic ward where studies were begun 44 daysafter the accident. Laboratory studies: serum calcium10.7 mgm. per cent; serum phosphorus 3.3 mgm. per cent;serum alkaline phosphatase 2.7 Bodansky units; serum

total protein 6.7 grams per cent. This case has beenmentioned briefly elsewhere (23).

Case 9. C. M. (M.G.H. 348774), a male of 24 years,sustained a fracture of the pelvis and of the right femur inan automobile accident 9 months before study. The fe-

54


mur failed to unite properly and, although the patient wasactive and able to walk about with a cane, he had un-usual motion and instability in his right femur because ofthe poor union. He was readmitted for bone grafting.Physical examination revealed a young adult male whowas normal in all respects except for the incomplete un-ion of his right femur; his blood pressure was 105/60.Laboratory studies: serum calcium 10.3 mgm. per cent;serum phosphorus 4.5 mgm. per cent; serum alkalinephosphatase 2.9 Bodansky units, and serum total protein6.0 grams per cent. This case has been mentioned brieflyelsewhere (24).

Case 10. B. V. (M.G.H. 74372), a female of 25 years,with Cushing's syndrome of 5 years duration. The casehistory of this patient has been published elsewhere (2[Case 1]). This case has been mentioned also in otherprevious communications (6, 9, 20 [Case 37]).

Case 11. R. B. (M.G.H. 3397), a female of 50 years,with Cushing's syndrome of 5 years duration. The casehistory of this patient has been published elsewhere (2[Case 2]). This case has been mentioned also in otherprevious communications (6, 9, 20 [Case 36], 25 [Case2]).

Case 12. B .A. (M.G.H. 234190), a female of 43 years,with Cushing's syndrome of 6 years duration. A completecase history with autopsy findings is reported elsewhere(26). This case has also been mentioned in previouscommunications (2 [Case 3], 20 [Case 38]).

BIBLIOGRAPHY

1. Albright, F., Bloomberg, E., and Smith, P. H., Post-menopausal osteoporosis. Tr. Assoc. Am. Physi-cians, 1940, 55, 298.

2. Albright, F., Parson, W., and Bloomberg, E., Cush-ing's syndrome interpreted as hyperadrenocorticismleading to hypergluconeogenesis; results of treat-ment with testosterone propionate. J. Clin. Endo-crinol., 1941, 1, 375.

3. Albright, F., Smith, P. H., and Richardson, A. M.,Post-menopausal osteoporosis: its clinical features.J. A. M. A., 1941, 116, 2465.

4. Reifenstein, E. C., Jr., and Albright, F., Paget'sdisease: its pathologic physiology and the impor-tance of this in the complications arising fromfracture and immobilization. New Eng. J. Med.,1944, 231, 343.

5. Albright, F., Burnett, C. H., Cope, O., and Parson,W., Acute atrophy of bone (osteoporosis) simulat-ing hyperparathyroidism. J. Clin. Endocrinol.,1941, 1, 711.

6. Albright, F., Cushing's syndrome. Its pathologicalphysiology, its relationship to the adrenogenitalsyndrome, and its connection with the problem ofthe reaction of the body to injurious agents ("alarmreaction" of Selye). The Harvey Lecture Series,1942-1943, 38, 123.

7. Selye, H., The alarm reaction. Cyclopedia Med.Surg. and Spec., F. A. Davis Company, Phila-

delphia, 1940, 15. Also, Selye, H., The generaladaptation syndrome and the diseases of adapta-tion. J. Clin. Endocrinol., 1946, 6, 117.

8. Reifenstein, E. C., Jr., Kinsell, L. W., and Albright,F., Observations on the use of the serum phos-phorus level as an index of pituitary growth hor-mone activity; the effect of estrogen therapy inacromegaly. Endocrinol., 1946, 39, 71. Also Con-ference on Metabolic Aspects of Convalescence In-cluding Bone and Wound Healing. Trans. of 12thMeeting, February 4-5, 1946, p. 97; distributed byJosiah Macy, Jr. Foundation, New York.

9. Reifenstein, E. C., Jr., Albright, F., and Wells, S. L.,The accumulation, interpretation, and presentationof data pertaining to metabolic balances, notablythose of calcium, phosphorus, and nitrogen. J.Clin. Endocrinol., 1945, 5, 367.

10. Talbot, N. B., Saltzman, A. H., Wixom, R. L., andWolfe, J. K., The colorimetric assay of urinarycorticosteroid-like substances. J. Biol. Chem., 1945,160, 535.

11. Klinefelter, H. F., Jr., Albright, F., and Griswold,G. C., Experience with a quantitative test fornormal or decreased amounts of follicle stimulatinghormone in the urine in endocrinological diagnosis.J. Clin. Endocrinol., 1943, 3, 529.

12. Abels, J. C., and Dobriner, K., Conference on Meta-bolic Aspects of Convalescence Including Bone andWound Healing, Transactions of Seventh Meeting,June 9-10, 1944, p. 122; distributed by Josiah Macy,Jr. Foundation, New York.

13. Farquharson, R. F., Salter, W. T., Tibbets, D. M.,and Aub, J. C., Studies of calcium and phosphorusmetabolism. XII. The effect of the ingestion ofacid-producing substances. J. Clin. Invest., 1931,10, 221.

14. Howard, J. E., Parson, W., and Bigham, R. S., Jr.,Studies on fracture convalescence. III. The uri-nary excretion of calcium and phosphorus. Bull.Johns Hopkins Hosp., 1945, 77, 291.

15. Forbes, A. P., Donaldson, E. C., Reifenstein, E. C.,Jr., and Albright, F., The effect of trauma anddisease on the urinary 17-ketosteroid excretion inman. J. Clin. Endocrinol. To be published.

16. Browne, J. S. L., Conference on Metabolic Aspects ofConvalescence Including Bone and Wound Heal-ing, Transactions of the Fifth Meeting, October8-9, 1943, p. 91; distributed by Josiah Macy, Jr.Foundation, New York.

17. Shorr, E., Bernheim, A. R., and Taussky, H., Therelation of urinary citric acid excretion to themenstrual cycle and the steroidal reproductive hor-mones. Science, 1942, 95, 606.

18. Reifenstein, E. C., Jr., and Albright, F., Conferenceson Metabolic Aspects of Convalescence IncludingBone and Wound Healing, Transactions of theFifth Meeting, October 8-9, 1943, p. 79; distributedby Josiah Macy, Jr. Foundation, New York.

19. Fremont-Smith, M., Graham, R. M., Janzen, L. T.,and Meigs, J. V., The vaginal smear in the diag-

55


nosis of uterine cancer. J. Clin. Endocrinol.,1945, 5, 40.

20. Fraser, R. W., Forbes, A. P., Albright, F., Sulko-witch, H., and Reifenstein, E. C., Jr., Colorimetricassay of 17-ketosteroids in urine; a survey of theuse of this test in endocrine investigation, diagno-sis, and therapy. J. Clin. Endocrinol., 1941, 1, 234.

21. Reifenstein, E. C., Jr., Albright, F., Parson, W., andBloomberg, E., The effect of estradiol benzoate,of testosterone propionate, and of combinations ofboth on post-menopausal osteoporosis and senileosteoporosis. Endocrinol., 1942, 30, S1024.

22. Reifenstein, E. C., Jr., and Albright, F., Conferenceson Metabolic Aspects of Convalescence IncludingBone and Wound Healing, Transactions of FirstMeeting, September 11-12, 1942, p. 37; Transac-tions of Second Meeting, December 11-12, 1942, p.69 and 96; and Transactions of Fourth Meeting,June 11-12, 1943, p. 77; distributed by Josiah Macy,Jr. Foundation, New York.

23. Reifenstein, E. C., Jr., and Albright, F., Conferenceson Metabolic Aspects of Convalescence IncludingBone and Wound Healing, Transactions of ThirdMeeting, March 12-13, 1943, p. 63; and Transac-tions of Fourth Meeting, June 11-12, 1943, p. 77;distributed by Josiah Macy, Jr. Foundation, NewYork.

24. Reifenstein, E. C., Jr., and Albright, F., Conferenceson Metabolic Aspects of Convalescence IncludingBone and Wound Healing, Transactions of FourthMeeting, June 11-12, 1943, p. 77; distributed byJosiah Macy, Jr. Foundation, New York.

25. Reifenstein, E. C., Jr., Forbes, A. P., Albright, F.,Donaldson, E., and Carroll, E., Effect of methyltestosterone on urinary 17-ketosteroids of adrenalorigin. J. Clin. Invest., 1945, 24, 416.

26. Albright, F., and MacMahon, H. E., Clinical Patho-logical Conference. Bull. New Eng. Med. Center,1941, 3, 35.

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