1164 Dr D. Foskett. Royal Berkshire Dr A. J. Karlish, Dr A. Kircher. Princess Margaret Hospital, Swindon: Dr E. O’Donovan, Dr J. Waddell. United Oxford Hospitals: Dr J. Black, Dr K. Durrant, Dr W. Hamilton, Dr D. Lane, Dr R. Marshall, Dr C. Paine, Dr G. Wiermk. We thank Dr R. H. Cowdell and Dr A. I. Spriggs for reviewing the histological and cytological material from all patients in this tnah and Mrs L. Pilling, the clinical trials secretary, who was assisted by Miss V. Francis and Mrs J. Holloway. A grant for secretarial support was made by the Oxford Regional Hospital Board and by the Cancer Research Fund, Radiotherapy Department, Churchill Hospital. During this study R.J.B. was a member of the M.R.C. external scientific staff. Requests for reprints should be addressed to A.H.L.

Dische. Battle

Hospital, Reading: Hospital, Reading: Dr J. Bunting,

REFERENCES

Days 3-Survival curves for received chemotherapy.

Fig.

to death

"optional"

and

"mandatory" patients

who

superior vena cava: all 6 patients presenting with this complication were assigned to the mandatory section of the trial. That the two groups were very similar is confirmed by the survival curves of the patients treated in a similar fashion in both groups-i.e., by chemotherapy (fig. 3). It thus seems likely that our conclusions are applicable to all cases of inoperable carcinoma of the bronchus. Although treatment with procarbazine did have the advantage of the convenience of oral administration, we were surprised by the high incidence of gastrointestinal symptoms ofsufficient severity to frustrate treatment whose intent was only palliative.’ The fact that the level

1. Durrant, K. R., Berry, R. J., Ellis, F., Ridehalgh, F. R., Black, J. M., Hamilton, W. S. Lancet, 1971, i, 715. 2. Laing, A. H., Berry, R. J., Newman, C. R., Smith, P. ibid, 1975, i, 129. 3. Bonadonna, G., Monfardini, S., Oldini, C., Guzzon, A, Di Pietro, S. Tumori, 1969, 55, 277. 4. Kenis, Y., De Smedt, J., Tagnon, H. J. Eur. J. Cancer, 1966, 2, 51. 5. Samuels, M., Leary, W., Howe, C. Cancer Chemother. Rep. 1969. 53, 135. 6. Peto, R., Pike, M. C. Biometrics, 1973, 29, 579. 7. Dowling, M. D., Krakoff, I. H., Karnofsky, D. A. in Chemotherapy of Cancer (edited by W. H. Cole); p. 61. Philadelphia, 1970. 8. De Vita, V. T., Schein, P. S. New Engl. J. Med. 1973, 288, 998.

‘

of gastrointestinal complications observed in those patients was much higher than that in patients with Hodgkin’s disease treated with procarbazine may be related to the higher median age of the patients with carcinoma of the bronchus. In view of the improved understanding of the dynamics of cytotoxic therapy, particularly in a resistant tumour, there would appear to be no indication in future for the use of single-agent continuous chemotherapy in carcinoma of the bronchus.8 The intermittent combinatiön chemotherapy of the type given was in retrospect too intensive and required more frequent admission to hospital than is desirable in palliative treatment. However, in those patients who survived the treatment, a higher proportion had their symptoms controlled till death than in the other treatment groups. Intermittent combination chemotherapy in any future trial should be carried out as an outpatient procedure and should aim to keep hospital visits down to intervals of three or four weeks. Finally this trial confirms the finding of the first Oxford carcinoma of the bronchus trial that "no immediate treatment" is the best policy in patients with inoperable carcinoma of the bronchus. This is particularly so for patients who are symptom-free or have mild symptoms. Any advance in the treatment of this unpleasant disease must come from clinical trials in which a no-immediatetreatment group is included as the reference arm. We acknowledge gratefully the help of the following chest physicians and radiotherapists who entered their patients into this trial, treated many of them, and completed a vast number of trial forms: Tindal General Hospital, Aylesbury: Dr W. Bermingham, Dr E. Hills, Dr E. Hope. Horton General Hospital, Banbury: Dr R. Adam. Harefield Hospital: Dr J. Angel. Wycombe General Hospital, High Wycombe: Dr A. Robson. Creaton General Hospital, Northampton: Dr G. C. Ferguson. Northampton General Hospital: Dr P. H. Cole, Dr P. C. Robertson. Mount Vernon Hospital, Northwood: Dr S.

BROMOCRIPTINE THERAPY IN ACROMEGALY Y. SACHDEV M. G. TUNBRIDGE W. D. R. WEIGHTMAN

A. GOMEZ-PAN A. DUNS R. HALL

Endocrine Unit,

Department of Medicine, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP S. K. GOOLAMALI

Department of Dermatology, University of Newcastle upon Tyne

Bromocriptine (CB-154, Sandoz) has to 21 acromegalic patients a period of 6-10 months. (11 mean serum The growth-hormone (G.H.) levels ranged from 10 µg/l to 512 µg/l before therapy. Bromocriptine suppressed G.H. values to 5 µg/l or less in 4 patients and to less than 10 µg/l in a further 8 patients, but in 2 patients G.H. levels did not show any significant reduction. Bromocriptine did not block stressinduced G.H. secretion. It did not disturb pituitary function other than secretion of prolactin and had negligible side-effects. Its effect on tumour size is uncertain and it is therefore unsuitable for patients with suprasellar extension of the tumour. Otherwise it seems reasonable to offer a trial of bromocriptine to all patients with acromegaly where therapy is deemed Summary

been given 10 female, male) for

necessary. In those who show a full response of G.H. levels with a dose of 20-40 mg of bromocriptine per day, external radiation to the pituitary can be used to prevent tumour expansion and bromocriptine withdrawn at intervals to assess the effect of the radiation. In patients with a partial response to bromocriptine, the decision to offer alternative therapy depends on the extent of the response and on the age and medical condition of the patient. In patients who

fail to respond to bromocriptine, particularly those younger patients with active disease, more definitive

1165 local treatment (e.g., trans-sphenoidal removal of the

six-hourly;

yttrium-90 implantation) would be indicated. Bromocriptine may also be used with benefit in the large number of patients who have shown a partial response to other forms of therapy.

and and increment,

tumour or

Introduction BROMOCRIPTINE (2-brom-fx-ergocryptine methane sulphonate ; CB-154 Sandoz) is a semisynthetic ergot alkaloid comprising a lysergic-acid residue and a cyclic tripeptide moiety.’ It activates dopamine receptors in the neostriatum and the median eminence of the rat hypothalamus.23 It has recently been shown to lower circulating growth-hormone (G.H.) levels in acromegaly.4A trial with bromocriptine was undertaken to evaluate its role in the treatment of patients with acromegaly.

Patients and Methods 21 acromegalic patients (11 female, 10 male), aged 33-68 years, were studied. 11 were previously untreated while 10 had received pituitary irradiation (yttrium-90 implant, 5;

external radiation, 4; proton beam, 1) one previously. All patients had persistently

year

or more

elevated

G.H.

levels which did not suppress normally (i.e., to < 5 ,ug/1) during a standard glucose-tolerance test (G.T.T.). The following complications were present among the patients: diabetes mellitus (7, 4 overt and 3 chemical), hypertension on therapy (4), carpal tunnel syndrome (4), galactorrhoea (3), and diabetes insipidus (1). 5 patients were on replacement therapy with hydrocortisone, and 2 with L-thyroxine. No patient had a visual field defect and suprasellar extension was excluded by an air encephalogram before entry in the trial. Serial serum samples for G.H. (G.H. profile) were taken at two-hour intervals via an indwelling venous catheter starting at 8 A.M. The first sample was taken with the patient fasting and recumbent and subsequent samples with the patient ambulant and eating normal meals. In addition to the G.H. profile, an augmented insulintolerance test (I.T.T.) with blood sugar, G.H., and plasma 11-hydroxycorticosteroids (11-OHc.s.) estimations were performed. Plasma luteinising hormone (L.H.) and folliclestimulating hormone (F.S.H.) were measured in each subject. An oral G.T.T. was carried out to assess carbohydrate tolerance and G.H. suppressibility. Protein-bound-iodine (P.B.I.; Technicon ’AutoAnalyzer’ method 56), ’Thyopac-3’ (Amersham),6were measured and the free thyroxine index7 was calculated. An intravenous thyrotrophin-releasinghormone test (T.R.H. test)8 for G.H. as well as thyrotrophin (T.S.H.) response was performed on each patient. Serum G.H.,9 T.s.H.," L.H., and F.S.H.l1 were estimated by specific radioimmunoassays using Medical Research Council (M.R.C) standard A H.G.H., M.R.C. standard 68/38 H.T.S.H., and M.R.C. standard b8/40 L.H. and 69/104 F.S.H. respectively. Blood-sugar was measured by the Technicon autoanalyzer 1l, glucose-oxidase method" and plasma 11-OHc.s. by a fluorimetric method." Sebum excretion (s.E.R.) was measured from the forehead skin by the method of Strauss and Pochi 14 as modified by Cunliffe and Shuster.15 Sebum measurements were made at the same time of the day to avoid circadian fluctuations.16 Liverfunction tests, full blood-count, and blood urea and electrolytes were estimated every three weeks. Radiological studies included anteroposterior and lateral skull films, tomography of the pituitary fossa, and heel-pad and skin thickness. Bromocriptine was given orally in an initial dose of 2.5 mg at twelve hourly intervals. The dose was increased stepwise at intervals of not less than two weeks to 2.5 mg eight-hourly; 2.5 mg six-hourly; 5 mg six-hourly; 10 mg

ment

at

maximum of 15 mg

six-hourly. Clinical repeated at each dose full biochemical and radiological reassessthree-monthly intervals. 18 patients have been to a

assessment

a

G.H. profile

were

at least six months, and some up to ten months. Therapy was discontinued in 3 patients after three months. Criteria of Response The following criteria were followed in assessing the patients’ response to bromocriptine :-

treated for

Full response: obvious clinical remission and G.H.

profile


5 ug/1. Absent response: no significant change in clinical features or G.H. values.

The

Results levels during the

mean serum G.H.

G.H.

profile

ranged from 10 g/1 to 512 .g/1 before treatment. With the institution of bromocriptine therapy the G.H. levels fell in 19 patients. In 2 patients (nos. 4 and 20) no significant change in G.H. levels was seen during therapy with doses of up to 60 mg daily after three months and therapy was discontinued (fig. 1 and table). A third patient (no. 17) who showed a partial response emigrated and continued supervision was impracticable. The greatest fall in G.H. levels was seen when the daily dose of bromocriptine was 20 mg or less; thereafter, G.H. reduction was less marked even when the dose was increased to a maximum of 60 mg a day (table). In 2 patients (nos.and 18) where G.H. was suppressed to 13% and 47% of the basal values, the G.H. levels "escaped" after six months’ therapy and increased to 35-5% and 107% respectively whilst the patient was receiving 60 mg bromocriptine daily. In 19 patients, the values fell to 50% of basal levels or less irrespective of the initial range, in 12 the G.H. values were reduced to less than 10 g/1, and in 4 these were suppressed to 5 ,g/1 or below. 2 patients discontinued bromocriptine therapy after partial suppression in G.H. levels had been achieved. In each of them an overswing of G.H. to values higher than the pre-therapy levels was observed within one week. One of them resumed bromocriptine therapy and G.H. levels fell again in eight days.

Fig. 1.-Mean

serum

growth-hormone levels ( pretreatment

[-] minimum post-treatment) in 21 patients with acromegaly

during bromocriptine therapy.

1166

reduction was accompanied by subjective in soft-tissue texture and thickness. 16 volunteered that there had beena reduction in their facial features. 14 noticed reduction in handsize, 5 admitted that their rings had become loose, while 2 were able to wear rings which they had discarded over the past ten years. The shoes were loose in 11 patients, 2 were able to wear half a size smaller G.H.

changes patients

shoes. One patient noticed reduction in the size of his shirt collar. Galactorrhoea disappeared rapidly in 3 patients. Prolactin levels were not measured as the effects of bromocriptine on prolactin secretion are already well established)7 Acroparoesthesix. resolved in the early stages of therapy in 4 patients. Sexual performance improved in 8 male patients, but L.H. and F.S.H. values were unaffected. Other pituitary functions were unchanged. In 2 patients tested before and during therapy, when the basal G.H. value was suppressed to less than 5 t-g/1, the G.H. response to T.R.H. was unchanged (fig. 2). Similarly in one patient in whom the basal G.H. level was suppressed to < 5 .g/1 during treatment with bromocriptine, an increase of G.H. level from 3 {ig/1 to 75 .g/1 was observed during an I.T.T. Carbohydrate tolerance improved in all diabetic patients. Chemical diabetes mellitus disappeared in all 3 patients, and in 1 of the 4 overtly diabetic subjects hypoglycxmic agents could be omitted. The H-index was calculated for glucose tolerance)8 Pre-therapy and

u au

ou

.7u

J’U

Fig.

IOU

2.-Serum growth hormone response to thyrotrophin-re. leasing hormone in a patient with acromegaly before and after treatment with

bromocriptine.

post-therapy values were compared in 15 non-diabetic subjects excluding 4 diabetic patients on therapy, 1 patient with diabetes insipidus on chlorpropamide, and 1 patient who had stopped bromocriptine therapy

CLINICAL AND BIOCHEMICAL DATA ON ACROMEGALIC PATIENTS BEFORE AND DURING BROMOCRIPTINE THERAPY

*Figures in parentheses represent G.H. values expressed as % basal.

iau

MINUTES

1167 the time of second G.T.T. The mean post-therapy H index fell but just failed to reach conventional levels of significance (P ==0-059). Blood-pressure readings were unaffected, and antihypertensive therapy was continued unchanged in the hypertensive patients. Radiological reduction in heelpad thickness greater than 5 mm assessed by a radiologist in a double-blind manner was observed in only 2 patients (both had G.H. levels which were suppressed to less than 5 p.g/l). In others a difference of 1 to 2 mm

at

patients irrespective of the change in G.H. level. These changes might be due to reduction in serum prolactin induced by bromocriptine though objective measurement of the S.E.R. failed to show any significant change. The improvement in carbohydrate tolerance was

associated with a fall in G.H. levels and could be due to decreased insulin antagonism. Nausea is known to be due to a central effect of bromocriptine and is reduced when the capsules are taken with meals and the dose is increased gradually. was not regarded as significant. The pituitary fossa Bromocriptine is superior to levodopa in the treatment of acromegaly since it has a longer duration of and visual fields were unaffected. The mean s.E.R. in 10 male values acromegalic patients before and after action.21 It has advantages over growth hormonerelease inhibiting hormone. (G.H.-R.I.H.) as it can be therapy were 1-46:0-10 p.gJcm2Jminute (S.E.M.) and 1-41:0-18 !J-gJcm2Jminute (S.E.M.) respectively. given orally, has a longer action, and is free from In 11 female patients the mean s.E.R. was 1-03± haematological side-effects, and its actions on other 0.19 fLgJcm2Jminute (S.E.M.) before treatment and hormones are less widespread.24 25 Bromocriptine does not block G.H. secretion in response to T.R.H. or 0’98i0’21 jj.g/cm2/minute (S.E.M.) after treatment. these are values than Although significantly higher hypoglycaemia. Compared with other forms of availthose obtained from age and sex matched non-acroable treatment for acromegaly, bromocriptine does not yield the definite results obtained by transmegalic controls there was no significant effect of sphenoidal surgery26 but has less morbidity. Morebromocriptine on s.E.R. over results compare favourably with those achieved by irradiation either external or internal26-29 but are Side-effects much more rapid. Transient nausea was reported by all patients in the It is not possible at present to determine whether initial stages of therapy but this resolved spontaneously as was even the dose was increased. Mild constipation bromocriptine has any effect on tumour growth, nor is the mechanism by which it suppresses G.H. levels experienced by 6 patients; in 2, laxatives had to be in acromegaly established. In prolactin producing prescribed. One patient complained of spasm and tumours it is known to act at pituitary level, but in 60 on with of two while mg therapy fingers blanching it appears to have a different site of action to reduced dose was subsided when the This acromegaly daily. since a direct stimulus to G.H. release such as T.R.H. of not recorded in was 10 mg daily. Hypotension any is not overcome liver-function by bromocriptine-unlike G.H.-R.I.H. the patients. Full blood-counts, tests, which acts directly on the somatotroph and has been urea, and electrolytes remained unchanged. shown to block the T.R.H.-induced G.H. release in acromegaly.30 Moreover, a hypothalamic stimulus to Discussion G.H. release such as insulin-induced hypoglycaemia Bromocriptine was originally described as a specificis also able to bypass the suppression of G.H. levels by inhibitor of prolactin secretion; and it has been bromocriptine. effectively used to inhibit prolactin secretion and galactorrhoea.19-22 del Pozo and Audibert23 reported no Conclusions reduction in G.H. levels in normal subjects. Liuzzi et does not appear to be contraindicated Bromocriptine aJ.4 used a single oral dose of 2-5 mg of bromocriptine in with any patient acromegaly, but in view of the in 7 acromegalic patients and observedsignificant G.H. about its effect on tumour size it would reduction two to five hours later. Thorner et al.5 uncertainty to administer it to a patient with a suprabe unwise found it "a safe, effective and non-invasive" method sellar extension of the tumour because of the possibility to control G.H. levels in acromegaly. In our study, of further expansion and the risk to vision. The bromocriptine was fully effective in 4 patients (19%) of its effect, its selective action on G.H. and partially effective in 15 (71%), and ineffective in rapidity secretion, and its low toxicity make it prolactin 2 (9-5%). The optimum therapeutic daily dose was suitable for early mild acromegaly in 20 mg or less; no significant further fall in G.H. levels particularly it which may be important to preserve other pituitary was seen in most of those who were given higher secretion. It doses. The G.H. reduction was sustained when bromo- functions, particularly gonadotrophin be for also suitable elderly patients particularly criptine was repeated every five to six hours. The may unsuitable for or radiation, and for found surgery cause of the "escape phenomenon" observed in 2 external radiation treatment pending the patients is not known. These patients denied having patients given of this effect which may take several years; it may stopped their therapy though escape was observed in further also benefit in patients who have respondgive 2 other patients who admitted temporary cessation or not at all to previous treatment by ed partially of treatment. Bromocriptine is selective in its action other procedures. and does not appear to affect the secretion of pituitary In the light of our experience we now adopt the hormones other than G.H. and prolactin. In none of the patients maintained on L-thyroxine or hydrocorti- following guidelines in the use of bromocriptine in acromegalic patients. If the patient has a suprasellar sone was alteration of replacement therapy required. extension or field defect, transfrontal surgical decomThe subjective feeling of well-being and general improvement in facial features, hands, feet, and pression of the optic chiasma is the first line of treatment, followed by external radiation; and bromoall hyperhidrosis occurred early and was

reported by

1168

criptine may be given subsequently to control the endocrinopathy if this is not relieved by surgery and radiation. In patients in whom the tumour is confined to the pituitary fossa a trial of bromocriptine is undertaken. In those in whom a full response, as previously defined, is obtained, external radiation is applied to the tumour and bromocriptine is continued, to be withdrawn annually to ascertain if the radiation has suppressed G.H. secretion. When a partial response is obtained with bromocriptine the decision to continue this alone or offer external radiation or more definitive local treatment (e.g., yttrium-90 implantation or trans-sphenoidal hypophysectomy) depends on many factors, particularly the extent of the response and the age and medical condition of the individual patient. If there is no response to bromocriptine, definitive local therapy remains the treatment of choice particularly in younger acromegalics with active disease. The dosage regimen is now 2.5mg twice daily with meals for one week to allow the patient to become accustomed to the drug, then 2’5 mg six-hourly for a week and 5 mg six-hourly subsequently. Clinical and biochemical effects can be assessed within a month, but this interval is too short for radiological changes to be apparent. We are grateful to Dr J. Anderson for evaluation of the Hindex ; to Mr A. L. Crombie for ophthalmic assessment; to Dr J. Marks and Mrs J. Alcock for S.E.R. estimation; to Dr A. Burridge for radiological assessment, to Sister G. M. Smith and Sister P. M. Fletcher for their help; to Mr W. M. Ross and Mr R. M. Kalbag for their cooperation; to Dr W. P. Maclay and the late Dr. E. R. Evans (Sandoz Ltd.) for the supply of bromocriptine ; to Dr W. R. Butt for the gift of antisera of L.H./F.S.H. and purified pituitary F.S.H.; and to Dr Anne Stockell-Hartree for pituitary L.H. used for labelling.

TREATMENT OF OSTEOPOROSIS OF AGEING WITH 1&agr;-HYDROXYCHOLECALCIFEROL

O. H. SØRENSEN Medical Department E, Frederiksberg Hospital; Department of Physical Medicine, City Hospital; Royal Dental College; and Department

Chiodini, P. G., Botalia, L., Cremascoli, G., Muller, E. E. Silverstrini, F. J. clin. Endocr. Metab. 1974, 38, 910. 5. Thorner, M. O., Chait, A., Aitken, M., Benker, G., Bloom, S. R., Mortimer, C. H., Sanders, P., Stuart-Mason, A., Besser, G. M. Br. med. J. 1975, i, 299. 6. Clark, F., Brown, H. J. ibid. 1970, i, 713. 7. Clark, F., Brown, H. J. ibid. 1970, ii, 543. 8. Ormston, B. J., Garry, R., Cryer, R. J., Besser, G. M., Hall, R. Lancet, 1971, ii, 10. 9. Hartog, M., Gaafar, M. A., Meisser, B., Fraser, T. R. Br. med. J. 1964, ii, 1229. 10. Hall, R., Amos, J., Ormston, B. J. ibid. 1971, i, 582. 11. Shaw, R. W., Butt, W. R., London, D. R., Marshall, J. C. J. Obstet. Gynœc. Br. Commonw. 1974, 81, 632. 12. Trinder, P. Ann. Clin. Biochem. 1969, 6, 24. 13. Mattingly, D.J. clin. Path. 1962, 15, 374. 14. Strauss, J. S., Pochi, P. E.J. invest. Derm. 1961, 36, 293. 15. Cunliffe, W. J., Shuster, S. Br. J. Derm. 1969, 81, 697. 16. Burton, J. L., Cunliffe, W. J., Shuster, S. ibid. 1970, 82, 497. 17. Fluckiger, E., Wagner, H. R. Experientia, 1968, 24, 1130. 18. Billewicz, W. Z., Anderson, J., Lind, T. Br. med. J. 1973, i, 573. 19. Lutterback, P. M., Pryor, J. S., Varga, L., Wenner, R. ibid. 1971, iii, 228. 20. Besser, G. M., Parke, L., Edwards, C. R. W., Forsyth, I. A., McNeilly, A. S. ibid. 1972, iii, 669. 21. del Pozo, E., Brundel, Re R., Varga, L., Friesen, H. J. clin. Endocr. Metab. 1972, 35, 768. 22.

Rolland, R., Schellekens, L. A., Liquin, R. M. Clin. Endocr. 1974, 3,

155. 23. del Pozo, E., Audibert, A. New Engl.J. Med. 1972, 287, 723. 24. Besser, G. M., Paxton, A. M., Johnson, S. A. N., Moody, E.

J., Mortimer, C. H., Hall, R., Gomez-Pan, A., Schally, A. V., Kastin, A. J., Coy, D. H. Lancet, 1975, i, 1166.

Seven

were

cal fitness. Increased bone formation and mineralisation were seen on iliac-crest bone biopsy, and this was sup-

ported by an increased osteoblastic activity demonstrated by histochemical measurement of alkaline-phosphatase activity. Bone histology furthermore showed a reduced bone resorption, which was supported by a reduced urinary excretion of total hydroxyproline. Photon absorptiometry of the forearm accorded with the histological findings, showing a significant increase in the bone mineral

content.

Serum-calcium

rose

in all

developing transitory hypercalcæurinary excretion of calcium and magnesium significantly. The serum concentrations of 25-hydroxycholecalciferol and parathyroid hormone were not significantly affected by the treatment. It is

patients,

one

a severe

mia. The increased

concluded that 1&agr;-H.C.C. is an effective tool in the treatment of senile osteoporosis. Introduction

1.

1972. 4. Liuzzi, A.,

of Orthopœdic Surgery, University Hospital, Copenhagen, Denmark

patients with osteoporosis of agetreated with synthetic 1&agr;-hying droxycholecalciferol (1&agr;-H.C.C.) for 3-4 months. The compound was given at a daily oral dose of 2 µg together with an oral supplement of 1 g of calcium. Clinically there was a striking improvement in the patients’ physi-

Summary

REFERENCES

Griffith, R., Fluckiger, E. CB-154 Pharmacological and Toxicological data. Sandoz, Basle, Switzerland. December, 1972. 2. Corrodi, H., Fuxe, K., Hokfelt, T., Lidbrink, P., Ungerstedt, U. J. Pharmac. Pharmacol. 1973, 25, 409. 3. Hokfelt, T., Fuxe, K. Brain-endocrine Interactions; p. 181. Basle,

L. HJORTH I. REIMANN R. B. ANDERSEN

B. LUND I. KJAER T. FRIIS

osteoporosis of ageing, bone resorption exceeds bone formation. Many compounds have been used to reduce resorption or to stimulate formation, but none with convincing effect. The pathogenesis of age-related bone loss is not clear, but one explanation is the progresIN

sive decline in intestinal calcium absorption.’ Peacock et awl. have demonstrated that this malabsorption is not due to a basic defect in the intestinal calcium-transport mechanism, since it can be corrected with the active vitamin-D analogue, la-hydroxycholecalciferot (l