48

DISTRIBUTION OF SELECTED PSYCHOSOCIAL VARIABLES BY ER STATUS

*Two-tailed Wilcoxon rank

2: 1-5. 10. Ward HWC. Anti oestrogen therapy for breast cancer: a trial of tamoxifen levels. Br Med J 1973; i: 13-15.

sum test.

< 3 finol/mg; ER-positive tumours included those with values above these limits). After 4 years’ follow-up, significant survival differences were found for several psychosocial variables, most notably social support (unpublished data). However, there do not appear to be significant differences in the psychosocial data for the two groups of patients defined by ER status (table). Our findings would not support the hypothesis proposed by Razavi and colleagues that survival effects for psychosocial variables can be explained by their association with hormone receptor status. British Columbia Cancer Agency,

Vancouver,

T. GREG HISLOP

British Columbia V5Z 4E6, Canada

LISA KAN

1.

The prognostic significance of breast cancer. J Chron Dis 1987; 40: 729-35.

Hislop TG, et al.

Fornander T, Rutquist LE, Sjöberg HE. Long term adjuvant tamoxifen in early breast cancer: nsk of accelerated bone loss? Proc ASCO 1989; 8: 21. 5. Jordan VC, Phelps E, Lingren JU. Effects of antiestrogens on bone in castrated and intact female rats. Breast Cancer Res Treat 1987; 10: 31-35. 6. Neven P, Muylder XD, Vanbelle Y, Vanderick G, Muylder E. Tamoxifen and the uterus and endometrium Lancer 1989; i: 375. 7. Boccardo F, Bruzzi P, Rubagotti A, et al. Oestrogen-like action of tamoxifen on vaginal epithelium in breast cancer patients. Oncology 1981, 38: 281-85. 8. Fentiman IS, Caleffi M, Brame K, Chaudary MA, Hayward JL. Double blind controlled trial of tamoxifen therapy for mastalgia. Lancet 1986; i: 287-88. 9. Powles TJ, Ford HT, Gazet JC. A randomised clinical trial to compare tamoxifen and danazol for treatment of benign mammary dysplasia. Breast Dis (Senologia) 1987;

4.

psychosocial factors in women with

Tamoxifen and oestrogen replacement SiR,—The suggested use of oestrogen replacement therapy (ERT) as a control arm for breast cancer prevention trials using tamoxifen prompts Dr Spicer and Professor Pike (June 9, p 1397) to ask if tamoxifen can be given with, rather than instead of, ERT. In our feasibility and subsequent pilot trial of tamoxifen versus placebo given to healthy higher risk women with a family history of breast cancer, we have monitored bone mass, lipid profile, clotting factors, and hormone levels to detect any adverse antioestrogenic effects of tamoxifen. We have found that the fibrinogen/ antithrombin III ratio remains unaffected, cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B are reduced,! sexhormone-binding globulin is increasedand bone mass is unaffected,2although there is evidence that postmenopausal bone loss may be reduced by tamoxifen.3-5 There is also evidence that tamoxifen is oestrogenic on the female genital tract.6,7 It seems that tamoxifen, although effective for treatment of benign8,9 and malignant breast diseaseslO is not anti-oestrogenic and may be oestrogenic in other tissues. This would therefore not preclude the use of this "anti-oestrogen" with oestrogens in ERT. We have given hormone replacement (HRT) to women in the prevention programme on tamoxifen/placebo and also not excluded women already on HRT from entry into the trial. We have not identified any untoward interaction of tamoxifen with HRT and are now looking at any changes in lipid profile that may arise with the combination of tamoxifen and HRT. Perhaps a balance of tamoxifen with oestrogen and progestin could be achieved which would protect against cardiovascular disease, osteoporosis, and breast, ovarian, and uterine cancer in postmenopausal women. The aim of Spicer and Pike to reduce "total mortality" might be better achieved by combining tamoxifen and HRT rather than using them individually. Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK

TREVOR J. POWLES

TJ, Tillyer CR, Jones AL, et al. Prevention of breast cancer using tamoxifen: update on the Royal Marsden Hospital pilot programme. Eur J Cancer (in press). 2. Powles TJ, Hardy JR, Ashley SE, et al. A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer. Br J Cancer 1989; 60: 1. Powles an

126-31. 3. Turken S, Siris E, Seldin D, et al. Effects of tamoxifen women with breast cancer. JNCI 1989; 81: 1086-88.

on

spinal bone density in

at

low dose

SIR,-Several clinical studies suggest that tamoxifen acts as an oestrogen agonist in postmenopausal women. Dr Spicer and Professor Pike refer to the increased risk of endometrial carcinoma, the bone-preserving effect of the drug, and favourable effects on the lipid profile. This last benefit has also been observed in premenopausal women without any effect on clotting factors.’ Rapid growth of uterine fibroids was seen in postmenopausal women taking tamoxifen.2 Tamoxifen shares with 17p-oestradiol the property of potent inhibition of lipid peroxidation, which may be relevant to its antitumour activity.3 Unopposed oestrogen for postmenopausal replacement therapy is associated with an increased risk of endometrial cancer, but this risk is abolished when, as in current standard practice, a progestagen is added. Women would be better served by prospective studies evaluating the effects on breast cancer risk of cyclical versus continuous combined oestrogen and progestagen regimens rather than by studies on tamoxifen for breast cancer prevention. Women who have had a hysterectomy are the appropriate population for studies of unopposed oestrogen, or indeed unopposed tamoxifen. Department of Obstetrics and Gynaecology, St Mary’s Hospital Medical School, London W2 1PG, UK

R. W. STONES

M, Fentiman IS, Clark GM, et al. Effect of tamoxifen on oestrogen binding, lipid and lipoprotein concentrations and blood clotting parameters m premenopausal women with breast pain. J Endocrinol 1988; 119: 335-39. 2. Boudouris O, Ferrand S, Guillet JL, et al Effets paradoxaux du tamoxifene sur l’uterus de la femme. J Gynecol Obstet Biol Reprod 1989; 18: 372-78. 3. Wiseman E, Laughton MJ, Arnstein HRV, et al The antioxidant action of tamoxifen 1. Caletti

and its metabolites. FEES Lett 1990; 263: 192-94.

Fluoride treatment for

osteoporosis

SiR,—Your May 5 editorial is well balanced-except, I feel, for sodium fluoride, which is widely used in Europe. Sodium fluoride has been under attack since publication of the Mayo Clinic trial.! This "orphan" drug is cheap and unique in its ability to stimulate bone formation. However, the drug has to be enteric-coated (EC-NaF), and to promote the mechanical strength of bone it must be given not in excess, with much supplemental calcium, and without vitamin D when this is not necessary.2 Although we use the same fluoride/calcium regimen our data differ from those of Riggs and co-workers.! First, the gain in lumbar bone mineral density (BMD) was about half that seen in the Mayo Clinic study. Second, there was no appendicular bone loss, as measured at the forearm by rectilinear scanning at three scanning sites (whereas significant bone loss was seen in age and sex matched controls), thus confirming our previous results obtained from the ordinary transverse scanning of the radius.3 Third, we did not see any significant increase in serum alkaline phosphatase (AP). Fourth, after the first year of treatment Riggs et al showed an increasing trend of new vertebral fractures, whereas we noted a decreasing trend. Bone loss at the appendicular skeleton, a rise in AP, and an increasing trend in crush fractures are all signs of fluoride toxicity.2 We used 25 mg EC-NaF tablets (’Procal’) thrice daily, whereas in the Mayo Clinic study 30 mg non-enteric-coated (NEC) capsules were given in a regimen alternating between twice daily and thrice daily. We have evaluated4 the bioavailability of the capsules used in the Mayo Clinic trial (Mericon, lot number 35051, expiry date

49

RANDOMISED CROSSOVER COMPARISON IN 10 HEALTHY VOLUNTEERS OF BIOAVAILABILITY FROM ENTERIC-COATED AND NON-COATED SODIUM FLUORIDE CAPSULES*

D-aminoacids and microwaves SIR,-Professor Lubec (March 31, p 792) fails to appreciate my (Feb 24, p 470) that bacterial cell walls contain D-aminoacids (D-alanine and D-glutamic acid) as structural units statement

AUC: area under curve. *EC-NaF and NEC-NaF 30 mg taken fasting, t30mg EC- NaF tablets specially produced for this trial with same coatmg as in commercially available tablets (also same as that used m usual procal tablets as shown by our earlier work’).

August, 1992). A greater bioavailability from NEC-capsules (by a factor of at least 1-6) was seen (table). Thus the 75 mg NEC mericon capsules correspond to 120 mg of our EC-NaF procal tablets. We have no experience of such high doses. Conversely, our EC-NaF regimen corresponds to a NEC-NaF regimen not much different from that (about 55 mg daily) used previously by Riggs and co-workerss,6 without substantial appendicular bone loss or an increase in AP. Furthermore, the patients with increased vertebral trabeculation and thickening of the end-plates ("fluoridic" vertebrae) had only one-sixth the fracture rate of the other patients.5 Ultimately, 60% of the patients so treated had fluoridic vertebrae and were thus protected, prompting Riggs et aF to state that "the substantial gain in bone mass may increase net bone strength". This view is contrary to your statement that it is likely that any dose of fluoride that increases bone density will result in new bone of inferior quality. That bioavailability is important has been demonstrated by Delmas et al,8 who compared EC-NaF (50 mg, 22mg of F ion) with monofluorophosphate (200 mg, 26 4 mg of F ion), and obtained with the latter drug (whose bioavailability equals that of NEC-NaF capsules8), a lumbar-BMD gain similar to that seen in the Mayo Clinic study.’ New crush fractures occurred in 6% of the EC-NaF group, versus 24% in the monofluorophosphate 8 group, a highly significant difference. Thus high bioavailability of fluoride can be deleterious to bone if the dose is not adjusted.9 One could wish for a larger therapeutic window for fluoride, but fluoride should not be condemned on the basis of the Mayo Clinic trial, especially since controlled studies with lower doses seemed promising. !0.11 Departments of Rheumatology and Biochemistry, CHARLES NAGANT DE DEUXCHAISNES Louvain University in Brussels. JEAN-PIERRE DEVOGELAER St-Luc University Hospital, 1200 Brussels, Belgium FRÉDÉRIC STEIN

Riggs BL, Hodgson SF,

O’Fallon WM, et al. Effect of fluonde treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1990; 322: 802-09. 2. Nagant de Deuxchaisnes C, Devogelaer JP, Depresseux G, Malghem J, Maldague B. Treatment of the vertebral crush fracture syndrome with enteric-coated sodium fluonde tablets and calcium supplements. Bone Miner Res 1990; 5 (supply: S5-26. J 3. Devogelaer JP, Résumont P, Huaux JP, Nagant de Deuxchaisnes C. Effect of sodium fluonde on bone mineral content of the radius in postmenopausal osteoporosis. In: Christiansen C, Arnaud CD, Nordin BEC, Parfitt AM, Peck WA, Riggs BL, eds. Osteoporosis. Copenhagen: Aalborg Suftsbogtrykkeri, 1984: 689-91. 4. Devogelaer JP, Nagant de Deuxchaisnes C, Stein F. Bioavailability of enteric-mated sodium fluoride tablets as affected by the administration of calcium supplements at different time intervals. J Bone Miner Res 1990; 5 (suppl 1): S75-79. 5. Riggs BL, Hodgson SF, Hoffman DL, Kelly PJ, Johnson KA, Taves D. Treatment of primary osteoporosis with fluonde and calcium: clinical tolerance and fracture occurence. JAMA 1980; 242: 446-49. 6. Riggs BL, Seeman E, Hodgson SF, Taves DR, O’Fallon WM. Effect of the fluoride/calcium regimen on vertebral fracture occurrence in postmenopausal osteoporosis. NEngl J Med 1982; 306: 446-50. 7 Riggs BL, Hodgson SF, Muhs J, Wahner HW. Fluoride treatment of osteoporosis: clinical and bone densitometric responses. In: Christiansen C, Johansen JS, Riis BJ, eds. Osteoporosis. Viborg Norhaven 1987: 817-23. 8. Delmas PD, Dupuis J, Duboeuf F, Chapuy MC, Meunier PJ. Treatment of vertebral osteoporosis with disodium monofluorophosphate. Comparison with sodium fluoride. J Bone Miner Res 1990; 5 (suppl 1). S143-47. 9 Heaney RP, Baylink DJ, Johnston CC Jr, et al. Fluoride therapy for the vertebral crush fracture syndrome. Ann Intern Med 1989; 111: 678-80. 10. Mamelle N, Meunier PJ, Dusan R, et al. Risk-benefit ratio of sodium fluoride treatment in primary vertebral osteoporosis. Lancet 1988; ii: 361-65. 11. Buckle RM. 3 year study of sodium fluoride treatment on vertebral fracture incidence in osteoporosis J Bone Miner Res 1989, 4 (suppl 1) S186. 1.

of their peptidoglycan cell-wall structures. This is not merely "my view"; it is a fact.’ Lubec questions my claim that D-aminoacid oxidases would convert ingested D-aminoacids to tx-ketoacids. He also suggests that racemases could convert D-aminoacids to the L-isomers-a strange suggestion since aminoacid racemases occur only in bacteria, fungi, the earthworm, and some insects.2,3 His concern about the neurotoxicity of minute amounts of D-proline is strange because substantial amounts of other D-aminoacids are well tolerated: he himself refers to studies involving the ethical administration of D-methionine to man, and D-phenylalanine (a health-food product) is recommended as an analgesic. Finally, we have found that the D-aminoacid oxidase in the cerebellum of mice, sheep, and rats actually produces D-alanine.4,5 Department of Biochemistry, University of Western Australia,

WOLFE SEGAL

Nedlands, Western Australia 6009

1. Ito E, Strominger JL. Enzymatic synthesis of the peptide in bacterial uridine nucleotides II: enzymatic synthesis and addition of D-alanyl-D-alanine. J Biol Chem 1962; 237: 2696-703. 2. Adams E. Aminoacid racemases and epimerases. In: Boyer PD, ed. The enzymes: vol VI, 3rd ed. New York: Academic Press, 1972: 479-507. 3. Cohen PP, Sallach HJ. In: Greenberg DM, ed. Metabolic pathways: vol II. New York: Academic Press, 1961: 53. 4. Keating PJ, Segal W. A proposed function for D-amino add oxidase in mammalian brain. 12th International Congress of Biochemistry (Perth, Western Australia, 1982); POS 001-216:145; Proc Aust Biochem Soc 1984; 16: 28. 5 Keating PJ. PhD thesis, University of Western Australia, 1990.

Intrapartum fetal ECG electrodes SIR,-Early recordings of the fetal electrocardiogram (ECG) during labour were made with nickel/silver wound-clip electrodes.1 Since this initial work, routine monitoring of the fetal heart rate has been done with electrodes, either clip or spiral, which are universally made of stainless steel. This material has mechanical advantages and is more biocompatible than silver but, as an electrode, it is inadequate for recording the ECG waveform. The heart rate is only part of the information that is available from the ECG, and there is interest in detailed analysis of the ECG waveform itself.2 The raw signal from a stainless steel electrode is far from ideal for this purpose. Stainless steel acts as a high pass filter and the metal does not adopt a stable potential with the scalp, resulting in pronounced drifting of the baseline (figure, upper trace). To some extent the signal can be improved by averaging and filtering. We feel that a better solution would be to return to silver-based electrodes. We have constructed such electrodes modelled on the Copeland clip (Surgicraft). These electrodes were silver plated, partly chloridised, and then coated with a biocompatible, electrically conducting polymer. The polymer coating overcomes the difficulty of silver chloride’s

STAINLESS STFEL

I

SIL VER/SIL VER CHLORIDE

Representative segments of two intrapartum fetal ECG signals with different electrodes. Both

recordings filtered at 0 8-80

Hz.