Chewing gum and hypokalaemia SIR,-A 55-year old man was referred to our hospital in 1991 because of atypical abdominal pain. He had a history of chronic neurosis, appendectomy, cholecystectomy, and an inferior myocardial infarction in 1987. After his myocardial infarction he was advised to quit smoking, which he did, but to wean from this habit he chewed gum. Several months later his family doctor repeatedly noted increased blood pressure and a calcium antagonist was started, resulting in blood pressure becoming normal. In 1991 blood pressure was 158/98 mm Hg and pulse was 72/min. Heart, lungs, and abdomen were normal. Serum potassium was 3-0 mmol/L (normal 3-5-4-5), which was confirmed several times. The patient denied use of diuretics or liquorice. Active renin was low (7-55 ng/L,normal 10-30), whereas serum adrenocorticotropic hormone, cortisol, and aldosterone were normal. Microscopic urine examination, computed tomography of the abdomen and adrenal glands, intravenous pyelography, and barium enema of large intestine were also normal. The increased blood pressure, hypokalaemia, and a low active renin suggested the use of an aldosterone-like substance. More thorough questioning revealed that the patient had consumed two packs of Stimerol gum daily since 1987 when he stopped smoking. Stimerol contains glycyrrhizinic acid (24 mg per pack of 16 g manufacturer’s data), an aldosterone-like substance and the main component of liquorice.l Liquorice induces sodium retention and potassium loss, eventually resulting in hypertension.2,3 The cause of the abdominal pain remained unclear although hypokalaemia can cause abdominal tenderness and eventually paralytic ileus.1 Although the amount of glycyrrhizinic acid in Stimerol is low compared with that in liquorice, the patient was advised to quit any use of chewing gum. Four weeks later, serum potassium was normal (3-7 mmol/L), and he no longer complained of abdominal tendemess. Furthermore, his antihypertensive treatment had to be stopped because of hypotension. Three months after stopping any use of chewing gum he was still free of complaints, had a blood pressure of 124/80 mm Hg and serum potassium of 3.9 mmol/L. Department of Internal Medicine, University Hospital (AZ-VUB), 1090 Brussels, Belgium
MICHAEL ROSSEEL DANNY SCHOORS
1. Reynolds JEF, ed. Martindale: the extra pharmacopoeia. 29th ed. London: Pharmaceutical Press, 1989: 1093-94. 2. Brandon S. Liquorice and hypertension. Lancet 1991; 337: 557 3. Blanchley JD, Knochel JP. Tobacco chewer’s hypokalemia: licorice revisited. N Engl J Med 1980; 302: 784-85. 4. Carter DC. The acute abdomen. In: Shearman DJC, Finlayson NDC, eds Diseases of the gastrointestinal tract and liver. 2nd ed. Edinburgh: Churchill Livingstone, 1989: 505-30.
SIR,-We do not agree with the conclusion drawn by the Finnish Leukaemia Group study workers (Oct 31, p 1049) that clodronate is an "effective and safe adjunct in the management of multiple myeloma", because no clinical advantage was demonstrated compared with standard chemotherapy. Delay of progression of osteolytic bone lesions did not translate into either decreased analgesic consumption or a reduction in non-vertebral fractures. The percentage increase of patients who felt no pain was stated to be higher in the clodronate arm than in the controls, but did not differ significantly. Radiotherapy, orthopaedic, or hospital treatment requirements were not examined and therefore no conclusions can be made with respect to the clinical relevance of the different progression rates of osteolytic lesions or vertebral fractures. Radiographic assessment alone cannot be used as a clinical outcome measure since bone lesions have no prognostic significance in multiple myeloma and do not, in any case, quantify bone involvement as shown by histiometric analysis.! The corrected serum calcium and urinary calcium excretion were significantly reduced in both groups but these differences only related to measurements in the normal range. The urinary calcium excretion at baseline was significantly lower in the placebo arm, suggesting a lower index of bone resorption in this group; this
difference may render subsequent serial comparisons invalid .2 Again, important clinical outcomes such as terminal hypercalcaemia are not discussed. Comparisons of equivalence of the two groups were further marred by the significantly higher proportion of younger people ( < 65 years) in the clodronate group than among controls. The serum &bgr;2-microglobulin, substratified for age, is the most powerful prognostic index of myelomatosis.3 Absorption of a single dose of clodronate is less than 5% even under ideal conditions." Patients are generally recommended to avoid food for at least 1 h before and after taking the capsules.5 This makes an eight-hourly dose regimen difficult to adhere to and must impinge upon their quality of life. The investigators’ conclusions would add c3793 per year to the cost of treating one patient.5 We cannot recommend the routine use of clodronate in multiple myeloma on the basis of this study, which reaffirms the difficulty in interpreting radiological and biochemical data as clinical outcome measures.
Department of Clinical Oncology, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 0NN, UK
HARPREET S. WASAN
1. Bataille R, Chappard D, Klein B. Mechanisms of bone lesions in multiple myeloma. Haem Oncol Clin N Am 1992; 6: 285-95. 2. Mundy G, Bertolini D. Bone destruction and hypercalcemia in plasma cell myeloma.
Semin Oncol 1986; 13: 291-99. 3. Dune B, Stock-Novack D, Salmon S, et al. Prognostic value of pretreatment serum &bgr;2-microglobulin in myeloma: a South-West Oncology Group study. Blood 1990; 75: 823-30. 4. Yakatan C, Poynor W, Talbert R, et al. Clodronate kinetics and bioavailability. Clin Pharm Ther 1982; 31: 521-24. 5. British National Formulary. No 24, September, 1992. London: British Medical Association and Royal Pharmaceutical Society of Great Britain, 1992: 281.
SIR,-Dr Wasan and Dr Waxman criticise our study on the effects of clodronate in the treatment of patients with multiple myeloma. They believe that radiographic assessment alone cannot be used as a clinical outcome measure because bone lesions have no prognostic significance in multiple myeloma. Our published findings show that bone lesions had a substantial effect on 2-year survival of the patients in our study. On the basis of univariate logistic regression analysis, the number of osteolytic lesions at baseline (p < 0-001) and the number of non-vertebral fractures at baseline (p 0-035) were significantly related to the risk of death from any cause during the 24 months’ follow-up. Similarly, the progression of osteolytic lesions (p=0004), vertebral fractures (p=0001), and non-vertebral fractures (p = 0-002) were significantly associated with the risk of death during the 24 months’ follow-up. Therefore, we do not agree with Wasan and Waxman’s conclusion that bone lesions do not have prognostic significance in this disease. In fact, bone lesions were as good a predictor of the risk of death as was baseline albumin-corrected serum calcium (p < 0-001) and were a better predictor than baseline urinary calcium excretion (p = 0-052). Thus, the selection of radiographic findings as the major endpoint in our trial is not only valid but should also perhaps be the primary endpoint in other trials aiming to investigate the effects of different treatments in multiple =
myeloma. Wasan and Waxman also criticise our results for changes in and urinary calcium concentrations. With respect to serum calcium we agree that patients receiving clodronate treatment had significantly lower serum calcium than those receiving placebo at 12 and 24 months only when serum calcium was analysed as a continuous variable. However, high albumin-corrected serum caldum ( 2-65 mmol/1) was more frequent in the clodronate group at baseline than in the placebo group (38,1 % vs 32-9%, not significant), but fewer patients receiving clodronate had high serum calcium at 24 months than those on placebo (4-6% vs 7-2%), although the difference was not statistically significant. Furthermore, the patients receiving clodronate had higher urinary calcium excretion than patients receiving placebo at baseline (0-84 vs 0-61, p < 005), but the reduction in urinary calcium excretion was serum