243
Fluoride and vertebral fractures SiR,—Your May 5 editorial (p 1065) takes a negative view of fluoride treatment for osteoporosis, citing the double-blind study of Riggs et all with high doses of a high potency sodium fluoride but ignoring our large randomised study3 with much lower doses given as enteric-coated tablets. Riggs and colleagues’ paper questions our results and misquotes many of them. They suggest that our patients treated with sodium fluoride had a non-significant 25% reduction in vertebral fractures (a figure not given in our paper) in comparison with patients whose osteoporosis had been treated in other ways. On re-analysis of our data we can confirm this percentage but not its non-significance when calculated by the methods used by Riggs et al. From table ni in our paper we calculated rates per person-year and found, between 0 and 24 months, 173 crush fractures per 360 patient-years (0-48) in the fluoride group and 174 fractures per 272 patient-years (0-64) in the non-fluoride group, this 25% reduction is significant ( = 15-8; p < 0’001). Moreover, the results presented by Riggs et al ignore the significant effects of fluoride treatment at the second and third years on the ground that the 4th year relative risk was not significant (this may be due to toxicity during the 4th year, from the accumulation of fluoride in bone). Analysis of Riggs and colleagues’ data suggests a discrepancy between the calculated relative risks and the 95% confidence intervals (CI). Using the X2 based method to calculate the 95% CI we find that the relative risks in favour of fluoride after 2 and 3 years of treatment are significant (p < 0.01 and p < 0001, respectively) and after the entire period also (p = 0-05). The CIs were large and not in agreement with the rates and relative risks given. The only explanation for such unfavourable CIs seems to be adjustment for co-variables, as mentioned in the paper’s section on statistical analysis-but in that case, the adjusted relative risks should be different from those given by Riggs et al. Furthermore, it is surprising to not find any precise figures about the multidimensional statistical analyses. Statistical reappraisal of Riggs’ data might lead to a more optimistic view of the effects of sodium fluoride on the vertebral fracture rate, at least during the second and third years of therapy. NICOLE MAMELLE PIERRE-JEAN MEUNIER PATRICK NETTER,
INSERM Units 265 and 234, Hôpital Edouard Herriot, 69437 Lyon, France 1.
2 3.
for GETOP
Study Group
Riggs BL, Hodgson SF, O’Fallon M, et al Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1990; 322: 802-09. Nagant de Deuxchaisnes C, Devogelaer JP, Stein F. Fluoride treatment for osteoporosis Lancet 1990, 336: 48. Mamelle N, Meunier PJ, Dusan R, et al Risk-benefit of sodium fluoride treatment in primary vertebral osteoporosis Lancet 1988; ii. 361-65
Ovarian relaxin is not essential for dilatation of cervix SIR,-The transformation of the uterine cervix from a firm and inextensible structure to one that at delivery is compliant and distensible is thought to be a major physiological function of relaxin. It has been proposed that relaxin acts in concert with substances such as progestins, oestrogens, catecholamines, and prostaglandins, but the precise contribution of this hormone has not been identified; nor has it been proved that relaxin is essential for this transformation. That aspect of relaxin can be studied by looking at pregnancies achieved by in vitro fertilisation (IVF) in women who lack ovaries and so have no major source of relaxin. A 32-year-old woman with a balanced chromosome translocation (1/X) had had premature ovarian failure diagnosed at 19 years and she and her husband chose IVF with donated ova. Artificial menstrual cycles were established in the recipient and four embryos were transferred after IVF of donor ova. One normal pregnancy was confirmed by ultrasound. Serial blood samples were collected for assay of pregnancy hormones. Relaxin was measured by radioimmunoassay at 39 weeks plus 3 and 6 days after embryo transfer, at 40 weeks (induction of labour), during labour and delivery, 5 and 15 h after delivery, and daily on days 2-9. The
of variation for the relaxin assay’ were 10-9% at 50 pg/ml, 6-7% at 100 pg/ml, and 4-8% at 180 pg/ml, and the inter-assay coefficient of variation was 7-7% at 97-0 pg/ml
intra-assay coefficients (n=16).
The pregnancy was uncomplicated and at 37 weeks’ gestation pelvimetry was done before a trial of vaginal delivery. All pelvic measurements were normal. Labour was induced at 40 weeks. At 0830 hours the cervix was 3 cm dilated. An oxytocin infusion was started and at 1800 hours the cervix was 5 cm dilated, full dilatation being achieved 2hours later. There was no cephalopelvic disproportion or constriction ring. A boy weighing 3760 g was born after a forceps delivery needing firm traction. The placenta was removed without difficulty. The delivery was complicated by post-partum haemorrhage due to uterine atony, and three units of blood were transfused. Serum relaxin was not measurable (less than 11pg/ml) in any of the fifteen samples collected before, during, or nine days after delivery. The concentrations of other hormones, in samples taken in pregnancy, were similar to those in other studies of IVF 3 pregnancy cycles. The absence of measurable relaxin in the peripheral circulation
early
during pregnancy in this patient supports the thesis that if relaxin is synthesised outside the ovary, it is produced in very small amounts and may not enter the general circulation.4 Relaxin has been detected in non-ovarian tissues but its synthesis in tissues other than the corpus luteum has not been proven. Administration of porcine relaxin at the cervix before labour has been associated with
improved cervical scores and easier delivery, supporting the proposal that relaxin has a role in preparing the cervix for parturition.5,6 The delivery described here was difficult. However, the cervix was dilated and structural changes during labour were achieved in the absence of relaxin from the ovary. It remains to be demonstrated conclusively that relaxin is crucial to the changes in the cervix seen in labour.
Supported by grants from the National Health and Medical Research Council (Australia) and the National Institutes of Health (USA). Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, Victoria 3052, Australia, and Department of Obstetrics and Gynaecology, Monash University
L. W. EDDIE I. T. CAMERON J. F. LEETON D. L. HEALY P. RENOU
1. Eddie LW, Bell RJ, Lester A, et al. Radioimmunoassay of relaxin in pregnancy with an analogue of human relaxin. Lancet 1986; i: 1344-46. 2. Eddie LW, Sutton B, Fitzgerald S, Bell RJ, Johnston PD, Tregear GW. Relaxin in paired samples of serum and milk from women following term and pre-term delivery. Am J Obstet Gynecol 1989; 161: 970-73. 3. McLachlin RI, Burger HG, Healy DL, de Kretser DM, Robertson DM. Circulating immunoreactive inhibin in the luteal phase and early gestation of women undergoing ovulation induction. Fertil Steril 1987; 48: 1001-05. 4. Bryant-Greenwood G, Ali S, Mandel M, Greenwood F. Ovarian and decidual relaxins in human pregnancy. Adv Exp Med Biol 1987; 219: 709-13. 5. MacLennan AH, Green RC, Bryant-Greenwood GD, Greenwood FC, Seamark RF. Ripening of the human cervix and induction of labour with purified porcine relaxin. Lancet 1980; 1: 220-23. 6. Evans MI, Dougan MB, Moawad AH, Evans WJ, Bryant-Greenwood GD, Greenwood FC. Ripening of the human cervix with porcine ovarian relaxin. Am J
Obstet Gynecol 1983; 147: 410-14.
Anti-HCV
positive patients in dialysis units?
SIR,-We read with interest the letters on antibody to hepatitis C (HCV) in patients on haemodialysis (June 9, p 1409). In 141 haemodialysis patients treated in our department the frequency of anti-HCV (Ortho Diagnostic Systems) was 17-3%, but the frequency varied from 0% to 70% among groups of patients treated in the six different sections of the department. The number of blood transfusions did not clearly influence the prevalence of seroconversion, and even non-transfused patients had HCV antibodies. The seroconverters had been on haemodialysis for longer than the others. These findings, indicating nosocomial transmission of HCV, raise an important question, not addressed in the above reports-namely, how should HCV seroconverters in dialysis units be handled? virus
Fluoride and vertebral fractures SiR,—Your May 5 editorial (p 1065) takes a negative view of fluoride treatment for osteoporosis, citing the double-blind study of Riggs et all with high doses of a high potency sodium fluoride but ignoring our large randomised study3 with much lower doses given as enteric-coated tablets. Riggs and colleagues’ paper questions our results and misquotes many of them. They suggest that our patients treated with sodium fluoride had a non-significant 25% reduction in vertebral fractures (a figure not given in our paper) in comparison with patients whose osteoporosis had been treated in other ways. On re-analysis of our data we can confirm this percentage but not its non-significance when calculated by the methods used by Riggs et al. From table ni in our paper we calculated rates per person-year and found, between 0 and 24 months, 173 crush fractures per 360 patient-years (0-48) in the fluoride group and 174 fractures per 272 patient-years (0-64) in the non-fluoride group, this 25% reduction is significant ( = 15-8; p < 0’001). Moreover, the results presented by Riggs et al ignore the significant effects of fluoride treatment at the second and third years on the ground that the 4th year relative risk was not significant (this may be due to toxicity during the 4th year, from the accumulation of fluoride in bone). Analysis of Riggs and colleagues’ data suggests a discrepancy between the calculated relative risks and the 95% confidence intervals (CI). Using the X2 based method to calculate the 95% CI we find that the relative risks in favour of fluoride after 2 and 3 years of treatment are significant (p < 0.01 and p < 0001, respectively) and after the entire period also (p = 0-05). The CIs were large and not in agreement with the rates and relative risks given. The only explanation for such unfavourable CIs seems to be adjustment for co-variables, as mentioned in the paper’s section on statistical analysis-but in that case, the adjusted relative risks should be different from those given by Riggs et al. Furthermore, it is surprising to not find any precise figures about the multidimensional statistical analyses. Statistical reappraisal of Riggs’ data might lead to a more optimistic view of the effects of sodium fluoride on the vertebral fracture rate, at least during the second and third years of therapy. NICOLE MAMELLE PIERRE-JEAN MEUNIER PATRICK NETTER,
INSERM Units 265 and 234, Hôpital Edouard Herriot, 69437 Lyon, France 1.
2 3.
for GETOP
Study Group
Riggs BL, Hodgson SF, O’Fallon M, et al Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1990; 322: 802-09. Nagant de Deuxchaisnes C, Devogelaer JP, Stein F. Fluoride treatment for osteoporosis Lancet 1990, 336: 48. Mamelle N, Meunier PJ, Dusan R, et al Risk-benefit of sodium fluoride treatment in primary vertebral osteoporosis Lancet 1988; ii. 361-65
Ovarian relaxin is not essential for dilatation of cervix SIR,-The transformation of the uterine cervix from a firm and inextensible structure to one that at delivery is compliant and distensible is thought to be a major physiological function of relaxin. It has been proposed that relaxin acts in concert with substances such as progestins, oestrogens, catecholamines, and prostaglandins, but the precise contribution of this hormone has not been identified; nor has it been proved that relaxin is essential for this transformation. That aspect of relaxin can be studied by looking at pregnancies achieved by in vitro fertilisation (IVF) in women who lack ovaries and so have no major source of relaxin. A 32-year-old woman with a balanced chromosome translocation (1/X) had had premature ovarian failure diagnosed at 19 years and she and her husband chose IVF with donated ova. Artificial menstrual cycles were established in the recipient and four embryos were transferred after IVF of donor ova. One normal pregnancy was confirmed by ultrasound. Serial blood samples were collected for assay of pregnancy hormones. Relaxin was measured by radioimmunoassay at 39 weeks plus 3 and 6 days after embryo transfer, at 40 weeks (induction of labour), during labour and delivery, 5 and 15 h after delivery, and daily on days 2-9. The
of variation for the relaxin assay’ were 10-9% at 50 pg/ml, 6-7% at 100 pg/ml, and 4-8% at 180 pg/ml, and the inter-assay coefficient of variation was 7-7% at 97-0 pg/ml
intra-assay coefficients (n=16).
The pregnancy was uncomplicated and at 37 weeks’ gestation pelvimetry was done before a trial of vaginal delivery. All pelvic measurements were normal. Labour was induced at 40 weeks. At 0830 hours the cervix was 3 cm dilated. An oxytocin infusion was started and at 1800 hours the cervix was 5 cm dilated, full dilatation being achieved 2hours later. There was no cephalopelvic disproportion or constriction ring. A boy weighing 3760 g was born after a forceps delivery needing firm traction. The placenta was removed without difficulty. The delivery was complicated by post-partum haemorrhage due to uterine atony, and three units of blood were transfused. Serum relaxin was not measurable (less than 11pg/ml) in any of the fifteen samples collected before, during, or nine days after delivery. The concentrations of other hormones, in samples taken in pregnancy, were similar to those in other studies of IVF 3 pregnancy cycles. The absence of measurable relaxin in the peripheral circulation
early
during pregnancy in this patient supports the thesis that if relaxin is synthesised outside the ovary, it is produced in very small amounts and may not enter the general circulation.4 Relaxin has been detected in non-ovarian tissues but its synthesis in tissues other than the corpus luteum has not been proven. Administration of porcine relaxin at the cervix before labour has been associated with
improved cervical scores and easier delivery, supporting the proposal that relaxin has a role in preparing the cervix for parturition.5,6 The delivery described here was difficult. However, the cervix was dilated and structural changes during labour were achieved in the absence of relaxin from the ovary. It remains to be demonstrated conclusively that relaxin is crucial to the changes in the cervix seen in labour.
Supported by grants from the National Health and Medical Research Council (Australia) and the National Institutes of Health (USA). Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, Victoria 3052, Australia, and Department of Obstetrics and Gynaecology, Monash University
L. W. EDDIE I. T. CAMERON J. F. LEETON D. L. HEALY P. RENOU
1. Eddie LW, Bell RJ, Lester A, et al. Radioimmunoassay of relaxin in pregnancy with an analogue of human relaxin. Lancet 1986; i: 1344-46. 2. Eddie LW, Sutton B, Fitzgerald S, Bell RJ, Johnston PD, Tregear GW. Relaxin in paired samples of serum and milk from women following term and pre-term delivery. Am J Obstet Gynecol 1989; 161: 970-73. 3. McLachlin RI, Burger HG, Healy DL, de Kretser DM, Robertson DM. Circulating immunoreactive inhibin in the luteal phase and early gestation of women undergoing ovulation induction. Fertil Steril 1987; 48: 1001-05. 4. Bryant-Greenwood G, Ali S, Mandel M, Greenwood F. Ovarian and decidual relaxins in human pregnancy. Adv Exp Med Biol 1987; 219: 709-13. 5. MacLennan AH, Green RC, Bryant-Greenwood GD, Greenwood FC, Seamark RF. Ripening of the human cervix and induction of labour with purified porcine relaxin. Lancet 1980; 1: 220-23. 6. Evans MI, Dougan MB, Moawad AH, Evans WJ, Bryant-Greenwood GD, Greenwood FC. Ripening of the human cervix with porcine ovarian relaxin. Am J
Obstet Gynecol 1983; 147: 410-14.
Anti-HCV
positive patients in dialysis units?
SIR,-We read with interest the letters on antibody to hepatitis C (HCV) in patients on haemodialysis (June 9, p 1409). In 141 haemodialysis patients treated in our department the frequency of anti-HCV (Ortho Diagnostic Systems) was 17-3%, but the frequency varied from 0% to 70% among groups of patients treated in the six different sections of the department. The number of blood transfusions did not clearly influence the prevalence of seroconversion, and even non-transfused patients had HCV antibodies. The seroconverters had been on haemodialysis for longer than the others. These findings, indicating nosocomial transmission of HCV, raise an important question, not addressed in the above reports-namely, how should HCV seroconverters in dialysis units be handled? virus
