Endocrinology

Alvin L K Chia,* Stephen Shumack,† Peter Foley‡ * Research Fellow, † Dermatologist, St George Dermatology and Skin Cancer Centre, Level 3, 22 Belgrave St, Kogarah, NSW 2217; ‡ Dermatologist, St Vincent’s Hospital, Melbourne, VIC. sshumackATbigpond.com To the Editor: We read with alarm the extraordinary statements in the position statement on vitamin D and adult bone health published recently in the Journal.1 The suggestion that “it is a fallacy that Australians receive adequate vitamin D from casual exposure to sunlight” is not true. The suggested basis for this statement is an extraordinary extrapolation from a single study in which a small number of volunteers had whole body exposure on one occasion for 10–15 minutes to midday summer sun in Boston. It is not possible to extrapolate in such a way from this single demonstration, as the effect of shorter exposure times or repeated daily exposures were not examined. In fact, a study in Australia showed that the adult population (including those aged over 70 years) received sufficient sunlight while using sunscreen to ensure that no-one was found to have vitamin D deficiency during the study period.2 While it is well accepted that ultraviolet B (UVB) radiation is essential for the formation of vitamin D3 in the skin, it is equally well established that continued exposure of vitamin D to UVB radiation results in its degradation. Hence, the importance of knowing the effect of lower sun exposures on vitamin D production. It is intriguing that the authors of the position statement recommended a daily sun exposure dose that they calculate will produce 1000 IU of vitamin D, but, if sun exposure is not possible, a vitamin D supplement of at least 400 IU per day. The high prevalence of vitamin D deficiency among institutionalised older Australians is a tragedy, but this cannot be used as the basis of advice for the general population who do receive daily sun exposure and appear to be the target of the statement. Nor can the mild vitamin D deficiency found in a single study in southern Victoria be used to recommend sun exposure in more northern Australian climes. Finally, while vitamin D supplementation has been shown to reduce the risk of fractures in the elderly, the proposed beneficial effect of deliberate sun exposure has not been demonstrated. Recently, a joint position statement was approved by the Australian and New Zealand Bone and Mineral Society, Osteoporosis Australia, the Australasian College of Dermatologists and the Cancer Council Australia. This included the statement that “The majority of Australians generally have sufficient ultraviolet radiation exposure to enable adequate vitamin D production . . . to form and maintain healthy, strong bones”.3 This statement, endorsed only a few weeks ago, is in obvious conflict with the position statement from the same organisations that was published in this Journal. The latter puts the vast majority of Australians at further risk of skin cancers, which are already epidemic in our country.4

Alvin L K Chia · Stephen Shumack · Peter Foley

Huy A Tran Director and Associate Professor, Department of Clinical Chemistry, University of Newcastle, John Hunter Hospital, Locked Bag No. 1, Hunter Region Mail Centre, New Lambton Heights, NSW 2310. huy.tranAThnehealth.nsw.gov.au To the Editor: The interesting article by Gordon et al1 warrants further discussion with regard to the hypophosphataemia, “inappropriately” high level of serum 25‑hydroxyvitamin D, biochemical diagnosis of pancreatitis and management of hypercalcaemia. Fibroblast growth factor-23 (FGF-23) is a recently described 254‑amino-acid peptide that has been shown to have significant phosphaturic effect. It probably plays a major role in phosphate metabolism and homeostasis by rising after an oral phosphate load and falling after dietary phosphate restriction. In the patient discussed by Gordon et al, elevated FGF-23 level may, hypothetically, have been a major contributing factor to the low serum phosphate level. Although the understanding of this factor is still in its infancy, measuring the serum level of FGF-23 in the patient might have shed more light on the role of FGF-23 in phosphate homeostasis. However, FGF-23 levels do not correlate directly with serum phosphate levels, suggesting that FGF-23 exercises control via renal tubular cells, regulation of calcitriol levels or intestinal phosphate absorption. FGF-23 levels are also markedly elevated in chronic renal failure, partly in response to the chronic hyperphosphataemia and partly because of reduced renal clearance.2 Its action is independent of the traditional and better understood regulators of phosphate level, including parathyroid hormone and parathyroid hormone-related protein. The triad of high vitamin D level, hypercalcaemia and hypophosphataemia points strongly to a diagnosis of vitamin D intoxication, despite a patient history to the contrary. An alternative explanation is an inaccurate vitamin D assay from the supporting laboratory. This issue, which has been highlighted recently, has therapeutic relevance in monitoring vitamin D replacement therapy.3 In supporting the diagnosis of pancreatitis, serum lipase level remains the best biochemical test and is more specific than amylase level.4 The practice of dual amylase and lipase ordering in the investigation of such conditions is excessive, confusing and costly to the community and should be discouraged. The indication for bisphosphonate treatment in milk-alkali syndrome remains unclear and contradicts the underlying pathogenesis, which is believed to be that of excessive calcium ingestion. In the patient in question, excessive calcium ingestion overwhelmed the calcium homeostatic mechanism, resulting in severe hypercalcaemia. In such a milieu, osteoclasts would be heavily suppressed and inhibited, and thus the use of a bisphosphonate, whose major action is also by osteoclastic suppression, would be of little value other than in precipitating hypocalcaemia.5 Thus, expectant management as outlined by the authors would be sufficient to achieve normocalcaemia. As bisphosphonates are not without adverse effects,6 they should only be used after a clear diagnosis of hypercalcaemia has been made.

Huy A Tran

Terrence H Diamond,* John A Eisman,† Rebecca S Mason,‡ Caryl A Nowson,§ Julie A Pasco,¶ Philip N Sambrook,** John D Wark†† * Associate Professor, Endocrinology, University of NSW, Sydney, NSW; † Professor and Director, Bone and Mineral Research Program, Garvan Institute of Medical Research, Sydney, NSW; ‡ Associate Professor of Physiology, ** Professor of Rheumatology, University of Sydney, NSW; § Associate Professor, School of Health Sciences, Deakin University, Melbourne, VIC; ¶ Senior Research Fellow, Clinical and Biomedical Sciences: Barwon Health, The University of Melbourne, PO Box 281, Geelong, VIC 3220; †† Professor of Medicine, The University of Melbourne, VIC. juliepATbarwonhealth.org.au In reply: We agree with Vanlint that any individual who has limited mobility, or is housebound or institutionalised, is at risk of vitamin D deficiency, as highlighted in Box 3 of the position statement.1 Disability in general is likely to be a risk, with motor disability as well as intellectual disability liable to limit sun exposure. The problem may be further exaggerated by any increased risk of falls or convulsions. Chia and colleagues have raised important issues. After a number of meetings, the Cancer Council of Australia, the Australasian College of Dermatologists and the Australian and New Zealand Bone and Mineral Society developed a considered consensus statement on vitamin D deficiency, risk of skin cancers and sunlight exposure, which was published at <http://www.cancer.org.au/documents/Risks_Benefits_Sun_Exposure_MAR05.pdf>. This document refers to the position statement published in this Journal in relation to sun-exposure guidelines for vitamin D. Chia and colleagues’ objection to the abstract of this position statement appears ill-founded. If “a significant number of Australians are deficient in vitamin D”, then it follows logically that “it is a fallacy that Australians receive adequate vitamin D from casual exposure to sunlight”, as sunlight is the main source of vitamin D in Australia. The significant number of Australians deficient in vitamin D are not the majority, as was clearly shown in the article, so this statement does not conflict with the complementary statement in the risks and benefits statement. We stand by our original claim that a number of groups in the Australian community have a high prevalence of vitamin D deficiency, including elderly men with hip fracture (63%), Muslim women (68%), elderly ambulant men with prostate cancer (34%), “healthy” elderly men living in Southern Sydney (16%), healthy community-dwelling, ambulatory women in Geelong (20% in the age group 20–39 years, increasing to 53% in older age groups), men and women (some with psychiatric disorders) in south-east Queensland (23%), and even pregnant women in south-eastern Australia (7%) (references are available from the authors on request). As noted in the position statement, and by Chia and colleagues, continued exposure to ultraviolet (UV) radiation may lead to degradation of pre-vitamin D, so that short exposures are likely to be more efficient. This degradation is marked only at relatively high UV doses.2 Studies that used lower UV doses2,3 produced indirect UV equivalence data similar to those quoted in the position statement.1 As the relationship between UV exposure and vitamin D dosage varies from person to person, and as sun exposure is also likely to be variable and on most days, rather than every day, the recommendation that vitamin D supplementation be at least 400 IU/day in people likely to be at risk of inadequate skin-derived vitamin D is entirely appropriate. We strongly agree with Chia and colleagues about the need to avoid sun damage while still obtaining the small amount of sun exposure needed to make adequate vitamin D, which is why the position statement advocates short exposures, easily achieved by casual exposure, and reiterates other Sun-Safe messages, such as avoidance of exposure in peak UV periods and the use of sunscreens where appropriate.

Terrence H Diamond · John A Eisman · Rebecca S Mason · Caryl A Nowson · Julie A Pasco · Philip N Sambrook · John D Wark

Adam P Morton Physician, Mater Hospital, Raymond Terrace, Brisbane, QLD 4101. AmortonATmater.org.au To the Editor: I read with interest the Lessons from Practice article on milk-alkali syndrome during pregnancy.1 I would like to offer the following comments. The patient’s alkalosis was in fact more impressive than presented, as the authors used the reference range for serum bicarbonate in non-pregnant patients. During pregnancy, serum bicarbonate levels typically fall by about 4 mmol/L to compensate for the respiratory alkalosis caused by elevated progesterone levels stimulating respiratory drive. Given the patient’s life-threatening calcium level on presentation, I am interested to know whether calcitonin treatment or even dialysis was considered while waiting for the pamidronate to take effect. An important aspect that the authors did not discuss in relation to this case is the reassuring data on the safety of both proton-pump inhibitors and H2-receptor antagonists in pregnancy. While there is more experience with the latter, two recent studies found no evidence of teratogenicity in almost 900 cases of exposure to proton-pump inhibitors in the first trimester.2,3 Clinicians should feel comfortable about prescribing these medications in pregnancy. After reporting a similar case,4 I wrote to Walco, the manufacturers of Quick-Eze, who subsequently changed their product labelling to include a warning about the number of tablets that could be safely taken each day. Disappointingly, they did not include a warning about ingestion during pregnancy, as I suggested.

Adam P Morton

Michelle V Gordon,* P Shane Hamblin,† Lawrence P McMahon‡ * Registrar, † Head, Department of Endocrinology, Western Hospital, Private Bag, Gordon Street, Footscray, VIC 3011; ‡ Head, Department of Obstetric Medicine, Sunshine Hospital, St Albans, VIC. hamblin1ATbigpond.net.au In reply: Our case appears to be consistent with typical milk-alkali syndrome. While measuring fibroblast growth factor-23 (FGF-23) level might have been of hypothetical interest, it is unlikely that it would have influenced management. Vitamin D intoxication was considered once the 25-hydroxyvitamin D results became available, and we closely questioned our patient in relation to this possibility. She was insistent that she had not taken any vitamin D supplements. It is possible either that the patient did not wish to admit to taking vitamin D or that the assay was misleading, as suggested by Tran. We agree that bisphosphonate therapy should not be advocated when the diagnosis of milk-alkali syndrome is clear. In this case, however, the patient was drowsy and very ill; the full history relating to antacid ingestion was not obtained until after the bisphosphonate therapy had been given. With regard to Morton’s comments, the hypercalcaemia settled promptly, so fortunately calcitonin treatment and other measures did not need to be considered. Drug safety in pregnancy is a difficult issue, as the effects of fetal or neonatal damage may carry lifelong implications, and even relatively rare associations need to be considered with care. In addition, many pregnant women are uncomfortable about taking prescription medications during pregnancy, even though their doctors may have a more relaxed view. Currently, over-the-counter antacids are classed as category A drugs for pregnancy, whereas H2-receptor antagonists and proton-pump inhibitors are category B1 and B3, respectively. Cimetidine has been associated rarely with neonatal hepatic abnormalities,1 and it is still too early to state with confidence that proton-pump inhibitors are “safe”, despite promising initial analyses. Ironically, the potential dangers of over-the-counter calcium-containing antacids, as demonstrated in this case report and others, are not currently adequately acknowledged. We have written to the manufacturers of Rennie tablets requesting a package label warning advising consumers not to exceed six tablets a day.

Michelle V Gordon · P Shane Hamblin · Lawrence P McMahon

CorrectionRe: “Point-of-care testing of HbA1c and blood glucose in a remote Aboriginal Australian community” in the 16 May 2005 issue of the Journal (Med J Aust 2005; 182: 524-527). The authors of this article have requested that Max K Bulsara (School of Population Health, University of Western Australia; and Centre for Child Health Research, University of Western Australia, Telethon Institute of Child Health Research, Subiaco, WA) be included as an author. The corrected list of authors is David D Martin, Mark D S Shephard, Hayley Freeman, Max K Bulsara, Timothy W Jones, Elizabeth A Davis, Graeme P Maguire. The online version of this article (html and pdf) was corrected on 27 May 2005.

David D Martin MB BS, PhD · Timothy W Jones DCH, FRACP · Elizabeth A Davis FRACP · Mark D S Shephard MSc, MAACB · Hayley Freeman RN · Graeme P Maguire MPHTM, FRACP, PhD

Objectives: To assess the accuracy of point-of-care (POC) measurements of capillary blood glucose and glycosylated haemoglobin (HbA1c) levels in a remote Aboriginal community with high diabetes prevalence.Design: Cross-sectional study comparing POC capillary glucose and HbA1c results with those from corresponding venous samples measured in a reference laboratory.Participants and setting: 152 residents aged 11–76 years (representing 76% of population aged over 11 years) had POC glucose measurement in November 2003; 88 with POC glucose level ≥ 5.0 mmol/L, or self-reported diabetes, had POC HbA1c and laboratory glucose and HbA1c measurements.Main outcome measures: POC fasting capillary levels of glucose (HemoCue Glucose 201 analyser, Medipac Scientific, Sydney) and HbA1c (DCA 2000+ analyser, Bayer Australia, Melbourne); correlation and mean difference between capillary POC and venous blood laboratory measurements of glucose and HbA1c.Results: Mean and median POC capillary glucose levels were 7.99 mmol/L and 6.25 mmol/L, respectively, while mean and median laboratory venous plasma glucose concentrations were 7.63 mmol/L and 5.35 mmol/L. Values for POC capillary HbA1c and laboratory HbA1c were identical: mean, 7.06%; and median, 6.0%. The correlation coefficient r for POC and laboratory results was 0.98 for glucose and 0.99 for HbA1c. The mean difference in results was 0.36 mmol/L for glucose (95% CI, 0.13–0.62; limits of agreement [LOA], − 2.07 to 2.79 mmol/L; P = 0.007) and < 0.01% for HbA1c (95% CI, − 0.07% to 0.07%; LOA, − 0.66% to 0.66%; P = 0.95), respectively.Conclusions: POC capillary HbA1c testing, in particular, offers an accurate, practical, community-friendly way of monitoring diabetes in rural and remote clinical settings. POC capillary glucose results should be confirmed by a laboratory test of venous plasma if the results are likely to significantly influence clinical decisions.

David D Martin MB BS, PhD · Timothy W Jones DCH, FRACP · Elizabeth A Davis FRACP · Mark D S Shephard MSc, MAACB · Hayley Freeman RN · Graeme P Maguire MPHTM, FRACP, PhD · Max K Bulsara MSc

Adam P Morton,* H David McIntyre† * Endocrinologist, † Director, Endocrinology and Obstetric Medicine, Mater Hospital, Raymond Terrace, Sth Brisbane, QLD 4101. AmortonATmater.org.au To the Editor: We read with interest the article by Hussein and colleagues on their experience with thiazolidinediones (TZDs).1 These agents are only approved by the Pharmaceutical Benefits Scheme as part of dual therapy. We wish to present our experience of adding TZDs to metformin and sulfonylureas — hence, triple therapy — in patients with suboptimally controlled type 2 diabetes mellitus. The records of 28 patients (15 men, 13 women) with type 2 diabetes, for whom pioglitazone was added to maximal doses of metformin and sulfonylurea because of suboptimal control, were reviewed. Baseline patient characteristics are shown in . Mean follow-up was 9.6 months (range, 3–24 months); the average pioglitazone dose was 31.3 mg. The mean fall in the level of glycohaemoglobin (HbA1c) was 1.26% — 10 patients achieving an HbA1c level of less than 7% at last review. Four patients did not respond to therapy; none withdrew because of side effects. Eight patients whose HbA1c fell less than 0.5% after 3 months continued taking pioglitazone, achieving an average fall in HbA1c of 1.25% after a mean of 12 months follow-up. Mean weight gain was 3.35 kg (– 3.2 kg to 11.6 kg). Mean changes in HbA1c level and weight compared with baseline over 24 months are shown in . There was no correlation between these outcomes, and no baseline characteristic predicted glycaemic response. Six studies have reported the efficacy of TZDs in triple therapy (), and show a consistent fall in HbA1c level at the expense of weight gain, with a low rate of withdrawals because of adverse effects. Our findings were similar to those of these previous reports in terms of glycaemic response and low rate of side effects. The much higher rate of side effects reported by Hussein et al1 is likely to be the result of the coprescription of TZDs with insulin in 64% of patients in their study. While fluid retention has been reported in up to 5% of patients taking TZDs as monotherapy or in combination with oral hypoglycaemics, 15% of patients using TZDs with insulin may develop significant oedema. Most reports describing precipitation of cardiac failure with TZDs have been in patients using combination therapy with insulin. It would be interesting to know what proportion of the patients who developed peripheral and pulmonary oedema in the study by Hussein et al1 were also receiving insulin. One prospective randomised trial comparing the addition of pioglitazone and bedtime insulin to maximal metformin and sulfonylurea found similar efficacy in improving glucose control, but less hypoglycaemia and improved high density lipoprotein cholesterol levels with pioglitazone.3 A study of the long-term efficacy of triple therapy found 26 of 35 patients (74%) had good control after a mean follow-up of 37 months, their HbA1c level having fallen from 8.7% to 6.9%.8 In conclusion, the experience of our unit and the published literature is that TZDs are efficacious in improving suboptimal diabetic control in patients on maximal doses of metformin and sulfonylurea. Eight individuals in our group had a significant improvement in control subsequent to minimal response after the initial 3 months of treatment, suggesting a longer trial of TZDs should be employed before classifying patients as non-responders. It is to be hoped that the regulatory authorities will allow the use of TZDs in triple therapy. 1 Characteristics of our 28 patients at baseline Variable Mean (range) Age (years) 57.4 (31–74) Weight (kg) 96.3 (56–137) Body mass index (kg/m2) 34.6 (24–50.3) Duration of diabetes (years) 11 years (1–48) Glycohaemoglobin (HbA1c) level (%) 9.0 (7.1–10.4) 2 Changes in glycohaemoglobin (HbA1c) level and weight compared with baseline values 3 Studies of thiazolidinediones added to maximal dose metformin and sulfonylurea Variable Roy et al2 Aljabri et al3 Dailey et al4 Kiayias et al5 Kiayias et al5 Byrne et al6 Yale et al7 Thiazolidinedione Rosiglitazone Pioglitazone Rosiglitazone Rosiglitazone* Rosiglitazone† Rosiglitazone Troglitazone Duration (weeks) 16 16 24 20 20 nr 24 No. of patients 48 30 181 19 19 24 101 Baseline body mass index (kg/m2) nr 26 32 31 31 nr 30.1 Baseline HbA1c level (%) 9.3 9.7 8.1 8.9 9 9.6 9.6 Fall in HbA1c level (%) 1.8 1.9 0.9 1.1 1.4 1.2 1.3 Weight gain (kg) nr 2.6 3 4.2 4.6 0.7 0.9 % Patients withdrawn 4.2 0 5.5 0 0 0 2 % Patients with satisfactory control (HbA1c level) 65 (< 7.5) 23 (< 7) 42 (< 7) nr nr nr 43 (< 8) HbA1c = glycohaemoglobin. nr = not reported. * 4 mg/day; † 8 mg/day.

Adam P Morton · H David McIntyre

Nirusha Arnold,* Mark McLean,† David R Chipps,† N Wah Cheung† * Advanced Endocrinology Trainee, † Endocrinologist, Centre for Diabetes and Endocrinology Research, Westmead Hospital, Hawkesbury Road, Westmead, NSW 2145. nirusha_arnoldATozemail.com.au To the Editor: It was with interest that we read the recent article on real-life experience with thiazolidinediones by Hussein et al.1 The authors noted the absence of severe liver toxicity with the newer agents, rosiglitazone and pioglitazone, in contrast to troglitazone, which was withdrawn because of cases of hepatic failure.2 However, the sample was too small to conclude that these thiazolidinediones (TZDs) carry no hepatic risk, and they endorsed the current Pharmaceutical Benefits Scheme recommendations that liver function tests (LFTs) be monitored every 2 months. We have collected similar clinic data showing that the development of significant abnormalities in results of LFTs with TZD therapy is uncommon, and in fact, there are often improvements in LFT findings. We reviewed the files of 166 patients with type 2 diabetes treated with TZDs between 1 August 2000 and 30 November 2002, with the aim of assessing their long-term effect on LFT results. Therapy was discontinued within 3 months in 26 patients. The reasons were non-compliance (7), therapy ineffective (8), weight gain (5), dyspnoea (1), peripheral oedema (1), malaise (1), dizziness (1), angio-oedema (1), and pre-existing LFT abnormality (1). We analysed data on the remaining 140 patients (see Box) treated for a mean of 188 ± 4 days with either pioglitazone (109 patients) or rosiglitazone (31 patients). All LFT results improved significantly (Box). At baseline, 90 patients had abnormal findings on LFTs. These findings normalised in 43 of these patients (including one with steatohepatitis proven on biopsy); improved in 29 patients; and were unchanged in nine patients. LFT findings deteriorated in nine patients, leading to cessation of therapy in two. Most patients with normal LFT results at baseline experienced improvements of these parameters within the normal range. Three patients developed new abnormalities in their LFT findings, and therapy was stopped in one patient, leading to resolution of LFT abnormalitites. Changes in glycohaemoglobin (HbA1c) levels correlated positively with changes in activity of alkaline phosphatase (correlation coefficient [r], 0.33; P < 0.01), aspartate aminotransferase (r, 0.27; P < 0.01) and alanine aminotransferase (r, 0.29; P < 0.01). Our findings support those of Hussein et al, that TZD therapy is usually stopped for reasons other than hepatic dysfunction. In contradistinction to early concerns about their hepatic safety, the improvements in LFT findings seen in our patients suggest that TZDs may even benefit hepatic function. In patients with diabetes, abnormal findings on LFTs are often attributed to fatty liver, which predisposes to steatohepatitis. TZDs may well alleviate or prevent steatohepatitis,3 thereby providing benefits beyond that of improved glycaemic control, and mild abnormalities in LFTs should not discourage their use in patients with diabetes. Changes in liver function and glycohaemoglobin (HbA1c) level Variable Baseline 6-month follow-up Change P* Weight (kg) 93 ± 2 96 ± 2 3 ± 0.4 < 0.001 HbA1c (%) 8.9 ± 0.1 7.9 ± 0.1 – 1.0 ± 0.1 < 0.001 Albumin (g/L) 41 ± 0.2 41 ± 0.2 – 0.5 ± 0.2 < 0.02 Bilirubin (μmol/L) 9.4 ± 0.4 8.5 ± 0.3 – 0.9 ± 0.3 < 0.003 ALP (U/L) 92 ± 2 79 ± 2 – 13 ± 2 < 0.001 GGT (U/L) 44 ± 3 31 ± 2 – 13 ± 2 < 0.001 AST (U/L) 26 ± 1 22 ± 1 – 3 ± 1 < 0.001 ALT (U/L) 33 ± 2 25 ± 1 – 8 ± 2 < 0.001 ALP = alkaline phosphatase. GGT = γ-glutamyl transferase. AST = aspartate aminotransferase. ALT = alanine aminotransferase. * Paired t test.

Nirusha Arnold · Mark McLean · David R Chipps · N Wah Cheung

Huong V Nguyen,* Katherine B Ingram,† Jonathan Beilin‡ * Endocrinology Registrar, ‡ Endocrinologist, Royal Perth Hospital, Box X2213 GPO, Perth, WA 6847; † Geriatrician, Swan District Hospital, Middle Swan, WA Huong. NguyenAThealth.wa.gov.au To the Editor: Zoledronic acid is a new bisphosphonate treatment for hypercalcaemia of malignancy, multiple myeloma and documented bone metastases from solid tumours, in conjunction with standard chemotherapy.1 Transient hypocalcaemia, a side effect of bisphosphonate therapy, can occur with zoledronic acid.2 We describe a patient with transient severe hypocalcaemia after zoledronic acid treatment. An 88-year-old white woman with multiple myeloma presented with left hip pain. Imaging revealed multiple lytic lesions in the spine, pelvis and upper femurs. She was commenced on zoledronic acid 4 mg and a 5-day course of melphalan 10 mg/day and prednisolone 100 mg/day. At this stage, her serum calcium concentration was 2.38 mmol/L (normal, 2.15–2.55 mmol/L) and serum phosphate concentration was 0.8 mmol/L (normal, 0.8–1.5 mmol/L). She had renal impairment with reduced creatinine clearance of 35 mL/min. Nine days later, she underwent surgical repair of a duodenal ulcer. Post-operatively, she was found to be hypocalcaemic, with serum calcium concentration of 1.34 mmol/L and ionised calcium concentration of 0.78 mmol/L (normal, 1.14–1.29 mmol/L). Serum phosphate concentration was 0.4 mmol/L and magnesium concentration was 0.87 mmol/L (normal, 0.70–0.90 mmol/L). Her serum 25-hydroxyvitamin D concentration was 14 nmol/L (normal > 50 nmol/L) and her parathyroid hormone level was 44 pmol/L (normal, 1.5–8.0 pmol/L). The patient displayed no symptoms of hypocalcaemia and had negative Chvostek and Trousseau signs. Her QTc interval was normal. Her hypocalcaemia was managed with oral calcium carbonate 4.5 g/day and calcitriol 0.5 g/day. Ten days later, her total serum calcium concentration rose to 2.31 mmol/L and her phosphate concentration was 0.9 mmol/L. Bisphosphonates inhibit osteoclast-mediated bone resorption, thereby reducing serum calcium concentration. Compensatory secondary hyperparathyroidism prevents significant hypocalcaemia by enhancing renal calcium conservation, 1,25-hydroxyvitamin D production, and osteoclastic bone resorption.1,2 In our patient, the 1,25-hydroxyvitamin D concentration was not measured. However, in view of the low 25-hydroxyvitamin D and impaired renal function, this level may have been low, further exacerbating the hypocalcaemia. Transiently low phosphate concentration in this patient may be due to fasting and co-administration of 5% dextrose, as our patient was fasted for 3 days peri-operatively and given a combination of intravenous 5% dextrose and normal saline. Vitamin D insufficiency afflicts a large proportion of the elderly population,3 and its existence needs to be recognised before commencement of bisphosphonate therapy, so that adequate calcium and vitamin D supplementation can be given to reduce the occurrence of hypocalcaemia.

Huong V Nguyen · Katherine B Ingram · Jonathan Beilin

Clinical recordsIn 2003, five patients presented to the Oral and Maxillofacial Surgery Unit at Royal Adelaide Hospital, South Australia, with painful exposed bone in the maxilla, or both the maxilla and mandible (Box 1 and Box 2 ). All patients were receiving either pamidronate (Aredia [Novartis]) or alendronate (Fosamax [Merck Sharp & Dohme]). Pamidronate was being given intravenously monthly at a dose of 60mg (one patient) or 90 mg (three patients). The patient taking alendronate received a daily oral dose of 40mg. Duration of bisphosphonate therapy was 6 months to 6 years. Associated risk factors for the development of avascular necrosis included renal impairment in one patient and hypoproteinaemia in another. Initial management of these patients comprised surgical debridement of the exposed bone. Histopathological assessment of surgical specimens showed no histological evidence of myelomatous deposits or Paget's disease from the affected sites in the jaws in any of the patients. None had exposed bone elsewhere in the body. Here we present five cases of osteonecrosis of the jaw associated with bisphosphonate use. In North America, several preliminary reports have been published of unusual cases of avascular necrosis of the jaw in patients using second-and third-generation nitrogen-containing bisphosphonates.1-4 These included pamidronate, alendronate, risedronate and zoledronic acid.2,3 In Australia, bisphosphonates have been available for several years and are commonly prescribed for a range of conditions, including osteoporosis, Paget’s disease, multiple myeloma,5,6 hypercalcaemia of malignancy, and bone metastases of malignancies such as breast and prostate cancer. An estimated 200 000 patients in Australia receive these drugs. Commonly reported adverse reactions involve gastrointestinal symptoms. Bone-marrow depression and thrombocytopenia are also reported rarely. The second- and third-generation bisphosphonates are significantly more potent than their first-generation predecessors, (etidronate, clodronate and tiludronate). They inhibit bone resorption by osteoclastic inhibition, through selective concentration at the interface of the active osteoclast and the bone-resorption surface. The specific mechanism of this inhibition is unknown, but there is evidence for several actions, including inhibition of osteoclast development from precursor cells, increase in osteoclast apoptosis,7 stimulation of osteoclast inhibitory factor, reduction of osteoclast activity, and down-regulation of matrix metalloproteinases. The resulting reduction in osteoclastic activity reduces bone resorption, supporting the use of bisphosphonates for the above indications. However, osteoclastic function is part of the cycle of bone turnover; osteocytes have a life span of about 150 days, after which osteoclasts resorb the mineral matrix of bone and release bone morphogenetic protein and insulin-like growth factors, which in turn induce local stem cells to differentiate into osteoblasts and form new bone. This cycle is critical to maintaining bone stocks and bone viability. If osteoclastic function is too severely impaired, dead and dying osteocytes are not replaced, and the capillary network in the bone is not maintained, resulting in avascular bone necrosis. Dental disease and denture-wearing are ubiquitous. Studies involving larger patient numbers have shown that nearly 80% of cases were initiated by tooth removal.3 Patients who have been using potent bisphosphonates for more than 6 months appear to be at highest risk.2 Other apparent risk factors are residual multiple myeloma or other malignancy, hypoproteinaemia, renal impairment from disease or drugs, and chemotherapy. Although a definite cause-and-effect relationship is yet to be established, the association between bisphosphonate therapy and osteonecrosis of the jaw appears strong.2-4,8-10 The incidence of the potential complication appears low. In South Australia in 2003, about 14 000 patients received prescriptions for the potent second- and third-generation nitrogen-containing bisphosphonates, with about 10% having intravenous administration. Our five patients probably represented all cases of the complication, as our Department is the only oral and maxillofacial surgery service in SA and receives referrals from around the state.8,9 Checking with colleagues and related hospital services has not revealed further cases in SA, but we are aware of other cases in all states of Australia. Indeed, the Adverse Drug Reactions Advisory Committee recently reported another nine cases.10 At present, there is no effective treatment for the condition. Patients are usually referred to oral and maxillofacial surgeons, but surgical intervention is difficult as it often exposes further bone, and, as bisphosphonates affect the whole skeleton, locating viable bone margins may be impossible. Furthermore, removal of painful teeth, while initially alleviating pain, also further exposes bone, causing more pain. Covering exposed bone with tissue flaps has been found ineffective because of the development of fistulae around the flaps and possible complete dehiscence (Box 1). Compounding the problem, some patients must continue with bisphosphonate therapy and/or other chemotherapies to control hypercalcaemia. Hyperbaric oxygen therapy is not useful in bisphosphonate-induced necrosis, and antibiotics are indicated only to treat secondary infection. Because of the lack of effective treatment for the condition, second- and third-generation bisphosphonates should be used only when benefits clearly outweigh risks. When intravenous or high-dose oral bisphosphonates are considered appropriate, referral for full dental assessment and treatment before the start of therapy should be considered. Once bisphosphonate therapy has begun, there should be regular clinical monitoring of oral health. Avoiding tooth removal and dental implants, non-surgical control of periodontal disease, and use of soft liners on dentures also seem prudent. In addition, major debridement surgeries should be avoided if at all possible. In established cases, the primary goals are palliation and control of osteomyelitis. In most cases, progression has been controlled with long-term or intermittent courses of dicloxacillin or cephalexin (to treat any secondary infection), chlorhexidine mouthwash (Savacol), and periodic minor debridement of soft-textured sequestrating bone and wound irrigation. The rapid expansion of indications for bisphosphonates has resulted in their widespread use across many medical disciplines, including endocrinology, rheumatology, medical oncology, haematology and general practice. Most medical practitioners are unaware of this serious and potentially permanent complication. Before prescribing bisphosphonates, medical practitioners should analyse the risks versus benefits for the individual patient, consider alternative drugs, and obtain informed consent after discussing this potential adverse reaction. We also encourage vigilant surveillance of patients who are using a bisphosphonate. Summary Five patients presented to the Royal Adelaide Hospital, South Australia, in 2003 with painful exposed bone in the maxilla, or both the maxilla and mandible. All had been receiving potent second- or third-generation bisphosphonate therapy — monthly intravenous pamidronate in four cases and daily oral alendronate in the other. These cases are among the earliest reported occurrences of this condition in association with bisphosphonate therapy in Australia. The condition presented after tooth extraction in four cases and denture pressure in the other. Osteonecrosis continued for more than a year in three patients despite treatment. 1 Necrosis of the maxilla in a 57-year-old man receiving pamidronate for multiple myeloma The oral cavity showing exposed necrotic maxillary bone and a large oro-antral communication. Computed tomography showing significant bone destruction in the right maxilla (outlined). 2 Clinical details of five patients with avascular necrosis of the jaw in South Australia, 2003 Age, sex Presentation Precipitant Bisphosphonate [indication] Other medications Treatment Outcome 57, M Painful exposed bone in maxilla and mandible Tooth extraction Pamidronate (90 mg IV monthly for 6 years) [multiple myeloma] Dexamethasone, methotrexate, warfarin, folic acid, ranitidine, metformin, hydroxychloroquine, verapamil, sertraline, morphine Hyperbaric oxygen, Le Fort I level maxillectomy, bisphosphonate continued Persistent necrosis of midface and mandible 64, M Ulcer in right hard palate with bone sequestrum Tooth extraction Pamidronate (90 mg IV monthly for 2 years) [multiple myeloma] Prednisolone, cyclosporin, itraconazole, sulfamethoxazole–trimethoprim, ranitidine, penicillin Sequestrectomy, local debridement, bisphosphonate continued Resolution 73, M Pain, swelling of anterior maxillary alveolus Tooth extractions Alendronate (40 mg orally daily for 5 years) [Paget’s disease] Amlodipine, tramadol, perindopril Local debridement, sequestrectomies, primary flap closure, bisphosphonate ceased Resolution 78, F Painful exposed bone in maxilla Denture pressure Pamidronate (90 mg IV monthly for 18 months) [Paget’s disease] None Hyperbaric oxygen, local debridement, denture reline, bisphosphonate ceased Persistent areas of exposed bone 84, F Non-healing extraction site in left maxillary alveolus Tooth extraction Pamidronate (60 mg IV monthly for 6 months) [Paget’s disease] Diltiazem, simvastatin, ferrous sulfate, aspirin, bendrofluazide Wide intraoral resection with primary flap closure, bisphosphonate ceased Persistent fistula IV = intravenous.

Glen Carter BDS, MB BS, FRACDS(OMS) · Alastair N Goss DDSc, FRACDS(OMS) · Chris Doecke BPharm, PhD

Clinical records The Adverse Drug Reactions Advisory Committee (ADRAC) has recently received 13 reports of osteonecrosis of the jaw associated with bisphosphonate use — 12 after intravenous bisphosphonate use, and one after oral alendronate use (Box). Ten of the reports implicated zoledronic acid, one pamidronate, and the other implicated both drugs in circumstances where the patient had switched from pamidronate to zoledronic acid. In the nine cases with information on bisphosphonate dose, the monthly doses accorded with those recommended in the product information (90 mg of pamidronate, 4 mg of zoledronic acid). Time to onset varied from 1 month to more than 4 years, although most reports did not specify date of onset, possibly because onset was insidious. Presenting symptoms included localised pain, numbness and altered sensation, exposed bone in the oral cavity, soft tissue infection and, in one case, loosening of several teeth. One report described a dental abscess after radiotherapy. All the reports described the osteonecrosis as occurring in the jaw; four specified the mandible, and two the maxilla. With the exception of the report implicating oral alendronate for treatment of osteoporosis, the reports indicated that the bisphosphonate was being used in the context of malignancy. Four reports documented dental extraction during bisphosphonate therapy in the months before the onset. One patient had had several teeth extracted because they had become loose during bisphosphonate therapy. A further report stated that onset of osteonecrosis occurred before dental extraction. Many of the 13 reports were received soon after diagnosis, but, in at least four cases, the problem had persisted for 2 to 3 months after withdrawal of the bisphosphonate. None of the 13 patients had recovered at the time of reporting. Recently, the United States Food and Drug Administration drew attention to the problem of osteonecrosis (also described as avascular or aseptic necrosis) of the mandible and/or maxilla, occurring in association with intravenously administered bisphosphonates used to control hypercalcaemia in metastatic bone disease.1 In addition, two case series were published recently summarising 99 case reports of osteonecrosis of the jaw associated with bisphosphonates.2,3 Combined with smaller case series, they bring the total reported to 129 cases.4-8 Not all bisphosphonates have been implicated. Most commonly associated with the problem were zoledronic acid and pamidronate, possibly because these are the only intravenous bisphosphonates in widespread use, and because zoledronic acid has been approved for regular use in metastatic disease. However, seven reports implicated oral alendronate or risedronate used to treat osteoporosis.4,6 Osteonecrosis of the jaw closely resembles the occupational disorder “fossy jaw”, which occurred in workers in match factories using white phosphorus in manufacturing.9 The condition was distressingly painful, refractory to treatment and disfiguring to the extent that some sufferers committed suicide. Bisphosphonates are not metabolised and have a strong binding affinity with osteoclasts. They can persist in bone for months and sometimes years after the drug has been discontinued. Accordingly, withdrawal of bisphosphonate therapy does not appear to hasten recovery of the osteonecrosis. Other treatments, including mouth rinses, systemic antibiotics, hyperbaric oxygen and surgical debridement have been tried, but so far none has proven consistently effective. The mechanism underlying the reaction is unknown, but it has been postulated that bisphosphonates inhibit new vessel formation, thereby impairing healing. Although dental extractions and other oral surgery have been identified as precipitants in many cases, there is evidence suggesting that alveolar bone can be involved before, and independently of, such procedures. Indeed, the clinical presentation may closely simulate dental abscesses, “toothaches”, denture sore spots, and osteomyelitis. Documented risk factors include a diagnosis of cancer, concomitant therapies (eg, chemotherapy, radiotherapy and corticosteroids) and comorbid conditions (eg, anaemia, coagulopathies, infection, and pre-existing oral disease).10 Concomitant chemotherapy and corticosteroid treatment, in particular, may result in immunosuppression and thereby predispose to ongoing local sepsis after minor trauma. Because this condition and its complications result in significant chronic pain, dysfunction and disfigurement which are difficult to treat, the focus should be on prevention. It is important that all health professionals, especially dentists, oncologists and oral surgeons, be aware of the possibility that patients being considered for dental extractions or other oral surgery are undergoing intravenous bisphosphonate therapy. Also, it is important for patients to be informed of the risk of this complication of bisphosphonate therapy, so that they have the opportunity to assess the need for dental treatment before starting therapy.11 It is not known at this stage whether discontinuing bisphosphonates before major dental procedures can help prevent the problem, but, given the persistence of bisphosphonates in bone, it is unlikely. Prescribers should also be aware that osteonecrosis of the jaw can occur in association with oral bisphosphonate therapy for osteoporosis. Summary 13 cases of osteonecrosis of the jaw associated with bisphosphonate use have recently been reported to the Adverse Drug Reactions Advisory Committee. Most cases were associated with intravenous bisphosphonate therapy (11 cases with zoledronic acid and one with pamidronate), but one was associated with oral alendronate used to treat osteoporosis. The condition causes chronic pain, dysfunction and disfigurement; no treatment has proven consistently effective, and withdrawing the bisphosphonate does not seem to hasten recovery. The focus should be on prevention through attending to any necessary dental treatment before bisphosphonate therapy begins. Clinical characteristics of 13 patients reported to ADRAC with osteonecrosis associated with bisphosphonate use Age, sex Bisphosponate used, other therapy Indication for bisphosponate Time to onset Symptoms Outcome 42, F Zoledronic acid (4 mg IV every 3–4 weeks), capecitabine, celecoxib, ranitidine, radiotherapy Breast carcinoma 6 months Tooth abscess, osteoradionecrosis (site not specified) Unknown* 46, F Zoledronic acid (4 mg IV monthly), previously pamidronate (90 mg), dexamethasone Breast carcinoma 4–6 months Jaw necrosis (site not specified) Not recovered† 46, F Zoledronic acid (4 mg IV monthly) Breast carcinoma 5 months Maxillofacial pain, exposed bone in oral cavity, dental extractions, gingival swelling, impaired healing Unknown† 57, M Zoledronic acid (4 mg IV, frequency not stated), corticosteroids, chemotherapy Prostate carcinoma > 2 years Exposed, painful bone in mandible, numbness, soft tissue infection Not recovered‡ 67, F Alendronate (oral) prednisolone, leflunomide, celecoxib Osteoporosis ns Maxillary alveolar necrosis, spontaneous loss of teeth, osteomyelitis, oro-antral fistula, condition recurred after surgery Not recovered* 73, M Pamidronate (90 mg IV monthly), thalidomide, corticosteroids Multiple myeloma 1 year Mandibular pain, hypoaesthesia, loosening of teeth, dental extractions, impaired healing, exposed bone Slowly improving§ 75, M Zoledronic acid (4 mg IV, frequency not stated), corticosteroids, chemotherapy Prostate carcinoma > 2 years Exposed, painful bone in mandible, numbness, dysaesthesia Not recovered‡ 79, M Pamidronate (90 mg IV monthly), prednisolone, melphalan Multiple myeloma 1 month Mandibular pain, dysaesthesia, dental extraction, impaired healing, exposed bone, osteomyelitis, recurrent soft tissue infection Not recovered† 80, M Zoledronic acid (4 mg, reduced to 2 mg IV monthly) Prostate carcinoma 8 months Jaw necrosis (site not specified), recent dental surgery Not recovered† 83, M Zoledronic acid (4 mg IV monthly) Prostate carcinoma 4.5 years Jaw necrosis (site not specified) Unknown† ns, F Zoledronic acid (dosage ns) Breast carcinoma ns Jaw necrosis (site not specified) after two dental extractions Unknown* ns, F Zoledronic acid (dosage ns) Breast carcinoma ns Jaw necrosis (site not specified) Unknown* ns, M Zoledronic acid (dosage ns) Multiple myeloma ns Jaw necrosis (site not specified), exposed bone (spontaneous) Unknown* IV = intravenous. ns = not stated. * Not known whether patient continued bisphosphonate therapy after presentation. † Patient stopped bisphosphonate therapy after presentation. ‡Patient continued bisphosphonate therapy after presentation. §Pamidronate was replaced by zoledronic acid, which was ongoing.

Patrick M Purcell MB BS · Ian W Boyd PhD

A significant number of Australians are deficient in vitamin D — it is a fallacy that Australians receive adequate vitamin D from casual exposure to sunlight. People at high risk of vitamin D deficiency include elderly people (particularly those in residential care), people with skin conditions where avoidance of sunlight is advised, those with dark skin (particularly if veiled), and those with malabsorption. Exposure of hands, face and arms to one-third of a minimal erythemal dose (MED) of sunlight (the amount that produces a faint redness of skin) most days is recommended for adequate endogenous vitamin D synthesis. However, deliberate sun exposure between 10:00 and 14:00 in summer (11:00–15:00 daylight saving time) is not advised. If this sun exposure is not possible, then a vitamin D supplement of at least 400 IU (10 μg) per day is recommended. In vitamin D deficiency, supplementation with 3000–5000 IU ergocalciferol per day (Ostelin [Boots]; 3–5 capsules per day) for 6–12 weeks is recommended. Larger-dose preparations of ergocalciferol or cholecalciferol are available in New Zealand, Asia and the United States and would be useful in Australia to treat moderate to severe vitamin D deficiency states in the elderly and those with poor absorption; one or two annual intramuscular doses of 300 000 IU of cholecalciferol have been shown to reverse vitamin D deficiency states.

Working Group of the Australian and New Zealand Bone and Mineral Society, Endocrine Society of Australia and Osteoporosis Australia*

Andrew Firestone Psychiatrist, 30 Burke Road, East Malvern, VIC 3145. afireATtpg.com.au To the Editor: The drug company-funded article Diabetes, psychotic disorders and antipsychotic therapy: a consensus statement by Lambert and Chapman1 tests some ethical boundaries. Firstly, although categorised as a position statement, it does not express the position of any professional body. The cumbersome title was probably inspired by a recent landmark review of the same topic.2 But there, the American Diabetes Association (ADA), with others, recommended that prescribers bear in mind the strong association of olanzapine and clozapine with diabetes when choosing an antipsychotic drug. The MJA article does not dispute the ADA data, which rate a brief mention. But — and here is the second, more serious, ethical issue — the key ADA recommendation, that the varying diabetogenic potential of antipsychotic drugs should be a factor to consider when choosing an antipsychotic drug, is not mentioned at all. Instead, the article appears to be trying to use the weight of an impressive consultation process to influence prescribers to ignore the present state of knowledge. One cannot take issue with the Australian recommendations, which echo those of an important North American 2002 conference.3 But the funding source means that the omission of the ADA recommendations is an ethical problem: one must question why they have been omitted. To end on a positive note, the Australian recommendation for a prospective comparison trial of antipsychotic drugs for weight gain and diabetes is certainly a good one. It is high time that a university took this up —and published the results without drug company assistance.

Andrew Firestone

Timothy J R Lambert,* Leon H Chapman† * Director, OPEN (Office for Psychiatric Evaluation and Educational NewMedia), Department of Psychiatry, University of Melbourne, 7th Floor, Charles Connibere Building, Royal Melbourne Hospital, Melbourne, VIC 3050; † Diabetologist, International Diabetes Institute, Melbourne, VIC. lamberttATunimelb.edu.au In reply: Our article did not ignore the relative diabetic potential of various antipsychotic drugs. We wrote “clozapine and olanzapine are associated with greater weight gain and a higher occurrence of diabetes and dyslipidaemia than risperidone and quetiapine”, and so on.1 However, the article was not aimed to influence prescribing habits, but rather to alert health professionals to the relative metabolic risks both inherent in people with psychosis and arising from treatment with antipsychotic drugs in general, and the consequent need for constant assessment. The article tried to emphasise the need to balance risk versus benefit. We also tried to underline the need to effectively treat the illness (ie, the psychosis) with the most appropriate agent. Ignoring this would be akin to not using corticosteroids in severe asthma for fear of metabolic consequences. Finally, the article is a pointer to the full consensus statement, which is available on the Internet at www.psychiatry.unimelb.edu.au/open/diabetes_consensus/ and may be downloaded without charge.

Timothy J R Lambert · Leon H Chapman

Various claims have been made about the benefits of transdermal progesterone creams for relieving symptoms of menopause. Peer-reviewed articles have reported that the creams can raise plasma progesterone levels slightly, but have no effect on vasomotor, psychosexual or mood symptoms, bone metabolism or plasma lipid levels. Currently available progesterone creams can not be recommended for treatment of symptoms associated with menopause.

Barry G Wren MD, MHPEd, FRANZCOG

Ursula Bayliss,* Christopher Cowell,† James Hong,‡ Veronica Wiley,§ Bridget Wicken¶ * Clinical Nurse Consultant, §Principal Scientist, ¶ Clinical Director, NSW Newborn Screening Programme, † Head, Institute of Endocrinology & Diabetes, The Children's Hospital at Westmead, Westmead, NSW 2145; ‡ Paediatrician, North Gosford Medical Centre, North Gosford, NSW. bridgetwATchw.edu.au To the Editor: We report an acute presentation of congenital hypothyroidism in a child almost 6 years old. The condition was not detected by newborn screening. Screening of all neonates started in New South Wales in July 1977, with thyroid stimulating hormone (TSH) being measured in dried blood spots taken from a heel-prick blood sample (currently at 2–3 days of age). A whole-blood TSH level of 40 mIU/L or above triggers a request for full thyroid function testing, whereas with a level of 20–39 mIU/L a second sample is requested. We have screened over 2.3 million babies and detected 690 babies with congenital hypothyroidism. Ten babies with dyshormonogenesis or ectopic thyroid tissue had normal results and were missed by the screening test. Since screening started, “juvenile hypothyroidism” not associated with thyroid antibodies has all but disappeared. A healthy girl aged 5 years 11 months presented with acute dysphagia and drooling. There were no previous dysphagic symptoms. Initially, epiglottitis was suspected; however, at endoscopy a lingual thyroid was visualised at the base of her tongue, and this was confirmed by a technetium scan. She had normal growth and development, with both height and weight at the 50th centiles, a pulse rate of 90 beats/min, and normal deep tendon reflexes. The whole-blood TSH level at newborn screening on Day 3 was 40 mIU/L (reference range [RR], < 20 mIU/L). Thyroid function testing at another hospital on Day 10 showed a serum TSH level of 16.6 mIU/L and a serum free thyroxine (FT4) level within the normal range (12 pmol/L; RR, 11–30 pmol/L). These results were interpreted as normal, whereas, in fact, the TSH level was above the reference range for 10 days of age (< 10 mIU/L), although within the reference range for 2–7 days. On the patient’s admission for treatment of acute dysphagia, the TSH level was 10.9 mIU/L and the FT4 level was 18 pmol/L. A diagnosis was made of compensated hypothyroidism secondary to the ectopically placed lingual thyroid. Thyroxine treatment was commenced on diagnosis, and regular follow-up arranged. Three months after the start of treatment, the results of thyroid function tests (FT4, 17 pmol/L; TSH, 2.7 mIU/L) were within the normal range. Acute presentation of a lingual thyroid is most unusual.1 This case emphasises that further investigations must be performed when thyroid function test results are equivocal. Unfortunately, the thyroid status was considered normal because the FT4 value was within the normal range. All babies whose TSH results remain elevated while the FT4 levels are normal should have a thyroid scan, as we recommend when reporting results.

Ursula Bayliss · Christopher Cowell · James Hong · Veronica Wiley · Bridget Wicken

A 66-year-old man presented with a 12-month history of progressive gait disturbance with cerebellar ataxia and extrapyramidal features. Computed tomography of the head showed calcification of the basal ganglia and dentate nuclei of the cerebellum, and periventricular calcification (Box). Biochemical testing showed serum level of calcium, 1.19 mmol/L (reference range [RR], 2.15–2.55 mmol/L); ionised calcium, 0.61 mmol/L (RR, 1.14–1.29 mmol/L); phosphate, 1.8 mmol/L (RR, 0.8–1.5 mmol/L); and parathyroid hormone, 0.9 pmol/L (RR, 1.5–8.0 pmol/L). The patient was diagnosed with hypocalcaemia caused by idiopathic hypoparathyroidism. He was treated with calcitriol (2 μg daily) and calcium carbonate (6.0 g daily). His gait showed some improvement, and serum calcium levels became normal over several weeks. The pathophysiology of intracerebral calcification in hypoparathyroidism, which appears paradoxical, is unknown. It is usually asymptomatic. When neurological effects occur, they are thought to be caused by microvascular degeneration from massive perivascular calcium deposition in high-metabolic areas. Computed tomography of the head, showing cerebral calcification A: Calcification of the basal ganglia. B: Calcification of the dentate nuclei of the cerebellum. C: Periventricular calcification.

Huong Van Nguyen MB BS · Seng Khee Gan FRACP

Huy A Tran Director, Department of Clinical Chemistry, Hunter Area Pathology Service, John Hunter Hospital, Locked Bag No. 1, Hunter Region Mail Centre, New Lambton Heights, NSW 2310. huy.tranAThunter.health.nsw.gov.au To the Editor: I read with interest the recent review of Paget’s disease by Walsh.1 I would recommend that calcium and phosphate levels should be included in the initial biochemical assessment, as both tests are cheap and readily available. As Paget’s disease predominantly afflicts the older population, coexisting vitamin D deficiency is likely. Low (but within the normal range) calcium and phosphate levels may support this diagnosis. Conversely, hypercalcaemia, a rare event in Paget’s disease except in prolonged immobilisation,2 may indicate primary hyperparathyroidism, which is significantly associated with Paget’s disease,3 or, less commonly, metastatic bone disease. Both these conditions have prognoses and management distinctly different from those of Paget’s disease. Serum total alkaline phosphatase levels may not be elevated in 15% of active Paget’s disease.4 While bone-specific alkaline phosphatase level is more useful in these situations, this test is not readily available in some laboratories and, even among those in which it is available, some only provide qualitative results, making it less useful for monitoring Paget’s disease and the response to therapy. A suitable alternative test is urinary deoxypyridinoline/creatinine ratio, which can be done either on a random urine sample or a 24-hour urine collection. In addition, the serum total alkaline phosphatase level can be spuriously low in malnourishment, and specifically in zinc deficiency,5 a frequent occurrence in elderly people. I describe here a case highlighting such a problem. A 72-year-old socially isolated widower of 8 years presented with progressively worsening pain in his right hip in the preceding 3 months. He had poor appetite and had lost 6 kg in weight, but had no symptoms of malignancy. Clinical examination showed a thin man (body mass index, 20 kg/m2), who was otherwise normal with no features of zinc deficiency. A plain x-ray of the pelvis showed bilateral osteosclerosis. His total alkaline phosphatase level was 28 U/L (reference range, 35–110 U/L). Other investigations for metabolic bone disease gave normal results, including one for vitamin D level. Among other nutritional parameters, his zinc level was 5.2 mol/L (reference range, 10.0–18.0 mol/L). A computed tomography scan of the thorax and abdomen showed no evidence of malignancy, and a bone scan was consistent with Paget’s disease. A zinc supplement was prescribed and his diet optimised. At 6-week review, the serum zinc level had improved to 12.5 mol/L, but the serum total alkaline phosphatase level was 250 U/L. This confirmed that the patient’s acquired hypophosphatasia was secondary to zinc deficiency, with zinc being a critical cofactor for alkaline phosphatase activity.4 In light of the “correct” total alkaline phosphatase level, the patient was given intravenous pamidronate, with resulting marked resolution of his symptoms, including a 5-kg weight gain and normalisation of total alkaline phosphatase level. Although this case is unusual, it nevertheless highlights the need to consider occult and coexisting nutritional morbidities in an elderly population.

Huy A Tran

Barry N J Walters,* Sivanthi Senaratne† * Physician in Obstetric Medicine, University of Western Australia, Subiaco, WA; † Registrar in Obstetric Medicine, Sir Charles Gairdner Hospital, Perth, WA. banjowATiinet.net.au To the Editor: The “Consensus statement on diabetes control in preparation for pregnancy”1 presents a counsel of perfection that is, regrettably, a cry in the wilderness in this most imperfect of all imperfect worlds. None will deny that the glycaemic target specified would represent a wonderful achievement in a woman attending in early pregnancy. Unfortunately, we are far from achieving this goal, for a variety of reasons. Firstly, and most importantly, “preparation for pregnancy” is unusual. At our clinic (King Edward Memorial Hospital, Perth), where we see up to 90 women each year whose diabetes (types 1 and 2) antedated pregnancy, fewer than 15% have been seen for preconceptional counselling, and a similar proportion have an HbA1c level below 7%. Moreover, at the same hospital, the rate of unplanned pregnancy in the general antenatal clinic exceeds 50%. Studies elsewhere have shown that the rate of unplanned pregnancy in women with diabetes is the same or greater,2 and this figure accords with our own observations. Finally, in many women of reproductive age with diabetes, glycaemic targets as recommended by the Diabetes Control and Complications Trial Research Group3 and the recent consensus statement1 are infrequently met. One study of young adults in a type 1 diabetes clinic4 revealed that “. . . only 3.4% . . . achieved an average HbA1c of less than 7% during 11 years of study . . . despite regular specialist physician, specialist diabetes nurse and dietitian input and repeatedly following up failed appointments”. Australian findings are probably not substantially better in this group. Unfortunately, levels espoused by the above authorities are difficult to attain outside the sequestered environment of a clinical trial. Thus, the realisation of the St Vincent declaration,5 which sought to normalise obstetric outcome for women with diabetes, has proven elusive. Statements that recommend ideal levels of glycaemic control before pregnancy, while laudable, are unlikely to improve the high rates of miscarriage, congenital abnormality, preterm birth and perinatal mortality that we observe. What, then, can we do? The most important intervention in the care of fertile women with diabetes is effective contraception, with the aim of preventing pregnancy until adequate control of diabetes has been achieved. Numerous studies have shown that women who plan their pregnancy and attend for preconceptional care demonstrate better periconceptional glycaemic control and, accordingly, lower rates of adverse events in pregnancy.6 Only by raising the matter of family planning repeatedly with all our younger female patients can we hope to avoid the disappointing observation of an unplanned pregnancy, with all its adverse consequences for the woman with diabetes and her baby.

Barry N J Walters · Sivanthi Senaratne

H David McIntyre,* Jeff R Flack† * Director, Endocrinology and Obstetric Medicine, Mater Health Services, South Brisbane, QLD; † Director, Diabetes Centre, Bankstown–Lidcombe Hospital, Bankstown, NSW. David. McIntyreATmater.org.au In reply: Walters and Senaratne raise two important points — that specific preparation for pregnancy is the exception rather than the rule, and that many people with diabetes (including women of childbearing age) demonstrate poor glycaemic control. As a first step to improving this situation, we believe it is reasonable to set a goal. We sought to alert clinicians, especially those with limited experience in this area, to the importance of optimal glycaemic control in preparation for pregnancy. We hope that the consensus statement represents a “signpost” rather than a forlorn “cry in the wilderness”. Many opinions were sought in developing the consensus statement. Some, for reasons similar to those given by Walters and Senaratne, thought the “HbA1c < 7%” goal too strict, while others believed it to be far too lax. In the end, we agreed to include this figure, with the proviso that the level of glycaemia should be the best achievable for each individual patient. We must educate women of childbearing potential with diabetes and their caring health professionals about the need for preconceptional diabetes control as part of their care. In some clinical circumstances, such as assisted reproduction, the timing of conception is actually determined by the treating doctor. In this setting, optimal glycaemic control should be a prerequisite for active treatment. Rather than taking a nihilistic view, clinicians should devote their combined talents and energy to providing optimal pre-pregnancy care to those women with diabetes who do plan their pregnancies, to promoting pre-pregnancy care (including contraception) for those who currently do not, and to assuming an advocacy role in promoting access to and funding for intensive treatment programs for all people with diabetes.

H David McIntyre · Jeff R Flack

Re: “Postnatal evaluation of vitamin D and bone health in women who were vitamin D-deficient in pregnancy, and in their infants”, by Thomson K, Morley R, Grover SR and Zacharin MR in the 1 November 2004 issue of the Journal (Med J Aust 2004; 181: 486-488). The first author’s name was incorrectly given as “Katherine Thompson”. The correct name is “Katherine Thomson”. The html and pdf versions of the article published in the eMJA were corrected on 30 November 2004.

Katherine Thomson MB BS · Margaret R Zacharin MB BS, FRACP · Ruth Morley BA, MB BChir, FRCPCH · Sonia R Grover MB BS, FRACOG

Objective: To assess effectiveness and side effects of thiazolidinediones (TZDs) as adjunctive therapy in suboptimally controlled patients with type 2 diabetes.Design and setting: Review of a prospectively recorded database at the Royal Melbourne Hospital diabetes clinic.Participants: 203 patients with type 2 diabetes who received pioglitazone or rosiglitazone between 1 May 2000 and 31 October 2002.Outcome measures: Response in glycohaemoglobin (HbA1c) level, lipid profile changes and side effects, including hypoglycaemia, weight gain, oedema and precipitation of cardiac failure.Results: Both pioglitazone and rosiglitazone improved glycaemic control, with a reduction in the HbA1c level of 1.02% (range, 0.85%–1.19%) and 0.96% (range, 0.81%–1.11%), respectively, in the first 6 months of therapy. Rosiglitazone was associated with a 0.45 mmol (range, 0.31–0.59 mmol) increase in cholesterol level and 0.99 mmol (range, 0.60–1.38 mmol) increase in triglyceride level, while pioglitazone was associated with insignificant declines in cholesterol and triglyceride levels. There was reduced requirement for insulin, but not for oral hypoglycaemic agent (OHA), in most patients who used these agents. Pioglitazone and rosiglitazone were associated with increased rates of hypoglycaemia (17% and 11% of patients, respectively), significant weight gain (48% and 58%) and oedema (33% and 21%). There were four cases of acute left ventricular failure and two cases of reversible liver dysfunction in patients treated with TZDs.Conclusions: Adding pioglitazone or rosiglitazone therapy to OHA or insulin in patients with type 2 diabetes significantly improved glycaemic control. However, the use of these drugs in routine clinical practice was associated with more frequent adverse events than previously reported in clinical trials.

Zanariah Hussein MB BS · John M Wentworth MB BS, PhD · Alison J Nankervis MD, FRACP · Joseph Proietto FRACP, PhD · Peter G Colman FRACP, MD

Psychotic illness and its treatment are associated with an increased rate of diabetes and worsening blood sugar control. The newer, second-generation antipsychotic agents are more likely to produce this effect than the first-generation agents, but both contribute to the problem. The effect is usually related to insulin resistance through weight gain, but other mechanisms may exist. Diabetic ketoacidosis is rare. Management of psychosis takes priority over concerns about the potential metabolic sequelae of treatment, but the prevalence of the latter requires that all patients taking antipsychotic agents be actively screened and treated. Patients treated with antipsychotic agents need baseline and regular checks, including weight, blood glucose and lipid levels and blood pressure. Management of psychosis with its attendant medical problems requires a multidisciplinary approach, with primary health practitioners playing a central role. Mortality and medical morbidity is higher in those with psychosis than expected; preventive measures, combined with early detection and treatment of hyperglycaemia and other metabolic problems, is a key public health issue.

Tim J R Lambert BSc, FRANZCP · Leon H Chapman FRACP

Objective: To determine the postnatal vitamin D status and bone health of women identified as vitamin D-deficient in pregnancy, and of their infants.Design and participants: Retrospective audit conducted between 27 August and 5 November 2003. The study included women delivering between August and October 2002 at the Royal Women’s Hospital, Melbourne, who had had a 25-hydroxyvitamin D (25-[OH]D) level < 30 nmol/L in pregnancy, and their infants at age 4–10 months.Setting: The outpatient clinic at the Royal Children’s Hospital, Melbourne.Main outcome measures: Maternal and infant serum levels of vitamin D, total alkaline phosphatase (tALP), parathyroid hormone (PTH), calcium and phosphorus; x-ray results in children with clinical or laboratory findings suggestive of rickets.Results: Of 69 mother–infant pairs invited to participate, 47 (68%) attended. All 47 women had 25-(OH)D levels < 50 nmol/L, and 39 (83%) had levels < 30 nmol/L. Vitamin D supplements had been prescribed in pregnancy for 35 women (74%), and 19/35 reported having taken them as prescribed. None had continued to take supplements postnatally, but one had recently started taking them again. Among 45 infants from whom blood samples were successfully obtained, 18 (40%) had 25-(OH)D levels < 50 nmol/L, and 14 (31%) had levels < 30 nmol/L. Twelve of 16 breastfed infants had 25-(OH)D levels < 30 nmol/L, compared with 2/29 fed formula milk (P = 0.001).Conclusions: Most mothers who had been vitamin D-deficient in pregnancy were also deficient postnatally, indicating that treatment offered, counselling and/or treatment compliance were inadequate. Their infants, especially if breastfed, were at high risk of vitamin D deficiency and increased bone formation. Breastfed infants of mothers at high risk of vitamin D deficiency should receive vitamin D supplements.

Katherine Thomson MB BS · Margaret R Zacharin MB BS, FRACP · Ruth Morley BA, MB BChir, FRCPCH · Sonia R Grover MB BS, FRACOG