Volume 172 Issue 5

Healthcare Implementing clinical practice guidelines: a community-based audit of breast cancer treatment Paul S Craft, Yanping Zhang, Jennifer Brogan, Noel Tait, John M Buckingham, and the Australian Capital Territory and South Eastern New South Wales Breast Cancer Treatment Group MJA 2000; 172: 213-216 For editorial comment, see Redman & Reeve Abstract - Methods - Results - Discussion - Acknowledgement - References - Authors' details - - More articles on Oncology Abstract Objective: To improve breast cancer management by facilitating implementation of treatment guidelines. Design: A prospective, longitudinal study (developed by clinicians and consumers) of all patients with newly diagnosed breast cancer. Four locally agreed breast cancer management guidelines were established (based on 1995 National Health and Medical Research Council guidelines) as practice indicators. Setting: Breast cancer treatment facilities and medical practices in the Australian Capital Territory and South Eastern New South Wales, May 1997 to July 1998. Main outcome measures: Actual treatment received by patients for primary breast cancer during the study period. Results: During the 14 months of the study, 19 clinicians registered 221 new patients with a proven diagnosis of breast cancer. Of 191 women with localised invasive breast cancer, 112 (59%) had tumours 2 cm or less in diameter. Axillary surgery in 173 (91%) of these women showed 107 (56%) had no axillary lymph node involvement. Of 87 women treated with breast-conserving surgery for locally invasive cancer, 85 (98%) also received postoperative radiotherapy. Some form of systemic adjuvant therapy was indicated in 99 women (axillary nodes positive or tumours > 2 cm diameter) and this treatment was received by 95 (96%). All 27 women aged under 50 years with node-positive disease received adjuvant chemotherapy. Conclusions: Enhancing uptake of breast cancer management guidelines is feasible at a regional level with an audit program and broad support among clinicians and consumers. Breast cancer is a major health problem in Australia, with 9800 new cases diagnosed each year.1 Management guidelines for early breast cancer were developed in 1995 by the National Health and Medical Research Council (NHMRC) to assist clinicians and consumers make decisions about treatment and thus to improve health outcomes.2 Observed differences in treatment outcome between populations suggest that opportunities for improvement are available.3 Moreover, potentially important variations in clinical practice are well documented in Australia and elsewhere.4-6 Treatment practice which appears to be informed by evidence, for example greater use of breast-conserving surgery, has been observed more frequently among clinicians who regularly treat patients with breast cancer.7 Furthermore, congruence of treatment practice with published guidelines has been directly associated with improved patient survival;8 improved treatment practice has the potential to improve survival by up to 10%.8,9 Therefore, enhanced implementation of soundly developed, evidence-based treatment guidelines is an appropriate goal for health services and individual clinicians. In 1996, clinicians and consumers involved in breast cancer diagnosis and treatment in the Australian Capital Territory (ACT) and South Eastern New South Wales (SE NSW) formed a cooperative group aimed at improving breast cancer management and facilitating implementation of treatment guidelines. A prospective, longitudinal, community-based study of breast cancer treatment was established to assist with guidelines implementation. Our report describes the results of the first 14 months of this ongoing project. Methods Breast Cancer Treatment Group All surgeons, radiation oncologists, medical oncologists, radiologists, pathologists, nurses and other health professionals who were known by the ACT Breast Screen Program to be involved in the treatment of breast cancer in the ACT and SE NSW were invited by mail to participate in a multidisciplinary breast cancer treatment group. Consumer representatives from "The Bosom Buddies", a community organisation of women with a history of breast cancer, were also invited to join the group. Fifty consumers and clinicians expressed interest and continue to receive all correspondence, with meetings every two months attracting between 15 and 30 attendees. A general practitioner representative from the ACT Division of General Practice also participated. The Breast Cancer Treatment Group adopted treatment guidelines based on the NHMRC Clinical Practice Guidelines, commenced a community-based audit, and later developed a set of agreed practice indicators against which treatment decisions could be compared. The 1998 estimated populations of the ACT and South Eastern NSW were 311 000 and 118 000 respectively (source: Australian Bureau of Statistics, Estimated Residential Populations, 30 June 1998). Practice indicators The group adopted four indicators for which unanimous local agreement about the relevant guideline was available: Women with operable invasive breast cancer should undergo some form of axillary surgery sufficient to develop a prognosis based on axillary node status; Women undergoing less than total mastectomy for operable invasive breast cancer should receive postoperative adjuvant radiotherapy; Women with a completely resected invasive breast cancer tumour greater than two centimetres in diameter or with involved axillary lymph nodes should receive adjuvant systemic therapy (either chemotherapy, endocrine therapy or both); and Women under the age of 50 years with completely resected axillary lymph node positive breast cancer should receive adjuvant chemotherapy. Audit A prospective study of breast cancer treatment was commenced in May 1997. The study was designed as a quality assurance project and notified as such under Section 7 of the Health Act 1993 (ACT) in June 1997. The study was approved by the Ethics Committee of the ACT Department of Health and Community Care. All clinicians involved specifically with the care of patients with breast cancer were invited to participate in the study. Participating clinicians agreed to approach all of their patients presenting with newly diagnosed breast cancer requesting permission to include them in the study. Eligible patients were women or men with newly diagnosed invasive or in-situ breast cancer. For each eligible patient a brief notification form was completed and submitted by mail to the study centre at the Women's Health Program of ACT Community Care. Written informed consent was obtained from the patient by the notifying clinician, and subsequently a detailed data form was completed giving details of presentation, clinical and pathological staging, and treatment. The dataset was based on a prior survey conducted by the Provincial Surgeons of Australia (Dr David Adamthwaite, President of the Provincial Surgeons of Australia, personal communication). Additional data relating to enrolled patients were obtained from treatment units in the region. Information from the audit forms, supplemented where necessary from pathology reports and treatment facility records, was entered into a secure database developed by the project officer. As well as facilitating project management, the database allows individualised, confidential reports to be produced for each participating clinician, providing detailed feedback about each clinician's practice, with comparisons across the group and against the agreed criteria. Aggregated data across the whole clinician group are presented at regular meetings of the treatment group. Data collected during the first 14 months of the project, and analysed to provide an initial report to contributing clinicians, form the basis of our report. Accrual of patients to the project is ongoing. Results Specialist participation Since commencement of the project, 23 of 24 medical specialists known to treat breast cancer within the region have registered as participants, with 19 specialists contributing data to the study to date (13 surgeons, three radiation oncologists and three medical oncologists). All of the radiation and medical oncologists were based in Canberra, while the principal practices of six surgeons were based in SE NSW. Patient accrual During 14 months from May 1997 to July 1998, 221 patients, including four men, with a diagnosis of primary breast cancer were registered for the study (Box 1). Some 123 new cases of invasive breast cancer (excluding male patients and patients with in-situ disease only) were registered with ACT addresses. In comparison, the observed mean annual incidence of breast cancer in the ACT during 1993-1996 was 134.1 Thus, during the 14-month study period, about 156 incident cases would be expected. The project therefore detected 79% of predicted ACT incident cases during the study period. Of the 221 registered patients, there were 10 with distant metastases, 16 with carcinoma-in-situ only and four men, leaving 191 women with primary, localised, invasive breast cancer. It is to these women that the treatment guidelines apply. In five women with bilateral synchronous tumours, details are given of the tumour judged by the treating clinician to have the worse prognosis. Eighty-one per cent of tumours were oestrogen receptor (ER) positive or progesterone receptor (PgR) positive by immunohistochemical analysis done in routine diagnostic histopathology laboratories. The pathological characteristics of the tumours in these 191 women are presented in Box 2. Comparisons with practice indicators (Box 3) Axillary surgery was undertaken in 173 women. One elderly patient declined to have any surgery. Thus, 17 of 190 patients did not undergo any form of axillary surgery, at variance with the guideline. Of these women, six were aged 80 years or older. Seven of the remaining 11 patients had tumours less than 1 cm in diameter. Among women having axillary surgery, five (3%) had four or fewer nodes resected. Only two of 87 women who underwent breast-conserving surgery did not also receive postoperative radiotherapy. Of the 191 patients with invasive breast cancer, 103 (54%; 95% CI, 47-61) underwent mastectomy. The overall concordance of treatment with the practice indicators relating to systemic adjuvant therapy was strong. Of 33 women with tumours greater than 2 cm in diameter and negative or unknown axillary lymph node status, 32 (97%) received either tamoxifen (18), chemotherapy (4), or both (10). Of 66 women with axillary lymph node involvement, 63 (95%) received systemic adjuvant therapy with either tamoxifen (14), chemotherapy (19) or both (30). Thus, only four of 99 women for whom adjuvant systemic therapy was considered appropriate under the guidelines did not receive such therapy. All 27 women under 50 years of age with axillary lymph node involvement received adjuvant chemotherapy. Data quality The project officer actively sought clarification of ambiguous or missing data items. Initial notification forms required clarification for 192 of 221 registrations. Of these queries, one follow-up data request was required for 91 patients, two requests for 60 patients and three requests for 41 patients. After these data requests, 3.6% of records remained incomplete in some way. Initial under-reporting of adjuvant treatments received was noted, particularly in regard to postoperative radiotherapy. Discussion Our report demonstrates the feasibility of regionally based multidisciplinary groups adopting treatment guidelines and then assessing their implementation. Strong concordance of practice with the four practice indicators was observed. Despite a third of our patients living in rural areas, there were high rates of postoperative radiotherapy after breast-conserving surgery. The rate of axillary surgery was lower than recommended, but in almost all of these women a partial explanation was available (advanced age or very small primary tumour). Whether the decision not to perform axillary surgery in these patients was appropriate is the subject of debate and ongoing clinical trials. Given the degree of involvement of clinicians in establishing the data collection and practice indicators, the strong concordance with actual practice observed is not surprising. The practice indicators chosen were not particularly controversial, enabling rapid consensus among the group members. Indicators relating to the use of breast-conserving surgery for early breast cancer and to the use of adjuvant chemotherapy for node-negative disease, although more contentious, are appropriate further areas for local consensus and audit. Observed concordance with guidelines for adjuvant chemotherapy in node-negative breast cancer has been relatively low, presumably because of the more modest benefits of treatment (in absolute terms) in this group.11 Implementing guidelines successfully can be difficult. Just producing and publishing guidelines for breast cancer treatment does not ensure their uptake into clinical practice.12 Over time clinical practice may adhere more closely to published guidelines, although a causal relationship cannot be easily proven.13 In a survey of clinicians in Sydney, most respondents supported the NHMRC Clinical Practice Guidelines, but only 20% believed the guidelines had influenced clinical practice.14 The introduction of guidelines has been a stimulus for institutionally focused audits of surgical practice.15 Audits incorporating structured feedback to clinicians may be a critical strategy in implementing guidelines. Organisations such as the Royal Australasian College of Surgeons have recognised audit as an important tool in the treatment of breast cancer, and Clinical Indicator 7.1 of the Australian Council of Healthcare Standards Internal Medicine Indicators, version 2, measures the proportion of premenopausal women with node-positive early breast cancer receiving chemotherapy.16 Many factors affect treatment decisions in primary breast cancer. Women bring to the process their own preferences and needs. Many of the treatment decisions require trade-offs between long term gain and unpleasant treatments, such as chemotherapy. We did not examine the decision-making processes followed by these patients and their attending health professionals. Entry of any individual patient into the audit was voluntary, both for the clinician and for the patient. Participating clinicians undertook to offer enrolment to all of their patients, and every effort was made to enhance compliance. Nevertheless, complete enrolment was not achieved and this may have introduced bias, with patients receiving multimodality care possibly being more likely to be enrolled. An advantage of our audit was that it was community based and prospective. Surgical audits have generally been based on retrospective casenote review and, as such, have sometimes been hampered by missing data.17 Some community-based studies assessing the process of treatment have relied on the secondary analysis of administrative data with linkage to population-based cancer registries.18 In Canada, a population-based cancer registry has been linked to clinical records to obtain treatment details and allow comparisons with treatment guidelines.19 Successful collection of community-based audit data requires both enthusiasm and trust on the part of the treating clinicians voluntarily submitting information about their own practice. We believe this may be best achieved within a framework of agreed treatment guidelines and indicators. An enthusiastic project officer and involvement of practice staff and institutional data managers is crucial. As new ways of managing breast cancer (and other diseases) become available, an ongoing implementation process with agreed, clinically relevant indicators and guidelines, and a regionally based audit, can be an effective tool. Members of the Australian Capital Territory and South Eastern New South Wales Breast Cancer Treatment Group contributing to the study Chairperson Dr Doris Zonta. Surgeons Bega, NSW: Dr Andrew Thomson. Canberra, ACT: Dr Guan Chong, Dr Ian Davis, Dr Dennis Dyason, Dr Diarmid McKeown, Dr John Stuchbery Goulburn, NSW: Dr Margaret Beevors, Dr John Hayman. Moruya, NSW: Dr Peter Gough, Dr John Groome, Dr David Thomson. Medical Oncologists Canberra, ACT: Associate Professor Robin Stuart-Harris, Dr William Coupland. Radiation Oncologists Canberra, ACT: Dr Deborah Thornton, Dr George Jacob, Dr Kenneth Sunderland. Epidemiologist Canberra, ACT: Dr Bruce Shadbolt. Pathologists Canberra, ACT: Dr Jane Dahlstrom, Dr Sanjiv Jain. Acknowledgement Initial funding was provided by the Commonwealth Department of Health and Aged Care Cancer Screening Unit. References Australian Institute of Health and Welfare. Breast and cervical cancer screening in Australia 1996-1997. Canberra: AIHW, 1998: 33. (Cancer Series no. 8.) National Health and Medical Research Council. Clinical practice guidelines. The management of early breast cancer. Canberra: NHMRC, 1995. Richards M, Sainsbury R, Kerr D. Inequalities in breast cancer care and outcome. Br J Cancer 1997; 76: 634-638. Craft PS, Primrose JG, Lindner JA, McManus PR. Surgical management of breast cancer in Australian women in 1993: analysis of Medicare statistics. Med J Aust 1997; 166: 626-629. Nattinger AB, Goottlieb MS, Veum J, et al. Geographic variation in the use of breast-conserving treatment for breast cancer. N Engl J Med 1992; 326: 1102-1107. Samet JM, Hunt WC, Farrow DC. Determinants of receiving breast-conserving surgery. The surveillance, epidemiology and end results program 1983-1986. Cancer 1994; 73: 2344-2351. Hill DJ, White VM, Giles GG, et al. Changes in the investigation and management of primary operable breast cancer in Victoria. Med J Aust 1994; 161: 110-122. Sainsbury R, Haward B, Rider L, et al. Influence of clinician workload and patterns of treatment on survival from breast cancer. Lancet 1995; 345: 1265-1270. Gillis CR, Dole D. Survival outcome of care by specialist surgeons in breast cancer: a study of 3786 patients in the west of Scotland. BMJ 1996; 312: 145-148. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 1991; 19: 403-410. Sawaka C, Olivotto I, Coldman A, et al. The association between population-based treatment guidelines and adjuvant therapy for node-negative breast cancer. Br J Cancer 1997; 75: 1534-1542. Chouillet AM, Bell CM, Hiscox JG. Management of breast cancer in southeast England. BMJ 1994; 308: 168-171. Ray-Coquard I, Philip T, Lehmann M, et al. Impact of a clinical guidelines program for breast and colon cancer in a French cancer center. JAMA 1997; 278: 1591-1595. Ward JE, Boyages J, Gupta L. Local impact of the NHMRC early breast cancer guidelines: where to from here? Med J Aust 1997; 167: 362-365. McCarthy DO, Blamey RW, Robertson JF, Mitchell AK. A one-year audit of 255 operable breast cancers. Eur J Surg Oncol 1997; 23: 399-402. Australian Council on Healthcare Standards. Clinical indicators in summary. Revised edition. Sydney: ACHS, 1998. Clamp SE. Management of breast cancer. Incomplete case notes hamper research. BMJ 1994; 308: 715. Hillner BE, McDonald MK, Penberthy L, et al. Measuring standards of care for early breast cancer in an insured population. J Clin Oncol 1997; 15: 1401-1408. Olivotto IA, Coldman AJ, Hislop TG, et al. Compliance with practice guidelines for node-negative breast cancer. J Clin Oncol 1997; 15: 216-222. (Received 29 Jul, accepted 4 Dec, 1999) Authors' details Medical Oncology Unit, The Canberra Hospital, Canberra, ACT. Paul S Craft, MPH, FRACP, Director. Women's Health Program, ACT Community Care, Canberra, ACT. Yanping Zhang, Project Officer; Jennifer Brogan, Director. The Calvary Clinic, Canberra, ACT. Noel Tait, FRACS, Consultant Surgeon; John M Buckingham, FRACS, Consultant Surgeon. Reprints: Dr P S Craft, Medical Oncology Unit, The Canberra Hospital, PO Box 11, Woden, ACT 2606. Paul_CraftATact.gov.au Make a comment 1: Patient and tumour characteristics for all registered breast cancer patients (n=221)nPercentage (95% CI)Median age, 57 years (range, 25-88)SexMale42% (1%-5%)Menopausal statusPremenopausal63 29% (23%-35%)Postmenopausal12557% (50%-63%)Perimenopausal2712% (8%-17%)Unknown or male63% (1%-6%)Place of residenceAustralian Capital Territory14767% (61%-73%)DiagnosisIn-situ disease only167% (4%-11%)Invasive carcinoma20593% (89%-96%)Tumour extentDistant metastases at diagnosis105% (3%-9%)Synchronous bilateral tumours52% (1%-5%) Back to text 2: Pathological characteristics of the tumour in 191 women with invasive breast cancer and no distant metastases CharacteristicnPercentage (95% CI)Tumour size (mm)0-103016% (11%-22%)11-208243% (36%-50%)21-506233% (27%-40%)>50147% (4%-12%)Unknown32% (1%-5%) Axillary lymph node statusNegative107 56% (49%-63%)Positive66 35% (29%-42%)No axillary surgery168% (5%-13%)Unknown21% (1%-5%) CharacteristicnPercentage (95% CI)Tumour type and grade*Invasive ductalGrade 12915% (11%-21%)Grade 26635% (29%-42%)Grade 35328% (22%-35%)Invasive lobular2010% (7%-15%)Special types†2312% (8%-17%)Receptor statusER positive or PgR positive15581% (75%-86%)ER negative and PgR negative3016% (11%-22%)Unknown63% (1%-6%) *See Elston and Ellis.10 †Includes seven tubular, four mucinous, six cribriform, one papillary, one medullary, one squamous cell, and one metaplastic carcinoma. There was also one spindle cell tumour and one cystosarcoma phylloides tumour reported. ER=Oestrogen receptor. PgR=Progesterone receptor. Back to text 3: Women with breast cancer - comparison of treatment received with practice indicators Indicatorn Percentage (95% CI)Breast-conserving surgeryRadiotherapy8598% (92%-99%)No radiotherapy22% (1%-8%)Total87 100%Surgery for invasive cancerAxillary surgery17391% (86%-94%)No axillary surgery179% (6%-14%)Total190 100%Axillary nodes positive or tumours >2 cmSome form of adjuvant systemic therapy95 96% (90%-98%)No adjuvant systemic therapy44% (2%-10%)Total99100%Women aged less than 50 years with positive axillary nodesAdjuvant chemotherapy27100%No adjuvant chemotherapy00Back to text

Paul S Craft · Yanping Zhang · Jennifer Brogan · Noel Tait · John M Buckingham

Sports Medicine Deaths due to brain injury among footballers in Victoria, 1968-1999 Paul R McCrory, Samuel F Berkovic and Stephen M Cordner MJA 2000; 172: 217-219 Abstract - Introduction - Methods - Results - Discussion - References - Authors' details - - More articles on Sports medicine Abstract Objectives: To determine the frequency and nature of fatal brain injuries occurring in Australian football. Setting: State of Victoria, January to July 1999. Design: Retrospective case series of football-related deaths identified from the coronial autopsy records of the Victorian Institute of Forensic Medicine (1990-1999) and newspaper reports (1968-1989). Main outcome measures: Coronial autopsy findings and circumstances of injury. Results: 25 deaths associated with Australian football were identified, nine due to brain injury. Coronial findings in the brain-injury deaths were intracranial haemorrhage in eight patients and infarct in the territory of the middle cerebral artery in one. In three of four cases of subarachnoid haemorrhage, vertebral artery trauma was noted. In all but one case, injury occurred as an accidental part of play. Conclusions: The most common findings in deaths due to brain injury in Australian football were intracranial haemorrhage, including subarachnoid haemorrhage from vertebral artery injury. Introduction Traumatic brain injury is common in contact and collision sports. In Australian (rules) football the epidemiology of mild head injury has been well studied. Based on prospective studies, the incidence of concussion in professional play is about 4 per 1000 player hours or 1 per 125 player games.1,2 However, a concern for team physicians is the very rare possibility of severe brain injuries, including intracranial haematomas, sometimes complicated by diffuse cerebral oedema, leading to permanent neurological impairment or death.3-7 To our knowledge there is no systematic, published information on severe and fatal brain injury in any code of football in Australia. Our study aimed to determine the frequency and nature of fatal brain injuries that occurred in football played in the State of Victoria, comprising Australian football and rugby union, in the 32 years to 1999. Methods In Victoria, the Coroners Act 1985 (Vic.) requires all unexplained deaths or deaths due to accident or injury to be reported to the Coroner. In such cases, an autopsy is usually performed and the circumstances surrounding the death are investigated by the Coroner before a formal finding is made.8 The Victorian Institute of Forensic Medicine (VIFM) is responsible for providing pathology services and medical expertise to the Coroner. VIFM records from 1990 onwards are available on a computerised database, while earlier records are filed chronologically according to date of death and archived off-site. We performed a computerised search of the VIFM database for the period January 1990 to July 1999. A keyword search for the term "football" was used, noting where this word occurred in the coronial findings or the forms detailing the circumstances of the injury. Deaths of officials and spectators at football matches were excluded from the study. As pre-1990 VIFM records are not on a computerised database, we could not search by text word. Further, as they comprise more than 50 000 case records stored with limited accessibility, a manual search was considered logistically unfeasible. Instead, we searched the clipping libraries of the major daily Victorian newspapers (The Age, the Herald-Sun) for the period January 1968 to December 1996 for cases of football-related fatalities. Reported details of names, injuries and dates of events were compared against coronial case records. The original records of identified cases were extracted for analysis of the circumstances surrounding the injury and the neuropathological findings. The coronial autopsy always involved gross examination of the brain, but histological and detailed neuropathological examination was not always performed. When necessary, original hospital records were obtained for further details of injuries and neurosurgical findings. This study was approved by the VIFM Ethics Committee and by the Ethics Committee of the Austin & Repatriation Medical Centre, Melbourne, Vic. Results We identified 25 football-related deaths in the period 1968-1999. Fourteen of these occurred in the 10 years 1990-1999 and were found by computerised search of the VIFM database, while 11 occurred in the 22 years 1968-1989 and were found by newspaper searches. Both search strategies were used for the period 1990-1996, and each identified the same nine cases. Details of the 25 deaths are shown in the Box. All but three were in Australian rules players, with the remainder in rugby union players (Patients 9, 21 and 22). Nine deaths were due to brain injury, all but one in Australian rules players. The remaining 16 were due to other causes, predominantly unrecognised ischaemic or congenital heart disease. For the brain-injury deaths, coronial findings were intracranial haemorrhage (in eight patients) and infarct in the territory of the middle cerebral artery (in one). In three of four cases of subarachnoid haemorrhage, vertebral artery trauma was noted. Diffuse cerebral oedema was noted in five patients -- in conjunction with surgically treated subdural haematomas (Patients 2, 6 and 8), a large subdural haematoma that was not surgically treated (Patient 9), and infarct in the territory of the middle cerebral artery (Patient 7). Analysis of the circumstances of the fatal injury from coronial depositions, police records and newspaper reports suggested that all but one of the nine brain-injury deaths occurred largely because of accidental injury during normal play. In Patient 9, no injury was noted. Discussion This study adds to knowledge of the severe end of the brain-injury spectrum in Australian football. We identified nine deaths due to brain injury associated with Australian football in Victoria in the 32 years to 1999. The most common coronial finding was intracranial haemorrhage, including three cases of traumatic subarachnoid haemorrhage from vertebral artery injury. Determination of football-related deaths is limited in part by the difficulties of case ascertainment. Computerisation of Victorian coronial records began in 1990, and text-word searches are limited to this period. Mortality data based on death certification through the Australian Bureau of Statistics do not adequately identify injury risk factors such as sport participation. We used a novel case-ascertainment method -- searching newspaper records -- on the assumption that deaths from football are likely to be "newsworthy" and that the reports are likely to contain narrative details of the incident. Indeed, we found that when the searches overlapped (1990-1996), the two methods had identical case ascertainment (nine cases). The presence of diffuse cerebral oedema was noted in five cases, all of which were associated with a major intracranial lesion. The mechanism of the middle cerebral artery territory stroke was not established at autopsy. However, given that hemiplegia was evident within minutes of the injury, it was more likely to have been caused by a traumatic middle cerebral artery occlusion than by raised intracranial pressure. An area of concern shown in epidemiological studies of football injury is the higher concussion rates that occur in elite junior competitive football (age under 18 years) compared with senior levels of competition.9-11 It has been postulated that junior players may not have fully developed the necessary evasive strategies to avoid the elements of the game that put them at risk of brain injury. In our study, three of the nine fatal brain injuries were in teenagers and were associated with vertebral artery injury. Traumatic vertebral artery dissection is the most common reported mechanism of stroke in sport.12 The combination of unilateral neck pain or headache after head or neck trauma should prompt suspicion of vertebral artery dissection, even in the face of seemingly trivial trauma.12 Focal neurological signs, such as vertigo, diplopia, ataxia, dysarthria, cranial nerve palsies or altered mental function, should be an absolute indication for urgent neurological consultation and hospital admission.13 Our results show that, although Australian football has one of the highest participation rates of sports in Victoria, the potential for fatal brain injury is extremely low. We did not identify any risk factors that could be modified to prevent brain injury. All team physicians, regardless of the level of participation, need to be conversant with the appropriate clinical pathways for the safe and efficient triage of neurologically injured athletes.14 Many deaths were due to cardiac causes, such as congenital cardiac disease, unrecognised ischaemic cardiac disease and commotio cordis (sudden death due to low-energy trauma to the chest wall, mechanism unknown, but presumed to be arrhythmia). The first two occurred mostly in teenagers, whereas the last occurred exclusively in players aged between 35 and 44 years. A high frequency of ischaemic cardiac death in football has also been observed in Aboriginal players in the Northern Territory.15 Pre-participation medical screening should be considered by football administrators throughout the country for high-risk groups. The role of a body to monitor injury over a range of sports in this country should also be considered. Although sport-related deaths are few, detecting injury patterns and identifying injury risk factors are important to ensure safe participation in sport. This task will be easier once the National Coroners' Information System, administered by the Monash University National Centre for Coronial Information, becomes fully functional in six to 12 months' time. References Seward H, Orchard J, Hazard H, Collinson D. Football injuries in Australia at the elite level. Med J Aust 1993; 159: 298-301. McCrory P. Neurological injuries in rugby and Australian rules football. In: Jordan B, Tsaris P, Warren R, editors. Sports Neurology. 2nd ed. Philadelphia: Lippincott-Raven Publishers; 1998: 441-449. Jennett B. Epidemiology of head injury. J Neurol Neurosurg Psych 1996; 60: 362-369. Jordan B, Tsaris P, Warren R, editors. Sports neurology. 2nd ed. Philadelphia: Lippincott-Raven Publishers, 1998: 45-71. Adams J. Head injury. In: Adams JH, Duchen LW, editors. Greenfield's neuropathology. 5th ed. London: Oxford University Press, 1992: 106-152. Cantu RC, Voy R. Second impact syndrome: a risk in any contact sport. Phys Sportsmed 1995; 23: 27-34. McCrory PR, Berkovic SF. Second impact syndrome. Neurology 1998; 50: 677-683. Breen K, Plueckahn V, Cordner S. Ethics, law and medical practice. Sydney: Allen and Unwin, 1997. Orchard J, Wood T, Seward H, Broad A. Comparison of injuries in elite senior and junior Australian football. J Sci Med Sport 1998; 1: 83-88. McMahon KA, Nolan T, Bennett CM, Carlin JB. Australian Rules football injuries in children and adolescents. Med J Aust 1993; 159: 301-306. National Health and Medical Research Council. Football injuries of the head and neck. Canberra: NHMRC, 1995. McCrory P. Stroke in athletes. In: Cantu R, editor. Neurologic athletic head and spine injuries. Philadelphia: WB Saunders and Co, 2000. In press. Showalter W, Esekogwu V, Newton K, Henderson S. Vertebral artery dissection. Acad Emerg Med 1997; 4: 991-995. McCrory PR. Were you knocked out? A team physician's approach to initial concussion management. Med Sci Sports Exerc 1997; 29 (7 Suppl): S207-S212. Young M, Fricker P, Thomson N, Lee K. Sudden death due to ischaemic heart disease in young Aboriginal sportsmen in the Northern Territory, 1982-1996. Med J Aust 1999; 170: 425-428. (Received 12 Jul 1999, accepted 21 Jan 2000) Authors' details Department of Medicine (Neurology), University of Melbourne, Austin and Repatriation Medical Centre, Melbourne, VIC. Paul R McCrory, FRACP, FACSP, Neurology Research Fellow; Samuel F Berkovic, MD, FRACP, Professor. Department of Forensic Medicine, Monash University, and Victorian Institute of Forensic Medicine, Melbourne, VIC. Stephen M Cordner, FRCPA, FRCPath(UK), Professor and Director. Reprints will not be available from the authors. Correspondence: Dr P R McCrory, 31 Grosvenor Parade, Balwyn, VIC 3103. pmccroryATcompuserve.com Make a comment Football-related deaths* in Victoria, 1968-1999 Patient Age (years) Details of injury Time to death Coronial findings Brain Injury 1 15 Accidental blow to neck when shepherded during play, fell to ground unconscious and died in hospital 6 hours Traumatic subarachnoid haemorrhage from vertebral artery injury, subdural haematoma 2 17 Accidental knock to the head during game, complained of tinnitus and headache, found unconscious next morning; craniotomy performed because of computed tomography evidence of extradural haematoma 16 hours Extradural and subdural haematomas cerebral contusion, cerebral oedema noted postoperatively 3† 19 Collision during normal play, no head contact reported, collapsed several minutes later and died in hospital 1 day Traumatic subarachnoid haemorrhage from vertebral artery injury 4 20 Accidental blow to occipital region during match, immediate collapse and declared brain dead at hospital 1 day Traumatic subarachnoid haemorrhage from vertebral artery injury 5 21 Forearm to face in tackle during match, may have subsequently hit head on ground, immediately confused and then suffered generalised seizure 2 days Subarachnoid haemorrhage (no comment on vertebral artery findings), cerebral contusion 6† 24 Accidental clash of heads during match and died in hospital after craniotomy 3 days Extradural haematoma, cerebral oedema noted postoperatively 7 26 Accidental knock to the back of the head while marking ball, noted to be "dazed" by team mates and collapsed about 10 minutes later; described as hemiplegic at that time 3 days Cerebral oedema, middle cerebral artery territory infarction 8† 36 Collision during play, fell backward hitting head on ground, immediately unconscious followed by respiratory arrest; craniotomy performed in hospital 6 hours Large subdural haematoma, cerebral noted oedema postoperatively 9† 41 Rugby union player, collapsed during match; no obvious trauma 4 hours Large subdural haematoma, cerebral oedema Other causes 10† 16 Collapsed after a football game, past history of heart problems DOA Hypertrophic obstructive cardiomyopathy with acute cardiac failure 11 19 Collapsed at football during game DOA Hypertrophic obstructive cardiomyopathy with acute cardiac failure 12 16 Collapsed and died during game DOA Myocardial ischaemia and arrhythmia associated with congenital aortic valve stenosis 13 19 Collapsed and died at football during match DOA Anomalous origin of left coronary artery 14† 20 Collapsed on field, no obvious trauma DOA Anomalous origin of left coronary artery 15 19 Bumped on chest during play, took kick and then collapsed, unable to be revived DOA Commotio cordis‡ 16† 19 Hit on chest in collision, took free kick then collapsed DOA Commotio cordis 17 24 Hit in the chest and collapsed DOA Commotio cordis 18 35 Collapsed and died during game DOA Coronary artery occlusion 19 37 Collapsed and died during game DOA Coronary artery occlusion 20† 37 Collapsed and died during game DOA Coronary artery occlusion 21† 43 Rugby union player, collapsed and died during game DOA Coronary artery occlusion 22† 44 Rugby union player, collapsed and died during game DOA Coronary artery occlusion 23† 24 Collision followed by respiratory distress DOA Acute asthma complicated by tension pneumothorax 24 22 Collision during match DOA Liver rupture and haemorrhage 25 18 Collapse during football match; no obvious trauma DOA No obvious abnormalities, neuropathological findings DOA=dead on arrival at hospital. *All deaths were associated with Australian rules football unless otherwise stated. †Deaths in the period 1990-1999, found by computerised database search. ‡ Sudden death after low-energy trauma to the chest wall, characteristically with no structural damage to the chest wall, thoracic cavity or heart -- mechanism unknown, presumed arrhythmia. 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Paul R McCrory · Samuel F Berkovic · Stephen M Cordner

Position Statement Use, misuse and abuse of androgens The Endocrine Society of Australia consensus guidelines for androgen prescribing Ann J Conway, David J Handelsman, Douglas W Lording, Bronwyn Stuckey, Jeffrey D Zajac on behalf of the Endocrine Society of Australia MJA 2000; 172: 220-224 Abstract - Use of androgens - Misuse of androgens - Abuse of androgens - Key references - Authors' details - - More articles on Endocrinology Abstract Androgen replacement therapy (ART) is usually life-long, and should only be started after androgen deficiency has been proven by hormone assays. The therapeutic goal is to maintain physiological testosterone levels. Testosterone rather than synthetic androgens should be used. Oral 17α-alkylated androgens are hepatotoxic and should not be used for ART. There is no indication for androgen therapy in male infertility. Although androgen deficiency is an uncommon cause of erectile dysfunction, all men presenting with erectile dysfunction should be evaluated for androgen deficiency. If androgen deficiency is confirmed, investigation for the underlying pathological cause is required. Contraindications to androgen therapy are prostate and breast cancer. Precautions include using lower starting doses for older men and induction of puberty. Intramuscular injections should be avoided in men with bleeding disorders. Androgen-sensitive epilepsy, migraine, sleep apnoea, polycythaemia or fluid overload need to be considered. Competitive athletes should be warned about the risks of disqualification. ART should be initiated with intramuscular injections of testosterone esters, 250 mg every two weeks. Maintenance requires tailoring treatment modality to the patient's convenience. Modalities currently available include testosterone injections, implants, or capsules. Choice depends on convenience, cost, availability and familiarity. There is no convincing evidence that, in the absence of proven androgen deficiency, androgen therapy is effective and safe for older men per se, in men with chronic non-gonadal disease, or for treatment of non-specific symptoms. Until further evidence is available, such treatment cannot be recommended. Androgens are hormones that are based on the structure of testosterone, the major male sex hormone, and are capable of developing and maintaining masculine sexual characteristics (including the genital tract, secondary sexual characteristics, and fertility) and the anabolic status of somatic tissues. All androgens have similar biological effects because they all act through the single androgen receptor. Their effects in different tissues are diversified by metabolism of testosterone to its active metabolites by the enzymes 5α reductase (which converts testosterone to 5α-dihydrotestosterone, an androgen with enhanced potency acting on the androgen receptor) and aromatase (which converts testosterone to oestradiol, which acts on the oestrogen receptor). Use of androgens The main medical use of androgens (Box 1) is as androgen replacement therapy (ART) for established androgen deficiency.1-3 Classical androgen deficiency occurs in about 1 in 200 men, due to testicular disorders that directly reduce testosterone output, or hypothalamic-pituitary disorders that reduce pituitary luteinising hormone (LH) secretion, which is the main drive to testosterone production by the interstitial (Leydig) cells of the testes. Although classical androgen deficiency is relatively easy to recognise, diagnosis of less severe androgen deficiency can be more difficult. Owing to its subtle and variable clinical features, the diagnosis may easily be missed, denying patients simple and effective medical treatment with often striking subjective benefits. Potential extensions of classical indications to partial androgen deficiency remain to be fully evaluated for clinical safety and efficacy. These indications include age, androgen deficiency secondary to a chronic medical condition or its treatment, hormonal male contraception, and postmenopausal symptoms.4-6 Until more definitive objective evidence is available regarding the safety and efficacy of prescribing androgens for these indications, they remain suitable for carefully monitored, controlled clinical research trials, but not for routine medical treatment. Pharmacological applications of androgens (Box 1) usually represent second-line therapy where more specific treatments are not yet available or have failed. Androgen treatment can evoke a strong placebo response. In men without genuine androgen deficiency, this placebo effect invariably wanes with time, leading to confusion and dissatisfaction with treatment. In addition, once androgen therapy has commenced, the biochemical changes can cloud further interpretation of results for months. Therefore, androgen replacement therapy should be commenced only after androgen deficiency is clearly established.2,3 Diagnosis of androgen deficiency1-3 Diagnosis of androgen deficiency involves the recognition of appropriate clinical features, with confirmation by biochemical testing. Important clinical features required to evaluate testicular function include reproductive history (including pubertal development), fertility status, changes in sexual function and body hair growth, known testicular pathology, drug use, and occupation. Physical examination should record androgenisation (secondary sexual characteristics, especially body hair distribution, musculature and gynaecomastia) and testis volumes (by orchidometry). Serum LH, follicle-stimulating hormone and testosterone levels should be measured, on at least two separate days and preferably in the morning, to minimise the effects of random and laboratory fluctuations and diurnal rhythms. Direct measurements of free testosterone, if available, may help establish the diagnosis of androgen deficiency, but require extensive validation. Indirect measurements of free testosterone, such as the free androgen index (testosterone/sex hormone binding globulin [SHBG] ratio), correspond poorly with direct measurements and lack empirical validation as a diagnostic test. Additional tests that may be required to identify underlying disorders include karyotyping, pituitary radiology and measurement of prolactin levels, serum ferritin levels, iron saturation and, increasingly, genetic diagnosis. Androgen deficiency is unlikely in men with mean testis volume > 20 mL without atrophy, with a plasma testosterone level consistently above 20 nmol/L, or presenting with erectile dysfunction and a plasma testosterone level consistently above 8 nmol/L (Box 2). Where the diagnosis is not clear, referral to a clinical endocrinologist with experience in this area is recommended.1 Androgen replacement therapy1-3 ART is indicated to rectify androgen deficiency of any cause sufficient to cause clinical consequences. After puberty, there is no age limit to ART. Androgen-deficiency effects may manifest as changes in one or more androgen-sensitive functions; for example, psychosexual function, or loss of anabolic effects on bone, muscle, blood-forming marrow and other androgen-responsive tissues. Apart from decreased spermatogenesis, ART can rectify all clinical features of androgen deficiency, which usually respond within 1-2 months of starting therapy, although the full effect may take longer. Dosage: Standard ART is either testosterone enanthate (Primoteston in castor oil; Schering) or mixed testosterone esters (Sustanon in arachis oil; Organon) as 250 mg in 1 mL oil at 14-day intervals. Deep intramuscular injections are usually given into the upper and outer quadrant of the buttock, although some patients prefer the deltoid or lateral thigh muscle sites. Few men can manage self-injection with the viscous oil vehicle. For all ART, testosterone and its esters should be used in preference to synthetic androgens, because of their established safety and efficacy, as well as ease of dose-titration and assay monitoring. Lower starting doses may occasionally be needed, especially in previously untreated elderly men and during first induction of puberty. Less frequent dosing intervals (eg, every three weeks) are occasionally necessary for those unable or unwilling to have standard dosage, but are accompanied by more extreme peaks and troughs in blood testosterone levels, which may exaggerate symptom fluctuations. An inadequate clinical response raises doubt about androgen deficiency as the cause of recalcitrant symptoms. Rarely, an inadequate clinical response may require increased dosage. If suboptimal symptomatic benefit is supported by biochemical evidence of inadequate maintenance of androgen levels (low trough testosterone levels with or without persistently supranormal LH levels in primary hypogonadism), the same dose may be injected at 10-day intervals. Persistently inadequate responses indicate that unresponsive symptoms are not due to androgen deficiency; further escalation in dose or frequency is not warranted. Men with mild or partial androgen resistance due to androgen-receptor mutations may benefit from high-dose androgen therapy. As the underlying disorders are almost always permanent, life-long ART after the age of puberty is usually necessary. Long term therapeutic compliance depends on an acceptable regimen. Crossover studies indicate that patients strongly prefer the stable testosterone levels and smoother clinical effects provided by implants or transdermal formulations, compared with the wide fluctuations in testosterone levels and symptoms during intramuscular testosterone ester injections. Thus, although ART should commence with injections, alternative modalities (Box 3) may improve compliance. Factors to consider include cost, convenience, availability, familiarity with alternatives, and tolerance for frequent injections. Monitoring: Monitoring of ART is mainly to ensure effective androgen replacement by a regimen tailored to the patient's needs, aiming to maintain adequate therapeutic compliance by continuation of treatment. Serial clinical observation of clinical well-being and major symptoms of androgen deficiency, together with limited numbers of hormonal assays, is usually adequate. Restoration of sexual function has a low threshold for androgen action, so adequate libido and potency is a necessary, but not sufficient, indication of clinically adequate androgen replacement. Blood hormone assays have limited utility in optimising an ART regimen at the start of treatment and in evaluating androgen replacement. Trough blood testosterone levels (ie, before the next scheduled dose) within the eugonadal reference range can be a valuable guide to the adequacy of parenteral androgen replacement, but random blood testosterone levels are not useful for monitoring with either oral or injectable testosterone. In men with hypergonadotropic hypogonadism, suppression of blood LH levels into the eugonadal reference range indicates adequate ART, whereas persistent non-suppression of LH after 3-6 months of regular treatment indicates inadequate dosage or compliance. In hypogonadotropic hypogonadism, blood gonadotropin levels are uninterpretable. Serial evaluation of bone density (especially vertebral trabecular bone) by dual-photon absorptiometry at 1-2-year intervals may be useful in evaluating the adequacy of long-term androgen effects on bone. Other biochemical indices of androgen action, such as haemoglobin, SHBG, and high density lipoprotein cholesterol levels, reflect only supraphysiological effects and are too insensitive for routine monitoring of ART. Androgen deficiency is protective against prostate disease, and ART may restore the risks to those equivalent to, but no more than, eugonadal men of similar age. Screening of men receiving ART for cardiovascular and prostate disease need be no more intensive than for men of similar age not on ART. Precautions and side effects14-17 Adverse effects of androgen treatment are uncommon. Virilisation may occur with androgen therapy in women or children; androgen therapy in these settings requires expert management. Truncal acne and hair growth, weight gain, gynaecomastia and male-pattern hair loss may be observed, and should be managed symptomatically. Certain side effects are characteristic of specific therapeutic modalities (eg, discomfort from intramuscular injections, extrusion of subdermal implants, gastrointestinal disturbance from oral testosterone undecanoate). Polycythaemia may occur disproportionately often in older men treated with testosterone ester injections. In addition, certain testosterone formulations have distinctive effects due to their pharmacokinetic features (eg, reduced levels of SHBG, high density lipoprotein cholesterol and other hepatic proteins due to supraphysiological hepatic testosterone exposure). This may be due to injectable testosterone esters (via high peak blood testosterone concentrations) or oral testosterone undecanoate (via high first-pass portal testosterone concentrations), whereas more steady formulations (transdermal, implants) exhibit fewer or no such effects. Oral synthetic androgens that have a 17α-alkyl substituent (oxandrolone, fluoxymesterone, danazol) are inherently hepatotoxic, causing cholestatic hepatitis, peliosis hepatis and hepatic tumours. Other classes of synthetic androgen, such as 19-nortestosterone derivatives (nandrolone, MENT) and the 1-methyl androgens (mesterolone, methenolone), are not hepatotoxic. Absolute contraindications to androgen therapy are prostate or breast cancer in men. Androgen therapy should be started in men over the age of 40 only after exclusion of undiagnosed prostate disease. Precautions are required for: older men starting androgen treatment, where it may precipitate urinary obstruction or unfamiliar increases in libido; pubertal boys, in whom excessive dosage may accelerate epiphyseal closure, leading to shortened final stature; parenteral androgen therapy in men with bleeding disorders; competitive athletes, who may be disqualified; androgen-sensitive epilepsy, migraine, sleep apnoea or polycythaemia; and cardiac or renal failure or severe hypertension susceptible to fluid overload from sodium and fluid retention. Misuse of androgens Medical misuse of androgens involves prescription with no acceptable medical indication. Some common examples of misguided prescribing of androgens in the absence of established androgen deficiency include: Male infertility: There is no indication for androgen therapy in male infertility. The only likely consequence is an adverse effect of suppressing spermatogenesis. Male sexual dysfunction or impotence: Androgen deficiency (with or without hyperprolactinaemia) is an uncommon (< 5%) cause of men presenting with erectile dysfunction. In such men, excluding androgen deficiency as a readily treatable underlying cause is essential. In the unusual event of severe androgen deficiency presenting with erectile dysfunction, the underlying cause needs to be identified, and plans for life-long ART need to be established. "Male menopause" or "andropause": There is still no evidence that the modest decreases in circulating blood testosterone levels which commence during mid-life have any clinical importance. The risks and benefits of androgen supplementation for partially androgen-deficient older men require further evaluation by placebo-controlled studies. Androgen treatment may be inappropriate, wasteful, and involve placebo effects. Terms such as "male menopause" and "andropause" are misleading; they have little place in meaningful medical or scientific discourse. Elderly men (> 65 years):18 There is no basis for androgen therapy based on age per se. Further controlled clinical trials are needed to evaluate the potential role of androgen supplementation in ageing. While some preliminary placebo-controlled studies suggest short-term benefits for muscle, bone and quality of life, findings are not yet consistent and the identification of appropriate treatment objectives and target subgroups, as well as overall analyses of risks, benefits and costs, are lacking. Specifically, it remains to be determined whether androgen supplementation has significant and sustained clinical benefits in older men with low-normal plasma total testosterone and normal LH levels. At present, there is no basis for androgen treatment outside properly designed clinical trials. Treatment of non-specific symptoms: There is no basis for androgen therapy based on symptoms in the absence of established androgen deficiency. In addition to the unproven safety and efficacy, the placebo effect of androgen injections may be confusing to both doctor and patient. When placebo effects wane, further confusion and dissatisfaction with treatment may be expected. Abuse of androgens Illicit use of androgens19-24 ("anabolic steroids") depends largely on obtaining androgens without legal prescription to be used in the absence of any medical indication. Illicit androgen use became epidemic over the past four decades, since androgens were reportedly first used in elite competitive power sports. A recent placebo-controlled study has shown that high-dose androgen administration does improve muscle size and strength in healthy eugonadal men. Whether these changes enhance athletic performance, whether they are sustained, and whether they apply to older men remains to be clarified. Medical prescription appears to support only a small proportion of illicit androgen use, but such activity has been formally ruled as a breach of professional standards by medical boards in most States and by the Royal Australasian College of Physicians. Highly motivated young men can be very sophisticated in manipulating and pressuring general practitioners while attempting to obtain prescriptions for androgens. The doctor is often led to believe that other practitioners are prescribing androgens for young men, and that he or she is being uncaring or negligent by not acceding to the patient's wishes. We recommend that general practitioners resist these pressures. Fortunately, most people appear ultimately to lose interest in this form of drug abuse. Background and evidence basis of recommendations The Endocrine Society of Australia (ESA) Consensus Guidelines for Androgen Prescribing were written on behalf of the Endocrine Society of Australia. The ad hoc Writing Committee commissioned by the ESA's Council was Dr A J Conway, Professor D J Handelsman (Chair), Associate Professor D W Lording, Dr B Stuckey, and Associate Professor J D Zajac. The draft guidelines were extensively circulated for comment to active members of the ESA with clinical expertise or interests in male reproductive endocrinology. Comments were incorporated into the final document, which was ratified by the ESA's Council. Androgen therapy, in regular clinical use for over 60 years, is one of the oldest hormonal regimens in modern therapeutics. As a long established standard and effective form of hormone replacement for many decades, placebo-controlled studies are unavailable and now unacceptable. Consequently, the NHMRC Quality of Evidence Ratings for these recommendations are those appropriate to an expert committee reviewing all available evidence from controlled experimental and observational studies as well as clinical experience. Key references Diagnosis and management of androgen deficiency Behre HM, Yeung CH, Nieschlag E. Diagnosis of male infertility and hypogonadism. In: Nieschlag E, Behre HM (eds): Andrology: Male Reproductive Health and Dysfunction. Berlin:Springer, 1997: 87-111. Plymate SR. Male Hypogonadism. In: Becker KL (ed): Principles and Practice of Endocrinology and Metabolism. 2nd ed. Philadelphia: J B Lippincott Company, 1995: 1056-1082. Nieschlag E, Wang C, Handelsman DJ, et al (eds) (1992). Guidelines for the use of androgens in men. Geneva, Special Programme of Research, Development and Research Training in Human Reproduction of the World Health Organisation. Male contraception Cummings DE, Bremner WJ. Prospects for new hormonal male contraceptives. In: Bremner WJ (ed): Clinical Andrology. Philadelphia: W B Saunders Company, 1994: 893-922. Handelsman DJ. Contraception in the male. In: DeGroot LJ (ed): Endocrinology. 3rd ed. Philadelphia: W B Saunders, 1994: 2449-2458. Androgen therapy in systemic disease Liu PY, Handelsman DJ. Androgen therapy in non-gonadal disease. In: Nieschlag E, Behre HM (eds):Testosterone: Action, Deficiency and Substitution. 2nd ed. E Nieschlag, Behre HM (eds), Berlin, Springer-Verlag, 1998. Comparative pharmacology of androgen formulations Bals-Pratsch M, Langer K, Place VA, Nieschlag E. Substitution therapy of hypogonadal men with transdermal testosterone over one year. Acta Endocrinologica 1988; 118: 7-13. Behre HM, Oberpenning F, Nieschlag E. Comparative pharmacokinetics of androgen preparations: application of computer analysis and simulation. In: Nieschlag E, Behre HM (eds): Testosterone: Action, Deficiency and Substitution. Berlin: Springer-Verlag, 1990: 115-135. Cantrill JA, Dewis P, Large DM et al. Which testosterone replacement therapy? Clin Endocrinol (Oxf) 1984; 24: 97-107. Conway AJ, Boylan LM, Howe C, Ross G, Handelsman DJ. A randomised clinical trial of testosterone replacement therapy in hypogonadal men. Int J Androl 1988; 11: 247-264. Handelsman DJ, Conway AJ, Boylan LM. Pharmacokinetics and pharmacodynamics of testosterone pellets in man. J Clin Endocrinol Metab 1990; 71: 216-222. Meikle AW, Mazer NA, Moellmer JF, et al. Enhanced transdermal delivery of testosterone across nonscrotal skin produces physiological concentrations of testosterone and its metabolites in hypogonadal men. J Clin Endocrinol Metab 1992; 74: 623-628. Snyder PJ, Lawrence DA. Treatment of male hypogonadism with testosterone enanthate. J Clin Endocrinol Metab 1980; 51: 1335-1339. Safety of androgens Alexandersen P, Haarbo J, Christiansen C. The relationship of natural androgens to coronary heart disease in males: a review. Atherosclerosis 1996; 125: 1-13. Barrett-Connor E. Testosterone, HDL-cholesterol and cardiovascular disease. In: Bhasin S, Gabelnick HL, Spieler JM et al (eds): Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. New York: Wiley-Liss, 1996: 215-223. Behre HM, Bohmeyer J, Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxf) 1994; 40: 341-349. Gooren LJ, Polderman KH. Safety aspects of androgen therapy. In: Nieschlag E, Behre HM (eds): Testosterone: Action, Deficiency and Substitution. Berlin: Springer-Verlag, 1990: 182-203. Androgen and the ageing male Tenover JL. Androgen therapy in aging men. In: Bhasin S, Gabelnick HL, Spieler JM, et al (eds): Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. New York: Wiley-Liss, 1996: 309-318. Androgen abuse Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 1996; 335: 1-7. Handelsman DJ, Gupta L. Prevalence and risk factors for anabolic-androgenic steroid abuse in Australian secondary school students. Int J Androl 1997; 20: 159-164. Lin GC, Erinoff L (eds). (1990). Anabolic Steroid Abuse. National Institute on Drug Abuse Research Monograph Series. Rockville, US Department of Health and Human Services. Wilson JD. Androgen abuse by athletes. Endocr Rev 1988; 9: 181-199. Yesalis CE, Kennedy NJ, Kopstein AN, Bahrke MS. Anabolic-androgenic steroid use in the United States. JAMA 1993; 270: 1217-1221. Young NR, Baker HWG, Liu G, Seeman E. Body composition and muscle strength in healthy men receiving testosterone enanthate for contraception. J Clin Endocrinol Metab 1993; 77: 1028-1032. Authors' details Endocrine Society of Australia, Sydney, NSW. Ann J Conway, MB BS, FRACP; David J Handelsman, MB BS, PhD, FRACP; Douglas W Lording, MB BS, FRACP; Bronwyn Stuckey, MB BS, FRACP; Jeffrey D Zajac, PhD, FRACP. Reprints will not be available from the authors. Correspondence: Associate Professor J D Zajac, Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC 3050. j.zajacATmedicine.unimelb.edu.au Make a comment 1: Use, misuse and abuse of androgens Use Physiological (androgen deficiency) 1-3 Classical androgen deficiency ("hypogonadism") Age-related partial androgen deficiency Micropenis (neonatal) Delayed puberty Aged men* Androgen deficiency secondary to chronic disease* Induced androgen deficiency Hormonal male contraception* Pharmacological (non-androgen deficiency)4-6 Osteoporosis Anaemia due to marrow or renal failure Advanced breast cancer Excessively tall stature in boys Misuse Inappropriate indications In absence of proven androgen deficiency: Male infertility Sexual dysfunction/impotence "Male menopause", "andropause" Older men (>65 years) Non-specific symptoms Abuse19-24 Absence of medical indication Sporting Competitive power sports (athletics, weightlifting, football, swimming, rowing, boxing) RecreationalBodybuilding Cosmetic"Body beautiful" subculture OccupationalSecurity, police, armed forces, professional sports * These indications remain to be fully evaluated for safety and efficacy in controlled clinical trials. Back to text 2: Biochemical evaluation of the diagnosis of androgen deficiency in men with clinical features consistent with hypogonadism* Testosterone level†Luteinising hormone level†Diagnosis<8 nMHigh‡Androgen deficiency (hypergonadotropic hypogonadism§)<8 nMNot highAndrogen deficiency (hypogonadotropic hypogonadism§)8-15 nMHigh‡Androgen deficiency (Leydig cell failure)8-15 nMNot highAndrogen deficiency not confirmed: unproven therapeutic benefit of androgen replacement therapy>20 nMAnyExcludes androgen deficiency>30 nM**High‡Androgen resistance*There is necessarily an arbitrary component to this type of table. It is based on current experience and should be subject to changes according to further clinical evidence. †Blood sample classification based on at least two separate morning blood samples. ‡"High" luteinising hormone level is defined as > 1.5 times the upper limit of the eugonadal reference range for young men. §Hypergonadotropic and hypogonadotropic hypogonadism are also referred to as primary and secondary hypogonadism, respectively. Compensated Leydig cell failure is a form of partial androgen deficiency in which androgen replacement is often beneficial. **Elevated testosterone is defined as above the upper limit of the eugonadal reference range for young men. Back to text 3: Androgen treatment modalities7-13 Testosterone implants Fused cylindrical pellets of pure crystalline testosterone that form a subdermal depot Provide stable, physiological levels of testosterone for 4-6 months following a single implantation of four 200 mg (800 mg) implants Implantation uses a trochar and cannula technique under office sterile conditions, and requires local anaesthesia Main adverse effect is extrusion of implants via the insertion site 1-2 months after implantation Extrusion rate (about 10%) depends on operator experience and patient's physical activity Minor adverse effects related to the minor office surgery (bleeding, infection) are infrequent (<5%) Should only be used for patients who have demonstrated satisfactory tolerance of androgen effects with shorter-acting preparations Transdermal testosterone Administered daily via androgen-impregnated adhesive skin patches or hydroalcoholic gels (not yet available in Australia) Other depot testosterone formulations Newer injectable esters (testosterone undecanoate, testosterone buciclate) Testosterone-laden biodegradable microspheres Both these formulations deliver stable, physiological testosterone levels for 2-3 months following injection Oral testosterone undecanoate Useful where parenteral testosterone is undesirable (eg, bleeding disorders or anticoagulation) or poorly tolerated Administered as 160-240 mg (four to six 40 mg capsules), divided into 2-4 doses per day Second-line formulation for routine ART, because of frequency of administration, high hepatic load, gastrointestinal intolerance, and higher cost Back to text

Ann J Conway · David J Handelsman · Douglas W Lording · Bronwyn Stuckey · Jeffrey D Zajac

New Drugs, Old Drugs Osteoporosis prevention and treatment Phillip N Sambrook and John A Eisman MJA 2000; 172: 226-229 Abstract - Introduction - Overview of the evidence - Recommendations - Disclosure - References - Authors' details - - More articles on Endocrinology Abstract Patients with low bone density or any prior low trauma fracture should be considered for therapeutic intervention. Oestrogen replacement therapy remains the first choice for prevention of bone loss in early postmenopausal women with low bone density In postmenopausal women with existing fractures, the rank order of treatments is firstly alendronate, secondly raloxifene and thirdly less potent bisphosphonates, such as etidronate, or active vitamin D metabolites, such as calcitriol. For men with osteoporosis, if hypogonadism is present, it should be treated with testosterone replacement therapy. Despite limited data, a bisphosphonate should then be considered in conjunction with calcium. Supplementation with simple vitamin D should be considered in elderly patients who are housebound or live in institutions, as they are at risk of vitamin D deficiency and osteomalacia. Introduction The prevention and treatment of osteoporosis (low bone density) was reviewed at the Australian Consensus Conference on Osteoporosis, held in 1996, and a series of position statements about its management were developed.1 For the treatment of postmenopausal osteoporosis, these statements ranked hormone replacement therapy (HRT) with oestrogen as first-line therapy for most patients, but in those intolerant or unable to take this medication the rank order of choice was considered to be alendronate, followed by etidronate or calcitriol. Since that meeting, the results of new trials with drugs such as raloxifene, further efficacy data for bisphosphonates, and postmarketing safety data for alendronate and calcitriol have become available. Moreover, increased dietary calcium intake and phyto-oestrogens are promoted in the media. The benefit of all these various agents versus their risk of side effects in this epidemic condition is gradually becoming clearer. Overview of the evidence Drugs used for treating and preventing osteoporosis, and the relevant evidence for this, are discussed below, and brief drug profiles, including recommended doses, are given in Box 1. Calcium Controlled trials6 have shown that calcium supplementation can prevent bone loss in postmenopausal women (E1) (see Box 2 for an explanation of level-of-evidence codes) and this has been associated with a modest reduction in fracture risk in longer-term studies (E2). There is also evidence (E1) to suggest calcium supplementation augments the effect of oestrogen on bone density.8 Gastrointestinal absorption appears to be similar from milk or soy-drink products and supplements. As most controlled trials of new agents have used calcium as baseline therapy, it is appropriate to add a calcium supplement to most active agents described below. Calcium supplements have a better bone-sparing effect when taken at night. Vitamin D A study in institutionalised elderly people in France showed treatment with calcium plus vitamin D significantly reduced the rate of hip fractures (E2),9 but a similar effect could not be shown in those who lived in the community.10 Australian data also indicate a substantial proportion of institutionalised (or housebound) elderly people may be vitamin D deficient,11 and the observed reduction in fractures in the French study may have reflected treatment of subclinical osteomalacia. Hence, vitamin D supplementation is recommended in institutionalised or housebound elderly people who have limited exposure to sunlight. Calcitriol Calcitriol is the active hormonal form of vitamin D. Controlled trials of its effect on bone density have shown conflicting effects,12,13 with studies showing increases, no change or even apparent loss of bone density with calcitriol therapy (although suboptimal doses may account for some of these discrepancies). A recent larger study suggests the effect on bone density is less than that seen with oestrogen.14 One large controlled trial addressing the efficacy of calcitriol in preventing fractures found a threefold difference in vertebral deformity rates favouring calcitriol15 (E2), but used a less strict fracture criterion than in more recent studies. In that study, fracture rates remained stable in calcitriol-treated patients but increased in the calcium-treated patients. Calcitriol treatment may be appropriate in patients with known or presumed calcium malabsorption. Although calcitriol is approved for osteoporosis in men in Australia, a recent small study suggested that calcitriol may be less effective than calcium supplementation alone.16 Etidronate Etidronate was the first bisphosphonate developed for clinical use, and there is extensive experience of its use in Paget's disease. There have been a number of relatively small controlled trials with etidronate, showing increases in bone density averaging 5% over 2-3 years17 and suggesting a 50% reduction in vertebral fracture rate (E1). However, these trials also used fracture criteria less strict than those used in more recent clinical trials.18-21 Non-randomised studies based in general practice suggest its effectiveness increases with duration of use.3 Alendronate Several controlled clinical trials of the bisphosphonate alendronate have shown a reduction of vertebral, and even peripheral, fracture rates by about 50%18-20 (E1). Some, but not all, studies have shown a reduction in hip fracture rates.4,19 Reduction of fracture rates was apparent in individuals with bone mineral density (BMD) T scores below - 2.5 (T scores are multiples of the standard deviation from the population mean, based on a young, healthy, sex-matched reference population), even without prior fractures,20 suggesting an important threshold at which to consider intervention. Oestrogen While calcium supplementation may reduce bone loss, a number of controlled clinical trials with oestrogen have shown long-term increases in bone density averaging 5% over three years (E1).22 Lower doses may be effective with concomitant calcium.8 Although only a few randomised clinical trials have addressed the effect on fractures,23,24 epidemiological studies indicate antifracture efficacy at all sites for oestrogen is comparable to that of other agents (E32).25 Epidemiological studies also suggest primary cardioprotective effects of oestrogen. However, this was not observed in a recent trial of the effects of oestrogen on secondary prevention of cardiovascular mortality and morbidity, despite improvements in surrogate measures of efficacy such as total and low density lipoprotein cholesterol levels.26 Raloxifene This selective oestrogen-receptor modulator, as well as acting to decrease bone resorption, improves lipid profiles (thought to be surrogates for cardiovascular risk) and reduces breast cancer incidence (in studies at 3.5 years).27 Importantly, raloxifene does not cause breast or uterine symptoms. Controlled clinical trials have shown modest increases in bone density, generally somewhat less than those seen with hormone replacement therapy.28 However, a 50% reduction in vertebral, but not as yet peripheral, fractures has been observed (E2).21 This may be a statistical power effect and longer-term studies are ongoing. Anabolic steroids Forearm bone mass has been shown to increase modestly after treatment with nandrolone decanoate (E33), but at higher dosages and shorter intervals than are generally used in Australia. The effect on spinal bone density is unclear.29 Although nandrolone is commonly used in general practice in Australia, and may have a beneficial effect on muscle mass which may help to reduce the risk of falls in the elderly, there have been no studies showing antifracture efficacy. "Natural therapies" A variety of so called "natural" therapies, including soy, red clover (Promensil [Novogen]), black cohosh (Remifemin [Scinat]), wild yam and topical progesterone, are frequently used for treating menopausal symptoms in Australia. Soy products have been associated with small effects on bone density in animal studies.30 There are no studies addressing either their efficacy on fractures or long term safety in humans at this time. The risk of adverse events with these agents is unclear, as there have been no controlled studies of long-term safety. The efficacy and safety of these agents are yet to be documented in controlled clinical trials. Topical progesterone does not provide protection from endometrial changes of unopposed oestrogen in a woman with an intact uterus. Recommendations Adequate dietary calcium intake, regular exercise and avoidance of risk factors, such as smoking and excessive alcohol intake, are important lifestyle recommendations for preventing osteoporosis, but they have only modest efficacy. For people with low BMD, and particularly those with any prior low trauma fracture, these measures will be insufficient to prevent further osteoporotic fractures and pharmacological therapy must be considered. Box 3 shows an appropriate approach to managing osteoporosis in postmenopausal women. HRT remains the mainstay of therapy for osteoporosis, particularly in early postmenopause. Although most women are at relatively low risk of osteoporotic fracture for the first five to 10 years after menopause, this will vary according to their bone density and other risk factors, such as propensity to falls. Although "natural" therapies may have some effect on menopausal symptoms, there is currently no evidence for their efficacy or safety in the prevention or treatment of osteoporosis. Older postmenopausal women, especially those with existing fractures, are at high risk of further osteoporotic fractures. The rank order of treatments of osteoporosis in this group, based on the current published evidence, is alendronate, followed by raloxifene, before less potent bisphosphonates, such as etidronate, or active vitamin D compounds, such as calcitriol. Simple vitamin D should be considered in house-bound or institutionalised elderly people, who are at risk of vitamin D deficiency and osteomalacia. Dietary calcium supplementation should be used in conjunction with all of the above therapies except calcitriol, with which overall calcium intake should be limited. For men with osteoporosis, hypogonadism, if present, should be treated with testosterone replacement therapy. In the absence of hypogonadism, although there are limited data, the rank order of treatment of osteoporosis in men is a bisphosphonate and calcium supplementation. Most importantly, the benefit in fracture prevention from treatment increases progressively with worsening osteoporosis. As a result, while it is never too early to consider prevention, it is never too late to start treatment. Failure to at least consider therapeutic options in a patient who has sustained an osteoporotic fracture is not reasonable medical practice. As in many other chronic diseases, no therapy can be effective without long term compliance. This is strongly dependent on regular positive feedback to patients from their general practitioners. Important messages for patients are given in Box 4. Disclosure The authors act as advisers to, and receive funding from, Roche; Merck, Sharpe & Dohme; Lilly; Pharmacia & Upjohn; Aventis; Novartis; and the Australian Dairy Corporation. References O'Neill S, Eisman JA, Glasziou P, et al. The prevention and treatment of osteoporosis [consensus statement]. Med J Aust 1997; 167 (Suppl): S4-S15. Calcitriol and hypercalcaemia. Aust Adverse Drug React Bull 1997; 16: 2. Van Staa T, Abenheim L, Cooper C. Upper gastrointestinal adverse events and cyclical etidronate. Am J Med 1997; 103: 462-467. A gut feeling for alendronate. Aust Adverse Drug React Bull 1999; 18 (3): 11. Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. New Engl J Med 1995; 332: 1589-1593. Nordin BEC. Calcium and osteoporosis. Nutrition 1997; 13: 664-686. National Health and Medical Research Council. A guide to the development, implementation and evaluation of clinical practice guidelines. Canberra: NHMRC, AusInfo 1999. Nieves JW, Komar L, Cosman F, Lindsay R. Calcium potentiates the effect of oestrogen and calcitonin on bone mass: review and analysis. Am J Clin Nutr 1998; 67: 18-24. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. New Engl J Med 1992; 327: 1637-1642. Lips P, Graafmans WC, Ooms ME, et al. Vitamin D supplementation and fracture incidence in elderly persons. Ann Intern Med 1996; 124: 400-406. Brock KE, Reid JF, Greenoak GG, Fraser DR, The effect of sunlight on 25-hydroxy vitamin D plasma levels in an elderly Sydney population [abstract]. Australian and New Zealand Bone and Mineral Society Proceedings, 1997, Abstract No. 38. Gallagher JC, Goldgar D. Treatment of postmenopausal osteoporosis with high dose synthetic calcitriol. Ann Intern Med 1990; 113: 649-655. Ott SM, Chestnut CH. Calcitriol is not effective in postmenopausal osteoporosis. Ann Intern Med 1989; 110: 267-274. Gallagher JC, Fowler S. Effect of estrogen, calcitriol and a combination of estrogen and calcitriol on bone mineral density and fractures in elderly women [abstract]. J Bone Mineral Res 1999; 14: Abstract no. T364. Tilyard MW, Spears GF, Thomson J, Dovey S. Treatment of postmenopausal osteoporosis with calcitriol or calcium. New Engl J Med 1992; 326: 357-362. Ebeling PR, Yeung S, Poon C, et al. Effects of baseline active calcium absorption on bone mineral density responses to calcitriol or calcium treatment in men with idiopathic osteoporosis [abstract]. J Bone Mineral Res 1999; 14: Abstract no. SA419. Storm T, Thamsborg G, Steiniche T, et al. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in postmenopausal osteoporosis. New Engl J Med 1990; 322: 1265-1271. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. New Engl J Med 1995; 333: 1437-1443. Black DM, Cummings SR, Karpf D, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348: 1535-1541. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures. JAMA 1998; 280: 2077-2082. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3 year randomised controlled trial. JAMA 1999; 282: 637-645. Writing group for the PEPI trial. Effects of hormone therapy on bone mineral density. JAMA 1996; 276: 1389-1396. Lufkin EG, Wahner HW, O'Fallon WM, et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med 1992; 117: 1-9. Windeler J, Lange S. Events per person year -- a dubious concept. BMJ 1995; 310: 454-456. Cauley JA, Seeley, Ensrud K, et al. Estrogen replacement therapy and fractures in older women. Ann Intern Med 1995; 122: 9-16. Hulley S, Grady D, Bush T, et al. Randomised trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280: 605-613. Cummings SR, Eckert S, Krueger KA. The effect of raloxifene on risk of breast cancer in postmenopausal women. JAMA 1999; 281: 2189-2197. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effect of raloxifene on bone mineral density, serum cholesterol concentrations and uterine endometrium in postmenopausal women. New Engl J Med 1997; 337: 1641-1647. Flicker L, Hopper JL, Larkins RG, et al. Nandrolone decanoate and intranasal calcitonin as therapy in established osteoporosis. Osteoporosis Int 1997; 7: 29-35. Arjmandi BH, Birnbaum R, Goyal NV, et al. Bone sparing effect of soy protein in ovarian hormone deficient rats is related to its isoflavone content. Am J Clin Nutr 1998; 68 (Suppl): 1364S-1368S. Authors' details The Institute of Bone and Joint Research, University of Sydney, Royal North Shore Hospital, Sydney, NSW. Phillip N Sambrook, MD, FRACP, Professor of Rheumatology. Garvan Institute, St Vincent's Hospital, Sydney, NSW. John A Eisman, PhD, FRACP, Professor of Medicine, and Head of Bone and Mineral Research Program. Reprints will not be available from the authors. Correspondence: Professor P N Sambrook, The Institute of Bone and Joint Research, Level 4, Block 4, Royal North Shore Hospital, St Leonards, NSW 2065. sambrookATmed.usyd.edu.au Make a comment 1: Profiles of agents for prevention and treatment of osteoporosis Calcium Action: Calcium is weakly antiresorptive and supplementation may reduce negative calcium balance and so reduce bone resorption, particularly in older patients. Dosing: Balance studies suggest a daily intake of 1500mg per day is required in postmenopausal women not using hormone replacement therapy. Adverse effects: Calcium is a relatively safe medication but may cause mild gastrointestinal intolerance. The risk of renal calculi is very low except in those at risk. Vitamin D Action: Vitamin D undergoes several metabolic steps in the body, so it is important to distinguish between simple vitamin D and its active metabolites (such as calcitriol), which have distinctly different pharmacological profiles. Simple vitamin D can be converted to calcitriol, and has a similar, but less potent, effect on increasing gastrointestinal absorption. Dosing: Simple vitamin D is mainly available in Australia as ergocalciferol (1000IU per capsule; Ostelin 1000; Boots Healthcare Australia). It is no longer available on the Pharmaceutical Benefits Scheme, but is a relatively inexpensive over-the-counter medication. Small amounts of vitamin D are contained in some calcium and vitamin supplements (eg, Caltrate + Vitamin D [Whitehall Laboratories] contains 200IU per tablet and cod liver oil tablets approximately 400IU). An appropriate dose for supplementation is 1000IU daily. Adverse effects: Chronic ingestion of large doses of vitamin D, usually at doses in excess of 50000 to 100000IU per day, is required to produce hypercalcaemia in normal patients. Thus, given the amounts of vitamin D contained in available preparations, intoxication is practically impossible. Calcitriol Action: The primary action of calcitriol is thought to be to increase gastrointestinal calcium absorption, and so indirectly reduce bone resorption. It may also increase bone formation, but at higher doses that may increase bone resorption. Dosing: The usual dose is 0.5mg daily. Adverse effects: Hypercalcaemia and hypercalciuria are uncommon in patients treated with the usual dose (above), but may occur in patients who increase their calcium intake substantially. Hence, calcium supplements should be avoided and dietary intake should be limited to less than 800mg daily. The Adverse Drug Reactions Advisory Committee (ADRAC) reported four cases of calcitriol-related hypercalcaemia in four years of postmarketing surveillance up to 1997.2 Etidronate Action: Etidronate is a first-generation bisphosphonate, and is relatively less potent in its effects on inhibiting bone resorption than later bisphosphonates. The balance of these effects can result in osteomalacia if the drug is used continuously in doses effective on bone resorption for osteoporosis. Dosing: In osteoporosis, etidronate is used in a cyclical regimen at 400mg daily usually for two weeks every three months to reduce the risk of mineralisation defects. Adverse effects: Etidronate has been associated with lower, but not upper, gastrointestinal events.3 The risk of mineralisation defect with the cyclical regimen is very low. Alendronate Action: This aminobisphosphonate is a potent inhibitor of bone resorption at doses that do not affect bone formation or mineralisation. Dosing: 10mg daily. Adverse effects: Clinical trials with alendronate have repeatedly shown no increase in adverse effects compared with control groups. However, there have been reports of oesophagitis after alendronate therapy, and recent postmarketing surveillance by ADRAC listed 331 adverse event reports among approximately 49000 patients in Australia taking alendronate.4 These included dyspepsia (44), nausea (43) and abdominal pain (37), and ulceration or stricture was confirmed endoscopically in 26 of 52 reports of oesophagitis. Although a causal relationship remains unproven, there appears to be a real but low incidence of upper gastrointestinal problems with alendronate. This is consistent with precautions in its administration requiring the patient to stay in an upright position and to fast for half an hour after taking it in the morning (as is required for adequate absorption). Oestrogen Action: Oestrogen is an antiresorptive drug, possibly mediated by effects on local release of various cytokines and growth factors in bone. Dosing: Conjugated equine, 0.625mg daily; piperazine oestrone sulfate, 1.25mg daily; transdermal oestradiol, 4mg patch. Adverse effects: Breast tenderness and abdominal swelling are not uncommon, but these problems usually settle, and starting with low doses can minimise them. Hormone replacement therapy has been associated with an increased risk of deep venous thrombosis. Transdermal routes of administration may reduce this risk. Controversy exists as to whether there may be an increased risk of breast cancer with long term oestrogen use. Studies that do suggest a small increase in risk indicate that they show no increase in risk in the first five years of treatment.5 Raloxifene Action: Like oestrogen, raloxifene is a selective oestrogen receptor modulator (SERM) which acts to decrease bone resorption, but, unlike oestrogen, it does not stimulate the breast or uterus. Dosing: 60mg daily. Adverse effects: An increased risk of venous thrombosis has been reported with raloxifene users, similar in extent to that seen with hormone replacement therapy. Unlike hormone replacement therapy, raloxifene is not useful for control of, and may worsen, menopausal symptoms. Anabolic steroids Action: Anabolic steroids are weak androgens and appear to exert a weak inhibitory effect on bone resporption. However, any effect on bone mass may in fact be secondary to effects on muscle mass. Dosing: Nandrolone decanoate, 50mg intramuscular injection every three weeks. Adverse effects: There is a high incidence of virilisation with these dosages and there are no long term safety data. Back to text 2: Level-of-evidence codes Evidence for the statements made in this article is graded according to the NHMRC system7 for assessing the level of evidence: E1Level I: Evidence obtained from a systematic review of all relevant randomised controlled trials. E2Level II: Evidence obtained from at least one properly designed randomised controlled trial. E31Level III-1: Evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or some other method). E32Level III-2: Evidence obtained from comparative studies with concurrent controls and allocation not randomised (cohort studies), case-control studies, or interrupted time series without a parallel control group. E33Level III-3: Evidence obtained from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group. E4Level IV: Evidence obtained from case-series, either post-test or pre-test and post-test. Back to text Back to text 4: Important messages for patients It is never too late to start treatment. A number of new therapies have been shown to significantly reduce fracture risk. The overall risk of gastrointestinal problems with bisphosphonates is low. The effects of natural therapies in preventing osteoporosis are unproven. Back to text

Phillip N Sambrook · John A Eisman

Viewpoint Transport and health: en route to a healthier Australia? The medical profession can show leadership in promoting "active transport" Chloë Mason MJA 2000; 172: 230-232 Abstract - Introduction - Health impacts of transport - The case for "active transport" - Healthier transport policy and urban design - The health sector's role - References - Author's details - - More articles on Public and environmental health Abstract We have been slow to recognise the impact that decisions about transport, land use and infrastructure have on health. Apart from encouraging a sedentary lifestyle, reliance on motor vehicle transport has a range of adverse health effects (traffic accidents, air and noise pollution, and greenhouse gas emissions). Physical activity equivalent to 30 minutes (in total) of brisk walking on all, or most, days of the week provides preventive and protective benefits for a wide range of health conditions (including cardiovascular disease, diabetes, depression and osteoporosis). "Active transport" -- walking, cycling and/or using public transport instead of car travel -- could have dual health benefits by providing physical activity and reducing the adverse health effects of motor vehicle transport. Doctors, medical administrators and health advocates can encourage the use of "active transport", and influence community-based programs and policy development about land use planning and travel demand management. Introduction In June 1999, at the Third Ministerial Conference on Environment and Health, held in London, ministers responsible for health, environment and transport from 54 countries adopted the World Health Organization (WHO Europe) Charter on Transport, Environment and Health.1 A summary substantiation paper reviewing the evidence of health risks from transport concluded that we have been too slow to recognise the full health impacts of motor vehicle transport (traffic accidents, pollution, noise and psychosocial effects), and to appreciate the benefits to health of walking and cycling as a means of transport.1 While noting that health arguments should be central to the debate about the continuing expansion of motor vehicle transport in Europe (a debate which also applies to Australia and the wider Asian region), the WHO report stresses the complementarity of transport, land-use policies and health issues. I review these developments and consider opportunities for doctors in Australia to engage in the debate about transport and health and to support a new transport agenda. Some practical ways in which doctors can promote this agenda in clinical practice, medical administration, and health advocacy are suggested. Health impacts of transport The British Medical Association's report Road transport and health gives the composite picture of the health impacts of transport ("the movement of people and goods between places").2 This picture has been obscured by the separate consideration of the impact of health issues, such as traffic accident deaths and injuries, the environmental hazards of motor vehicle pollution, and the health risks of a sedentary lifestyle. Measures to reduce these adverse effects have tended to be implemented in isolation3 rather than as part of an improved, integrated transport policy. Over the past 50 years in Western countries, several factors have made the links between transport, health and the environment more apparent: More trips are being made by car, with increases in both the number and length of car trips, while the share of trips made by foot, bicycle or public transport has declined.4 Moreover, the flow of vehicles is given priority, causing difficulties and risks for pedestrians and cyclists. From the 1980s, the proportion of Australian adults who are overweight, obese or inactive has increased in parallel with our greater reliance on car transport.5 There is greater recognition of transport's contribution to global warming, added to the other environmental problems of air and noise pollution, which adversely affect health. Any attempts to moderate these trends, or even to reverse them, by replacing car travel by alternative modes of transport (foot, bicycle, public transport, or even "teleaccess") could have net positive health effects. The case for "active transport" Benefits of daily physical activity Physical activity has been described as "today's best buy in public health".6 Yet a recent analysis of the medical media shows that medical readers, not confined to Australia, are less exposed to research about the benefits of physical activity than they are to the benefits of controlling hypertension, lowering cholesterol levels, and stopping smoking -- the other traditional risk factors for cardiovascular disease.7 Compelling evidence attests to physical activity lending preventive and protective benefits to a wide range of health conditions beyond its well-known benefits for preventing cardiovascular disease.8,9 Other important health benefits of physical activity include decreased mortality (all causes); cancer prevention (particularly colon cancer); improved psychological health (relief of symptoms of anxiety and depression); reduced risk of obesity, adult-onset diabetes, and osteoporosis;10 and better retention of mobility and independence by older people.8,9 People who were fit in early adulthood and become sedentary later in life do not retain the lower risk profiles of their youth. However, it is never too late to become physically active; even people who have a history of being sedentary can obtain a significant health benefit.10 At a recent national symposium11 on the National Health and Medical Research Council's report Acting on Australia's weight, participants supported the strategy of complementing the management of food intake with the promotion of "transport exercise" or "active transport" to prevent weight gain and obesity. Active transport is about walking and cycling, or other physically active ways of travelling, that can be done alone or combined with catching public transport, often involving the benefits of climbing stairs. Active transport modes can displace car travel. Walking and cycling Walking is the main option for increasing physical activity in sedentary populations.12 Brisk walking for 30 minutes on most days of the week fulfils the recommended level of moderate-intensity physical activity and provides a level of protection to confer significant health benefits.9 Walking or cycling can be understood as activities fitting more easily into everyday life and life's tasks than the addition of recreational exercise,14 with its extra time and cost commitments.15 Walking has the further benefit of being available to most people regardless of income, location or age. Walking is highly efficient in its use of urban space and energy, it rarely causes injury and it gives streets vitality and personal security. Many car trips are quite short, less than 2 km, indicating that walking could be a feasible alternative and contribute to reducing the pollution from a cold-start vehicle travelling only a short distance. Physically active transport in childhood, such as cycling to school, can help to establish the use of cycling for transport later in life, as a habitual physical activity,16 with considerable benefits for health.17 Promoting active transport In the United Kingdom, several local programs promote active transport. In Glasgow, "Fit for life and healthy transport" includes a range of programs for cardiac rehabilitation, as well as health promotion in workplaces and secondary schools, to assist car travellers and school students to adopt healthier travel regimens.18 The UK Health Education Authority's guide, Active transport, aims to encourage local initiatives for promoting walking and cycling. It gives some case studies, for example initiatives by general practice surgeries to foster walking or cycling among patients attending an angina management clinic.19 There is a need for similar programs in Australia. Healthier transport policy and urban design Since existing transport infrastructure tends to support car travel over any other mode of transport, transport policy initiatives are needed to ensure that infrastructure can be modified to make walking and cycling an attractive option and a feasible substitute for car travel. A UK Health Education Authority briefing paper20 explains that transport has inherent problems that make the alliance with health invaluable. Health and transport policy-makers now recognise that:20 "It is not possible to build enough roads to meet demand, even if the economic, environmental and health costs were ignored. Consequently, the demand for road space must be managed, and emphasis must be placed on efficient use of existing road space." "The need to travel, or to travel longer distances, should be reduced by landuse planning, so that walking, cycling and public transport can be real choices." The phenomenon of growth in car use is as true for cities and towns in Australia as it is in the United Kingdom. It is this growth that is magnifying the adverse health effects of motor vehicle transport. Implementation of new transport measures needs to be coordinated to secure benefits for health and the environment, as well as a safe arrival at one's destination.21 This "new realism" in transport thinking fosters opportunities for converging interests to protect and promote health.22 Responsibility for changing transport patterns can be shared, as illustrated by a program at the University of New South Wales, a major "trip generator" organisation.23 Australian planners in cities and regions are coming to recognise how land use and appropriate urban design can reduce the need for motor vehicle transport and allow more walking and cycling trips.24-26 Creating neighbourhoods and communities that are less dependent on cars requires a denser pattern of development, with residential areas and services (shops, schools, sports facilities, libraries and clubs) located together (mixed-use neighbourhoods), and good public transport infrastructure linking the communities with employment opportunities. In urban improvement projects (and transport infrastructure development), planners are trying to concentrate employment opportunities around railway stations, provide mixed-use residential areas, and promote the principles of "active transport". These urban design and infrastructure changes can markedly reduce greenhouse gas emissions. The annual car-related emissions per dwelling vary greatly by neighbourhood type: conventional neighbourhoods remote from services and dependent on road transport produce 3.3 tonnes of CO2 per dwelling, while mixed-use neighbourhoods that facilitate the use of public and active transport produce 1.4 tonnes of CO2 per dwelling, a reduction of 57%, with associated health benefits of walking, cycling, and reduced exposure to motor vehicle accidents.27 The health sector's role The WHO Charter1 invites health authorities to examine their own use of transport, and the UK Government encourages all hospitals, as organisations generating motor vehicle trips, to show leadership in "promoting active transport" to their communities, while adopting organisational-based programs for cutting car use by staff members and visitors.28-30The Box outlines ways in which the health sector in Australia can support and foster active transport programs and influence policy development. References World Health Organization (WHO Europe). Charter on Transport, Environment and Health. <www.who.dk/London99/WelcomeE.htm> Accessed 10 Feb 2000. British Medical Association. Road transport and health. London: British Medical Association, 1997. Report of the Road Safety Committee on the Inquiry into the Incidence and Prevention of Pedestrian Accidents. Walking Safely. Parliament of Victoria. Melbourne: Victorian Government Printer, 1999. Bureau of Transport Economics. Urban transport -- looking ahead. Canberra: Bureau of Transport Economics, 1999. (Information Sheet 14.) National Health and Medical Research Council. Acting on Australia's weight: a strategic plan for the prevention of overweight and obesity. Summary report. Canberra: NHMRC/AGPS, 1997. Morris JN. Exercise in the prevention of coronary heart disease: today's best buy in public health. Med Sci Sports Exerc 1994; 26: 807-814. Dupen F, Bauman AE, Lin R. The sources of risk factor information for general practitioners: is physical activity under-recognised? Med J Aust 1999; 171: 601-603. US Department of Health and Human Services. A report of the Surgeon General. Atlanta, Ga: Centers for Disease Control and Prevention, 1996. URL: <http://www.cdc.gov/nccdphp/sgr/sgr.htm> Accessed 10 Feb 2000. NSW Health Department. Physical activity and health: a special communication from the Chief Health Officer, 2nd ed. Sydney: NSW Health, 1996. Commonwealth Department of Health and Family Services. Developing an active Australia: a framework for action for physical activity and health. Canberra: The Department, 1998. Commonwealth Department of Health and Aged Care and the Australasian Society for the Study of Obesity. Symposium on the NHMRC's report Acting on Australia's weight. Children and their families; 1999 Aug 23, Sydney. Morris JN, Hardman AE. Walking to health. Sports Med 1997; 23 (5): 306-332. Pears A. Global warming: cool it! Canberra: Environment Australia, 1997. US National Heart, Lung and Blood Institute. Simple lifestyle changes boost physical activity/cardiovascular health. January 1999. URL: <http://www.nhlbi.nih.gov/new/index.htm> Accessed 10 Feb 2000. NSW Physical Activity Taskforce. Simply active everyday: a plan to promote physical activity in NSW, 1998-2002. Sydney: NSW Health 1998. Gardner G. Identifying potential cyclists. European Transport Conference, 27-29 September 1999. Cambridge, UK. Proceedings Vol B: Transport planning, policy and practice, p 405-414. London: PTRC Education & Research Services Ltd, 1999. Roberts I, Owen H, Lumb P, MacDougall C. Pedalling health: health benefits of a model transport shift. Adelaide: SA Department of Transport, 1996. University of Glasgow, Greater Glasgow Health Board, Glasgow City Council, Strathclyde Passenger Transport. Fit for life and healthy transport. Undated. Davis A. Active transport: a guide to the development of local initiatives to promote walking and cycling. London: UK Health Education Authority; 1999. UK Health Education Authority. Transport and Health: a briefing paper for health professionals and local authorities. London: Health Education Authority; 1998. Dora C. A different route to health: implications of transport policies. BMJ 1999; 318: 1686-1689. Goodwin P. Are transport policies driven by health concerns? In: Fletcher T, McMichael AJ, editors. Health at the crossroads: transport policy and urban health. Chichester: John Wiley & Sons,1997: 271-278. Black J, Mason C, Stanley K. Travel demand management: an application by University of New South Wales (UNSW) as a large trip generator. Transport Engineering in Australia. 1999. In press. NSW Government. Action for Transport 2010: an integrated transport plan for Sydney. Sydney: Department of Transport, 1998. NSW Government. Action for air: NSW Government's 25 year air quality management plan. Sydney: EPA, 1998. NSW Government. Shaping our cities. Sydney: Department of Urban Affairs and Planning, 1998. Greenhouse Neighbourhood Project: the low energy suburb. Summary report. Prepared for Victorian Department of Planning and Development, EPA, and Energy Victoria by Loder & Bayly Consulting Group, RJ Nairn & Partners, Sustainable Solutions, PPK Consultants, 1993. Peden S. Southampton University Hospitals, NHS Trust, UK: traffic demand management in action, European Transport Conference, 27-29 September 1999. Cambridge, UK. Proceedings Vol D: Civilising the city, p 11-18, London: PTRC Education & Research Services Ltd, 1999. Transport 2000 Trust. The Healthy Transport Toolkit: a guide to reducing car trips to NHS facilities. Supported by UNISON, the Department of Health, the Health Education Authority and the Department of Environment, Transport and Regions. London: Transport 2000 Trust, 1998. Hanratty B, Patterson W. Three quarters of delegates drove to conference on impact of environment on health. BMJ 1998; 316: 775. -2004 Australian cycling. The National Strategy. Sydney: Austroads,1999. Authors' details PO Box A973, Sydney, NSW. Chloë Mason, PhD, Consultant in Sustainable Transport. Reprints: Dr C Mason, PO Box A973, Sydney, NSW 1235. chloemasonATbigpond.com Make a comment Walking or cycling 1km to the railway station instead of driving saves 0.2-0.3kg greenhouse gas emissions, other air pollutants, and fuel cost. The traveller's moderate physical activity in walking to the station and climbing the station steps to the train would meet a third to a half of his or her daily requirements for physical activity.13 Practical ways for the health sector to encourage active transport and a new, healthier transport agenda Clinical practice "Prescribe" or encourage active transport, preferably displacing car journeys, at least for some trips. Run demonstration projects on the benefits and applications of "active transport" in coronary rehabilitation, the prevention of obesity or the treatment of depression. Medical administration Doctors' surgeries, hospitals and other health services, and government health departments all function as "trip generators" by attracting people to their sites as patients, visitors, or staff members. Produce a Transport access guide or update Practice information sheets to show access to the site -- public transport services, cycling and walking routes and end-of-trip facilities (eg, cycle parking, showering facilities) -- to inform people about the alternatives to car travel, with emphasis on the benefits to health. Develop "healthy transport plans" for the organisation and ensure practices are consistent with encouraging people to reduce car travel to reach the site for work, to attend conferences, or to visit patients. Health advocacy Doctors can become more actively involved in community education and policy development about land use planning, transport infrastructure, and travel demand management (such as raising car parking charges to discourage car travel) and highlight the health impacts of the transport system. Doctors could support new initiatives, such as "Safe routes to school" schemes, and implementation of Australia's national cycling strategy,31 and support reforms to reduce subsidies for parking and car travel which operate by fringe benefits taxation concessions. Medical professional organisations could produce an Australian version of the BMA's report Road transport and health2 to influence national and regional transport policy. Back to text

Chloe Mason