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AD_ 0 3 7 _ _ _ J UL 1 1 _ 0 8 . PDF Pa ge 1 7 / 3 / 0 8 , 2 : 3 6 PM How to treat Pull-out section w w w. a u s t r a l i a n d o c t o r. c o m . a u Complete How to Treat quizzes online (www.australiandoctor.com.au/cpd) to earn CPD or PDP points. inside Diagnosis & investigation Established and new therapies Issues for debate Case studies The author DR RODERICK J CLIFTON-BLIGH, staff specialist in endocrinology, Royal North Shore Hospital, St Leonards; and senior lecturer in medicine, University of Sydney, NSW. OSTEOPOROSIS Background OSTEOPOROSIS is defined as a metabolic bone disease characterised by low bone mass and deterioration in the architecture of bone tissue, which in combination leads to bone fragility and fracture. It is one of the leading diseases affecting our ageing population. Its genesis is mostly explained either by failure to achieve normal peak bone mass during growth and young adulthood, or by excessive bone loss caused by agerelated factors in both genders, and more particularly after menopause in women. Normally, at a cellular level, new bone is formed by osteoblasts as older bone is resorbed by osteoclasts, with these two processes coupled together to ensure maintenance of skeletal integrity. Disruption of this balance causes bone loss and skeletal fragility. For example, oestrogen deficiency after menopause causes excessive osteoclastic activity unmatched by commensurate osteoblastic reformation. Successful osteoporosis therapy therefore targets either the overactive osteoclast (anti-resorptive) or the www.australiandoctor.com.au underperforming osteoblast (anabolic), or both (figure 1, page 39). Osteoporotic fractures The clinical expression of osteoporosis is fracture. Of course, any bone will break under sufficient force, so that osteoporotic fractures are limited to those occurring with cont’d page 39 11 July 2008 | Australian Doctor | 37 AD_039___JUL11_08 Page 2 3/7/08 2:09 PM from page 37 so-called minimal trauma such as falling from standing height. Classic osteoporotic fractures occur at the hip, spine or forearm, although fragility fracture of any bone (except the skull) might be due to osteoporosis. In 2001 an estimated two million Australians had osteoporosis, with fractures occurring every 8.1 minutes and costing $1.9 billion in direct care. About one in two women, and one in three men over 60 will have a fracture in their remaining lifetime. Between 10% and 20% of those with hip fracture will die within a year of the event and 20-30% will require nursing home care. Vertebral fractures (figure 2) are also associated with significant morbidity and increased mortality. Osteoporosis is an increasing global problem, and the number of hip fractures worldwide is expected to increase from 1.7 million in 1990 to 6.3 million in 2050. Osteoporosis is a major problem for the individual and community alike. Figure 1: Bone biology and cellular targets of osteoporosis therapies. Osteoblasts form new bone whereas osteoclasts resorb bone. Osteoporosis develops from an imbalance between these two processes. Osteoblasts stimulate osteoclastic activation via a protein called RANK ligand (RANKL, shown as ). PTH = parathyroid hormone, SERMs = selective oestrogen-receptor modulators. (RANKL inhibitors) teriparatide (PTH 1-34) osteoblasts osteoclast Figure 2: A thoracic vertebral wedge fracture in a patient with postmenopausal osteoporosis. Note the 30% reduction of anterior vertebral body height relative to the posterior vertebral height. A vertebral fracture is defined as a *20% reduction in height of the anterior or mid-portion of a vertebral body relative to the posterior height of that body, or a *20% reduction in any of these heights compared with the vertebral body above or below the affected vertebral body. bisphosphonates oestrogen osteoid SERMs bone strontium Most osteoporotic fractures occur in people over 60. Osteoporosis can also occur in children and young adults, but discussion of this is beyond the scope of this review and should probably be managed in a specialist setting. Preventing the consequences of osteoporosis relies on three strategies: ■ Identifying those who need treatment. ■ Choosing from a range of effective therapies. ■ Maintaining adherence to treatment, and monitoring for treatment response. Diagnosis Who needs to be treated? Stratifying fracture risk GENERALLY speaking, a postmenopausal woman (or man over 50) with a fragility fracture will be at sufficiently high risk of a further fracture to warrant specific treatment. They have already failed their skeletal stress test. Investigations (such as bone mineral density [BMD] measurement — see below) may help ensure compliance with therapy, and can be used to monitor progress. On some occasions the history of fracture is not immediately obvious, such as the woman with progres- sive height loss and chronic back pain due to as yet unrecognised vertebral fracture. After the diagnosis has been established by plain radiography of the lateral spine, this patient also needs specific therapy to prevent further fractures. For those without a preexisting clinical fracture, the decision to treat relies on stratifying fracture risk and determining which elements of that risk are amenable to treatment. These factors are summarised below. Bone strength At present, BMD is most conveniently and accurately esti- mated by dual-energy X-ray absorptiometry (DEXA). This technique actually measures so-called ‘areal’ bone density 2 (g/cm ), which is bone mass normalised to the size of the projected bone area. A wealth of data associates reduced BMD measured by DEXA with increased fracture risk. Each standard deviation reduction in femoral neck BMD increases age-adjusted risk of hip fracture 2-3.5-fold, and the risk of any fracture 1.7-2.4-fold. Lumbar spine BMD is a slightly better predictor of vertebral fracture (1.9-2.8-fold risk per SD) although the presence of degenerative spine dis- ease or aortic calcification can spuriously elevate BMD at this site. Precision of DEXA is excellent (1-2%) but because usual rates of change in BMD either with age or treatment are usually no more than 1-2% per year, an interval of two years is typically required to detect a significant change in the measurement. The BMD result is usually interpreted as a T-score, which is the number of standard deviations from young normal mean BMD. The WHO defines: ■ Normal bone density as a Tscore of > –1. ■ Osteopenia as a T-score between –1 and –2.5. Osteoporosis as a T-score of ) –2.5. The nationwide introduction of a standardised Australian reference range based on data from the Geelong Osteoporosis Study is now in progress.1 Whereas BMD in the osteoporotic range was previously regarded as a threshold for offering treatment, more recently there have been moves towards developing gradient-of-risk models that incorporate other clinical risk factors (figure 3, page 41). Two cardinal factors in addition to BMD are age and presence of fracture. The ■ decrease in bone strength that occurs with age is not fully captured by BMD alone. Fracture risk increases with age for any given BMD, which is also partly related to the increased risk of falls with age.2 A history of previous fragility fracture (after age 50) increases the risk of another fracture between 2- and 5fold. Sometimes vertebral fractures may not be clinically apparent. Particularly in older patients or patients with lower BMD (eg, T-scores <–2.0), lateral spine radiographs may be useful in identifying asymptomatic vertebral deformities. Vertebral fracture assessment cont’d next page One Australian life is lost to heart disease every 20 minutes1,2 1 in 7 patients with a history of CAD* will suffer a major event (heart attack, stroke or CV death) or hospitalisation within 1 year. 3 *CAD refers to coronary artery disease. For PBS Information refer to primary advertisement. BEFORE PRESCRIBING PLEASE REVIEW PRODUCT INFORMATION IN THE PRIMARY ADVERTISEMENT IN THIS PUBLICATION. Plavix (clopidogrel 75 mg). References: 1. www.heartfoundation.com.au (accessed Nov 2007), media release date 14/9/07. 2. The Shifting Burden of Cardiovascular Disease in Australia. Access Economics; 2005. Downloaded from www.heartfoundation.org.au; 1 April 2008. 3. Steg PG, et al. JAMA 2007; 297(11):1197-1206. sanofi-aventis australia pty ltd ABN 31 008 558 807, Talavera Corporate Centre, Building D, 12-24 Talavera Road, Macquarie Park, NSW 2113. Plavix is a registered trademark of sanofi-aventis. HSX0364/AD/1 www.australiandoctor.com.au 11 July 2008 | Australian Doctor | 39 AD_040___JUL11_08 Page 3 3/7/08 3:47 PM How to treat – osteoporosis from previous page by DEXA is a potentially more costeffective alternative that also involves less ionising radiation. However, this technique requires an appropriate densitometer and software, which are not yet widely available. Operation of these three key factors is illustrated by considering the following individuals with about equal fracture risk in the next 5-10 years (assuming no difference in other risk factors or risk of falling): ■ A 60-year-old woman with one existing vertebral fracture and BMD T-score of –2.5. ■ A 75-year-old woman with no prior history of fracture and BMD T-score of –2.5 ■ A 60-year-old woman without previous fracture and BMD T-score of –3.5. Other important clinical risk factors that are at least semi-independent of age and BMD include: ■ Low body weight (<58kg). ■ Maternal history of hip fracture. ■ Current smoking. ■ Inability to stand up from a chair without using arms. However, it is less certain whether the presence of these latter factors confers risk that alters with treatment. Another important category The principal determinant of bone strength is its mineral density, but clinical risk factors (in particular age and the presence of fracture) provide important additive information for calculating individual fracture risk. of risk involves iatrogenic factors, most particularly the use of systemic corticosteroids, which are dealt with separately below. So who should have a BMD measurement? The MBS criteria for rebate of a BMD scan now include those aged *70, and younger individuals with either fracture or selected clinical conditions associated with osteoporosis. Falls risk Most hip and peripheral fractures result from a fall. The risk of falling increases with age, such that 50% of those aged *85 will fall each year and 50% have had a previous fall. A history of falling in the previous 12 months has been shown to be an independent risk for fracture (after accounting for age, BMD, etc) in several studies. Identifying falls risk is therefore an important adjunct when considering management to prevent fracture. Note that this is bi-directional: a patient with low bone mass should be assessed for risk of falling, and the patient with frequent falls should have their bone density measured. Falls risk factors may be either environmental (such as home hazards or unsuitable footwear) or intrinsic, including a wide range of medical conditions such as impaired vision or cognition, previous stroke, Parkinson’s disease or use of sedative medications. Clinical examination should include an assessment of postural sta- bility. One simple screening tool is the timed up-and-go test, in which the patient is asked to rise from a chair, walk 3m at normal pace (and with usual walking aids), return to the chair and sit down. A time of *15 seconds to complete this is regarded as abnormal. More complex and comprehensive assessment tools are available that more accurately determine falls risk and identify key impairments that might respond to targeted intervention.3 Although it is reasonable to assume that preventing falls would reduce the burden of fractures in the elderly, there is little published evidence yet to confirm this. Iatrogenic osteoporosis Use of systemic corticosteroids is associated with rapid bone loss via a combination of negative calcium balance and direct effects on bone tissue. Increased fracture risk is particularly evident in postmenopausal women and older men. Fracture risk is influenced by daily corticosteroid dose and duration of use. For example, taking at least 7.5mg prednisone daily for longer than two months increases the risk of vertebral fractures 2.8-fold and hip fractures 2.2-fold. The risk of verte- bral fracture is increased by up to 14-fold in those taking *30mg prednisone daily for a cumulative exposure of *5g. Fracture risk decreases after corticosteroid therapy is discontinued. Fracture risk with corticosteroid use appears to increase when BMD T-score falls below –1.5, so intervention may be appropriate at higher BMD values than typically used to consider treatment for postmenopausal osteoporosis. Several other medications can adversely affect fracture risk. Aromatase inhibitors are now increasingly used in the treatment of breast cancer, and the risk of fracture (mostly vertebral fractures) with these agents may be increased by up to 60%. Bone turnover increases after an aromatase inhibitor is started, which suggests that even the small residual oestradiol levels present in postmenopausal women are important for bone health. A woman starting an aromatase inhibitor should have her bone density measured and be offered treatment if it is low (figure 3, page 41). A similar effect on fracture risk is seen in men having medical or surgical orchidectomy for treatment of prostate cancer. Investigations IF low bone mass has been discovered, the purpose of further investigations is to exclude potentially treatable secondary causes (table 1). Although a long list of medical conditions is associated with osteoporosis (including rheumatoid arthritis, chronic kidney or liver diseases, inflammatory bowel disease, and Cushing’s syndrome), most of these are readily evident before a BMD test. Other secondary causes of accelerated bone loss are important because they may be clinically silent, and specific treatment may improve Table 1: Investigations for secondary causes of bone loss Serum 25-hydroxyvitamin D (and serum parathyroid hormone [PTH] if the 25(OH)D level is low) ■ Serum calcium (and PTH if calcium level is elevated) ■ Serum TSH (and free T4/T3 if TSH level is abnormal) ■ Anti-transglutaminase IgA antibody (total IgA levels may need to be checked in case of IgA deficiency) ■ FBC ■ Creatinine, liver function ■ Testosterone in men ■ Serum and urinary electrophoretogram/ immunoelectrophoretogram if there is rapid bone loss, osteoporosis or multiple fractures ■ 24-hour urinary free cortisol if Cushing’s syndrome is clinically suspected ■ bone strength. Hypogonadism is of course the principal cause of postmenopausal osteoporosis, but hypogonadism should also be routinely excluded in men with low bone mass. Other conditions include vitamin D deficiency, hyperthyroidism, coeliac disease and primary hyperparathyroidism. Multiple myeloma is rarely diagnosed (<1%) in otherwise asymptomatic patients with osteoporosis. Diagnosis of monoclonal gammopathy of uncertain significance (MGUS) is not uncommon but there are no data on fracture risk that would otherwise guide treatment decisions for low bone mass in this condition. Patients with MGUS should be periodically monitored to exclude progression to myeloma. Several markers of dynamic bone turnover are now available that reflect either bone formation (eg, serum bone-specific ALP, osteocalcin, and aminoterminal propeptide of type I collagen [PINP]) or bone resorption (eg, urinary Nterminal telopeptides of type 1 collagen [NTX] or urinary deoxypyridinoline [DPD]). At present these markers have a biological variability such that a single measurement has low predictive value for individual fracture risk. However, an elevated bone resorption marker in addition to low BMD may strengthen the argument for treatment of that individual. Moreover, demonstrating a reduced resorption measurement after three months of therapy generally indicates adequate treatment response. Management )THE goal of therapy is to prevent fracture. Several therapies are now available that have been shown to reduce fractures in selected high-risk populations. The choice of therapy will depend on the nature of fracture risk (spine or non-spine), the presence of contraindications to specific therapies, and patient preference. Therapies differ with respect to their mechanism of action (figure 1, page 39), but all target the skeleton to improve bone strength. Fractures may not be prevented with these therapies in patients at high risk of falling unless their bone density is also demonstrably low. Oral bisphosphonates (Level 1 evidence for prevention of vertebral and non-vertebral fractures) These drugs are analogues of pyrophosphate and bind tightly to skeletal hydroxyapatite. They are potent inhibitors of osteoclastic bone resorption. Further bone loss is thereby prevented and mineral density is increased, but little if any new bone is formed. Orally administered 40 | Australian Doctor | 11 July 2008 bisphosphonates have low bioavailability (<1%), which is further reduced if taken with food, calcium or iron. Three oral bisphosphonates are available in Australia for osteoporosis treatment: alendronate, risedronate and etidronate. In the case of alendronate and risedronate, multiple studies confirm efficacy in treating osteoporosis. Both reduce the relative risk of vertebral (by 40-50%) and non-vertebral fracture (by 20-40%) in patients with osteoporosis and at least one pre-existing vertebral fracture. Hip fractures are reduced by 3050% by these two oral bisphosphonates in similarly high-risk patients. There are also data showing that these two oral bisphosphonates prevent spine fractures (by about 50%) in patients with low BMD even without pre-existing fracture. Overall, the effect on fracture risk is seen within 12 months after starting these agents. In the only two head-to-head studies, alendronate was associated with significantly greater increases in hip and spine BMD, and greater reduc- sis and may still have some role in those patients intolerant of other agents. Selective oestrogen-receptor modulators (Level 1 evidence for vertebral fracture prevention) Hip fractures may be reduced by 30-50% by use of alendronate or risedronate in high-risk patients. tion in bone turnover, than risedronate over 12 months.4,5 However, it is important to emphasise that no difference in anti-fracture efficacy has been demonstrated between the two agents. There are much fewer data to support the utility of etidronate. Improvement in BMD is less than that seen with either alendronate or risedronate, and fracture prevention has only been shown for spinal fractures. Nevertheless, etidronate is available on the PBS (authority required) for treatment of established osteoporowww.australiandoctor.com.au Selective oestrogen-receptor modulators (SERMs) are non-hormonal analogues of oestrogen that activate the oestrogen receptor in bone but antagonise it in other tissues such as uterus and breast. Raloxifene is the only SERM registered for use in osteoporosis. Raloxifene reduces the relative risk of vertebral fracture by 36% in postmenopausal women with osteoporosis.6 Recent data have also demonstrated reduced risk of clinical vertebral fractures in women not otherwise selected on the basis of osteoporosis risk factors such as low BMD. Raloxifene does not appear to prevent non-vertebral fractures. The effect on bone density with raloxifene is typically less than that seen with the use of bisphosphonates, despite broadly comparable reduction in vertebral fracture risk with either class of agent. Raloxifene has also been associated with a 55-70% reduction in the relative risk of oestrogen-receptorpositive breast cancer, equivalent to 1.2 fewer invasive breast cancers per 1000 women treated for one year.6,7 Raloxifene increases relative risk of venous thromboembolism by 44%, equivalent to 1.2 more events per 1000 women-years of treatment.6 In a recent trial involving women with an already high risk for coronary heart disease there was an excess relative risk of fatal stroke with raloxifene (increased by 49%) equivalent to 0.7 extra events per 1000 womenyears.7 Raloxifene use may also exacerbate hot flushes, leg cramps and peripheral oedema. Strontium (Evidence for prevention of vertebral [level 1] and non-vertebral [level 2] fractures) Strontium is a naturally occurring trace element, a divalent cation like AD_041___JUL11_08 Page 4 3/7/08 3:47 PM calcium but with greater molecular weight. It is given as ranelate salt to improve its palatability. While its exact mechanism of action is unknown, strontium stimulates bone formation via increased pre-osteoblast cell number and bone formation rate, while at the same time inhibiting osteoclast resorption activity (although its antiresorptive activity is less than that of bisphosphonates). Two multinational phase III studies have now reported a significant relative reduction in risk of vertebral (by 41%)8 and non-vertebral fractures (by 16%) 9 in postmenopausal women with osteoporosis given strontium ranelate. In these studies, relative risk of vertebral fractures was also significantly reduced in women with osteopenia10 and in women aged >80 years.11 Relative hip fracture risk was reduced by 36% in a post-hoc analysis of women aged *74 years with BMD T-scores ) –2.4.9 Strontium ranelate significantly increases bone density at both spine and hip, although about 50% of the observed change is due to a small interchange of strontium for skeletal calcium. Its use is associated with an increased incidence of GI side effects such as diarrhoea, and a small increased risk of venous thromboembolism (0.9% compared with 0.6% in the placebo group).9 Drug rash with eosinophilia and systemic symptoms has been recently reported as a very rare reaction. There is still much to learn about the potential uses of strontium in osteoporosis management. There are no data yet to confirm its efficacy in patients who have previ- Figure 3: Managing osteoporosis: gradient-of-risk model incorporating other clinical risk factors besides BMD. Clinical fragility fracture No Yes Clinical suspicion BMD (to monitor treatment) Treat (PBS authority) Offer treatment BMD T-score ) –3 Aged * 70 T-score ) –2 or ) –1 with clinical risk factors* T-score ) –1 and > –2 and no clinical risk factors T-score > –1 VFA or spine X-ray Monitor (BMD in 2 years) Reassure Fracture No fracture *Clinical risk factors for fragility fracture include older age, family history, smoking, weight < 58kg, frequent falls and drugs (corticosteroids, aromatase inhibitors, GnRH agonists). VFA = vertebral fracture assessment. ously been treated with other agents (such as bisphosphonates), nor whether its effects might be additive to those of purely anti-resorptive agents. Studies in men, or in patients with glucocorticoid-induced bone loss, are also awaited. Oestrogen (Level 1 evidence for prevention of vertebral and non-vertebral fractures) Many studies have shown oestrogen therapy is effective at preventing menopausal bone loss. The utility of HRT in preventing osteoporotic fractures was conclusively demonstrated in the Women’s Health Initiative trial.12 Women randomised to combined HRT had 24% fewer fractures, including 34% fewer hip fractures (absolute risk decrease of 0.05% per annum) over the seven years of that study. However, the skeletal benefits of HRT in that trial were outweighed by an excess risk of breast cancer, stroke, pulmonary embolism and coronary events, even though the absolute risk for each was increased by less than 0.1% per annum.12 In women who had previously undergone hysterectomy and were randomised to oestrogen alone, there was a comparable reduction in fracture risk, which was again counterbalanced by an excess number of strokes and venous thromboembolic events. The main indication for HRT continues to be the control of menopausal symptoms. At this stage, it is unclear whether there is a particular subgroup of otherwise asymptomatic postmenopausal women for whom the skeletal benefits of HRT outweigh the risks. General measures should be avoided in patients with a history of renal calculi in the presence of hypercalciuria. A recent trial conducted in New Zealand has raised a cautionary note regarding use of calcium citrate as monotherapy for treating osteoporosis, particularly in older women.14 This study found that postmenopausal women aged 74 ± 4.2 years given 1000mg calcium citrate daily for five years had significantly more vascular events (relative risk of MI 2.12). When interpreting these findings we should bear in mind that vascular risk was not a primary endpoint of this study but rather a safety endpoint analysed in secondary analyses. Further studies are therefore needed before a firm conclusion can be drawn regarding any adverse vascular effect, or whether there is a risk with calcium carbonate. Indeed, the Women’s Health Initiative reported that calcium carbonate was not associated with excess cardiovascular event rates. Calcium Dietary intake of 1200mg of calcium per day (equivalent to three or more servings of dairy products) is generally recommended, although there is still controversy regarding any primary anti-fracture efficacy of calcium monotherapy. A recent meta-analysis showed that calcium supplementation prevented menopausal bone loss, with a trend towards fewer vertebral fractures but no effect on non-vertebral fractures.13 It is important to emphasise that trials of the effective antiosteoporosis agents discussed above have generally included calcium as adjunctive therapy in both treatment and control groups. Calcium supplements Vitamin D Vitamin D is important for skeletal health across all ages. Most vitamin D is obtained from UV-B action in the skin. Exposure of hands, face and arms to adequate sunlight (about 5-8 minutes daily in summer and 20-30 minutes in winter, although these times vary by latitude) should produce about 1000 units of vitamin D daily. Elderly skin or increased cutaneous melanin is associated with less vitamin D production. The major risk factors for vitamin D deficiency are therefore older age, dark skin pigment and sun avoidance (including residential care, religious veiling, certain medical conditions). Some but not all studies show that supplemental vitamin D reduces the risk of osteoporotic fractures, with a more obvious effect seen in vitamin D-deficient populations. Vitamin D supplementation with cholecalciferol is recommended to achieve a target serum 25-hydroxyvitamin D (25[OH]D) of at least 50nmol/L. There is only weak (level 3) evidence to support the use of calcitriol (Rocaltrol) in osteoporosis treatment. There is some evidence to support its use in preventing glucocorticoid-induced osteoporosis. It may still have some role in treating patients with osteoporosis who are intolerant of the more effective therapies discussed above. It is PBS listed (authority required) for the treatment of osteoporosis in patients with a pre-existing minimal trauma fracture. Exercise and other nonpharmacological therapies Weight-bearing exercise is usually recommended for preventing osteoporosis (level 3 evidence). Meta-analyses of short-term trials have shown that resistance training (3-5 times a week) or regular walking (90-280 minutes a week) produces a small increase in spinal BMD without any consistent effect on hip BMD. As noted above, specific programs for muscle strengthening and balance training can reduce falls in high-risk groups. However, there is no evidence yet that any of these interventions protect against fractures. Hip protectors have been shown in some studies to reduce hip fractures in patients at high risk of falls. However, their use is limited by compliance. Plavix + aspirin gives ACS patients added protection † against future CV events1–3 * †ACS refers to acute coronary syndrome: UA/NSTEMI/STEMI. *Compared to aspirin alone. For PBS Information refer to primary advertisement. BEFORE PRESCRIBING PLEASE REVIEW PRODUCT INFORMATION IN THE PRIMARY ADVERTISEMENT IN THIS PUBLICATION. Plavix (clopidogrel 75 mg). References: 1. CURE Trial Investigators. N Engl J Med 2001;345(7): 494-502. 2. Sabatine MS, et al, for the CLARITY-TIMI 28 Investigators. N Engl J Med 2005; 352:1179-1189. 3. COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Lancet 2005; 366:1607-1621. sanofi-aventis australia pty ltd ABN 31 008 558 807, Talavera Corporate Centre, Building D, 12-24 Talavera Road, Macquarie Park, NSW 2113. Plavix is a registered trademark of sanofi-aventis.HSX0364/AD/2 www.australiandoctor.com.au 11 July 2008 | Australian Doctor | 41 AD_ 0 4 2 _ _ _ J UL 1 1 _ 0 8 . PDF Pa ge 1 7 / 3 / 0 8 , 4 : 0 9 PM How to treat – osteoporosis Issues for debate Non-responders A KEY unresolved issue in osteoporosis management is identifying patients who do not respond to a given therapy. Although BMD assessment is clearly useful in identifying those at increased risk of fracture, change in BMD with treatment only explains a small proportion of antifracture efficacy. For example, raloxifene reduces the relative risk of vertebral fracture by 30-60%, yet observed change in spinal BMD with this treatment is only 2-3% in three years — that is, only 4% of fracture reduction is explained by the change in BMD. The proportion of fracture risk reduction explained by change in BMD seen with oral bisphosphonate treatment is only 16-18%. Conversely, significant reduction in fracture risk is observed within 3-6 months of starting bisphosphonate therapy — well before maximum BMD gains with these treatments. Therefore there is reasonable evidence to suggest that anti-resorptive therapy is efficacious, provided BMD remains at least stable. Recurrence of multiple fractures, and/or loss of BMD after starting anti-resorptive therapy, places the patient and clinician in a difficult situation without adequate evidence to guide decision-making. Compliance with treatment should be carefully reviewed, particularly in the case of bisphosphonates, when contemporaneous ingestion of food, calcium or iron will impair absorption. Calcium supplementation (and repletion of vitamin D) should be checked, and other secondary causes of accelerated bone loss should be re-evaluated (table 1, page 40). After these factors have been corrected or excluded, changing to another anti-osteoporosis therapy might be considered. An IV bisphosphonate is an attractive option because this overcomes the problem of poor GI absorption and variable compliance, but osteoporosis is not yet a registered indication for these agents in Australia. In patients at very high risk of In cases of non-response to therapy, calcium supplementation (and repletion of vitamin D) should be checked, and other secondary causes of accelerated bone loss should be reevaluated. recurrent fracture, use of subcutaneous teriparatide (parathyroid hormone [PTH]; see below) might be considered but this is costly (and not PBS listed) and may not be as effective after prolonged initial therapy with bisphosphonates. Combining two anti-resorptive therapies has not been shown to additively reduce fracture risk, but does increase the risk of side effects. There are no data as yet on switching to strontium ranelate in patients who have previously taken other osteoporosis therapies. Treatment duration A connected theme in this discussion is the issue of how long treatment should continue. The primary aim of treatment ideally should be to achieve adequate bone strength to resist fracture and, secondarily, to restore bone turnover to a physiological range such that ongoing bone loss does not occur. There have been some fears that oversuppression of bone turnover might predispose to microdamage accumulation. The little evidence there is to support this hypothesis comes from animal models. Discontinuing oestrogen or raloxifene results in a return of postmenopausal bone loss and decreases in BMD within 12 months. Bisphos- phonates have a longer skeletal retention time, and BMD gains are preserved for some time after their discontinuation. Recent data from the Fracture Intervention Trial Long-term Extension Trial showed that women who stopped alendronate after five years of treatment had stable lumbar spine BMD over the subsequent five years, but a significant decrease in hip BMD occurred within 1-2 years.15 Continuing alendronate in this trial resulted in fewer clinical vertebral fractures, but no further reduction in incidence of non-vertebral fractures. Even after 10 years of alendronate treatment, there was no evidence on transiliac bone biopsy that bone remodelling was over-suppressed.15 Therefore, women who have taken alendronate for up to five years might elect to suspend therapy for 1-2 years if their vertebral fracture risk is low; but for women at high risk of recurrent fracture, therapy should not be discontinued. Other bisphosphonates differ in their affinity for bone, so the alendronate data cannot be extrapolated to risedronate or etidronate. Osteonecrosis of the jaw Osteonecrosis of the jaw (ONJ) is a potential complication of bisphosphonate therapy that deserves partic- ular mention. First recognised in 2003, it has since been mainly reported in patients with cancer receiving higher total doses of bisphosphonates. Bisphosphonate-associated ONJ is defined as ‘confirmed’ when an area of exposed bone in the maxillofacial region does not heal within eight weeks after identification in a patient receiving a bisphosphonate who has not had radiation therapy to the area. Exposed alveolar bone present for less than eight weeks is termed a ‘suspected’ ONJ case. The defect may be accompanied by pain, swelling, paraesthesia and infection. The pathophysiology of the condition is not well understood but may initially relate to soft tissue inflammation causing a persistent ulcer with or without oral super-infection. The incidence of ONJ is still unclear. An Australian study that surveyed oral and maxillofacial surgeons and the Commonwealth Adverse Drug Reaction Committee identified 158 cases, including 26 patients with osteoporosis.16 Comparing these data with estimates of bisphosphonate exposure in the population generated risks of between one in 2260 and one in 8470 (0.010.04%) patients treated with oral bisphosphonates for osteoporosis.16 Most cases had occurred after dental extraction. The risk was higher for patients receiving IV bisphosphonates for treatment of malignancy (0.88-1.15%) and the condition may be more severe in these patients. The median time to onset of ONJ was 12 months for zoledronic acid, and 24 months for alendronate. German registry data presented in abstract form have estimated a lower risk of ONJ in osteoporosis patients (<1 in 100,000 patient-treatment years).17 Other risk factors for ONJ appear to include pre-existing dental or periodontal disease, alcohol or tobacco abuse and glucocorticoid treatment. Patients must be properly informed about the risk of ONJ before starting a bisphosphonate, and advised to inform their dentist of the treatment. Patients should be encouraged to maintain good oral hygiene and, ideally, have regular dental visits. Periodontal disease should be non-surgically treated if possible. Endodontic treatment is preferable to extraction. If a dental extraction has to be performed, some experts recommend temporary discontinuation of bisphosphonates for a period before and after the procedure, although there are no data to support improved dental outcomes by doing so. Current information suggests that taking bisphosphonates is not a contraindication to dental implants. Management of established ONJ should be by dental specialists, and guidelines include appropriate use of analgesia, oral microbial rinses, and systemic antibiotics if infection is evident. Surgical treatment should be conservative, and delayed if possible. Osteoporosis patients may be less prone to severe ONJ than cancer patients receiving higher bisphosphonate doses. At least temporary withdrawal of bisphosphonate therapy is recommended when ONJ has developed, until healing has occurred. New therapies Teriparatide STUDIES over many years had uncovered a curious paradox about PTH: whereas continuous exposure to PTH (such as in primary hyperparathyroidism) causes bone loss, intermittent dosing with PTH actually stimulates osteoblastic activity and new bone formation. In 2001, daily SC administration of a synthetic fragment of PTH (teriparatide) was reported to reduce vertebral fractures by 65% and non-vertebral fractures by 53% in postmenopausal women with osteoporosis.18 This trial was stopped prematurely after 20 months because of concerns that rodents developed osteosarcomas during high-dose and long-term administration of the drug. 42 Only one human case of osteosarcoma has been reported after teriparatide treatment in more than 550,000 treated patients worldwide — an incidence that approximates the expected occurrence of this rare bone malignancy. Current recommendations are that: ■ PTH therapy should be limited to patients at high risk of osteoporotic fracture. ■ Treatment duration should not exceed 18 months. ■ Teriparatide should be avoided in patients at increased risk of osteosarcoma (eg, Paget’s disease of bone or previous chest wall radiotherapy). The major limitations of teriparatide are its cost and the need for daily SC injections. Otherwise it is gener- | Australian Doctor | 11 July 2008 ally well tolerated. The hope that concurrent therapy with teriparatide and anti-resorptive therapies would be of additive benefit was not borne out in recent studies; indeed, previous treatment with bisphosphonates appeared to blunt the anabolic effect of teriparatide. Conversely, new bone formed by teriparatide is quickly lost unless followed by sequential antiresorptive treatment. IV bisphosphonates: zoledronate In a recent osteoporosis trial, patients randomised to receive an annual 15-minute infusion of zoledronate (5mg) for three years had an impressive reduction in risk of clinical vertebral fractures (by 70%), hip fractures (41%) and overall non-ver- Evidence-based practice The strongest risk factors for osteoporotic fractures are older age, low bone density and the presence of a fragility fracture (level 1). ■ Fracture risk is reduced by treatment in patients who have already had a fracture and who have low bone density (T-score at spine or hip <–2) (level 1). ■ Oral bisphosphonates (alendronate, risedronate) reduce vertebral and non-vertebral fractures in patients with osteoporosis (level 1). ■ Strontium ranelate reduces vertebral (level 1) and non-vertebral fractures (level 2) in patients with osteoporosis. ■ Raloxifene reduces vertebral fractures and also reduces risk of oestrogen-receptor-positive breast cancer (level 1). ■ Oestrogen replacement reduces fracture risk in postmenopausal women (level 1) but benefit may be outweighed by risk of venous thromboembolism and stroke (and breast cancer with combined HRT). ■ Oral bisphosphonates prevent glucocorticoid-induced bone loss (level 2). ■ Falls-prevention strategies reduce falls in high-risk patients (level 2). ■ tebral fractures (25%) compared with those taking placebo.19 Zoledronate was also associated with increases of 6.7% and 4% in lumbar spine and femoral neck BMD, respectively.19 First-dose reactions, including fever, myalgias and www.australiandoctor.com.au arthralgias and headaches, were common (32%) but transient (usually less than three days). Serious AF occurred more frequently in the zoledronate group (1.3% vs 0.5%) but there was no excess risk of stroke. ONJ was reported in one patient in the zoledronate group and in one case in the placebo group. A parallel trial studied 2127 patients after hip fracture and demonstrated that an annual zoledronate infusion was associated with a 28% relative reduction in mortality compared with AD_ 0 4 3 _ _ _ J UL 1 1 _ 0 8 . PDF placebo. 20 Zoledronate (Aclasta) is now registered for use in post-menopausal osteoporosis, or in women or men aged >50 with a prior low trauma hip fracture. At this stage, treatment should be restricted to three annual doses. RANK ligand inhibitors An anti-resorptive drug in late clinical development is denosumab, a monoclonal antibody that binds and inhibits RANK ligand (the osteoblast signal that triggers osteoclast activation [figure 1, page 39]). Phase II evaluation of denosumab showed similar increases in BMD at spine and hip, and suppression of bone resorption markers, compared with alendronate. Future challenges At this point in time, the major obstacle in successful osteoporosis management continues to be getting appropriate patients to start and adhere to available therapies, rather than the effi- Pa ge 1 7 / 3 / 0 8 , cacy of these therapies per se. Modelling suggests that, if all women aged over 60 with osteoporosis were prescribed, and complied with, appropriate treatment, the population burden of fractures could be reduced by as much as 28%. Nevertheless, new strategies are needed for preventing the remaining 72% of fragility fractures. A key deficiency is being able to reliably identify patients with osteopenia who will fracture. Several studies have examined various combinations of clinical risk factors, BMD measurements and markers of bone turnover to find a cost-effective algorithm that identifies patients who would benefit from treatment. One such ‘risk calculator’ has been created by researchers at the Garvan Institute in Sydney, using data from the Dubbo Osteoporosis Epidemiology Study 21 and is available online (see Online resources, below). Utility of this and other risk calculators requires validation in prospective intervention studies. 4 : 0 9 PM Summary and recommendations Osteoporosis is a major public health burden: one in two women, and one in three men, over 60 will have a fracture in their remaining lifetime. ■ Measurement of BMD by DEXA identifies patients at risk of fracture; each standard deviation reduction in femoral neck BMD increases age-adjusted risk of hip fracture about threefold, and the risk of any fracture about twofold. ■ Clinical risk factors (in particular, age and previous fracture, but also maternal fracture, current smoking and glucocorticoid use) also identify patients at risk. ■ A postmenopausal woman (or man over 50) with a fragility fracture will generally be at sufficiently high risk to warrant therapy to prevent further fractures; measurement of BMD in this situation may improve compliance and help monitor therapeutic response. ■ The presence of a vertebral fracture should be considered in patients with progressive height loss and/or chronic back pain. ■ Most hip and peripheral fractures result from a fall; a patient with low bone mass should be assessed for risk of falling, and the patient with frequent falls should ideally have their bone density measured. ■ The timed up-and-go test is a simple screening test for postural instability. ■ Use of systemic corticosteroids is associated with rapid bone loss and increased fracture risk; aromatase inhibitors and GnRH agonists are also associated with osteoporosis. ■ A few simple investigations (serum 25(OH)D, calcium, TSH, transglutaminase IgA antibody) may be appropriate in patients with osteoporosis, to exclude potentially reversible causes; hypogonadism should be routinely excluded in men with low BMD. ■ A range of different therapies that can reduce fracture risk in people with pre-existing fracture or low bone density is available (see Evidence-based practice, below). ■ BMD can be remeasured 12-24 months after starting treatment; progressive fall in BMD should prompt evaluation of adherence to therapy and exclusion of secondary causes of bone loss. ■ Calcium supplementation to achieve daily intake of at least 1000mg is recommended in patients with osteoporosis; vitamin D supplements should be given when the 25(OH)D level is low (<50nmol/L). ■ The risk of ONJ is low in patients taking bisphosphonates for the treatment of osteoporosis (between 1:5000 and 1:100,000 per annum); most cases are associated with dental extraction. Good oral hygiene is essential, and regular dental reviews desirable, to prevent ONJ. ■ References Available on request from julian.mcallan@reedbusiness. com.au Online resources ■ Garvan Institute researchers. Osteoporosis risk calculator: www.garvan.org.au/ promotions/bonefracture-risk ■ WHO Fracture Risk Assessment Tool (FRAX): www.shef.ac.uk/FRAX/ index.htm Author’s case study An unusual cause of osteoporosis A 62-YEAR-old woman was found to have rapid bone loss after discontinuing combined HRT. Menopause had occurred at age 50 and she had then taken oral conjugated oestrogen and medroxyprogesterone acetate for four years until 2002. She had no history of fracture or back pain. Her bone density was first measured in 2000 and showed mild osteopenia of the femoral neck (Tscore –1.40) and normal spine BMD (T-score –0.2). Bone density was remeasured 12 months after stopping HRT; spine and hip BMD had both decreased by 6.8%. She had adequate calcium intake, which had been supplemented with calcium carbonate 1200mg daily for the past five years. She was regularly active. She had had a brief course of oral corticosteroids to treat an exacerbation of asthma five years before, and she was on regular low-dose inhaled corticosteroids. She did not smoke and there was no known family history of osteoporosis. She weighed 65.7kg and had not lost any height over the preceding three years. Physical examination was unremarkable. Her rapid bone loss was above that expected for age, even considering the recent cessation of HRT. Serum calcium and TSH measurements were normal. Serum 25(OH)D was low at 20nmol/L, and IgA tissue transglutaminase antibodies were strongly positive. The patient was referred to a gastroenterologist, and endoscopy and small-bowel biopsy confirmed coeliac disease. Although GI symptoms were not particularly obvious at the time, she did feel noticeably better after starting a gluten-free diet. Bone density was re-measured 12 months later and showed a 10% improvement in spine BMD and 6% improvement in hip BMD. Comment Coeliac disease is diagnosed in about 3% of patients referred to a specialist osteoporosis service. Symptoms may be subtle. Clues to the diagnosis include rapid bone loss and/or unexpectedly low 25(OH)D levels or iron deficiency. Some recovery of bone loss can occur with a gluten-free diet. Any bone loss that had occurred during this patient’s brief course of oral steroid treatment would most probably have recovered within a few months, and inhaled corticosteroid treatment typically has only minor effects on bone density. Add Plavix early and continue long term so ACS patients can enjoy rewarding events. 1 For PBS Information refer to primary advertisement. BEFORE PRESCRIBING PLEASE REVIEW PRODUCT INFORMATION IN THE PRIMARY ADVERTISEMENT IN THIS PUBLICATION. Reference: 1. Plavix Approved Product Information, August 2007. sanofi-aventis australia pty ltd. ABN 31 008 558 807, Talavera Corporate Centre, Building D, 12-24 Talavera Road, Macquarie Park, NSW 2113. Plavix is a registered trademark of sanofi-aventis. AU.CL0.08.05.03 Saatchi & Saatchi Healthcare HSX0364/AD/3 www.australiandoctor.com.au 1 11 July 2008 | Australian Doctor | 43 AD_ 0 4 4 _ _ _ J UL 1 1 _ 0 8 . PDF Pa ge 1 7 / 3 / 0 8 , 2 : 3 7 PM How to treat – osteoporosis GP’s contribution DR ROSS WHITE Beecroft, NSW Case study TED, a 47-year old clerk, was diagnosed with ankylosing spondylitis at age 28. He takes diclofenac when his back pain is severe. He has had two bouts of iritis, the last about four years ago. After a recent fractured wrist, the doctor in the emer- gency department recommended BMD testing with DEXA. The radiologist reported that, because of lumbar syndesmophytes from the ankylosing spondylitis, lumbar BMD was difficult to assess, but the femoral neck BMD T-score was –2.3. After discussion with Ted, a once-weekly bisphosphonate was prescribed. Ted returned after reading the consumer medicine information (CMI), concerned because of the warning in the CMI that patients should see their doctor immediately if blurred vision, pain or redness of the eyes occurred — symptoms that he had with his iritis. more likely to be associated with ocular complications such as conjunctivitis, iritis or uveitis. It is not clear whether these reactions occur more often in patients with a history of iritis. Oral bisphosphonates are rarely reported to be associated with these complications. Questions for the author What is the risk of a bisphosphonate reactivating Ted’s iritis, and is any one bisphosphonate less likely to cause this side effect? IV bisphosphonates are How to Treat Quiz 2. Which TWO statements about investigation of osteoporosis are correct? a) The gold standard for osteoporosis diagnosis remains dual-energy X-ray absorptiometry (DEXA) measurement at spine and hip b) Hypogonadism should be routinely excluded in men with low bone mass c) Potentially treatable secondary causes of osteoporosis include hypothyroidism and primary hypoparathyroidism d) A single baseline measurement of bone turnover markers is highly predictive of individual fracture risk 3. Joan’s bone density measured by DEXA shows osteoporosis of the hip (T-score –2.6) and osteopenia of the spine (T-score –2.0). Simple screening reveals no secondary cause of her osteoporosis. You advise Joan that specific therapy for osteoporosis is recommended and discuss the options. Which TWO statements about oral bisphosphonate therapy are correct? General questions for the author For people with chronic autoimmune diseases stabilised on immunosuppres- sants, not on regular steroids and with a normal initial BMD (and no history of fracture), how often should BMD be measured? There are no clear data to guide this decision, but I would consider remeasuring BMD once more in two years in a postmenopausal woman (or man older than 50) and, if stable, then reassuring the patient that fracture risk is low, providing the inflammatory activity of the underlying disease is well controlled. In younger patients I would reassure and not repeat BMD unless corticosteroid treatment is required. INSTRUCTIONS Complete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points. We no longer accept quizzes by post or fax. The mark required to obtain points is 80%. Please note that some questions have more than one correct answer. Osteoporosis — 11 July 2008 1. Joan, 59, asks you if she should have a bone mineral density (BMD) test. Further history reveals she fractured her wrist four years ago when she slipped and fell. Which TWO statements about risk of osteoporosis and fractures are correct? a) Each standard deviation reduction in femoral neck BMD increases age-adjusted risk of vertebral fracture about threefold, and the risk of any fracture about twofold b) Important clinical risk factors for osteoporosis include low body weight, maternal history of hip fracture, smoking and inability to stand up from a chair without using arms c) A history of falling in the previous 12 months has been shown to be an independent risk for fracture d) Use of systemic corticosteroids is associated with bone loss but only if taken in doses of at least 10mg prednisone daily for longer than six months If Ted declines bisphosphonate therapy, which other measures should be advised to minimise progression of the osteopenia? Ted’s serum testosterone should be measured and androgen replacement therapy might be considered if he were hypogonadal. Similarly, Ted’s serum 25(OH)D should be measured and replaced if low (<70nmol/L). Calcium supplements should be given so that Ted’s total daily calcium intake is 1000mg. Ted should be encouraged to keep physically active. Specific physical therapy intervention for his ankylosing spondylitis may help prevent deformity. Control of any inflammatory component of his disease may also help prevent ongoing bone loss. ONLINE ONLY www.australiandoctor.com.au/cpd/ for immediate feedback a) Oral bisphosponates are potent stimulators of bone formation and, to a lesser degree, inhibit bone resorption b) Alendronate and risedronate reduce vertebral and non-vertebral fractures in patients with osteoporosis c) Oral bisphosphonates prevent glucocorticoid-induced bone loss d) Although a weaker agent than the other two oral bisphosphonates, etidronate has been shown to prevent both vertebral and nonvertebral fractures 4. Which THREE statements about other agents for the treatment of osteoporosis are correct? a) Raloxifene reduces vertebral fractures and also reduces risk of oestrogen-receptorpositive breast cancer b) Oestrogen replacement reduces fracture risk in postmenopausal women but benefit may be outweighed by risk of venous thromboembolism and stroke (and breast cancer with combined HRT) c) Strontium ranelate reduces vertebral and non-vertebral fractures in postmenopausal women with osteoporosis d) Strontium has been shown to be effective in patients who have been previously treated with bisphosphonates 5. Which TWO statements about nonpharmacological management of osteoporosis are correct? a) Resistance training or regular walking produces a small increase in spinal BMD, without any consistent effect on hip BMD b) Resistance training or regular walking has been shown to reduce rates of vertebral fractures but not non-vertebral fractures c) Specific programs for muscle strengthening and balance training have been shown to reduce fracture rates in high-risk groups d) Hip protectors have been shown in some studies to reduce hip fractures in patients at high risk of falls 6. Which TWO statements about calcium and vitamin D and osteoporosis are correct? a) Dietary intake of 1200mg of calcium per day (equivalent to three or more servings of dairy products) is generally recommended b) A recent meta-analysis showed that calcium supplementation prevented menopausal bone loss, with a trend towards fewer vertebral and non-vertebral fractures c) Vitamin D supplementation with cholecalciferol is recommended to achieve a target serum 25-hydroxyvitamin D level of at least 50nmol/L d) Studies have consistently shown that vitamin D supplementation reduces the risk of both vertebral and non-vertebral fractures, regardless of patients’ baseline 25-hydroxyvitamin D levels 7. Regina, 62, has been taking an oral bisphosphonate for two years. Follow-up shows a progressive fall in BMD. Which THREE statements about non-response to therapy are correct? a) It is important to check that Regina has been taking her bisphosphonate correctly b) Regina should be re-assessed regarding secondary causes of accelerated bone loss c) Changing to another anti-osteoporosis therapy might be considered d) Adding a second anti-resorptive therapy will additively reduce her fracture risk 8. Martha, 72, has been treated for osteoporosis with alendronate for the past seven years. Recent DEXA shows stable BMD measurements of hip (T-score – 2.5) and spine (T-score – 2.1) for the past 12 months. Martha says she heard the medication should be stopped after seven years. Which TWO statements about duration of therapy are correct? a) Data from the Fracture Intervention Trial Long-term Extension Trial showed that women who stopped alendronate after five years had a significant decrease in hip BMD within 1-2 years b) Data from the Fracture Intervention Trial Long-term Extension Trial showed that continuing alendronate beyond five years resulted in fewer vertebral and non-vertebral fractures c) There was no evidence in the Fracture Intervention Trial Long-term Extension Trial that bone remodelling was over-suppressed even after 10 years of alendronate therapy d) The alendronate data regarding skeletal retention time can be extrapolated to both risedronate and etidronate 9. Which THREE statements about osteonecrosis of the jaw (ONJ) and bisphosphonate therapy are correct? a) Bisphosphonate-associated ONJ is confirmed when an area of exposed bone in the maxillofacial region does not heal within three months b) The risk of ONJ in patients taking bisphosphonates for the treatment of osteoporosis is low (between 1:5000 and 1:100,000 per annum) c) Most cases of ONJ are associated with dental extraction d) Patients must be informed about the risk of ONJ before starting a bisphosphonate, and advised to inform their dentist of the treatment 10. Which TWO statements about new therapies and future challenges for osteoporosis are correct? a) Parathyroid hormone (PTH) therapy (teriparatide) should be limited to patients at high risk of osteoporotic fracture b) PTH therapy for osteoporosis can be used for up to five years c) Teriparatide should be avoided in patients who have Paget’s disease of bone, or who have had previous chest wall radiotherapy d) Modelling suggests that if all women over 60 with osteoporosis were treated appropriately, population burden of fractures could be reduced by 5% CPD QUIZ UPDATE The RACGP now requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the 2008-10 triennium. You can complete this online along with the quiz at www.australiandoctor.com.au. Because this is a requirement, we are no longer able to accept the quiz by post or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online. HOW TO TREAT Editor: Dr Wendy Morgan Co-ordinator: Julian McAllan Quiz: Dr Wendy Morgan NEXT WEEK Despite otitis media being documented since the start of recorded history, no international consensus on best practice management has emerged, and Australian Aboriginal children remain the world’s most vulnerable children in terms of prevalence and severity. The next How to Treat presents the latest on treating otitis media in children. The author is Dr Hasantha Gunasekera, clinical research fellow and general paediatrician, The Children’s Hospital at Westmead; and clinical lecturer, University of Sydney, NSW. 44 | Australian Doctor | 11 July 2008 www.australiandoctor.com.au