Abstract
Ginkgo biloba no better than placebo in preventing dementia
Such benefits are believed to be dependent on the antioxidant effect of the flavanoids found in the leaves of the G. biloba tree, one of the world's oldest living tree species, whose age can extend to a thousand years or more. So, with an antioxidant effect and anecdotal evidence suggesting improvements in cognitive function and mood disorders (especially depression), G. biloba had become widely used as a medication in dementia, and even in Alzheimer's disease.
However, the Ginkgo Evaluation of Memory (GEM) study of 2009, a randomized trial in more than 3000 elderly subjects, found that G. biloba was no more effective than placebo in reducing the rate of dementia and Alzheimer's disease.1,2 And an editorial accompanying the report in JAMA was less than enthusiastic: ‘Preclinical scientific reports exude promise but generally have not identified the relevant active molecules of this biochemically complex extract, and the preclinical promise has not translated to clinical research benefits.’
Now, these doubts over the efficacy of G. biloba have been doubly underlined in a further study of its role in Alzheimer's disease, and yet again there is no evidence of benefit over placebo. 3 The study, which was the first major trial of G. biloba to be conducted outside the USA, assessed the effect of a twice-daily dose of 120 mg G. biloba extract on the risk of Alzheimer's disease. The study took place over five years and involved 2854 French people over the age of 70, who had presented to their family doctor with memory complaints.
By five years, 61 participants in the ginkgo group had been diagnosed with probable Alzheimer's disease (1.2 cases per 100 person-years) and 73 participants in the placebo group, a statistically non-significant difference. Incidence of serious adverse events (death, stroke) was also much the same between the two groups.
Lead author Professor Bruno Vellas of the Hôpital Casselardit in Toulouse, France, said in a press statement: ‘While our trial appears to have shown that regular use of G. biloba does not protect elderly patients from progression to Alzheimer's disease, more studies are needed on long-term exposure. The fact that prevalence of this debilitating disorder is expected to quadruple by 2050 suggests that research into preventive therapies for this disease needs to receive urgent attention.’
An editorial commenting on the study in the Lancet Neurology proposed that, if G. biloba were a drug and not marketed as a food supplement, ‘clinical testing for efficacy against Alzheimer's disease and cognitive impairment would have ended long ago’. ‘Nevertheless,’ the editorial continued, ‘it would be unfortunate if users of G. biloba … are led to believe that the extract prevents the dementia. Some users will rationalize that, in the absence of effective treatments, G. biloba could still possibly help and, appearing safe, will not harm them. Other users of G. biloba, however, might now consider letting it go.’
Treatment failure in osteoporosis
The figures come from the International Osteoporosis Foundation (IOF) and serve as the prelude to a new position paper on treatment failure in osteoporosis. 1 The report outlines how the response to treatment in patients who have been complying with treatment for at least six months can be assessed on the basis of the number of fractures, changes in bone mineral density (BMD) and bone turnover markers.
According to Professor Cyrus Cooper, chair of the IOF's Committee of Scientific Advisers, the management of a patient who sustains a fracture while on treatment, is ‘an increasingly frequent clinical conundrum’ but need not always be a sign of treatment failure. Thus, the objective of the new guidance, he added, ‘was to provide a clinical pathway whereby physicians can ascertain whether a patient has failed to respond adequately to an anti-osteoporosis treatment. As a result, doctors will be able to define treatment failure more effectively, and take appropriate action.’
Judging treatment failure on the number of fractures (and emphasizing that treatment aims to reduce, not eliminate fracture risk), the guidelines ‘recommend that the occurrence of a second fragility fracture be used to infer that treatment has failed’. They note by way of explanation that in clinical trials ‘a second or third fracture during therapy is generally markedly reduced by 80-90% in comparison to the placebo-treated’.
On the definition of treatment failure according to measurements of BMD, the report notes that ‘rates of bone loss or gain are most often modest compared to the errors incurred in the measurement of BMD’. Thus, while the rate of loss in BMD at the femoral neck in untreated women with postmenopausal osteoporosis is typically 1-2% per year, this is also the same rate as the precision error of the measurement of BMD at the same site. So the change in BMD which ‘confidently’ predicts fracture risk has been termed the ‘least significant change’, which depends upon the precision error of the technique applied and the confidence needed to assume a change. Decreases in BMD greater than the least significant change are rarely found in patients who adhere to therapy.
On markers of bone turnover, the IOF has recommended that serum C-telopeptide of type I collagen (βCTX) and serum procollagen type 1 N-terminal propeptide (PINP) are considered as reference markers. The new report thus recommends that a decrease in βCTX and PINP less than the least significant change at 95% confidence is considered as an indicator of failure to respond to treatment with anti-resorptive agents and that an increase in PINP less than the least significant change at 95% confidence is considered as an indicator of failure with parathyroid hormone peptides.
The guidance thus recommends that treatment should be changed in the following cases: with two or more incident fragility fractures; one incident fracture and elevated serum βCTX or PINP at baseline with no significant reduction during treatment, a significant decrease in BMD, or both; and no significant decrease in serum βCTX or PINP and a significant decrease in BMD.
As for treatment changes, the IOF notes that a weaker antiresorptive is reasonably replaced by a more potent drug of the same class, an oral drug is reasonably replaceable by an injected drug, and a strong antiresorptive is reasonably replaceable by an anabolic agent.
Fifteen medical societies agree on hormone therapy statement
The major points of agreement among the societies include the conclusions that:
Hormone therapy is an acceptable option for the relatively young (up to age 59 or within ten years of menopause) and healthy women who are bothered by moderate to severe menopausal symptoms. If women have only vaginal dryness or discomfort with intercourse, the preferred treatments are low doses of vaginal estrogen. Women who still have a uterus need to take a progestogen (progesterone or a similar product) along with the estrogen to prevent cancer of the uterus. Women who have had their uterus removed can take estrogen alone. Both estrogen alone and combined therapy increase the risk of venous thrombosis and pulmonary embolism, similar to that of oral and transdermal contraceptives and vaginal rings. Although the risks of blood clots and stroke increase with either type of hormone therapy, the risk is rare in women ages 50-59. An increased risk in breast cancer is seen with five or more years of continuous estrogen with progestogen therapy, possibly earlier. The risk decreases after hormone therapy is stopped.
The first WHI decade, says the statement, has seen ‘a complete abandonment of hormone therapy in some settings accompanied by reluctance to treat women who would benefit from relief of their symptoms’. As a result, some women have sought unproven alternative therapies.
‘We believe that too many symptomatic women are missing out on the proven benefits of hormone therapy because of the results of the WHI, which studied the long-term use of hormones to prevent chronic disease, were misinterpreted for women with menopausal symptoms,’ said Margery Gass, Executive Director for NAMS. ‘Women and clinicians are frustrated by the many conflicting recommendations. That's why we initiated this effort to bring these notable medical organizations together in agreement regarding the use of hormone therapy.’
Meanwhile - and avoiding any of the controversies of hormone therapy - the latest report from the WHI has concluded that weight loss as part of a healthy lifestyle may help eliminate vasomotor symptoms among postmenopausal women. 2 The findings come from the WHI Dietary Modification trial, which enrolled a diverse group of 48,835 postmenopausal women between 1993 and 1998 at 40 US centres. Results show that symptomatic women not taking hormones and on a diet low in fat and high in whole grains, fruit and vegetables, and who lost weight (10 or more pounds or 10 or more percent of their baseline body weight) were more likely to reduce or eliminate hot flushes and night sweats after one year than those in a control group who maintained their weight.
HRT reduces cardiovascular endpoints in ten-year trial
Those on HRT were given two formulations: triphasic estradiol and norethisterone acetate for those with an intact uterus, and daily estradiol (2 mg) if hysterectomized. Treatment was stopped after 11 years or so, mainly because of the fall-out from the Women's Health Initiative (WHI), but participants were followed-up for the composite cardiovascular endpoints for up to 16 years.
After 10 years of intervention, 16 women in the treatment group had suffered a cardiovascular event compared with 33 in the control group (HR 0.48, 95% CI 0.26-0.87). The authors also found that this reduction in cardiovascular events was not associated with an increase in any cancer (36 in treated group v 39 in control group).
Those commenting on the results pointed out that this was the first randomized trial to ‘substantiate’ the ‘timing hypothesis’ of the WHI's secondary analysis for coronary heart disease. 2 John Stevenson, speaking on behalf of the British Menopause Society to the Daily Mail, urged the UK authorities to update guidance on HRT (that HRT should be offered only to women with severe menopausal symptoms for the shortest duration). ‘The strength of the Danish study,’ said Stevenson ‘is its long duration’.
Britain's Department of Health was, not surprisingly, less outspoken, but an official did remind journalists that a Clinical Guideline on the menopause had been commissioned from the National Institute for Health and Clinical Excellence (NICE) and was scheduled for publication in July 2015. The scoping process, according to NICE, is set to begin in May 2013.