HIGHLIGHTS OF THE MEETING
The morning session of Friday April 11 started with the communication of Professor Compston who reminded us that in many countries only a minority of patients with osteoporotic fractures receive appropriate treatment despite the existence of evidence-based guidelines (PL5). She also told us that a range of options is currently available for the prevention of osteoporotic fractures in postmenopausal women and some of these are also approved for fracture prevention in men and in individuals treated with glucocorticoids. However, there is an urgent need more fully to translate current knowledge into clinical practice.
Assessment of risk factors for fractures
Fractures are a major cause of pain and disability, and are associated with a high mortality rate, particularly in elderly people who have suffered hip fractures. Bruyere et al, from Belgium, presented the results of their research showing that, in 1933 women followed for 3 years, the highest decrease, over time, in femoral neck BMD was associated with the highest hip fracture incidence (OC34). In contrast to women, few studies concern the risk factor for hip fracture in men. Dilsen et al. showed that, after multivariate analysis, reversible risk factors such as BMI, exercise, exposure to sunlight, consumption of alcohol, tea and tobacco remained independent risk factors accounting for 54% of hip fractures (OC42). An important point has also been raised by Professor Cooper who showed that concomitant use of bisphosphonate and acid suppressant medication was associated with an increased risk of fracture compared to bisphosphonate use alone (OC37). There was some evidence of a dose-dependent effect, with fracture risk increasing with higher doses. He concluded that given the frequency of co-prescription of acid-suppressive medication and bisphosphonates, this issue requires further attention.
Clinical management of osteoporosis
Clinical management of osteoporosis was also taken into account during this second session of the meeting. For example, it has been shown in a post-hoc analysis that first infusions of zoledronic acid given as early as 2 weeks after hip fracture repair reduce clinical fractures and mortality (OC26). In another posthoc analysis, Professor Devogelaer has shown that strontium ranelate is an efficient and safe treatment against vertebral and clinical vertebral fractures in postmenopausal women with severe osteoporosis and aged less than 65 years (OC27).
The results obtained with bazedoxifene, a novel selective estrogen receptor modulator (SERM), are also of interest (OC40). The authors reported the results of a 3-year, Phase III study that evaluated the effect of bazedoxifene therapy on the incidence of new vertebral fracture compared with placebo and raloxifene in postmenopausal women with osteoporosis. The authors concluded that bazedoxifene treatment significantly reduced the risk of new vertebral fractures compared to placebo, and in subjects at higher risk for fractures, was associated with a significant reduction in non vertebral fractures.
Vitamin D and falls
It has already been shown, in the previous ECCEO meetings, that inadequate vitamin D level is associated with secondary hyperparathyroidism, increased bone turnover and bone loss, which increase fracture risk. The result of a 3-year population- based randomized trial that hypothesized that vitamin D and calcium supplementation decreases falls in ambulatory postmenopausal women (OC 32) was presented yesterday. The authors showed that there were 432 falls in 180 women in vitamin-D and calcium supplementation group and 540 falls in 209 women in the control group [risk ratio (RR) 0.93, 95% CI 0.82- 1.04]. However, multiple falls (2 or more) were significantly reduced in the intervention group compared to the control group. The authors concluded that postmenopausal women could benefit from calcium and vitamin D supplementation.
Phase I and II studies
Yesterday, results of phase I or II trials have also been presented. For example, it has been shown that sclerostin-neutralizing monoclonal antibody pharmacokinetics following administration to healthy men or postmenopausal women were nonlinear with dose, as observed with other monoclonal antibody (OC35). Single doses of sclerostin-neutralizing monoclonal antibody resulted in significant increases in bone formation markers, decreases in serum CTX-I and increases in BMD. Sclerostin- neutralizing monoclonal antibody was well tolerated following single dose administration.
The results of 48 months of continuous denosumab treatment and the effects of denosumab discontinuation and retreatment on BMD and bone turnover makers were also presented yesterday (OC36). Interestingly, RANKL inhibition with denosumab increased BMD and suppressed bone turnover markers over 48 months. These effects were reversed with discontinuation. Retreatment increased BMD and suppressed bone turnover markers to levels observed before discontinuation.
Adherence and persistance
It is well known that adherence to current therapeutic regimens remains suboptimal and that poor compliance and non-persistence are significantly associated with greater likelihood of hip fracture and higher direct medical cost for hip fracture. Almost all the studies concluded that strategies should be developed to improve both compliance and adherence in order to achieve better therapeutic outcomes in osteoporosis treatment. Improving adherence with osteoporosis therapies could have an implicit economic value in addition to the clinical value of reduced fractures. Cotté et al presented yesterday a model that was developed to estimate the economic impact of persistence improvement, especially when due to a less dosing frequency of biphosphonate (i.e. daily to weekly and weekly to monthly) (OC28). This Markov model followed over ten years the overall population of women diagnosed for postmenopausal osteoporosis in France.
The authors showed that over the 10-year period and compared to the no treatment strategy, 113, 158 and 183 fractures per thousand patients were avoided with daily, weekly and monthly bisphosphonates respectively. Compared to a daily treatment, the gain in persistence represented a decrease in fracture costs of 215 and 455 per patient with weekly and monthly biphosphonate respectively. The authors concluded that the model predictions indicated that incidences and thus, costs of fractures were decreasing with persistence improvement. However, those gains were globally diminished by the drug cost increase due to better persistence.
Clinical management of osteoarthritis
On Friday April 11, some communications dealt with the management of osteoarthritis. It started with the plenary lecture of Professor Guillemin who reminded us that increasing with aging of the population in Western countries, the burden of osteoarthritis relies on its prevalence, its degree of severity, and its social impact. Cost of illness studies in osteoarthritis underscores a large variability across countries. Similarly, large variations have been observed internationally in hip replacement rate. He also pointed out that the benefit of early treatment and later interventions should be assessed in cost-effectiveness studies, conducted for various therapies proposed, like exercise, education or water-based programme. At last, he emphasized the fact that among the consequences of treatments at younger ages, it is necessary to consider employability and work site intervention.
In relation with the plenary lecture, Rother et al reported data of a 3-month extension of a 12-week study, being the first trial providing 24-week safety and efficacy data for a locally applied NSAID (OC29). The local application NSAID was Diractin, a new, carrier-based NSAID formulation for local application that have previously shown efficacy comparable to oral celecoxib in a 6-week study of knee osteoarthritis. The results presented yesterday showed that epicutaneous osteoarthritis treatment with ketoprofen in Diractin maintained efficacy for a treatment period of up to 24 weeks. Patients profited from switching from placebo to Diractin even after 12 weeks of treatment.
At last, the results of a study aiming at assessing the analgesic efficacy and safety of naproxcinod 375 mg bid and 750 mg bid as compared to placebo and naproxen 500 mg bid were presented (OC38). Naproxcinod, the first representative of the CINOD (COX-Inhibiting Nitric Oxide Donor) class of anti-inflammatory analgesic agents, exerts its effects by a dual mechanism of action: inhibiting both COX-1 & COX-2 enzymes and releasing nitric oxide. The results showed that naproxcinod at both doses demonstrated superior efficacy to placebo on relieving the signs and symptoms of knee osteoarthrits. The effect of naproxcinod on systolic blood pressure was comparable to that seen with placebo, favourable compared to naproxen and sustained for 13 weeks. However, these first phase 3 findings deserve to be confirmed in planned and ongoing clinical trials.