Reducing vertebral fractures

Natalya Anderson reviews a study which found that the risk of vertebral fracture in young postmenopausal women could be reduced with strontium ranelate treatment

Strontium ranelate may reduce the risk of vertebral fracture in young postmenopausal women with severe osteoporosis, according to study results published by the Annals of the Rheumatic Diseases. (1)
“Vertebral fractures represent 27 per cent of all osteoporotic fractures coming to clinical attention and their deleterious consequences on health are now well recognised,” the study authors wrote. “Clinical vertebral fractures increase mortality in the elderly. Prevalent vertebral fractures increase the risk of subsequent vertebral and non-vertebral fractures, as well as the risk of hip fracture with at least a twofold excess.
“The risk of further fracturing has been shown to be higher among younger people compared with the elderly. Few data are available in clinical trials in patients younger than 65 years.”
In order to evaluate the efficacy of strontium ranelate as a method of reducing the risk of vertebral fracture in postmenopausal women with osteoporosis and a prevalent vertebral fracture, Prof C Roux of the University Paris-Descartes, Paris and colleagues used data from the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial.
A total of 1,649 postmenopausal patients aged 50 years or more were enrolled in that randomised, double blind, placebo-controlled clinical trial. Inclusion criteria were presence of at least one vertebral fracture and a lumbar spine bone mineral density (BMD) of 0.840 g/cm or less.
“The vertebral fracture incidence was the main efficacy criterion of the study,” the authors explained. “The assessment of this criterion was performed over three years (main statistical analysis) showing an early and sustained significant reduction in the vertebral fracture risk by 49 per cent over the first year and by 41 per cent over three years.”
Reduction
The authors further explained that, over a four-year period, a pre-planned analysis was performed. It demonstrated a reduction of 33 per cent (relative risk (RR) 0.67; 95 per cent confidence interval (CI) 0.55 to 0.81, p<0.001) in the risk of sustaining a vertebral fracture over four years.
Prof Roux and colleagues selected the subset of women aged from 50 to 65 years old from the SOTI for their post-hoc analysis.
The women were blinded to treatment and randomised to either 2g per day of strontium ranelate or placebo. Patients were administered calcium and vitamin D supplements at lunchtime each day throughout the study.
In order to assess outcome, the team obtained radiographs of the spine at baseline annually and assessed them centrally.
“A semi-quantitative visual assessment of each vertebrae from T4 to L4 was performed by the same reader throughout the study, using the semi-quantitative grading scale as previously described by Genant et al.,” the study authors explained of their use of other studies for reference in their work. “BMD at the lumbar spine and proximal femur was measured by dual-energy x-ray absorptiometry at baseline and at six-month intervals.
“For patient diagnostic categorisation, lumbar spine and femoral neck BMD T-scores were calculated using a reference population previously described. Femoral neck BMD T-scores were also recalculated using the National Health and Nutrition Examination Survey III (NHANES III) reference.”
The primary endpoint of the study was the incidence in patients experiencing a new vertebral fracture. The team estimated this according to the Kaplan–Meier method. An adjusted Cox model was also used to compare groups and to estimate the RR of experiencing a new vertebral fracture and its 95 per cent CI.
The incidence of non-vertebral fractures and spine and hip BMD changes were secondary endpoints. The adjusted Cox model considered the treatment effects, as well as country, L2/L4 BMD at baseline and prevalent vertebral fractures as covariates.
“Early osteoporotic fractures have a great impact on disease progression, the first fracture being a major risk factor for further fractures,” the study authors explained.
Results in depth
Drawing on data from the SOTI study, Prof Roux’s team found that 385 of the original 1649 women studied fell within the 50-to-65 years age range. Of those, 353 met inclusion criteria for the strontium ranelate study. The team indicates that there was not a statistically significant difference between the 2g/day strontium ranelate group and the placebo group (N = 168 and N = 185, respectively).
The risk of vertebral fracture was reduced by 43 per cent in the strontium ranelate group over a three-year period (RR 0.57; 95 per cent CI 0.36 to 0.92, p=0.019).
Compared with placebo (29.6 per cent), an incidence of vertebral fractures of 16.9 per cent was found in the strontium ranelate group. Over a four-year period of treatment with strontium ranelate, the risk reduction efficacy against vertebral fractures was sustained with a reduction rate of 35 per cent (RR 0.65, 95 per cent CI 0.42 to 0.99, p=0.049) and an incidence of vertebral fractures of 21.6 per cent, compared to 32.8 per cent in the placebo group.
Although reportedly not statistically significant, a trend towards a reduction in the risk of vertebral fracture over the first year was noted by the authors. The team defined symptomatic vertebral fractures as radiological fractures plus concomitant back pain or a decrease in body height by at least 1cm.
They found significant effect of strontium ranelate compared with placebo in this area as well. Over three years, a 54 per cent reduction in the risk of symptomatic vertebral fracture was noted (RR 0.46; 95 per cent CI 0.22 to 0.97, p=0.033). This was sustained over four years with a 52 per cent reduction (RR 0.48; 95 per cent CI 0.24 to 0.95, p=0.030).
The team found no difference in the incidence of non-vertebral fractures between groups over a four-year period, with 14.5 per cent in the strontium ranelate group and 14.6 per cent in the placebo group.
From baseline, over a three-year period in the treated group, the BMD mean change at spine sites was 11.8 per cent and 4.5 per cent at hip sites. In the placebo group, results were -2.8 per cent at spine sites and -3.0 per cent at hip sites. A mean increase in BMD of 15.8 per cent at spine and 7.1 per cent at hip was further noted in the strontium ranelate group over four years. In the placebo group, these changes were lower (-2.4 per cent at spine and -2.8 per cent at hip, p<0.001).
Clinical, serious, drug-related adverse effects included nausea, diarrhoea, headache, dermatitis, eczema and venous thromboembolism events, but there was no clinical significance in incidents of these in either groups over the four-year study period.
There was no observed case of pulmonary embolism or hypersensitive reaction in the study population; the overall safety profile was very similar to that outlined for the entire SOTI study population over three and four years.
Discussion
The authors maintain that treatment with 2g/day of strontium ranelate decreased the risk of vertebral fractures in women aged 50 to 65 with severe osteoporosis over a four-year period. They stressed that while incidence of fracture increases with age, women in this younger postmenopausal category do experience fractures.
“This highlights the importance of diagnosing and treating appropriately as soon as possible this youngest postmenopausal population at high further risk,” they explain. “In the present study, the incidence of vertebral and nonvertebral fractures over four years in the placebo group was high (32.8 per cent and 14.6 per cent, respectively).
“This demonstrates in this population aged less than 65 years that the presence of prevalent fractures leads to a dramatic increase in the overall fracture risk, not limited to vertebral fractures,” the authors continued. “Over the first year, the incidence of vertebral fractures was 8.3 per cent, which reinforces the indication of a prompt and effective treatment in this population.”
The authors suggest that the presence of strontium in bone might lend to overestimation of BMD measurement, due to the fact that it is a heavier element than calcium.
“However, a strong association has been demonstrated for strontium ranelate-treated patients between the increase in total hip and/or femoral neck BMD and the subsequent decrease in fracture incidence,” they offer, in reference to their examination of previous studies.
Oestrogen
“Few studies are available with other antiosteoporotic drugs in women aged 50 to 65 years. The Women’s Health Initiative showed that treatment with oestrogens alone, or oestrogen plus progestin, reduces the incidence of fractures compared with control, but the study was conducted in healthy postmenopausal women.
Young age was not a significant factor in affecting the efficacy of raloxifene, in a population of postmenopausal women with a prevalence of 37 per cent of vertebral fractures.
“Several studies have shown the absence of effect of age on response to antiosteoporotic treatment, but this point was assessed either in patients older than 65 years or in a population with a mean age of 70 years.
“Our study indicates a significant efficacy of strontium ranelate in reducing the risk of subsequent vertebral fractures in young postmenopausal women with severe osteoporosis.
“These data, together with previous reports, confirm the efficacy of this antiosteoporotic drug at all ages,” the authors concluded.
Reference: (1) C Roux, J Fechtenbaum, S Kolta, G Isaia, J B Cannata Andia and J-P Devogelaer; Ann Rheum Dis 2008;67;1736-1738; originally published online 19 Aug 2008; doi:10.1136/ard.2008.094516.