( PDF ) Rev Osteoporos Metab Miner. 2010; 2 (1) suplemento: 27-30

Del Pino Montes J, Gómez Castro S, Carpio Pérez A, Montilla Morales CA
Servicio de Reumatología – Hospital Universitario de Salamanca

 

IntroductionStrontium ranelate is a therapeutic agent intro-duced in recent years for the treatment of osteo-porosis with dual action on bone metabolism. The conditions which need to be satisfied by any drug for its use in the treatment of osteoporosis include safety and efficacy in the prevention of fractures. The evidence in relation to strontium ranelate come principally from the two multi-centric, clinical reference trials in phase 3, the SOTI (Spinal Osteoporosis Therapeutic Intervention)1 study and the TROPOS (Treatment of Peripheral Osteoporosis) study2. The first was designed to access the preventative effect on vertebral fractures, whilst the second had as an objective the evaluation of non-vertebral fractures. These are the anti-osteoporotic drug trials which give results over the longest term, 4 years for the first and 5 for the second3. Additional data comes from other older trials in phase 2, the STRATOS (Strontium Ranelate for Treatment of Osteoporosis) trial4 and the PREVOS (Prevention of Osteoporosis) trial5 which had the objective of assessing the effect on bone mass and biochemical markers for bone turnover in patients with established vertebral fractures in the first, and in the second, in women in the first years of menopause.

Safety of strontium ranelate

The SOTI and TROPOS studies included 3,352 women who received treatment with strontium ranelate, of whom 2,315 followed the treatment for at least 36 months. The adverse effects detected in these patients were no different from those observed in the group treated with placebos, and in general, were moderate and transitory. The most frequent were related to the digestive system: nausea (6.6% and 4.3% respectively) and diarrhoea (6.5% and 4.6 % respectively). Both adverse effects diminished after the first 3 months of treatment. In terms of the biochemistry, a small reduction in the concentration of blood calcium and an increase in blood phosphate was observed, neither clinically significant1,2. Table 1 includes the adverse effects most frequently detected in these two trials. In patients older than 80 years the most frequent adverse effect was headache, 3.3% in the group with ranelate as opposed to 1.7% in the control group with a confidence interval of 95%: 0.01-3.3 followed by the adverse effects of the digestive system6.
One of the controversial problems is venous thrombosis. Although taken separately, in each of the studies no increase in thromboembolic disease was found, in a subsequent analysis of aggregated data, and increase was found. A meta-analysis of the two reference studies in phase 3 found that after 5 years of treatment with strontium ranelate the annual incidence of cases of thromboembolic disease was 0.9%, as opposed to 0.6% in the placebo group, with a relative risk (RR) or 1.4, CI 95%; 1.0-2.07. The cause of this effect is unknown and does not have a reasonable scientific explanation. As a consequence, the technical information for the product includes the recommendation that precautions should be taken with patients with increased risk of thromboembolic disease, especially in cases with previous history of venous thromboembolism. Recently, this effect has been investigated using the classic general medicine research database of the United Kingdom (General Practice Research Database), which includes 1,754 patients being treated with strontium ranelate, and the authors found that there had been a significant increase in episodes of deep vein thrombosis8. In another study with the same GPRD database, an increase in risk of suffering deep vein thrombosis was observed in women with osteoporosis as opposed to non-osteoporotic women. The annual incidence was 5.6 in the first group of women as opposed to 3.2 per 1,000 in the second (RR 1.75; 95% CI 1.09-1.84). In the osteoporotic women there were no differences between those treated with alendronate or ranelate, and those not treated9.
Notable was the description of the few cases of DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms) in patients in treatment with strontium ranelate. This is a reaction of hypersensitivity which is very infrequent and which appears after 3-6 weeks of treatment, consisting of fever, exanthema, eosinophilia and systemic affectation such as adenopathy, hepatitis, nephritis, etc10,11. The EMEA has assessed the data and recommends that patients should be informed that they should cease treatment when exanthema appears and seek medical attention. Exanthema is an adverse reaction described both in treated patients and in those in the placebo group, and it should be taken into account that not all exanthemas have sufficient manifestations, or are sufficiently serious to be considered as symptoms of DRESS.
Although there are no data of patients with renal insufficiency, it is thought that strontium ranelate can increase its concentration in cases of reduced renal function and the consequent decrease in its elimination by the kidney. In this situation the strontium may accumulate to excess when the clearance of creatinin is lower than 30 mL/min. Its effect is not known during pregnancy, lactation or in children, due to lack of information.

Results of using strontium ranelate

There is much data related to the treatment of osteoporosis with strontium ranelate. That the treatment is considered efficacious is due to its capacity to reduce the frequency of osteoporotic fractures. The known data are related to vertebral and non-vertebral factures. In addition, there are data concerning surrogates of fractures, such as BMD and histomorphometry. We will present a summary of these results, given that these data are commented on in greater detail in another chapter of this monograph.

Prevention of vertebral fractures

The first great reference study, called, in its abbreviated form, SOTI, included 1,649 women over 50 years of age, whose average age was 69 years, having been postmenopausal for a period of at least 5 years. They were randomly selected into two groups, one treated with 2 mg of strontium ranelate and the other with a placebo. In addition both groups received calcium and vitamin D supplements to guarantee the provision of the recommended daily dose. All the women had at least one earlier vertebral fracture due to their fragility, and a lumbar bone mineral density (BMD) below 0.840 g per cm2 measured by a Hologic densitometer, equivalent to a T-score of -1.9. The assessment of the vertebral fractures was made through Genant’s quantitative morphometric method in lateral X-rays of the lumbar and thoracic spinal column, taken at their inclusion in the trial and annually during the follow up.
A decrease in the frequency of radiographical vertebral fractures was observed of 49% (6.4% as opposed to 12.2% RR 0.51; CI 95%: 0.36-0.74) in the group treated with strontium ranelate at the end of the first year of follow up. In the same period, the risk of symptomatic vertebral fractures was reduced by 52% (3.1% as opposed to 6.4%; RR= 0.48; CI 95%: 0.29-0.80). At the end of the three years of treatment the results were similar. The radiological vertebral fractures were reduced by 41% (20.9% as opposed to 32.8%; RR= 0.59; CI 95%; 0.48-0.73) and the symptomatic fractures by 38% (11.3% as opposed to 17.4%; RR= 0.62; CI 95%: 0.47-0.83). At the end of the fourth year the reduction in risk of radiological fracture was 33% (RR= 0.67; CI 95%: 0.55-0.81; p<0.001)12.
The TROPOS study was designed to assess the efficacy of strontium ranelate in the prevention of non-vertebral fractures, but results were also obtained for vertebral fractures. In 71% of the 5091 women included in this study, x-rays of the spinal column were taken and it was observed that 66.4% of them had earlier fractures, which was a criterion for inclusion in the SOTI study. After 3 years of treatment, a reduction in risk of vertebral fractures of 39% (RR= 0.61; CI 95%: 0.51-0.73) was observed in those women who had been incorporated in the group having treatment with strontium ranelate, there already having been observed after the first year, a reduction of 45% in the risk of fracture (RR= 0.55; CI 95%:0.39-0.77; p<0.001). This reduction affected both those women with an earlier vertebral fracture and those who did not have previous fractures.
A joint analysis was carried out of the results of the third year of both the SOTI and TROPOS studies. 5082 women were evaluated, in whom the risk of vertebral fracture was reduced to 40% (RR= 0.60; CI 95%: 0.65-0.87). The anti-fractural result observed during the first three years was maintained during the extension phase up to the fifth year. In these two last years, a tendency to a reduction in efficacy was observed. However, this fact was not interpreted as a reduction in the anti-fractural effect of the drug, but to the fact of the patients remaining in the study brings with it a loss of randomness in distribution, since those patients remaining in the placebo group are those who have a lower risk of fracture3.
One of the characteristics of the population included in the SOTI and TROPOS studies is the large group of women over 80 years of age who made up over 20% of the total. In a sub-analysis of the results of this group a reduction in risk of fracture of 32% was observed. But the anti-fractural effect is not very different in the remaining age groups, since in the youngest (less than 70 years of age) the reduction was 37%, and 42% in those women between the ages of 70 and 8013. The number of patients it is necessary to treat (NNT) to avoid a vertebral fracture at three years is 1314.
With the objective of seeing if the effect was independent of the risk of fracture in the patients, a sub-analysis was carried out, analysing the efficacy according to the number of earlier vertebral fractures. The main risk to these women was verified in the placebo group, since the incidence of new vertebral fractures increased according to the number of previous fractures, being 40.3% higher in the group with two or more fractures. In the group of patients treated there was a reduction in the risk of new fractures independent of the number of fractures they had before the start of treatment, 25.2% in patients with only one fracture and 40.3% in those who had two or more fractures. The risk of experiencing a first fracture, a second, or more than two fractures was reduced by 48%, 45% and 33% respectively13.
The drug was also efficacious in women with osteopenia, both in those who had a previous fracture, of 41% (RR 0.59; CI 95%: 0.43-0.82), as well as those who did not, of 38% (RR 0.62; CI 95%: 0.44-0.88)6.

Prevention of non-vertebral fracture

The efficacy of treatment with strontium ranelate in the prevention of non-vertebral fractures was investigated in the TROPOS trial, which included, as we have already stated, 5091 women with an average age of 77 years. The criteria for inclusion were to have a BMD in the femoral neck lower than 0.600 g/cm2, which is the equivalent to a T-score of -2.2, and to be older than 74 years or between 70 and 74 years old with at least one of the following risk factors: previous history of fracture, or maternal history of fracture. The patients were randomly chosen to receive 2 g of strontium ranelate or placebo, and received calcium and vitamin D supplements.
All non-vertebral fractures were recorded, with the exception of those not related to osteoporosis: coccyx, cranium, jaw, face, phalangeal and ankle. In the 3 year follow up period, there was a reduction of 16% in all non-vertebral fractures (11.2% as opposed to 12.9%; RR= 0.84; IC 95%: 0.702-0.995: NNT to avoid one fracture was 49). The principal non-vertebral fractures considered were of the hip, wrist, pelvis, sacrum, ribs, sternum, clavicle and humerus. There was a reduction of 19% (8.7% as opposed to 10.4%; RR= 0.81; IC 95%: 0.66-0.98; NNT= 59). The global risk of fracture of the hip was reduced by 15%, but the difference was not significant since the study was not designed with sufficient power to investigate this anti-fractural effect. However, in a sub-group of high risk patients, aged over 74 years and BMD with a T-score lower than -2.3, there was a reduction of 36% in hip fractures (4.3% as opposed to 6.4%; RR= 0.64; IC 95%:0.412-0.997; NNT= 48).
In the period of extension to 5 years, the TROPOS study the efficacy was maintained, with a reduction of 15% in the reduction of non-vertebral fractures (RR= 0.85; IC 95%: 0.73-0.99). The SOTI study was not powerful enough to assess the efficacy in relation to non-vertebral fractures. However, the fractures in 234 women after 3 years were recorded (with an incidence of 15.5% as opposed to 16.8%; RR= 0.90; IC95%: 0.69-1.17). In the study of the aggregated data from the two studies – SOTI and TROPOS – the global reduction in non-vertebral fractures was 15% (11.6% as opposed to 13.1%; RR= 0.85; IC 95%: 0.74-0.99)15. In the SOTI and TROPOS cohort of over 80 years, the reduction in the risk of non-vertebral fracture was 1% (14.2% as opposed to 19.7%; RR= 0.69; IC 95%: 0.52-0.92)6.
As with other chronic diseases, the effect of treatment is related to compliance. In those patient with good compliance with the treatment the risk of fracture reduces to 38% in relation to those patients who are non-compliant16. Compliance in those patients in the TROPOS study was very high at the end of 5 years of follow up, higher than 80%.

Bone mineral density and makers for bone remodeling

Treatment with strontium ranelate increases BMD considerably. After 3 years of treatment the SOTI study noted an increase of 14.4% in the lumbar spinal column and 9.8% in total hip with respect to that observed in the placebo group1. The period of extension of the TROPOS study showed an increased BMD in the lumbar spinal column of 4.9%, 1.8% in the femoral neck, and 2% in the total hip3.
However, this major increase in BMD measured by double energy X-ray absorptiometry (DXA) requires an interpretation due to the physical characteristics of strontium. Its high atomic number attenuates the X-rays more than calcium, which produces an overestimation of the values of BMD. Blake has studied this phenomenon quantitatively and calculates that the artificial component of the density could approximate to 50%17.
The SOTI study studied the modifications produces in the markers for bone formation and resorption. These biochemical markers are an indirect measure of bone metabolism. They are useful as indicators of the therapeutic response and are an indirect measure of compliance. The SOTI study observed that the bone iso-enzyme alkaline phosphatase increased by 8.1% more in patients treated than in those in the placebo group from the first three months of treatment1. In the case of the markers for resorption, the C-terminal with bridges fragment (CTX) diminished 12.2% in the first few months. This behaviour is different from the increase which the anabolics produce and the significant decrease produced by the most commonly used anti-resorptives. The results observed in the STRATOS and PREVOS studies had a similar profile4,5. These modifications are compatible with the action mechanism proposed or strontium ranelate which is that it stimulates the formation and reduces the resorption of bone.

Histology

There are biopsy data from the iliac crest which come from the STRATOS, SOTI and TROPOS studies, obtained over 5 years of treatment1,3,4. The positive effect on bone formation is confirmed by the finding of an increase in the osteoblastic surface area and in the rate of mineral apposition in the trabecular and cortical bone. No changes were seen in the frequency of activation. The effect on the parameters of bone resorption indicate its reduction, although not statistically significant. Neither were any changes in primary bone mineralisation found. Recently, the results of a 3D using micro-TAC study were published, observing that treatment with strontium ranelate improves the indices which contribute to an increase in the biomechanical competence of bone and which explain the anti-fractural effect of strontium ranelate18.

Conclusions

The available evidence indicates that strontium ranelate is a safe drug, with a preventative effect on vertebral and non-vertebral fractures. This effect is maintained for at least 5 years and is independent of age, including in women over 80 years of age. Prevention is seen in women with osteopenia, with non-established osteoporosis and with fractures. The biochemical markers for bone turnover and data from biopsies confirm for us its dual action mechanism, moderately stimulating bone formation and inhibiting resorption.

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