STRONTIUM RANELATE ARISTO Granules Ref.[8499] Active ingredients: Strontium ranelate

Pharmacotherapeutic group: Drugs for the treatment of bone diseases – Other drugs affecting bone structure and mineralisation
ATC code: M05BX03

Mechanism of action

In vitro, strontium ranelate:

• increases bone formation in bone tissue culture as well as osteoblast precursor replication and collagen synthesis in bone cell culture;
• reduces bone resorption by decreasing osteoclast differentiation and resorbing activity. This results in a rebalance of bone turnover in favour of bone formation.

The activity of strontium ranelate was studied in various non-clinical models. In particular, in intact rats, strontium ranelate increases trabecular bone mass, trabeculae number and thickness; this results in an improvement of bone strength.

In bone tissue of treated animals and humans, strontium is mainly adsorbed onto the crystal surface and only slightly substitutes for calcium in the apatite crystal of newly formed bone. Strontium ranelate does not modify the bone crystal characteristics. In iliac crest bone biopsies obtained after up to 60 months of treatment with strontium ranelate 2 g/day in phase III trials, no deleterious effects on bone quality or mineralisation were observed.

The combined effects of strontium distribution in bone (see section 5.2) and increased X-ray absorption of strontium as compared to calcium, leads to an amplification of bone mineral density (BMD) measurement by dual-photon X-ray absorptiometry (DXA). Available data indicate that these factors account for approximately 50% of the measured change in BMD over 3 years of treatment with strontium ranelate 2 g/day. This should be taken into account when interpreting BMD changes during treatment with Strontium ranelate Aristo. In phase III studies, which demonstrated the anti-fracture efficacy of strontium ranelate treatment, measured mean BMD increased from baseline with strontium ranelate by approximately 4% per year at the lumbar spine and 2% per year at the femoral neck, reaching 13% to 15% and 5% to 6% respectively after 3 years, depending on the study.

In phase III studies, as compared to placebo, biochemical markers of bone formation (bone-specific alkaline phosphatase and C-terminal propeptide of type I procollagen) increased and those of bone resorption (serum C-telopeptide and urinary N-telopeptide cross links) decreased from the third month of treatment up to 3 years.

Secondary to the pharmacological effects of strontium ranelate, slight decreases in calcium and parathyroid hormone (PTH) serum concentrations, increases in blood phosphorus concentrations and in total alkaline phosphatase activity were observed, with no observed clinical consequences.

Clinical efficacy

Osteoporosis is defined as BMD of the spine or hip 2.5 SD or more below the mean value of a normal young population. A number of risk factors are associated with postmenopausal osteoporosis including low bone mass, low bone mineral density, early menopause, a history of smoking and a family history of osteoporosis. The clinical consequence of osteoporosis is fractures. The risk of fractures is increased with the number of risk factors.

Treatment of postmenopausal osteoporosis

The anti-fracture studies program of strontium ranelate was made up of two placebo-controlled phase III studies: SOTI study and TROPOS study. SOTI involved 1,649 postmenopausal women with established osteoporosis (low lumbar BMD and prevalent vertebral fracture) and a mean age of 70 years. TROPOS involved 5,091 postmenopausal women with osteoporosis (low femoral neck BMD and prevalent fracture in more than half of them) and a mean age of 77 years. Together, SOTI and TROPOS enrolled 1,556 patients over 80 years at inclusion (23.1% of the study population). In addition to their treatment (2 g/day strontium ranelate or placebo), the patients received adapted calcium and vitamin D supplements throughout both studies.

Strontium ranelate reduced the relative risk of new vertebral fracture by 41% over 3 years in the SOTI study (table 1). The effect was significant from the first year. Similar benefits were demonstrated in women with multiple fractures at baseline. With respect to clinical vertebral fractures (defined as fractures associated with back pain and/or a body height loss of at least 1 cm), the relative risk was reduced by 38%. Strontium ranelate also decreased the number of patients with a body height loss of at least 1 cm as compared to placebo. Quality of life assessment on the QUALIOST specific scale as well as the General Health perception score of the SF-36 general scale indicated benefit of strontium ranelate, compared with placebo.

Efficacy of strontium ranelate to reduce the risk of new vertebral fracture was confirmed in the TROPOS study, including for osteoporotic patients without fragility fracture at baseline.

Table 1. Incidence of patients with vertebral fracture and relative risk reduction:

In patients over 80 years of age at inclusion, a pooled analysis of SOTI and TROPOS studies showed that strontium ranelate reduced the relative risk of experiencing new vertebral fractures by 32% over 3 years (incidence of 19.1% with strontium ranelate vs. 26.5% with placebo).

In an a-posteriori analysis of patients from the pooled SOTI and TROPOS studies with baseline lumbar spine and/or femoral neck BMD in the osteopenic range and without prevalent fracture but with at least one additional risk factor for fracture (N=176), strontium ranelate reduced the risk of a first vertebral fracture by 72% over 3 years (incidence of vertebral fracture 3.6% with strontium ranelate vs. 12.0% with placebo).

An a-posteriori analysis was performed on a subgroup of patients from the TROPOS study of particular medical interest and at high-risk of fracture [defined by a femoral neck BMD T-score ≤ -3 SD (manufacturer’s range corresponding to -2.4 SD using NHANES III) and an age ≥ 74 years (n=1,977, i.e. 40% of the TROPOS study population)]. In this group, over 3 years of treatment, strontium ranelate reduced the risk of hip fracture by 36% relative to the placebo group (table 2).

Table 2. Incidence of patients with hip fracture and relative risk reduction in patients with BMD ≤ -2.4 SD (NHANES III) and age ≥74 years:

Treatment of Osteoporosis in men

The efficacy of strontium ranelate was demonstrated in men with osteoporosis in a 2-year, double- blind,placebo-controlled study with a main analysis after one year in 243 patients (Intention to treat population, 161 patients received strontium ranelate) at high risk of fracture (mean age 72,7 years; mean lumbar BMD T-score value of -2.6; 28% of prevalent vertebral fracture).

All patients received daily supplemental calcium (1000 mg) and vitamin D (800 UI).

Statistically significant increases in BMD were observed as early as 6 months following initiation of strontium ranelate treatment versus placebo.

Over 12 months, a statistically significant increase in mean lumbar spine BMD, main efficacy criteria (E (SE) = 5.32% (0.75); 95%CI = [3.86; 6.79]; p<0,001), similar to that observed in the pivotal anti- fracture phase III studies carried-out in postmenopausal women, was observed.

Statistically significant increases in femoral neck BMD and total hip BMD (p<0,001) were observed after 12 months.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with the reference medicinal product containing strontium ranelate in all subsets of the paediatric population in osteoporosis (see section 4.2 for information on paediatric use).