Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial.

BACKGROUND: Strontium ranelate is currently used for osteoporosis. The international, double-blind, randomised, placebo-controlled Strontium ranelate Efficacy in Knee OsteoarthrItis triAl evaluated its effect on radiological progression of knee osteoarthritis. METHODS: Patients with knee osteoarthritis (Kellgren and Lawrence grade 2 or 3, and joint space width (JSW) 2.5-5 mm) were randomly allocated to strontium ranelate 1 g/day (n=558), 2 g/day (n=566) or placebo (n=559). The primary endpoint was radiographical change in JSW (medial tibiofemoral compartment) over 3 years versus placebo. Secondary endpoints included radiological progression, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and knee pain. The trial is registered (ISRCTN41323372). RESULTS: The intention-to-treat population included 1371 patients. Treatment with strontium ranelate was associated with smaller degradations in JSW than placebo (1 g/day: -0.23 (SD 0.56) mm; 2 g/day: -0.27 (SD 0.63) mm; placebo: -0.37 (SD 0.59) mm); treatment-placebo differences were 0.14 (SE 0.04), 95% CI 0.05 to 0.23, p<0.001 for 1 g/day and 0.10 (SE 0.04), 95% CI 0.02 to 0.19, p=0.018 for 2 g/day. Fewer radiological progressors were observed with strontium ranelate (p<0.001 and p=0.012 for 1 and 2 g/day). There were greater reductions in total WOMAC score (p=0.045), pain subscore (p=0.028), physical function subscore (p=0.099) and knee pain (p=0.065) with strontium ranelate 2 g/day. Strontium ranelate was well tolerated. CONCLUSIONS: Treatment with strontium ranelate 1 and 2 g/day is associated with a significant effect on structure in patients with knee osteoarthritis, and a beneficial effect on symptoms for strontium ranelate 2 g/day.

The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis.

BACKGROUND: Osteoporotic structural damage and bone fragility result from reduced bone formation and increased bone resorption. In a phase 2 clinical trial, strontium ranelate, an orally active drug that dissociates bone remodeling by increasing bone formation and decreasing bone resorption, has been shown to reduce the risk of vertebral fractures and to increase bone mineral density. METHODS: To evaluate the efficacy of strontium ranelate in preventing vertebral fractures in a phase 3 trial, we randomly assigned 1649 postmenopausal women with osteoporosis (low bone mineral density) and at least one vertebral fracture to receive 2 g of oral strontium ranelate per day or placebo for three years. We gave calcium and vitamin D supplements to both groups before and during the study. Vertebral radiographs were obtained annually, and measurements of bone mineral density were performed every six months. RESULTS: New vertebral fractures occurred in fewer patients in the strontium ranelate group than in the placebo group, with a risk reduction of 49 percent in the first year of treatment and 41 percent during the three-year study period (relative risk, 0.59; 95 percent confidence interval, 0.48 to 0.73). Strontium ranelate increased bone mineral density at month 36 by 14.4 percent at the lumbar spine and 8.3 percent at the femoral neck (P<0.001 for both comparisons). There were no significant differences between the groups in the incidence of serious adverse events. CONCLUSIONS: Treatment of postmenopausal osteoporosis with strontium ranelate leads to early and sustained reductions in the risk of vertebral fractures.

Current understanding of osteoporosis according to the position of the World Health Organization (WHO) and International Osteoporosis Foundation.

The study documents a general change of position on osteoporosis (definition, diagnosis, aim of treatment). Taking into consideration a multifactorial nature of bone fragility in osteoporosis we do not diagnose "osteoporosis" but a total, individual 10-year fracture risk (AR-10) on the basis of independent and self-sufficient risk factors. These are: advanced age, prior fragility fracture, parental history of proximal femur fracture, low BMI, low bone mass, glicocortycosteroids treatment, rheumatoid arthritis, smoking, overuse of alcohol. The treatment should be implemented in persons burdened with a fracture risk higher than a population risk. The intervention threshold is a result of an agreement and a result of work of various working groups of experts. According to Johnell AR-10 below 8% does not require a therapeutical intervention; above 14% justifies the treatment independently of BMD measurement. AR-10 between 8% and 14% is an indication for BMD measurement precising fracture risk. The aim of the treatment is to decrease fracture risk. It combines a limitation of fracture risk factors effects including fall prevention and improvement of bone quality with applying pharmacotherapy. This study highlights that a bone mineral measurement, so far accepted as a criteria for diagnosis of osteoporosis or its exclusion should not be made in aim of diagnosis but to evaluate an absolute fracture risk. Spinal X-rays are performed in aim to diagnose vertebral fractures, which mean a multiple increase of risk of further fractures. The principles of low bone mass differential diagnosis and current possibility of pharmacological treatment are also described. Guidelines for fall avoidance in fracture prevention are described.

Efficacy and safety of oral strontium ranelate for the treatment of knee osteoarthritis: rationale and design of randomised, double-blind, placebo-controlled trial.

OBJECTIVE: The osteoporosis drug strontium ranelate dissociates bone remodelling processes. It also inhibits subchondral bone resorption and stimulates cartilage matrix formation in vitro. Exploratory studies in the osteoporosis trials report that strontium ranelate reduces biomarkers of cartilage degradation, and attenuates the progression and clinical symptoms of spinal osteoarthritis, suggesting symptom- and structure-modifying activity in osteoarthritis. We describe the rationale and design of a randomised trial evaluating the efficacy and safety of strontium ranelate in knee osteoarthritis. RESEARCH DESIGN, METHODS, AND RESULTS: This double-blind, placebo-controlled trial (98 centres, 18 countries) includes ambulatory Caucasian men and women aged ≥50 years with primary knee osteoarthritis of the medial tibiofemoral compartment (Kellgren and Lawrence grade 2 or 3), joint space width (JSW) 2.5 to 5 mm, and knee pain on most days in the previous month (intensity ≥40 mm on a visual analogue scale). Patients are randomly allocated to three groups (strontium ranelate 1 or 2 g/day, or placebo). Follow-up is expected to last 3 years. The primary endpoint is radiographic change in JSW from baseline in each group versus placebo. The main clinical secondary endpoint is WOMAC score at the knee. Safety is assessed at every visit. It is estimated that 1600 patients are required to establish statistical significance with power >90% (0.2 mm ± 10% between-group difference in change in JSW over 3 years). Recruitment started in April 2006. The results are expected in spring 2012. CLINICAL TRIAL REGISTRATION: The trial is registered on www.controlled-trials.com (number ISRCTN41323372). CONCLUSIONS: This randomised, double blind, placebo-controlled study will establish the potential of strontium ranelate in improving structure and symptoms in patients with knee osteoarthritis.

The application of FRAX® to determine intervention thresholds in osteoporosis treatment in Poland.

INTRODUCTION: FRAX®, an assessment algorithm for estimating fracture probability, has been widely used for the evaluation of osteoporosis since 2008. Its clinical use requires that osteoporotic fracture probability is established at which treatment can be recommended. OBJECTIVES: The aim of the present study was to explore possible treatment thresholds for Poland. PATIENTS AND METHODS: The FRAX-based probabilities were calculated in 1608 unselected postmenopausal women from Bialystok using the British model (version 3.1). Intervention thresholds were set at fracture probability equal to women with a bone mass density (BMD) T-score of -2.5 standard deviation (criterion A), equal to women with a prior fracture using a fixed threshold irrespective of age (criterion B), or an age-dependent threshold (criterion C). Additionally, we assumed that all women with a prior fracture would be eligible for treatment plus those with a fracture probability equal to women with a prior fracture using a fixed threshold (criterion D). RESULTS: Mean 10-year probability of a major osteoporotic fracture was 10.9% when BMD was not included in the FRAX calculation and 11.6% with BMD included. In women with a prior fragility fracture, the respective probabilities were 18.0% and 17.4%. For criterion A, 39% women aged 50 years or more would be eligible for treatment, for criterion D--35%, and for criteria B and C--16%. For criteria B and C, women with higher risk would be eligible for treatment compared with criteria A and D. Assuming a relative fracture risk reduction of 30%, the number needed to treat (NNT) to prevent a major fracture was lower for criteria B and C (NNT = 13 and 14, respectively) than for criteria A and D (NNT = 18). CONCLUSIONS: The use of intervention thresholds based on the probabilities equal to women with a prior fracture is most efficient. The use of an age-specific threshold may be more clinically appropriate than a fixed probability threshold for all ages.

The characteristics of osteoporotic fractures in the region of Bialystok (BOS-2). The application of the WHO algorithm, FRAX®BMI and FRAX®BMD assessment tools to determine patients for intervention.

BACKGROUND: The 2007 WHO guidelines for the treatment of osteoporosis require that we know the population risk of an osteoporotic fracture for each country to classify patients requiring treatment. MATERIAL AND METHODS: Studies have been carried out among a random cohort of 1,608 women over the age of 40 to assess a ten-year absolute risk of main osteoporotic fractures (AR-10 m.o.fx.) and hip fractures (AR-10 h.fx.) by using FRAX®BMI and FRAX®BMD based on the epidemiology of fractures in England. RESULTS: Both methods gave similar results in assessing the probability of fracture, showing the increase of AR-10 m.o.fx. in subsequent life decades to rise from 5% in the fifth decade to 25% in the ninth, mean result 11%, and AR-10 h.fx. to rise over the same period from 0.5% to 13%, mean result 3%. The number of fractures increases up to the seventh and eighth decades, and decreases according to the number of patients in the age group. The commonest fracture risks reported, other than old age and low BMI, were a prior fracture, a family history of hip fracture and smoking. CONCLUSIONS: Comparative analysis of examined parameters of FRAX between people with and without fractures showed considerable differences only in age and AR-10 m.o.fx. This doubled in people with previous fractures (ca. 18% vs. 9%) and AR-10 h.fx. (ca. 5% vs. 2.5%). The "middle" area between the average population risks (AR-10 m.o.fx. 11% and AR-10 h.fx. 3%) and the risks in patients with fractures (AR-10 m.o.fx. 18% and AR-10 h.fx. 9%) could work as an indicator: below those values the risk is low and no treatment is required; above those values, the risk is high, and intervention is necessary; the middle area implies a BMD examination and reassessment of the fracture risk.

A phase 2 randomized, double-blind study of AMG 108, a fully human monoclonal antibody to IL-1R, in patients with rheumatoid arthritis.

INTRODUCTION: Preclinical work has suggested that IL-1 plays a critical role in the pathogenesis of rheumatoid arthritis (RA). The objective of the present study was to determine the effect of a long-acting IL-1 receptor inhibitor, AMG 108, in a double-blind, placebo-controlled, parallel-dosing study in patients with active RA who were receiving stable methotrexate (15 to 25 mg/week). METHODS: Patients were randomized equally to receive placebo or 50, 125, or 250 mg AMG 108 subcutaneously every 4 weeks for 6 months. The primary efficacy endpoint was a 20% improvement in the American College of Rheumatology response (ACR20) at week 24; other efficacy endpoints included the ACR50, the ACR70, and the RA disease activity score (28-joint count Disease Activity Score) responses, patient-reported outcomes, and pharmacokinetic parameters. Safety endpoints included treatment-emergent adverse events (AEs), infectious AEs, serious AEs, serious infections, injection site reactions, laboratory abnormalities, and antibodies to AMG 108. RESULTS: Of 813 patients enrolled in the study, 204 patients were randomized to the 50 mg group, 203 to the 125 mg group, 203 to the 250 mg group, and 203 to placebo. At week 24, 40.4% of the 250 mg group, 36% of the 125 mg group, 30.9% of the 50 mg group, and 29.1% of the placebo group achieved an ACR20 (P = 0.022, 250 mg vs. placebo). Of the individual ACR components, numerical dose-dependent improvements were only seen in tender joint counts, pain (visual analog scale), and the acute phase reactants, erythrocyte sedimentation rate and C-reactive protein. No dose-related increase was observed in the incidence of treatment-emergent AEs. No deaths were reported, and the incidence of AEs and infections, serious AEs and infections, and withdrawals from study for safety were similar in the AMG 108 and placebo groups. CONCLUSIONS: This large double-blind randomized trial with a long-acting IL-1 receptor blocker, AMG 108, is consistent with the experience of other IL-1 blockers, represents a definitive experiment showing that IL-1 inhibition provides only moderate symptomatic amelioration of arthritis activity in the majority of RA patients, and provides an answer to a question that has been discussed for many years in the rheumatologic community. TRIAL REGISTRATION: ClinicalTrials.gov NCT00293826.