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author:("bruyere, O")
1.  Republished: Value of biomarkers in osteoarthritis: current status and perspectives 
Postgraduate Medical Journal  2013;90(1061):171-178.
Osteoarthritis affects the whole joint structure with progressive changes in cartilage, menisci, ligaments and subchondral bone, and synovial inflammation. Biomarkers are being developed to quantify joint remodelling and disease progression. This article was prepared following a working meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis convened to discuss the value of biochemical markers of matrix metabolism in drug development in osteoarthritis. The best candidates are generally molecules or molecular fragments present in cartilage, bone or synovium and may be specific to one type of joint tissue or common to them all. Many currently investigated biomarkers are associated with collagen metabolism in cartilage or bone, or aggrecan metabolism in cartilage. Other biomarkers are related to non-collagenous proteins, inflammation and/or fibrosis. Biomarkers in osteoarthritis can be categorised using the burden of disease, investigative, prognostic, efficacy of intervention, diagnostic and safety classification. There are a number of promising candidates, notably urinary C-terminal telopeptide of collagen type II and serum cartilage oligomeric protein, although none is sufficiently discriminating to differentiate between individual patients and controls (diagnostic) or between patients with different disease severities (burden of disease), predict prognosis in individuals with or without osteoarthritis (prognostic) or perform so consistently that it could function as a surrogate outcome in clinical trials (efficacy of intervention). Future avenues for research include exploration of underlying mechanisms of disease and development of new biomarkers; technological development; the ‘omics’ (genomics, metabolomics, proteomics and lipidomics); design of aggregate scores combining a panel of biomarkers and/or imaging markers into single diagnostic algorithms; and investigation into the relationship between biomarkers and prognosis.
doi:10.1136/postgradmedj-2013-203726rep
PMCID: PMC3934547  PMID: 24534711
Osteoarthritis; Outcomes research; Inflammation
2.  Cost-effectiveness of strontium ranelate in the treatment of male osteoporosis 
Osteoporosis International  2013;24(8):2291-2300.
Summary
The results of this study suggest that, under the assumption of same relative risk reduction of fractures in men as for women, strontium ranelate could be considered a cost-effective strategy compared with no treatment for the treatment of osteoporotic men from a Belgian healthcare payer perspective.
Introduction
This study was conducted to estimate the cost-effectiveness of strontium ranelate in the treatment of osteoporotic men.
Methods
A previously validated Markov microsimulation model was adapted to estimate the cost (€2,010) per quality-adjusted life-year (QALY) gained of strontium ranelate compared with no treatment. Similar efficacy data on lumbar spine and femoral neck bone mineral density (BMD) between men with osteoporosis at high risk of fracture (MALEO Trial) and postmenopausal osteoporotic women (pivotal SOTI, TROPOS trials) supports the assumption, in the base-case analysis, of the same relative risk reduction of fractures in men as for women. Analyses were conducted, from a Belgian healthcare payer perspective, in the population from the MALEO Trial who is a men population with a mean age of 73 years, and BMD T-score ≤−2.5 or prevalent vertebral fracture (PVF).
Results
In the MALEO population, strontium ranelate compared with no treatment was estimated at €49,798 and €25,584 per QALY gained using efficacy data from the intent-to-treat analysis and the per-protocol analysis including only adherent patients, respectively. In men with a BMD T-score ≤−2.5 or with PVF, the cost per QALY gained of strontium ranelate fall below thresholds of €45,000 and €25,000 per QALY gained based on efficacy data from the entire population of the clinical trial and from the per-protocol analyses, respectively.
Conclusions
The results of this study suggest that, under the assumption of same relative risk reduction of fractures in men as for women, strontium ranelate could be considered cost-effective compared with no treatment for male osteoporosis.
doi:10.1007/s00198-013-2272-2
PMCID: PMC3706715  PMID: 23371359
Cost-effectiveness; Fractures; Men; Osteoporosis; Strontium ranelate
3.  Maintenance of antifracture efficacy over 10 years with strontium ranelate in postmenopausal osteoporosis 
Osteoporosis International  2011;23(3):1115-1122.
Summary
In an open-label extension study, BMD increased continuously with strontium ranelate over 10 years in osteoporotic women (P < 0.01). Vertebral and nonvertebral fracture incidence was lower between 5 and 10 years than in a matched placebo group over 5 years (P < 0.05). Strontium ranelate's antifracture efficacy appears to be maintained long term.
Introduction
Strontium ranelate has proven efficacy against vertebral and nonvertebral fractures, including hip, over 5 years in postmenopausal osteoporosis. We explored long-term efficacy and safety of strontium ranelate over 10 years.
Methods
Postmenopausal osteoporotic women participating in the double-blind, placebo-controlled phase 3 studies SOTI and TROPOS to 5 years were invited to enter a 5-year open-label extension, during which they received strontium ranelate 2 g/day (n = 237, 10-year population). Bone mineral density (BMD) and fracture incidence were recorded, and FRAX® scores were calculated. The effect of strontium ranelate on fracture incidence was evaluated by comparison with a FRAX®-matched placebo group identified in the TROPOS placebo arm.
Results
The patients in the 10-year population had baseline characteristics comparable to those of the total SOTI/TROPOS population. Over 10 years, lumbar BMD increased continuously and significantly (P < 0.01 versus previous year) with 34.5 ± 20.2% relative change from baseline to 10 years. The incidence of vertebral and nonvertebral fracture with strontium ranelate in the 10-year population in years 6 to 10 was comparable to the incidence between years 0 and 5, but was significantly lower than the incidence observed in the FRAX®-matched placebo group over 5 years (P < 0.05); relative risk reductions for vertebral and nonvertebral fractures were 35% and 38%, respectively. Strontium ranelate was safe and well tolerated over 10 years.
Conclusions
Long-term treatment with strontium ranelate is associated with sustained increases in BMD over 10 years, with a good safety profile. Our results also support the maintenance of antifracture efficacy over 10 years with strontium ranelate.
doi:10.1007/s00198-011-1847-z
PMCID: PMC3277702  PMID: 22124575
BMD; Long-term treatment; Osteoporotic fracture; Strontium ranelate
4.  Words, words, words 
doi:10.1186/0778-7367-69-1
PMCID: PMC3436648  PMID: 22958413
5.  Assessment of health claims in the field of bone: a view of the Group for the Respect of Ethics and Excellence in Science (GREES) 
Osteoporosis International  2011;23(1):193-199.
Summary
Health claims for food products in Europe are permitted if the nutrient has been shown to have a beneficial nutritional or physiological effect. This paper defines health claims related to bone health and provides guidelines for the design and the methodology of clinical studies to support claims.
Introduction
Regulation (EC) no. 1924/2006 on nutrition and health claims targeting food products was introduced in Europe stating that health claims shall only be permitted if the substance in respect of which the claim is made has been shown to have a beneficial nutritional or physiological effect. The objective of this paper is to define health claims related to bone health and to provide guidelines for the design and the methodology of clinical studies which need to be adopted to assert such health claims.
Methods
Literature review followed by a consensus discussion during two 1-day meetings organized by the Group for the Respect of Ethics and Excellence in Science (GREES).
Results
The GREES identified six acceptable health claims related to bone health based on the potential of food products to show an effect on either the bioavailability of calcium or osteoclast regulatory proteins or bone turnover markers or bone mineral density or bone structure or fracture incidence. The GREES considers that well-designed human randomized controlled trial on a relevant outcome is the best design to assess health claims. The substantiation of health claim could also be supported by animal studies showing either an improvement in bone strength with the food product or showing the relationship between changes induced by the food product on a surrogate marker and changes in bone strength.
Conclusion
The consensus reached is that the level of health claim may differ according to the surrogate endpoint used and on additional animal studies provided to support the claim.
doi:10.1007/s00198-011-1561-x
PMCID: PMC3249193  PMID: 21350895
Bone; Health claim; Nutrition; Surrogate
6.  Vertebral anti-fracture efficacy of strontium ranelate according to pre-treatment bone turnover 
Osteoporosis International  2009;21(2):233-241.
Summary
Osteoporotic post-menopausal women patients in two randomised trials comparing the anti-fracture efficacy of strontium ranelate with placebo were separated into tertiles according to their baseline levels of biochemical markers of bone formation and resorption. The vertebral anti-fracture efficacy of strontium ranelate was shown to be independent of baseline bone turnover levels.
Introduction
Bone turnover (BTO) levels vary among women at risk of osteoporotic fracture. Strontium ranelate is an anti-osteoporotic treatment increasing bone formation and reducing bone resorption. It was hypothesised that its anti-fracture efficacy would be independent of baseline BTO levels.
Methods
Post-menopausal women with osteoporosis from two pooled studies were stratified in tertiles according to baseline levels of two BTO markers: bone-specific alkaline phosphatase (b-ALP, n = 4995) and serum C-telopeptide cross-links (sCTX, n = 4891). Vertebral fracture risk was assessed over 3 years with strontium ranelate 2 g/day or placebo.
Results
In the placebo group, relative risk of vertebral fractures increased with BTO tertiles by 32% and 24% for patients in the highest tertile for b-ALP and CTX, respectively, compared to those in the lowest tertile. In the strontium ranelate group, incidences of vertebral fracture did not differ significantly across BTO tertiles. Significant reductions in vertebral fractures with strontium ranelate were seen in all tertiles of both markers, with relative risk reductions of 31% to 47% relative to placebo. Risk reduction did not differ among tertiles (b-ALP: p = 0.513; sCTX: p = 0.290).
Conclusion
The vertebral anti-fracture efficacy of strontium ranelate was independent of baseline BTO levels. Strontium ranelate offers clinical benefits to women across a wide range of metabolic states.
doi:10.1007/s00198-009-0940-z
PMCID: PMC2801841  PMID: 19436941
Anti-fracture efficacy; Biochemical marker; Bone turnover; Osteoporosis; Strontium ranelate; Vertebral fracture
7.  Value of biomarkers in osteoarthritis: current status and perspectives 
Annals of the Rheumatic Diseases  2013;72(11):1756-1763.
Osteoarthritis affects the whole joint structure with progressive changes in cartilage, menisci, ligaments and subchondral bone, and synovial inflammation. Biomarkers are being developed to quantify joint remodelling and disease progression. This article was prepared following a working meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis convened to discuss the value of biochemical markers of matrix metabolism in drug development in osteoarthritis. The best candidates are generally molecules or molecular fragments present in cartilage, bone or synovium and may be specific to one type of joint tissue or common to them all. Many currently investigated biomarkers are associated with collagen metabolism in cartilage or bone, or aggrecan metabolism in cartilage. Other biomarkers are related to non-collagenous proteins, inflammation and/or fibrosis. Biomarkers in osteoarthritis can be categorised using the burden of disease, investigative, prognostic, efficacy of intervention, diagnostic and safety classification. There are a number of promising candidates, notably urinary C-terminal telopeptide of collagen type II and serum cartilage oligomeric protein, although none is sufficiently discriminating to differentiate between individual patients and controls (diagnostic) or between patients with different disease severities (burden of disease), predict prognosis in individuals with or without osteoarthritis (prognostic) or perform so consistently that it could function as a surrogate outcome in clinical trials (efficacy of intervention). Future avenues for research include exploration of underlying mechanisms of disease and development of new biomarkers; technological development; the ‘omics’ (genomics, metabolomics, proteomics and lipidomics); design of aggregate scores combining a panel of biomarkers and/or imaging markers into single diagnostic algorithms; and investigation into the relationship between biomarkers and prognosis.
doi:10.1136/annrheumdis-2013-203726
PMCID: PMC3812859  PMID: 23897772
Osteoarthritis; Outcomes research; Inflammation

Results 1-7 (7)