Re: Efficacy and safety of oral strontium ranelate for the treatment of knee osteoarthritis: rationale and design of randomised, double-blind, placebo-controlled trial. Cooper C, Reginster JY, Chapurlat R, et al. Curr Med Res Opin 2012;28:231–9.
Dear Editor,
I read with great interest the paper by Cooper et al. entitled ‘Efficacy and safety of oral strontium ranelate for the treatment of knee osteoarthritis: rationale and design of randomised, double-blind, placebo-controlled trial’Citation1. This work addressed that strontium improved structure and symptoms of knee osteoarthritis. I would like to complete the discussion of Cooper and colleagues by introducing a major complementary route by which strontium could reduce osteoarthritic symptoms.
Recent studies have revealed that severity of osteoarthritis is associated with an increased level of the ligand for receptor activator of nuclear factor kappa B (RANKL). The important role of RANKL in osteoarthritis is evidenced by the inhibitory effect of osteoprotegerin (a decoy receptor of RANKL) on interleukin-1-mediated arthritisCitation2,Citation3. Also, insulin growth factor (IGF) can inhibit nuclear factor kappa B which subsequently reduce osteoarthritis through down regulation of interleukin-1Citation4.
Strontium, which is traditionally used against osteoporosis, not only stimulates IGF, but also produces the osteoprotegerin which can lead to significant reduction in osteoarthritisCitation5,Citation6. Therefore, these important mechanisms should be borne in mind as the major mechanisms for strontium-reduced osteoarthritis.
Hamid Namazi
Shiraz University of Medical Sciences-Shiraz-Iran
Shiraz 98 711 6246093, Islamic Republic of Iran
References
- Cooper C, Reginster JY, Chapurlat R, et al. Efficacy and safety of oral strontium ranelate for the treatment of knee osteoarthritis: rationale and design of randomised, double-blind, placebo-controlled trial. Curr Med Res Opin 2012;28:231-9
- Saklatvala J. Inflammatory signaling in cartilage: MAPK and NF-kappaB pathways in chondrocytes and the use of inhibitors for research into pathogenesis and therapy of osteoarthritis. Curr Drug Targets 2007;8:305-13
- Tat SK, Pelletier JP, Velasco CR, et al. New perspective in osteoarthritis: the OPG and RANKL system as a potential therapeutic target? Keio J Med 2009;58:29-40
- Muddasani P, Norman JC, Ellman M, et al. Basic fibroblast growth factor activates the MAPK and NFkappaB pathways that converge on Elk-1 to control production of matrix metalloproteinase-13 by human adult articular chondrocytes. J Biol Chem 2007;282:31409-21
- Gulhan I, Bilgili S, Gunaydin R, et al. The effect of strontium ranelate on serum insulin like growth factor-1 and leptin levels in osteoporotic post-menopausal women: a prospective study. Arch Gynecol Obstet 2008;278:437-41
- Hamdy NA. Strontium ranelate improves bone microarchitecture in osteoporosis. Rheumatology (Oxford) 2009;48:9-13
Author’s response to Letter to the Editor
Cyrus Cooper
Re: Efficacy and safety of oral strontium ranelate for the treatment of knee osteoarthritis: rationale and design of randomised, double-blind, placebo-controlled trial. Cooper C, Reginster JY, Chapurlat R, et al. Curr Med Res Opin 2012;28:231-9
Dear Editor,
We thank Dr Hamid Namazi for his interest in our paper entitled ‘Efficacy and safety of oral strontium ranelate for the treatment of knee osteoarthritis: rationale and design of randomised, double-blind, placebo-controlled trial’ and for his proposed hypotheses on the mechanism of action of strontium ranelate on osteoarthritis (OA). In his letter, Hamid Namazi developed our hypothesis of an effect of strontium ranelate through the OPG/RANKL pathway. We take this opportunity to add that strontium ranelate could also have a positive effect in vitro on OA pathophysiology by down-regulating MMP2 and MMP9, inhibiting the synthesis of membranous RANKL and increasing OPG synthesis in subchondral bone osteoblastsCitation1. Furthermore, recent data in women confirmed that strontium ranelate treatment significantly increases OPG serum levels after 3 months, the beneficial effect being persistent up to 3 yearsCitation2.
Dr Namazi also suggested a new interesting mode of action of strontium ranelate in OA. IGF1 might mediate part of the strontium ranelate beneficial effect on OA. Indeed, strontium ranelate has been demonstrated to enhance IGF-1 levels in post-menopausal osteoporotic womenCitation3. IGF1 has also been shown to suppress IL1-β-induced cartilage degradation through down-regulation of NFκB signalling in primary canine chondrocytesCitation4. This hypothesis is in accordance with previous results showing that strontium ranelate is able to enhance the stimulatory effect of IGF-1 on proteoglycan synthesis in human chondrocytesCitation5.
Overall, these results suggest that strontium ranelate would have a beneficial effect on OA by acting both on subchondral bone and cartilage.
Sincerely,
Cyrus Cooper
Jean-Yves Reginster
References
- Tat SK, Pelletier JP, Mineau F, et al. Strontium ranelate inhibits key factors affecting bone remodelling in human osteoarthritic subchondral bone osteoblasts. Bone 2011;49:559-67
- Reginster JY, Bruyere O, Collette J. Strontium ranelate treatment increases osteoprotegerin serum levels in postmenopausal osteoporotic women. Bone Jan 12. Epub ahead of print. doi:10.1016/j.bone.2011.12.024
- Gulhan I, Bilgili S, Gunaydin R, et al. The effect of strontium ranelate on serum insulin like growth factor-1 and leptin levels in osteoporotic post-menopausal women: a prospective study. Arch Gynecol Obstet 2008;278:437-41
- Montaseri A, Busch F. Mobasheri A, et al. IGF-1 and PDGF-bb suppress IL1-β-induced cartilage degradation though down-regulation of NFκB signalling: involvement of Src/PI-3K/AKT pathway. PloS One 2011;6(12)e28663.doi:10.1371/journal.pone.0028663
- Henrotin Y, Labasse A, Zheng SX, et al. Strontium ranelate increases cartilage matrix formation. J Bone Miner Res 2001;16:299-308