Advertisement

Selective estrogen receptor modulators (SERMs): New alternatives for osteoarthritis?

      Abstract

      The dramatic rise in the prevalence rate of osteoarthritis (OA) after the menopause and the presence of estrogen receptors in joint tissues suggest that estrogen may help protect against the development of OA. Trials of estrogen therapy have produced inconclusive results, however, partly because of flaws in study design and partly because of the complexity of the mechanisms underlying estrogen's effects on joint tissues. Initial studies of the use of selective estrogen receptor modulators (SERMs) have reported beneficial effects in OA. These agents may exert both a direct effect upon joint cartilage and indirect effects on subchondral bone, synovium, muscle, tendons and ligaments. SERMs may be particularly beneficial for postmenopausal patients with osteoporotic OA, a phenotype defined by decreased bone density, associated with high remodeling in subchondral bone. More research is needed, though, before SERMs can become a therapeutic option for OA.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Maturitas
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Lane N.E.
        • Brandt K.
        • Hawker G.
        • Peeva E.
        • Schreyer E.
        • Tsuji W.
        • et al.
        OARSI-FDA initiative: defining the disease state of osteoarthritis.
        Osteoarthritis Cartil. 2011; 19: 478-482
        • Herrero-Beaumont G.
        • Roman-Blas J.A.
        • Castañeda S.
        • Jimenez S.A.
        Primary osteoarthritis no longer primary: three subsets with distinct etiological, clinical, and therapeutic characteristics.
        Semin Arthritis Rheum. 2009; 39: 71-80
        • Roman-Blas J.A.
        • Castañeda S.
        • Largo R.
        • Herrero-Beaumont G.
        Osteoarthritis associated with estrogen deficiency.
        Arthritis Res Ther. 2009; 11: 241
        • De Klerk B.M.
        • Schiphof D.
        • Groeneveld F.P.
        • Koes B.W.
        • van Osch G.J.
        • van Meurs J.B.
        • et al.
        Limited evidence for a protective effect of unopposed oestrogen therapy for osteoarthritis of the hip: a systematic review.
        Rheumatology (Oxford). 2009; 48: 104-112
        • Nevitt M.C.
        • Cummings S.R.
        • Lane N.E.
        • Hochberg M.C.
        • Scott J.C.
        • Pressman A.R.
        • et al.
        Association of estrogen replacement therapy with the risk of osteoarthritis of the hip in elderly white women. Study of osteoporotic fractures research group.
        Arch Intern Med. 1996; 156: 2073-2080
        • Spector T.D.
        • Nandra D.
        • Hart D.J.
        • Doyle D.V.
        Is hormone replacement therapy protective for hand and knee osteoarthritis in women. The Chingford study.
        Ann Rheum Dis. 1997; 56: 432-444
        • Hannan M.T.
        • Felson D.T.
        • Anderson J.J.
        • Naimark A.
        • Kannel W.B.
        Estrogen use and radiographic osteoarthritis of the knee in women: the Framingham Osteoarthritis Study.
        Arthritis Rheum. 1990; 33: 525-532
        • Hart D.J.
        • Doyle D.V.
        • Spector T.D.
        Incidence and risk factors for radiographic knee osteoarthritis in middle-aged women: the Chingford Study.
        Arthritis Rheum. 1999; 42: 17-24
        • Zhang Y.
        • McAlindon T.E.
        • Hannan M.T.
        • Chaisson C.E.
        • Klein R.
        • Wilson P.W.
        • et al.
        Estrogen replacement therapy and worsening of radiographic knee osteoarthritis: the Framingham Study.
        Arthritis Rheum. 1998; 41: 1867-1873
        • Cirillo D.J.
        • Wallace R.B.
        • Wu L.
        • Yood R.A.
        Effect of hormone therapy on risk of hip and knee joint replacement in the Women's Health Initiative.
        Arthritis Rheum. 2006; 54: 3194-3204
        • Carbone L.D.
        • Nevitt M.C.
        • Wildy K.
        • Barrow K.D.
        • Harris F.
        • Felson D.
        • et al.
        Health, aging and body composition study: the relationship of antiresorptive drug use to structural findings and symptoms of knee osteoarthritis.
        Arthritis Rheum. 2004; 50: 3516-3525
        • Wise B.L.
        • Niu J.
        • Zhang Y.
        • Felson D.T.
        • Bradley L.A.
        • Segal N.
        • et al.
        The association of parity with osteoarthritis and knee replacement in the Multicenter Osteoarthritis Study.
        Osteoarthritis Cartil. 2013; 21: 1849-1854
        • Liu B.
        • Balkwill A.
        • Cooper C.
        • Roddam A.
        • Brown A.
        • Beral V.
        • Million Women Study Collaborators
        Reproductive history, hormonal factors and the incidence of hip and knee replacement for osteoarthritis in middle-aged women.
        Ann Rheum Dis. 2009; 68: 115-1170
        • Seo S.K.
        • Yang H.I.
        • Lim K.J.
        • Jeon Y.E.
        • Choi Y.S.
        • Cho S.
        • et al.
        Changes in serum levels of cartilage oligomeric matrix protein after estrogen and alendronate therapy in postmenopausal women.
        Gynecol Obstet Invest. 2012; 74: 143-150
        • Prieto-Alhambra D.
        • Javaid M.K.
        • Judge A.
        • Maskell J.
        • Cooper C.
        • Arden N.K.
        On behalf of the COASt Study Group. Hormone replacement therapy and mid-term implant survival following knee or hip arthroplasty for osteoarthritis: a population-based cohort study.
        Ann Rheum Dis. 2014; ([Epub ahead of print], doi: 10.1136/annrheumdis-2013-204043)
        • Sniekers Y.H.
        • Weinans H.
        • Bierma-Zeinstra S.M.
        • van Leeuwen J.P.
        • van Osch G.J.
        Animal models for osteoarthritis: the effect of ovariectomy and estrogen treatment—a systematic approach.
        Osteoarthritis Cartil. 2008; 16: 533-541
        • Oestergaard S.
        • Sondergaard B.C.
        • Hoegh-Andersen P.
        • Henriksen K.
        • Qvist P.
        • Christiansen C.
        • et al.
        Effects of ovariectomy and estrogen therapy on type II collagen degradation and structural integrity of articular cartilage in rats: implications of the time of initiation.
        Arthritis Rheum. 2006; 54: 2441-2451
        • Ham K.D.
        • Carlson C.S.
        Effects of estrogen replacement therapy on bone turnover in subchondral bone and epiphyseal metaphyseal cancellous bone of ovariectomized cynomolgus monkeys.
        J Bone Miner Res. 2004; 19: 823-829
        • Olson E.J.
        • Lindgren B.R.
        • Carlson C.S.
        Effects of long-term estrogen replacement therapy on the prevalence and area of periarticular tibial osteophytes in surgically postmenopausal cynomolgus monkeys.
        Bone. 2007; 41: 282-289
        • Olson E.J.
        • Lindgren B.R.
        • Carlson C.S.
        Effects of long-term estrogen replacement therapy on bone turnover in periarticular tibial osteophytes in surgically postmenopausal cynomolgus monkeys.
        Bone. 2008; 42: 907-913
        • Sniekers Y.H.
        • Weinans H.
        • van Osch G.J.
        • van Leeuwen J.P.
        Oestrogen is important for maintenance of cartilage and subchondral bone in a murine model of knee osteoarthritis.
        Arthritis Res Ther. 2010; 12: R182
        • Funck-Brentano T.
        • Lin H.
        • Hay E.
        • Ah Kioon M.D.
        • Schiltz C.
        • Hannouche D.
        • Nizard R.
        • Lioté F.
        • Orcel P.
        • de Vernejoul M.C.
        • Cohen-Solal M.E.
        Targeting bone alleviates osteoarthritis in osteopenic mice and modulates cartilage catabolism.
        PLoS One. 2012; 7: e33543
        • Yang J.H.
        • Kim J.H.
        • Lim D.S.
        • Oh K.J.
        Effect of combined sex hormone replacement on bone/cartilage turnover in a murine model of osteoarthritis.
        Clin Orthop Surg. 2012; 4: 234-241
        • Yoshida A.
        • Morihara T.
        • Matsuda K.
        • Sakamoto H.
        • Arai Y.
        • Kida Y.
        • et al.
        Immunohistochemical analysis of the effects of estrogen on intraarticular neurogenic inflammation in a rat anterior cruciate ligament transection model of osteoarthritis.
        Connect Tissue Res. 2012; 53: 197-206
        • Wang X.D.
        • Kou X.X.
        • Meng Z.
        • Bi R.Y.
        • Liu Y.
        • Zhang J.N.
        • et al.
        Estrogen aggravates iodoacetate-induced temporomandibular joint osteoarthritis.
        J Dent Res. 2013; 92: 918-924
        • Christgau S.
        • Tankó L.B.
        • Cloos P.A.
        • Mouritzen U.
        • Christiansen C.
        • Delaissé J.M.
        • et al.
        Suppression of elevated cartilage turnover in postmenopausal women and in ovariectomized rats by estrogen and a selective estrogen-receptor modulator (SERM).
        Menopause. 2004; 11: 508-518
        • Karsdal M.A.
        • Bay-Jensen A.C.
        • Henriksen K.
        • Christiansen C.
        The pathogenesis of osteoarthritis involves bone, cartilage and synovial inflammation: may estrogen be a magic bullet.
        Menopause Int. 2012; 18: 139-146
        • Fujita T.
        • Fujii Y.
        • Munezane H.
        • Ohue M.
        • Takagi Y.
        Analgesic effect of raloxifene on back and knee pain in postmenopausal women with osteoporosis and/or osteoarthritis.
        J Bone Miner Metab. 2010; 28: 477-484
        • Rosner I.A.
        • Malemud C.J.
        • Goldberg V.M.
        • Papay R.S.
        • Getzy L.
        • Moskowitz R.W.
        Pathologic and metabolic responses of experimental osteoarthritis to estradiol and an estradiol antagonist.
        Clin Orthop Relat Res. 1982; : 280-286
        • Rosner I.A.
        • Boja B.A.
        • Goldberg V.M.
        • Moskowitz R.W.
        Tamoxifen therapy in experimental osteoarthritis.
        Curr Ther Res. 1983; 34: 409-414
        • Tsai C.L.
        • Liu T.K.
        Inhibition of estradiol-induced early osteoarthritic changes by tamoxifen.
        Life Sci. 1992; 50: 1943-1951
        • Colombo C.
        • Butler M.
        • Hickman L.
        • Selwyn M.
        • Chart J.
        • Steinetz B.
        A new model of osteoarthritis in rabbits II. Evaluation of anti-osteoarthritic effects of selected antirheumatic drugs administered systemically.
        Arthritis Rheum. 1983; 26: 1132-1139
        • Høegh-Andersen P.
        • Tankó L.B.
        • Andersen T.L.
        • Lundberg C.V.
        • Mo J.A.
        • Heegaard A.M.
        • et al.
        Ovariectomized rats as a model of postmenopausal osteoarthritis: validation and application.
        Arthritis Res Ther. 2004; 6: R169-R180
        • Kavas A.
        • Cagatay S.T.
        • Banerjee S.
        • Keskin D.
        • Tezcaner A.
        Potential of raloxifene in reversing osteoarthritis-like alterations in rat chondrocytes: an in vitro model study.
        J Biosci. 2013; 38: 135-147
        • Tinti L.
        • Niccolini S.
        • Lamboglia A.
        • Pascarelli N.A.
        • Cervone R.
        • Fioravanti A.
        Raloxifene protects cultured human chondrocytes from IL-1β induced damage: a biochemical and morphological study.
        Eur J Pharmacol. 2011; 670: 67-73
        • Hattori Y.
        • Kojima T.
        • Kato D.
        • Matsubara H.
        • Takigawa M.
        • Ishiguro N.
        A selective estrogen receptor modulator inhibits tumor necrosis factor-α-induced apoptosis through the ERK1/2 signaling pathway in human chondrocytes.
        Biochem Biophys Res Commun. 2012; 421: 418-424
        • Roman-Blas J.A.
        • Castañeda S.
        • Largo R.
        • Lems W.F.
        • Herrero-Beaumont G.
        An OA phenotype may obtain major benefit from bone-acting agents.
        Semin Arthritis Rheum. 2014; 43: 421-428
        • Herrero-Beaumont G.
        • Roman-Blas J.A.
        Osteoarthritis: osteoporotic OA: a reasonable target for bone-acting agents.
        Nat Rev Rheumatol. 2013; 9: 448-450