Maturitas 77 (2014) 380–384
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Mini review
Selective estrogen receptor modulators (SERMs): New alternatives for osteoarthritis? L. Lugo, A. Villalvilla, R. Largo, G. Herrero-Beaumont, J.A. Roman-Blas ∗ Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz. Universidad Autónoma, Madrid, Spain
a r t i c l e
i n f o
Article history: Received 26 October 2013 Received in revised form 20 January 2014 Accepted 22 January 2014 Keywords: Hormone therapy Estrogen receptors Osteoarthritis Selective estrogen receptor modulators
a b s t r a c t 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. © 2014 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2.
3.
4. 5. 6. 7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Estrogen therapy: current evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Selective estrogen receptor modulators (SERMs): Encouraging data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Development of novel SERMs and selective estrogen ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Practice points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Research agenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
∗ Corresponding author. Tel.: +34 91 550 49 18; fax: +34 91 544 2636. E-mail addresses: [email protected] (L. Lugo), [email protected] (A. Villalvilla), [email protected] (R. Largo), [email protected] (G. Herrero-Beaumont), [email protected] (J.A. Roman-Blas). http://dx.doi.org/10.1016/j.maturitas.2014.01.016 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.
Osteoarthritis (OA) is a chronic progressive disorder that affects the whole joint and finally leads to organ failure. Genetic factors, as well as hormone-dependent and age-related factors such as obesity, local mechanical factors and acute injury, promote molecular, biochemical and biomechanical changes in any joint tissue, leading to joint tissue damage and failure of repair [1,2].
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Fig. 1. The actions of estrogen/SERMs on articular tissues. Estrogen/SERM therapy may produce a dual effect: a direct action upon joint cartilage and an indirect effect on subchondral bone, as well as on synovium, muscle and/or other articular tissue. An ideal SERM would include the beneficial effects of estrogen in musculoskeletal tissues, heart, central nervous system and serum lipids, but have no effect on endometrium, and antagonistic effects in the breast, as well as an absence of the adverse effects associated with estrogen therapy.
Two observations suggest that estrogen may help protect against the development of OA: the dramatic rise in the prevalence of OA after the menopause and the presence of estrogen receptors (ER) in joint tissues, including articular cartilage, subchondral bone, synovial membrane, muscle and ligaments [3]. Recent studies have supported the notion that estrogen or selective estrogen receptor modulators (SERMs) may have a beneficial effect in OA (Fig. 1). 2. Estrogen therapy: current evidence 2.1. Human studies Although there is some evidence of a protective effect of estrogen therapy (ET) for hip OA, a systematic review concluded that there was no clear overall beneficial effect of ET on OA [4]. Eighteen observational studies and one randomized clinical trial were included in that analysis. The heterogeneity in hormones and outcome measurements used in the different studies contributed to the failure to reach clear conclusions. Regarding prevalence, long-term ET did reduce the risk of radiographic hip OA in the study of osteoporotic fractures [5]. Similarly, initial cross-sectional analyses of the Chingford Study and the Framingham Osteoarthritis Study, two of the largest observational studies, found an inverse association between ET and radiographic knee OA [6,7]. Regarding incidence, however, subsequent followup analyses in the latter two studies failed to show that ET protected against either the development or the progression of knee OA, as determined radiographically [8,9]. Furthermore, contradictory results have been reported regarding the association between ET and the need for joint replacement in OA [4]. Nevertheless, in the large Women’s Health Initiative study, women who received estrogen alone had fewer arthroplasties, particularly in the hip (less so
in the knee) [10]. In turn, in a large cross-sectional study, knee MRI scans showed that women receiving estrogen or alendronate had less OA-related subchondral bone attrition and fewer bone marrow edema-like abnormalities than women not receiving these antiresorptives [11]. A recent longitudinal observational study found no association between ET and the incidence of knee replacement [12]; however, a prospective study of 1.3 million women revealed that ET was associated with a high incidence of hip and knee replacement [13]. In contrast, a beneficial effect of ET on cartilage turnover has been reported, as indicated by decreased serum levels of cartilage oligomeric matrix protein (COMP), after 6 months, in postmenopausal women with osteopenia or osteoporosis [14]. Moreover, a newly released study reveals that ET reduced by almost 40% the revision rates after knee or hip arthropasty [15]. 2.2. In vivo studies ET had mixed effects on the joint cartilage of ovariectomized (OVX) animals in a systematic review that included only wellcontrolled studies [16]. In fact, only 11 out of 22 animal studies reported a beneficial effect, whereas three studies described no effect and a further two no clear effect, while the other six studies showed a deleterious effect. While intra-articular estradiol injections had detrimental effects on the knee cartilage of OVX rabbits, favorable effects of long-term ET were seen in other models [16]. Furthermore, early estrogen administration maximized its positive effects on cartilage [17]. In OVX cynomolgus monkeys, ET has been found to limit the formation of both subchondral bone and epiphyseal/metaphyseal cancellous bone in the proximal tibia and to reduce the prevalence of marginal osteophytes, particularly in the lateral tibial plateau [18,19]. However, neither the cross-sectional area of osteophytes
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Table 1 Selective estrogen receptor modulators (SERMs) in joint tissues. Drug name
Type of study
Effect on joint tissue
Reference
Raloxifene
In vitro rat chondrocyte OA-like model
Decrease of MMP-13, MMP-3, ALP and collagen X expression, and caspase-3 activity by chondrocytes. Increased of collagen II deposition and improvement of mechanical properties Increase of PG levels and decrease of MMP-3 and NO in the culture medium. Increase of cell viability Prevention of caspase-3-dependent apoptosis induced by TNF-␣ by activating ERs and ERK1/2 signaling pathway Reduction of CTX-II and CTX-I levels at 12 month Raloxifene and alfacalcidol have greater analgesic effect than alfacalcidol alone taken daily for 6 months Decrease of cartilage damage Decrease of cartilage damage Decrease of cartilage damage Antagonism of the chondrodestructive effects of high dose estradiol I.A. Inhibited the OVX-induced acceleration of cartilage and bone turnover, and suppressed cartilage damage Reduction of CTX-II and CTX-I levels at 12 month. Reversal of CTX-II levels after treatment Inhibited the OVX-induced acceleration of cartilage and bone turnover, and suppressed cartilage damage
Kavas et al. [34]
In vitro agarose-chondrocyte disc model In vitro IL-1 treated human chondrocytes In vitro Human chondrocytes Postmenopausal women Postmenopausal women with OP or OA Tamoxifen
In vivo rabbit model with OVX + MMX-OA In vivo rabbit model with MMX-OA In vivo intact male rabbit model of OA In vivo rabbit model with OVX + MMX-OA
Levormeloxifen
In vivo OVX Sprague-Dawley rats Postmenopausal women
Cis-3,4-7-hydroxy-3phenyl-4-(4-(2pyrrolidinoethox) phenyl)chromane
In vivo OVX Sprague-Dawley rats
Tinti et al. [35] Hattori et al. [36] Karsdal et al. [27] Fujita et al. [28] Rosner et al. [29] Rosner et al. [30] Colombo et al. [32] Tsai et al. [31] Christgau et al. [2]
Høegh-Andersen et al. [33]
OA: osteoarthritis; OP: osteoporosis; OVX: ovariectomy; MMX-OA: medial meniscectomy-induced OA.
nor the static or dynamic histomorphometric parameters of osteophytes were influenced by ET [20]. Recent studies have only added to the uncertainty regarding the effect of ET on joint health. Exogenous estrogen has been found to inhibit tibial and patellar subchondral cortical thinning, and to protect against patellar cartilage damage in OVX mice [21]. Likewise, estrogen was found to restore subchondral bone loss but not to provide significant protection against cartilage structural lesions, despite reducing ADAMTS-4 and -5 expression in the cartilage of osteopenic mice [22]. The administration of estrogen in OVX Sprague-Dawley rats improved the histological integrity of joint cartilage, and reduced the turnover of both cartilage and bone [23]. In addition, ET decreased the synovial density of substance P and calcitonin gene-related peptide immunoreactive nerve fibers in a rat anterior cruciate ligament transection model of OA, suggesting that estrogen partly regulates neurogenic inflammation in OA joints [24]. However, ET potentiated cartilage degradation, subchondral bone erosion and apoptotic gene expression in iodoacetate-induced temporomandibular OA in OVX rats [25]. The mechanisms underlying estrogen’s effects on joint tissues involve crucial factors at multiple levels. These factors include the tissue distribution of ER subtypes, the nature of the ligand that binds to them, the cell transcription machinery, the interaction with coregulatory proteins and the activated cell signaling pathway. The complexity of these mechanisms may have contributed to the inconclusive results obtained with estrogen administration in OA.
3. Selective estrogen receptor modulators (SERMs): Encouraging data SERMs are a group of structurally different agents that bind to ERs. Each ER ligand exerts specific actions in the target cell in a tissue-dependent manner. While initial studies with SERMs have suggested they may have some benefit in the treatment of OA, there are some concerns about their long-term safety and some doubts about patient compliance.
3.1. Human studies In the large cross-sectional Health ABC study, raloxifene use was not associated with any OA-related MRI feature in knees [11]. Further studies have, though, suggested a beneficial effect of SERMs on cartilage metabolism. Levormeloxifene decreased by approximately 50% levels of the cartilage and bone biomarkers CTX-II and CTX-I at 12 months compared with baseline [26]. Likewise, raloxifene reduced levels of these biomarkers in postmenopausal women [27]. Interestingly, CTX-II levels reverted to baseline values while CTX-I remained strongly suppressed after the women ceased levormeloxifene treatment. This suggests that SERMs may exert a short-term effect on the cartilage, but a long-term effect on bone [27]. In a recent proof-of-concept study, raloxifene plus alfacalcidol administered daily had a greater analgesic effect than alfacalcidol alone, taken daily for 6 months, on back and/or knee pain, as assessed by electroalgometry and visual rating scales in postmenopausal women with osteoporosis or OA [28]. 3.2. In vivo studies Unlike the inconclusive effects of estrogen, SERM administration has shown clear benefits on articular cartilage in experimental models of OA. In all six studies included in a systematic review, a positive effect of SERMs on joint health was found [16]. Tamoxifen decreased cartilage damage and antagonized the chondrodestructive effects of high-dose estradiol intraarticularly administered in different rabbit models of OA [29–32]. Tamoxifen even protected articular cartilage in intact male rabbits, suggesting that its therapeutic effect may be not only related to its anti-estrogenic properties [32]. In addition, both cis-3,4-7-hydroxy-3-phenyl4-(4-(2pyrrolidinoethoxy)phenyl)chromane and levormeloxifene inhibited the OVX-induced acceleration of cartilage and bone turnover, and they significantly suppressed cartilage damage in female Sprague-Dawley rats [26,33]. The mechanisms underlying the effects of SERMs on articular tissues are only now being elucidated [34–36] (Table 1). Besides their actions on ERs and their interactions with co-regulator proteins to form transcriptional complexes, some of the clinical
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effects of SERMs may implicate rapid actions mediated by GPER1, with subsequent activation of PI3K/Akt and/or PKC/MAPK cascades, since raloxifene and tamoxifen have been recognized as GPER1 agonists.
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Competing interests The authors declare they have no conflicts of interest. Funding
4. Development of novel SERMs and selective estrogen ligands New-generation SERMs with novel chemical structures have been developed. These have shown comparable efficacy to conventional estrogen replacement therapy (ERT) and have an improved safety profile in animal models. Lasofoxifene and bazedoxifene are currently marketed in Europe. Moreover, the pairing of a SERM (bazedoxifene) with conjugated estrogens, known as tissue selective estrogen complex (TSEC), has recently been approved in the USA. This compound has the beneficial effects of estrogens and SERMS in bone and on postmenopausal symptoms, while being safer than either therapy alone. Finally, novel ER ligands, both pathway- and ER-selective, have displayed a potent anti-inflammatory activity in the absence of conventional estrogenic activity in different animal models of inflammatory diseases. Accordingly, these novel approaches may have utility as treatments for OA.
5. Conclusions Despite flaws in study design, there do seem to be beneficial effects on OA of therapy with estrogen and, especially, some SERMs. These agents may have a dual effect: a direct action upon joint cartilage and an indirect effect on subchondral bone, synovium, muscle and/or other articular tissue. 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 [37,38]. Further research is needed, though, before these agents can become a therapeutic option for OA.
6. Practice points • OA is a progressive disease that affects the whole joint and its prevalence increases rapidly in women after the menopause. • Although estrogen administration has shown mixed results in OA, perhaps because of methodological flaws in these studies, SERMs have achieved encouraging early positive results in OA. • Postmenopausal women with osteoporotic OA may benefit from treatment with SERMs.
7. Research agenda • To increase knowledge of the mechanisms of action of SERMS on joint tissue in menopause-induced OA. • To develop new SERMS with anti-arthritic effects on joint tissues, and an improved safety profile in other organs. • To conduct well-designed clinical trials to determine the effects of SERMs in postmenopausal patients with early OA, whether or not associated with osteoporosis.
Contributors All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version.
This work was supported by research grants from Fondo de Investigación Sanitaria (FIS) (PS09/01625 and PI12/00144). Mrs Amanda Villalvilla is the recipient of a fellowship from the Fundación Conchita Rábago. Dr Raquel Largo’s work was funded by the Instituto de Salud Carlos III through a research staff stabilization program. Provenance and peer review Commissioned and externally peer reviewed. Acknowledgments The authors thank Dr. Lenny A. Mendoza Torres for her assistance in preparing the figure. References [1] Lane NE, Brandt K, Hawker G, Peeva E, Schreyer E, Tsuji W, et al. OARSIFDA initiative: defining the disease state of osteoarthritis. Osteoarthritis Cartil 2011;19:478–82. ˜ [2] Herrero-Beaumont G, Roman-Blas JA, Castaneda S, Jimenez SA. Primary osteoarthritis no longer primary: three subsets with distinct etiological, clinical, and therapeutic characteristics. Semin Arthritis Rheum 2009;39:71–80. ˜ [3] Roman-Blas JA, Castaneda S, Largo R, Herrero-Beaumont G. Osteoarthritis associated with estrogen deficiency. Arthritis Res Ther 2009;11:241. [4] De Klerk BM, Schiphof D, Groeneveld FP, Koes BW, van Osch GJ, van Meurs JB, et al. Limited evidence for a protective effect of unopposed oestrogen therapy for osteoarthritis of the hip: a systematic review. Rheumatology (Oxford) 2009;48:104–12. [5] Nevitt MC, Cummings SR, Lane NE, Hochberg MC, Scott JC, Pressman AR, 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;156:2073–80. [6] Spector TD, Nandra D, Hart DJ, Doyle DV. Is hormone replacement therapy protective for hand and knee osteoarthritis in women. The Chingford study. Ann Rheum Dis 1997;56:432–44. [7] Hannan MT, Felson DT, Anderson JJ, Naimark A, Kannel WB. Estrogen use and radiographic osteoarthritis of the knee in women: the Framingham Osteoarthritis Study. Arthritis Rheum 1990;33:525–32. [8] Hart DJ, Doyle DV, Spector TD. Incidence and risk factors for radiographic knee osteoarthritis in middle-aged women: the Chingford Study. Arthritis Rheum 1999;42:17–24. [9] Zhang Y, McAlindon TE, Hannan MT, Chaisson CE, Klein R, Wilson PW, et al. Estrogen replacement therapy and worsening of radiographic knee osteoarthritis: the Framingham Study. Arthritis Rheum 1998;41:1867–73. [10] Cirillo DJ, Wallace RB, Wu L, Yood RA. Effect of hormone therapy on risk of hip and knee joint replacement in the Women’s Health Initiative. Arthritis Rheum 2006;54:3194–204. [11] Carbone LD, Nevitt MC, Wildy K, Barrow KD, 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;50:3516–25. [12] Wise BL, Niu J, Zhang Y, Felson DT, Bradley LA, Segal N, et al. The association of parity with osteoarthritis and knee replacement in the Multicenter Osteoarthritis Study. Osteoarthritis Cartil 2013;21:1849–54. [13] 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;68:115–70. [14] Seo SK, Yang HI, Lim KJ, Jeon YE, Choi YS, 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;74:143–50. [15] Prieto-Alhambra D, Javaid MK, Judge A, Maskell J, Cooper C, Arden NK. On behalf of the COASt Study Group. Hormone replacement therapy and midterm 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. [16] Sniekers YH, Weinans H, Bierma-Zeinstra SM, van Leeuwen JP, van Osch GJ. Animal models for osteoarthritis: the effect of ovariectomy and estrogen treatment—a systematic approach. Osteoarthritis Cartil 2008;16:533–41.
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[27] Karsdal MA, Bay-Jensen AC, Henriksen K, Christiansen C. The pathogenesis of osteoarthritis involves bone, cartilage and synovial inflammation: may estrogen be a magic bullet. Menopause Int 2012;18:139–46. [28] 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;28:477–84. [29] Rosner IA, Malemud CJ, Goldberg VM, Papay RS, Getzy L, Moskowitz RW. Pathologic and metabolic responses of experimental osteoarthritis to estradiol and an estradiol antagonist. Clin Orthop Relat Res 1982:280–6. [30] Rosner IA, Boja BA, Goldberg VM, Moskowitz RW. Tamoxifen therapy in experimental osteoarthritis. Curr Ther Res 1983;34:409–14. [31] Tsai CL, Liu TK. Inhibition of estradiol-induced early osteoarthritic changes by tamoxifen. Life Sci 1992;50:1943–51. [32] 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;26:1132–9. [33] Høegh-Andersen P, Tankó LB, Andersen TL, Lundberg CV, Mo JA, Heegaard AM, et al. Ovariectomized rats as a model of postmenopausal osteoarthritis: validation and application. Arthritis Res Ther 2004;6:R169–80. [34] Kavas A, Cagatay ST, 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;38:135–47. [35] Tinti L, Niccolini S, Lamboglia A, Pascarelli NA, Cervone R, Fioravanti A. Raloxifene protects cultured human chondrocytes from IL-1 induced damage: a biochemical and morphological study. Eur J Pharmacol 2011;670:67–73. [36] Hattori Y, Kojima T, Kato D, Matsubara H, Takigawa M, Ishiguro N. A selective estrogen receptor modulator inhibits tumor necrosis factor-␣-induced apoptosis through the ERK1/2 signaling pathway in human chondrocytes. Biochem Biophys Res Commun 2012;421:418–24. ˜ [37] Roman-Blas JA, Castaneda S, Largo R, Lems WF, Herrero-Beaumont G. An OA phenotype may obtain major benefit from bone-acting agents. Semin Arthritis Rheum 2014;43:421–8. [38] Herrero-Beaumont G, Roman-Blas JA. Osteoarthritis: osteoporotic OA: a reasonable target for bone-acting agents. Nat Rev Rheumatol 2013;9:448–50.
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Mini review
Selective estrogen receptor modulators (SERMs): New alternatives for osteoarthritis? L. Lugo, A. Villalvilla, R. Largo, G. Herrero-Beaumont, J.A. Roman-Blas ∗ Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz. Universidad Autónoma, Madrid, Spain
a r t i c l e
i n f o
Article history: Received 26 October 2013 Received in revised form 20 January 2014 Accepted 22 January 2014 Keywords: Hormone therapy Estrogen receptors Osteoarthritis Selective estrogen receptor modulators
a b s t r a c t 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. © 2014 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2.
3.
4. 5. 6. 7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Estrogen therapy: current evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Selective estrogen receptor modulators (SERMs): Encouraging data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Development of novel SERMs and selective estrogen ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Practice points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Research agenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
380 381 381 381 382 382 382 383 383 383 383 383 383 383 383 383 383
1. Introduction
∗ Corresponding author. Tel.: +34 91 550 49 18; fax: +34 91 544 2636. E-mail addresses: [email protected] (L. Lugo), [email protected] (A. Villalvilla), [email protected] (R. Largo), [email protected] (G. Herrero-Beaumont), [email protected] (J.A. Roman-Blas). http://dx.doi.org/10.1016/j.maturitas.2014.01.016 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.
Osteoarthritis (OA) is a chronic progressive disorder that affects the whole joint and finally leads to organ failure. Genetic factors, as well as hormone-dependent and age-related factors such as obesity, local mechanical factors and acute injury, promote molecular, biochemical and biomechanical changes in any joint tissue, leading to joint tissue damage and failure of repair [1,2].
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Fig. 1. The actions of estrogen/SERMs on articular tissues. Estrogen/SERM therapy may produce a dual effect: a direct action upon joint cartilage and an indirect effect on subchondral bone, as well as on synovium, muscle and/or other articular tissue. An ideal SERM would include the beneficial effects of estrogen in musculoskeletal tissues, heart, central nervous system and serum lipids, but have no effect on endometrium, and antagonistic effects in the breast, as well as an absence of the adverse effects associated with estrogen therapy.
Two observations suggest that estrogen may help protect against the development of OA: the dramatic rise in the prevalence of OA after the menopause and the presence of estrogen receptors (ER) in joint tissues, including articular cartilage, subchondral bone, synovial membrane, muscle and ligaments [3]. Recent studies have supported the notion that estrogen or selective estrogen receptor modulators (SERMs) may have a beneficial effect in OA (Fig. 1). 2. Estrogen therapy: current evidence 2.1. Human studies Although there is some evidence of a protective effect of estrogen therapy (ET) for hip OA, a systematic review concluded that there was no clear overall beneficial effect of ET on OA [4]. Eighteen observational studies and one randomized clinical trial were included in that analysis. The heterogeneity in hormones and outcome measurements used in the different studies contributed to the failure to reach clear conclusions. Regarding prevalence, long-term ET did reduce the risk of radiographic hip OA in the study of osteoporotic fractures [5]. Similarly, initial cross-sectional analyses of the Chingford Study and the Framingham Osteoarthritis Study, two of the largest observational studies, found an inverse association between ET and radiographic knee OA [6,7]. Regarding incidence, however, subsequent followup analyses in the latter two studies failed to show that ET protected against either the development or the progression of knee OA, as determined radiographically [8,9]. Furthermore, contradictory results have been reported regarding the association between ET and the need for joint replacement in OA [4]. Nevertheless, in the large Women’s Health Initiative study, women who received estrogen alone had fewer arthroplasties, particularly in the hip (less so
in the knee) [10]. In turn, in a large cross-sectional study, knee MRI scans showed that women receiving estrogen or alendronate had less OA-related subchondral bone attrition and fewer bone marrow edema-like abnormalities than women not receiving these antiresorptives [11]. A recent longitudinal observational study found no association between ET and the incidence of knee replacement [12]; however, a prospective study of 1.3 million women revealed that ET was associated with a high incidence of hip and knee replacement [13]. In contrast, a beneficial effect of ET on cartilage turnover has been reported, as indicated by decreased serum levels of cartilage oligomeric matrix protein (COMP), after 6 months, in postmenopausal women with osteopenia or osteoporosis [14]. Moreover, a newly released study reveals that ET reduced by almost 40% the revision rates after knee or hip arthropasty [15]. 2.2. In vivo studies ET had mixed effects on the joint cartilage of ovariectomized (OVX) animals in a systematic review that included only wellcontrolled studies [16]. In fact, only 11 out of 22 animal studies reported a beneficial effect, whereas three studies described no effect and a further two no clear effect, while the other six studies showed a deleterious effect. While intra-articular estradiol injections had detrimental effects on the knee cartilage of OVX rabbits, favorable effects of long-term ET were seen in other models [16]. Furthermore, early estrogen administration maximized its positive effects on cartilage [17]. In OVX cynomolgus monkeys, ET has been found to limit the formation of both subchondral bone and epiphyseal/metaphyseal cancellous bone in the proximal tibia and to reduce the prevalence of marginal osteophytes, particularly in the lateral tibial plateau [18,19]. However, neither the cross-sectional area of osteophytes
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Table 1 Selective estrogen receptor modulators (SERMs) in joint tissues. Drug name
Type of study
Effect on joint tissue
Reference
Raloxifene
In vitro rat chondrocyte OA-like model
Decrease of MMP-13, MMP-3, ALP and collagen X expression, and caspase-3 activity by chondrocytes. Increased of collagen II deposition and improvement of mechanical properties Increase of PG levels and decrease of MMP-3 and NO in the culture medium. Increase of cell viability Prevention of caspase-3-dependent apoptosis induced by TNF-␣ by activating ERs and ERK1/2 signaling pathway Reduction of CTX-II and CTX-I levels at 12 month Raloxifene and alfacalcidol have greater analgesic effect than alfacalcidol alone taken daily for 6 months Decrease of cartilage damage Decrease of cartilage damage Decrease of cartilage damage Antagonism of the chondrodestructive effects of high dose estradiol I.A. Inhibited the OVX-induced acceleration of cartilage and bone turnover, and suppressed cartilage damage Reduction of CTX-II and CTX-I levels at 12 month. Reversal of CTX-II levels after treatment Inhibited the OVX-induced acceleration of cartilage and bone turnover, and suppressed cartilage damage
Kavas et al. [34]
In vitro agarose-chondrocyte disc model In vitro IL-1 treated human chondrocytes In vitro Human chondrocytes Postmenopausal women Postmenopausal women with OP or OA Tamoxifen
In vivo rabbit model with OVX + MMX-OA In vivo rabbit model with MMX-OA In vivo intact male rabbit model of OA In vivo rabbit model with OVX + MMX-OA
Levormeloxifen
In vivo OVX Sprague-Dawley rats Postmenopausal women
Cis-3,4-7-hydroxy-3phenyl-4-(4-(2pyrrolidinoethox) phenyl)chromane
In vivo OVX Sprague-Dawley rats
Tinti et al. [35] Hattori et al. [36] Karsdal et al. [27] Fujita et al. [28] Rosner et al. [29] Rosner et al. [30] Colombo et al. [32] Tsai et al. [31] Christgau et al. [2]
Høegh-Andersen et al. [33]
OA: osteoarthritis; OP: osteoporosis; OVX: ovariectomy; MMX-OA: medial meniscectomy-induced OA.
nor the static or dynamic histomorphometric parameters of osteophytes were influenced by ET [20]. Recent studies have only added to the uncertainty regarding the effect of ET on joint health. Exogenous estrogen has been found to inhibit tibial and patellar subchondral cortical thinning, and to protect against patellar cartilage damage in OVX mice [21]. Likewise, estrogen was found to restore subchondral bone loss but not to provide significant protection against cartilage structural lesions, despite reducing ADAMTS-4 and -5 expression in the cartilage of osteopenic mice [22]. The administration of estrogen in OVX Sprague-Dawley rats improved the histological integrity of joint cartilage, and reduced the turnover of both cartilage and bone [23]. In addition, ET decreased the synovial density of substance P and calcitonin gene-related peptide immunoreactive nerve fibers in a rat anterior cruciate ligament transection model of OA, suggesting that estrogen partly regulates neurogenic inflammation in OA joints [24]. However, ET potentiated cartilage degradation, subchondral bone erosion and apoptotic gene expression in iodoacetate-induced temporomandibular OA in OVX rats [25]. The mechanisms underlying estrogen’s effects on joint tissues involve crucial factors at multiple levels. These factors include the tissue distribution of ER subtypes, the nature of the ligand that binds to them, the cell transcription machinery, the interaction with coregulatory proteins and the activated cell signaling pathway. The complexity of these mechanisms may have contributed to the inconclusive results obtained with estrogen administration in OA.
3. Selective estrogen receptor modulators (SERMs): Encouraging data SERMs are a group of structurally different agents that bind to ERs. Each ER ligand exerts specific actions in the target cell in a tissue-dependent manner. While initial studies with SERMs have suggested they may have some benefit in the treatment of OA, there are some concerns about their long-term safety and some doubts about patient compliance.
3.1. Human studies In the large cross-sectional Health ABC study, raloxifene use was not associated with any OA-related MRI feature in knees [11]. Further studies have, though, suggested a beneficial effect of SERMs on cartilage metabolism. Levormeloxifene decreased by approximately 50% levels of the cartilage and bone biomarkers CTX-II and CTX-I at 12 months compared with baseline [26]. Likewise, raloxifene reduced levels of these biomarkers in postmenopausal women [27]. Interestingly, CTX-II levels reverted to baseline values while CTX-I remained strongly suppressed after the women ceased levormeloxifene treatment. This suggests that SERMs may exert a short-term effect on the cartilage, but a long-term effect on bone [27]. In a recent proof-of-concept study, raloxifene plus alfacalcidol administered daily had a greater analgesic effect than alfacalcidol alone, taken daily for 6 months, on back and/or knee pain, as assessed by electroalgometry and visual rating scales in postmenopausal women with osteoporosis or OA [28]. 3.2. In vivo studies Unlike the inconclusive effects of estrogen, SERM administration has shown clear benefits on articular cartilage in experimental models of OA. In all six studies included in a systematic review, a positive effect of SERMs on joint health was found [16]. Tamoxifen decreased cartilage damage and antagonized the chondrodestructive effects of high-dose estradiol intraarticularly administered in different rabbit models of OA [29–32]. Tamoxifen even protected articular cartilage in intact male rabbits, suggesting that its therapeutic effect may be not only related to its anti-estrogenic properties [32]. In addition, both cis-3,4-7-hydroxy-3-phenyl4-(4-(2pyrrolidinoethoxy)phenyl)chromane and levormeloxifene inhibited the OVX-induced acceleration of cartilage and bone turnover, and they significantly suppressed cartilage damage in female Sprague-Dawley rats [26,33]. The mechanisms underlying the effects of SERMs on articular tissues are only now being elucidated [34–36] (Table 1). Besides their actions on ERs and their interactions with co-regulator proteins to form transcriptional complexes, some of the clinical
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effects of SERMs may implicate rapid actions mediated by GPER1, with subsequent activation of PI3K/Akt and/or PKC/MAPK cascades, since raloxifene and tamoxifen have been recognized as GPER1 agonists.
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Competing interests The authors declare they have no conflicts of interest. Funding
4. Development of novel SERMs and selective estrogen ligands New-generation SERMs with novel chemical structures have been developed. These have shown comparable efficacy to conventional estrogen replacement therapy (ERT) and have an improved safety profile in animal models. Lasofoxifene and bazedoxifene are currently marketed in Europe. Moreover, the pairing of a SERM (bazedoxifene) with conjugated estrogens, known as tissue selective estrogen complex (TSEC), has recently been approved in the USA. This compound has the beneficial effects of estrogens and SERMS in bone and on postmenopausal symptoms, while being safer than either therapy alone. Finally, novel ER ligands, both pathway- and ER-selective, have displayed a potent anti-inflammatory activity in the absence of conventional estrogenic activity in different animal models of inflammatory diseases. Accordingly, these novel approaches may have utility as treatments for OA.
5. Conclusions Despite flaws in study design, there do seem to be beneficial effects on OA of therapy with estrogen and, especially, some SERMs. These agents may have a dual effect: a direct action upon joint cartilage and an indirect effect on subchondral bone, synovium, muscle and/or other articular tissue. 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 [37,38]. Further research is needed, though, before these agents can become a therapeutic option for OA.
6. Practice points • OA is a progressive disease that affects the whole joint and its prevalence increases rapidly in women after the menopause. • Although estrogen administration has shown mixed results in OA, perhaps because of methodological flaws in these studies, SERMs have achieved encouraging early positive results in OA. • Postmenopausal women with osteoporotic OA may benefit from treatment with SERMs.
7. Research agenda • To increase knowledge of the mechanisms of action of SERMS on joint tissue in menopause-induced OA. • To develop new SERMS with anti-arthritic effects on joint tissues, and an improved safety profile in other organs. • To conduct well-designed clinical trials to determine the effects of SERMs in postmenopausal patients with early OA, whether or not associated with osteoporosis.
Contributors All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version.
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