Several experimental studies have shown that estrogens are implicated in the regulation of cartilage metabolism. Indeed, 17β-estradiol (E₂) enhances glycosaminoglycan synthesis in cultures of rabbit joint chondrocytes through the up-regulation of the uridine diphosphate glucose dehydrogenase gene 15. Furthermore, estrogen (1 to 100 M) significantly impairs the release of C-telopeptide of type II collagen from TNF-α and oncostatin M-stimulated bovine cartilage explants ex vivo in a dose-dependent manner 16. In addition, E₂ inhibits cyclooxygenase-2 mRNA expression in bovine articular chondrocytes and protects them from reactive oxygen species-induced damage 1718. However, the effects of high doses of estrogen on chondrocytes are contradictory. High concentrations of E₂ lead to deleterious effects such as suppression of DNA synthesis in human chondrocytes 19, as well as the inhibition of proteoglycan synthesis and cell division in both bovine chondrocytes and cartilage explants 2021. A significant difference in ER affinity for its ligand as a function of age was observed. Human chondrocytes from early pubertal individuals display a maximal response to estrogens, while chondrocytes from neonatal children do not respond at all 22. Similarly, ERs from pubertal rabbit chondrocytes exhibit higher affinity for estrogens than pre-pubertal chondrocytes 23. Thus, estrogen dose and donor age are the main factors that influence chondrocyte response to estrogen.

These and many other relevant findings in vitro (discussed below) clearly show that estrogen influences the activity of all joint tissues through complex molecular mechanisms acting at multiple levels.

The effects of estrogen on joint tissues have primarily been studied in ovariectomized (OVX) animal models. Despite these studies, the influence of estrogen deficiency on cartilage remains unclear, even though there is significant evidence of the detrimental effect of estrogen loss in mature female animals 7. An increase in cartilage turnover and surface erosion was observed in OVX Sprague-Dawley rats 24, as well as in cynomolgus macaques subjected to bilateral OVX 25. Significantly, intact females had less severe OA than OVX females and although intact male mice showed more severe OA than intact females, orchiectomized mice develop less OA than intact males 26. By contrast, such associations could not be shown in other earlier studies 7.

Relevant changes have also been described in the subchondral bone of OVX animals. Indeed, OVX cynomolgus monkeys have higher indices of bone turnover in subchondral bone compared to epiphyseal/metaphyseal cancellous bone of the proximal tibia 27. Moreover, the marginal osteophyte area is positively correlated with subchondral bone thickness in the medial tibial plateau of these animals 28. Significantly, subchondral bone remodeling has also been described in conjunction with changes in joint cartilage in a guinea pig model of spontaneous OA 29. We found that rabbit subchondral bone has mixed densitometric characteristics with a marked predominance of cortical bone 30. In fact, subchondral knee bone mineral density (BMD) is significantly correlated with the BMD of the spine, and trabecular and cortical knee bone in healthy, OA, OP and OP/OA rabbits 31.

Our rabbit model is a valuable tool to study OP because rabbits have much faster bone turnover than rodents or primates, and in contrast to rodents, they reach skeletal maturity soon after their sexual development is complete 32. Moreover, since OVX itself only causes mild osteopenia, which may be insufficient to provoke OP in these animals, moderate doses of methylprednisolone were administrated to ensure OP development 33. We evaluated whether estrogen deficiency alone can induce OA alterations in healthy cartilage or, by contrast, whether OP subchondral bone is the origin of the cartilage changes in these animals. Estrogen deficiency leads to mild OA changes 22 weeks after isolated OVX in healthy articular cartilage, while OVX and methylprednisolone-induced OP play an additional role in these osteoarthritic changes (Figure 2). Thus, estrogen deprivation might produce a dual effect: a main direct action upon joint cartilage and a minor indirect effect on subchondral bone.

The influence of estrogen on the remaining joint tissues has not been studied directly in OA animal models. However, the involvement of these tissues in OA and the changes produced by estrogen in related animal models suggest a potential role of estrogen in OA changes. Indeed, the remodeling of the cruciate ligament is thought to occur early during knee OA in guinea pigs 29 and the potential role of endogenous estrogens in the disproportionate number of anterior cruciate ligament (ACL) injuries seen in female athletes has been studied in different animal models, although to date with negative results 34. Besides, significant attenuation of histochemical and biochemical indices of muscle damage and inflammatory response were found in female rats after downhill running when compared with their male counterparts. Such an effect may possibly be explained by the higher circulating estrogen levels in these rats 35. In addition, estrogen deficiency following OVX is often accompanied by an increase in fat mass, which in turn leads to increased adipokine levels, the role of which in OA is also now being investigated.

Associations between polymorphisms in the human ERα gene (ESR1) and OA have been studied in different populations with mixed results. Haplotypes of the PvuII and XbaI polymorphisms in the ERα gene have been associated with an increased prevalence of clinical and radiographic knee OA 363738. In addition, the exon 8 G/A BtgI polymorphism was also associated with knee OA in Asian populations 38. However, other studies showed either no or only a modest inverse relationship between ERα gene polymorphisms and OA in Caucasian populations 3940.

Numerous clinical studies have also shown that OA is related to estrogen levels 8941424344454647. Thus, the prevalence of OA is greater in women than men and a clear increase in OA prevalence is associated with the peak age of menopause 8941. Indeed, a nationwide population survey showed that radiographic generalized OA is three times more common in women aged 45 to 64 years compared to their male counterparts 9, and a hospital-based study found a high female to male ratio of 10:1 for OA, with a peak at 50 years of age 42. In addition, 64% of females with knee OA suffered the onset of symptoms either perimenopausally or within 5 years of natural menopause or hysterectomy. In fact, the onset of symptoms of knee OA occurred before 50 years of age in 58% of females as opposed to only 20% of males 43.

Since the earliest studies of OA, generalized involvement of joints was described in postmenopausal females, and predominant node formation with early signs of inflammation was observed in the proximal and distal interphalangeal joints of the hands 44. Nodular hand OA is often associated with a polyarticular and symmetric involvement of major joints such as knees and hips 45. Erosions may occur in the inter-phalangeal joints and are characteristic of erosive OA. This disorder tends to occur in middle-aged women, and it is often an acute condition with features of inflammation that subside over a period of months to years, leaving deformed joints and occasional ankylosis 46. Lower levels of serum E₂ and its metabolite 2-hydroxyestrone in urine were recently reported in postmenopausal women who developed radiographically defined knee OA 47.

Failure of estrogen production at menopause is associated with a relevant loss of muscle mass and, therefore, significant impairment of muscle performance and functional capacity 48. Diminished strength of the quadriceps in women but not men predict knee OA 49, and peri- and postmenopausal women also seem to have less lean body mass when compared with pre-menopausal women 50. In addition, varus-valgus laxity has more frequently been described in women than in men 51.

Estrogen primarily exerts its effects on target tissues by binding to and activating ERs. ERs act as ligand-activated transcription factors in the nucleus that specifically bind to estrogen response elements (EREs) in the promoters of target genes such as the human oxytocin, prolactin, cathepsin D, progesterone receptor, vascular endothelial growth factor, insulin-like growth factor (IGF)-1, or c-fos genes 61, as diagrammatically shown in Figure 3 (pathway 1). The ERE is a 13 base-pair inverted sequence that binds ERs as dimers. Because imperfect palindromic EREs, or even half EREs, are often seen in the regulatory region of estrogen target genes, transcriptional synergism might occur that could include the co-operative recruitment of co-activators, direct interaction between ER dimers, or allosteric modulation of the DNA-ER complexes 62.

ERs contain four functional domains. The variable amino-terminal A/B domain harbors the constitutive activation function (AF)-1, which modulates transcription in a gene- and cell-specific manner. The central and most conserved C domain contains the DNA binding domain, and it also mediates receptor dimerization. The D domain is a less well understood region. Finally, the carboxy-terminal multifunctional E/F domain holds the ligand-binding domain as well as sites for cofactors, transcriptional activation (AF-2) and nuclear localization (Figure 4) 63. There are two receptor subtypes, ERα and ERβ, which are different proteins encoded by distinct genes located on chromosomes 6 (q24-q27) and 14 (q21-q22), respectively 64. These two receptor subtypes have 96% amino acid homology in the DNA binding domain but only 53% identity in the ligand-binding domain. As a result, similar ERE binding properties have been associated with a partially distinct spectrum of ligands for each receptor, although with similar affinities for estrogen. Even weaker amino acid identity is found in the A/B domain of ERα and ERβ (Figure 4). Both receptors also show little conservation in AF-2 and, therefore, several proteins may direct ERα and ERβ to different targets as observed in their contrasting effects at the activator protein (AP)-1 site of the collagenase promoter. Thus, ERα and ERβ have different transcriptional activities that may contribute to their distinct tissue-specific actions 6365.

Both ERs are distributed widely throughout the body, displaying distinct but overlapping expression in a variety of tissues. ERα is highly expressed in classical estrogen target tissues such as the uterus, placenta, pituitary and cardiovascular system, whereas ERβ is more abundant in the ventral prostate, urogenital tract, ovarian follicles, lung, and immune system. However, the two ERs are co-expressed in tissues such as the mammary gland, bone, and certain regions of the brain 66. Although both ER subtypes can be expressed in the same tissue, they may not be expressed in the same cell type. Nonetheless, in cells where the two ER subtypes are co-expressed, ERβ can antagonize ERα-dependent transcription 64. The generation of human ERα and ERβ mRNA transcripts is a complex process that is controlled by sophisticated regulatory mechanisms leading to the generation of several isoforms/variants for each receptor subtype. Most ERα variants only differ at the 5' untranslated region and they are involved in tissue-specific regulation of ERα gene expression. Several species-specific and common ERβ isoforms have been described, many of which are expressed as proteins in tissues 67.

In articular tissues, both ER types are expressed by the chondrocytes 10, subchondral bone cells 11, synoviocytes 12, ligament fibroblasts 13 and myoblasts 14 in humans and other species. However, ERα is predominant in cortical bone and ERβ predominates in cartilage, cancellous bone and synovium 101268. More mRNA transcripts for both subtypes of ERs were found in male than in female human cartilage, but there were no differences between different joints, or between cartilage from OA patients and the normal population 10. In bone, ERα and ERβ are expressed by OBs and they are differentially expressed during rat OB maturation 69. Pre-osteoclasts express ERα, while osteoclast maturation and bone resorption is associated with the loss of ERα expression 70. ERβ mRNA and protein are predominantly found in the stroma and lining cells of normal human synovium, independent of sex or menopausal status of the tissue donor 12. Fibroblasts from human ACL, medial cruciate ligament and patellar tendon express functional ER transcripts. Indeed, 4 to 10% of ACL cells express ERs in patients with acute ACL injuries, approximately twice the proportion found in control subjects 1371. In human skeletal muscle, ERα mRNA expression was 180-fold higher than that of ERβ 72. Remarkably, individuals that undergo high endurance training have more ERα and ERβ mRNA transcripts in skeletal muscles than moderately active individuals 73.

Characterizing the phenotypes of knockout models has advanced our understanding of the role of ER in biological processes. Indeed, ERβ plays a significant role in bone remodeling in female ER knockout mice, whereas ERα does so in both sexes. Thus, male and female ERα^-/- mice show decreased bone turnover and greater cancellous bone volume, even though the cortical thickness and BMD was reduced. Female ERβ^-/- mice have slightly increased trabecular bone volume, while male animals do not show any change in their bones. Male and female double ER^-/- mice showed significant defects in cortical bone and BMD, while female mice alone displayed a profound decrease in trabecular bone volume 74. A recent study has shown that ERα^-/-β^-/- double knockout increased osteophytosis and thinning of the lateral subchondral plate, both osteoarthritic characteristics, in the knee of transgenic mice 75. These results confirm the relevant changes described in subchondral bone of OVX animal models 272829. However, no difference in cartilage damage was observed between the ERα^-/-, ERβ^-/- and ERα^-/-β^-/- double knockout and wild-type mice at 6 months of age, although the cartilage damage was very mild in all mice 75. Whether the absence of significant cartilage damage in all ER knockout mice groups reflects some important differences between ER knockout mice, which lack ER expression since birth, and OVX models that show significant OA cartilage changes associated with estrogen depletion at a later age 7242526 remains to be established.

As regards muscle, ERα^-/- mice have lower tetanic tension per calculated anatomical cross-sectional and fiber areas in tibialis anterior and gastrocnemius than in wild-type mice. In contrast, ERβ^-/-and wild-type mice were comparable in all measures. These results suggest that the effects of estrogen on skeletal muscle are mainly mediated by ERα 76. With respect to ligaments, no changes in medial cruciate ligament or ACL viscoelastic or tensile mechanical properties were observed in ERβ^-/- mice 77.

The second genomic mechanism involves the interaction of ligand-bound ERs with other transcription factors like Fos/Jun (AP-1-responsive elements), c-Jun/NF-κB and specificity protein 1 (Sp1) recruiting co-regulators to form initiation complexes that regulate the transcription of genes whose promoters do not harbor EREs 6478. In this tethering mechanism, ERs do not bind directly to DNA (Figure 3, mechanism 2) and, thus, ERs can up-regulate the expression of promoters containing AP-1 sites, such as the collagenase and IGF-1 genes. Interestingly, E₂ exerts distinct transcriptional activation on the AP-1 site of the collagenase promoter depending on whether ERα or ERβ is involved: it elicits transcriptional activation with ERα, while it represses transcription with ERβ 6578. The interaction of ERs with Sp1 activates uteroglobin, retinoic acid receptor alpha, IGF-binding protein 4 (IGFBP4), TGF-α, bcl2 and the low-density lipoprotein receptor genes 6178. Similarly, suppression of IL-6 expression by E₂ occurs through interactions of the ligand bound ER with the NF-κB complex 64.

Ligand-dependent activation of ERs, both ERE and non-ERE-mediated, attracts co-regulator molecules that modify the chromatin state, thereby recruiting or hindering the transcriptional complex and representing another level of control in ER gene regulation 616379. Co-activators stimulate transcription by interacting with helix 12 (H12) of the AF-2 region through their short 'nuclear receptor boxes', transducing ligand signals to the basal transcriptional machinery. The best characterized co-activators include the steroid receptor co-activator (SRC) family (SRC1, SRC2 and SRC3) and members of the mammalian mediator complex (thyroid receptor associated proteins, vitamin-D receptor interacting proteins, activator-recruited cofactor) 6379. Alternatively, co-repressors that impede transcription include the nuclear receptor co-repressor (NCoR) and the silencing mediator for the retinoic acid and thyroid hormone receptor (SMRT), which interact with ligand-free ER through an elongated amino acid sequence called the CoRNR-box. By contrast, if H12 assumes a 'charge clamp' configuration in response to agonist binding, then it could not hold the long NCoR/SMRT helices. Thus, agonist binding reduces the affinity of ERs for co-repressors and increases their affinity for co-activators 6379. In addition, both SMRT and NCoR recruit the protein SIN3 and histone deacetylases to form a large co-repressor complex, implicating histone deacetylation in transcriptional repression 79.

In rabbit articular chondrocytes, ERα activation inhibits NF-κB p65 activity and, subsequently, decreases IL-1β-stimulated inducible nitric oxide synthase expression and nitric oxide production 80. Moreover, ERα and, particularly, ERβ transfection significantly enhances MMP-13 promoter activity through an AP-1 site, which may be modulated through the sites of the Runt-related (Runx) and PEA-3 Ets transcription factors in a rabbit synovial cell line lacking endogenous ER 81. A normal balance between classic ERE-mediated and non-ERE-mediated ERα, genomic and non-genomic, pathways in cortical bone have also been described in ERα^-/NERKI mice and its disruption can lead to an aberrant response to estrogen 82.

Estrogens may also exert their ligand-dependent effects through non-genomic mechanisms that are responsible for more rapid effects, occurring within seconds or minutes of stimulating cell signal transduction pathways, such as the mitogen activated protein (MAP) kinases, in particular the extracellular signal regulated kinase 1/2 (ERK 1/2), p38 and phosphatidylinositol-3 (PI3) kinase/Akt pathways 64. A small ER population and/or a G-protein-coupled receptor termed GP30, localized at or close to the cell membrane, may elicit these responses 8384. ER translocation to the cell membrane is nourished by its interaction with membrane proteins such as caveolin 1/2, striatin and the adaptor proteins Shc and p130 Cas 64. S-palmitoylation and myristoylation of ERα also promote ERα association with the plasma membrane and its interaction with caveolin-1 64. Furthermore, interaction between ER, the tyrosine kinase cSrc and an adaptor protein called modulator of nongenomic action of estrogen receptors (MNAR) generates a signaling complex that may be crucial for the important cSrc activation and further kinase phosphorylation 85. Thus, several molecular processes have been shown to mediate the non-genomic effects of ER (Figure 3, pathway 3). However, the precise mechanisms involved in ER localization in the cell membrane, as well as the interaction between ERs and signaling pathways, are yet to be fully established.

There appears to be sexual dimorphism in the non-genomic pathways described in human articular and rat growth plate chondrocytes. Thus, only female cells respond to estrogens by promoting a rapid protein kinase C (PKC)-α-mediated increase in proteoglycan production and alkaline phospha-tase activity (PKC increase occurred within 9 minutes and was maximal at 90 minutes). Treatment with the PKC inhibitor chelerythrine blocked these effects 8687. PKC activation initiated a signaling cascade involving the ERK1/2 and p38 MAP kinase pathways, which in turn mediate the downstream biological effects of estrogen on alkaline phosphatase activity and [(35)S]-sulfate incorporation in rat growth plate chondrocytes. A membrane receptor has been proposed to elicit this response, although its precise nature remains to be established 88.

Estrogen also regulates intracellular calcium concentrations ([Ca²⁺]_i) in a sex-specific and cell maturation state-dependent manner in rat growth plate chondrocytes. Indeed, E₂ more rapidly increased [Ca²⁺]_i in resting zone chondrocytes than in growth-zone chondrocytes from female rats, while no effect was observed in chondrocytes from male rats. This effect is mediated by membrane-associated events, phospholipase C-dependent inositol triphosphate-3 production and Ca²⁺release from the endoplasmic reticulum 89. In the light of the higher prevalence of OA in postmenopausal females, it has been proposed that these intrinsic sex-specific differences may contribute to OA development 86. In addition, inclusion of the gender variable when interpreting experimental data and the functional adaptation of donor cells in transplants between organisms of different sexes should be considered 86.

Both ERK phosphorylation kinetics and the duration of phospho-ERK nuclear retention determine the pro- or anti-apoptotic effects of estrogen in bone cells. In fact, E₂-induced transient ERK phosphorylation (lasting 30 minutes) leads to anti-apoptotic effects in OBs and osteocytes, whereas it produces pro-apoptotic signals in osteoclasts through sustained ERK phosphorylation (for at least 24 hours) 90. Also, the ERK 1/2 and PI3K/Akt/Bad pathways mediate the anti-apoptotic effect of estrogens in C2C12 muscle cells following activation of ERα and ERβ located in diverse cellular compartments such as the mitochondria and perinucleus 91. Divergent ER-induced gene expression has been found depending on whether the genomic or non-genomic signaling pathways are activated in different cell types. In osteoblastic OB-6 cells, E₂ stimulated complement 3 (C3) and IGF-1 expression after 24 hours, which did not occur following estren administration. This discrepancy is explained by the ERE present in the promoter of the C3 gene and by ER regulating IGF-1 through a protein-protein interaction that influences the AP-1 enhancer. Since estren is a non-genotropic ER activator, it did not activate these ERE-or AP-1-containing genes 92.

The stimulation of growth factors such as those of the IGF-1, epidermal growth factor, TGF-β/SMAD and Wnt/β-catenin signaling pathways can activate ERs or associated co-regulators via kinase phosphorylation in the absence of ER ligands 64939495. In turn, ERα may also regulate growth factor signaling 64939495. Crosstalk between growth factors and ERs occurs in both the nuclear and cytoplasmic compartments, promoting highly active interactions 64939495 (Figure 3, pathway 4).

In OBs, estrogen and TGF-β/SMAD signaling pathways may interact at several levels: activation of the TGF-β pathway by estrogens via TGF-β mRNA induction; increase of estrogen and TGF-β/SMAD signaling due to cytoplasmic MAP kinase activity; direct interaction between ERs and the SMAD proteins in the cytoplasm or nucleus; and interaction between ERs and the TGF-β-inducible early-response gene (TIEG) and Runx-2 transcription factors in the nucleus. Both TIEG and Runx-2 expression are induced by E₂ and TGF-β and, furthermore, TIEG appears to be required for the E₂ and TGF-β-induced regulation of Runx2 expression 95. Thus, a relevant inhibition of osteoclastic bone resorption by osteocytes occurs as a result of TGF-β enhancement by estrogen 96.

ERs can interact with members of the Wnt/β-catenin signaling system in both the presence and absence of the ligand 97. Bone response to mechanical forces can be influenced by interactions between the β-catenin and T-cell factor nuclear complex, and ERα in OBs. Indeed, ER modulators suppressed the accumulation of active β-catenin in the nucleus of OBs in vitro within 3 hours following a single period of dynamic strain of magnitude similar to the estimated strain that OBs regularly experience in vivo. Accordingly, microarray analysis performed with RNA extracted from the tibia of ERα^-/- mice demonstrated the abrogation of dynamic axial loading-induced expression of Wnt-responsive genes (compared with RNA from the tibia of wild-type mice) 98. These results suggest that ERα is required for early Wnt/β-catenin-induced bone cell responses to mechanical strain. Indeed, the reduced effectiveness of the bone cell responses to mechanical load associated with estrogen deficiency may alter the bone mass in postmenopausal OP women.

In cynomolgus monkey joint cartilage, IGFBP2-mediated activation of the IGF system induces IGF-1 production, which in turn leads to increased sulfate incorporation into proteoglycans following estrogen administration 99. In addition, ERs might interact with the TGF-β and Wnt/β-catenin signaling cascades in articular chondrocytes. Both the Wnt/β-catenin and TGF-β/SMAD signaling pathways play a prominent role in bone and cartilage biology. The TGF-β/SMAD pathway fulfils a beneficial role in bone and cartilage maintenance/repair, although it is also an important protagonist of osteophyte formation 95100. In turn, the Wnt/β-catenin system is essential in many biological aspects of bone, from differentiation, proliferation and cellular apoptosis to bone mass regulation and its ability to respond to mechanical load 101. Activation of the Wnt/β-catenin pathway has also been implicated in OA cartilage damage, and Wnt inhibitors such as the secreted frizzled related protein 3 and Dickkopf-1 might modulate the susceptibility to, and the progress of, hip OA 102.

Although our understanding of the different molecular mechanisms by which estrogen deficits could act on articular tissues and their contribution to OA development has advanced significantly in recent years, it is still limited and more research will be necessary to identify therapeutic targets for this very prevalent disease.

Estrogen administration in OVX animals has paradoxical effects on joint cartilage, in contrast to the clear benefits of SERM administration 24. While intra-articular E₂ injections 103 and high supraphysiological estrogen concentrations 104 caused deleterious effects on joint cartilage in a dose-and time-dependent fashion, the beneficial effects of long-term estrogen treatment have been seen in different models 242599. Early estrogen administration maximizes its positive effects on cartilage 16 and, in turn, tamoxifen decreases cartilage damage in a rabbit model of OA, even in males 105. Furthermore, tamoxifen antagonized the chondro-destructive effects of high dose intra-articular E₂ during early knee OA in rabbits 106. Also, NNC 45-0781 and levormeloxifen both inhibited the OVX-induced acceleration of cartilage and bone turnover, and they significantly suppressed cartilage damage in female Sprague-Dawley rats 24107.

In subchondral bone, the effects of long-term ERT have only recently begun to be studied. ERT limits bone formation in both subchondral bone and epiphyseal/metaphyseal cancellous bone of the proximal tibia in OVX cynomolgus monkeys 27. ERT also reduces the prevalence of marginal osteophytes, particularly in the lateral tibial plateau, while the presence of axial osteophytes is not affected. However, neither the cross-sectional area in osteophytes nor its static and dynamic histomorphometric parameters are significantly influenced by ERT 28108. In addition, a significant effect of ERT has been described on several components of the IGF system in the synovial fluid of OVX female adult cynomolgus monkeys, suggesting a potential stimulatory effect of estrogen on joint tissues in vivo 109. In turn, estrogen administration reversed OVX-induced contractile muscle and myosin dysfunction, as well as the OVX-induced increase of muscle wet mass in mature female mice caused by fluid accumulation 110.

The effect of ERT on the risk of developing OA and on its progression in postmenopausal women remains unclear. Unlike observational clinical studies, some radiographic studies have suggested a protective effect of ERT on the radiographic detection of OA or its progression 111112113114115. In a cross-sectional study, ERT significantly reduced the risk of radiographic hip OA, particularly in long-term users 111. Similarly, an initial cross-sectional analysis of two of the largest studies found an inverse association between ERT use and radiological knee OA, suggesting that ERT may have a chondroprotective effect. However, a subsequent follow-up analysis failed to show significant ERT protection against either the development or progression of radiographic knee OA 112113114115. Additionally, contradictory results were described regarding the association between ERT and the requirement for arthroplasty 116. Nevertheless, in the largest study, females that received estrogen alone had significantly fewer arthroplasties, particularly in the hip. Thus, unopposed estrogen administration might have a protective effect against the risk of joint replacement, an effect that may be particularly relevant in hip compared to knee OA 117.

Magnetic resonance imaging-estimated subchondral bone attrition and bone-marrow abnormalities associated with cartilage degradation in knee OA was delayed or prevented by ERT or alendronate in postmenopausal women 118. In turn, ERT may preserve muscle performance. A 12-month trial showed that ERT protects against the detrimental effects of estrogen deficiency on skeletal muscle in early postmenopausal women, thereby positively influencing muscle performance and structure. Moreover, high-impact physical training provided additional benefits 119.

Recently, novel ER ligands, both pathway-selective and ERβ-selective, have been developed due to the potent anti-inflammatory activity they have been attributed 120121 (Table 1). Indeed, the pathway-selective ER ligands WAY-169916 and WAY-204688 inhibit NF-κB transcriptional activity in the absence of conventional estrogenic activity in different animal models of inflammatory diseases 122123.

The suppressive effects of estrogen on inflammatory mediators, including NF-κB, inducible nitric oxide synthase, cyclooxygenase-2, and reactive oxygen species in articular chondrocytes 171880, in association with other selective estrogenic benefits on joint tissues might reflect their potential utility in OA treatment.