The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 13, 2019
REVIEW ARTICLE

Vitamin D, Inflammation and Osteoporosis in Rheumatoid Arthritis



Pier Paolo Sainaghi1, 2, *, Antonello Gibbin3
1 Immuno-Rheumatology Outpatient Unit, Division of Internal Medicine, “Maggiore della Carità Hospital”, Novara, Italy
2 Interdisciplinary Research Center of Autoimmune Diseases, Novara, Italy
3 Division of Internal Medicine, “Sant’Andrea Hospital”, Vercelli, Italy

Abstract

Patients with Rheumatoid Arthritis (RA) commonly develop osteoporosis and fragility fractures. This fact cannot be explained only with the use of glucocorticoids, known to be detrimental for bone health. RA is characterized by a chronic inflammation caused by the continuous activation of innate and adaptive immunity with proinflammatory cytokines overproduction. This process is detrimental for several organs and physiological processes, including the impairment of bone remodeling. We will briefly review the pathogenesis of inflammation-related bone loss in RA, describing well-known and new molecular pathways and focusing on vitamin D and Parathyroid Hormone role.

Keywords: Vitamin D, Osteoporosis, Rheumatoid arthritis, Inflammation, Inflammatory arthritis, Bone health.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 12
Issue: Suppl-1, M9
First Page: 300
Last Page: 312
Publisher Id: TORJ-12-300
DOI: 10.2174/1874312901812010300

Article History:

Received Date: 22/4/2018
Revision Received Date: 1/8/2018
Acceptance Date: 12/9/2018
Electronic publication date: 27/12/2018
Collection year: 2018

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© 2018 Sainaghi and Gibbin.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the “Maggiore della Carità Hospital”, Corso Mazzini 18, 28100 Novara, Italy, Tel: +3903213737512, Fax: +3903213733600; E-mail: pierpaolo.sainaghi@med.uniupo.it




1. OSTEOPOROSIS IN RHEUMATOID ARTHRITIS: EPIDEMIOLOGICAL EVIDENCES AND RISK FACTORS

Patients affected by inflammatory arthritis in general, and Rheumatoid Arthritis (RA) in particular, show an increased risk of generalized bone loss; this is the result of the coexistence of common risk factors, such as age, female gender, smoke and body mass index along with RA-related features [1Güler-Yüksel M, Hoes JN, Bultink IEM, Lems WF. Glucocorticoids, inflammation and bone. Calcif Tissue Int 2018; 102(5): 592-606.[http://dx.doi.org/10.1007/s00223-017-0335-7] [PMID: 29313071] ].

Generalized osteoporosis, defined as a T-score -2.5 Standard Deviations (SD) in the hip and/or in lumbar spine as proposed by the World Health Organization (WHO), is highly prevalent among RA patients: in a large study on RA patients, a two-fold increase in osteoporosis rate was seen in 394 women, with respect to a control group; similarly a doubled rate of reduced Body Mass Density (BMD) was reported in men [2Haugeberg G, Uhlig T, Falch JA, Halse JI, Kvien TK. Reduced bone mineral density in male rheumatoid arthritis patients: Frequencies and associations with demographic and disease variables in ninety-four patients in the oslo county rheumatoid arthritis register. Arthritis Rheum 2000; 43(12): 2776-84.[http://dx.doi.org/10.1002/1529-0131(200012)43:12<2776::AID-ANR18>3.0.CO;2-N] [PMID: 11145036] , 3Haugeberg G, Uhlig T, Falch JA, Halse JI, Kvien TK. Bone mineral density and frequency of osteoporosis in female patients with rheumatoid arthritis: Results from 394 patients in the oslo county rheumatoid arthritis register. Arthritis Rheum 2000; 43(3): 522-30.[http://dx.doi.org/10.1002/1529-0131(200003)43:3<522::AID-ANR7>3.0.CO;2-Y] [PMID: 10728744] ]. In a more recent cohort of 304 RA consecutive patients, the prevalence of osteoporosis was 29.9%, almost two-fold of the one observed in 904 controls matched for age and sex [4Hauser B, Riches PL, Wilson JF, Horne AE, Ralston SH. Prevalence and clinical prediction of osteoporosis in a contemporary cohort of patients with rheumatoid arthritis. Rheumatology (Oxford) 2014; 53(10): 1759-66.[http://dx.doi.org/10.1093/rheumatology/keu162] [PMID: 24764264] ].

Consistently, patients with RA are at higher risk for vertebral and non-vertebral fractures: according to a retrospective observational study on more than 47,000 RA patients, the incidence rate for osteoporotic fracture at typical sites was 9.6 per 1,000 person-years, 1.5 times higher than the rate observed in subjects not affected by RA [5Kim SY, Schneeweiss S, Liu J, et al. Risk of osteoporotic fracture in a large population-based cohort of patients with rheumatoid arthritis. Arthritis Res Ther 2010; 12(4): R154.[http://dx.doi.org/10.1186/ar3107] [PMID: 20682035] ]. Moreover, Weiss et al in 2010, reported a 2.9 OR for hip fractures and a 2.7 OR for vertebral fractures in patients with RA with respect to the general population [6Weiss RJ, Wick MC, Ackermann PW, Montgomery SM. Increased fracture risk in patients with rheumatic disorders and other inflammatory diseases - A case-control study with 53,108 patients with fracture. J Rheumatol 2010; 37(11): 2247-50.[http://dx.doi.org/10.3899/jrheum.100363] [PMID: 20889599] ].

It has been argued that the increased risk of fractures can be explained by the use of Glucocorticoids (GC), however this is only one of the RA-related factors explaining bone loss in inflammatory arthritis. Consistently, Van Staa et al. found out-patients with RA who were never exposed to GC, were in any case characterized by an increased Relative Risk (RR) (1.5, CI 95%: 1.2-1.9) for vertebral fractures up to 1.7 (CI 95%: 1.5-2.0) for hip fractures, suggesting that disease by itself is an important and independent risk factor for accelerated bone loss [7van Staa TP, Geusens P, Bijlsma JW, Leufkens HG, Cooper C. Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis. Arthritis Rheum 2006; 54(10): 3104-12.[http://dx.doi.org/10.1002/art.22117] [PMID: 17009229] ]. The increased risk of fractures in RA is, therefore, multifactorial and includes the general background risk (clinical risk factors, BMD) on top of RA-specific risk factors (Table 1) [8Briot K, Geusens P, Em Bultink I, Lems WF, Roux C. Inflammatory diseases and bone fragility. Osteoporos Int 2017; 28(12): 3301-14.[http://dx.doi.org/10.1007/s00198-017-4189-7] [PMID: 28916915] ].

Table 1
The table shows general risk factors for osteoporosis versus RA related risk factors.


Interestingly, bone loss occurs very early in the course of the disease, when other risk factors such as reduced mobilization are rarely present, testifying the relevance of the inflammatory state. In early arthritis, in fact, the bone loss is evidently related to the parameters of inflammation [9Forslind K, Keller C, Svensson B, Hafström I. Reduced bone mineral density in early rheumatoid arthritis is associated with radiological joint damage at baseline and after 2 years in women. J Rheumatol 2003; 30(12): 2590-6.[PMID: 14719199] -12Güler-Yüksel M, Bijsterbosch J, Goekoop-Ruiterman YP, et al. Changes in bone mineral density in patients with recent onset, active rheumatoid arthritis. Ann Rheum Dis 2008; 67(6): 823-8.[http://dx.doi.org/10.1136/ard.2007.073817] [PMID: 17644545] ].

2. BONE LOSS AND SYSTEMIC INFLAMMATION

It is nowadays well known that systemic inflammation influences bone turnover, favoring bone resorption and dampening its formation. Proinflammatory mediators are involved in this process, as witnessed by their involvement in the pathogenesis of hormonal deficiency-induced bone loss. Nude female mice deficient in T cells, as well as TNF knock-out mice, are protected against bone loss induced by ovariectomy, while bone loss occurs if these mice are injected with T cells from wild-type mice [13Roggia C, Tamone C, Cenci S, Pacifici R, Isaia GC. Role of TNF-alpha producing T-cells in bone loss induced by estrogen deficiency. Minerva Med 2004; 95(2): 125-32.[PMID: 15272247] ]. Similarly, IL6-deficient mice are protected from oestrogen deficiency-induced bone loss [14Wong PK, Quinn JM, Sims NA, van Nieuwenhuijze A, Campbell IK, Wicks IP. Interleukin-6 modulates production of T lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis. Arthritis Rheum 2006; 54(1): 158-68.[http://dx.doi.org/10.1002/art.21537] [PMID: 16385511] ]. Moreover, in postmenopausal women, anti-IL1 or anti-TNF therapy can limit the increase in bone resorption markers which occurs after discontinuation of oestrogen replacement therapy [15Charatcharoenwitthaya N, Khosla S, Atkinson EJ, McCready LK, Riggs BL. Effect of blockade of TNF-alpha and interleukin-1 action on bone resorption in early postmenopausal women. J Bone Miner Res 2007; 22(5): 724-9.[http://dx.doi.org/10.1359/jbmr.070207] [PMID: 17295604] ].

In the last years, new insights into the field of osteoimmunology expanded our knowledge, leading to a better comprehension of the biological systems involved in this process.

The best known molecular pathway involved in inflammatory osteoporosis is, probably, represented by Receptor Activator of Nuclear Factor Kappa B (RANK) / RANK ligand (RANKL) system. Since early ‘80s, it has been proposed that osteoblasts could regulate osteoclasts activity, based on the observation that osteoblasts, but not osteoclasts, express receptors of bone-resorbing factors, such as PTH and prostaglandin E2 [16Rodan GA, Martin TJ. Role of osteoblasts in hormonal control of bone resorption - A hypothesis. Calcif Tissue Int 1981; 33(4): 349-51.[http://dx.doi.org/10.1007/BF02409454] [PMID: 6271355] ]. In the following years, an osteoblastic transmembrane protein, called RANKL was cloned and shown to be upregulated by bone-resorbing factors [17Teitelbaum SL. Bone resorption by osteoclasts. Science 2000; 289(5484): 1504-8.[http://dx.doi.org/10.1126/science.289.5484.1504] [PMID: 10968780] ]. It acts via binding its receptor, RANK, on osteoclasts precursor, in a cell-to-cell interaction which induces osteoclasts differentiation and activation Fig. (1) [18Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93(2): 165-76.[http://dx.doi.org/10.1016/S0092-8674(00)81569-X] [PMID: 9568710] , 19Takahashi N, Udagawa N, Suda T. Vitamin D endocrine system and osteoclasts. Bonekey Rep 2014; 3: 495.[http://dx.doi.org/10.1038/bonekey.2014.17] [PMID: 24605212] ]. A decoy receptor, which suppresses osteoclasts differentiation, has also been cloned (Osteoprotegerin - OPG) [20Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: A novel secreted protein involved in the regulation of bone density. Cell 1997; 89(2): 309-19.[http://dx.doi.org/10.1016/S0092-8674(00)80209-3] [PMID: 9108485] ]. Proinflammatory cytokines, such as Tumor Necrosis Factor α (TNF-α), interleukin (IL)-1, IL-6 and IL-17, enhance RANKL mediated differentiation, proliferation and activity of osteoclasts [8Briot K, Geusens P, Em Bultink I, Lems WF, Roux C. Inflammatory diseases and bone fragility. Osteoporos Int 2017; 28(12): 3301-14.[http://dx.doi.org/10.1007/s00198-017-4189-7] [PMID: 28916915] , 17Teitelbaum SL. Bone resorption by osteoclasts. Science 2000; 289(5484): 1504-8.[http://dx.doi.org/10.1126/science.289.5484.1504] [PMID: 10968780] , 21Geusens P, Lems WF. Osteoimmunology and osteoporosis. Arthritis Res Ther 2011; 13(5): 242.[http://dx.doi.org/10.1186/ar3375] [PMID: 21996023] -23Axmann R, Böhm C, Krönke G, Zwerina J, Smolen J, Schett G. Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo. Arthritis Rheum 2009; 60(9): 2747-56.[http://dx.doi.org/10.1002/art.24781] [PMID: 19714627] ]. T-cells, and Th17 in particular have the most relevant role in creating a “osteoclastogenic” environment during systemic inflammation by releasing IL-17, RANKL, TNF, IL-1, and IL-6 [8Briot K, Geusens P, Em Bultink I, Lems WF, Roux C. Inflammatory diseases and bone fragility. Osteoporos Int 2017; 28(12): 3301-14.[http://dx.doi.org/10.1007/s00198-017-4189-7] [PMID: 28916915] ] thus enhancing osteoclasts differentiation and bone resorption.

In the last years, a direct correlation between autoimmunity and bone loss in RA has been unveiled; in fact, the classical antibodies of seropositive RA, Rheumatoid Factor and antibodies recognizing citrullinated proteins, have been proposed as potent osteoclasts inducers [24Schett G. Autoimmunity as a trigger for structural bone damage in rheumatoid arthritis. Mod Rheumatol 2017; 27: 193-7.[PMID: 23169527] ].

Fig. (1)
The figure shows RANK/RANKL system. Multinucleated osteoclasts are formed by cell–cell fusion of mononuclear preosteoclasts. Osteoclast precursors express DC-STAMP (Dendritic cells-specific transmembrane protein) which is the protein responsible of the fusion process. Moreover, they express on their membrane RANK and c-Fms, which is the receptor of M-CSF (Macrophage colony stimulating factor). In presence of M-CSF, osteoblasts regulate the fusion process by RANKL expression. As shown in the figure, the active form of vitamin D is between the stronger inducers of RANKL expression [19Takahashi N, Udagawa N, Suda T. Vitamin D endocrine system and osteoclasts. Bonekey Rep 2014; 3: 495.[http://dx.doi.org/10.1038/bonekey.2014.17] [PMID: 24605212] ].


A further biological system which is involved in “inflammatory osteoporosis” is Wnt/ß catenin pathway. ß catenin is a transcriptional co-activator normally degraded in the cytoplasm by a multiprotein degradation complex, consisting of the tumor suppressors Axin and Adenomatous Polyposis Coli (APC), Ser/Thr kinases GSK-3 and CK1, Protein Phosphatase 2A (PP2A) and the E3-ubiquitin ligase β-TrCP; this complex starts the degradation process of β-catenin by targeting it for ubiquitination, after which β-catenin is subsequently digested by the proteasome [25]. The activation of the Wnt signaling pathway leads to the accumulation of ß catenin. In fact, when a member of the Wnt protein family binds the transmembrane receptor Frizzled (Fz) and its coreceptors LRP 4, 5 or 6 (lipoprotein receptor-related proteins), axin is removed from the degradation complex and β catenin is released, thus accumulating itself in the cytoplasm [26Duan P, Bonewald LF. The role of the wnt/β-catenin signaling pathway in formation and maintenance of bone and teeth. Int J Biochem Cell Biol 2016; 77(Pt A): 23-9.[http://dx.doi.org/10.1016/j.biocel.2016.05.015] [PMID: 27210503] ] Fig. (2). Finally, β catenin translocates to the nucleus where it links to other transcriptional factors (TCF/LEF, T-cell factor/lymphoid enhancing factor) creating a complex which enhances the transcription of target genes [27MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: Components, mechanisms, and diseases. Dev Cell 2009; 17(1): 9-26.[http://dx.doi.org/10.1016/j.devcel.2009.06.016] [PMID: 19619488] ]. Several secreted protein families antagonize or modulate Wnt/β-catenin signaling: sFRPs (secreted Frizzled-related proteins) and WIF (Wnt inhibitory protein) bind to Wnt, and in the case of sFRPs, also to Fz acting as Wnt antagonists [28Bovolenta P, Esteve P, Ruiz JM, Cisneros E, Lopez-Rios J. Beyond Wnt inhibition: New functions of secreted Frizzled-related proteins in development and disease. J Cell Sci 2008; 121(Pt 6): 737-46.[http://dx.doi.org/10.1242/jcs.026096] [PMID: 18322270] ]. Other important Wnt inhibitors are the members of Dickkopf (Dkk) family and Sclerostin, which are LRP5 and 6 ligands/antagonists; they prevent Wnt proteins to bind to LRP5/6, thus inhibiting the Wnt/β-catenin signaling [29Takahashi N, Udagawa N, Suda T. Vitamin D endocrine system and osteoclasts. Bonekey Rep 2014; 3: 495.[http://dx.doi.org/10.1038/bonekey.2014.17] [PMID: 24605212] , 30Semënov M, Tamai K, He X. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem 2005; 280(29): 26770-5.[http://dx.doi.org/10.1074/jbc.M504308200] [PMID: 15908424] ]. Wnt signaling is essential for skeletal formation and development and is involved in chondrogenesis, in differentiation, survival and proliferation of osteoblasts [31Day TF, Guo X, Garrett-Beal L, Yang Y. Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 2005; 8(5): 739-50.[http://dx.doi.org/10.1016/j.devcel.2005.03.016] [PMID: 15866164] , 32Glass DA II, Karsenty G. Canonical Wnt signaling in osteoblasts is required for osteoclast differentiation. Ann N Y Acad Sci 2006; 1068: 117-30.[http://dx.doi.org/10.1196/annals.1346.015] [PMID: 16831912] ], synthesis of bone matrix as well as differentiation and function of osteoclasts during development [33Bonewald LF, Johnson ML. Osteocytes, mechanosensing and Wnt signaling. Bone 2008; 42(4): 606-15.[http://dx.doi.org/10.1016/j.bone.2007.12.224] [PMID: 18280232] ]. During systemic inflammatory disease, TNF-α induces osteocytes to synthetize sclerostin and DKK-1 [34Schett G, Saag KG, Bijlsma JW. From bone biology to clinical outcome: State of the art and future perspectives. Ann Rheum Dis 2010; 69(8): 1415-9.[http://dx.doi.org/10.1136/ard.2010.135061] [PMID: 20650876] ], thus negatively affecting osteoblasts activity and blocking new bone formation. In a TNF-α transgenic mouse model, DKK-1 is overexpressed, blocking osteoblasts differentiation and promotes sclerostin expression and osteocyte death [35Heiland GR, Zwerina K, Baum W, et al. Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression. Ann Rheum Dis 2010; 69(12): 2152-9.[http://dx.doi.org/10.1136/ard.2010.132852] [PMID: 20858621] ]. Sclerostin, plays a crucial role in these activities, since its inhibition in the same model reverted the inflammation-related bone loss [36Chen D, Li Y, Zhou Z, et al. HIF-1α inhibits Wnt signaling pathway by activating Sost expression in osteoblasts. PLoS One 2013; 8(6): e65940.[http://dx.doi.org/10.1371/journal.pone.0065940] [PMID: 23776575] ]. Likewise, IL-6 has been described to inhibit Wnt signaling in synovial fibroblasts and in osteoblasts [37Malysheva K, de Rooij K, Lowik CW, et al. Interleukin 6/Wnt interactions in rheumatoid arthritis: Interleukin 6 inhibits Wnt signaling in synovial fibroblasts and osteoblasts. Croat Med J 2016; 57(2): 89-98.[http://dx.doi.org/10.3325/cmj.2016.57.89] [PMID: 27106351] ].

Fig. (2)
The figure shows Wnt/ß-catenin system. ß-catenin is normally degraded by a multiprotein complex, consisting of Axin1, Adenomatous Polyposis Coli (APC), GSK-3 and CK1, the protein phosphatase 2A (PP2A) and the E3-ubiquitin ligase β-TrCP; after ubiquitination, β-catenin is digested by the proteasome (A). When a member of the Wnt protein family becomes available, the transmembrane receptor Frizzled (Fz) and its coreceptors LRP 4, 5 or 6 (Lipoprotein Receptor-related Proteins) are activated and phosphorylated leading to the recruitment of the protein Disheveled (Dvl). Axin is seized and the degradation complex undergoes inhibitory rearrangements, leading to the accumulation of ß-catenin and its translocation to the nucleus where it acts as a co-transcription factor (B). Proinflammatory cyrokines are able to inhibit this pathway by enhanincg the production of inhibitory molecules like DKK and sclerostin, which prevent the interaction between Wnt and its receptors.


In a study by Terpos et al. on RA patients, an osteoprotegerin/RANKL ratio 5 times lower than that observed in healthy controls has been reported, with an inverse correlation between circulating osteoprotegerin levels and disease activity (as DAS28 score) and a positive correlation between RANKL and C-reactive protein. Furthermore, DKK-1 and sclerostin levels were higher in RA patients than in healthy controls. After two months of treatment with tocilizumab (a humanized anti-interleukin-6 receptor antibody), the osteoprotegerin/RANKL ratio increased proportionally to clinical improvement and suppression of inflammation; at the same time, sclerostin concentration increased while DKK-1 decreased with respect to baseline [38Terpos E, Fragiadaki K, Konsta M, Bratengeier C, Papatheodorou A, Sfikakis PP. Early effects of IL-6 receptor inhibition on bone homeostasis: A pilot study in women with rheumatoid arthritis. Clin Exp Rheumatol 2011; 29: 921-5.]. Consistently, prospective studies have reported a protective effect of antiTNF agents on bone loss [39Vis M, Havaardsholm EA, Haugeberg G, et al. Evaluation of bone mineral density, bone metabolism, osteoprotegerin and receptor activator of the NFkappaB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis. Ann Rheum Dis 2006; 65: 1495-9., 40Wijbrandts CA, Klaasen R, Dijkgraaf MG, Gerlag DM, van Eck-Smit BL, Tak PP. Bone mineral density in rheumatoid arthritis patients 1 year after adalimumab therapy: Arrest of bone loss. Ann Rheum Dis 2009; 68(3): 373-6.[http://dx.doi.org/10.1136/ard.2008.091611] [PMID: 18408246] ].

The improvement of our knowledge about the mechanisms underlying bone loss, helped in the development of novel treatment strategies [41Khosla S, Hofbauer LC. Osteoporosis treatment: Recent developments and ongoing challenges. Lancet Diabetes Endocrinol 2017; 5(11): 898-907.[http://dx.doi.org/10.1016/S2213-8587(17)30188-2] [PMID: 28689769] , 42Fassio A, Rossini M, Viapiana O, et al. New strategies for the prevention and treatment of systemic and local bone loss; From pathophysiology to clinical application. Curr Pharm Des 2017; 23(41): 6241-50.[http://dx.doi.org/10.2174/1381612823666170713104431] [PMID: 28707576] ]. In fact, in the last decades, new drugs were developed. RANK/RANKL system has been the first targeted; in fact, a human monoclonal antibody, denosumab, targeting RANKL is the first biological drug developed for the treatment of osteoporosis. According to the results of the FREEDOM trial, the use of denosumab twice yearly for 36 months was associated with a 68% reduction in vertebral fractures (RR 0.32, 95% CI 0.26-0.41) and a 40% reduction in hip fractures (HR 0.60, 95% CI 0.37-0.97) [43Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009; 361(8): 756-65.[http://dx.doi.org/10.1056/NEJMoa0809493] [PMID: 19671655] ]. In the open-label extension of the FREEDOM trial, denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD [44Bone HG, Wagman RB, Brandi ML, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: Results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol 2017; 5(7): 513-23.[http://dx.doi.org/10.1016/S2213-8587(17)30138-9] [PMID: 28546097] ]. Interestingly, targeting RANKL in the specific setting of RA seems to collaterally give protection against the development of erosions [45Deodhar A, Dore RK, Mandel D, et al. Denosumab-mediated increase in hand bone mineral density associated with decreased progression of bone erosion in rheumatoid arthritis patients. Arthritis Care Res (Hoboken) 2010; 62(4): 569-74.[http://dx.doi.org/10.1002/acr.20004] [PMID: 20391513] ]; on this basis, denosumab might be considered a promising novel treatment for the management of RA [46Chiu YG, Ritchlin CT. Denosumab: Targeting the RANKL pathway to treat rheumatoid arthritis. Expert Opin Biol Ther 2017; 17(1): 119-28.[http://dx.doi.org/10.1080/14712598.2017.1263614] [PMID: 27871200] ].

More recently, neutralisation of sclerostin emerged as a novel therapeutic approach. Romosozumab, a monoclonal antibody anti-sclerostin, induced a significantly higher increase in BMD than alendronate, teriparatide or placebo in a phase 2 study on 419 postmenopausal women [47McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 2014; 370(5): 412-20.[http://dx.doi.org/10.1056/NEJMoa1305224] [PMID: 24382002] ]. In the phase 3 trial FRAME [48Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016; 375(16): 1532-43.[http://dx.doi.org/10.1056/NEJMoa1607948] [PMID: 27641143] ], romosozumab was effective in reducing the risk of vertebral fracture after 12 months of treatment, although no effect was seen on non-vertebral fractures. Ongoing clinical trials will better clarify the clinical usefulness and safety of this molecule.

Finally, a further new drug has been recently proposed for the use in the management of osteoporosis. Odacatinib is a selective inhibitor of Cathepsin K, a protein secreted by mature osteoclasts to degrade bone matrix [49Costa AG, Cusano NE, Silva BC, Cremers S, Bilezikian JP. Cathepsin K: Its skeletal actions and role as a therapeutic target in osteoporosis. Nat Rev Rheumatol 2011; 7(8): 447-56.[http://dx.doi.org/10.1038/nrrheum.2011.77] [PMID: 21670768] ]. Although the interim results of the phase 3 study (LOFT) were promising in terms of BMD improvement [50Bone HG, Dempster DW, Eisman JA, et al. Odanacatib for the treatment of postmenopausal osteoporosis: Development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial. Osteoporos Int 2015; 26(2): 699-712.[http://dx.doi.org/10.1007/s00198-014-2944-6] [PMID: 25432773] ], following the demonstration of an increased HR for strokes, Merck announced the discontinuation of the development of odanacatib [51Mullard A. Merck & Co. Drops osteoporosis drug odanacatib. Nat Rev Drug Discov 2016; 15(10): 669.[PMID: 27681784] ].

3. VITAMIN D/PTH AXIS AND BONE HEALTH

Vitamin D3 is a pleiotropic hormone, the main activities of which are the result of the interaction of its active metabolite (1,25(OH)2 vitamin D3, also called calcitriol) with the Vitamin D Receptor (VDR). When 1,25(OH)2 vitamin D3 becomes available, the VDR heterodimerizes with Retinoid X Receptor (RXR) and moves from cytoplasm to nucleus, where it binds specific DNA regions (Vitamin D Responsive Elements, VDRE). VDR, indeed, acts as a transcriptional factor, either up- or downregulating many different target genes [52Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling. Nature 1992; 355(6359): 446-9.[http://dx.doi.org/10.1038/355446a0] [PMID: 1310351] , 53Kato J, Kaziro Y, Satoh T. Activation of the guanine nucleotide exchange factor Dbl following ACK1-dependent tyrosine phosphorylation. Biochem Biophys Res Commun 2000; 268(1): 141-7.[http://dx.doi.org/10.1006/bbrc.2000.2106] [PMID: 10652228] ]. Although recent evidences have related vitamin D to many different aspects of human physiology, the more relevant activity of this hormone is related to bone homeostasis and calcium/phosphate balance as a result of the actions on several targets: kidney, gut, parathyroid gland, bone.

1,25(OH)2 vitamin D3 co-participates with Parathyroid hormone (PTH) in the maintenance of calcium plasma concentration in the narrow range of normality; indeed, this has relevant implications in bone homeostasis, being bone the main storage site of calcium in human body. Calcitriol is able to increase calcium concentration, by enhancing its absorption in the gastrointestinal tract [54Christakos S, Seth T, Wei R, et al. Vitamin D and health: Beyond bone. MD Advis 2014; 7(3): 28-32.[PMID: 25485749] ]; the active transcellular calcium absorption, mediated by 1,25(OH)2 vitamin D3, is a saturable process that involves the passage of calcium across the luminal brush border membrane, its transfer into the cell cytoplasm and its active extrusion through the basolateral membrane. 1,25(OH)2 vitamin D3 upregulates some key genes in calcium intake, such as calcium channel TRPV6 [55Peng JB, Brown EM, Hediger MA. Apical entry channels in calcium-transporting epithelia. News Physiol Sci 2003; 18: 158-63.[PMID: 12869616] ], Calbindin-D9k [56Derler I, Hofbauer M, Kahr H, et al. Dynamic but not constitutive association of calmodulin with rat TRPV6 channels enables fine tuning of Ca2+-dependent inactivation. J Physiol 2006; 577(Pt 1): 31-44.[http://dx.doi.org/10.1113/jphysiol.2006.118661] [PMID: 16959851] ] and the basolateral active channel intestinal plasma membrane ATPase (PMCA1b) [57Ghijsen WE, Van Os CH. 1 alpha, 25-Dihydroxy-vitamin D-3 regulates ATP-dependent calcium transport in basolateral plasma membranes of rat enterocytes. Biochim Biophys Acta 1982; 689(1): 170-2.[http://dx.doi.org/10.1016/0005-2736(82)90202-4] [PMID: 6285974] ]. Moreover, calcitriol acts on the kidney, stimulating calcium intake by inducing the expression of key genes involved in calcium handling in tubules, like TRPV5, TRPV6 and calbindin-D28k [58Jeon US. Kidney and calcium homeostasis. Electrolyte Blood Press 2008; 6(2): 68-76.[http://dx.doi.org/10.5049/EBP.2008.6.2.68] [PMID: 24459525] ].

PTH synergistically acts together with vitamin D to maintain calcium plasma concentrations. In fact, PTH secretion is regulated by Calcium Sensing Receptor (CaSR) [59Thakker RV. Disorders of the calcium-sensing receptor. Biochim Biophys Acta 1998; 1448(2): 166-70.[http://dx.doi.org/10.1016/S0167-4889(98)00140-2] [PMID: 9920407] ]; in response to decrements in serum ionized calcium, CaSR induces the secretion of PTH which is able to directly enhance calcium reabsorption in the distal tubule through regulation of TRPV5 [60de Groot T, Lee K, Langeslag M, et al. Parathyroid hormone activates TRPV5 via PKA-dependent phosphorylation. J Am Soc Nephrol 2009; 20(8): 1693-704.[http://dx.doi.org/10.1681/ASN.2008080873] [PMID: 19423690] ]. Moreover, it is a strong inducer of CYP27B1 the hydroxylase which mediates the last step of vitamin D activation [61Garabedian M, Holick MF, Deluca HF, Boyle IT. Control of 25-hydroxycholecalciferol metabolism by parathyroid glands. Proc Natl Acad Sci USA 1972; 69(7): 1673-6.[http://dx.doi.org/10.1073/pnas.69.7.1673] [PMID: 4340153] ].

Along with calcium plasma concentration, vitamin D also regulates phosphate metabolism. Serum phosphate levels are not as tightly regulated as serum calcium, and they rise with a high phosphorus diet, particularly after meals. Approximately 70% of dietary phosphate is absorbed in the small intestine. Phosphate absorption mainly occurs by a passive, concentration-dependent diffusion process. However, a fraction of phosphorus is absorbed through a saturable, active transport, which is facilitated by 1,25(OH)2 vitamin D3 [62Williams KB, DeLuca HF. Characterization of intestinal phosphate absorption using a novel in vivo method. Am J Physiol Endocrinol Metab 2007; 292(6): E1917-21.[http://dx.doi.org/10.1152/ajpendo.00654.2006] [PMID: 17299082] ]. On the contrary, PTH has a phosphaturic effect on kidney [63Forte LR, Nickols GA, Anast CS. Renal adenylate cyclase and the interrelationship between parathyroid hormone and vitamin D in the regulation of urinary phosphate and adenosine cyclic 3′,5′-monophosphate excretion. J Clin Invest 1976; 57(3): 559-68.[http://dx.doi.org/10.1172/JCI108311] [PMID: 175088] ]. Taking together all these actions, vitamin D is responsible for an increase of calcium and phosphate plasma concentration, while PTH has hypercalcemic and hypophosphatemic effects.

More interestingly for the aim of the present review, both vitamin D and PTH directly act on bone. 1,25(OH)2 vitamin D3 acts on RANK/RANKL regulatory system. 1,25(OH)2 vitamin D3 is one of the stronger inducers of RANKL in osteoblasts [64Kim S, Yamazaki M, Zella LA, et al. Multiple enhancer regions located at significant distances upstream of the transcriptional start site mediate RANKL gene expression in response to 1,25-dihydroxyvitamin D3. J Steroid Biochem Mol Biol 2007; 103(3-5): 430-4.[http://dx.doi.org/10.1016/j.jsbmb.2006.12.020] [PMID: 17197168] ] and, on the other hand, a suppressor of OPG synthesis [65Khosla S. Minireview: The OPG/RANKL/RANK system. Endocrinology 2001; 142(12): 5050-5.[http://dx.doi.org/10.1210/endo.142.12.8536] [PMID: 11713196] ], acting as a master regulator of physiological bone turnover. Similarly, PTH increases calcium and phosphate efflux through stimulation of RANKL by osteoblasts, which in turn stimulates osteoclast-mediated bone resorption [66Silva BC, Bilezikian JP. Parathyroid hormone: Anabolic and catabolic actions on the skeleton. Curr Opin Pharmacol 2015; 22: 41-50.[http://dx.doi.org/10.1016/j.coph.2015.03.005] [PMID: 25854704] ]. Vitamin D and PTH interplay in a crosstalking balance. In fact, if on one hand PTH enhances vitamin D activation, calcitriol both indirectly and directly downregulates PTH production and release [67Demay MB, Kiernan MS, DeLuca HF, Kronenberg HM. Sequences in the human parathyroid hormone gene that bind the 1,25-dihydroxyvitamin D3 receptor and mediate transcriptional repression in response to 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 1992; 89(17): 8097-101.[http://dx.doi.org/10.1073/pnas.89.17.8097] [PMID: 1325645] ]. Moreover, 1,25 (OH)2Vitamin D3 inhibits parathyroid cells proliferation [68Cozzolino M, Lu Y, Finch J, Slatopolsky E, Dusso AS. p21WAF1 and TGF-alpha mediate parathyroid growth arrest by vitamin D and high calcium. Kidney Int 2001; 60(6): 2109-17.[http://dx.doi.org/10.1046/j.1523-1755.2001.00042.x] [PMID: 11737585] ]. This explains why, in case of inadequate vitamin D plasma concentration, PTH plasma concentrations increase, aiming to maintain calcium concentration within physiological ranges, leading to the so-called secondary hyperparathyroidism [69Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992; 327(23): 1637-42.[http://dx.doi.org/10.1056/NEJM199212033272305] [PMID: 1331788] ].

From the previous discussion, it is evident that the maintenance of vitamin D/PTH axis is essential for bone health since both hormones have effects on the two main mechanisms leading to bone formation: bone turnover and bone mineralization, by regulating calcium/phosphate balance. Although historically well characterized, new lights have been shed on this hormonal axis after the discovery of novel mediators of bone homeostasis, which interact with vitamin D and PTH. Fibroblasts Growth Factor 23 (FGF23) was firstly identified in mouse brain in 2000 [70Yamashita T, Yoshioka M, Itoh N. Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem Biophys Res Commun 2000; 277(2): 494-8.[http://dx.doi.org/10.1006/bbrc.2000.3696] [PMID: 11032749] ] and has two main physiological functions: a phosphaturic effect emanating directly from bone that coordinates bone phosphate flux and a counter-regulatory effect to vitamin D activity. It is mainly expressed by osteocytes [71Rhee Y, Bivi N, Farrow E, et al. Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo. Bone 2011; 49(4): 636-43.[http://dx.doi.org/10.1016/j.bone.2011.06.025] [PMID: 21726676] ] and osteoblasts [72Masuyama R, Stockmans I, Torrekens S, et al. Vitamin D receptor in chondrocytes promotes osteoclastogenesis and regulates FGF23 production in osteoblasts. J Biol Chem 2006; 281: 6120-3.[PMID: 16436388] ] and its activity is mediated by FGF23 receptor together with an obligate coreceptor, αKlotho [73Kurosu H, Ogawa Y, Miyoshi M, et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006; 281(10): 6120-3.[http://dx.doi.org/10.1074/jbc.C500457200] [PMID: 16436388] ]. FGF23 synthesis is induced by Phosphate-regulating neutral endopeptidase X-linked (PHEX), Dentin Matrix Protein (DMP)-1, sustained phosphate load, 1,25 (OH)2 vitamin D3, low Klotho, PTH and serum ionized calcium [74Hu MC, Shiizaki K, Kuro-o M, Moe OW. Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol 2013; 75: 503-33.[http://dx.doi.org/10.1146/annurev-physiol-030212-183727] [PMID: 23398153] ]. Its main action is to counter-regulate vitamin D activity by suppressing CYP27B1 and enhancing the inactivating enzyme CYP24A1 in the kidney [75Liu S, Tang W, Zhou J, et al. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 2006; 17(5): 1305-15.[http://dx.doi.org/10.1681/ASN.2005111185] [PMID: 16597685] ]. Moreover, FGF23 directly inhibits phosphate reabsorption in the kidney [76Gattineni J, Bates C, Twombley K, et al. FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Renal Physiol 2009; 297(2): F282-91.[http://dx.doi.org/10.1152/ajprenal.90742.2008] [PMID: 19515808] ] and suppresses PTH synthesis by parathyroid cells [77Krajisnik T, Björklund P, Marsell R, et al. Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 2007; 195(1): 125-31.[http://dx.doi.org/10.1677/JOE-07-0267] [PMID: 17911404] ]. Consistently with these findings, the major consequences of FGF23 excess are hypophosphatemia, aberrant vitamin D metabolism, impaired growth, and rickets/osteomalacia. Inversely, deletion of FGF23 in mice results in hyperphosphatemia, excess in calcitriol and soft tissue calcifications [78Martin A, David V, Quarles LD. Regulation and function of the FGF23/klotho endocrine pathways. Physiol Rev 2012; 92(1): 131-55.[http://dx.doi.org/10.1152/physrev.00002.2011] [PMID: 22298654] ]. The discovery of FGF23 allowed us to understand that the relationship between vitamin D and bone is bidirectional; if, on one hand, vitamin D is essential for bone health, on the other hand, a bone-derived mediator is able to modulate vitamin D metabolism, generating an intricate crosstalk. The relevance of vitamin D in bone health is confirmed by clinical data; in fact, in vivo, a deficient vitamin D status and the consequent secondary hyperparathyroidism cause osteoporosis and osteomalacia, which are often undetected but lead to a decrease in BMD and to an increased risk of fractures. In young children who have little mineral in their skeleton, this defect results in a variety of skeletal deformities classically known as rickets [79Holick MF. Resurrection of vitamin D deficiency and rickets. J Clin Invest 2006; 116(8): 2062-72.[http://dx.doi.org/10.1172/JCI29449] [PMID: 16886050] ]. The definition of the optimal vitamin D threshold for bone health is still largely controversial, however, a 75 nmol/l plasma level is deemed adequate by many for fracture prevention [80Bischoff-Ferrari HA. Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol 2014; 810: 500-25.[PMID: 25207384] ].

4. RA-RELATED OSTEOPOROSIS: THE ROLE OF VITAMIN D

The maintenance of a normal vitamin D status remains of paramount relevance in RA; in fact, an inadequate vitamin D status can magnify the deleterious effect of inflammation on bone density [81Bragazzi NL, Watad A, Neumann SG, et al. Vitamin D and rheumatoid arthritis: An ongoing mystery. Curr Opin Rheumatol 2017; 29(4): 378-88.[http://dx.doi.org/10.1097/BOR.0000000000000397] [PMID: 28463872] -83Bellan M, Pirisi M, Sainaghi PP. Osteoporosis in rheumatoid arthritis: Role of the vitamin D/parathyroid hormone system. Rev Bras Reumatol 2015; 55(3): 256-63.[http://dx.doi.org/10.1016/j.rbr.2014.10.007] [PMID: 25582993] ]. Moreover, some authors postulated a potential role of vitamin D as a modulator of inflammation in RA, although the evidences are still inconclusive [81Bragazzi NL, Watad A, Neumann SG, et al. Vitamin D and rheumatoid arthritis: An ongoing mystery. Curr Opin Rheumatol 2017; 29(4): 378-88.[http://dx.doi.org/10.1097/BOR.0000000000000397] [PMID: 28463872] ]. RA patients show a decreased BMD, being therefore at higher risk for osteoporosis and fractures [84Bultink IE, Vis M, van der Horst-Bruinsma IE, Lems WF. Inflammatory rheumatic disorders and bone. Curr Rheumatol Rep 2012; 14(3): 224-30.[http://dx.doi.org/10.1007/s11926-012-0252-8] [PMID: 22477520] ] so an impairment of vitamin D status can be claimed as a potential pathogenetic factor of RA-related osteoporosis.

First of all, a very high prevalence of hypovitaminosis D has been reported in patients affected by Autoimmune Rheumatic Diseases (ARD) in general and in RA patients specifically. Considering non-supplemented patients, the prevalence of hypovitaminosis D, in a rheumatology outpatient clinic in Northern Italy, has been reported to be as high as 87% [85Sainaghi PP, Bellan M, Carda S, et al. Hypovitaminosis D and response to cholecalciferol supplementation in patients with autoimmune and non-autoimmune rheumatic diseases. Rheumatol Int 2012; 32(11): 3365-72.[http://dx.doi.org/10.1007/s00296-011-2170-x] [PMID: 22045518] ]. Similar prevalences have been reported in other cohorts of rheumatic patients who were not undergoing cholecalciferol supplementation, all over the world [86Mouyis M, Ostor AJ, Crisp AJ, et al. Hypovitaminosis D among rheumatology outpatients in clinical practice. Rheumatology (Oxford) 2008; 47(9): 1348-51.[http://dx.doi.org/10.1093/rheumatology/ken203] [PMID: 18499714] -88Zheng ZH, Gao CC, Wu ZZ, et al. High prevalence of hypovitaminosis D of patients with autoimmune rheumatic diseases in China. Am J Clin Exp Immunol 2016; 5(3): 48-54.[PMID: 27335701] ]. However, whether ARD are independent risk factors for hypovitaminosis is highly debated; although lower plasma 25(OH) vitamin D concentrations have been described in ARD patients with respect to the general population by some authors [89-91], others did not confirm this observation [92Nielen MM, van Schaardenburg D, Lems WF, et al. Vitamin D deficiency does not increase the risk of rheumatoid arthritis: Comment on the article by Merlino et al. Arthritis Rheum 2006; 54(11): 3719-20.[http://dx.doi.org/10.1002/art.22191] [PMID: 17075887] -94Grazio S, Naglić ĐB, Anić B, et al. Vitamin D serum level, disease activity and functional ability in different rheumatic patients. Am J Med Sci 2015; 349(1): 46-9.[http://dx.doi.org/10.1097/MAJ.0000000000000340] [PMID: 25310509] ]. Specifically looking at RA patients, a prevalence of 85% and 45% has been reported for insufficiency and deficiency, respectively considering the thresholds of 75 and 50 nmol/l [88Zheng ZH, Gao CC, Wu ZZ, et al. High prevalence of hypovitaminosis D of patients with autoimmune rheumatic diseases in China. Am J Clin Exp Immunol 2016; 5(3): 48-54.[PMID: 27335701] , 95Kerr GS, Sabahi I, Richards JS, et al. Prevalence of vitamin D insufficiency/deficiency in rheumatoid arthritis and associations with disease severity and activity. J Rheumatol 2011; 38(1): 53-9.[http://dx.doi.org/10.3899/jrheum.100516] [PMID: 20952475] ]. Despite these discrepancies, there is a general agreement about the association of vitamin D levels with disease activity [91Lee YH, Bae SC. Vitamin D level in rheumatoid arthritis and its correlation with the disease activity: A meta-analysis. Clin Exp Rheumatol 2016; 34(5): 827-33.[PMID: 27049238] , 96Cecchetti S, Tatar Z, Galan P, et al. Prevalence of vitamin D deficiency in rheumatoid arthritis and association with disease activity and cardiovascular risk factors: Data from the COMEDRA study. Clin Exp Rheumatol 2016; 34(6): 984-90.[PMID: 27749232] ].

In this context it is relevant to underline the immunoregulatory actions of vitamin D. In fact, the active form of vitamin D regulates the activity of monocytes and macrophages [97Xu H, Soruri A, Gieseler RK, Peters JH. 1,25-Dihydroxyvitamin D3 exerts opposing effects to IL-4 on MHC class-II antigen expression, accessory activity, and phagocytosis of human monocytes. Scand J Immunol 1993; 38(6): 535-40.[http://dx.doi.org/10.1111/j.1365-3083.1993.tb03237.x] [PMID: 8256111] ], B and T cells [98Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 2007; 179(3): 1634-47.[http://dx.doi.org/10.4049/jimmunol.179.3.1634] [PMID: 17641030] -101Joshi S, Pantalena LC, Liu XK, et al. 1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol Cell Biol 2011; 31(17): 3653-69.[http://dx.doi.org/10.1128/MCB.05020-11] [PMID: 21746882] ]. Interestingly, vitamin D is able to decrease the production of crucial proinflammatory cytokines, such as IL-6 and TNFα which are involved in the pathogenesis of bone loss [102Zhang Y, Leung DY, Richers BN, et al. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol 2012; 188(5): 2127-35.[http://dx.doi.org/10.4049/jimmunol.1102412] [PMID: 22301548] ]; it could be therefore argued that the deficient vitamin D status might enhance the proinflammatory milieu characterizing RA, thus favouring the bone loss.

An indirect evidence of the implication of vitamin D in the pathogenesis of osteoporosis in RA is derived by the evidence that a VDR polymorphism has been linked to bone loss in RA [103Ranganathan P. Genetics of bone loss in rheumatoid arthritis-role of vitamin D receptor polymorphisms. Rheumatology (Oxford) 2009; 48(4): 342-6.[http://dx.doi.org/10.1093/rheumatology/ken473] [PMID: 19151030] ]; in particular Rass and colleagues [104Rass P, Pákozdi A, Lakatos P, et al. Vitamin D receptor gene polymorphism in rheumatoid arthritis and associated osteoporosis. Rheumatol Int 2006; 26(11): 964-71.[http://dx.doi.org/10.1007/s00296-006-0106-7] [PMID: 16447061] ] found a lower BMD in RA patients carrying the BB and Bb genotypes of the VDR BsmI polymorphism with respect to carriers of the bb genotype. These results suggest that the B allele may be a marker for increased bone reabsorption and bone loss in RA.

Finally, a further element of interest is related to a recent observation according to which ARD patients show an impairment of vitamin D/PTH axis. In fact patients affected by inflammatory rheumatic diseases have higher plasma PTH than controls for similar vitamin D concentrations; in other words, PTH suppression seems to be more refractory to plasma vitamin D than in general population, contributing to the development of a “relative hyperparathyroidism” [105Sainaghi PP, Bellan M, Antonini G, Bellomo G, Pirisi M. Unsuppressed parathyroid hormone in patients with autoimmune/inflammatory rheumatic diseases: Implications for vitamin D supplementation. Rheumatology (Oxford) 2011; 50(12): 2290-6.[http://dx.doi.org/10.1093/rheumatology/ker314] [PMID: 22019806] ]. Consistently, PTH concentration correlates with disease activity in RA, irrespectively of vitamin D concentration; in fact, patients with erosive disease seem to show higher plasma PTH concentrations [106Rossini M, Bagnato G, Frediani B, et al. Relationship of focal erosions, bone mineral density, and parathyroid hormone in rheumatoid arthritis. J Rheumatol 2011; 38(6): 997-1002.[http://dx.doi.org/10.3899/jrheum.100829] [PMID: 21459948] ]. Different models might explain these findings. Chronic inflammatory processes may reduce parathyroid cells sensitivity to active vitamin D. Alternatively, immune cells might consume 1,25(OH)2 vitamin D3, at the expense of the amount available to act on bone health [105Sainaghi PP, Bellan M, Antonini G, Bellomo G, Pirisi M. Unsuppressed parathyroid hormone in patients with autoimmune/inflammatory rheumatic diseases: Implications for vitamin D supplementation. Rheumatology (Oxford) 2011; 50(12): 2290-6.[http://dx.doi.org/10.1093/rheumatology/ker314] [PMID: 22019806] ]. In fact, vitamin D can be directly activated in calcitriol by CYP27B1, which is expressed by human macrophages [107Monkawa T, Yoshida T, Hayashi M, Saruta T. Identification of 25-hydroxyvitamin D3 1alpha-hydroxylase gene expression in macrophages. Kidney Int 2000; 58(2): 559-68.[http://dx.doi.org/10.1046/j.1523-1755.2000.00202.x] [PMID: 10916079] , 108Smith SJ, Hayes ME, Selby PL, Mawer EB. Autocrine control of vitamin D metabolism in synovial cells from arthritic patients. Ann Rheum Dis 1999; 58(6): 372-8.[http://dx.doi.org/10.1136/ard.58.6.372] [PMID: 10340962] ] and dendritic cells [109Fritsche J, Mondal K, Ehrnsperger A, Andreesen R, Kreutz M. Regulation of 25-hydroxyvitamin D3-1 alpha-hydroxylase and production of 1 alpha,25-dihydroxyvitamin D3 by human dendritic cells. Blood 2003; 102(9): 3314-6.[http://dx.doi.org/10.1182/blood-2002-11-3521] [PMID: 12855575] ].

The main issue is how to correct vitamin D status in RA. A guideline dealing with cholecalciferol dietary requirements and supplementation in general population has been released in 2011 by The Endocrine Society Task Force [110Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2011; 96(7): 1911-30.[http://dx.doi.org/10.1210/jc.2011-0385] [PMID: 21646368] ]. In case of inadequate vitamin D status, the Task Force suggests the use of 50,000 IU of vitamin D2 or vitamin D3 once a week for 8 weeks to achieve a blood level of 25(OH) vitamin D above 75 nmol/l, followed by a maintenance therapy of 1500– 2000 IU/d. However, this recommendation is still largely debated and not universally accepted [111Bouillon R, Van Schoor NM, Gielen E, et al. Optimal vitamin D status: A critical analysis on the basis of evidence-based medicine. J Clin Endocrinol Metab 2013; 98(8): E1283-304.[http://dx.doi.org/10.1210/jc.2013-1195] [PMID: 23922354] ]; the best regimen in the specific subset of RA patients is even less defined. It has been shown that a high loading dose of 300,000 IU, followed by a maintenance daily dose of 800–1000 IU cholecalciferol [112Sainaghi PP, Bellan M, Nerviani A, et al. Superiority of a high loading dose of cholecalciferol to correct hypovitaminosis d in patients with inflammatory/autoimmune rheumatic diseases. J Rheumatol 2013; 40(2): 166-72.[http://dx.doi.org/10.3899/jrheum.120536] [PMID: 23242183] ], could be of advantage, being more effective in inducing PTH suppression along with vitamin D normalization (Table 2). The potential advantages of this regimen need to be weighted at the light of recent findings [113Sanders KM, Nicholson GC, Ebeling PR. Is high dose vitamin D harmful? Calcif Tissue Int 2013; 92(2): 191-206.[http://dx.doi.org/10.1007/s00223-012-9679-1] [PMID: 23250508] ] suggesting an increase in falls and fractures risk in patients treated with a high cholecalciferol dose (500,000 IU). This last observation has been recently replicated in a randomized clinical trial; although higher monthly doses of vitamin D (60,000 IU) were effective in reaching normal 25(OH) vitamin D plasma concentrations, they had no benefit on lower extremity function and were associated with increased risk of falls compared with 24,000 IU. More specific studies on RA are required to better ponder the potential risks and advantages of high doses regimens in this population [114Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, et al. Monthly high-dose vitamin D treatment for the Prevention of functional decline: A randomized clinical trial. JAMA Intern Med 2016; 176(2): 175-83.[http://dx.doi.org/10.1001/jamainternmed.2015.7148] [PMID: 26747333] ].

Table 2
The table summarizes the principle evidences of the role of vitamin D in RA related osteoporosis.


CONCLUSION

In conclusion, osteoporosis is the main issue in the management of RA patients, being a typical comorbidity of inflammatory arthritis. Systemic inflammation is crucial in the development of bone loss, since it causes the impairment of different biological system involved in the maintenance of bone homeostasis. Vitamin D/PTH axis is involved in bone health and different considerations support the hypothesis that vitamin D status is particularly relevant for the development of osteoporosis in RA patients. Although further studies are required to better elucidate this topic, obtaining a normal vitamin D status is paramount in preventing RA-related osteoporosis; therefore, the correction of a deficient vitamin D status should be suggested to each rheumatic patient. Currently, there is no consensus on the best regimen for these patients and further studies are required to better address this important aspect of the management of RA patients.

CONSENT FOR PUBLICATION

Not applicable

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

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Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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