International Journal of Molecular Sciences Review Osteoporosis in Skin Diseases Maria Maddalena Sirufo 1,2, Francesca De Pietro 1,2, Enrica Maria Bassino 1,2, Lia Ginaldi 1,2 and Massimo De Martinis 1,2,* 1 Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; [email protected] (M.M.S.); [email protected] (F.D.P.); [email protected] (E.M.B.); [email protected] (L.G.) 2 Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, AUSL 04 64100 Teramo, Italy * Correspondence: [email protected]; Tel.: +39-0861-429548; Fax: +39-0861-211395 Received: 1 June 2020; Accepted: 1 July 2020; Published: 3 July 2020 Abstract: Osteoporosis (OP) is defined as a generalized skeletal disease characterized by low bone mass and an alteration of the microarchitecture that lead to an increase in bone fragility and, therefore, an increased risk of fractures. It must be considered today as a true public health problem and the most widespread metabolic bone disease that affects more than 200 million people worldwide. Under physiological conditions, there is a balance between bone formation and bone resorption necessary for skeletal homeostasis. In pathological situations, this balance is altered in favor of osteoclast (OC)-mediated bone resorption. During chronic inflammation, the balance between bone formation and bone resorption may be considerably affected, contributing to a net prevalence of osteoclastogenesis. Skin diseases are the fourth cause of human disease in the world, affecting approximately one third of the world’s population with a prevalence in elderly men. Inflammation and the various associated cytokine patterns are the basis of both osteoporosis and most skin pathologies. Moreover, dermatological patients also undergo local or systemic treatments with glucocorticoids and immunosuppressants that could increase the risk of osteoporosis. Therefore, particular attention should be paid to bone health in these patients. The purpose of the present review is to take stock of the knowledge in this still quite unexplored field, despite the frequency of such conditions in clinical practice. Keywords: osteoporosis; dermatology; skin; skin diseases; bone; skeletal health; psoriasis; eczema; atopic dermatitis; urticaria; pemphigus; vitiligo 1. Introduction Osteoporosis (OP) is defined as a generalized skeletal disease characterized by low bone mass and an alteration of the microarchitecture that lead to an increase in bone fragility and, therefore, an increased risk of fractures [1–3]. OP must be considered today as a true public health problem and the most widespread metabolic bone disease that affects more than 200 million people worldwide [4], with a prevalence of 15% in women 50 to 60 years old and of 45% in women over 70 years old. Nonetheless, but to a lesser extent, men are also concerned with a prevalence of 2.4% between 50 and 60 years old and 17% over 70 years old [5]. The prevalence of OP increases with age and the constant aging of the population makes it grow. Most cases of osteoporosis concern menopausal women due to the lack of estrogen. In up to 40% of post-menopausal women and 60% of men with osteoporosis, an underlying disease affecting bone health is present [6,7], and among the pathologies leading to a secondary form of osteoporosis, dermatologic disorders—representing the fourth cause of human disease—are often overlooked. The repercussions that OP has in terms of quality of life, morbidity, and mortality, as well as the socioeconomic impact, make it important to carry out interventions aimed Int. J. Mol. Sci. 2020, 21, 4749; doi:10.3390/ijms21134749 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 4749 2 of 17 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 18 aimedat prevention. at prevention. Under Under physiological physiological conditions, conditions there, isthere a balance is a balance between between bone formationbone formation and bone and boneresorption resorption necessary necessary for skeletal for skeletal homeostasis. homeostasis. In pathological In pathological situations, situations this compensation, this compensation is altered is alteredin favor in of favor osteoclast of osteoclast (OC)-mediated (OC)-m boneediated resorption bone resorption [8,9]. The [8, metabolic9]. The metabolic activation activation of OCs to of enhance OCs to enhancebone resorption bone resorption capacity requires capacity complex requires signaling complex mechanisms signaling mechanisms between osteoclastic between lineageosteoclastic cells, lineagemesenchymal cells, mesenchymal cells, and lymphocytes cells, and [10 lymphocytes–13]. These interactions[10–13]. These are controlledinteractions by are several controlled cytokines by seandveral the cytokines nuclear factor- and theκB receptornuclear factor activator-κB (NF-receptorκB) ligandactivator (RANKL). (NF-κB) RANKL ligand (RANKL). is a factor RANKL that belongs is a factorto the familythat belongs of tumor to the necrosis family factors, of tumor produced necrosis by factors different, produced types of cells,by different including types some of ofcells, the includingimmune system, some of such the as immune activated system, T lymphocytes, such as activated vascular wall T lymp cells,hocytes, and osteoblasts vascular [1wall]. The cells, binding and osteoblastsof RANKL with[1]. The its RANKbinding receptor, of RANKL positioned with its onRANK the OCreceptor, precursors, positioned promotes on the the OC diff precursors,erentiation promotesof the latter the into differentiation osteoclasts of [14 the]. Inlatter addition into osteoclasts to RANKL, [14 osteoblasts]. In addition also to produceRANKL, osteoprotegerinosteoblasts also (OPG),produce a osteoprotegeri soluble proteinn (OPG), which, whena soluble combined protein withwhich, RANKL, when combined prevents itwith from RANKL, binding prevents to RANK. it fromUnder binding inflammatory to RANK. conditions, Under inflammatory T cells, interleukin conditions, (IL)-1 T cells, and interleukin tumor necrosis (IL)-1 factorand tumor (TNF) necrosis act as factorco-stimulators (TNF) act of as osteoclastogenesis, co-stimulators of osteoclastogenesis promoting the expression, promoting of NF- theκB expression and other transcriptionof NF-κB and factors other transcriptioninvolved in bone factors resorption involved and in directlybone resorption stimulating and OCsdirectly (Figure stimulating1)[1]. OCs (Figure 1) [1]. Figure 1. κ κ Figure 1. TheThe nuclear nuclear factor- factorB- receptorκB receptor activator activator (NF- B)(NF RANK-κB)/ RANKLRANK//RANKLOPG pathway./OPG Thepathway production. The of nuclear factor-κB receptor activator (NF-κB) ligand (RANKL) leads to a greater differentiation production of nuclear factor-κB receptor activator (NF-κB) ligand (RANKL) leads to a greater of macrophages into osteoclasts. Bone resorption is stimulated by active osteoclasts, RANKL, differentiation of macrophages into osteoclasts. Bone resorption is stimulated by active osteoclasts, and parathyroid hormone (PTH), while it is inhibited by osteoprotegerin (OPG). RANKL, and parathyroid hormone (PTH), while it is inhibited by osteoprotegerin (OPG). 1.1. Vitamin D and Skin Diseases 1.1. Vitamin D and Skin Diseases Vitamin D (VD) plays a fundamental role in a wide range of physiological functions and often its deficitVitamin has D been(VD) associatedplays a fundamental with many role acute in a orwide chronic range pathologies of physiological including functions some and tumors, often itscardiovascular deficit has been diseases, associated type II with diabetes, many autoimmune acute or chronic diseases, pathologies alteration including of calcium some metabolism, tumors, cardiovascularand infections. diseases, VD has a type leading II diabetes, role in the autoimmun calcium ande diseases, phosphorus alteration metabolism of calcium in maintaining metabolism the, andadequate infections. concentrations VD has a ofleading minerals role for in metabolic the calcium functions and phosphorus and bone mineralization. metabolism in Themaintaining achievement the adequateof adequate concentrations VD values, with of appropriate minerals supplementation,for metabolic functions is positively and related bone tomineralization. muscle strength The and posturalachievement and dynamicof adequate balance. VD values, with appropriate supplementation, is positively related to muscleVD strength promotes and the postural cyclin-dependent and dynamic kinase balance. (CDK) inhibitor synthesis, influences several growth factorsVD and promotes their signalingthe cyclin- pathwaysdependent (insulin-like kinase (CDK) growth inhibitor factor synthesis, 1 (IGF-1), influence transformings several growth factorsfactor β and(TGF theirβ), signaling Wnt/β-catenin, pathways MAP (insu kinaselin-like 5 (MAPK5), growth factor and nuclear1 (IGF-1), factor transformingκB (NF-κ B)),growth promotes factor pro-apoptoticβ (TGFβ), Wnt/β mechanisms,-catenin, MAP induces kinase diff erentiation5 (MAPK5) and, and also nuclear regulates factor androgen κB (NF and-κB) estrogen), promote receptors pro- apoptoticsignaling [mechanisms,15,16]. The capability induces ofdifferentiation VD to regulate and chemokine also regulate production,s androgen counteracting and estrogen autoimmune receptor signalinginflammation, [15,16]. and The to c induceapability diff oferentiation VD to regulate of immune chemokine cells production, in a way that counteracting promotes self-tolerance autoimmune