# The Emerging Role of Cyclodextrin Metal-Organic Frameworks in Ostheotherapetics
## 1 Introduction  
Metal-Organic Frameworks (MOFs) are coordination compounds typically described by a tri-dimensional network of bonds and are built of repeating units of organic molecules, also called linkers, coordinated to metal centres. The network may have only one type of metal or it may be comprised by a combination of different metals or clusters of metals [1]. Similarly, the organic molecules that act as the metal-linking subunits may be more than one of a kind. The first structures presently recognised as MOFs date back to the 1960s [2]. However, the term Metal-Organic Framework was only coined by [PERSON] in the 1990s [1], a decade that witnessed the blooming of research in this field. Ever since the first reported structures, MOFs were known for their porosity, with early applications being in the field of gas sorption. Since then, many other properties were explored, with MOFs currently being materials of interest in the field of catalysis [3, 4] and analytics [5, 6, 7, 8], among many others. A new class of biocompatible MOFs, or bioMOFs [9], is presently under steady growth for biological and drug delivery applications. The large dimensions of the pores of these materials make them able to load not only gases, as previously mentioned, but also a plethora of molecules, with highlight given to active pharmaceutical ingredients (APIs). In alternative, drug delivery with MOFs can be achieved by using APIs as their building blocks. This method offers the possibility of slowing down the release of the API, which no longer occurs as a mere result of diffusion (observed when APIs are inside the pore of the MOF), being rather controlled by the rate of degradability of the API-metal coordination framework in a particular biological medium [9, 10]. The use of \(\gamma\)-cyclodextrintrin (\(\gamma\)-CD), a highly symmetrical, octameric \(\alpha_{1,4}\)-linked D-glucose ring, as a building block for 'edible' MOFs was reported in 2010 by the groupof [PERSON] and [PERSON] [11]. Naturally occurring cyclodextrins such as \(\gamma\)-CD and their smaller counterparts, \(\alpha\)-CD and \(\beta\)-CD, having six and seven glucose units, respectively, are molecules of widespread use for the controlled delivery, solubilisation and shelf-life extension of active ingredients in the pharmaceutical, cosmetic and food industries [12; 13; 14; 15]. Native cyclodextrins are 'generally recognised as safe' (GRAS) by the US Food and Drugs Administration (FDA) [16; 17; 18], they are approved as excipients by the European Medicines Agency (EMA) [19] and they have been classified as adequate additives for use in food by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) [20; 21; 22]. MOFs built with \(\gamma\)-CD have an open porous framework that makes them able to support a high load. In tandem with their biocompatibility, this property has attracted much attention for the applications of \(\gamma\)-CD-MOFs in drug delivery. \(\gamma\)-CD-MOFs have been reported to include APIs such as lanzoprazole [23] and diaazepm [24], and nutraceuticals such as curcumin [25] and folic acid [26]. In this work, we focus on the delivery of APIs for the treatment of bone-related disorders using MOFs that contain cyclodext. This is the first review on the applications of CD-MOFs in bone diseases, an emerging application for these materials. This paper is organised into two main sections. Section 2 describes the use of CDs in the coating layer on the surface of the MOFs and the subsequent use of these materials for the controlled release of bisphosphonates, drugs that regulate bone metabolism. Section 3 reports the use of \(\gamma\)-CD molecules as building units for \(\gamma\)-CD-MOFs.