Vitamin D in Dentoalveolar and Oral Health

C H A P T E R

29 Vitamin D in Dentoalveolar and Oral Health Brian L. Foster1, Philippe P. Hujoel2 1The

Ohio State University, Columbus, OH, United States; 2University of Washington, Seattle, WA, United States

O U T L I N E Experimental Models of Vitamin D-Dependent Rickets and Vitamin D-Resistant Rickets 509 Other Genetic Considerations for Diagnosing Dental Rickets510

Introduction497 A Brief Primer on Dentoalveolar Cells and Tissues

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Vitamin D Metabolism and Mechanisms of Action on Dental Cells

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Vitamin D, Rickets, and the Oral Tissues History of Vitamin D and Oral Tissues Nutritional Rickets and the Dentoalveolar Complex Hypervitaminosis D and Teeth

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Hereditary Vitamin D-Related Diseases and Dentoalveolar Tissues Vitamin D-Dependent Rickets Vitamin D-Resistant Rickets

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Conclusions513

INTRODUCTION Teeth are mineralized organs composed of three unique dental hard tissues, enamel, dentin, and cementum, and attached by an unmineralized periodontal ligament (PDL) to the surrounding alveolar bone that composes the tooth socket. Although the process of tooth formation, or odontogenesis, differs from osteogenesis in several respects, tooth biomineralization occurs through parallel processes as skeletal mineralization, employing a similar “tool kit” of molecular signals, extracellular matrix (ECM) proteins, and regulators (see Chapter 23). In this respect, tooth formation is susceptible to similar types of failures as bone when mineral metabolism is disturbed. In addition to disturbances in skeletal form and function (see chapters in Section III, Mineral and Bone Homeostasis), individuals suffering from vitamin D-related disorders such as rickets have developmental disorders in both the teeth and craniofacial skeleton and an increased susceptibility to dental diseases.

Vitamin D, Volume 1: Biochemistry, Physiology and Diagnostics, Fourth Edition http://dx.doi.org/10.1016/B978-0-12-809965-0.00029-X

Vitamin D and Oral Health 511 Vitamin D Supplementation and Incidence of Dental Caries511 Vitamin D Intake and Other Dental and Craniofacial Consequences511 Acknowledgments513 References513

Vitamin D deficiencies have been associated with significant changes in dental-oral-craniofacial structures. The most relevant consequences from a public health perspective are the dental manifestations. Vitamin D has been related to dental hypoplasias, delayed eruption of teeth, dental caries, and periodontal symptoms ranging from gingival bleeding to bone loss. The level of evidence in support of the causality of these associations ranges considerably. The evidence in favor of dental hypoplasias and delayed eruption of teeth is strong and widely recognized by institutions such as the World Health Organization. Unequivocal evidence from pivotal trials remains missing on whether vitamin D supplementation will lower caries risk. Vitamin D deficiencies may lead to altered craniofacial growth and contribute to consequences ranging from the well-accepted frontal and occipital bossing, to the more controversial consequence of orthodontic malocclusions. This chapter reviews the effects of vitamin D on target cells and tissues in the dentoalveolar complex, describes dental disorders resulting from nutritional vitamin D deficiency

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© 2018 Elsevier Inc. All rights reserved.

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29.  VITAMIN D IN DENTOALVEOLAR AND ORAL HEALTH

and associated hereditary diseases, and summarizes what is known about vitamin D and oral health, including susceptibility to dental caries and periodontal disease.

A BRIEF PRIMER ON DENTOALVEOLAR CELLS AND TISSUES Although the dentition and skeleton have in common their mineralized natures, tooth formation is markedly different than bone. Teeth originate from sequential, reciprocal, and reiterative cross talk between the specialized odontogenic epithelium and the ectomesenchyme that descends from migrating cranial neural crest cells [1,2]. Major signaling families are involved, namely transforming growth factor β (including bone morphogenetic proteins; BMPs), fibroblast growth factors (FGFs), Hedgehog, and Wnt. An early important step in odontogenesis is induction of transcription factors including PAX9 (paired box gene 9), MSX1 and 2 (Msh homeobox genes 1 and 2), and DLX1 and 2 (Distal-less homeobox genes 1 and 2) in the ectomesenchyme by epithelial expressed BMPs and FGFs. Tooth crown formation is often discussed in terms of several stages that are defined by progressive changes in morphology; these include dental lamina, bud, cap and bell stages, and root development, as outlined below (Fig. 29.1A–D). In the earliest sign of tooth formation, a thickened stripe of epithelial cells, the dental lamina, forms at future sites of the maxillary and mandibular dental arches. In the bud stage, epithelial cells invaginate into the underlying ectomesenchyme and are surrounded by condensations of proliferating ectomesenchymal cells (Fig. 29.1A). In the following cap stage, the epithelial bud enlarges by asymmetric cell division at the edges to assume a convex caplike shape (Fig. 29.1B). During cap stage, the enamel organ is generated as epithelial cells differentiate into several distinct cell layers, including inner and outer enamel epithelium surrounding the stellate reticulum. A signaling center within the enamel organ, the primary enamel knot, directs cell proliferation in surrounding cells. The underlying ectomesenchyme becomes segregated by the cap, with dental papilla (future dental pulp) confined within the cap and dental follicle (future periodontium, as well as pericoronal follicle cells on unerupted teeth) surrounding the cap. By the following bell stage, secondary enamel knots influence the number and shape of the future cusps of the tooth crown (thus playing a role in determining tooth type, e.g., incisor, canine, premolar, or molar). The three dimensional shape of the tooth crown has taken form and is being populated by the highly specialized dental secretory cells, ameloblasts that form enamel, and odontoblasts that form dentin (Fig. 29.1C). During the remainder of the bell stage, and leading into tooth root development (described below), enamel and dentin matrices are elaborated and matured to prepare for eruption of the crown into the oral cavity (Fig. 29.1D). The highly columnar ameloblasts are derived from the inner enamel epithelium and synthesize the enamel, a unique epithelial mineralized tissue that is the hardest tissue in the human body (Fig. 29.1E) [3,4]. As ameloblasts differentiate, they become organized and polarized in the presecretory phase, then entering the secretory phase, where a partially mineralized

organic enamel matrix is synthesized. A suite of semispecific ameloblast-expressed proteins, including amelogenin (AMELX), ameloblastin (AMBN), and enamelin (ENAM), regulate aspects of amelogenesis, including guiding hydroxyapatite crystallite deposition to form long and thin enamel rods. Matrix metalloproteinase 20 (MMP20; enamelysin), a proteinase that can cleave AMELX, AMBN, and ENAM, is expressed by ameloblasts in late secretory and early maturation phase [5]. In maturation phase, the organic enamel ECM is further degraded by secretion of another proteinase, kallikrein 4 [5]. Removal of proteins and water from the enamel ECM allows for thickening of enamel rods by addition of hydroxyapatite mineral until enamel reaches ∼95% mineral (mostly hydroxyapatite, with smaller amounts of fluorapatite) content. Inherited loss-of-function mutations in these critical regulatory genes cause enamel defects that fall under the diagnostic umbrella of amelogenesis imperfecta (AI) (OMIM 301200, 204650, 104500, 616270, 612529, 204700, and others). AI can be further classified as hypoplastic AI (thin enamel layer), hypocalcified AI (defect in hydroxyapatite crystals), or hypomaturation AI (enamel organic matrix insufficiently removed) [6,7]. Following maturation stage, the enamel organ becomes reduced and is ultimately lost when the tooth erupts into the oral cavity. The bulk of the tooth crown and root is composed of dentin, which is secreted by odontoblasts derived from the ectomesenchymal dental papilla (Fig. 29.1F) [8,9]. Odontoblast differentiation is marked by cell elongation, polarization, and organization. The initial dentin organic matrix is secreted as unmineralized predentin, where mineralization of this ECM to dentin proper occurs as a second discrete step. This process is analogous to the two steps in intramembranous ossification where osteoblasts first produce unmineralized osteoid that is subsequently mineralized by deposition of hydroxyapatite. The initial, relatively thin, outermost layer of dentin is the mantle dentin, whereas the majority of tooth dentin closer to the pulp space is called circumpulpal dentin [8]. As circumpulpal dentin formation continues, odontoblasts migrate inward and leave an elongating odontoblast process within a dentinal tubule. The dentin surrounds the pulp chamber, a vascular and innervated soft tissue home to a heterogeneous population of cell types. Mineralization of mantle dentin is dependent on matrix vesicles [10–13], small membrane-bound vesicles that also participate in bone and cartilage mineralization [14–16]. After rupture of matrix vesicles, mineralization foci nucleated within vesicles grow larger and merge into a united mineralization front. Control of mineralization of circumpulpal dentin is thought to rely more heavily on ECM proteins. The small integrin binding ligand N-linked glycoprotein (SIBLING) family plays a role in directing mineralization of dentin, as well as bone and cementum [17,18]. The SIBLING family represents a related group of multifunctional, noncollagenous ECM proteins associated with mineralized tissues. In dentin, SIBLING proteins involved in the mineralization process include dentin sialoprotein (DSP) and dentin phosphoprotein (DPP) [8,19]. Mutations in the gene DSPP, which encodes both DSP and DPP, have been linked to dentinogenesis imperfecta (DI), a hereditary dentin defect (OMIM 125490, 125500, 125420, and others) [6,20,21]. DI features dentin defects

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FIGURE 29.1  Stages of tooth development and cells and mineralized tissues of the dentoalveolar complex. Tooth development arises from interactions between the dental epithelium and neural crest cell-derived ectomesenchyme, shown here in the four primary stages of odontogenesis using a mouse molar as a model. (A) In bud stage, epithelial cell condensations invaginate into the underlying ectomesenchyme and become surrounded by condensations of proliferating ectomesenchymal cells. (B) In cap stage, the epithelial bud enlarges to a convex caplike surface and epithelial cells differentiate into distinct cell layers to become the enamel organ, including inner and outer enamel epithelium surrounding the stellate reticulum, and the enamel knot, a signaling center. The epithelial cap segregates the ectomesenchyme into the dental papilla (future pulp-dentin complex) and dental follicle (future periodontal complex). (C) In bell stage, the three dimensional shape of the crown becomes apparent and terminal differentiation of ameloblasts and odontoblasts is achieved, setting the stage for secretion of enamel (purple) and dentin (green) and continuation of tooth growth to root formation. (D) Following crown formation, the tooth root elongates and the periodontium develops and organizes, including cementum, periodontal ligament (PDL), and alveolar bone. The teeth and supporting tissues are home to four unique mineralized tissues, highlighted in panels E–H. (E) The enamel (shown here as secretory stage, not yet mineralized enamel ECM) is the product of ameloblast cells of the epithelial enamel organ. (F) The dentin forming the bulk of tooth crown and root is produced by odontoblasts. (G) The tooth root cementum is produced by cementoblasts and anchors the unmineralized PDL to the tooth root surface. (H) The surrounding alveolar bone is synthesized by osteoblasts and houses osteocytes and supports and attaches the tooth to the jawbone. Histological images are from H&E stained 14 day postnatal (dpn) mouse first molar, where crown morphology is mature and root elongation and tooth eruption are underway (similar to the stage depicted in the model in panel D). Images (A–H) adapted from Foster BL, Nociti Jr FH, Somerman MJ. The rachitic tooth. Endocr Rev 2014;35(1):1–34; Copyright Endocrine Society, reproduced by permission.

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including disorganized dentinal tubules and disrupted mineralization patterns such as interglobular dentin. The histological pattern of interglobular dentin results from inability of mineralization foci to properly merge, leaving regions of hypomineralized dentin matrix. Dentin defects similar to DI can arise from distinct conditions, such as osteogenesis imperfecta (OI), a heritable skeletal disorder caused by mutations in collagenencoding genes (COL1A1, COL1A2; OMIM 166200, 166210, 259420, and 166220) or in genes encoding factors that modify or chaperone collagen proteins (e.g., CRTAP, P3H1, PPIB, and others; OMIM 610682, 610915, 259440) [21–23]. Teeth must erupt from their bony crypts to assume their functional position in the oral cavity. The process of tooth eruption is highly orchestrated, and the dental follicle surrounding the tooth bud is essential for providing the necessary molecular cues. Resorption of alveolar bone overlying the tooth crown by osteoclasts creates an eruption pathway. The coronal dental follicle expresses colony stimulating factor-1 and monocyte chemotactic protein-1 (MCP-1; also known as CC chemokine ligand 2 or CCL2) to recruit monocytes to the bone in this region and downregulates osteoprotegerin (OPG; TNFRSF11B) and upregulates receptor activator of nuclear factor kappa B ligand (RANKL; TNFSF11) to induce differentiation of monocytes into mature bone-resorbing osteoclast cells [24]. Parathyroid hormone-related protein (PTHRP or PTHLH) signaling through the PTH1 receptor (PTH1R) has been indicated to be an important signal for the signaling cascade activating osteoclasts to allow tooth eruption [25]. The basal dental follicle surrounding the apical portion of the tooth bud promotes bone formation that provides a motive force to the tooth during the intraosseous phase of eruption, employing osteoinductive factors such as bone morphogenetic protein 2. If either the coronal bone resorbing (osteoclast) actions or basal bone forming (osteoblast) activities are sufficiently disrupted, failure of eruption can occur. As the tooth begins to erupt toward the oral cavity, the nascent root simultaneously elongates [26]. Hertwig’s epithelial root sheath (HERS), a derivative of the enamel organ, undergoes directed cell proliferation to grow apically and define the shape and size of the root(s). In the root, dentinogenesis proceeds as described for the crown, however, odontoblast differentiation is directed by signaling from HERS rather than ameloblasts. The periodontal complex is largely derived from the ectomesenchyme and includes the root-covering cementum, the unmineralized PDL, and the alveolar bone that surrounds the tooth root forming the socket (Fig. 29.1G) [26–31]. After inducing odontoblast differentiation, HERS structure becomes disrupted, exposing the root dentin surface. Cells from the dental follicle can then contact the root dentin, and cementoblasts differentiate and initiate cementum mineralization. Acellular cementum covers the cervical portion of the root and is critical for attachment of the tooth to the PDL via inserted and mineralized Sharpey’s fibers. Cellular cementum is a thicker, more bonelike tissue that covers the apical root and adjusts tooth position as enamel is worn down during life. The vascular and innervated PDL stretches between the tooth and the surrounding alveolar bone, serving as a shock absorber and source for progenitor cells for periodontal repair. The surrounding alveolar bone is a specialized part of the

maxillary and mandibular bone that functions as an important structural support for the teeth (Fig. 29.1H) [28]. An important distinction between tooth and bone is that the dental hard tissues do not undergo the osteoclast-mediated physiological remodeling that is routine to the skeleton. Osteoclastic resorption of dental tissues is physiological only when primary teeth are resorbed to allow replacement by the secondary dentition. During tooth shedding, osteoclasts (called odontoclasts in this context) are directed to root cementum and dentin (by mechanisms still poorly understood) to resorb the root structure and disconnect PDL attachment. When sufficient root structure is removed, the primary tooth is exfoliated, clearing the eruption pathway for its successor. Throughout life, both cementum and dentin grow by apposition, with no role for odontoclastic remodeling or turnover. Therefore, in erupted and functional teeth, odontoclastic resorption of cementum or dentin is considered to be pathological. In most normal individuals, a small amount of cementum resorption probably occurs throughout life; however, existing cementoblasts or cementoprogenitors have the capability to promote reparative cementum formation. More significant root resorption resulting from trauma, infection, rapid orthodontic tooth movement, severe periodontitis, or idiopathic mechanisms can compromise tooth structure, stability, and attachment, possibly leading to fracture and premature tooth loss [32–34]. Although both dentin and cementum have an ability for repair and regeneration, enamel may exhibit minor changes in mineral density during life but has no capability for active cellular repair [35,36]. There does appear to be the potential for remineralization of early initial caries lesions. Conversely, the PDL and surrounding alveolar bone of the periodontium are responsive to mechanical loading and remodel based on mechanical cues received from the forces of occlusion [28,30]. Alveolar bone has been described as the fastest remodeling bone in the body, possibly due to frequent mechanostimulation from occlusal forces. Therefore, presence of osteoclasts on alveolar bone surfaces is normal, as is the routine influx of monocyte and macrophage precursors into the periodontal space. Knowledge of the schedule of tooth initiation, formation, mineralization, and eruption is essential for understanding the impact of diseases on these processes and has important implications for fields ranging from archeology to clinical medicine. To illustrate how perturbations can differentially affect primary and permanent teeth, as well as specific tooth types (incisors, canines, premolars, and molars), timing of stages of the primary and secondary dentition is summarized in Table 29.1 [37,38]. In humans, under normal physiological conditions, primary (deciduous) teeth begin forming by 4 weeks in utero, mineralize between 3 months in utero and 10 years postnatal, and typically erupt between postnatal ages of 6 months and 2 years. Secondary (permanent) teeth variably begin to form in utero and at postnatal ages, mineralize in postnatal months and years, and erupt between 6 and 18 years, depending on tooth type. Primary teeth are typically shed between ages 6 and 12 years in an anterior-toposterior pattern, during which time the secondary (permanent, adult) dentition is completing its development and erupting to replace the primary antecedents.

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Vitamin D Metabolism and Mechanisms of Action on Dental Cells

TABLE 29.1 Schedule of Formation, Mineralization, and Eruption of Primary and Secondary Dentition Dentition Tooth Type

Crown Mineralization Begins (m in Utero/m Postnatal, y Postnatal)

Crown Mineralization Completed (m/y Postnatal)

Root Completed (y Postnatal)

Order of Eruption

Emergence Into Oral Cavity (m/y Postnatal)

PRIMARY DENTITION, UPPER Central incisors

3–4 m in utero

1–5 m

1–2 y

3

7–8 m

Lateral incisors

4 m

2–5 m

2 y

4

9 m

Canines

4–5 m

9 m

3–4 y

8

18 m

First molars

3–4 m

6 m

2–3 y

6

14 m

Second molars

3–5 m

10–12 m

3 y

10

24 m

PRIMARY DENTITION, LOWER Central incisors

4–5 m in utero

2–5 m

1–2 y

1

6 m

Lateral incisors

4–5 m

3–5 m

1–2 y

2

7 m

Canines

5 m

9 m

3–4 y

7

16 m

First molars

3–4 m

5–6 m

2–3 y

5

12 m

Second molars

3–5 m

10–12 m

3 y

9

20 m

SECONDARY DENTITION, UPPER Central incisors

3–4 m

3–5 y

9–11 y

5

7–9 y

Lateral incisors

10–12 m

3–5 y

9–11 y

6

8–9 y

Canines

4–5 m

4–7 y

12–14 y

8

9–11 y

First premolars

1–2 y

5–6 y

12–14 y

9

9–11 y

Second premolars

2–3 y

6–7 y

12–14 y

11

10–12 y

First molars

Birth

2–3 y

9–10 y

3

7–8 y

Second molars

2–3 y

6–8 y

13–15 y

13

11–13 y

Third molars

7–9 y

12–16 y

18–19 y

16

17–18 y

SECONDARY DENTITION, LOWER Central incisors

3–4 m

3–5 y

8–9 y

1

6–8 y

Lateral incisors

3–4 m

3–5 y

9–10 y

4

7–8 y

Canines

4–5 m

4–7 y

11–14 y

7

9–11 y

First premolars

1–2 y

5–6 y

12–14 y

10

10–12 y

Second premolars

2–3 y

6–7 y

12–14 y

12

10–12 y

First molars

Birth

2–3 y

9–10 y

2

7–8 y

Second molars

2–3 y

6–7 y

13–15 y

14

11–13 y

Third molars

8–10 y

12–16 y

18–19 y

15

17–18 y

m, months; y, years. Gray shading indicates prenatal months in utero.

VITAMIN D METABOLISM AND MECHANISMS OF ACTION ON DENTAL CELLS It is useful to briefly review the major steps in vitamin D metabolism (for more detail, see chapters in Section I) and mechanisms of action (for more detail, see chapters in Section

II), to better understand the dentoalveolar etiopathologies described in the following sections. 1α, 25-dihydroxyvitamin D3 [1,25(OH)2D3] is the active form of vitamin D. The vitamin D3 hormone precursor, derived from ingestion or endogenously produced from skin exposure to ultraviolet (UV) rays, is hydroxylated by the cytochrome P450s (CYP2R1 and CYP27A1) in the liver to form the inactive

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form, 25-hydroxyvitamin D3 [25(OH)D3]. This major circulating form of vitamin D is transported by the vitamin D-binding protein (DBP) to the proximal tube of the kidney for a second hydroxylation by 1α-hydoxylase (CYP27B1) to be transformed to its active metabolic form, 1,25(OH)2D3. Circulating levels of 1,25(OH)2D3 are controlled by 1α-hydoxylase/CYP27B1, and CYP24A1, the catabolic enzyme that initiates degradation of 25(OH)D3 and 1,25(OH)2D3. 1,25(OH)2D3 functions in mineral metabolism by stimulating intestinal absorption of calcium (Ca2+), phosphate (Pi), and magnesium (Mg2+). Vitamin D deficiency contributes to development of hypocalcemia and hypophosphatemia. Parathyroid hormone (PTH), secreted by the parathyroid glands, acts as another arm in the hormonal regulation of Ca2+ and Pi (see Chapter 46). Increased PTH secretion as a result of hypocalcemia acts to return serum Ca2+ to the normal range by promoting increased 1,25(OH)2D3 (increasing intestinal absorption of Ca2+), increasing renal reabsorption of Ca2+, increasing bone turnover (via osteoblast-osteoclast signaling) to release Ca2+ into the bloodstream, and reducing serum Pi by a phosphaturic effect on kidneys. Thus hypophosphatemia due to vitamin D deficiency is exacerbated by secondary hyperparathyroidism (spurred by hypocalcemia). The resulting low concentrations of Ca2+ and Pi prevent proper mineralization of the organic bone matrix, and furthermore, loss of 1,25(OH)2D3 signaling to skeletal-and dental-associated cells (e.g., osteoblasts, chondrocytes, osteoclasts, and dental cells, as described in more detail below) plays a role in the resulting skeletal and dental mineralization defects. Vitamin D and PTH interact with a third factor, the phosphaturic hormone fibroblast growth factor 23 (FGF23), to direct the gut–kidney– bone axis of systemic Pi metabolism (see Chapter 47). The role of FGF23 in dentoalveolar development and function will not be substantially discussed in this chapter, though has been covered elsewhere [39]. Circulating 1,25(OH)2D3 initiates signaling primarily via the vitamin D receptor (VDR), a widely expressed intracellular steroid receptor that once activated, participates in the modulation of 1,25(OH)2D3-responsive genes (see chapters in Section II). The VDR and its heterodimeric binding partner, retinoid X receptor, recognize vitamin D responsive elements (VDREs) in the promoter regions of 1,25(OH)2D3-responsive genes, directly affecting transcription of genes in biological networks including bone, mineral metabolism, immune response, cell life cycle and migration, skeletal muscle, detoxification, and energy metabolism (see chapters in Sections III–V for the full scope of vitamin D in human physiology). Cells of the dentoalveolar complex cells respond to 1,25(OH)2D3-mediated signaling. Ameloblasts, odontoblasts, osteoblasts, and other cells of the developing periodontium express VDR and 1,25(OH)2D3-responsive calbindin-D9k and D28k genes [40–46]. In addition to transcription effects, 1,25(OH)2D3 is reported to produce rapid, nongenomic (i.e., VDRE-independent) responses, linked to Ca2+fluxes and activation of protein kinase C signaling [47]. Ameloblasts, odontoblasts, osteoblasts, and osteoclasts in the developing dental–craniofacial complex were also implicated to

participate in the nongenomic pathway based on localization and expression of the membrane-associated rapid-response steroid–binding protein for 1,25(OH)2D3 [48]. Vitamin D has been recognized to directly regulate transcription of a large and diverse array of target genes, and these include several key bone and tooth-related genes. For some 1,25(OH)2D3-responsive genes, the mechanism of transcriptional regulation has been demonstrated through recognized VDREs, whereas for other genes, the mechanism is less defined. 1,25(OH)2D3 positively regulates Lrp5 through recognized VDREs in mouse [49,50]. The encoded protein, low-density lipoprotein receptor 5, is a coreceptor integral for Wnt signaling, setting up vitamin D as an important upstream regulator of Wnt signaling in the dentoalveolar complex and elsewhere. Vitamin D regulates expression of several transcription factors involved in tooth development, potentially modulating many downstream targets. RUNX2, an early regulator of tooth bud formation and controller of osteoblast and odontoblast differentiation, is negatively regulated by 1,25(OH)2D3 [51]. There is also evidence that vitamin D controls expression of MSX and DLX during odontogenesis; these transcription factors are expressed in response to early epithelial–mesenchymal cross talk and are implicated in differentiation of ameloblasts, odontoblasts, and osteoblasts [52–54]. In addition to the vitamin D-responsive genes explicitly discussed below, it is likely there are additional and presently unidentified direct and indirect effects of vitamin D on factors that direct dentoalveolar formation and function. Vitamin D signaling regulates several key ECM proteins that participate in bone and tooth formation (many of which were introduced in the section on tooth formation above). 1,25(OH)2D3 modulates BGLAP, the gene that encodes osteocalcin (OCN), through identified VDREs in human, rat, and mouse genomes [55–57]. OCN is expressed by osteoblasts, odontoblasts, and cementoblasts and has been proposed to regulate mineralization, in addition to acting as a hormone that bridges bone-energy metabolic networks. 1,25(OH)2D3 modulates SPP1 through identified VDREs in the mouse genome [58–60]. SPP1 encodes OPN, a member of the SIBLING family of mineralization-associated ECM proteins that is expressed by osteoblasts, odontoblasts, and cementoblasts. OPN is a multifunctional protein that regulates mineralization and provides integrin-mediated cell signaling and has been implicated in the recruitment of osteoclasts to sites of bone remodeling. Vitamin D has also been indicated to regulate IBSP in a transgenic mouse line [58]. IBSP encodes the BSP protein, a SIBLING family member closely related to OPN and important in cementum and bone mineralization [61]. There is also in vitro evidence that vitamin D downregulates transcription of DMP1, a SIBLING family member expressed by osteocytes and odontoblasts that also has a role in regulating FGF23 expression and systemic mineral metabolism [62,63]. Vitamin D has been inferred to regulate a suite of enamel-selective genes in a rat model, including AMELX, AMBN, and ENAM [64,65]. Vitamin D regulates transcription of key markers of osteoclasts, the cells responsible for resorbing bone. 1,25(OH)2D3

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Vitamin D, Rickets, and the Oral Tissues

increases expression of TNFSF11, the gene encoding RANKL, a key cytokine that promotes osteoclast maturation and activation. 1,25(OH)2D3 also increases expression of CA2, encoding carbonic anhydrase II, an enzyme that regulates osteoclast intracellular Ca2+ concentration and pH, as well as differentiation. VDREs have been identified in the regulatory elements for the mouse Tnfsf11 gene and chicken Ca2 gene [66–68]. Vitamin D is also reported to downregulate expression of TNFRSF11B, encoding the protein OPG, which suppresses osteoclast differentiation [69]. Although expression of VDR in osteoclasts remains controversial [46], these effects to promote osteoclast differentiation and activation, as well as direct actions on osteoclasts and their precursors [70], implicate vitamin D to be an important coordinator of bone resorption. Although it is beyond the scope of this chapter to include an in-depth review of PTH signaling (see Chapter 46), it is appropriate and important to address the topic of PTH responsiveness in dental cells, as PTH secretion is often altered following derangement of 1,25(OH)2D3 metabolism. Secondary hyperparathyroidism occurs because of parathyroid hyperplasia from loss of negative regulation by 1,25(OH)2D3, and because of increased PTH secretion due to hypocalcemia. PTH affects cells directly, in addition to adjusting mineral homeostasis. PTH signals through the PTH1R (or PPR in mice), a G-protein coupled receptor expressed in bone cells [71], as well as in dental cells including ameloblasts, odontoblasts, cementoblasts, and follicle cells [72–77]. PTH1R activation signals adenylate cyclase, phospholipase C pathways, and others, to regulate target gene transcription, where target genes include growth and differentiation factors, transcription factors, and skeletal regulatory factors [71,78–81]. Notably, PTH can have anabolic or catabolic effects on bone depending on dose and continuous or intermittent administration [82–89]. The well-characterized catabolic effect of PTH on skeleton to increase serum Ca2+ relies in part on OPG and RANKL expression by osteoblasts, in turn promoting increased osteoclast resorption to release Ca2+ and Pi.

VITAMIN D, RICKETS, AND THE ORAL TISSUES Rickets strikes during the period of bone development in children (for detailed descriptions, see chapters in Section III). Bone, which is rapidly modeling and remodeling during these early periods of growth, remains as hypomineralized osteoid as a result of disrupted mineral metabolism of rickets, leaving it mechanically unsound and prone to fractures. The combination of excess osteoid (hyperosteoidosis) and increasing load (e.g., weight gain and onset of walking in toddlers) leads to rachitic bowing of the legs (genu valgum and genu varum). Rickets also manifests as disruptions in areas of rapid skeletal growth, including epiphyseal growth plates in long bones and costochondral junctions, and can cause short stature, enlarged cranial sutures and fontanelles, delayed fontanelle closing, and malformations of the cranium, including parietal and occipital flattening and frontal bossing [90–92]. Unfortunately,

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the dentoalveolar tissues are also developing in utero and in the early postnatal years and also bear the brunt of rachitic defects during this stage [39].

History of Vitamin D and Oral Tissues Although early reports of bone deformities resembling rickets are attributed to physicians from the 1st and 2nd centuries AD [93], the first detailed description was published in 1650 by Glisson et al. in a medical treatise published in England [94,95]. The authors highlighted clinical signs including limb deformities and widened joints at the wrists and ankles. Effects on the dentition were also recognized, where an earlier brief monograph published in 1645 identified delayed tooth eruption associated with rachitic skeletal disease [96]. The destructive effects of rickets on the dentition were better known by the time an 1883 publication in the British Journal of Dental Sciences reported that in rickets, “The evolution of the teeth is retarded or if commenced interrupted and when the teeth do appear they are carious black and soon fall from their sockets” [97]. Nutritional experiments conducted in the early 20th century by Elmer McCollum, Sir Edward Mellanby, and others, revealed that the etiology of rickets lay in the lack of an antirachitic factor, and this newly discovered vitamin was dubbed vitamin D (see Chapter 1) (also reviewed in Refs. [91,93,98]). Studies on rachitic animal models over the past century have elucidated the role of 1,25(OH)2D3 in skeletal mineralization and mechanisms for rachitic changes in bones. In these studies, rickets was induced experimentally using diets deficient in vitamin D, Ca2+, or Pi, or some combination of these, with additional insights provided by “experiments of nature,” where dietary interventions reversed rachitic conditions (as summarized in Refs. [99,100]). The influence of diet on tooth development was largely unappreciated around the time of the discovery of vitamin D. From 1918 onward, May Mellanby, wife of Edward Mellanby, performed an astounding number of dietary experiments using rats, rabbits, and dogs and was the first to provide critical insights into the role of 1,25(OH)2D3 on tooth mineralization (as summarized in Ref. [101]). Lady Mellanby concluded that diets deficient in vitamin D-containing fats caused severely hypoplastic enamel and defects in dentin, including poorly calcified and interglobular dentin. She recognized the “calcifying” influence of 1,25(OH)2D3, and its necessity for optimal use of dietary Ca2+ and Pi in tooth mineralization, with a particularly strong association between vitamin D, Ca2+, and quality of enamel. Notably, these realizations preceded understanding that vitamin D increased efficiency of Ca2+ and Pi absorption in the gut, and interacted with PTH to control mineral ion homeostasis. May Mellanby’s insights appear prescient in light of later dietary experiments that extended her work. Harrand and Hartles altered Ca2+:Pi ratio in the presence and absence of 1,25(OH)2D3, observing that teeth were more sensitive than bone to deprivation of Ca2+, likely a result of unrecognized changes in PTH activity, however, these authors did not discriminate between effects on enamel and dentin [102–105].

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Numerous additional dietary rickets experiments were performed that identified disturbed enamel formation and ultrastructure, hypomineralized dentin, and altered mineral ratios in dental tissues (for examples, see Refs. [103,106–114]). Later studies focused on tissue-specific and cell signaling effects of 1,25(OH)2D3 deprivation. Important experiments by Berdal et al. demonstrated that vitamin D-deficient rats featured dysmorphic enamel organ and odontoblasts, with defects in enamel and dentin matrix secretion and mineralization [41,115].

Nutritional Rickets and the Dentoalveolar Complex Vitamin D deficiency, which rose with changing dietary habits of the agricultural revolution, and then became rare in the 20th century, is once again a worldwide public health concern in the 21st century. Processed foods and modern nutritional recommendations sometimes fail to provide an adequate dietary supply of vitamin D under conditions of reduced endogenous vitamin D production, e.g., in those avoiding the sun for fear of UV exposure or for cultural reasons, dark-skinned people living in northern or cloudy climates, at the extremes of age, and in mothers and fetuses during winter pregnancies [98,116– 120] [see also Chapter 61 (vol. 2 of this book); Chapter 67 (vol. 2 of this book)]. Nutritional rickets caused by vitamin D deficiency persists worldwide in the modern era [121–125]. Public health strategies for rickets prevention focus on fortifying and supplementing diets, and early recognition of vitamin D insufficiency and deficiency, especially for those at greater risk [121,122]. Vitamin D deficiency during pregnancy is associated with osteomalacia in the mother and congenital rickets in the child, which will also affect development and mineralization of the child’s primary dentition. Vitamin D deficiency during early childhood in turn affects the child’s permanent dentition. Timing and severity of nutritional vitamin D deficiency can differentially affect both sets of teeth, as well as specific tooth classes within each set. For reference, the timing of mineralization of primary and secondary dentition is reviewed in Table 29.1. Given the multitude of ways that vitamin D influences mineralized tissue cells and mineral metabolism (outlined above), it is not surprising that the scope of dentoalveolar effects of nutritional rickets includes all of the mineralizing cells types and tissues of the tooth. These include enamel hypoplasia, high incidence of caries, thin dentin, widened pulp chambers, indistinct lamina dura (bundle bone lining the tooth socket, as observed by radiography), delayed formation and/or eruption of teeth, and malocclusion (incorrect relation between the maxillary and mandibular teeth). Four cases of nutritional rickets are presented in Fig. 29.2 and serve to underscore the importance of timing and severity of vitamin D deficiency in causing dental defects. In the first case, a 12-year-old dark-skinned girl was exclusively breastfed from birth until 7 months old, when vitamin D supplements were introduced [38]. She presented with jaw pain, mild and localized enamel defects on incisors, and deep caries on all of

her permanent first molars (Fig. 29.2A–C), with one requiring extraction due to severe pulpitis. The timing of likely vitamin D deficiency (birth to 7 months) corresponds to crown mineralization of the incisors and molars (Table 29.1). In the second case, an 11-year-old dark-skinned girl originally from Cameroon suffered vitamin D deficiency until 4 years of age, when she was administered vitamin D supplements [38]. She presented with severe enamel hypoplasia on incisors, canines, permanent first molars, and her last remaining primary molar (Fig. 29.2D–E). Permanent premolars appeared to be unaffected in this case. This vitamin D deficiency was likely more severe than the individual described in the first case and was prolonged over the first 4 years, leading to more severe enamel defects distributed among more tooth groups of the primary and secondary dentition. Apparent correction of enamel and dentin formation has been associated in some cases with onset of treatment for rickets. Severely hypoplastic enamel in both maxillary and mandibular incisors and molars resulted from nutritional rickets in a 7-year-old female subject who was diagnosed and treated at 16 months (Fig. 29.2F and G) [114]. In this subject, cervical enamel in incisors and molars appears normalized (yellow arrows), reflecting correction of amelogenesis following treatment. In another case, a 2.5-year-old female born to Vietnamese parents in Canada presented with features of nutritional rickets in her skeleton and dentition (Fig. 29.2H and I) [126]. Dental examination revealed carious lesions in numerous incisors and molars, large pulp chambers with unusual pulpal horn extensions, and indistinct lamina dura and bone trabeculation. Following 2 years treatment with vitamin D and calcium supplements, as well as dietary changes, authors reported improvements to the alveolar bone (Fig. 29.2J) in parallel to general improvements in the skeleton.

Hypervitaminosis D and Teeth Although vitamin D deficiency is well known to negatively affect dental development, excess ingestion of vitamin D, or hypervitaminosis D, can also profoundly disturb dental mineralization. Severe excess vitamin D toxicity causes systemic perturbations including anorexia, vomiting, headache, and diarrhea [see Chapter 81 (vol. 2 of this book)]. Hypervitaminosis D accelerates Ca2+ absorption and bone resorption, promoting hypercalcemia that induces ectopic calcification of vascular tissues. Hypervitaminosis D case reports in humans and experimental diet studies in animals relate dentoalveolar disturbances including enamel hypoplasia and hypomineralization, dental pulp calcification, deformed root formation, and periodontal abnormalities and tooth root resorption [127–131]. A case report of hypervitaminosis D is presented in Fig. 29.3. In this case, hypervitaminosis D was experienced by this 7-year-old female patient between 10 and 15 months of age because of ingestion of milk overfortified with vitamin D [127]. Timing of toxicity is reflected by the location of the most severe enamel defects on maxillary central incisors, apparent as hypomineralized white lines and a hypoplastic defect near the gumline (Fig. 29.3A). A periapical

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FIGURE 29.2  Dental defects associated with vitamin D deficiency and nutritional rickets. (A) Intraoral photographs showing mild and localized enamel defects (yellow arrow) in a 12-year-old female patient who experienced vitamin D deficiency from birth to 7 months. (B, C) The patient experienced deep caries on all of her permanent first molars. (D, E) Intraoral photographs showing severe enamel hypoplasia on incisors, canines, and permanent first molars (yellow arrow in E) in an 11-year-old female patient who suffered vitamin D deficiency until 4 years of age, when she was administered vitamin D supplements. Permanent premolars appeared to be unaffected in this case. (F, G) General appearance of severely hypoplastic enamel in (F) maxillary and mandibular incisors and (G) molars, in a case of nutritional rickets in a 7-year-old female diagnosed and treated at 16 months. Note that cervical enamel in incisors and molars appears normalized (yellow arrows), reflecting correction following treatment. (H, I) A 2-year-old female with nutritional rickets presented with numerous carious lesions (yellow arrows), thin dentin, large pulp chambers (yellow asterisks), abnormal pulpal horn extensions, and indistinct lamina dura and bone trabeculation. (J) Following 2 years of vitamin D and calcium supplementation, bony defects were abrogated. Note restoration on crowns to treat carious lesions. Panels (A–E) included by permission of Dr. Tiphaine Davit-Béal (Université Paris Descartes, Paris, France). Panels (F and G) adapted from Berdal A, Molla M, Descroix V, Vitamin D and oral health. In: Feldman D, Pike JW, Adams JS, editors. Vitamin D. 3rd ed. USA: Academic Press; 2011. 521–532; Copyright Elsevier, reproduced by permission. Panels (H–J) adapted from McDonnell D, Derkson G, Zhang L, Hlady J. Nutritional rickets in a 2-year-old child: case report. Pediatr Dent 1997;19:127–30; Copyright American Academy of Pediatric Dentistry, reproduced by permission.

radiograph further reveals pulp calcification (Fig. 29.3B). The role of the hypercalcemia in dental defects associated with hypervitaminosis D is supported by genetic studies in mice lacking calcium-sensing receptor function [132], though association of orodental defects with hypercalcemia disorders in humans, such as Williams–Beuren syndrome (OMIM 194050) and hypercalciuric hypercalcemia (OMIM 145980), remains

unclear at present. Primary hyperparathyroidism (OMIM 145000 and 145001) and the resulting hypercalcemia is associated with orodental alterations such as development of tori (bony protuberances) and changes in periodontal parameters such as PDL width and alveolar bone density [133], though the range and severity of symptoms is likely related to age of onset (typically middle age or older) and duration prior to diagnosis

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FIGURE 29.3  Effects of hypervitaminosis D on teeth. Hypervitaminosis D was experienced by this 7-year-old female patient between ages 10 and 15 months due to ingestion of milk overfortified with vitamin D. (A) Clinical photograph indicates enamel defects on maxillary central incisors, apparent as hypomineralized white lines and hypoplastic defect (yellow arrow) near the gumline. (B) Periapical radiograph of maxillary central incisors indicating hypoplastic defects (yellow arrows) and hypermineralized/pulp stones in the dental pulp (yellow asterisk). Images in (A and B) adapted from Giunta JL Dental changes in hypervitaminosis D. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85:410–3; Copyright Elsevier, reproduced by permission.

and treatment. Secondary hyperparathyroidism arises from a range of conditions, including the hereditary vitamin D deficiencies described in detail in the next section.

HEREDITARY VITAMIN D-RELATED DISEASES AND DENTOALVEOLAR TISSUES Vitamin D-Dependent Rickets In addition to nutritional deficiency and/or lack of exposure to sunlight as sources for vitamin D insufficiency, there exist hereditary deficiencies caused by mutations in genes encoding elements of the vitamin D metabolic machinery. Initial recognition of hereditary pseudovitamin D deficiency rickets revealed that very high vitamin D intake was required to maintain health [134]. Therefore, this condition was classified as vitamin D-dependent rickets (VDDR), and later genetic analyses of VDDR identified loss-of-function mutations in CYP27B1 or CYP2R1. Mutations in CYP27B1 cause VDDR type 1A (VDDR1A) due to loss of 1α(OH)ase enzyme activity (OMIM #264700). Mutations in CYP2R1 cause VDDR type 1B (VDDR1B) due to loss of activity in cytochrome P450 family 2 subfamily R member 1 (CYP2R1; OMIM# 600081), a vitamin D 25-hydroxylase that functions in the liver. Both types of VDDR feature classic signs of vitamin D-deficient rickets, including short stature, bowed legs, widening of wrists, and others described in later chapters [Chapter 71 (vol. 2 of this book); Chapter 72 (vol. 2 of this book); Chapter 73 (vol. 2 of this book)]. Skeletal and other manifestations of VDDR are amenable to improvement with physiological doses of dietary calcitriol (and Pi). VDDR1A is the most commonly reported form of VDDR reported to date, with case reports spanning several decades. Case presentations have identified clinical signs including hypoplastic enamel, dentin mineralization defects, large pulp chambers, short roots, malocclusion, and persistent periodontal disease [135–143]. Enamel and dentin defects are

highlighted in Fig. 29.4A–G, in photographs, radiographs, and histology from a subject diagnosed with VDDR1A [135]. Importantly, dietary intervention has been shown to improve dental (as well as skeletal) formation and mineralization when implemented early in development [139]. VDDR1B has been infrequently reported since its initial discovery in 1994, with few disease-associated CYP2R1 mutations identified to date [144–147]. No detailed dental data have been published for any of these mutation analyses. Tosson and Rose reported on an individual with skeletal signs of rickets and 25-hydroxylase deficiency (low circulating 25(OH)D), though a mutation in CYP2R1 could not be definitively identified [148]. Although delayed tooth eruption was not reported in this individual, chipping of incisors and rampant tooth decay by the age of 4 years are signs suggestive of enamel defects associated with rickets.

Vitamin D-Resistant Rickets Unlike the forms of VDDR described in the preceding section, some forms of hereditary pseudovitamin D deficiency were found to be refractory to even large doses of vitamin D, thus the term, vitamin D-resistant rickets (VDRR). Loss of VDR function or signaling from mutations in the VDR gene causes a distinct disease entity, VDDR type 2 (VDDR2A; OMIM #277440). VDRR encompasses the endocrine and skeletal feature of VDDR, while also frequently including other signs such as alopecia [See Chapter 72 (vol. 2 of this book)]. Although skeletal and some dentoalveolar manifestations of VDDR1A and B are amenable to improvement with physiological doses of dietary calcitriol (and Pi), forms of VDRR are refractory because VDR function or downstream signaling is defective. Case reports on VDRR have identified clinical signs including oligodontia, delayed tooth eruption, hypoplastic enamel, high incidence of caries, large pulp chambers, pulp stones, short or deformed roots, spontaneous dental abscesses, and

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FIGURE 29.4  Dental defects associated with vitamin D-dependent rickets (VDDR1A). Mutations in CYP27B1 cause vitamin D-dependent rickets type 1A (VDDR1A) in humans. (A and B) Clinical photographs of the dentition of a 10-year-old female diagnosed with VDDR1A, showing discoloration indicative of enamel hypoplasia. (C) Panoramic and (D and E) periapical radiographs of the subject demonstrated teeth with enamel defects (yellow asterisk) and large pulp chambers and short, thin roots (yellow arrows). Note extensive restoration of carious lesion in panel E. (F) Histology of a deciduous premolar further demonstrated mineralization defects including wide predentin (PD) and variable dentin (DENT) mineralization, and (G) interglobular patterns (yellow asterisk) in circumpulpal dentin. Images in (A–G) adapted from Zambrano M, Nikitakis NG, Sanchez-Quevedo MC, Sauk JJ, Sedano H, Rivera H Oral and dental manifestations of vitamin D-dependent rickets type I: report of a pediatric case. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95:705–9; Copyright Elsevier, reproduced by permission.

tooth loss [136,137,149–151]. In the most detailed dental case reports to date, three Japanese children with VDRR2A presented with alopecia, signs of rickets, hypopcalcemia, hypophosphatemia, yet high 1,25(OH)2D3 [136,137]. The two milder cases featured large pulp chambers and thin dentin, however, obvious enamel hypoplasia was not noted, and only a few teeth featured carious lesions (Fig. 29.5A–E). A more severely affected third subject exhibited gingival swelling, caries, and severe periapical abscesses that required

affected teeth to be extracted (Fig. 29.5I–K). Sections from extracted teeth showed signs of disorganized dentinogenesis and interglobular dentin, indicating inhibition of mineralization. All three subjects were administered increasingly large daily doses of vitamin D supplements, though because of the nature of the likely causative mutations (affecting VDR function), the disease was recalcitrant. With provision of up to 3.0 μg/kg/day of 1α-(OH)D3 over several months, the authors reported biochemical and phenotypic improvement

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in the milder subjects, including some degree of correction in the dentition (Fig. 29.5F–H). However, the severely affected third individual did not respond positively (Fig. 29.5I–L) and was instead treated for caries and provided instructions on eating habits. With these sorts of anecdotal case reports, it should be kept in mind that effect of treatment remains uncertain because of lack of control subjects. In these subjects with apparent improvement, it is unclear how the vitamin D supplementation promoted enhanced mineralization in light

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of VDR defects, allowing for alternate explanations such as continued mineralization of the teeth as a function of time, development, or other factors. The more recently defined VDRR2B (OMIM 600785) features unaffected VDR, but end-organ vitamin D resistance due to interference in VDR–DNA interaction from suspected defects in riboprotein function. To our knowledge, no reports on the oral–dental phenotypes of subjects with VDRR2B have been reported to date.

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FIGURE 29.5  Dental defects associated with vitamin D-resistant rickets (VDRR2A). Mutations in VDR cause vitamin D-resistant rickets type 2A (VDRR2A) in humans. Female subject 1 (A–H) was more mildly affected, whereas male subject 3 (I–L) featured more severe manifestations of VDRR2A. (A and B) Subject 1 presented with VDRR2A at 3 years and 1 month, with no obvious enamel hypoplasia and a few carious lesions. (C–E) Radiographs of subject 1 revealed thin dentin and widened pulp chambers (yellow asterisks) and caries (yellow arrows). (F–H) After 25 weeks of vitamin D treatment, subject 1 exhibited improvements in dentin thickness and radiopacity. Note that caries have been restored at this time. (I and J) Subject 3 presented with VDRR2A at 2 years and 2 months with gingival swellings, caries, and severe periapical abscesses. Radiographs of subject 3 revealed thin dentin and widened pulp chambers (yellow asterisks) and abnormal enamel and caries (yellow arrows). (K) Extracted tooth from subject 3 shows enamel and dentin appearance more clearly. (L) Administration of vitamin D did not significantly improve dental tissues in subject 3. Images in (A–L) adapted from Nishino MM, Kamada KK, Arita KK, Takarada TT. Dentofacial manifestations in children with vitamin D-dependent Rickets type II. Shoni Shikagaku Zasshi (Jpn J Pediatr Dent) 1990;28:346–58; Copyright Japanese Society of Pediatric Dentistry, reproduced by permission.

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Experimental Models of Vitamin D-Dependent Rickets and Vitamin D-Resistant Rickets Transgenic mice featuring loss-of-function of 1α(OH)ase or VDR (models for VDDR1A and VDDR2A, respectively) have allowed for detailed analysis of tooth development in the face of loss of vitamin D signaling. 1α(OH)ase or VDR-null mice reproduce the biochemical and skeletal features of rickets, namely hypocalcemia, hypophosphatemia, growth plate disorders, and mineralization defects [152–157] (see also Chapter 36). Dietary administration of either vitamin D or high Ca2+, Pi, and lactose, was able to rescue hypocalcemia and correct secondary hyperparathyroidism and skeletal hypomineralization in 1α(OH)ase null mice [158,159], and a similar rescue diet (though not vitamin D alone) improved VDR null mouse skeletal mineralization as well [152]. More recently, Cyp2r1−/− mice were developed to evaluate the relative importance of CYP2R1 in 25-hydroxylation of vitamin D3. Cyp2r1−/− mice exhibited significantly reduced circulating 25(OH)D3 levels but normal 1,25(OH)D3 concentrations [160]. Skeletons of Cypr21−/− mice appeared normal, and the dentition was not examined. These results suggest that CYP2R1 is a major 25-hydroxylase, but that one or more others exist that share overlapping functions. Histology of mandibular molars of a 6-week old wild-type (WT) control and 1α(OH)ase null mouse are compared in Fig. 29.6. Compared with WT controls, 1α(OH)ase null mice feature reduced bone and dentin formation and mineralization [161]. Furthermore, 1α(OH)ase null mouse teeth feature widened predentin, thin mineralized dentin, and an enlarged pulp chamber, as well as interglobular dentin. These bone and dentin defects parallel those in the VDR null mouse, wherein mineralization defects in enamel have also been identified

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[52,162–167]. Periodontal defects in VDR-null mice were evidenced by poor PDL insertion into bone, as well as severe tooth root resorption. Only recently were contributions of mineral imbalance and maternal vitamin D considered independently in the VDR null mouse model [168]. Descroix and colleagues demonstrated that maternal vitamin D contributed to molar crown morphogenesis, whereas dietary rescue of Ca2+ and Pi reinforced the notion that enamel and dentin mineralization defects were largely due to hypocalcemia and hypophosphatemia. Importantly, although biomineralization could be improved by dietary intervention, remaining crown defects likely reflect important direct actions of 1,25(OH)2D3 on cell differentiation. In VDR-null mice, although incisor enamel was reduced in thickness and easily abraded, dentin was the most severely affected tissue. Dental defects described in the 1α(OH)ase and VDR null mouse models match those reported in VDDR1 and 2 in affected individuals and implicate the resulting mineral ion deficiencies as causative factors in defective enamel and dentin mineralization. Early on, Nikiforuk and Fraser reported an association of enamel hypoplasia in human subjects with VDDR, where there is hypocalcemia, but not in rickets with normal Ca2+, hypothesizing that enamel defects arose from low serum Ca2+ during development [140–142], and rescue of enamel by dietary correction of serum Ca2+ in the VDR null mouse supports that [168]. These and other studies [114,169– 171] contributed to the theory that 1,25(OH)2D3 affects dental formation only by regulating systemic Ca2+ and Pi. The picture becomes more complicated when the role of PTH is considered, and when studies are designed to elucidate the individual roles of 1,25(OH)2D3 and PTH as mineral ion regulators versus signaling molecules. Greater appreciation

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FIGURE 29.6  Dental phenotype of a mouse model of VDDR1A. Loss-of-function in Cyp27b1 causes a VDDR1A-like condition in 1α(OH)ase −/− mice. Compared with (A) control mouse mandibles, (C) 1α(OH)ase−/− mouse mandibles feature extensive hypomineralization of bone and molar and incisor teeth by radiography. (B, D, E–J) By histology, 1α(OH)ase −/− mouse teeth feature thinner dentin (DE), widened predentin (PD), and erratic predentin margins. Interglobular dentin (indicated by yellow asterisk in panel I) was observed in teeth. (G, J) von Kossa staining confirms that the mineralized portion (stained black) of the molar dentin is decreased in 1α(OH)ase−/− versus controls. Images in (A–J) adapted from Liu H, Guo J, Wang L, Chen N, Karaplis A, Goltzman D, Miao D. Distinctive anabolic roles of 1,25-dihydroxyvitamin D(3) and parathyroid hormone in teeth and mandible versus long bones. J Endocrinol 2009;203:203–13; Copyright Society for Endocrinology, reproduced by permission.

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of the role of hyperparathyroidism and its effect on Ca2+ in vitamin D-deficient skeletal and dental disorders came later, when genetic mouse models could be used for dissecting the distinct roles, and especially the interactions, of PTH and 1,25(OH)2D3. Ablation of 1α(OH)ase in mice resulted in longterm hyperparathyroidism, found to increase bone formation through increased numbers of osteoblasts, osteoid, and trabecular volume by the anabolic actions of PTH [155,156,172,173]. Normalization of PTH and Ca2+ in 1α(OH)ase null mice ultimately revealed reduced endochondral ossification versus controls, confirming a direct anabolic role for 1,25(OH)2D3 in bone formation. Comparing 1α(OH)ase null, PTH null, and double null mice, underscored that while both factors contribute to Ca2+ homeostasis, 1,25(OH)2D3 primarily affects endochondral bone formation and bone length, and PTH primarily affects appositional bone growth [173,174]. In contrast to the expanded volume of trabecular bone in the femur, 1α(OH) ase mice featured reduced and hypomineralized tooth dentin and alveolar bone, even in the face of elevated PTH, suggesting distinct effects of 1,25(OH)2D3 and PTH in the dentoalveolar complex versus long bones [161]. Direct effects of loss of vitamin D signaling were reported in osteoblast, odontoblast, and ameloblast activities and gene expression profiles [114,161,168], and in the larger scheme, these and other results from VDR-null mice [52,162–167] argue for a signaling role for 1,25(OH)2D3 in formation of dental tissues, in addition to its established role in mineralization by controlling circulating Ca2+ and Pi concentrations. The nature of the dental defects is elucidated by histologic and scanning electron microscopy analyses that have identified interglobular mineralization patterns in crown and root dentin. Control of mantle dentin mineralization is highly dependent on matrix vesicles [10–13] to nucleate mineralization foci. After rupture of matrix vesicles, these foci grow larger and merge into a united mineralization front. The rate of mineralization is thought to be further directed by dentin ECM proteins, including DSP and DPP [8,13,19]. Vitamin D deficiency in rats has been associated with disturbances in dentin ECM proteins including phosphoproteins and fibronectin, which could further hamper dentin mineralization [as summarized in [114]]. The interglobular patterns in dentin in human subjects with VDDR or 1α(OH)ase/VDR-null mice thus reflect an inability of mineralization foci to fully fuse into a unified mineralization front during circumpulpal dentin mineralization [138,139,175], resulting in a hypomineralized dentin and root morphological defects, and ultimately, teeth prone to fracture and infection.

Other Genetic Considerations for Diagnosing Dental Rickets In addition to the genes associated with VDDR and VDRR that are described above, it is likely that other factors involved in vitamin D metabolism contribute to dental formation and mineralization. Although genetics studies have identified polymorphisms in these alleles as contributing to circulating vitamin D levels (see Vitamin D and Oral Health section below), none of these factors have yet been linked to skeletal

FIGURE 29.7  Effects of vitamin D dysregulation on dentoalveolar tissues. This tooth model summarizes common manifestations on dentoalveolar tissues of nutritional vitamin D deficiency, vitamin D-dependent rickets, and vitamin D-resistant rickets. Adapted from Foster BL, Popowics TE, Fong HK, Somerman MJ. Advances in defining regulators of cementum development and periodontal regeneration. Curr Top Dev Biol 2007;78:47–126; Copyright Elsevier, reproduced by permission.

or dental rickets. Several polymorphisms have been identified in GC, the gene encoding DBP (OMIM 139200). Mutations in CYP24A1, the catabolic enzyme that initiates degradation of 1,25(OH)2D3, have been linked to infantile hypercalcemia, but with no reports to date on dentoalveolar or craniofacial effects (OMIM 143880). From the summary of human case reports and experimental animal models discussed above, it becomes apparent that vitamin D deficiency and the associated byproduct of dysfunctional mineral metabolism affects dentoalveolar structures in a multitude of ways, disrupting enamel, dentin, the periodontium, and the eruption process (Fig. 29.7). Although they share many clinical features, vitamin D/calcium deficiency and hypophosphatemic rickets (HR) (VDDR or VDRR) may present a distinct dental presentation that allows for discriminating between these conditions. Vitamin D or calcium deficiency is suspected on the differential diagnosis list when there is a high past caries experience or enamel hypoplasia, and further clues include differential effects between primary and secondary dentitions or between tooth types (that form at staggered times during development; see Table 29.1) [38,176], Vitamin D supplementation may offer effective caries prevention to reduce dental caries incidence in pediatric patients [38,177], a topic discussed in more detail in Vitamin D and Oral Health section below. On the other hand, acute dental pain without visible signs of dental decay or a history of trauma may be a relatively unique clinical sign for HR, where patients are susceptible to spontaneous abscesses from defects in dentin and/or enamel mineralization [135–142]. Dental sealants have been suggested to offer a preventive approach to alleviate the dental suffering associated with HR [178]. HR can be furthermore characterized by changes in physical appearance (e.g., frontal bossing), a high caries experience, enamel hypoplasia, and radiographs showing large pulp chambers [179].

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The dental defects presented in nutritional rickets, VDDR, and VDRR can sometimes be mistaken for other syndromic and isolated types of developmental defects. Patients presenting with dental manifestations consistent with any of these diseases may warrant referral to practitioners who specialize in treatment of individuals with rare dental-oral-craniofacial conditions. Nutritional rickets may be differentially diagnosed from genetic causes by observation of the pattern of primary and secondary teeth affected (as shown in Fig. 29.2 above), whereas genetic causes such as VDDR and VDRR are expected to affect all tooth groups in both dentitions (barring treatment effects from intervention) [38]. Enamel defects in nutritional rickets, VDDR, and VDRR, may be mistaken for AI from loss-of-function mutations in enamel proteins (as outlined in A Brief Primer on Dentoalveolar Cells and Tissues section above). Dentin defects may be diagnosed as DI from loss-of-function mutations in dentin proteins (as outlined in A Brief Primer on Dentoalveolar Cells and Tissues section above). Enamel and dentin defects in nutritional rickets, VDDR, and VDRR can be misdiagnosed as HR. HR is caused by loss-of-function mutations in the genes PHEX (X-linked hypophosphatemia; XLH; OMIM 307800), DMP1 (autosomal recessive hypophosphatemic rickets 1; OMIM 241520), or ENPP1 (autosomal recessive hypophosphatemic rickets 2; OMIM 613312). All of these forms of HR involve pathologically increased FGF23, hypophosphatemia, and derangement of vitamin D and PTH metabolism [see Chapter 70 (vol. 2 of this book)] [22,39]. Confusingly, XLH is frequently referred to as vitamin D resistant rickets (VDRR) in the literature going back to the 1970s, though it is distinct in etiology and presentation as compared with VDRR2A and 2B outlined above. Dental defects from other inborn causes may overlap in presentation with vitamin D disorders, and some of these include hypophosphatasia (OMIM 241500, 241510, and 146300), OI (OMIM 166200, 166210, 259420, 166220, 610682, 610915, 259440, and others), Raine syndrome (OMIM 259775), fibrous dysplasia/ McCune-Albright Syndrome (OMIM 174800), and idiopathic hypoparathyroidism [22,39].

VITAMIN D AND ORAL HEALTH Vitamin D Supplementation and Incidence of Dental Caries There is a strong biological and epidemiological argument for ensuring a lifestyle that, either through sun or dietary practices, ensures adequate sources of vitamin D. Experimental animal studies combined with case-studies, case-series, casecontrol studies, and cohort studies, unequivocally linked vitamin D deficiencies during prepubertal growth and development to dental and craniofacial abnormalities (as outlined above). Such developmental anomalies have in turn been linked to an increased incidence of diseases, including dental decay. The historical and epidemiological evidence appears similarly overwhelming that vitamin D supplementation in the food supply will largely eliminate the scourge of rickets and its associated craniofacial abnormalities.

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However, whether vitamin D supplementation will lead to a growth and development that is within evolutionary normal limits, and that reduces the incidence of dental diseases, is less clear. Hypothesized mechanisms by which vitamin D can prevent or arrest dental caries included optimized tooth development (through actions on ameloblasts and odontoblasts), better mineralization of teeth (optimal Ca2+ and Pi during enamel and dentin mineralization), and through effects on the immune system that would abrogate the cariogenic microbial component of caries production. The effect of vitamin D supplementation on dental caries rates has been studied in a series of controlled trials published between 1924 and 1995 on a total of about 3000 children [180–209], as summarized by systematic review and metaanalysis [210]. Overall, the results of these trials suggest that vitamin D supplementation reduces dental caries rates by 48% (Fig. 29.8). UV reduced the caries rate by 65%, vitamin D3 by 49%, and vitamin D2 by 36%, though these differences were not statistically significant within the limits of the metaanalysis. Interpreting the results of these trials is challenging because most of the studies were conducted in an era when control for biases in clinical trial design and analysis was minimal, diets were different, and control for conflicts of interest was nonexistent.

Vitamin D Intake and Other Dental and Craniofacial Consequences Evidence is much more limited and ambiguous on the effects of vitamin D supplementation on other craniofacial consequences, such as periodontal health, orthodontic malocclusions, and facial characteristics. Conducting controlled trials in this area is challenging, and realistically, answers likely remain decades away. The only strong hint in this regard originates from a pivotal medical trial where vitamin D supplementation combined with Ca2+ reduced tooth loss rates [211]. As the cause of tooth loss was not documented in this trial, it remains unclear whether this vitamin D effect was mediated through reduced susceptibility to periodontal disease, as opposed to dental caries or some other effect. Experimental animal studies have provided suggestive evidence on the mechanisms by which vitamin D may relate to periodontal health, especially focusing on potential immunomodulatory actions of vitamin D [212–215]. Similar promising evidence has been identified in epidemiological investigations. Two intervention studies on vitamin D supplementation among individuals with periodontitis have suggested beneficial effects [216,217]. Some longitudinal studies have similarly indicated that decreased vitamin D levels at baseline are related to periodontal tooth loss or worsening of periodontal parameters during the follow-up [218,219], or conversely, that vitamin D supplementation can improve surgery and wound healing outcomes in subjects with chronic periodontitis [220]. Other prospective studies related vitamin D intake with a decreased level of periodontal progression [221]. The possibility exists that the mechanisms for osteoporosis and periodontal bone loss are similar, which would imply that both are pediatric diseases and that a full understanding of the effects

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FIGURE 29.8  Metaanalysis of relative rate of dental caries associated with vitamin D supplementation. Relative rate (RR) of caries formation in children enrolled in clinical trials between 1924 and 1995 and administered 1,25(OH)2D3 (vitamin D3), 25(OH)2D2 (vitamin D2), or ultraviolet therapy to stimulate endogenous 1,25(OH)2D3 synthesis. The author name listed on the left does not correspond in all cases with the first author in the cited references but matches a list of controlled clinical trials accepted into the metaanalysis in the original publication [210]. Updated from Hujoel PP. Vitamin D and dental caries in controlled clinical trials: systematic review and meta-analysis. Nutr Rev 2013;71:88–97; Copyright Oxford University Press, reproduced by permission.

of vitamin D on periodontal tooth loss will require a life course epidemiological approach. The question of whether vitamin D supplementation provides benefits in terms of dental caries risk is of significant public relevance. Hypovitaminosis D is a global public health

problem [222], and dental diseases remain ubiquitous. If one had to make best guesses based on available evidence it would appear than vitamin D3 would be superior to vitamin D2, and, that combining vitamin D with ample minerals is superior to vitamin D without minerals. One key unresolved question for

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References

the planning of a pivotal trial is whether the vitamin D dose required for dental diseases is higher than for other diseases, such as rickets prevention. The suggestion for a need for higher vitamin D doses for dental caries prevention was mostly generated by a trial conducted by the Medical Research Council in the United Kingdom [181]. It is our opinion that recommending vitamin D supplementation with the goal to prevent dental diseases is contraindicated until such a pivotal trial is conducted. The arrogance of preventive medicine has already caused many harms [223]; supplementation trials in general often caused harm, rather that providing benefits [224]. Until such trials are conducted, there appears to be minimal harm associated with recommending a lifestyle in terms of sun exposures and diet that ensures ample intake of all necessary ingredients, including vitamin D, to minimize risk for morbidity and mortality. A high-fat diet as a result will provide two immediate benefits for dental health. First, it will largely reduce the risk for dental diseases [225]. Second, it will decrease vitamin D needs [226]. Vitamin D requirements (just as for vitamin C), increase as the carbohydrate content of foods increases, and simple sugars in the diet can also serve as fuel for cariogenic bacteria. Vitamin D may be one of the most challenging hormones to regulate through lifestyle. Sun exposure is an attractive source of vitamin D3 as one can obtain large doses of endogenous vitamin D3 without concern for vitamin D toxicity. The current fear of sun (exposure to UV rays) appears misplaced when considering the evolutionary normality and the current epidemiology on benefits and harms of sun exposures. Dietary sources of vitamin D include eggs, wild salmon, and cod liver oil. It is useful to remember within this context that cod liver oil was for most of history a household product and not a branded pharmaceutical product. Such dietary sources of vitamin D may be challenging to obtain. One alternative nonnatural but probably effective manner in which to supplement a diet with vitamin D may be vitamin D milk, which was from 1944 until 1957 endorsed by the American Medical Association as preventing dental caries [176,227]. Adequate intake may present a challenge for those with restricted diets, especially vegans. For strict vegans (who avoid milk), vitamin D supplements may be considered as an alternative and be taken in combination with minerals, as either vitamin D alone or minerals alone have not been shown to be provide systemic benefits.

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similar failures as bone under rachitic conditions, such as defective vitamin D metabolism. We discussed conditions including dietary vitamin D deficiency and inherited errors of vitamin D metabolism such as VDDR and VDRR. Loss of vitamin D signaling directly affects dental cell functions, and hypophosphatemia and hypocalcemia impact the mineralization process. It appears unequivocal that vitamin D deficiencies can lead to multiple adverse craniofacial consequences, one of which is dental caries. Whether vitamin D supplementation can remedy such deficiencies remains unclear. Clearly, a focus should be on adopting a diet and lifestyle that ensures adequate sources of vitamin D within the framework that vitamin D has been present during evolution. This chapter would not be complete without some closing comments on the potential for treatment and improvement of vitamin D-associated defects described above. As outlined above, standards of care for nutritional or hereditary rickets aiming to improve skeletal mineralization and function will in some cases provide improvements to dental mineralization as well, provided that intervention is early and prolonged enough to impact the developing teeth. Even if it is considered likely that under treatment for skeletal disorders, the dentition will improve as well (which may not be the case, as outlined by tooth-bone differences italicized throughout the text), it should be standard procedure, as soon as a mineralized tissue disorder is recognized, to refer these individuals to dentists for detailed examination to establish their baseline dental health and provide personalized dental care, including for example, use of sealants and fluoride to help prevent and stop caries progression, and appropriate procedures to protect against rapid progression of infectious diseases of the dentoalveolar complex. Ultimately, early diagnosis and preventative dental treatment in these circumstances will minimize major dental pathologies requiring more extensive interventions. Periodontal and orthodontic treatment can improve outcome in terms of tooth retention and function and also may significantly add to dental aesthetics and quality of life for patients [228]. Dental tissues may respond favorably to novel therapies targeting the skeletal defects resulting from rickets. Studies using animal models, as well as collection of dental-oral-craniofacial data points from patients enrolled in clinical trials, will add much to the understanding how interventions can improve dental function.

Acknowledgments CONCLUSIONS In this chapter, we have summarized the current state of knowledge on vitamin D metabolism and oral health, focusing on the dentoalveolar complex, using insights from case reports and transgenic mouse models of hereditary disorders, and examining evidence for effects of vitamin D on caries and periodontal health. Teeth are mineralized organs comprise three unique hard tissues, enamel, dentin, and cementum (and the integrated soft tissues), and supported by the specialized and rapidly remodeling alveolar bone. Although odontogenesis differs from osteogenesis in several respects, tooth mineralization is susceptible to

The authors thank Alan Hoofring (National Institutes of Health Division of Medical Arts, Bethesda, MD, USA) for artwork depicted in Fig. 29.1 and Luke Wallace (University of Washington School of Dentistry, Seattle, WA, USA) for tooth image art shown in Fig. 29.7.

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