Inherited Phosphate and Pyrophosphate Disorders: New Insights and Novel Therapies Changing the Oral Health Landscape

Abstract

Background.

Mineral metabolism is critical for proper development of hard tissues of the skeleton and dentition. The dentoalveolar complex includes four unique mineralized tissues: enamel, dentin, cementum, and alveolar bone. Developmental processes of these tissues are affected by inherited disorders that disrupt phosphate and pyrophosphate homeostasis, though manifestations are distinct from those in the skeleton.

Types of Studies Reviewed.

The authors discuss original data from experiments and comparative analyses and review articles describing effects of inherited phosphate and pyrophosphate disorders on dental tissues. A particular emphasis is placed on how new therapeutic approaches for these conditions may impact oral health and dental treatments of affected individuals.

Results.

Disorders of phosphate and pyrophosphate metabolism can lead to reduced mineralization (hypomineralization) or inappropriate (ectopic) calcification of soft tissues. Disruptions in phosphate levels in X-linked hypophosphatemia (XLH) and hyperphosphatemic familial tumoral calcinosis (HFTC), and disruptions in pyrophosphate levels in hypophosphatasia (HPP) and generalized arterial calcification of infancy (GACI), contribute to dental mineralization defects. Traditionally there have been few options to ameliorate dental health problems arising from these conditions. New antibody and enzyme replacement therapies bring possibilities to improve oral health in affected individuals.

Practical Implications.

Research over the past two decades has exponentially expanded our understanding of mineral metabolism and led to novel treatments for mineralization disorders. Recently implemented and emerging therapeutic strategies affect the dentoalveolar complex and interact with aspects of oral healthcare that must be considered for dental treatment, clinical trial design, and coordination of multidisciplinary care teams.

Introduction

Mineral metabolism is critical for proper formation of hard tissues. Mineral metabolism refers to processes that regulate the absorption, distribution, use, and excretion of minerals in the body. We include in this terminology how hard tissues of the body are regulated by these processes and cellular activities. During development, mineralized tissues of the body depend on a regular supply of molecular building blocks. Hydroxyapatite is a calcium phosphate mineral that serves as the inorganic component of our bones and teeth, adding mechanical strength to these hard tissues¹. Hydroxyapatite forms by regulated precipitation of calcium and phosphate ions. These mineral crystals grow, merge, and integrate with the organic extracellular matrix produced by our cells. We are truly composite beings.

Calcium and phosphorus are rich in the environment, and we typically acquire enough of these elements through diet. Ionic forms of calcium (Ca²⁺) and phosphorus (inorganic phosphate, P_i; PO₄³⁻) circulate at millimolar (mM) concentrations in our bloodstream, supplying cells and tissues for multiple important physiologic functions. However, these ion levels are sufficiently high that spontaneous calcium phosphate precipitation is a risk. Inappropriate, or ectopic, calcification can be disastrous for soft tissues of the body, including the heart and cardiovascular system, skin, and muscle. To prevent ectopic calcification in soft tissues, inhibitors of mineralization are produced by the body, which prevent calcium phosphate precipitation in several ways. One example is inorganic pyrophosphate (PP_i), a small circulating molecule that is a potent inhibitor of hydroxyapatite crystal growth. Mineralization of bones and teeth therefore becomes a negotiation between positive and negative regulators of hydroxyapatite formation². When the system works properly, bones and teeth mineralize, and other body tissues do not. When the system does not function properly, reduced mineralization (hypomineralization) or inappropriate (ectopic) calcification can occur.

The dentoalveolar complex includes four unique mineralized tissues: enamel, dentin, cementum, and alveolar bone, in addition to the unmineralized periodontal ligament (PDL) and dental pulp (Figure 1)³. Alterations in genes/proteins, microbiome, immune function, diet, and other variables, often have disparate effects on these tissues because of their distinctive developmental biology, unique cell populations, and specific physiology.

Figure 1. Dental and periodontal tissues.

Schematic showing tissues of the dentoalveolar complex, including the hard tissues: Enamel, dentin, acellular and cellular cementum, and alveolar bone. Dentin encloses the dental pulp that includes vasculature and innervation. The unmineralized gingivae and periodontal ligament are connective tissues that contribute to periodontal attachment.

This review focuses on a few key inherited disorders that cause dysregulation of P_i (essential nutrient) and PP_i (inhibitor of mineralization) homeostasis, leading to improper mineralization of the skeleton and dentition or ectopic calcification in other tissues. Research over the past two decades has exponentially expanded our understanding of P_i and PP_i regulatory mechanisms and how these affect hard and soft tissues. This intensive research has also led to novel treatments for these disorders. Particular attention will be given to recently implemented and emerging therapeutic strategies and how these may affect the dentoalveolar complex and interact with aspects of oral healthcare, considerations sometimes overlooked or minimized in preclinical models, clinical trials, and treatment of patients.

An overview of the disorders discussed is provided in Table 1. Disorders of P_i metabolism include X-linked hypophosphatemia (XLH) and hyperphosphatemic familial tumoral calcinosis (HFTC), both related to altered levels of fibroblast growth factor 23 (FGF23). Disorders of PP_i homeostasis include hypophosphatasia (HPP) from loss-of-function of tissue-nonspecific alkaline phosphatase (TNAP) and generalized arterial calcification of infancy (GACI) from genetic variants causing loss-of-function in ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). These are described in detail below.

Table 1.

Mineral metabolism and homeostasis disorders discussed in this review include disorders of phosphate and pyrophosphate metabolism. Associated genes and proteins, functions, pathologies of the disorders, and current and future therapies are summarized in the table and described in more detail in the text, along with references.

Disorder	Gene/Protein	Function	Pathology	Therapy
X-linked hypophosphatemia (XLH)	PHEX/PHEX loss-of-function increases circulating FGF23	PHEX regulates bone production of FGF23, which regulates levels of Pi and vitamin D	Rickets, osteomalacia, dental hypomineralization	Currently, conventional treatment (Oral phosphorus and vitamin D) or FGF23-targeting antibody (Burosumab, Crysvita®) In the future, possibly gene therapy
Hyperphosphatemic Familial Tumoral Calcinosis (HFTC)	FGF23/FGF23 or GALNT3/GALNT3 loss-of-function reduces circulating FGF23	FGF23 regulates levels of Pi and vitamin D	Hyperphosphatemia, ectopic calcifications in soft tissues	Currently, intervention includes attempts to lower blood Pi levels In the future, possibly FGF23 replacement therapy (or inhibitors of NaPi2a)
Hypophosphatasia (HPP)	ALPL/TNAP loss-of-function	TNAP reduces PPi levels to promote mineralization	HPP causes increased circulating PPi, hypomineralization of bones and teeth	Currently, TNAP enzyme replacement therapy (Asfotase alpha, Strensiq®) In the future, gene therapy
Generalized Arterial Calcification of Infancy (GACI)	ENPP1/ENPP1 loss-of-function	ENPP1 hydrolyzes ATP to increase PPi levels	GACI causes decreased circulating PPi, ectopic calcifications in vascular tissues and organs; secondary manifestations include elevated plasma FGF23 and hypophosphatemic rickets (ARHR2)	Currently, ENPP1 enzyme replacement therapy (INZ-701) is in clinical trials

Disorders of Phosphate Metabolism

Endocrine regulation of P_i metabolism is accomplished through a complex network of feedback between regulators, including vitamin D, parathyroid hormone (PTH), and FGF23 (Represented in Figure 2 and described in more detail below).

Figure 2. Phosphate Metabolism.

Endocrine regulation of inorganic phosphate (P_i) metabolism is accomplished through a complex network of feedback between regulators, including 1,25 dihydroxyvitamin D (1,25D), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23), which operate through an axis of kidney-gut-bone-parathyroid interactions. P_i levels are determined by gut absorption and kidney reabsorption.

Vitamin D, a fat-soluble vitamin, serves as a key nutrient for maintenance of mineral homeostasis⁴. The biologically active form of 1,25-dihydroxyvitamin D (1,25D) promotes intestinal calcium and P_i absorption. In states of vitamin D or calcium deficiency, PTH secretion acts to maintain eucalcemia (normal calcium range) by increasing 1,25D production, mobilizing skeletal calcium stores, increasing urinary calcium reabsorption, and reducing urinary P_i reabsorption. Mobilization of skeletal calcium release by PTH typically maintains eucalcemia in all but the most severe cases of vitamin D deficiency, despite reduced dietary calcium absorption. However, hypophosphatemia is a common sequelae of vitamin D deficiency, due to the combined effects of secondary hyperparathyroidism and reduced intestinal P_i absorption.

FGF23 is a bone-derived hormone that plays a critical role in P_i metabolism⁵. By binding FGF receptor 1 (FGFR1) and its co-receptor KLOTHO, it reduces expression of sodium-phosphate cotransporters NPT2a and NPT2c in the proximal renal tubule, resulting in increased urinary P_i. FGF23 also decreases formation of active 1,25D. Taken together, the net effect of these actions is to reduce blood P_i levels. FGF23 production is regulated in a classic negative feedback loop, with increased production stimulation by blood P_i and 1,25D.

X-linked Hypophosphatemia

Disorders of FGF23 excess or deficiency result in altered P_i levels, leading to a broad range of skeletal and dental effects. The most common FGF23-related disorder is X-linked hypophosphatemia (XLH; OMIM #307800), a condition of FGF23 excess due to loss-of-function mutations in the PHEX gene⁶. Affected individuals typically present in childhood with rickets and osteomalacia, including bowing deformities, disproportionate short stature, craniosynostosis (premature closure of cranial sutures), and muscle weakness (Figure 3A–E). Adults experience complications of childhood disease, such as osteoarthritis and impaired mobility. Enthesopathies, or mineralization of the tendon/ligament insertion sites, commonly arise in early adulthood and contribute to joint pain and stiffness⁷.

Figure 3. X-linked Hypophosphatemia.

Radiographs of (A) knee and (B) wrist in an individual with XLH shows characteristic widening of growth plates (yellow arrows) and other features characteristic of disturbed mineralization during rapid bone growth. (C) Photo showing bowing of legs in a child with XLH. Masson’s trichrome staining of an undecalcified iliac crest biopsy shows (D) normally mineralized bone with minimal osteoid (red regions indicated black arrow) compared to (E) bone biopsy from an individual with XLH showing excessive accumulation of osteoid (yellow arrows). (F) Periapical radiographs show thin enamel, thin dentin, and enlarged pulp chambers (yellow asterisks) in primary teeth of a 3-year-old male with XLH. (G) Transverse 2D micro-computed tomography image of a primary tooth from an individual with XLH showing in green the substantial accumulation of hypomineralized interglobular dentin (DE) (<450 mg/cm³ hydroxyapatite), where mineralized DE is in white and enamel is in gray. (H) Toluidine blue staining of histological section revealing interglobular DE defects (white spaces, indicated by red asterisks) in a primary tooth from an individual with XLH. Images in panels A-E adapted with permission from Carpenter et al., 2017, Nat Rev Dis Primers 3:17101, 2017. Images in panels F-H adapted from Clayton et al, 2021, JBMR Plus 5(4):e10463; Published under Creative Commons license 4.0, reproduced in accordance with Creative Commons license.

The XLH dental phenotype includes enamel defects, thin dentin, enlarged pulp chambers, altered root size and shape, alveolar bone hypomineralization, and increased prevalence of periodontal disease later in life (Figure 3F)^8–14. The most prominent dental defect results from inhibition of dentin mineralization, producing interglobular dentin that appears in histology as large swaths of hypomineralized dentin matrix (Figure 3G, H). Interglobular dentin and prominent pulp horns from reduced dentin thickness are responsible for the most common and problematic clinical manifestations, pulp necrosis due to bacterial invasion and subsequent dental abscesses. Reduced acellular cementum was reported in studies on the primary and permanent dentitions in XLH, potentially contributing to increased incidence of periodontal disease^{8, 15}. Dental defects are recapitulated in the Hyp mutant mouse model of XLH^16–18.

Other rare triggers of FGF23 excess may cause similar symptoms. These include autosomal dominant hypophosphatemic rickets (ADHR; OMIM #193100) arising from mutations in the FGF23¹⁹ gene, causing a gain-of-function, and autosomal recessive hypophosphatemic rickets type 1 (ARHR1; OMIM #241520) due to loss-of-function mutations in dentin matrix protein 1 (DMP1)²⁰. Dental defects in ARHR1 largely mimic those in XLH, including thin enamel and dentin, widened pulp chambers, dental abscess formation, and periodontal breakdown^{21, 22}. These have been explored further in the Dmp1 knockout mouse model^{23, 24}.

Management of FGF23 excess centers on healing rickets/osteomalacia, improving growth and physical function, and reducing bone and joint pain. Classically, treatment has involved repletion with P_i supplements (to account for renal and gastrointestinal P_i) and active vitamin D analogs (to correct deficiencies in 1,25D production)²⁵. This approach is partly effective; however, treatment is typically limited by gastrointestinal intolerance and renal calcifications, making normalization of serum P_i an impractical goal. Burosumab (Crysvita^®) is a monoclonal antibody to FGF23 shown to correct hypophosphatemia in patients with XLH, leading to its approval for these conditions in 2018 by the FDA and EMA^26–28. Burosumab is administered by subcutaneous injection every 2 or 4 weeks. Case reports suggest burosumab may also be effective in rare genetic forms of FGF23 excess, such as ARHR1, though further studies are needed²⁹. The small number of reports describing the effects of burosumab on oral health offer conflicting observations of either increased or decreased prevalence of dental abscesses or caries^30–33. Treatment of Hyp mice with FGF23-inactivating antibody have reported opposing outcomes ranging from minimal effects on dentoalveolar mineralization³⁴ to substantial amelioration of defects³⁵. These variable outcomes suggest additional pathologic mechanisms in XLH that are not being addressed by current therapies. A key factor familiar to oral health providers sometimes overlooked by other clinicians is the prenatal development and mineralization of both primary and secondary dentitions. If interventions are initiated later in childhood, their potential to improve dentoalveolar tissues will be diminished. This is particularly true for enamel (no capacity for cellular repair), but also applies to dentin and cementum (limited reparative ability). Timing of therapy should therefore be a key criterion in designing clinical trials and in the decision to prescribe new treatments. The need for early intervention brings emphasis to the importance of recognizing dental manifestations and promptly obtaining an accurate diagnosis.

Hyperphosphatemic Familial Tumoral Calcinosis

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare disorder of FGF23 deficiency or resistance. It is most commonly caused by loss-of-function mutations in GALNT3 (OMIM# 211900), leading to impaired FGF23 O-glycosylation, or by mutations in FGF23 (OMIM# 617993), leading to increased cleavage of the active hormone³⁶. Patients develop hyperphosphatemia due to inappropriately increased urinary P_i reabsorption and 1,25D production. These metabolic disturbances lead to formation of ectopic calcifications in subcutaneous tissue, particularly in peri-articular areas such as the hips, elbows, and shoulders (Figure 4A, B). Lesions may be large and accompanied by painful ulcerations with severe functional impairment. Inflammatory disease is often present, including cortical hyperostosis and diaphysitis.

Figure 4. Hyperphosphatemic Familial Tumoral Calcinosis.

(A) Photograph of an individual with HFTC with swelling of the left shoulder (yellow arrow). Altered skin pigmentation and increased vascularity are apparent overlying the affected area (black arrowhead). (B) A corresponding 3D CT scan of the individual in panel A shows a large, calcified mass in the left shoulder (yellow arrow). (C) Panoramic radiograph of an individual with HFTC showing short bulbous roots (arrow) with partial to complete pulp obliteration (arrowhead) in all teeth. (D) Periapical radiograph showing thistle shaped root and pulp obliteration in mandibular incisor of individual with severe HFTC. (E) Micro-CT analysis of a tooth from an individual with HFTC shows altered crown and root morphologies and reduced pulp and root canals due to ectopic calcification (shown in isolated pulp images). Mineralization heat maps show reduced mineralization of enamel (EN) and dentin (DE). Images in panels A and B adapted from Boyce et al, Front Endocrinol (Lausanne), 11:293, 2020; Published under Creative Commons license 4.0, reproduced in accordance with Creative Commons license. Images in C-E adapted from Lee et al, 2021, JBMR Plus 5(5):e10470; Published under Creative Commons license 4.0, reproduced in accordance with Creative Commons license.

Dental manifestations include a striking phenotype observed in HFTC1 patients with FGF23 and GALNT3 mutations, including most prominently, thistle shaped roots, obliteration of pulp chambers and root canals, and increased prevalence of dental abscesses (Figure 4C–E)^{12, 37, 38}. Histological evaluation reveals disruptions in dentin and cementum formation. Similar dentoalveolar manifestations were reported in the Fgf23 knockout mouse model of HFTC1^{11, 17}.

Multiple treatment strategies have attempted to reduce blood P_i levels, calcifications, and their associated morbidity³⁹. These include low P_i diets⁴⁰, medications to inhibit gastrointestinal P_i absorption^{39, 41}, medications to increase renal P_i excretion^{39, 41, 42}, anti-inflammatories^{39, 43}, and anti-mineralization treatments^{39, 44}. However, data are limited to case reports and small series, and there is no convincing evidence to support consistent efficacy of any of these approaches. Hormone replacement therapy with recombinant or synthetic FGF23 would be an optimal strategy for patients with FGF23 deficiency, and is an important unmet need for future research³⁶. It remains unclear how therapeutic approaches will impact dental manifestations in HFTC1.

Disorders of Pyrophosphate Homeostasis

Hypophosphatasia

In skeletal and dental tissues, hydroxyapatite deposition is a carefully orchestrated biochemical process that balances the concentrations of P_i and PP_i (covered above) to establish a proper P_i/PP_i ratio that enables regulated mineralization to take place⁴⁵. Extracellular PP_i is a potent inhibitor of mineralization⁴⁶ that has been referred to as “the body’s natural water softener”⁴⁷ as it efficiently prevents inappropriate soft tissue calcification. In blood, PP_i concentrations are in the micromolar (μM) range while P_i levels are a thousand-fold higher in the millimolar (mM) range. Therefore, small changes in the extracellular PP_i concentrations lead to significant changes in the P_i/PP_i ratio that have profound implications for the control of physiological mineralization and ectopic calcification.

Two enzymes regulate the extracellular P_i/PP_i ratio. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) produces PP_i and P_i from ATP, and tissue-nonspecific alkaline phosphatase (TNAP) hydrolyses both ATP and PP_i to form P_i⁴⁸ (Figure 5). ENPP1 is described in the next section. Loss-of-function causing mutations in the ALPL gene encoding TNAP lead to hypophosphatasia (HPP), a soft bones disease with a wide spectrum of severity and penetrance, attributed to accumulation of extracellular PP_i. HPP is characterized by rickets in children and/or hypomineralization in adults (Figure 6A–D), and dental abnormalities described below⁴⁹. More than 440 mutations have been identified in the ALPL gene database (https://alplmutationdatabase.jku.at/), inherited as either recessive or dominant alleles and associated with HPP spanning the severity of disease presentation (perinatal, infantile, childhood and/or adult; OMIM# 241500, 241510, and 146300). This contributes to the extremely heterogeneous clinical presentations of HPP among patients.

Figure 5. Pyrophosphate Homeostasis.

Two cell surface enzymes regulate the extracellular concentration of inorganic pyrophosphate (PP_i). Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) produces PP_i and adenosine monophosphate (AMP) from adenosine triphosphate (ATP). Loss-of-function of ENPP1 leads to reduced PP_i levels, contributing to generalized arterial calcification of infancy (GACI). Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyses PP_i to form P_i. The P_i can be incorporated into hydroxyapatite mineral. Loss-of-function of TNAP leads to increased PPi levels, contributing to hypophosphatasia (HPP). TNAP has additional substrates, including ATP and phosphorylated proteins, from which it liberates P_i molecules.

Figure 6. Hypophosphatasia.

(A) Deformities of legs in a boy with severe childhood HPP. (B) Radiograph of leg from the boy in panel A showing intramedullary rod in the tibia to correct bowing from rickets. (C) Radiograph of the knee from a child with severe childhood HPP showing tongues of radiolucency (yellow star) extending from the distal metaphysis of the femur. Bone biopsy from (D) an individual with normal bone mineralization compared to (E) biopsy from an adult HPP shows unmineralized osteoid accumulation (red layer indicated by yellow arrow) on surfaces of mineralized bone (green). (F) Oral photograph of a 2.5-year-old child with HPP revealing premature loss of primary lower incisors. (G) Primary incisors that spontaneously exfoliated from a child with HPP exhibit “fully rooted” appearance pathognomonic for HPP. (H) Oral radiograph of a 20-year-old individual with HPP showing loss of secondary incisor, endodontic treatment after fracture, splinting to try and stabilize remaining anterior teeth, and generalized alveolar bone loss (yellow star). (I, J) 3D and 2D microCT images and histology showing lack of acellular cementum (AC) in primary teeth of individuals with HPP. EN: enamel; DE: dentin; PDL: periodontal ligament. * in panel I histology indicates plaque on the tooth root surface. (K-M) Von Kossa-stained histology (left panels) and H&E stained histology (right panels) showing that asfotase alfa enzyme replacement therapy (ERT) restores DE mineralization (black stain) and AC in the mouse model of severe HPP. In K, # indicates DE mineralization defects and * indicates lack of AC. Images in panels A and B reproduced with permission from Bowden and Foster, Drug Des Devel Ther. 12:3147–3161, 2018. Image in panel C reproduced with permission from Whyte, Bone, 102:15–25, 2017. Images in panels D and E reproduced with permission from Berkseth et al, Bone 54(1):21–7, 2013. Image in F reproduced in accordance with BMC’s open access policy from Reibel et al, Orphanet J Rare Dis. 4:6, 2009. Image in G reproduced with permission from Whyte, J Bone Miner Res 32(4):667–675, 2017. Image in H reproduced with permission from Rodrigues et al., Clinical Correlate: Case Study of Identical Twins with Cementum and Periodontal Defects Resulting From Odontohypophosphatasia, In: Mineralized Tissues in Oral and Craniofacial Science, 2012. Images in I and J reproduced with permission from Kramer et al, Bone 143:115732, 2021. Von Kossa images in panels K-M are reproduced with permission from Millán JL et al, J Bone Miner Res. 23(6):777–87, 2008. H&E histology in images K-M are reproduced with permission from Bowden and Foster, Drug Des Devel Ther 12:3147–3161, 2018.

Dental defects have been described across the spectrum from mild to severe clinical forms of HPP^{12, 50}, and include acellular cementum hypoplasia or aplasia associated with premature loss of primary teeth and/or loss of secondary teeth, delayed eruption, periodontal disease, enamel alterations, thin and hypomineralized dentin, widened pulp chambers, and short and/or malformed roots^{12, 50–52}. Of the clinical signs listed above, premature exfoliation of fully rooted primary teeth is likely the most commonly recognized manifestation and most pathognomonic for HPP. Primary teeth prematurely exfoliated from children with HPP generally exhibit substantial remaining root structure compared to healthy control teeth (sometimes described as “fully rooted teeth), reflecting exfoliation prior to physiologic tooth root resorption (Fig. 6E–G). Teeth affected by HPP often lack a recognizable cementum layer, reflecting the most severe effects of HPP on any of the dental tissues. Root surfaces can show accumulation of dental plaque, an unusual observation reflecting lack of periodontal attachment, allowing bacterial invasion deep into the periodontal tissues (Fig. 6H, I)⁵².

Pediatric and general dentists play a key role in the diagnosis of HPP given the premature exfoliation of primary teeth. Odonto-HPP, a milder clinical form with mostly dental manifestations, typically presents with early loss of one or more primary teeth (before the age of 5 years) and individuals with childhood and adult HPP experience early loss of permanent teeth characterized by loss of surrounding bone and tooth mobility^{53, 54}. A reasonable question arises related to treatment options for patients with early loss of primary and permanent teeth in the context of HPP. It is critical that the dental provider be aware of the diagnosis and severity of HPP in each patient, as well as the disease management. Currently, there are very few publications related to dental treatment and outcomes for HPP patients. Early loss of primary teeth can create arch length loss or space loss contributing to crowding in the permanent dentition. The best way to manage this is through growth and development monitoring to anticipate space loss management. Alveolar ridges can be affected by early loss of teeth, creating challenges for denture rehabilitation. There are limited reports on outcomes of dental implant therapy in HPP. The severity of HPP and reduced TNAP levels and potential impact on implant placement and longevity should be considered when establishing a care plan for affected individuals. One case report described a 24-year-old female diagnosed with HPP in childhood, who experienced premature loss of all primary teeth followed by loss of many permanent teeth.⁵⁵ Despite excellent oral hygiene, she was diagnosed with periodontitis in the absence of gingivitis related to lack of cementum. Full mouth rehabilitation was undertaken due to extensive bone loss and tooth mobility, including 16 implants placed. Importantly, the patient received regular cleanings and oral hygiene instructions, demonstrating the key role dental providers play in the management of oral health for HPP patients. Efficacy of periodontal, orthodontic, and prosthodontic treatments remain unclear in the context of HPP. Best practices and potential adverse effects need to be better defined in the case report literature to provide guidance for other clinicians treating patients with HPP.

Manifestations of HPP in dentoalveolar tissues have been recapitulated in several animal models^56–65 enhancing the ability to study pathologic mechanisms underlying HPP and develop targeted drug therapies. Asfotase alfa (Strensiq^®), is a mineral-targeted alkaline phosphatase enzyme replacement therapy (ERT) designed to prevent and treat the clinical manifestations of HPP. The drug consists of a modified human TNAP sequence with a negatively charged deca-aspartate acid (D₁₀) tail to confer bone-targeting properties⁶⁶. The first preclinical trial using daily subcutaneous injections of asfotase alfa in newborn Alpl gene knockout (Alpl^−/−) mice preserved life and prevented rickets and pyridoxal-responsive epileptic seizures, reduced the elevated concentrations of PP_i and plasma pyridoxal-5-phosphate (PLP) concentrations, and preserved acellular cementum and dentoalveolar mineralization in this model of lethal HPP disease (Figure 6J–L)^{58, 59, 66–69}. After clinical trials demonstrated normalization of extracellular PP_i concentrations, improvement in lifespan, amelioration of the skeletal phenotype, motor function, and the quality of life of patients with HPP⁷⁰, Strensiq was approved in 2015 for pediatric-onset HPP. While asfotase alfa treatment is life-saving, the need for multiple injections per week, severe injection site reactions,^{71, 72} and the associated high medical costs^{57, 73}, have prompted preclinical studies of alternative strategies for treating HPP. Several types of viral vectors expressing TNAP-D₁₀ were shown to prolong life, prevent seizures, and improve the skeletal phenotype of Alpl^−/− mice after a single injection^74–78. A considerable refinement of this therapeutic principle was recently achieved using a single intramuscular administration of an adeno-associated virus 8 (AAV8) encoding TNAP-D₁₀^{79, 80} to increase the lifespan and improve the skeletal and dentoalveolar phenotypes in Alpl^−/− mice while obviating the need for the multiple weekly injections in this mouse model of infantile HPP. Such a gene therapy approach could revolutionize HPP therapy and disease burden for many affected individuals.

To date, the number of case reports remain sparse regarding effects of ERT on dentoalveolar aspects of HPP. As discussed above for XLH, timing of treatment will be critical in terms of the limited window of opportunity to positively affect development and mineralization of primary and secondary dentitions. The most comprehensive study to date enrolled 11 children with infantile HPP from the clinical trial for asfotase alfa. Children receiving ERT during infancy lost significantly fewer primary teeth than children enrolled at a later age⁸¹. Anecdotal reports note reduced tooth mobility after ERT⁸². In treatment planning, it will be important to coordinate oral health care with a managing endocrinologist to ensure adequate TNAP levels and knowledge regarding ERT in each patient. Understanding the underlying mechanism of ERT, its effects on bone quality, as well as the oral hygiene of the patient will be critical in treatment planning for dental needs. It is likely that as the ERT landscape improves, there will be opportunities for affected individuals to seek implants and orthodontic treatment to manage tooth replacement and space loss, respectively. Regardless of therapeutic approaches, HPP patients will require multidisciplinary dental care in addition to consultation with managing physicians for best long term oral and overall health outcomes.

Generalized Arterial Calcification of Infancy

ENPP1 is an enzyme that represents the main source of circulating PP_i and also provides extracellular PP_i in the microenvironment of cells, as shown in vascular smooth muscle cells and aortas in culture^{83, 84}. PP_i is the main physiological inhibitor of soft tissue calcification, with concentrations as low as 10⁻⁷M able to completely prevent hydroxyapatite deposition⁸⁵. ENPP1 deficiency leads to low PP_i and consequently ectopic calcification of arteries, organs, and around joints (Figure 7A–C). This phenotype, seen in Generalized Arterial Calcification of Infancy (GACI; OMIM #208000) represents the most severe end of the phenotypic spectrum of ENPP1 deficiency and leads to narrowing of the arteries (as a consequence of AMP deficiency) with reduced blood flow⁸⁶, which in turn contributes to a high mortality during infancy (50.4% before 6 months of age)⁸⁷. A milder presentation of ENPP1 deficiency, or that seen in patients who survive infancy, is FGF23-mediated hypophosphatemic rickets, a phenotype known as Autosomal Recessive Hypophosphatemic Rickets type 2 (ARHR2; OMIM #613312; see section on FGF23-related Disorders).

Figure 7. Generalized Arterial Calcification of Infancy.

(A) Coronal CT of a 4-week-old infant with GACI showing calcification of the distal abdominal aorta and proximal bilateral iliac arteries (yellow arrows). (B) 3D CT reconstruction of a 5-year-old child with GACI showing bilateral external iliac artery occlusion (yellow arrows) with prominent collaterals. (C) Histopathology of the aorta of an infant with GACI showing pronounced thickening of the tunica intima (yellow line in affected aorta and in the insert depicting a normal aorta) with luminal narrowing, as well as ectopic calcifications (red arrowheads) in the internal elastic lamina. (D, E) Clinical oral photographs of a 6-year-old child with GACI showing infraoccluded primary maxillary lateral incisors (yellow arrows). (F) Periapical radiograph of the same child at 7-years-old shows eruption of permanent maxillary incisors while primary lateral incisors remain infraoccluded (yellow arrows) and secondary lateral incisors are unerupted. (G) Bitewing radiograph reveals protruding cervical root morphology (yellow arrowheads) in primary and secondary molars; cementum appears to overlap enamel at the cementum-enamel junction in some teeth. (H) 2D microCT images and histology (H&E) show increased acellular cementum (AC) thickness in primary teeth from this child compared to control. EN=enamel; DE=dentin. Images in panels A-C adapted with permission from Ferreira et al, Genet Med 23(2):396–407, 2021. Images in panels D-I adapted under Creative Commons license from Thumbigere-Math et al., J Dent Res 97(4):432–441, 2018.

Opposite to the acellular cementum hypoplasia of HPP, teeth from individuals with GACI exhibit dramatic hypercementosis on cervical root surfaces, confirming that cementogenesis is very responsive to modulation by PP_i levels (Fig. 7D–I)⁸⁸. There are no apparent effects on enamel or dentin in GACI. Several individuals affected by GACI reported delayed tooth exfoliation, tooth-bone ankylosis, and/or slow orthodontic tooth movement. Histological evidence suggested that physiologic resorption of primary tooth roots may have been “reversed” by reparative cementum production in GACI, an insight that may in part explain irregularities in tooth eruption and exfoliation in this cohort. Though the number of affected individuals described in the literature remains small, developmental hypercementosis and reduced tooth movement were recapitulated in the Enpp1^−/− mouse model of GACI, indicating evolutionarily conserved mechanisms^{61, 62, 88}. To date, dental manifestations of ARHR2 have not been reported in individuals with GACI, though the number of individuals with a detailed dental analysis remain in single digits⁸⁸.

Although earlier literature suggested that bisphosphonates might be beneficial given their physicochemical analogy to PP_i, current evidence shows that bisphosphonates are of limited benefit⁸⁷. Given the severe mortality and morbidity associated with the disease, better therapeutic approaches are currently under investigation. A targeted treatment approach in the form of ENPP1 ERT was first proposed in 2015; administration of recombinant ENPP1 prevented calcification as well as mortality in a mouse model of ENPP1 deficiency⁸⁹. Subsequent studies showed that ERT improves blood pressure and cardiovascular function⁹⁰, suppresses vascular cell proliferation and intimal hyperplasia⁸⁶, and prevents pathological calcification in organs in Enpp1^−/− mouse models⁹¹. The preclinical benefits of ERT extend beyond the cardiovascular system, as ERT prevented osteomalacia, increased bone density, and markedly improved bone strength in mutant mice, and it partially prevented calcification of the enthesis⁹². Phase 1/2 clinical trials are currently underway to evaluate the safety and efficacy of ERT in patients with ENPP1 deficiency. It remains to be seen if ENPP1 ERT will reverse periodontal effects of GACI; this may be dependent on severity of disease and timing of therapeutic intervention in terms of primary and secondary tooth development and eruption.

Conclusions

Knowledge of P_i and PP_i-associated disorders affecting skeletal and dental mineralized tissues has advanced greatly in recent years, resulting in novel and more effective treatments. Because these disorders affect dental development and oral health, it is important for oral health care providers to be knowledgeable about these types of conditions. Dental expertise is critically needed as part of the multidisciplinary medical care team to assess and mitigate the challenging oral manifestations that affect health and quality of life. As outlined in this review, dental clinicians and researchers are also needed to evaluate efficacy and outcomes of new and emerging therapeutics on oral tissues. To combat the dearth of information in the scientific literature on dental treatment of individuals affected by these disorders, investigations and case reports are needed to advance our knowledge on orthodontic, periodontal, prosthetic and endodontic approaches and outcomes. New insights and novel therapies for P_i and PP_i disorders are already changing the oral health landscape and it is incumbent upon oral health clinicians and researchers to keep up.

Abbreviation Key

AMP

Adenosine monophosphate

ATP

Adenosine triphosphate

D₁₀

Deca-aspartate

ENPP1

Ectonucleotide pyrophosphate phosphodiesterase 1

EMA

European Medicines Agency

FDA

United States Food and Drug Administration

FGF23

Fibroblast growth factor 23

FGFR1

FGF receptor 1

GACI

Generalized arterial calcification of infancy

GALNT3

Polypeptide N-acetylgalactosaminyltransferase 3

HFTC

Hyperphosphatemic familial tumoral calcinosis

HPP

Hypophosphatasia

NPT2a

Solute carrier family 34 (sodium phosphate) member 1

NPT2c

Solute carrier family 34 (sodium phosphate) member 3

PHEX

Phosphate regulating endopeptidase X-linked

P_i

Inorganic phosphate

PPi

Inorganic pyrophosphate

PTH

Parathyroid hormone

TNAP

Tissue-nonspecific alkaline phosphatase

XLH

X-linked hypophosphatemia