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Therapeutic management of hypophosphatemic rickets from infancy to adulthood

Therapeutic management of hypophosphatemic rickets from infancy to adulthood In children, hypophosphatemic rickets (HR) is revealed by delayed walking, waddling gait, Key Words leg bowing, enlarged cartilages, bone pain, craniostenosis, spontaneous dental abscesses, " calcium and growth failure. If undiagnosed during childhood, patients with hypophosphatemia " bone present with bone and/or joint pain, fractures, mineralization defects such as " rare diseases/syndromes osteomalacia, entesopathy, severe dental anomalies, hearing loss, and fatigue. Healing " X-linked hypophosphatemic rickets rickets is the initial endpoint of treatment in children. Therapy aims at counteracting consequences of FGF23 excess, i.e. oral phosphorus supplementation with multiple daily intakes to compensate for renal phosphate wasting and active vitamin D analogs (alfacalcidol or calcitriol) to counter the 1,25-diOH-vitamin D deficiency. Corrective surgeries for residual leg bowing at the end of growth are occasionally performed. In absence of consensus regarding indications of the treatment in adults, it is generally accepted that medical treatment should be reinitiated (or maintained) in symptomatic patients to reduce pain, which may be due to bone microfractures and/or osteomalacia. In addition to the conventional treatment, optimal care of symptomatic patients requires pharmacological and non-pharmacological management of pain and joint stiffness, through appropriated rehabilitation. Much attention should be given to the dental and periodontal manifestations of HR. Besides vitamin D analogs and phosphate supplements that improve tooth mineralization, rigorous oral hygiene, active endodontic treatment of root abscesses and preventive protection of teeth surfaces are recommended. This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 2–18 3 : R14 Current outcomes of this therapy are still not optimal, and therapies targeting the pathophysiology of the disease, i.e. FGF23 excess, are desirable. In this review, medical, dental, surgical, and contributions of various expertises to the treatment of HR are described, with an effort to highlight the importance of coordinated care. Endocrine Connections (2014) 3, R13–R30 Introduction Phosphate wasting ineluctably leads to hypophosphate- matrix protein 1 (DMP1) (11) or ENPP1 (12),and mia and numerous consequences including mineral- uncontrolled secretion of FGF23 by mesenchymal tumors, ization defects. In children, hypophosphatemia is a condition known as tumor-induced osteomalacia (TIO) revealed by vitamin D-resistant rickets and results in (13). Except for the latter, mineralization defects involving variable degrees of delayed walking, waddling gait, leg bone and teeth are caused by hypophosphatemia and bowing, enlarged cartilages, bone pain, craniostenosis, FGF23 excess and, in addition, by a direct effect of the spontaneous dental abscesses, and growth failure. If absence of functional PHEX (or DMP1) on bone or tooth undiagnosed during childhood, hypophosphatemia is extracellular matrix (ECM) mineralization (14). suspected when patients present with bone and/or joint Secondly, phosphate wasting may be due to a primary pain, fractures, mineralization defects such as osteo- renal tubular defect, i.e. hereditary HR with hypercalciuria malacia, entesopathy, severe dental anomalies, hearing (HHRH) due to molecular defects of the sodium-phos- loss, and fatigue. Symptoms might be present, although phate channel NPT2c, diseases affecting several renal to a lesser degree, in adults who underwent the conven- tubular functions such as Dent or Lowe syndromes, or tional treatment throughout their childhood and adoles- tubular toxicity of drugs (15, 16). All these conditions cence. Causes of phosphate wasting are mostly due to share a diminished capacity to transport phosphate from genetic defects in factors necessary for phosphate the glomerular filtrate to the blood circulation. In handling; for a review read (1). They have been sum- response to hypophosphatemia, FGF23 secretion is ade- marized in Table 1. In this review, we will consider two quately suppressed, and 1,25-diOH-vitamin D production different types of phosphate wasting. Firstly, phosphate and absorption of calcium through the gut and urinary calcium excretion are consequently enhanced. wasting may be secondary to increased fibroblast growth factor 23 (FGF23) signaling, which is a circulating factor Besides acquired disorders like tumors or drug secreted by osteoblasts, odontoblasts, and osteocytes (2). toxicity, most conditions leading to phosphate wasting In the renal proximal tubule, FGF23 inhibits the sodium- are congenital and will continue throughout the patient’s phosphate transport through ion channels, NPT2a and lifetime. To this day, therapy has mostly been evaluated NPT2c, and prevents 1,25-diOH-vitamin D production. in children. Enormous progress has been made since As a consequence, both renal and digestive absorption the availability of vitamin D analogs, such as calcitriol of phosphate are diminished. Recently, extra renal effects and alfacalcidol, in the mid-1970s and the evolution of of FGF23 have been reported, such as immune function surgical procedures. However, two major issues remain: in human monocytes (3), iron (4, 5), glucose (6) and i) the growth retardation and recurrent dental infections lipid metabolism (7, 8). in children and ii) the necessity of adequate therapeutic Causes of phosphate wasting secondary to elevated strategies in adults. Indeed, the disease remains physically FGF23 mainly encompass not only X-linked hypo- apparent and the global objective of therapies (medical, phosphatemic rickets (XLHR) due to loss-of-function dental, and surgical) should be to limit, and in best cases mutations in PHEX, an endopeptidase encoded by a avoid, sequel by correcting leg deformities, promoting gene localized on the X chromosome (9), but also auto- growth and preserving dentition. In this context, we will somal dominant hypophosphatemic rickets (ADHR) describe in this review the current and future treatments due to recurrent heterozygous mutations affecting the available to counteract phosphate wasting, restore 176 179 RXXR motif in FGF23 (10), autosomal recessive serum phosphate and allow adequate bone and tooth HR (ARHR) due to loss-of-function mutations in Dentin mineralization. This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 3–18 3 : R15 Table 1 Causes of hypophosphatemic rickets (HR). Gene Transmission Reference Main features HR sharing elevated FGF23 circulating levels and inappropriately low or normal 1,25-diOH-vitamin D XLHR PHEX X-linked (9) HR with similar phenotype in males and females ADHR FGF23 Autosomal (10) HR dominant ARHR DMP1 Autosomal (11) HR recessive ARHR2 ENPP1 Autosomal (12) HR associated with arterial calcifications of recessive infancy (GACI syndrome) ARHR3 FAM20c Autosomal (95) Hypophosphatemia associated with osteo- recessive sclerosis of the bone rather than rickets, dysmorphy, and cerebral calcifications; severe dental phenotype OGD FGFR1 (96) HR associated with frequent craniosynos- tosis, dysmorphy, and dwarfism HR associated with congenital sporadic disorders due to heterozygous post-zygotic mutations in genes activating signaling pathways and elevated FGF23 MAS (97) Characterized by the triad precocious puberty, cafe-au-lait spots and fibrous dysplasia (FD); HR is rare, and secondary to increased FGF23 production by the FD Mosaic cutaneous disorders include nevus KRAS and (98) HR associated with bone lesions and sebaceous and Schimmelpenning syndrome NRAS extended cutaneous congenital lesions HR associated with mesenchymatous tumors secreting FGF23 TIO (13) Acquired and often severe hypophos- phatemia and phosphate wasting. Hypocalcemia may be present as the consequence of suppressed 1,25-diOH- vitamin D production HR sharing appropriately suppressed FGF23 and elevated 1,25-diOH-vitamin D; defects in renal phosphate transporters HHRH SLC34A3 Autosomal (16) HR with nephrocalcinosis and kidney stones recessive Diseases affecting the renal distal tubule Lowe syndrome, Dent syndrome (CLCN5 gene), Toni-Debre ´ -Fanconi XLHR, X-linked HR; ADHR, autosomal dominant HR; ARHR; autosomal recessive HR type 1; ARHR2, autosomal recessive HR type 2; ARHR3, autosomal recessive HR type 3; OGD, osteoglophonic dysplasia; MAS, McCune–Albright syndrome; TIO, tumor-induced osteomalacia; HHRH, hereditary hypophosphatemic rickets with hypercalciuria. ALP levels (Fig. 1B), iii) improve growth (Fig. 1C), and iv) Therapy in children restore straight legs and improve teeth health. Medical treatment for phosphate wasting Nowadays, the medical treatment is aimed at counter- Healing rickets by normalizing serum alkaline phosphatase acting consequences of FGF23 excess, i.e. oral phosphorus (ALP) levels and radiological signs is the initial endpoint supplementation with multiple daily intakes to compen- sate for renal phosphate wasting and active vitamin D in children. Treating rickets will promote growth, pro- analogs (alfacalcidol or calcitriol) to counter the 1,25- gressively correct leg deformities (Fig. 1A), and facilitate tooth mineralization. In infants diagnosed before they diOH-vitamin D deficiency (Table 3). The daily doses of even show signs of rickets, the treatment goal for them will phosphorus supplements range between 40 (adolescents) be not to develop rickets (Fig. 1A). Earlier treatment has and 60 (toddlers) mg/kg per day (Table 4). Multiple been shown to lead to better results (17). Objectives, which daily doses of phosphate supplements are mandatory could also be described as expected results, are described in throughout childhood and adolescence, because, in the Table 2. The treatment intends to, in the following order: context of diminished phosphate reabsorption, serum i) reduce bone pain, ii) normalize (or near-normalize) phosphate level is back to low baseline few hours after This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 4–18 3 : R16 COUCHE BC 200 200 +2 SDS 180 +2 SDS –2 SDS –2 SDS 40 40 Mean final height: 1.60 m Mean final height: 1.53 m 400 20 0 1 2 3 4 5 6 7 8 9 10 11 12 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 Months after start of treatment Figure 1 Evolution of clinical (leg bowing and growth) and biochemical parameters girl who started therapy at the age of 4 months. Diagnosis of XLHR was (alkaline phosphatase levels) during treatment with vitamin D analogs and made in the context of familial disease (mother and two sisters affected). phosphate supplements in children. (A) Patient 1 is a 2-year-old girl (left an (B) Evolution of alkaline phosphatase levels throughout the first year of middle panels) recently diagnosed with XLHR and a de novo mutation of therapy in 30 patients affected with HR and elevated FGF23. (C) Growth PHEX. The same girl is shown at the age of 5 years with straight legs (right pattern (range between C2 and K2 SDS is shadowed) in 32 girls and 29 panel). Patient 2 is a 14-year-old boy who was treated since the age of four boys affected with HR and elevated FGF23 and receiving vitamin D analogs (XLHR and a de novo mutation of PHEX). Patient 3 is a 13-year-old girl who and phosphate supplements throughout childhood and puberty. Mean, presents with persistent leg bowing despite being treated since she was C2, and K2 SDS of French reference growth charts are represented by 3 years old (XLHR and a de novo mutation of PHEX). Patient 4 is a 2-year-old colored lines. This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Patient 2 Patient 1 Alkaline phosphatases (UI/l) Patient 3 Patient 4 Review A Linglart et al. Therapy of hypophosphatemia 5–18 3 : R17 Table 2 Objectives and timeline for the conventional rickets, for initial dosage of vitamin D analogs to be treatment of HR in children. decreased to maintenance doses. As for many chronic diseases, compliance to oral Interval after treatment is a major issue, even in expert hands. For start of treatment Objective optimal dosage, it is difficult to base our guidance on doses Few weeks Decrease in bone pain reported in published studies, which are all over 20 years 6–12 months Normalization of alkaline phosphatase level old and report a very wide range of doses between 10 and 1 year Increase in growth velocity 3–4 years Straightening of legs: 1 cm decrease in 80 ng/kg per day of calcitriol and 30 and 180 mg/kg per day intercondylian (genu varum) or inter- of elemental phosphorus (18, 19, 20, 21, 22, 23, 24). Our malleolar (genu valgum) distance every recommendations are based on over 30 years of experience 6 months at our center in treating over 250 patients with HR and are similar to the guidelines advised recently by Carpenter et al. phosphate intake. At these doses, digestive complaints (25). In addition, we prescribe 25-OH-vitamin D supple- are extremely rare. The daily dose of phosphate supple- ments and optimize dietary calcium intake in children, ments is adjusted to efficacy (i.e., ALP levels, leg bowing, although no published studies support this point. and growth velocity), patient’s weight, and PTH levels. Healing active rickets promotes growth and after Note that serum phosphate is not used to adjust 2 years of successful treatment, patients’ growth velocity phosphate therapy. On the contrary, as fasting phosphate is restored to its maximal potential in a majority of patients. is not restored by treatment, increasing phosphate However, 25–40% of patients with well-controlled XLHR supplement doses leads to intestinal discomfort and show linear growth failure despite optimal treatment and secondary (sometimes tertiary) hyperparathyroidism. have a final height underK2 SDS (19, 21, 26, 27, 28, 29, 30, Urinary phosphate measured on a 24-h collection should 31, 32, 33) (and our experience, Fig. 1C). Until recently, parallel the daily intake of phosphate supplements, and only limited pilot studies (small patient numbers, limited may be used to check for compliance. Prescribing period of observation, lack of controls and randomizations) phosphate intake is a balance between excessive dosage have been conducted, which suggest a beneficial effect of tending to hyperparathyroidism and insufficient dosage recombinant growth hormone (rGH) treatment on growth slowing the healing of rickets. 1a-hydroxylated vitamin D velocity in patients with XLHR (29, 34, 35, 36, 37, 38). The analogs constitute the second pillar of conventional only randomized study by Zivicnjak et al. (39) showed treatment. Their half-life is sufficient to allow for single significant improvement of linear growth (C1.1 height and twice daily oral doses of alfacalcidol and calcitriol SDS) in eight patients treated with rGH out of 16 short respectively. The starting dose of vitamin D analogs (mean height SDS K3.3) prepubertal children with XLHR. (usually 1–2 mg/day alfacalcidol or 0.5–1 mg/day calcitriol) Addition of rGH induces a rise in mineral needs, which depends on growth velocity. Higher doses (1–3 mg/day should be accompanied with a 20–30% increment in alfacalcidol or 0.5–1.5 mg/day calcitriol) are associated vitamin D analogs dosage. Only well-observant patients with periods of high growth velocity, such as early with healed rickets can benefit from rGH. childhood and adolescence. Vitamin D analog doses are In patients with HHRH, 1,25-diOH-vitamin D adjusted to give the maximum dose for efficacy based on synthesis is enhanced and PTH secretion often suppressed, ALP levels, leg bowing, and growth velocity, without both conditions favoring hypercalciuria (40); therefore, reaching toxicity, mainly hypercalciuria. Hypercalciuria patients require treatment with phosphate supplements does not usually occur until ALP levels are normalized. solely. Doses and adjustment rules are similar to that used As it is not invasive to collect urine, we recommend for XLHR patients. In this condition, 25-OH-vitamin D measuring urinary calcium and creatinine every 3 months supplementation should be monitored very carefully by on a spot urine collection in young children and on a 24-h trained physicians to avoid increase in 1,25-diOH-vitamin collection in older children (O5) toilet trained. Hypercal- D generation and hypercalciuria. ciuria is defined by urinary calcium/urinary creatinine above 1 mmol/mmol (0.35 mg/mg) in toddlers and 24-h Orthopedic and surgical management in children urinary calcium excretion above 5 mg/kg per day in older children. We recommend screening for nephrocalcinosis Hypophosphatemia induces progressive bowing of the with yearly ultrasound (every second year in the absence legs that becomes apparent with the onset of weight of episodes of hypercalciuria). It is common, after healing bearing (Fig. 1A), and may hinder the walking capacity. This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 6–18 3 : R18 This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Table 3 Reports of vitamin D analogs and phosphate supplements in patients with HR. Reference Therapy Subjects Aim of study Main outcomes (19) Phosphate alone 1.2–3.6 g/day in five nZ11 X-rays and bone histology Combined phosphate and calcitriol has several doses advantages over previously described treatment regimens: Phosphate in five doses ergocalciferol Aged 1.75–11.5 years Induced mineralization of the growth plate 25 000–50 000 IU/day Phosphate in five doses calcitriol Improved the mineralization of trabecular bone 1 mg/day (99) Calcitriol mean dose 30 ng/kg per day nZ11 Effects of calcitriol on biochemistry Calcitriol raised serum phosphorus in all pre- and mineralization pubertal patients but only 2/6 pubertal patients No change in renal phosphate threshold Improved trabecular bone mineralization (24) Calcitriol and phosphorus nZ9 Heals rickets Changes growth rate Decreases alkaline phosphatases Symptomatic improvement (22) Phase 1 nZ10 Biochemistry On calcitriol Phosphorus 1.5–3.6 g/day Age 11.9G2.6 years Lower PTH levels VitD2 10–75 000 U/day Higher serum phosphorus levels Duration 438 months Lower alkaline phosphatases Phase 2 Lower urinary calcium excretion Phosphorus 1.5–3.6 g/day Improved stature Calcitriol 17–34 ng/kg per day (100) Calcitriol 58.0G8.5 ng/kg per day in two nZ19 Growth and mineral metabolism Improves doses upon switching from ergocalciferol to calcitriol Phosphorus 2167G174 mg/m per day in Blood phosphate five doses Growth velocity (101) Group 1 (1963–1968): nZ40 Comparison of three treatment 1-aOHD3 promoted catch-up growth and 75% groups and effect on growth and attained normal adult height final height Phosphorus !1 g/day Aged two and up Better results than previous treatment regimens Cholecalciferol or ergocalciferol 0.5–2 mg/day Group 2 (1968–1978) Phosphorus 0.7–2 g/day 25-Hydroxyvitamin D3 or alfacalcidiol 50–200 mg/day Group 3 (after 1978) Phosphorus 0.7–2 g/day Calcitriol 1–3 mg/day Review A Linglart et al. Therapy of hypophosphatemia 7–18 3 : R19 These mal-alignments are characterized by diaphyseal– metaphyseal regions of lower limbs long bones bowing in frontal plan with varus or valgus combined with a degree of flexion. Internal torsion of the tibia and fibula is frequent, as well as anteverted femoral neck. As a consequence, patients report lower limb pain; they also may develop patellar dysplasia including chondromalacia, lateral femoro-patellar subluxation, and gait troubles. Usually, the response of pain and skeletal deformities to medical treatment with adequate doses of calcitriol and phosphorus G class I analgesics (acetaminophen, paracetamol, some NSAIDs) is good, but bowing may not be entirely resolved and moderate bone pain may persist. Physiotherapy can be useful at this stage to prevent complete patellar dislocation and improve muscle fitness; sitting on the feet should be prohibited in children to decrease femoral neck anteversion. A disproportionate muscular insufficiency was described, but the relative responsibility of hypophosphatemia versus lower limb bowing – which modifies the muscular work – was not evaluated (41). Most of our patients show joint hyperlaxity and increased skin elasticity. Physiother- apy to improve joint stability with muscle reinforcement can be offered to patients. When leg bowing persists despite ‘optimal’ treat- ment, bone distortions should be assessed through the low-irradiating EOS system, which provides a 3D recon- struction of lower limbs bones in standing position. It may be combined with CT scanning to measure the degree of torsion. Surgery during childhood should be avoided. Because of open epiphyses, patients present a significant risk of recurrence of the bowing at the level of osteotomy or secondary to the adjacent epiphysiodesis (Fig. 2). When necessary, due to major bone deformities, surgery should be combined with adjusted doses of phosphate supplements and vitamin D analogs in order to prevent recurrence as previously evoked. The actual place of the surgery is the correction of residual deformities at the end of growth (Fig. 2). The achievement of horizontal knee joints often requires bifocal femoral and tibiae metaphyseal–diaphyseal osteo- tomies. Osteosynthesis is done by locking plates or intramedullary nails (42). Progressive correction using external fixation is an alternative that provides precise 3D angular deformities management (43). Distal tibiae varus with significant ankle joints obliquity should be operated upon with supramalleolar dome osteotomy (44). Fusion is usually acquired, without tendency of delayed fusion or pseudarthrosis. In case of significant lateral subluxation after alignment correction, surgery of the femoro-patellar joint is also required. However, ever since the This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Table 3 Continued Reference Therapy Subjects Aim of study Main outcomes (21) Calcitriol 25.6G16.9 ng/kg per day nZ24 Comparison to 16 untreated Treatment with phosphate and calcidiol increases patients (!1971) for height and growth velocity nephrocalcinosis Phosphate 100G34 mg/kg per day Age: 1–16 years (med- Nephrocalcinosis is a complication of therapy and is ianZ5.3 years) associated to the dose of phosphorus (not correlated to the dose of vitamin D analogs or duration of therapy) (102) Phosphorus 53–90 mg/kg per day nZ13 Identify treatment factors that Patients with tertiary hyperparathyroidism (nZ2) might be associated to transition had earlier onset and longer duration of treat- of secondary hyperparathyroid- ment, higher dose of phosphorus and longer ism to tertiary hyperpara- duration of treatment with very high phosphorus thyroidism doses (O100 mg/kg per j) compared with patients with secondary hyperparathyroidism (nZ11) Calcitriol dose 11–27 ng/kg per day (17) Phosphate 80–99 mg/kg per day nZ8 aged 0.15–0.58 years Patients who started the treatment earlier (group 1) had best controlled alkaline phosphatases, a better growth and predicted adult height Calcitriol 20 ng/kg per day nZ11 aged 1.3–8 years At start of treatment Review A Linglart et al. Therapy of hypophosphatemia 8–18 3 : R20 Table 4 Ranges of doses of phosphate supplements and vitamin D analogs throughout life, and their respective markers of efficacy and safety as applied in our center. Vitamin D analogs Period Phosphate supplements (alfacalcidol only ) Surveillance for efficacy and safety Frequency Infancy (dose) 55–70 mg/kg per day 1.5–2.0 mg/day Clinical: height, weight, cranial circumference Every 3 months divided into once/day four times/day Blood: alkaline phosphatases, total calcium, PTH, creatinine Urines (spot): calcium/creatinine Childhood (dose) 45–60 mg/kg per day 1.0–2.0 mg/day Clinical: height, weight, leg bowing, teeth Every 6 months divided into three times/day once/day Blood: alkaline phosphatases, total calcium, Every 6 months PTH, creatinine Urines (24-h): calciuria, phosphaturia Every 3 months Renal ultrasound Every year Puberty (dose) 35–50 mg/kg per day 1.5–3.0 mg/day Clinical: height, weight, leg bowing, teeth Every 6 months divided into three times/day once/day Blood: alkaline phosphatases, total calcium, Every 6 months PTH, creatinine Urines (24-h): calciuria, phosphaturia Every 3 months Renal ultrasound Every year Adulthood (dose) 0–2000 mg/day 0–1.5 mg/day Clinical: weight, mobility, pain, teeth Every year divided into two times/day once/day Blood: bone alkaline phosphatases, total Every year calcium, PTH, creatinine Urines (24-h): calciuria Every 6 months Renal ultrasound Every other year Pregnancy (dose) 2000 mg/day 1–1.5 mg/day Clinical: weight, mobility, pain Every 3 months divided into two times/day once/day Blood: total calcium, PTH, creatinine, 25-OH Every 3 months vitamin D Urines (24-h): calciuria Every 3 months Menopause (dose) 0–2000 mg/day 0–1.5 mg/day Clinical: weight, mobility, pain, teeth Every year divided into two times/day once/day Blood: bone alkaline phosphatases, total Every year calcium, PTH, creatinine Urines (24-h): calciuria Every 6 months Renal ultrasound Every other year Equivalent dose in calcitriol was obtained divided by a factor 2. implementation of the usage of vitamin D analogs, mineralization and skeletal growth, young adult patients surgical indications have been considerably diminished. with hereditary hypophosphatemia (HH) often stop In our experience, recourse to surgery dropped from 89 to treatment. Lessened parental surveillance, poor taste of 11% when we started to use the modern medical phosphate preparations, and lack of convincing demon- treatment in patients born after 1975. stration of therapeutic benefits in asymptomatic individ- Most hypophosphatemic patients present with uals contribute to the low compliance in (young) adults. increased head length and frontal bossing. Craniosynos- Nevertheless, the metabolic and endocrine consequences tosis and sometimes Chiari malformations giving rise to of chronic phosphate wasting persist life long. Adult headaches and vertigo may also affect patients and require endocrinologist following patients with HH thus necess- neurosurgery when symptomatic. arily faces two key questions: i) whom to treat and ii) what kind of treatment to give? There is no consensus regarding indications of the Therapy in adults treatment in adult patients. It is generally accepted that treatment should be reinitiated (or maintained) in all Metabolism symptomatic patients in order to reduce pain, which may After the years of burdensome therapy over the ‘pediatric’ be duetobonemicrofracturesand/orosteomalacia period, which is essential to ensure adequate bone matrix (25, 45) (Fig. 3). Patients with significant reduction in This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 9–18 3 : R21 Post-operative Post-operative Pre-operative Pre-operative AB C Figure 2 Surgeries in children and adolescents with XLHR. (A) Bilateral lower limbs with XLHR and severe pre-operative deformations impeding joints mal-alignment including distal right femur valgus and proximal left tibia mobility. Recurrence of leg bowing after surgery likely due to compliance varus – pre- and post-operative aspects (distal right femur varization and issues to phosphate and vitamin D analogs. Bilateral medial proximal tibiae proximal left tibia valgization osteotomies). (B) Pre- and post-operative epiphysiodesis inducing varus deformations. radiological aspect of the patient displayed in (A). (C) Eight-year-old girl pain symptoms remain the most compliant. Patients with on health, given the numerous beneficial effects of planed surgical interventions (i.e., corrective osteotomy, vitamin D on metabolism, cardiovascular system, cancer dental implants) should also be temporarily treated to prevention, and immune functions (50).Treatment promote bone mineralization (25). The conventional should be initiated at least in situations of increased treatment in these adult patients is based on oral demands on phosphate and calcium, such as pregnancy, phosphate salts, usually given twice daily, and active to ensure adequate mineralization of the fetal skeleton, vitamin D metabolites. The aim of the treatment is to or lactation, to enable sufficient galactopoiesis, and in improve the symptoms, not to normalize serum phos- both cases to prevent worsening of the phosphate deficit phate levels. Careful monitoring of plasma calcium, PTH, in the maternal organism (51). creatinine, and 24-h urinary calcium excretion is required Conventional medical therapies of FGF23-related (25, 46) in order to prevent tertiary hyperparathyroidism, hypophosphatemic disorders consist in substituting the induced by phosphate overdose (47), and hypercalciuria consequences of the FGF23 excess (46). Nevertheless, with nephrocalcinosis and renal insufficiency, resulting increased FGF23 levels may have deleterious effects on from calcitriol overtreatment (48). In our experience, health per se, especially on metabolism and cardiac tertiary hyperparathyroidism in patients with XLHR is functions (8, 52, 53). New therapeutic approaches target- rare (A Linglart, P Kamenicky, D Prie, A Rothenbuhler, ing FGF23 actions in general, including its impact on unpublished observations) and should be preferentially glucose and lipid metabolism, are very interesting in adult treated surgically, even though beneficial effects of patients with HH, since they frequently present with adjunctive therapy by 24,25-dihydroxyvitamin D has reduced mobility and are thus prone to develop obesity also been reported in one study (49). and metabolic syndrome. Considering the lack of evidence for clinical benefit and the possible side effects, indication of the conven- Rheumatology tional phosphate- and vitamin D analog-based therapy in asymptomatic patients is questionable. Long-term Although disease severity is variable, adults with HR may consequences of chronic hypophosphatemia in adult suffer from osteoarticular symptoms, such as pain and individuals are not known. Chronically decreased 1,25- joint stiffness, leading to disability of physical function diOH-vitamin D synthesis may have a significant impact and poor quality of life (25). The conventional treatment This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 10–18 3 : R22 Figure 3 Various burdens of the disease in adults leading to resume therapy with (D) Dramatic consequences of rickets and osteomalacia in a 30-year-old phosphate supplements and vitamin D analogs. (A) Osteoarthritis of the patient who did not receive vitamin D analogs. Arrows show insufficiency knee in a 28-year-old woman with persistent bone deformities after fractures. Bone demineralization and hip osteoarthritis are visible. adolescence. (B) Spinal enthesopathies of a 35-year-old patient with XLHR. (E) Delayed healing of fibulae fractures in the same patient following (C) Lower limb deformities in a young adult requiring corrective surgery. corrective surgeries on both tibias. with vitamin D analogs and phosphate supplements aims sites. This leads to the formation of enthesophytes in to decrease osteoarticular symptoms and improve physi- fibrocartilaginous tissues, often painful and causing joint cal function. However, only limited data supports the dysfunction. Risk factors associated with the occurrence efficiency of the therapy in adults presenting these of enthesopathy are unknown; vitamin D analogs and complications. Moreover, bone/joint pain may have phosphate supplements do not prevent this complica- different origin such as osteomalacia, insufficiency frac- tion (54). Apart from symptomatic patients at increased tures, osteoarthritis, and enthesopathy (Fig. 3). Identify- risk of insufficiency fractures and osteomalacia, treatment ing the cause of the pain should be considered as the first has been proposed to patients with planed surgical step for the optimal management of osteoarticular interventions (osteotomy, joint replacement) (see symptoms. Osteomalacia and spontaneous insufficiency above). Treatment should be also discussed in asympto- fractures, which occur in the lower extremities of the matic women at the time of menopause, in the absence weight bearing bones, should trigger treatment in adults. of estrogen substitution, to prevent osteomalacia. In In an open-label study conducted in 16 symptomatic addition to the conventional treatment, optimal care adult patients with XLHR, Sullivan et al. (45) showed that of symptomatic patients requires pharmacological and the combination of calcitriol and phosphate supple- non-pharmacological management of pain and joint ments decreases bone pain, increases serum phosphate, stiffness, through appropriated rehabilitation. Individua- and reduces the extent of osteomalacia quantified by pre- lized exercises and adapted physical activity should be and post-treatment bone biopsies. Moreover, insufficiency proposed to improve physical function and reduce the fractures usually heal faster with this conventional metabolic consequences of XLHR. treatment. Despite the mineralization defect, so-called Novel therapies targeting FGF23 actions (see below) osteomalacia, adults with XLHR present with paradoxical are awaited to fulfill the current unmet needs, such as heterotopic ossifications of tendon and ligament insertion diminished motor function or prevention of enthesis This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 11–18 3 : R23 ossification. For the latter, enthesis fibrocartilage cells of extend up to the dentino–enamel junction (64). Exten- Hyp mice (murine homolog of XLHR) specifically express sive enamel cracking and fissuring can be observed on FGFR3 and Klotho, thereby suggesting that FGF23 histologic sections, as well as dentin mineralization inhibition might prevent fibrocartilage ossification (54). defects. Unmerged dentin calcospherites are observed and are separated by large non-mineralized interglobular spaces (66, 67) (Fig. 4F). The endodontic infections Ears are believed to result from rapid dental pulp necrosis, Patients with HR present inconstant and variable hearing a consequence of the abnormal dentin mineralization loss depending on age and cause of phosphate wasting. and enamel cracks that allow invasion of the pulp by Hearing impairment has been described in mouse models oral bacteria (68). and human disorders due to increased FGF23 signaling, The dentin ECM is secreted by odontoblasts which, yet not with primary renal tubular defect. Hearing like osteoblasts, express high levels of proteins involved in difficulties appear during adulthood in treated patients mineral ion homeostasis and in the binding and proteo- with XLHR (55). Patients may have mild-to-severe lytic processing of other proteins and peptides regulating sensorineural hearing loss, affecting mainly low and high mineralization (69, 70). Hence, the abnormal hypo- frequencies (56). Some patients also present with tinnitus phosphatemic dentin contains degraded fragments of and vertigo associated with low frequencies hearing loss noncollagenous phosphorylated matrix proteins includ- similar to that of Menie ` re’s disease (57). X-rays show ing matrix extracellular phosphoglycoprotein (MEPE), generalized osteosclerosis and thickening of the petrous DMP1, and osteopontin (OPN), and particularly peptides bone, with narrowed internal auditory meatus (58).In with the acidic serine- and aspartate-rich motif (ASARM) rodents models mimicking XLHR, mice display variable (71, 72). Interestingly, PHEX is the only known enzyme expressions of deafness, circling behavior, lack of postural capable of cleaving ASARM peptides, whose accumulation reflexes, and cranial dysmorphology (59, 60, 61). Differ- leads to inhibition of mineralization. ently, hearing loss has been reported in HR children with Because the pain and swelling that result from tooth mutations in ENPP1 – as early as 9 days of life – or DMP1 abscesses are usually detected by patients or their families (62, 63). Overall, hearing loss resembling stapes otosclero- and will bring them to consult, much attention has been sis occurs early in life in ARHR patients, while hearing drawn to the dental manifestation of HR. However, it is loss resembling Menie ` re’s disease develops after the becoming clear that their periodontal health is also second decade in XLHR patients. We presently do not affected, especially in adults. Comparing the periodontal know whether phosphate supplements and vitamin D status of ten adults with familial HR with age-matched analogs modify the hearing evolution. controls (73), it was observed that the prevalence of periodontitis was high in hypophosphatemic patients (60% vs 3.6% to 7.3% in controls). Our unpublished data Dental and periodontal defects on the periodontal status of more than 20 consecutive The presence of severe dental manifestations in patients adult patients with HR revealed an increased prevalence with HR resulting either from PHEX mutations or from and severity of periodontitis when compared with age- other causes summarized above, including mutations matched controls, despite a similar gingival inflammation in DMP1 or FGF23, is now well recognized (Fig. 4). (Fig. 3A, D and E). Although, no published studies have The dominant feature is the occurrence of spontaneous explored non-surgical and surgical periodontal treatments infection of the dental pulp tissue, resulting in tooth in adults with low phosphate, we observed a favorable abscesses. In contrast with common endodontic infec- response to these treatments. The importance of the tion, these abscesses develop in teeth without any signs supportive periodontal therapy in these patients cannot of trauma or decay, affecting both the deciduous and be overlooked. One case of implant placement along with permanent dentition (64, 65). Clinically, teeth of guided bone regeneration in a XLH adult patient was patients with HR look normal, complicating the identifi- reported with satisfactory outcomes after 42 months (74). cation of the causal tooth and the diagnosis of the Consistent with constitutional defects of periodontal endodontic origin of the infection. Radiographically, tissues, mice lacking Dmp1 or Phex have a defective the enamel layer appears thinner while the dentin layer alveolar bone and cementum (75, 76). is more radiolucent. Pulp chambers are enlarged, Conventional therapy with vitamin D analogs and resembling taurodontism and prominent pulp horns phosphate supplements has a substantial beneficial This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 12–18 3 : R24 A B R L R L CD F Pulp Predentin Dentin IS IS IS IS 100 µm Figure 4 Dental defects in patients with X-linked hypophosphatemia (XLH). a 6-year-old XLH patient. (E) Alveolar bone loss in a 45-year-old XLH (A) Orthopantomogram of a 35-year-old XLH patient. Note multiple absent patient. (F) Toluidine blue-stained section of a third molar germ of a teeth and endodontic lesions. (B) Orthopantomogram of a 30-year-old XLH 14-year-old female with XLH showing abnormal dentin mineralization. patient that benefited from vitamin D analogs and phosphate supplements Numerous nonmineralized interglobular spaces (IS) are observed between during growth with good compliance. No dental or periodontal defects are unmerged calcospherites in the dentin body (document laboratory EA2496, evident. (C) Intraoral view and corresponding X-ray of an endodontic Dental school University Paris Descartes, France). Asterisks indicate calco- infection (arrows) affecting the intact central right lower incisor in a spherites, single arrow indicates dentin secreting cells, odontoblasts, and 35 year-old XLH patient. (D) Enlarged pulp chambers, prominent pulp double head arrow indicates extent of predentin. horns, radiolucent hypomineralized dentin and endodontic infection in impact on oral health that will depend on the onset, sealing. However, these abscesses, especially those occur- compliance, and duration of the treatment. Missing and ring on primary teeth, spread rapidly in the jawbone and filled teeth index of patients treated since early childhood toothextractionisoften necessary.Preventionof is similar to the index of healthy, age-matched controls abscesses includes sealing the tooth surface (primary and (64) and dentin mineralization of permanent teeth, which permanent teeth) with a dental resin to form a barrier to mineralize after birth, can be rescued by the treatment (77) bacterial penetration (77). For primary teeth, this non- (Figs 4B and 5). The tooth phenotype correlates well invasive and painless approach consists in applying an with the overall bone phenotype and can be used to adhesive system (preferably no rinsing step called ‘self- evaluate the benefits on mineralization of this treatment etching’) and then a light-cured flowable resin. This (68, 78, 79). Future studies will determine the benefit procedure must be repeated regularly (every year) due to of treatment on the periodontal status. gradual wear of the resin until the natural exfoliation of the tooth. In parallel, we recommend rigorous oral hygiene and preventive procedures. Daily use of fluoride Clinical approaches toothpaste adapted to age and regular fluoride varnish Spontaneous dental abscesses can be treated by the applications at the dental chair, considering that conventional endodontic approach, e.g. root canal clean- they present a higher risk of dental infection, is of ing to remove the infected pulp tissues and endodontic utmost importance (80). The orthodontic treatment is This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 13–18 3 : R25 XLH deciduous molar XLH permanent molar A B C 500 µm 50 µm 1 mm XLH permanent molar Control permanent molar DF E Enamel Dentin Pulp 1 mm 2 mm 2 mm Figure 5 Scanning electron microscopy views (documents laboratory EA2496, Dental is abnormally mineralized. (D and E). Permanent third molar of a 15-year school University Paris Descartes, France) of (A) A deciduous molar of a old male patient with XLH who was treated during growth with a good 6-year-old male patient with XLHR, born from a XLH mother, showing that compliance to therapy but a late onset. Remaining calcospherites are the major bulk of dentin (arrow) is abnormally mineralized. (B) At higher observed in the outer part of dentin (full arrow) corresponding to magnification (white rectangle), the dentin appears extremely porous with infancy, whereas good mineralization (dotted arrow) is seen in the inner multiples unmineralized spaces. (C) Permanent molar of an adult XLH part of dentin corresponding to the treatment period. (F) Control patient hich was not treated during growth. All the dentin bulk (arrow) permanent molar. possible (81), especially in teenagers with HR controlled patients, complete absorption and sustained effect on by the conventional treatment since infancy. In our serum phosphate and TmP/GFR beyond 4 weeks upon a Reference Center, this treatment is offered to compliant single s.c. injection (85). A Phase 2 clinical trial is ongoing teenagers under conventional treatment when the wave of in the USA and Canada (86). Two issues may arise with the abscesses occurring in deciduous teeth has ended. long-term use of FGF23 antibody. Firstly, it is likely that the anti-FGF23 antibodies will probably not rescue the direct impact of PHEX deficiency on calcified tissue mineral- Novel therapies ization that depends on MEPE- or OPN-derived ASARM peptides presence in the ECM. Secondly, FGF23 exerts In the recent years, novel strategies that efficiently numerous actions including prevention of ectopic calcifi- manipulate molecular effectors of the mineral metabolism cation through the control of the calcium-phosphate have been described. Several of them aim at inhibiting product. Precise modulation of FGF23 signaling will be downstream FGF23 signaling. Monoclonal FGF23 necessary to avoid off-target actions of FGF23 antibodies. antibodies with neutralizing effect on FGF23 action have Another approach was taken by Goetz et al. (87); they been generated (82). When administered intravenously to showed that a C-terminal fragment of FGF23 competes Hyp mice (murine homolog of XLHR), FGF23 antibodies with the full-length protein for receptor binding, yet normalized phosphatemia, increased levels of 1,25-diOH- without activating downstream signaling. Infusion of this vitamin D, increased the expression of the Npt2a cotran- FGF23 C-tail in normal rats triggered hyperphosphatemia sporter, and tempered the 24-hydroxylase overexpression. and renal phosphate retention. In Hyp mice, serum Repeated injections to juvenile mice promoted growth and phosphate was increased and the fractional excretion of ameliorated mineralization and cartilage development phosphate was decreased compared with control. Despite (83). Multiple injections into adult mice were shown to improve spontaneous motor activity as well as muscle these promising data, there is no information indicating strength (84). These promising data prompted the elabor- a possible clinical transition for this elegant approach ation of a humanized antibody, which showed, in XLH as of today. This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 14–18 3 : R26 The pharmacological inhibition of downstream FGF23 inhibit mineralization (93, 94). In XLHR and ARHR, signaling was also probed using selective pan-specific FGFR ASARM peptides abundance is increased in the ECM of antagonists in Hyp and Dmp1-null mice. Oral adminis- bone and teeth, and probably contributes to the mineral- tration of the small molecule NVP-BGJ398 led to an ization defects that hallmark the disease (64, 72). Counter- improved ion metabolism, restored the structure of the acting ASARM peptides may therefore help in improving mineralization plate and partly corrected the bone growth bone, dental and periodontal features in XLHR and impairment (88). Even if the molecule is already in Phase 1 related diseases. trial in human for cancer therapy, the application to HR will warrant more investigation regarding the selectivity of Conclusion the molecule, notably towards other FGFR-mediated physiological processes beyond phosphate metabolism. Symptoms associated with phosphate wasting result from Noteworthy, parathyroid cells also express the FGF23 FGF23 excessive signaling and accumulation of ASARM receptor. FGF23 represses PTH secretion, but endocrine peptides in bone and dental tissues. Current therapy with feedback loops, while still controversial, have been phosphate supplements and vitamin D analogs partly suggested (89). Normalization of phosphatemia in a TIO correct rickets and osteomalacia. It is obvious that patient after parathyroidectomy has been reported outcomes of therapy are still not optimal and that recently (90), and manipulation of PTH secretion may therapies targeting the pathophysiology of the disease therefore help to counteract downstream effects of are required. Along this line, FGF23 antibodies are very excessive FGF23 on phosphate and vitamin D metabolism. promising but their benefit remains to be investigated In contrast to the above-mentioned strategies that during growth in children with PHEX, FGF23, or DMP1 target either FGF23 or its FGFR/KLOTHO co-receptor in the mutation. kidney, other efforts are directed toward osteocytic targets. Today, and in the future, coordination between The osteocyte is the primary site of production of FGF23 caregivers is required for the optimal treatment of this and hosts PHEX and DMP1 (malfunctioning in XLHR and rare disorder and involves various specialists in pediatric ARHR respectively). Osteocytes express the calcitonin and adult fields. While attention is focused in children on receptor and it was recently reported that a single s.c. legs straightening and growth, adults should be none- administration of calcitonin in one patient affected with theless regularly monitored for the prevention and XLHR results in a decrease in the concentration of FGF23 limitation of bone pain, joint stiffness, and periodontal and increases in phosphatemia and circulating level of inflammation. Extra-osseous issues should be considered calcitriol (85). A Phase 1 study is currently evaluating early in life, as well as audition, sport practice, and glucose repeated daily intranasal calcitonin in XLHR (91). and lipid metabolism, with the help of physiotherapists The identification of a decreased proprotein conver- and nutritionists. In addition, the contribution of tase 2 (PC2) activity in bone cells of Hyp mice (92) provides psychologist and social workers is necessary, especially in another potential curative option. PC2, and its associated patients born before 1970 who did not receive vitamin D chaperone 7B2, were shown to participate in the proteo- analogs and present multiple and sometime devastating lytic regulation of the FGF23 protein expression. When complications. Finally, in the era of globalized communi- hexa-D-arginine (D6R), a PC2 agonist, was administered cation, active networking involving not only reference i.p. into Hyp mice, normalization of 7B2 expression and centers for rare diseases or scientific societies but also concomitant decrease in Fgf23 mRNA was observed. patients organization and biopharmaceutical companies Although only partial reduction in the levels of serum should facilitate the translation of recent discoveries into Fgf23 was noted in D6R-treated animals, bone modeling novel therapies. was restored, phosphatemia was sub-normalized, as were the related markers Npt2a and Cyp27b2 encoding the 24-hydroxylase. Declaration of interest The authors declare that there is no conflict of interest that could be Therapies that would be capable of restoring the perceived as prejudicing the impartiality of the review. bone and tooth mineralization process are also desirable. The SIBLINGs phosphoproteins MEPE, DMP1, and OPN all contain ASARM motifs (reviewed in (2)). Upon proteolytic Funding cleavage orchestrated by PHEX, released phosphorylated This research did not receive any specific grant from any funding agency in ASARM peptides interact with hydroxyapatite crystals and the public, commercial or not-for-profit sector. This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 15–18 3 : R27 13 Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Author contribution statement Takeuchi Y, Fujita T, Fukumoto S & Yamashita T. 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Therapeutic management of hypophosphatemic rickets from infancy to adulthood

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Abstract

In children, hypophosphatemic rickets (HR) is revealed by delayed walking, waddling gait, Key Words leg bowing, enlarged cartilages, bone pain, craniostenosis, spontaneous dental abscesses, " calcium and growth failure. If undiagnosed during childhood, patients with hypophosphatemia " bone present with bone and/or joint pain, fractures, mineralization defects such as " rare diseases/syndromes osteomalacia, entesopathy, severe dental anomalies, hearing loss, and fatigue. Healing " X-linked hypophosphatemic rickets rickets is the initial endpoint of treatment in children. Therapy aims at counteracting consequences of FGF23 excess, i.e. oral phosphorus supplementation with multiple daily intakes to compensate for renal phosphate wasting and active vitamin D analogs (alfacalcidol or calcitriol) to counter the 1,25-diOH-vitamin D deficiency. Corrective surgeries for residual leg bowing at the end of growth are occasionally performed. In absence of consensus regarding indications of the treatment in adults, it is generally accepted that medical treatment should be reinitiated (or maintained) in symptomatic patients to reduce pain, which may be due to bone microfractures and/or osteomalacia. In addition to the conventional treatment, optimal care of symptomatic patients requires pharmacological and non-pharmacological management of pain and joint stiffness, through appropriated rehabilitation. Much attention should be given to the dental and periodontal manifestations of HR. Besides vitamin D analogs and phosphate supplements that improve tooth mineralization, rigorous oral hygiene, active endodontic treatment of root abscesses and preventive protection of teeth surfaces are recommended. This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 2–18 3 : R14 Current outcomes of this therapy are still not optimal, and therapies targeting the pathophysiology of the disease, i.e. FGF23 excess, are desirable. In this review, medical, dental, surgical, and contributions of various expertises to the treatment of HR are described, with an effort to highlight the importance of coordinated care. Endocrine Connections (2014) 3, R13–R30 Introduction Phosphate wasting ineluctably leads to hypophosphate- matrix protein 1 (DMP1) (11) or ENPP1 (12),and mia and numerous consequences including mineral- uncontrolled secretion of FGF23 by mesenchymal tumors, ization defects. In children, hypophosphatemia is a condition known as tumor-induced osteomalacia (TIO) revealed by vitamin D-resistant rickets and results in (13). Except for the latter, mineralization defects involving variable degrees of delayed walking, waddling gait, leg bone and teeth are caused by hypophosphatemia and bowing, enlarged cartilages, bone pain, craniostenosis, FGF23 excess and, in addition, by a direct effect of the spontaneous dental abscesses, and growth failure. If absence of functional PHEX (or DMP1) on bone or tooth undiagnosed during childhood, hypophosphatemia is extracellular matrix (ECM) mineralization (14). suspected when patients present with bone and/or joint Secondly, phosphate wasting may be due to a primary pain, fractures, mineralization defects such as osteo- renal tubular defect, i.e. hereditary HR with hypercalciuria malacia, entesopathy, severe dental anomalies, hearing (HHRH) due to molecular defects of the sodium-phos- loss, and fatigue. Symptoms might be present, although phate channel NPT2c, diseases affecting several renal to a lesser degree, in adults who underwent the conven- tubular functions such as Dent or Lowe syndromes, or tional treatment throughout their childhood and adoles- tubular toxicity of drugs (15, 16). All these conditions cence. Causes of phosphate wasting are mostly due to share a diminished capacity to transport phosphate from genetic defects in factors necessary for phosphate the glomerular filtrate to the blood circulation. In handling; for a review read (1). They have been sum- response to hypophosphatemia, FGF23 secretion is ade- marized in Table 1. In this review, we will consider two quately suppressed, and 1,25-diOH-vitamin D production different types of phosphate wasting. Firstly, phosphate and absorption of calcium through the gut and urinary calcium excretion are consequently enhanced. wasting may be secondary to increased fibroblast growth factor 23 (FGF23) signaling, which is a circulating factor Besides acquired disorders like tumors or drug secreted by osteoblasts, odontoblasts, and osteocytes (2). toxicity, most conditions leading to phosphate wasting In the renal proximal tubule, FGF23 inhibits the sodium- are congenital and will continue throughout the patient’s phosphate transport through ion channels, NPT2a and lifetime. To this day, therapy has mostly been evaluated NPT2c, and prevents 1,25-diOH-vitamin D production. in children. Enormous progress has been made since As a consequence, both renal and digestive absorption the availability of vitamin D analogs, such as calcitriol of phosphate are diminished. Recently, extra renal effects and alfacalcidol, in the mid-1970s and the evolution of of FGF23 have been reported, such as immune function surgical procedures. However, two major issues remain: in human monocytes (3), iron (4, 5), glucose (6) and i) the growth retardation and recurrent dental infections lipid metabolism (7, 8). in children and ii) the necessity of adequate therapeutic Causes of phosphate wasting secondary to elevated strategies in adults. Indeed, the disease remains physically FGF23 mainly encompass not only X-linked hypo- apparent and the global objective of therapies (medical, phosphatemic rickets (XLHR) due to loss-of-function dental, and surgical) should be to limit, and in best cases mutations in PHEX, an endopeptidase encoded by a avoid, sequel by correcting leg deformities, promoting gene localized on the X chromosome (9), but also auto- growth and preserving dentition. In this context, we will somal dominant hypophosphatemic rickets (ADHR) describe in this review the current and future treatments due to recurrent heterozygous mutations affecting the available to counteract phosphate wasting, restore 176 179 RXXR motif in FGF23 (10), autosomal recessive serum phosphate and allow adequate bone and tooth HR (ARHR) due to loss-of-function mutations in Dentin mineralization. This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 3–18 3 : R15 Table 1 Causes of hypophosphatemic rickets (HR). Gene Transmission Reference Main features HR sharing elevated FGF23 circulating levels and inappropriately low or normal 1,25-diOH-vitamin D XLHR PHEX X-linked (9) HR with similar phenotype in males and females ADHR FGF23 Autosomal (10) HR dominant ARHR DMP1 Autosomal (11) HR recessive ARHR2 ENPP1 Autosomal (12) HR associated with arterial calcifications of recessive infancy (GACI syndrome) ARHR3 FAM20c Autosomal (95) Hypophosphatemia associated with osteo- recessive sclerosis of the bone rather than rickets, dysmorphy, and cerebral calcifications; severe dental phenotype OGD FGFR1 (96) HR associated with frequent craniosynos- tosis, dysmorphy, and dwarfism HR associated with congenital sporadic disorders due to heterozygous post-zygotic mutations in genes activating signaling pathways and elevated FGF23 MAS (97) Characterized by the triad precocious puberty, cafe-au-lait spots and fibrous dysplasia (FD); HR is rare, and secondary to increased FGF23 production by the FD Mosaic cutaneous disorders include nevus KRAS and (98) HR associated with bone lesions and sebaceous and Schimmelpenning syndrome NRAS extended cutaneous congenital lesions HR associated with mesenchymatous tumors secreting FGF23 TIO (13) Acquired and often severe hypophos- phatemia and phosphate wasting. Hypocalcemia may be present as the consequence of suppressed 1,25-diOH- vitamin D production HR sharing appropriately suppressed FGF23 and elevated 1,25-diOH-vitamin D; defects in renal phosphate transporters HHRH SLC34A3 Autosomal (16) HR with nephrocalcinosis and kidney stones recessive Diseases affecting the renal distal tubule Lowe syndrome, Dent syndrome (CLCN5 gene), Toni-Debre ´ -Fanconi XLHR, X-linked HR; ADHR, autosomal dominant HR; ARHR; autosomal recessive HR type 1; ARHR2, autosomal recessive HR type 2; ARHR3, autosomal recessive HR type 3; OGD, osteoglophonic dysplasia; MAS, McCune–Albright syndrome; TIO, tumor-induced osteomalacia; HHRH, hereditary hypophosphatemic rickets with hypercalciuria. ALP levels (Fig. 1B), iii) improve growth (Fig. 1C), and iv) Therapy in children restore straight legs and improve teeth health. Medical treatment for phosphate wasting Nowadays, the medical treatment is aimed at counter- Healing rickets by normalizing serum alkaline phosphatase acting consequences of FGF23 excess, i.e. oral phosphorus (ALP) levels and radiological signs is the initial endpoint supplementation with multiple daily intakes to compen- sate for renal phosphate wasting and active vitamin D in children. Treating rickets will promote growth, pro- analogs (alfacalcidol or calcitriol) to counter the 1,25- gressively correct leg deformities (Fig. 1A), and facilitate tooth mineralization. In infants diagnosed before they diOH-vitamin D deficiency (Table 3). The daily doses of even show signs of rickets, the treatment goal for them will phosphorus supplements range between 40 (adolescents) be not to develop rickets (Fig. 1A). Earlier treatment has and 60 (toddlers) mg/kg per day (Table 4). Multiple been shown to lead to better results (17). Objectives, which daily doses of phosphate supplements are mandatory could also be described as expected results, are described in throughout childhood and adolescence, because, in the Table 2. The treatment intends to, in the following order: context of diminished phosphate reabsorption, serum i) reduce bone pain, ii) normalize (or near-normalize) phosphate level is back to low baseline few hours after This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 4–18 3 : R16 COUCHE BC 200 200 +2 SDS 180 +2 SDS –2 SDS –2 SDS 40 40 Mean final height: 1.60 m Mean final height: 1.53 m 400 20 0 1 2 3 4 5 6 7 8 9 10 11 12 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 Months after start of treatment Figure 1 Evolution of clinical (leg bowing and growth) and biochemical parameters girl who started therapy at the age of 4 months. Diagnosis of XLHR was (alkaline phosphatase levels) during treatment with vitamin D analogs and made in the context of familial disease (mother and two sisters affected). phosphate supplements in children. (A) Patient 1 is a 2-year-old girl (left an (B) Evolution of alkaline phosphatase levels throughout the first year of middle panels) recently diagnosed with XLHR and a de novo mutation of therapy in 30 patients affected with HR and elevated FGF23. (C) Growth PHEX. The same girl is shown at the age of 5 years with straight legs (right pattern (range between C2 and K2 SDS is shadowed) in 32 girls and 29 panel). Patient 2 is a 14-year-old boy who was treated since the age of four boys affected with HR and elevated FGF23 and receiving vitamin D analogs (XLHR and a de novo mutation of PHEX). Patient 3 is a 13-year-old girl who and phosphate supplements throughout childhood and puberty. Mean, presents with persistent leg bowing despite being treated since she was C2, and K2 SDS of French reference growth charts are represented by 3 years old (XLHR and a de novo mutation of PHEX). Patient 4 is a 2-year-old colored lines. This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Patient 2 Patient 1 Alkaline phosphatases (UI/l) Patient 3 Patient 4 Review A Linglart et al. Therapy of hypophosphatemia 5–18 3 : R17 Table 2 Objectives and timeline for the conventional rickets, for initial dosage of vitamin D analogs to be treatment of HR in children. decreased to maintenance doses. As for many chronic diseases, compliance to oral Interval after treatment is a major issue, even in expert hands. For start of treatment Objective optimal dosage, it is difficult to base our guidance on doses Few weeks Decrease in bone pain reported in published studies, which are all over 20 years 6–12 months Normalization of alkaline phosphatase level old and report a very wide range of doses between 10 and 1 year Increase in growth velocity 3–4 years Straightening of legs: 1 cm decrease in 80 ng/kg per day of calcitriol and 30 and 180 mg/kg per day intercondylian (genu varum) or inter- of elemental phosphorus (18, 19, 20, 21, 22, 23, 24). Our malleolar (genu valgum) distance every recommendations are based on over 30 years of experience 6 months at our center in treating over 250 patients with HR and are similar to the guidelines advised recently by Carpenter et al. phosphate intake. At these doses, digestive complaints (25). In addition, we prescribe 25-OH-vitamin D supple- are extremely rare. The daily dose of phosphate supple- ments and optimize dietary calcium intake in children, ments is adjusted to efficacy (i.e., ALP levels, leg bowing, although no published studies support this point. and growth velocity), patient’s weight, and PTH levels. Healing active rickets promotes growth and after Note that serum phosphate is not used to adjust 2 years of successful treatment, patients’ growth velocity phosphate therapy. On the contrary, as fasting phosphate is restored to its maximal potential in a majority of patients. is not restored by treatment, increasing phosphate However, 25–40% of patients with well-controlled XLHR supplement doses leads to intestinal discomfort and show linear growth failure despite optimal treatment and secondary (sometimes tertiary) hyperparathyroidism. have a final height underK2 SDS (19, 21, 26, 27, 28, 29, 30, Urinary phosphate measured on a 24-h collection should 31, 32, 33) (and our experience, Fig. 1C). Until recently, parallel the daily intake of phosphate supplements, and only limited pilot studies (small patient numbers, limited may be used to check for compliance. Prescribing period of observation, lack of controls and randomizations) phosphate intake is a balance between excessive dosage have been conducted, which suggest a beneficial effect of tending to hyperparathyroidism and insufficient dosage recombinant growth hormone (rGH) treatment on growth slowing the healing of rickets. 1a-hydroxylated vitamin D velocity in patients with XLHR (29, 34, 35, 36, 37, 38). The analogs constitute the second pillar of conventional only randomized study by Zivicnjak et al. (39) showed treatment. Their half-life is sufficient to allow for single significant improvement of linear growth (C1.1 height and twice daily oral doses of alfacalcidol and calcitriol SDS) in eight patients treated with rGH out of 16 short respectively. The starting dose of vitamin D analogs (mean height SDS K3.3) prepubertal children with XLHR. (usually 1–2 mg/day alfacalcidol or 0.5–1 mg/day calcitriol) Addition of rGH induces a rise in mineral needs, which depends on growth velocity. Higher doses (1–3 mg/day should be accompanied with a 20–30% increment in alfacalcidol or 0.5–1.5 mg/day calcitriol) are associated vitamin D analogs dosage. Only well-observant patients with periods of high growth velocity, such as early with healed rickets can benefit from rGH. childhood and adolescence. Vitamin D analog doses are In patients with HHRH, 1,25-diOH-vitamin D adjusted to give the maximum dose for efficacy based on synthesis is enhanced and PTH secretion often suppressed, ALP levels, leg bowing, and growth velocity, without both conditions favoring hypercalciuria (40); therefore, reaching toxicity, mainly hypercalciuria. Hypercalciuria patients require treatment with phosphate supplements does not usually occur until ALP levels are normalized. solely. Doses and adjustment rules are similar to that used As it is not invasive to collect urine, we recommend for XLHR patients. In this condition, 25-OH-vitamin D measuring urinary calcium and creatinine every 3 months supplementation should be monitored very carefully by on a spot urine collection in young children and on a 24-h trained physicians to avoid increase in 1,25-diOH-vitamin collection in older children (O5) toilet trained. Hypercal- D generation and hypercalciuria. ciuria is defined by urinary calcium/urinary creatinine above 1 mmol/mmol (0.35 mg/mg) in toddlers and 24-h Orthopedic and surgical management in children urinary calcium excretion above 5 mg/kg per day in older children. We recommend screening for nephrocalcinosis Hypophosphatemia induces progressive bowing of the with yearly ultrasound (every second year in the absence legs that becomes apparent with the onset of weight of episodes of hypercalciuria). It is common, after healing bearing (Fig. 1A), and may hinder the walking capacity. This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 6–18 3 : R18 This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Table 3 Reports of vitamin D analogs and phosphate supplements in patients with HR. Reference Therapy Subjects Aim of study Main outcomes (19) Phosphate alone 1.2–3.6 g/day in five nZ11 X-rays and bone histology Combined phosphate and calcitriol has several doses advantages over previously described treatment regimens: Phosphate in five doses ergocalciferol Aged 1.75–11.5 years Induced mineralization of the growth plate 25 000–50 000 IU/day Phosphate in five doses calcitriol Improved the mineralization of trabecular bone 1 mg/day (99) Calcitriol mean dose 30 ng/kg per day nZ11 Effects of calcitriol on biochemistry Calcitriol raised serum phosphorus in all pre- and mineralization pubertal patients but only 2/6 pubertal patients No change in renal phosphate threshold Improved trabecular bone mineralization (24) Calcitriol and phosphorus nZ9 Heals rickets Changes growth rate Decreases alkaline phosphatases Symptomatic improvement (22) Phase 1 nZ10 Biochemistry On calcitriol Phosphorus 1.5–3.6 g/day Age 11.9G2.6 years Lower PTH levels VitD2 10–75 000 U/day Higher serum phosphorus levels Duration 438 months Lower alkaline phosphatases Phase 2 Lower urinary calcium excretion Phosphorus 1.5–3.6 g/day Improved stature Calcitriol 17–34 ng/kg per day (100) Calcitriol 58.0G8.5 ng/kg per day in two nZ19 Growth and mineral metabolism Improves doses upon switching from ergocalciferol to calcitriol Phosphorus 2167G174 mg/m per day in Blood phosphate five doses Growth velocity (101) Group 1 (1963–1968): nZ40 Comparison of three treatment 1-aOHD3 promoted catch-up growth and 75% groups and effect on growth and attained normal adult height final height Phosphorus !1 g/day Aged two and up Better results than previous treatment regimens Cholecalciferol or ergocalciferol 0.5–2 mg/day Group 2 (1968–1978) Phosphorus 0.7–2 g/day 25-Hydroxyvitamin D3 or alfacalcidiol 50–200 mg/day Group 3 (after 1978) Phosphorus 0.7–2 g/day Calcitriol 1–3 mg/day Review A Linglart et al. Therapy of hypophosphatemia 7–18 3 : R19 These mal-alignments are characterized by diaphyseal– metaphyseal regions of lower limbs long bones bowing in frontal plan with varus or valgus combined with a degree of flexion. Internal torsion of the tibia and fibula is frequent, as well as anteverted femoral neck. As a consequence, patients report lower limb pain; they also may develop patellar dysplasia including chondromalacia, lateral femoro-patellar subluxation, and gait troubles. Usually, the response of pain and skeletal deformities to medical treatment with adequate doses of calcitriol and phosphorus G class I analgesics (acetaminophen, paracetamol, some NSAIDs) is good, but bowing may not be entirely resolved and moderate bone pain may persist. Physiotherapy can be useful at this stage to prevent complete patellar dislocation and improve muscle fitness; sitting on the feet should be prohibited in children to decrease femoral neck anteversion. A disproportionate muscular insufficiency was described, but the relative responsibility of hypophosphatemia versus lower limb bowing – which modifies the muscular work – was not evaluated (41). Most of our patients show joint hyperlaxity and increased skin elasticity. Physiother- apy to improve joint stability with muscle reinforcement can be offered to patients. When leg bowing persists despite ‘optimal’ treat- ment, bone distortions should be assessed through the low-irradiating EOS system, which provides a 3D recon- struction of lower limbs bones in standing position. It may be combined with CT scanning to measure the degree of torsion. Surgery during childhood should be avoided. Because of open epiphyses, patients present a significant risk of recurrence of the bowing at the level of osteotomy or secondary to the adjacent epiphysiodesis (Fig. 2). When necessary, due to major bone deformities, surgery should be combined with adjusted doses of phosphate supplements and vitamin D analogs in order to prevent recurrence as previously evoked. The actual place of the surgery is the correction of residual deformities at the end of growth (Fig. 2). The achievement of horizontal knee joints often requires bifocal femoral and tibiae metaphyseal–diaphyseal osteo- tomies. Osteosynthesis is done by locking plates or intramedullary nails (42). Progressive correction using external fixation is an alternative that provides precise 3D angular deformities management (43). Distal tibiae varus with significant ankle joints obliquity should be operated upon with supramalleolar dome osteotomy (44). Fusion is usually acquired, without tendency of delayed fusion or pseudarthrosis. In case of significant lateral subluxation after alignment correction, surgery of the femoro-patellar joint is also required. However, ever since the This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Table 3 Continued Reference Therapy Subjects Aim of study Main outcomes (21) Calcitriol 25.6G16.9 ng/kg per day nZ24 Comparison to 16 untreated Treatment with phosphate and calcidiol increases patients (!1971) for height and growth velocity nephrocalcinosis Phosphate 100G34 mg/kg per day Age: 1–16 years (med- Nephrocalcinosis is a complication of therapy and is ianZ5.3 years) associated to the dose of phosphorus (not correlated to the dose of vitamin D analogs or duration of therapy) (102) Phosphorus 53–90 mg/kg per day nZ13 Identify treatment factors that Patients with tertiary hyperparathyroidism (nZ2) might be associated to transition had earlier onset and longer duration of treat- of secondary hyperparathyroid- ment, higher dose of phosphorus and longer ism to tertiary hyperpara- duration of treatment with very high phosphorus thyroidism doses (O100 mg/kg per j) compared with patients with secondary hyperparathyroidism (nZ11) Calcitriol dose 11–27 ng/kg per day (17) Phosphate 80–99 mg/kg per day nZ8 aged 0.15–0.58 years Patients who started the treatment earlier (group 1) had best controlled alkaline phosphatases, a better growth and predicted adult height Calcitriol 20 ng/kg per day nZ11 aged 1.3–8 years At start of treatment Review A Linglart et al. Therapy of hypophosphatemia 8–18 3 : R20 Table 4 Ranges of doses of phosphate supplements and vitamin D analogs throughout life, and their respective markers of efficacy and safety as applied in our center. Vitamin D analogs Period Phosphate supplements (alfacalcidol only ) Surveillance for efficacy and safety Frequency Infancy (dose) 55–70 mg/kg per day 1.5–2.0 mg/day Clinical: height, weight, cranial circumference Every 3 months divided into once/day four times/day Blood: alkaline phosphatases, total calcium, PTH, creatinine Urines (spot): calcium/creatinine Childhood (dose) 45–60 mg/kg per day 1.0–2.0 mg/day Clinical: height, weight, leg bowing, teeth Every 6 months divided into three times/day once/day Blood: alkaline phosphatases, total calcium, Every 6 months PTH, creatinine Urines (24-h): calciuria, phosphaturia Every 3 months Renal ultrasound Every year Puberty (dose) 35–50 mg/kg per day 1.5–3.0 mg/day Clinical: height, weight, leg bowing, teeth Every 6 months divided into three times/day once/day Blood: alkaline phosphatases, total calcium, Every 6 months PTH, creatinine Urines (24-h): calciuria, phosphaturia Every 3 months Renal ultrasound Every year Adulthood (dose) 0–2000 mg/day 0–1.5 mg/day Clinical: weight, mobility, pain, teeth Every year divided into two times/day once/day Blood: bone alkaline phosphatases, total Every year calcium, PTH, creatinine Urines (24-h): calciuria Every 6 months Renal ultrasound Every other year Pregnancy (dose) 2000 mg/day 1–1.5 mg/day Clinical: weight, mobility, pain Every 3 months divided into two times/day once/day Blood: total calcium, PTH, creatinine, 25-OH Every 3 months vitamin D Urines (24-h): calciuria Every 3 months Menopause (dose) 0–2000 mg/day 0–1.5 mg/day Clinical: weight, mobility, pain, teeth Every year divided into two times/day once/day Blood: bone alkaline phosphatases, total Every year calcium, PTH, creatinine Urines (24-h): calciuria Every 6 months Renal ultrasound Every other year Equivalent dose in calcitriol was obtained divided by a factor 2. implementation of the usage of vitamin D analogs, mineralization and skeletal growth, young adult patients surgical indications have been considerably diminished. with hereditary hypophosphatemia (HH) often stop In our experience, recourse to surgery dropped from 89 to treatment. Lessened parental surveillance, poor taste of 11% when we started to use the modern medical phosphate preparations, and lack of convincing demon- treatment in patients born after 1975. stration of therapeutic benefits in asymptomatic individ- Most hypophosphatemic patients present with uals contribute to the low compliance in (young) adults. increased head length and frontal bossing. Craniosynos- Nevertheless, the metabolic and endocrine consequences tosis and sometimes Chiari malformations giving rise to of chronic phosphate wasting persist life long. Adult headaches and vertigo may also affect patients and require endocrinologist following patients with HH thus necess- neurosurgery when symptomatic. arily faces two key questions: i) whom to treat and ii) what kind of treatment to give? There is no consensus regarding indications of the Therapy in adults treatment in adult patients. It is generally accepted that treatment should be reinitiated (or maintained) in all Metabolism symptomatic patients in order to reduce pain, which may After the years of burdensome therapy over the ‘pediatric’ be duetobonemicrofracturesand/orosteomalacia period, which is essential to ensure adequate bone matrix (25, 45) (Fig. 3). Patients with significant reduction in This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 9–18 3 : R21 Post-operative Post-operative Pre-operative Pre-operative AB C Figure 2 Surgeries in children and adolescents with XLHR. (A) Bilateral lower limbs with XLHR and severe pre-operative deformations impeding joints mal-alignment including distal right femur valgus and proximal left tibia mobility. Recurrence of leg bowing after surgery likely due to compliance varus – pre- and post-operative aspects (distal right femur varization and issues to phosphate and vitamin D analogs. Bilateral medial proximal tibiae proximal left tibia valgization osteotomies). (B) Pre- and post-operative epiphysiodesis inducing varus deformations. radiological aspect of the patient displayed in (A). (C) Eight-year-old girl pain symptoms remain the most compliant. Patients with on health, given the numerous beneficial effects of planed surgical interventions (i.e., corrective osteotomy, vitamin D on metabolism, cardiovascular system, cancer dental implants) should also be temporarily treated to prevention, and immune functions (50).Treatment promote bone mineralization (25). The conventional should be initiated at least in situations of increased treatment in these adult patients is based on oral demands on phosphate and calcium, such as pregnancy, phosphate salts, usually given twice daily, and active to ensure adequate mineralization of the fetal skeleton, vitamin D metabolites. The aim of the treatment is to or lactation, to enable sufficient galactopoiesis, and in improve the symptoms, not to normalize serum phos- both cases to prevent worsening of the phosphate deficit phate levels. Careful monitoring of plasma calcium, PTH, in the maternal organism (51). creatinine, and 24-h urinary calcium excretion is required Conventional medical therapies of FGF23-related (25, 46) in order to prevent tertiary hyperparathyroidism, hypophosphatemic disorders consist in substituting the induced by phosphate overdose (47), and hypercalciuria consequences of the FGF23 excess (46). Nevertheless, with nephrocalcinosis and renal insufficiency, resulting increased FGF23 levels may have deleterious effects on from calcitriol overtreatment (48). In our experience, health per se, especially on metabolism and cardiac tertiary hyperparathyroidism in patients with XLHR is functions (8, 52, 53). New therapeutic approaches target- rare (A Linglart, P Kamenicky, D Prie, A Rothenbuhler, ing FGF23 actions in general, including its impact on unpublished observations) and should be preferentially glucose and lipid metabolism, are very interesting in adult treated surgically, even though beneficial effects of patients with HH, since they frequently present with adjunctive therapy by 24,25-dihydroxyvitamin D has reduced mobility and are thus prone to develop obesity also been reported in one study (49). and metabolic syndrome. Considering the lack of evidence for clinical benefit and the possible side effects, indication of the conven- Rheumatology tional phosphate- and vitamin D analog-based therapy in asymptomatic patients is questionable. Long-term Although disease severity is variable, adults with HR may consequences of chronic hypophosphatemia in adult suffer from osteoarticular symptoms, such as pain and individuals are not known. Chronically decreased 1,25- joint stiffness, leading to disability of physical function diOH-vitamin D synthesis may have a significant impact and poor quality of life (25). The conventional treatment This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 10–18 3 : R22 Figure 3 Various burdens of the disease in adults leading to resume therapy with (D) Dramatic consequences of rickets and osteomalacia in a 30-year-old phosphate supplements and vitamin D analogs. (A) Osteoarthritis of the patient who did not receive vitamin D analogs. Arrows show insufficiency knee in a 28-year-old woman with persistent bone deformities after fractures. Bone demineralization and hip osteoarthritis are visible. adolescence. (B) Spinal enthesopathies of a 35-year-old patient with XLHR. (E) Delayed healing of fibulae fractures in the same patient following (C) Lower limb deformities in a young adult requiring corrective surgery. corrective surgeries on both tibias. with vitamin D analogs and phosphate supplements aims sites. This leads to the formation of enthesophytes in to decrease osteoarticular symptoms and improve physi- fibrocartilaginous tissues, often painful and causing joint cal function. However, only limited data supports the dysfunction. Risk factors associated with the occurrence efficiency of the therapy in adults presenting these of enthesopathy are unknown; vitamin D analogs and complications. Moreover, bone/joint pain may have phosphate supplements do not prevent this complica- different origin such as osteomalacia, insufficiency frac- tion (54). Apart from symptomatic patients at increased tures, osteoarthritis, and enthesopathy (Fig. 3). Identify- risk of insufficiency fractures and osteomalacia, treatment ing the cause of the pain should be considered as the first has been proposed to patients with planed surgical step for the optimal management of osteoarticular interventions (osteotomy, joint replacement) (see symptoms. Osteomalacia and spontaneous insufficiency above). Treatment should be also discussed in asympto- fractures, which occur in the lower extremities of the matic women at the time of menopause, in the absence weight bearing bones, should trigger treatment in adults. of estrogen substitution, to prevent osteomalacia. In In an open-label study conducted in 16 symptomatic addition to the conventional treatment, optimal care adult patients with XLHR, Sullivan et al. (45) showed that of symptomatic patients requires pharmacological and the combination of calcitriol and phosphate supple- non-pharmacological management of pain and joint ments decreases bone pain, increases serum phosphate, stiffness, through appropriated rehabilitation. Individua- and reduces the extent of osteomalacia quantified by pre- lized exercises and adapted physical activity should be and post-treatment bone biopsies. Moreover, insufficiency proposed to improve physical function and reduce the fractures usually heal faster with this conventional metabolic consequences of XLHR. treatment. Despite the mineralization defect, so-called Novel therapies targeting FGF23 actions (see below) osteomalacia, adults with XLHR present with paradoxical are awaited to fulfill the current unmet needs, such as heterotopic ossifications of tendon and ligament insertion diminished motor function or prevention of enthesis This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 11–18 3 : R23 ossification. For the latter, enthesis fibrocartilage cells of extend up to the dentino–enamel junction (64). Exten- Hyp mice (murine homolog of XLHR) specifically express sive enamel cracking and fissuring can be observed on FGFR3 and Klotho, thereby suggesting that FGF23 histologic sections, as well as dentin mineralization inhibition might prevent fibrocartilage ossification (54). defects. Unmerged dentin calcospherites are observed and are separated by large non-mineralized interglobular spaces (66, 67) (Fig. 4F). The endodontic infections Ears are believed to result from rapid dental pulp necrosis, Patients with HR present inconstant and variable hearing a consequence of the abnormal dentin mineralization loss depending on age and cause of phosphate wasting. and enamel cracks that allow invasion of the pulp by Hearing impairment has been described in mouse models oral bacteria (68). and human disorders due to increased FGF23 signaling, The dentin ECM is secreted by odontoblasts which, yet not with primary renal tubular defect. Hearing like osteoblasts, express high levels of proteins involved in difficulties appear during adulthood in treated patients mineral ion homeostasis and in the binding and proteo- with XLHR (55). Patients may have mild-to-severe lytic processing of other proteins and peptides regulating sensorineural hearing loss, affecting mainly low and high mineralization (69, 70). Hence, the abnormal hypo- frequencies (56). Some patients also present with tinnitus phosphatemic dentin contains degraded fragments of and vertigo associated with low frequencies hearing loss noncollagenous phosphorylated matrix proteins includ- similar to that of Menie ` re’s disease (57). X-rays show ing matrix extracellular phosphoglycoprotein (MEPE), generalized osteosclerosis and thickening of the petrous DMP1, and osteopontin (OPN), and particularly peptides bone, with narrowed internal auditory meatus (58).In with the acidic serine- and aspartate-rich motif (ASARM) rodents models mimicking XLHR, mice display variable (71, 72). Interestingly, PHEX is the only known enzyme expressions of deafness, circling behavior, lack of postural capable of cleaving ASARM peptides, whose accumulation reflexes, and cranial dysmorphology (59, 60, 61). Differ- leads to inhibition of mineralization. ently, hearing loss has been reported in HR children with Because the pain and swelling that result from tooth mutations in ENPP1 – as early as 9 days of life – or DMP1 abscesses are usually detected by patients or their families (62, 63). Overall, hearing loss resembling stapes otosclero- and will bring them to consult, much attention has been sis occurs early in life in ARHR patients, while hearing drawn to the dental manifestation of HR. However, it is loss resembling Menie ` re’s disease develops after the becoming clear that their periodontal health is also second decade in XLHR patients. We presently do not affected, especially in adults. Comparing the periodontal know whether phosphate supplements and vitamin D status of ten adults with familial HR with age-matched analogs modify the hearing evolution. controls (73), it was observed that the prevalence of periodontitis was high in hypophosphatemic patients (60% vs 3.6% to 7.3% in controls). Our unpublished data Dental and periodontal defects on the periodontal status of more than 20 consecutive The presence of severe dental manifestations in patients adult patients with HR revealed an increased prevalence with HR resulting either from PHEX mutations or from and severity of periodontitis when compared with age- other causes summarized above, including mutations matched controls, despite a similar gingival inflammation in DMP1 or FGF23, is now well recognized (Fig. 4). (Fig. 3A, D and E). Although, no published studies have The dominant feature is the occurrence of spontaneous explored non-surgical and surgical periodontal treatments infection of the dental pulp tissue, resulting in tooth in adults with low phosphate, we observed a favorable abscesses. In contrast with common endodontic infec- response to these treatments. The importance of the tion, these abscesses develop in teeth without any signs supportive periodontal therapy in these patients cannot of trauma or decay, affecting both the deciduous and be overlooked. One case of implant placement along with permanent dentition (64, 65). Clinically, teeth of guided bone regeneration in a XLH adult patient was patients with HR look normal, complicating the identifi- reported with satisfactory outcomes after 42 months (74). cation of the causal tooth and the diagnosis of the Consistent with constitutional defects of periodontal endodontic origin of the infection. Radiographically, tissues, mice lacking Dmp1 or Phex have a defective the enamel layer appears thinner while the dentin layer alveolar bone and cementum (75, 76). is more radiolucent. Pulp chambers are enlarged, Conventional therapy with vitamin D analogs and resembling taurodontism and prominent pulp horns phosphate supplements has a substantial beneficial This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 12–18 3 : R24 A B R L R L CD F Pulp Predentin Dentin IS IS IS IS 100 µm Figure 4 Dental defects in patients with X-linked hypophosphatemia (XLH). a 6-year-old XLH patient. (E) Alveolar bone loss in a 45-year-old XLH (A) Orthopantomogram of a 35-year-old XLH patient. Note multiple absent patient. (F) Toluidine blue-stained section of a third molar germ of a teeth and endodontic lesions. (B) Orthopantomogram of a 30-year-old XLH 14-year-old female with XLH showing abnormal dentin mineralization. patient that benefited from vitamin D analogs and phosphate supplements Numerous nonmineralized interglobular spaces (IS) are observed between during growth with good compliance. No dental or periodontal defects are unmerged calcospherites in the dentin body (document laboratory EA2496, evident. (C) Intraoral view and corresponding X-ray of an endodontic Dental school University Paris Descartes, France). Asterisks indicate calco- infection (arrows) affecting the intact central right lower incisor in a spherites, single arrow indicates dentin secreting cells, odontoblasts, and 35 year-old XLH patient. (D) Enlarged pulp chambers, prominent pulp double head arrow indicates extent of predentin. horns, radiolucent hypomineralized dentin and endodontic infection in impact on oral health that will depend on the onset, sealing. However, these abscesses, especially those occur- compliance, and duration of the treatment. Missing and ring on primary teeth, spread rapidly in the jawbone and filled teeth index of patients treated since early childhood toothextractionisoften necessary.Preventionof is similar to the index of healthy, age-matched controls abscesses includes sealing the tooth surface (primary and (64) and dentin mineralization of permanent teeth, which permanent teeth) with a dental resin to form a barrier to mineralize after birth, can be rescued by the treatment (77) bacterial penetration (77). For primary teeth, this non- (Figs 4B and 5). The tooth phenotype correlates well invasive and painless approach consists in applying an with the overall bone phenotype and can be used to adhesive system (preferably no rinsing step called ‘self- evaluate the benefits on mineralization of this treatment etching’) and then a light-cured flowable resin. This (68, 78, 79). Future studies will determine the benefit procedure must be repeated regularly (every year) due to of treatment on the periodontal status. gradual wear of the resin until the natural exfoliation of the tooth. In parallel, we recommend rigorous oral hygiene and preventive procedures. Daily use of fluoride Clinical approaches toothpaste adapted to age and regular fluoride varnish Spontaneous dental abscesses can be treated by the applications at the dental chair, considering that conventional endodontic approach, e.g. root canal clean- they present a higher risk of dental infection, is of ing to remove the infected pulp tissues and endodontic utmost importance (80). The orthodontic treatment is This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 13–18 3 : R25 XLH deciduous molar XLH permanent molar A B C 500 µm 50 µm 1 mm XLH permanent molar Control permanent molar DF E Enamel Dentin Pulp 1 mm 2 mm 2 mm Figure 5 Scanning electron microscopy views (documents laboratory EA2496, Dental is abnormally mineralized. (D and E). Permanent third molar of a 15-year school University Paris Descartes, France) of (A) A deciduous molar of a old male patient with XLH who was treated during growth with a good 6-year-old male patient with XLHR, born from a XLH mother, showing that compliance to therapy but a late onset. Remaining calcospherites are the major bulk of dentin (arrow) is abnormally mineralized. (B) At higher observed in the outer part of dentin (full arrow) corresponding to magnification (white rectangle), the dentin appears extremely porous with infancy, whereas good mineralization (dotted arrow) is seen in the inner multiples unmineralized spaces. (C) Permanent molar of an adult XLH part of dentin corresponding to the treatment period. (F) Control patient hich was not treated during growth. All the dentin bulk (arrow) permanent molar. possible (81), especially in teenagers with HR controlled patients, complete absorption and sustained effect on by the conventional treatment since infancy. In our serum phosphate and TmP/GFR beyond 4 weeks upon a Reference Center, this treatment is offered to compliant single s.c. injection (85). A Phase 2 clinical trial is ongoing teenagers under conventional treatment when the wave of in the USA and Canada (86). Two issues may arise with the abscesses occurring in deciduous teeth has ended. long-term use of FGF23 antibody. Firstly, it is likely that the anti-FGF23 antibodies will probably not rescue the direct impact of PHEX deficiency on calcified tissue mineral- Novel therapies ization that depends on MEPE- or OPN-derived ASARM peptides presence in the ECM. Secondly, FGF23 exerts In the recent years, novel strategies that efficiently numerous actions including prevention of ectopic calcifi- manipulate molecular effectors of the mineral metabolism cation through the control of the calcium-phosphate have been described. Several of them aim at inhibiting product. Precise modulation of FGF23 signaling will be downstream FGF23 signaling. Monoclonal FGF23 necessary to avoid off-target actions of FGF23 antibodies. antibodies with neutralizing effect on FGF23 action have Another approach was taken by Goetz et al. (87); they been generated (82). When administered intravenously to showed that a C-terminal fragment of FGF23 competes Hyp mice (murine homolog of XLHR), FGF23 antibodies with the full-length protein for receptor binding, yet normalized phosphatemia, increased levels of 1,25-diOH- without activating downstream signaling. Infusion of this vitamin D, increased the expression of the Npt2a cotran- FGF23 C-tail in normal rats triggered hyperphosphatemia sporter, and tempered the 24-hydroxylase overexpression. and renal phosphate retention. In Hyp mice, serum Repeated injections to juvenile mice promoted growth and phosphate was increased and the fractional excretion of ameliorated mineralization and cartilage development phosphate was decreased compared with control. Despite (83). Multiple injections into adult mice were shown to improve spontaneous motor activity as well as muscle these promising data, there is no information indicating strength (84). These promising data prompted the elabor- a possible clinical transition for this elegant approach ation of a humanized antibody, which showed, in XLH as of today. This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 14–18 3 : R26 The pharmacological inhibition of downstream FGF23 inhibit mineralization (93, 94). In XLHR and ARHR, signaling was also probed using selective pan-specific FGFR ASARM peptides abundance is increased in the ECM of antagonists in Hyp and Dmp1-null mice. Oral adminis- bone and teeth, and probably contributes to the mineral- tration of the small molecule NVP-BGJ398 led to an ization defects that hallmark the disease (64, 72). Counter- improved ion metabolism, restored the structure of the acting ASARM peptides may therefore help in improving mineralization plate and partly corrected the bone growth bone, dental and periodontal features in XLHR and impairment (88). Even if the molecule is already in Phase 1 related diseases. trial in human for cancer therapy, the application to HR will warrant more investigation regarding the selectivity of Conclusion the molecule, notably towards other FGFR-mediated physiological processes beyond phosphate metabolism. Symptoms associated with phosphate wasting result from Noteworthy, parathyroid cells also express the FGF23 FGF23 excessive signaling and accumulation of ASARM receptor. FGF23 represses PTH secretion, but endocrine peptides in bone and dental tissues. Current therapy with feedback loops, while still controversial, have been phosphate supplements and vitamin D analogs partly suggested (89). Normalization of phosphatemia in a TIO correct rickets and osteomalacia. It is obvious that patient after parathyroidectomy has been reported outcomes of therapy are still not optimal and that recently (90), and manipulation of PTH secretion may therapies targeting the pathophysiology of the disease therefore help to counteract downstream effects of are required. Along this line, FGF23 antibodies are very excessive FGF23 on phosphate and vitamin D metabolism. promising but their benefit remains to be investigated In contrast to the above-mentioned strategies that during growth in children with PHEX, FGF23, or DMP1 target either FGF23 or its FGFR/KLOTHO co-receptor in the mutation. kidney, other efforts are directed toward osteocytic targets. Today, and in the future, coordination between The osteocyte is the primary site of production of FGF23 caregivers is required for the optimal treatment of this and hosts PHEX and DMP1 (malfunctioning in XLHR and rare disorder and involves various specialists in pediatric ARHR respectively). Osteocytes express the calcitonin and adult fields. While attention is focused in children on receptor and it was recently reported that a single s.c. legs straightening and growth, adults should be none- administration of calcitonin in one patient affected with theless regularly monitored for the prevention and XLHR results in a decrease in the concentration of FGF23 limitation of bone pain, joint stiffness, and periodontal and increases in phosphatemia and circulating level of inflammation. Extra-osseous issues should be considered calcitriol (85). A Phase 1 study is currently evaluating early in life, as well as audition, sport practice, and glucose repeated daily intranasal calcitonin in XLHR (91). and lipid metabolism, with the help of physiotherapists The identification of a decreased proprotein conver- and nutritionists. In addition, the contribution of tase 2 (PC2) activity in bone cells of Hyp mice (92) provides psychologist and social workers is necessary, especially in another potential curative option. PC2, and its associated patients born before 1970 who did not receive vitamin D chaperone 7B2, were shown to participate in the proteo- analogs and present multiple and sometime devastating lytic regulation of the FGF23 protein expression. When complications. Finally, in the era of globalized communi- hexa-D-arginine (D6R), a PC2 agonist, was administered cation, active networking involving not only reference i.p. into Hyp mice, normalization of 7B2 expression and centers for rare diseases or scientific societies but also concomitant decrease in Fgf23 mRNA was observed. patients organization and biopharmaceutical companies Although only partial reduction in the levels of serum should facilitate the translation of recent discoveries into Fgf23 was noted in D6R-treated animals, bone modeling novel therapies. was restored, phosphatemia was sub-normalized, as were the related markers Npt2a and Cyp27b2 encoding the 24-hydroxylase. Declaration of interest The authors declare that there is no conflict of interest that could be Therapies that would be capable of restoring the perceived as prejudicing the impartiality of the review. bone and tooth mineralization process are also desirable. The SIBLINGs phosphoproteins MEPE, DMP1, and OPN all contain ASARM motifs (reviewed in (2)). Upon proteolytic Funding cleavage orchestrated by PHEX, released phosphorylated This research did not receive any specific grant from any funding agency in ASARM peptides interact with hydroxyapatite crystals and the public, commercial or not-for-profit sector. This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections Review A Linglart et al. Therapy of hypophosphatemia 15–18 3 : R27 13 Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Author contribution statement Takeuchi Y, Fujita T, Fukumoto S & Yamashita T. 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Prolonged high-dose phosphate (doi:10.1086/427956) treatment: a risk factor for tertiary hyperparathyroidism in X-linked 97 Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, hypophosphatemic rickets. Clinical Endocrinology 2003 58 163–168. Waguespack S, Gupta A, Hannon T, Econs MJ et al. FGF-23 in fibrous (doi:10.1046/j.1365-2265.2003.01685.x) Received in final form 2 February 2014 Accepted 18 February 2014 This work is licensed under a Creative Commons http://www.endocrineconnections.org  2014 The authors Attribution 3.0 Unported License. DOI: 10.1530/EC-13-0103 Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 01/31/2022 08:25:39PM via Deepdyve Endocrine Connections

Journal

Endocrine Connections – Bioscientifica

Published: Mar 1, 2014

Keywords: calcium

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