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Hypophosphataemic rickets/osteomalacia--is there light at the end of the tunnel?

In this issue, Bhansali and colleagues (1) describe the clinical and biochemical presentation and response to treatment in a series of 17 patients with hypophosphataemic rickets/osteomalacia (HRO) whom they had seen over a 7 yr period. As is noted by the authors, the presentation and aetiology are varied. In their situation the presentation is skewed to the adult age range due to patients being seen in an adult endocrinology service, and this might also have influenced the frequency of the various forms of rickets/osteomalacia seen at the clinic compared to the pattern reported from primarily paediatric services. Nevertheless, the paper serves to highlight the range of different aetiologies that make up the syndrome of HRO (Table). It is clear that one of the major role-players in isolated hypophosphataemic rickets is fibroblast growth factor 23 (FGF23).

Since the original description of the role of FGF23 in autosomal dominant hypophosphataemic rickets (ADHR) by Kenneth White and his colleagues some 10 yr ago (2), considerable advances have been made in understanding the role of FGF23 in phosphate homeostasis. The discovery has also led to the establishment of a whole new class of phosphate regulating hormones, the phosphatonins, which may also play varying and complex roles in bone mineralization. The term 'phosphatonin', which refers to a circulating factor that influences and controls renal handling of phosphate, was first coined to describe the then putative circulating factor (hormone) in X-linked hypophosphataemic rickets (XLH) and tumour induced osteomalacia (TIO) which was thought to be responsible for the defect in renal phosphate reabsorption characteristic of the diseases. The most studied of the phosphatonins has been FGF23, which is a member of the FGF family and is secreted by bone forming cells and in particular the osteocyte. The secreted protein of 227 amino acids has a proteolytic cleavage site between [sup.179]Arg and [sup.180]Ser which when cleaved produces inactive fragments. It is a mutation at this cleavage site in ADHR that results in increased circulating levels of FGF23 and consequent osteomalacia/rickets and hypophosphataemia. It appears that a major function of circulating FGF23 is the control of the expression of the renal tubular sodium dependent phosphate co-transporters (NaPi 2a and 2c) and thus renal tubular phosphate reabsorption. FGF23 also suppresses 25-hydroxyvitamin D-1[alpha]-hydroxylase activity and enhances the expression of 24-hydroxylase, which results in the suppression of circulating 1,25-dihydroxyvitamin D concentrations in conditions of FGF23 excess, for example in XLH and TIO. The role of FGF23 in influencing the fluctuations of serum phosphate following meals is unclear. Unlike parathyroid hormone (PTH), which also controls renal phosphate handling through altering the expression of the renal phosphate co-transporters, FGF23 does so as a primary response to changes in serum phosphate rather than in response to changes in serum calcium as in the case of PTH. Another factor regulating FGF23 production and providing a feedback loop is 1,25-dihydroxyvitamin D [[1,25-(OH).sub.2]D]; increased concentrations of which stimulate FGF23 production, which in turn suppresses [1,25(OH).sub.2]D production (3).

There is evidence to suggest that FGF23 acts through the formation of a heterotrimer with Klotho and the FGFR1 receptor (4). Experimental studies have shown that in both Klotho and FGF23 deficient mice, the phenotypes are similar with markedly elevated [1,25-(OH).sub.2]D concentrations, hyperphosphataemia and intravascular and soft tissue calcification. In Klotho null mice, FGF23 concentrations are markedly elevated. Blocking Klotho activity through injecting anti-Klotho antibodies results in a similar phenotype to that of Klotho deletion (4).

Each of the osteomalacic conditions listed in the Table as being associated with FGF23 has elevated FGF23 concentrations which are believed to be responsible for the hypophosphataemia and inappropriately normal or suppressed [1,25-(OH).sub.2]D concentrations, yet there remain a number of unanswered questions in these diseases relating to the mechanisms of FGF23 control and its role in the bone disease. X-linked hypophosphataemic rickets (XLH), which is the commonest of the hypophosphataemic syndromes, is caused by inactivating mutations in the PHEX gene, which result in elevations of FGF23. One of the histologic characteristics of XLH, besides the presence of rickets and osteomalacia, is the finding of peri-osteocytic mineralization defects. Correction of the hypophosphataemia by phosphate supplementation is effective in healing the rickets and variably improving the osteomalacia but the periosteocytic lesions persist, suggesting an intrinsic defect in osteocyte function in XLH (5). Studies conducted in the Hyp mouse model, the murine homologue of XLH, in which bone from affected Hyp mice was transplanted into normal wild type mice, have found evidence that an intrinsic defect in osteoblast and osteocyte function, which results in increased FGF23 production by osteocytes, is responsible for the persistence of osteomalacia despite correction of the hypophosphataemia and almost complete rescue of the rachitic lesions (6). This intrinsic defect in bone forming cells in XLH probably explains the frequently poor response of affected children to the current forms of therapy, the mainstay of which is phosphate supplementation and the provision of [1,25-(OH).sub.2]D to counteract the calcium perturbations caused by phosphate supplementation. In a recently published report of the effect of FGF23 antibodies on the biochemical abnormalities and bone histology of Hyp mice (7), the hypophosphataemia, suppressed [1,25-(OH).sub.2]D and elevated PTH concentrations were corrected. Furthermore, growth was markedly improved as were the growth plate abnormalities and features of osteomalacia. These exciting findings may offer possible avenues for more appropriate pharmacological treatments in the future.

Autosomal recessive hypophosphataemic rickets (ARHR) also provides some insight into FGF23 control and function. The disease is caused by inactivating mutations in dentin matrix protein 1 (DMP1), an extracellular matrix glycoprotein belonging to the SIBLING family of proteins (8). DMP1 is secreted by osteoblasts/osteocytes and localizes to the mineralization front where it acts as a nucleator for mineralization of extracellular matrix. Besides the presence of rickets and osteomalacia, DMP1 deficiency results in elevated concentrations of FGF23, which are responsible for the alterations in phosphate and [1,25-(OH).sub.2]D homeostasis characteristic of ARHR. Studies also suggest that the biochemical abnormalities consequent on the elevation of FGF23 concentrations (and not the direct effect of DMP1 deficiency) are mainly responsible for the growth plate and diffuse osteomalacic lesions seen in ARHR. PHEX, DMP1 and FGF23 are expressed by the osteocyte, but it is unclear how PHEX and DMP1 regulate FGF23 production.

Another member of the SIBLING family that has received considerable attention is matrix extracellular phosphoglycoprotein (MEPE), as it is markedly upregulated in Hyp osteoblasts and is one of the proteins that is secreted in excess from tumours responsible for TIO. Part of the C terminal of MEPE is composed of ASARM (acidic, serine- and aspartic acid-rich motif), which binds avidly to hydroxyapatite when phosphorylated, preventing mineralization, in other words, the ASARM peptide is a minhibin, a factor which inhibits mineralization. It appears that the ASARM peptide may be the substrate for PHEX, which degrades ASARM allowing mineralization to take place (9). Thus in XLH where PHEX is nonfunctional, ASARM peptides accumulate in bone matrix, preventing mineralization from occurring (5). Circulating concentrations of ASARM peptide are increased some five-fold in patients with XLH (10), while MEPE concentrations in normal adult subjects have been found to be age dependent, inversely related to serum PTH and directly correlated to serum phosphate and bone mineral density (11).

Polyostotic fibrous dysplasia or McCune Albright syndrome when associated with skin hyperpigmentation and endocrine dysfunction is another condition associated with elevated FGF23 concentrations. The degree of elevation of FGF23 concentrations is related to the extent of the fibrous dysplasia, which in turn correlates with the degree of hypophosphataemia and the presence and severity of hypophosphataemic rickets (12).

From the above brief outline of the role of FGF23 in the pathogenesis of the various forms of hypophosphataemic rickets/osteomalacia, it is clear that we still have a lot to learn about the control of FGF23 and its role not only in phosphate homeostasis but also in the pathogenesis of the mineralization defects in rickets and osteomalacia. Nevertheless, the discovery of the phosphatonins and minhibins has provided new hope for the more effective management of children and adults with the various forms of HRO syndromes through the development of more appropriate pharmaceutical agents.


(1.) Bhadada SK, Bhansali A, Upreti V, Dutta P, Santosh R, Das S, et al. Hypophosphataemic rickets/osteomalacia: A descriptive analysis. Indian J Med Res 2010; 131 : 399-404.

(2.) White KE, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ.Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Intl 2001; 60 : 2079-86.

(3.) Saito H, Maeda A, Ohtomo Si, Hirata M, Kusano K, Kato S, et al. Circulating FGF-23 is regulated by 1{alpha},25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem 2005; 280 : 2543-9.

(4.) Gattineni J, Baum M. Regulation of phosphate transport by fibroblast growth factor 23 (FGF23): implications for disorders of phosphate metabolism. Pediatr Nephrol 2009 (in press).

(5.) Martin A, David V, Laurence JS , Schwarz PM, Lafer EM, Hedge AM, et al. Degradation of MEPE, DMP1, and release of SIBLING ASARM-peptides (Minhibins): ASARM-peptide(s) are directly responsible for defective mineralization in HYP. Endocrinology 2008; 149 : 1757-72.

(6.) Liu S, Tang W, Zhou J, Vierthaler L, Quarles LD. Distinct roles for intrinsic osteocyte abnormalities and systemic factors in regulation of FGF23 and bone mineralization in Hyp mice. Am J Physiol Endocrinol Metab 2007; 293 : E1636-44.

(7.) Aono Y, Yamazaki Y, Yasutake J, Kawata T, Hasegawa H, Urakawa I, et al. Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/osteomalacia. J Bone Miner Res 2009; 24 : 1879-88.

(8.) Liu S, Zhou J, Tang W, Menard R, Feng JQ, Quarles LD. Pathogenic role of Fgf23 in Dmp1-null mice. Am J Physiol Endocrinol Metab 2008; 295 : E254-61.

(9.) Addison WN, Nakano Y, Loisel T, Crine P, McKee MD. MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: An inhibition regulated by PHEX cleavage of ASARM. J Bone Miner Res 2008; 23 : 1638-49.

(10.) Bresler D, Bruder J, Mohnike K, Fraser WD, Rowe PS. Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets. J Endocrinol 2004; 183 : R1-9.

(11.) Jain A, Fedarko NS, Collins MT, Gelman R, Ankrom MA, Tayback M, et al. Serum levels of matrix extracellular phosphoglycoprotein (MEPE) in normal humans correlate with serum phosphorus, parathyroid hormone and bone mineral density. J Clin Endocrinol Metab 2004; 89 : 4158-61.

(12.) Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest 2003; 112 : 683-92.

John M. Pettifor

MRC Mineral Metabolism Research Unit

Department of Paediatrics

Chris Hani Baragwanath Hospital & the University of the Witwatersrand


South Africa
Table. The various conditions associated with hypophosphataemic
rickets/osteomalacia and possible mechanisms for the

Condition Abnormality

FGF23 related:
 X-linked hypophosphataemic Inactivating mutation of PHEX
 rickets (XLH)
 Autosomal dominant hypophosphataemic Activating mutation of FGF-23
 rickets (ADHR)
 Autosomal recessive Inactivating mutation of DMP1
 hypophosphataemic rickets (ARHR)
 Polyostotic fibrous dysplasia Excessive production of FGF-23
 with or without McCune Albright by the fibrous dysplasia
 syndrome (somatic activating mutation
 in GNAS1 gene)
 Tumour induced rickets/ Excessive production of
 osteomalacia (TIO) phosphatonin (e.g., FGF23,
 FRP4, MEPE) by tumour
 Neurocutaneous syndromes e.g., Excess production of FGF23
 epidermal naevus syndrome
Abnormalities of renal Na
dependent P co-transporter:
 Hereditary hypophosphataemic Inactivating mutation in
 rickets with hypercalciuria SLC34A3 gene
Other defects of renal tubular
 Fanconi syndrome
 Proximal renal tubular acidosis
 Distal renal tubular acidosis

FGF23, fibroblast growth factor 23; PHEX, phosphate regulating gene
with homologies to endopeptidases on the X chromosome; DMP1, dentin
matrix protein 1; FRP4, Frizzled-related protein 4; MEPE, matrix
extracellular phosphoglycoprotein; SLC34A3, type IIc sodium-
phosphate co-transporter
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Title Annotation:Commentary
Author:Pettifor, John M.
Publication:Indian Journal of Medical Research
Article Type:Report
Geographic Code:9INDI
Date:Mar 1, 2010
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