High-yield overview
X-Linked Hypophosphataemia (XLH) and Tumour-Induced Osteomalacia (TIO)
Excess FGF23The shared mechanism
Phosphate wastingLow phosphate, low/normal 1,25-vitD
BurosumabAnti-FGF23 antibody
TIO = resectTumour removal is curative
The two FGF23 disorders
X-linked hypophosphataemia (XLH)
PatternINHERITED (PHEX gene, X-linked dominant); the commonest heritable rickets. Childhood rickets/bowing/short stature, dental abscesses, enthesopathy; adult osteomalacia/pseudofractures.
Treatment
Tumour-induced (oncogenic) osteomalacia (TIO)
PatternACQUIRED, paraneoplastic - a usually small benign PHOSPHATURIC MESENCHYMAL TUMOUR secretes FGF23; adult-onset osteomalacia, bone pain, weakness, fractures; CURED by tumour resection.
Treatment
Shared biochemistry
PatternLow phosphate with renal phosphate wasting, inappropriately LOW/normal 1,25-vitamin D, NORMAL calcium, NORMAL/high ALP, high FGF23.
Treatment
Critical Must-Knows
- FGF23 is a phosphaturic hormone made by osteocytes; its EXCESS causes RENAL PHOSPHATE WASTING (it downregulates the proximal-tubule sodium-phosphate cotransporters) AND suppresses 1-alpha-hydroxylase, giving an inappropriately LOW (or normal) 1,25-dihydroxyvitamin D - the combination produces HYPOPHOSPHATAEMIA and impaired mineralization (RICKETS in children, OSTEOMALACIA in adults).
- X-LINKED HYPOPHOSPHATAEMIA (XLH) is the commonest heritable form: an X-linked dominant PHEX gene mutation leads to excess FGF23. Children present with RICKETS, lower-limb BOWING (genu varum/valgum), short stature, bone pain, dental abscesses and enthesopathy; adults have osteomalacia, pseudofractures, enthesopathy and early osteoarthritis.
- TUMOUR-INDUCED (ONCOGENIC) OSTEOMALACIA (TIO) is an ACQUIRED paraneoplastic syndrome in which a usually small, benign PHOSPHATURIC MESENCHYMAL TUMOUR secretes FGF23, causing adult-onset osteomalacia with bone pain, muscle weakness and fractures; the great challenge is LOCALISING the small tumour (functional imaging such as 68Ga-DOTATATE PET/CT, octreotide scintigraphy, and selective venous sampling).
- The BIOCHEMISTRY is distinctive: LOW serum PHOSPHATE with renal phosphate wasting (low TmP/GFR, high fractional phosphate excretion), inappropriately LOW or normal 1,25-vitamin D, NORMAL calcium, NORMAL or HIGH alkaline phosphatase (osteomalacia), normal/mildly raised PTH, and elevated FGF23 - importantly the ALP is NOT low (contrast with hypophosphatasia, where ALP is LOW).
- CONVENTIONAL treatment is oral PHOSPHATE supplements plus ACTIVE vitamin D (calcitriol/alfacalcidol), but this is burdensome and risks GI upset, secondary/tertiary hyperparathyroidism and nephrocalcinosis; the targeted therapy BUROSUMAB, a monoclonal antibody against FGF23, addresses the underlying mechanism and is first-line for XLH (children and adults) and for inoperable/metastatic TIO.
- For TIO, complete SURGICAL RESECTION of the FGF23-secreting tumour is the DEFINITIVE, curative treatment (FGF23, phosphate and symptoms normalise); when the tumour cannot be found or resected, burosumab or conventional phosphate/active-vitamin-D therapy is used. Orthopaedic care addresses pseudofractures, deformity (osteotomy timed around medical optimisation) and enthesopathy.
Clinical Pearls
- “XLH (PHEX, inherited) and TIO (FGF23 tumour, acquired) both = EXCESS FGF23 -> renal phosphate wasting + low/normal 1,25-vitD -> rickets/osteomalacia.
- “Biochemistry: LOW phosphate + phosphate wasting + low/normal 1,25-vitD + NORMAL calcium + NORMAL/high ALP + high FGF23 (ALP NOT low - unlike hypophosphatasia).
- “TIO: localise the tumour (68Ga-DOTATATE PET) -> resection is curative. Burosumab (anti-FGF23) is first-line for XLH and inoperable TIO.
Low Phosphate with a NORMAL/High ALP - Think FGF23
FGF23 osteomalacia (XLH/TIO)
Low phosphate + renal phosphate wasting + low/normal 1,25-vitD + NORMAL/high ALP + high FGF23. Treat with phosphate/active vitamin D, burosumab, and (TIO) tumour resection.
Don't confuse with hypophosphatasia
Hypophosphatasia also has a 'hypophosphat-' name but a LOW ALP and is treated with asfotase alfa (and bisphosphonates are contraindicated). (See our Hypophosphatasia topic.)
Mechanism: Too Much FGF23
FGF23 Wastes Phosphate and Blocks Vitamin D Activation
FGF23, secreted by osteocytes, normally keeps phosphate in check; in excess it does two things that cause disease: it downregulates the sodium-phosphate cotransporters in the proximal renal tubule, causing renal phosphate wasting and a low serum phosphate, and it suppresses 1-alpha-hydroxylase, so 1,25- dihydroxyvitamin D is inappropriately low or normal (it should rise in response to low phosphate). The result is chronic hypophosphataemia and a failure of bone mineralization - rickets in the growing child and osteomalacia in the adult. In XLH the FGF23 excess is driven by an inherited PHEX mutation; in TIO it is driven by an FGF23-secreting tumour.
XLH vs TIO & Workup
Inherited Child vs Acquired Adult - and the Tumour Hunt
- XLH: suspect in a child with rickets, lower-limb bowing, short stature, dental abscesses or a family history (X-linked dominant PHEX); confirm with the phosphate-wasting biochemistry and genetics. Adults have osteomalacia, pseudofractures and enthesopathy.
- TIO: suspect in an adult with new, unexplained osteomalacia, severe hypophosphataemia, bone pain, weakness and fractures, and no family history; the tumour is usually a small, benign phosphaturic mesenchymal tumour in bone or soft tissue (often extremities/head and neck) that is hard to find - functional imaging (68Ga-DOTATATE PET/CT, octreotide scintigraphy) and selective venous sampling for FGF23 help localise it.
- Biochemistry (both): low phosphate with renal phosphate wasting (low TmP/GFR, high fractional excretion), inappropriately low/normal 1,25-vitamin D, normal calcium, normal/high ALP, normal/mildly raised PTH, and elevated FGF23 - the normal/high ALP distinguishes these from hypophosphatasia.
- Radiographs show rickets (children: physeal widening/cupping/bowing) or osteomalacia with Looser-zone pseudofractures (adults).
Management
Phosphate/Vitamin D, Burosumab, and Resect the Tumour
- Conventional medical therapy: oral phosphate supplements (divided doses) plus active vitamin D (calcitriol/alfacalcidol) - effective but burdensome, with risks of GI upset, secondary/tertiary hyperparathyroidism and nephrocalcinosis; monitor calcium, PTH and renal tract.
- Burosumab (anti-FGF23 monoclonal antibody): targets the underlying excess FGF23 and is first-line for XLH in children and adults, healing rickets/osteomalacia and improving symptoms; also used for inoperable/metastatic TIO.
- TIO - surgery: complete resection of the FGF23-secreting tumour is definitive and curative - FGF23, phosphate and symptoms normalise; when the tumour cannot be localised/resected, use burosumab or conventional therapy.
- Orthopaedic care: manage pseudofractures, correct deformity (e.g. tibial/femoral osteotomy, timed around medical optimisation to aid union), and address enthesopathy and secondary osteoarthritis; optimise phosphate/vitamin D peri-operatively to support healing.
Find the Tumour - and Don't Mislabel the Biochemistry
In an adult with new osteomalacia and severe hypophosphataemia, actively pursue a hidden FGF23-secreting tumour, because resection is curative and the disease otherwise persists - use functional imaging and venous sampling rather than giving up after negative cross-sectional scans. And be precise with the biochemistry: a LOW phosphate with a normal or high alkaline phosphatase points to an FGF23 disorder, whereas a LOW alkaline phosphatase points to hypophosphatasia - two very different diseases with opposite treatments.
Evidence & Key Studies
Evidence
X-linked hypophosphatemia and tumour-induced osteomalacia in the era of burosumab: a narrative review
Brandi ML, Eller Vainicher C, Fintini D, et al. • Orphanet Journal of Rare Diseases (2025)
Key Findings:
- XLH and TIO are both caused by persistent excess FGF23 leading to renal phosphate wasting and reduced phosphate availability.
- Traditional oral phosphate and active vitamin D have limitations; burosumab directly targets FGF23 and is recommended first-line for XLH (1-17 years and adults).
- For TIO, tumour resection is the definitive treatment (success depends on localisation and surgical expertise), with burosumab or conventional therapy when surgery is not feasible.
Evidence
Burosumab for FGF23-associated hypophosphatemia in fibrous dysplasia/McCune-Albright syndrome
Stelmachowska-Banas M, Cylke-Falkowska K, Zgliczynski W, Bilezikian JP, Misiorowski W • JBMR Plus (2025)
Key Findings:
- FGF23 overproduction can cause hypophosphataemia beyond XLH/TIO - here in fibrous dysplasia/McCune-Albright syndrome.
- Burosumab (anti-FGF23) normalised calcium-phosphate metabolism and markedly reduced alkaline phosphatase, with no further fractures over 24 months.
- Demonstrates the central role of FGF23 and the efficacy of targeting it, while noting more data are needed in non-XLH settings.
Evidence Attribution
According to PubMed, the shared FGF23 mechanism of XLH and TIO, the first-line role of burosumab for XLH and the curative role of tumour resection for TIO come from the cited Brandi review, and the central role of FGF23 and the response to burosumab from the cited Stelmachowska-Banas case. The phosphate-wasting biochemistry, the contrast with hypophosphatasia's low ALP, and the rickets/osteomalacia radiology are standard, well-established teaching. (See also our Hypophosphatasia, Rickets/Osteomalacia and Calcium/Metabolic Bone topics.)
Clinical Decision Scenarios
Practise clinical reasoning and management decisions out loud
Viva scenarioStandard
Clinical prompt
“An adult presents with osteomalacia, bone pain and severe hypophosphataemia with renal phosphate wasting. What is the likely mechanism, what would you look for, and how is it treated?”
Practical approach
An adult with new osteomalacia, bone pain and severe hypophosphataemia due to renal phosphate wasting most likely has an FGF23-mediated disorder, and in an adult with no family history the key diagnosis to pursue is tumour-induced or oncogenic osteomalacia, in which a usually small benign phosphaturic mesenchymal tumour secretes FGF23. FGF23 excess causes renal phosphate wasting by downregulating the proximal-tubule sodium-phosphate cotransporters and suppresses 1-alpha-hydroxylase, so 1,25-vitamin D is inappropriately low or normal, producing hypophosphataemia and impaired mineralization. I would confirm the biochemistry: a low phosphate with renal phosphate wasting shown by a low TmP to GFR ratio and a high fractional excretion of phosphate, an inappropriately low or normal 1,25-vitamin D, normal calcium, a normal or high alkaline phosphatase, and an elevated FGF23 - importantly the alkaline phosphatase is not low, which distinguishes this from hypophosphatasia. I would then hunt for the tumour, because resection is curative, using functional imaging such as 68Ga-DOTATATE PET-CT or octreotide scintigraphy and, if needed, selective venous sampling for FGF23. The definitive treatment is complete surgical resection of the tumour, after which FGF23, phosphate and symptoms normalise; if the tumour cannot be found or removed, I would treat with the anti-FGF23 antibody burosumab or with conventional oral phosphate and active vitamin D, monitoring for hyperparathyroidism and nephrocalcinosis.
Key clinical points
Adult osteomalacia + phosphate wasting + no family history -> tumour-induced (oncogenic) osteomalacia (FGF23)
FGF23 excess -> renal phosphate wasting + low/normal 1,25-vitD -> hypophosphataemia/osteomalacia
Biochemistry: low phosphate, low/normal 1,25-vitD, NORMAL/high ALP, high FGF23 (ALP not low)
Localise the tumour (DOTATATE PET) -> resection curative; otherwise burosumab / phosphate + active vitamin D
Common pitfalls
Mislabelling it as hypophosphatasia (that has a LOW ALP)
Giving up the tumour hunt after negative cross-sectional imaging
Forgetting to monitor for hyperparathyroidism/nephrocalcinosis on conventional therapy
Further questions
“What imaging localises an FGF23-secreting tumour? - 68Ga-DOTATATE PET/CT (+ octreotide scan, venous sampling)”
“What is the curative treatment for TIO? - Complete tumour resection”
Viva scenarioStandard
Clinical prompt
“How does X-linked hypophosphataemia present and how is it managed, and how does the biochemistry differ from hypophosphatasia?”
Practical approach
X-linked hypophosphataemia is the commonest heritable form of rickets, caused by an X-linked dominant PHEX gene mutation that leads to excess FGF23. Children present with rickets, lower-limb bowing such as genu varum or valgum, short stature, bone pain, dental abscesses and enthesopathy, often with a family history, and adults have osteomalacia, pseudofractures, enthesopathy and early osteoarthritis. The biochemistry is that of FGF23 excess: a low phosphate with renal phosphate wasting, an inappropriately low or normal 1,25-vitamin D, normal calcium, a normal or high alkaline phosphatase, and a high FGF23. Management has traditionally been oral phosphate supplements with active vitamin D such as calcitriol, which works but is burdensome and risks secondary or tertiary hyperparathyroidism and nephrocalcinosis, so it needs monitoring; the targeted treatment burosumab, a monoclonal antibody against FGF23, is now first-line for both children and adults and heals the rickets and osteomalacia. Orthopaedically I would manage deformity with osteotomy timed around medical optimisation. The crucial contrast with hypophosphatasia is the alkaline phosphatase: in X-linked hypophosphataemia and the FGF23 disorders the alkaline phosphatase is normal or high, whereas in hypophosphatasia it is characteristically low, and the treatments are opposite - burosumab versus asfotase alfa - so getting the alkaline phosphatase right is essential.
Key clinical points
XLH = X-linked dominant PHEX mutation -> excess FGF23; commonest heritable rickets
Children: rickets/bowing/short stature/dental abscesses; adults: osteomalacia/pseudofractures/enthesopathy
Treat: phosphate + active vitamin D (monitor PTH/nephrocalcinosis); burosumab first-line; osteotomy for deformity
Contrast: FGF23 disorders have NORMAL/high ALP (burosumab); hypophosphatasia has LOW ALP (asfotase alfa)
Common pitfalls
Confusing XLH with hypophosphatasia (ALP normal/high vs low; opposite treatments)
Operating on deformity without optimising phosphate/vitamin D first
Overlooking hyperparathyroidism/nephrocalcinosis from conventional therapy
Further questions
“What gene/inheritance causes XLH? - PHEX, X-linked dominant”
“How does the ALP differ from hypophosphatasia? - Normal/high in XLH/FGF23 disorders vs LOW in hypophosphatasia”
Mnemonics & Memory Aids
Mnemonic
FGF23
F
Phosphate wasting (renal) -> low serum phosphate
G
Gene PHEX (XLH) or tumour (TIO) drives excess FGF23
F
Falls in 1,25-vitamin D (suppressed 1-alpha-hydroxylase)
2
Two diseases: XLH (inherited child) + TIO (acquired adult)
3
Three treatments: phosphate+active vit D, burosumab, tumour resection (TIO)
Hook:FGF23 excess wastes phosphate and lowers active vitamin D.
Mnemonic
ALP TELLS
N
Normal/high ALP + low phosphate = FGF23 disorder (XLH/TIO) -> burosumab
L
LOW ALP + low phosphate = hypophosphatasia -> asfotase alfa (no bisphosphonates)
Hook:Let the ALP tell you: normal/high = FGF23 (XLH/TIO); low = hypophosphatasia.
Exam day cheat sheet
XLH / Oncogenic Osteomalacia - Exam Day Cheat Sheet
Mechanism
- Excess FGF23 -> renal phosphate wasting + suppressed 1,25-vitamin D
- -> hypophosphataemia -> rickets (children) / osteomalacia (adults)
- XLH = PHEX (inherited); TIO = FGF23-secreting tumour (acquired)
Biochemistry
- LOW phosphate + renal phosphate wasting (low TmP/GFR)
- Inappropriately low/normal 1,25-vitD; normal calcium; NORMAL/high ALP; high FGF23
- ALP NOT low (contrast with hypophosphatasia)
Diagnosis
- XLH: childhood rickets/bowing + family history (PHEX) + genetics
- TIO: adult osteomalacia, no family history; localise tumour (68Ga-DOTATATE PET, venous sampling)
- Radiographs: rickets (child) / Looser-zone pseudofractures (adult)
Management
- Conventional: oral phosphate + active vitamin D (monitor PTH/nephrocalcinosis)
- Burosumab (anti-FGF23): first-line for XLH; inoperable TIO
- TIO: tumour resection is curative; osteotomy for deformity (optimise phosphate first)