# Osteomalacia

Evaluate suspected osteomalacia by separating vitamin D or calcium deficiency from renal phosphate wasting. A low phosphate value requires assessment of renal phosphate handling, vitamin D metabolites, alkaline phosphatase, parathyroid hormone, and targeted evaluation for FGF23-mediated disease or acquired malabsorption.

**Clinical question:** How should clinicians identify the biochemical cause of osteomalacia and direct cause-specific evaluation?

Updated: 2026-09-16T00:29:40.094633+00:00

## What matters in practice
- Do not attribute osteomalacia to vitamin D deficiency without measuring 25-hydroxyvitamin D, phosphate, calcium, alkaline phosphatase, parathyroid hormone, creatinine, and renal phosphate handling. [6][22]
- In hypophosphatemia, a reduced TmP/GFR establishes inappropriate renal phosphate loss and redirects evaluation toward FGF23-mediated and proximal tubular disorders. [6][21]
- Low or inappropriately normal 1,25-dihydroxyvitamin D with hypophosphatemia and renal phosphate wasting supports an FGF23-mediated process; measure FGF23 before treatment when possible. [6][7]
- Adult-onset FGF23-mediated osteomalacia without a lifelong skeletal phenotype should prompt evaluation for tumor-induced osteomalacia, a potentially curable paraneoplastic cause of renal phosphate wasting. [1][7][8]
- For FGF23-mediated disorders, conventional oral phosphate plus active vitamin D can cause gastrointestinal intolerance and renal toxicity; burosumab is an approved targeted therapy for X-linked hypophosphatemia and tumor-induced osteomalacia. [9][14][16]

## Order a mineralization-focused panel before assigning a cause

Use biochemical pattern recognition to decide whether the dominant defect is vitamin D/calcium related or phosphate related.

In adults with bone pain, proximal weakness, insufficiency fractures, or suspected impaired mineralization, obtain serum phosphate, calcium, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and creatinine. Obtain spot urine phosphate, creatinine, and calcium concurrently to calculate tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR) and urinary calcium:creatinine ratio. [6]

An elevated alkaline phosphatase supports active rickets or osteomalacia but is not etiologic. In adults, use bone-specific alkaline phosphatase when available because approximately half of circulating total alkaline phosphatase originates from hepatocytes. Persistently elevated alkaline phosphatase with low urinary calcium is described in undertreated hypophosphatemic rickets or osteomalacia; alkaline phosphatase usually falls and urinary calcium rises with skeletal healing. [6]

Very low 25-hydroxyvitamin D favors nutritional vitamin D deficiency as a mineralization defect. Osteomalacia related to vitamin D deficiency is typically associated with 25-hydroxyvitamin D concentrations below 15 to 30 nmol/L; vitamin D deficiency can cause osteomalacia, muscle weakness, and worsen osteopenia or osteoporosis. [2][22]
- Draw serum phosphate before initiating phosphate replacement when feasible; treatment can obscure the renal phosphate-wasting pattern. [6]
- Interpret alkaline phosphatase with hepatic tests or bone-specific measurement in adults when liver disease is plausible. [6]
- A normal serum calcium does not exclude deficient body calcium stores or nutritional osteomalacia. [11]

*Biochemical patterns that direct the next etiologic step in osteomalacia. [6][7][21][22]*

| Pattern | Discriminating findings | Next action |
| --- | --- | --- |
| Vitamin D-related osteomalacia | Very low 25-hydroxyvitamin D; calcium may not reflect total body calcium stores. [11][22] | Identify deficient intake, malabsorption, or other causes of vitamin D depletion; use the biochemical response to repletion to confirm correction of the mineralization defect. [2][22] |
| Renal phosphate wasting | Hypophosphatemia with reduced TmP/GFR. [6][21] | Determine whether phosphate loss is isolated or accompanied by other tubular losses; then assess the FGF23/1,25-dihydroxyvitamin D pattern. [21] |
| FGF23-mediated phosphate wasting | Reduced TmP/GFR with low or low-normal 1,25-dihydroxyvitamin D; FGF23 is inappropriately elevated in the hypophosphatemic state. [6][7] | Differentiate inherited hypophosphatemic rickets from tumor-induced osteomalacia using age at onset, family history, dental and skeletal phenotype, and tumor-directed evaluation when acquired. [6][7][8] |
| Non-FGF23 proximal tubular disorder | Renal phosphate wasting accompanied by additional tubular losses. [21] | Evaluate the associated proximal tubular abnormalities rather than labeling the disorder as isolated FGF23-mediated osteomalacia. [21] |

## Use TmP/GFR to distinguish renal loss from nonrenal phosphate depletion

A low serum phosphate alone does not establish the mechanism of osteomalacia.

Calculate TmP/GFR from paired serum and spot urine phosphate and creatinine in patients with hypophosphatemia. A low TmP/GFR documents impaired tubular phosphate reabsorption and establishes renal phosphate wasting; this is the pivotal branch point before pursuing FGF23-mediated disorders, inherited phosphate-wasting conditions, or generalized proximal tubular dysfunction. [6][21]

After renal phosphate wasting is documented, determine whether loss is isolated or occurs with other tubular solute losses. Isolated phosphate wasting is compatible with FGF23-mediated disease, whereas associated tubular losses redirect the evaluation to proximal tubular disorders. [21]

Measure 1,25-dihydroxyvitamin D and FGF23 in the untreated state when possible. FGF23 physiologically increases renal phosphate wasting and suppresses active vitamin D; therefore, hypophosphatemia with low-normal 1,25-dihydroxyvitamin D is a characteristic FGF23-excess pattern. FGF23 measurements are most informative before therapy, and assay-specific reference ranges vary substantially. [6][7]
- Do not interpret a low 1,25-dihydroxyvitamin D result in isolation; its diagnostic value is strongest when paired with hypophosphatemia and reduced TmP/GFR. [6][7]
- A low 25-hydroxyvitamin D level does not rule out hypophosphatemic rickets or osteomalacia. [21]
- Use the laboratory-specific FGF23 assay and reference interval; a result must be interpreted relative to the concurrent hypophosphatemia. [6]

*Clinical discriminators after renal phosphate wasting is established. [6][7][18][21]*

| Feature | Inherited FGF23-mediated disease | Tumor-induced osteomalacia | HHRH or other non-FGF23 renal phosphate wasting |
| --- | --- | --- | --- |
| Typical timing | Childhood or longstanding disease, often with family history. [18] | Acquired adult presentation is typical. [1][7][8] | May present with rickets or osteomalacia; nephrolithiasis has been reported in adulthood with HHRH. [21] |
| Renal phosphate handling | Reduced TmP/GFR. [18] | Reduced TmP/GFR. [6][7] | Reduced TmP/GFR. [21] |
| FGF23 and active vitamin D pattern | FGF23 elevation with low-to-normal 1,25-dihydroxyvitamin D. [18] | Hypophosphatemia with low-normal 1,25-dihydroxyvitamin D and tumor-associated FGF23 excess. [7][8] | Genetically distinct renal phosphate wasting; assess urinary calcium and clinical features rather than assuming FGF23 excess. [21] |
| Clinical clues | Rickets, growth impairment, lower-limb deformity, dental abnormalities, and possible craniosynostosis or intracranial hypertension. [4][6] | Progressive bone pain, weakness, fatigue, fragility fractures, height loss, and delayed diagnosis are characteristic. [7] | Bone pain, weakness, pseudofractures, and absence of dental abnormalities are described in HHRH. [21] |

## Differentiate inherited hypophosphatemia from tumor-induced osteomalacia

Age at onset and phenotype determine whether to seek a hereditary disorder or an occult phosphaturic tumor.

A lifelong history of rickets, short stature or growth failure, lower-limb deformity, dental abnormalities, or a family history supports inherited hypophosphatemic disease. The recommended clinical evaluation for X-linked hypophosphatemia includes assessment for rickets, growth failure, dental abnormalities, and craniosynostosis or intracranial hypertension, with radiologic grading of rickets or osteomalacic lesions and biochemical measurement of phosphate handling. [4][6]

Consider tumor-induced osteomalacia in an adult with acquired progressive bone pain, muscle weakness, fatigue, insufficiency or fragility fractures, hypophosphatemia, low TmP/GFR, elevated alkaline phosphatase, and low-normal 1,25-dihydroxyvitamin D. Tumor-induced osteomalacia is a rare paraneoplastic form of renal phosphate wasting caused by FGF23-secreting tumors, which are often small and may produce years of diagnostic delay. [1][7][8]

The key clinical consequence of recognizing tumor-induced osteomalacia is potential cure: complete excision of the responsible tumor is associated with dramatic symptomatic improvement and correction of metabolic abnormalities. Once the biochemical phenotype supports acquired FGF23 excess, shift the workup from empiric supplementation alone to localization and definitive tumor-directed treatment. [7]
- Do not use absence of a visible mass to exclude tumor-induced osteomalacia; the responsible tumors are typically small. [7]
- Document baseline bone pain, weakness, fracture burden, alkaline phosphatase, serum phosphate, and TmP/GFR before definitive treatment to assess biochemical and clinical resolution. [6][7]
- If the phenotype is acquired but no tumor is identified, maintain management of FGF23-mediated phosphate wasting while continuing tumor-directed evaluation. [8][10]

## Treat the cause and monitor biochemical healing

Treatment differs materially between nutritional osteomalacia, inherited FGF23 excess, and tumor-induced osteomalacia.

For nutritional osteomalacia, correct the documented vitamin D and calcium deficit and address the source of deficiency, including malabsorption when present. Nutritional osteomalacia may respond to low doses of calcium and vitamin D, whereas vitamin D deficiency rickets is described as responsive to small vitamin D doses; regimen selection and monitoring should be individualized because the cited literature does not provide a universal adult dosing protocol. [22]

For FGF23-mediated hypophosphatemia, conventional management has used oral phosphate with active vitamin D analogs. This approach may be limited by gastrointestinal intolerance and renal toxicity, can increase FGF23 concentrations, and often does not normalize serum phosphate, leaving persistent skeletal risk. [9]

Burosumab is a monoclonal antibody against FGF23 and is approved for X-linked hypophosphatemia and tumor-induced osteomalacia. It provides a targeted option when these diagnoses are established, including tumor-induced osteomalacia in which a tumor cannot be identified or cannot be definitively treated; its use should be paired with serial biochemical and skeletal assessment. [14][16][17]
- Use alkaline phosphatase as a treatment-response biomarker for active rickets or osteomalacia; declining values support healing, but interpret total alkaline phosphatase cautiously in adults with possible hepatobiliary contribution. [6]
- Monitor serum phosphate and renal phosphate handling during management of phosphate-wasting osteomalacia, because symptom improvement alone does not establish correction of the underlying renal leak. [6][7]
- After complete resection of a tumor-induced osteomalacia lesion, confirm correction with serum phosphate and the previously abnormal metabolic markers rather than assuming cure from surgery alone. [7]

*Cause-directed management priorities in osteomalacia. [6][7][9][14][16][22]*

| Etiology | Definitive priority | Monitoring target or limitation |
| --- | --- | --- |
| Nutritional vitamin D/calcium deficiency | Replace documented vitamin D and calcium deficits and identify the driver of depletion or malabsorption. [22] | Follow biochemical correction and alkaline phosphatase activity; normal calcium alone is not an adequate marker of calcium stores. [6][11] |
| Inherited FGF23-mediated hypophosphatemia | Use disease-specific management; burosumab is approved for X-linked hypophosphatemia. [14][16] | Monitor phosphate, renal phosphate handling, alkaline phosphatase, and skeletal manifestations. [6] |
| Tumor-induced osteomalacia with localized lesion | Pursue complete tumor excision, which can correct metabolic abnormalities and symptoms. [7] | Confirm postoperative normalization of phosphate-related abnormalities and clinical recovery. [7] |
| Tumor-induced osteomalacia without identifiable or treatable tumor | Manage FGF23-mediated hypophosphatemia; burosumab is approved for tumor-induced osteomalacia. [14][16] | Conventional phosphate plus active vitamin D has gastrointestinal and renal toxicity limitations and may not normalize serum phosphate. [9] |

## Escalate acquired renal phosphate wasting to tumor-directed evaluation

The combination of adult onset and FGF23-mediated renal phosphate wasting should not be managed as nutritional deficiency alone.

Obtain radiologic evaluation to identify and grade osteomalacic lesions when the diagnosis is suspected or disease activity must be established. In an adult with biochemical FGF23-mediated phosphate wasting and no childhood phenotype, use the imaging strategy to support localization of an occult phosphaturic tumor rather than to merely document fractures. [6][7][8]

Refer patients with suspected tumor-induced osteomalacia for coordinated endocrine, metabolic bone, and tumor-localization evaluation because complete lesion excision is the intervention linked to correction of the syndrome. Thermal ablation has been reported as a treatment approach for tumor-induced osteomalacia, but complete excision remains the documented curative mechanism in the cited clinical literature. [7][15]

Escalate promptly when progressive weakness, multiple fragility fractures, height loss, or persistent biochemical phosphate wasting is present. These findings are described in delayed tumor-induced osteomalacia and signal ongoing mineralization failure rather than uncomplicated low bone density. [7]
- Use the adult-versus-childhood onset distinction as a localization trigger: acquired FGF23-mediated osteomalacia warrants focused consideration of tumor-induced osteomalacia. [1][7][8]
- Do not substitute osteoporosis terminology for a phosphate-wasting evaluation when alkaline phosphatase is elevated and hypophosphatemia is persistent. [6][7]
- If treatment has already begun, interpret FGF23 cautiously because measurement is most informative in untreated patients. [6]

## Common questions

### Can a normal serum calcium exclude nutritional osteomalacia?

No. Serum calcium is a poor marker of total body calcium status; assess 25-hydroxyvitamin D, parathyroid hormone, alkaline phosphatase, phosphate, and the clinical context rather than using calcium alone. [11][22]

### When should tumor-induced osteomalacia be suspected?

Suspect it in acquired adult hypophosphatemic osteomalacia with reduced TmP/GFR, low-normal 1,25-dihydroxyvitamin D, and an FGF23-excess phenotype, especially with progressive bone pain, weakness, fractures, or height loss. [1][7][8]

## References
1. Tumor-Induced Osteomalacia | Geriatrics - JAMA Network — jamanetwork.com — https://jamanetwork.com/journals/jama/article-abstract/201505
2. Vitamin D Deficiency | New England Journal of Medicine — www.nejm.org — https://www.nejm.org/doi/full/10.1056/NEJMra070553
3. Vitamin D Metabolism in Hypophosphatemic Rickets | JAMA Pediatrics — jamanetwork.com — https://jamanetwork.com/journals/jamapediatrics/fullarticle/510660
4. Burosumab Therapy in Children with X-Linked Hypophosphatemia — www.nejm.org — https://www.nejm.org/doi/full/10.1056/NEJMoa1714641
5. Fibroblast Growth Factor 23 in Oncogenic Osteomalacia and X ... — www.nejm.org — https://www.nejm.org/doi/full/10.1056/NEJMoa020881
6. Clinical practice recommendations for the diagnosis and ... - Nature — www.nature.com — https://www.nature.com/articles/s41581-019-0152-5
7. FGF23 and Phosphate Wasting Disorders | Bone Research — www.nature.com — https://www.nature.com/articles/boneres20139
8. Tumour-induced osteomalacia | Nature Reviews Disease Primers — www.nature.com — https://www.nature.com/articles/nrdp201744
9. A phase 2 trial of burosumab for treatment of fibroblast growth factor-23-mediated hypophosphatemia in children and adults with fibrous dysplasia | Bone Research — www.nature.com — https://www.nature.com/articles/s41413-026-00523-7
10. Burosumab in Unidentifiable Tumor‐Induced Osteomalacia — onlinelibrary.wiley.com — https://onlinelibrary.wiley.com/doi/pdf/10.1002/ccr3.71600
11. Nutritional rickets & osteomalacia — journals.lww.com — https://journals.lww.com/ijmr/fulltext/2020/52040/nutritional_rickets___osteomalacia__a_practical.6.aspx
12. Phosphate, Fractures, and Frustration—A Missed Diagnosis of ... — onlinelibrary.wiley.com — https://onlinelibrary.wiley.com/doi/full/10.1002/ccr3.70790
13. induced osteomalacia - Wiley Online Library — onlinelibrary.wiley.com — https://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fjoim.13593
14. Burosumab, a Transformational Treatment in a Pediatric Patient With ... — academic.oup.com — https://academic.oup.com/jcemcr/article/2/10/luae184/7823785
15. Thermal Ablation for Treating Tumor-induced Osteomalacia in a ... — academic.oup.com — https://academic.oup.com/jcemcr/article/1/4/luad086/7232442
16. Burosumab use in fibroblast growth factor-23-mediated ... — academic.oup.com — https://academic.oup.com/jcemcr/article/4/6/luag086/8670639
17. Burosumab treatment for fibroblast growth factor-23-associated ... — academic.oup.com — https://academic.oup.com/jbmrplus/article/9/9/ziaf125/8212267
18. Familial Hypophosphatemic Rickets - an overview | ScienceDirect Topics — www.sciencedirect.com — https://www.sciencedirect.com/topics/medicine-and-dentistry/familial-hypophosphatemic-rickets
19. Evaluation of Hypophosphatemia: Lessons From Patients With Genetic Disorders - ScienceDirect — www.sciencedirect.com — https://www.sciencedirect.com/science/article/abs/pii/S0272638611014363
20. Intact Fibroblast Growth Factor 23 Concentrations in Hypophosphatemic Disorders - ScienceDirect — www.sciencedirect.com — https://www.sciencedirect.com/science/article/abs/pii/S1530891X23000022
21. Hypophosphatemic rickets : Indian Journal of Endocrinology and Metabolism — journals.lww.com — https://journals.lww.com/indjem/fulltext/2012/16020/hypophosphatemic_rickets.6.aspx
22. Rickets and Osteomalacia - Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism - Wiley Online Library — onlinelibrary.wiley.com — https://onlinelibrary.wiley.com/doi/abs/10.1002/9781119266594.ch89
23. FGF23 and disorders of phosphate homeostasis - ScienceDirect — www.sciencedirect.com — https://www.sciencedirect.com/science/article/abs/pii/S1359610105000031
24. PHEX gene and hypophosphatemia - Kidney International — www.kidney-international.org — https://www.kidney-international.org/article/S0085-2538%2815%2946700-6/fulltext

## Editorial note

Prepared from cited clinical literature using Astra's research workflow. Verify recommendations against current guidance and patient-specific factors.