What is the most likely diagnosis for a patient presenting with bone pain, proximal muscle weakness, and recurrent fractures, with lab results showing hypocalcemia, severe hypophosphatemia, normal Parathyroid Hormone (PTH) levels, normal Vitamin D levels, and hyperphosphaturia?

Tumor-Induced Osteomalacia

The most likely diagnosis is D. Tumor-induced osteomalacia (TIO), given the constellation of severe hypophosphatemia (0.4 mmol/L), high urinary phosphate excretion, normal PTH, normal vitamin D, and classic symptoms of bone pain, proximal muscle weakness, and recurrent fractures in an adult patient. 1, 2

Diagnostic Reasoning

Why Tumor-Induced Osteomalacia is Most Likely

The biochemical profile is pathognomonic for FGF23-mediated hypophosphatemia:

• Severe isolated hypophosphatemia (0.4 mmol/L) with renal phosphate wasting (high urinary phosphate) indicates inappropriate renal losses rather than nutritional deficiency 1, 2
• Normal PTH levels exclude primary hyperparathyroidism and distinguish this from PTH-mediated causes of hypophosphatemia 1, 3
• Normal vitamin D levels exclude vitamin D deficiency, which would typically present with elevated PTH and low-normal or low calcium 1
• Low-normal calcium is characteristic of TIO, as opposed to the hypercalcemia seen in hyperparathyroidism 2, 4

The clinical presentation strongly supports TIO:

• Bone pain, proximal muscle weakness, and recurrent fractures are the classic triad of TIO 2, 5, 6
• These symptoms reflect progressive osteomalacia from chronic severe hypophosphatemia 2, 6
• TIO typically affects adults with acquired (not congenital) hypophosphatemia 4, 6

Why Other Options Are Excluded

A. Primary hyperparathyroidism is ruled out because PTH is normal, not elevated, and calcium would typically be elevated rather than low-normal 1, 3

B. Vitamin D deficiency is excluded because:

• Vitamin D levels are explicitly normal 1
• Vitamin D deficiency would cause elevated PTH (secondary hyperparathyroidism), not normal PTH 1
• Severe vitamin D deficiency causing osteomalacia presents with low calcium, low phosphate, elevated PTH, and elevated alkaline phosphatase 1

C. Fanconi syndrome is less likely because:

• Fanconi syndrome involves generalized proximal tubular dysfunction, not isolated phosphate wasting 1
• The diagnostic workup should show concurrent glucosuria, aminoaciduria, and low-molecular-weight proteinuria, which are not mentioned 1
• FGF23 levels would be suppressed (low) in Fanconi syndrome, whereas they are elevated or inappropriately normal in TIO 1

E. Osteoporosis is excluded because:

• Osteoporosis does not cause hypophosphatemia or hyperphosphaturia 1
• The severe biochemical abnormalities indicate a metabolic bone disease (osteomalacia), not osteoporosis 2, 6
• Proximal muscle weakness is characteristic of osteomalacia, not osteoporosis 2, 5

Confirmatory Testing Required

To confirm TIO diagnosis, the following tests are essential:

• Serum intact FGF23 measurement: Elevated or inappropriately normal FGF23 (≥30 RU/mL) in the setting of hypophosphatemia confirms FGF23-mediated disease 1, 2, 4
• Calculate TmP/GFR (tubular maximum reabsorption of phosphate per GFR) using spot urine phosphate, creatinine, and serum values to quantify renal phosphate wasting 1, 3
• Measure 1,25-dihydroxyvitamin D: Should be low or inappropriately normal despite hypophosphatemia (FGF23 inhibits 1α-hydroxylase) 1, 2, 4
• Alkaline phosphatase: Typically elevated in active osteomalacia 3, 5
• Exclude Fanconi syndrome by checking urine for glucose, amino acids, and low-molecular-weight proteins 1

Tumor Localization Strategy

Once TIO is biochemically confirmed, systematic tumor localization is critical:

• Start with functional imaging: 18F-FDG PET/CT or 68Ga-DOTATATE PET/CT are first-line for detecting small mesenchymal tumors 2, 4, 6
• Anatomical imaging (MRI or CT) of suspicious areas identified on functional imaging 2, 6
• Selective venous sampling with FGF23 measurement if imaging is non-localizing 2, 6
• Thorough physical examination for palpable soft tissue masses, particularly in extremities 2, 6

Critical Clinical Pitfalls

Delayed diagnosis is extremely common in TIO:

• Patients often suffer for years (average 2.5-5 years) before correct diagnosis due to nonspecific symptoms 6
• The causative tumors are typically small (<3 cm), benign, slow-growing mesenchymal tumors that can occur anywhere in bone or soft tissue 2, 6
• Do not dismiss hypophosphatemia as a laboratory error—persistent hypophosphatemia in an adult with bone pain warrants immediate investigation 4, 6

FGF23 measurement timing matters:

• FGF23 should be measured before initiating phosphate or vitamin D therapy for accurate interpretation 3
• In true hypophosphatemia from other causes, FGF23 should be suppressed (low), not elevated 1

Treatment Approach

Surgical resection is curative when tumor is localized:

• Complete tumor removal results in immediate normalization of phosphate levels and symptom resolution 2, 4, 5
• Post-operative monitoring confirms cure with normalized serum phosphate within days 4, 5

Medical management if tumor cannot be localized or resected:

• Oral phosphate supplementation (divided doses, 4-6 times daily) plus active vitamin D (calcitriol or alfacalcidol) 1, 2
• Monitor for complications: secondary hyperparathyroidism, hypercalciuria, nephrocalcinosis 1, 2
• Novel anti-FGF23 monoclonal antibody therapy (burosumab) is available for refractory cases 1, 2