AACE Podcast Episode 73 Summary

Title: Understanding Hypophosphatemia: Recognition, Diagnosis, and Treatment
Date: December 11, 2025
Host: Dr. Steven Pitak
Guests: Dr. Layla Tabatabhai, Dr. Basma Abdulhadi

Episode Overview

This episode offers a comprehensive exploration of hypophosphatemia—a frequently overlooked but clinically significant disorder. The panel of endocrine experts delves into the nuances of recognition, diagnosis, and treatment across age groups and discusses both common and rare causes. They aim to elevate clinical awareness by providing practical diagnostic strategies and insights about modern therapeutic approaches.

Key Discussion Points & Insights

1. Osteoporosis vs. Osteomalacia

• Osteoporosis:
  • Defined as a quantitative bone problem; reduced bone mass with normal mineralization.
• Osteomalacia:
  • A qualitative defect—impaired mineralization, usually due to vitamin D or phosphate deficiency.
  • Presents with bone pain, muscle weakness, and pseudo-fractures (Looser zones).
  • Lab markers: elevated alkaline phosphatase, low phosphate, sometimes low/inappropriately normal 1,25(OH)₂D.
• Quote:
  • “Osteomalacia can bring bone pain, muscle weakness and what we call pseudo fractures, or what's known as Looser zones.” —Dr. Tabatabhai [02:17]

2. Recognizing Hypophosphatemia in Children and Adults

• Children:
  • Symptoms: Growth delay, rickets, lower extremity deformities, dental abscesses (notably in XLH).
• Adults:
  • Symptoms: Diffuse bone pain, proximal muscle weakness, difficulty with stairs/chair, fatigue, pseudo-fractures.
  • Severe cases: Rhabdomyolysis, respiratory muscle weakness, paresthesia, potential cardiac dysfunction.
• Clinical Pearl:
  • “The core message is we'll miss hypophosphatemia if we don't measure phosphate level.” —Dr. Pitak [04:49]

3. Lab Testing and Diagnosis

• Phosphate Testing:
  • Not included in standard BMP or CMP panels.
  • Must be specifically ordered, especially if patient has bone pain, muscle weakness, suspicious fractures, or risk factors (malabsorption, antacids, gastric bypass, recent IV iron).
• Assay Interference:
  • Pseudohypophosphatemia can result from paraproteins/monoclonal gammopathies.
  • “If the number doesn't make sense, you always have to ask the lab for dilution studies, deprotonization or an alternative method of checking the phosphate levels.” —Dr. Abdulhadi [06:22]
• Prodiagnostic Guidance:
  • Always interpret lab findings in context, and correlate with clinical picture and additional labs (alkaline phosphatase, tubular reabsorption, etc.).
  • Always check phosphate alongside vitamin D and PTH in metabolic bone evaluations.

4. Differential Diagnosis of Hypophosphatemia [07:28]

• Three Main Buckets:
  1. Redistribution: (e.g., respiratory alkalosis, insulin therapy, refeeding syndrome, “hungry bone” post-parathyroidectomy)
  2. Decreased Absorption: (GI malabsorption, celiac, IBD, bariatric surgery, phosphate binders, excessive antacids, alcoholism, vitamin D deficiency/resistance)
  3. Increased Urinary Losses (Renal Wasting): (Fanconi, tubular defects, meds like tenofovir/cisplatin, post-transplant, hyperparathyroidism, FGF23-mediated disorders like XLH, TIO, ADHR, ARHR)
• Diagnostic Nugget:
  • “If urinary phosphate excretion is high in the setting of low serum phosphate, then you're looking at renal wasting and FGF 23 mediated causes rise to the top of the differential.” —Dr. Abdulhadi [10:01]

5. Recommended Workup for Suspected Hypophosphatemia [10:16–12:05]

• Initial Labs:
  • Fasting serum phosphate, calcium, creatinine/GFR, alkaline phosphatase, bicarb, 25(OH)D, 1,25(OH)₂D, PTH.
  • Renal phosphate handling: 24-hr urine phosphate or spot urine for fractional excretion/TMP-GFR.
• FGF23 Testing:
  • Measure when TMP/GFR is low and hypophosphatemia is present.
  • “FGF23 decreases renal phosphate reabsorption... suppresses 1 alpha hydroxylase, so lowers 1,25 vitamin D.” —Dr. Abdulhadi [12:31]

6. FGF23-Mediated Disorders and Modern Therapy [12:59 & 15:41]

• Classic Labs:
  • Low serum phosphate, low/inappropriately normal 1,25(OH)₂D, high alkaline phosphatase, and low TMP/GFR.
• Iron Infusions:
  • Ferric carboxymaltose can cause severe hypophosphatemia via increasing FGF23 (enhanced by low weight, baseline low phos, and vitamin D deficiency).
  • Monitor phosphate before and after infusions, especially if symptoms are present.
• X-Linked Hypophosphatemia (XLH):
  • X-linked dominant; presents with short stature, dental abscesses, family history of rickets, leg deformities.
  • Conventional therapy: High-dose phosphate + active vitamin D — high pill burden, risks of hyperparathyroidism, hypercalciuria, nephrocalcinosis.
  • Burosumab:
    • First-line: Anti-FGF23 monoclonal antibody.
    • Improves biochemistry, rickets healing, fracture repair, pain.
    • “Burosumab will raise the serum phosphate and normalize the levels in the vast majority of patients.” —Dr. Tabatabhai [15:41]
    • Do not combine with oral phosphate/calcitriol; specialist management required.

7. Other FGF23-Mediated and Rare Causes [18:38]

• ADHR/ARHR:
  • ADHR: FGF23 mutations (resists cleavage), worsens with iron deficiency.
  • ARHR: DMP1/ENPP1 variants.
  • Genetic testing clarifies the subtype.

8. Tumor-Induced Osteomalacia (TIO) [19:18–21:15]

• Diagnosis:
  • Biochemical: Low phos, low TMP, high FGF23, low/inappropriately normal 1,25(OH)₂D, elevated alk phos.
  • Imaging: MRI/CT of extremities, head/neck, pelvis; Gallium dotatate PET scan most sensitive.
• Treatment:
  • Surgery is curative—serum phosphate normalizes within days post-resection.
  • If tumor is unresectable or occult, Burosumab is an option, as are phosphate/calcitriol or octreotide (if SSTR-positive tumors).
  • Radiation/ablation may be considered.

9. Clinical Checklist & Take-Home Messages [21:26–23:48]

• Stepwise Approach:
  • Order phosphate when indicated (not part of standard lab panels).
  • If low: Work up with alk phos, 25(OH)D, 1,25(OH)₂D, PTH, Ca, Cr.
  • Calculate TMP-GFR/fractional excretion.
  • If renal wasting present, measure FGF23.
  • Use family/story/age/presentation to differentiate XLH vs. TIO.
  • Consider Burosumab for FGF23-mediated disease; if using conventional therapy, monitor for complications.
• Quote:
  • “The single most important actionable message today is to check a phosphate. It's not on the typical chem panel so you have to order it when the story fits.” —Dr. Pitak [23:48]

Notable Quotes & Memorable Moments

• “If you're checking a vitamin D and you're checking a PTH, you must check a phosphate.” —Dr. Tabatabhai [06:53]
• “We don't want to get fixated on a single lab value that contradicts the clinical picture.” —Dr. Tabatabhai [06:53]
• “Burosumab is a first line treatment for children over the age of 6 months who have XLH. And it's also indicated for adults with symptomatic osteomalacia, pseudo fractures or significant pain and functional limitation.” —Dr. Tabatabhai [15:41]
• “We don't stop treating XLH when growth plates are closed. Very, very important to keep treating XLH across the lifespan.” —Dr. Tabatabhai [15:41]

Important Timestamps

| Timestamp | Segment/Topic | |------------|--------------------------------------------------| | 02:17 | Osteoporosis vs. Osteomalacia explained | | 03:42 | Hypophosphatemia in children/adults: Symptoms | | 05:10 | Why phosphate is missed in routine labs | | 06:22 | Assay interference/pseudohypophosphatemia | | 07:28 | Differential diagnosis of hypophosphatemia | | 10:16 | Recommended workup and renal handling | | 12:21 | FGF23 mechanism and approach | | 13:48 | Hypophosphatemia after ferric carboxymaltose | | 15:06 | XLH: Diagnosis and therapy | | 19:18 | Tumor-induced osteomalacia (TIO) diagnosis | | 21:26 | Checklist for clinicians | | 23:48 | Actionable take-home message—always check phosphate |

Summary Table: Clinical Workup for Hypophosphatemia

| Step | Purpose | |--------------------------------------|---------------------------------------| | Order serum phosphate | Not on CMP/BMP—must request separately| | If low: check alk phos, 25D, 1,25D, PTH, Ca, Cr | Initial metabolic bone assessment | | Calculate TMP-GFR/fractional excretion| Assess renal wasting | | Measure FGF23 | If renal loss suspected | | History/family/presentation | Distinguish XLH, TIO, genetic causes | | Imaging (if TIO suspected) | Localize tumor | | Consider Burosumab or conventional Rx | Tailored therapy |

Final Takeaways

• Hypophosphatemia is easy to miss unless actively sought—always order a serum phosphate in the right context.
• A systematic approach—starting with labs and narrowing the differential by assessing renal handling and FGF23—leads to an accurate diagnosis and optimal treatment.
• Modern therapies (e.g., Burosumab) have transformed the outlook for FGF23-mediated hypophosphatemia.
• Ongoing education is critical—always coordinate with multidisciplinary teams for best outcomes, especially in complex cases.

For further episodes and resources, visit AACE.com/podcasts.