What is the recommended treatment for a 14‑year‑old female with markedly elevated alkaline phosphatase, severe 25‑hydroxyvitamin D deficiency, low iron saturation, and low ferritin?

Management of Severe Vitamin D Deficiency with Iron Deficiency and Elevated Alkaline Phosphatase in an Adolescent

This 14-year-old requires immediate high-dose vitamin D repletion (ergocalciferol 50,000 IU weekly for 12 weeks), oral iron supplementation (elemental iron 60-120 mg daily), and close monitoring for rickets/osteomalacia given the constellation of severe vitamin D deficiency (4.2 ng/mL), iron deficiency (ferritin 11, iron saturation 13%), and markedly elevated alkaline phosphatase (451 U/L). 1

Immediate Vitamin D Repletion Protocol

Severe vitamin D deficiency is defined as 25(OH)D levels ≤5 ng/mL, and this patient's level of 4.2 ng/mL places her at high risk for rickets or osteomalacia 1. The elevated alkaline phosphatase (451 U/L) is a critical red flag suggesting active bone disease, as ALP elevation is a hallmark of rickets and osteomalacia 1, 2.

Treatment Regimen

• Ergocalciferol 50,000 IU weekly for 12 weeks, then monthly maintenance 1
• This aggressive dosing is warranted because 25(OH)D levels <5 ng/mL indicate rickets or osteomalacia may be present 1
• After the loading phase, continue monthly 50,000 IU doses to maintain adequate levels 1

Why Ergocalciferol Over Cholecalciferol

• Ergocalciferol (vitamin D2) is the preferred formulation for treating severe deficiency, though doses needed are larger than cholecalciferol 1
• Do not use calcitriol or other 1-hydroxylated vitamin D sterols to treat nutritional vitamin D deficiency 1
• Active vitamin D should only be added if there is evidence of renal phosphate wasting or chronic hypophosphatemia requiring phosphate supplementation 1, 3

Iron Deficiency Management

The combination of ferritin 11 ng/mL and iron saturation 13% confirms iron deficiency anemia 4. Importantly, vitamin D deficiency and iron deficiency frequently coexist, and vitamin D status affects iron recovery 4.

Iron Supplementation Protocol

• Elemental iron 60-120 mg daily (typical adolescent dosing)
• Iron-deficient women with 25(OH)D ≥50 nmol/L (20 ng/mL) show higher increases in transferrin saturation during iron recovery compared to those with 25(OH)D <50 nmol/L 4
• This means correcting vitamin D deficiency will enhance iron repletion efficacy 4

Timing Consideration

• Iron and vitamin D supplements can be given together; there is no contraindication to concurrent administration
• However, phosphate supplements (if needed) must never be given with calcium-containing foods or supplements, as precipitation reduces absorption 1, 3

Critical Monitoring Requirements

Baseline Assessment (Before Treatment)

• Serum calcium and phosphorus to rule out hypocalcemia/hypophosphatemia 1
• Parathyroid hormone (PTH) to assess for secondary hyperparathyroidism 1, 2
• Renal function (eGFR) to guide dosing and monitor for complications 3
• Plain radiographs of wrists/knees if rickets is suspected clinically (bone pain, leg bowing, growth failure) 1

The relationship between vitamin D and PTH is critical: PTH elevation begins when 25(OH)D falls below 34 nmol/L (13.6 ng/mL), and this patient's level of 4.2 ng/mL virtually guarantees secondary hyperparathyroidism 2.

Follow-Up Monitoring

• Repeat 25(OH)D, calcium, phosphorus, and ALP at 4-6 weeks to assess response 3
• Target 25(OH)D level >30 ng/mL (75 nmol/L) for optimal bone health 1
• ALP should normalize as rickets/osteomalacia heals; persistent elevation suggests inadequate treatment 1
• Repeat iron studies (ferritin, iron saturation, hemoglobin) at 4-8 weeks to assess iron repletion 4

When to Add Phosphate Supplementation

Do not start phosphate supplementation empirically in this patient without first checking serum phosphorus levels 3, 5. Phosphate supplementation is only indicated if:

• Serum phosphorus is documented to be low (typically <2.5 mg/dL) 3, 5
• There is evidence of renal phosphate wasting (elevated urinary phosphate with low serum phosphate) 1
• Rickets persists despite adequate vitamin D repletion 1

If Phosphate Supplementation Becomes Necessary

• Initial dose: 20-60 mg/kg/day of elemental phosphorus, divided into 4-6 doses daily 1, 3
• Maximum dose: 80 mg/kg/day to prevent gastrointestinal discomfort and secondary hyperparathyroidism 3
• Phosphate must always be combined with active vitamin D (calcitriol 20-30 ng/kg/day or alfacalcidol 30-50 ng/kg/day) to prevent secondary hyperparathyroidism 1, 3
• Never give phosphate with calcium-containing foods or supplements; separate by several hours 1, 3

Differential Diagnosis Considerations

Nutritional Rickets vs. X-Linked Hypophosphatemia (XLH)

The elevated ALP in the setting of severe vitamin D deficiency most likely represents nutritional rickets/osteomalacia 1, 2. However, consider XLH if:

• Family history of rickets, short stature, or leg deformities 1
• Persistent hypophosphatemia despite vitamin D repletion 1
• Dental abscesses or tooth abnormalities 1
• Leg bowing or skeletal deformities that developed in early childhood 1

If XLH is suspected, genetic testing for PHEX gene mutations and measurement of FGF23 levels are indicated 1.

Secondary Causes to Exclude

• Malabsorption disorders (celiac disease, inflammatory bowel disease, H. pylori gastritis) can impair vitamin D and iron absorption 6, 7
• Renal tubular acidosis can cause osteomalacia with hypophosphatemia and should be considered if metabolic acidosis is present 7
• Chronic kidney disease affects vitamin D metabolism and phosphate handling 1

Common Pitfalls and How to Avoid Them

Pitfall 1: Using Active Vitamin D Instead of Ergocalciferol

• Calcitriol should not be used to treat nutritional vitamin D deficiency 1
• Active vitamin D bypasses the need for 25-hydroxylation but does not replete body stores 1
• Reserve active vitamin D for patients requiring phosphate supplementation or those with CKD 1

Pitfall 2: Inadequate Vitamin D Dosing

• Standard "maintenance" doses (400-800 IU daily) are insufficient for severe deficiency 1
• The 50,000 IU weekly regimen for 12 weeks is necessary to rapidly correct severe deficiency 1

Pitfall 3: Starting Phosphate Without Active Vitamin D

• Phosphate alone promotes secondary hyperparathyroidism and worsens renal phosphate wasting 1, 3
• If phosphate supplementation is needed, always combine with active vitamin D 1, 3

Pitfall 4: Ignoring the Iron-Vitamin D Connection

• Vitamin D deficiency impairs iron recovery; concurrent treatment of both deficiencies is more effective than treating iron alone 4
• Women with adequate vitamin D status show better iron repletion responses 4

Pitfall 5: Insufficient Monitoring

• Weekly monitoring of calcium and phosphorus is essential during the first month of high-dose vitamin D therapy to detect hypercalcemia or hypercalciuria 3, 5
• Failure to monitor can result in nephrocalcinosis, especially if phosphate supplementation is added 3, 5

Expected Clinical Course

• Bone pain and muscle weakness should improve within 4-8 weeks of adequate vitamin D repletion 1, 7
• ALP should begin to decline as rickets/osteomalacia heals, typically normalizing over 3-6 months 1, 3
• Growth velocity may improve if rickets was limiting linear growth 1
• Iron parameters should normalize over 8-12 weeks with adequate supplementation 4

If symptoms persist or ALP remains elevated despite adequate vitamin D and iron repletion, reassess for secondary causes including malabsorption, renal tubular disorders, or genetic phosphate-wasting conditions 1, 7.