What is the most likely cause of an elevated parathyroid hormone level with normal serum calcium and low vitamin D, and how should it be managed?

Secondary Hyperparathyroidism Due to Vitamin D Deficiency

This presentation represents secondary hyperparathyroidism caused by vitamin D deficiency, and the primary treatment is vitamin D repletion—not parathyroid surgery or active vitamin D analogs. 1, 2

Understanding the Diagnosis

Elevated PTH with normal calcium and low vitamin D is the classic biochemical signature of secondary hyperparathyroidism due to vitamin D deficiency. 1, 2 This differs fundamentally from primary hyperparathyroidism, where calcium is elevated (or inappropriately normal-high) alongside elevated PTH. 1

Key Diagnostic Features

• Vitamin D deficiency (<20 ng/mL) causes secondary hyperparathyroidism by reducing intestinal calcium absorption, which stimulates compensatory PTH secretion to maintain normal serum calcium. 2, 3
• The parathyroid glands are functioning appropriately—they are responding to the physiologic signal of inadequate calcium availability caused by vitamin D deficiency. 3
• Serum calcium remains normal because the elevated PTH successfully mobilizes calcium from bone and increases renal calcium reabsorption. 1, 3

Critical Distinction from Primary Hyperparathyroidism

• Primary hyperparathyroidism presents with elevated or inappropriately normal PTH in the presence of hypercalcemia (>10.2 mg/dL). 1
• Vitamin D deficiency must be excluded before diagnosing primary hyperparathyroidism, as deficiency causes secondary hyperparathyroidism and can mask hypercalcemia in true primary disease. 1, 4
• In rare cases, primary hyperparathyroidism can coexist with severe vitamin D deficiency, presenting with normal or even low calcium—but this requires parathyroid imaging and surgical confirmation. 5, 4

Treatment Protocol

Step 1: Vitamin D Repletion (Loading Phase)

Initiate ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) 50,000 IU once weekly for 8–12 weeks. 2

• Use 12 weeks for severe deficiency (<10 ng/mL) and 8 weeks for moderate deficiency (10–20 ng/mL). 2
• Cholecalciferol (D3) is preferred over ergocalciferol (D2) because it maintains serum levels longer and has superior bioavailability, particularly with intermittent dosing. 2

Step 2: Ensure Adequate Calcium Intake

Maintain dietary calcium intake of 1,000–1,200 mg daily from food plus supplements if needed. 1, 2

• Calcium supplements should be taken in divided doses of no more than 600 mg at once for optimal absorption. 2
• Total elemental calcium intake should not exceed 2,000 mg/day from all sources. 1

Step 3: Monitoring During Treatment

Recheck 25-hydroxyvitamin D and PTH levels 3 months after completing the loading phase. 2

• The 3-month interval allows vitamin D levels to plateau and PTH to respond, as PTH suppression is delayed. 2, 6
• Measuring earlier will not reflect true steady-state levels and may lead to inappropriate dose adjustments. 2
• Monitor serum calcium and phosphorus at least every 3 months during vitamin D supplementation, and discontinue vitamin D immediately if calcium exceeds 10.2 mg/dL. 2

Step 4: Maintenance Therapy

After achieving target 25(OH)D ≥30 ng/mL, transition to maintenance dosing of 800–2,000 IU daily or 50,000 IU monthly (equivalent to ~1,600 IU daily). 2

• The target 25(OH)D level is ≥30 ng/mL for optimal bone health and fracture prevention. 2
• For elderly patients (≥65 years), a minimum of 800 IU daily is recommended, though 700–1,000 IU daily more effectively reduces fall and fracture risk. 2

Expected Outcomes

PTH levels should normalize or significantly decrease within 3–6 months of vitamin D repletion if secondary hyperparathyroidism was the sole cause. 2, 6

• If PTH remains elevated despite achieving 25(OH)D ≥30 ng/mL and adequate calcium intake, consider alternative diagnoses including normocalcemic primary hyperparathyroidism or chronic kidney disease. 1, 4, 7
• Vitamin D-replete individuals have PTH reference values that are 20% lower than those with unknown vitamin D status. 1

Critical Pitfalls to Avoid

Do Not Use Active Vitamin D Analogs

Never use calcitriol, alfacalcidol, doxercalciferol, or paricalcitol to treat nutritional vitamin D deficiency. 2, 6

• Active vitamin D analogs bypass normal regulatory mechanisms, do not correct 25(OH)D levels, and carry a much higher risk of hypercalcemia. 2, 6
• These agents are reserved for advanced chronic kidney disease (CKD stage 4–5) with impaired 1α-hydroxylase activity and persistently elevated PTH despite nutritional vitamin D repletion. 6

Do Not Pursue Parathyroid Surgery

Parathyroidectomy is not indicated for secondary hyperparathyroidism due to vitamin D deficiency. 1, 6

• Surgery is reserved for primary hyperparathyroidism with hypercalcemia or severe refractory secondary hyperparathyroidism in dialysis patients (PTH >800 pg/mL with hypercalcemia/hyperphosphatemia despite medical therapy). 1, 6

Do Not Ignore Chronic Kidney Disease

Measure serum creatinine and calculate eGFR to exclude chronic kidney disease as a contributor to secondary hyperparathyroidism. 6, 8

• CKD patients (eGFR <60 mL/min/1.73 m²) require modified management, including phosphate control and potentially active vitamin D therapy if PTH remains elevated despite nutritional repletion. 6
• For CKD stages 3–4, use standard nutritional vitamin D (cholecalciferol or ergocalciferol) for deficiency treatment, not active analogs. 2, 6

Verify Compliance and Malabsorption

If PTH fails to normalize after 3–6 months of adequate vitamin D supplementation, verify patient adherence and consider malabsorption syndromes. 2

• Malabsorption conditions (post-bariatric surgery, inflammatory bowel disease, celiac disease, pancreatic insufficiency) may require intramuscular vitamin D or substantially higher oral doses (4,000–5,000 IU daily). 2
• Intramuscular cholecalciferol 50,000 IU results in significantly higher 25(OH)D levels and lower rates of persistent deficiency compared to oral supplementation in malabsorption. 2

Special Consideration: Normocalcemic Primary Hyperparathyroidism

In rare cases, patients may have normocalcemic primary hyperparathyroidism (NPHPT) coexisting with vitamin D deficiency. 4, 7

• NPHPT is defined by persistently elevated PTH with consistently normal albumin-corrected calcium after exclusion of all secondary causes, including vitamin D deficiency (25[OH]D >20 ng/mL). 1, 4
• Vitamin D deficiency can mask hypercalcemia in true primary hyperparathyroidism, leading to underestimation of disease severity. 4
• If PTH remains elevated after achieving 25(OH)D ≥30 ng/mL with adequate calcium intake and normal renal function, refer to endocrinology for evaluation of possible NPHPT. 1, 4
• Some studies suggest that measured free 25(OH)D levels may be low in NPHPT despite normal total 25(OH)D, indicating that some "NPHPT" cases may actually represent secondary hyperparathyroidism. 7