In a dialysis patient with chronic kidney disease (CKD) who has low parathyroid hormone (PTH), what is the clinical significance and how should it be managed?

Clinical Significance of Low PTH in Dialysis Patients

Low PTH in dialysis patients is clinically significant because it indicates adynamic bone disease, which increases hip fracture risk 4-fold, impairs the skeleton's ability to buffer calcium and phosphorus loads, and predisposes to hypercalcemia and vascular calcification. 1

Defining Low PTH in Dialysis

• PTH levels below 150 pg/mL in dialysis patients indicate relative hypoparathyroidism and are associated with adynamic bone disease. 1, 2
• The K/DOQI guidelines recommend maintaining intact PTH between 150-300 pg/mL in Stage 5 CKD patients on dialysis to balance risks of both high-turnover and low-turnover bone disease 2
• A PTH threshold of 60 pg/mL can diagnose low-turnover bone disorders with 70% sensitivity and 87% specificity 2
• PTH values below 100 pg/mL should prompt concern for adynamic bone disease development 1

Pathophysiology and Consequences

Adynamic bone disease represents a state of abnormally low bone turnover where the skeleton loses its normal regulatory function for calcium and phosphorus homeostasis. 1

Bone-Related Complications

• The relatively inert, adynamic bone cannot appropriately modulate calcium and phosphate levels, failing to release or take up calcium normally 1
• This leads to a 4-fold increased risk of hip fractures compared to the general population, with age, dialysis duration, female sex, and diabetes conferring additional risk 1
• Increased risk of vertebral collapse fractures occurs in association with reduced bone density and low PTH values 1

Calcium Dysregulation

• Minimal calcium loading often leads to marked hypercalcemia because the bone cannot buffer calcium appropriately 1
• With impaired bone calcium accretion, other tissues become vulnerable to calcium accumulation in the form of metastatic calcification 1
• Calciphylaxis represents the most dreaded complication, and recent cases are associated with low PTH levels and adynamic bone histology on biopsy 1

Risk Factors for Low PTH

Multiple factors can suppress PTH and contribute to adynamic bone disease beyond just excessive treatment. 1

• Hypercalcemia from any cause suppresses PTH secretion 1
• Increased vitamin D levels (iatrogenic or endogenous) 1
• Diabetes mellitus is independently associated with low PTH 1, 3
• Increasing age predisposes to lower PTH levels 1
• Malnutrition-inflammation complex syndrome (MICS) is an underrecognized cause of low PTH in dialysis patients 4, 3
• History of parathyroidectomy (17.7% of low PTH cases in one series) 5

Association with Malnutrition-Inflammation Complex

Low PTH may represent another facet of the malnutrition-inflammation complex rather than solely indicating adynamic bone disease. 3

• Low serum PTH is associated with markers of protein-energy wasting and inflammation in hemodialysis patients 3
• This association confounds the relationship between serum PTH and alkaline phosphatase 3
• After controlling for malnutrition-inflammation markers, moderately low PTH (100-150 pg/mL) was associated with the greatest survival compared to other PTH levels 3
• The optimal management of hypoparathyroidism associated with MICS is not well established, and it remains unclear whether improving nutritional and inflammatory status will address low PTH levels 4

Management Approach

Step 1: Identify the Cause of Low PTH

Classify low PTH patients into distinct categories to guide appropriate management. 5

• Post-parathyroidectomy (PTX): Younger patients with longer dialysis duration who need calcium and vitamin D to prevent hypocalcemia 5
• Hypocalcemic tendency without PTX: Older women with high comorbidities requiring calcium and vitamin D therapy 5
• Iatrogenic oversuppression: Diabetic patients receiving excessive PTH-lowering treatments (calcium-based binders, vitamin D, cinacalcet) - requires treatment reduction 5
• Endogenous hypercalcemia: Patients with immobilization, cancer, or granulomatosis - may require bisphosphonates 5
• Spontaneous low PTH: Most common (54% of cases), typically older diabetic patients not on PTH-lowering treatments with otherwise normal biochemistry 5

Step 2: Adjust Dialysate Calcium

For patients with PTH <150 pg/mL, reduce dialysate calcium concentration to 1.0-2.0 mEq/L to stimulate PTH secretion and increase bone turnover. 1, 6

• Lower dialysate calcium (1.5-2.0 mEq/L) stimulates PTH and increases bone turnover 1
• The goal is to allow PTH to rise to at least 100 pg/mL to avoid low-turnover bone disease 1
• Monitor carefully to avoid overstimulation - if PTH exceeds 300 pg/mL, dialysate calcium may need adjustment again 1
• Extremely low dialysate calcium (1.0-1.5 mEq/L) should not be prolonged as it leads to marked bone demineralization 1

Step 3: Reduce or Eliminate PTH-Suppressing Medications

Discontinue or reduce calcium-based phosphate binders and vitamin D therapy in patients with adynamic bone disease. 1, 6

• Lower doses of calcium-based phosphate binders or entirely eliminate such therapy 1
• Reduce or discontinue vitamin D sterols 1
• Total elemental calcium intake (dietary plus binders) should not exceed 2,000 mg/day 7
• Only iatrogenic oversuppression (approximately 25% of low PTH cases) requires therapeutic modifications 5

Step 4: Optimize Magnesium Management

Adjust dialysate magnesium concentration based on PTH levels to prevent worsening adynamic bone disease. 6

• For PTH <150 pg/mL, reduce magnesium dialysate to 0.25-0.50 mmol/L 6
• Avoid high magnesium dialysate (>0.75 mmol/L) in patients with PTH <150 pg/mL as it may worsen adynamic bone disease 6
• Monitor magnesium levels every 1-2 months in patients at risk of adynamic bone disease 6

Step 5: Monitor Response

PTH should be measured monthly for at least 3 months after intervention, then every 3 months once stable. 2, 7

• Measure serum calcium and phosphorus at least every 2 weeks for 1 month, then monthly 7
• Interpret PTH as trends rather than isolated values due to assay variability 2
• The target is to allow PTH to rise into the 150-300 pg/mL range 2, 6

Critical Pitfalls to Avoid

Do not attempt to maintain PTH in the "normal" range (<65 pg/mL) in dialysis patients, as this causes adynamic bone disease. 1, 2

• Normal ranges for the general population are inappropriate for CKD patients 1, 2
• Attempting to normalize PTH leads to low bone formation and adynamic bone disease 1
• Stage-specific targets must be used instead of targeting "normal" PTH ranges 7

Do not automatically treat all low PTH cases - approximately 75% do not require therapeutic modifications. 5

• Spontaneous low PTH with normal biochemistry (54% of cases) can be maintained without intervention 5
• Post-PTX and hypocalcemic patients need calcium and vitamin D, not PTH-lowering treatment reduction 5
• Only iatrogenic oversuppression and endogenous hypercalcemia require active treatment changes 5

Do not ignore malnutrition-inflammation complex as a contributor to low PTH. 4, 3

• Low PTH associated with markers of protein-energy wasting and inflammation may not represent true adynamic bone disease 3
• Consider nutritional assessment and inflammatory markers when evaluating low PTH 4, 3
• The relationship between improving nutritional status and PTH levels remains unclear 4

Bone biopsy may be necessary when PTH levels are indeterminate (65-450 pg/mL) to definitively diagnose bone turnover status before initiating vitamin D therapy. 8

• Serum PTH alone cannot predict bone turnover in 30% of hemodialysis and 51% of peritoneal dialysis patients with intermediate PTH values 8
• All patients with PTH within or below normal range have low or normal bone turnover 8
• PTH above 450 pg/mL is 100% specific for high bone turnover in hemodialysis patients 8