What causes hypercalcemia in an older adult with Primary Hyperparathyroidism (PHPT) and a history of kidney stones or osteoporosis?

Hypercalcemia in Primary Hyperparathyroidism

In older adults with Primary Hyperparathyroidism (PHPT), hypercalcemia is caused by autonomous overproduction of parathyroid hormone (PTH) from parathyroid adenomas (80% of cases) or hyperplasia, which inappropriately increases calcium reabsorption in the kidneys and mobilizes calcium from bone. 1

Pathophysiologic Mechanism

PTH-mediated hypercalcemia in PHPT operates through three distinct mechanisms:

• Increased renal tubular calcium reabsorption is the primary driver, with PTH directly stimulating calcium retention in the distal tubule despite elevated serum calcium levels 1, 2
• Enhanced bone resorption occurs as elevated PTH removes calcium from bone, leading to osteoporosis and increased fracture risk in this population 1, 3
• Increased intestinal calcium absorption results from PTH-stimulated production of 1,25-dihydroxyvitamin D (calcitriol), which enhances gut calcium uptake 1, 4

Biochemical Hallmark

The diagnostic signature is hypercalcemia with elevated or inappropriately normal PTH levels - this distinguishes PHPT from other causes of hypercalcemia such as malignancy, sarcoidosis, or bone metastases where PTH would be suppressed 1, 5

Underlying Pathology

Single parathyroid adenoma accounts for 80% of PHPT cases in older adults, with the remaining 15-20% due to multigland hyperplasia and less than 1% from parathyroid carcinoma 1, 3

• The adenoma or hyperplastic glands autonomously overproduce PTH that is not downregulated by the calcium-sensing receptor despite hypercalcemia 4
• This autonomous production persists regardless of serum calcium levels, creating a pathologic positive feedback loop 1

Age-Related Considerations

PTH concentrations physiologically increase with age due to declining glomerular filtration rate (GFR), which can complicate diagnosis in older adults 1

• The steady decline in GFR leads to higher baseline PTH concentrations in people over 60 years old 1
• This age-related elevation must be distinguished from pathologic PTH elevation in PHPT 1

Clinical Consequences in This Population

The combination of PHPT with pre-existing kidney stones or osteoporosis represents target organ damage from chronic hypercalcemia:

• Kidney stones and nephrocalcinosis develop from hypercalciuria, as the kidneys attempt to excrete excess filtered calcium despite increased tubular reabsorption 1, 3
• Osteoporosis results from PTH-mediated calcium removal from bone, with the skeleton serving as a calcium reservoir to maintain the elevated serum levels 1, 3
• These complications indicate more severe or longstanding disease and are surgical indications even in otherwise asymptomatic patients 1

Important Diagnostic Pitfalls

Vitamin D deficiency must be excluded before confirming PHPT, as it causes secondary hyperparathyroidism with elevated PTH but normal or low calcium 1, 5

• PTH reference values are 20% lower in vitamin D-replete individuals compared to those with unknown vitamin D status 1, 5
• Secondary hyperparathyroidism from vitamin D deficiency presents with hypocalcemia or normal calcium, not hypercalcemia 5

PTH assay variability can affect interpretation, with measurements varying up to 47% between different assay generations 1, 5

• Use assay-specific reference values and EDTA plasma rather than serum for most stable PTH measurement 1, 5
• Biological variation of PTH is substantial (20% in healthy individuals), so differences must exceed 54% to be clinically significant 5

Cardiovascular Mortality Risk

Adjusted cardiovascular mortality risk is increased almost threefold in individuals with PHPT who do not meet surgical criteria, highlighting the systemic impact of chronic PTH excess beyond calcium and bone 6