Why does secondary hyperparathyroidism develop in chronic renal failure? How does this lead to bone disease?
Secondary hyperparathyroidism starts relatively early, when the glomerular filtration rate (GFR) drops below 60 mL/minute, as evidenced by increased levels of PTH and histological changes in bone. As renal function deteriorates, these changes become more dramatic. Several factors in patients with chronic renal failure contribute to the sustained increases in PTH secretion and, ultimately, to parathyroid gland hyperplasia.
- • Relative hyperphosphatemia resulting from impaired renal excretion occurs early and becomes overt as GFR drops to <20 mL/minute.
- • Impaired renal hydroxylation of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (calcitriol) attributable to reduced 1-α hydroxylase activity occurs early even before hyperphosphatemia develops as a result of the diseased kidney parenchyma. This enzyme is further inhibited by hyperphosphatemia and by increased fibroblast growth factor-23 (FGF-23) levels caused by reduced GFR. Notably, 1,25-dihydroxyvitamin D normally inhibits both parathyroid gland growth and PTH secretion; therefore low levels cause secondary hyperparathyroidism.
- • Decreased free calcium owing to poor gastrointestinal (GI) absorption resulting from reduced 1,25-dihydroxyvitamin D levels, skeletal resistance to PTH, and calcium deposition into vasculature, soft tissues, and viscera as a result of high calcium–phosphate product caused by hyperphosphatemia.
- • Insensitivity of the parathyroid gland to the suppressive effects of calcium on PTH secretion.
The end result of each of these defects (high phosphate, reduced calcitriol, and decreased free calcium) is stimulation of the parathyroid chief cell causing a sustained increase in PTH release. This increase in PTH (and FGF-23) is attempting to decrease phosphorous levels by reducing the renal reabsorption of phosphate as well as trying to stimulate 1-α hydroxylase activity. However, as kidney disease worsens and GFR decreases, this becomes ineffective and the resulting high PTH levels stimulate osteoclast activation and rapid bone resorption leading to osteitis fibrosa. This is usually asymptomatic but can be associated with bone pain/tenderness and proximal muscle weakness.
