Etiology: The parathyroid glands act to maintain a normal circulating calcium concentration. Synthesis and secretion of parathyroid hormone (PTH) are regulated by the parathyroid calcium sensing receptor, which increases PTH in response to hypocalcemia. PTH then has many effects that function to restore the serum calcium concentration. PTH promotes bone resorption to mobilize calcium. In the kidney, PTH upregulates renal 1-α-hydroxylase to produce calcitriol (1,25[OH]₂-vitamin D) which then acts on the gut to absorb calcium. PTH also decreases renal calcium excretion and increases phosphate excretion.

Bone resorption is mediated by multinucleated osteoclasts, which are derived from the monocyte–macrophage lineage. Their development is stimulated by osteoclast differentiation factor that is produced by osteoblasts. Osteoclast differentiation factor (RANK-ligand or RANKL) binds to a cell surface receptor called RANK. PTH has a major role in stimulating osteoclastic bone resorption, probably acting both directly and indirectly through stimulation of RANKL. Calcitriol also stimulates osteoclastic differentiation and function through RANKL, whereas calcitonin transiently inhibits osteoclastic resorption. Activated osteoclasts then form a sealed-off compartment along the resorption surface. Within this localized compartment, bone is dissolved by highly concentrated enzymes in acidified extracellular fluid.

Primary HPTH may be caused by diffuse parathyroid hyperplasia or parathyroid adenoma. Parathyroid adenomas are infrequent in children and are usually associated with multiple endocrine neoplasia (MEN) I. Parathyroid hyperplasia may be seen with MEN II and MEN III.

In secondary HPTH, PTH secretion is increased in response to hypocalcemia. Secondary HPTH is more frequent than primary HPTH in children and most often caused by chronic renal failure. Rickets and some other disorders of calcium metabolism may also cause secondary HPTH. HPTH in children is most often caused by chronic renal failure.

Imaging: PTH stimulation of osteoclasts leads to bone resorption at multiple sites.3–6 The most specific radiographic manifestation of HPTH is subperiosteal resorption, initially seen along the radial aspects of the index and the middle finger middle phalanges (Fig. 141-1). The distal phalangeal terminal tufts are also involved relatively early. With progression, subperiosteal resorption is noted along the ulnar aspects of the phalanges and other bones including the medial aspects of the humeral and femoral necks and the medial aspects of the proximal tibial metaphyses. Although less specific than subperiosteal resorption, HPTH may lead to intracortical resorption, or “tunneling,” causing a striated appearance of the cortex, as well as endosteal, subchondral, and subligamentous resorption (Fig. 141-2). Subphyseal resorption (a form of subchondral resorption) leads to resorption of the zone of provisional calcification and metaphyseal bone beneath the physis, simulating the appearance of rickets. Additional findings of HPTH include resorption of the lamina dura, which forms the thin opaque line surrounding tooth roots (Figs. 141-3 and 141-4), cystic-appearing “brown tumors” (osteoclastomas), and bone sclerosis. Although brown tumors are more characteristic of primary HPTH, overall, they are seen more often in secondary HPTH because it is much more common than primary HPTH in children. Osteosclerosis, most often seen with renal osteodystrophy, may be generalized or most pronounced subjacent to the vertebral end plates, resulting in a “rugger jersey” appearance (Fig. 141-5).

Slipped epiphyses (e-Fig. 141-6) are an important complication of renal osteodystrophy in children, accounting for more cases than other predisposing conditions such as hypothyroidism, hypogonadism, and growth hormone deficiency. Although subphyseal resorption can mimic the radiographic appearance of rickets, the radiolucent material beneath the growth plate is fibrous tissue of osteitis fibrosa cystica, which is weaker than the nonmineralized cartilage and osteoid in true rickets, accounting for slipped epiphyses in renal osteodystrophy but not true rickets. Radiographic findings indicating a particularly high risk of slippage include coxa vara with reorientation of the physis from horizontal toward vertical, increased width of the growth plate, and subperiosteal resorption of the adjacent metaphysis. The risk of epiphyseal slippage is particularly high when growth hormone is used to treat short stature, a major clinical problem in children with chronic renal failure. Although slipped epiphyses are seen most frequently in the proximal femur, many other sites may also be involved.

True rickets and osteomalacia may also be seen from decreased production of calcitriol. It is often not possible to distinguish true rickets from the rachitic appearance of osteitis fibrosa cystica. Looser zones, if present, indicate osteomalacia. Renal osteodystrophy usually manifests a “high turnover” state from HPTH. Less often, an adynamic “low turnover” state may also be seen. Previously, adynamic bone disease was often due to aluminum toxicity, which occurred as a complication of dialysis or aluminum-based phosphate binders. Presently, causes of adynamic bone disease include calcitriol therapy (which suppresses PTH), malnutrition, immobilization, corticosteroid therapy, and prior parathyroidectomy. Fractures may occur in renal osteodystrophy with HPTH predisposing to metaphyseal fractures (e-Fig. 141-7).

Treatment and Follow-up: Treatment of secondary HPTH in children with chronic renal disease is directed toward normalization of mineral metabolism to improve growth, decrease skeletal deformity and fragility, and prevent extraskeletal calcification, most importantly vascular calcification.4,7 Treatment is often initiated at stage 3 chronic renal disease (GFR <60 mL/min/1.73 m²) when positive phosphate balance and calcitriol deficiency appear. Dietary phosphate restriction is often difficult to achieve while maintaining adequate protein intake. Hence, intestinal phosphate binders are used. Although calcium-containing phosphate binders such as calcium carbonate have been used extensively, they pose a risk of hypercalcemia and vascular calcification, particular when used along with calcitriol. Aluminum-containing phosphate binders may cause aluminum bone disease and should be avoided. Sevelamer is a newer phosphate binder that does not contain calcium and has been shown to lower phosphate and control the skeletal lesions of HPTH without the adverse effects on vascular calcification that are seen with calcium-containing binders.

Vitamin D analogs are also important in control of second-degree HPTH, beginning with vitamin D repletion, as many patients are deficient. Additionally, active vitamin D metabolites, most often calcitriol, act to lower PTH both indirectly by increasing intestinal calcium absorption and directly by inhibiting transcription for the gene encoding PTH. The use of calcitriol requires monitoring for hypercalcemia. Hypercalcemia can be managed by decreasing or discontinuing calcium-containing phosphate binders or reducing calcitriol. Specific vitamin D analogs, which lower PTH mostly by inhibiting its gene transcription with relatively little effect on intestinal calcium absorption, are also available. Calcimimetics are allosteric modulators of the parathyroid calcium sensing receptor, which increase the sensitivity of the receptor to calcium. This effectively lowers the level at which the circulating calcium concentration suppresses PTH synthesis and secretion, thereby lowering both calcium and PTH.

Despite medical therapy, parathyroidectomy may still be needed in some patients with renal osteodystrophy and severe HPTH. Documentation of severe HPTH and absence of aluminum accumulation by bone biopsy prior to parathyrodectomy has been suggested. Postoperative hypocalcemia should be expected and managed accordingly.