The prevention and treatment of senile and postmenopausal osteoporosis includes exercise, appropriate calcium and vitamin D intake, and pharmacologic agents that decrease resorption (bisphosphonates). Bisphosphonates reduce osteoclast activity and induce osteoclast apoptosis. Denosumab, an anti-RANKL antibody that blocks osteoclast activation, has shown promise in treating some forms of postmenopausal osteoporosis. The major challenge in pharmacotherapy of osteoporosis has been the inability to uncouple bone formation and resorption. Novel agents are currently undergoing clinical trials in an attempt to overcome this limitation. Although menopausal hormone therapy has been used to prevent fracture, complications, particularly deep venous thrombosis and stroke, have prompted the search for more selective estrogen receptor modulators.
Both rickets and osteomalacia are manifestations of vitamin D deficiency or its abnormal metabolism (detailed in Chapter 8). Rickets refers to the disorder in children, in whom it interferes with the deposition of bone in the growth plates. Osteomalacia is the adult counterpart, in which bone formed during remodeling is undermineralized, resulting in a predisposition to fractures. The fundamental defect is an impairment of mineralization and a resultant accumulation of unmineralized matrix.
Excess production and activity of PTH result in increased osteoclast activity, bone resorption, and osteopenia. Although the entire skeleton is affected, the osteopenia in some bones (e.g., phalanges) is more conspicuous radiographically. Isolated hyperparathyroidism peaks in middle adulthood and slightly earlier if presenting as a component of multiple endocrine neoplasia (MEN, types I and IIA).
As discussed in Chapter 20, PTH plays a central role in calcium homeostasis through the following effects:
Osteoclast activation, increasing bone resorption, and calcium mobilization. PTH mediates the effect indirectly by increased RANKL expression on osteoblasts.
Increased resorption of calcium by the renal tubules.
Increased urinary excretion of phosphates.
Increased synthesis of active vitamin D, 1,25(OH)2-D, by the kidneys, which in turn enhances calcium absorption http://ebooksmedicine.net from the gut and mobilizes bone calcium by inducing RANKL on osteoblasts.
The net result of the actions of PTH is an elevation in serum calcium, which, under normal circumstances, inhibits further PTH production. However, excessive or inappropriate levels of PTH can result from autonomous parathyroid secretion (primary hyperparathyroidism) or can occur in the setting of underlying renal disease (secondary hyperparathyroidism) (see Chapter 20). PTH is directly responsible for the bone changes seen in primary hyperparathyroidism. Abnormalities stemming from chronic renal insufficiency that contribute to bone disease in secondary hyperparathyroidism include inadequate 1,25-(OH)2-D synthesis, hyperphosphatemia, metabolic acidosis, and aluminum deposition in bone (in those undergoing renal dialsysis).
MORPHOLOGYSymptomatic,untreatedprimaryhyperparathyroidismmanifestswiththreeinterrelatedskeletalabnormalities:osteoporosis,browntumors,andosteitisfibrosacystica.Osteoporosisisgeneralized,butismostsevereinthephalanges,vertebrae,andproximalfemur.Osteoclastsmaytunnelintoanddissectcentrallyalongthelengthofthetrabeculae,creatingtheappearanceofrailroadtracksandproducingwhatisknownasdissecting osteitis (
Fig.21.8 ).Themarrowspacesaroundtheaffectedsurfacesarereplacedbyfibrovasculartissue.Thecorrelativeradiographicfindingisadecreaseinbonedensity.