(compact) bone and trabecular (cancellous) bone. More than 80% of the skeleton is
composed of cortical bone, a dense tissue that is 90% calcified. Inorganic and organic
components are both present in bone; the highly dense, crystalline inorganic component
is hydroxyapatite. The principal calcium salt contained in the hydroxyapatite crystalline
lattice is Ca 10 (PO 4 ) 6 (OH) 2. Although primarily an inorganic material, bone is dynamic
in its structure, undergoing a continuous process of resorption and formation.
Approximately 3% of cortical bone is remodeled yearly. Two different cells assist this
remodeling process:osteoblastspermit new bone to be laid down; osteoclastsenable
old bone to be reabsorbed.
A variety of diseases can affect bone and its structure. Paget’s disease, for example, is
a disorder arising from abnormal osteoclasts, characterized by excessive bone resorption
followed by replacement of the normal mineralized bone with structurally weak, poorly
mineralized tissue. However, the most important bone disease is osteoporosis. This is a
skeletal bone disease characterized by microarchitectural deterioration of bony tissue
and loss of bone mass, yielding increased susceptibility to bone fracture and bone
fragility. In the United States, osteoporosis results in 1.5 million bone fractures annually,
with 250,000 of these being hip fractures that sometimes ultimately culminate in patient
death. There is a variety of therapies for the prevention and treatment of osteoporosis.
Bisphosphonates.Bisphosphonates are synthetic compounds designed to function
as mimics of pyrophosphate, in which the oxygen atom in P-O-P is replaced with a car-
bon atom, creating a non-hydrolyzable backbone structure. The bisphosphonates selec-
tively bind to the hydroxyapatite portion of the bone, decreasing the number of sites
along the bone surface at which osteoclast-mediated bone resorption can occur. This
permits the osteoblasts to lay down well-mineralized new bone without competition
from osteoclasts. Clinically employed bisphosphonates include etidronate (8.109), tilu-
dronate (8.110), risedronate (8.111), alendronate (8.112), and pamidronate (8.113).
Inorganic Calcium Salts. Adequate intake of Ca^2 +salts in adolescence and early
adulthood should increase bone mineral density, subsequently, in theory, reducing risk
536 MEDICINAL CHEMISTRY