Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)

A once-yearly infusion of zoledronic acid during a 3-year period significantly reduced the risk of vertebral, hip, and other fractures. (ClinicalTrials.gov number, NCT00049829.)

P rogress in understanding the pathogenesis of bone fragility is hampered by the inaccessibility of bone for investigation. Bone densitometry is an effective, noninvasive, and quantitative method for the assessment of the risk of fracture, but structures such as the vertebral body are depicted as a twodimensional image -the areal bone mineral density cast by the attenuation of photons by mineral during their passage through bone. Just as the shadow of the earth, cast on the moon, reveals nothing of the topology of the earth's mountain ranges, the densitometric image tells us little about the two properties that determine bone strength: its material composition and its structural design. 1,2 In this review, we define how the composition and structure of bone determine its strength, describe bone modeling and remodeling -the cellular machinery responsible for constructing bone during growth and reconstructing it during adulthood, demonstrate how age-related abnormalities in these processes compromise the composition and structure of bone, and show how the mechanisms underlying the structural decay of bone offer rational approaches to the use of drugs that inhibit bone resorption and stimulate bone formation. Fa br ic a nd S truc t ur e of Bone -Lev er s a nd Spr ingsThe strength of bone is determined by its material composition and structure. 2 Bone must be stiff and able to resist deformation, thereby making loading possible. Bone must also be flexible: it must be able to absorb energy by deforming, to shorten and widen when compressed, and to lengthen and narrow in tension without cracking. If bone is brittle (i.e., too stiff and unable to deform a little), the energy imposed during loading will be released by structural failure -initially by the development of microcracks and then by complete fracture. If bone is too flexible and deforms beyond its peak strain, it will also crack. Bone must also be light to facilitate movement. A unique feature of bone is that it can serve these contradictory needs of stiffness yet flexibility and lightness yet strength. 3 Composition of BoneBone is composed of type I collagen stiffened by crystals of calcium hydroxyapatite. An increase in tissue mineral density increases the stiffness of the fabric but sacrifices flexibility. 2,4 Variations in tissue mineral density affect function. Auditory ossicles are 90 percent mineral, conferring the stiffness essential for the fidelity of sound transmission (like tuning forks). Animal antlers are 40 percent mineral, conferring the flexibility needed to absorb energy during head butting to defeat suitors in mating season. Human bone is about 60 percent mineralized. The composition and degree of collagen cross-linking also influence function. 5-8 The tripleThe New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF VIRGINIA on September 24, 2012. For personal use only. No other uses without permission.