Osteoporosis is defined elsewhere in this issue as a condition of skeletal fragility characterized by reduced bone mass and microarchitectural deterioration of bone tissue with a consequent increase in risk of fracture. Low bone mass is thus visualized as a risk factor for fracture. According to recent World Health Organization (WHO) criteria, the term osteoporosis is also used to designate a bone mass value more than 2.5 standard deviations (SD) below the young adult mean.<sup>17 Kanis J.A., Melton L.J., Christiansen C. , e al. The diagnosis of osteoporosis J Bone Miner Res 1994 ;  9 : 1137-1141  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> The presence of osteoporosis designates both one of the risk factors for fragility and the condition of fragility itself in the same manner as the term hypertension designates both the blood pressure level and the condition of increased risk of untoward vascular events.

Recognition of both sides of this ambivalent definition is important, because, ultimately, the pathophysiology of osteoporosis involves the development of not only low bone mass but of both the other skeletal components of fragility and the extraskeletal factors that lead to fracture. The interplay of the multiplicity of these pathogenetic mechanisms is illustrated in Figure 1, which situates the more important groups of causal factors relative to the undesired outcome, fracture. A consequence of this multifactorial pathophysiology is the realization that a comprehensive approach to prevention must be multifaceted.

Before beginning a systematic survey of pathogenetic factors, it is useful to examine the relative importance of mass and nonmass factors. Although mass is frequently considered to be the most important determinant of fragility, this is probably not correct. Simulations suggest that mass explains less than half of the observed fracture risk,<sup>14 Heaney R.P. Is there a role for bone quality in fragility fractures? Calcif Tissue Int 1993 ;  53 : S3-S5

Cliccare qui per andare alla sezione Riferimenti</sup> and clinical studies have demonstrated that expressed fragility (e.g., in the form of a prior vertebral fracture) is a stronger predictor of future fracture than is low bone mass.<sup>29 Ross P.D., Davis J.W., Epstein R.S. , e al. Pre-existing fractures and bone mass predict vertebral fracture incidence in women Ann Intern Med 1991 ;  114 : 919-923

Cliccare qui per andare alla sezione Riferimenti</sup> The reasons for this nonmass-related fragility are discussed later in this article. Figure 2 illustrates their aggregate importance. Age-specific fracture risk gradients are presented for various values of forearm bone mineral density (BMD). Three features stand out: (1) risk rises with declining bone mass, as expected; (2) risk also rises with age, even when bone mass is held constant; and (3) the gradients are steeper with advancing age, that is, a given deficiency of bone makes a bigger difference in an older person than in a younger one. As Figure 2 also shows, the age effect is actually larger than the bone mass effect.

Age, of course, is a surrogate for a multiplicity of factors. These include the tendency to fall more often; slow postural reflexes which cause a person to fall in such a way as to strike vulnerable bony parts (e.g., falling to the side); loss of soft-tissue protection over bony prominences; the accumulation of bony material with reduced strength, either intrinsically when formed or as a result of unremodeled fatigue damage; and the loss of critical trabecular connectivity.

Several of the other articles in this issue deal with the treatment of low bone mass or the prevention of bone loss. Bone mass, as already noted, is but one of the factors contributing to osteoporosis. Although the primary focus of this article is on pathophysiology, a discussion of preventive approaches for nonmass pathogenetic factors is also included.