Physiology and pathology of bone remodeling. Cellular basis of bone structure in health and in osteoporosis.

SUMMARY AND CONCLUSIONS Osteoporosis is defined morphologically as a decreased mineralized bone volume (osteopenia) due to a reduced total bone volume. A distinction between total and mineralized bone volumes is important from the point of view of the diagnsois of this disorder, its pathogenesis, and assessment of the efficacy of its treatment. Because the bone modeling process creates a space consisting of evolving remodeling sites that in toto represent a potentially reversible bone tissue deficit, the total bone volume equals the mineralized bone volume plus the bone remodeling space. Under normal circumstances the remodeling space in relation to the total and mineralized bone volume is small; however, under certain conditions it may expand significantly, reducing the volume of mineralized bone tissue on which, among other things, the mechanical competence of the skeleton depends. The reversible expansion of the bone remodeling space at the expense of the mineralized bone volume is usually due to altered dynamics of the individual remodeling units or to an enhanced activation frequency at the bone tissue level. In adults, however, the permanent losses in total and mineralized bone volumes occur because of a negative bone balance in the individual sites of bone turnover. Since methods used for the assessment of the bone volume often measure only the bone mineral content or the volume of mineralized bone tissue they cannot distinguish between the changes in the bone remodeling space and those in total bone volume. Consequently, therapeutic measures that produce a temporary positive balance of mineral and mineralized bone tissue often turn out to be ineffective in the long run because these balances reflect a contraction of the bone remodeling space rather than any true increase in total bone volume. Throughout life the bone marrow cavity expands as a result of the negative bone balance associated with remodeling on the endosteal surface. During the growth period, it is related to the growth of the bone marrow. The relentless, universal age-related bone loss after maturity is caused by a continuation of this process, which becomes uncompensated by longitudinal and transverse bone growth. This age-related bone loss in itself does not constitute a disease. All other causes of pathologic osteoporosis are grafted onto this basic remodeling mechanism. Thus, one can begin to lose bone with less bone accumulated at the time of maturity, or one may lose it faster because of additional factors. Age-related bone loss is accentuated in women following a decline in estrogen secretion at the time of menopause and in both sexes after periods of inactivity or during thyrotoxicosis or other conditions characterized dynamically by a persistently increased bone turnover rate. Clinically, therefore, osteoporosis has two points of reference. In an asymptomatic stage the total bone volume is located somewhere between the norm for age and sex on the one hand and the minimal permissible or volume-related fracture threshold on the other. It becomes symptomatic when the latter is reached. The greater ratio of bone surface to volume in spongy bone as compared with compacta explains why, for the same degree of bone loss on a unit of the endosteal surface, fractures will occur earlier in the vertebrae and distal radius (spongy bone) than in the upper femur (strong cortical component). The negative bone balance within the individual remodeling sites may have various origins, some related to bone cell kinetics and some to the functions of osteoclasts and osteoblasts, each of which, in turn, may have multiple etiologies. At the present, the mode of interaction of etiologic factors with the bone cells is not clear in most instances. Its understanding is necessary, however, for the elaboration of effective prevention and therapy. Prevention aims at building up an adequate bone bank during growth and maintaining it during maturity by limiting excessive losses from the endosteal envelope. The objective of treatment of an established osteoporosis is to increase the total bone volume. This can be achieved by attaining a positive bone balance within the individual remodeling sites. Such therapy may be more effective before any permanent loss of structure associated with the loss of total bone volume (loss of trabeculae) occurs because, although the total bone volume may increase by effective therapy, the optimal structural reconstruction cannot be achieved. In other words, a factor that may contribute to the positive bone balance during the skeleton's development and growth (calcium, estrogen) and to its maintenance subsequently will be much less effective in restoring the bone volume when substantial loss with its associated structural components has already occurred. There are some indications that the bone fragility observed in the aging population may not result from osteoporosis alone. A decreased bone turnover rate and accumulation of microdamage may compound it. On the other hand, a certain proportion of aging patients exhibit a superimposed mild osteomalacia or osteitis fibrosa due to secondary hyperparathyroidism. Although not necessarily related etiologically to the osteoporosis per se, such factors may predispose to fractures by further reducing the mineralized bone volume. In these patients treatment of only the osteoporosis may not be sufficient. Finally, there are some indications that the increasing incidence of fractures in the aging population is not only due to the increased bone fragility, but also to the decreased muscular strength and impaired neuromuscular stability predisposing to falling and trauma. Again, in such cases, exclusive preoccupation with osteoporosis will not constitute an adequate therapy.