Targeting Bone Remodeling for the Treatment of Osteoporosis: Summary of the Proceedings of an ASBMR Workshop

In december 2007, the ASBMR sponsored a Workshop on “Targeted Bone Remodeling for the Treatment of Osteoporosis.” This workshop brought together international thought leaders who convened for 2 days, discussing some of the latest breakthroughs and concepts in one of the most exciting fields of bone biology. Those who contributed to this Workshop through presentations and discussions are listed and acknowledged in the Appendix. Bone loss with aging occurs at most skeletal sites in both sexes. However, the pattern of bone loss, the magnitude, and the underlying cellular mechanisms differ significantly between men and women. In cancellous bone, aging in men is associated with a gradual decline in bone volume. The cellular basis for this decline is not known, with possible explanations being related to defects in osteoblast recruitment, differentiation, and/or function. Trabeculae thin but remain connected to each other.1,2 The result is a reduction in cancellous bone volume with age. The reduction in wall thickness is associated with a decrease in the linear rate of matrix deposition and an increase in duration of the bone formation phase of the remodeling cycle.3 This may be the result of a decrease in the number of osteoblasts and/or in the amount of bone matrix synthesized by each osteoblast. Bone loss in women is more complex and more deleterious to bone strength. Women experience gradual trabecular thinning and bone loss by the same mechanism as men until menopause, when there is an acceleration in the rate of bone loss because of estrogen deficiency. Rapid postmenopausal bone loss is caused by enhanced osteoclastic resorption.4 With the increase in bone turnover rate, the number of active resorption sites per unit time is increased. Enhanced osteoclast activity could also lead to deeper cavities. Trabeculae are perforated and ultimately removed, resulting in a greater age-related loss of trabecular number and connectivity in women than in men.1,5 Bone diameter increases as age advances, but the cortices thin because periosteal apposition is less than ongoing endocortical resorption.6,7 The loss of bone from the endocortical surface is thus not compensated for by periosteal apposition. Whether periosteal apposition is greater in men than in women is uncertain, but if so, the greater peak cross-sectional area and possible greater periosteal apposition would result in greater cross-sectional moment of inertia in men.8 A theoretical construct with which to understand homeostatic forces linking the coupled processes of bone formation and bone resorption is presented here. In the process of bone formation, mineralization, once initiated, is an essentially passive process that extracts calcium from blood flowing past the forming site. Because a single cubic centimeter of bone contains approximately as much calcium as the entire blood volume, mineralization of newly forming bone creates an appreciable hypocalcemic stimulus, which, in the absence of concurrent absorptive input from the gut, evokes secretion of PTH. PTH, in turn, is a principal quantitative determinant of the amount of bone remodeling going on in the total skeleton at any given moment.9 Because the first phase of remodeling is bone resorption, the calcium removed from a remodeling site becomes available to replenish the calcium drawn from the blood stream at formation sites, wherever they may be located in the skeleton. Thus, whether the focus is modeling, as during growth and anabolic therapy, or remodeling, as may be the case for most adult bone turnover, it follows that bone mineralization is the main systemic stimulus for driving bone resorption, altogether apart from, or in addition to, local coupling factors or cross-communication between osteoblasts and osteoclasts. This local coupling is important in determining the sites at which resorption occur, whereas the systemic coupling is important in determining the quantity of resorption/remodeling in the total skeleton. The remodeling transient and the concept of “filling in the remodeling space” are now well-recognized phenomena.10,11 They occur whenever treatment agents alter either bone resorption or bone formation. The typical description of treatment-induced changes in bone mass or density tends to ignore the transient and is reported in terms of rates of change, which, unfortunately, are not time invariant.12 For example, with a resorption suppressive regimen, there will be a short-term rise in measured bone mass, as the cavities excavated before treatment deposit a volume of bone, typically peaking at 6–12 mo into the course of therapy, after which there will be a linear trend of bone mass or density as a function of time. If only the starting and the terminal values are used to define the magnitude of the treatment-induced change, the resulting difference will be a function of the time base, whereas separation of the transient from the post-transient steady state produces a time-invariant result. Not taking the transient into account produces misleading results that cannot easily be pooled across studies of different duration. When the outcome variable of a treatment-related study is BMD or BMC, an adequate description of the effect must have two components: the size of the induced transient and the rate of change in bone balance during the post-transient steady state. These descriptors produce a complete and time-invariant characterization of the effect of treatment. Bone remodeling rate increases when bone is underloaded or overloaded.5 Unloading of bone activates osteoclasts and allows bone remodeling to increase, resulting in bone loss. In overloaded bone, microdamage develops, and this in turn stimulates local removal and replacement of the damaged bone. Mechanical loads cause bone formation at the periosteal surface, which has a disproportionately positive effect on bone strength at an organ level. Thus, it is clear that bone tissue possesses a mechanosensing apparatus that directs osteogenesis to where it is most needed for improving bone strength. Most importantly, tissue added in regions of high mechanical stress provides the most efficient means for improving bone strength. Consequently, small additions (5–8%) of BMD in such efficient distribution caused by mechanical loading can improve bone strength by as much as 64%, increase energy to induce fracture by as much as 94%, and extend bone fatigue life by 100-fold.13 Loading must be dynamic to stimulate bone formation. Static loads have little effect on bone cells. Osteocytes, the most likely sensors of mechanical loads, are visco-elastically coupled to the bone matrix so that their biological response increases with loading rate. Loading must be applied for only a short time to stimulate bone formation. Bone apparently desensitizes to continuous bone loading but, if loading is stopped for a short period, full mechano-sensitivity returns to the bone tissue. Several mechano-transduction pathways in bone are proposed in response to mechanical loading, including membrane ion channels, ATP signaling, prostaglandins, NO, and Wnt signaling. Sclerostin, an inhibitor of canonical Wnt signaling, is almost exclusively expressed by osteocytes. The expression of sclerostin in osteocytes is suppressed 12 h after mechanical loading and is upregulated by unloading. Because suppression of sclerostin production can enhance Wnt signaling that, in turn, enhances osteoblastic bone formation, changes in sclerostin production may play an important role in the regulation of bone formation by mechanical stimuli.14 Bone must be stiff-resistant to deformation, yet sufficiently flexible to absorb energy imposed by loading.15 Because energy cannot be destroyed, if not absorbed, it must be dissipated by structural failure, namely fracture. Bone must also be light to facilitate mobility. These contradictory properties are achieved by bone's material composition and structural design. Material composition is similar in land-dwelling mammals16 Variability in bone strength is largely the result of structural diversity and this structural diversity has in The magnitude of the in such as trabecular or cross-sectional and bone mass are before and not increase as age number to be at the growth of a bone in the number of per unit area of growth is as a bone by the increase in trabecular density is the result of of and not their the difference in starting bone size before and in periosteal apposition in is similar to that in and less to starting Thus, because of their can the amount of bone mass needed for their to of a the mass to also BMD is in as endocortical resorption a a they are more is in more because less endocortical resorption a a to the of in cellular activity at each the periosteal and endocortical the of the The and of two and mass that function more peak loading and are by apposition as trabecular of thickness and forming Thus, and remodeling structural diversity and between and is and mass is only a single for or for The of this to to loads is during but not during aging when changes in cellular and bone's material composition and structural are by the of osteoblasts into cells. 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