Targeting Bone Remodeling for the Treatment of Osteoporosis: Summary of the Proceedings of an ASBMR Workshop (2009)

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 its origins in growth.17 The magnitude of the variance 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 its cellular and bone's material composition and structural are by the of osteoblasts into cells. These osteocytes are the matrix by the mineralization of than of in the adult skeleton are and of osteocytes with are through the of bone at the of and the of processes into and are to bone stress into between and with on the bone surface to and are for osteocytes. a is an and has a role in process is a that canonical Wnt signaling by Wnt to the first of and are expressed in osteocytes and play important in through growth is also expressed in osteocytes and is to play an important role in bone can their local by the size of their and the matrix is from of bone matrix and is In the adult osteocytes are and the has than the skeleton. bone remodeling by as a to stress by mechanical stress to bone. studies have or in the skeleton. increase in either size of and/or number of changes the of magnitude of This may in the adult skeleton bone and to increase or bone mass with is an and is expressed in bone and but not in or and are because of by These in and and mass and but energy In of in results in and 2 is change in or Thus, osteoblast or of changes in and that osteoblasts that and is expressed in The is located at where the 2 is In and are in the of its effect on and the regulation of by occurs at in through but not can the of and is the active for the that of In is in These results are with the that from osteoblasts enhances and and that by of remodeling occurs a of of and cells. These play a role in bone turnover, but their function is on the of the skeleton or Because can into osteoblasts or the and at which into a occurs has a area of is the role of For example, in aging and BMD and bone formation is to enhanced the rate of peak trabecular bone is at its in such as can stimulate at the of that into one may from In the is associated with greater bone formation, a more of with not have enhanced whereas of are associated with greater in the by a loss of function in the bone formation is but bone is These that and/or is site and by including the and signaling have to the of and have a for the expression of during of energy of the role of as it to bone remodeling will light on skeletal and may an important for that will the of in osteoclast signaling are and The a a between its membrane and bone matrix a and the of the in which the for resorption of bone are and their the its and at the between the bone calcium matrix and the This a is the site at which an is for of both calcium and the The osteoclast bone and that the and the that are to the are to bone and thus the osteoclasts of are by with that its in with to the of the a signaling with a complex of factors to cause the to from its to its active This of the osteoclast and its to bone. of the in this if or will the osteoclast such that it will be of bone. of osteoclasts is on signaling by and have a for which, with results in their into osteoclasts. This the of osteoblasts that produce both and The same osteoblasts produce a for osteoblasts factors that both stimulate and to osteoclasts. in a bone and bone When or in that with osteoclasts and osteoblasts in the in to each but not in the These studies that osteoblasts the for osteoclasts and must be and active for osteoclasts to in the for The of in bone is caused by their to bone which allows to to the of osteoclasts during The of to bone resorption on their for bone and their effect on osteoclast The is by the a in the of used for the of small for osteoclast function and The of the in the of is for the of and for their more than to and as a have of the may less but is because of increases in to a in in between the are small and on in to bone on the one and their and on the and studies of have that amount of by the skeleton on the rate of bone turnover, and the of the for The of the skeleton to is and of sites is with the used in the treatment of The of from bone is and may be after of The first effect of treatment is the decrease of the rate of bone resorption that is by a decrease of the rate of bone formation caused by the coupling of the two processes and the of a steady state at a rate of bone The of this steady state and on the underlying the and the of of the of the of and of the of skeletal together with the of more that the of at variable have to the of treatment for of a fracture during treatment with associated with absence of in bone have to that some have reduction of bone remodeling on to The mechanism is that remodeling that is to of microdamage has or thus to of fracture The of remodeling in to into the in Thus, the of the increase in bone turnover after and in is not and it can only the skeleton. that the of the effect of not to the increase in bone mass, but caused by reduction in The is whether remodeling or only remodeling, remodeling The to this is whether the effect is during treatment. The thus not to of bone A is that a small of have suppressed remodeling rates in the absence of Thus, in during treatment with the cannot be whether the suppression of remodeling before treatment. experience this is that adult with bone mass, who and are of little These are and there is a to the skeletal of and to so that treatment will be These will not to and in the can be if a small amount of remodeling is by of the is as the of bone in the that not after its by a on available the of associated with for to be between in and in the is and may be The in with with high of is in the of per and on the duration of A number of factors for have including duration of with and The underlying may be related to the reduction in bone remodeling, possible and a effect of on the of mechanisms has to be or may be for the of that of is a to and treatment on a small of of to have and a of that they that for can be by the to which the is The study on on who not have in the reported by are one would by of the effect of to bone In the absence of a this is and may lead and to when the suppressed is for the effect of the studies are needed to define the and factors for the of the of of are a decrease in osteoclast and increase in osteoblast These changes are in in that results in an increase in bone resorption and decrease in bone formation in The production of a number of also increases after of in In postmenopausal women who are with estrogen and have estrogen treatment with either a or to an for in increases in bone is also associated with an increase in production by bone and is associated with an increase in by a rise in bone formation bone formation to bone studies in and in have there are a number of from to For example, whereas is expressed in with of expression in is much more with typically have Thus, of estrogen on bone in may not in of to be related to in the expression of or the which the has on the of its and the of and in a that can with the and for have These estrogen through estrogen or a the has approximately that with the In has a number of and and this can be to such as and available estrogen the of and and and treatment of and of are in phase or and Because the of the estrogen on to a given is different for each and for each is different and to be has a with and the principal for of and distribution properties of different a the magnitude of the biological response by either improving systemic or into important estrogen A focus for in is to that and a tissue in on that estrogen may have in the of that may be in is also an important osteoblast by signaling through their and the in signaling by on osteoclast osteoblasts osteoclast by of and thus can of osteoclast formation. also osteoblast through the function of a of which is a of the Thus, have bone mass because of osteoclast and bone resorption enhanced bone formation. bone formation is at but it may be caused by an by osteoclast or osteoclasts. studies have also an important role for osteoclasts and osteoclast in factors that their function as as including cells. Thus, in with osteoclast in bone and are from there to they to such as and and factors that not only osteoclast formation and but also of also stimulates osteoclasts and osteoclast to produce and the growth growth which increases and is also associated with of expression in osteoblasts needed for bone formation of with growth and Bone and formation and mineralization of an bone matrix by expression through of their cellular which with factors that the activity of and are needed for bone formation. each of osteoblast factors the and their of the of in of and remodeling needed for during bone formation has the of for bone and have for anabolic that will stimulate bone formation. and are with for Wnt in the Wnt in lead to the whereas lead to the high bone mass In the whereas the the for an one of and both of have a more than that both in bone mass Wnt signaling to the of of and of including osteoblast Several Wnt signaling are being in the activity of Wnt of the or and of signaling of are to the first where of the Wnt will be in A is whether will be on the reported of Wnt with This is by that the expression of some of the Wnt such as sclerostin and are to the bone the of Wnt signaling in bone and in Thus, of the Wnt in bone is the most to bone is that the its properties through the Wnt The first of a on the With mechanical is which, in turn, in a by to in osteocytes to and of This results in an change in the expression of including of function. In the to the complex and the and the signaling response to the of in bone is likely to for of to skeletal such as The of mechanical to the skeleton in with may a and means for bone Sclerostin, a of the is as an important of and of PTH. is a of the and is expressed exclusively in osteocytes in bone. the Wnt signaling by to the Wnt and that sclerostin in a to osteoblast Thus, loss of in the high bone mass and In of the to bone bone expression is by and mechanical that lead to bone formation. Thus, of as as of this sclerostin expression in of in osteocytes in is to expression and to the Wnt signaling to a increase in bone expression is also by mechanical this with the of the mechanisms by which and yet to be skeletal for the treatment of by osteocytes. The of is caused by an increase in osteoblast to bone formation and of trabecular and bone. In cancellous bone, increases bone formation as as on to the activates pathways resulting in osteoblast and production and/or of growth of a to the osteoblast number in cancellous also of from the which may the for and of that and to and of may also increase by which this increases osteoblast number and bone formation also in periosteal bone where the of osteoblast is that the of of on osteoblasts at this site is if of osteoblast bone formation in periosteal bone, that and on osteoblast are of and cellular mechanisms underlying the anabolic of may in the of for anabolic The important for osteoclastic resorption and osteoblast are now In the case of bone resorption, the and with from In the case of osteoblast differentiation, they the by the by and the a increase in on the of the there are a number of in bone including the of the mechanisms for of bone remodeling, the mechanisms the from osteoclastic resorption to osteoblast and differentiation, the of the bone formation process and and the mechanisms for the in bone remodeling that occur in the in the coupling of bone formation to bone With of of for are being with and and The of a of in cells. This with that in activity at the to that of the of the with the of the on the membrane surface, the the first only to the in the of the This a to in the for small and some is being with lead the between and with is also being for The change in the by energy For example, different between and with the more These of for the of for The of the as a means of secretion has The is the first to on any the to the signaling response to the thus the for secretion and a of The has in as a treatment of in and in in a to the by as an at the of the The of the calcium to a of The is to a that the of PTH, namely by a and transient increase in The mechanisms by which bone formation be coupled to bone resorption in the remodeling process are the of much A is that growth factors from the bone matrix during resorption to signaling and of bone formation. The osteoclast produce one or more that to the of osteoblast in in which to be of bone, the osteoclasts to be of to bone The to of the anabolic PTH, in which the role of the osteoclast to be important with a effect on the osteoblast. A of and and of production of by in osteoblasts in and in effect on any of the or of to the local associated with in bone. The of sclerostin and associated with its has to concepts of anabolic The role of sclerostin as a of the Wnt signaling has In studies of and sclerostin as an anabolic by bone formation increases in bone formation rates and in of trabecular bone increase in resorption In a single of in postmenopausal to significantly bone formation for and a trend to resorption These may lead to a to anabolic for the skeleton. play an important role in recruitment, and of adult and the same signaling pathways in skeletal with their as and The are for bone formation, and their are by with and a such that when a activates a the to The have to be agents in the adult skeleton and are being used in fracture and and The of at sites to their as systemic but their to increases in bone mass the of their as The of and has given rise to to The increase in of bone formation with is a by resorption The concept has that much of the anabolic is with of formation on by of the entire bone remodeling This concept has to a the anabolic in which first stimulates processes associated with bone formation by bone resorption The time between two has anabolic have to this anabolic and thus to greater of the anabolic properties of PTH. have used an that is on mo a of continuous In this with to the response in terms of increases in bone resorption whereas the of bone formation in which to anabolic have given With estrogen or as the the response to is whereas results with as the have the of or on to When increases in bone formation and in BMD by or greater in who to in with with or with has in and In both the of to the response to or This to by to study with an that not bone remodeling as as the In this of concept with and associated with in BMD than The time of time that and has for the whether an is needed The study of the of anabolic with an Bone of in of The of of of and of of of of of of of for of of of and