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Keywords:

  • coupling;
  • bone resorption;
  • bone formation;
  • osteoclasts;
  • osteoblasts;
  • PTH;
  • ClC-7

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. OSTEOCLAST ACTIVITY IS NOT RESTRICTED TO BONE RESORPTION
  5. BONE FORMATION AND BONE RESORPTION ARE UNCOUPLED IN SOME CASES OF OSTEOPETROSIS
  6. SOME, BUT NOT ALL, OSTEOPETROTIC ANIMAL MODELS EXHIBIT UNCOUPLING
  7. CONTROL OF BONE FORMATION BY THE OSTEOCLASTS
  8. REVERSAL PHASE IS AN IMPORTANT COMMUNICATION STEP BETWEEN OSTEOCLASTS AND OSTEOBLASTS
  9. POTENTIAL FACTORS FROM OSTEOCLASTS MEDIATING SIGNALS TO OSTEOBLASTS
  10. CONCLUSIONS AND FUTURE PERSPECTIVES: CAN THESE NOVEL INSIGHTS AID THE DEVELOPMENT OF NEW ANTIRESORPTIVE STRATEGIES?
  11. REFERENCES

Some osteopetrotic mutations lead to low resorption, increased numbers of osteoclasts, and increased bone formation, whereas other osteopetrotic mutations lead to low resorption, low numbers of osteoclasts, and decreased bone formation. Elaborating on these findings, we discuss the possibility that osteoclasts are the source of anabolic signals for osteoblasts. In normal healthy individuals, bone formation is coupled to bone resorption in a tight equilibrium. When this delicate balance is disturbed, the net result is pathological situations, such as osteopetrosis or osteoporosis. Human osteopetrosis, caused by mutations in proteins involved in the acidification of the resorption lacuna (ClC-7 or the a3-V-ATPase), is characterized by decreased resorption in face of normal or even increased bone formation. Mouse mutations leading to ablation of osteoclasts (e.g., loss of macrophage-colony stimulating factor [M-CSF] or c-fos) lead to secondary negative effects on bone formation, in contrast to mutations where bone resorption is abrogated with sustained osteoclast numbers, such as the c-src mice. These data indicate a central role for osteoclasts, and not necessarily their resorptive activity, in the control of bone formation. In this review, we consider the balance between bone resorption and bone formation, reviewing novel data that have shown that this principle is more complex than originally thought. We highlight the distinct possibility that osteoclast function can be divided into two more or less separate functions, namely bone resorption and stimulation of bone formation. Finally, we describe the likely possibility that bone resorption can be attenuated pharmacologically without the undesirable reduction in bone formation.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. OSTEOCLAST ACTIVITY IS NOT RESTRICTED TO BONE RESORPTION
  5. BONE FORMATION AND BONE RESORPTION ARE UNCOUPLED IN SOME CASES OF OSTEOPETROSIS
  6. SOME, BUT NOT ALL, OSTEOPETROTIC ANIMAL MODELS EXHIBIT UNCOUPLING
  7. CONTROL OF BONE FORMATION BY THE OSTEOCLASTS
  8. REVERSAL PHASE IS AN IMPORTANT COMMUNICATION STEP BETWEEN OSTEOCLASTS AND OSTEOBLASTS
  9. POTENTIAL FACTORS FROM OSTEOCLASTS MEDIATING SIGNALS TO OSTEOBLASTS
  10. CONCLUSIONS AND FUTURE PERSPECTIVES: CAN THESE NOVEL INSIGHTS AID THE DEVELOPMENT OF NEW ANTIRESORPTIVE STRATEGIES?
  11. REFERENCES

Bone is a dynamic tissue, which is continuously remodeled throughout life not only to maintain calcium homeostasis but also to repair microdamage and thus maintain bone quality.(1) This continuous remodeling of bone involves the function of cells that strive to achieve a coordinated and balanced resorption of old bone (osteoclasts) and of those responsible for adequate formation of new bone (osteoblasts), in a local, coordinated and sequential manner referred to as coupling.(2–5)

The coupling process is understood as a bone formation response that results from bone resorption, with an amount of bone formed equal to that resorbed.(2,3,5–7) Uncoupling occurs when the balance between formation and resorption is dissociated, which can lead to either osteopetrosis or osteoporosis.(8,9) Although it has long been appreciated that bone formation is tightly coupled to bone resorption in normal adult bone turnover,(1) this coupling can be dissociated in some circumstances, for example during skeletal growth, in postmenopausal osteoporosis, and in some, but not all, osteopetrotic mutations.(5,10)

Loss of ovarian sex steroids in postmenopausal women results in an acceleration of bone turnover with predominance of bone resorption over bone formation.(11) The related negative calcium balance promotes bone loss, increases bone fragility, and thereby the risk of future fractures.(12) A rational approach to counter these unwanted processes is to inhibit bone resorption, which until now also has led to inhibition of bone formation, caused by the coupling between these cellular events.(13–15)

Osteoclast activity has traditionally been viewed as restricted to bone resorption, but may not be limited to this. In this review, we discuss alternative activities of osteoclasts, namely stimulation of bone formation. We discuss how manipulation of bone resorption either by nature, exemplified by monogenic human disorders, or by different antiresorptive treatment modalities can modulate bone formation leading to a positive bone balance.

OSTEOCLAST ACTIVITY IS NOT RESTRICTED TO BONE RESORPTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. OSTEOCLAST ACTIVITY IS NOT RESTRICTED TO BONE RESORPTION
  5. BONE FORMATION AND BONE RESORPTION ARE UNCOUPLED IN SOME CASES OF OSTEOPETROSIS
  6. SOME, BUT NOT ALL, OSTEOPETROTIC ANIMAL MODELS EXHIBIT UNCOUPLING
  7. CONTROL OF BONE FORMATION BY THE OSTEOCLASTS
  8. REVERSAL PHASE IS AN IMPORTANT COMMUNICATION STEP BETWEEN OSTEOCLASTS AND OSTEOBLASTS
  9. POTENTIAL FACTORS FROM OSTEOCLASTS MEDIATING SIGNALS TO OSTEOBLASTS
  10. CONCLUSIONS AND FUTURE PERSPECTIVES: CAN THESE NOVEL INSIGHTS AID THE DEVELOPMENT OF NEW ANTIRESORPTIVE STRATEGIES?
  11. REFERENCES

Osteoclasts are important for the calcium balance and shaping the skeleton, but may be important also for sustaining bone quality.(16–23) Secondary to resorption, bone formation is initiated, which could indicate that some aspects of osteoclast activity are important for initiation of bone formation. Compelling evidence for this is the fact that, in the normal adult skeleton, bone formation is almost exclusively initiated in areas having undergone resorption.(2–5,24) Consistent with this, the number of nuclei in osteoclasts has been shown to correlate to the number of osteoblasts,(25) indicating local signaling events between osteoclast and osteoblasts. Traditionally, an array of bone resorption–derived cytokines and growth factors, including the TGF-β superfamily and IGFs,(26–29) was thought to mediate the activation of the osteoblasts leading to bone formation. Original evidence supporting this hypothesis originates from Howard et al.,(30) who showed the release of an anabolic factor (i.e., a coupling factor) from actively resorbing bones in organ cultures. This study also eluted to the possibility that actively resorbing osteoclasts do not always secrete the anabolic signal,(30) potentially indicating that the anabolic signal is not derived solely from resorption of the bone matrix. Thus, a function of the osteoclasts that might have been overlooked is initiation of bone formation by hereto-unknown signals. As a consequence of this hypothesis, it may be of interest to study whether these signals can be manipulated to allow a reduction in resorption while bone formation is maintained.

In summary, osteoclast function may be essential for maintenance of the quality of the adult skeleton and may, in addition, contribute to the level of bone formation taking place secondary to bone resorption. Whether these potential coupling signals are independent of bone resorption remains to be addressed, although there is emerging evidence for non–matrix-derived signal(s), as will be discussed.

BONE FORMATION AND BONE RESORPTION ARE UNCOUPLED IN SOME CASES OF OSTEOPETROSIS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. OSTEOCLAST ACTIVITY IS NOT RESTRICTED TO BONE RESORPTION
  5. BONE FORMATION AND BONE RESORPTION ARE UNCOUPLED IN SOME CASES OF OSTEOPETROSIS
  6. SOME, BUT NOT ALL, OSTEOPETROTIC ANIMAL MODELS EXHIBIT UNCOUPLING
  7. CONTROL OF BONE FORMATION BY THE OSTEOCLASTS
  8. REVERSAL PHASE IS AN IMPORTANT COMMUNICATION STEP BETWEEN OSTEOCLASTS AND OSTEOBLASTS
  9. POTENTIAL FACTORS FROM OSTEOCLASTS MEDIATING SIGNALS TO OSTEOBLASTS
  10. CONCLUSIONS AND FUTURE PERSPECTIVES: CAN THESE NOVEL INSIGHTS AID THE DEVELOPMENT OF NEW ANTIRESORPTIVE STRATEGIES?
  11. REFERENCES

The most compelling evidence for the cellular origin of coupling activity originates from patients suffering from osteopetrosis. Patients with mutations in the chloride channel 7 (ClC-7) or the a3 subunit of the osteoclast proton pump (a3-V-ATPase) either suffer from autosomal recessive osteopetrosis (ARO) or from autosomal dominant osteopetrosis type II (ADOII). These patients have reduced bone resorption caused by attenuated acidification of the resorption lacunae.(31,32) A particularly interesting finding in these patients is that, despite reduced bone resorption, these patients have normal or even increased bone formation,(33–35) which is in contrast to the secondary decrease in bone formation normally observed. Interestingly, these patients have increased numbers of nonresorbing osteoclasts that are otherwise normal in appearance.(36) Furthermore, the number of the nonresorbing osteoclasts has been shown to correlate to the number of active osteoblasts.(34,35) This increase in osteoclast numbers is likely because of increased survival caused by the lowered dissolution of the inorganic phase of the bone.(35,37) These data support the concept of a non–bone-derived osteoclast activity, which supports bone formation.

In contrast to the patients with defective acidification of the resorption lacuna, patients with pycnodysostosis, who have defective cathepsin K, have no apparent uncoupling of formation and resorption, and they characteristically have poorly remodeled bone,(4,38) despite the presence of normal numbers of osteoclasts.(39) Thus, not all osteopetrotic mutations result in the same phenotype, even though osteoclast function is specifically abrogated.

SOME, BUT NOT ALL, OSTEOPETROTIC ANIMAL MODELS EXHIBIT UNCOUPLING

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. OSTEOCLAST ACTIVITY IS NOT RESTRICTED TO BONE RESORPTION
  5. BONE FORMATION AND BONE RESORPTION ARE UNCOUPLED IN SOME CASES OF OSTEOPETROSIS
  6. SOME, BUT NOT ALL, OSTEOPETROTIC ANIMAL MODELS EXHIBIT UNCOUPLING
  7. CONTROL OF BONE FORMATION BY THE OSTEOCLASTS
  8. REVERSAL PHASE IS AN IMPORTANT COMMUNICATION STEP BETWEEN OSTEOCLASTS AND OSTEOBLASTS
  9. POTENTIAL FACTORS FROM OSTEOCLASTS MEDIATING SIGNALS TO OSTEOBLASTS
  10. CONCLUSIONS AND FUTURE PERSPECTIVES: CAN THESE NOVEL INSIGHTS AID THE DEVELOPMENT OF NEW ANTIRESORPTIVE STRATEGIES?
  11. REFERENCES

Studies of human osteopetrosis, although limited, have supported the hypothesis that osteoclast function may be of two pathways: bone resorption and signaling to osteoblasts for initiation and progression of bone formation. Supplementing these valuable human data are animal models of osteopetrosis that may aid the understanding of whether these different osteoclast activities coexist.

There are selected animal models that exhibit decreased or absent bone resorption but normal or increased bone formation.(40,41) Mice deficient in c-src have increased numbers of osteoclasts that are unable to resorb bone because of a defect in formation of the sealing zone.(42,43) These mice have increased bone formation despite reduced resorption.(40) However, there are in vitro data suggesting an intrinsic activation of bone formation in the osteoblasts.(40) Thus, at present, it is unclear whether signals from osteoclasts to osteoblasts are part of the increased osteoblast activity in the c-src model. More compelling evidence is found in mice deficient for either ClC-7 or the a3 subunit of the V-ATPase, which both have phenotypes indicating that bone formation continues in the absence of resorption.(41,44) This genetic evidence was supported by the finding that pharmaceutical intervention against either ClC-7 or the V-ATPase inhibited bone resorption, without inhibiting bone formation.(37,45–47)

In contrast to osteoclast-rich osteopetrosis are those osteopetrotic models where the osteoclasts are reduced or absent (osteoclast-poor).(48–50) In these important examples, bone formation is reduced, but still ongoing, as evident in the macrophage-colony stimulating factor (M-CSF) and M-CSF receptor–deficient mice, which have no osteoclasts because of a defect in osteoclastogenesis.(48,49) Even though this information is at present limited to mouse models, bone formation in the absence of osteoclasts appeared in cell clusters randomly distributed in the matrix, indicating that they have lost the polarity of their matrix secretion. In general, cells of the osteoblast lineage seemed disorganized in the complete absence of osteoclasts and the focal recruitment of osteoblasts normally seen was lost,(5) thus resulting in a lower quality of bone, as determined by breaking strength.(48,49) In addition, the tl/tl rats, which lack M-CSF,(51) have reduced osteocalcin levels and reduced bone strength,(52,53) indicating that their bone formation is impaired in the absence of osteoclasts, in alignment with the op/op mice.

In alignment, the c-fos–deficient mice, which have no osteoclasts, have >50% reduced levels of serum osteocalcin, indicating that their bone formation is reduced.(54)

These results suggest that the initiation of bone formation is both through a central signal that is present even in the absence of osteoclasts and a local signal, which lacks directional signaling, resulting in lower quality of bone in the absence of osteoclasts. In addition, because bone formation is lower in these osteopetrotic mice,(48,49) the factor(s) originating from osteoclasts may act both by enhancing and propelling directional osteoblast function, resulting in optimal bone quality. Thus, the presence of osteoclasts may be essential for optimal quality and the level of bone formation.

CONTROL OF BONE FORMATION BY THE OSTEOCLASTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. OSTEOCLAST ACTIVITY IS NOT RESTRICTED TO BONE RESORPTION
  5. BONE FORMATION AND BONE RESORPTION ARE UNCOUPLED IN SOME CASES OF OSTEOPETROSIS
  6. SOME, BUT NOT ALL, OSTEOPETROTIC ANIMAL MODELS EXHIBIT UNCOUPLING
  7. CONTROL OF BONE FORMATION BY THE OSTEOCLASTS
  8. REVERSAL PHASE IS AN IMPORTANT COMMUNICATION STEP BETWEEN OSTEOCLASTS AND OSTEOBLASTS
  9. POTENTIAL FACTORS FROM OSTEOCLASTS MEDIATING SIGNALS TO OSTEOBLASTS
  10. CONCLUSIONS AND FUTURE PERSPECTIVES: CAN THESE NOVEL INSIGHTS AID THE DEVELOPMENT OF NEW ANTIRESORPTIVE STRATEGIES?
  11. REFERENCES

The anabolic effect of PTH is well known,(55) and the presence of signaling from osteoblasts to osteoclasts in the presence of PTH is well established.(24) However, an interesting question is whether the anabolic effect of PTH is solely on cells of the osteoblast lineage or whether it also requires signals from the osteoclasts back to the osteoblasts (e.g., potential coupling factors).

An interesting model system for this question is the c-fos−/− animals, which do not have osteoclasts, but normal functioning osteoblasts in vitro.(54) Intermittent PTH treatment of c-fos−/− animals showed no anabolic effects,(54) suggesting that osteoclast activity is needed for a full anabolic response to PTH. Furthermore, it was shown that the anabolic effect of PTH is normal in c-src−/− mice, which have increased numbers of nonresorbing osteoclasts.(56) In direct agreement with this, Koh et al.(56) showed that OPG treatment of animals resulted in decreased osteoclast numbers, and as a consequence of that, attenuated the anabolic effect of PTH.

In addition, signals from osteoclasts to osteoblasts were recently shown to be dependent on glucocorticoid action. These experiments were performed in mice deficient for the glucocorticoid receptor specifically in the osteoclasts, and they showed that the detrimental effects of the glucocorticoids on bone formation(57) were mediated through the osteoclasts, further indicating the osteoclasts are directly involved in the control of bone formation.

REVERSAL PHASE IS AN IMPORTANT COMMUNICATION STEP BETWEEN OSTEOCLASTS AND OSTEOBLASTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. OSTEOCLAST ACTIVITY IS NOT RESTRICTED TO BONE RESORPTION
  5. BONE FORMATION AND BONE RESORPTION ARE UNCOUPLED IN SOME CASES OF OSTEOPETROSIS
  6. SOME, BUT NOT ALL, OSTEOPETROTIC ANIMAL MODELS EXHIBIT UNCOUPLING
  7. CONTROL OF BONE FORMATION BY THE OSTEOCLASTS
  8. REVERSAL PHASE IS AN IMPORTANT COMMUNICATION STEP BETWEEN OSTEOCLASTS AND OSTEOBLASTS
  9. POTENTIAL FACTORS FROM OSTEOCLASTS MEDIATING SIGNALS TO OSTEOBLASTS
  10. CONCLUSIONS AND FUTURE PERSPECTIVES: CAN THESE NOVEL INSIGHTS AID THE DEVELOPMENT OF NEW ANTIRESORPTIVE STRATEGIES?
  11. REFERENCES

Locally, bone resorption is followed by a lag phase in which osteoclasts are removed from the resorption pits, and the pit is prepared for bone formation.(58) This is referred to as the reversal phase and allows deposition of osteoclast-derived signals into the bone surface to be “read” by osteoblasts. Therefore, chemotactic factors for osteoblasts sequestered in the cement lines by the osteoclasts during bone resorption,(5) as seen in Fig. 1, could both initiate and provide directional information for osteoblastic bone formation. This is line with the finding that osteoblasts preferentially form bone in resorption pits.(59,60) Therefore, factors, that interact with the reversal phase, positive or negative, could affect the balance between bone resorption and bone formation. Interestingly, the cement lines have different appearances in various osteopetrotic mutations. In patients with osteopetrosis caused by defective acidification of the resorption lacuna, accumulations of TRACP are found in the resorption pits,(36) and there is some evidence that TRACP activates osteoblastogenesis.(61,62) This suggests that the resorbed bone surface somehow is important for recruitment of osteoblasts, although whether this is involved in the “uncoupling” seen in these patients is currently not known. The role of the reversal phase is shown in Fig. 1, where a potential signal is sequestered by the osteoclasts.

thumbnail image

Figure Figure 1. Schematic representation of the release of an anabolic signal from osteoclasts under different circumstances. (A) Normal bone turnover in which osteoclasts resorb bone and secrete potential coupling factors indicated by green arrows. In addition, osteoclasts during bone resorption osteoclasts encounter proapoptotic factors as indicated by the read arrows. (B) Nonresorbing osteoclasts have increased life span resulting in increased numbers of osteoclasts, caused by attenuated release of proapoptotic factors (red arrows). However, secretion of the coupling factor is normal and correlates to osteoclast number rather that activity. (C) Situations where osteoclasts have attenuated bone resorption caused by impaired acidification, but still secrete the coupling factor(s). In addition, the coupling factor may be sequestered (green circles) in the cement line of the bone matrix, thereby recruiting and stimulating osteoblastic bone formation. Modified from Am J Pathol 2005;166:467–476 with permission from the American Society for Investigative Pathology.

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There is a possibility that the resorption pits, an integrated part of the reversal phase, mediate the difference between patients with defective acidification of the resorption lacuna compared with that of pycnodysostotic patients. The pycnodysostotic patients have no apparent uncoupling of formation and resorption, in combination with poorly remodeled bone,(4,38) despite the presence of normal numbers of osteoclasts.(39) The “resorption phenotype” in the patients with pycnodysostosis is characterized by the presence of nonresorbed collagen fibers in the resorption pits,(63) in contrast to the acidification-deficient phenotype where lack of dissolution of the inorganic phase of bone does lead to exposure of collagen fibers. In the cathepsin K–deficient patients, very small amounts of active osteoblasts are found.(38) The secondary decrease in trabecular bone formation, caused by specific cathepsin K inhibitors, was recently reproduced in studies using both rats and monkeys.(64,65) These findings strongly indicate that modulation of the resorbed surface is involved in the recruitment of osteoblasts. Furthermore, the reduction in bone formation may in part be explained by the finding that exposed RGD motifs induce osteoblast apoptosis,(66) because the collagen fibers remaining in the resorption pits likely contain RGD motifs. These findings are further supported by a study showing that bone formation in the cathepsin K–deficient mice is disorganized, leading to fragile bones.(67)

This complex cell-to-cell communication system between osteoclasts and osteoblasts involving the matrix undergoing reconstruction is shown in Fig. 1. Normal osteoclasts excavate bone until a determined depth and undergo apoptosis, possibly caused by apoptotic factors in the bone.(37) Inhibition of osteoclastic resorption of the inorganic phase of the bones results in increased numbers of nonresorbing osteoclasts, likely because of a reduction in osteoclast apoptosis.(37,40) The increased numbers of osteoclasts could mediate the increased signaling to the osteoblasts (Fig. 1B).(34,35) Finally, patients with defective acidification of the resorption lacuna have amorphous material containing large amounts of TRACP in the resorbed area,(36) indicating that the reversal phase could be part of the signal for the osteoblasts, as indicated on Fig. 1C.

Thus, it is a likely possibility that the resorptive activity of osteoclasts does not control the coupling, but more likely it is the osteoclasts themselves that secrete or produce factor(s) contributing to induction of bone formation by osteoblasts. In addition, remnants from osteoclasts and the preparation of the formation area seem to play important roles in the bone formation process

POTENTIAL FACTORS FROM OSTEOCLASTS MEDIATING SIGNALS TO OSTEOBLASTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. OSTEOCLAST ACTIVITY IS NOT RESTRICTED TO BONE RESORPTION
  5. BONE FORMATION AND BONE RESORPTION ARE UNCOUPLED IN SOME CASES OF OSTEOPETROSIS
  6. SOME, BUT NOT ALL, OSTEOPETROTIC ANIMAL MODELS EXHIBIT UNCOUPLING
  7. CONTROL OF BONE FORMATION BY THE OSTEOCLASTS
  8. REVERSAL PHASE IS AN IMPORTANT COMMUNICATION STEP BETWEEN OSTEOCLASTS AND OSTEOBLASTS
  9. POTENTIAL FACTORS FROM OSTEOCLASTS MEDIATING SIGNALS TO OSTEOBLASTS
  10. CONCLUSIONS AND FUTURE PERSPECTIVES: CAN THESE NOVEL INSIGHTS AID THE DEVELOPMENT OF NEW ANTIRESORPTIVE STRATEGIES?
  11. REFERENCES

The potential anabolic response of osteoclasts may be mediated to osteoblasts in vivo by a secreted factor, factors sequestered in the matrix, or a combination of both, as delineated in Fig. 1. A large array of cytokines can induce bone formation both in vitro and in vivo, such as IGF-1,(68) TGF-β,(69) BMP-2,(70) IL-6,(71) IL-7,(72) Wnt,(73) and, as previously described, TRACP.(61,62) Some of these factors, such as TGF-β and IGF-1, are synthesized by osteoclasts independent of their resorptive activity,(68,74,75) which is in agreement with the finding that bone formation occurs independent of resorption in osteopetrotic patients and animals.(33,35) Further emphasizing the role of IGF-1 is the fact that genetic ablation of the IGF-1 receptor specifically in osteoblasts results an osteopenic phenotype caused by defective osteoblast function.(76) In addition, IGF-1 was shown to mediate the anabolic effect of PTH,(77) which in turn was shown to be dependent on the presence of osteoclasts.(56) In agreement with the hypothesis of secreted anabolic coupling factors, preliminary data have recently supported the possibility that osteoclasts, cultured in vitro, secrete non–bone-derived factors, which induce bone nodule formation.(78,79)

Others investigators have focused on cell-surface factors present on osteoclasts. A recent report indicated that cell-surface signaling from osteoclasts to osteoblasts by the EphrinB2–EphB4 interaction is important for induction of bone formation.(80,81) This study showed that osteoclasts express EphrinB2, which subsequently enhanced osteoblast differentiation through activation of EphB4. On the other hand, the expression of EphB4 on the osteoblasts led to inhibition of osteoclastogenesis through its binding to EphrinB2, thus establishing a forward–reverse signaling loop, which could play a role in controlling bone turnover, in a process independent of resorption.(80,81)

Taken together, several cytokines/growth factors and proteins have the required abilities of a coupling factor; however, whether any of these factor(s) are responsible for the uncoupling observed in patients with osteopetrosis with defective acidification of the resorption lacuna still remains to be determined.

CONCLUSIONS AND FUTURE PERSPECTIVES: CAN THESE NOVEL INSIGHTS AID THE DEVELOPMENT OF NEW ANTIRESORPTIVE STRATEGIES?

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. OSTEOCLAST ACTIVITY IS NOT RESTRICTED TO BONE RESORPTION
  5. BONE FORMATION AND BONE RESORPTION ARE UNCOUPLED IN SOME CASES OF OSTEOPETROSIS
  6. SOME, BUT NOT ALL, OSTEOPETROTIC ANIMAL MODELS EXHIBIT UNCOUPLING
  7. CONTROL OF BONE FORMATION BY THE OSTEOCLASTS
  8. REVERSAL PHASE IS AN IMPORTANT COMMUNICATION STEP BETWEEN OSTEOCLASTS AND OSTEOBLASTS
  9. POTENTIAL FACTORS FROM OSTEOCLASTS MEDIATING SIGNALS TO OSTEOBLASTS
  10. CONCLUSIONS AND FUTURE PERSPECTIVES: CAN THESE NOVEL INSIGHTS AID THE DEVELOPMENT OF NEW ANTIRESORPTIVE STRATEGIES?
  11. REFERENCES

This review has focused on the presence of an osteoclast-derived anabolic factor. The presented data highlight the likely possibility that the coupling signal described by Howard et al.(30) does not solely derive from the resorptive activity of the osteoclasts but that the osteoclasts themselves, in addition to matrix-derived factors, also play an important role in mediating anabolic signals to the osteoblasts (see Fig. 1).

Osteopetrotic mutations and pharmacological intervention in animals models have taught us that in some, but not all, cases, bone resorption and bone formation can be dissociated.(24,37) As delineated in Fig. 2A, in postmenopausal women, osteoclast number and bone resorption is elevated. Bone formation is not increased to similar levels, resulting in osteoporosis.(82) In some osteopetrotic mutations, osteoclast number is elevated, with decreased resorption but with bone formation equal to that of the osteoclast number, thus resulting in increased bone mass, also presented in Fig. 2A.(35) In contrast, osteopetrotic mutations with absence of osteoclasts have defective bone formation at least in mice.(48,49,52)

thumbnail image

Figure Figure 2. Schematic representation of the correlation between osteoclast number, osteoclastic bone resorption, and bone formation in (A) normal and different pathological situations and (B) various treatments of postmenopausal osteoporosis. HRT, hormone replacement treatment.

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In existing pharmacological treatments for osteoporosis, a decrease in bone formation is observed secondary to the reduction in bone resorption. As presented in Fig. 2B, this has been reported for anti-RANKL,(50,83) bisphosphonates,(13,14) and estrogen replacement.(84) Interestingly, novel treatments that will be able to sustain osteoclast numbers, and only attenuate the antiresorptive activity of osteoclasts and not potential coupling factors, could result in a continuous uncoupling of bone resorption and bone formation.(24,37) Even though preliminary, this compilation of data suggests novel focus points for the development of new antiresorptive strategies.

The current discussion provides a potential explanation for the lack of additive effects observed when combining PTH with bisphosphonate treatment.(85,86) Because bisphosphonates suppress osteoclastic activities in vivo, through a reduction of osteoclast numbers, it is likely that release of the osteoclast-derived anabolic signal is reduced or even abolished in these cases, thus explaining the absence of additive effects when using PTH in combination with this drug.(85,86) These findings correlate well with the study showing that osteoclasts are needed for the anabolic effect of PTH.(56)

In conclusion, there are several studies indicating that osteoclast activities can now be divided into two more or less separate categories: the first being the well-known function in bone resorption, and the second, which is independent of resorptive activity, being the secretion of anabolic factors to osteoblasts.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. OSTEOCLAST ACTIVITY IS NOT RESTRICTED TO BONE RESORPTION
  5. BONE FORMATION AND BONE RESORPTION ARE UNCOUPLED IN SOME CASES OF OSTEOPETROSIS
  6. SOME, BUT NOT ALL, OSTEOPETROTIC ANIMAL MODELS EXHIBIT UNCOUPLING
  7. CONTROL OF BONE FORMATION BY THE OSTEOCLASTS
  8. REVERSAL PHASE IS AN IMPORTANT COMMUNICATION STEP BETWEEN OSTEOCLASTS AND OSTEOBLASTS
  9. POTENTIAL FACTORS FROM OSTEOCLASTS MEDIATING SIGNALS TO OSTEOBLASTS
  10. CONCLUSIONS AND FUTURE PERSPECTIVES: CAN THESE NOVEL INSIGHTS AID THE DEVELOPMENT OF NEW ANTIRESORPTIVE STRATEGIES?
  11. REFERENCES
  • 1
    Baron R 2003 Anatomy and Biology of Bone Matrix and Cellular Elements, Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. American Society for Bone and Mineral Research, Washington, DC, USA.
  • 2
    Hattner R, Epker BN, Frost HM 1965 Suggested sequential mode of control of changes in cell behaviour in adult bone remodelling. Nature 206: 489490.
  • 3
    Takahashi H, Epker B, Frost HM 1964 Resorption precedes formative activity. Surg Forum 15: 437438.
  • 4
    Sarnsethsiri P, Hitt OK, Eyring EJ, Frost HM 1971 Tetracycline-based study of bone dynamics in pycnodysostosis. Clin Orthop 74: 301312.
  • 5
    Parfitt AM 1982 The coupling of bone formation to bone resorption: A critical analysis of the concept and of its relevance to the pathogenesis of osteoporosis. Metab Bone Dis Relat Res 4: 16.
  • 6
    Martin TJ 1993 Hormones in the coupling of bone resorption and formation. Osteoporos Int 3(Suppl 1): 121125.
  • 7
    Nakamura M, Udagawa N, Matsuura S, Mogi M, Nakamura H, Horiuchi H, Saito N, Hiraoka BY, Kobayashi Y, Takaoka K, Ozawa H, Miyazawa H, Takahashi N 2003 Osteoprotegerin regulates bone formation through a coupling mechanism with bone resorption. Endocrinology 144: 54415449.
  • 8
    Teitelbaum SL, Ross FP 2003 Genetic regulation of osteoclast development and function. Nat Rev Genet 4: 638649.
  • 9
    Goltzman D 2002 Discoveries, drugs and skeletal disorders. Nat Rev Drug Discov 1: 784796.
  • 10
    Tolar J, Teitelbaum SL, Orchard PJ 2004 Osteopetrosis. N Engl J Med 351: 28392849.
  • 11
    Rodan GA 1991 Mechanical loading, estrogen deficiency, and the coupling of bone formation to bone resorption. J Bone Miner Res 6: 527530.
  • 12
    Garnero P, Sornay-Rendu E, Claustrat B, Delmas PD 2000 Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: The OFELY study. J Bone Miner Res 15: 15261536.
  • 13
    Ravn P, Hosking D, Thompson D, Cizza G, Wasnich RD, McClung M, Yates AJ, Bjarnason NH, Christiansen C 1999 Monitoring of alendronate treatment and prediction of effect on bone mass by biochemical markers in the early postmenopausal intervention cohort study. J Clin Endocrinol Metab 84: 23632368.
  • 14
    Ravn P, Clemmesen B, Christiansen C 1999 Biochemical markers can predict the response in bone mass during alendronate treatment in early postmenopausal women. Alendronate Osteoporosis Prevention Study Group. Bone 24: 237244.
  • 15
    Ravn P, Thompson DE, Ross PD, Christiansen C 2003 Biochemical markers for prediction of 4-year response in bone mass during bisphosphonate treatment for prevention of postmenopausal osteoporosis. Bone 33: 150158.
  • 16
    Burr DB, Robling AG, Turner CH 2002 Effects of biomechanical stress on bones in animals. Bone 30: 781786.
  • 17
    Burr DB 2002 Targeted and nontargeted remodeling. Bone 30: 24.
  • 18
    Burr DB, Turner CH 2003 Biomechanics of Bone. American Society for Bone and Mineral Research, Washington, DC, USA.
  • 19
    Li J, Sato M, Jerome C, Turner CH, Fan Z, Burr DB 2005 Microdamage accumulation in the monkey vertebra does not occur when bone turnover is suppressed by 50% or less with estrogen or raloxifene. J Bone Miner Metab 23(Suppl): 4854.
  • 20
    Mashiba T, Mori S, Burr DB, Komatsubara S, Cao Y, Manabe T, Norimatsu H 2005 The effects of suppressed bone remodeling by bisphosphonates on microdamage accumulation and degree of mineralization in the cortical bone of dog rib. J Bone Miner Metab 23(Suppl): 3642.
  • 21
    Li J, Mashiba T, Burr DB 2001 Bisphosphonate treatment suppresses not only stochastic remodeling but also the targeted repair of microdamage. Calcif Tissue Int 69: 281286.
  • 22
    Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB 2001 Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone 28: 524531.
  • 23
    Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston CC, Burr DB 2000 Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 15: 613620.
  • 24
    Martin TJ, Sims NA 2005 Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol Med 11: 7681.
  • 25
    Thompson ER, Baylink DJ, Wergedal JE 1975 Increases in number and size of osteoclasts in response to calcium or phosphorus deficiency in the rat. Endocrinology 97: 283289.
  • 26
    Mundy GR, Bonewald LF 1990 Role of TGF beta in bone remodeling. Ann N Y Acad Sci 593: 9197.
  • 27
    Centrella M, McCarthy TL, Canalis E 1991 Transforming growth factor-beta and remodeling of bone. J Bone Joint Surg Am 73: 14181428.
  • 28
    Hayden JM, Mohan S, Baylink DJ 1995 The insulin-like growth factor system and the coupling of formation to resorption. Bone 17: 93S98S.
  • 29
    Baylink DJ, Finkelman RD, Mohan S 1993 Growth factors to stimulate bone formation. J Bone Miner Res 8(Suppl 2): S565S572.
  • 30
    Howard GA, Bottemiller BL, Turner RT, Rader JI, Baylink DJ 1981 Parathyroid hormone stimulates bone formation and resorption in organ culture: Evidence for a coupling mechanism. Proc Natl Acad Sci USA 78: 32043208.
  • 31
    Taranta A, Migliaccio S, Recchia I, Caniglia M, Luciani M, De Rossi G, Dionisi-Vici C, Pinto RM, Francalanci P, Boldrini R, Lanino E, Dini G, Morreale G, Ralston SH, Villa A, Vezzoni P, Del Principe D, Cassiani F, Palumbo G, Teti A 2003 Genotype-phenotype relationship in human ATP6i-dependent autosomal recessive osteopetrosis. Am J Pathol 162: 5768.
  • 32
    Henriksen K, Gram J, Schaller S, Dahl BH, Dziegiel MH, Bollerslev J, Karsdal MA 2004 Characterization of osteoclasts from patients harboring a G215R mutation in ClC-7 causing autosomal dominant osteopetrosis type II (ADOII). Am J Pathol 164: 15371545.
  • 33
    Bollerslev J, Steiniche T, Melsen F, Mosekilde L 1989 Structural and histomorphometric studies of iliac crest trabecular and cortical bone in autosomal dominant osteopetrosis: A study of two radiological types. Bone 10: 1924.
  • 34
    Alatalo SL, Ivaska KK, Waguespack SG, Econs MJ, Vaananen HK, Halleen JM 2004 Osteoclast-derived serum tartrate-resistant acid phosphatase 5b in Albers-Schonberg disease (type II autosomal dominant osteopetrosis). Clin Chem 50: 883890.
  • 35
    Del Fattore A, Peruzzi B, Rucci N, Recchia I, Cappariello A, Longo M, Fortunati D, Ballanti P, Iacobini M, Luciani M, Devito R, Pinto R, Caniglia M, Lanino E, Messina C, Cesaro S, Letizia C, Bianchini G, Fryssira H, Grabowski P, Shaw N, Bishop N, Hughes D, Kapur R, Datta H, Taranta A, Fornari R, Migliaccio S, Teti A 2005 Clinical, genetic and cellular analysis of forty-nine osteopetrotic patients: Implications for diagnosis and treatment. J Med Genet 43: 315325.
  • 36
    Bollerslev J, Marks SC Jr, Pockwinse S, Kassem M, Brixen K, Steiniche T, Mosekilde L 1993 Ultrastructural investigations of bone resorptive cells in two types of autosomal dominant osteopetrosis. Bone 14: 865869.
  • 37
    Karsdal MA, Henriksen K, Sorensen MG, Gram J, Schaller S, Dziegiel MH, Heegaard AM, Christophersen P, Martin TJ, Christiansen C, Bollerslev J 2005 Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption. Am J Pathol 166: 467476.
  • 38
    Fratzl-Zelman N, Valenta A, Roschger P, Nader A, Gelb BD, Fratzl P, Klaushofer K 2004 Decreased bone turnover and deterioration of bone structure in two cases of pycnodysostosis. J Clin Endocrinol Metab 89: 15381547.
  • 39
    Nishi Y, Atley L, Eyre DE, Edelson JG, Superti-Furga A, Yasuda T, Desnick RJ, Gelb BD 1999 Determination of bone markers in pycnodysostosis: Effects of cathepsin K deficiency on bone matrix degradation. J Bone Miner Res 14: 19021908.
  • 40
    Marzia M, Sims NA, Voit S, Migliaccio S, Taranta A, Bernardini S, Faraggiana T, Yoneda T, Mundy GR, Boyce BF, Baron R, Teti A 2000 Decreased c-Src expression enhances osteoblast differentiation and bone formation. J Cell Biol 151: 311320.
  • 41
    Kornak U, Kasper D, Bosl MR, Kaiser E, Schweizer M, Schulz A, Friedrich W, Delling G, Jentsch TJ 2001 Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell 104: 205215.
  • 42
    Soriano P, Montgomery C, Geske R, Bradley A 1991 Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64: 693702.
  • 43
    Horne WC, Neff L, Chatterjee D, Lomri A, Levy JB, Baron R 1992 Osteoclasts express high levels of pp60c-src in association with intracellular membranes. J Cell Biol 119: 10031013.
  • 44
    Li YP, Chen W, Liang Y, Li E, Stashenko P 1999 Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification. Nat Genet 23: 447451.
  • 45
    Visentin L, Dodds RA, Valente M, Misiano P, Bradbeer JN, Oneta S, Liang X, Gowen M, Farina C 2000 A selective inhibitor of the osteoclastic V-H(+)-ATPase prevents bone loss in both thyroparathyroidectomized and ovariectomized rats. J Clin Invest 106: 309318.
  • 46
    Rzeszutek K, Sarraf F, Davies JE 2003 Proton pump inhibitors control osteoclastic resorption of calcium phosphate implants and stimulate increased local reparative bone growth. J Craniofac Surg 14: 301307.
  • 47
    Schaller S, Henriksen K, Sveigaard C, Heegaard AM, Helix N, Stahlhut M, Ovejero MC, Johansen JV, Solberg H, Andersen TL, Hougaard D, Berryman M, Shiodt CB, Sorensen BH, Lichtenberg J, Christophersen P, Foged NT, Delaisse JM, Engsig MT, Karsdal MA 2004 The chloride channel inhibitor n53736 prevents bone resorption in ovariectomized rats without changing bone formation. J Bone Miner Res 19: 11441153.
  • 48
    Dai XM, Zong XH, Akhter MP, Stanley ER 2004 Osteoclast deficiency results in disorganized matrix, reduced mineralization, and abnormal osteoblast behavior in developing bone. J Bone Miner Res 19: 14411451.
  • 49
    Sakagami N, Amizuka N, Li M, Takeuchi K, Hoshino M, Nakamura M, Nozawa-Inoue K, Udagawa N, Maeda T 2005 Reduced osteoblastic population and defective mineralization in osteopetrotic (op/op) mice. Micron 36: 688695.
  • 50
    McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, Peacock M, Miller PD, Lederman SN, Chesnut CH, Lain D, Kivitz AJ, Holloway DL, Zhang C, Peterson MC, Bekker PJ 2006 Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 354: 821831.
  • 51
    Dobbins DE, Sood R, Hashiramoto A, Hansen CT, Wilder RL, Remmers EF 2002 Mutation of macrophage colony stimulating factor (Csf1) causes osteopetrosis in the tl rat. Biochem Biophys Res Commun 294: 11141120.
  • 52
    Lian JB, Marks SC Jr 1990 Osteopetrosis in the rat: Coexistence of reductions in osteocalcin and bone resorption. Endocrinology 126: 955962.
  • 53
    Tuukkanen J, Koivukangas A, Jamsa T, Sundquist K, MacKay CA, Marks SC Jr 2000 Mineral density and bone strength are dissociated in long bones of rat osteopetrotic mutations. J Bone Miner Res 15: 19051911.
  • 54
    Demiralp B, Chen HL, Koh AJ, Keller ET, McCauley LK 2002 Anabolic actions of parathyroid hormone during bone growth are dependent on c-fos. Endocrinology 143: 40384047.
  • 55
    Burr DB 2005 Does early PTH treatment compromise bone strength? The balance between remodeling, porosity, bone mineral, and bone size. Curr Osteoporos Rep 3: 1924.
  • 56
    Koh AJ, Demiralp B, Neiva KG, Hooten J, Nohutcu RM, Shim H, Datta NS, Taichman RS, McCauley LK 2005 Cells of the osteoclast lineage as mediators of the anabolic actions of parathyroid hormone in bone. Endocrinology 146: 45844596.
  • 57
    Kim HJ, Zhao H, Kitaura H, Bhattacharyya S, Brewer JA, Muglia LJ, Ross FP, Teitelbaum SL 2006 Glucocorticoids suppress bone formation via the osteoclast. J Clin Invest 116: 21522160.
  • 58
    Everts V, Delaisse JM, Korper W, Jansen DC, Tigchelaar-Gutter W, Saftig P, Beertsen W 2002 The bone lining cell: Its role in cleaning Howship's lacunae and initiating bone formation. J Bone Miner Res 17: 7790.
  • 59
    Jones SJ, Gray C, Boyde A 1994 Simulation of bone resorption-repair coupling in vitro. Anat Embryol (Berl) 190: 339349.
  • 60
    Schwartz Z, Lohmann CH, Wieland M, Cochran DL, Dean DD, Textor M, Bonewald LF, Boyan BD 2000 Osteoblast proliferation and differentiation on dentin slices are modulated by pretreatment of the surface with tetracycline or osteoclasts. J Periodontol 71: 586597.
  • 61
    Sheu TJ, Schwarz EM, Martinez DA, O'Keefe RJ, Rosier RN, Zuscik MJ, Puzas JE 2003 A phage display technique identifies a novel regulator of cell differentiation. J Biol Chem 278: 438443.
  • 62
    Sheu TJ, Schwarz EM, O'Keefe RJ, Rosier RN, Puzas JE 2002 Use of a phage display technique to identify potential osteoblast binding sites within osteoclast lacunae. J Bone Miner Res 17: 915922.
  • 63
    Gowen M, Lazner F, Dodds R, Kapadia R, Feild J, Tavaria M, Bertoncello I, Drake F, Zavarselk S, Tellis I, Hertzog P, Debouck C, Kola I 1999 Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res 14: 16541663.
  • 64
    Lark MW, Stroup GB, James IE, Dodds RA, Hwang SM, Blake SM, Lechowska BA, Hoffman SJ, Smith BR, Kapadia R, Liang X, Erhard K, Ru Y, Dong X, Marquis RW, Veber D, Gowen M 2002 A potent small molecule, nonpeptide inhibitor of cathepsin K (SB 331750) prevents bone matrix resorption in the ovariectomized rat. Bone 30: 746753.
  • 65
    Kumar S, Rehm S, Boyce B, Birmingham J, Stroup GB, Jerome C, Weir P 2005 Treatment of young male monkeys for 12 months with a highly potent inhibitor of cathepsin K inhibits bone resorption and increases bone mineral density and strength. J Bone Miner Res 20S1; F232.
  • 66
    Adams CS, Shapiro IM 2003 Mechanisms by which extracellular matrix components induce osteoblast apoptosis. Connect Tissue Res 44(Suppl 1): 230239.
  • 67
    Li CY, Jepsen KJ, Majeska RJ, Zhang J, Ni R, Gelb BD, Schaffler MB 2006 Mice lacking cathepsin K maintain bone remodeling but develop bone fragility despite high bone mass. J Bone Miner Res 21: 865875.
  • 68
    Hayden JM, Mohan S, Baylink DJ 1995 The insulin-like growth factor system and the coupling of formation to resorption. Bone 17: 93S98S.
  • 69
    Baylink DJ, Finkelman RD, Mohan S 1993 Growth factors to stimulate bone formation. J Bone Miner Res 8:S2; S565S572.
  • 70
    Mundy G, Garrett R, Harris S, Chan J, Chen D, Rossini G, Boyce B, Zhao M, Gutierrez G 1999 Stimulation of bone formation in vitro and in rodents by statins. Science 286: 19461949.
  • 71
    Sims NA, Jenkins BJ, Quinn JM, Nakamura A, Glatt M, Gillespie MT, Ernst M, Martin TJ 2004 Glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways. J Clin Invest 113: 379389.
  • 72
    Weitzmann MN, Roggia C, Toraldo G, Weitzmann L, Pacifici R 2002 Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency. J Clin Invest 110: 16431650.
  • 73
    Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP 2002 High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346: 15131521.
  • 74
    Lazowski DA, Fraher LJ, Hodsman A, Steer B, Modrowski D, Han VK 1994 Regional variation of insulin-like growth factor-I gene expression in mature rat bone and cartilage. Bone 15: 563576.
  • 75
    Robinson JA, Riggs BL, Spelsberg TC, Oursler MJ 1996 Osteoclasts and transforming growth factor-beta: Estrogen-mediated isoform-specific regulation of production. Endocrinology 137: 615621.
  • 76
    Zhang M, Xuan S, Bouxsein ML, von Stechow D, Akeno N, Faugere MC, Malluche H, Zhao G, Rosen CJ, Efstratiadis A, Clemens TL 2002 Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. J Biol Chem 277: 4400544012.
  • 77
    Bikle DD, Sakata T, Leary C, Elalieh H, Ginzinger D, Rosen CJ, Beamer W, Majumdar S, Halloran BP 2002 Insulin-like growth factor I is required for the anabolic actions of parathyroid hormone on mouse bone. J Bone Miner Res 17: 15701578.
  • 78
    Henriksen K, Neutzsky-Wulff AV, Christiansen C, Martin TJ, Karsdal MA 2006 Osteoclasts secrete non-bone derived signals that induce bone nodule formation. J Bone Miner Res 21:S1; M198.
  • 79
    Henriksen K, Nielsen RH, Neutzsky-Wulff AV, Christiansen C, Martin TJ, Karsdal MA 2006 Osteoclast number but not activity may be the determinant factor for sustained osteoclast effect on bone formation. J Bone Miner Res 21:S1; SA418.
  • 80
    Zhao C, Irie N, Takada Y, Shimoda K, Miyamoto T, Nishiwaki T, Suda T, Matsuo K 2006 Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell Metab 4: 111121.
  • 81
    Mundy GR, Elefteriou F 2006 Boning up on ephrin signaling. Cell 126: 441443.
  • 82
    Iki M, Akiba T, Matsumoto T, Nishino H, Kagamimori S, Kagawa Y, Yoneshima H 2004 Reference database of biochemical markers of bone turnover for the Japanese female population. Japanese Population-based Osteoporosis (JPOS) Study. Osteoporos Int 15: 981991.
  • 83
    Bekker PJ, Holloway DL, Rasmussen AS, Murphy R, Martin SW, Leese PT, Holmes GB, Dunstan CR, DePaoli AM 2004 A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res 19: 10591066.
  • 84
    Greenspan SL, Parker RA, Ferguson L, Rosen HN, Maitland-Ramsey L, Karpf DB 1998 Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy in representative elderly women: A randomized clinical trial. J Bone Miner Res 13: 14311438.
  • 85
    Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF, Garnero P, Bouxsein ML, Bilezikian JP, Rosen CJ 2003 The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 349: 12071215.
  • 86
    Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer RM 2003 The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 349: 12161226.