Update in New Anabolic Therapies for Osteoporosis

Abstract

Skeletal anabolic agents enhance bone formation, which is determined by the number and function of osteoblasts. Cell number is controlled by factors that regulate the replication, differentiation, and death of cells of the osteoblastic lineage, whereas cell function is controlled by signals acting on the mature osteoblast. Bone morphogenetic proteins (BMP) and Wnt induce the differentiation of mesenchymal cells toward osteoblasts, and IGF-I enhances the function of mature osteoblasts. The activity of BMP, Wnt, and IGF-I is controlled by proteins that, by binding to the growth factor or to its receptors, can antagonize its effects. Changes in the expression or binding affinity of these extracellular antagonists can be associated with increased or decreased bone formation and bone mass. Novel approaches to anabolic therapies for osteoporosis may include the use of factors with anabolic properties, or the neutralization of a growth factor antagonist. Selected approaches include the use of neutralizing antibodies to Wnt antagonists, the enhancement of BMP signaling by proteasome inhibitors, or the use of activin soluble receptors, IGF-I, or PTH analogs. An anabolic agent needs to be targeted specifically to the skeleton to avoid unwanted nonskeletal effects and ensure safety. Clinical trials are being conducted to test the long-term effectiveness and safety of novel bone anabolic agents.

Cellular events that lead to an anabolic response in bone and ways to modify them to develop novel therapeutic alternatives for osteoporosis are described.

Osteoporosis is a major health problem affecting 8 million women and 2 million men in the United States. A larger number of individuals have decreased bone mass, which, in the presence of additional risk factors, also is a cause of fractures. Fragility fractures are the most significant consequences of osteoporosis, and therapies for this disease are judged by their effectiveness to reduce their incidence (1). Bone remodeling consists of two processes, bone resorption and bone formation, which need to be in balance to maintain bone mass. Postmenopausal osteoporosis is characterized by a state of high bone remodeling leading to decreased bone mass (2). Agents that reduce bone resorption are effective in stabilizing bone architecture and reduce the incidence of fractures in osteoporosis. Antiresorptive therapy plays a central role in the management of osteoporosis, but it cannot restore the bone structure that has been lost due to increased remodeling. Possibly, this can be achieved to an extent by anabolic agents, which by increasing bone formation can increase bone mass. Whether an anabolic agent can normalize bone architecture is not known. Whereas numerous agents with antiresorptive properties are available, the only anabolic agent approved by the Food and Drug Administration (FDA) for the treatment of osteoporosis in the United States is teriparatide, a 1-34 amino acid fragment of human recombinant PTH [PTH (1-34)]. In Europe, the full-length PTH (1-84) molecule also is approved for therapy. Because of their potential to increase bone mass, novel anabolic agents are being investigated.

Bone Remodeling

Bone remodeling is a tightly regulated process resulting in the coordinated resorption and formation of skeletal tissue carried out in basic multicellular units (3). In these microscopic units, osteoclasts resorb bone, and when resorption is completed, a reversal period follows, after which osteoblasts fill the cavity with collagenous matrix, which is then mineralized. Osteoclasts are multinucleated cells derived from pluripotential hematopoietic cells, and osteoblasts are mononuclear cells derived from mesenchymal cells (4). Signals that determine the replication, differentiation, function, and death of cells of both lineages dictate the degree of bone remodeling, a process necessary to maintain calcium homeostasis and to remove and prevent the accumulation of aged or weakened bone. In the postmenopausal years, estrogen deficiency leads to excessive bone resorption and bone loss. The target cell of antiresorptive agents is the osteoclast, whereas the target cell of an anabolic agent is a cell of the osteoblastic lineage. An increase in bone formation can be achieved by increasing the number or the activity of these bone-forming cells. An increase in the osteoblastic cell pool can be achieved by an increase in the replication or differentiation of preosteoblastic cells or by a decrease in the death of mature cells. An increase in the function of mature osteoblasts can augment bone formation. Consequently, anabolic agents can target signals increasing the osteoblastic cellular pool or the function of the mature cell. Classic growth factors display primarily mitogenic activity for cells of the osteoblastic lineage, but whether the cells differentiate into mature osteoblasts or not will determine their anabolic potential. Often, mitogenic factors inhibit the differentiated function of the osteoblast; therefore, factors that induce the differentiation of cells of the osteoblastic lineage into mature osteoblasts are more appropriate therapeutic targets if an effect on bone formation is to be achieved (5). Bone morphogenetic proteins (BMPs) and Wnt induce the differentiation of mesenchymal cells toward mature osteoblasts (6,7). IGF enhances the differentiated function of the mature cell (8). The activities of Wnt, BMPs, and IGF-I are tightly controlled not only at the level of their synthesis and receptor binding, but also by specific extracellular and intracellular regulatory proteins. One could conceive therapeutic approaches that enhance the synthesis or activity of a growth regulator or that target extracellular growth factor antagonists (8,9,10). Intracellular proteins can potentiate or attenuate an anabolic signal but are more difficult to target in pursuit of an anabolic response (6). The proteasome is a multicatalytic protease complex recognized as the major intracellular system for protein degradation (11). There, specific intracellular proteins required for the signal cascade of an anabolic agent are degraded, and proteasome inhibitors, by stabilizing these proteins, can enhance the anabolic signal (12).

Signals Determining Osteoblastic Cell Fate and Function

Wnt and Wnt antagonists

Wnts constitute a family of proteins important in cell differentiation. The Wnt/β-catenin signaling pathway plays a critical role in osteoblastic cell differentiation and bone formation. Mutations in Wnt receptors leading to alterations in Wnt signaling result in profound changes in bone mass (13). In skeletal cells, Wnt uses the canonical Wnt/β-catenin signaling pathway (13). In this pathway, when Wnt receptor binding interactions are absent, β-catenin is phosphorylated by glycogen-synthase kinase-3β (GSK-3β), leading to the degradation of β-catenin in the proteasome. Upon binding of Wnt to Frizzled receptors and to the low-density lipoprotein receptor-related protein (LRP) coreceptors -5 and -6, the activity of GSK-3β is inhibited, leading to the stabilization of β-catenin and its translocation to the nucleus. There, it associates with T cell factor 4 or lymphoid enhancer binding factor 1 to regulate gene transcription. Wnts also signal through β-catenin-independent or noncanonical signaling pathways. These operate during vertebrate development but can be used by selected Wnts to promote osteoblast differentiation and bone formation (14,15). Importantly, the noncanonical pathway can promote β-catenin degradation and oppose the Wnt canonical pathway; and its ultimate role in bone formation is not as well established as that of the Wnt canonical signaling pathway (16). Wnt induces osteoblastogenesis and bone formation, and it suppresses osteoclastogenesis and bone resorption, making Wnt a suitable target to obtain a bone anabolic response (17,18). The importance of the Wnt/β-catenin signaling pathway is documented by a number of skeletal and nonskeletal disorders that occur when this pathway is altered (13). Activating mutations of the Wnt coreceptor LRP-5 that prevent its association with Wnt inhibitors result in increased bone mass. Conversely, mutations of LRP-5 that prevent Wnt/β-catenin signaling result in osteopenia. Although these effects imply direct interactions of Wnt and LRP-5 in skeletal cells, LRP-5 also has been shown to decrease serotonin expression in enterochromaffin cells of the duodenum and through this mechanism increase bone formation (19). It is important to note that glucocorticoids inhibit Wnt/β-catenin signaling in bone, explaining the impaired osteoblastogenesis observed after glucocorticoid exposure (20). Consequently, a potential therapeutic target for glucocorticoid-induced osteoporosis could be the Wnt signaling pathway (21).

Wnt activity is modulated by extracellular antagonists, transmembrane modulators, or intracellular signals (10). Secreted Wnt antagonists can act by binding Wnt or by preventing its interactions with its receptor Frizzled or its coreceptors LRP-5/6. Secreted Wnt antagonists that interact with Wnt include Wnt inhibitory factor (WIF) 1, secreted Frizzled-related proteins, and Cerberus. Secreted Wnt antagonists that interact with Wnt coreceptors LRP-5/6 include sclerostin and Dickkopf (Dkk-1). Sclerostin, Dkk-1, secreted frizzled-related protein, and WIF are among the Wnt antagonists examined in greater detail for their effects in cells of the osteoblastic lineage and bone formation. Sclerostin, the product of the sost gene, is expressed by osteoblasts, osteocytes, and osteoclasts. Sclerostin has Wnt and BMP antagonistic properties, but its ligand specificity is different from that of classic BMP antagonists (22). The synthesis of scelerostin in osteoblasts and osteocytes is suppressed by the continuous as well as by the intermittent PTH administration; this results in enhanced Wnt signaling and contributes to the anabolic effect of PTH in bone (23,24,25). The Dickkopf family is composed of five members: Dkk-1, -2, -3, -4, and a unique Dkk-3-related protein product of soggy (10). Dkk-1 binds to the Wnt coreceptor LRP-5/6, and also promotes its endocytosis to disrupt Wnt signaling (10). Gain of function mutations of LRP-5 that impair interactions of Dkk-1 or sclerostin with LRP-5 cause increased bone mass (13). In line with these observations, transgenic overexpression of Dkk-1 causes osteopenia, and inactivation of secreted frizzled-related protein-1, sost, or dkk-1 results in increased bone formation and bone mass (26,27,28). These observations offer clues to potential ways by which Wnt signaling can be modified to produce an anabolic response in the skeleton.

BMPs, activin, and their antagonists

BMPs are members of the TGFβ superfamily of polypeptides and were identified because of their ability to induce endochondral bone formation (6). BMP-3 is an exception because it inhibits osteogenesis (29). BMPs interact with type IA or activin receptor-like kinase (ALK)-3 and type IB or ALK-6, and BMP type II receptors. Upon ligand binding, dimers of the type I and type II receptor initiate a signal transduction cascade activating the signaling mothers against decapentaplegic (Smad) or the MAPK pathways (30). The pathway used is dependent on the cell type, its degree of differentiation, and the state of dimerization of the BMP receptors. BMPs stimulate chondrocyte maturation and function and induce endochondral ossification and chondrogenesis (6). In cells of the osteoblastic lineage, BMPs induce the maturation of osteoblasts. By enhancing the expression of receptor activator of nuclear factor-κB ligand, BMPs induce osteoclastogenesis and increase bone resorption and, as a result, have the potential to cause bone loss (31).

Activin, a BMP-related protein, is constituted by homodimers and heterodimers of inhibin β_A and β_B subunits. Activin stimulates the release of FSH by pituitary cells, has mitogenic properties for cells of the osteoblastic lineage, favors osteoblastogenesis, and enhances osteoclastogenesis (32,33). Some studies have suggested inhibitory effects of activin on bone formation. Four activin receptors have been described, two type I (ActRIA or ALK-3 and ActRIB or ALK-6) and two type II (ActRIIA and IIB) receptors. Activin receptors do not activate BMP signaling, but BMP-3, an inhibitor of bone formation, binds to activin receptors (29). Recent studies have demonstrated that a soluble activin receptor type II fused to IgG-Fc can decrease bone resorption and enhance bone formation (34). The mechanism of the anabolic effect is not clear. It is possible that under certain circumstances activin has inhibitory activity on bone formation or that its soluble receptor, by binding the inhibitory BMP-3, causes an anabolic response.

The effects of BMPs are regulated by an extensive family of extracellular proteins, the BMP antagonists. Extracellular BMP antagonists bind BMPs and prevent BMP signaling. Often, their synthesis is induced by BMPs themselves, suggesting the existence of local feedback mechanisms necessary to modulate BMP activity. Of the many BMP antagonists described, noggin, gremlin, and twisted gastrulation have been characterized for their effects on skeletal tissue. Noggin overexpression causes osteopenia, but its inactivation may not result in a skeletal anabolic response due to its limited concentration in bone (35). Gremlin is a member of the “Differential screening– selected gene aberrative in neuroblastoma” (Dan) family of genes. Gremlin is detectable in the skeleton, its overexpression causes osteopenia and fractures, and its conditional inactivation in skeletal tissue results in increased bone formation (36,37). These observations make gremlin a potential therapeutic target. Because BMPs are critical for the differentiation and function of many cellular systems besides the skeleton, the global inactivation of a BMP antagonist, such as gremlin, often results in severe developmental abnormalities and lethality. The effects of BMP and other skeletal regulators that extend beyond the skeleton lead one to conclude that their activity should be targeted specifically to skeletal tissue to prevent potential unwanted effects at nonskeletal sites. It is of interest that gremlin expression is induced by high glucose concentrations, and gremlin is highly expressed in kidneys of experimental models of diabetes mellitus and in biopsy specimens of patients with diabetic nephropathy (38). Gremlin could play a role in the skeletal manifestations of diabetes either directly by blocking skeletal BMPs or indirectly by contributing to the renal disease. If this were the case, gremlin could serve as a therapeutic target in diabetic patients with nephropathy or skeletal disease.

IGF-I

IGF is a peptide synthesized in the liver and other tissues. The synthesis of IGF-I in the liver is GH dependent, and IGF-I mediates the effects of GH on longitudinal bone growth (8). The physiology of IGF-I is complex because it acts as a circulating GH-dependent hormone as well as a local growth factor (39). In bone cells, the production of IGF-I is primarily dependent on PTH, and IGF-I is required to obtain an anabolic response to PTH in bone (40,41). GH seems to play a modest role in the production of IGF-I in the skeletal tissue (42). Six IGF binding proteins control IGF-I transport, availability, and activity (8). IGF-I signals through a transmembrane tyrosine receptor, which activates the insulin receptor substrates (IRS) to initiate signaling through either the phosphatidylinositol-3 kinase-protein kinase B (PKB/Akt) or the MAPK pathway (43,44). IGF-I enhances the differentiated function of the osteoblast but does not induce the differentiation of mesenchymal cells toward a mature osteoblast. Whatever role IGF might have on osteoblast differentiation could be explained by an enhancement of Wnt signaling through the stabilization of β-catenin (45). IGF-I is necessary for skeletal development and the maintenance of bone mass (8). Overexpression of skeletal IGF-I results in an increase in cancellous bone volume secondary to an increase in bone formation without changes in osteoblast number, confirming that IGF-I plays only a minor role in cell replication and differentiation (46). IGF-I can increase the synthesis of receptor activator of nuclear factor-κB ligand by the osteoblast, and as a consequence it can enhance osteoclast recruitment and bone resorption (47,48). Several experimental models have demonstrated that circulating IGF-I contributes to cortical bone integrity, whereas skeletal IGF-I plays a more significant role in the maintenance of trabecular bone integrity (46,49,50). The importance of IGF-I in the maintenance of bone mass was substantiated in insulin receptor substrate (irs)-1 and -2 null mice (51). IRS’ are critical elements of IGF-I signaling, and irs-1 null mice develop low turnover osteoporosis.

Novel Approaches to Anabolic Therapies for Osteoporosis

Neutralization of Wnt antagonists

Sclerostin neutralization

Sclerostin, the product of the sost gene, inhibits osteoblastogenesis, and Irp5 mutations preventing interactions between sclerostin and the Wnt coreceptor cause increased bone mass syndrome. Mutations of sost resulting in absent expression of sclerostin are responsible for sclerosteosis and van Buchem disease. Both skeletal dysplasias are characterized by marked increases in bone mass (52,53). Sclerosteosis is caused by a mutation of sost near the amino terminus of the coding region, leading to the creation of a stop codon and absent sclerostin expression. Sclerosteosis is an autosomal recessive disease found in the Afrikaner population of South Africa and characterized by hyperostosis, syndactyly, facial palsy, deafness, and absent nails (52). van Buchem disease affects Dutch families and is caused by a deletion of an enhancer element downstream of the coding region of sost. van Buchem disease is characterized by endosteal hyperostosis of the skull and long bones, protruding chin, high forehead, and facial nerve palsy (53). It is noteworthy that individuals with sclerosteosis, as well as heterozygous gene carriers, have increased bone mineral density (BMD). The clinical findings in high bone mass syndrome, sclerosteosis, and van Buchem disease indicate that inactivation or neutralization of sclerostin could be used as an approach to enhance Wnt signaling and obtain an anabolic response in bone (27). It is reassuring that, except for the skeletal manifestations and those secondary to nerve compression, individuals suffering from these conditions live a fairly normal life. This would suggest that inactivation of sclerostin, and as a consequence activation of Wnt signaling in the skeleton, is a reasonably safe approach. Humanized monoclonal antibodies to sclerostin cause enhanced Wnt signaling and an increase in bone mass in rodents and nonhuman primates (54). Antisclerostin antibodies reverse the bone loss in ovariectomized rats, increasing trabecular bone volume and the structural properties of the skeleton in this model of osteoporosis (54). A subsequent phase I study in humans demonstrated that antisclerostin antibodies can increase BMD and biochemical markers of bone formation in humans. A phase II study is currently under way to assess the impact of a humanized antisclerostin antibody on BMD in postmenopausal women with low BMD.

Dickkopf-1 neutralization

Gain of function mutations of lrp5 that impair Dkk-1 interactions with LRP-5 cause increased bone mass (13). Dkk-1 levels are increased by glucocorticoids, explaining in part the suppression of bone formation in glucocorticoid-induced osteoporosis. These clinical observations, as well as those in mouse models of Dkk-1 misexpression, have established that Dkk-1 functions as an inhibitor of Wnt signaling and could be a potential therapeutic target for osteoporosis. This led to the development and testing of Dkk-1 antibodies in preclinical models. Dkk-1 neutralization causes an increase in BMD, trabecular bone volume, osteoblast surface, and bone formation in rodents, suggesting that Dkk-1, like sclerostin, neutralization could be pursued as an anabolic approach in the treatment of osteoporosis, but no studies in humans have been reported (55). Therefore, neutralization of sclerostin seems to be at a more advanced stage of development as a potential new treatment for osteoporosis.

Frizzled receptor-1 neutralization and alternate approaches to enhance Wnt activity

Recently, a small molecule antagonist of secreted frizzled receptor-1 was reported to enhance Wnt signaling and bone formation, offering a future nonbiological approach to the development of bone anabolic agents (56). Other potential ways to enhance Wnt signaling could entail the inhibition of GSK-3β, the kinase that phosphorylates β-catenin to initiate its degradation by the proteasome. Lithium chloride and other inhibitors of GSK-3β stabilize β-catenin and enhance Wnt signaling in osteoblasts (45,57). In vivo, lithium chloride increased bone formation in a preclinical model of multiple myeloma, but the skeletal benefit of lithium chloride in humans has not been established, and the side effects of lithium may make this approach impractical (58).

Areas of concern

Although the inactivation of Wnt antagonists is a novel and plausible approach for the development of bone anabolic agents, it is not without potential shortcomings. Indiscriminate Wnt activation could result in unwanted side effects and possible tumorigenicity in nonskeletal tissues. Activating mutations of the Wnt signaling pathway are associated with colorectal cancer, hepatocellular carcinoma, and other malignancies (59). The risk of these malignancies may be minimized by the relatively specific expression of sclerostin and Dkk-1 in skeletal cells. It is reassuring that patients with high bone mass syndrome and sclerosteosis have not been reported to have a higher incidence of malignancies. However, it is important to note that the promoter of the Wnt antagonist WIF is hypermethylated and epigenetically silenced in osteosarcoma, so that WIF is not expressed in 75% of human osteosarcomas, causing increased Wnt signaling (60). Furthermore, the inactivation of the Wnt antagonist WIF was found to predispose mice to osteosarcoma. These observations and findings from an experimental model of multiple myeloma, where activation of Wnt signaling rescues the skeletal disease but favors the invasion of soft tissue by myeloma cells, are concerns that may temper the enthusiasm for this anabolic approach (61). Potential solutions include the neutralization of Wnt antagonists specifically in skeletal cells and their use for limited periods of time.

Regulating BMP and activin signaling

Soluble activin receptors

Activin enhances bone resorption and has complex effects on bone formation (32). Recently, a soluble activin receptor II fused to IgG-Fc (ActRII-IgG1) was reported to increase bone volume in preclinical rodent models. The soluble receptor acts as a decoy receptor and binds activin, and as a consequence, it prevents the effects of activin on osteoclastogenesis and also elicits an anabolic response in mice (34). The mechanism of the anabolic effect may be the result of the binding of the inhibitor BMP-3 by the soluble activin receptor II (29). The ActRII-fusion protein increases trabecular bone mass and strength in rhesus monkeys; and in a phase I trial in humans, it was well tolerated and shown to increase markers of bone formation (62,63). Because activin stimulates the release of FSH by the pituitary, the serum levels of this hormone decrease after exposure to the agent. Phase 2 and phase 3 trials to determine the tolerability and efficacy of ActRII-fusion protein have not been reported.

Enhancing BMP signaling by targeting the osteoblast proteasome

BMPs are used locally for the treatment of nonunion fractures and to enhance the formation of spinal fusions. But, there is no information on their value for the treatment of osteoporosis. The systemic administration of BMPs would be limited by their nonskeletal effects, mitogenicity, and short half-life. A major pathway for intracellular protein degradation is the ubiquitin-proteasomal pathway, and this could be targeted with the use of specific inhibitors. Such inhibitors harbor skeletal anabolic activity (11,12). The mechanism involves inhibition of the proteolytic processing of intracellular proteins, and as a consequence enhanced BMP-2 expression. Although these findings suggest the potential value of proteasome inhibitors as future anabolic therapies for osteoporosis, their usefulness will depend on their specificity for skeletal tissue and their safety profile. This is a critical issue because proteasome inhibitors can induce cell toxicity and death, and the prolonged inhibition of proteasomal enzymes can lead to the unwanted intracellular accumulation of misfolded and damaged proteins (11). Another concern is that enhanced BMP activity can result in increased bone resorption so that despite the anabolic response, there may be no net gain in bone mass. Although proteasome inhibitors are being studied for their value in the management of various malignancies, there are no studies reported in humans to assess their potential as future therapeutic options for osteoporosis.

IGF-I

GH and IGF-I play an important role in the acquisition of bone mass during adolescence and in the maintenance of skeletal architecture during adult life (64). A decline in GH and IGF-I secretion and in the cortical bone content of IGF-I occurs during aging and may play a role in the pathogenesis of osteoporosis. There is a correlation between serum IGF-I levels and BMD in postmenopausal women, and igf1 promoter polymorphisms have been linked to bone mass (65). Recombinant human IGF-I is available for the treatment of severe growth retardation caused by IGF-I deficiency secondary to mutations of the gh receptor or the igf1 gene. Human studies to define the effects of IGF-I on bone turnover are limited. At high doses, IGF-I increases bone remodeling, whereas at low doses it increases bone formation without an effect on bone resorption (66). These observations would suggest that at low doses IGF-I can increase osteoblast function without an effect on bone resorption.

Anorexia nervosa is associated with bone loss and decreased serum levels of IGF-I, secondary to severe malnutrition (67). Although patients with anorexia nervosa are hypogonadal, estrogen replacement alone does not reverse the osteopenia. Administration of IGF-I at doses that normalize serum IGF-I, in combination with estrogen replacement therapy, increases BMD in anorexia nervosa (68). Notwithstanding these encouraging results, the long-term efficacy and safety of IGF-I for the treatment of osteoporosis, in the context or not of anorexia nervosa, remain to be determined. Side effects, the lack of tissue specificity, and the potential role of IGF-I in the development and propagation of malignancies are issues that need to be considered (69). Another consideration related to the use of IGF-I is the fact that systemic IGF-I might have a predominant role in cortical, but not trabecular, bone integrity. Other constraints are the expense, the need for parenteral administration, and the careful monitoring of the dose administered to avoid deleterious effects secondary to increased bone resorption. Although one may elect to use GH as an alternative to increase the levels of systemic IGF-I, the efficacy of GH replacement therapy has been documented only in the GH-deficient state, and it is not clear that GH has beneficial skeletal effects in the absence of GH deficiency (70,71). In postmenopausal osteoporotic patients, the effects of GH are inconsistent, and well-designed longitudinal studies to demonstrate fracture risk reduction in this condition have not been reported (72). Currently, there are no trials to assess the safety and efficacy of IGF-I in the treatment of postmenopausal osteoporosis.

PTH and its analogs

Currently, the only anabolic agent approved for the treatment of osteoporosis is PTH. The intermittent administration of low-dose PTH results in a skeletal anabolic response, secondary to direct effects of PTH on cells of the osteoblastic lineage and indirect effects through the regulation of selected skeletal growth factors (73,74). PTH induces IGF-I synthesis, inhibits sclerostin expression, and activates Wnt signaling. A limitation of PTH is the need for its daily sc administration. Therefore, alternate delivery systems, such as oral, transdermal, and intranasal have been tested, but their efficacy is uncertain. Another approach is the stimulation of endogenous PTH secretion by agents that interfere with the calcium-sensing receptor on the parathyroid cell. Oral calcilytic agents stimulate endogenous PTH secretion in rodents, and they are being studied for their effects in humans (75). The PTH-related peptide also is being examined for its potential anabolic effects in humans. Initial studies in postmenopausal women with osteoporosis suggested that PTHrP increases vertebral BMD (76).

Conclusions

During the past decade, we have witnessed significant progress in the understanding of cellular events that regulate osteoblastic cell differentiation and function. This is leading to the development of new agents that can enhance bone formation, and as a consequence might restore bone structure. BMPs, Wnt, and IGF-I are major factors regulating the fate and function of the osteoblast, and their activities are modulated by extracellular and intracellular proteins. Anabolic agents have a place in the management of severe osteoporosis and in specific forms of the disease characterized by decreased bone formation and remodeling, such as glucocorticoid-induced osteoporosis. Glucocorticoids interfere with Wnt signaling, impair osteoblastogenesis, and inhibit osteoblastic function directly and by inhibiting IGF-I synthesis (21). Consequently, a potential therapeutic target for glucocorticoid-induced osteoporosis could be the Wnt signaling pathway. PTH enhances IGF-I synthesis and Wnt signaling, and teriparatide (PTH 1-34) causes greater increases in BMD and in the reduction of new vertebral fractures than alendronate in glucocorticoid-induced osteoporosis (77). The administration of systemic growth factors for the management of osteoporosis is limited by a lack of skeletal specificity. The possibility of modifying the activity of an anabolic signal specifically in the skeletal environment could offer a novel therapeutic avenue for the treatment of osteoporosis.