Received: July 30, 2014 Revised: August 23, 2014 Accepted: September 16, 2014
Corresponding Author: Hee-Jeong Choi, Department of Family Medicine, Eulji University School of Medicine, 1306, Dunsan-dong, Seo-gu, Eulji University Hospital, Daejeon 302-799, Korea
Tel: +82-42-611-3231, Fax: +82-42-611-3776, E-mail: ohinia@daum.net
Emerging Anabolic Therapies for Osteoporosis
Hee-Jeong Choi, MD, PhD
Department of Family Medicine, Eulji University School of Medicine, Daejeon, Korea
Osteoporosis is defined as low bone mineral density (BMD) associated with fragility fractures. It is characterized by unbalanced bone remodeling activity leading to bone loss and eventually fractures.
Osteoporosis-related fractures are one of the leading causes of significant morbidity and disability in elderly and increase burden to patients, society, and healthcare systems. The goal of osteoporosis treatment is to prevent fractures. Present antiresorptive agents are effective, but they have relative lack of efficacy on nonvertebral fractures because their effects are restricted to remodeling-based activities.
Also, there is a great need for additional and reasonable anabolic agents in situations of severe osteoporosis and extensive bone loss. The two main bone anabolic pathways are parathyroid hormone (PTH) signaling and canonical wingless-int (Wnt)/β-catenin signaling. These pathways stimulate bone formation through increasing the activation frequency or direct activation of bone modeling or a combination of both. Especially, the discovery of the Wnt signaling pathway and its activity in bone tissue has led to the development of novel anabolic agents that can enhance Wnt signaling in skeletal cells.
This review aims at providing an overview of the currently available anabolic agents and an insight into promising investigational anabolic agents for the treatment of osteoporosis.
Key Words: Osteoporosis, Postmenopausal, Anabolic Agents, Therapeutics
Osteoporosis is defined as low bone mineral density (BMD) associated with fragility fractures. It is charac- terized by unbalanced bone remodeling activity leading to bone loss, microstructural deterioration of bone, and eventually fractures. The fractures most commonly occur in the spine, hip, or wrist, but other bone such as the trochanter, humerus, or ribs can be affected.
Recently performed the Korean Nationwide-database Osteoporosis Study (KNOS) reported that osteoporosis was present in 2.51 million people or approximately 19.3% of people over 50 years of age in Korea.1 The lifetime risks of osteoporosis-related fractures for indi- viduals over age 50 were estimated to be 59.5% for women and 23.8% for men.1 Osteoporosis-related frac-
tures are one of the leading causes of significant morbidity and disability in elderly and increase burden to patients, society, and healthcare systems.2 From a patient’s perspective, a fracture and the subsequent loss of mobility and independency often represent a reduction in quality of life. Moreover, osteoporotic fractures of the hip convey a 12-month excess mortality up to 18% in Korea, because they require hospitali- zation and they have subsequently enhanced risk of other complications, such as pneumonia or thrombo- embolic disease due to chronic immobilization.3 The goal of osteoporosis treatment is to prevent fractures. Present antiresorptive agents are effective, but some are limited by adverse effects, concurrent comor-
bidities, and inadequate long-term adherence. There is a great need for additional and reasonable anabolic agents in situations of severe osteoporosis and extensive bone loss. This review aims at providing an overview of the currently available anabolic agents and an insight into promising investigational anabolic agents for the treatment of osteoporosis.
CURRENT TREATMENT WITH ANTIRESORPTIVE AGENTS
Current therapeutic options for osteoporosis have comprised mostly antiresorptive agents, in particular bisphosphonates. The bisphosphonates were shown to reduce the risk of new vertebral, nonvertebral, and hip fractures. However, these agents reduce the risk up to 40～70% for vertebral fractures and around 20% for nonvertebral fractures,4-9 still 50 to 80% of these frac- tures cannot be prevented. Fundamentally, antiresorptive agents cannot restore bone mass and its structure. They only prevent further loss of bone and do not stimulate new bone formation. They have relative lack of effi- cacy on nonvertebral fractures because their effects are restricted to remodeling-based activities. Furthermore, the antiresorptive agents decrease the activation fre- quency, thus inducing a secondary decrease in bone formation rate, which in turn limits further increases trabecular bone mass.10 Recently, there are safety concerns with the long-term treatment of bisphospho- nates such as osteonecrosis of the jaw and atypical subtrochanteric fractures.11 In relation to the limitations of current antiresorptive agents, a search for new agents has focused on bone anabolic agents that increase bone formation directly without affecting bone resorption.
These anabolic agents have the potential to restore quantitatively and qualitatively normal bone.
BONE ANABOLIC PATHWAYS The two main bone anabolic pathways are parathyroid
hormone (PTH) signaling and canonical wingless-int (Wnt)/β-catenin signaling. These pathways stimulate bone formation through increasing the activation frequency or direct activation of bone modeling or a combination of both. The canonical Wnt pathway might be more dependent on bone modeling, potentially increasing bone mass independent of bone resorption and activation frequency.10 In contrast, PTH anabolic function is dependent on increasing the activation frequency, which may in part limit its therapeutic window.10
1. PTH pathway
Human PTH is an 84-amino acid peptide playing a central role in the maintenance of calcium homeostasis.
PTH is considered to have mixed catabolic and ana- bolic effects on the bone depending on the pattern and duration of PTH elevation. Bone exposed to sustained high levels of PHT shows a marked increase in activation frequency and bone resorption. Although trabecular bone is often preserved or even slightly increased, the enhanced bone resorption leads to an increased cortical porosity. Conversely, animal studies demonstrated that intermittent exposure to PTH could dissociate the bone anabolic response from the bone catabolic response, more obvious in the trabecular bone than in the cortical bone.12
PTH acts on PTH receptor (PTH1R) on osteoblasts or stromal cells. PTH increases the commitment of mesenchymal precursor cells to the osteoblast lineage, promotes osteoblast maturation, stimulates transfor- mation of lining cells into active osteoblast, reduces production of sclerostin, and inhibits osteoblast apoptosis, thereby increasing osteoblast number and function.13 As revealed recently, binding of PTH to the PTH1R also activates the canonical Wnt/β-catenin pathway in the absence of Wnt ligands by forming a complex with low-density lipoprotein receptor-related protein5/6 (LRP5/6).14 Intermittent PTH has been shown to increase the osteoblast number and their
activity, the bone remodeling rate along with the amount of bone deposited in each remodeling cycle, trabecular thickness and trabecular connectivity, and cortical thickness and bone size.15
2. Canonical Wnt/β-catenin pathway At the molecular level, activation of the canonical Wnt/β-catenin pathway is the master switch for osteoblastic differentiation. Wnts or Wnt ligands cons- titute a family of secreted, lipid-modified, cysteine-rich glycoproteins which play an important role in the regulation of cell differentiation and proliferation.16 In osteoblasts, Wnt ligands act either through the Wnt/β- catenin canonical pathway or the non-canonical (β- catenin independent) pathways. The non-canonical Wnt pathway includes Wnt/planar cell polarity signaling, the Wnt-cGMP/Ca2+ pathway, and a protein kinase A pathway but the net effect of their activation on bone metabolism is not fully clarified.17 In the Wnt/β- catenin pathway, when Wnt receptor binding interac- tions are absent, β-catenin is phosphorylated and degraded in the proteasome and cytoplasmic β-catenin levels are normally kept low through continuous degradation. On the other hand, in the presence of Wnt ligands (Wnt1, Wnt3A, Wnt8, and Wnt10b), β-catenin degradation is inhibited, resulting in its accumulation in the cytoplasm and its translocation into the nucleus, where nuclear β- catenin interacts with T cell-specific transcription factor/lymphoid enhancer-binding factor1 (TCF/LEF) to promote the transcriptional response of Wnt target genes.18 Wnt target genes including several osteoblast marker genes and osteoprotegerin (OPG), thus poten- tially activating bone formation and decreasing bone resorption at the same time.19
The Wnt/β-catenin canonical pathway is modulated by a complex network of extracellular antagonists, trans- membrane modulators or intracellular signals.20 In humans, known antagonists of the Wnt/β-catenin cano- nical pathway include Wnt Inhibitory Factor 1 (WIF-1), secreted frizzled related proteins (sFRPs), Dickkopf-1
(Dkk-1), and sclerostin. WIF-1 and sFRPs are extra- cellular proteins which bind to Wnt proteins, thus preventing them from activating the canonical and non-canonical Wnt pathway.21 On the other hand, Dkk-1 binds to transmembrane Dkk receptors (Kremens proteins) and forms a complex that internalizes LRP5/6, disrupting the Wnt/β-catenin canonical pathway.22 Sclerostin, the product of the SOST gene, produced almost exclusively by osteocytes, binds to LRP5/6 and antagonizes LRP5/6-mediated Wnt signaling.23
Certain genetic disorders provide insight into the effects of the enhancement or disruption of the Wnt signaling in in vivo models. The osteoporosis- pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder of severe juvenile osteoporosis and congenital blindness due to loss-of-function mutations in the LRP5 gene.24 Sclerosteosis and van Buchem disease caused by inactivating mutations in the SOST gene and deletion in regulatory elements of SOST transcription respectively, result in absence of sclerostin expression and progressive generalized high bone mass.25,26 Thus, these rare human genetic mutations demonstrated that Wnt signaling is a dominant regulator of bone density in humans.
EMERGING BONE ANABOLIC TREATMENT OPTIONS FOR
OSTEOPOROSIS
1. New approaches to PTH
To date, injectable forms of recombinant human PTH (rhPTH(1-34)) are the only approved anabolic drugs on the market for the treatment of osteoporosis. PTH(1-84) has been approved in several countries to treat osteo- porosis. Intermittent rhPTH administration not only attains documented efficacy in increasing bone mass and preventing fractures but also improves bone quality. In a study of postmenopausal women, teripara- tide administered as a 20μg daily subcutaneous injection increased vertebral BMD by 9% and femoral
BMD by 3% over 21-month. There was a 65% reduction in new vertebral fractures and a 53% reduction in nonvertebral fractures.27
rhPTH reduces the vertebral fracture risk much greater than that of hip or nonvertebral bones. This site-specific difference may be due to the remodeling- based increase in bone formation. Even if administered intermittently, chronic use of rhPTH increases bone formation in part through an increase the activation frequency (remodeling-based anabolic) and this ultimately leads to an increase in bone resorption.10 Although the net effect is still a gain in trabecular bone mass at early time points, it appears that bone resorption slowly catches up with bone formation, leading to a plateauing the net anabolic effect after 18～24 months.27
Many patients who are candidates for anabolic therapy with rhPTH have been treated previously with bisphosphonates or raloxifene. Although the results of clinical studies are inconsistent, it appears that alendro- nate that cause a potent decrease in bone turnover may sluggish response to rhPTH.28 Moreover, because discontinuation of rhPTH leads to a rapid decline in BMD, causing 4% bone loss in the first year after teriparatide withdrawal, it is advisable to use an antiresorptive agent after treatment with rhPTH in order to maintain the BMD gains achieved with rhPTH.29 rhPTH is expensive and is administered by daily subcutaneous injection. The recommended duration of teriparatide therapy (2 years in the US and 18 months in Europe) is relatively short because its safety and efficacy were not evaluated after 2 years in clinical trials. Although both teriparatide and PTH(1-84) are usually well tolerated, a few adverse effects are observed in patients, including hypercalcemia, nausea, headache, dizziness, and leg cramps. Reducing the impact of some of these limitations constitutes the basis for current attempts to use less frequently or different routes of hrPTH administration and to develop small molecules affecting the secretion of endogenous PTH.
1) Once-weekly rhPTH injection
Numerous studies show that the less frequent the doses, the higher the compliance. Nakamura et al,30 conducted the teriparatide once-weekly efficacy research (TOWER) trial for 72 weeks to determine whether once-weekly teriparatide (56.5μg) subcutaneous injec- tion would reduce the risk of vertebral fractures in subjects with primary osteoporosis including older men and postmenopausal women. Treatment with once- weekly injection of teriparatide significantly decreased the risk of new vertebral fractures by 80% compared with placebo. At 72 weeks, once-weekly teriparatide injection increased BMD by 6.4% and 2.3% at the lumbar spine and femoral neck respectively. Even though the dropout rates by adverse events were more frequent in teriparatide group, but adverse events were generally mild and tolerable. On the other hand, Black et al,31 studied the efficacy of once-weekly PTH(1-84) injection in postmenopausal women who had a total hip BMD T-score of -1.0 and -2.0, and no history of osteoporotic fractures or presence of morphometric fractures on x-ray. At 12 months, spine areal BMD and volumetric BMD increased 2.1% and 3.8%, respec- tively, in once-weekly PTH(1-84) treated women compared with placebo. Weekly subcutaneous adminis- tration of teriparatide or PTH(1-84) may provide another option of treatment in patients with osteoporosis.
2) Teriparatide-coated microneedle patch
A novel transdermal patch may provide a desirable alternative to daily subcutaneous teriparatide injections.
Zosano Pharma is developing products using a novel transdermal microneedle drug delivery system (MacrofluxⓇ, ALZA Corp). The patch system incorpo- rates a drug-coated titanium microneedle array and a reusable applicator. A patch coated with 40μg (ZP-PTH 40) were applied to the lateral abdomen and worn for 30 min. In phase I study, ZP-PTH patch delivery demonstrated a rapid PTH plasma pulse profile with Tmax 3 times shorter and apparent T1/2 2 times shorter
than teriparatide.32 In phase II study, ZP-PTH 20, 30 and 40μg doses showed a proportional increase in plasma PTH AUC. All patch doses produced a significant increase in spine BMD. Moreover, the ZP- PTH 40μg dose showed a statistically significant increase in total hip BMD at 6 months (1.3%, P<0.05) over both placebo and teriparatide injection.33 These studies suggest that this novel ZP-PTH patch system can deliver a consistent and therapeutically relevant PTH PK profile.
2. PTH-related protein (PTHrP)
PTHrP is currently being studied for its potential anabolic effects in humans. PTHrP acts as a paracrine regulator in several tissues, including cartilage, mam- mary, developing tooth, central nervous system, and smooth muscle.34 It is also considered the most common cause of humoral hypercalcemia of malig- nancy.35 Although PTHrP and PTH are products of different genes, PTH and PTHrP show structural homology within the 1–13 and 29–34 sequences of both polypeptides. This partial homology determines their interaction with a common G-protein coupled receptor, the PTH/PTHrP receptor (PTH1R) in their target cells, such as osteoblasts and renal tubular cells.36 Further- more, primary sequences of PTH and PTHrP com- pletely differ beyond this N-terminal region which suggests that these proteins might exhibit distinct bioactivities.
Intermittent administration of PTHrP(1-34) has been found to increase bone mass in a small group of postmenopausal women with low BMD or osteoporosis tested over a short period of time (3 months).37 In this study, the principal observations are that PTH(1-36) and PTHrP(1-34) cause similar increases in spine BMD but PTHrP(1-36) also significantly increased hip BMD.
PTH(1-34) induced greater changes in bone turnover markers than PTHrP(1-36) even dough PTHrP(1-36) was associated with mild transient hypercalcemia. In phase 2 placebo-controlled study, abaloparatide (synthetic
analog of PTHrP(1-34)) 80μg subcutaneous daily significantly increased spine and total hip BMD at 24 weeks by 5.1% and 2.2% respectively, compared to placebo.38 Teriparatide 20μg subcutaneous daily also increased spine BMD by 3.9%, but had no significant effect on total hip BMD compared to placebo. The bone turnover markers, especially those of resorption were substantially higher with teriparatide compared to abaloparatide.
In another study, a short-wear-time transdermal patch coated with various doses of abaloparatide increased spine and total hip BMD at 24 weeks.39 The increases seen with abaloparatide 80μg subcutaneous daily were somewhat greater than those with abaloparatide transdermal patch. However, the increases in hip BMD at 24 weeks with all three doses of abaloparatide transdermal patch greatly exceeded those seen with teriparatide in a previously mentioned phase 2 study at the same time point.38,39 Abaloparatide is currently in a phase 3, 18-month, placebo- and teriparatide-controlled fracture study (NCT01343004). Abaloparatide is a one of promising therapy for osteoporosis treatment.
3. Calcium sensing receptor (CaSR) anta- gonists
Theoretically, pulsatile PTH could be achieved by acutely stimulating the release of endogenous PTH by inhibiting the CaSR.34 It has been suggested that transient, short-acting antagonists of the CaSR, resulting in transient, rapid bursts in PTH, would favor new bone formation, mimicking intermittent PTH administ- ration.40 However, the study in which a ronacaleret, an oral CaSR antagonist, has been used in postmenopausal women with low bone mass only showed that a ronacaleret increased spine BMD at 10-12 months and the magnitudes of these changes were substantially smaller than that attained with either alendronate or teriparatide.41 Moreover, total hip BMD was even slightly decreased after 12 months of treatment with ronacaleret compared with the increase seen with
rhPTH or alendronate. The effects of ronacaleret on intact PTH, serum calcium, and bone turnover markers, along with densitometric effects, suggest that ronaca- leret may induce a mild hyperparathyroid state.41 The result from the bone turnover markers suggest that the anabolic window is too narrow to create a bone anabolic effect. These disappointing results have led to the interruption of the clinical development of this compound for osteoporosis treatment.
4. Antagonists of Wnt inhibitors
SOST expression is limited to skeletal tissue. The inhibition of sclerostin is a particularly attractive target because it would affect bone but limit the risk of off-target effects.19 Romosozumab (AMG 785/CDP7851, Amgen and UCB Pharma) is a humanized monoclonal anti-sclerostin antibody. In a phase 1 study, single injections of romosozumab stimulated bone formation, decreased bone resorption, and increased BMD in healthy men and postmenopausal women.42 In post- menopausal women with low bone mass, romosozumab was associated with not only increased BMD and bone formation but also decreased bone resorption, resulting in a large anabolic window. In a phase 2, multicenter, international, randomized, placebo-controlled, parallel group, eight-group study, all dose levels of romoso- zumab were associated with significant increases in BMD at the lumbar spine, including an increase of 11.3% with the 210 mg monthly dose, as compared with a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide.43 Romosozumab was also associated with large increases in BMD at the total hip and femoral neck, as well as transitory increases in bone formation markers and sustained decreases in a bone resorption marker. Except for mild, generally nonrecurring injection-site reactions with romosozumab, adverse events were similar among groups. The increase in BMD at the lumbar spine and proximal femur was rapid and substantial with romoso- zumab by 3 months, and by 6 months the increase was
greater with the 210 mg monthly dose of romoso- zumab than with either active comparator.43 The effects of romosozumab on bone turnover reflect a rapid, marked, and transitory increase in bone formation and a moderate but more sustained decrease in bone resorption. The consequence of these divergent effects on bone formation and bone resorption with romo- sozumab is a strongly positive balance in bone turnover, accounting for the rapid and large increases in BMD. Two additional phase II fracture healing studies with romosozumab have been completed (NCT00907296, NCT01081678). In addition, recruitment for phase III studies in postmenopausal osteoporosis has recently begun to evaluate the effectiveness of romosozumab to reduce fracture risk in women with postmenopausal osteoporosis (NCT01631214). If successful, romosozumab may be an important treatment option for patients with severe osteoporosis who are in need of skeletal restoration.
POTENTIAL CONCERNS WITH BONE ANABOLIC AGENTS
Tumor formation is a general concern with bone anabolic agents. Factors that have limited to use of rhPTH are its cost and concerns about its potential link to osteosarcoma. Currently, treatment of osteoporosis with rhPTH is limited to 24 months in the U.S. and 18 months in Europe due to the risk of cancer because treatment of rats with high doses of rhPTH 1-34 increased the prevalence of osteosarcoma.44 However, it should be noted that at present no connection has been demonstrated between elevated serum PTH levels in the context of hyperparathyroidism or rhPTH treatment and the occurrence of osteosarcoma in humans.
Wnt signaling has been associated with human malig- nancies such as colorectal and hepatocellular carcinoma.
More importantly, the WIF-1, an endogenous inhibitor of Wnt signaling was absent in 75% of osteosarcomas leading to enhanced Wnt signaling.45 Findings from an
experimental model of multiple myeloma revealed that the activation of Wnt signaling rescues the skeletal disease, but favors the invasion of soft tissue by myeloma cells.46 Although patients with van Buchem’s disease and sclerosteosis carry no increased risk of malignancies, long-term blockade and Wnt antagonists needs careful monitoring for skeletal and extraskeletal safety.47 These observations are a concern, and this class of anabolic agents will probably be used for limited periods of time to obtain a rapid increase in bone mass, which can then be stabilized by anti- resorptive agents.48
Patients with lifelong homozygous or heterozygous genetic deficiency of sclerostin provide insight into the expected safety of inhibiting sclerostin signaling.
Homozygous persons exhibit bony overgrowth and skeletal deformity, especially of the skull and face, which are observed during growth and which can result in symptoms related to compression of the VII and VIII cranial nerves. However, heterozygous carriers of the SOST mutation have
increased bone density and modestly increased markers of bone formation but none of the sequelae of bony overgrowth.49,50 These potential complications due to bone overgrowth can be avoided by pharmacological inhibition of sclerostin over a limited period of time in adults.
CONCLUSION
With the exception of teriparatide, all the agents currently available reduce bone resorption. Although emphasis is being placed in the development of new anabolic agents, new antiresorptive agents are being pursued with the hope to develop therapies with good efficacy, tolerability, and simplicity of administration.
Anabolic agents will 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 osteo-
porosis. The administration of systemic growth factors for the management of osteoporosis is limited by a lack of skeletal specificity and potential adverse effects. The discovery of the Wnt signaling pathway and its activity in bone tissue has led to the development of novel anabolic agents that can enhance Wnt signaling in skeletal cells. Efforts should target anabolic signals specifically in the skeletal environment as new thera- peutic avenues for the treatment of osteoporosis emerge.
Conflict of Interest: None REFERENCES
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