|Year : 2018 | Volume
| Issue : 1 | Page : 13-21
Recent advances and current trend in the pharmacotherapy of postmenopausal osteoporosis
Olumuyiwa John Fasipe1, Oluwatosin Beatrice Ibiyemi1, Alex Adedotun Adelosoye2, Ayodeji Adebayo Idowu3
1 Department of Pharmacology and Therapeutics, University of Medical Sciences, Ondo City, Ondo State, Nigeria
2 Department of Family Medicine, University of Medical Sciences, Ondo City, Ondo State, Nigeria
3 Department of General Surgery, Ekiti State University Teaching Hospital, Ado-Ekiti, Ekiti State, Nigeria
|Date of Submission||09-Dec-2017|
|Date of Acceptance||24-Jan-2018|
|Date of Web Publication||30-Apr-2018|
Dr. Olumuyiwa John Fasipe
Department of Pharmacology and Therapeutics, University of Medical Sciences, Ondo City, Ondo State
Source of Support: None, Conflict of Interest: None
Estrogen deficiency (most especially low level of β-estradiol isoform) is the major contributing factor to bone loss after menopause. Supplementation with calcium and Vitamin D is an essential baseline therapy for osteoporosis prevention and treatment. Newer emerging agents that will further expand osteoporosis therapeutic options include strontium compound (a bone selective calcium-sensing receptor [CaSR] agonist or calcimimetic which is currently licensed for use in Europe but not in the US that has both osteoanabolic and antiresorptive activity); Lasofoxifene (a new selective estrogen receptor modulator [SERM] or estrogen agonist-antagonist [EAA] with partial agonist activity at both estrogen receptors ERα and ERβ); odanacatib and balicatib (inhibitors of the resorptive enzyme cathepsin K); abaloparatide (a parathyroid hormone [PTH]-related protein analog); ostabolin-C (a new cyclicised PTH analog); romosozumab and blosozumab (monoclonal antibody inhibitors to sclerostin) which are currently undergoing clinical trial for Food and Drug Administration approval. Other agents in preclinical development include anti-dickkopf antibody (BHQ880) which targets specific protein molecules of the Wnt/β-catenin pathway involved in stimulating new bone formation by osteoblast cells; parathyroid selective short-acting calcium-sensing receptor antagonists or calcilytics (SB-423562, SB-423557, JTT-305/MK-5442, and NPS-2143) that will lead to a transient release of PTH from the parathyroid glands; and saracatinib (a novel orally available competitive inhibitor of the enzyme Src kinase and Abl kinase family shown to inhibit osteoclast-mediated bone resorption). This review article discusses these newer evolving agents that will introduce and incorporate remarkable improvements into the management of postmenopausal osteoporosis in the nearer future.
Keywords: Antiresorptive agents, current trend, osteoanabolic agents, osteoporosis, pharmacotherapy, postmenopausal, recent advances
|How to cite this article:|
Fasipe OJ, Ibiyemi OB, Adelosoye AA, Idowu AA. Recent advances and current trend in the pharmacotherapy of postmenopausal osteoporosis. J Health Res Rev 2018;5:13-21
|How to cite this URL:|
Fasipe OJ, Ibiyemi OB, Adelosoye AA, Idowu AA. Recent advances and current trend in the pharmacotherapy of postmenopausal osteoporosis. J Health Res Rev [serial online] 2018 [cited 2020 Jul 2];5:13-21. Available from: http://www.jhrr.org/text.asp?2018/5/1/13/231531
| Introduction|| |
Postmenopausal osteoporosis (PMO) is usually a subtle, asymptomatic disease in most cases, with no obvious clinical manifestation until fractures occur. It is characterized by low bone mineral density (BMD) and changes in bone microarchitecture that reduce bone strength and increase fracture risk., Supplementation with calcium and Vitamin D is an essential baseline therapy for osteoporosis prevention and treatment. Bone remodeling is important for a healthy skeletal growth through phagocytosis of dead and senile bone tissues by the osteoresorptive action of osteoclasts, while osteoblasts account for the osteogenesis of new bone matrix.,, Estrogen deficiency (most especially low level of β-estradiol isoform) is the major contributing factor to bone loss after menopause. Low estrogen level during the menopausal period induce an increase in the receptor activator for nuclear factor-κB ligand (RANKL) production by cells of the osteoblastic lineage and activated T-cells with a corresponding decrease in osteoprotegerin (OPG) secretion from osteoblasts, fibroblasts, endothelial cells, smooth muscle cells, lymphoid cells, and other cell types. Free RANKL bind to activate its RANK receptor on the surface of the preosteoclast precursors, which induces their differentiation and activation to mature osteoclast cells  [Figure 1]. At the molecular level, there is upregulation of intracellular signal transducers which are involved in cytoskeletal organization, cell motility, growth, and survival. Some of the signal transducers also bind nuclear factor-κB (NF-κB) which after ubiquitination and degradation by proteasomes, releases free NF-κB into the cytoplasm. Accumulated NF-κB can then migrate to the nucleus where it upregulates transcriptional regulators that start osteoclastogenic gene transcription [Figure 2]. This imbalance that tilted in favour of the osteoclastic bone resorption pathway at the expense of the osteoblastic bone formation will result in fast bone loss and increase risk of fractures., Bone remodeling needs a complex array of proliferating factors: hormones; growth factors; Vitamins D and K; and cytokines such as macrophage colony-stimulating factor (M-CSF), RANKL, and notably OPG. The OPG/RANK/RANKL and Wnt/β-catenin canonical signaling pathways are responsible for maintaining the balance between the activity of osteoblasts and osteoclasts to prevent bone loss and ensure a normal bone turnover. Bone turnover through the OPG/RANK/RANKL pathway involves the maturation of osteoclast precursors into multinucleated preosteoclast cells under the influence of proliferating factors.,,,,, Each of the multinucleated preosteoclast cells differentiates into an activated osteoclast in the presence of M-CSF and RANKL. Once activated, the osteoclasts start degrading bone surface to form a lacuna by secreting hydrochloric acid and enzyme proteinases such as the collagenases cathepsin K, L, and V that dissolve calcium phosphate hydroxyapatite crystals and degrade Type I collagen fibers of bone matrix respectively [Figure 1]. Thereafter, OPG antagonizes the persistent binding of RANKL on RANK receptors, thereby leading osteoclasts to their apoptosis. Finally, bone formation process starts with the preosteoblasts that have matured into osteoblasts to synthesize new bone osteoid matrices.,,,,,,,
|Figure 1: RANK/receptor activator for nuclear factor-κB ligand/osteoprotegerin signaling system in bone|
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|Figure 2: Receptor activator for nuclear factor-κB ligand molecular signaling pathway|
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| Current Therapeutic Approach to the Management of Postmenopausal Osteoporosis|| |
Prevention is an important part of dealing with any disease. Non-pharmacological approach to the prevention of PMO involves considerable lifestyle changes such as smoking cessation, limiting alcohol intake, decrease caffeine consumption, nutritional guidance in addition to dietary supplementation, and physical exercise.,,
Currently available pharmacological agents for PMO include calcium and Vitamin D supplementation; bisphosphonates such as alendronate, risedronate, or zoledronate; hormone therapy with conjugated equine estrogen; selective estrogen receptor (ER) modulators/estrogen agonist-antagonists (SERMs/EAAs) such as raloxifene or bazedoxifene; denosumab; salmon calcitonin; and parathyroid hormone (PTH) analogs such as teriparatide or rhPTH1-84.,, Most of these drugs (with the exception of PTH analogs) are antiresorptive agents that improve bone strength and reduce the risk of fracture primarily by decreasing bone turnover and maintaining or increasing BMD. PTH analogs are osteoanabolic agents that exert their effects primarily by increasing bone formation ,,, [Table 1].
|Table 1: Osteoporosis therapies currently approved by the United States Food and Drug Administration|
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The National Osteoporosis Foundation guideline recommends starting with a bone formation medication such as teriparatide first and then switching over to an antiresorptive agent such as bisphosphonate or denosumab after 2 years of its use. However, the challenge and limitation hindering clinicians from adhering to this guideline today is the expensive cost of teriparatide.
While the guideline from the American Association of Clinical Endocrinologists (AACE), published in 2010, include the following recommendations for choosing drugs to treat osteoporosis:
- First-line agents: alendronate, risedronate, zoledronic acid, denosumab
- Second-line agent: ibandronate
- Second- or third-line agent: raloxifene (SERMs)
- Last-line agent: calcitonin
- Treatment for patients with very high fracture risk or in whom bisphosphonate therapy has failed: teriparatide.
| Newer Osteoporosis Therapeutic Approach and Their Mechanisms of Action|| |
Lasofoxifene – new selective estrogen receptor modulators/estrogen agonist-antagonists
Lasofoxifene is a partial agonist that binds to both ERα and ERβ with significant affinity. It has a longer half-life with an improved oral bioavailability compare to raloxifene. The PEARL (Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene) study evaluated the dose of 0.5 mg/day among 8556 women with osteoporosis and showed a reduction of the vertebral fracture risk by 42% (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.47–0.70) at 3 years, and nonvertebral fractures, primarily forearm and wrist by 24% (HR 0.76; 95% CI, 0.64–0.91) at 5 years; reduced risk of estrogen receptor (ER)-positive breast cancer (HR 0.19; 95% CI, 0.07–0.56), coronary heart disease (HR 0.68; 95% CI, 0.50–0.93), and stroke (HR, 0.64; 95% CI, 0.41–0.99), but increased the risk of venous thromboembolic events, vasomotor symptoms, and leg cramps. There was also an increased risk of uterine polyps and endometrial hypertrophy, but no increased risk of endometrial cancer nor hyperplasia. A new drug application for lasofoxifene was submitted to the United States' Food and Drug Administration in September 2008, but license request was declined with a response demanding for more background information on the drug. Currently, lasofoxifene at a dose of 0.5 mg/day is licensed for the treatment of PMO by the European Union Medicine Agency counterpart in 2009 and is available as a prescription drug over there.,,
Ostabolin-C – new cyclicised parathyroid hormone analog
Intermittent administration of low-dose PTH analog enhances osteoblastic activity and bone formation without stimulating bone resorption. Ostabolin-C mechanism of action involves stimulating the same PTH-1 type receptor activated by teriparatide and rhPTH1-84. But unlike teriparatide (or rhPTH1-84) that activates both adenylyl cyclase and phospholipase C; ostabolin-C activates only adenylyl cyclase alone but no action on phospholipase C. These selective mode of actions reduce its adverse/side effects. The simultaneous use of bisphosphonates will enhance BMD improvement and attenuate fracture risk seen with ostabolin-C alone. It is advised that maximum treatment duration should not exceed 2 years with ostabolin-C because laboratory studies with animals revealed an increased risk of osteosarcoma. Ostabolin-C should be avoided in children, adolescents, Paget's bone disease, bone metastasis, skeletal irradiation, or unexplained elevations of bone specific alkaline phosphatase because of the increased tendency to develop osteosarcoma.,,
Strontium compounds – bone selective calcium-sensing receptor agonist/calcimimetic
Strontium ranelate has not been licensed by the Food and Drug Administration (FDA) in the United States but is currently being used in the European Union for the treatment of osteoporosis. It has two atoms of strontium bound to an organic anion, ranelic acid. Strontium malonate is another similar compound that is currently being investigated in clinical trials (phase II study completed) by the FDA for the treatment of osteoporosis. The pharmacodynamics actions of strontium are mainly mediated via calcium-sensing receptors (CaSR) on the osteoblasts. It is a bone selective calcium-sensing receptor [CaSR] agonist (i.e, bone selective calcimimetic) that stimulates osteoblastic activity through the phospholipase C dependent phosphatidyl inositol 4,5 bisphosphate (PIP2)- diacylglycerol (DAG)- inositol triphosphate (IP3) pathway in order to downregulate the OPG/RANK/RANKL signalling; while at the same time upregulating the Wnt/β-catenin canonical signalling. Strontium ranelate blocks the differentiation and maturation of pre-osteoclasts to mature osteoclasts and promotes their apoptosis, thus inhibiting bone resorption process; but at the same time, it also enhances and promotes the differentiation and maturation of pre-osteoblasts to osteoblasts which increase new bone formation. This shows that strontium has both antiresorptive and osteoanabolic activity. The antiresorptive activity of strontium is mediated via the CaSR to promote the inhibition of RANKL synthesis thereby leading to a reduction in RANKL-induced nuclear translocation on the osteoclasts and also due to increase production of OPG that will antagonises the continuous binding of RANKL to its RANK receptors on the membrane surface of osteoclasts. While the osteoanabolic activity of strontium is also being mediated via activation of the same CaSR on osteoblastic cells which further leads to the activation and upregulation of the Wnt/β-catenin canonical signalling pathway that subsequently leads to the release of nonphosphorylated β-catenin from a signal transducer proteasome complex containing glycogen synthase kinase 3β (GSK3β), and its subsequent accumulation and translocation into the nucleus. In the nucleus, nonphosphorylated β-catenin then binds with the T-cell transcription factor (TCF)/lymphoid enhancer-binding factor (LEF) and initiates target gene transcription that leads to increased osteoblastic activity and new osteoid matrix formation.,,, Large clinical trials have demonstrated its efficacy in increasing BMD and decreasing fractures in the spine and hip. Toxicities reported thus far are similar to placebo. It should be avoided in individuals who had high tendency to develop venous thromboembolism, current or history of ischemic/coronary heart disease, peripheral arterial disease and/or cerebrovascular disease, those with poorly controlled hypertension, and temporary or permanent immobilization. Administration of strontium has been shown to prevent bone loss associated with estrogen deficiency. Findings in other models of osteopenia indicate an increase in bone formation with strontium. The results of in vitro studies suggest that this may be the result of strontium's role in influencing bone cell recruitment and function. As strontium has a higher atomic number than calcium, it attenuates more X-rays than calcium does. This attenuation can result in an overestimation of BMD if adjustment factor for bone strontium content is not being done.,
Cathepsin K inhibitors – odanacatib and balicatib
Cathepsin K is a major collagenase lysosomal enzyme produced by the osteoclast to break down the bone matrix during osteoresorption process [Figure 1]. Odanacatib (MK-0822) and balicatib (AAE581) are antiresorptive agents that specifically inhibit this enzyme [Figure 3].
|Figure 3: New drug targets in RANK/receptor activator for nuclear factor-κB ligand/osteoprotegerin signaling system|
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Odanacatib is currently, the most potent inhibitor of cathepsin K and the most advanced in clinical research. Its oral bioavailability depends on the formulation, but being higher than the oral bioavailability of bisphosphonates. It is metabolized by cytochrome P450 enzymes and it may interact with other medications. Studies with odanacatib shows that oral doses of 50 mg and 100 mg, once a week, reduce serum concentrations of the C-terminal telopeptide of collagen type 1 (CTXs), a marker of bone resorption, by 62%, while daily administration of odanacatib (100 mg) reduces serum concentrations of CTXs by 81%. Odanacatib is a lipophilic compound with poor solubility, the dosage of fat in the diet increases the secretion of bile, which can further increase the dissolution of the drug. Pharmacokinetic studies showed that foods with high-fat content increase the area under the curve of this cathepsin K inhibitor by approximately 110%. A high-fat content breakfast before dosing, for doses of 25–300 mg, produced an approximately two-fold increase in plasma concentrations in relation with fasting.,,,,,,
Balicatib (AAE581) is a highly selective cathepsin K inhibitor, but it is not so selective in the cells because of its high concentration in the lysosomes. Previous studies showed that it reduced bone resorption markers (CTXs and NTXu) with no change in bone formation markers and was associated with a dose-related increase in BMD at the lumbar region and total hip with the weekly dose of 50 mg. Despite these results, it was discontinued due to adverse events related to the skin, including drug-induced eruptions and scleroderma-like, morphea lesions.
Relacatib acts nonselectively on cathepsins K, L, and V. Clinical trials with this drug were stopped, after Phase I, due to the drug–drug interactions with commonly prescribed medications such as acetaminophen, ibuprofen, and atorvastatin.
Parathyroid hormone-related protein analog – abaloparatide
Abaloparatide is a PTH-related protein (PTHrP) analog drug recently approved by the United states' Food and Drug Administration (FDA) in March 2017 for the treatment of osteoporosis. Like the other related drugs – teriparatide and ostabolin-C, but unlike bisphosphonates, it is an osteoanabolic (bone growing) agent. Abaloparatide interacts differently with the PTH receptor than does teriparatide, resulting in less stimulation of bone resorption and a greater osteoanabolic effect. In earlier studies, abaloparatide increased BMD more (and faster) than did teriparatide, suggesting that abaloparatide might be an effective therapy for osteoporosis in the nearer future as it will be a better substitute and replacement for teriparatide in both the IOF and AACE guidelines. A subcutaneous injection formulation of the drug has completed a Phase III trial for osteoporosis, and a transdermal patch formulation is also in development.,
Anti-sclerostin and anti-dickkopf-1 antibodies
Sclerostin is a protein product of the SOST gene produced almost exclusively by osteocytes and some chondrocytes; and its function is to prevent and inhibit the Wnt (wingless)/β-catenin pathway mediating osteoblastogenesis. Sclerostin production is inhibited by PTH, mechanical loading, and cytokines including prostaglandin E2, oncostatin M, cardiotrophin 1, and leukemia inhibitory factor. Sclerostin production is increased by calcitonin. Thus, osteoblast activity is self-regulated by a negative feedback mechanism system. The activation of Wnt/β-catenin pathway in the cell membrane of osteoblasts strongly induces bone formation.,
Wnt/β-catenin signaling is activated by 1 of 19 secreted Wnt proteins binding to 1 of 10 frizzled receptors, to initiating signaling cascade which results in the release of nonphosphorylated β-catenin from a signal transducer proteasome complex containing glycogen synthase kinase 3β (GSK3β), and its subsequent accumulation and translocation into the nucleus [Figure 4]. In the nucleus, nonphosphorylated β-catenin then binds with the T-cell transcription factor (TCF)/lymphoid enhancer-binding factor (LEF) and initiates target gene transcription that leads to increased osteoblastic activity and osteoid formation.,, LRP5 is a co-receptor along with the frizzled receptors for Wnt proteins. Both sclerostin and dickkopf-1 protein (DKK-1) block the binding of Wnt protein to LRP5 (or the related LRP6 receptor), thereby antagonizing osteoblast stimulation.,, Sclerostin and DKK-1 are part of the four proteins that negatively regulate the Wnt/β-catenin canonical signaling pathway. While activation of Wnt pathway mediates the translocation of nonphosphorylated β-catenin into the nucleus with consequent activation of TCF/LEF, the binding of either sclerostin or DKK-1 to LRP5/6 and Kremen receptors ultimately induces β-catenin degradation by the proteasome complex containing GSK3β [Figure 4]. Wnt pathway is active both in embryonic as well as in adult life. It is involved in cell proliferation, motility, and apoptosis, while in embryos, it regulates the development of head and limbs as well as heart formation., Wnt pathway is also implicated in the regulation of the hematopoietic stem cell niche; and in adult life, it maintains bone homeostasis and bone mass, enhancing osteoblast differentiation and function. Sclerostin and DKK-1 not only affect osteoblastogenesis through the modulation of OPG/RANKL ratio but also affect osteoclastogenesis indirectly because sclerostin or DKK-1 promotes RANKL synthesis/secretion while inhibiting OPG synthesis/secretion by osteoblasts. More interestingly, given that osteoclasts and osteoblasts are an integral part of the bone marrow microenvironment, the effect of Wnt/DKK-1 antagonism may affect tumor growth negatively through impact on the bone marrow milieu as seen in multiple myeloma (MM).,,,,, Sclerostin and DKK-1 molecules are produced only by bone tissues under normal physiologic conditions. Recently researches have shown that certain pathological conditions such as rheumatoid arthritis, malignant breast cancer cells, renal cancer cells, MM cells, and osteolytic phenotype of prostate cancer cells elaborate and secrete very high amount of soluble DKK-1 into the systemic circulation which is responsible for their osteolytic and osteoporotic effects on vertebral and nonvertebral bone tissues. DKK-1 is an important regulator of bone formation in the bone microenvironment, while its broad expression in MM and other osteolytic malignant tumors but highly restricted expression in normal tissues, together with its functional roles as an osteoblast formation inhibitor and a potential myeloma growth enhancer, make DKK-1 an ideal and universal target for immunotherapy.,
|Figure 4: Wnt/β-catenin canonical pathway in osteoblasts. Antibodies to both sclerostin (romosozumab, blosozumab) and dickkopf-1 protein (BHQ880) are potential osteoanabolic agent (osteoblast-stimulating) for osteoporosis therapies|
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Romosozumab and blosozumab are humanized monoclonal antibody against sclerostin that has shown promising therapeutic goal for the treatment/prevention of osteoporosis. Both agents are still undergoing clinical trial for the FDA approval., Romosozumab and blosozumab are antagonists of sclerostin in the Wnt/β-catenin pathway. BHQ880 is a humanized monoclonal antibody (mAb) against DKK-1 that is presently under preclinical trial for the treatment of nontumor-induced and tumor-induced osteoporotic bone disease based on promising results in animal models. This fully human anti-DKK-1 mAb (BHQ880) has demonstrated improvement in the bone parameters of murine models and also appears to have direct effects on the MM cell growth, possibly through interactions with the bone marrow stem cells and the interleukin-6-related pathways. Some researchers are also evaluating BHQ880 in combination with zoledronic acid in a Phase II study for treating patients with relapsing/refractory MM (NCT00741377) and studies in early MM (i.e., smoldering MM) are also underway.,, Individually, romosozumab, blosozumab, and BHQ880 have both osteoanabolic and antiresorptive activity. Therapies that focused on other molecules in the Wnt/β-catenin pathway, for example, lithium chloride as an inhibitor of GSK3β (the enzyme that degrades β-catenin in the absence of Wnt protein signalling ) is not a suitable option because of its widespread systemic distributions.,
| Parathyroid Selective Short-Acting Calcium-Sensing Receptor Antagonists (Calcilytics)|| |
Parathyroid selective short-acting calcium-sensing receptor antagonists (calcilytics) enhance and promote transient release of PTH from the parathyroid glands due to their short half-lives. Calcilytics are chemical substances that enhance PTH secretion by antagonizing CaSR in the parathyroids and their effect is usually osteoanabolic in nature. Short-acting CaSR antagonists under experimental consideration are SB-423562, SB-423557, JTT-305/MK-5442, and NPS-2143. They elicit transient PTH release from the parathyroid gland in several preclinical species and in humans. Their osteoanabolic effects on bone tissues are not associated with hyperplasia of the parathyroid glands. Data from early proof of principle in humans constitute and provide the basis for further development of this class of compound as a novel, orally administered bone-forming agents to treat osteoporosis in the nearer future.,,,,,,,,
| Src Kinase Inhibitors – Saracatinib|| |
Src kinase enzyme is a nonreceptor tyrosine kinase and a member of the Src family of protein kinases which plays an important role in activity and survival of osteoclast cells. Src kinase is essential for the functioning of osteoclasts in bone resorption. It plays role in many of the signaling pathways responsible for the survival, the motility, and the activation of osteoclasts by RANKL. Saracatinib (AZD0530) is a novel orally available competitive inhibitor of the enzyme Src kinase and Abl kinase family, implied in cell proliferation, differentiation, and response to oxidative stress. During a randomized, double-blind, placebo-controlled, multiple ascending – dose phase I trial treatment with saracatinib; it inhibited osteoclast-mediated bone resorption in healthy men without any significant adverse effects. The result from the study shows that saracatinib has the potential to become an agent for the treatment of PMO.,,,,
| Other Novel Therapeutic Targets|| |
The glucagon-like peptide (GLP-2) can decouple the bone resorption process from bone formation at night and during normal postprandial periods. Since GLP-2 has a short plasma half-life of about 7 min, it reduces the nocturnal and postprandial bone resorption process without affecting bone formation according to the evaluation of serum CTXs. It was found to increase BMD after repeated administrations.,,,,,, There should be more research into GLP-2 receptor agonists that can be potentially useful as antiresorptive agent for treating osteoporosis in the nearer future.
| Conclusion|| |
PMO is often a common, subtle, and asymptomatic clinical condition with an expected trend, increasing incidence, and prevalence due to the worldwide aging of the population. Bone loss and sometimes fracture follow the decrease estrogen level in the postmenopausal period. The adequacy of calcium intake and Vitamin D status are important priority measures before starting osteoporosis treatment with specific drugs, as well as encouraging physical activity and prevention of fall. Several drugs are already available with proven clinical efficacy against fractures and excellent safety profiles. The challenge today is to improve the early detection and diagnosis of PMO and convincing health-care professionals to refer at-risk patients for prompt treatment. Further elucidation of the role of Wnt/β-catenin signaling and other related pathways in osteoblast has unraveled more treatment options for the management of this disorder with more attention and emphasis on osteoanabolic agents. These agents will also be useful in combination with the existing antiresorptive agents, further expanding available therapeutic options in the nearer future.
What is already known about the pharmacotherapy of postmenopausal osteoporosis?
- Sclerostin and dickkopf endogenous proteins are potential targets for the pharmacotherapy of osteoporosis because they are potent inhibitors of the Wnt/β-catenin canonical pathway of bone formation in osteoblast cells
- Currently available pharmacological agents for PMO treatment include calcium and Vitamin D supplementation, bisphosphonates, hormone therapy with estrogen, SERMs/EAAs, denosumab, salmon calcitonin, and PTH analogs.
What this reviewed study adds to the body of knowledge about the pharmacotherapy of postmenopausal osteoporosis?
- Abaloparatide or ostabolin-C is a potential osteoanabolic agent that can serve as substitute or replacement for teriparatide in the IOF and AACE guidelines for the management of osteoporosis in the nearer future
- It elaborate clinical efficacy with their respective mechanism of action for strontium compounds, cathepsin K inhibitors, saracatinib, anti-sclerostin, and anti-dickkopf antibodies as a potential agents for the management of PMO in the nearer future with more emphases on those with osteoanabolic properties
- A call for more active research investigation into the use of parathyroid selective short-acting calcilytics and the synthesis of GLP-2 receptor agonists for the treatment of osteoporosis.
The authors of this research work want to specially acknowledge and thank the Almighty God for granting us wisdom and understanding to prepare this research work for publication.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Osteoporosis prevention, diagnosis, and therapy. NIH Consens Statement 2000;17:1-45.
Amin S, Achenbach SJ, Atkinson EJ, Khosla S, Melton LJ 3rd
. Trends in fracture incidence: A population-based study over 20 years. J Bone Miner Res 2014;29:581-9.
Cummings SR, Black DM, Rubin SM. Lifetime risks of hip, Colles', or vertebral fracture and coronary heart disease among white postmenopausal women. Arch Intern Med 1989;149:2445-8.
Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet 2002;359:1761-7.
Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996;312:1254-9.
Cummings SR, Black DM, Nevitt MC, Browner W, Cauley J, Ensrud K, et al.
Bone density at various sites for prediction of hip fractures. The study of osteoporotic fractures research group. Lancet 1993;341:72-5.
Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, et al.
Clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int 2014;25:2359-81.
Compston J, Bowring C, Cooper A, Cooper C, Davies C, Francis R, et al.
Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National osteoporosis guideline group (NOGG) update 2013. Maturitas 2013;75:392-6.
Papaioannou A, Morin S, Cheung AM, Atkinson S, Brown JP, Feldman S, et al.
2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: Summary. CMAJ 2010;182:1864-73.
Yates CJ, Chauchard MA, Liew D, Bucknill A, Wark JD. Bridging the osteoporosis treatment gap: Performance and cost-effectiveness of a fracture liaison service. J Clin Densitom 2015;18:150-6.
Hinton PS, Nigh P, Thyfault J. Effectiveness of resistance training or jumping-exercise to increase bone mineral density in men with low bone mass: A 12-month randomized, clinical trial. Bone 2015;79:203-12.
Evans RK, Negus CH, Centi AJ, Spiering BA, Kraemer WJ, Nindl BC, et al.
Peripheral QCT sector analysis reveals early exercise-induced increases in tibial bone mineral density. J Musculoskelet Neuronal Interact 2012;12:155-64.
Bauer DC. Clinical practice. Calcium supplements and fracture prevention. N
Engl J Med 2013;369:1537-43.
Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al.
Calcium plus vitamin D supplementation and the risk of fractures. N
Engl J Med 2006;354:669-83.
Murad MH, Drake MT, Mullan RJ, Mauck KF, Stuart LM, Lane MA, et al.
Clinical review. Comparative effectiveness of drug treatments to prevent fragility fractures: A systematic review and network meta-analysis. J Clin Endocrinol Metab 2012;97:1871-80.
LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for Vitamin D deficiency: A systematic review for the U.S. Preventive services task force. Ann Intern Med 2015;162:109-22.
Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, LaCroix AZ, et al.
Effects of estrogen plus progestin on risk of fracture and bone mineral density: The women's health initiative randomized trial. JAMA 2003;290:1729-38.
Jackson RD, Wactawski-Wende J, LaCroix AZ, Pettinger M, Yood RA, Watts NB, et al.
Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: Results from the women's health initiative randomized trial. J Bone Miner Res 2006;21:817-28.
Richman S, Edusa V, Fadiel A, Naftolin F. Low-dose estrogen therapy for prevention of osteoporosis: Working our way back to monotherapy. Menopause 2006;13:148-55.
Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al.
Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3-year randomized clinical trial. Multiple outcomes of raloxifene evaluation (MORE) investigators. JAMA 1999;282:637-45.
Cummings SR, Tice JA, Bauer S, Browner WS, Cuzick J, Ziv E, et al.
Prevention of breast cancer in postmenopausal women: Approaches to estimating and reducing risk. J Natl Cancer Inst 2009;101:384-98.
Crandall CJ, Newberry SJ, Diamant A, Lim YW, Gellad WF, Booth MJ, et al.
Comparative effectiveness of pharmacologic treatments to prevent fractures: An updated systematic review. Ann Intern Med 2014;161:711-23.
Khosla S, Bilezikian JP, Dempster DW, Lewiecki EM, Miller PD, Neer RM, et al.
Benefits and risks of bisphosphonate therapy for osteoporosis. J Clin Endocrinol Metab 2012;97:2272-82.
Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, et al.
Atypical subtrochanteric and diaphyseal femoral fractures: Second report of a task force of the American society for bone and mineral research. J Bone Miner Res 2014;29:1-23.
Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O'Ryan F, et al.
Diagnosis and management of osteonecrosis of the jaw: A systematic review and international consensus. J Bone Miner Res 2015;30:3-23.
Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al.
Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture intervention trial research group. Lancet 1996;348:1535-41.
Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, et al.
Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: Results from the fracture intervention trial. JAMA 1998;280:2077-82.
Black DM, Thompson DE, Bauer DC, Ensrud K, Musliner T, Hochberg MC, et al.
Fracture risk reduction with alendronate in women with osteoporosis: The fracture intervention trial. FIT research group. J Clin Endocrinol Metab 2000;85:4118-24.
Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, et al.
Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: A randomized controlled trial. Vertebral efficacy with risedronate therapy (VERT) study group. JAMA 1999;282:1344-52.
Reginster J, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, et al.
Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral efficacy with risedronate therapy (VERT) study group. Osteoporos Int 2000;11:83-91.
McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, et al.
Effect of risedronate on the risk of hip fracture in elderly women. Hip intervention program study group. N
Engl J Med 2001;344:333-40.
Chesnut CH 3rd
, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth A, et al.
Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 2004;19:1241-9.
Eisman JA, Civitelli R, Adami S, Czerwinski E, Recknor C, Prince R, et al.
Efficacy and tolerability of intravenous ibandronate injections in postmenopausal osteoporosis: 2-year results from the DIVA study. J Rheumatol 2008;35:488-97.
Modi A, Siris ES, Tang J, Sen S. Cost and consequences of noncompliance with osteoporosis treatment among women initiating therapy. Curr Med Res Opin 2015;31:757-65.
Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, et al.
Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N
Engl J Med 2007;356:1809-22.
Lyles KW, Colón-Emeric CS, Magaziner JS, et al.
Zoledronic acid in reducing clinical fracture and mortality after hip fracture. N
Engl J Med 2007;357:1799-809.
Reid IR, Gamble GD, Mesenbrink P, Lakatos P, Black DM. Characterization of and risk factors for the acute-phase response after zoledronic acid. J Clin Endocrinol Metab 2010;95:4380-7.
Wark JD, Bensen W, Recknor C, Ryabitseva O, Chiodo J 3rd
, Mesenbrink P, et al.
Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg. Osteoporos Int 2012;23:503-12.
Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al.
Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N
Engl J Med 2009;361:756-65.
Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, et al.
Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N
Engl J Med 2001;344:1434-41.
Cosman F. Anabolic and antiresorptive therapy for osteoporosis: Combination and sequential approaches. Curr Osteoporos Rep 2014;12:385-95.
Black DM, Bilezikian JP, Ensrud KE, Greenspan SL, Palermo L, Hue T, et al.
One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis. N
Engl J Med 2005;353:555-65.
Yun H, Curtis JR, Guo L, Kilgore M, Muntner P, Saag K, et al.
Patterns and predictors of osteoporosis medication discontinuation and switching among medicare beneficiaries. BMC Musculoskelet Disord 2014;15:112.
Schilcher J, Koeppen V, Aspenberg P, Michaëlsson K. Risk of atypical femoral fracture during and after bisphosphonate use. N
Engl J Med 2014;371:974-6.
Gedmintas L, Solomon DH, Kim SC. Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: A systematic review and meta-analysis. J Bone Miner Res 2013;28:1729-37.
Feldstein AC, Black D, Perrin N, Rosales AG, Friess D, Boardman D, et al.
Incidence and demography of femur fractures with and without atypical features. J Bone Miner Res 2012;27:977-86.
Black DM, Kelly MP, Genant HK, Palermo L, Eastell R, Bucci-Rechtweg C, et al.
Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N
Engl J Med 2010;362:1761-71.
Hellstein JW, Adler RA, Edwards B, Jacobsen PL, Kalmar JR, Koka S, et al.
Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: Executive summary of recommendations from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc 2011;142:1243-51.
Adler RA, El-Hajj Fuleihan G, Bauer DC, Camacho PM, Clarke BL, Clines GA, et al.
Managing osteoporosis in patients on long-term bisphosphonate treatment: Report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2016;31:1910.
Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, et al.
Effects of continuing or stopping alendronate after 5 years of treatment: The fracture intervention trial long-term extension (FLEX): A randomized trial. JAMA 2006;296:2927-38.
Black DM, Reid IR, Boonen S, Bucci-Rechtweg C, Cauley JA, Cosman F, et al.
The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: A randomized extension to the HORIZON-pivotal fracture trial (PFT). J Bone Miner Res 2012;27:243-54.
Black DM, Bauer DC, Schwartz AV, Cummings SR, Rosen CJ. Continuing bisphosphonate treatment for osteoporosis – For whom and for how long? N
Engl J Med 2012;366:2051-3.
Cosman F, Cauley JA, Eastell R, Boonen S, Palermo L, Reid IR, et al.
Reassessment of fracture risk in women after 3 years of treatment with zoledronic acid: When is it reasonable to discontinue treatment? J Clin Endocrinol Metab 2014;99:4546-54.
Bauer DC, Schwartz A, Palermo L, Cauley J, Hochberg M, Santora A, et al.
Fracture prediction after discontinuation of 4 to 5 years of alendronate therapy: The FLEX study. JAMA Intern Med 2014;174:1126-34.
North American Menopause Society. Management of osteoporosis in postmenopausal women: 2006 position statement of The North American Menopause Society. Menopause 2006;13:340-67.
Iba K, Takada J, Hatakeyama N, Kaya M, Isogai S, Tsuda H, et al.
Underutilization of antiosteoporotic drugs by orthopedic surgeons for prevention of a secondary osteoporotic fracture. J Orthop Sci 2006;11:446-9.
Vestergaard P, Rejnmark L, Mosekilde L. Osteoporosis is markedly underdiagnosed: A nationwide study from Denmark. Osteoporos Int 2005;16:134-41.
Downey TW, Foltz SH, Boccuzzi SJ, Omar MA, Kahler KH. Adherence and persistence associated with the pharmacologic treatment of osteoporosis in a managed care setting. South Med J 2006;99:570-5.
Clowes JA, Peel NF, Eastell R. The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: A randomized controlled trial. J Clin Endocrinol Metab 2004;89:1117-23.
Dennison E, Cooper C. Epidemiology of osteoporotic fractures. Horm Res 2000;54 Suppl 1:58-63.
Looker AC, Orwoll ES, Johnston CC Jr., Lindsay RL, Wahner HW, Dunn WL, et al.
Prevalence of low femoral bone density in older U.S. Adults from NHANES III. J Bone Miner Res 1997;12:1761-8.
Gajic-Veljanoski O, Sebaldt RJ, Davis AM, Tritchler D, Tomlinson G, Petrie A, et al.
Age and drug therapy are key prognostic factors for first clinical fracture in patients with primary osteoporosis. Osteoporos Int 2007;18:1091-100.
Johnell O, Kanis J. Epidemiology of osteoporotic fractures. Osteoporos Int 2005;16 Suppl 2:S3-7.
Wainwright SA, Marshall LM, Ensrud KE, Cauley JA, Black DM, Hillier TA, et al.
Hip fracture in women without osteoporosis. J Clin Endocrinol Metab 2005;90:2787-93.
Cawston TE, Young DA. Proteinases involved in matrix turnover during cartilage and bone breakdown. Cell Tissue Res 2010;339:221-35.
Sommerfeldt DW, Rubin CT. Biology of bone and how it orchestrates the form and function of the skeleton. Eur Spine J 2001;10 Suppl 2:S86-95.
Ahlborg HG, Johnell O, Nilsson BE, Jeppsson S, Rannevik G, Karlsson MK, et al.
Bone loss in relation to menopause: A prospective study during 16 years. Bone 2001;28:327-31.
Christakos S, Dhawan P, Shen Q, Peng X, Benn B, Zhong Y, et al.
New insights into the mechanisms involved in the pleiotropic actions of 1,25dihydroxyvitamin D3. Ann N
Y Acad Sci 2006;1068:194-203.
Kamel HK. Secondary prevention of hip fractures among the hospitalized elderly: Are we doing enough? J Clin Rheumatol 2005;11:68-71.
Atik OS, Gunal I, Korkusuz F. Burden of osteoporosis. Clin Orthop Relat Res 2006;443:19-24.
Silverman SL, Christiansen C, Genant HK, Vukicevic S, Zanchetta JR, de Villiers TJ, et al.
Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: Results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res 2008;23:1923-34.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]