Current Drug Targets (v.14, #13)
Editorial (Thematic Issue: Novel Agents in the Treatment of Osteoporosis and Its Complications) by Ahmad Nazrun Shuid, Ima Nirwana Soelaiman, Srijit Das (1523-1523).
Update on Statins: Hope for Osteoporotic Fracture Healing Treatment by Nurul `Izzah Ibrahim, Norazlina Mohamed, Ahmad Nazrun Shuid (1524-1532).
Fracture healing is a process of recovering injured bone tissue forms and functions. Osteoporosis can delay thehealing process, which contributes to personal suffering and loss of activities. Osteoporosis patients tend to lose bonemass at the metaphyseal region which require treatment to increase bone mass. Postmenopausal osteoporosis is the mostcommon osteoporosis that occurs in women which subsequently resulted in fractures even under slight trauma. EstrogenReplacement Therapy (ERT), the recommended therapy for postmenopausal osteoporosis, is associated with higher risk ofbreast cancer, ovarian cancer and cardiovascular diseases. As osteoporotic fractures are becoming a public health issue, alternativetreatment is now being thoroughly explored. The potential agent is statins, the HMG-CoA reductase inhibitorwhich is widely used for hypercholesterolemia treatment. Statins have been found to increase bone mass by stimulation ofBone morphogenetic protein-2 (BMP-2) expression and Vascular Endothelial Growth Factor (VEGF) production. However,these bone forming effects were achieved at very high systemic doses. Therefore, studies on locally applied statinsare required to further explore the ability of statins to stimulate bone formation at acceptable doses for better fracture healing.This review highlights the animal and clinical studies on fracture healing promotions by statins and the mechanismsinvolved.
A Review of the Possible Mechanisms of Action of Tocotrienol - A Potential Antiosteoporotic Agent by Kok-Yong Chin, Huanbiao Mo, Ima-Nirwana Soelaiman (1533-1541).
Osteoporosis is posing a tremendous healthcare problem globally. Much effort has been invested in findingnovel antiosteoporotic agents to stop the progression of this disease. Tocotrienol, one of the isoforms of vitamin E, ispoised as a potential antiosteoporotic agent. Previous studies showed that tocotrienol as a single isomer or as a mixturedemonstrated both anabolic and antiresorptive effects in various rodent models of osteoporosis. In vitro experiments furtherdemonstrated that tocotrienol could up-regulate genes related to osteoblastogenesis and modify receptor activator ofnuclear factor kappa B signaling against osteoclastogenesis. Additionally, tocotrienol was also shown to be a strong 3-hydroxy-3-methyl-glutaryl-CoA reductase down-regulator with a mechanism different from that of statins. Inhibition ofthe mevalonate pathway affects both osteoblast and osteoclast formation in favor of the former. Tocopherol, a more commonlyused isoform of vitamin E does not possess similar effects. Tocotrienol is also a potent antioxidant. It can scavengefree radicals and prevent oxidative damage on osteoblast thus promoting its survival. It may also up-regulate the antioxidantdefense network in osteoclast and indirectly act against free radical signaling essential in osteoclastogenesis. The effectsof tocotrienol on Wnt/β-catenin signaling essential in osteoblastogenesis have not been determined. More mechanisticstudies need to be conducted to illustrate the antiosteoporotic effects of tocotrienol. Clinical trials are also required toconfirm its effects in humans. In conclusion, tocotrienol demonstrates great potential as an antiosteoporotic agent andmuch research effort should be invested to develop it as an agent to curb osteoporosis.
Micro-CT Assessments of Potential Anti-Osteoporotic Agents by Nadia Mohd Effendy, Mohd Fadhli Khamis, Ahmad Nazrun Shuid (1542-1551).
Bone quality assessment is important in assessments of potential agents for the prevention and treatment of osteoporosis.Bone density, microarchitecture and strength are important determinants in osteoporotic study which arewidely studied using Dual-Energy X-ray Absorptiometry (DXA), histomorphometry and radiological imaging techniques.In recent years, high resolution micro-CT has become feasible for in vitro or in vivo evaluation of bone architecture.Three-dimensional images of micro-CT reflected high correlations with the conventional histomorphometry and DXA. Incomparison to other imaging techniques, micro-CT is the most effective tool in detecting early bone changes for fractureprediction and assessments of potential anti-osteoporotic agents. It is crucial to define an ideal setting with safe radiationdoses and appropriate methods for image reconstruction and segmentation to obtain high resolution images. Micro-CTevaluation provides a better insight of bone structure as well as non-metric parameters such as connectivity density, structuralmodel index (SMI) and degree of anisotropy (DA). This non- invasive imaging technique is also equipped with finiteelement analysis for evaluation of bone biomechanical strength. Micro-CT allows a compressive understanding of the relationshipsbetween bone density, microarchitecture and strength which is fundamental to development of pharmacologicalinterventions.
The Effects of TNF α Antagonist Therapy on Bone Metabolism in Rheumatoid Arthritis: A Systematic Review by Rajalingham Sakthiswary, Srijit Das (1552-1557).
Osteoporosis is a common complication observed in rheumatoid arthritis (RA). Accelerated bone loss is alwaysa matter of concern. The pathogenesis of RA may be important for better understanding of the bone loss. The mechanisminvolved in the bone loss in RA is not well understood although cytokines such as interleukin 1 and tumour necrosis factorα (TNF α) have been strongly implicated. TNF α antagonists have revolutionised the treatment of RA in the recent years.Beyond the control of disease activity in RA, accumulating evidence suggests that this form of therapy may provide beneficialeffects to the bone metabolism and remodeling. An extensive search of the literature was performed in the Medline,Scopus and EBSCO databases to evaluate the documented research on the effects of TNF α antagonists in RA on bonemineral density and bone turnover markers. The available data based on our systematic review, depict a significant associationbetween TNF α antagonists treatment and suppression of bone resorption.
Drug Delivery Systems for Prevention and Treatment of Osteoporotic Fracture by Ahmad Nazrun Shuid, Nurul `Izzah Ibrahim, Mohd Cairul Iqbal Mohd Amin, Isa Naina Mohamed (1558-1564).
Anti-osteoporotic drugs are available for treatment of osteoporosis and for preventing osteoporosis complicationsespecially fractures. Most of the current anti-osteoporotic drugs are administered orally or parenterally to target theosteoporosis-affected bones. However, bone is a peripheral organ with limited blood supply. Therefore, the drugs deliveredare exposed to various physicochemical and biological factors which affect the bioavailability of the drugs. In preclinicalresearch, the dose of a potential anti-osteoporotic agent used in animal model may be too high for human applicationwhen administered via the conventional route of administration. The current anti-osteoporotic drugs need to be administeredat higher doses to account for pharmacological interactions. However, this will expose the patients to adverseeffects such as the cancer risks of postmenopausal women who took estrogen replacement therapy. There is also problemwith patient compliance as anti-osteoporotic drugs may have to be taken for prolonged duration. The current deliveries ofdrugs need to be improved to overcome these problems. This review discussed several potential drug delivery systemswhich are able to contain the anti-osteoporosis drugs and release them slowly to the targeted bone. Among them are variouscarriers, polymers and microsponges, which may not only increase drug efficacy but also reduce adverse effects. Thedelivery systems allow the drugs to be administered locally at the targeted bone for longer duration, therefore reducingdrug frequency and improving patient's compliance. It is hoped that these delivery systems may be applicable for thetreatment of osteoporosis in the future to keep tab of the rising osteoporotic fracture incidence.
Pomegranate Use to Attenuate Bone Loss in Major Musculoskeletal Diseases: An Evidence-Based Review by Ahmad Nazrun Shuid, Isa Naina Mohamed (1565-1578).
This review explores the effects of pomegranate on the pathogenesis of bone loss in osteoporosis, osteoarthritisand rheumatoid arthritis. A systematic review of the literature was conducted to identify the relevant studies on pomegranateand osteoporosis/osteoarthritis/rheumatoid arthritis. A comprehensive search was conducted in Medline and CINAHLfor relevant studies published between the years 1946 to 2012. The main inclusion criteria were research articlespublished in English, studies had to report the association or effect of pomegranate and these bone and joint diseases: osteoporosis,osteoarthritis or rheumatoid arthritis. The literature search identified 35 potentially relevant articles, whereby 8met the inclusion criteria. Two animal studies, two combinations of animal and in vitro studies, three in vitro studies andone human study were included in this review. All the studies reported positive effects of pomegranate extract or juice onosteoporosis, osteoarthritis and rheumatoid arthritis. This evidence-based review highlighted the potential of pomegranateextract being used for treating bone loss in osteoporosis, osteoarthritis and rheumatoid arthritis. Further studies are requiredto identify the active ingredients and molecular mechanisms before controlled human observational studies areconducted to provide stronger evidence.
A Review on the Use of Statins and Tocotrienols, Individually or in Combination for the Treatment of Osteoporosis by Saif Abdul-Majeed, Norazlina Mohamed, Ima-Nirwana Soelaiman (1579-1590).
Skeletal tissue undergoes continuous remodeling which makes it unique among other body tissues. Osteoporosisis a common bone metabolic disorder affecting both men and women. Osteoporosis and its complications mainly osteoporoticfractures, have a high impact on health and economy. Current approved medications are associated with numerousside effects, which limit their use. Identification of a new and safe therapy is mandatory. Statins, also known asHMGCoA reductase inhibitors, are frequently used for the treatment of hypercholesterolemia and for the prevention ofmorbidity and mortality associated with cardiovascular disease. Statins improved bone health status in intact and ovariectomisedrodents following high clinically intolerable oral doses. However, this beneficial effect of statins could not besignificantly demonstrated in humans. The reason behind this discrepancy might be due to the safety and bioavailability ofthe currently used oral statins. Vitamin E, especially the tocotrienols at the dose 60 mg/kg/day provided significant antiosteoporoticeffects in different animal models of osteoporosis. The use of the aforementioned dose of tocotrienols wasshown to be safe in both humans and animals. Enhancement of bone formation and reduction of bone resorption wereachieved more effectively by a combination of tocotrienols and statins than by either treatment when supplemented separatelyat clinically tolerable doses. Therefore, the adverse effects associated with high statin doses might be avoided withthe coadministration of tocotrienols. Moreover, the combination therapy strategy might be useful for patients who are athigh risk of osteoporosis, cardiovascular events and hypercholesterolaemia.
Cathepsin K Inhibitors: A Novel Target but Promising Approach in the Treatment of Osteoporosis by Asadul Mazid Helali, Farhana Matin Iti, Isa Naina Mohamed (1591-1600).
Osteoporosis is a pathologic process characterized by low bone mass with skeletal fragility and an increasedrisk of fracture. It occurs due to an imbalance between bone resorption and formation. Although current antiresorptivetherapy halts bone loss, it does not cure the condition as it also inhibits bone formation. Recent preclinical and clinical trialssuggest that the inhibition of resorption by cathepsin K inhibitors increases bone formation. Cathepsin K is a papainlikecysteine protease with high potent collagenase activity and predominantly expressed in osteoclasts. While allowingdemineralization, cathepsin K inhibitors suppress the degradation of type I collagen (the major organic matrix of bone)and thus enhancing bone formation. Many of these inhibitors have passed preclinical studies and are presently in clinicaltrials at different stages of advancement. This review explores the promising role of cathepsin K as a novel antiresorptivefor the treatment of osteoporosis.
Pathogenesis of Alcohol-Induced Osteoporosis and its Treatment: A Review by Seham S. Abukhadir, Norazlina Mohamed, Norliza Mohamed (1601-1610).
Osteoporosis is the most common bone disease in humans; it represents a major public health problem. Thischronic disease is characterized by increase in bone fracture due to: reduced bone mass, deterioration of micro architecturaland decreased bone strength, bone fragility; and bone mineral density 2.5 or more standard deviations below thenormal mean. Secondary osteoporosis is a common cause of osteoporosis, and there are many underlying risk factors forosteoporosis. Chronic alcohol abuse is one of the modifiable risk factors in osteoporosis. There is evidence of correlationbetween chronic alcohol abuse and low bone mass. Alcohol is directly toxic to the bone; with increased incidence of fracturesand complications. Although there is a paucity of studies regarding alcohol induced osteoporosis therapy, it can beclassified into antiresorptive therapy and anabolic therapy. Bisphosphonates have been demonstrated to be clinically relevantto prevent bone damage associated with alcohol use while parathyroid hormone increased bone mineralization aswell as bone formation in alcohol treated rats. Vitamin D supplementation could prevent bone toxicity in chronic drinkers.This review discussed the pathogenesis of alcohol-induced osteoporosis and the agents available for its treatment. Otherpotential therapies are also discussed.
Beneficial Effects of Plant Sources on the Treatment of Osteoporosis by Ipek Süntar, Esra Küpeli Akkol (1611-1618).
Osteoporosis causes bone loss, and makes bone to susceptible to fracture. The main cause of osteoporosis is estrogendeficiency. Estrogen, calcitonin, calcium, vitamin D and antioxidants can be used to prevent osteoporosis. For thetreatment of osteoporosis, the potential biological activities of traditional medicines have been subjected to scientificevaluation, since synthetic drugs are considered to have several side effects and they lack efficacy. Therefore, more extensiveresearch should be carried out to investigate the medicinal plants to be used as an alternative treatment for osteoporosis.The present review focuses on the scientific researches on the assessment of anti-osteoporotic activity of medicinalplants.
Functions and Mechanisms of Green Tea Catechins in Regulating Bone Remodeling by Chwan-Li Shen, In-Sook Kwun, Shu Wang, Huanbiao Mo, Lixia Chen, Marjorie Jenkins, Gordon Brackee, Chung-Hwan Chen, Ming-Chien Chyu (1619-1630).
Osteoporosis is caused by an imbalance in bone remodeling, a process involving bone-building osteoblasts andbone-resorptive osteoclasts. Excessive reactive oxygen species and inflammatory responses have been shown to stimulatedifferentiation and function of osteoclasts while inducing osteoblast apoptosis and suppressing osteoblastic proliferationand differentiation via extracellular signal-regulated kinases (ERK), ERK-dependent nuclear factor-κB and Wnt/β-cateninsignaling pathways. The anti-oxidant and anti-inflammatory green tea catechins (GTC) have been shown to promote osteoblastogenesis,suppress osteoclastogenesis and stimulate the differentiation of mesenchymal stem cells into osteoblastsrather than adipocytes by modulating the signaling pathways. This paper reviews the pharmacokinetics and metabolism ofGTC, their bone-protective activities evidenced in in vitro and in vivo studies, and the limited clinical studies supportingthese preclinical findings. In light of the physical, economical, and social burdens due to osteoporosis, easily accessibleand affordable preventive measures such as GTC deserves further clinical studies prior to its clinical application.