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Experimental fracture protocols in assessments of potential agents for osteoporotic fracture healing using rodent models

Ibrahim N', Mohamad S, Mohamed N, Shuid AN

Curr Drug Targets, 2013 Dec;14(14):1642-50.
PMID: 24350807

Osteoporosis may cause bone fracture even under slight trauma. Osteoporotic fracture has become a major public health problem but until today, the treatments available are not satisfactory. Many pre-clinical testings on animals were done to find new agents that can be sourced from natural products and synthetic drugs for osteoporotic fracture healing. Animal models are more appropriate for fracture healing study than human subject due to several reasons including the ethical issues involved. The bones of rodents are similar to human in term of their morphological change and response to therapy. Small rodents such as rats and mice are suitable animal models for fracture healing studies as they have a similar bone remodeling system to human. To date, there is no specific guideline to carry out fracture healing studies in animal models for the evaluation of new agents. This paper highlights the protocols of various fracture and fixation methods for experimental osteoporotic fracture healing using rodent models.

Matched MeSH terms: Osteoporosis/drug therapy
Pathogenesis of alcohol-induced osteoporosis and its treatment: a review

Abukhadir SS, Mohamed N, Mohamed N

Curr Drug Targets, 2013 Dec;14(13):1601-10.
PMID: 24138635

Osteoporosis is the most common bone disease in humans; it represents a major public health problem. This chronic disease is characterized by increase in bone fracture due to: reduced bone mass, deterioration of micro architectural and decreased bone strength, bone fragility; and bone mineral density 2.5 or more standard deviations below the normal mean. Secondary osteoporosis is a common cause of osteoporosis, and there are many underlying risk factors for osteoporosis. Chronic alcohol abuse is one of the modifiable risk factors in osteoporosis. There is evidence of correlation between chronic alcohol abuse and low bone mass. Alcohol is directly toxic to the bone; with increased incidence of fractures and complications. Although there is a paucity of studies regarding alcohol induced osteoporosis therapy, it can be classified into antiresorptive therapy and anabolic therapy. Bisphosphonates have been demonstrated to be clinically relevant to prevent bone damage associated with alcohol use while parathyroid hormone increased bone mineralization as well 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. Other potential therapies are also discussed.

Matched MeSH terms: Osteoporosis/drug therapy*
Milk thistle: a future potential anti-osteoporotic and fracture healing agent

Mohd Fozi NF, Mazlan M, Shuid AN, Isa Naina M

Curr Drug Targets, 2013 Dec;14(14):1659-66.
PMID: 24093748

Osteoporosis is a progressive disease of the skeleton characterised by bone fragility due to a reduction in bone mass and possibly to alteration in bone architecture that lead to a propensity to fracture with minimum trauma. Most osteoporotic fractures occur at locations rich in trabecular or cancellous bone and usually related to post menopausal women. Recently, silymarin received attention due to its alternative beneficial effect on bone formation. It is a mixture of flavonoids with powerful antioxidant properties. This review focuses on the use of milk thistle or silymarin for the treatment of osteoporosis that may be related to fracture bone. Silymarin shows potent antioxidant herb that may modulate multiple genes in favour of helping to build bone and prevent bone loss. In the mouse fracture healing model, silymarin supplementation improved tibial healing with elevated BMD and serum levels of ALP and osteocalcin. Silymarin also demonstrated clear estrogenic antiosteoporotic effects in bone structure. Silymarin appears to play a crucial role to prevent bone loss and might regulate osteogenesis and may be beneficial for fracture healing. If silymarin is considered for the use of post menopausal women, it may be used for the treatment of osteoporosis. It would be of great benefit to postmenopausal women to develop an oestrogen antagonist that is as potent and efficacious as oestrogen in preventing bone loss without the major side effect associated with HRT.

Matched MeSH terms: Osteoporosis/drug therapy*
The effects of Cosmos caudatus (Ulam Raja) supplementation on bone biochemical parameters in ovariectomized rats

Mohamed N, Yin CM, Shuid AN, Muhammad N, Babji AS, Soelaiman IN

Pak J Pharm Sci, 2013 Sep;26(5):1027-31.
PMID: 24035963

Cosmos caudatus (ulam raja) contains high mineral content and possesses high antioxidant activity which may be beneficial in bone disorder such as postmenopausal osteoporosis. The effects of C. caudatus on bone metabolism biomarkers in ovariectomized rats were studied. 48 Sprague-Dawley rats aged three months were divided into 6 groups. One group of rats was sham-operated while the remaining rats were ovariectomized. The ovariectomized rats were further divided into 5 groups: the control, three groups force-fed with C. caudatus at the doses of 100mg/kg, 200mg/kg or 300mg/kg and another group supplemented with calcium 1% ad libitum. Treatments were given 6 days per week for a period of eight weeks. Blood samples were collected twice; before and after treatment. Parameters measured were bone resorbing cytokine; interleukin-1 and the bone biomarkers; osteocalcin and pyridinoline. Serum IL-1 and pyridinoline levels were significantly increased in ovariectomized rats. Supplementation of C. caudatus was able to prevent the increase of IL-1 and pyridinoline in ovariectomized rats. Besides that, C. caudatus showed the same effect as calcium 1% on biochemical parameters of bone metabolism in ovariectomized rats. In conclusion, Cosmos caudatus was as effective as calcium in preventing the increase in bone resorption in ovariectomized rats.

Matched MeSH terms: Osteoporosis/drug therapy*
A review of the possible mechanisms of action of tocotrienol - a potential antiosteoporotic agent

Chin KY, Mo H, Soelaiman IN

Curr Drug Targets, 2013 Dec;14(13):1533-41.
PMID: 23859472

Osteoporosis is posing a tremendous healthcare problem globally. Much effort has been invested in finding novel antiosteoporotic agents to stop the progression of this disease. Tocotrienol, one of the isoforms of vitamin E, is poised as a potential antiosteoporotic agent. Previous studies showed that tocotrienol as a single isomer or as a mixture demonstrated both anabolic and antiresorptive effects in various rodent models of osteoporosis. In vitro experiments further demonstrated that tocotrienol could up-regulate genes related to osteoblastogenesis and modify receptor activator of nuclear 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 of the mevalonate pathway affects both osteoblast and osteoclast formation in favor of the former. Tocopherol, a more commonly used isoform of vitamin E does not possess similar effects. Tocotrienol is also a potent antioxidant. It can scavenge free radicals and prevent oxidative damage on osteoblast thus promoting its survival. It may also up-regulate the antioxidant defense network in osteoclast and indirectly act against free radical signaling essential in osteoclastogenesis. The effects of tocotrienol on Wnt/β-catenin signaling essential in osteoblastogenesis have not been determined. More mechanistic studies need to be conducted to illustrate the antiosteoporotic effects of tocotrienol. Clinical trials are also required to confirm its effects in humans. In conclusion, tocotrienol demonstrates great potential as an antiosteoporotic agent and much research effort should be invested to develop it as an agent to curb osteoporosis.

Matched MeSH terms: Osteoporosis/drug therapy*
Piper sarmentosum: a new hope for the treatment of osteoporosis

Mohd Ramli ES, Suhaimi F, Ahmad F, Shuid AN, Mohamad N, Ima-Nirwana S

Curr Drug Targets, 2013 Dec;14(14):1675-82.
PMID: 24107234

Osteoporosis is a major global health problem. Osteoporosis is characterized by the loss of bone mass and strength which leads to an increased risk of fracture. Glucocorticoid treatment is the leading cause of secondary osteoporosis. Glucocorticoid action in bone depends upon the expression of 11beta-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1). The oestrogen deficient state causes osteoporosis due to enhancement of osteoclastogenesis by oxidative stress which leads to increased bone resorption. Piper sarmentosum (Daun Kaduk) is commonly used in the local cuisine of South East Asia. It is also traditionally used to treat many diseases such as inflammation, dermatitis and joint pain. Studies have revealed antioxidant properties through its flavonoids compound naringenin which acts as a superoxide scavenger that may help in the endogenous antioxidant defence system to protect bone against osteoporosis. Recent studies found that Ps extract has the ability to inhibit the expression and activity of 11β-HSD1 in adipose tissue and bone which restored bone structure and strength. It also accelerates fracture healing in the oestrogen deficient state through its antioxidant properties. The cost of conventional treatment is high and together with the adverse effects it leads to noncompliance. Treatment modalities with herbal medicine, less side effects and is cheaper need to be explored.This review focused on the therapeutic effect of Ps extract on fracture healing in ovariectomized rats and its protective effects against glucocorticoid induced osteoporotic rats.

Matched MeSH terms: Osteoporosis/drug therapy*
A review on the use of statins and tocotrienols, individually or in combination for the treatment of osteoporosis

Abdul-Majeed S, Mohamed N, Soelaiman IN

Curr Drug Targets, 2013 Dec;14(13):1579-90.
PMID: 23848479

Skeletal tissue undergoes continuous remodeling which makes it unique among other body tissues. Osteoporosis is a common bone metabolic disorder affecting both men and women. Osteoporosis and its complications mainly osteoporotic fractures, have a high impact on health and economy. Current approved medications are associated with numerous side effects, which limit their use. Identification of a new and safe therapy is mandatory. Statins, also known as HMGCoA reductase inhibitors, are frequently used for the treatment of hypercholesterolemia and for the prevention of morbidity and mortality associated with cardiovascular disease. Statins improved bone health status in intact and ovariectomised rodents following high clinically intolerable oral doses. However, this beneficial effect of statins could not be significantly demonstrated in humans. The reason behind this discrepancy might be due to the safety and bioavailability of the currently used oral statins. Vitamin E, especially the tocotrienols at the dose 60 mg/kg/day provided significant antiosteoporotic effects in different animal models of osteoporosis. The use of the aforementioned dose of tocotrienols was shown to be safe in both humans and animals. Enhancement of bone formation and reduction of bone resorption were achieved more effectively by a combination of tocotrienols and statins than by either treatment when supplemented separately at clinically tolerable doses. Therefore, the adverse effects associated with high statin doses might be avoided with the coadministration of tocotrienols. Moreover, the combination therapy strategy might be useful for patients who are at high risk of osteoporosis, cardiovascular events and hypercholesterolaemia.

Matched MeSH terms: Osteoporosis/drug therapy*
Fulltext Eurycoma longifolia upregulates osteoprotegerin gene expression in androgen- deficient osteoporosis rat model

Shuid AN, El-arabi E, Effendy NM, Razak HS, Muhammad N, Mohamed N, et al.

BMC Complement Altern Med, 2012;12:152.
PMID: 22967165 DOI: 10.1186/1472-6882-12-152

Eurycoma longifolia (EL) has been shown recently to protect against bone calcium loss in orchidectomised rats, the model for androgen-deficient osteoporosis. The mechanism behind this is unclear but it may be related to its ability to elevate testosterone levels or it may directly affect bone remodeling. The aim of this study is to determine the mechanism involved by investigating the effects of EL extract on serum testosterone levels, bone biomarkers, biomechanical strength and gene expression of Receptor Activator of Nuclear Factor kappa-B ligand (RANKL), Osteoprotegerin (OPG) and Macrophage-Colony Stimulating Factor (MCSF) in orchidectomised rats.

Matched MeSH terms: Osteoporosis/drug therapy*
The anti-osteoporotic effect of Eurycoma Longifolia in aged orchidectomised rat model

Shuid AN, Abu Bakar MF, Abdul Shukor TA, Muhammad N, Mohamed N, Soelaiman IN

Aging Male, 2011 Sep;14(3):150-4.
PMID: 20874437 DOI: 10.3109/13685538.2010.511327

Osteoporosis in elderly men is becoming an important health issue with the aging society. Elderly men with androgen deficiency are exposed to osteoporosis and can be treated with testosterone replacement. In this study, Eurycoma longifolia (EL), a plant with androgenic effects, was supplemented to an androgen-deficient osteoporotic aged rat as alternative to testosterone. Aged 12 months old Sprague-Dawley rats were divided into groups of normal control (NC), sham-operated (SO), orchidectomised-control (OrxC), orchidectomised and supplemented with EL (Orx + El) and orchidectomised and given testosterone (Orx + T). After 6 weeks of treatment, serum osteocalcin, serum terminal C-telopeptide Type 1 collagen (CTX) and the fourth lumbar bone calcium were measured. There were no significant differences in the osteocalcin levels before and after treatment in all the groups. The CTX levels were also similar for all the groups before treatment. However, after treatment, orchidectomy had caused significant elevation of CTX compared to normal control rats. Testosterone replacements in orchidectomised rats were able to prevent the rise of CTX. Orchidectomy had also reduced the bone calcium level compared to normal control rats. Both testosterone replacement and EL supplementation to orchidectomised rats were able to maintain the bone calcium level, with the former showing better effects. As a conclusion, EL prevented bone calcium loss in orchidectomised rats and therefore has the potential to be used as an alternative treatment for androgen deficient osteoporosis.

Matched MeSH terms: Osteoporosis/drug therapy*
Bilateral atypical femoral diaphyseal fractures in a patient treated with alendronate sodium

Lee JK

Int J Rheum Dis, 2009 Jul;12(2):149-54.
PMID: 20374333 DOI: 10.1111/j.1756-185X.2009.01396.x

Antiresorptive agents have been used as primary or first-line therapy in managing patients with osteoporosis. Bisphosphonates in particular are used widely to reduce bone resorption, increase bone mineral density, improve bone quality and therefore reduce fracture risk. However, prolonged use of bisphosphonates may cause over-suppression of bone resorption, leading on to accumulation of micro-damage in bone. This in turn might lead on to atypical femoral fractures. A patient treated with alendronate sodium for 8 years, and presenting with bilateral atypical femoral diaphyseal fractures is reported. X-rays of both femurs showed typical horizontal fracture line involving the thick lateral cortex with short oblique fracture pattern over the medial cortex. This fracture pattern was further confirmed with intra-operative examination of the fracture ends. Histopathological examination of the endocortical fragment removed from the proximal fracture end showed absence of osteoclasts and osteoblasts. Bone mineral density with dual energy X-ray absorptiometry (DXA) scan showed osteopenia over the femoral neck. Blood investigations did not show significant abnormalities. Bone turnover marker levels were not reliable, as presence of fracture might have altered the marker levels. Both femoral fractures united well. The patient reported here had complete pictures on X-ray examination, intra-operative findings, histopathological examination, DXA, as well as blood test results. Complete data should be collected from patients treated with alendronate sodium presenting with atypical femoral fractures to show any link between the use of alendronate sodium with atypical fracture of femur.

Matched MeSH terms: Osteoporosis/drug therapy*
Identifying Potential Therapeutics for Osteoporosis by Exploiting the Relationship between Mevalonate Pathway and Bone Metabolism

Hasan WNW, Chin KY, Jolly JJ, Ghafar NA, Soelaiman IN

Endocr Metab Immune Disord Drug Targets, 2018;18(5):450-457.
PMID: 29683099 DOI: 10.2174/1871530318666180423122409

BACKGROUND: Osteoporosis is a silent skeletal disease characterized by low bone mass and destruction of skeletal microarchitecture, leading to an increased fracture risk. This occurs due to an imbalance in bone remodelling, whereby the rate of bone resorption is greater than bone formation. Mevalonate pathway, previously known to involve in cholesterol synthesis, is an important regulatory pathway for bone remodelling.
OBJECTIVE: This review aimed to provide an overview of the relationship between mevalonate pathway and bone metabolism, as well as agents which act through this pathway to achieve their therapeutic potential.
DISCUSSION: Mevalonate pathway produces farnesyl pyrophosphate and geranylgeranyl pyrophosphate essential in protein prenylation. An increase in protein prenylation favours bone resorption over bone formation. Non-nitrogen containing bisphosphonates inhibit farnesyl diphosphate synthase which produces farnesyl pyrophosphate. They are used as the first line therapy for osteoporosis. Statins, a well-known class of cholesterol-lowering agents, inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-determining enzyme in the mevalonate pathway. It was shown to increase bone mineral density and prevent fracture in humans. Tocotrienol is a group of vitamin E commonly found in palm oil, rice bran and annatto bean. It causes degradation of HMG-CoA reductase. Many studies demonstrated that tocotrienol prevented bone loss in animal studies but its efficacy has not been tested in humans.
CONCLUSION: Mevalonate pathway can be exploited to develop effective antiosteoporosis agents.

Matched MeSH terms: Osteoporosis/drug therapy*
Effects of tocotrienol from Bixa orellana (annatto) on bone histomorphometry in a male osteoporosis model induced by buserelin

Mohamad NV, Soelaiman IN, Chin KY

Biomed Pharmacother, 2018 Jul;103:453-462.
PMID: 29674281 DOI: 10.1016/j.biopha.2018.04.083

INTRODUCTION: Osteoporosis is a debilitating skeletal side effect of androgen deprivation therapy based on gonadotropin-releasing hormone (GnRH) agonist in men. Tocotrienol from Bixa orellana (annatto) has been demonstrated to offer protection against osteoporosis by exerting anabolic effects on bone. Thus, it may prevent osteoporosis among GnRH agonist users.
OBJECTIVE: This study aimed to determine the effectiveness of annatto-tocotrienol on the bone turnover markers and bone histomorphometry in a model of male osteoporosis induced by buserelin (a GnRH agonist).
METHODS: Forty-six three-months-old male Sprague-Dawley rats (three months old; 300-350 g) were randomly divided into six groups. The baseline control group (n = 6) was sacrificed at the onset of the study. The normal control group (n = 8) received corn oil (the vehicle of tocotrienol) orally daily and normal saline (the vehicle of buserelin) subcutaneously daily. The buserelin control (n = 8) received corn oil orally daily and subcutaneous buserelin injection 75 μg/kg/day daily. The calcium control (n = 8) received 1% calcium in drinking water and subcutaneous buserelin injection 75 μg/kg/day. The remaining rats were treated with two different treatments, i.e., (1) oral annatto tocotrienol at 60 mg/kg/day plus subcutaneous buserelin injection 75 μg/kg/day (n = 8); (2) oral annatto tocotrienol at 100 mg/kg/day plus subcutaneous buserelin injection 75 μg/kg/day (n = 8). The rats were injected with calcein twice before being sacrificed to label the bones. The rats were euthanized, and their blood and right femur were harvested at the end of the treatment for bone turnover markers and bone histomorphometry examination.
RESULTS: Both serum osteocalcin and C-telopeptide of type 1 collagen were not significantly different between treated groups and buserelin control (P > 0.05). The buserelin control group had a significantly lower bone volume and higher eroded surface compared with the normal control group (P 

Matched MeSH terms: Osteoporosis/drug therapy*
Berberine and musculoskeletal disorders: The therapeutic potential and underlying molecular mechanisms

Wong SK, Chin KY, Ima-Nirwana S

Phytomedicine, 2020 Jul 15;73:152892.
PMID: 30902523 DOI: 10.1016/j.phymed.2019.152892

BACKGROUND: Musculoskeletal disorders are a group of disorders that affect the joints, bones, and muscles, causing long-term disability. Berberine, an isoquinoline alkaloid, has been previously established to exhibit beneficial properties in preventing various diseases, including musculoskeletal disorders.
PURPOSE: This review article aims to recapitulate the therapeutic potential of berberine and its mechanism of action in treating musculoskeletal disorders.
METHODS: A wide range of literature illustrating the effects of berberine in ameliorating musculoskeletal disorders was retrieved from online electronic databases (PubMed and Medline) and reviewed.
RESULTS: Berberine may potentially retard the progression of osteoporosis, osteoarthritis and rheumatoid arthritis. Limited studies reported the effects of berberine in suppressing the proliferation of osteosarcoma cells. These beneficial properties of berberine are mediated in part through its ability to target multiple signaling pathways, including PKA, p38 MAPK, Wnt/β-catenin, AMPK, RANK/RANKL/OPG, PI3K/Akt, NFAT, NF-κB, Hedgehog, and oxidative stress signaling. In addition, berberine exhibited anti-apoptotic, anti-inflammatory, and immunosuppressive properties.
CONCLUSION: The current evidence indicates that berberine may be effective in preventing musculoskeletal disorders. However, findings from in vitro and in vivo investigations await further validation from human clinical trial.

Matched MeSH terms: Osteoporosis/drug therapy
Fulltext Establishing an Animal Model of Secondary Osteoporosis by Using a Gonadotropin-releasing Hormone Agonist

Mohamad NV, Che Zulkepli MAA, May Theseira K, Zulkifli N, Shahrom NQ, Ridzuan NAM, et al.

Int J Med Sci, 2018;15(4):300-308.
PMID: 29511366 DOI: 10.7150/ijms.22732

Introduction: Orchidectomy is currently the preferred method to induce bone loss in preclinical male osteoporosis model. Gonadotropin-releasing hormone (GnRH) agonists used in prostate cancer treatment can induce testosterone deficiency but its effects on bone in preclinical male osteoporosis model are less studied. Objective: This study aimed to evaluate the skeletal effect of buserelin (a GnRH agonist) in male rats and compare it with orchidectomy. Methods: Forty-six three-month-old male Sprague-Dawley rats were divided into three experimental arms. The baseline arm (n=6) was sacrificed at the onset of the study. In the buserelin arm, the rats received a daily subcutaneous injection of either normal saline (n=8), buserelin acetate at 25 µg/kg (n=8) or 75 µg/kg (n=8). In the orchidectomy arm, the rats were either sham-operated (n=8) or orchidectomized (n=8). All groups underwent in-vivo X-ray micro-computed tomography scanning at the left proximal tibia every month. Blood was collected at the beginning and the end of the study for testosterone level evaluation. The rats were euthanized after the three-month treatment. The femurs were harvested for biomechanical strength and bone calcium determination. Results: The results showed that buserelin at both doses caused a significant decline in testosterone level and deterioration in bone microstructure (p<0.05), but did not affect bone calcium content (p>0.05). Buserelin at 25 µg/kg decreased displacement and strain of the femur significantly (p<0.05). Similar changes were observed in the orchidectomized group compared to the sham-operated group but without any significant changes in biomechanical strength (p>0.05). Conclusion: Buserelin can induce testosterone deficiency and the associated deterioration of bone microarchitecture similar to orchidectomy in three months. However, it may require a longer time to show significant effects on bone strength and mineral content.

Matched MeSH terms: Osteoporosis/drug therapy*
Bisphosphonates, healthcare professionals and oral health

Raj DV, Abuzar M, Borromeo GL

Gerodontology, 2016 Mar;33(1):135-43.
PMID: 25039439 DOI: 10.1111/ger.12141

OBJECTIVE: General medical and dental practitioner and pharmacists all encounter patients on bisphosphonates and as such require adequate knowledge regarding osteonecrosis of the jaw, a potential complication associated with its use. The cross-sectional study investigated perceived implications of and attitudes towards bisphosphonate use in oral health among general medical and dental practitioners and pharmacists.
MATERIALS AND METHODS: Medical and dental practitioners and pharmacists registered in Victoria, Australia, completed an online survey (SurveyMonkey©). Data analysis consisted of chi-square tests with significance as p < 0.05.
RESULTS: One hundred and thirty six doctors (general medical practitioners, GMPs), 283 dentists (GDPs) and 26 pharmacists (PHs) participated. 70, 38 and 80%, respectively, reviewed patients prescribed bisphosphonates (BPs). GMPs (88%), GDPs (76%) and PHs (85%) were aware of osteonecrosis of the jaws (ONJ). GMPs (76%) and PHs (100%) advised patients to inform dentists. GMPs (45%) referred patients for dental assessments prior to commencing BPs with 71.9% of GDPs received such referrals. In terms of available information on oral health and BPs, GMPs (56%), GDPs (50%) and PH (53.8%) were either unsure any existed or reported receiving sufficient information.
CONCLUSIONS: Discrepancies exist amongst different healthcare professionals in terms of BP use and oral health, and common consensus guidelines are warranted.
KEYWORDS: bisphosphonates; clinical guidelines; drug therapy; oral health; osteonecrosis.

Matched MeSH terms: Osteoporosis/drug therapy
Fulltext Probiotics (Bifidobacterium longum) Increase Bone Mass Density and Upregulate Sparc and Bmp-2 Genes in Rats with Bone Loss Resulting from Ovariectomy

Parvaneh K, Ebrahimi M, Sabran MR, Karimi G, Hwei AN, Abdul-Majeed S, et al.

Biomed Res Int, 2015;2015:897639.
PMID: 26366421 DOI: 10.1155/2015/897639

Probiotics are live microorganisms that exert beneficial effects on the host, when administered in adequate amounts. Mostly, probiotics affect the gastrointestinal (GI) tract of the host and alter the composition of gut microbiota. Nowadays, the incidence of hip fractures due to osteoporosis is increasing worldwide. Ovariectomized (OVX) rats have fragile bone due to estrogen deficiency and mimic the menopausal conditions in women. Therefore, this study aimed to examine the effects of Bifidobacterium longum (B. longum) on bone mass density (BMD), bone mineral content (BMC), bone remodeling, bone structure, and gene expression in OVX rats. The rats were randomly assigned into 3 groups (sham, OVX, and the OVX group supplemented with 1 mL of B. longum 10(8)-10(9) colony forming units (CFU)/mL). B. longum was given once daily for 16 weeks, starting from 2 weeks after the surgery. The B. longum supplementation increased (p < 0.05) serum osteocalcin (OC) and osteoblasts, bone formation parameters, and decreased serum C-terminal telopeptide (CTX) and osteoclasts, bone resorption parameters. It also altered the microstructure of the femur. Consequently, it increased BMD by increasing (p < 0.05) the expression of Sparc and Bmp-2 genes. B. longum alleviated bone loss in OVX rats and enhanced BMD by decreasing bone resorption and increasing bone formation.

Matched MeSH terms: Osteoporosis/drug therapy
Fulltext The effects of targeted deliveries of lovastatin and tocotrienol on ossification-related gene expressions in fracture healing in an osteoporosis rat model

Ibrahim N', Mohamed N, Soelaiman IN, Shuid AN

Int J Environ Res Public Health, 2015 Oct;12(10):12958-76.
PMID: 26501302 DOI: 10.3390/ijerph121012958

Osteoporotic drugs are used to prevent fragility fractures, but their role in fracture healing still remains unknown. Thus, alternative agents with suitable mode of delivery are needed to promote fracture healing. This study was performed to investigate the effects of direct deliveries of lovastatin and tocotrienol to fracture sites on ossification-related gene expression in fracture healing in a postmenopausal osteoporosis model. Forty-eight Sprague Dawley female rats were divided into six groups. Group I comprised the sham-operated rats, while Groups II-VI were ovariectomized rats. After 8 weeks, the right tibiae of all rats were fractured and stabilized. Group I and Group II were given two single injections of lovastatin and tocotrienol carriers. Group III was given an estrogen preparation at 64.5 µg/kg daily via oral gavages. Group IV was injected with lovastatin particles (750 µg/kg), while Group V was injected with tocotrienol particles (60 mg/kg). Group VI received two single injections of 750 µg/kg lovastatin particles and 60 mg/kg tocotrienol particles. After 4 weeks, the gene expressions were measured. Group VI showed significantly higher gene expressions of osteocalcin, BMP-2, VEGF-α, and RUNX-2 compared to Group II. In conclusion, combined treatment of lovastatin and tocotrienol upregulated the expression of genes related to fracture healing.

Matched MeSH terms: Osteoporosis/drug therapy
Pregnancy-associated osteoporosis: a UK case series and literature review

Hardcastle SA, Yahya F, Bhalla AK

Osteoporos Int, 2019 May;30(5):939-948.
PMID: 30671611 DOI: 10.1007/s00198-019-04842-w

Mini Abstract: Pregnancy-associated osteoporosis (PAO) is a rare syndrome affecting women during late pregnancy and the early postpartum period. We set out to review the clinical features of ten cases of PAO from a single UK centre. Patients had attended the Royal National Hospital for Rheumatic Diseases, Bath (RNHRD) between January 2000 and June 2016. The principal criterion for inclusion was the occurrence of low trauma fractures either during pregnancy or the immediate post-partum period. Data were obtained from retrospective review of medical notes. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (Hologic ®Discovery system) at the lumbar spine and hip. Data pertaining to the pregnancy, as well as type and duration of treatment received, were reviewed. All ten cases presented with vertebral fractures. In four patients, no risk factors for fracture other than pregnancy or breastfeeding could be identified. Four patients were found to have vitamin D insufficiency at the time of diagnosis, and a further two patients had received treatment with low molecular weight heparin (LMWH). In one case, further investigation led to a diagnosis of osteogenesis imperfecta (OI) confirmed on genetic testing. In terms of treatment, eight out of the ten patients in this series received a bisphosphonate, most commonly risedronate due to its relatively short skeletal retention time. Clinicians should be aware of PAO, a rare but recognised complication of pregnancy. The condition should be especially considered in women presenting with new onset back pain in pregnancy or the postpartum period.

Matched MeSH terms: Osteoporosis/drug therapy
The Effects of Annatto Tocotrienol on Bone Biomechanical Strength and Bone Calcium Content in an Animal Model of Osteoporosis Due to Testosterone Deficiency

Chin KY, Gengatharan D, Mohd Nasru FS, Khairussam RA, Ern SL, Aminuddin SA, et al.

Nutrients, 2016 Dec 14;8(12).
PMID: 27983628

Osteoporosis reduces the skeletal strength and increases the risk for fracture. It is an underdiagnosed disease in men. Annatto tocotrienol has been shown to improve bone structural indices and increase expression of bone formation genes in orchidectomized rats. This study aimed to evaluate the effects of annatto tocotrienol on biomechanical strength and calcium content of the bone in orchidectomized rats. Thirty three-month-old male Sprague-Dawley rats were randomly assigned to five groups. The baseline control (BC) group was sacrificed at the onset of the study. The sham-operated group (SHAM) received olive oil (the vehicle of tocotrienol) orally daily and peanut oil (the vehicle of testosterone) intramuscularly weekly. The remaining rats were orchidectomized and treated with three different regimens, i.e., (1) daily oral olive oil plus weekly intramuscular peanut oil injection; (2) daily oral annatto tocotrienol at 60 mg/kg plus weekly intramuscular peanut oil injection; (3) daily oral olive oil plus weekly intramuscular testosterone enanthate injection at 7 mg/kg. Blood, femur and tibia of the rats were harvested at the end of the two-month treatment period for the evaluation of serum total calcium and inorganic phosphate levels, bone biomechanical strength test and bone calcium content. Annatto-tocotrienol treatment improved serum calcium level and tibial calcium content (p < 0.05) but it did not affect femoral biomechanical strength (p > 0.05). In conclusion, annatto-tocotrienol at 60 mg/kg augments bone calcium level by preventing calcium mobilization into the circulation. A longer treatment period is needed for annatto tocotrienol to exert its effects on bone strength.

Matched MeSH terms: Osteoporosis/drug therapy*
Piper sarmentosum Effects on 11β-Hydroxysteroid Dehydrogenase Type 1 Enzyme in Serum and Bone in Rat Model of Glucocorticoid-Induced Osteoporosis

Mohamad Asri SF, Mohd Ramli ES, Soelaiman IN, Mat Noh MA, Abdul Rashid AH, Suhaimi F

Molecules, 2016 Nov 15;21(11).
PMID: 27854305

Glucocorticoid-induced osteoporosis is one of the common causes of secondary osteoporosis. Piper sarmentosum (Ps) extract possesses antioxidant and anti-inflammatory activities. In this study, we determined the correlation between the effects of Ps leaf water extract with the regulation of 11β-hydroxysteroid dehydrogenase (HSD) type 1 enzyme activity in serum and bone of glucocorticoid-induced osteoporotic rats. Twenty-four Sprague-Dawley rats were grouped into following: G1: sham-operated group administered with intramuscular vehicle olive oil and vehicle normal saline orally; G2: adrenalectomized (adrx) control group given intramuscular dexamethasone (120 μg/kg/day) and vehicle normal saline orally; G3: adrx group given intramuscular dexamethasone (120 μg/kg/day) and water extract of Piper sarmentosum (125 mg/kg/day) orally. After two months, the femur and serum were taken for ELISA analysis. Results showed that Ps leaf water extract significantly reduced the femur corticosterone concentration (p < 0.05). This suggests that Ps leaf water extract was able to prevent bone loss due to long-term glucocorticoid therapy by acting locally on the bone cells by increasing the dehydrogenase action of 11β-HSD type 1. Thus, Ps may have the potential to be used as an alternative medicine against osteoporosis and osteoporotic fracture in patients on long-term glucocorticoid treatment.

Matched MeSH terms: Osteoporosis/drug therapy

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