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Role of Simvastatin on fracture healing and osteoporosis: a systematic review on in vivo investigations

Moshiri A, Sharifi AM, Oryan A

Clin Exp Pharmacol Physiol, 2016 Jul;43(7):659-84.
PMID: 27061579 DOI: 10.1111/1440-1681.12577

Simvastatin is a lipid lowering drug whose beneficial role on bone metabolism was discovered in 1999. Several in vivo studies evaluated its role on osteoporosis and fracture healing, however, controversial results are seen in the literature. For this reason, Simvastatin has not been the focus of any clinical trials as yet. This systematic review clears the mechanisms of action of Simvastatin on bone metabolism and focuses on in vivo investigations that have evaluated its role on osteoporosis and fracture repair to find out (i) whether Simvastatin is effective on treatment of osteoporosis and fracture repair, and (ii) which of the many available protocols may have the ability to be translated in the clinical setting. Simvastatin induces osteoinduction by increasing osteoblast activity and differentiation and inhibiting their apoptosis. It also reduces osteoclastogenesis by decreasing both the number and activity of osteoclasts and their differentiation. Controversial results between the in vivo studies are mostly due to the differences in the route of administration, dose, dosage and carrier type. Local delivery of Simvastatin through controlled drug delivery systems with much lower doses and dosages than the systemic route seems to be the most valuable option in fracture healing. However, systemic delivery of Simvastatin with much higher doses and dosages than the clinical ones seems to be effective in managing osteoporosis. Simvastatin, in a particular range of doses and dosages, may be beneficial in managing osteoporosis and fracture injuries. This review showed that Simvastatin is effective in the treatment of osteoporosis and fracture healing.

Matched MeSH terms: Fractures, Bone/drug therapy
The effects of alpha-tocopherol supplementation on fracture healing in a postmenopausal osteoporotic rat model

Mohamad S, Shuid AN, Mohamed N, Fadzilah FM, Mokhtar SA, Abdullah S, et al.

Clinics (Sao Paulo), 2012 Sep;67(9):1077-85.
PMID: 23018307

OBJECTIVE: Osteoporosis increases the risk of bone fractures and may impair fracture healing. The aim of this study was to investigate whether alpha-tocopherol can improve the late-phase fracture healing of osteoporotic bones in ovariectomized rats.
METHOD: In total, 24 female Sprague-Dawley rats were divided into three groups. The first group was sham-operated, and the other two groups were ovariectomized. After two months, the right femora of the rats were fractured under anesthesia and internally repaired with K-wires. The sham-operated and ovariectomized control rat groups were administered olive oil (a vehicle), whereas 60 mg/kg of alpha-tocopherol was administered via oral gavage to the alpha-tocopherol group for six days per week over the course of 8 weeks. The rats were sacrificed, and the femora were dissected out. Computed tomography scans and X-rays were performed to assess fracture healing and callus staging, followed by the assessment of callus strengths through the biomechanical testing of the bones.
RESULTS: Significantly higher callus volume and callus staging were observed in the ovariectomized control group compared with the sham-operated and alpha-tocopherol groups. The ovariectomized control group also had significantly lower fracture healing scores than the sham-operated group. There were no differences between the alpha-tocopherol and sham-operated groups with respect to the above parameters. The healed femora of the ovariectomized control group demonstrated significantly lower load and strain parameters than the healed femora of the sham-operated group. Alpha-tocopherol supplementation was not able to restore these biomechanical properties.
CONCLUSION: Alpha-tocopherol supplementation appeared to promote bone fracture healing in osteoporotic rats but failed to restore the strength of the fractured bone.

Matched MeSH terms: Fractures, Bone/drug therapy*
Osteoporotic fracture healing: potential use of medicinal plants from the tropics

Abdul Jalil MA, Shuid AN, Muhammad N

Curr Drug Targets, 2013 Dec;14(14):1651-8.
PMID: 24354586

With improvements in living standards and healthcare, life expectancy has been increasing dramatically in most parts of the world. These situations lead to the increase in the reported cases of geriatrics-related diseases such as hypogonadal osteoporosis with skeletal fracture being the ultimate outcome, which eventually causes significant morbidity and mortality. The deficient gonadal hormones, which are the main cause of hypogonadal osteoporosis, could be substituted with hormone replacement therapy to hinder bone loss. However, the artificial hormonal therapy has been linked to grievous conditions such as breast and prostate cancers. In view of the various adverse effects associated with conventional treatment, many researchers are now focusing on finding alternative remedies from nature. This article explores the possibilities of certain medicinal plants native to Malaysia that possess androgenic and antioxidant properties to potentially be used in the treatment of fracture due to osteoporosis in ageing people.

Matched MeSH terms: Fractures, Bone/drug therapy*
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: Fractures, Bone/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: Fractures, Bone/drug therapy*
Fulltext Effects of α-tocopherol on the early phase of osteoporotic fracture healing

Shuid AN, Mohamad S, Muhammad N, Fadzilah FM, Mokhtar SA, Mohamed N, et al.

J Orthop Res, 2011 Nov;29(11):1732-8.
PMID: 21547940 DOI: 10.1002/jor.21452

Fracture healing is a complex process, which is more complicated if the bone is osteoporotic. One of the vitamin E isomers, α-tocopherol, has been found to prevent osteoporosis and improve bone fracture healing but its role in the healing of osteoporotic fractures is still unclear. We carried out a study on the effects of α-tocopherol supplementation on osteoporotic fracture healing using an ovariectomized rat model, whereby we focused on the early phase of fracture healing, that is, the phase with excessive production of free radicals. Twenty-four female Sprague-Dawley rats were divided into three groups: sham-operated (SO), ovariectomized-control (OVC), and ovariectomized + α-tocopherol supplementation (ATF) groups. The right femora of all the rats were fractured at mid-diaphysis and K-wires were inserted for internal fixation. After 2 weeks of treatment, the rats were euthanized and the femora were dissected out for measurement of callous volume by CT-scan and radiological staging of callous formation and fracture healing. The oxidative parameters of the fractured femora were also measured. The results showed that the callous volume and callous staging were not different between the groups. However, the fracture healing stage of the OVC group was lower than the SO group, while α-tocopherol supplementation in the ATF group had improved the healing until it was comparable to the SO group. The activities of the anti-oxidatant enzymes, superoxide dismutase, and glutathione peroxidase in the ATF group were found to be significantly higher than in the OVC group. In conclusion, α-tocopherol improved fracture healing but had no effect on the callous volume and staging. The improvement in fracture healing may be due to the increased activities of the anti-oxidatant enzymes in the bone during the early phase of fracture healing of osteoporotic bone.

Matched MeSH terms: Fractures, Bone/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: Fractures, Bone/drug therapy