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Tocotrienols for bone health: a translational approach

Shen CL, Klein A, Chin KY, Mo H, Tsai P, Yang RS, et al.

Ann N Y Acad Sci, 2017 Aug;1401(1):150-165.
PMID: 28891093 DOI: 10.1111/nyas.13449

Osteoporosis, a degenerative bone disease, is characterized by low bone mass and microstructural deterioration of bone tissue resulting in aggravated bone fragility and susceptibility to fractures. The trend of extended life expectancy is accompanied by a rise in the prevalence of osteoporosis and concomitant complications in the elderly population. Epidemiological evidence has shown an association between vitamin E consumption and the prevention of age-related bone loss in elderly women and men. Animal studies show that ingestion of vitamin E, especially tocotrienols, may benefit bone health in terms of maintaining higher bone mineral density and improving bone microstructure and quality. The beneficial effects of tocotrienols on bone health appear to be mediated via antioxidant/anti-inflammatory pathways and/or 3-hydroxy-3-methylglutaryl coenzyme A mechanisms. We discuss (1) an overview of the prevalence and etiology of osteoporosis, (2) types of vitamin E (tocopherols versus tocotrienols), (3) findings of tocotrienols and bone health from published in vitro and animal studies, (4) possible mechanisms involved in bone protection, and (5) challenges and future direction for research.

Matched MeSH terms: Bone and Bones/pathology
Light chain multiple myeloma: an evaluation of its biochemical investigations

Zahari Sham SY, C Thambiah S, Samsudin IN, Lim SM

Malays J Pathol, 2017 Dec;39(3):311-315.
PMID: 29279596 MyJurnal

Multiple myeloma is a type of plasma cell dyscrasia, characterised by presence of paraprotein or monoclonal (M)-protein in serum or urine. The M-protein may consist of an intact immunoglobulin, the heavy chain only or the light chain only. The latter, designated as light chain multiple myeloma (LCMM) makes up almost 20% of myelomas. Clinical manifestation is often heralded by hypercalcaemia, renal impairment, normocytic normochromic anaemia and bone lesions, reflecting end-organ damage, collectively known as the acronym CRAB. In particular, free light chain nephrotoxicity accounts for the high prevalence of renal impairment seen in LCMM. This case illustrates a typical presentation of LCMM with focal discussion on its initial and diagnostic, as well as prognostic biochemical investigations.

Matched MeSH terms: Bone and Bones/pathology
Skeletal-related events among breast and prostate cancer patients: towards new treatment initiation in Malaysia's hospital setting

Ezat SW, Syed Junid SM, Noraziani K, Zafar A, Saperi S, Nur AM, et al.

Asian Pac J Cancer Prev, 2013;14(5):3357-62.
PMID: 23803129

The human skeleton is the most common organ to be affected by metastatic cancer and bone metastases are a major cause of cancer morbidity. The five most frequent cancers in Malaysia among males includes prostate whereas breast cancer is among those in females, both being associated with skeletal lesions. Bone metastases weaken bone structure, causing a range of symptoms and complications thus developing skeletal-related events (SRE). Patients with SRE may require palliative radiotherapy or surgery to bone for pain, having hypercalcaemia, pathologic fractures, and spinal cord compression. These complications contribute to a decline in patient health- related quality of life. The multidimensional assessment of health-related quality of life for those patients is important other than considering a beneficial treatment impact on patient survival, since the side effects of treatment and disease symptoms can significantly impact health-related quality of life. Cancer treatment could contribute to significant financial implications for the healthcare system. Therefore, it is essential to assess the health-related quality of life and treatment cost, among prostate and breast cancer patients in countries like Malaysia to rationalized cost-effective way for budget allocation or utilization of health care resources, hence helping in providing more personalized treatment for cancer patients.

Matched MeSH terms: Bone and Bones/pathology*
The use of selective estrogen receptor modulators on bone health in men

Wong SK, Mohamad NV, Jayusman PA, Shuid AN, Ima-Nirwana S, Chin KY

Aging Male, 2019 Jun;22(2):89-101.
PMID: 29508640 DOI: 10.1080/13685538.2018.1448058

Selective estrogen receptor modulators (SERMs) represent a class of drugs that act as agonist or antagonist for estrogen receptor in a tissue-specific manner. The SERMs drugs are initially used for the prevention and treatment of osteoporosis in postmenopausal women. Bone health in prostate cancer patients has become a significant concern, whereby patients undergo androgen deprivation therapy is often associated with deleterious effects on bone. Previous preclinical and epidemiological findings showed that estrogens play a dominant role in improving bone health as compared to testosterone in men. Therefore, this evidence-based review aims to assess the available evidence derived from animal and human studies on the effects of SERMs on the male skeletal system. The effects of SERMs on bone mineral density (BMD)/content (BMC), bone histomorphometry, bone turnover, bone strength and fracture risk have been summarized in this review.

Matched MeSH terms: Bone and Bones/pathology
Glycyrrhizic acid (GCA) as 11β-hydroxysteroid dehydrogenase inhibitor exerts protective effect against glucocorticoid-induced osteoporosis

Ramli ES, Suhaimi F, Asri SF, Ahmad F, Soelaiman IN

J. Bone Miner. Metab., 2013 May;31(3):262-73.
PMID: 23274351 DOI: 10.1007/s00774-012-0413-x

Rapid onset of bone loss is a frequent complication of systemic glucocorticoid therapy which may lead to fragility fractures. Glucocorticoid action in bone depends upon the activity of 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1). Regulations of 11β-HSD1 activity may protect the bone against bone loss due to excess glucocorticoids. Glycyrrhizic acid (GCA) is a potent inhibitor of 11β-HSD. Treatment with GCA led to significant reduction in bone resorption markers. In this study we determined the effect of GCA on 11β-HSD1 activity in bones of glucocorticoid-induced osteoporotic rats. Thirty-six male Sprague-Dawley rats (aged 3 months and weighing 250-300 g) were divided randomly into groups of ten. (1) G1, sham operated group; (2) G2, adrenalectomized rats administered with intramuscular dexamethasone 120 μg/kg/day and oral vehicle normal saline vehicle; and (3) G3, adrenalectomized rats administered with intramuscular dexamethasone 120 μg/kg/day and oral GCA 120 mg/kg/day The results showed that GCA reduced plasma corticosterone concentration. GCA also reduced serum concentration of the bone resorption marker, pyridinoline and induced 11β-HSD1 dehydrogenase activity in the bone. GCA improved bone structure, which contributed to stronger bone. Therefore, GCA has the potential to be used as an agent to protect the bone against glucocorticoid induced osteoporosis.

Matched MeSH terms: Bone and Bones/pathology
Noni leaf and black tea enhance bone regeneration in estrogen-deficient rats

Shalan NA, Mustapha NM, Mohamed S

Nutrition, 2017 Jan;33:42-51.
PMID: 27908549 DOI: 10.1016/j.nut.2016.08.006

OBJECTIVE: Black tea and Nonileaf are among the dietary compounds that can benefit patients with bone resorption disorders. Their bone regeneration effects and their mechanisms were studied in estrogen-deficient rats.
METHODS: Noni leaves (three doses) and black tea water extracts were fed to ovariectomized rats for 4 mo, and their effects (analyzed via mechanical measurements, micro-computed tomography scan, and reverse transcriptase polymerase chain reaction mRNA) were compared with Remifemin (a commercial phytoestrogen product from black cohosh).
RESULTS: The water extracts (dose-dependently for noni leaves) increased bone regeneration biomarker (runt-related transcription factor 2, bone morphogenetic protein 2, osteoprotegerin, estrogen receptor 1 [ESR1], collagen type I alpha 1A) expressions and reduced the inflammatory biomarkers (interleukin-6, tumor necrosis factor-α, nuclear factor [NF]-κB, and receptor activator of NF-κB ligand) mRNA expressions/levels in the rats. The extracts also improved bone physical and mechanical properties. The extracts demonstrated bone regeneration through improving bone size and structure, bone mechanical properties (strength and flexibility), and bone mineralization and density.
CONCLUSIONS: The catechin-rich extract favored bone regeneration and suppressed bone resorption. The mechanisms involved enhancing osteoblast generation and survival, inhibiting osteoclast growth and activities, suppressing inflammation, improving bone collagen synthesis and upregulating ESR1 expression to augment phytoestrogenic effects. Estrogen deficiency bone loss and all extracts studied (best effect from Morinda leaf at 300 mg/kg body weight) mitigated the loss, indicating benefits for the aged and menopausal women.

Matched MeSH terms: Bone and Bones/pathology
Fulltext Effect of tocotrienol from Bixa orellana (annatto) on bone microstructure, calcium content, and biomechanical strength in a model of male osteoporosis induced by buserelin

Mohamad NV, Ima-Nirwana S, Chin KY

Drug Des Devel Ther, 2018;12:555-564.
PMID: 29588572 DOI: 10.2147/DDDT.S158410

Background: Patients receiving androgen deprivation therapy experience secondary hypogonadism, associated bone loss, and increased fracture risk. It has been shown that tocotrienol from Bixa orellana (annatto) prevents skeletal microstructural changes in rats experiencing primary hypogonadism. However, its potential in preventing bone loss due to androgen deprivation therapy has not been tested. This study aimed to evaluate the skeletal protective effects of annatto tocotrienol using a buserelin-induced osteoporotic rat model.
Methods: Forty-six male Sprague Dawley rats aged 3 months were randomized into six groups. The baseline control (n=6) was sacrificed at the onset of the study. The normal control (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) daily. The calcium control (n=8) was supplemented with 1% calcium in drinking water and daily subcutaneous buserelin injection (75 µg/kg). The remaining rats were given daily oral annatto tocotrienol at 60 mg/kg (n=8) or 100 mg/kg (n=8) plus daily subcutaneous buserelin injection (75 µg/kg) (n=8). At the end of the experiment, the rats were euthanized and their blood, tibia, and femur were harvested. Structural changes of the tibial trabecular and cortical bone were examined using X-ray micro-computed tomography. Femoral bone calcium content and biomechanical strength were also evaluated.
Results: Annatto tocotrienol at 60 and 100 mg/kg significantly prevented the deterioration of trabecular bone and cortical thickness in buserelin-treated rats (P<0.05). Both doses of annatto tocotrienol also improved femoral biomechanical strength and bone calcium content in buserelin-treated rats (P<0.05). The effects of annatto tocotrienol were comparable to calcium supplementation.
Conclusion: Annatto tocotrienol supplementation is effective in preventing degeneration of the bone induced by buserelin. Therefore, it is a potential antiosteoporotic agent for men receiving androgen deprivation therapy.

Matched MeSH terms: Bone and Bones/pathology*
Bisphenol A exposure disturbs the bone metabolism: An evolving interest towards an old culprit

Thent ZC, Froemming GRA, Muid S

Life Sci, 2018 Apr 01;198:1-7.
PMID: 29432759 DOI: 10.1016/j.lfs.2018.02.013

Bisphenol A (BPA) (2,2,-bis (hydroxyphenyl) propane), a well-known endocrine disruptor (ED), is the exogenous chemical that mimic the natural endogenous hormone like oestrogen. Due to its extensive exposure to humans, BPA is considered to be a major toxicological agent for general population. Environmental exposure of BPA results in adverse health outcomes including bone loss. BPA disturbs the bone health by decreasing the plasma calcium level and inhibiting the calcitonin secretion. BPA also stimulated differentiation and induced apoptosis in human osteoblasts and osteoclasts. However, little is known about the underlying mechanisms of the untoward effect of BPA against bone metabolism. The present review gives an overview on the possible mechanisms of BPA towards bone loss. The previous literature shows that BPA exerts its toxic effect on bone cells by binding to the oestrogen related receptor-gamma (ERγ), reducing the bone morphogenic protein-2 (BMP-2) and alkaline phosphatase (ALP) activities. BPA interrupts the bone metabolism via RANKL, apoptosis and Wnt/β-catenin signaling pathways. It is, however, still debated on the exact underlying mechanism of BPA against bone health. We summarised the molecular evidences with possible mechanisms of BPA, an old environmental culprit, in bone loss and enlightened the underlying understanding of adverse action of BPA in the society.

Matched MeSH terms: Bone and Bones/pathology
Catechin-rich oil palm leaf extract enhances bone calcium content of estrogen-deficient rats

Bakhsh A, Mustapha NM, Mohamed S

Nutrition, 2013 Apr;29(4):667-72.
PMID: 23290096 DOI: 10.1016/j.nut.2012.09.005

Postmenopausal estrogen deficiency often causes bone density loss and osteoporosis. This study evaluated the effects of an oral administration of oil palm leaf extract (OPL) on bone calcium content and structure, bone density, ash weights, and serum total alkaline phosphatase (T-ALP) of estrogen-deficient ovariectomized (OVX) rats.

Matched MeSH terms: Bone and Bones/pathology
A new stable GIP-Oxyntomodulin hybrid peptide improved bone strength both at the organ and tissue levels in genetically-inherited type 2 diabetes mellitus

Mansur SA, Mieczkowska A, Flatt PR, Bouvard B, Chappard D, Irwin N, et al.

Bone, 2016 06;87:102-13.
PMID: 27062994 DOI: 10.1016/j.bone.2016.04.001

Obesity and type 2 diabetes mellitus (T2DM) progress worldwide with detrimental effects on several physiological systems including bone tissue mainly by affecting bone quality. Several gut hormones analogues have been proven potent in ameliorating bone quality. In the present study, we used the leptin receptor-deficient db/db mice as a model of obesity and severe T2DM to assess the extent of bone quality alterations at the organ and tissue levels. We also examined the beneficial effects of gut hormone therapy in this model by using a new triple agonist ([d-Ala(2)]GIP-Oxm) active at the GIP, GLP-1 and glucagon receptors. As expected, db/db mice presented with dramatic alterations of bone strength at the organ level associated with deterioration of trabecular and cortical microarchitectures and an augmentation in osteoclast numbers. At the tissue level, these animals presented also with alterations of bone strength (reduced hardness, indentation modulus and dissipated energy) with modifications of tissue mineral distribution, collagen glycation and collagen maturity. The use of [d-Ala(2)]GIP-Oxm considerably improved bone strength at the organ level with modest effects on trabecular microarchitecture. At the tissue level, [d-Ala(2)]GIP-Oxm ameliorated bone strength reductions with positive effects on collagen glycation and collagen maturity. This study provides support for including gut hormone analogues as possible new therapeutic strategies for improving bone quality in bone complications associated to T2DM.

Matched MeSH terms: Bone and Bones/pathology*