Osteoprotective Effects in Postmenopausal Osteoporosis Rat Model: Oral Tocotrienol vs. Intraosseous Injection of Tocotrienol-Poly Lactic-Co-Glycolic Acid Combination

Abstract

Osteoporosis, the most common bone disease, is associated with compromised bone strength and increased risk of fracture. Previous studies have shown that oxidative stress contributes to the progression of osteoporosis. Specifically, for postmenopausal osteoporosis, the reduction in estrogen levels leads to increased oxidative stress in bone remodeling. Tocotrienol, a member of vitamin E that exhibits antioxidant activities, has shown potential as an agent for the treatment of osteoporosis. Most studies on the osteoprotective effects of tocotrienols had used the oral form of tocotrienols, despite their low bioavailability due the lack of transfer proteins and high metabolism in the liver. Several bone studies have utilized tocotrienol combined with a nanocarrier to produce a controlled release of tocotrienol particles into the system. However, the potential of delivering tocotrienol–nanocarrier combination through the intraosseous route has never been explored. In this study, tocotrienol was combined with a nanocarrier, poly lactic-co-glycolic acid (PLGA), and injected intraosseously into the bones of ovariectomized rats to produce targeted and controlled delivery of tocotrienol into the bone microenvironment. This new form of tocotrienol delivery was compared with the conventional oral delivery in terms of their effects on bone parameters. Forty Sprague–Dawley rats were divided into five groups. The first group was sham operated, while other groups were ovariectomized (OVX). Following 2 months, the right tibiae of all the rats were drilled at the metaphysis region to provide access for intraosseous injection. The estrogen group (OVX + ESTO) and tocotrienol group (OVX + TTO) were given daily oral gavages of Premarin (64.5 mg/kg) and annatto-tocotrienol (60 mg/kg), respectively. The locally administered tocotrienol group (OVX + TTL) was given a single intraosseous injection of tocotrienol–PLGA combination. After 8 weeks of treatment, both OVX + TTO and OVX + TTL groups have significantly lower bone markers and higher bone mineral content than the OVX group. In terms of bone microarchitecture, both groups demonstrated significantly higher trabecular separation and connectivity density than the OVX group (p < 0.05). Both groups also showed improvement in bone strength by the significantly higher stress, strain, stiffness, and Young’s modulus parameters. In conclusion, daily oral tocotrienol and one-time intraosseous injection of tocotrienol–PLGA combination were equally effective in offering protection against ovariectomy-induced bone changes.

Biomaterials-Based Antioxidant Strategies for the Treatment of Oxidative Stress Diseases

“…Tocotrienol, a member of vitamin E family, possesses antioxidant capacity. To increase its bioavailability, Gao et al have combined it with PLGA NPs and injected into the bones of a postmenopausal osteoporosis rat model, achieving higher mineral content and an improvement in bone strength, compared with controls [207]. Polaprezinc (Zinc L-carnosine), a commercially available drug that acts as a potent inducer of antioxidant enzymes such as SOD and glutathione peroxidase, was effectively incorporated into polycaprolactone/gelatine hybrid electrospun nanofibres to produce a membrane with antioxidant and pro-osteogenesis capabilities.…”

Ameliorative Effect of Tocotrienols on Perimenopausal-Associated Osteoporosis—A Review

“…A marked decrease of plasma antioxidants was also reported in both aged or osteoporotic rats and human subjects. However, the effects of oxidative stress could be reversed by antioxidants [ 15 ]. Numerous studies have been conducted on the antioxidative effects of tocotrienols on bone health.…”

“…Due to the high potential therapeutic effects of tocotrienols on bone loss but low bioavailability, Ibrahim et al investigated the potential of combining synthetic and biodegradable polymers with tocotrienols and delivering them in a controlled manner [ 15 ]. A formulation of nanocarrier polylactic-co-glycolic acid (PLGA) and tocotrienols was injected intra-osseously once into the bones of ovariectomized rats and compared to rats given daily oral tocotrienols for 8 weeks.…”

“…A formulation of nanocarrier polylactic-co-glycolic acid (PLGA) and tocotrienols was injected intra-osseously once into the bones of ovariectomized rats and compared to rats given daily oral tocotrienols for 8 weeks. Their results revealed similar potency; significant improvements were noted in lower bone markers, higher bone mineral content, higher trabecular separation and connectivity density, and better bone strength [ 15 ]. With these results, a rapid and safer method was born, and it will be beneficial to patients for whom venous access is difficult as well as those in coma or immobile, with fewer compliance issues and fewer side effects [ 53 ].…”