Targeted Delivery of Lovastatin and Tocotrienol to Fracture Site Promotes Fracture Healing in Osteoporosis Model: Micro-Computed Tomography and Biomechanical Evaluation

Abstract

Osteoporosis is becoming a major health problem that is associated with increased fracture risk. Previous studies have shown that osteoporosis could delay fracture healing. Although there are potential agents available to promote fracture healing of osteoporotic bone such as statins and tocotrienol, studies on direct delivery of these agents to the fracture site are limited. This study was designed to investigate the effects of two potential agents, lovastatin and tocotrienol using targeted drug delivery system on fracture healing of postmenopausal osteoporosis rats. The fracture healing was evaluated using micro CT and biomechanical parameters. Forty-eight Sprague-Dawley female rats were divided into 6 groups. The first group was sham-operated (SO), while the others were ovariectomized (OVx). After two months, the right tibiae of all rats were fractured at metaphysis region using pulsed ultrasound and were fixed with plates and screws. The SO and OVxC groups were given two single injections of lovastatin and tocotrienol carriers. The estrogen group (OVx+EST) was given daily oral gavages of Premarin (64.5 µg/kg). The Lovastatin treatment group (OVx+Lov) was given a single injection of 750 µg/kg lovastatin particles. The tocotrienol group (OVx+TT) was given a single injection of 60 mg/kg tocotrienol particles. The combination treatment group (OVx+Lov+TT) was given two single injections of 750 µg/kg lovastatin particles and 60 mg/kg tocotrienol particles. After 4 weeks of treatment, the fractured tibiae were dissected out for micro-CT and biomechanical assessments. The combined treatment group (OVx+Lov+TT) showed significantly higher callus volume and callus strength than the OVxC group (p<0.05). Both the OVx+Lov and OVx+TT groups showed significantly higher callus strength than the OVxC group (p<0.05), but not for callus volume. In conclusion, combined lovastatin and tocotrienol may promote better fracture healing of osteoporotic bone.

Inflammation, fracture and bone repair

“…Compromised bone formation events lead to dysregulated homeostasis in cortical bone, especially in the femoral neck, leading to increased number of fragility fractures in the aged population [40, 140]. Fragility fractures are associated with disturbed callus formation and an increased risk of delayed fracture healing and non-union [144, 145]. This presents an opportunity to modulate inflammation and impede bone resorption.…”

Potential mechanisms and applications of statins on osteogenesis: Current modalities, conflicts and future directions

“…Impregnation and repeated local injection are the classic methods [3,5,[119][120][121][122]. In the former, determination of the dose and dosage of the drug may not be possible and thus, it may be an unreliable method [5,122,123].…”

“…Osteoporosis, osteoporosis related fractures and large bone defects (LBDs) are the current problems in orthopedic research [1][2][3][4][5][6][7]. In a normal bone, there is a balance between new bone formation (NBF) and osteoclastic reaction (OR) which is responsible for bone health and mechanical properties [1,5,8].…”

“…In a normal bone, there is a balance between new bone formation (NBF) and osteoclastic reaction (OR) which is responsible for bone health and mechanical properties [1,5,8]. In osteoporotic patients, such balance is altered; thus the biomechanical and morphological features of such bone is significantly altered which result in bone weakening and fracture injuries [1,3,4]. After occurrence of vehicle traumas, high energy traumas, comminuted-, compound-, multiple-and complicated fractures, bone tumors, burns, osteonecrosis, osteomyelitis and osteoporosis related fractures, it is often necessary to remove the damaged bony segment/s and stabilize the remaining bone [6].…”

Labisia pumila improves wound healing process in ovariectomized rat model

“…After ovariectomized of rats, they were kept for a minimum of two weeks to observe for estrogen deficiency state (Kalu, 1991). Mixing solution of ketamine (100 mg/mL) and xylazil (20 mg/mL) as 1:1 ratio were injected intraperitoneally to anesthetize the rats before all surgical procedures (Ibrahim et al, 2014). After two weeks ovariectomy observation, wound treatment of rats was done by using excision wound model (Latif et al, 2015).…”