Zinc has insulin-mimetic properties which enhance spinal fusion in a rat model.

BACKGROUND CONTEXT: Previous studies have found that insulin or insulin-like growth factor treatment can stimulate fracture healing in diabetic and normal animal models, and increase fusion rates in a rat spinal fusion model. Insulin-mimetic agents, such as zinc, have demonstrated antidiabetic effects in animal and human studies, and these agents that mimic the effects of insulin could produce the same beneficial effects on bone regeneration and spinal fusion. PURPOSE: The purpose of this study was to analyze the effects of locally applied zinc on spinal fusion in a rat model. STUDY DESIGN/SETTING: Institutional Animal Care and Use Committee-approved animal study using Sprague-Dawley rats was used as the study design. METHODS: Thirty Sprague-Dawley rats (450-500 g) underwent L4-L5 posterolateral lumbar fusion (PLF). After decortication and application of approximately 0.3 g of autograft per side, one of three pellets were added to each site: high-dose zinc calcium sulfate (ZnCaSO4), low-dose ZnCaSO4 (half of the high dose), or a control palmitic acid pellet (no Zn dose). Systemic blood glucose levels were measured 24 hours postoperatively. Rats were sacrificed after 8weeks and the PLFs analyzed qualitatively by manual palpation and radiograph review, and quantitatively by micro-computed tomography (CT) analysis of bone volume and trabecular thickness. Statistical analyses with p-values set at .05 were accomplished with analysis of variance, followed by posthoc tests for quantitative data, or Mann-Whitney rank tests for qualitative assessments. RESULTS: Compared with controls, the low-dose zinc group demonstrated a significantly higher manual palpation grade (p=.011), radiographic score (p=.045), and bone formation on micro-CT (172.9 mm(3) vs. 126.7 mm(3) for controls) (p<.01). The high-dose zinc also demonstrated a significantly higher radiographic score (p=.017) and bone formation on micro-CT (172.7 mm(3) vs. 126.7 mm(3)) (p<.01) versus controls, and was trending toward higher manual palpation scores (p=.058). CONCLUSIONS: This study demonstrates the potential benefit of a locally applied insulin-mimetic agent, such as zinc, in a rat lumbar fusion model. Previous studies have demonstrated the benefits of local insulin application in the same model, and it appears that zinc has similar effects.

The resistance of cortical bone tissue to failure under cyclic loading is reduced with alendronate.

Bisphosphonates are the most prescribed preventative treatment for osteoporosis. However, their long-term use has recently been associated with atypical fractures of cortical bone in patients who present with low-energy induced breaks of unclear pathophysiology. The effects of bisphosphonates on the mechanical properties of cortical bone have been exclusively studied under simple, monotonic, quasi-static loading. This study examined the cyclic fatigue properties of bisphosphonate-treated cortical bone at a level in which tissue damage initiates and is accumulated prior to frank fracture in low-energy situations. Physiologically relevant, dynamic, 4-point bending applied to beams (1.5 mm × 0.5 mm × 10 mm) machined from dog rib (n=12/group) demonstrated mechanical failure and micro-architectural features that were dependent on drug dose (3 groups: 0, 0.2, 1.0mg/kg/day; alendronate [ALN] for 3 years) with cortical bone tissue elastic modulus (initial cycles of loading) reduced by 21% (p<0.001) and fatigue life (number of cycles to failure) reduced in a stress-life approach by greater than 3-fold with ALN1.0 (p<0.05). While not affecting the number of osteons, ALN treatment reduced other features associated with bone remodeling, such as the size of osteons (-14%; ALN1.0: 10.5±1.8, VEH: 12.2±1.6, ×10(3) µm2; p<0.01) and the density of osteocyte lacunae (-20%; ALN1.0: 11.4±3.3, VEH: 14.3±3.6, ×10(2) #/mm2; p<0.05). Furthermore, the osteocyte lacunar density was directly proportional to initial elastic modulus when the groups were pooled (R=0.54, p<0.01). These findings suggest that the structural components normally contributing to healthy cortical bone tissue are altered by high-dose ALN treatment and contribute to reduced mechanical properties under cyclic loading conditions.

Ovariectomy increases vascular calcification via the OPG/RANKL cytokine signalling pathway.

BACKGROUND: Observational studies suggest a strong relationship between menopause and vascular calcification. Receptor activator of nuclear factor-kappaBeta ligand (RANKL) and osteoprotegerin (OPG) are critical regulators of bone remodelling and modulate vascular calcification. We assessed the hypothesis that ovariectomy increases vascular calcification via the OPG/RANKL axis. MATERIALS AND METHODS: Age-matched sexually mature rabbits were randomized to ovariectomy (OVX, n = 12) or sham procedure (SHAM, n = 12). One month post-procedure, atherosclerosis was induced by 15 months 0.2%-cholesterol diet and endothelial balloon denudations (at months 1 and 3). Aortic atherosclerosis was assessed in vivo by magnetic resonance imaging (MRI) at months 9 and 15. At sacrifice, aortas were harvested for ex vivo microcomputed tomography (microCT) and molecular analysis of the vascular tissue. RESULTS: Vascular calcification density and calcific particle number were significantly greater in OVX than SHAM (8.4 +/- 2.8 vs. 1.9 +/- 0.6 mg cm(-3), P = 0.042, and 94 +/- 26 vs. 33 +/- 7 particles cm(-3), P = 0.046, respectively). Calcification morphology, as assessed by the arc angle subtended by the largest calcific particle, showed no difference between groups (OVX 33 +/- 7 degrees vs. SHAM 33 +/- 5 degrees , P = 0.99). By Western blot analysis, OVX increased the vascular OPG:RANKL ratio by 66%, P = 0.029, primarily by decreasing RANKL (P = 0.019). At month 9, MRI demonstrated no difference in atheroma volume between OVX and SHAM, and no significant change was seen by the end of the study. CONCLUSIONS: In contrast to bone, vascular OPG:RANKL ratio increased in response to ovariectomy with a corresponding fourfold increase in arterial calcification. This diametrical organ-specific response may explain the comorbid association of osteoporosis with calcifying atherosclerosis in post-menopausal women.

Loading induces site-specific increases in mineral content assessed by microcomputed tomography of the mouse tibia.

Adaptation to mechanical loading has been studied extensively in cortical, but not cancellous bone. However, corticocancellous sites are more relevant to osteoporosis and related fracture risk of the hip and spine. We tested the hypotheses that adaptation in a long bone would be greater at cancellous than cortical sites and would depend on the term of daily in vivo cyclic axial loading. We applied compressive loads to the adolescent, 10-week old, male C57BL/6 mouse tibia to examine the skeletal response immediately prior to attainment of peak bone mass. Adaptation was quantified at the completion of either 2-week (n = 8) or 6-week (n = 12) loading terms by directly comparing volumetric bone mineral content between loaded and contralateral limbs by microcomputed tomography. The increase in mineral content was site specific with a greater response found in the corticocancellous proximal metaphysis (14%) than the cortical mid-shaft (2%) after 6 weeks of loading. Furthermore, bone volume fraction and average trabecular thickness of cancellous bone in the proximal tibia increased after 6 weeks by 15% and 12% respectively. Diaphyseal response was only evident proximal to the mid-shaft as indicated by an 8% increase in maximum principal moment of inertia. Both loading terms produced similar results for mineral content, volume fraction, and moments of inertia. Our finding that non-invasive loading increases the bone volume and fraction at a corticocancellous site by as much as 15% motivates exploring the use of mechanical loading to attain greater peak bone mass and inhibit osteoporosis.

Whole-body vibration in the skeleton: development of a resonance-based testing device.

Whole-body vibration (WBV) has been demonstrated to have a strong influence on physiological systems, ranging from severely destructive to potentially beneficial. Unfortunately, the study of WBV in a controlled manner is commonly constrained by space and budgetary factors, particularly where vibration in the low frequency range is considered. In the work presented here, a small, low-cost device for performing WBV of the human skeleton is developed to assist in studies of vertical acceleration in a clinical setting. The device design consists of a spring-supported plate driven by an 18 N peak-force electromagnetic actuator, and the associated driving and monitoring electronics. Animal and human lumped-mass models have been coupled with a model of the loading device to seek a resonance response in the vicinity of 30 Hz. This approach minimizes the loading requirements of such a device, and thus a major component of the cost, yet can provide peak accelerations of 0.15 g at a frequency of 30 Hz in a small, lightweight package capable of use in a clinical or laboratory setting.