Bone loss after severe spinal cord injury coincides with reduced bone formation and precedes bone blood flow deficits

Diminished bone perfusion develops in response to disuse and has been proposed as a mechanism underlying bone loss. Bone blood flow (BF) has not been investigated within the unique context of severe contusion spinal cord injury (SCI), a condition that produces neurogenic bone loss that is precipitated by disuse and other physiologic consequences of central nervous system injury. Herein, 4-mo-old male Sprague-Dawley rats received T9 laminectomy (SHAM) or laminectomy with severe contusion SCI (N=20/group). Time course assessments of hindlimb bone microstructure and bone perfusion were performed in vivo at 1- and 2-wks post-surgery via microCT and intracardiac microsphere infusion, respectively, and bone turnover indices were determined via histomorphometry. Both groups exhibited cancellous bone loss beginning in the initial post-surgical week, with cancellous and cortical bone deficits progressing only in SCI thereafter. Trabecular bone deterioration coincided with uncoupled bone turnover after SCI, as indicated by signs of ongoing osteoclast-mediated bone resorption and a near-complete absence of osteoblasts and cancellous bone formation. Bone BF was not different between groups at 1-wk, when both groups displayed bone loss. In comparison, femur and tibia perfusion was 30-40% lower in SCI vs SHAM at 2-wks, with the most pronounced regional BF deficits occurring at the distal femur. Significant associations existed between distal femur BF and cancellous and cortical bone loss indices. Our data provide the first direct evidence indicating bone BF deficits develop in response to SCI and temporally coincide with suppressed bone formation and with cancellous and cortical bone deterioration.

Physical Activity and Bone Vascularization: A Way to Explore in Bone Repair Context?

Physical activity is widely recognized as a biotherapy by WHO in the fight and prevention of bone diseases such as osteoporosis. It reduces the risk of disabling fractures associated with many comorbidities, and whose repair is a major public health and economic issue. Bone tissue is a dynamic supportive tissue that reshapes itself according to the mechanical stresses to which it is exposed. Physical exercise is recognized as a key factor for bone health. However, the effects of exercise on bone quality depend on exercise protocols, duration, intensity, and frequency. Today, the effects of different exercise modalities on capillary bone vascularization, bone blood flow, and bone angiogenesis remain poorly understood and unclear. As vascularization is an integral part of bone repair process, the analysis of the preventive and/or curative effects of physical exercise is currently very undeveloped. Angiogenesis–osteogenesis coupling may constitute a new way for understanding the role of physical activity, especially in fracturing or in the integration of bone biomaterials. Thus, this review aimed to clarify the link between physical activities, vascularization, and bone repair.

Regional femoral bone blood flow rates in laying and non-laying chickens estimated with fluorescent microspheres

The metabolic rate of vertebrate bone tissue is related to bone growth, repair and homeostasis, which are all dependent on life stage. Bone metabolic rate is difficult to measure directly, but absolute blood flow rate (Q̇) should reflect local tissue oxygen requirements. A recent ‘foramen technique’ has derived an index of blood flow rate (Qi) by measuring nutrient foramen sizes of long bones. Qi is assumed to be proportional to Q̇, however, the assumption has never been tested. This study used fluorescent microsphere infusion to measure femoral bone Q̇ in anaesthetised non-laying hens, laying hens and roosters. Mean cardiac output was 338±38 ml min−1 kg−1, and the two femora received 0.63±0.10 % of this. Laying hens had higher wet bone mass-specific Q̇ to femora (0.23±0.09 ml min−1 g−1) than the non-laying hens (0.12±0.06 ml min−1 g−1) and roosters (0.14±0.04 ml min−1 g−1), presumably associated with higher bone calcium mobilization during eggshell production. Estimated metabolic rate of femoral bone was 0.019 ml O2 min−1 g−1. Femoral Q̇ increased significantly with body mass, but was not correlated with nutrient foramen radius (r), probably due to a narrow range in foramen radius. Over all 18 chickens, femoral shaft Q̇/r was 1.07±0.30 ml min−1 mm−1. Mean Qi in chickens was significantly higher than predicted by an allometric relationship for adult cursorial bird species, possibly because the birds were still growing.

Physical Activity and Bone Vascularization: A Way to Explore in Bone Repair Context?

Physical activity is widely recognized as a biotherapy by WHO in the fight and prevention of bone diseases such as osteoporosis. It reduces the risk of disabling fractures associated with many comorbidities, and whose repair is a major public health and economic issue. Bone tissue is a dynamic supportive tissue that reshapes itself according to the mechanical stresses to which it is exposed. Physical exercise is recognized as a key factor for bone health. However, the effects of exercise on bone quality depend on exercise protocols, duration, intensity and frequency. Today, the effects of different exercise modalities on capillary bone vascularization, bone blood flow and bone angiogenesis remain poorly understood and unclear. As vascularization is an integral part of bone repair process, the analysis of the preventive and/or curative effects of physical exercise is currently very undeveloped. Angiogenesis-osteogenesis coupling may constitute a new way for understanding the role of physical activity, especially in fracturing or in the integration of bone biomaterials. Thus, this review aims to clarify the link between physical activities, vascularization and bone repair.

Mechanisms of bone blood flow regulation in humans

Bone is a highly vascularized tissue. However, despite the importance of appropriate circulationfor bone health, regulation of bone blood flow remains poorly understood. Invasive animalstudies suggest that the sympathetic activity plays an important role in bone flow control.However, it remains unknown if bone vasculature evidences robust vasoconstriction in responseto sympathoexcitatory stimuli. Here, we characterized bone blood flow in young healthyindividuals (N=13,(4F)) in response to isometric handgrip exercise (IHE) and cold pressor test(CPT). These provide a strong stimulus for active vasoconstriction in the inactive muscle, andperhaps also in the bone. During sustained IHE to fatigue and CPT, we measured blood pressure,whole leg blood flow, and tibial perfusion using near-infrared spectroscopy. Tibia perfusion wasdetermined as oxy- and deoxy-hemoglobin. For both stimuli, tibial metabolism remainedconstant (i.e., no change in deoxyhemoglobin) and thus tibial arterial perfusion was representedby oxyhemoglobin. During IHE, oxyhemoglobin declined (beginning -0.20±1.04μM; end -1.13±3.71μM, both p<0.01) slower than whole leg blood flow (beginning -0.85±1.02cm/s; end -2.72±1.64cm/s, both =p<0.01). However, during CPT, both oxyhemoglobin (beginning -0.46 ±1.43μM; end -0.60±1.59μM, both p<0.01) and whole leg blood flow (beginning -1.52±1.63 cm/s;end -0.69±1.51cm/s, both p<0.01) declined with a similar time course, even though themagnitudes of decline were smaller than during IHE. These responses are likely due the differenttime courses of sympathetically mediated vasoconstriction in bone and muscle. These resultsindicate that sympathetic innervation of the bone vasculature serves a functional role in thecontrol of flow in young healthy individuals.

The Case for Measuring Long Bone Hemodynamics With Near-Infrared Spectroscopy

Diseases and associated fragility of bone is an important medical issue. There is increasing evidence that bone health is related to blood flow and oxygen delivery. The development of non-invasive methods to evaluate bone blood flow and oxygen delivery promise to improve the detection and treatment of bone health in human. Near-infrared spectroscopy (NIRS) has been used to evaluate oxygen levels, blood flow, and metabolism in skeletal muscle and brain. While the limited penetration depth of NIRS restricts its application, NIRS studies have been performed on the medial aspect of the tibia and some other prominent bone sites. Two approaches using NIRS to evaluate bone health are discussed: (1) the rate of re-oxygenation of bone after a short bout of ischemia, and (2) the dynamics of oxygen levels during an intervention such as resistance exercise. Early studies have shown these approaches to have the potential to evaluate bone vascular health as well as the predicted efficacy of an intervention before changes in bone composition are detectable. Future studies are needed to fully develop and exploit the use of NIRS technology for the study of bone health.

Imaging of Bone Perfusion and Metabolism in Subjects Undergoing Total Ankle Arthroplasty Using 18F-Fluoride Positron Emission Tomography

Background: Total ankle arthroplasty (TAA) continues to exhibit a relatively high incidence of complications and need for revision surgery compared to knee and hip arthroplasty. One common mode of failure in TAA is talar component subsidence. This may be caused by disruption in the talar blood supply related to the operative technique. The purpose of this study was to quantify changes in talar bone perfusion and turnover before and after TAA with the INBONE II system using 18F-fluoride positron emission tomography / computed tomography (PET/CT). Methods: Nine subjects (5 M/4 F) aged 68.9 ± 8.2 years were enrolled for 18F-fluoride PET/CT imaging before and 3 months after TAA. Regions of interest (ROI) were placed on the postoperative CT images in the body of the talus beneath the talar component and overlaid on the fused static PET images. Standard uptake values (SUVs) along with dynamic K1 (bone blood flow) and ki (bone metabolism or osteoblastic turnover) were calculated. Results: The SUV underneath the talar component compared to that measured at baseline before surgery was 1.93 ± 0.29 preoperatively vs 2.47 ± 0.37 postoperatively ( P > .05). K1 was 0.84 ± 0.16 mL/min/mL preoperatively vs 1.51 ± 0.23 mL/min/mL postoperatively ( P = .026). ki was constant at 0.09 ± 0.03 mL/min/mL preoperatively vs 0.12 ± 0.03 mL/min/mL postoperatively ( P > .05). Conclusion: Our study was the first to link 18F-fluoride PET/CT with pre-post evaluation of total ankle replacements. The study quantified perfusion within the talus beneath the TAA implant supporting the hypothesis that perfusion of the talus remained intact after surgery. Level of Evidence: Level II, prospective cohort study with development of diagnostic criteria.

2019 Roger A. Mann Award Winner: Imaging of Bone Perfusion and Metabolism in Subjects Undergoing Total Ankle Arthroplasty Using 18F-Positron Emission Tomography

Category: Ankle Arthritis Introduction/Purpose: Total ankle replacement (TAR) continues to exhibit a relatively high incidence of complications and need for revision surgery, particularly when compared to knee and hip arthroplasty. One common mode of failure in TAR is talar component subsidence. This may be caused by disruption in the talar blood supply related to the surgical technique. Positron emission tomography (PET) imaging with [18F]-Fluoride has demonstrated utility in evaluating bone perfusion, and PET-CT in particular is useful in the setting of total joint replacement. In this study we aim to quantify changes in talar perfusion before and after TAR with the INBONE II system (Wright Medical Technology, Inc., Memphis, TN) using [18F]-Fluoride PET-CT. It is our hypothesis that perfusion to the talus would decrease after TAR. Methods: Eight subjects (5M/3F) aged 70.4 ± 7.5 years [Range 61-83] were enrolled for 18F-PET/CT imaging prior to and 3 months following TAR. 5–10 mCi of 18F-Fluoride was administered and dynamic acquisition in list mode for 45 minutes was performed on the operative and non-operative ankles simultaneously on a Siemens mCT Biograph scanner. Static acquisition of the whole body was also performed one hour after injection. Regions of interest (ROI’s) were placed on the postoperative CT images in the body of the talus beneath the INBONE II talar component. These regions were manually delineated on the preoperative CT scans, and were drawn to replicate the ROIs placed on the postoperative studies. ROI’s were overlaid on the fused static 18F-PET images and standard uptake values (SUVs) calculated for these regions as well as the whole foot. Changes in SUVs were analyzed using a paired t-tests with a significance level of 0.05. Results: We found no significant difference in bone perfusion in the talus after TAR in our cohort of patients. 18F uptake in the ROI underneath the talar component compared to that measured at baseline prior to surgery was 3.36 +/- 1.44 SUV postoperatively vs. 2.65 ± 1.24 SUV preoperatively, (p=0.33). Similar results were seen in the whole foot: 2.99 +/- 1.22 SUV postoperatively vs. 2.47 ± 0.75 SUV preoperatively (p=0.16). Figure 1 displays preoperative and postoperative uptake in the bone in the area corresponding to the base of the talar component. Although we did not find a significant difference in our initial study, the observed increase in perfusion to the talus after TAR may reach significance with a larger cohort of patients. Conclusion: 18F-PET demonstrates the ability to quantify changes in bone perfusion and metabolism following TAR. Our results suggest that the vascular blood supply to the talus is not disrupted after TAR. Additional pharmacokinetic analysis of the dynamic activity curves will also allow for estimates of bone blood flow and osteoblastic turnover via compartmental modeling. These results may be used to confirm the presence of adequate bone blood flow and vascularity in the body of the talus following total ankle replacement.