Bone Blood Flow Research Articles

THE ‘OSTEOSTASIS’ AND ITS FIVE PRINCIPLES: APPLICATION IN LIMB LENGTHENING

IntroductionHumans Functions (locomotion, protection of organs, reproduction) require a strong support system (bones). The ‘Osteostasis’ is the ability of maintaining the bone structure, its mechanical characteristics and function. Five principles are required for an efficient bone system:Basic Requirements:1) Stability and 2) Function. Repair System (like house building in desert or sea):3) Roads (vessels), 4) Materials (calories, proteins), 5) Workers (bone cells).Analysis of bone problems through these principles bring to optimised treatments.Materials & MethodsMeasurements (>700 lengthening, 32-year follow-up, Full WB Albizzia/G-Nails FWBAG): Bone-DEXA, WB conditions, muscle, fat, etc.Principle-1. Solid bone replacement with a 100% biocompatible and reliable FWBAG with sports (POD0).Principle-2. Bone, Muscle & neural integrity for function Principle-3. Vascular flow lesions induce non-healing (arteriography). Muscle activity accounts for 90% of bone blood flow, ×10 by sports. Required: Checks (arteriography) and treatments (training)Principle-4. Food (NRV Kcal × 2–3, 20–25% proteins).Principle-5. Maintain bone cells and increase them. Suppress ‘opening’, ‘venting’, ‘drainages’.ResultsPrinciple1. Nail fracture (1.2%), nail dysfunction (0%) with FWBAG.Principle2. Intensive sports preop and from POD0 - Principle3. Increased preop vascular supply & muscle force, postop resistance sports fasten recovery. Wheel-chair or low activity decreases healing.Principle4. 6–9 cm circumference loss (non WB-nails or no proper training); 0 cm circumference loss (gain <10 cm) with intense resistance training + high calory intake. - Principle5. Bone cells preservation (no opening, IM saw, increasing bone cells) allow Healing Index down to 8D/cm.ConclusionsThe ‘5P’ allow reaching treatment targets by optimisation of problem solving, maintaining Osteostasis. What would I like or tolerate for me? How can I reach it? Full WB and sports from POD0 was a target 38 years-ago, still not enforced by most of us. Resistance sports, high-calory intake suppress muscle loss and fasten healing, thanks to muscle blood flow and the ‘5P’.

Is Osteoarthritis a Vascular Disease?

Osteoarthritis (OA) is now considered as a multifaceted disease affecting various articular tissues, including cartilage, bone, synovium, and surrounding ligaments. The pathophysiology strongly implicates intricate chemical communication, primarily through cytokines, leading to the production of degradative enzymes in cartilage, inflammatory peptides in synovium, and structural changes in bone, resulting in characteristic clinical features such as joint deformities and loss of cartilage space seen on X-rays. Recent studies highlight the previously underestimated role of subchondral bone in OA, revealing its permeability to cytokines and raising questions about the influence of abnormal perfusion on OA pathophysiology, suggesting a vascular component in the disease's etiology. In essence, alterations in bone perfusion, including reduced venous outflow and intraosseous hypertension, play a crucial role in influencing the physicochemical environment of subchondral bone, impacting osteoblast cytokine expression and contributing to trabecular remodeling, changes in chondrocyte phenotype, and ultimately cartilage matrix degeneration in OA. Dynamic contrast (gadolinium) enhanced magnetic resonance imaging (DCE-MRI) was used to quantify perfusion kinetics in normal and osteoarthritic subchondral bone, demonstrating that decreased perfusion temporally precedes and spatially correlates with cartilage lesions in both young Dunkin-Hartley (D-H) guinea pigs and humans with osteoarthritis. Pharmacokinetic analysis of DCE-MRI generated data reveals decreased tracer clearance and outflow obstruction in the medial tibial plateau of osteoarthritic guinea pigs, coinciding with progressive cartilage degradation, loss of Safranin O staining, and increased expression of matrix metalloproteinases and interleukin-1. Positron emission tomographic (PET) scanning using 18F-Fluoride reveals a relationship among bone blood flow, cartilage lesions, and 18F-Fluoride influx rate in OA, highlighting the intricate relationships between decreased perfusion, altered bone metabolism, and the progression of osteoarthritis. These findings, supported by 18F-Fluoride PET data, suggest the presence of venous stasis associated with outflow obstruction, emphasizing the role of decreased subchondral bone perfusion in the pathophysiology of OA and its association with reduced osteoblast activity and advanced cartilage degeneration.

Adaptations of bone and bone vasculature to muscular stretch training.

The magnitude of bone formation and remodeling is linked to both the magnitude of strain placed on the bone and the perfusion of bone. It was previously reported that an increase in bone perfusion and bone density occurs in the femur of old rats with moderate aerobic exercise training. This study determined the acute and chronic effects of static muscle stretching on bone blood flow and remodeling. Old male Fischer 344 rats were randomized to either a naive or stretch-trained group. Static stretching of ankle flexor muscles was achieved by placement of a dorsiflexion splint on the left ankle for 30min/d, 5d/wk for 4wk. The opposite hindlimb served as a contralateral control (nonstretched) limb. Bone blood flow was assessed during and after acute stretching in naive rats, and at rest and during exercise in stretch-trained rats. Vascular reactivity of the nutrient artery of the proximal tibia was also assessed in stretch-trained rats. MicroCT analysis was used to assess bone volume and micro-architecture of the trabecular bone of both tibias near that growth plate. In naive rats, static stretching increased blood flow to the proximal tibial metaphasis. Blood flow to the proximal tibial metaphysis during treadmill exercise was higher in the stretched limb after 4wk of daily stretching. Daily stretching also increased tibial bone weight and increased total volume in both the proximal and distal tibial metaphyses. In the trabecular bone immediately below the proximal tibial growth plate, total volume and bone volume increased, but bone volume/total volume was unchanged and trabecular connectivity decreased. In contrast, intravascular volume increased in this region of the bone. These data suggest that blood flow to the tibia increases during bouts of static stretching of the hindlimb muscles, and that 4wk of daily muscle stretching leads to bone remodeling and an increase in intravascular volume of the tibial bone.

Vascular deficits contributing to skeletal fragility in type 1 diabetes.

Over 1 million Americans are currently living with T1D and improvements in diabetes management have increased the number of adults with T1D living into later decades of life. This growing population of older adults with diabetes is more susceptible to aging comorbidities, including both vascular disease and osteoporosis. Indeed, adults with T1D have a 2- to 3- fold higher risk of any fracture and up to 7-fold higher risk of hip fracture compared to those without diabetes. Recently, diabetes-related vascular deficits have emerged as potential risks factors for impaired bone blood flow and poor bone health and it has been hypothesized that there is a direct pathophysiologic link between vascular disease and skeletal outcomes in T1D. Indeed, microvascular disease (MVD), one of the most serious consequences of diabetes, has been linked to worse bone microarchitecture in older adults with T1D compared to their counterparts without MVD. The association between the presence of microvascular complications and compromised bone microarchitecture indicates the potential direct deleterious effect of vascular compromise, leading to abnormal skeletal blood flow, altered bone remodeling, and deficits in bone structure. In addition, vascular diabetic complications are characterized by increased vascular calcification, decreased arterial distensibility, and vascular remodeling with increased arterial stiffness and thickness of the vessel walls. These extensive alterations in vascular structure lead to impaired myogenic control and reduced nitric-oxide mediated vasodilation, compromising regulation of blood flow across almost all vascular beds and significantly restricting skeletal muscle blood flow seen in those with T1D. Vascular deficits in T1D may very well extend to bone, compromising skeletal blood flow control, and resulting in reduced blood flow to bone, thus negatively impacting bone health. Indeed, several animal and ex vivo human studies report that diabetes induces microvascular damage within bone are strongly correlated with diabetes disease severity and duration. In this review article, we will discuss the contribution of diabetes-induced vascular deficits to bone density, bone microarchitecture, and bone blood flow regulation, and review the potential contribution of vascular disease to skeletal fragility in T1D.

Blood flow rates to leg bones of extinct birds indicate high levels of cursorial locomotion

AbstractForamina of bones are beginning to yield more information about metabolic rates and activity levels of living and extinct species. This study investigates the relationship between estimated blood flow rate to the femur and body mass among cursorial birds extending back to the Late Cretaceous. Data from fossil foramina are compared with those of extant species, revealing similar scaling relationships for all cursorial birds and supporting crown bird–like terrestrial locomotor activity. Because the perfusion rate in long bones of birds is related to the metabolic cost of microfracture repair due to stresses applied during locomotion, as it is in mammals, this study estimates absolute blood flow rates from sizes of nutrient foramina located on the femur shafts. After differences in body mass and locomotor behaviors are accounted for, femoral bone blood flow rates in extinct species are similar to those of extant cursorial birds. Femoral robustness is generally greater in aquatic flightless birds than in terrestrial flightless and ground-dwelling flighted birds, suggesting that the morphology is shaped by life-history demands. Femoral robustness also increases in larger cursorial bird taxa, probably associated with their weight redistribution following evolutionary loss of the tail, which purportedly constrains femur length, aligns it more horizontally, and necessitates increased robustness in larger species.

Vasculogenic gene therapy: No role for revitalization of structural bone allografts.

Segmental bone defects are often performed with cryopreserved allografts. They provide immediate stability, but risk nonunion, infection and late stress fracture. Improving the rate and extent of bone revitalization may improve results. Angiogenesis from surgically placed arteriovenous (AV) bundles improves bone blood flow and vitality in cryopreserved rat femora, augmented by vasculogenic growth factors. This study tests the same principal in Yucatan mini-pigs with a tibial diaphyseal defect, combining surgical angiogenesis with angiogenic gene therapy within cryopreserved orthotopically-placed allografts. Tibial diaphyseal defects were reconstructed with cryopreserved allografts and rigid internal fixation in 16 mini pigs. Half of the cranial tibial AV bundles placed within the allograft medullary canal were transfected with an adeno-associated virus containing vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) genes (AAV9.VEGF.PDGF). Bone remodeling, angiogenesis, and allograft healing were assessed. During the postoperative survival period 5 of 8 transfected animals developed cutaneous benign vascular lesions at sites remote from the operated hindlimb, causing excessive bleeding. Within the allograft, both medullary (p = 0.013) and cortical (p = 0.009) vascular volumes were higher and vessels more mature than nontransfected allografts. Bone turnover (p = 0.013), bone mineralization (p = 0.018), bone healing (p = 0.008) and graft incorporation (p = 0.006) were all significantly higher in the gene therapy group. In a large animal tibial defect model, gene therapy of implanted AV bundles improved revascularization, remodeling and healing of cryopreserved allografts used for limb reconstruction. However, benign vascular lesions causing excessive bleeding developed in 5 out of 8 pigs transfected with AAV containing genes for VEGF and PDGF. This unforeseen complication makes vasculogenic gene therapy unacceptable for clinical use.

After Total Ankle Arthroplasty, When Does Bone Perfusion and Metabolic Activity at the Bone-Implant Interface Normalize? A PET/CT Study

Category: Ankle Arthritis Introduction/Purpose: Radionuclide bone scintigraphy in combination with computed tomography (CT) has been used to evaluate painful total hip and knee arthroplasties, and has also been used in the evaluation of the painful total ankle arthroplasty (TAA). Increased tracer uptake around implants may indicate loosening, but uptake characteristics of bone-seeking radiopharmaceuticals in asymptomatic total ankle patients have not been clarified. While findings of increased metabolic activity may prompt surgical intervention, there has been no work performed to define when postoperatively periprosthetic activity normalizes, if at all. In this study, we plan to establish normative data on 18F sodium fluoride (18F-NaF) positron emission tomography/CT (PET/CT) uptake ratios around TAA implants at various time intervals after surgery in asymptomatic TAA patients. Methods: The majority of the arthroplasty literature has investigated use of SPECT/CT performed with 99mTc-labeled bisphosphonates. However, data suggest that 18F-NaF PET/CT may be superior for this indication, with more favorable pharmacokinetics and similar sensitivity to detect aseptic loosening. In the present study, asymptomatic patients who underwent TAA with a modern fixed-bearing TAA prosthesis (either the Wright Infinity Adaptis or Exactech Vantage prosthesis) for posttraumatic arthritis were eligible for inclusion. Patients with ipsilateral hindfoot fusion and with any periprosthetic lucencies or cysts were excluded. Patients were enrolled at one of four time intervals following TAA: 6, 12, 18, or 24 months. Standard uptake values were measured at the bone-implant interface for the tibial and talar components on static PET, in regions of interest defined on axial CT scan slices. Periprosthetic bone blood flow (K1) and bone turnover (flux) were assessed at each time interval in each periprosthetic region using dynamic PET. Results: Sixteen asymptomatic patients underwent PET/CT: 4 patients at 6 months postoperatively, 6 at 12 months, and 6 at 24 months. We are currently still in data collection and at this time only 2 patients at 18 months have completed the scan, therefore their data were excluded. The average age was 65 years (range, 55 to 80) and 6 patients were female (38%), with individual patient data shown in the Table. Talar K1 and flux both appeared to increase from 6 to 12 months, and decrease between 12 and 24 months, although there was no statistically significant difference between timepoints. Overall tibial K1 and flux appeared to decrease slightly from 6 to 12 months, and stayed relatively stable between 12 and 24 months, again with no significant difference between timepoints (Figure). Conclusion: There is currently no normative data to help guide interpretation of radionuclide bone scintigraphy for the painful TAA. The present study utilizing 18F-NaF PET/CT scans demonstrates that even in asymptomatic patients, periprosthetic bone blood flow and bone turnover remain elevated up to 24 months following modern fixed-bearing TAA. Not only do these values remain elevated at 24 months, but we found that there does not appear to be any significant decrease in either measurement over time from 6 to 24 months postoperatively. Our findings suggest that radionuclide bone scintigraphy should be cautiously interpreted when performed within 2 years of TAA.

Rational Design of Bisphosphonate Lipid-like Materials for mRNA Delivery to the Bone Microenvironment

The development of lipid nanoparticle (LNP) formulations for targeting the bone microenvironment holds significant potential for nucleic acid therapeutic applications including bone regeneration, cancer, and hematopoietic stem cell therapies. However, therapeutic delivery to bone remains a significant challenge due to several biological barriers, such as low blood flow in bone, blood-bone marrow barriers, and low affinity between drugs and bone minerals, which leads to unfavorable therapeutic dosages in the bone microenvironment. Here, we construct a series of bisphosphonate (BP) lipid-like materials possessing a high affinity for bone minerals, as a means to overcome biological barriers to deliver mRNA therapeutics efficiently to the bone microenvironment in vivo. Following in vitro screening of BP lipid-like materials formulated into LNPs, we identified a lead BP-LNP formulation, 490BP-C14, with enhanced mRNA expression and localization in the bone microenvironment of mice in vivo compared to 490-C14 LNPs in the absence of BPs. Moreover, BP-LNPs enhanced mRNA delivery and secretion of therapeutic bone morphogenetic protein-2 from the bone microenvironment upon intravenous administration. These results demonstrate the potential of BP-LNPs for delivery to the bone microenvironment, which could potentially be utilized for a range of mRNA therapeutic applications including regenerative medicine, protein replacement, and gene editing therapies.

Vascular myogenic control of tibial bone blood flow in young healthy individuals

Bone health is critically dependent on adequate blood flow supplied by its extensive vascular network. Without adequate perfusion to provide oxygen and essential nutrients critical for bone metabolism, nearly all skeletal functions are compromised. However, despite the importance of blood flow to bone, regulation of bone blood flow is poorly understood in humans. The broad hypothesis of the current work is that the primary regulators of blood flow to bone are not different from other vascular beds. We have recently shown that sympathetic innervation of the bone vasculature has an active role in controlling bone blood flow in young healthy individuals. This work furthers our previous findings by investigating additional key bone blood flow regulators ‐ myogenic vasodilation and vasoconstriction. While vascular myogenic control has been investigated in soft tissue, to our knowledge there has been no research in the bone vasculature in humans, with only a handful of animal studies.In young healthy individuals (N=8), we characterized myogenic control of tibial blood flow via novel custom‐made near infrared spectroscopy (NIRS). Tibial blood flow via NIRS was measured as oxy‐, deoxy‐, and total hemoglobin (Hb). We employed reactive hyperemia and leg dependency to assess myogenic vasodilation and vasoconstriction in the whole calf and in the tibia. The magnitude of maximum myogenic vasodilation was defined by the peak reactive blood flow response to sustained ischemia. Arterial flow to the lower leg was occluded by rapidly inflating a pneumatic thigh cuff above the knee to 220 mmHg in supine subjects. Tibial blood flow was assessed via NIRS and whole leg blood flow velocity in the popliteal artery of the same leg was measured via Doppler ultrasound during 1 min of rest, 10 min of cuff inflation, and 5 min of recovery. Myogenic vasoconstriction was assessed via leg dependency, i.e., during two levels of increased transmural pressure achieved by lowering the leg below heart level. Only tibial blood flow was assessed during 5 min in supine position, 5 min in seated upright position, and 5 min in seated position with legs lowered at 90deg knee flexion.During cuff occlusion, there was a time dependent decrease in bone oxyHb accompanied by an increase in deoxyHb indicating lack of flow with continued metabolism. Tibial total Hb (sum of oxy‐ and deoxy‐Hb) did not change significantly during cuff inflation, but increased rapidly and markedly with cuff release, far surpassing baseline values when flow was restored. A similar overshoot response was seen in whole leg blood flow with cuff release. Thus, the response of tibial flow to reactive hyperemia follows the same behavior as the whole limb, indicating an active myogenic vasodilator response in bone similar to other vascular beds. During leg dependency, despite increases in arterial perfusion pressure at both levels (ΔP, 25.8 + 3.67, and 40.0 + 3.02 mmHg), there was no change in tibial flow (total Hb, ‐0.39 + 7.40, and ‐0.29 + 16.2 μM). Hence, unchanged tibial flow despite increased pressure indicates a compensatory vasoconstrictor response in the tibia. Our results indicate that similar to other vascular beds, myogenic control plays an active role in regulating the bone vasculature in young healthy individuals. Characterizing blood flow regulation in bone constitutes the basis of defining its role in overall bone health and its contribution to numerous bone loss conditions.

Single-Sided Ultrasound Imaging of the Bone Cortex: Anatomy, Tissue Characterization and Blood Flow.

In this chapter, we first review the reasons why conventional ultrasonography fails to image the interior of bones. Next we show our recent work on imaging a cortical bone layer with ultrasound. Revealing the shape of the cortex of a bone, in particular its thickness, is of interest for evaluating bone strength. In addition we describe how the process of reconstructing a truthful image of the bone cortex includes the estimation of ultrasound wave-speed in cortical bone tissue. Cortical bone exhibits elastic anisotropy, which causes anisotropy of ultrasound wave-speed as well. Therefore a faithful and high-quality picture of the bone cortex is obtained if wave-speed anisotropy is taken into account during image reconstruction. Capitalizing on prior knowledge on the elastic anisotropy of cortical bone, a procedure for estimating wave-speed and its anisotropy is described. It is based on the measurement of a head-wave velocity and an autofocus approach. The latter relies on the fact that the reconstructed ultrasound image shows optimal quality if the wave-speed model is correct. In order to achieve real-time imaging of a bone cortex, image reconstruction is performed with a delay-and-sum algorithm. Finally, we report recent advances in the measurement of blood flow in cortical bone.

Revealing Intraosseous Blood Flow in the Human Tibia With Ultrasound.

ABSTRACTIntraosseous blood circulation is thought to have a critical role in bone growth and remodeling, fracture healing, and bone disorders. However, it is rarely considered in clinical practice because of the absence of a suitable noninvasive in vivo measurement technique. In this work, we assessed blood perfusion in tibial cortical bone simultaneously with blood flow in the superficial femoral artery with ultrasound imaging in five healthy volunteers. After suppression of stationary signal with singular‐value‐decomposition, pulsatile blood flow in cortical bone tissue is revealed, following the heart rate measured in the femoral artery. Using a method combining transverse oscillations and phase‐based motion estimation, 2D vector flow was obtained in the cortex of the tibia. After spatial averaging over the cortex, the peak blood velocity along the long axis of the tibia was measured at four times larger than the peak blood velocity across the bone cortex. This suggests that blood flow in central (Haversian) canals is larger than in perforating (Volkmann's) canals, as expected from the intracortical vascular organization in humans. The peak blood velocity indicates a flow from the endosteum to the periosteum and from the heart to the foot for all subjects. Because aging and the development of bone disorders are thought to modify the direction and velocity of intracortical blood flow, their quantification is crucial. This work reports for the first time an in vivo quantification of the direction and velocity of blood flow in human cortical bone. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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 physiological 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-wk postsurgery via microcomputed tomography (microCT) and intracardiac microsphere infusion, respectively, and bone turnover indices were determined via histomorphometry. Both groups exhibited cancellous bone loss beginning in the initial postsurgical 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 versus SHAM at 2 wk, 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 that bone BF deficits develop in response to SCI and temporally coincide with suppressed bone formation and with cancellous and cortical bone deterioration.NEW & NOTEWORTHY We provide the first direct evidence indicating femur and tibia blood flow (BF) deficits exist in conscious (awake) rats after severe contusion spinal cord injury (SCI), with the distal femur displaying the largest BF deficits. Reduced bone perfusion temporally coincided with unopposed bone resorption, as indicated by ongoing osteoclast-mediated bone resorption and a near absence of surface-level bone formation indices, which resulted in severe cancellous and cortical microstructural deterioration after SCI.

Morphology of the nutrient artery and its foramen in relation to femoral bone perfusion rates of laying and non-laying hens.

If arteries penetrate bones through foramina, regional artery blood flow rates can be estimated from the foramen sizes. Femoral bone blood flow rates estimated from nutrient foramen sizes were previously not absolute, but only a relative blood flow index (Qi ), because the size relationship between the foramen and the occupying artery was unknown. The current study used vascular contrast and micro-computerized tomographic scanning to investigate femoral nutrient foramen and nutrient artery sizes in three groups of sub-adult chickens (non-laying hens, laying hens, and roosters) of similar ages. The results indicate that the cross-sectional area of the nutrient artery lumen occupies approximately 20.2±4.1% of the foramen for femora with only one foramen. Artery lumen size is significantly correlated with foramen size. Vascular contrast imaging is capable of estimating blood flow rates through nutrient arteries, as blood flow rates estimated from artery lumen casts are similar to blood flow rates measured by infusion of fluorescent-labeled microspheres. Laying hens tend to have higher nutrient artery perfusion rates than non-laying hens, probably due to extra oxygen and calcium requirements for eggshell production, although the calculated blood flow difference was not statistically significant. Histological embedding and sectioning along with vascular contrast imaging reveal variable nutrient foramen morphology and nutrient artery location among femora with more than one nutrient foramen.

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

ABSTRACTThe 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 () should reflect local tissue oxygen requirements. A recent ‘foramen technique’ has derived an index of blood flow rate () by measuring nutrient foramen sizes of long bones. is assumed to be proportional to ; however, the assumption has never been tested. This study used fluorescent microsphere infusion to measure femoral bone in anaesthetized non-laying hens, laying hens and roosters. Mean mass-specific 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 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 increased significantly with body mass, but was not correlated with nutrient foramen radius (r), probably because of a narrow range in foramen radius. Over all 18 chickens, femoral shaft was 1.07±0.30 ml min−1 mm−1. Mean 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 aimed to clarify the link between physical activities, vascularization, and bone repair.

MO645BONE MINERAL DENSITY IN POSTMENOPAUSAL WOMEN WITH TYPE 2 DIABETES MELLITUS WITH AND WITHOUT DIABETIC NEPHROPATHY

Abstract Background and Aims Diabetes mellitus and osteoporosis are both common human diseases. Diabetic nephropathy is characterized by the presence of pathological quantities of urine albumin excretion, diabetic glomerular lesions, and loss of glomerular filtration rate in diabetics. Little evidence has been reported on relationships between BMD and albuminuria. The aim of this study is to compare the bone mineral density (BMD) in postmenopausal women with type 2 diabetes mellitus (T2DM) with and without diabetic nephropathy. Method We retrospectively analyze the BMD of the lumbar spine and femur using dual-energy X-ray absorptiometry in 84 postmenopausal women with T2DM with (39) and without (45) diabetic nephropathy. The serum levels of calcium, phosphorus, total alkaline phosphatase, and urine albumin excretion were measured in all participants. Diagnosis of albuminuria was based on albumin-creatinine ratio (ACR). Results Age, body mass index (BMI) and time since menopause were not significantly different between the two groups. The T-scores of basal BMD at L4 were significantly lower in patients with diabetic nephropathy (-0,94 ± 0,40) compared to patients without nephropathy. No significant differences in serum creatinine were detected between two groups of patients. Our data suggest that ACR was negatively associated with lumbar spine and femoral neck BMD. Conclusion Our results suggest that postmenopausal women with diabetic nephropathy have a lower BMD and are at increased risk of osteoporosis in the lumbar spine compared with postmenopausal women without diabetic nephropathy. ACR was negatively associated with lumbar spine and femur neck BMD. One of the explanations that has been proposed for the association between albuminuria and osteoporosis is that albuminuria is associated with reduced bone blood flow, resulting in a decreased rate of bone remodeling and the development of osteoporosis.

Mechanisms of bone blood flow regulation in humans.

Bone is a highly vascularized tissue. However, despite the importance of appropriate circulation for bone health, regulation of bone blood flow remains poorly understood. Invasive animal studies suggest that sympathetic activity plays an important role in bone flow control. However, it remains unknown if bone vasculature evidences robust vasoconstriction in response to sympathoexcitatory stimuli. Here, we characterized bone blood flow in young healthy individuals [n = 13, (four females)] in response to isometric handgrip exercise (IHE) and cold pressor test (CPT). These provide a strong stimulus for active vasoconstriction in the inactive muscle, and perhaps 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 was determined as oxy- and deoxyhemoglobin. For both stimuli, tibial metabolism remained constant (i.e., no change in deoxyhemoglobin) and thus tibial arterial perfusion was represented by oxyhemoglobin. During IHE, oxyhemoglobin declined (beginning -0.20 ± 1.04 μM; end -1.13 ± 3.71 μM, both P < 0.01) slower than whole leg blood flow (beginning -0.85 ± 1.02 cm/s; end -2.72 ± 1.64 cm/s, both P < 0.01). However, during CPT, both oxyhemoglobin (beginning -0.46 ± 1.43 μM; end -0.60 ± 1.59 μM, both P < 0.01) and whole leg blood flow (beginning -1.52 ± 1.63 cm/s; end -0.69 ± 1.51 cm/s, both P < 0.01) declined with a similar timecourse, even though the magnitudes of decline were smaller than during IHE. These responses are likely due to the different timecourses of sympathetically mediated vasoconstriction in bone and muscle. These results indicate that sympathetic innervation of the bone vasculature serves a functional role in the control of flow in young healthy individuals.NEW & NOTEWORTHY The current study is the first one to noninvasively investigate control of bone blood perfusion in vivo in humans, on a moment-by-moment basis. Our results indicate that tibial bone vasculature demonstrates active vasoconstriction in response to sympathoexcitatory stimuli in young healthy individuals. Compared with whole leg vasculature, bone vasoconstrictor response seems to be smaller, delayed, and more variable.

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.

Bone blood flow regulation in humans

Bone is a highly vascularized organ with an extensive network of arteries, arterioles, and capillaries that is critical for bone development, maintenance, and repair. Despite the importance of bone circulation to bone health, the regulation of blood flow to bone is not well understood in humans. One of the potential factors controlling bone blood flow is the sympathetic nervous system, bone vasculature being innervated by a rich network of sympathetic nerves. While no human studies have been conducted, animal data suggests that sympathetic activation reduces bone blood flow. If this were not the case, bone vasculature would respond simply as a passive pressure system. Therefore, we characterized bone blood flow regulation in health young individuals (N=12 (8M; 4F), 23±0.7 years) in response to isometric handgrip to fatigue (IHE). Sustained IHE is a profound pressor stimulus, resulting in active vasoconstriction in the nonactive leg and progressive increases in blood pressure. During IHE at 30% of maximal voluntary contraction, we measured blood pressure, whole leg blood flow (via Doppler ultrasound), and tibial blood perfusion (via near infrared spectroscopy). Tibial blood perfusion was determined as changes from resting baseline in oxygenated and deoxygenated hemoglobin content. Data is presented as mean change from resting baseline ± standard error. To account for different IHE time courses, all variables were normalized to 100% duration and averaged across individuals. Blood pressure increased progressively to end of IHE (at 10%: 5.46 ± 1.30 mmHg; at 100%: 48.0 ± 4.32 mmHg). Whole leg blood flow decreased progressively throughout IHE, suggesting active sympathetic vasoconstriction in the leg (at 10%: −0.70 ± 0.28 cm/s; at 100%: −2.26 ± 0.50 cm/s). Similarly, tibial oxygenated hemoglobin decreased progressively throughout the test (at 10%: −0.21 ± 0.31 μM; at 100%: −1.19 ± 1.12 μM) whereas tibial deoxygenated hemoglobin did not change significantly throughout IHE (at 10%: 0.06 ± 0.07 μM; at 100%: −0.4 ± 0.32 μM). This indicates that arterial flow (oxygenated hemoglobin) declined while bone metabolism (deoxygenated hemoglobin) remained unchanged in response to IHE. It should be noted that the decline in oxygenated hemoglobin was slower and lesser than that in whole leg blood flow. This data suggests that sympathetic activity is involved in controlling bone circulation, but vasoconstrictor responses is not as fast or as robust in bone as it is in the whole leg.Support or Funding InformationParalyzed Veterans of America (AED)

Effects of Aging and Exercise Training on Vasomotor Function of Bone Resistance Arteries and Bone Blood Flow

Adequate skeletal perfusion is necessary to maintain bone remodeling processes, and decrements in bone arterial function and regional blood flow may lead to conditions such as osteoporosis. Aging elicits progressive bone loss, associated with impaired bone vasomotor function and perfusion, that can lead to osteoporosis. Although these age‐related adaptations are ameliorated via exercise training, the specific mechanisms underlying exercise‐induced alterations of bone vasomotor function with aging remain largely unknown. The purpose of this study was to elucidate the age‐ and exercise‐induced vasomotor adaptations of the bone principal nutrient artery and subsequent alterations in bone blood flow.Young and old male Fischer‐344 rats underwent treadmill exercise training (15 m/min, 15° incline, 1hr/day, 5 days/wk for 10–12 wks) or remained sedentary in cages. At the end of the experimental period, the femoral principal nutrient artery (PNA) was isolated, cannulated, and pressurized for vascular response studies. Vasoconstrictor responses of the PNA were assessed in vitro using α‐adrenergic agonist phenylephrine (PE, 10−9–10−4 M), receptor‐independent potassium chloride (KCl, 10–100 mM) and myogenic responsiveness to increasing intraluminal pressure (0 to 140 cmH2O). Endothelium‐dependent (ACh, 10−9–10−4 M) and ‐independent (Dea‐NONOate, 10−9–10−4 M) vasodilator responses were also evaluated. Additionally, regional blood flow to the femur was measured at rest and during exercise using radiolabeled microspheres.Vasomotor responses to agonists for constriction (PE, KCl) and dilation (ACh, Dea‐NONOate) decreased with aging. In contrast, myogenic responsiveness in old rats was greater compared with young rats (p&lt;0.05). Vasoconstrictor response to KCl was greater after training in both young and old rats as compared to the sedentary rats. Exercise‐trained old rats also showed increased vasoconstrictor responses to PE and myogenic responsiveness; however, no significant difference was shown in young rats (p&lt;0.05). Exercise training enhanced endothelium‐dependent vasodilation in both young and old rats; however, no significant exercise effect was observed in endothelium‐independent vasodilation (p&lt;0.05). Regional femur blood flow to the proximal and distal metaphysis and epiphysis, as well as diaphyseal marrow, was lower in aged rats compared to young rats at rest. However, exercise‐trained old rats showed significantly increased regional blood flow during exercise compared with old SED rats (p&lt;0.05).These results demonstrate vasomotor responses are impaired in the femoral PNA from aged rats; however, endurance training intervention at advancing age can reverse vasomotor deficits including vasoconstrictor and vasodilator response in bone resistance arteries and enhance regional bone and marrow blood flow. Such changes in bone and marrow perfusion could play an important role in enhancing the quality and strength of bone in old age following exercise training.Support or Funding InformationNIH grant AG055029