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Trial record 1 of 1 for:    NCT04083794
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Exploration of Blood Flow Regulation to Bone in Humans

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ClinicalTrials.gov Identifier: NCT04083794
Recruitment Status : Recruiting
First Posted : September 10, 2019
Last Update Posted : March 23, 2020
Sponsor:
Collaborator:
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Information provided by (Responsible Party):
J. Andrew Taylor, Spaulding Rehabilitation Hospital

Brief Summary:
Without blood flow, bone cannot maintain its integrity. Bone blood flow responds to various local and systemic factors, however, bone perfusion in humans remains relatively unstudied. The investigators will study key mechanisms that regulate bone perfusion in able-bodied and contrast responses to those with spinal cord injury (SCI). SCI is a model of chronic reduced loading with loss of sympathetic regulation. In tibial cortical bone, the investigators will: 1) determine the impact of compressive loading with and without muscle contractions; 2) determine the impact of vascular sympathetic activity and systemic perfusion pressure; 3) compare the response between able-bodied and those with SCI. Acute metabolic needs of bone due to loading increase flow substantially. In addition, the bone vasculature is innervated by a rich network of sympathetic nerves that serve a functional purpose in the control of blood flow. A critical limitation to the study of bone blood flow in humans has been the lack of non-invasive assessments. Previously, the investigators developed a near infrared spectroscopy (NIRS) device to non-invasively assess blood content in bone and assessed tibial perfusion in response to exercise. Here, the investigators will test the hypothesis that bone blood flow increases proportional to loading conditions in both able-bodied individuals and those with SCI. The investigators will also test the hypothesis that there are decreases in blood bone flow that are proportional to increases in leg vascular sympathetic outflow in the able-bodied, but that changes in bone blood flow are proportional to changes in blood pressure in those with SCI. The proposed research will be some of the first to determine the control of bone flow in humans.

Condition or disease Intervention/treatment Phase
Bone Blood Flow Regulation Other: Laboratory based assessments Not Applicable

Detailed Description:

All tissues of the human body require adequate perfusion to provide oxygen and nutrients to meet metabolic demands. It has long been known that the arterial system in bone is of overwhelming importance and that without blood flow, bone cannot maintain its integrity. Indeed, there is an extensive network of arteries, arterioles, and capillaries that supply human bone. Moreover, blood flow to bone is responsive to various local and systemic factors that can determine the overall health of bone. However, bone perfusion in humans remains relatively unstudied and so the underlying mechanisms that regulate bone blood flow are not well understood. The investigators propose to study key mechanisms that regulate bone perfusion in able-bodied individuals and to contrast them with spinal cord injured (SCI) individuals. SCI represents a human 'model' of chronic reduced loading with loss of sympathetic regulation below the level of injury that likely alters control of bone perfusion. Accordingly, our aims are to: 1) Determine the impact of compressive loading with and without associated muscle contractions on tibial perfusion; 2) Determine the impact of vascular sympathetic activity and systemic perfusion pressure on tibial perfusion; 3) Compare the changes in tibial perfusion in response to local and systemic factors between able-bodied and those with SCI.

The majority of work in bone blood flow has been in animals and/or has focused on the association between adequate or inadequate perfusion and bone health. For example, inadequate flow has been associated with bone loss, impaired growth, and delayed fracture healing. However, the acute metabolic needs of bone due to loading either with or without associated muscle contractions increase flow substantially. Indeed, within two minutes of isolated muscle contractions alone, tibial perfusion has been shown to increase significantly. Furthermore, when there is compressive loading with associated muscle contractions, flow to bone can double. Similarly, skeletal unloading for as short as ten minutes cuts femoral perfusion by half. Although it is unclear what specific local factors (e.g., metabolic by-products) with loading might be responsible for regulation of blood flow, these data strongly suggest that perfusion to bone is highly responsive to skeletal loading. Indeed, it appears that similar regulatory mechanisms may be at play in control of flow to bone and skeletal muscle during exercise. In addition, the bone vasculature is richly innervated by sympathetic nerves. Application of norepinephrine decreases blood flow to both intact bone and isolated bone. Likewise, sympathetic stimulation decreases flow to bone via alpha-adrenergic receptor activation. Moreover, smooth muscle of arterioles in bone respond as expected to vasodilators and vasoconstrictors. Hence, sympathetic innervation of the bone vasculature serves a functional purpose in control of flow. If this were not the case, independent of the link between bone metabolism and bone flow, the arterial network in bone would act as a simple pressure passive system.

A critical limitation to the study of bone flow in humans has been the lack of noninvasive assessments. Thus, it has been difficult to elucidate the mechanisms that control perfusion to bone. The dense nature of bone makes it difficult to investigate perfusion and the techniques used to quantify circulation in other tissues are either difficult or impossible to apply to bone in vivo. the investigators recently demonstrated the efficacy of a near infrared spectroscopy (NIRS) system to non-invasively detect changes in hemoglobin content in the tibia. Although our preliminary work showed the utility of NIRS, it was not designed to provide insight to blood flow regulation and disentangle the various possible contributors to bone perfusion. Here the investigators propose to study different mechanisms that control blood flow to bone in both able-bodied and spinal cord injured (SCI). The SCI population will offer valuable insights to the mechanisms of perfusion as several contributors (i.e. loading and vascular sympathetic control) are either reduced or disrupted.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: This is a Basic Experimental study with Humans with able-bodied individuals and individuals with spinal cord injury (SCI). This study is a cross sectional assessment and will have 1 or 2 visits consisting of 2 protocols where individuals will undergo several physical maneuvers during which bone perfusion response will be assessed. Protocol #1 will investigate tibial perfusion response to tibial loading. Protocol #2 will investigate tibial perfusion response to isometric handgrip exercise and tilt. Volunteers can choose to do one or both protocols during 1 or 2 laboratory visits.
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Exploration of Blood Flow Regulation to Bone in Humans
Actual Study Start Date : November 26, 2019
Estimated Primary Completion Date : February 1, 2021
Estimated Study Completion Date : February 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Health Checkup

Arm Intervention/treatment
Laboratory based assessments
The current study has no arms; it is a cross-sectional assessment where all participants will undergo the same procedures.
Other: Laboratory based assessments
physical maneuvers to assess physiological responses in bone blood flow
Other Names:
  • handgrip
  • tilt
  • tibial loading




Primary Outcome Measures :
  1. Tibial blood perfusion [ Time Frame: 1 day ]
    Concentration of hemoglobin content assessed in response to several physical maneuvers (tibial loading, isometric handgrip, and tilt)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • healthy males and females
  • individuals with spinal cord injuries, between 3 and 24 months post injury, with complete injuries according to the American Spinal Injury Association Impairment Scale A and B, with injuries at T6 and below

Exclusion Criteria:

  • clinical signs or symptoms of heart disease
  • hypertension
  • coronary disease
  • diabetes
  • other neurological disease
  • cancer
  • recent weight change >15 pounds
  • abnormal resting ECG
  • pregnant and/or breastfeeding women
  • underweight and obese individuals (body mass index between 18.5 and 29.9)
  • use of amphetamines (Ritalin, Adderall, Concerta) in the past 48 hours
  • tibial fracture or tibial stress fracture in the past year
  • those with SCI will have no extreme spasticity to avoid spontaneous contractions
  • use of baclofen for those with SCI

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04083794


Contacts
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Contact: Adina E Draghici, PhD 6177585508 adraghici@mgh.harvard.edu
Contact: J. A Taylor, PhD 6177585503 jandrew_taylor@hms.harvard.edu

Locations
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United States, Massachusetts
Spaulding Rehabilitation Cambridge/ Cardiovascular Laboratory Recruiting
Cambridge, Massachusetts, United States, 02138
Contact: Adina E Draghici, PhD    617-758-5508    adraghici@mgh.harvard.edu   
Contact: Glen Picard    6177585511    gpicard@partners.org   
Principal Investigator: J. A Taylor, PhD         
Sponsors and Collaborators
Spaulding Rehabilitation Hospital
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Investigators
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Principal Investigator: J. A Taylor, PhD Harvard Medical School/Spaulding Rehabilitation Hospital
Publications:

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Responsible Party: J. Andrew Taylor, Associate Chair for Research, Spaulding Rehabilitation Hospital
ClinicalTrials.gov Identifier: NCT04083794    
Other Study ID Numbers: 2018P000156
R21AR074054-01A1 ( U.S. NIH Grant/Contract )
First Posted: September 10, 2019    Key Record Dates
Last Update Posted: March 23, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by J. Andrew Taylor, Spaulding Rehabilitation Hospital:
bone perfusion
bone blood flow regulation
vascular sympathetic activity
skeletal loading
spinal cord injury