- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04083794
Exploration of Blood Flow Regulation to Bone in Humans
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Anticipated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Adina E Draghici, PhD
- Phone Number: 6177585508
- Email: adraghici@mgh.harvard.edu
Study Contact Backup
- Name: J. A Taylor, PhD
- Phone Number: 6177585503
- Email: jandrew_taylor@hms.harvard.edu
Study Locations
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Massachusetts
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Cambridge, Massachusetts, United States, 02138
- Recruiting
- Spaulding Rehabilitation Cambridge/ Cardiovascular Laboratory
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Contact:
- Adina E Draghici, PhD
- Phone Number: 617-758-5508
- Email: adraghici@mgh.harvard.edu
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Contact:
- Glen Picard
- Phone Number: 6177585511
- Email: gpicard@partners.org
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Principal Investigator:
- J. A Taylor, PhD
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Other: Laboratory based assessments
The current study has no arms; it is a cross-sectional assessment where all participants will undergo the same procedures.
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physical maneuvers to assess physiological responses in bone blood flow
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Tibial blood perfusion
Time Frame: 1 day
|
Concentration of hemoglobin content assessed in response to several physical maneuvers (tibial loading, isometric handgrip, and tilt)
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1 day
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Collaborators and Investigators
Investigators
- Principal Investigator: J. A Taylor, PhD, Harvard Medical School/Spaulding Rehabilitation Hospital
Publications and helpful links
General Publications
- BROOKES M. Femoral growth after occlusion of the principal nutrient canal in day-old rabbits. J Bone Joint Surg Br. 1957 Aug;39-B(3):563-71. doi: 10.1302/0301-620X.39B3.563. No abstract available.
- Laroche M, Moulinier L, Leger P, Lefebvre D, Mazieres B, Boccalon H. Bone mineral decrease in the leg with unilateral chronic occlusive arterial disease. Clin Exp Rheumatol. 2003 Jan-Feb;21(1):103-6.
- Portal-Nunez S, Lozano D, Esbrit P. Role of angiogenesis on bone formation. Histol Histopathol. 2012 May;27(5):559-66. doi: 10.14670/HH-27.559.
- Kanczler JM, Oreffo RO. Osteogenesis and angiogenesis: the potential for engineering bone. Eur Cell Mater. 2008 May 2;15:100-14. doi: 10.22203/ecm.v015a08.
- Caulkins C, Ebramzadeh E, Winet H. Skeletal muscle contractions uncoupled from gravitational loading directly increase cortical bone blood flow rates in vivo. J Orthop Res. 2009 May;27(5):651-6. doi: 10.1002/jor.20780.
- Stabley JN, Moningka NC, Behnke BJ, Delp MD. Exercise training augments regional bone and marrow blood flow during exercise. Med Sci Sports Exerc. 2014 Nov;46(11):2107-12. doi: 10.1249/MSS.0000000000000342.
- Stabley JN, Prisby RD, Behnke BJ, Delp MD. Chronic skeletal unloading of the rat femur: mechanisms and functional consequences of vascular remodeling. Bone. 2013 Dec;57(2):355-60. doi: 10.1016/j.bone.2013.09.003. Epub 2013 Sep 19.
- Gross PM, Heistad DD, Marcus ML. Neurohumoral regulation of blood flow to bones and marrow. Am J Physiol. 1979 Oct;237(4):H440-8. doi: 10.1152/ajpheart.1979.237.4.H440.
- Ye Z, Wood MB, Vanhoutte PM. Alpha-adrenergic receptor responsiveness in vascular smooth muscle of canine bone. Clin Orthop Relat Res. 1993 Feb;(287):286-91.
- Briggs PJ, Moran CG, Wood MB. Actions of endothelin-1, 2, and 3 in the microvasculature of bone. J Orthop Res. 1998 May;16(3):340-7. doi: 10.1002/jor.1100160310.
- Draghici AE, Potart D, Hollmann JL, Pera V, Fang Q, DiMarzio CA, Andrew Taylor J, Niedre MJ, Shefelbine SJ. Near infrared spectroscopy for measuring changes in bone hemoglobin content after exercise in individuals with spinal cord injury. J Orthop Res. 2018 Jan;36(1):183-191. doi: 10.1002/jor.23622. Epub 2017 Jun 28.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Other Study ID Numbers
- 2018P000156
- R21AR074054-01A1 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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