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A Biopsychosocial Approach to Understanding the Influence of Vitamin D Deficiency and Race on Chronic Knee Osteoarthriti...

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Title:
A Biopsychosocial Approach to Understanding the Influence of Vitamin D Deficiency and Race on Chronic Knee Osteoarthritic Pain in Older Adults
Physical Description:
1 online resource (121 p.)
Language:
english
Creator:
Glover, Toni L
Publisher:
University of Florida
Place of Publication:
Gainesville, Fla.
Publication Date:

Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Nursing Sciences, Nursing
Committee Chair:
Horgas, Ann L
Committee Members:
Yoon, Saun-Joo
Riley, Joseph Leo
Fillingim, Roger Benton

Subjects

Subjects / Keywords:
aging -- disparities -- osteoarthritis -- pain -- vitamind
Nursing -- Dissertations, Academic -- UF
Genre:
Nursing Sciences thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract:
This dissertation research examined the relationship between vitamin D inadequacy, race, and pain in older adults with knee osteoarthritis. Research has demonstrated the vitamin D endocrine system is important to systemic health. Adequate levels of vitamin D function as a total system regulator that decreases cardiometabolic burden. Chronic vitamin D inadequacy is hypothesized to contribute to disparities in several health conditions for black Americans. A review of the state of the science on health disparities in osteoarthritis pain related to vitamin D inadequacy was conducted. Clinical trials on this topic have been sparse and have yielded inconsistent results. In the first data-driven manuscript, our cross-sectional study demonstrated older black Americans had significantly lower levels of vitamin D compared to whites, demonstrated greater clinical pain, and showed greater sensitivity to heat and mechanical pain. Race group differences in experimental pain were mediated by differences in vitamin D levels, suggesting that vitamin D deficiency may be a risk factor for increased knee osteoarthritis pain in older black Americans. In the second data-driven chapter, we focused on vitamin D level and obesity in relationship to clinical and functional measures of knee osteoarthritis pain. We hypothesized a significant interaction between vitamin D level and obesity, such that obese individuals with low vitamin D levels would have greater osteoarthritis pain and dysfunction. Although the findings did not support our hypothesis, the topic warrants further research and suggestions were made for future analytic approaches. The results of this dissertation contribute to the expanding field of vitamin D research. Taken together, the findings suggest 1) vitamin D deficiency should be assessed and treated in older black Americans, who are at greater risk for the most severe levels of deficiency; 2) race group differences in experimental pain were mediated by differences in vitamin D levels, suggesting that vitamin D deficiency may be a risk factor for increased knee osteoarthritis pain in older black Americans; and 3) the combination of low levels of vitamin D and obesity correlates with a worsening osteoarthritis phenotype that warrants further study.
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility:
by Toni L Glover.
Thesis:
Thesis (Ph.D.)--University of Florida, 2013.
Local:
Adviser: Horgas, Ann L.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2015-08-31

Record Information

Source Institution:
UFRGP
Rights Management:
Applicable rights reserved.
Classification:
lcc - LD1780 2013
System ID:
UFE0045701:00001

MISSING IMAGE

Material Information

Title:
A Biopsychosocial Approach to Understanding the Influence of Vitamin D Deficiency and Race on Chronic Knee Osteoarthritic Pain in Older Adults
Physical Description:
1 online resource (121 p.)
Language:
english
Creator:
Glover, Toni L
Publisher:
University of Florida
Place of Publication:
Gainesville, Fla.
Publication Date:

Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Nursing Sciences, Nursing
Committee Chair:
Horgas, Ann L
Committee Members:
Yoon, Saun-Joo
Riley, Joseph Leo
Fillingim, Roger Benton

Subjects

Subjects / Keywords:
aging -- disparities -- osteoarthritis -- pain -- vitamind
Nursing -- Dissertations, Academic -- UF
Genre:
Nursing Sciences thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract:
This dissertation research examined the relationship between vitamin D inadequacy, race, and pain in older adults with knee osteoarthritis. Research has demonstrated the vitamin D endocrine system is important to systemic health. Adequate levels of vitamin D function as a total system regulator that decreases cardiometabolic burden. Chronic vitamin D inadequacy is hypothesized to contribute to disparities in several health conditions for black Americans. A review of the state of the science on health disparities in osteoarthritis pain related to vitamin D inadequacy was conducted. Clinical trials on this topic have been sparse and have yielded inconsistent results. In the first data-driven manuscript, our cross-sectional study demonstrated older black Americans had significantly lower levels of vitamin D compared to whites, demonstrated greater clinical pain, and showed greater sensitivity to heat and mechanical pain. Race group differences in experimental pain were mediated by differences in vitamin D levels, suggesting that vitamin D deficiency may be a risk factor for increased knee osteoarthritis pain in older black Americans. In the second data-driven chapter, we focused on vitamin D level and obesity in relationship to clinical and functional measures of knee osteoarthritis pain. We hypothesized a significant interaction between vitamin D level and obesity, such that obese individuals with low vitamin D levels would have greater osteoarthritis pain and dysfunction. Although the findings did not support our hypothesis, the topic warrants further research and suggestions were made for future analytic approaches. The results of this dissertation contribute to the expanding field of vitamin D research. Taken together, the findings suggest 1) vitamin D deficiency should be assessed and treated in older black Americans, who are at greater risk for the most severe levels of deficiency; 2) race group differences in experimental pain were mediated by differences in vitamin D levels, suggesting that vitamin D deficiency may be a risk factor for increased knee osteoarthritis pain in older black Americans; and 3) the combination of low levels of vitamin D and obesity correlates with a worsening osteoarthritis phenotype that warrants further study.
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility:
by Toni L Glover.
Thesis:
Thesis (Ph.D.)--University of Florida, 2013.
Local:
Adviser: Horgas, Ann L.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2015-08-31

Record Information

Source Institution:
UFRGP
Rights Management:
Applicable rights reserved.
Classification:
lcc - LD1780 2013
System ID:
UFE0045701:00001


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1 A BIOPSYCHOSOCIAL AP PROACH TO UNDERSTAND ING THE INFLUENCE OF VITAMIN D DEFICIENCY AND RACE ON CHRONIC KNEE OSTEOARTHRITIC PAIN IN OLDER ADULTS By TONI L. GLOVER A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2013

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2 2013 Toni L. Glover

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3 ACKNOWLEDGMENTS I am deeply grateful to my mentor, Dr Ann Horgas, for her continual support and guidance during my doctoral education. Early in the program, she encouraged me to apply for the John A. Hartford Foundation Building Academic Geriatric Nursing Capacity Scholar s program. Receiving this prestigious funding support paved the way for me to make the transition from a study nurse and research coordinator to a nurse scientist capable of carrying a research idea from conception to completion. I am also indebted to Dr. Roger Fillingim, the Director of the Pain Research and Intervention Center of Excellence, whom I have had the good fortune to work with for the past 13 years, including the three years of my doctoral education. Dr. Fillingim encouraged my educational aspir ations and substantively supported my research idea by allowing me to append my study onto one of his existing protocols and covering the costs of the vitamin D analyte. I was doubly fortunate to have two outstanding mentors. Also, I would like to thank Dr Saunjoo Yoon and Dr. Joseph Riley for serving on my dissertation committee and providing valuable feedback on my research. I am deeply appreciative to all of the research participants that have taken part in the Understanding Pain and Limitations in Oste oArthritic Disease (UPLOAD) study, many who were participating in a research study for the first time. We could not conduct research without individuals willing to participate and I am deeply thankful for their time and commitment to the protocol. Finally, I would like to thank my f amily for their ceaseless support. Although my father could not be here to see me graduate, he would have been so proud to call his my daughter, often picking her up from school when I was in class, or caring for her when I was away at conferences. I especially thank my daughter, Emma Glover, who

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4 tolerated her mom being a student and, thus, spending too much time studying, and occasionally forced to miss momentous events. I hope I conveyed, and passed on, a lifelong love for learning and the courage to follow your dreams.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 3 LIST OF TABLES ................................ ................................ ................................ ............ 7 LIST OF FIGURES ................................ ................................ ................................ .......... 8 ABSTRACT ................................ ................................ ................................ ..................... 9 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .... 11 Background and Significance ................................ ................................ ................. 13 Aging ................................ ................................ ................................ ................ 13 Pain ................................ ................................ ................................ .................. 14 Knee Osteoarthritic Pain in Older Adults ................................ .......................... 16 Vitamin D ................................ ................................ ................................ .......... 18 Theoretical Framework ................................ ................................ ........................... 19 Purpose Statement and Specific Aims ................................ ................................ .... 21 Detailed Description of the Manuscripts for Chapters 2 4 ................................ ....... 23 Disparities in Osteoarthritis Pain for Black Americans: Does Long Standing Vitamin D Inadequacy Play a Role? A Review ................................ .............. 23 Vitamin D, Race, and Experimental Pain Sensitivity in Older Adults with Knee Osteoarthritis ................................ ................................ ....................... 23 Vitamin D, Obesity, and Measures of Pain and Dysfunction in Older Adults with Knee Osteoarthritis ................................ ................................ ................ 25 2 DISPARITIES IN OSTEO ARTHRITIS PAIN FOR B LACK A MERICANS: DOES LONG STANDING VITAMIN D I NADEQUACY PLAY A ROL E? A REVIEW ......... 34 Methods ................................ ................................ ................................ .................. 38 Racial Disparities in Osteoarthritis Pain and Disability ................................ ............ 38 Vitamin D Inadequacy and Osteoarthritis ................................ ................................ 40 Discussion ................................ ................................ ................................ .............. 42 3 VITAMIN D, RACE, AND EXPERIMENTAL PAIN SE NSITIVITY IN OLDER ADULTS WITH KNEE OST EOARTHRITIS ................................ ............................ 49 Patients and Methods ................................ ................................ ............................. 52 Study Design ................................ ................................ ................................ .... 52 Participants ................................ ................................ ................................ ....... 52 Procedures ................................ ................................ ................................ ....... 53 Self Report Measures ................................ ................................ ...................... 54 Quantitative Sensory Testing ................................ ................................ ........... 54

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6 Vitamin D Assay ................................ ................................ ............................... 56 Data Analysi s ................................ ................................ ................................ ... 56 Results ................................ ................................ ................................ .................... 57 Sample Characteristics and Examination of Covariates ................................ ... 57 Group Differences in Clinical and Experime ntal Pain ................................ ....... 58 Group Differences in Vitamin D Level ................................ .............................. 59 Vitamin D Level and Pain ................................ ................................ ................. 59 Testing Vitamin D Level as a Simple Mediator ................................ ................. 60 Discussion ................................ ................................ ................................ .............. 61 4 VITAMIN D, OBESITY, AND MEASURES OF PAIN AND FUNCTION IN OLDER ADULTS WITH KN EE OSTEOARTHRITIS ................................ ............... 72 Methods ................................ ................................ ................................ .................. 75 Participants and Procedures ................................ ................................ ............ 75 Measures ................................ ................................ ................................ .......... 77 Data Analysis ................................ ................................ ................................ ... 80 Results ................................ ................................ ................................ .................... 82 Discussion ................................ ................................ ................................ .............. 84 5 CONCLUSIONS AND NURSING IMPLICATIONS ................................ ................. 96 Limitations ................................ ................................ ................................ ............... 98 Implications for Nursing ................................ ................................ .......................... 98 Future Directions ................................ ................................ ................................ .. 100 LIST OF REFERENCES ................................ ................................ ............................. 101 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 121

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7 LIST OF TABLES Table page 1 1 A biopsychosocial model applied to knee osteoarthritic pain in older adults: Construct, concepts, and empirical indicators. ................................ ................... 28 2 1 Vitamin D and Osteoarthritis Research Studies on Black and White Americans. ................................ ................................ ................................ .......... 46 3 1 ................ 68 3 2 Descriptive data for key study variables across groups. ................................ ..... 69 3 3 Vitamin D mediates group differences in heat pain threshold at the index knee (model 1) an d ipsilateral forearm (model 2). ................................ .............. 70 3 4 Vitamin D mediates group differences in pressure pain threshold at the ind ex knee (model 3) and ipsilateral forearm (model 4). ................................ ..... 71 4 1 Participant characteristics. ................................ ................................ .................. 89 4 2 Pearson correlations of key study variables. ................................ ...................... 90 4 3 Significant main effect for obesity on WOMAC total scores. ............................... 91 4 4 Significant main effect for obesity on KOOS PS scores. ................................ .... 92 4 5 Significant interaction effect for obesity and vitamin D level on SPPB scores. ... 93 4 6 Probed interaction effect for non obese participants and vitamin D level on SPPB scores. ................................ ................................ ................................ ..... 94 4 7 Probed interaction effect for obese participants and vitamin D level on SPPB scores. ................................ ................................ ................................ ................ 95

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8 L IST OF FIGURES Figure page 1 1 M ................................ ................................ .... 29 1 2 A biopsychosocial model applied to knee osteoarthritic pain in older adults. ..... 30 1 3 Study model for Chapter 2: The influence of vitamin D inadequacy on racial disparities in the osteoarthritis phenotype. ................................ ......................... 31 1 4 Study model for Chapter 3: Test vitamin D as a mediator of the relationship between race and clinical and experimental in older adults with knee osteoarthritis pain. ................................ ................................ .............................. 32 1 5 Study model for Chapter 4: Test the interactive influence of vitamin D level and obesity on self reported pain and functional performance in older adults with symptomatic knee osteoarthritis. ................................ ................................ 33 3 1 Mediation model. The effect of race on vitamin D level is represented by a the dire ct effect of vitamin D level on pain measures is represented by b and the total effect of race on pain measures is represented by c ........................... 66 3 2 Flow diagram of the study participants. QST = quantitative sensory testing; HAS = health assessment session; AA = African American. .............................. 67

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9 Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy A BIOPSYCHOSOCIAL AP PROACH TO UNDERSTAND ING THE INFLUENCE OF VITAMIN D DEFICIENCY AND RACE ON CHRONIC KNEE OSTEOARTHRITIC PAIN IN OLDER ADULTS By Toni L. Glover August 2013 Chair: Ann Horgas Major: Nursing Science s This dissertation research examined t he relationship between vitamin D inadequacy, race, and pain in older adults with knee osteoarthritis. Research has demonstrated the vitamin D endocrine system is important to systemic health. Adequate levels of vitamin D function as a total system regulat or that decreases cardiometabolic burden. Chronic vitamin D inadequacy is hypothesized to contribute to disparities in several health conditions for black Americans. A review of the state of the science on health disparities in osteoarthritis pain related to vitamin D inadequacy was conducted. Clinical trials on this topic have been sparse and have yielded inconsistent results. In the first data driven manuscript, our cross sectional study demonstrated older black Americans had significantly lower levels o f vitamin D compared to whites, demonstrated greater clinical pain, and showed greater sensitivity to heat and mechanical pain. Race group differences in experimental pain were mediated by differences in vitamin D levels, suggesting that vitamin D deficien cy may be a risk factor for increased knee osteoarthritis pain in older black Americans

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10 In the second data driven chapter, we focused on vitamin D level and obesity in relationship to clinical and functional measures of knee osteoarthritis pain. We hypoth esized a significant interaction between vitamin D level and obesity, such that obese individuals with low vitamin D levels would have greater osteoarthritis pain and dysfunction. Although the findings did not support our hypothesis, the topic warrants fur ther research and suggestions were made for future analytic approaches. The results of this dissertation contribute to the expanding field of vitamin D research. Taken together, the findings suggest 1) vitamin D deficiency should be assessed and treated i n older black Americans, who are at greater risk for the most severe levels of deficiency; 2) r ace group differences in experimental pain were mediated by differences in vitamin D levels, suggesting that vitamin D deficiency may be a risk factor for increa sed knee osteoarthritis pain in older black Americans; and 3) the combination of low levels of vitamin D and obesity correlates with a worsening osteoarthritis phenotype that warrants further study.

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11 CHAPTER 1 INTRODUCTION Advances in life span have led to an unprecedented growth in the number of older adults. In 2010, Americans age 65+ numbered at 40.4 million, or one in every eight individuals (Administration on Aging, 2011) With the aging of the population, the prevalence of chronic pain is also on the rise. The Institute of Medicine (IOM) estimates 100 million adults in the United States exp erience chronic pain (Institute on Medicine, 2011c) More than 50 percent of older adults contend with osteoarthritis pain the leading cause of disability in older adults (Hunter, McDougall, & Keefe, 2008; Zhang & Jordan, 2010). Racial and ethnic divers ity is increasing in all age groups, including older adults (Vincent & Velkoff, 2010) Though advances in lifespan have improved for all Americans, there are notable health disparities in morbidity and mortality for black Americans. O n average, white males live about seven years longer than black men, and white women live more than five years longer than their black counterparts (Cullen, Cummins, & Fuchs, 2012) Regarding treatment for pain related conditions, black Americans have less access to healthcare, less effective pain assessment and treatment, and less availability of pain relieving prescription medications in their neighborhoods (Green et al., 2003; Anderson, Green, & Payne, 2009; Mossey, 2011) Lifestyle changes, along with the increased prevalen ce of obesity, have contributed to widespread low levels of vitamin D cited in epidemiological studies (Ginde, Liu, & Camargo, 2009) Research has demonstrated he alth effects of this vitamin hormone, far beyond its previously well established role in skeletal health (Holick, 2007) The ability to effectively synthesize vitamin D during ultraviolet B (UVB)

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12 exposure decreases with age placing older adults at risk fo r vitamin D inadequacy (Holick, 2006) B lack Americans of all ages are d isproportionately affected by vitamin D in adequacy including the highest rates of severe deficiency, because increased melanin content in darker skin slows vitamin D synthesis Chroni c low levels of vitamin D among black Americans have been posited as a contributor to health disparities (Grant & Peiris, 2010) Low levels of vitamin D have been implicated in a number of painful conditions, however, the mechanism of if its role in the ex perience of pain is not fully understood. It is likely that vitamin D influences pain and pain processing via numerous mechanisms. The goal of this research is to e lucidate the role of vitamin D in chronic knee osteoarthritis pain in older adults, and mor e specifically, investigate vitamin D deficiency as a contributor to disparities in knee osteoarthritis pain for black Americans. In the proposed dissertation research, vitamin D will be operationalized to include serum 25(OH)D levels as well as biological ly active vitamin D, and low levels of vitamin D or vitamin D inadequacy will be operationalized to include both vitamin D insufficiency and deficiency. selected terminology of those authors. The following sections will present the background and significance of the problem, the theoretical framework for the proposed work, and the purpose statement and research questions. This will be followed by a detailed description of the three manuscripts proposed for this non traditional dissertation research

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13 Background and Significance Aging properties at the cellular, tissue, and organ level that lead to a loss of homeostasis, decreased ability to adapt to internal or external stimuli, and increased vulnerability to (American Geriatrics Society, 2011, p. 8). Beyond simply adding years to life, the goal of preventive health care and medical advances has been to add life to years. In other words, the quality of years lived may be just as important as the number. The aging of the baby boomers (those born between 1946 and 1964) heralded the approaching Silver Tsunami with 10,000 individuals turning 65 every day since January 1, 2011 (Alliance for Aging Research, 2006) This trend will persist until 20 30. Forecasters expect the population of those age 65+ will increase to 88.5 million by 2050, more than double the current number. For the first time in history, in most countries the older population will outnumber the young (Kinsella & Wan, 2009) Aging within the older population has lead to distinctions amongst the young old, middle old, and oldest old. In 2010, 14% of the older population was age 85+, the fastest growing group of the oldest old. These distinctions are important because the prevalence o f chronic pain, limitations in physical and functional capacity, frailty, disability, and polypharmacy all increase with advanced age, necessitating more frequent caregiving and family and societal support (Vincent & Velkoff, 2010) Although pain is under treated across all age groups, the lack of appropriate pain treatment is exacerbated in older individuals due to complex comorbid conditions, cognitive impairments that impact the ability to self report pain, and the common

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14 (Hadjistavropoulos et al., 2007; Bruckenthal, Reid, & Reisner, 2009; Horgas, Elliott, & Marsiske, 2009) Increased pain in older adults is associated with greater frailty, and frailty places older adults at ris k for a loss of independence (Shega et al., 2012) Pain experience associated with actual or potential tissue damage, or described in terms of (Merskey & Bogduk, 1994) Nu definition of pain remains relevant today is whatever the experiencing person (McCaffery, 1968, p. 95). Pain can be acute or chronic. Chronic pain is defined as p ersistent pain after the injury has healed, typically lasting longer than 3 to 6 months Recent research suggests the brain reorganizes in the presence of chronic pain, which may reflect fundamental changes in how the brain processes pain related informati on (Apkarian, Baliki, & Geha, 2009) gate control theory of pain irrevocably influenced the expanding field of pain research in the mid twentieth century (Melzack & Wall, 1965) The gate control theory describe s how messages are communicated between the peripheral and central nervous system. With tissue damage, the peripheral nerves se nd signals to the spinal cord via nocioceptors. T he dorsal horn of the spinal cord determines which pain signals get forwarded to the brain (ascend ing pathways). A through; if the gate is partially closed, fewer pain signals are transferred to the brain. When pain signals go through the gate, the brain processes and interprets the signals before communicating information back to the periphery (descending pathways). Thus

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15 our thoughts, emotions, and beliefs affect our perception of pain. The gate control theory described three dimensions of pain: the sensory discr iminative, the affective motivational, and the evaluative cognitive aspects of pain experience (Loeser & Melzack, 1999; Melzack, 1999) Biological mechanisms of nociception comprise predominantly sensory discriminative aspects of pain while affective motiv ational and evaluative cognitive aspects of pain are influenced by psychological and sociocultural factors. However, the separation of these constructs serves primarily heuristic purposes it is likely biological, psychological, and sociocultural factors continually influence one another in the experience of chronic pain (Campbell & Edwards, 2009) Melzack expanded the gate control theory into the construct of the body self neuromatrix (Melzack, 1999, 2001) A model of the body self neuromatrix is included in Figure 1 1. Despite advances in the basic science understanding of pain pathways and processing, the vast individual differences in response s to pain and its treatment remain incompletely understood. Quantitative sensory testing (QST) employs pain mea sures that can be standardized and quantified. Experimental pain m odalities include mechanical (pressure, punctuate, vibratory, and light touch), thermal (cold pain and heat pain), and electrical stimuli (Werner, Mjobo, Nielsen, & Rudin, 2010) QST has bee n correlated with clinically reported pain, offers a standardized method for measuring pain reports between individuals, and may have prognostic value for somatosensory changes (R. R. Edwards, Sarlani, Wesselmann, & Fillingim, 2005) Black Americans report increased clinical pain and demonstrate increased pain in response to QST (C. L. Edwards,

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16 Fillingim, & Keefe, 2001; Riley et al., 2002; Campbell, Edwards, & Fillingim, 2005; F. B. Rahim Williams et al., 2007; B. Rahim Williams, Riley, Williams, & Fillingi m, 2012) Knee Osteoarthritic Pain in Older Adults Osteoarthritis is a degenerative joint disease which affects the joints of the knees, hips, hands and spine of nearly 27 million Americans m ost of them age 65+ (Lawrence et al., 2008) The osteoarthriti s phenotype is clinically characterized by knee pain on most days, stiffness, crepitus, and bony tenderness or enlargement, regardless of radiographic evidence of osteoarthritis for adults age 50+ (Altman et al., 1986) In fact, the prevalence of symptomatic osteoarthritis has increas ed while radiographic knee osteoarthritis has remained stable (Nguyen et al., 2011) Obesity contributes to increased knee osteoarthritis symptoms due to stress on the knee joints (Murphy e t al., 2008; Macfarlane, de Silva, & Jones, 2011) In the National Health and Nutrition Examination Survey (NHANES) for 2005 2006, approximately 69% of adults age 60+ were overweight or obese (Houston, Nicklas, & Zizza, 2009) Obesity among older adults is projected to contribute to an increased prevalence of advanced osteoarthritis over the next 10 years (Holt et al., 2011) Chronic osteoarthritis related pain and loss of function is associated with increased depression and a decreased quality of life (Lin 2008; Gerrits et al., 2012) The primary treatment for osteoarthritis pain includes analgesics and anti inflammatory agents (Gloth, 2011) However, prolonged use of pain medications, whether they be acetaminophen, nonsteroidal anti inflammatory drugs (NS AIDs), or opioid medications, carry risk of adverse events in the older adult population due to the physiologic changes associated with normal aging (American Geriatrics Society, 2009) When taken improperly, acetaminophen can cause liver injury or failure Older adults

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17 are more likely to have upper gastrointestinal bleeding with prolonged NSAID use. Acetaminophen and NSAIDs may also exacerbate hypertension, a common condition among older adults (Bruckenthal et al., 2009) Opioids may cause or worsen consti pation and also cause sedation and confusion, requiring more frequent monitoring (Chou et al., 2009) Many older adults refrain from taking pain medications to avoid unpleasant side effects (D'Arcy, 2008) A number of new medications for pain have been dev eloped, however, evidence supporting their long term use for chronic pain is limited (Chapman et al., 2010) For reasons that are not fully understood, older black Americans also have more medication related problems and higher rates of medication non adhe rence (Roth, Esserman, Ivey, & Weinberger, 2011) Costs of and access to medications, poor health literacy, quality of the relationship between prescriber and patient, and individual attitudes and health beliefs contribute to non adherence among older black Americans (Armstrong, 2007) Many b lack participants enrolled in our NIH funded protocol, Understanding Pain and Limitations in OsteoArthritic Disease (UPLOAD) anecdotally report they prefer not to take any oral medications for their knee pain and r ely instead on topical medications (for example, menthol rubbing alcohol) or nonpharmacologic coping strategies (such as rest, ice or heating pad, and/or prayer). Jones and colleagues (Jones et al., 2008) found older black veterans with osteoarthritis pain and functional disability were more likely to use hoping and praying as a coping strategy, compared to whites. Yoon (Yoon, 2006) found older black women used significantly less number of nonprescribed medications, compared to their white counterparts, tho ugh there was no difference in herbal use.

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18 Nonpharmacologic approaches are increasingly recommended to augment the treatment of chronic osteoarthritis pain (Bruckenthal, 2010) To this end, an expert panel of the American College of Rheumatology (Marc C. Hochberg et al., 2012) advises all patients with osteoarthritis be enrolled in aerobic and/or resistance based exercise; recommends weight loss for those overweight; participation in osteoarthritis self management programs, including psychosocial intervent ions; physical therapy; and, instruction in the use of thermal agents, bracing, and walking aids. The use of nutraceuticals (i.e., dietary supplements) for chronic pain comprises a new area of research. Given the risk of side effects from medications typic ally employed for osteoarthritis pain and consumer interest in complementary and alternative approaches to pain treatment, maintaining adequate vitamin D levels may provide a new strategy to reduce osteoarthritis pain, with reduced risk of adverse side eff ects. Furthermore, vitamin D is inexpensive and readily available. Vitamin D T he pleiotropic role of biologically active vitamin D acts as a sentinel for cellular health by protecting cells from age related dysfunction, modulating immune response, and de creasing inflammation (Holick, 2007) Humans primarily meet their vitamin D needs through exposure to (UVB) radiation. Seasonal variation in the angle of UVB rays decrease opportunities for vitamin D synthesis in northern latitudes (above 37 degrees north) during the winter months. With UVB exposure, the precursor 7 dehydrocholesterol is converted to previtamin D3, which then becomes vitamin D3. In the bloodstream, vitamin D binds with a vitamin D binding protein and is stored in adipose tissue or transport ed to the liver where it is hydroxylated to 25 hydroxyvitamin D (25(OH)D, calcidiol). Finally, vitamin D is converted to the biologically active form

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19 (1,25(OH) 2 hydroxylase (CYP27b1) in the kidneys, as well as other tissues. According to experts, clinical laboratory assessment of serum 25 hydroxyvitamin D best characterizes vitamin D status because it reflects vitamin D synthesized cutaneously as well as dietary intake (Cannell & Holl is, 2008; Heaney, 2011) Vitamin D receptors (VDR) are ubiquitous throughout the body and some cells can convert 25(OH)D to the biologically active form of vitamin D (Mizwicki & Norman, 2009) This process is dependent up on adequate serum 25(OH)D. The opt imal serum concentration of vitamin D is currently debated, but believed to be between 30 60 ng/mL. Clinical practice guidelines cite vitamin D (serum 25(OH)D) levels <30 ng/mL as inadequate. Values between 21 29 ng/mL are defined as insufficient, values < 20 ng/mL as deficient, and values less than10 ng/mL are defined as severe deficiency ( Holick et al., 2011) In light of the lack of strong evidence on the extra skeletal effects of vitamin D, the IOM (Institute on Medicine, 2011a) suggested a conservative increase in the recommended daily intake of vitamin D 600 international units (IU) of daily vitamin D for adults up to age 70 and 800 IU daily for healthy people age 71 + years of age. To facilitate research on the extra skeletal effects of vitamin D, the IOM raised the safe daily dose of vitamin D to 4,000 IU per day. Theoretical Framework Fawcett (Fawcett, 1978) compares theory and research to the double strands of DNA inextricably intertwined. The use of theory directs research and research findings help shape the development of theory T heories contain testable variables applicable to nursing practice while a conceptual model provides a more general framework to examine research phenomena (Walker & Avant, 2011)

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20 Around the same time the gate control theory of pain emerged, Engel conceptualized the biopsychosocial model (G.L. Engel, 1962; G. L. Engel, 1977, 1981) as an inclusive conceptual framework to study the antecedents of illness and disease. The biopsychosoci al model examines the cause of illness from the perspective of three interrelated viewpoints: biological, psychological, and social factors. The biopsychosocial model was synthesized and applied to the field of medicine from general systems theory, propose d by V on Bertalanffy in the 1940s (Von Bertalanffy, 1950) Psychological Development in Health and Disease, was The need for a new medical model: A challenge for biomedicine impacted scientific thinking about the antecedents of illness. Today, it is commonly accepted that chronic health conditions have genetic and environmental determinants. Pain can only be truly understood by examining the individual interp lay of biological, psychological, and sociocultural contributors to the perception, modulation, and interpretation of pain (Hadjistavropoulos et al., 2011) Loscalzo and colleagues defects in a comp lex genetic network operating with in a dynamic environmental (Loscalzo, Kohane, & Barabasi, 2007, p. 2) The evolution of the systems theory and the biopsychosocial approach is regaining attention under the heading of systems biology (Barabasi, 2007; Goh et al., 2007) Biological changes that lead to vitamin D inadequacy include physiological changes associated with aging and variation in skin pigmentation. However, sociocultural changes such as spending less time outdoors, using sunscreen prote ction,

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21 the increasing prevalence of obesity, and changes in dietary patterns have also contributed to widespread low levels of vitamin D. Geriatric assessment and treatment focuses on preserving functional health and quality of life (Rockwood, Silvius, & F ox, 1998; Elsawy & Higgins, 2011) Maintaining an adequate vitamin D level may help preserve function and prevent or reduce chronic pain. Thus, a biopsychosocial research framework, incorporating the gate control theory of pain, is most appropriate to exam ine the complex interrelationships among vitamin D, race, and knee osteoarthritis pain and function in older adults (Melzack & Wall, 1965; Gatchel, Peng, Peters, Fuchs, & Turk, 2007) (G. L. Engel, 1977, 198 1) adapted for my research is depicted in Figure 1 2. Purpose Statement and Specific Aims The purpose of this research is to elucidate the role of vitamin D in chronic knee osteoarthritis pain in older adults, and investigate vitamin D inadequacy as a contributor to disparities in knee osteoarthritis pain for black Americans. Vitamin D levels influence many health conditions which disproportionately impact black Americans (Ginde, Liu, et al., 2009; Grant, 2009; Grant & Peiris, 2010, 2012) To date there have been a limited number of research studies focusing on vitamin D level and chronic pain and even fewer have examined chronic vitamin D inadequacy as a key factor in health disparities for black Americans. With the biopsychosocial model (G. L. E ngel, 1977, 1981; Gatchel et al., 2007) serving as the overarching con ceptual model supporting my dissertation research, the following specific aims will be examine d. Each aim relates to proposed manuscripts for Chapters 2 4 and each manuscript examines al ternative models which elucidate the relationship between vitamin D level, race, and osteoarthritis pain.

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22 Constructs, concepts and empirical indicators used to examine these aims are depicted in Table 1 1. Aim 1: To describe and analyze the research liter ature on vitamin D inadequacy in the context of disparities in osteoarthritis pain and dysfunction for older black Americans. Aim 2: To investigate whether vitamin D level functions as a mediator of clinically and experimentally measured pain in older black Americans with symptomatic knee osteoarthritis. Aim 3: To examine the interactive influence of vitamin D level and obesity on self reported pain and functional performance in older adults with symptomatic knee osteoarthritis The se aims have been incorporated as a substudy of a larger ongoing research project that aims to enhance the understanding of racial/ethnic differences in pain and limitations among individuals with osteoarthritic disease (Understanding Pain and Limitations in OsteoArthritic Disease, UPLOAD). The UPLOAD study enrolls participants at the University of Florida and the University of Alabama at Birmingham. P articipants were recruited via posted fliers, radio and print media advertisements, orthopedic clinic recruitment, and word of mouth referral. All study procedures were reviewed and approved by the University of Florida and University of Alabama Birmingham Institutional Review Boards. Participants provided written informed consent and were compensated for their participation.

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23 Detailed Description of the Manuscripts for Chapters 2 4 Disparities in Osteoarthritis Pain for Black Americans: Does Long Standing Vitamin D Inadequacy Play a Role? A Review Research statement: What is the current state of the science on disparities in osteoarthritis pain and dysfunction for black Americans and the potential contributing role of vitamin D inadequacy? The purpose of th e first manuscript w as to review the research literature on disparities in osteoarthritis impacting the health of older black Americans in relation to the burgeoning literature on vitamin D and health. The evidence for the role of vitamin D inadequacy a s a biological contributor to health disparities in pain for black Americans remains inconclusive (Grant & Peiris, 2010; Straube, Moore, Derry, Hallier, & McQuay, 2010) Observational studies with rigorous methodological control and randomized controlled tria ls are needed R esearch trials on vitamin D and health outcomes must strive to enroll adequate numbers of racially diverse populations to allow further understanding of the role vitamin D plays in achieving health equity. Screening for vitamin D deficiency among black Americans may be warranted especially those with chronic pain. This manuscript will be submitted to Journal of Pain or Clinical Journal of Pain. Vitamin D, Race, and Experimental Pain Sensitivity in Older Adults with Knee Osteoarthritis Res earch question: Does vitamin D level mediate racial differences in self reported and experimental pain in older adults with knee osteoarthritis ? The principal research question addressed in the second manuscript is whether low levels of vitamin D contribute d to a cumulative health disadvantage (Kim & Miech, 2009) in knee osteoarthritis pain for black Americans.

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24 model (Baron & Kenny, 1986) along with Preacher and Hayes bootstrapped confidence intervals (Preacher & Haye s, 2008) were used to examine the complex relationships between vitamin D level, race, and pain. Specifically, the paper examine d the meditational effect of vitamin D level in race differences in clinical pain ratings and laboratory based experimental pain testing. The Western Ontario and McMaster Universities Index of Osteoarthritis (WOMAC) served as the clinical measure of knee osteoarthritis pain, stiffness, and physical dysfunction T hermal and mechanical pain measures comprise d experimentally induced pain assessment. In a preli minary analys is of UPLOAD participants, there were significant differences in vitamin D level and pain reports between blacks and whites, and a statistically significant link was found between vitamin D level and experimental pain sensitivity that has not yet been established in the current literature. Preliminary results were presented on posters at the Southern Research Nursing Society meeting (T.L. Glover, Horgas, & Fillingim, 2011, February) and the A merican Pain Society meeting (T.L. Glover et al., 2011, May) In the final analysis, t his cross sectional study demonstrated older black Americans had significantly lower levels of vitamin D compared to whites, demonstrated greater clinical pain, and showe d greater sensitivity to heat and mechanical pain. Low levels of vitamin D predicted increased experimental pain sensitivity, but not self reported clinical pain. Race group differences in experimental pain were mediated by differences in vitamin D levels, suggesting that vitamin D deficiency may be a risk factor for increased knee osteoarthritis pain in older black Americans. This manuscript has been published in Arthritis & Rheumatism (T. L. Glover et al., 2012)

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25 Vitamin D, Obesity, and Measures of Pain a nd Dysfunction in Older Adults with Knee Osteoarthritis Research question: Is there an interactive influence of vitamin D level and obesity on self reported pain and functional performance in older adults with symptomatic knee osteoarthritis? Using a hi erarchical multiple regression model, this manuscript focused on vitamin D level and obesity in relationship to clinical and functional measures of symptomatic knee osteoarthritis pain. We hypothesized 1) obesity will be associated with decreasing vitamin D levels and greater osteoarthritis related pain and dysfunction; and 2) there will be a significant interaction between vitamin D level and obesity, such that obese individuals with low vitamin D levels will have the greatest osteoarthritis pain and dysfu nction. If higher serum levels of vitamin D can be shown to reduce pain and decrease functional limitation in older adults with knee osteoarthritis, it would provide an alternate strategy in the clinical armamentarium to prevent or slow the progression of osteoart hritis related disability. UPLOAD p d demographic questionnaires at the hea lth assessment session. Additionally, anthropometric measurements and knee radiographs were obtained. Vitamin D level was assessed by high performance liquid chromatography. For this manuscript, the Western Ontario and McMaster Universities i ndex of Osteoarthritis (WOMAC ), the Knee Injury and Osteoarthritis Outcome Score, Physical Function Short Form (KOOS PS), and the Short Physical Performance Battery (SPPB ) served as the clinical measures of knee osteoarthritis pain, stiffness, and physical dysfunction

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26 Vitamin D represents a potentially important contributor to both obesity and osteoarthritis related symptoms. Obesity exacerbates the osteoarthritis sympto ms and contributes to low levels of vitamin D. The study findings demonstrated o besity was associated with low levels of vitamin D and greater osteoarthritis pain and dysfunction (hypotheses 1). However, contrary to hypothesis 2 lower vitamin D levels di d not demonstrate either a main or interaction effect on self reported osteoarthritis pain or dysfunction in a hierarchical regression model. For functional performance measures (SPPB) there was a significant interaction effect between vitamin D level an d obesity on SPPB total score, however further probing of this finding revealed non significant associations between vitamin D level and SPPB scores in both obese and non obese participants, suggesting the significant interaction may have limited clinical significance. Reasons for these unexpected findings are explored and a plan for future research on this topic is described. Black Americans are more likely to have low levels of vitamin D due to increased melanin slowing UVB synthesis of vitamin D blocki ng effects (Ginde, Liu, et al., 2009) However, in the current analysis, the small number of black participants with a BMI < 30 kg/m 2 precluded meaningful comparisons. Black participants had lower levels of vitamin D and an increased prevalence of severe deficiency (levels < 10ng/mL) Due to widespread inadequate vitamin levels among black Americans, recruiting black participants with adequate vitamin D levels represents a research challenge and a health disparity that may require changes in vitamin D screening guidelines to effectively address. Ultimately, t he knowledge gained will be used to make holistic and evidence based recommendations to improve the comprehensive symptom management for older

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27 Americans with osteoarthri tis pain and dysfunction (Meghani et al., 2012; Pizzo & Clark, 2012) This manuscript will be submitted to Pain or Clinical Journal of Pain.

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28 Table 1 1. A biopsychosocial model applied to knee osteoarthritic pain in older adults: Construct, concepts an d empirical indicators. Constructs Concepts Empirical Indicators Biological Factors Nervous System Organ/Organ Systems Tissue Cell Organelle Molecule Psychological Factors Person (experience and behaviors) Sociocultural Factors Biosphere Society Nation Culture Subculture (age, sex, class, religion, education, economic, etc.) Community (Health care, work, neighborhood, social, recreational, etc.) Family (nuclear, extended) Two Person (doctor, family member, coworker, friend, etc.) Ou tcome Illness or Disease Vitamin D Osteoarthritis Severity Obesity Depression Race Income Education Clinical reports of knee pain Quantitative Sensory Testing Vitamin D level serum 25(OH)D level measured with high performance liquid chromatography (HPLC). Osteoarthritis clinical pain ratings and radiographic evaluation of index knee (most painful knee). Obesity height (cm) and weight (kg) measured without shoes to calculate BMI. Depression Center for Epidemi ological Studies Depression s cale (CES D). Race self report, based on U.S. Census categories. Income and Education Demographic data collected via questionnaires. Clinical Pain Western Ontario and McMaster Universities i ndex of Osteoarthr itis (WOMAC). Knee Injury and Osteoarthritis Outcome Score, Physical Function Short Form (KOOS PS). Short Physical Performance Battery (SPPB). Experimental Pain Thermal stimuli delivered using a computer controlled Medoc Pathway Thermal Sensory Analyzer. Mechanical pressure pain assessed with a handheld Medoc digital pressure algometer. Punctuate stimuli assessed with von Frey monofilaments. Cold Pressor Pain cold water bath. Numerical Rating Pain scales (0 100). Measures will be further des cribed in the manuscripts serving as Chapters 2 4.

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29 Figure 1 1.

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3 0 Figure 1 2 A biopsychosocial model applied to knee osteoarthritic pain in older adults.

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31 Figure 1 3 Study model for Chapter 2: The influence of vitamin D inadequacy on racial disparities in the osteoarthritis phenotype.

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32 Figure 1 4 Study model for Chapter 3: Test vitamin D as a mediator of the relationship between race and clinical and experimental in older adults with knee osteoarthritis pain.

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33 Figure 1 5 Study model for Chapter 4: Test the interactive influence of vitamin D level and obesity on self reported pain and functional performance in older adults with symptomatic knee osteoarthritis.

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34 CHAPTER 2 DIS PARITIES IN OSTEOART HRITIS PAIN FOR BLAC K AMERICANS: DOES LO NG STANDING VITAMIN D I NADEQUACY PLAY A ROL E? A REVIEW The Ins titute of Medicine (IOM) report Relieving Pain in America (Institute on Medicine, 2011c) highlights the undertreatment, and often inadequate treatment, of pain. As the United States (U.S.) population is graying, the prevalence of pain is increasing. An estimated 100 million adults live with chronic pain. Disparities in the diagnosis and clinic al management of painful conditions for racial and ethnic minorities are well documented (Anderson et al., 2009) .The U.S. spends upwards of $635 billion on pain each year more than the costs for cancer, heart disease, and diabetes combined (Pizzo & Clark 2012) A reinvigorated national agenda requires a comprehensive approach to improve pain care, educat ion of the healthcare workforce on the effective and compassionate treatment of pain, and eliminat ion of disparities in the diagnosis and treatment of th ose with pain (Meghani et al., 2012) a particular type of health difference that is closely linked (U.S. Department of Health and Human Services (HHS), 2008, p. 28) Health disparity implies m ore than difference; disparity is often used synonymously with inequity and inequality (Carter Pokras & Baquet, 2002) A n Agency for Healthcare Research and Quality (AHRQ) report (Cohen & Yu, 2010) indicates 1% of the population utilizes 22% of healthcare resources The one percent tends to be older, white, and female. Cullen and colleagues (Cullen et al., 2012) found, on average, white males live about 7 years longer compared to black men, and that white women live more than 5 years longer than their black counterparts. Charged with improving the health of Americans, the U.S. Department of Health and Human Services

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35 (HHS) has made recommendations for addressing health disparities. In Healthy People 2000, the recommendation was to reduce health disparities ; b y 2010, the emphasis was strengthened to eliminate health disparities The goal for Healthy People 2020 is to achieve health equity, eliminate disparities, and improve the health of all groups (Institute on Medicine, 2011c) Health equity implies finding w ays to align the health potential of those currently disadvantaged with those who have benefitted from available healthcare resources. Health disparities are often attributed to differences in access to care, poor health literacy, provider bias, and lack o f cultural competence (Agency for Healthcare Research and Quality (AHRQ), 2011) However, disparities in diagnosis and treatment of painful conditions for black Americans persist even after income, education and access to healthcare are controlled (Institute on Medicine, 2003) Vitamin D inadequacy has been suggested as a biological difference contributing to health disparities for black Americans (Grant, 2009; Grant & Peiris, 2010, 2012). Osteoarthritis is the most common musculoskeletal disorder a mong older adults and the phenotype is characterized by pain and progressive functional decline (Hunter et al., 2008) Murphy and colleagues (Murphy et al., 2008) found nearly half of older adults will develop symptomatic knee osteoarthritis by 85 years of age. There is no cure for osteoarthritis clinical management focuses on symptom control and the prevention of disability. A growing body of research cites an association between vitamin D inadequacy and poor health outcomes (Holick, 2007) Heaney posits long latency chronic diseases are related to insufficient micronutrients over extended periods (Heaney, 2003) Thus, in theory, long standing vitamin D deficiency in black Americans represents a cumulative risk factor for poor health outcomes (Hicken, Gra gg, & Hu,

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36 2011) Humans primarily meet their vitamin D needs through exposure to ultraviolet B (UVB) radiation. Black Americans are disproportionately affected by vitamin D inadequacy including the most severe deficiency, because increased melanin content in darker skin slows vitamin D synthesis during UVB exposure. In the National Health and Nutrition Examination Survey (NHANES III and NHANES), Ginde and colleagues (Ginde, Liu, et al., 2009) found 97% of black Americans ha ve insufficient or deficient leve ls of vitamin D. Most chronic health conditions have genetic as well as environmental determinants. From an evolutionary perspective, changes in skin color have been adaptive the role of melanin pigmentation is to regulate the effects of UV radiation on the skin (Jablonski & Chaplin, 2000, 2010, 2012) As our ancestors migrated away from tropical areas, skin pigmentation adaptively lightened to allow more vitamin D synthesis. Carson (Carson, 2009) posits t he forced migration of Africans into slavery more than 300 years ago has resulted in chronic widespread vitamin D deficiency among black Americans. The purpose of this manuscript is to analyze the research literature on vitamin D deficiency in the context of disparities in osteoarthritis pain and dysfunc tion for older black Americans According to experts, clinical laboratory assessment of serum 25 hydroxyvitamin D best characterizes vitamin D status because it reflects vitamin D synthesized cutaneously as well as dietary intake (Cannell & Hollis, 200 8; Heaney, 2011) Clinical practice guidelines cite vitamin D (serum 25(OH)D) levels <30 ng/mL as inadequate. Values between 21 29 ng/mL are defined as insufficient values <20 ng/mL as deficient and values less than 10 ng/mL are defined as severe deficie ncy (Holick et al., 2011) With sun exposure, the precursor 7 dehydrocholesterol is converted to pre vitamin D3,

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37 which then becomes vitamin D3. In the bloodstream, vitamin D binds with a vitamin D binding protein and is either stored in adipose tissue or t ransported to the liver where it is hydroxylated to 25 hydroxyvitamin D (25(OH)D, calcidiol). Finally, vitamin D is converted to the biologically active form (1,25(OH) 2 hydroxylase (CYP27b1) in the kidneys, as well as other tissues (Holick, 2007) Vitamin D receptors (VDR) are present on all nucleated cells (Mason, Sequeira, & Gordon Thomson, 2011) The VDR are located both within the nucleus where they influence gene transcription and in the cytoplasm where they can activate signaling cascades that generate nongenomic responses (Mizwicki & Norman, 2009) In relation to pain, they are specifically located on muscle, bone, cells in the spinal column and brain cells; cells of the adaptive an d innate immune system; and, cells of the intestinal tract (Mizwicki & Norman, 2009) The mechanism for how vitamin D may contribute to the osteoarthritis pain experience is not completely understood. I t is likely the pleiotropic role of this vitamin hormo ne influences pain and pain processing via multiple mechanisms (Heaney, 2003; Bischoff Ferrari, Zhang, Kiel, & Felson, 2005; Bergink et al., 2009) However, v itamin D level has unequivocally been established as a cause of bone pain in osteomalacia though t to be due to the hydrated bone matrix exerting outward pressure on the periosteum (Holick, 2003, 2007) In this review, vitamin D will represent serum 25(OH)D and vitamin D inadequacy will be used to encompass both vitamin D insufficiency and deficiency. individuals who self cited, I used the selected terminology of those authors.

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38 Methods The National Library of Medicine PubMed database at http://www.pubmed.gov (National Library of Medicine, 2013) was utilized to locate journal articles, using the steoarthritis disparities AND African Americans e reviewed. Additional references were identified in the reviewed articles. At the present time (March, 2013), there is a paucity of well designed clinical trials on vitamin D supplementation for osteoarthritis symptoms, and none have enrolled adequate num bers of black Americans. Thus, this review was selective. Although vitamin D is being studied around the world, this review focused on vitamin D inadequacy and the osteoarthritis phenotype in black Americans. Additionally, the review focused on studies pu blished in the preceding 17 years Racial Disparities in Osteoarthritis Pain and Disability Although black and white Americans have similar prevalence rates of osteoarthritis, blacks report more osteoarthritis related pain and pain related disability (Losi na et al., 2011; Louie & Ward, 2011; Parmelee, Harralson, McPherron, DeCoster, & Schumacher, 2012) In the Johnston County Osteoarthritis Project, black Americans had more severe tibiofemoral osteoarthritis compared to whites, were more likely to have tricompartmental osteoarthritis, increased bone sclerosis, and increased prevalence and severity of oste ophytes and joint space narrowing (Allen, 2010) Furthermore, older black Americans report greater knee osteoarthritis pain but are less likely to undergo total knee replacement one factor that can explain increased rates of disability in older black adu lts with knee osteoarthritis (Dunlop et al., 2008; Centers for Disease & Prevention, 2009; Blum & Ibrahim, 2012)

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39 Obesity exacerbates osteoarthritis pain and dysfunction (Allen et al., 2009) As a condition characterized by inflammation, the osteoarthrit is phenotype has been suggested as a sequelae of metabolic syndrome (Katz, Agrawal, & Velasquez, 2010) Weight reduction for overweight or obese individuals with osteoarthritis is recommended to reduce pain and preserve function (M. C. Hochberg et al., 201 2) In obesity, vitamin D is sequestered in fat cells, decreasing its availability for hormonal actions in the bloodstream (Holick, 2007; Rosen et al., 2012) Although obesity rates have increased for all older Americans, black women have higher rates of o besity compared to their white counterparts (Freedman, Centers for Disease, & Prevention, 2011) Low income is associated with an increased prevalence of obesity However, Whitson and colleagues (Whitson et al., 2011) found obesity contributes to racial di sparities in disability, even after controlling for socioeconomic status. A frican American women with excess body weight and osteoarthritis had poorer functional outcomes at four years compared to white women (Colbert et al., 2013) African Americans with osteoarthritis have lower rates of meeting physical activity guidelines (Song et al., 2013) and report a greater number of barriers to participation in community and home based arthritis self management programs (Mingo, McIlvane, Jefferson, Edwards, & Hale y, 2013) Allen and colleagues (Allen et al., 2010) found the psychological variables of self efficacy, affect, and emotion focused coping were important mediators of racial differences in osteoarthritis related pain and dysfunction. Weight reduction, along with a comprehensive pain treatment program has been shown to lessen osteoarthritis related pain in a sample of predominantly black and white Americans (Somers et al., 2012)

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40 Additionally, weight loss has been shown to improve vitamin D status in ob ese individuals with osteoarthritis (Christensen et al., 2012) Vitamin D Inadequacy and Osteoarthritis Research on vitamin D inadequacy and vitamin D supplementation for osteoarthritis has demonstrated inconsistent results. However, when functional measur es of osteoarthritis (self reported pain and function, joint swelling, performance based tests such as the chair stand and timed walking test) are included, some studies have shown an impact of vitamin D inadequacy. These functional measures may be more im experience of osteoarthritis symptoms and contribute to quality of life and progression to disability. The field of research is hampered by a lack of scientific consensus on the ide al level of vitamin D for non skeletal actions (Cannell & Hollis, 2008) ; the use of various methods to measure serum vitamin D that yield disparate results (high performance liquid chromatography is considered the gold standard for serum 25(OH)D assessment (Holick, 2009) ); and, the potential synergistic effects of micronutrients which do not lend themselves to compartmentalizing inherent in randomized controlled trials (Luxwolda, Kuipers, Kema, Dijck Brouwer, & Muskiet, 2012; Misra et al., 2013) The review ed studies are summarized in Table 2 1. In a recent randomized controlled clinical trial, McAlindon and colleagues (T. McAlindon et al., 2013) found vitamin D supplementation to levels of 36 ng/mL did not improve the Western Ontario and McMaster Universiti es Osteoarthritis i ndex (WOMAC) pain severity score or slow knee cartilage volume loss over a period of two years. However, only 6 1 % of the vitamin D treatment group reached the target vitamin D level. Of note, t he team found a small difference in pain sco res that favored the treated group but did not have

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41 adequate power to determine if this finding was due to chance. Additionally, the researchers assessed physical function with a time d 20 meter walk and chair rise test with results approaching significance for the vitamin D treatment group ( p = .07). In examining two large longitudinal studies, Felson and colleagues (Felson et al., 2007) also found no association between vitamin D levels and structural progression of knee osteoarthritis. Health Initiative, researchers (Brunner et al., 2008) found calcium and vitamin D supplementation did not improve self reported or objective measures of physical functioning over a 7 year period. Using the same dataset, Jackson and colleague s (Jackson et al., 2006) found that vitamin D supplementation diminished bone loss at the hip but did not significantly reduce the incidence of hip fractures in postmenopausal women. This protocol supplemented participants with 400 IUs of vitamin D, an amo unt considered nominal, especially in those with pre existing vitamin D inadequacy (Vieth, 2006; Cannell & Hollis, 2008) Some observational studies have found an association of vitamin D inadequacy and the osteoarthritis phenotype. Chlebowski and colleagu es (Chlebowski et al., 2011) found postmenopausal women with the lowest levels of vitamin D reported higher joint pain scores. In a study of older adults with persistent musculoskeletal pain including osteoarthritis Plotiknoff and Quigley (Plotnikoff & Quigley, 2003) found all black ng/mL). McAlindon and colleagues (T. E. McAlindon et al., 1996) studied a subset of the Framingham study and found participants with low intake of vitamin D and vitamin D levels < 30 ng/mL were three times more likely to have progression of pre existing osteoarthritis. However, vitamin D intake or level was not associated with the incidence

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42 of new cases of osteoarthritis. Lane and colleagues (Lane et al., 1999) found h ip joint space narrowing was increased for participants in the middle and lowest vitamin D tertiles compared to those in the highest tertile However, v itamin D level was not associated with the development of new hip osteoarthritis o r changes in osteophytes for those with hip osteoarthritis Research in our lab (T. L. Glover et al., 2012) demonstrated older black Americans had significantly lower levels of vitamin D compared to whites, demonstrated greater clinical pain, and showed gr eater sensitivity to heat and mechanical pain. Low levels of vitamin D predicted increased experimental pain sensitivity, but not self reported clinical pain. Race group differences in experimental pain were mediated by differences in vitamin D levels, sug gesting that vitamin D deficiency may be a risk factor for increased knee osteoarthritis pain in older black Americans. Discussion A principal research question motivating this review was whether chronic vitamin D inadequacy contribute s to a cumulative h ealth disadvantage in osteoarthritis pain and dysfunction for black Americans. Although the evidence is inconsistent, many of the reviewed studies did not include race as a key study variable. C hronic low levels of vitamin D among black Americans potential ly contribute to several disparities in health. In 2011, a committee of the Institute of Medicine (Institute on Medicine, 2011a) reviewed the literature on vitamin D and increased the recommended daily intake to 600 international units (IU) of daily vitamin D for adults up to age 70 and 800 IU daily for healthy people age 71 + years of age. One of the challenges the committee faced was the scarcity of randomized controlled trials on vitamin D supplementation and health outcomes. To this end, the IOM ra ised the safe daily dose of vitamin D to 4,000 IU per

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43 day to augment research on various levels of supplementation. More recently, the U.S. Preventive Services Task Force (USPSTF) (Moyer, 2013) also found insufficient evidence to recommend noninstitutional ized postmenopausal women supplement with vitamin D and calcium as primary prevention for fractures. However, the USPSTF recognizes adequate vitamin D is important to overall health and is currently evaluating their vitamin D screening recommendations. A h ost of clinical studies of vitamin D supplementation and health outcomes are presently underway (Cao et al., 2012; U.S. National Institutes of Health, 2013) Regarding skeletal health, it has been suggested that different normative values of vitamin D may be warranted for black Americans who demonstrate a low rate of bone turnover and decreased urinary excretion of calcium in the presence of vitamin D deficiency and secondary hyperparathyroidism (Cosman, Nieves, Dempster, & Lindsay, 2007; Wright et al., 20 11) However, the last 40 years have demonstrated that the vitamin D endocrine system (Norman, 2008; Norman & Bouillon, 2010) has system wide effects on maintaining good health beyond the skeleton. A recent study by Luxwolda and colleagues (Luxwolda et al. 2012) shows that traditionally living East Africans have vitamin D levels averaging 44 48 ng/mL. The Masaai and the Hadzabe people have very dark skin, live hunter gatherer lifestyles, and spend most of their days outdoors in year round sunlight, althoug h they avoid direct exposure. None of the tribe members had values below 20 ng/mL and the highest vitamin D value measured was 68.4 ng/mL. These findings among traditionally living dark skinned individuals contradict the argument for different normative va lues by race.

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44 The Centers for Disease Control (CDC) 2012 report on nutritional indicators in the U.S. population found race and ethnicity significantly influenced the likelihood of vitamin D deficiency, with blacks having the lowest concentrations of vit amin D and whites having the highest concentrations (Centers for Disease Control, 2012) Dietary sources of vitamin D are limited (shiitake mushrooms, cod liver oil, and fatty fish such as herring, mackerel, salmon, sardines, and tuna). Dairy products and cereals are fortified with nominal amounts of vitamin D (Institute on Medicine, 2011a) However, black Americans consume less milk, cereals, and vitamin D supplements, compared with white Americans (Calvo, Whiting, & Barton, 2004) New food sources of vita min D fortified foods are needed which appeal to those at highest risk for vitamin D inadequacy (Calvo & Whiting, 2012) The findings presented should be viewed in light of their limitations. This review does not represent a comprehensive or systematic rev iew of the literature on disparities in painful conditions and the effects of vitamin D. Rather, the focus was on the recent research findings on health care disparities in osteoarthritis pain and dysfunction impacting older black and white Ame ricans and h ow vitamin D inadequacy may further explain disparities in pain. Nonetheless, adequate levels of vitamin D appear important for human health beyond preventing osteomalacia Improving vitamin D status may be an intervention that elicits progress toward heal th equity for black Americans. There is wide variability in monitoring and prescribing or recommending vitamin D supplementation. Health care consumers are fascinated with the potential of vitamin D as a health panacea and may supplement indiscriminately. Though rare, vitamin D toxicity can cause hypercalcemia, kidney stones, and vascular calcification (Vieth, 2007;

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45 Howland, 2011) Thus, health care providers need reliable evidence based guidelines regarding screening and treatment of vitamin D inadequacy. While the current evidence may not be conclusive, it seems prudent to implement initiatives addressing the diagnosis and treatment of severe v itamin D deficiency which occurs more frequently in black Americans. Many older individuals find themselves living in environments that preclude adequate vitamin D synthesis. Fortunately, correcting vitamin D insufficiency with supplementation is typically successful, cost effective and without signific ant risk of adverse side effects for most individuals. Screening may be warranted for older Americans especially those with chronic pain or disease. Furthermore, continued research trials on vitamin D must strive to enroll adequate numbers of racially di verse populations to allow further understanding of vitamin D in achieving health equity.

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46 Table 2 1. Vitamin D and Osteoarthritis Research Studies on Black and White Americans. Lead Author Year Primary Purpose Study Design Total Sample Size # of Black Americans Findings McAlindon et al., 2013 Examined whether vitamin D supplementation to 36 ng/mL reduced knee osteoarthritis symptoms (WOMAC P) and reduced cartilage volume loss. 2 year randomized, placebo contro lled double blind clinical trial. N = 146 Black participants = 16 (22%) in treatment group; 8 (11% in placebo group. No significant differences in knee pain or percentage of cartilage volume loss between treatment group and placebo. Glover et al., 2012 Examine whether variations in vitamin D levels contribute to race differences in knee osteoarthritis pain. Cross sectional N = 94 Black participants = 45 (48%) Low levels of vitamin D predicted increased experimental pain sensitivity, but not self reporte d clinical pain. Race group differences in experimental pain were mediated by differences in vitamin D levels. Chlebowski et al., 2011 Examined whether low vitamin D levels (dietary intake and supplementation) in post menopausal women would be associat ed with a higher frequency of joint pain and swelling (yes/no; mild/moderate/severe). Cross sectional N = 1993 subset Black women = 114 (5.7%) Calcium plus Vitamin D clinical trial. Lower vitamin D levels were associated with higher pain scores for women in the lowest sextile of vitamin D concentrations (<28.9 nmol/L or <11.56 ng/mL). Chaganti et al., 2010 Examined serum levels of vitamin D in association with the prevalence of radiographic hip osteoarthritis in elderly m en. Cross sectional N = 1,104 substudy Black men = number not included; race variable was not analyzed. Osteoporotic Fractures in Men (MrOS) Study = 5,995 Black Americans = 4.1% Men with insufficient vitamin D were twice as likely to have radiographic hip osteoarthritis.

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47 Table 2 1 Continued Lead Author Year Primary Purpose Study Design Total Sample Size # of Black Americans Findings Brunner et al., 2008 Examined whether treatment with calcium plus vitamin D affected self reported and objectives measures of physical function over a 7 year period. Randomized, double blind, placebo controlled trial of calcium (1,000 mg) plus vitamin D3 versus placebo. N = 33,067 total postmenopausal women, 18,176 in the treatment group and 18,106 in the placebo grou p. Black participants = 1,682 (9.3%) in the treatment group and 1,635 (9%) in the placebo group; race variable was not analyzed. Calcium/vitamin D supplementation did not improve self reported or objective measures of physical fun ctioning. Felson et al., 2007 Examined whether vitamin D levels predicted worsening of osteoarthritis as measured by radiographic joint space loss or worsening cartilage score on MRI. Two longitudinal cohorts Framingham Offspring Study = 715 Boston Osteo arthritis of the Knee Study = 277 Black participants = number not included; race variable was not analyzed. No association between vitamin D tertiles and structural progression of osteoarthritis. Jackson et al., 2006 Examined whether treatment with calcium plus vitamin D would have a lower risk of hip fracture over a 7 year period. Randomized, double blind, placebo controlled trial of calcium (1,000 mg) plus vitamin D3 versus placebo. N = 36,282 total postmenopausal women, 18,176 in the treatment gro up and 18,106 in the placebo group. Black participants = 1,682 (9.3%) in the treatment group and 1,635 (9%) in the placebo group; race variable was not analyzed. Calcium and vitamin D supplementation resulted in a significant impr ovement in hip bone mineral density, but did not significantly reduce hip fracture. Women in the treatment group were at increased risk for kidney stones.

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48 Table 2 1 Continued Lead Author Year Primary Purpose Study Design Total Sample Size # of Black Americans Findings Plotnikoff et al., 2003 Examined the prevalence of hypovitaminosis D in primary care outpatients with persistent nonspecific musculoskeletal pain syndromes (including osteoarthritis). Cross sectional N = 150 Black participants = 22 (15%) Widespread vitamin D deficiency was found and was more pronounced in younger age groups. All black participants had vitamin D ng/mL). Lane et al., 1999 Examined the relationship between vita min D levels and incidence of, and changes in, radiographic hip osteoarthritis over an 8 year period. Longitudinal cohort study N = 237 women A subset of the Study of Osteoporotic Fractures. The parent study excluded black women due to their low inciden ce of hip fracture. Hip joint space narrowing, but not osteophytes, was increased for participants in the middle and lowest tertiles compared to those in the highest tertile. Vitamin D level was not associated with the development of new hip osteoarthriti s. McAlindon at al., 1996 Examined whether dietary intake and serum levels of vitamin D would predict the incidence and progression of osteoarthritis. Prospective observational study N = 788 normal and 126 osteoarthritis knees subset Black participants = number not included; race variable was not analyzed. Framingham Study Participants with osteoarthritis and vitamin D levels in the lowest and middle tertiles (less than 30 ng/mL) had a three fold increased risk of radiographic worsening of osteoarthritis. However, vitamin D level did not influence onset of osteoarthritis in a previously normal knee.

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49 CHAPTER 3 VITAMIN D, RACE, AND EXPERIMENTAL PAIN SE NSITIVITY IN OLDER A DULTS W ITH KNEE OSTEOARTHRI TIS The last decade has witnessed a dramatic increase in research related to the nonskeletal effects of vitamin D. In its known role as a vitamin, this micronutrient aids calcium absorption. However, recent research on vitamin D has focused on its hormonal act ions. Recommended daily intake of vitamin D has historically been aimed at primary prevention of osteomalacia and osteoporosis. In its biologically active form, vitamin D is a secosteroid involved in regulating cell differentiation, proliferation, angiogen esis, and apoptosis (Holick, 2007) Vitamin D is synthesized through the skin with adequate exposure to ultraviolet B (UVB) light. Following synthesis and conversion, vitamin D is hydroxylated in the liver, then in the kidneys. Vitamin D receptors can be found on nearly all nucleated cells (Mason et al., 2011) Vitamin D deficiency D has been correlated with diabetes, cancer, and decreased immunity (Holick, 2007) Less than sufficient circulating serum levels of 25 hydroxyvitamin D (referred to hereafter as vitamin D) have been noted across populations in epidemiological studies. vitamin D synthesis in northern latitudes and in the winter months. Other factors contributing to inadequate vitamin D levels include more time spent indoors, increased use of sunscreen, and the prevalence of obesity (Holick & Chen, 2008) As a fat soluble nutrient, vitamin D is sequestered in fat cells, decreasin g its availability for hormonal Reprinted with permission from John Wiley and Sons Glover, T. L., Goodin, B. R., Horgas, A. L., Kindler, L. L., King, C. D., Sibille, K. T., . Fillingim, R. B. (2012). Vitamin D, race, and experimental pain sensitivity in older adults with knee osteoarthritis. Arthritis & Rheumatism, 64 (12), 3926 3935. doi: 10.1002/art.37687

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50 acti with aging (Holick & Chen, 2008) ; thus, older adults are at greater risk of inadequate vitamin D levels. Additionally, vitamin D synthesis requires longer periods of sun exposure for those with dark skin pigmentation. Thus, low levels of vitamin D are prevalent in black Americans, including the most severe levels of deficiency. Estimates indicate 70% of white Americans and > 95% of black Americans have insufficient levels of vitamin D (Holick & Chen, 2008) Greater vitamin D deficiency in black Americans may, in part, explain their increased incidence of chronic health conditions and provide a key to reducing health disparities (Holick & Chen, 2008; Ginde, Liu, et al., 200 9; Grant & Peiris, 2010, 2012) The optimal serum concentration of vitamin D is currently debated but is believed to be between 30 60 ng/mL. Recent clinical practice guidelines define vitamin D levels <20 ng/mL as deficient and values of 21 29 ng/mL as i nsufficient (Holick et al., 2011) It has been suggested that different normative values of vitamin D may be warranted for black and white Americans based on the inverse relationship between vitamin D and parathyroid hormone levels (Wright et al., 2011) H owever, variation in the vitamin D parathyroid hormone relationship by race and age is not fully understood and clinical trials on vitamin D supplementation are needed (Harris, Soteriades, Coolidge, Mudgal, & Dawson Hughes, 2000; Dawson Hughes, 2004; Wilki ns, Birge, Sheline, & Morris, 2009; Wright et al., 2011) In 2011, the Institute of Medicine report, Dietary Reference Intakes for Calcium and Vitamin D, (Institute on Medicine, 2011a) increased the recommended daily intake of vitamin D from 400 to 600 IU per day. Many experts feel this dose is still too low (Heaney & Holick, 2011) The Institute of Medicine report

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51 recommended interventional research on vitamin D supplementation to ascertain its effect on disease, aging, and racial health disparities and, t herefore, raised the maximum safe daily dose to 4,000 IU. Although vitamin D has been correlated with many health conditions, few studies have considered the relationship of vitamin D to chronic pain (T. E. McAlindon et al., 1996; Atherton et al., 2009; St raube, Andrew Moore, Derry, & McQuay, 2009; Chaganti et al., 2010; Straube et al., 2010) Chronic pain is a disease. The 2011 Institute of Medicine report, Relieving Pain in America, (Institute on Medicine, 2011c) estimates annual spending on pain to be between $560 billion and $635 billion. Many older adults contend with pain from osteoarthritis the most common joint condition and the leading cause of disability in older adults (Centers for Disease & Prevention, 2005; Wieland, Michaelis, Kirschbaum, & Rudolphi, 2005; Hunter et al., 2008) Research suggests that the brain reorganizes in the presence of chronic pain, which may reflect fundamental changes in how the brain processes pain related information (Apkarian et al., 2009) Despite advances in the b asic science understanding of pain pathways and processing, there remain vast individual differences in response to the clinical treatment of pain. Furthermore, pain remains undertreated, especially for older adults and non white populations (C. L. Edwards et al., 2001; Green et al., 2003; Hadjistavropoulos et al., 2007; Anderson et al., 2009; Green & Hart Johnson, 2010) Previous research in our laboratory has found ethnic differences in quantitative sensory testing, with blacks reporting increased pain se nsitivity (Campbell et al., 2005; F. B. Rahim Williams et al., 2007) The triage theory, proposed by Ames (Ames, 2006) hypothesizes that long term micronutrient deficiencies trigger chronic inflammation. In turn, chronic inflammation

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52 leads to chronic health conditions, many of which are characterized by pain as a disabling symptom. Recent research by Lee et al., (Lee et al., 2011) supports the hypothesis that the etiology of osteoarthritis includes a systemic inflammatory component. He aney (Heaney, 2003) theorizes long latency chronic diseases are related to insufficient micronutrients over extended periods. The U.S. nutritional recommendations for micronutrients are based on preventing short latency diseases and not on optimizing the p reventive health effects of micronutrient therapy. These theories may help to explain relationships between vitamin D level and chronic pain. The purpose of this study was to examine whether variations in vitamin D levels contribute to race differences in symptomatic knee osteoarthritic pain. We hypothesized low levels of vitamin D would contribute to self reported and experimental knee pain and that vitamin D level would mediate the relationship between race (referred to as group differences) and knee pai n. Patients and Methods Study Design This cross sectional study design examined the relationship between low levels of vitamin D and symptomatic knee osteoarthritic pain among older adults. The project is a substudy of an ongoing study examining ethnic di fferences in knee osteoarthritis pain. The measures and procedures described are limited to those involved in the current study. Participants were recruited at the University of Florida between January 2010 and August, 2011. Participants Participants wer e recruited via posted fliers, radio and print media advertisements, clinic recruitment, and word of mouth referral. The inclusion criteria

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53 were as follows: 1) between 45 85 years; 2) unilateral or bilateral symptomatic knee osteoarthritis based upon Ameri can College of Rheumatology criteria (Altman et al., 1986) regardless of radiographic evidence of osteoarthritis; and, 3) availability to complete the 2 session protocol. Participants were excluded if they met any of the following criteria: 1) prosthetic knee replacement or nonarthroscopic surgery to the affected knee; 2) uncontrolled hypertension (>150/95), heart failure, or history of acute myocardial infarction; 3) peripheral neuropathy; 4) systemic rheumatic disorders including rheumatoid arthritis, systemic lupus erythematosus, and fibromyalgia; 5) daily opioid use; 6) cognitive impairment (Mini Mental Status Exam (MMSE) (Folstein, Folstein, & McHugh, 1975) procedures (intravenous (IV) catheter inse rtion, quantitative sensory testing procedures); and, 8) hospitalization within the preceding year for psychiatric illness. All procedures were reviewed and approved by the University of Florida Institutional Review Board. Participants provided informed co nsent and were compensated for their participation. Procedures Within 1 week prior to the health assessment session, participants completed study questionnaires. At the health assessment session, the following measures were obtained: anthropometric data, vital signs, health history, current medications, MMSE score, and a bilateral joint exam of the hand and knee joints. Using the American College of Rheumatology criteria (Altman et al., 1986) for symptomatic knee matic/painful knee was designated the index knee. Within 4 weeks of the health assessment session, participants were scheduled for the quantitative sensory testing session. Additional questionnaires were completed prior

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54 to and during this session. Quantita tive sensory testing procedures included: vital signs, IV insertion for blood collection, and assessment of thermally induced and mechanically induced pain. Self R eport M easures Center for E pidemiological S tudies D epression scale (CES D) The CES D is a 20 item self report tool that measures symptoms of depression including depressed mood, guilt/worthlessness, helplessness/hopelessness, psychomotor retardation, loss of appetite and sleep disturbance (Radloff, 1977) The total score of the CES D (range 0 depressive symptoms. The validity and internal consistency of the CES D in the general population have been reported to be acceptable (Beekman et al., 1997) Western Ontario and McMaster Universities index of O steoarthritis (WOMAC) The WOMAC (Bellamy, Buchanan, Goldsmith, Campbell, & Stitt, 1988) is frequently used in research to assess symptoms of knee and hip osteoarthritis. The subscales measure pain, stiff ness, and physical function. The total WOMAC score was used in analysis (range 0 96). High construct validity and test retest reliability has been found in paper and computerized versions of the WOMAC (Theiler et al., 2002) Quantit ative Sensory T esting Thermal testing procedures All thermal stimuli were delivered using a computer controlled Medoc Pathway Thermal Sensory Analyzer (Ramat Yishai Israel ). Heat pain thresholds and heat pain tolerances were assessed using an ascending method of limits. From a baseline of 32 o C, thermode temperature increased at a rate of 0.5 o C per second until the participant responded by pressing a button on a handheld device. For heat pain threshold, participants were instructed to press the button when

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55 3 for tolerance were delivered to the index knee. The position of the thermode was moved among three sites (the medial joint line, the patella, and the tibial tuberosity distal to the joint) between trials to avoid sensitization and/or habituation of cutaneous receptors. The results of the 3 individual trials were averaged together to create overall heat pain threshold and heat pain tolerance scores for the index knee. Similarly, 3 trials for threshold and 3 for tolerance were delivered to the ipsilateral forearm. The position of the thermode was moved among three sites an inch above the ventral wris t and an inch below the antecubital space. The results of the 3 individual trials were averaged together to create overall heat pain threshold and heat pain tolerance scores for the ipsilateral forearm. Mechanical testing procedures T o determine sensitiv ity at the site of clinical pain, 6 total trials of pressure pain threshold were assessed at the medial (3 trials) and lateral (3 trials) joint lines of the index knee. Additionally, 3 pressure pain threshold trials were assessed at the dorsal ipsilateral forearm. A handheld Medoc digital pressure algometer ( Ramat Yishai Israel ) was used for the mechanical procedures. An application rate of 30 kilopascals (kPa) per second was used. To assess pressure pain threshold, the examiner applied a constant rate of pressure and the participant was the device recorded the pressure in kPa. The average of the 3 trials was computed separately for the medial and lateral knee and subsequ ently combined to create an overall pressure pain sensitivity score for the index knee. Likewise, the average of the 3

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56 trials for the ipsilateral forearm were calculated to create an overall pressure pain sensitivity score. The overall pain index scores fo r the index knee and ipsilateral forearm were included in statistical analysis. Vitamin D A ssay Serum was collected at the beginning of the quantitative sensory testing session. Following collection, plasma was stored in a freezer at 80 o C. The analyte was subjected to analysis within 6 months of collection. Vitamin D analysis was performed by high performance liquid chromatography (total 25 hydroxyvitamin D = 25(OH)D 2 plus 25(OH)D 3 ). 30 ng/mL, they were encouraged to discuss this result with their primary care provider. Data Analysis Statistical analysis was performed using SPSS software, version 19.0 (IBM Chicago, IL ). Bivariate relationships among continuously measured variables we re analysis of variance (ANOVA). Group differences by race were adjusted for covariates and assessed using analysis of covariance (ANCOVA). The relationships between vitamin D level and pain were examined using multiple regressions. P values less than 0.05 were considered significant. To test whether vitamin D level significantly mediated (Figure 3 1) the association between race and clinical and experimental pain measures, we conducted a bootstrap analysis. Bootstrapping, as put forth by Preacher and Hayes (Preacher & Hayes, 2008; Hayes, 2009) is a nonparametric resampling procedure that has been shown to be a viable alternative to the Baron and Kenny (Baron & Kenny, 1986) approach to testing intervening variable effects. Percentile bootstrap confidence intervals were used to

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57 minimize Type 1 error rate (Fritz, Taylor, & MacKinnon, 2012) A percentile bootstrap 95% CI was calculated, using the SPSS macro for simple mediation (Preacher & Hayes, 2008) to determine the significance of the mediator. In the current study, path c represents the total effect of the independent variable (race) on the dependent variable (clinical and experimental pain measures). Path a denotes the eff ect of race on vitamin D level (mediator) and path b is the effect of vitamin D level on clinical and experimental pain measures. The bootstrapped mediation analysis indicates whether the total effect (path c) is comprised of a significant direct effect (p experimental pain measures and a significant indirect effect (path a x b) of race on clinical and experimental pain measures through the mediator vitamin D level. R esults Sample Characteristics and Examination of Covariate s A total of 107 participants with symptomatic knee osteoarthritis were recruited. Vitamin D data were available for 94 participants at the time of analyses. Figure 3 2 shows a flow diagram for participant matriculation through the study. relations for key study variables are shown in Table 3 1. Vitamin D level significantly and inversely with the total WOMAC score, suggesting that lower vitamin D levels are associated with greater knee osteoarthritis pain and dysfunction. For experimental pain measures, vitamin D level correlated significantly with heat threshold and heat tolerance at the index knee and at the ipsilateral forearm. Finally, vitamin D level correlated significantly with pressure pain thresholds at the knee and at the ipsilate ral forearm. Age and CES D score did not correlate significantly with vitamin D level; however, CES D score correlated positively with WOMAC score and heat pain threshold at the knee.

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58 Women demonstrated lower heat pain tolerance at the forearm (F(1,92) = 4.76, p = .03) and lower pressure pain thresholds at the knee (F(1,92) = 12.92, p = .001) and forearm (F(1,92) = 13.75, p < .001) compared to men. There was a greater proportion of black current smokers compared to white current smokers ( 2 = 4.64, p < .05). However, clinical and experimental pain, as well as vitamin D level, did not differ significantly according to smoking status (all p smokers). Participant age, sex, body mass index (BMI), and CES D score correla ted with pain response and were included as statistical controls in all subsequent data analyses. Group Differences in Clinical and Experimental Pain Using the total WOMAC score, ANCOVA revealed a significant group difference (F(1,88) = 5.67, p = .02). As shown in Table 3 2, the mean SD WOMAC score for black participants was 41.5 21.66, compared to a mean SD of 29.4 18.76, for white participants, indicating that blacks reported more knee pain, stiffness, and limitations in physical function. Addi tionally, black participants demonstrated greater sensitivity to experimental pain measures compared to whites. For example, blacks demonstrated significantly lower mean heat pain threshold (F(1,88) = 5.36, p = .02) and heat pain tolerance (F(1,88) = 23.1 4, p < .001) at the index knee. Similar results were found for the ipsilateral forearm, such that blacks demonstrated significantly lower heat pain threshold (F(1,88) = 9.32, p = .003) and heat pain tolerance (F(1,88) = 17.81, p < .001) compared to whit es. For mechanically induced pain, black participants demonstrated significantly lower mean pressure pain threshold at the index knee

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59 (F(1,88) = 10.13, p = .002) and at the ipsilateral forearm (F(1,88) = 3.96, p = .05) compared to whites. Group Differenc es in Vitamin D Level Adjusted for covariates, ANCOVA revealed that black participants were characterized by significantly lower mean vitamin D levels than their white counterparts (F(1,88) = 16.03, p < .001). The mean SD vitamin D level in black partic ipants was 19.9 8.6 ng/mL, which based on the most recent guidelines (Holick et al., 2011) indicates vitamin D deficiency, compared to a mean SD vitamin D level of 28.2 8.6 ng/mL in whites, which indicates vitamin D insufficiency. Low levels of vitamin D were observed across the sample but were found disproportionately in black participants ; 38 of 45 black participants (84%) had vitamin D levels <30 ng/mL compared to 25 of 49 white participants (51%) ( 2 = 11.86, p < .001). Vitamin D Level and Pain Adjusted multiple regression analyses, controlling for the effects of age, sex, BMI, CES D, a nd group, revealed vitamin D level was not significantly associated with the total WOMAC score ( coefficient 0.06, p = 0.56). However, low levels of vitamin D predicted increased pain sensitivity and lower experimental pain thresholds. Diminished vitamin D levels were significantly associated with lower heat pain thresholds at the index knee ( coefficient 0.23, p = 0.05) and ipsilateral forearm ( coefficient 0.25, p = 0.03). Additionally, lower vitamin D levels were significantly associated with greater sensitivity to pressure pain (i.e., lower threshold) at the index knee ( coefficient 0.23, p = 0.02) and the ipsilateral forearm ( coefficient 0.31, p < 0.01). However, the vitamin D level was not significantly related to heat pain tolerance at the inde x knee ( coefficient 0.10, p = 0.37) and the ipsilateral forearm ( coefficient 0.13, p = 0.22). Accordingly,

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60 only heat pain thresholds and pressure pain thresholds at the index knee and ipsilateral forearm were examined in the mediational analyses. Testi ng Vitamin D Level as a Simple Mediator We tested the indirect effects of group differences in heat pain thresholds and pressure pain thresholds through vitamin D level (i.e., simple mediation). Table 3 3 displays the results of the analyses that examined whether vitamin D level mediated group differences in heat pain thresholds at the index knee (model 1) and ipsilateral forearm (model 2) after adjusting for covariates. The vitamin D level was found to significantly mediate the group difference in heat pa in threshold at the index knee (percentile bootstrap 95% CI 0.01 to 1.11) and at the ipsilateral forearm (percentile bootstrap 95% CI 0.09 to 1.22) using the percentile bootstrap 95% CI, with 5,000 resamples. These results indicate that indirect effects th rough vitamin D level are significantly different from zero. Thus, group differences in heat pain thresholds are mediated by group differences in vitamin D levels. More specifically, blacks possessed lower vitamin D levels than whites and, in turn, lower v itamin D levels significantly predicted lower heat pain thresholds at the index knee and ipsilateral forearm. Table 3 4 displays the results of the analyses that examined whether the vitamin D level also mediated group differences in pressure pain thresho lds at the index knee (model 3) and ipsilateral forearm (model 4) after adjusting for covariates. Vitamin D level was shown to significantly mediate the group differences in pressure pain threshold at the index knee (percentile bootstrap 95% CI 3.43 60.8 6) and at the ipsilateral forearm (percentile bootstrap 95% CI 12.44 67.55) using the percentile bootstrap 95% CI, with 5,000 resamples. As mentioned above, these results indicate that indirect effects

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61 through the vitamin D level are significantly differ ent from zero. Thus, group differences in pressure pain thresholds are mediated by group differences in vitamin D levels. D iscussion In the present study, we examined the extent to which the vitamin D level mediated the relationship between race and pain in older adults with symptomatic knee osteoarthritis. The results revealed that group differences in response to experimental pain, but not self reported pain, for blacks and whites are mediated by group differences in vitamin D level. Low levels of vitami n D mediated the relationship between race and experimental pain in older adults with symptomatic knee osteoarthritis. The study hypothesis expected these findings at the painful knee. Similar results were demonstrated at a non painful testing site on the forearm. Even in a sunny southern environment, low levels of vitamin D were endemic across the sample with black participants having more pronounced vitamin D deficiency. Black participants demonstrated greater pain sensitivity in thermal and mechanical te sting at the index knee and the ipsilateral forearm. These findings are consistent with previous research demonstrating significant differences in responses to quantitative sensory testing in black Americans (Campbell et al., 2005; Hastie, Riley, & Filling im, 2005; F. B. Rahim Williams et al., 2007) Although there is an established link between low levels of vitamin D and pain due to osteomalacia (Holick, 2007) no clear biologic or psychological mechanisms explain how low levels of vitamin D may affect pain sensitivity or relate causally to other chronic pain conditions. Interestingly, significant mediation was found for heat pain threshold but not for pain tolerance. This outcome suggests vitamin D level may be related to pain pathways involved in init ial perception of pain but not how much pain an

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62 to endure noxious stimulation, which is not necessarily related to vitamin D level. In contrast, since there are vitamin D receptors in nucleated cells throughout the peripheral and central nervous system, less than sufficient levels of vitamin D could affect both the transmission and modulation of painful stimuli (Hunter et al., 2008; Ro esel, 2009; Straube et al., 2009; Lee et al., 2011) Using a rodent model, Tague and colleagues (Tague et al., 2011) found vitamin D deficient rats had increased muscle innervation by nociceptors leading to reduced pain threshold for mechanical stimulation in hindlimb musculature. In vitro cultures revealed that vitamin D level was inversely correlated with growth of sensory neurons, leading the authors to hypothesize that vitamin D deficiency may induce muscle pain by stimulating nociceptor growth. Furthe rmore, inflammatory processes contribute to increased pain sensitivity among individuals with osteoarthritis (Hunter et al., 2008; Lee et al., 2011) Sufficient levels of cellular vitamin D have a protective effect on cell function and are believed to redu ce inflammation (Holick, 2007; McCann & Ames, 2008) Thus, a lterations in inflammation attributable to low levels of vitamin D may precipitate increased pain among individuals with osteoarthritis. Less than sufficient levels of vitamin D may explain the increase in symptomatic osteoarthritis without a concurrent increase in radiographic osteoarthritis (Nguyen et al., 2011) In thi D score did not correlate significantly with vitamin D level. However, other research has found an association between low levels of vitamin D and increased symptoms of depression. In a 4 year study of nearly 12,600 particip ants, low levels of vitamin D were associated with depression, especially in

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63 those that had previous episodes (Hoang et al., 2011) Higher levels of vitamin D were associated with fewer symptoms of depression, even among those with a history of depression. It is possible that vitamin D has a direct effect on mood since vitamin D supplementation in a placebo controlled double blind trial was shown to improve the mood and affect of individuals diagnosed with seasonal affective disorder (Lansdowne & Provost, 1 998) Vitamin D receptors are ample in structures and cells of the brain and may contribute to overall brain health and enhanced nerve conduction (Buell & Dawson Hughes, 2008) Given the substantial overlap between negative mood and chronic pain, vitamin D insufficiency may modulate pain perception through affective pathways (Melzack, 1999) As in most research, these findings should be interpreted in light of the study limitations. Participants represented a convenience sample of community dwelling adul ts and older adults. The age range of participants was between 45 71 years; however, the average age of 55.8 years represents a younger cohort. Although black participants were slightly younger than whites, they reported higher levels of osteoarthritis rel ated pain. The cross sectional examination of vitamin D level and clinical and experimental pain does not permit a full understanding of the direction of the relationship between vitamin D level and chronic pain. It is possible that people with osteoarthri tis pain spend less time outdoors and thus have reduced opportunities for vitamin D level, thus lending credence to our study model namely, that vitamin D mediates the relationship between race and experimental pain. Finally, although participants using regularly scheduled opioids were excluded from the study, and those

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64 using opioids as needed were asked to refrain from taking their medication 2 days prior to quanti tative sensory testing, we did not account for other analgesic medication use, which may have affected the results of pain testing. It is unclear why race differences in vitamin D level mediate group differences in experimental pain outcomes but do not mediate clinical osteoarthritis pain intensity, stiffness, or physical function on the WOMAC. This outcome may be related to the fact that osteoarthritis pain intensity measures were assessed retrospectively (i.e., pain over the past 48 hours) and were the refore subject to recall bias. Alternatively, vitamin D may influence certain aspects of pain processing reflected by pain thresholds, while osteoarthritis related symptoms assessed by the WOMAC are likely driven by multiple factors over and above nocicept ive processes. Moreover, a clinical threshold of vitamin D insufficiency may be necessary to better understand the relationship between lows levels of vitamin D, clinical knee pain, and total WOMAC score. In a systematic review of research on vitamin D and chronic pain, Straube and colleagues (Straube et al., 2009) did not find evidence to support a relationship between vitamin D and chronic pain. Results may have been affected by methodologic considerations, such as study design weakness and limited sample size. Similarly, in a review of 7 studies, Straube and colleagues (Straube et al., 2010) found insufficient evidence to support treating chronic pain in ethnic minority patients by correcting vitamin D deficiency. However, none of the studies were randomi zed controlled trials and only 2 case studies investigated vitamin D supplementation. Additional research is needed to strengthen these findings. High quality observational studies and randomized controlled trials with rigorous methodologic

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65 control and ad equate numbers of black participants are needed to understand the relationship between low levels of vitamin D, pain, and pain disparities experienced by black Americans. Improving vitamin D status is inexpensive and with low risk of adverse events. Thus, if additional research demonstrates improving vitamin D status lessens knee osteoarthritis pain, identifying and treating vitamin D insufficiency and deficiency may improve function for older adults with osteoarthritis and reduce health disparities for bla ck Americans.

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66 Figure 3 1. Mediation model. The effect of race on vitamin D level is represented by a the direct effect of vitamin D level on pain measures is represented by b and the total effect of race on pain measures is represented by c

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67 Figure 3 2. Flow diagram of the study participants. QST = quantitative sensory testing; HAS = health assessment session; AA = African American.

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68 Table 3 1. Variables (N = 94) 1 2 3 4 5 6 7 8 9 10 11 1. Age (years) ____ 2. BMI .02 ____ 3. Vitamin D .02 .33** ____ 4. CES D .18 .01 .07 ____ 5. WOMAC .03 .50** .27** .28** ____ 6. Heat pain threshold, knee .02 .02 .27** .23* .12 ____ 7. Heat pain tolerance, knee .11 .14 .27** .07 .22* .61** ____ 8. Heat pain threshold, forearm .07 .14 .35** .18 .15 .58** .59** ____ 9. Heat pain tolerance, forearm .16 .21* .30** .08 .20 .47** .88** .64** ____ 10. Pressure pain, knee .07 .38** .39** .05 .41** .37** .36** .37** .35** ____ 11. Pressure pain, forearm .19 .16 .34** .06 .22* .36** .35** .41** .37** .67** ____ Note: = p < .05, ** = p < .01 BMI = body mass index; CES D = Center for Epidemiologic Studies Depression Scale; WOMAC = Western Ontario and McMaster Universities Osteoarthritis i ndex.

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69 Table 3 2. Descriptive data for key study variables across groups. Blacks Whites n = 45 n = 49 Females = 3 1 Females = 39 Males = 14 Males = 10 Variables Mean SD Range Mean SD Range Age (years) 54.6 5.4 45 68 56.9 7.7 45 71 Vitamin D** (ng/mL) 19.9 8.6 8 40 28.2 8.6 7 48 BMI (%)* 32.4 8.0 18 50 29.0 6.7 19 49 CE S D 16.2 6.5 0 30 16.7 5.2 0 38 WOMAC* 41.5 21.7 4 94 29.4 18.8 4 86 Heat Pain Th reshold Knee (deg C) 41.3 3.0 36 46 42.7 2.9 36 48 Heat Pain Tolerance Knee (deg C)** 44.6 3.3 35 49 47.0 2.1 38 51 Heat Pain Threshold Forearm (deg C)* 40.9 3.3 34 47 42.8 2.7 35 47 Heat Pain Tolerance Forearm (deg C)** 45.2 2.7 37 50 47.0 2.1 39 51 Pressure Pain Threshold Knee (kPa) 263.6 149.0 53 588 362.4 164.4 81 598 Pressure Pain Threshold Forearm (kPa) 233.3 153.2 51 748 275.9 148.9 77 677 Note: = p < 0.05; ** = p < 0.001 BMI = body mass index; CES D = Center for Epidemiologic Studies Depression Scale; WOMAC = Western Ontario and McMaster Universities O steoarthritis Index.

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70 Table 3 3 Vitamin D mediates group differences in heat pain threshold at the index knee (model 1) and ipsilateral forearm (model 2) 95% percentile Effect Coefficient SE t Sig. confidence interval Model 1 c a 1.49 7.39 0.64 1.85 2.32 4.00 0.0229 0.0001 b 0.07 0.04 1.96 0.0531 0.96 0.69 1.39 0.1667 a x b 0.51 0.28 d (0.01 1.11) Model 2 c a 1.97 7.39 0.64 1.85 3.05 4.00 0.0030 0.0001 b 0.08 0.04 2.27 0.0258 1.36 0.68 1.98 0.0506 a x b 0.60 0.29 d (0.09 1.22) Shown are unstandardized coefficients for the mediated effect of group differences in heat pain threshold at the index knee and ipsilateral forearm through vitamin D level, controlling for age, sex, body mass index, and Center for Epidemiologic Studies Depression Scale score. Path c = total effect of race on heat pain threshold; path a= effect of race on vitamin D level; path b = direct effect of vitamin D level on heat pain threshold; path direct effect of race on heat pain threshold, controlling for vitamin D level; path a x b = indirect effect of race on heat pain threshold through vitamin D level. 95% CI = 95% confidence i nterval. d A p value for the indirect effect is not provided because such a p value is contingent upon a normal distribution of the indirect effect. Given that the product of the a and b path coefficients is always positively skewed, interpretation of this p value can be misleading (Preacher & Hayes, 2008).

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71 Table 3 4. Vitamin D mediates group differences in pressure pain threshold at the index knee ( m odel 3) and ipsilateral forearm ( m odel 4) 95% CI Effect Coefficient SE t Sig. Bias Corrected Model 3 c a 95.88 7.39 30.12 1.85 3.18 4.00 0.0020 0.0001 b 4.00 1.70 2.36 0.0205 66.31 31.93 2.08 0.0408 a x b 29.10 14.84 d (3.43 60.86) Model 4 c a 60.21 7.39 30.26 1.85 1.99 4.00 0.0497 0.0001 b 4.95 1.68 2.96 0.0040 23.61 31.54 0.75 0.4561 a x b 36.34 14.27 d (12.44 67.55) Shown are unstandardized coefficients for the mediated effect of group differences in heat pain threshold at the index knee and ipsilateral forearm through vitamin D level, controlling for age, sex, body mass index, and Center for Epidemiologic Studies Depression Scale score. Path c = total effect of race on heat pain threshold; path a= effect of race on vitamin D level; path b = d irect effect of vitamin D level on heat pain threshold; path direct effect of race on heat pain threshold, controlling for vitamin D level; path a x b = indirect effect of race on heat pain threshold through vitamin D level. 95% CI = 95% confidence interval. d A p value for the indirect effect is not provided because such a p value is contingent upon a normal distribution of the indirect effect. Given tha t the product of the a and b path coefficients is always positively skewed, interpretation of this p value can be misleading (Preacher & Hayes, 2008).

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72 CHAPTER 4 VITAMIN D, OBESITY, AND MEASURES OF PAIN AND FUNCTION IN OLDE R ADULTS WITH KNEE OST EOARTHRIT IS The phenotype of symptomatic osteoarthritis is characterized by pain, stiffness, and limitations in physical function. With the graying of the population, the prevalence of osteoarthritis is on the rise it is estimated over half of all adults aged 65+ have been diagnosed with osteoarthritis (Helmick et al., 2008) Increased pain in older adults is associated with greater frailty (Shega et al., 2012) In turn, frailty is a strong predictor of falls, loss of independence, institutionalization, and mortal ity (Fried et al., 2001; Shega et al., 2012) In fact, osteoarthritis is the leading cause of disability in older adults (Hunter et al., 2008; Zhang & Jordan, 2010) Obesity contributes to the osteoarthritis phenotype (Tanamas et al., 2013) and increases the likelihood of osteoarthritis related disability (Holt et al., 2011; Macfarlane et al., 2011) In the National Health and Nutrition Examination Survey (NHANES) for 2005 2006, approximately 69% of adults aged 60+ were overweight or obese ( Houston et al., 2009) Obesity among older adults is projected to contribute to an increased prevalence of advanced osteoarthritis over the next 10 years (Holt et al., 2011) The American College of Rheumatology (ACR) recommends exercise and weight loss fo r overweight and obese individuals as part of a nonpharmacologic strategy to prevent the cascade from knee pain to disability (M. C. Hochberg et al., 2012) Even modest amounts of weight loss are associated with a significant improvement in function and mo bility (Messier, Gutekunst, Davis, & DeVita, 2005; Riddle & Stratford, 2013) However, chronic knee pain can interfere with the motivation needed to change eating behaviors and participate in physical activities that could lead to weight loss (McBeth et al ., 2012; Somers et al., 2012)

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73 Vitamin D represents a potentially important contributor to both obesity and osteoarthritis related symptoms. In obese individuals, vitamin D is sequestered in fat cells, decreasing its bioavailability for hormonal actions (Cheng et al., 2010; Rosen et al., 2012; Vimaleswaran et al., 2013) Furthermore, obese individuals may expose less body surface area to the sun exposure, contributing to lower vitamin D status (Wortsman, Matsuoka, Chen, Lu, & Holick, 2000; Lagunova, Poroj nicu, Lindberg, Hexeberg, & Moan, 2009) In a study of post menopausal women, vitamin D level was associated with lower weight gains over a 4 5 year period (LeBlanc et al., 2012) Thus, adequate levels of vitamin D may help prevent weight gain associated w ith the physiologic changes of aging, including decreased caloric need and reduced energy expenditure. Humans primarily meet their vitamin D needs through exposure to ultraviolet B (UVB) radiation. The ability to effectively synthesize vitamin D during UVB exposure decreases with age, placing older adults at risk for vitamin D deficiency (Holick, 2006) Micronutrient deficiencies are associated with chronic disease and frailty in older adults (Heaney, 2003; Ames, 2006; Semba et al., 2006) The optimal serum concentration of vitamin D is believed to be between 30 60 ng/mL. Clinical practice guidelines cite vitamin D (serum 25(OH)D) levels <30 ng/mL as inadequate. Values between 21 29 ng/mL are defined as insufficient, values <20 ng/mL as deficient, and values less than10 ng/mL are defined as severe deficiency (Holick et al., 2011). C linical laboratory assessment of serum 25 hydroxyvitamin D best characterizes vitamin D status because it reflects vitamin D synthesized cutaneously as well as through dietary inta ke (Cannell & Hollis, 2008; Heaney, 2011)

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74 Among older adults, the prevalence of frailty, limitations in physical and functional capacity, disability, and polypharmacy all increase with age, necessitating more frequent caregiving and family and societal s upport (Vincent & Velkoff, 2010) Given the rapidly growing number of older Americans, improving the comprehensive treatment of chronic pain, addressing the prevalence of obesity, and preventing or delaying the untoward consequences of frailty is a nationa l priority (Ferrucci et al., 2004; Meghani et al., 2012; Pizzo & Clark, 2012) The primary treatment for osteoarthritis pain includes analgesics and anti inflammatory agents (Gloth, 2011) However, prolonged use of pain medications, whether they be acetami nophen, nonsteroidal anti inflammatory drugs (NSAIDs), or opioid medications, carry risk of adverse events in the older adult population due to the physiologic changes associated with normal aging (American Geriatrics Society, 2009) When taken improperly, acetaminophen can cause liver injury or failure. Older adults are more likely to have upper gastrointestinal bleeding with prolonged NSAID use. Acetaminophen and NSAIDs may also exacerbate hypertension, a common condition among older adults (Bruckenthal e t al., 2009; Guo, He, Zhang, & Walton, 2012) Opioids may cause or worsen constipation and also cause sedation and confusion, requiring more frequent monitoring (Chou et al., 2009) Many older adults refrain from taking pain medications to avoid unpleasant side effects (D'Arcy, 2008) A number of new medications for pain have been developed, however, evidence supporting their long term use for chronic pain is limited (Chapman et al., 2010) Nonpharmacologic approaches are increasingly recommended to augmen t the treatment of chronic osteoarthritis symptoms (Bruckenthal, 2010) To this end, an expert panel of the American College of Rheumatology (M. C. Hochberg et al., 2012) advises

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75 all patients with osteoarthritis be enrolled in aerobic and/or resistance bas ed exercise; recommends weight loss for those overweight or obese; and, advises participation in osteoarthritis self management programs, including psychosocial interventions, physical therapy and, instruction in the use of thermal agents, bracing, and wal king aids. The use of nutraceuticals (i.e., dietary supplements) for chronic pain comprises a new area of research. Given the risk of side effects from medications typically employed for osteoarthritis pain and heightened consumer interest in nutritional s upplement use (Gahche et al., 2011) maintaining adequate vitamin D levels may provide a low risk strategy to reduce osteoarthritis pain Furthermore, vitamin D is inexpensive and readily available. The aim of this study was to examine the interactive infl uence of vitamin D level and obesity on self reported knee pain and functional performance measures in a sample of older adults with symptomatic osteoarthritis. We hypothesized 1) obesity will be associated with decreasing vitamin D levels and greater oste oarthritis related pain and dysfunction; and 2) there will be a significant interaction between vitamin D level and obesity, such that obese individuals with low vitamin D levels will have the greatest osteoarthritis pain and dysfunction. If higher serum l evels of vitamin D can be shown to reduce pain and decrease functional limitation in older adults with knee osteoarthritis, it would provide an alternate strategy in the clinical armamentarium to prevent or slow the progression of osteoarthritis related di sability. Methods Participants and Procedures The current study is part of a larger ongoing project that aims to enhance the understanding of racial/ethnic differences in pain and limitations among individuals with

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76 osteoarthritic disease (Understanding P ain and Limitations in OsteoArthritic Disease, UPLOAD). The UPLOAD study enrolls participants at the University of Florida and the University of Alabama at Birmingham. Participants were recruited via posted fliers, radio and print media advertisements, ort hopedic clinic recruitment, and word of mouth referral. All study procedures were reviewed and approved by the University of Florida and University of Alabama Birmingham Institutional Review Boards. Participants provided written informed consent and were c ompensated for their participation. The individuals described in the current study were recruited at both study sites between January, 2010 and February, 2013. The measures and procedures described below are limited to those involved in the current study. Participants were provided a description of the protocol and screened for eligibility by recruitment staff via telephone. Criteria for inclusion into the study were as follows: 1) between 45 and 85 years of age; 2) unilateral or bilateral symptomatic knee osteoarthritis based upon American College of Rheumatology criteria (Altman et al., 1986) confirmed by radiographic examination; and, 3) availability to complete the two session protocol. Individuals were excluded from participation if they met any of the following criteria: 1) prosthetic knee replacement or other clinically significant surgery to the affected knee; 2) uncontrolled hypertension, heart failure, or history of acute myocardial infarction; 3) peripheral neuropathy; 4) systemic rheumatic disord ers including rheumatoid arthritis, systemic lupus erythematosus, and fibromyalgia; 5) daily (Folstein et al., 1975) ; 7) excessive anxiety regarding protocol procedures (e.g., blood draws or controlled noxious stimulation procedures); and, 8) hospitalization within the

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77 preceding year for psychiatric illness. Eligible participants were scheduled for an appointment at the clinical research unit. Health a ssessment s ession (HAS). Prior to the HAS, individuals completed the study questionnaires described below. The following demographic, socioeconomic and health data were obtained: age, self reported race, educational attainment, annual household income, and health history. Addition ally, participants completed questionnaires in which they rated the severity of knee osteoarthritis symptoms. A nthropometric data and vital signs were measured at the beginning of the HAS session. Cognitive capacity was assessed using the MMSE. The study r heumatologist or nurse practitioner 1) reviewed all current prescribed and over the counter medications, as well as complementary and alternative strategies used to promote health and reduce pain; and, 2) performed a bilateral knee joint evaluation and, u s ing the American College of Rheumatology criteria for identified was identified and classified as the index knee (Altman et al., 1986) Following these interventions, elig ible participants completed an assessment of lower extremity function and underwent radiographic examination of the knees. Measures Race. report regarding ethnicity and racial background using response options consistent with t he 2000 U.S. census survey. In view of the study objectives, the primary groups enrolled self identified as b lack/African American or non Hispanic white Weight and Body Mass Index. Using the same scale for all participants, weight was measured to the near est 0.1 kilogram (kg), without shoes. Height was measured to the nearest 0.1 centimeter (cm) using a wall mounted stadiometer which was calibrated daily

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78 with a standardized measuring rod. Body mass index (BMI) was calculated using SPSS syntax (weight in kg /height in m 2 ). A BMI of 25 to 29.9 kg/m 2 denotes overweight, while a BMI 2 indicates obesity, and a BMI > 40 denotes extreme obesity (C.L. Ogden & Carroll, 2010; Moyer & Force, 2012) Knee r adiographs. t symptomatic/ painful knee was designated as the index knee. However, if the participant had prosthetic knee replacement or other clinically significant surgery to the most painful knee, the non surgical knee was designated as the index knee, provided the participant had bilateral knee pain. Two radiographs were obtained: 1) an anterior posterior radiograph of both knees with the participant standing; and 2) a lateral view of the index knee in fixed flexion. The study rheumatologist at each site graded the radiographs using Kellgren Lawrence (KL) criteria (KL scores range 0 4). Kellgren Lawrence scores of 2 4 were used to designate mild, moderate, and severe knee osteoarthritis. Vitamin D assay. Blood was collected from an antecubital vein at the onset of the sensory testing session. Following collection and processing, plasma was stored in a 80 degree freezer. Vitamin D analysis was performed by high performance liquid chromatography (total 25 h ydroxyvitamin D = 25(OH)D2 plus 25(OH)D3) within six months of the date of collection. Results of vitamin D testing were shared with result with their primary care provide r. Short Physical Performance Battery (SPPB ). The SPPB assesses lower extremity function with balance, chair, and walking tests (Guralnik et al., 1994) Specifically, participants were asked to: 1) stand with their feet together in the side by

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79 side, semi tandem, and tandem positions; 2) rise from a seated position in a chair and return to a seated position five times; and 3) walk a 4 meter course two times. If the participant did not feel it was safe to perform the activity, they received a score reflecti ng non participation. Based on their performance in each category, they received a score of 0 4 in each of the categories (total score 0 12). In this case, a lower score indicates worse function and greater likelihood of disability (Guralnik, Ferrucci, Sim onsick, Salive, & Wallace, 1995) Western Ontario and McMaster Universities i ndex of O steoarthritis (WOMAC). The WOMAC is frequently used in clinical and research settings to assess report of knee and hip osteoarthritis sy mptoms over the preceding 48 hours (Bellamy et al., 1988) The WOMAC includes 24 items, and can be divided into subscales of pain, stiffness, and physical function. The total WOMAC score was used in this analysis (range 0 96). Higher scores indicate increa sed osteoarthritis phenotypic symptoms. The total WOMAC score does not demarcate between mild, moderate, and severe osteoarthritis. However, previous researchers have used the cutoff of 39 (based on a 100 point scale) to denote knee osteoarthritis warranti ng arthroplasty or joint replacement surgery (Hawker et al., 2000; Ackerman, 2009) Research in our lab has found significance for a WOMAC cut off score of 33 demarcating worsening osteoarthritis symptoms (based on the 96 point scale) (C. D. King et al., 2013, accepted) High construct validity and test retest reliability has been found in paper and computerized versions of the WOMAC for the overall measure and its respective subscales (Bellamy et al., 1988; Theiler et al., 2002)

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80 Knee Injury and Osteoarth ritis Outcome Score, Physical Function Short Form (KOOS PS). The KOOS PS (Roos & Lohmander, 2003) is a 7 item questionnaire that assesses physical function in daily living for those with knee osteoarthritis over the last week Scores range from 0 100, with higher scores indicating increased pain (Perruccio et al., 2008) The WOMAC and KOOS PS are the most common quantitative measures of pain and functional status for knee osteoarthritis. Center for E pidemiological S tudies D epression scale (CES D). The CES D is a 20 item self report tool that measures symptoms of depression including depressed mood, guilt/worthlessness, helplessness/hopelessness, psychomotor retardation, loss of appetite and sleep disturbance (Radloff, 1977) The total score of the CES D (ran ge 0 depressive symptomatology. The validity and internal consistency of the CES D in the cli nically relevant depressive symptoms (Beekman et al., 1997) Data Analysis The study sample consisted of 305 community dwelling older adults with chronic knee osteoarthritis pain. Vitamin D levels were not available for 78 participants at the time of analyses (unable to collect blood during the protocol or the blood sample not ye t been collected or analyzed). One participant was undergoing prescription vitamin D correction, resulting in a vitamin D level more than 2.5 standard deviations above the group mean. Excluding these participants from data analysis resulted in a sample siz e of 226 participants. All participants provided complete demographic data (e.g., sex, age, ethnicity/race); however, a small portion of missing data existed for the KOOS PS (<1%) and the SPPB

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81 functional measures (7%), and radiographic results (6%). Data appeared to be missing at random for the KOOS PS and the SPPB. Some radiographs (n=14) had not yet been evaluated by the study rheumatologist. Rather than exclude from analysis the participants for whom data was missing, a simple data imputation method wa s completed using the macro for Hot Deck imputation (Myers, 2011) This data imputation method is well validated and accepted in the statistical community, and resulted in complete study data for all of the 226 study participants included in data analysis. A ll data analysis was performed using SPSS, version 21 (IBM, Chicago, IL). The level of significance was set at p < .05. Bivariate relationships among clinical measures of knee osteoarthritis (WOMAC, KOOS PS, SPPB), as well as other continuously measure d variables such Serum 25(OH)D levels (hereafter referred to as vitamin D level) were examined as a continuous variable. To assess the effects of obesity, BMI was dichotomized su ch that BMI values < 30 kg/m 2 indicated normal weight to overweight status and BMI values kg/m 2 denote obesity to extreme obesity. Variables demonstrating significant bivariate correlations with vitamin D were controlled for in further analyses, inclu ding age, race, vitamin D supplementation, and CES D score. A series of hierarchical multiple regressions were completed to test the main effects of obesity and low levels of vitamin D as well as the ability of obesity to moderate the effect of decreased v itamin D level on osteoarthritis related outcomes (WOMAC, KOOS PS, SPPB function score and pain rating). Per the recommendations of Aiken and West (Aiken & West, 1991) for conducting tests of moderation with a categorical

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82 variable (obesity), vitamin D leve ls were centered by subtracting the sample mean from each value and a cross product interaction term was created by multiplying centered vitamin D levels with the binary obesity variable (i.e., obese versus non obese). Subtracting the mean vitamin D level for the sample from each participant's score resulted in centered vitamin D variable with a mean of zero. Thus, in subsequent analysis, the beta weight for obesity represents the difference between obese and non obese participants at the zero centered mean vitamin D level for the sample. In adjusted analyses, control variables were entered into the model (Step 1) before entering the centered vitamin D level and binary obesity main effects (Step 2) followed by the interaction term (Step 3). Results The study was comprised predominantly of women (66%) and the average age was 57.1 years (SD = 7.6) with a range of 45 85 years. The racial composition of the reporting as black/African American. Tw O white/Caucasian group for data analysis (hereafter referred to as black and white, resp ectively). The average BMI for the entire sample was 31.2 kg/m 2 (SD = 7.2) The mean vitamin D level was 23.2 ng/mL (SD = 9.4) with a range from 3.7 48.0 ng/mL (the excluded participant undergoing prescription vitamin D replacement had a level of 74.9 ng /mL). Of the the participants (55.8%) were not taking any supplemental vitamin D; while 44.2% were taking some form of vitamin D typically less than 1,000 IU per day in a multivita min. Table 4 1 summarizes the means for key study variables for obese and non obese individuals.

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83 Hypothesis 1. Obesity will be associated with lower vitamin D levels and greater osteoarthritis related pain and dysfunction. Obese individuals had a mean vitamin D level of 19.9 ng/mL compared to 26.4 ng/mL for non obese individuals. Examining the bivariate relationship of key study variables, lower levels of vitamin D were associated with greater self report of pain and dysfunc tion on the WOMAC and KOOS PS as well as greater pain ratings after performing the components of the SPPB functional measures. In contrast, obese and non obese individuals had minimally varying scores on the SPPB total score. Pearson correlations among ke y study variables for obese and non obese individuals are shown in Table 4 2. Hypothesis 2. There will be a significant interaction between vitamin D level and obesity, such that obese individuals with inadequate vitamin D levels will have the greatest os teoarthritis pain and dysfunction. In a hierarchical regression model, obesity, but not vitamin D level, was significant ly associated with WO MAC total and KOOS PS scores (Table s 4 3 4 4 ). Regarding the SPPB, there was a significant interaction between v itamin D and obesity in relation to the SPPB total score (Table 4 5 ). However, when we probed this interaction separately for obese and non obese individuals, the association between vitamin D level and SPPB total score were found to be non significant (Ta ble s 4 6, 4 7 ). Although the non significant relationship goes in the hypothesized direction for obese individuals, for non obese individuals the direction of relationship between vitamin D and SPPB total score is counterintuitive. In other words, for non obese individuals, as vitamin D levels increase, the SPPB scores go down (worsening function). The opposing direction of the relationship between vitamin D level and obesity and SPPB score in non obese and

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84 obese individuals could explain the significant i nteraction, indicating a spurious finding. If we examine the probed model without controlling for covariates, decreasing levels of p = .04, data not shown), and the relations hip goes in the hypothesized direction. Finally, when we examine the participant pain ratings associated with each SPPB component, there is a main effect for vitamin D on pain ratings for each component but a non significant interaction (data not shown). D iscussion Obesity was associated with low levels of vitamin D and greater osteoarthritis pain and dysfunction (hypotheses 1). However, contrary to hypothesis 2 lower vitamin D levels did not demonstrate either a main or interaction effect on self reported osteoarthritis pain or dysfunction in a hierarchical regression model. For functional performance measures (SPPB) there was a significant interaction effect between vitamin D level and obesity on SPPB total score, however this finding subsequently bec ame non significant when probed, indicating the finding likely occurred by chance. The mean BMI for obese participants was 3 7 kg/m 2 and the mean BMI for non obese participants was 25.5 kg/m 2 (overweight); thus, it is possible there was not enough difference b etween the two groups to demonstrate significant differences in outcomes. In future analysis, it may be helpful to parse BMI as a categorical variable (normal BMI < 25; overweight BMI 25.1 29.9; obese BMI 30 34.9; and, extreme obesity Previous research (Lane et al., 1999) employed a vitamin D threshold of < 30 ng/mL to demonstrate differences in pain and functional measures of knee osteoarthritis. On the whole, vitamin D levels in our sample reflected vitamin D insufficiency However, for non obese individuals there was greater variance in vitamin D levels. Since obesity implies lower vitamin D levels with less variance, it is possible

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85 this impacted our overall findings. Perhaps higher vitamin D levels are needed to demonstrate differe nces in osteoarthritis related pain and functional performance measures. E xperts in vitamin D research (Heaney, 2003; Holick, 2003; Vieth, 2011) suggest vitamin D levels should be at least 30 ng/ml, while others advocate levels between 40 70 ng/mL are idea l (Cannell & Hollis, 2008) There is compelling evidence on the protective role of adequate vitamin D in preserving muscle strength in older adults slowing the rate of bone loss, and reducing falls and fractures (Michael et al., 2010; Muir & Montero Oda sso, 2011; Bischoff Ferrari et al., 2012) Vitamin D level also correlates with frailty, mobility limitation, and disability (Ensrud et al., 2010; Houston et al., 2012) In fact, despite longer life expectancy, the aging baby boomers (those born between 19 46 and 1964) experience more chronic disease and disability and rate their overall health lower compared to previous generations (D. E. King, Matheson, Chirina, Shankar, & Broman Fulks, 2013; National Research Council, 2013) which may be related to increas ed prevalence of obesity and chronically low vitamin D levels (Ginde, Scragg, Schwartz, & Camargo, 2009; de Boer et al., 2012) Hunt and colleagues (Hunt, Walsh, Voegeli, & Roberts, 2010) suggest reductions in vitamin D commonly seen in aging individuals are associated with a pro inflammatory state conducive to chronic disease and frailty. Sufficient levels of cellular vitamin D have a protective effect on cell function and are believed to reduce inflammation (Holick, 2007; McCann & Ames, 2008) Inflammat ory processes contribute to increased pain sensitivity among individuals with osteoarthritis (Hunter et al., 2008; Lee et al., 2011) Low levels of vitamin D have been associated with chronic pain in women, but not men,

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86 leading researchers to hypothesize b iologically active vitamin D influences estrogen activity and may contribute to gender differences in chronic pain (Hicks et al., 2008; Atherton et al., 2009) In a recent randomized controlled clinical trial, McAlindon and colleagues (T. McAlindon et al. 2013) found vitamin D supplementation to levels of 36 ng/mL did not improve WOMAC pain severity score or slow knee cartilage volume loss over a period of two years. However, only 61% of the vitamin D treatment group reached the target vitamin D level. Th e researchers assessed physical function with a time 20 meter walk and chair rise test with results approaching significance for the vitamin D treatment group ( p = .07). In a non randomized trial, Huang and colleagues (Huang, Shah, Long, Crankshaw, & Tangp richa, 2012) found vitamin D supplementation in veterans resulted in significant decreases in pain level, number of pain locations, and use of pain medication as well as improvements in sleep and health related quality of life. Similarly, in a nationally r epresentative sample in England, Hirani (Hirani, 2012) found poor vitamin D status was associated with moderate to severe pain. Previous research in our lab (T. L. Glover et al., 2012) has established a significant relationship between vitamin D, race, a nd experimental pain sensitivity in black Americans with knee osteoarthritis. Black Americans are more likely to have low levels of vitamin D due to increased melanin slowing UVB synthesis of vitamin D blocking effects (Nesby O'Dell et al., 2002; Ginde, Liu, et al., 2009) However, in the current analysis, there were not a sufficient number of black participants with a BMI < 30 kg/m 2 (Cynthia L Ogden, 2009) For black participants, the mean vit amin D level was 19.8 ng/mL

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87 compared to 27.1 ng/mL for whites ( 2 = 165.1, p = .33). Furthermore, 16% of black participants had vitamin D levels consistent with severe deficiency, compared to only 4% of whites. Due to widespread inadequate vitamin levels a mong black Americans, recruiting black participants with adequate vitamin D levels represents a research challenge and a health disparity that may require changes in vitamin D screening guidelines to effectively address. Some important limitations of this study need to be considered when interpreting the results and will need to be addressed in future research. The cross sectional study design does not allow us to determine causality between vitamin D level and osteoarthritis related outcomes. It is possibl e that obesity precedes decreased vitamin D levels and thus influences worsening functional performance. However, for many older adults, behavioral changes which lead to sustained weight loss can be challenging. Optimizing vitamin D status with supplement ation is inexpensive and without serious side effects and may result in improved function for obese individuals with osteoarthritis related limitations. Despite the limitations, the current study highlights a relationship between obesity, low levels of v itamin D, and knee osteoarthritis related pain and dysfunction that deserves further study. Geriatric assessment and treatment focuses on preserving functional health and quality of life (Rockwood et al., 1998; Elsawy & Higgins, 2011) Vitamin D repletion in obese older adults may help preserve function and reduce chronic pain. Research trials on vitamin D and health outcomes must strive to enroll adequate numbers of racially diverse populations to allow further understanding of the role vitamin D plays in achieving health equity. Screening for vitamin D deficiency

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88 among obese Americans may be warranted especially those with chronic knee osteoarthritis pain.

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89 Table 4 1. Participant characteristics. Total Non obese Obese Sample BMI < 30 (n=226) (n = 114) (n = 112) p Age (years) 57.1(7.6) 57(8.1) 57.2(7.2) ns Sex ns Female 150(66%) 73(64%) 77(69%) Male 76(34%) 41(36%) 35(31%) Race .02* Black/African American 120(53%) 52(46%) 68(61%) White/Caucasian 106 (47%) 62(54%) 44(39%) Body Mass Index ( kg/m 2 ) 31.2(7.2) 25.5(2.7) 37(5.5) < .01 Radiographic osteoarthritis .01* No evidence KL I 83(37%) 51(45%) 32(29%) KL II KL IV 143(63%) 63(55%) 80(71%) Vitamin D Total (ng/mL) 23.2(9.4) 26.4(9.1) 19.9(8.6) < .01 Vitamin D Supplementation 100(44%) 53(47%) 47(42%) ns WOMAC Total Score 33.9(20.3) 29.5(19.4) 38.5(20.3) < .01 KOOS PS Score 44.5(23.9) 39.1(22.6) 49.9(24) < .01 SPPB Total Score 9.8(1.8) 10(1.9) 9.6(1.8) ns SPPB Pain Ratings 16.9(22.1) 15.1(20.2) 18.7(23.9) ns CES D Total 9.5(7.3) 9(6.7) 10.1(7.8) ns Data presented as means (SD) or n (%) ; *Race 2 = 5.17; Radiographic osteoarthritis 2 = 6.35; ns non significant difference between non obese and obese individuals; BMI Body mass index; KL Kellgren Lawrence osteoarthritis grading scale ; Vitamin D total total 25 hydroxyvitamin D = 25(OH)D2 plus 25(OH)D3 ; WOMAC Western Ontario and McMaster Universities i ndex of Osteoarth ritis ; KOOS PS Knee Injury and Osteoarthritis Outcome Score, Physical Function ; SPPB Short Physical Performance Battery ; SPPB Pain Ratings averaged across SPPB tasks on a 0 100 numerical rating scale ; CES D Center for Epidemiological Studies Depression s cale

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90 Table 4 2. Pearson correlations of key study variables Variable 1 2 3 4 5 6 7 8 9 10 11 12 1. Age ____ 2. Sex .05 ____ 3. Race .26** .01 ____ 4. BMI .09 .10 .15* ____ 5. Radiographic OA .07 .08 .00 .17** ____ 6. Vitamin D Total .21** .09 .39** .38** .11 ____ 7. Taking Vitamin D .20** .24** .18** .10 .04 .46** ____ 8. WOMAC .15* .02 .29** .29** .11 .27** .15* ____ 9. KOOS PS .14* .03 .21** .32** .18** .26** .14* .90** ____ 10. SPPB Total .05 .08 .31** .17** .12 .05 .00 .46** .38** ____ 11. SPPB Pain .12 .01 .31** .19** .04 .22** .08 .58** .50** .39** ____ 12. CES D .24** .03 .15* .03 .01 .13* .15* .38** .32** .23** .24** ____ Note: *= p < .05, **= p < .01; BMI = body mass index ( kg/m 2 ) ; Radiographic OA based on Kellgren Lawrence osteoarthritis grading scale; Vitamin D total total 25 hydroxyvitamin D = 25(OH)D2 plus 25(OH)D3; WOMAC Western Ontario and McMaster Universities i ndex of Osteoarthritis; KOOS PS Knee Injury and Osteoarth ritis Outcome Score, Physical Function Short Form; SPPB Short Physical Performance Battery; SPPB Pain ratings averaged across balance, chair and gait on a 0 100 numerical rating scale; C ES D Center for Epidemiological Studies Depression s cale.

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91 Table 4 3. Significant main effect for obesity on WOMAC total scores. B SE B R 2 R 2 F Step 1 20 .20 14.04 A ge Race Taking Vitamin D CES D .004 9.19 2.40 .94 .17 2.56 2.54 .17 .001 .23** .95 .34** Step 2 .2 4 .03 4.67 Vitamin D Level a .22 .16 .10 Obesity b 5.52 2.59 .14* Step 3 .2 4 .00 .13 Vitamin D x Obesity .10 .28 .07 = p < 0.05, ** = p < 0.01; a V itamin D level (ng/mL) centered cross product interaction term was created by subtracting the sample mean from each value and multiplying the centered vitamin D levels with the binary obesity variable (i.e., obese versus non obese); b Coded bod y mass index ( kg/m 2 ) variable (1 = BMI <

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92 Table 4 4 Significant main effect for obesity on KOOS PS scores. B SE B R 2 R 2 F Step 1 .1 3 .13 8.39 Age Race Taking Vitamin D CES D .07 6.97 2.93 .93 .21 3.14 3.11 .21 .02 .15* .06 .28** Step 2 .1 8 .04 5.82 Vitamin D Level a .33 .20 .13 Obesity b 7.15 3.16 .15* Step 3 .1 8 .00 .00 Vitamin D x Obesity .02 .34 .01 = p < 0.05, ** = p < 0.01; a V itamin D level (ng/mL) centered cross product interaction term was created by subtracting the sample mean from each value and multiplying the centered vitamin D levels with the binary obesity variable (i.e., obese versus non obese); b Coded body mass index ( kg/m 2 ) variab le (1 = BMI < 30

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93 Table 4 5 Significant interaction effect for obesity and vitamin D level on SPPB scores. B SE B R 2 R 2 F Step 1 .1 6 .16 10.88 Age Race Taking Vitamin D CES D .04 1.21 .22 .06 .02 .24 .24 .02 .18** .33** .06 .24** Step 2 .1 7 .01 .93 Vitamin D Level a .02 .02 .10 Obesity b .24 .24 .07 Step 3 .1 9 .02 4.74 Vitamin D x Obesity .06 .03 .44* = p < 0.05, ** = p < 0.01; a V itamin D level (ng/mL) centered cross product interaction term was created by subtracting the sample mean from each value and multiplying the centered vitamin D levels with the binary obesity variable (i.e., obese versus non obese); b Coded body mass index ( kg/m 2 ) variab le (1 = BMI < 30

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94 Table 4 6 Probed interaction effect for non obese participants and vitamin D level on SPPB scores. B SE B R 2 R 2 F Step 1 .1 6 .16 5.24 Age Race Taking Vitamin D CES D .04 1.06 .70 .06 .02 .34 .34 .03 .17 .29** .19* .23* Step 2 .1 8 .02 2.70 Vitamin D Level a .04 .02 .17 = p < 0.05, ** = p < 0.01; a V itamin D level (ng/mL) centered cross product interaction term was created by subtracting the sample mean from each value and multiplying the centered vitamin D levels with the binary obesity variable (i.e., obese versus non obese).

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95 Table 4 7 Probed interaction effect for obese pa rticipants and vitamin D level on SPPB scores. B SE B R 2 R 2 F Step 1 .1 9 .19 6.35 Age Race Taking Vitamin D CES D .04 1.29 .27 .06 .02 .34 .33 .02 .17 .35** .08 .24* Step 2 .1 9 .00 .03 Vitamin D Level a .004 .02 .02 = p < 0.05, ** = p < 0.01; a V itamin D level (ng/mL) centered cross product interaction term was created by subtracting the sample mean from each value and multiplying the centered vitamin D levels with the binary obesity variable (i.e., obese versus non obese).

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96 CHAPTER 5 CONCLUSIONS AND N URSING IMPLICATIONS This dissertation research examined the relationship between vitamin D level, race, obesity, and clinical pain and functional assessments of osteoarthritis pain utilizing an experimental pain testing model in older adults. Specifically, the role of vitamin D inadequacy as it relates to disparities in knee osteoarthritis pain for black Americans was explored. A review of the state of the science on health disparities in osteoarthritis pain related to vitamin D inadequacy was conducted. To date, clinical trials on this topic have been sparse and have yielded inconsistent results. Additionally, most studies have not enrolled adequate numbers of black Americans to make meaningful comparisons. Well designed intervention trials that enroll an a dequate number of ethnically diverse older adults are warranted. In the review chapter addressing widespread vitamin D inadequacy and osteoarthritis related health disparities for black Americans, the supposition that blacks may have different physiologic al needs for vitamin D is proposed in relation to markers of skeletal health. Black Americans, on average, have greater skeletal mass compared to whites, and thus, are less likely to have diseases such as osteoporosis. Also, blacks are not as prone to sec ondary hyperparathyroidism and urinary excretion of calcium related to low levels of vitamin D (Cosman et al., 2007; Wright et al., 2011) However, Luxwolda and colleagues (Luxwolda et al., 2012) demonstrated that traditionally living African tribes have m uch higher naturally occurring vitamin D levels compared to black Americans. Furthermore, research has amply demonstrated that the vitamin D endocrine system is important to systemic health and chronic vitamin D inadequacy is hypothesized to contribute to disparities in some cancers and immune disorders for

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97 black Americans (Grant & Peiris, 2010, 2012) Adequate levels of vitamin D function as a total system regulator that decreases metabolic and immunologic burden. In the first data driven manuscript, using a mediation model, our cross sectional study demonstrated older black Americans had significantly lower levels of vitamin D compared to whites, demonstrated greater clinical pain, and showed greater sensitivity to heat and mechanical pain. Low levels of v itamin D predicted increased experimental pain sensitivity, but not self reported clinical pain. Race group differences in experimental pain were mediated by differences in vitamin D levels, suggesting that vitamin D deficiency may be a risk factor for inc reased knee osteoarthritis pain in older black Americans (T. L. Glover et al., 2012) In the second data driven chapter, we focused on vitamin D level and obesity in relationship to clinical and functional measures of symptomatic knee osteoarthritis pain. We hypothesized that obesity would be associated with decreased vitamin D levels and greater osteoarthritis related pain and dysfunction; and 2) there will be a significant interaction between vitamin D level and obesity, such that obese individuals with low vitamin D levels will have the greatest osteoarthritis pain and dysfunction. Alth ough the findings did not support out second hypothesis, the topic warrants further research and suggestions were made for future research strategies and analytic approaches. The results of this dissertation contribute to the expanding field of vitamin D research, especially the relationship between vitamin D level and chronic osteoarthritis pain and health disparities in osteoarthritis for older black Americans. Taken together, these findings suggest 1) vitamin D deficiency should be assessed and treated in older black Americans, who are at greater risk for the most severe levels of deficiency due to

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98 dark skin; 2) r ace group differences in experimental pain were mediated by differences in vitamin D levels, suggesting that vitamin D deficiency may be a risk factor for increased knee osteoarthritis pain in older black Americans; and 3) the combination of low levels of vitamin D and obesity are correlated with a worsening osteoarthritis phenotype that warrants further study. Limitations The main limitation o f this research is the cross sectional design which does not allow us to establish a causal relationship between vitamin D inadequacy and chronic knee osteoarthritis pain. It is possible that knee osteoarthritis pain and dysfunction contributes to low leve ls of vitamin by decreasing outdoor activities, and hence, limiting the opportunity to synthesize vitamin D. I was fortunate to be able to append my research interests onto a large research trial examining ethnic differences in knee osteoarthritis pain, ho wever, the UPLOAD study was not designed to answer my dissertation research questions. A strength of the UPLOAD study was the large sample size and the near equal proportion of older black and white adults. In the UPLOAD protocol, a medication review was performed, including whether the participant was taking vitamin D. However, nutritional sources of vitamin D and daily amount of sunlight exposure were not assessed. In future research studies, it would be useful to assess these variables as well as, sk in tone, muscle strength, and fall history in relation to vitamin D level. Implications for Nursing As the United States population is aging, the prevalence of pain is increasing. An estimated 100 million adults live with chronic pain. The U.S. spends upwards of $635 billion on pain each year more than the costs for cancer, heart disease, and diabetes

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99 combined (Pizzo & Clark, 2012) Disparities in the diagnosis and clinical management of painful conditions for racial and ethnic minorities are well documented (Anderson et al., 2009) In the most recent UPLOAD analysis, 75.2% of the participants (n = 22 6) met the criteria for vitamin D inadequacy (< 30 ng/mL). If we use the more conservative cut point of 20 ng/mL, 38.1% are deficient. Finally, nine percent of the sample has severe deficiency, defined by a vitamin D < 10ng/mL. Black participants have aver age vitamin D levels one standard deviation below the mean vitamin D levels for whites (T. L. Glover et al., 2012) and are more likely to have severe deficiency. This finding has remained consistent since the onset of data collection. Although we may not h ave a complete understanding of the relationship of low levels of vitamin D and chronic pain, there is consistent evidence suggesting we should clinically assess for severe vitamin D deficiency in older black Americans with chronic pain, muscle weakness, o r frequent falls. Approximately 15% percent of our participants report they do not have access to a primary health care provider and many more have inadequate access to health care services. We perform vitamin D lab analysis once every six months and share the vitamin D lab results with each participant. Additionally, we call those with severe vitamin D deficiency. Although it is not part of this dissertation research, it would be interesting to follow up with those who have severe deficiency and are withou t access to health care. The increasing use of nurse practitioners is cited as an essential element to increasing access and improving health care under health care reform. Many organizations have called for increased autonomy of nurse practitioners and re moval of

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100 practice obstacles (Institute on Medicine, 2011b; Florida Tax Watch, 2012) Nurse practitioners are aptly suited to manage chronic conditions like knee osteoarthritis and vitamin D deficiency. Future Directions An intervention trial examining vita min D inadequacy in black and white older adults with osteoarthritis would represent a novel research study and one that is needed to begin to formulate evidence based practice recommendations for vitamin D screening and supplementation. Dependent variable s must include self report measures as well as functional assessments of osteoarthritis related pain and dysfunction. Body mass index and race (skin tone) are important covariates in studies of vitamin D and osteoarthritis symptoms which need to be address ed in future studies. Assessment of muscle strength and fall history should be included. Having explored my research questions in a cross sectional model, the next logical step is to test my hypotheses in a randomized controlled clinical intervention t rial on vitamin D supplementation in older black and white adults with symptomatic knee osteoarthritis. The goal of this research would be to further test the relationship between race and obesity in an osteoarthritis model while having the opportunity to evaluate the effects of vitamin D supplementation. More specifically, the goal would be to investigate vitamin D supplementation as strategy to reduce knee osteoarthritis pain and dysfunction and address disparities in knee osteoarthritis pain and dysfunct ion experienced by black Americans. The use of an experimental pain testing model would allow standardization of evoked pain stimuli. Chronic low levels of vitamin D found in black Americans are hypothesized to be an explanatory mechanism for racial dispar ities in knee osteoarthritis.

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121 BIOGRAPHICAL SKETCH Toni Lynn Glover was born in Chicago, Illinois to Donald Lee and Ann Marie Glover. She has two older sisters, Terry Lee Sullivan and Lori Ann Jannotte. The family moved to Florida in 1972. Toni attended Edison Community College in Fort Myers and subsequently moved to Gainesville to attend the Universit y of Florida (UF) graduating with a b a nthropology in 1980 In 1986, she again graduated from UF with a m p olitical s cience ( p ublic a dministration) and a Certificate in g erontology. An interest in serving older adults has been a consistent interest throughout her education and career. She worked at the Mid Florida Area Agency on Aging for five years before deciding to return to school to become a nurse. After graduating from Santa Fe Community College in 1993, she work ed as a staff nurse at Shands Hospital in the Bone Marrow Transplant Unit and Endoscopy unit for seven years (1993 2000) In 2000, she accepted a position as a research nurse and study coordinator in a pain research lab. During her 13 year tenure with wh at is now known as the Pain Research and Intervention Center of Excellence (PRICE) she returned to UF to earn her m (2009) a nd was ANCC board certified as a Family Nurse Practitioner. In 2010, she entered the PhD program at UF : as a graduate student, Toni received the prestigious John A. Hartford Foundation Building Academic Geriatric Nursing Capacity scholarship, along with additional support from the Mayday Fund. Her research interests included pain in older adults, the relations hip of low levels of vitamin D to knee osteoarthritis pain, and the role of chronic vitamin D inadequacy in contributing to health care disparities for older black Americans. After graduation, she plans to pursue an academic faculty position to continue h er program of research.