Hypoxia During Sleep and the Risk of Falls and Fractures in Older Men: The Osteoporotic Fractures in Men Sleep Study Jane A. Cauley, DrPH,a Terri L. Blackwell, MA,b Susan Redline, MD, MPH,c Kristine E. Ensrud, MD, MPH,d,e Sonia Ancoli-Israel, PhD,f Howard A. Fink, MD, MPH,d,e,g Eric S. Orwoll, MD,h and Katie L. Stone, PhD,b for the Osteoporotic Fractures in Men Study
OBJECTIVES: To test the hypothesis that low arterial oxygen saturation during sleep is associated with a greater risk of falls and fractures. DESIGN: Prospective cohort study. SETTING: Six U.S. clinical centers. PARTICIPANTS: Men aged 67 and older (N = 2,911). MEASUREMENTS: The primary exposure measure was percentage of sleep time with arterial oxygen saturation less than 90% measured using polysomnography. The main outcome measures were incident falls within 1 year and incident nonspine fractures over an average follow-up of 6.8 years. RESULTS: Men with 10% or more of sleep time at an arterial oxygen saturation of less than 90% were older, reported more comorbidities, had poorer physical function, and were more likely to have sleep disordered breathing than men with less than 10% sleep time at an arterial oxygen saturation of less than 90%. After multivariate adjustment, men with 10% or more of sleep time with arterial oxygen saturation of less than 90% had a greater risk of having one or more falls (relative risk (RR) = 1.25, 95% confidence interval (CI) = 1.04–1.51) and two or more falls (RR = 1.43, 95% CI = 1.06–1.92) than those with less than 10% of sleep time with less than 90% arterial oxygen saturation. Men with greater percentage of sleep time with arterial oxygen saturation less than 90% had a 30% to 40% greater risk of nonspine fracture than those
From the aUniversity of Pittsburgh, Pittsburgh, Pennsylvania; bCalifornia Pacific Medical Center, San Francisco, California; cDepartment of Medicine, Brigham and Women’s Hospital and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; d University of Minnesota, eVeterans Affairs Healthcare System, Minneapolis, Minnesota; fUniversity of California at San Diego, San Diego, California; gGeriatric Research, Education and Clinical Center, Veterans Affairs Healthcare System, Minneapolis, Minnesota; and h Oregon Health & Science University, Portland, Oregon. Address correspondence to Jane A. Cauley, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 Desoto Street, Crabtree A510, Pittsburgh, PA 15261. E-mail: [email protected] DOI: 10.1111/jgs.13069
JAGS 62:1853–1859, 2014 © 2014, Copyright the Authors Journal compilation © 2014, The American Geriatrics Society
with normal nocturnal oxygen saturation in models adjusting for sleep disordered breathing. CONCLUSION: Hypoxia during sleep may be a risk factor for falls and fractures in older men. Interventions aimed at decreasing nocturnal hypoxia may decrease falls and fractures. J Am Geriatr Soc 62:1853–1859, 2014.
Key words: nocturnal hypoxia; fractures; falls; mortality; older men
S
leep disordered breathing (SDB) is a common disorder in older adults, affecting up to 60%.1 Intermittent hypoxia is the hallmark of obstructive sleep apnea (OSA) and has been linked to a number of adverse cardiovascular consequences.2–4 Hypoxia has also been linked to poor physical function.5 To the knowledge of the authors of the current study, no previous study has linked nocturnal hypoxia to the risk of fractures and falls. A central question is the role of overnight hypoxemia as opposed to SDB on falls and fractures. Hypoxic stress could influence bone formation6 by itself in addition to the effect of SDB. The objective of the current analysis was to test the hypothesis that nocturnal hypoxia increases the risk of falls and fractures and that this association would be independent of SDB. This hypothesis was tested in a multicenter cohort of older men (Outcomes of Sleep Disorders in Older Men: Study of Osteoporotic Fractures in Men (MrOS) Sleep Study).
METHODS Participants From 2000 through 2002, 5,994 men aged 65 and older were recruited from population-based listings in Birmingham, Alabama; Minneapolis, Minnesota; Palo Alto, California; the Monongahela Valley near Pittsburgh, Pennsylvania, Pennsylvania; Portland, Oregon; and San Diego,
0002-8614/14/$15.00
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California.7,8 Men with a history of bilateral hip replacement and men who were unable to walk without the assistance of another person were excluded. From 2003 through 2005, the MrOS Sleep Study recruited 3,135 (105% of recruitment goal) participants for a comprehensive sleep assessment. Of the 2,860 who did not participate in the MrOS sleep examination, 1,997 declined participation, 150 were ineligible, 349 died, 39 terminated before the visit, and 324 were not contacted because recruitment goals had been achieved. Of the 3,135 who completed the MrOS sleep examination, 2,911 (93%) had technically adequate in-home polysomnography (PSG) data and are included in these analyses. All men provided written informed consent, and the institutional review board at each site approved the study.
Outcomes Information on falls and fractures that occurred after the sleep visit was obtained using a postcard follow-up system. Postcards were mailed every 4 months; more than 97% of these contacts were complete. All falls that occurred within 1 year of the sleep examination were included. All fractures were confirmed according to radiographic report. All fractures that occurred between the sleep examination and August 2012 were included in this analysis, with an average follow-up of 6.8 1.7 years (range 9 days to 8.4 years).
Collection of Polysomnography Data In-home sleep studies were completed using unattended, portable PSG (Safiro model; Compumedics, Inc., Melbourne, Australia). The recording montage was as follows: C3/A2 and C4/A1 electroencephalograms, bilateral electrooculograms, and a bipolar submental electromyogram to determine sleep stages; thoracic and abdominal respiratory inductance plethysmography to determine respiratory effort; airflow (by nasal-oral thermocouple and nasal pressure cannula); finger pulse oximetry (Nonin pulse oximeter; Nonin, Plymouth, MN); lead I electrocardiography; body position (mercury switch sensor); and bilateral leg movements (piezoelectric sensors). Centrally trained and certified staff performed home visits to set up the unit, verify the values of the impedances for each channel, confirm calibration of position sensors, and note any problems encountered during set up, similar to the protocol used in the Sleep Heart Health Study.9 Staff returned the next morning to collect the equipment and download the data to the Central Sleep Reading Center (Cleveland, OH) for scoring by a trained technician using standard criteria.10,11 Wake after sleep onset, a measure of sleep fragmentation, was defined as the minutes scored awake during the sleep period after sleep onset. Resting arterial oxygen saturation (SaO2) level was determined just before sleep using the PSG recorder’s oximeter finger pulse. Percentage of sleep time with SaO2 less than 90% was calculated after periods of artifact were manually deleted. Any saturations of less than 90% are considered clinically abnormal, but to allow for some misclassification, subjects with less than 1% of sleep time at SaO2 less than 90% were considered normal and formed the reference group. The remaining
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men were further divided a priori into three groups based on clinical judgment according to percentage of sleep time at less than 90% SaO2 (1.0–3.4%, 3.5–9.9%, ≥10.0%). Hypopneas were scored using criteria developed for the Sleep Heart Health Study,9 consistent with current recommendations.12 Briefly, the hypopnea definition requires a 30% or greater drop in flow for 10 seconds or longer in association with greater than 3% oxygen desaturation. The apnea hypopnea index (AHI) was calculated by dividing the average number of apneas and hypopneas by total sleep time. SDB was defined as an AHI of 15 or greater.13
Other Measurements Questionnaire data included information on demographic factors, lifestyle habits, self-reported health, race and ethnicity, and fall and medical history. Physical activity was assessed according to the Physical Activity Scale in the Elderly.14 Functional status was measured with information on five Instrumental Activities of Daily Living.15,16 The occurrence of nonspine fracture after the age of 50 was calculated by combining self-reported fracture data for the time period up to the start of the MrOS baseline visit and adjudicated fracture data from the time between the baseline visit and the sleep examination. Participants were asked to complete the Epworth Sleepiness Scale to classify subjective daytime sleepiness in people with sleeping disorders. Scores ranged from 0 to 24, with a score greater than 10 indicating excessive daytime sleepiness.17 At the clinic, visit body weight (kg) was measured in light indoor clothing on a standard balance beam or digital scale. Participants were asked to rise from a chair without using their arms five times. To test balance, men were asked to stay within a narrow walking path (20 cm) over 6 m. If a participant had three or more deviations from the path or no successful attempts, the trial was considered unsuccessful. Participants were asked to bring all current prescription and nonprescription medications used within the last 30 days. Information on all medications recorded in the clinics was stored in an electronic medications inventory database (San Francisco Coordinating Center, San Francisco, CA). Each medication was matched to its ingredient(s) based on the Iowa Drug Information Service Drug Vocabulary (College of Pharmacy, University of Iowa, Iowa City, IA).18 Bone mineral density (BMD) (g/cm2) of the total hip was measured using dual-energy X-ray absorptiometry (QDR 4500W; Hologic Inc., Waltham, MA). Standardized procedures for participant positioning and scan analysis were used for all scans. Cross-calibration studies performed found no linear differences between scanners.8
Statistical Analyses Characteristics of men according to category of nocturnal hypoxia were compared using analysis of variance, Kruskal-Wallis tests, or chi-square tests (Table 1). Loss to follow-up for fracture outcomes was addressed by censoring follow-up time to the last contact in proportional hazards models. The 22 men with missing follow-up for the
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Table 1. Baseline Characteristics According to Oxygen Saturation During Sleep: Percentage of Sleep Time with Oxygen Saturation (SaO2) Less Than 90% Percentage of Sleep Time Characteristic
OBJECTIVES: To test the hypothesis that low arterial oxygen saturation during sleep is associated with a greater risk of falls and fractures. DESIGN: Prospective cohort study. SETTING: Six U.S. clinical centers. PARTICIPANTS: Men aged 67 and older (N = 2,911). MEASUREMENTS: The primary exposure measure was percentage of sleep time with arterial oxygen saturation less than 90% measured using polysomnography. The main outcome measures were incident falls within 1 year and incident nonspine fractures over an average follow-up of 6.8 years. RESULTS: Men with 10% or more of sleep time at an arterial oxygen saturation of less than 90% were older, reported more comorbidities, had poorer physical function, and were more likely to have sleep disordered breathing than men with less than 10% sleep time at an arterial oxygen saturation of less than 90%. After multivariate adjustment, men with 10% or more of sleep time with arterial oxygen saturation of less than 90% had a greater risk of having one or more falls (relative risk (RR) = 1.25, 95% confidence interval (CI) = 1.04–1.51) and two or more falls (RR = 1.43, 95% CI = 1.06–1.92) than those with less than 10% of sleep time with less than 90% arterial oxygen saturation. Men with greater percentage of sleep time with arterial oxygen saturation less than 90% had a 30% to 40% greater risk of nonspine fracture than those
From the aUniversity of Pittsburgh, Pittsburgh, Pennsylvania; bCalifornia Pacific Medical Center, San Francisco, California; cDepartment of Medicine, Brigham and Women’s Hospital and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; d University of Minnesota, eVeterans Affairs Healthcare System, Minneapolis, Minnesota; fUniversity of California at San Diego, San Diego, California; gGeriatric Research, Education and Clinical Center, Veterans Affairs Healthcare System, Minneapolis, Minnesota; and h Oregon Health & Science University, Portland, Oregon. Address correspondence to Jane A. Cauley, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 Desoto Street, Crabtree A510, Pittsburgh, PA 15261. E-mail: [email protected] DOI: 10.1111/jgs.13069
JAGS 62:1853–1859, 2014 © 2014, Copyright the Authors Journal compilation © 2014, The American Geriatrics Society
with normal nocturnal oxygen saturation in models adjusting for sleep disordered breathing. CONCLUSION: Hypoxia during sleep may be a risk factor for falls and fractures in older men. Interventions aimed at decreasing nocturnal hypoxia may decrease falls and fractures. J Am Geriatr Soc 62:1853–1859, 2014.
Key words: nocturnal hypoxia; fractures; falls; mortality; older men
S
leep disordered breathing (SDB) is a common disorder in older adults, affecting up to 60%.1 Intermittent hypoxia is the hallmark of obstructive sleep apnea (OSA) and has been linked to a number of adverse cardiovascular consequences.2–4 Hypoxia has also been linked to poor physical function.5 To the knowledge of the authors of the current study, no previous study has linked nocturnal hypoxia to the risk of fractures and falls. A central question is the role of overnight hypoxemia as opposed to SDB on falls and fractures. Hypoxic stress could influence bone formation6 by itself in addition to the effect of SDB. The objective of the current analysis was to test the hypothesis that nocturnal hypoxia increases the risk of falls and fractures and that this association would be independent of SDB. This hypothesis was tested in a multicenter cohort of older men (Outcomes of Sleep Disorders in Older Men: Study of Osteoporotic Fractures in Men (MrOS) Sleep Study).
METHODS Participants From 2000 through 2002, 5,994 men aged 65 and older were recruited from population-based listings in Birmingham, Alabama; Minneapolis, Minnesota; Palo Alto, California; the Monongahela Valley near Pittsburgh, Pennsylvania, Pennsylvania; Portland, Oregon; and San Diego,
0002-8614/14/$15.00
1854
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California.7,8 Men with a history of bilateral hip replacement and men who were unable to walk without the assistance of another person were excluded. From 2003 through 2005, the MrOS Sleep Study recruited 3,135 (105% of recruitment goal) participants for a comprehensive sleep assessment. Of the 2,860 who did not participate in the MrOS sleep examination, 1,997 declined participation, 150 were ineligible, 349 died, 39 terminated before the visit, and 324 were not contacted because recruitment goals had been achieved. Of the 3,135 who completed the MrOS sleep examination, 2,911 (93%) had technically adequate in-home polysomnography (PSG) data and are included in these analyses. All men provided written informed consent, and the institutional review board at each site approved the study.
Outcomes Information on falls and fractures that occurred after the sleep visit was obtained using a postcard follow-up system. Postcards were mailed every 4 months; more than 97% of these contacts were complete. All falls that occurred within 1 year of the sleep examination were included. All fractures were confirmed according to radiographic report. All fractures that occurred between the sleep examination and August 2012 were included in this analysis, with an average follow-up of 6.8 1.7 years (range 9 days to 8.4 years).
Collection of Polysomnography Data In-home sleep studies were completed using unattended, portable PSG (Safiro model; Compumedics, Inc., Melbourne, Australia). The recording montage was as follows: C3/A2 and C4/A1 electroencephalograms, bilateral electrooculograms, and a bipolar submental electromyogram to determine sleep stages; thoracic and abdominal respiratory inductance plethysmography to determine respiratory effort; airflow (by nasal-oral thermocouple and nasal pressure cannula); finger pulse oximetry (Nonin pulse oximeter; Nonin, Plymouth, MN); lead I electrocardiography; body position (mercury switch sensor); and bilateral leg movements (piezoelectric sensors). Centrally trained and certified staff performed home visits to set up the unit, verify the values of the impedances for each channel, confirm calibration of position sensors, and note any problems encountered during set up, similar to the protocol used in the Sleep Heart Health Study.9 Staff returned the next morning to collect the equipment and download the data to the Central Sleep Reading Center (Cleveland, OH) for scoring by a trained technician using standard criteria.10,11 Wake after sleep onset, a measure of sleep fragmentation, was defined as the minutes scored awake during the sleep period after sleep onset. Resting arterial oxygen saturation (SaO2) level was determined just before sleep using the PSG recorder’s oximeter finger pulse. Percentage of sleep time with SaO2 less than 90% was calculated after periods of artifact were manually deleted. Any saturations of less than 90% are considered clinically abnormal, but to allow for some misclassification, subjects with less than 1% of sleep time at SaO2 less than 90% were considered normal and formed the reference group. The remaining
OCTOBER 2014–VOL. 62, NO. 10
JAGS
men were further divided a priori into three groups based on clinical judgment according to percentage of sleep time at less than 90% SaO2 (1.0–3.4%, 3.5–9.9%, ≥10.0%). Hypopneas were scored using criteria developed for the Sleep Heart Health Study,9 consistent with current recommendations.12 Briefly, the hypopnea definition requires a 30% or greater drop in flow for 10 seconds or longer in association with greater than 3% oxygen desaturation. The apnea hypopnea index (AHI) was calculated by dividing the average number of apneas and hypopneas by total sleep time. SDB was defined as an AHI of 15 or greater.13
Other Measurements Questionnaire data included information on demographic factors, lifestyle habits, self-reported health, race and ethnicity, and fall and medical history. Physical activity was assessed according to the Physical Activity Scale in the Elderly.14 Functional status was measured with information on five Instrumental Activities of Daily Living.15,16 The occurrence of nonspine fracture after the age of 50 was calculated by combining self-reported fracture data for the time period up to the start of the MrOS baseline visit and adjudicated fracture data from the time between the baseline visit and the sleep examination. Participants were asked to complete the Epworth Sleepiness Scale to classify subjective daytime sleepiness in people with sleeping disorders. Scores ranged from 0 to 24, with a score greater than 10 indicating excessive daytime sleepiness.17 At the clinic, visit body weight (kg) was measured in light indoor clothing on a standard balance beam or digital scale. Participants were asked to rise from a chair without using their arms five times. To test balance, men were asked to stay within a narrow walking path (20 cm) over 6 m. If a participant had three or more deviations from the path or no successful attempts, the trial was considered unsuccessful. Participants were asked to bring all current prescription and nonprescription medications used within the last 30 days. Information on all medications recorded in the clinics was stored in an electronic medications inventory database (San Francisco Coordinating Center, San Francisco, CA). Each medication was matched to its ingredient(s) based on the Iowa Drug Information Service Drug Vocabulary (College of Pharmacy, University of Iowa, Iowa City, IA).18 Bone mineral density (BMD) (g/cm2) of the total hip was measured using dual-energy X-ray absorptiometry (QDR 4500W; Hologic Inc., Waltham, MA). Standardized procedures for participant positioning and scan analysis were used for all scans. Cross-calibration studies performed found no linear differences between scanners.8
Statistical Analyses Characteristics of men according to category of nocturnal hypoxia were compared using analysis of variance, Kruskal-Wallis tests, or chi-square tests (Table 1). Loss to follow-up for fracture outcomes was addressed by censoring follow-up time to the last contact in proportional hazards models. The 22 men with missing follow-up for the
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Table 1. Baseline Characteristics According to Oxygen Saturation During Sleep: Percentage of Sleep Time with Oxygen Saturation (SaO2) Less Than 90% Percentage of Sleep Time Characteristic
