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Sleep disturbance negatively impacts many biological systems and may be detrimental to skeletal health. Bone remodeling, which is important for bone mass and strength, increases overnight, a time when millions experience disrupted sleep. Epidemiological data and animal studies suggest a link between sleep disturbance and bone but the direction and the mechanisms by which sleep affects bone are not fully understood. The overall objective of this project is to establish and quantify the skeletal effects of disrupted sleep and to investigate the mechanisms by which bone remodeling and sleep are linked. The central hypothesis is that sleep disturbance (e.g., sleep loss, circadian shifts) negatively impacts bone health by altering the balance between bone resorption and bone formation and is particularly detrimental during skeletally vulnerable periods such as during and after the menopausal transition.
The specific aims are:
1. Examine the physiological mechanisms that control rhythms in bone remodeling and investigate how circadian shifts and accumulating sleep loss affect bone turnover in otherwise healthy men. This aim will use samples from a previously performed clinical experiment that manipulated sleep-wake cycles.
2. Determine the association between sleep loss and bone turnover and bone mineral density in older men and peri- and post-menopausal women using cross-sectional analyses of observational cohort studies. This represents a novel inquiry into these cohorts to confirm the association between sleep and bone while exploring differences related to sex and sex hormone status.
3. Evaluate mechanisms by which sleep loss alters the balance in bone remodeling through a small, clinical intervention study. These preliminary data will support the development of an R01 grant application.
This research fills a knowledge gap in the fields of sleep and bone research that could impact the clinical evaluation and treatment of osteoporosis. If the hypothesis is shown to be true, sleep disruption could be a novel, modifiable risk factor for osteoporosis.
Ages Eligible for Study: 20 Years to 65 Years (Adult, Older Adult)
Sexes Eligible for Study: Male
Accepts Healthy Volunteers: Yes
- Adult men aged 20-65 years old who habitually sleep 7-9 hours/night.
- Regularly go to sleep after midnight;
- Shift work 1 year prior to study;
- Travel >1 time zone 4 weeks prior to study or need to travel during study;
- More than moderate activity level (>3 days of exercise per week >30 min of exercise per session);
- Current smokers (or within the previous year of study);
- Positive drug test at screening or laboratory admission;
- BMI > 30 kg/m2;
- Individuals who are concurrently participating in another research protocol that would influence their safe participation in this study. For example, participants involved in a study that requires blood draws or ingestion of experimental medication as this would increase the risk of participation in our study and/or compromise study results.
- Any clinically significant unstable medical or surgical condition within the last year (treated or untreated), including history of a clinically significant abnormality of the neurological system (including cognitive disorders or significant head injury) or any history of seizure (including febrile seizure—sleep loss has been used clinically to induce seizures in patients with epilepsy). Given the wide range of illnesses that are encountered in medical practice, it would not be possible to provide a comprehensive list of each and every disease that could serve as grounds for exclusion for the subject. However, the following is a list of illness categories that would certainly be grounds for exclusion: Connective Tissue and Joint Disorders; Neurologic/cognitive Disorders; Musculoskeletal Disorders; Immune Disorders; Chronobiologic Disorders; Cardiovascular Disorders; Respiratory Disorders; Kidney Disorders; Infectious Diseases; Hematopoietic Disorders; Neoplastic Diseases; and Endocrine and Metabolic Diseases.
- Self-reported or newly diagnosed medical condition that is still being investigated or is not under good control, including those identified on screening labs such as:
- Out-of-range values measured on a fasting blood sample: glucose > 100 mg/dl, thyroid stimulating hormone <0.5 or >5.0 uU/ml, abnormal alkaline phosphatase <39 or >117 U/l, creatinine, or hemoglobin <14.5 g/dl men
- Any clinically significant psychiatric condition, as defined by DSM-V. Individuals with a history of most psychiatric illnesses or psychiatric disorders will be excluded, such as but not limited to depression, anxiety, alcoholism, drug dependency, schizophrenic disorders, and personality disorders (performed by medical history and physician interview). However, a personal history of limited prior counseling, psychotherapy (e.g., for adjustment reactions) will NOT be exclusionary. Evaluation of Psychiatric/Psychological Suitability:
- Subjects must demonstrate a full understanding of the requirements and demands of the study.
- Each subject will complete psychological screening questionnaires. Exclusionary: Center for Epidemiological Studies Depression (CES-D) ≥ 16;. Subject responses to the CES-D are reviewed immediately and appropriate referrals are made if necessary.
- Individuals who are unaware of specific psychiatric diagnoses who have a history of having been treated with antidepressants, neuroleptic medications or major tranquilizers will be excluded from study.
- Use of anti-depressants or any like therapeutics prescribed by a physician is exclusionary
- Individuals with any clinically significant sleep disorder; Diagnosis or symptoms of sleep disorders (history of significant parasomnia as an adult [night terrors, frequent sleep walking], insomnia, including but not limited to hypersomnias such as apnea, periodic limb movements, narcolepsy). Sleep disorders will be screened by self-report and physician interview including use of validated sleep questionnaires (PSQI, Epworth sleepiness scale, and Berlin sleep questionnaire for sleep apnea).
- Individuals on medications known to affect bone turnover (e.g. glucocorticoids, osteoporosis medications);
- Use of medications/supplements/drugs that impact sleep or bone metabolism (such as but not limited to sleep medications, marijuana etc.) within one month (participants can be studied at a later date).
- Dwelling below Denver altitude (1,600 m) 6 months prior to testing;
- Greater than moderate caffeine (>500 mg/day) or alcohol use (>14 standard drinks/week or >5 drinks in one sitting);
- Subjects with a history of heparin-induced thrombocytopenia (HIT) or an allergy to heparin;
- Inability to travel to the CU-AMC campus for study visits.
- Individuals with restrictive diets (e.g., vegan)
- Individuals with 25OHD < 20 ng/mL;
- Individuals with eGFR < 60 mL/min/1.73m2 as this is known to affect CTX measurements;
- T-score ≤ -2.5 (men ≥50 years old) or Z-score < -2.0 (men <50 years old) for bone mineral density (BMD) at the L-spine, femoral neck, or total hip on baseline DXA as compared to the DXA machine's normative database;
- Symptoms of active illness (e.g., fever); note that subject can be studied at a later date.
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Clinical & Translational Research Centers (CTRC) UCHealth, Aurora, Colorado, United States, 80045