Bone Turnover Markers After Six Nights of Insufficient Sleep and Subsequent Recovery Sleep in Healthy Men.

PURPOSE: The goal of this study was to determine the bone turnover marker (BTM) response to insufficient and subsequent recovery sleep, independent of changes in posture, body weight, and physical activity. METHODS: Healthy men (N = 12) who habitually slept 7-9 h/night were admitted to an inpatient sleep laboratory for a baseline 8 h/night sleep opportunity followed by six nights of insufficient sleep (5 h/night). Diet, physical activity, and posture were controlled. Serum markers of bone formation (osteocalcin, PINP) and resorption (ß-CTX) were obtained over 24 h at baseline and on the last night of sleep restriction, and on fasted samples obtained daily while inpatient and five times after discharge over 3 weeks. Maximum likelihood estimates in a repeated measures model were used to assess the effect of insufficient and subsequent recovery sleep on BTM levels. RESULTS: There was no statistically or clinically significant change in PINP (p = 0.53), osteocalcin (p = 0.66), or ß-CTX (p = 0.10) in response to six nights of insufficient sleep. There were no significant changes in BTMs from the inpatient stay through 3 weeks of recovery sleep (all p [Formula: see text] 0.63). On average, body weight was stable during the inpatient stay (Δweight = - 0.55 ± 0.91 kg, p = 0.06). CONCLUSION: No significant changes in serum BTMs were observed after six nights of insufficient or subsequent recovery sleep in young healthy men. Changes in weight and physical activity may be required to observe significant BTM change in response to sleep and circadian disruptions. Clinical Trials Registration Registered at ClinicalTrials.gov (NCT03733483) on November 7, 2018.

Circadian Rhythm of Vascular Function in Midlife Adults.

Objective- Adverse cardiovascular events occur more frequently in the morning than at other times of the day. Vascular endothelial function (VEF)-a robust cardiovascular risk marker-is impaired during this morning period. We recently discovered that this morning impairment in VEF is not caused by either overnight sleep or the inactivity that accompanies sleep. We determined whether the endogenous circadian system is responsible for this morning impairment in VEF. We also assessed whether the circadian system affects mechanistic biomarkers, that is, oxidative stress (malondialdehyde adducts), endothelin-1, blood pressure, and heart rate. Approach and Results- Twenty-one (11 women) middle-aged healthy participants completed a 5-day laboratory protocol in dim light where all behaviors, including sleep and activity, and all physiological measurements were evenly distributed across the 24-hour period. After baseline testing, participants underwent 10 recurring 5-hour 20-minute behavioral cycles of 2-hour 40-minute sleep opportunities and 2 hours and 40 minutes of standardized waking episodes. VEF, blood pressure, and heart rate were measured, and venous blood was sampled immediately after awakening during each wake episode. Independent of behaviors, VEF was significantly attenuated during the subjective night and across the morning ( P=0.04). Malondialdehyde adducts and endothelin-1 exhibited circadian rhythms with increases across the morning vulnerable period and peaks around noon ( P≤0.01). Both systolic ( P=0.005) and diastolic blood pressure ( P=0.04) were rhythmic with peaks in the late afternoon. Conclusions- The endogenous circadian system impairs VEF and increases malondialdehyde adducts and endothelin-1 in the morning vulnerable hours and may increase the risk of morning adverse cardiovascular events in susceptible individuals. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02202811.

The Bone, Exercise, Alendronate, and Caloric Restriction (BEACON) trial design and methods.

BACKGROUND: Among older adults living with obesity, intentional weight loss (WL) improves prognosis of many comorbidities. However, concomitant decline in bone mineral density (BMD) limits overall benefit of WL by increasing osteoporotic fracture risk. Identification of intervention strategies to maximize body fat loss, while minimizing harm to the musculoskeletal system, is an important area of clinical research. The main objective of the Bone, Exercise, Alendronate, and Caloric Restriction (BEACON) trial (NCT05764733) is to compare the independent and combined effects of a 12-month intervention of resistance training (RT) plus bone-loading exercises and bisphosphonate use on dietary WL-associated bone loss among 308 older (≥60 years) adults living with an indication for WL and bisphosphonate use. METHODS: All participants will receive the same group-mediated dietary intervention targeting 8-10 % WL and be randomized to one of four groups: no RT and placebo capsules (NoRT+PL); progressive RT plus bone-loading exercises and placebo capsules (RT++PL); no RT and oral bisphosphonate (70 mg weekly oral alendronate; NoRT+BIS); or progressive RT plus bone-loading exercises and oral bisphosphonate (RT++BIS). Total hip areal (a)BMD measured via dual-energy x-ray absorptiometry (DXA) is the primary, powered study outcome. Secondary skeletal outcome measures include femoral neck and lumbar spine aBMD, high resolution peripheral quantitative computed tomography (HRpQCT) bone assessments of the radius and tibia, and biomarkers of bone turnover. DISCUSSION: BEACON will address an understudied, yet important, clinical research question by studying the independent and combined effects of two scalable intervention strategies aimed at optimizing skeletal integrity in older adults undergoing WL. CLINICAL TRIALS REGISTRATION: NCT05764733.

New Human Leukocyte Antigen (HLA) Antibody Formation and Creatinine Elevation With Abaloparatide in Kidney Transplant Recipient.

A 39-year-old female with a history of kidney transplant presented to the endocrinology clinic for osteoporosis evaluation after sustaining an ankle fracture from a fall. Her kidney transplant regimen (mycophenolate mofetil 360 mg twice a day, tacrolimus 0.5 mg every morning and 0.5-1 mg every evening, prednisone 5 mg/day) and baseline creatinine (1.0-1.2 mg/dL) had been stable for several years. After an appropriate secondary workup, she was started on abaloparatide 80 µg subcutaneous daily injections for osteoporosis. She had a good initial biochemical response to therapy. However, 5 months after abaloparatide initiation she was found to have a new elevation in serum creatinine (1.17 to 1.69 mg/dL) despite stable serum tacrolimus trough levels, and two new human leukocyte antigen (HLA) antibodies (anti-HLA antibodies detected to Cw7 and DP28). Abaloparatide was stopped due to concern for immunogenicity. There was no evidence of rejection on kidney biopsy and she was restabilized on her transplant regimen with a new baseline creatinine of 1.3-1.6 mg/dL. The patient was subsequently started on teriparatide 20 µg daily subcutaneous injections for 2 years with good biochemical response, significant improvement in bone mineral density, and stable transplant regimen without additional signs of immunogenicity or rejection. This is the first case report to raise concern about immunogenicity with abaloparatide in solid organ transplant recipients. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Acute catabolic bone metabolism response to exercise in young and older adults: A narrative review.

Exercise is recommended for cardiometabolic benefits and to preserve or improve bone health, especially for older adults at increased risk of fracture. However, exercise interventions have modest benefits on areal bone mineral density (aBMD), and exercise can lead to bone loss in young athletes under certain conditions. In this narrative review, we discuss evidence for a disruption in calcium homeostasis during exercise that may diminish the skeletal benefits of exercise. Topics include 1) a general overview of the effects of exercise on aBMD; 2) discussion of the exercise-induced disruption in calcium homeostasis; 3) factors that influence the magnitude of the exercise-induced disruption in calcium homeostasis, including age, sex, and exercise mode, intensity, and duration; 4) oral calcium supplementation to minimize the exercise-induced disruption in calcium homeostasis; and 5) potential for exercise-induced increase in parathyroid hormone to be both catabolic and anabolic to bone.

Sleep disruptions and bone health: what do we know so far?

PURPOSE OF REVIEW: This review briefly summarizes the growing body of literature addressing the skeletal consequences of sleep and circadian disruption. RECENT FINDINGS: The most recent data in the field suggest that the diurnal variation in bone turnover markers are because of endogenous circadian rhythmicity linked to clock genes in all bone cells; in a small human intervention study, cumulative sleep restriction with concurrent circadian disruption negatively alter bone turnover markers in a way that could explain the lower BMD and increased fracture risk identified in some prior night shift work studies; abnormal sleep duration and obstructive sleep apnea are associated with low BMD and increased fracture risk in some but not all studies. SUMMARY: Normal physiology and some animal and human intervention studies suggest that sleep and circadian disruptions, such as night shift work, abnormal sleep durations and obstructive sleep apnea are detrimental to skeletal health. However, additional research in this area is needed to determine which sleep/circadian disturbances are most detrimental to skeletal health, the reversibility of such impairments, and underlying mechanisms.

Maintaining serum ionized calcium during brisk walking attenuates the increase in bone resorption in older adults.

BACKGROUND: Endurance exercise can cause a decrease in serum ionized calcium (iCa) and increases in parathyroid hormone (PTH) and bone resorption, reflected by serum carboxy-terminal collagen crosslinks (CTX). We developed a calcium clamp to prevent the decrease in iCa during exercise, which attenuated increases in PTH and CTX during vigorous cycling in young men. The goal was to determine whether this occurs in older adults during brisk walking. METHODS: Twelve older adults (6 men, 6 women) performed two identical 60-min treadmill walking bouts with Ca gluconate or half-normal saline infusion. Blood sampling for iCa, total calcium (tCa), phosphate (P), PTH, and CTX, occurred before, during, and for 4 h after exercise. RESULTS: iCa decreased during exercise with the saline infusion (p = 0.04) and this provoked increases in PTH and CTX (both p < 0.01). The Ca clamp prevented the decrease in serum iCa during exercise and attenuated the PTH and CTX responses. CONCLUSIONS: Preventing the exercise-induced decrease in iCa markedly attenuated the increases in PTH and CTX. The cause of the decrease in iCa during exercise remains unclear, but the increases in PTH and CTX are likely counter-regulatory responses to defend serum iCa. This contention is supported by previous observations that the disruption of Ca homeostasis during exercise occurs regardless of training status. It will be important to establish whether this acute catabolic effect of exercise diminishes the potential chronic anabolic effects of exercise on bone.

Bone Mineral Density in Different Menopause Stages is Associated with Follicle Stimulating Hormone Levels in Healthy Women.

Although estradiol (E2) has been believed to be the most critical factor in the menopause-associated decrease in bone mineral density (BMD), the role of increasing follicle stimulating hormone (FSH) during menopause is relatively unclear. We determined the extent to which hip and lumbar spine BMD differ among the stages of menopause in healthy women, and whether BMD is associated with FSH and E2 levels. A cross-sectional study of 141 healthy women classified as premenopausal (Pre; 38 ± 6 yrs; mean ± SD, n = 30), early perimenopausal (EPeri; 50 ± 3yrs, n = 31), late perimenopausal (LPeri; 50 ± 4yrs, n = 30), early postmenopausal (EPost; 55 ± 3yrs, n = 24), or late postmenopausal (LPost; 62 ± 4 yrs, n = 26), was conducted. Spine/hip BMD and sex hormones were measured using dual-energy X-ray absorptiometry and enzymatic/colorimetric methods, respectively. Compared to EPeri, spine BMD was lower (p < 0.05) in LPeri, EPost, and LPost and hip BMD was lower (p < 0.05) in EPost and LPost. BMD was inversely associated with FSH (spine: r = -0.341; hip: r = -0.271, p < 0.05) and directly associated with E2 (spine: r = 0.274; hip: r = 0.256, p < 0.05). The menopause-related loss of spine and hip BMD is associated not only with low E2 but also higher FSH. Future studies are essential to delineating the mechanisms by which FSH regulates bone health in aging women.

Bone turnover marker responses to sleep restriction and weekend recovery sleep.

BACKGROUND: Prior data demonstrated three weeks of sleep restriction and concurrent circadian disruption uncoupled bone turnover markers (BTMs), indicating decreased bone formation and no change or increased bone resorption. The effect of insufficient sleep with or without ad libitum weekend recovery sleep on BTMs is unknown. METHODS: BTMs were measured in stored serum from 20 healthy adults randomized to one of three study groups consisting of a control group (N = 3 men; 9 h/night) or one of two nocturnal sleep restriction groups in an inpatient laboratory environment. One Sleep Restriction group ("SR"; N = 9; 4 women) had 5 h sleep opportunity per night for nine nights. The other sleep restriction group had an opportunity for ad libitum Weekend Recovery sleep ("WR"; N = 8; 4 women) after four nights of 5 h sleep opportunity per night. Food intake was energy balanced at baseline and ad libitum thereafter. Fasted morning BTM levels and hourly 24 h melatonin levels were obtained on study days 3 (baseline), 5 (after 1 night of sleep restriction for WR and SR), and 11 (after a sleep restricted workweek with weekend recovery sleep in WR or 7 nights of sleep restriction in SR). Linear mixed-effects modeling was used to examine the effect of study duration (e.g., change over time), study condition, age, and sex on BTMs. Pearson correlations were used to determine associations between changes in BTMs and changes in weight and morning circadian misalignment (i.e., duration of high melatonin levels after wake time). RESULTS: There was no significant difference between the three study groups in change over time (p ≥ 0.4 for interaction between assigned group and time for all BTMs), adjusted for age and sex. There was no significant change in N-terminal propeptide of procollagen type I (P1NP), osteocalcin, or C-telopeptide of type I collagen (CTX) from baseline to day 11 (all p ≥ 0.3). In women <25 years old, there was a non-significant decline in P1NP from day 3 to day 5 (= -15.74 ± 7.80 ng/mL; p = 0.06). Change in weight and morning circadian misalignment from baseline to day 11 were correlated with statistically non-significant changes in BTMs (all p ≤ 0.05). CONCLUSION: In this small secondary analysis, we showed that nine nights of prescribed sleep restriction with or without weekend recovery sleep and ad libitum food intake did not alter BTMs. It is possible that age, sex, weight change and morning circadian misalignment modify the effects of sleep restriction on bone metabolism.