Bone Loss in Obesity and Obstructive Sleep Apnea: A Review of Literature
2015; American Academy of Sleep Medicine; Volume: 11; Issue: 05 Linguagem: Inglês
10.5664/jcsm.4708
ISSN1550-9397
AutoresMarlene Chakhtoura, Mona Nasrallah, Hassan Chami,
Tópico(s)Restraint-Related Deaths
ResumoFree AccessCPAPBone Loss in Obesity and Obstructive Sleep Apnea: A Review of Literature Marlene Chakhtoura, MD, Mona Nasrallah, MD, Hassan Chami, MD, MSc Marlene Chakhtoura, MD Division of Endocrinology at the American University of Beirut, Beirut Lebanon , Mona Nasrallah, MD Division of Endocrinology at the American University of Beirut, Beirut Lebanon , Hassan Chami, MD, MSc Address correspondence to: Hassan Chami, MD MSc, Division of Pulmonary, Sleep and Critical Care Medicine at the American University of Beirut, Beirut Lebanon E-mail Address: [email protected] Division of Pulmonary, Sleep and Critical Care Medicine at the American University of Beirut, Beirut Lebanon Pulmonary Center at Boston University School of Medicine, Boston, MA Published Online:May 15, 2015https://doi.org/10.5664/jcsm.4708Cited by:11SectionsAbstractPDF ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutABSTRACTIntroduction:Obstructive sleep apnea (OSA) is a common sleep-related respiratory disorder. It is associated with many endocrinopathies including hypogonadotropic hypogonadism, hypercortisolism, and glucose intolerance that may lead to bone loss with secondary osteoporosis.Methods:We report the case of a 41-year-old man who presented with bilateral 9th rib fractures and was found to have obstructive sleep apnea and osteoporosis. We also present a literature review on this topic.Results:OSA can lead to bone loss through various mechanisms. Some are shared with obesity, including hypogonadism, altered adrenergic tone, inflammation, oxidative stress, vitamin D deficiency and diabetes mellitus; others are specific to OSA, such as hypoxia and altered glucocorticoids regulation.Conclusion:There are no guidelines on screening for osteoporosis in OSA. Further research is needed to assess the incidence of bone loss and fractures in OSA.Citation:Chakhtoura M, Nasrallah M, Chami H. Bone loss in obesity and obstructive sleep apnea: a review of literature. J Clin Sleep Med 2015;11(5):575–580.INTRODUCTIONObstructive sleep apnea (OSA) is a sleep-related respiratory disorder characterized by repeated episodes of apnea and hypopnea resulting in sleep fragmentation, nocturnal hypoxia and hypercapnia, and excessive daytime sleepiness.1 OSA has recently become a well-recognized problem in view of its high prevalence in the general population, affecting approximately 4% to 24% of adult males, with varying severity.1,2 Many endocrine disorders are associated with an increased risk of OSA including hypothyroidism, acromegaly, and diabetes mellitus.3 Conversely, OSA is associated with hypogonadotropic hypogonadism, hypercortisolism, and glucose intolerance.2,3 These endocrinopathies may lead to bone loss, with secondary osteoporosis. In this review, we present the case of a young man with bilateral cough-induced rib fractures who was found to have OSA, hypogonadism, and osteoporosis, and we review the potential mechanisms linking these disorders.Case PresentationThe patient was a 41-year-old Lebanese man who presented with acute right-sided chest pain, secondary to bilateral 9th rib fractures, revealed by CT chest (Figure 1). A bone scan confirmed the fractures and was otherwise normal (Figure 2). A DXA scan using a Hologic densitometer 4500 A QDR showed a Z-score of −3.1 (BMD = 0.741 g/cm2) at the lumbar spine (L1-L4), −0.2 (BMD = 0.975 g/cm2) at the femur (total), −0.9 (BMD = 0.739 g/cm2) at the femoral neck, and −2.2 (BMD = 0.687 g/cm2) at the forearm (33% mid-radius).Figure 1: Chest CT of the patients with red arrows pointing to the bilateral fractures of the 9th ribs at the mid-axilla.Download FigureFigure 2: Bone scan showing increase uptake at the level of the 9th ribs bilaterally.Download FigureThe patient was a known smoker and hypertensive on enalapril 10 mg daily. On review of systems, he had long-standing obesity, with a recent gain of 20 kg over the past two years. He admitted to snoring, feeling “always tired,” headaches, and a mild decrease in libido, but no change in erectile function.On examination, his body-mass index (BMI) was 37.5 kg/m2. He had significant acanthosis nigricans over the neck and exquisite tenderness bilaterally over the 9th rib at the mid-axillary line. Testicular exam was normal. Work-up for osteoporosis is shown in Table 1. It was pertinent for low testosterone level with inappropriately low/normal gonadotropins. Polysomnography showed positional moderately severe OSA with an overall apnea-hypopnea index (AHI) of 17 events per hour. The AHI was 23/h in the supine sleep position and 6/h in the side sleep position.Table 1 Results of work-up for secondary osteoporosis in a 41-year-old male patient.Table 1 Results of work-up for secondary osteoporosis in a 41-year-old male patient.Given his symptoms combined with the low free and total testosterone levels, he was diagnosed with hypogonadotropic hypogonadism4 and secondary osteoporosis. The hypogonadism, in turn was likely related to obesity and OSA. He was recommended weight loss, was prescribed CPAP therapy during sleep, and started on testosterone gel therapy, in addition to calcium and vitamin D supplements.DISCUSSIONTo our knowledge, this is the first reported case of bilateral cough-induced rib fractures in a young man with OSA, found to have hypogonadism and osteoporosis. In keeping with the aim of this report, we will review the clinical significance of rib fractures in men, discuss the causes of bone loss in men in general, and focus on the potential causes in men with OSA.Clinical Significance of Rib Fractures in MenRib fracture is one of the most common clinical fractures in older men.5 It predicts more than two-fold increased risk of future fracture of the rib, hip, or wrist, independent of other covariates, and is considered as an osteoporotic fracture.5 However, in the European prospective osteoporosis study, rib fracture predicted incident limb fractures only in women.6 Based on the possibility of increased fracture risk, it is suggested to perform a bone density scan and an osteoporosis work-up in men presenting with a rib fracture in the absence of trauma.5,7,8Causes of Bone Loss in MenOsteoporosis is defined by the NIH as “a skeletal disorder characterized by compromised bone strength, predisposing a person to an increased risk for fracture.”9 It affects not only women but also men, a frequently under-recognized fact.10,11 Osteoporotic fractures in men, although less frequent than in women, are associated with a higher mortality.12,13Following the diagnosis of an osteoporotic fracture, in addition to clinical evaluation and risk factors assessment (e.g. smoking), a work up should be done based on the most common etiologies. In men, 50% of cases are secondary to one of three conditions: endogenous or exogenous glucocorticoid excess, hypogonadism, and excessive alcohol consumption.10,11 In addition to these, idiopathic hypercalciuria—defined as urinary calcium > 3–4 mg/kg/day or 300 mg/24 h—is present in 8% of men with osteoporosis.10 At a minimum, measurement of serum calcium, phosphate, creatinine (with estimated glomerular filtration rate), alkaline phosphatase, liver function, 25-hydroxyvitamin D [25(OH)D], total testosterone, TSH, complete blood count, and 24-hour urinary calcium, creati-nine, and sodium is recommended.7,8Potential Causes of Bone Loss in Men with OSAChronic respiratory diseases, mostly COPD, are becoming increasingly known as secondary causes of osteoporosis.10–14 OSA, another chronic respiratory disorder, is not a known cause of osteoporosis, but could lead to bone loss and increased risk of fracture through multiple mechanisms, including hypogonadism, sympathetic activation, systemic inflammation, oxidative stress, hypercortisolism, and hypoxemia, as discussed next.Obesity and OSA are tightly related,15,16 as about 70% of people with OSA are obese. Conversely, more than one-third of obese people have OSA, the prevalence of which increases with increasing BMI.17 Since obesity is also associated with most of the factors that could link OSA to bone loss, it is difficult to distinguish the individual effects of obesity and OSA. We will therefore examine the potential mechanisms of bone loss common to both obesity and OSA, and the potential mechanisms specific to OSA separately.Mechanisms of Bone Loss Common to Obesity and OSAHypogonadismHypogonadism in obesity: There is good evidence for a link between obesity and hypogonadism. Obese patients have decreased mean serum level of testosterone, free testosterone, and SHBG-binding capacities compared to normal-weight controls.18,19 Furthermore, total and free testosterone levels are highly inversely correlated with BMI. Conversely, weight loss leads to a significant increase in gonadotropic hormone levels.20The decreased androgen level in obese individuals is potentially mediated through alteration in the pituitary secretion of gonadotropin. The mean diurnal LH levels, mean diurnal LH pulse amplitude, and the sum of all diurnal LH pulse amplitudes and secretory mass were all significantly lower in obese individuals than controls, although the LH pulse frequency was similar.19 The amplitude of the cortisol and ACTH secretory pulse was also decreased, suggesting a general alteration of hypothalamic-pituitary function in obese men.19 In another study, the mean baseline serum LH and the magnitude of the pituitary response to exogenous GnRH measured by the secretory burst mass, secretory amplitude, and half-duration of the LH pulses were similar in 7 obese and control subjects. Nevertheless, the apparent endogenous half-life of LH was significantly shorter in the obese group than in the control.21 Obesity is also associated with insulin resistance, which is in turn associated with decreased testosterone secretion in men. In fact, insulin receptors are present on Leydig cells, and a negative correlation was observed between testosterone and fasting insulin levels.22 In addition, hyperestrogenemia in obese individuals may be responsible for an inhibitory effect on pituitary gonadotropin secretion, leading to low testosterone.19 Finally, excess circulating leptin is thought to be an important contributor to the development of reduced androgen levels, including total and free testosterone, in obese males. In fact, leptin receptors are present on testicular tissue, and high leptin concentrations may have a direct inhibitory effect(s) on Leydig cell steroidogenic function by decreasing 17, 20-lyase activity.23 Knowing that physiological leptin concentrations are necessary for proper reproductive function, it seems that leptin excess in obesity may have an opposite, deleterious effect on the target steroidogenic cells.23Hypogonadism in OSA: OSA may affect the pituitary gonadal axis, leading to low androgen levels through pathways independent of obesity.24,25 Nocturnal LH and testosterone levels were significantly lower in OSA patients (sometimes reaching hypogonadal levels) than BMI-matched controls.25 Both intermittent hypoxemia and sleep fragmentation may mediate this association. Although some studies showed a significant correlation between hypoxemia and testosterone levels,24 a significant negative correlation was found between the amounts of LH and testosterone secreted at night and the respiratory disturbance index, but not with the degree of hypoxia, in another study, independent of BMI.25 Therefore, sleep fragmentation may be the culprit factor. Furthermore, nocturnal oxygen desaturation influences the circadian rhythm of testosterone secretion. Patients with severe oxygen desaturation exhibited delayed morning peak testosterone levels (at 10:00 instead of 06:00); the ratio of the testosterone level at 10:00 to that at 06:00 correlates well with total de-saturation time.26 On the other hand, the effect of OSA treatment on hypogonadism has been assessed in multiple studies. The results have been inconsistent: some showed increased LH27 and testosterone levels20,27 with CPAP therapy, while another study did not.2 Conversely, most OSA patients with pronounced erectile dysfunction experience some improvement with CPAP treatment.2,28Despite the evidence linking OSA and hypogonadism, screening with testosterone level in patients with OSA has not been recommended.29,30 Screening for chronic respiratory disease is recommended in patients with unexplained secondary hypogonadism27 and in unexplained secondary osteoporosis.10 However, screening for OSA specifically has not been recommended as part of the workup of hypogonadism and osteoporosis in men.4,10 The latter may be important in view of the linking mechanisms and the potential worsening of OSA with testosterone replacement, even though this effect is small.4,31,32Altered Adrenergic ToneOSA and obesity are associated with increased activity of the sympathetic nervous system (SNS) through variable mechanisms, including stimulation of baroreceptors and chemoreceptors and recurrent arousals.33–35 It has been demonstrated that SNS—directly or through leptin—plays a role in the regulation of bone remodeling. In fact, sympathetic and sensory nervous fibers are present in bone tissue, and adrenergic and neuropeptide receptors have been detected on osteoblastic and osteoclastic cells. When activated, those receptors lead to inhibition of bone formation and increase in bone resorption.36 Furthermore, high leptin levels have been found in OSA and obese patients.37 The effects of leptin on bone are complex: peripherally, leptin acts directly on osteoblasts to induce their differentiation and proliferation,38 while it inhibits osteoclasts through osteoprotegerin (OPG),39 resulting in increased bone growth. Centrally, leptin has dual and antagonistic effects; it inhibits bone loss through Cocaine Amphetamine Regulated Transcript (CART) regulated pathway40 and conversely activates the sympathetic nervous system,36 which stimulates bone loss through osteopontin mediated inhibition of osteoblasts and RANKL activation of osteoclast.40InflammationInflammatory markers including IL-1β, IL-6, and TNF-α are elevated in OSA and in obesity41; these markers are known regulators of the RANK/RANKL/OPG system and induce osteoclast differentiation and/or activation.42Oxidative StressOSA is characterized by intermittent hypoxia followed by re-oxygenation. Those repeated oxyhemoglobin desaturation episodes have been associated with increased oxidative stress and production of reactive oxygen species (ROS).43 On the other hand, oxidative stress has been also associated with increased adiposity.44 The effect of oxidative stress on bone has been widely studied. Free oxygen radicals enhance bone resorption by directly stimulating osteoclasts and indirectly facilitating the resorptive effect of PTH, IL-1 and TNF on bone.45 Furthermore, oxidative stress inhibits bone formation by antagonizing Wnt signaling in osteoblasts, a known important pathway in osteoblast activation.46 In fact, urinary excretion of the F2-isoprostane, a biomarker of oxidative stress, correlates negatively with BMD, after adjustment for many confounders including sex, age, BMI, and smoking.47Vitamin D DeficiencyAlthough serum 25-hydroxy vitamin D level was significantly lower in women with increasing OSA severity, obesity could have been a confounder.48 Obesity is a risk factor for vitamin D deficiency, leading to secondary hyperparathyroidism. Low serum 25-hydroxy vitamin D in obese subjects is due to feedback inhibition of hepatic synthesis of the metabolite by increased circulating 1,25(OH) vitamin D.48 Another explanation is decreased bioavailability of vitamin D from cutaneous and dietary sources because of its deposition in adipose tissue.49Altered Glucose Metabolism, Insulin Resistance, and Diabetes MellitusObesity is a known predisposing factor for insulin resistance and diabetes mellitus.50 On the other hand, cross-sectional studies have found that 20% to 30% of OSA patients have diabetes.51 Diabetes mellitus is a condition characterized by discrepant bone characteristics; despite an increased BMD, there is an increased risk of fracture, probably related to altered bone composition, hormonal changes, microvascular complications, and high prevalence of vita-min D deficiency.52Mechanisms Specific to OSAAltered Glucocorticoid Regulation in OSA:OSA had a mild but significant nocturnal elevation in cortisol levels, compared with non-apneic obese controls, independent of cortisol binding globulins levels.53 Excessive cortisol leads to increased osteoclast-mediated bone resorption and decreased osteoblast-mediated bone formation.54 This could in part explain the increase in the serum/urinary levels of bone resorption markers in OSA patients.41Although the enzyme 11-hydroxysteroid dehydrogenase type I, which activates cortisone into cortisol in adipose tissue may be over-expressed in obese individuals resulting in local cortisol excess, systemic cortisol levels have not been consistently found to be elevated in obese individuals.55Direct Effect of Hypoxia in OSA on BoneOxygen tension acts as a key regulator of osteoclastic bone resorption. In vitro studies have shown that hypoxia stimulates bone resorption directly by increasing the formation of large osteoclasts,56 and indirectly by increasing ATP release from osteoblasts which stimulates osteoclast activity.57 Furthermore, hypoxia decreases bone formation through an inhibitory effect on osteoblasts. This effect is mediated through stimulation of Notch signaling, a known inhibitor of mesenchymal progenitor differentiation into osteoblasts. Finally, hypoxia reduces collagen production, alkaline phosphatase, and osteocalcin gene expression, all of which are mediators of bone formation.58CONCLUSIONSOSA has been associated with several endocrinopathies which lead to bone loss and osteoporosis. Several potential mechanisms mediate this association, some shared with obesity such as hypogonadism and increased inflammation, and others specific to OSA, including hypoxia, sleep fragmentation, and altered HPA axis.While chronic respiratory diseases, specifically COPD, are important secondary causes of osteoporosis, bone disease is rarely taken into consideration in the approach to patients with OSA. There are no guidelines on screening for osteoporosis or risk factors such as hypogonadism or vitamin D deficiency in OSA. Further studies are needed to assess the incidence of bone loss and fractures in OSA patients in order to guide future recommendations.DISCLOSURE STATEMENTThis was not an industry supported study. The authors have indicated no financial conflicts of interest.ABBREVIATIONSAHIapnea-hypopnea indexBMIbody mass indexCARTcocaine amphetamine regulated transcriptOPGosteoprotegerinOSAobstructive sleep apnea25(OH)D25-hydroxyvitamin DROSreactive oxygen speciesSNSsympathetic nervous systemREFERENCES1 Young T, Peppard PE, Gottlieb DJEpidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med; 2002;165:1217-39, 11991871. CrossrefGoogle Scholar2 Meston N, Davies R, Mullins R, Jenkinson C, Wass J, Stradling JEndocrine effects of nasal continuous positive airway pressure in male patients with obstructive sleep apnoea. J Intern Med; 2003;254:447-54, 14535966. CrossrefGoogle Scholar3 Attal P, Chanson PEndocrine aspects of obstructive sleep apnea. J Clin Endocrinol Metab; 2010;95:483-95, 20061419. 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Vitamin D Improves Selected Metabolic Parameters but Not Neuropsychological or Quality of Life Indices in OSA: A Pilot StudyKerley C, Hutchinson K, Bramham J, McGowan A, Faul J and Cormican L Journal of Clinical Sleep Medicine, Vol. 13, No. 01, (19-26), Online publication date: 15-Jan-2017. Serum Vitamin D Is Significantly Inversely Associated with Disease Severity in Caucasian Adults with Obstructive Sleep Apnea SyndromeKerley C, Hutchinson K, Bolger K, McGowan A, Faul J and Cormican L Sleep, 10.5665/sleep.5430, Vol. 39, No. 2, (293-300), Online publication date: 1-Feb-2016. Multiple Integrated Complementary Healing Approaches: Energetics & Light for boneGray M, Lackey B, Patrick E, Gray S and Hurley S Medical Hypotheses, 10.1016/j.mehy.2015.10.030, Vol. 86, , (18-29), Online publication date: 1-Jan-2016. Obstructive Sleep Apnea and Osteoporosis RiskChakhtoura M, Nasrallah M and Chami H Journal of Clinical Sleep Medicine, Vol. 11, No. 09, (1071-1072), Online publication date: 15-Sep-2015.Obstructive Sleep Apnea is Not Associated with an Increased Risk of Osteoporosis: a Systematic Review and Meta-AnalysisUpala S, Sanguankeo A and Congrete S Journal of Clinical Sleep Medicine, Vol. 11, No. 09, (1069-1070), Online publication date: 15-Sep-2015. Volume 11 • Issue 05 • May 15, 2015ISSN (print): 1550-9389ISSN (online): 1550-9397Frequency: Monthly Metrics History Submitted for publicationOctober 1, 2014Submitted in final revised formOctober 1, 2014Accepted for publicationDecember 1, 2014Published onlineMay 15, 2015 Information© 2015 American Academy of Sleep MedicineKeywordsobstructive sleep apneabone losshypoxiafractureobesityPDF download
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