A Systematic Review of the Circadian Rhythm of Bone Markers in Blood.

There exists a marked circadian variation for several bone markers (BM), which is influenced by endogenous as well as exogenous factors including hormones, physical activity, and fasting. Consequently, was the aim of this review to provide an overview of the knowledge of the circadian variation of BM and which factors influence this rhythmicity. A systematic search of PubMed was performed for studies evaluating the circadian variation of BM and which factors influence this rhythmicity. The studies were screened for eligibility by a set of predetermined criteria including a list of relevant BM and a minimum study duration of 24 h with at least 3 blood samples of which two should be at least 6 h apart. In total were 29 papers included. There exists a marked circadian variation for most BM including Carboxy-terminal Cross-Linked Telopeptide of Type I Collagen (CTX) and osteocalcin (OC) with nighttime or early morning peak. Pro-collagen Type I N-terminal Propeptide (PINP) and PTH also showed circadian rhythm but with less amplitude. The inter-osteoblast-osteoclast regulatory markers such as OPG, RANKL, FGF23, and sclerostin showed no circadian rhythm. The markers were differently affected by exogenous factors like fasting, which greatly reduced the circadian variation of CTX but did not affect PINP or OC. The marked circadian variation and the factors which influence the rhythmicity, e.g., fasting are of great consequence when measuring BM. To reduce variation and heighten validity should circadian variation and fasting be kept in mind when measuring BM.

Patients With Cirrhosis Have Elevated Bone Turnover but Normal Hepatic Production of Osteoprotegerin.

CONTEXT: Severe osteodystrophy is common in patients with liver dysfunction. Markers of bone metabolism may help in early diagnosis of osteodystrophy and in understanding underlying pathophysiological mechanisms. OBJECTIVE: To elucidate changes in bone metabolism associated with cirrhosis and to determine the route of elimination for the markers. METHODS: Case-control study at a public university hospital. Fifty-nine patients with cirrhosis (47 alcoholic and 12 nonalcoholic cirrhosis) and 20 controls were included. Participants underwent catheterization of the femoral artery, and the hepatic, renal, and femoral veins with collection of blood from all 4 sites. Regional arteriovenous differences in concentrations of bone metabolism markers were determined: procollagen of type I collagen propeptide (PINP), C-terminal cross-linking telopeptide of type I collagen (CTX), osteocalcin, tartrate-resistant acid phosphatase isoform 5b (TRAcP5b), osteoprotegerin (OPG), and sclerostin and correlated with degree of disease (Child-Pugh classification). RESULTS: PINP concentration was higher (median: 87.9 µg/L) in patients with cirrhosis than in controls (52.6 µg/L) (P = .001), while hepatic extraction was lower (4.3% vs 14.5%) (P < .001). Both CTX and TRAcP5b were higher in patients with cirrhosis (340 ng/L and 3.20 U/L) than in controls (215 ng/L and 1.60 U/L) (P < .001 and P < .0001). Hepatic sclerostin extraction was lower in patients with cirrhosis (14.6%) than in controls (28.7%) (P < .0001). In both groups OPG showed a hepatic release rate (production) of 6%. CONCLUSION: Patients with cirrhosis have increased bone resorption, but unaltered bone formation. Sclerostin is eliminated through the liver while OPG is produced in the liver. Bone markers may prove useful in evaluating bone turnover in patients with cirrhosis.

Reference intervals in Danish children and adolescents for bone turnover markers carboxy-terminal cross-linked telopeptide of type I collagen (ß-CTX), pro-collagen type I N-terminal propeptide (PINP), osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP).

PURPOSE: Bone turnover markers (BTM) are gaining ground in clinical practice but to fully use their potential there is a need for establishing valid reference intervals (RI). Consequently, the purpose of the study was to establish general RI as well as suggested clinical RI for carboxy-terminal cross-linked telopeptide of type I collagen (ß-CTX), pro-collagen type I N-terminal propeptide (PINP), osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP) in children and adolescents. METHOD: BTM were measured on Danish children and adolescents participating in the CHAMPS-study DK. A total of 762 participants were included (8-18 years, 50.4% girls) contributing a total of 1410 study visits. The RI was calculated based on 2-years age spans. Participants with biochemical signs of metabolic bone disease were excluded. RESULTS: The differences in RI between age groups clearly reflect changes in growth with an initial increase in BTM, greatest in boys, and a subsequent decrease most pronounced in girls. ß-CTX and PINP are markers most affected by these changes, compared to OC and bone ALP. The suggested clinical 95% RI included participants with vitamin D insufficiency but no biochemical signs of metabolic bone disease which did not markedly alter the RI. CONCLUSION: RI for ß-CTX, PINP, OC and bone ALP varies with age and sex. ß-CTX and PINP which reflect bone resorption and formation processes are mostly affected by these changes. We suggest a set of clinically applicable 95% RI for the four BTM to heighten the usefulness and generalizability of the RI.

Metabolic bone disease in patients with epilepsy and the use of antiepileptic drugs - Insight from a Danish cross-sectional study.

BACKGROUND: Osteoporosis is a bone disorder defined by a decrease in bone mineral density (BMD) which can lead to an increased risk of fractures. Patients with epilepsy are more prone to having fractures. When accounting for seizure-related fractures, the epilepsy patient population still suffers from an increased risk of fractures. This can be attributed to adverse effects of antiepileptic drugs (AEDs). AIM: The aim of this study was to investigate the association between the use of AEDs and decreased BMD in a large unselected population of Danish patients with epilepsy. METHOD: The study was a cross-sectional study based on data retrieved from 835 patients visiting an outpatient Epilepsy Clinic in Glostrup, Denmark, from January 1st 2006 - January 31st 2018. The data included results from DXA-scans and demographic information. Logistic regression models and other statistical analyses were performed. RESULTS: The results showed that the odds for having osteoporosis when taking EIAEDs were 2.2 (95 % CI: 1.2-3.8, P = 0.007) times higher than those taking NEIAEDs. Furthermore, the odds for having osteoporosis increased with duration of epilepsy (OR = 1.0, 95 % CI: 1.0 - 1.0, P = 0.001) and when the patients consume two AEDs compared to one AED (OR = 2.3, 95 % CI: 1.3-4.1, P < 0.001). Additionally, consuming three AEDs compared to one lead to a 2.3 times higher risk of having osteoporosis (95 % CI: 1.2-4.4, P = 0.01). CONCLUSION: When accounted for many riskfactors, EIAEDs, polytherapy with AEDs and duration of epilepsy are correlated with osteoporosis. There is a need for using these known riskfactors as guidelines in indentifying patients at increased risk of developing osteoporosis.

The effect of normalization of sodium on bone turnover markers in patients with epilepsy. A randomized single-blinded placebo-controlled trial.

Hyponatremia [p[Na]<136 mmol/L] is an independent risk factor for decreased bone mineral density (BMD). However, whether hyponatremia represents a surrogate marker, or a direct causal relationship to bone loss remains unknown. The aim of the study was to investigate the effect of salt replacement therapy on bone turnover markers (BTM) and BMD in patients with epilepsy and chronic hyponatremia. This prospective single-blinded randomized trial investigated serum BTM and BMD, evaluated by Dual Energy X-ray Absorptiometry (DXA), in 21 patients at baseline and following three months of salt replacement therapy. Patients with two consecutive measurements of hyponatremia prior to baseline and no known osteoporosis were included from the epilepsy out-patient clinic at Rigshospitalet, Denmark. Seven patients were randomized to placebo and 14 to salt intervention. The baseline p[Na] was 134 (130.5-140) mmol/L (median (IQR)). All patients had BTM within age-specific reference ranges at baseline. Following 3 months of intervention with 3-9 g of salt daily there was no difference in levels of procollagen type 1 N-terminal propeptide (P1NP) or C-terminal cross-linking telopeptide of type 1 collagen (CTX) between placebo and intervention. Nor was there any difference in BMD evaluated at the lumbar spine (L1-L4) or at the femoral neck or total hip. In our study, salt replacement did neither affect BTM nor BMD. However, due to the small size of the study, more studies are needed to further investigate this.

Effects of carbamazepine, eslicarbazepine, valproic acid and levetiracetam on bone microarchitecture in rats.

BACKGROUND: Metabolic bone disease and fractures are a great problem for patients with epilepsy. The use of antiepileptic drugs (AEDs) is known to play an essential role in the progression of bone loss by various pathophysiological mechanisms. The aim of this study was to evaluate the effects of AEDs on bone microstructure as an additional cause of an increased fracture risk in patients with epilepsy. METHODS: Five groups of each of 12 female rats were orally dosed daily for 8 weeks with either carbamazepine (CBZ) (60 mg/kg), eslicarbazepine (ESL) (80 mg/kg), valproic acid (VPA) (300 mg/kg), levetiracetam (LEV) (50 mg/kg) or saline (control (CTL)). Following killing, dissected femurs were analyzed using X-ray micro-computed tomography (µCT), dual-energy X-ray absorptiometry (DXA) and biomechanical testing. In addition, serum bone turnover markers (BTM) were monitored throughout the experiment. RESULTS: Compared to CTL treatment, VPA decreased bone volume fraction by 19%, decreased apparent density by 14% and increased structural model index by 41%. No changes were observed in bone biomechanics nor mineral density evaluated by DXA or in levels of BTM. CONCLUSIONS: Our findings suggest that VPA affects the microarchitectural properties of the bone. The AEDs CBZ, ESL and LEV appear to have less adverse effects on bone biology and may be a better choice when treating patients with respect to bone health.

Effects of age and sex on osteocalcin and bone-specific alkaline phosphatase-reference intervals and confounders for two bone formation markers.

Bone formation markers bone-specific alkaline phosphatase and osteocalcin are used in many clinical situations. Therefore, we calculated reference intervals for the two markers and investigated how they are influenced by several factors including sex and age. Furthermore, we established clinically relevant reference intervals for the two markers. OBJECTIVE: The bone turnover markers (BTMs), bone-specific alkaline phosphatase (bone ALP), and osteocalcin (OC), are frequently measured formation markers. The purpose of this study was to establish reference intervals (RIs) for the two BTMs in a general adult Danish population. METHODS: Bone ALP and OC were measured on the iSYS (IDS Plc) automatic analyzer in samples from the Danish Health2006 5-year follow-up study on serum from 2308 participants (54% women, age range 24-76). Participants with self-reported diagnosis of osteoporosis or receiving hormonal replacement were excluded from analyses while participants on hormonal contraceptives were included. RESULTS: The geometric mean and 95%RI for bone ALP were 13.9 µg/L (7.6-25.6) for men and 13.8 µg/L (7.0-27.4) for women, while for OC 16.0 µg/L (7.5-34.4) for men and 18.6 µg/L (8.1-42.9) for women. Levels of bone ALP increased with increasing age (ß 1.004, p < 0.001), while female sex had no effect. OC levels decreased with increasing age (ß 0.998, p = 0.009) and increased with female sex (ß 1.104, p < 0.001). Based on our findings, we propose for bone ALP and OC three clinical RIs for men based on age and three clinical RI for women based on age and menopausal status. CONCLUSION: The RI for bone ALP and OC varies with age and sex and the BTMs are influenced differently by the two factors. Consequently, the need for establishing valid RIs is of great importance before the full potential of BTM can be used in clinical practice.

An explorative literature review of the multifactorial causes of osteoporosis in epilepsy.

PURPOSE: Patients with epilepsy have a greatly increased risk of osteoporosis and fractures. The literature is diverse and contradictory when dealing with the underlying pathophysiological mechanisms. Consequently, the purpose of this review was to shed light on the multifactorial causes behind the increased occurrence of metabolic bone disease in patients with epilepsy and to identify areas for future research. METHODS: A review of the literature was performed searching PubMed with relevant Medical Subject Headings MeSH terms. The results of the search were evaluated for relevance to the review based on the title and abstract of the publication. Publications in language other than English and publications pertaining only pediatric patients were excluded. For all studies, included reference lists were evaluated for further relevant publications. In total, 96 publications were included in this explorative review. RESULTS: The high occurrence of metabolic bone disease in patients with epilepsy is multifactorial. The causes are the socioeconomic consequences of having a chronic neurological disease but also adverse effects to antiepileptic drug treatment ranging from interference with calcium and vitamin D metabolism to hyponatremia-induced osteoporosis. CONCLUSION: The literature supports the need for awareness of bone health in patients with epilepsy. The pathophysiological mechanisms are many and various wanting for further research in the less well-characterized areas. Furthermore, great responsibility rests on the healthcare professionals in implementing comprehensive patient care and in assuring bone protective measures in clinical practice to prevent bone loss in patients with epilepsy.

Hyponatremia and metabolic bone disease in patients with epilepsy: A cross-sectional study.

AIM: Patients with epilepsy frequently develop hyponatremia due to the treatment with antiepileptic drugs and have an increased risk of developing metabolic bone disease. Hyponatremia is known to be associated with osteoporosis. The aim of the study was to investigate the association between hyponatremia and osteoporosis in patients with epilepsy. METHOD AND MATERIAL: This cross-sectional study included patients with epilepsy from a tertiary epilepsy out-patient clinic in Denmark, who had a Dual Energy X-ray Absorptiometry scan performed and an accompanying plasma sodium (p-Na) measured prior to or a maximum of 14 days after the scan. Information regarding the patients' health and medical conditions were obtained from their medical reports. RESULTS: A total of 695 patients (females 53.8%, age 49 (34:63) years (median (quartiles)) were included. 10.4% had hyponatremia (p-Na ≤ 135 mmol/L). The hyponatremic patients had significantly lower T-scores in the lumbar spine, femoral neck and total femur (all p < 0.023) and the odds ratio of osteoporosis (T-score < -2.5) was significantly increased (2.91 (1.61-5.27) (95% confidence interval) (p = 0.001)). When adjusting for potential confounders the patients with moderate and severe hyponatremia (p-Na < 129 mmol/L) had a significantly lower mean T-score in the lumbar spine (p = 0.030). CONCLUSION: We conclude that hyponatremia is common in patients with epilepsy and that moderate and severe hyponatremia is independently associated with decreased bone mineral density in the lumbar spine. Therefore, hyponatremia in a patient with epilepsy should warrant further examination of the patient for bone loss and osteoporosis.

Effects of liraglutide and ischemic postconditioning on myocardial salvage after I/R injury in pigs.

OBJECTIVES: Acute STEMI is routinely treated by acute PCI. This treatment may itself damage the tissue (reperfusion injury). Conditioning with GLP-1 analogs has been shown to reduce reperfusion injury. Likewise, ischemic postconditioning provides cardioprotection following STEMI. We tested if combined conditioning with the GLP-1 analog liraglutide and ischemic postconditioning offered additive cardioprotective effect after reperfusion of 45 min coronary occlusion of left anterior descending artery (LAD). DESIGN: Fifty-eight non-diabetic female Danish Landrace pigs (60 ± 10kg) were randomly assigned to four groups. Myocardial infarction (MI) was induced by occluding the LAD for 45 min. Group 1 (n = 14) was treated with i.v. liraglutide after 15 min of ischemia. Group 2 (n = 17) received liraglutide treatment concomitant with ischemic postconditioning, after 45 min of ischemia. Group 3 (n = 15) recieved ischemic postconditioning and group 4 (n = 12) was kept as controls. RESULTS: No intergroup differences in relative infarct size were detected (overall mean 57 ± 3%; p = 0.68). Overall mortality was 34% (CI 25-41%) including 26% post-intervention, with no intergroup differences (p = 0.99). Occurrence of ventricular fibrillation (VF) was 59% (CI 25-80%) including 39% postintervention with no intergroup differences (p = 0.65). CONCLUSIONS: In our closed-chest pig-model, we were unable to detect any cardioprotective effect of liraglutide or ischemic postconditioning either alone or combined.