Lisa-Ann Fraser

Elevated content of cortisol in hair of patients with severe chronic pain: A novel biomarker for stress

Hair analysis has been used to reflect long-term systemic exposure to exogenous drugs and toxins. Several studies have demonstrated the feasibility of measuring endogenous steroid hormones, e.g. cortisol, in hair. Recently, a study in macaques showed a significant increase in hair cortisol levels induced by stress. We explored whether hair cortisol levels may be used as a biomarker for long-term stress in humans. Patients with severe chronic pain, aged 18 years or older, receiving opioid treatment for at least one year were recruited. Controls were non-obese (body mass index, BMI < 30 mg/kg2) adults. The Perceived Stress Scale (PSS) questionnaire was used to assess perceived stress over the last 4 weeks. A hair sample was obtained from the vertex posterior. Cortisol was measured using an enzyme-linked immunosorbent assay. We included fifteen patients (nine females and six males) and 39 non-obese control subjects (20 females, 19 males). PSS scores (median and range) were significantly higher in chronic pain patients (24: 12–28) than in controls (12: 3–31)(P < 0.001). Hair cortisol contents (median and range) were significantly greater in chronic pain patients (83.1: 33.0–205 g/mg) than in controls (46.1: 27.2–200 pg/mg) (P < 0.01). We conclude that hair cortisol contents are increased in patients with major chronic stress. Measurement of cortisol levels in hair constitutes a novel biomarker of prolonged stress.

Hair analysis provides a historical record of cortisol levels in Cushing's syndrome.

The severity of Cushings Syndrome (CS) depends on the duration and extent of the exposure to excess glucocorticoids. Current measurements of cortisol in serum, saliva and urine reflect systemic cortisol levels at the time of sample collection, but cannot assess past cortisol levels. Hair cortisol levels may be increased in patients with CS, and, as hair grows about 1 cm/month, measurement of hair cortisol may provide historical information on the development of hypercortisolism. We attempted to measure cortisol in hair in relation to clinical course in six female patients with CS and in 32 healthy volunteers in 1 cm hair sections. Hair cortisol content was measured using a commercially available salivary cortisol immune assay with a protocol modified for use with hair. Hair cortisol levels were higher in patients with CS than in controls, the medians (ranges) were 679 (279-2500) and 116 (26-204) ng/g respectively (P<0.001). Segmental hair analysis provided information for up to 18 months before time of sampling. Hair cortisol concentrations appeared to vary in accordance with the clinical course. Based on these data, we suggest that hair cortisol measurement is a novel method for assessing dynamic systemic cortisol exposure and provides unique historical information on variation in cortisol, and that more research is required to fully understand the utility and limits of this technique.

The three-year incidence of fracture in chronic kidney disease

Knowing a persons fracture risk according to their kidney function, gender, and age may influence clinical management and decision-making. Using healthcare databases from Ontario, Canada, we conducted a cohort study of 679,114 adults of 40 years and over (mean age 62 years) stratified at cohort entry by estimated glomerular filtration rate ((eGFR) 60 and over, 45-59, 30-44, 15-29, and under 15 ml/min per 1.73 m(2)), gender, and age (40-65 and over 65 years). The primary outcome was the 3-year cumulative incidence of fracture (proportion of adults who fractured (hip, forearm, pelvis, or proximal humerus) at least once within 3-years of follow-up). Additional analyses examined the fracture incidence per 1000 person-years, hip fracture alone, stratification by prior fracture, stratification by eGFR and proteinuria, and 3-year cumulative incidence of falls with hospitalization. The 3-year cumulative incidence of fracture significantly increased in a graded manner in adults with a lower eGFR for both genders and both age groups. The 3-year cumulative incidence of fracture in women over 65 years of age across the 5 eGFR groups were 4.3%, 5.8%, 6.5%, 7.8%, and 9.6%, respectively. Corresponding estimates for men over 65 years were 1.6%, 2.0%, 2.7%, 3.8%, and 5.0%, respectively. Similar graded relationships were found for falls with hospitalization and additional analyses. Thus, many adults with chronic kidney disease will fall and fracture. Results can be used for prognostication and guidance of sample size requirements for fracture prevention trials.

Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women.

The effect of chronic oral opioids on hypothalamus-pituitary-gonadal axis in women, and on bone mineral density (BMD) in men and women is not known. The objective of this cross-sectional study was to determine the effect of long-term oral opioids on gonadal status and BMD in male and female patients with chronic non-cancer pain (CNCP). We included 26 community-dwelling CNCP patients, 12 men and 14 premenopausal women, treated with oral opioids for at least one year. We obtained Visual Analogue Scale for pain score, BMD and plasma LH and FSH in all patients; menstrual history and estradiol in women; free androgen index and total and free testosterone in men. Men were older then women (p<0.05) and had used opioids for a longer period (7.2+/-3.8 and 4.1+/-1.8 years, respectively; p<0.05), but there was no difference in opioid dose or pain score between sexes. The prevalence of hypogonadism was high in men (75%), while only 21% of the women reported oligo- or amenorrhea indicating hypogonadism (P<0.01, between sexes). Osteopenia was found in 50% of men and 21% of women (p=NS). We conclude that in CNCP patients receiving chronic opioid therapy there is a much higher prevalence of hypogonadism in men then in women. This needs to be considered clinical practice.

Risk factors for idiopathic intracranial hypertension in men: a case-control study

OBJECTIVE To identify risk factors for idiopathic intracranial hypertension (IIH) in men. DESIGN Case-control study. A 96-item telephone questionnaire, answered retrospectively, with cases recalling at the age of their diagnosis and controls recalling at the age of their corresponding cases diagnosis. SETTING Outpatient clinics in two US tertiary care centers. PARTICIPANTS The characteristics of 24 men with IIH were compared to those of 48 controls matched for sex, age, race, and World Health Organization body mass index (BMI) category. MAIN OUTCOME MEASURES Two previously validated questionnaires: the ADAM (Androgen Deficiency in Aging Males) questionnaire for testosterone deficiency and the Berlin questionnaire for obstructive sleep apnea (OSA), embedded within the telephone questionnaire. Analysis with Mantel-Haenszel odds ratios and mixed-effects logistic regression models accounted for matching. RESULTS Cases and controls had similar enrollment matching characteristics. Although matching was successful by BMI category, there was a small difference between BMI values of cases and controls (cases: median 31.7, controls: median 29.9; p=0.03). After adjustment by BMI value, men with IIH were significantly more likely than controls to have a positive ADAM questionnaire for testosterone deficiency (OR: 17.4, 95% CI: 5.6-54.5; p<0.001) and significantly more likely to have either a positive Berlin questionnaire for OSA or history of diagnosed OSA (OR: 4.4, 95% CI: 1.5-12.9; p=0.03). CONCLUSIONS Men with IIH are more likely than controls to have symptoms associated with testosterone deficiency and OSA. These associations suggest a possible role for sex hormones and OSA in the pathogenesis of IIH in men.

Fracture risk associated with continuation versus discontinuation of bisphosphonates after 5 years of therapy in patients with primary osteoporosis: a systematic review and meta-analysis

Purpose: The risks and benefits of continuing bisphosphonate therapy beyond 5 years in patients with primary osteoporosis have not been well established. Methods: We searched MedLine, EMBase, CENTRAL, CINAHL, and AgeLine prior to February 2010. Bibliographies were also searched and experts in the field contacted. The ProQuest Dissertations and Theses database and relevant conference proceedings were searched to identify unpublished or ongoing studies. Two authors independently reviewed search results. Randomized controlled trials and comparative nonrandomized controlled trials examining post-menopausal women or men ≥50 years of age with primary osteoporosis assigned to continue versus discontinue bisphosphonate therapy after ≥5 years of therapy were included. Of 1188 identified articles, three studies (n = 1443) met criteria for inclusion in data synthesis. Data were extracted and risk of bias assessed by two independent reviewers using predefined criteria. Results: No statistically significant association was found between fracture incidence and the discontinuation of therapy beyond 5 years for any type of fracture: clinical nonvertebral fracture (relative risk [RR] = 0.97; 95% confidence interval [CI] 0.77–1.23), clinical vertebral fracture (RR = 0.61; 95% CI 0.32–1.19), or morphometric vertebral fracture (RR = 0.90; 95% CI 0.5–1.64). No differences in adverse events were identified between the two groups. Conclusion: We found no significant difference in fracture risk or adverse events between postmenopausal women with primary osteoporosis who continued bisphosphonate therapy versus those who discontinued bisphosphonate therapy after 5 years of treatment. However, given the small number and limited quality of available studies, no firm conclusions or recommendations can be made.

Falls and Fractures With Atypical Antipsychotic Medication Use: A Population-Based Cohort Study

Discussion | In this study of health care utilization data, use of amiodarone but not of other antiarrhythmic drugs was associated with a 50% increased odds of acute pancreatitis among patients with NVAF. The odds were almost doubled in the 12 months after amiodarone therapy initiation and did not depend on cumulative use of amiodarone. Considering an incidence of acute pancreatitis of 3 to 4 cases per 10 000 adults per year,4 the observed association would result in approximately 1 to 2 additional cases of acute pancreatitis per 10 000 amiodarone users per year. A few isolated case reports of acute pancreatitis possibly linked to amiodarone use have been described in the literature.1-3 The mechanisms responsible for this association are unknown, although direct cytotoxicity or immune-mediated pathways, as described for amiodarone-related pulmonary toxic effects, could be potential explanations.5 Strengths of our study include the prospective assessment of medication use, the large sample size, and the availability of information on comorbidities and use of other medications potentially associated with increased risk of acute pancreatitis. Limitations are related to the use of health care utilization data: limited information on the validity of claims for acute pancreatitis, absence of clinical variables that characterize severity of the episode (eg, blood markers of acute pancreatitis), and the select group of patients included in this database. Our results indicate that acute pancreatitis could be an adverse effect of amiodarone use, an effect that may not be shared by other antiarrhythmic drugs. Even though the absolute risk of acute pancreatitis in the general population is low, health care professionals should be aware of this potential association in the treatment of patients with NVAF or acute pancreatitis. Further research should replicate our findings and determine potential mechanisms.

Glucocorticoid-induced osteoporosis: treatment update and review

Glucocorticoid-induced osteoporosis (GIO) is a serious consequence of glucocorticoid therapy leading to fractures in 30—50% of patients. A wide range of protective medications have been studied in this condition including calcium, vitamin D, vitamin D analogs, oral and intravenous bisphosphonates, sex hormones, anabolic agents and calcitonin. The mechanism of action, and evidence for these therapies, are reviewed — focusing on important trials and new evidence. Recently published guidelines are also reviewed and compared. Bisphosphonates are currently the recommended first-line therapy for the prevention and treatment of GIO. They have been shown to increase bone mineral density (BMD) at the spine and hip and to decrease the incidence of vertebral fractures (especially in postmenopausal women). Testosterone therapy and female hormone replacement therapy (HRT) have been found to increase lumbar spine BMD in hypogonadal patients on glucocorticoid therapy, but effects on hip BMD have not been consistent and there is no fracture data in the GIO population. Similarly, calcitonin increases lumbar spine BMD but has no proven fracture efficacy. The effect of selective estrogen receptor modulators, the oral contraceptive pill and strontium on GIO is relatively unknown. Parathyroid hormone (PTH 1-34) and zoledronic acid have emerged as exciting new options for the treatment of GIO. Both therapies have been found to result in gains in BMD at the spine and hip that are either noninferior or superior to those seen with oral bisphosphonate therapy. PTH 1-34 has also been found to decrease the incidence of new vertebral fractures and may be an option in high-risk patients established on long-term glucocorticoid therapy.

Fracture incidence in adult kidney transplant recipients

Background It remains uncertain whether kidney transplant recipients are a high-risk group for fracture. Methods We conducted a cohort study using Ontario, Canada health care databases to estimate the 3-, 5- and 10-year cumulative incidence of nonvertebral fracture (proximal humerus, forearm, hip) in adult kidney transplant recipients between 1994 and 2009, stratifying by sex and age (<50 versus ≥50 years) at transplant. We also assessed the 3-year cumulative incidence of all fracture locations (excluding skull, toes, and fingers) and falls, 10-year cumulative incidence of hip fracture alone, and nonvertebral fracture incidence in recipients compared to nontransplant reference groups matched on age, sex, and cohort entry year. We studied 4821 recipients (median age, 50 years). Results Among the age and sex strata, female recipients aged 50 years or older had the highest 3-year cumulative incidence of nonvertebral fracture (3.1%; 95% confidence interval [95% CI], 2.1-4.4%). Recipients had a higher 3-year cumulative incidence of nonvertebral fracture (1.6%; 95% CI, 1.3-2.0%) compared to the general population with no previous nonvertebral fracture (0.5%; 95% CI, 0.4-0.6%; P < 0.0001) and nondialysis chronic kidney disease (1.1%; 95% CI, 0.9-1.2%; P = 0.03), but a lower fracture incidence than the general population with a previous nonvertebral fracture (2.3%; 95% CI, 1.9-2.8%; P = 0.007). The 10-year cumulative incidence of hip fracture in all recipients was 1.7% (≥3% defined as high risk in clinical guidelines). Conclusions Kidney transplant recipients may have a lower fracture risk than previously suggested in the literature. Results inform our understanding of fracture incidence after kidney transplantation and how it compares to nontransplant populations.

Effect of Anticholinergic Medications on Falls, Fracture Risk, and Bone Mineral Density Over a 10-Year Period:

Background: Many medications used in older adults have strong anticholinergic (ACH) properties, which may increase the risk of falls and fractures. Use of these medications was identified in a population-based Canadian cohort. Objective: To identify the fall and fracture risk associated with ACH medication use. Methods: Data collection and analysis were conducted at baseline, year 5, and year 10. Cross-sectional analyses were performed to examine associations between ACH medication use and falls. Time-dependent Cox regression was used to examine time to first nontraumatic fracture. Finally, change in bone mineral density (BMD) over 10 years was compared in ACH medication users versus nonusers. Results: Strongly ACH medications were used by 618 of 7753 participants (8.0%) at study baseline, 592 (9.5%) at year 5, and 334 (7.7%) at year 10. Unadjusted ACH medication use was associated with falls at baseline (odds ratio = 1.50; 95% CI = 1.14-1.98; P = 0.004), but the association was no longer significant after covariate adjustment. Similar results occurred at years 5 and 10. ACH medication use was associated with increased incident fracture risk before (hazard ratio = 1.22; CI = 1.13-1.32; P < 0.001) but not after covariate adjustment. Mean (SD) change in femoral neck BMD T-score over 10 years, in those using ACH medications at both years 0 and 5, was −0.60 (0.63) in ACH users versus −0.49 (0.45) in nonusers (P = 0.041), but this was not significant after covariate adjustment. Conclusions: ACH medications were not found to be independently associated with an increased risk of falling, fractures, or BMD loss. Rather, factors associated with ACH medication use explained the apparent associations.