Grade 1 Vertebral Fractures Identified by Densitometric Lateral Spine Imaging Predict Incident Major Osteoporotic Fracture Independently of Clinical Risk Factors and Bone Mineral Density in Older Women.

Because prevalent vertebral fracture (VF) is a strong predictor of future fractures, they are important to identify in clinical practice as osteoporosis medications are effective and can be used to reduce fracture risk in postmenopausal women with VF. Lateral spine imaging (LSI) with dual-energy X-ray absorptiometry (DXA) can be used to diagnose VFs accurately but is not widespread in clinical practice. The prognostic value of grade 1 (20% to 25% compression) VFs diagnosed by LSI with DXA has been insufficiently studied. The aim of this study was to determine if grade 1 VF is associated with incident fracture in older women. Sahlgrenska University Hospital Prospective Evaluation of Risk of Bone Fractures (SUPERB) is a population-based study of 3028 older women from Gothenburg, Sweden. Included women were 75 to 80 years of age at baseline, answered questionnaires, and were scanned with DXA (Discovery A, Hologic, Waltham, MA, USA). LSI was used to diagnose VFs, which were classified using the Genant semiquantitative method. Cox regression models were used to estimate the association between VFs at baseline and X-ray-verified incident fractures, with adjustment for confounders. Women with a grade 1 VF (n = 264) or a grade 2-3 VF (n = 349) were compared with women without any fracture (n = 1482). During 3.6 years (median, interquartile range [IQR] 1.5 years) of follow-up, 260 women had any incident fracture and 213 a major osteoporotic fracture (MOF). Women with only grade 1 VF had increased risk of any fracture (hazard ratio [HR] = 1.67; 95% confidence interval [CI] 1.18-2.36) and MOF (HR = 1.86; 95% CI 1.28-2.72). For MOF, this association remained after adjustment for clinical risk factors and femoral neck bone mineral density (BMD). In conclusion, grade 1 VFs were associated with incident MOF, also after adjustment for clinical risk factors and BMD, indicating that all VF identified by DXA should be considered in the evaluation of fracture risk in older women. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..

Longitudinal associations between sex hormone-binding globulin and insulin resistance.

PURPOSE: We aimed to investigate the association between SHBG and the homeostatic model assessment of insulin resistance (HOMA-Ir) in men and women in a prospective observational study. METHODS: The Vara-Skövde cohort is a random population of 2816 participants living in southwestern Sweden, aged 30-74. It was recruited between 2002 and 2005, and followed up in 2012-2014. After excluding participants on insulin therapy or hormone replacement therapy, 1193 individuals (649 men, 544 women) were included in the present study. Fasting blood samples were collected at both visits and stored in biobank. All participants were physically examined by a trained nurse. SHBG was measured with immunoassay technique. Linear regressions were computed to investigate the association between SHBG and HOMA-Ir both in cross-sectional and longitudinal analyses, adjusting for confounding factors. RESULTS: The mean follow-up time was 9.7 ± 1.4 years. Concentrations of SHBG were significantly inversely associated with log transformed HOMA-Ir in all groups with estimated standardized slopes (95% CI): men: -0.20 (-0.3;-0.1), premenopausal women: -0.26 (-0.4;-0.2), postmenopausal women: -0.13 (-0.3;-0.0) at visit 1. At visit 2 the results were similar. When comparing the groups, a statistically significant difference was found between men and post-menopausal women (0.12 (0.0;0.2) P value = 0.04). In the fully adjusted model, SHBG at visit 1 was also associated with HOMA-Ir at visit 2, and the estimated slopes were -0.16 (-0.2;-0.1), -0.16 (-0.3;-0.1) and -0.07 (-0.2;0.0) for men, premenopausal and postmenopausal women, respectively. MAIN CONCLUSION: Levels of SHBG predicted the development of insulin resistance in both men and women, regardless of menopausal state.

Association Between Cortical Bone Microstructure and Statin Use in Older Women.

Context: Treatment with statins has been associated with increased bone mineral density, but whether this association depends on differences in cortical or trabecular volumetric bone microstructure is unknown. Objective: The aim of this study was to investigate if treatment with statins is associated with bone microstructure and geometry in older women. Design Setting and Participants: Older women were included in a population-based study of 3028 women (mean age ± SD, 77.8 ± 1.6 years) from the greater Gothenburg area in Sweden. Information regarding medical history, medication, and lifestyle factors was obtained from validated questionnaires. Main Outcome: Bone geometry and microstructure were measured at the ultradistal and distal (14%) site of radius and tibia using high-resolution peripheral quantitative computed tomography. Results: The 803 women in the cohort who used statins had higher body weight, worse physical function, and more frequent cardiovascular disease and diabetes than nonusers (P < 0.05). Statin users had lower cortical porosity (radius, 2.2 ± 1.9 vs 2.5 ± 2.0%; tibia, 5.2 ± 2.4 vs 5.4 ± 2.5; P = 0.01), higher cortical bone density (radius, 1008 ± 39.1 vs 1001 ± 38.4 mg/cm3; tibia, 919 ± 42.6 vs 914 ± 41.5; P < 0.01), and greater cortical area (radius, 60.5 ± 9.6 vs 58.6 ± 9.7 mm2; tibia, 150.0 ± 23.6 vs 146.7 ± 23.8; P < 0.01) than nonusers after adjustment for a large number of confounders, including age, weight, smoking, other medications, and prevalent diseases. Conclusions: Use of statins was associated with better cortical bone characteristics in older women.

The association between serum testosterone and insulin resistance: a longitudinal study.

The objective of this study was to investigate whether there is a bidirectional association between testosterone concentrations and insulin resistance, in a prospective population study. A random population sample of 1400 men, aged 30-74, was examined in 2002-2005 in southwestern Sweden and followed up in 2012-2014 (N = 657). After excluding subjects without information on sex hormones and insulin resistance, 1282 men were included in the baseline study. Fasting measurements of plasma glucose, insulin and hormones were performed. Insulin resistance was defined using HOMA-Ir. Mean age at baseline was 47.3 ± 11.4 years. From the follow-up survey 546 men were included, mean age 57.7 ± 11.6 years. Low concentrations of total testosterone at baseline were significantly associated with high logHOMA-Ir at follow-up in a multivariable model including age, waist-hip ratio, physical activity, alcohol intake, smoking, LDL, CRP, hypertension, diabetes and logHOMA-Ir at baseline as covariates (ß = -0.096, P = 0.006). Similar results were observed for bioavailable testosterone. Men within the lowest quartile of total testosterone at baseline had significantly higher logHOMA-Ir at follow-up than other quartiles (Q1 vs Q2 P = 0.008, Q1 vs Q3 P = 0.001, Q1 vs Q4 P = 0.052). Multivariable analysis of the impact of insulin resistance at baseline on testosterone levels at follow-up revealed no significant associations regarding testosterone concentrations (ß = -0.003, P = 0.928) or bioavailable testosterone (ß = -0.006, P = 0.873), when adjusting for baseline concentrations of total testosterone, age, waist-hip-ratio, LDL, CRP, physical activity, alcohol intake, smoking, hypertension and diabetes. Low testosterone concentrations at baseline predicted higher insulin resistance at follow-up, but high insulin resistance at baseline could not predict low testosterone at follow-up.

Normal Bone Microstructure and Density But Worse Physical Function in Older Women Treated with Selective Serotonin Reuptake Inhibitors, a Cross-Sectional Population-Based Study.

Depression in the elderly is today often treated with selective serotonin reuptake inhibitors (SSRIs) because of their favorable adverse effect profile. However, treatment with SSRIs is associated with increased risk of fractures. Whether this increased risk depends on reduced bone strength or increased fall risk due to reduced physical function is not certain. The aim was therefore to investigate if treatment with SSRIs is associated with impaired bone microstructure, bone density, or physical function in older women. From an ongoing population-based study, 1057 women (77.7 ± 1.5 years) were included. Validated questionnaires were used to assess information regarding medical history, medications, smoking, mental and physical health, and physical activity. Physical function was measured using clinically used tests: timed up and go, walking speed, grip strength, chair stand test, and one leg standing. Bone mineral density (BMD) was measured at the hip and spine with dual-energy X-ray absorptiometry (Hologic Discovery A). Bone geometry and microstructure were measured at the ultradistal and distal (14%) site of radius and tibia using high-resolution peripheral quantitative computed tomography (HR-pQCT; XtremeCT). Treatment with SSRIs was associated with higher BMD at the femoral neck, total hip, and lumbar spine, whereas no associations were found for any HR-pQCT-derived measurements. The use of SSRIs was associated with lower grip strength, walking speed, and fewer chair stand rises. These associations were valid also after adjustments for known risk factors for falls. Treatment with SSRIs was, independently of covariates, associated with worse physical function without any signs of inferior bone geometry and microstructure.

The Prevalence of Vertebral Fractures Is Associated With Reduced Hip Bone Density and Inferior Peripheral Appendicular Volumetric Bone Density and Structure in Older Women.

Vertebral fractures (VFs) are among the most severe and prevalent osteoporotic fractures. Their association with bone microstructure have been investigated in several retrospective case-control studies with spine radiography for diagnosis of VF. The aim of this population-based cross-sectional study of 1027 women aged 75 to 80 years was to investigate if prevalent VF, identified by vertebral fracture assessment (VFA) by dual-energy X-ray absorptiometry (DXA), was associated with appendicular volumetric bone density, structure, and bone material strength index (BMSi), independently of hip areal bone mineral density (aBMD). aBMD was measured using DXA (Discovery; Hologic); BMSi with microindentation (Osteoprobe); and bone geometry, volumetric BMD, and microstructure with high-resolution peripheral quantitative computed tomography (HRpQCT) (XtremeCT; Scanco Medical AG). aBMD was lower (spine 3.2%, total hip [TH] 3.8%) at all sites in women with VF, but tibia BMSi did not differ significantly compared to women without VF. In multivariable adjusted logistic regression models, radius trabecular bone volume fraction and tibia cortical area (odds ratio [OR] 1.26; 95% confidence interval [CI], [1.06 to 1.49]; and OR 1.27 [95% CI, 1.08 to 1.49], respectively) were associated with VF prevalence, whereas BMSi and cortical porosity were not. The risk of having one, two, or more than two VFs was increased 1.27 (95% CI, 1.04 to 1.54), 1.83 (95% CI, 1.28 to 2.61), and 1.78 (95% CI, 1.03 to 3.09) times, respectively, for each SD decrease in TH aBMD. When including either cortical area, trabecular bone volume fraction or TBS in the model together with TH aBMD and covariates, only TH aBMD remained independently associated with presence of any VF. In conclusion, TH aBMD was consistently associated with prevalent VFA-verified VF, whereas neither trabecular bone volume fraction, cortical area, cortical porosity, nor BMSi were independently associated with VF in older women. © 2017 American Society for Bone and Mineral Research.

Association Between Alendronate Use and Hip Fracture Risk in Older Patients Using Oral Prednisolone.

IMPORTANCE: Oral glucocorticoid treatment increases fracture risk, and evidence is lacking regarding the efficacy of alendronate to protect against hip fracture in older patients using glucocorticoids. OBJECTIVE: To investigate whether alendronate treatment in older patients using oral prednisolone is associated with decreased hip fracture risk and adverse effects. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study using a national database (N = 433 195) of patients aged 65 years or older undergoing a health evaluation (baseline) at Swedish health care facilities; 1802 patients who were prescribed alendronate after at least 3 months of oral prednisolone treatment (≥5 mg/d) were identified. Propensity score matching was used to select 1802 patients without alendronate use from 6076 patients taking prednisolone with the same dose and treatment time criteria. Follow-up occurred between January 2008 and December 2014. EXPOSURES: Alendronate vs no alendronate use; no patients had previously taken alendronate at the time of prednisolone initiation. MAIN OUTCOMES AND MEASURES: The primary outcome was incident hip fracture. RESULTS: Of the 3604 included patients, the mean age was 79.9 (SD, 7.5) years, and 2524 (70%) were women. After a median follow-up of 1.32 years (interquartile range, 0.57-2.34 years), there were 27 hip fractures in the alendronate group and 73 in the no-alendronate group, corresponding to incidence rates of 9.5 (95% CI, 6.5-13.9) and 27.2 (95% CI, 21.6-34.2) fractures per 1000 person-years, with an absolute rate difference of -17.6 (95% CI, -24.8 to -10.4). The use of alendronate was associated with a lower risk of hip fracture in a multivariable-adjusted Cox model (hazard ratio, 0.35; 95% CI, 0.22-0.54). Alendronate treatment was not associated with increased risk of mild upper gastrointestinal tract symptoms (alendronate vs no alendronate, 15.6 [95% CI, 11.6-21.0] vs 12.9 [95% CI, 9.3-18.0] per 1000 person-years; P = .40) or peptic ulcers (10.9 [95% CI, 7.7-15.5] vs 11.4 [95% CI, 8.0-16.2] per 1000 person-years; P = .86). There were no cases of incident drug-induced osteonecrosis and only 1 case of femoral shaft fracture in each group. CONCLUSIONS AND RELEVANCE: Among older patients using medium to high doses of prednisolone, alendronate treatment was associated with a significantly lower risk of hip fracture over a median of 1.32 years. Although the findings are limited by the observational study design and the small number of events, these results support the use of alendronate in this patient group.

Higher glucocorticoid replacement doses are associated with increased mortality in patients with pituitary adenoma.

OBJECTIVE: Patients with secondary adrenal insufficiency (AI) have an excess mortality. The objective was to investigate the impact of the daily glucocorticoid replacement dose on mortality in patients with hypopituitarism due to non-functioning pituitary adenoma (NFPA). METHODS: Patients with NFPA were followed between years 1997 and 2014 and cross-referenced with the National Swedish Death Register. Standardized mortality ratio (SMR) was calculated with the general population as reference and Cox-regression was used to analyse the mortality. RESULTS: The analysis included 392 patients (140 women) with NFPA. Mean ± s.d. age at diagnosis was 58.7 ± 14.6 years and mean follow-up was 12.7 ± 7.2 years. AI was present in 193 patients, receiving a mean daily hydrocortisone equivalent (HCeq) dose of 20 ± 6 mg. SMR (95% confidence interval (CI)) for patients with AI was similar to that for patients without, 0.88 (0.68-1.12) and 0.87 (0.63-1.18) respectively. SMR was higher for patients with a daily HCeq dose of >20 mg (1.42 (0.88-2.17)) than that in patients with a daily HCeq dose of 20 mg (0.71 (0.49-0.99)), P = 0.017. In a Cox-regression analysis, a daily HCeq dose of >20 mg was independently associated with a higher mortality (HR: 1.88 (1.06-3.33)). Patients with daily HCeq doses of ≤20 mg had a mortality risk comparable to patients without glucocorticoid replacement and to the general population. CONCLUSION: Patients with NFPA and AI receiving more than 20 mg HCeq per day have an increased mortality. Our data also show that mortality in patients substituted with 20 mg HCeq per day or less is not increased.

Incidence of malignant tumours in patients with a non-functioning pituitary adenoma.

Whether patients with non-functioning pituitary adenoma (NFPA) are at increased risk of developing malignant tumours has been sparsely studied and is a matter of debate. In this study, we have investigated the incidence of malignant tumours in a large and unselected group of patients with NFPA. The study was nationwide and included all patients diagnosed with NFPA between 1987 and 2011 (n = 2795) in Sweden, identified in the National Patient Register. Malignant tumours, occurring after the NFPA diagnosis, were identified in the Swedish Cancer Register between 1987 and 2014. Standardised incidence ratios (SIRs) for malignant tumours with 95% confidence intervals (CI) were calculated using the Swedish population as reference. In total, 448 malignant tumours were detected in 386 patients with NFPA, as compared to 368 expected malignancies in the general population (SIR 1.22 (95% CI 1.11-1.33)). The incidence of neoplasms of the brain was increased (SIR 5.83 (95% CI 4.03-8.14)). When analysing the total incidence of malignancies excluding neoplasms of the brain, the overall SIR was still increased (SIR 1.14 (95% CI 1.03-1.26)). The incidence of malignant neoplasm of skin other than malignant melanoma (SIR 1.99 (95% CI 1.55-2.52)) and malignant melanoma (SIR 1.62 (95% CI 1.04-2.38)) were increased, whereas the incidence of breast cancer (SIR 0.65 (95% CI 0.42-0.97)) was decreased. The incidence of other types of malignancies did not differ significantly from the expected incidence in the general population. In conclusion, patients with NFPA have an increased overall risk of developing malignancies. To what extent these findings are due to more frequent medical surveillance, genetic predisposition or endocrine changes, remains unknown.

Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency: a phase 3b, open-label, extension study.

OBJECTIVE: To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI). DESIGN: Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden. METHODS: Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruited. Safety and tolerability outcomes included adverse events (AEs), intercurrent illness episodes, laboratory parameters and vital signs. Quality of life (QoL) was evaluated using generic questionnaires. RESULTS: Total DR-HC exposure was 328 patient-treatment years. Seventy patients reported 1060 AEs (323 per 100 patient-years); 85% were considered unrelated to DR-HC by the investigator. The most common AEs were nasopharyngitis (70%), fatigue (52%) and gastroenteritis (48%). Of 65 serious AEs reported by 32 patients (20 per 100 patient-years), four were considered to be possibly related to DR-HC: acute AI (n = 2), gastritis (n = 1) and syncope (n = 1). Two deaths were reported (fall from height and subarachnoid hemorrhage), both considered to be unrelated to DR-HC. From baseline to 5 years, intercurrent illness episodes remained relatively stable (mean 2.6-5.4 episodes per patient per year), fasting plasma glucose (0.7 mmol/L; P < 0.0001) and HDL cholesterol (0.2 mmol/L; P < 0.0001) increased and patient-/investigator-assessed tolerability improved. QoL total scores were unchanged but worsening physical functioning was recorded (P = 0.008). CONCLUSIONS: In the first prospective study evaluating the long-term safety of glucocorticoid replacement therapy in patients with primary AI, DR-HC was well tolerated with no safety concerns observed during 5-year treatment.

Type 2 Diabetes Mellitus Is Associated With Better Bone Microarchitecture But Lower Bone Material Strength and Poorer Physical Function in Elderly Women: A Population-Based Study.

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of fractures according to several studies. The underlying mechanisms remain unclear, although small case-control studies indicate poor quality of the cortical bone. We have studied a population-based sample of women aged 75 to 80 years in Gothenburg, randomly invited from the population register. Areal bone mineral density (aBMD) was measured by dual-energy X-ray absorptiometry (Hologic Discovery A), bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT; ExtremeCT from Scanco Medical AG), and reference point indentation was performed with Osteoprobe (Active Life Scientific). Women with T2DM (n = 99) had higher aBMD compared to controls (n = 954). Ultradistal tibial and radial trabecular bone volume fraction (+11% and +15%, respectively), distal cortical volumetric BMD (+1.6% and +1.7%), cortical area (+11.5% and +9.3%), and failure load (+7.7% and +12.9%) were higher in diabetics than in controls. Cortical porosity was lower (mean ± SD: 1.5% ± 1.1% versus 2.0% ± 1.7%, p = 0.001) in T2DM in the distal radius but not in the ultradistal radius or the tibia. Adjustment for covariates (age, body mass index, glucocorticoid treatment, smoking, physical activity, calcium intake, bone-active drugs) eliminated the differences in aBMD but not in HR-pQCT bone variables. However, bone material strength index (BMSi) by reference point indentation was lower in T2DM (74.6 ± 7.6 versus 78.2 ± 7.5, p < 0.01), also after adjustment, and women with T2DM performed clearly worse in measures of physical function (one leg standing: -26%, 30-s chair-stand test: -7%, timed up and go: +12%, walking speed: +8%; p < 0.05-0.001) compared to controls. In conclusion, we observed a more favorable bone microarchitecture but no difference in adjusted aBMD in elderly women with T2DM in the population compared to nondiabetics. Reduced BMSi and impaired physical function may explain the increased fracture risk in T2DM. © 2016 American Society for Bone and Mineral Research.

Type 2 Diabetes and Risk of Hip Fractures and Non-Skeletal Fall Injuries in the Elderly: A Study From the Fractures and Fall Injuries in the Elderly Cohort (FRAILCO).

Questions remain about whether the increased risk of fractures in patients with type 2 diabetes (T2DM) is related mainly to increased risk of falling or to bone-specific properties. The primary aim of this study was to investigate the risk of hip fractures and non-skeletal fall injuries in older men and women with and without T2DM. We included 429,313 individuals (aged 80.8 ± 8.2 years [mean ± SD], 58% women) from the Swedish registry "Senior Alert" and linked the data to several nationwide registers. We identified 79,159 individuals with T2DM (45% with insulin [T2DM-I], 41% with oral antidiabetics [T2DM-O], and 14% with no antidiabetic treatment [T2DM-none]) and 343,603 individuals without diabetes. During a follow-up of approximately 670,000 person-years, we identified in total 36,132 fractures (15,572 hip fractures) and 20,019 non-skeletal fall injuries. In multivariable Cox regression models where the reference group was patients without diabetes and the outcome was hip fracture, T2DM-I was associated with increased risk (adjusted hazard ratio (HR) [95% CI] 1.24 [1.16-1.32]), T2DM-O with unaffected risk (1.03 [0.97-1.11]), and T2DM-none with reduced risk (0.88 [0.79-0.98]). Both the diagnosis of T2DM-I (1.22 [1.16-1.29]) and T2DM-O (1.12 [1.06-1.18]) but not T2DM-none (1.07 [0.98-1.16]) predicted non-skeletal fall injury. The same pattern was found regarding other fractures (any, upper arm, ankle, and major osteoporotic fracture) but not for wrist fracture. Subset analyses revealed that in men, the risk of hip fracture was only increased in those with T2DM-I, but in women, both the diagnosis of T2DM-O and T2DM-I were related to increased hip fracture risk. In conclusion, the risk of fractures differs substantially among patients with T2DM and an increased risk of hip fracture was primarily found in insulin-treated patients, whereas the risk of non-skeletal fall injury was consistently increased in T2DM with any diabetes medication. © 2016 American Society for Bone and Mineral Research.

Life expectancy in patients with pituitary adenoma receiving growth hormone replacement.

OBJECTIVE: Hypopituitarism has been associated with increased mortality. The excess mortality may be due to untreated growth hormone (GH) deficiency but also due to various underlying disorders. We therefore analysed mortality in patients with only one underlying disorder, non-functioning pituitary adenoma (NFPA), with and without GH replacement therapy (GHRT). DESIGN AND METHOD: Patients with NFPA in the western region of Sweden, 1997-2011, were identified through the National Patient Registry and cross-referenced with several National Health Registries. All patient records were reviewed. Standardised mortality ratios (SMRs) with 95% confidence intervals (CIs) were calculated using the general population as reference. Cox-regression models were performed to identify predictors of mortality. RESULTS: A total of 426 NFPA patients with 4599 patient-years were included, of whom 207 had used GHRT and 219 had not received GHRT. Median (range) follow-up in patients with and without GHRT was 12.2 (0-25) and 8.2 (0-27) years, respectively. Other pituitary hormone deficiencies were more frequent in the GHRT group than those in the non-GHRT group. SMR was 0.65 (95% CI, 0.44-0.94; P = 0.018) for the GHRT group and 1.16 (0.94-1.42; P = 0.17) for the non-GHRT group. Direct comparison between the groups showed reduced mortality among those who were GH replaced (P = 0.0063). The SMR for malignant tumours was reduced in the GHRT-group (0.29; 0.08-0.73; P = 0.004) but not in untreated patients. CONCLUSIONS: Selection bias explaining some of the results cannot be excluded. However, NFPA patients with GHRT had reduced overall mortality compared with the general population, and death due to malignancy was not increased. This suggests that long-term GHRT is safe in adult patients selected for treatment.

A High Amount of Local Adipose Tissue Is Associated With High Cortical Porosity and Low Bone Material Strength in Older Women.

Obesity is associated with increased risk of fractures, especially at skeletal sites with a large proportion of cortical bone, such as the humerus and ankle. Obesity increases fracture risk independently of BMD, indicating that increased adipose tissue could have negative effects on bone quality. Microindentation assesses bone material strength index (BMSi) in vivo in humans. The aim of this study was to investigate if different depots of adipose tissue were associated with BMSi and cortical bone microstructure in a population based group of 202 women, 78.2 ± 1.1 (mean ± SD) years old. Bone parameters and subcutaneous (s.c.) fat were measured at the tibia with an XtremeCT device. BMSi was assessed using the OsteoProbe device, and based on at least 11 valid reference point indentations at the mid-tibia. Body composition was measured with dual X-ray absorptiometry. BMSi was inversely correlated to body mass index (BMI) (r = -0.17, p = 0.01), whole body fat mass (r = -0.16,p = 0.02), and, in particular, to tibia s.c. fat (r = -0.33, p < 0.001). Tibia s.c. fat was also correlated to cortical porosity (Ct.Po; r = 0.19, p = 0.01) and cortical volumetric BMD (Ct.vBMD; r = -0.23, p = 0.001). Using linear regression analyses, tibia s.c. fat was found to be independent of covariates (age, height, log weight, bisphosphonates or glucocorticoid use, smoking, calcium intake, walking speed, and BMSi operator) and associated with BMSi (ß = -0.34,p < 0.001), Ct.Po (ß = 0.18, p = 0.01), and Ct.vBMD (ß = -0.32, p < 0.001). BMSi was independent of covariates associated with cortical porosity (ß = -0.14, p = 0.04) and cortical volumetric BMD (ß = 0.21, p = 0.02) at the distal tibia, but these bone parameters could only explain 3.3% and 5.1% of the variation in BMSi, respectively. In conclusion, fat mass was independently and inversely associated with BMSi and Ct.vBMD, but positively associated with Ct.Po, indicating a possible adverse effect of adipose tissue on bone quality and bone microstructure. Local s.c. fat in tibia was most strongly associated with these bone traits, suggesting a local or paracrine, rather than systemic, negative effect of fat on bone.

Excess Mortality in Women and Young Adults With Nonfunctioning Pituitary Adenoma: A Swedish Nationwide Study.

CONTEXT: Patients with hypopituitarism of various etiologies have excess mortality. The mortality in patients with nonfunctioning pituitary adenoma (NFPA), regardless of pituitary function, is less well studied. OBJECTIVE: Our aim was to investigate mortality in patients with NFPA and to examine whether age at diagnosis, gender, tumor treatments, or hormonal deficiencies influence the outcome. DESIGN: NFPA patients were identified and followed up in nationwide health registries in Sweden, 1987-2011. The criteria for identification were tested and validated in a subpopulation of the patients. SETTINGS: This was a nationwide, population-based study. PATIENTS: A total of 2795 unique patients with NFPA (1502 men, 1293 women) were identified and included in the study. Mean age at diagnosis was 58 years (men, 60 y; women, 56 y) and mean follow-up time was 7 years (range 0-25 y). INTERVENTION: There were no interventions. MAIN OUTCOME MEASURES: Standardized mortality ratios (SMRs) and annual incidence rates were calculated using the Swedish population as reference and presented with 95% confidence intervals. RESULTS: Annual incidence of NFPA was 20.3 (18.8-21.9) cases per 1 million inhabitants. During the observation period, 473 patients died against an expected 431, resulting in an SMR of 1.10 (1.00-1.20). Patients diagnosed at younger than 40 years of age had an increased SMR of 2.68 (1.23-5.09). The SMR for patients with hypopituitarism (n = 1500) was 1.06 (0.94-1.19), and for patients with diabetes insipidus (n = 145), it was 1.71 (1.07-2.58). The SMR was increased in women with NFPA (1.29; 1.11-1.48) but not in men (1.00; 0.88-1.12). Women, but not men, with a diagnosis of hypopituitarism and/or diabetes insipidus also had an increased mortality ratio. SMRs due to cerebrovascular (1.73; 1.34-2.19) and infectious diseases (2.08; 1.17-3.44) were increased, whereas the SMR for malignant tumors was decreased (0.76; 0.61-0.94). CONCLUSIONS: This nationwide study of patients with NFPA showed an overall excess mortality in women and in patients with a young age at diagnosis. Increased mortality was seen for cerebrovascular and infectious diseases.

Excess mortality and morbidity in patients with craniopharyngioma, especially in patients with childhood onset: a population-based study in Sweden.

CONTEXT: Craniopharyngiomas (CPs) in adults have been associated with excess mortality. OBJECTIVE: The aim of the study was to investigate mortality and morbidity in patients with childhood-onset and adult-onset CP. METHODS: PATIENTS with CP were identified and followed in Swedish national health registries, 1987 through 2011. The inclusion criteria for the CP diagnosis were internally validated against patient records in 28% of the study population. SETTINGS: This was a nationwide population-based study. PATIENTS: A total of 307 patients (151 men and 156 women) were identified and included (mean follow-up, 9 years; range, 0-25 years). The inclusion criteria had a positive predictive value of 97% and a sensitivity of 92%. INTERVENTION: There were no interventions. MAIN OUTCOME MEASURES: Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) with 95% confidence intervals were calculated using the Swedish population as the reference. RESULTS: During the study, 54 patients died compared with the expected number of 14.1, resulting in an SMR of 3.2 (2.2-4.7) for men and 4.9 (3.2-7.2) for women. PATIENTS with childhood-onset (n = 106) and adult-onset (n = 201) CP had SMRs of 17 (6.3-37) and 3.5 (2.6-4.6), respectively. PATIENTS with hypopituitarism (n = 250), diabetes insipidus (n = 110), and neither of these (n = 54) had SMRs of 4.3 (3.1-5.8), 6.1 (3.5-9.7), and 2.7 (1.4-4.6), respectively. The SMR due to cerebrovascular diseases was 5.1 (1.7-12). SIRs were 5.6 (3.8-8.0) for type 2 diabetes mellitus, 7.1 (5.0-9.9) for cerebral infarction, 0.7 (0.2-1.7) for myocardial infarction, 2.1 (1.4-3.0) for fracture, and 5.9 (3.4-9.4) for severe infection. The SIR for all malignant tumors was 1.3 (0.8-2.1). CONCLUSIONS: This first nationwide population-based study of patients with CP demonstrated excess mortality that was especially marked in patients with childhood-onset disease and among women. Death due to cerebrovascular diseases was increased 5-fold. Hypopituitarism and diabetes insipidus were negative prognostic factors for mortality and morbidity. PATIENTS with CP had increased disease burden related to type 2 diabetes mellitus, cerebral infarction, fracture, and severe infection.

Extracellular water and blood pressure in adults with growth hormone (GH) deficiency: a genotype-phenotype association study.

OBJECTIVES: Growth hormone deficiency (GHD) in adults is associated with decreased extracellular water volume (ECW). In response to GH replacement therapy (GHRT), ECW increases and blood pressure (BP) reduces or remains unchanged. Our primary aim was to study the association between polymorphisms in genes related to renal tubular function with ECW and BP before and 1 year after GHRT. The ECW measures using bioimpedance analysis (BIA) and bioimpedance spectroscopy (BIS) were validated against a reference method, the sodium bromide dilution method (Br(-)). DESIGN AND METHODS: Using a candidate gene approach, fifteen single-nucleotide polymorphisms (SNPs) in nine genes with known impact on renal tubular function (AGT, SCNN1A, SCNN1G, SLC12A1, SLC12A3, KCNJ1, STK39, WNK1 and CASR) were genotyped and analyzed for associations with ECW and BP at baseline and with their changes after 1 year of GHRT in 311 adult GHD patients. ECW was measured with the Br(-), BIA, and BIS. RESULTS: Both BIA and BIS measurements demonstrated similar ECW results as the reference method. At baseline, after adjustment for sex and BMI, SNP rs2291340 in the SLC12A1 gene was associated with ECW volume in GHD patients (p = 0.039). None of the SNPs influenced the ECW response to GHRT. One SNP in the SLC12A3 gene (rs11643718; p = 0.024) and three SNPs in the SCNN1G gene [rs5723 (p = 0.02), rs5729 (p = 0.016) and rs13331086 (p = 0.035)] were associated with the inter-individual differences in BP levels at baseline. A polymorphism in the calcium-sensing receptor (CASR) gene (rs1965357) was associated with changes in systolic BP after GHRT (p = 0.036). None of these associations remained statistically significant when corrected for multiple testing. CONCLUSION: The BIA and BIS are as accurate as Br(-) to measure ECW in GHD adults before and during GHRT. Our study provides the first evidence that individual polymorphisms may have clinically relevant effects on ECW and BP in GHD adults.

SNPs within the GH-signaling pathway are associated with the early IGF1 response to GH replacement therapy in GHD adults.

OBJECTIVE: GH-deficient (GHD) adults have reduced serum concentrations of IGF1. GH replacement therapy increases serum IGF1 concentrations, but the interindividual variation in treatment response is large and likely influenced by genetic factors. This study was designed to test the hypothesis that single-nucleotide polymorphisms (SNPs) in genes within the GH signaling pathway influence the serum IGF1 response to GH replacement. DESIGN AND METHODS: A total of 313 consecutive GHD adults (58.1% men; mean age 49.7 years) were studied before and after 1 week, 6 months, and 1 year of GH treatment. GH dose was individually titrated to normalize serum IGF1 levels. Six SNPs in the GH receptor (GHR) and the GH signaling pathway (JAK2, STAT5B, SOCS2, and PIK3CB) genes were selected for genotyping. The GHR exon 3-deleted/full-length (d3/fl) polymorphism was analyzed using tagSNP rs6873545. RESULTS: After 1 week of GH replacement, homozygotes of the fl-GHR showed a better IGF1 response to GH than carriers of the d3-GHR (P=0.016). Conversely, homozygotes of the minor allele of PIK3CB SNP rs361072 responded better than carriers of the major allele (P=0.025). Compared with baseline, both SNPs were associated with the IGF1 response at 6 months (P=0.041 and P=0.047 respectively), and SNP rs6873545 was further associated with the IGF1 response at 1 year (P=0.041). CONCLUSIONS: Our results indicate that common genetic variants in the GH signaling pathway may be of functional relevance to the response to GH replacement in GHD adults.