Cancer risk in patients treated with denosumab compared with alendronate: A population-based cohort study.

BACKGROUND: Antiresorptive treatment is currently used in millions of patients with osteoporosis and cancer worldwide. Early studies of denosumab suggested a small signal in ovarian cancer incidence and emerging data suggest that denosumab stimulates germ cell proliferation in the gonads. This study aims to determine the association between the use of denosumab and the risk of reproductive cancers compared with the use of alendronate. RESEARCH DESIGN AND METHODS: Using a cohort study design, we used the Danish nationwide registries to identify a population of subjects ≥50 years of age during 2010-2017 who started denosumab after being on alendronate treatment for at least six months. The cohort was matched 1:2 with patients who had been treated with alendronate alone for at least six months. The risk of reproductive cancers and the risk difference between groups were estimated using the Longitudinal Targeted Maximum Likelihood Estimation (L-TMLE) method. RESULTS: We identified 6054 Danish individuals who underwent treatment with denosumab. These individuals were matched with 12,108 receiving alendronate. The absolute risk of reproductive cancer was 1.05 % (95 % CI 0.75-1.34) after three years for denosumab users and was not different 0.03 % (-0.34-0.39) than for alendronate users. In supplemental analyses, there was no increased risk of non-reproductive cancers associated with the use of denosumab (risk difference of 0.54 % (-0.41-1.19). Analysis comparing denosumab users with the general population gave similar results. CONCLUSION: There was no difference in the risk of cancer following treatment with denosumab compared to treatment with alendronate assessed after a short follow-up of 3 years.

The effects of postprandial exercise and meal glycemic index on plasma glucose and glucoregulatory hormone responses after Roux-en-Y gastric bypass.

Postprandial hypoglycemia is a complication of Roux-en-Y gastric bypass (RYGB), but the effects of postprandial exercise and meal glycemic index (GI) on postprandial glucose and glucoregulatory hormone responses are unknown. Ten RYGB-operated and 10 age and weight-matched unoperated women completed four test days in random order ingesting mixed meals with high GI (HGI, GI = 93) or low GI (LGI, GI = 54), but matched on energy and macronutrient content. Ten minutes after meal completion, participants rested or cycled for 30 min at 70% of maximum oxygen uptake (V̇o2max). Blood was collected for 4 h. Postprandial exercise did not lower plasma nadir glucose in RYGB after HGI (HGI/rest 3.7 ± 0.5 vs. HGI/Ex 4.1 ± 0.4 mmol/L, P = 0.070). Replacing HGI with LGI meals raised glucose nadir in RYGB (LGI/rest 4.1 ± 0.5 mmol/L, P = 0.034) and reduced glucose excursions (Δpeak-nadir) but less so in RYGB (-14% [95% CI: -27; -1]) compared with controls (-33% [-51; -14]). Insulin responses mirrored glucose concentrations. Glucagon-like peptide 1 (GLP-1) responses were greater in RYGB versus controls, and higher with HGI versus LGI. Glucose-dependent insulinotropic polypeptide (GIP) responses were greater after HGI versus LGI in both groups. Postexercise glucagon responses were lower in RYGB than controls, and noradrenaline responses tended to be lower in RYGB, whereas adrenaline responses were similar between groups. In conclusion, moderate intensity cycling shortly after meal intake did not increase the risk of postprandial hypoglycemia after RYGB. The low GI meal increased nadir glucose and reduced glucose excursions compared with the high GI meal. RYGB participants had lower postexercise glucagon responses compared with controls.NEW & NOTEWORTHY We investigate the effect of moderate exercise after a high or a low glycemic index meal on nadir glucose and glucoregulatory hormones in gastric bypass-operated individuals and in matched unoperated controls. Cycling shortly after meal intake did not increase the risk of hypoglycemia in operated individuals. The low glycemic index meal increased glucose nadir and reduced excursions compared with the high glycemic index meal. Operated individuals had lower postexercise glucagon responses compared with controls.

Primary weight loss failure after Roux-en-Y gastric bypass is characterized by impaired gut-hormone mediated regulation of food intake.

BACKGROUND/OBJECTIVES: After Roux-en-Y gastric bypass (RYGB) a subset of patients never obtain excess BMI loss (EBMIL) > 50% and are categorized as having primary weight loss (WL) failure. We hypothesized that postprandial concentrations of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) would be lower in patients with primary WL failure compared with patients with successfully maintained WL. Furthermore, that inhibition of gut hormone secretions would increase ad libitum food intake less in patients with primary WL failure. SUBJECTS/METHODS: Twenty women with primary WL failure (LowEBMIL < 50%) were individually matched to twenty women with successful WL (HighEBMIL > 60%) on age, preoperative BMI and time from RYGB. On separate days performed in a random order, patient-blinded subcutaneous injections of octreotide or saline (placebo) were followed by a fixed breakfast and an ad libitum lunch with blood sampling for appetite regulating hormones and Visual-Analogue-Scale (VAS)-scoring of hunger/satiety. Furthermore, participants underwent gene variant analysis for GLP-1, PYY and their receptors, indirect calorimetry, dual-energy X-ray absorptiometry (DXA)-scans, 4-days at-home food registration and 14-days step counting. RESULTS: On placebo days, postprandial GLP-1, PYY and cholecystokinin (CCK) concentrations were similar between groups after breakfast. Fasting ghrelin was lower in LowEBMIL, but the postprandial suppression was similar. LowEBMIL had lower satiety VAS-scores and less suppression of hunger VAS-scores. Gene variants did not differ between groups. Octreotide diminished GLP-1, PYY, CCK and ghrelin concentrations in both groups. Octreotide did not affect ad libitum food intake in LowEBMIL (-1% [-13, 12], mean [95%CI]), while food intake increased in HighEBMIL (+23% [2,44]). CONCLUSIONS: Primary WL failure after RYGB was not characterized by impaired secretions of appetite regulating gut hormones. Interestingly, inhibition of gut hormone secretions with octreotide only increased food intake in patients with successful WL post-RYGB. Thus, an impaired central anorectic response to gut hormones may contribute to primary WL failure after RYGB.

No effect of multi-strain probiotic supplementation on metabolic and inflammatory markers and newborn body composition in pregnant women with obesity: Results from a randomized, double-blind placebo-controlled study.

BACKGROUND AND AIMS: Modulation of the gut microbiome composition with probiotics may have beneficial metabolic effects in pregnant women with obesity. The aim was to investigate the effect of probiotic supplementation during pregnancy on metabolic and inflammatory markers and the body composition of the offspring. METHODS AND RESULTS: A randomized double-blind trial in 50 pregnant women (pre-pregnancy BMI ≥30 and < 35 kg/m2) comparing multi-strain probiotics (Vivomixx®; 450 billion CFU/d) versus placebo from 14 to 20 weeks of gestation until delivery was carried out. Participants were followed with two predelivery visits at gestational week 27-30 and 36-37 and with one postdelivery visit. All visits included fasting blood samples (C-reactive protein (CRP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), insulin, C-peptide, glucose, glucagon, and glucagon-like peptide-1 (GLP-1)). At delivery, umbilical cord blood samples were collected (GLP-1 and glucagon). At the postdelivery visit, a dual-energy X-ray absorptiometry (DXA) scan of the newborn was performed. Forty-nine of 50 participants completed the study until delivery, and 36 mother-offspring dyads underwent postdelivery examinations including a DXA scan. There were no significant differences in changes in measured biomarkers between the probiotic versus the placebo group. No differences were found in newborn body composition or GLP-1 and glucagon. GLP-1 measured in umbilical blood samples was positively correlated to fat percent in offspring from the probiotic group. CONCLUSION: In this study of pregnant women with obesity and their newborns, there was no effect of probiotic supplementation in mothers or babies on metabolic or inflammatory biomarkers or on body composition of offspring. This study was registered at clinicaltrials.gov as NCT02508844.

Combination of exercise and GLP-1 receptor agonist treatment reduces severity of metabolic syndrome, abdominal obesity, and inflammation: a randomized controlled trial.

BACKGROUND: Identifying and reducing cardiometabolic risks driven by obesity remains a healthcare challenge. The metabolic syndrome is associated with abdominal obesity and inflammation and is predictive of long-term risk of developing type 2 diabetes and cardiovascular disease in otherwise healthy individuals living with obesity. Therefore, we investigated the effects of adherent exercise, a glucagon-like peptide 1 receptor agonist (GLP-1 RA), or the combination on severity of metabolic syndrome, abdominal obesity, and inflammation following weight loss. METHODS: This was a randomized, double-blinded, placebo-controlled trial. During an 8-week low-calorie diet (800 kcal/day), 195 adults with obesity and without diabetes lost 12% in body weight. Participants were then evenly randomized to four arms of one-year treatment with: placebo, moderate-to-vigorous exercise (minimum of 150 min/week of moderate-intensity or 75 min/week of vigorous-intensity aerobic physical activity or an equivalent combination of both), the GLP-1 RA liraglutide 3.0 mg/day, or a combination (exercise + liraglutide). A total of 166 participants completed the trial. We assessed the prespecified secondary outcome metabolic syndrome severity z-score (MetS-Z), abdominal obesity (estimated as android fat via dual-energy X-ray absorptiometry), and inflammation marker high-sensitivity C-reactive protein (hsCRP). Statistical analysis was performed on 130 participants adherent to the study interventions (per-protocol population) using a mixed linear model. RESULTS: The diet-induced weight loss decreased the severity of MetS-Z from 0.57 to 0.06, which was maintained in the placebo and exercise groups after one year. MetS-Z was further decreased by liraglutide (- 0.37, 95% CI - 0.58 to - 0.16, P < 0.001) and the combination treatment (- 0.48, 95% CI - 0.70 to - 0.25, P < 0.001) compared to placebo. Abdominal fat percentage decreased by 2.6, 2.8, and 6.1 percentage points in the exercise, liraglutide, and combination groups compared to placebo, respectively, and hsCRP decreased only in the combination group compared with placebo (by 43%, P = 0.03). CONCLUSION: The combination of adherent exercise and liraglutide treatment reduced metabolic syndrome severity, abdominal obesity, and inflammation and may therefore reduce cardiometabolic risk more than the individual treatments. Trial registration EudraCT number: 2015-005585-32, ClinicalTrials.gov: NCT04122716.

Transient osteoporosis of the hip.

Transient osteoporosis of the hip (TOH) is a rare condition with acute onset of hip pain. TOH is self-limiting and often leads to complete remission of symptoms within 6-12 months. This case report presents a 44-year-old male diagnosed with TOH. As part of the treatment plan, the patient received intravenous bisphosphonate with 5 mg zoledronic acid. A few weeks after administration, the patient reported almost full symptomatic remission.

Biochemical and clinical manifestations in adults with hypophosphatasia: a national cross-sectional study.

Hypophosphatasia (HPP) is a rare disease affecting bone mineralization. Adults with HPP have an increased occurrence of low-energy fractures, which cannot be explained by reduced bone mass assessed by dual energy X-ray absorptiometry. The bone phenotype in adults with HPP requires further studies investigating bone strength and bone structural parameters. INTRODUCTION: Hypophosphatasia (HPP) is a rare inherited disorder of bone and mineral metabolism, characterized by broad-ranging clinical manifestations and severity. However, studies investigating the clinical spectrum in adults with HPP compared to a control group are scarce. The aim of this study was to evaluate biochemical and clinical characteristics as well as bone health in a Danish cohort of adults with HPP. METHODS: We conducted a cross-sectional study assessing biochemical parameters, fracture prevalence, bone mineral density (BMD), bone turnover markers, physical performance and pain characteristics in 40 adults with HPP and 40 sex-, age-, BMI- and menopausal status-matched healthy controls. RESULTS: Patients with HPP had a significantly higher prevalence of non-vertebral, low-energy fractures (p = < 0.001). BMD at the lumbar spine, total hip, femoral neck, forearm and whole body did not differ between the groups. Low levels of the bone-specific alkaline phosphatase correlated significantly with higher BMD at the lumbar spine and femoral neck in both groups. The bone formation marker N-terminal propeptide of type 1 procollagen was significantly lower in patients with HPP than healthy controls (p = 0.006). Adults with HPP had significantly reduced walking capability (p = < 0.001) and lower body strength (p = < 0.001). Chronic pain was significantly more prevalent in adults with HPP than the control group (p = 0.029). CONCLUSIONS: The increased occurrence of low-energy fractures in adults with HPP is not explained by low BMD. Adults with HPP have reduced physical performance when compared with healthy controls.

Bone-microarchitecture and bone-strength in a sample of adults with hypophosphatasia and a matched reference population assessed by HR-pQCT and impact microindentation.

BACKGROUND: Hypophosphatasia (HPP) is an autosomal recessive or dominate disease affecting bone mineralization, and adults with HPP are in risk to develop metatarsal stress fractures and femoral pseudofractures. Given to the scarce data on the bone quality and its association to the fracture risk in adults with HPP, this study aimed to evaluate bone turnover, bone strength and structure in adults with HPP. METHODS: In this cross-sectional study, we included 14 adults with genetically verified HPP and 14 sex-, age-, BMI-, and menopausal status-matched reference individuals. We analyzed bone turnover markers, and measured bone material strength index (BMSi) by impact microindentation. Bone geometry, volumetric density and bone microarchitecture as well as failure load at the distal radius and tibia were evaluated using a second-generation high-resolution peripheral quantitative computed tomography system. RESULTS: Bone turnover markers did not differ between patients with HPP and reference individuals. BMSi did not differ between the groups (67.90 [63.75-76.00] vs 65.45 [58.43-69.55], p = 0.149). Parameters of bone geometry and volumetric density did not differ between adults with HPP and the reference group. Patients with HPP had a tendency toward higher trabecular separation (0.664 [0.613-0.724] mm vs 0.620 [0.578-0.659] mm, p = 0.054) and inhomogeneity of trabecular network (0.253 [0.235-0.283] mm vs 0.229 [0.208-0.252] mm, p = 0.056) as well as lower trabecular bone volume fraction (18.8 [16.4-22.7] % vs 22.8 [20.6-24.7] %, p = 0.054) at the distal radius. In addition, compound heterozygous adults with HPP had a significantly higher cortical porosity at the distal radius than reference individuals (1.5 [0.9-2.2] % vs 0.7 [0.6-0.7] %, p = 0.041). CONCLUSIONS: BMSi is not reduced in adults with HPP. Increased cortical porosity may contribute to the occurrence of femoral pseudofractures in compound heterozygous adults with HPP. However, further studies investigating larger cohorts of adults with HPP using methods of bone histomorphometry are recommended to adequately assess the bone quality in adults with HPP.

The effect of parathyroidectomy compared to non-surgical surveillance on kidney function in primary hyperparathyroidism: a nationwide historic cohort study.

BACKGROUND: Patients with primary hyperparathyroidism (pHPT) and impaired kidney function (estimated glomerular filtration rate (eGFR) < 60 mL/min) are offered parathyroidectomy (PTX) to protect them from further complications. Surprisingly, two recent uncontrolled cohort studies have suggested a further decrease in kidney function following PTX. We aimed to examine the effects of PTX compared to non-surgical surveillance on kidney function in pHPT patients. METHODS: Historic cohort study. From the Danish National Patient Registry (NPR) and major medical biochemistry laboratories in Denmark, we identified 3585 patients with biochemically confirmed pHPT among whom n = 1977 (55%) were treated with PTX (PTX-group) whereas n = 1608 (45%) were followed without surgery (non-PTX group). Baseline was defined as time of diagnosis and kidney function was re-assessed 9-15 months after PTX (PTX group) or 9-15 months after diagnosis (non-PTX group). RESULTS: At follow-up, eGFR had decreased significantly in the PTX- compared to the non-PTX-group (median - 4% vs. - 1%, p < 0.01). Stratification by baseline eGFR showed that the decrease was significant for those with a baseline eGFR value of 80-89 and > 90 mL/min, but not for those with lower eGFR values. Findings did not differ between patients with mild compared to moderate/severe hypercalcemia. However, after mutual adjustments, we identified baseline levels of calcium, PTH, and eGFR as well as age and treatment (PTX vs. no-PTX) as independent predictors for changes in kidney function. CONCLUSION: Compared to non-surgical surveillance, PTX is associated with a small but significant decrease in kidney function in pHPT patients with an initial normal kidney function.

Frailty and osteoporosis in patients with hip fractures under the age of 60-a prospective cohort of 218 individuals.

Research on younger patients with hip fractures is limited. This study adds knowledge on patient and injury characteristics, and DXA was investigated at the time of the fracture. Risk factors for osteoporosis and fractures were numerous among young patients, and osteoporosis was markedly more prevalent than in the general population. INTRODUCTION: Knowledge on younger patients with hip fractures is limited. Common preconceptions are that they suffer fractures due to high-energy trauma, alcohol or substance use disorder but not associated to osteoporosis. We aimed to descriptively analyze the characteristics of young and middle-aged patients with hip fractures and examine bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) at the time of the fracture. METHODS: A prospective multicenter cohort study on adult patients with hip fractures below age 60 collected detailed information on patient characteristics regarding demographics, trauma mechanism, previous fractures, comorbidity and medication, and lifestyle factors. DXA results were compared to population-based reference data. RESULTS: The cohort contains 91 women and 127 men, median age 53 (IQR 47-57). Most fractures, 83%, occurred in patients aged 45-59. Two-thirds of all fractures resulted from low-energy trauma. Half of the patients had prior fractures after age 20. Thirty-four percent were healthy, 31% had one previous disease, and 35% had multiple comorbidities. Use of medication associated with increased fracture risk was 32%. Smoking was prevalent in 42%, harmful alcohol use reported by 29%, and signs of drug-related problems by 8%. Osteoporosis according to WHO criteria was found in 31%, osteopenia in 57%, and normal BMD in 12%. CONCLUSION: In patients with hip fractures below age 60, risk factors for osteoporosis and fractures were numerous. Moreover, the prevalence of osteoporosis was markedly higher than in the general population. We suggest that young and middle-aged patients with hip fractures undergo a thorough health investigation including DXA, regardless of trauma mechanism.

Liraglutide changes body composition and lowers added sugar intake in overweight persons with insulin pump-treated type 1 diabetes.

AIMS: To present secondary outcome analyses of liraglutide treatment in overweight adults with insulin pump-treated type 1 diabetes (T1D), focusing on changes in body composition and dimensions, and to evaluate changes in food intake to identify potential dietary drivers of liraglutide-associated weight loss. MATERIALS AND METHODS: A 26-week randomized placebo-controlled study was conducted to investigate the efficacy and safety of liraglutide 1.8 mg daily in 44 overweight adults with insulin pump-treated T1D and glucose levels above target, and demonstrated significant glycated haemoglobin (HbA1c)- and body weight-reducing effects. For secondary outcome analysis, dual X-ray absorptiometry scans were completed at Weeks 0 and 26, and questionnaire-based food frequency recordings were obtained at Weeks 0, 13 and 26 to characterize liraglutide-induced changes in body composition and food intake. RESULTS: Total fat and lean body mass decreased in liraglutide-treated participants (fat mass -4.6 kg [95% confidence interval {CI} -5.7; -3.5], P < 0.001; lean mass -2.5 kg [95% CI -3.2;-1.7], P < 0.001), but remained stable in placebo-treated participants (fat mass -0.3 kg [95% CI -1.3;0.8], P = 0.604; lean mass 0.0 kg [95% CI -0.7;0.7]; P = 0.965 [between-group P values <0.001]). Participants reduced their energy intake numerically more in the liraglutide arm (-1.1 MJ [95% CI -2.0;-0.02], P = 0.02) than in the placebo arm (-0.9 MJ [95% CI -2.0;0.1], P = 0.22), but the between-group difference was statistically insignificant (P = 0.42). However, energy derived from added sugars decreased by 27% in the liraglutide arm compared with an increase of 14% in the placebo arm (P = 0.004). CONCLUSIONS: Liraglutide lowered fat and lean body mass compared with placebo. Further, liraglutide reduced intake of added sugars. However, no significant difference in total daily energy intake was detected between liraglutide- and placebo-treated participants.

Romosozumab Followed by Antiresorptive Treatment Increases the Probability of Achieving Bone Mineral Density Treatment Goals.

Increases in bone mineral density (BMD) with osteoporosis treatment are associated with reduced fracture risk. Increasing BMD is therefore a goal of osteoporosis therapy. Here, we compare the probability of achieving a T-score of > -2.5 over 3 years at the total hip (TH) or lumbar spine (LS) in women with osteoporosis, ≥55 years of age, after the following treatment sequences: 1 year romosozumab followed by 2 years denosumab (FRAME and FRAME extension trials), 1 year romosozumab followed by 2 years alendronate, or alendronate-only for 3 years (ARCH trial). Probabilities of attaining the BMD target within 1 year of treatment were also determined. At both skeletal sites, in women with a baseline Tscore ≥ -2.7, there was >50% probability of achieving the BMD target with any 3-year regimen. The probability of achieving the target BMD in those with a baseline TH Tscore equal to -3.0 was 61% with romosozumab/denosumab, 38% with romosozumab/alendronate, and 9% with alendronate. In those with a baseline LS Tscore equal to -3.0, the probability of achieving a T-score > -2.5 was 93% with romosozumab/denosumab, 81% with romosozumab/alendronate, and 55% with alendronate. With 1 year of treatment, in patients with a baseline TH T-score equal to -2.7, the probability of reaching the target Tscore with romosozumab was 71% to 78% and 38% with alendronate. For patients with an initial LS T-score equal to -3.0, the probability of achieving the target T-score over 1 year was 85% to 86% with romosozumab and 25% for alendronate. Our findings suggest baseline BMD and the probability of achieving BMD T-score goals are factors to consider when selecting initial treatment for patients with osteoporosis. As baseline T-score falls below -2.7 (TH) and -3.0 (LS), alendronate has <50% likelihood of achieving a BMD goal above osteoporosis range, whereas these probabilities remain relatively high for regimens beginning with romosozumab. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Severe hypocalcemia due to hypoparathyroidism associated with HIV: A case report.

Calcemia is not routinely determined among people living with human immunodeficiency virus (HIV). In people living with HIV, the most frequent electrolyte disturbance is hyponatremia and since symptoms of hypocalcemia often are unspecific, calcium is typically measured with some delay. Hypocalcemia in people living with HIV is mainly due to indirect causes such as vitamin D deficiency, renal failure, or drug related. However, in rare cases direct viral involvement of the parathyroid glands has been reported. We present a case of a 67-year-old male living with HIV who presented at an emergency department with symptomatic severe hypocalcemia, without any previous history of neck surgery, radiation therapy or large infections in the head and neck area. At the time of admission serum concentrations were for ionized calcium 0.98 mmol/L (ref. 1.18-1.32 mmol/L) and PTH 1.3 mmol/L (ref. 2.0-8.5 pmol/L). Vitamin D status was sufficient with 25OHD at 73 nmol/L to 112 nmol/L (ref. 60-160 nmol/L) from 2016 through 2019. The patient was diagnosed with primary hypoparathyroidism and was treated with Alphacalcidol 0,5 µg × 1/daily, calcium 500 mg × 4 the first day followed by 400 mg × 2 and magnesium 360 mg × 3, which induced rapid clinical recovery with dissolvement of muscular pain and biochemical improvement. This case study suggests that further studies are needed to investigate the added value of routine monitoring for hypocalcemia as part of clinical follow-up of people living with HIV.

Biochemical, clinical and genetic characteristics in adults with persistent hypophosphatasaemia; Data from an endocrinological outpatient clinic in Denmark.

BACKGROUND: Hypophosphatasia (HPP) is an inborn disease caused by pathogenic variants in ALPL. Low levels of alkaline phosphatase (ALP) are a biochemical hallmark of the disease. Scarce knowledge about the prevalence of HPP in Scandinavia exists, and the variable clinical presentations make diagnostics challenging. The aim of this study was to investigate the prevalence of ALPL variants as well as the clinical and biochemical features among adults with endocrinological diagnoses and persistent hypophosphatasaemia. METHODS: A biochemical database containing ALP measurements of 26,121 individuals was reviewed to identify adults above 18 years of age with persistently low levels of ALP beneath range (≤ 35 ± 2.7 U/L). ALPL genetic testing, biochemical evaluations and assessment of clinical features by a systematic questionnaire among included patients, were performed. RESULTS: Among 24 participants, thirteen subjects (54.2%) revealed a disease-causing variant in ALPL and reported mild clinical features of HPP, of which musculoskeletal pain was the most frequently reported (n = 9). The variant c. 571G > A; p.(Glu191Lys) was identified in six subjects, and an unreported missense variant (c.1019A > C; p.(His340Pro)) as well as a deletion of exon 2 were detected by genetic screening. Biochemical analyses showed no significant differences in ALP (p = 0.059), the bone specific alkaline phosphatase (BALP) (p = 0.056) and pyridoxal-5'-phosphate (PLP) (p = 0.085) between patients with an ALPL variant and negative genetic screening. Patients with a variant in ALPL had significantly higher PLP levels than healthy controls (p = 0.002). We observed normal ALP activity in some patients classified as mild HPP, and slightly increased levels of PLP in two subjects with normal genetic screening and four healthy controls. Among 51 patients with persistent hypophosphatasaemia, fifteen subjects (29.4%) received antiresorptive treatment. Two patients with unrecognized HPP were treated with bisphosphonates and did not show complications due to the treatment. CONCLUSIONS: Pathogenic variants in ALPL are common among patients with endocrinological diagnoses and low ALP. Regarding diagnostics, genetic testing is necessary to identify mild HPP due to fluctuating biochemical findings. Antiresorptive treatment is a frequent reason for hypophosphatasaemia and effects of these agents in adults with a variant in ALPL and osteoporosis remain unclear and require further studies.

Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined.

BACKGROUND: Weight regain after weight loss is a major problem in the treatment of persons with obesity. METHODS: In a randomized, head-to-head, placebo-controlled trial, we enrolled adults with obesity (body-mass index [the weight in kilograms divided by the square of the height in meters], 32 to 43) who did not have diabetes. After an 8-week low-calorie diet, participants were randomly assigned for 1 year to one of four strategies: a moderate-to-vigorous-intensity exercise program plus placebo (exercise group); treatment with liraglutide (3.0 mg per day) plus usual activity (liraglutide group); exercise program plus liraglutide therapy (combination group); or placebo plus usual activity (placebo group). End points with prespecified hypotheses were the change in body weight (primary end point) and the change in body-fat percentage (secondary end point) from randomization to the end of the treatment period in the intention-to-treat population. Prespecified metabolic health-related end points and safety were also assessed. RESULTS: After the 8-week low-calorie diet, 195 participants had a mean decrease in body weight of 13.1 kg. At 1 year, all the active-treatment strategies led to greater weight loss than placebo: difference in the exercise group, -4.1 kg (95% confidence interval [CI], -7.8 to -0.4; P = 0.03); in the liraglutide group, -6.8 kg (95% CI, -10.4 to -3.1; P<0.001); and in the combination group, -9.5 kg (95% CI, -13.1 to -5.9; P<0.001). The combination strategy led to greater weight loss than exercise (difference, -5.4 kg; 95% CI, -9.0 to -1.7; P = 0.004) but not liraglutide (-2.7 kg; 95% CI, -6.3 to 0.8; P = 0.13). The combination strategy decreased body-fat percentage by 3.9 percentage points, which was approximately twice the decrease in the exercise group (-1.7 percentage points; 95% CI, -3.2 to -0.2; P = 0.02) and the liraglutide group (-1.9 percentage points; 95% CI, -3.3 to -0.5; P = 0.009). Only the combination strategy was associated with improvements in the glycated hemoglobin level, insulin sensitivity, and cardiorespiratory fitness. Increased heart rate and cholelithiasis were observed more often in the liraglutide group than in the combination group. CONCLUSIONS: A strategy combining exercise and liraglutide therapy improved healthy weight loss maintenance more than either treatment alone. (Funded by the Novo Nordisk Foundation and others; EudraCT number, 2015-005585-32; ClinicalTrials.gov number, NCT04122716.).

Feasibility and preliminary effect of anabolic steroids in addition to strength training and nutritional supplement in rehabilitation of patients with hip fracture: a randomized controlled pilot trial (HIP-SAP1 trial).

BACKGROUND: Anabolic steroid has been suggested as a supplement during hip fracture rehabilitation and a Cochrane Review recommended further trials. The aim was to determine feasibility and preliminary effect of a 12-week intervention consisting of anabolic steroid in addition to physiotherapy and nutritional supplement on knee-extension strength and function after hip fracture surgery. METHODS: Patients were randomized (1:1) during acute care to: 1. Anabolic steroid (Nandrolone Decanoate) or 2. Placebo (Saline). Both groups received identical physiotherapy (with strength training) and a nutritional supplement. Primary outcome was change in maximal isometric knee-extension strength from the week after surgery to 14 weeks. Secondary outcomes were physical performance, patient reported outcomes and body composition. RESULTS: Seven hundred seventeen patients were screened, and 23 randomised (mean age 73.4 years, 78% women). Target sample size was 48. Main limitations for inclusion were "not home-dwelling" (18%) and "cognitive dysfunction" (16%). Among eligible patients, the main reason for declining participation was "Overwhelmed and stressed by situation" (37%). Adherence to interventions was: Anabolic steroid 87%, exercise 91% and nutrition 61%. Addition of anabolic steroid showed a non-significant between-group difference in knee-extension strength in the fractured leg of 0.11 (95%CI -0.25;0.48) Nm/kg in favor of the anabolic group. Correspondingly, a non-significant between-group difference of 0.16 (95%CI -0.05;0.36) Nm/Kg was seen for the non-fractured leg. No significant between-group differences were identified for the secondary outcomes. Eighteen adverse reactions were identified (anabolic = 10, control = 8). CONCLUSIONS: Early inclusion after hip fracture surgery to this trial seemed non-feasible, primarily due to slow recruitment. Although inconclusive, positive tendencies were seen for the addition of anabolic steroid. TRIAL REGISTRATION: Clinicaltrials.gov NCT03545347 .

The Antiresorptive Effect of GIP, But Not GLP-2, Is Preserved in Patients With Hypoparathyroidism-A Randomized Crossover Study.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are gut hormones secreted postprandially. In healthy humans, both hormones decrease bone resorption accompanied by a rapid reduction in parathyroid hormone (PTH). The aim of this study was to investigate whether the changes in bone turnover after meal intake and after GIP- and GLP-2 injections, respectively, are mediated via a reduction in PTH secretion. This was tested in female patients with hypoparathyroidism given a standardized liquid mixed-meal test (n = 7) followed by a peptide injection test (n = 4) using a randomized crossover design. We observed that the meal- and GIP- but not the GLP-2-induced changes in bone turnover markers were preserved in the patients with hypoparathyroidism. To understand the underlying mechanisms, we examined the expression of the GIP receptor (GIPR) and the GLP-2 receptor (GLP-2R) in human osteoblasts and osteoclasts as well as in parathyroid tissue. The GIPR was expressed in both human osteoclasts and osteoblasts, whereas the GLP-2R was absent or only weakly expressed in osteoclasts. Furthermore, both GIPR and GLP-2R were expressed in parathyroid tissue. Our findings suggest that the GIP-induced effect on bone turnover may be mediated directly via GIPR expressed in osteoblasts and osteoclasts and that this may occur independent of PTH. In contrast, the effect of GLP-2 on bone turnover seems to depend on changes in PTH and may be mediated through GLP-2R in the parathyroid gland. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Outcome of osteoporosis evaluation, treatment, and follow-up in patients referred to a specialized outpatient clinic compared to patients in care of general practitioners.

In Denmark, osteoporosis treatment is either handled by general practitioners or at more resource demanding specialist clinics. We evaluated the treatment adherence and persistence in the two settings, which were overall similar. The type of medical support did, however, differ and was provided to two very different patient populations. PURPOSE: The study aimed to investigate the effect of patient care by general practitioners (GPs) or specialists on treatment adherence among osteoporosis patients initiating treatment with oral bisphosphonates (OB). METHODS: Dual-energy X-ray absorption (DXA)-scanning data from 2005 to 2013 were extracted. Treatment naïve patients with a T-score ≤ - 2.5 (spine or hip) were included. Information on medical treatment, comorbidities, and socio-economic status was extracted from Danish registries. Scanning results were evaluated by a specialist. Subsequent treatment initiation and follow-up was either handled by GPs or specialists: GP population (GPP) vs. specialist population (SP). Primary adherence was defined as treatment initiating within 12 months from diagnosis and secondary adherence as days with medicine possession rates (MPR) > 80%. RESULTS: Of 11,201 DXA-scanned patients, 3685 met the inclusion criteria (GPP = 2177, SP = 1508). The GPP consisted of relatively more men, was older, had shorter education, lower income, and more comorbidities. There was no difference in baseline T-score or prior incidence of major osteoporotic fractures (MOFs). The GPP was primarily treated with OB and had better primary adherence (adjusted ORGPP/SP = 1.52 [1.31-1.75], p < 0.0001) than the SP that to a higher degree received another treatment. Secondary adherence was similar (adjusted ORGPP/SP: OR12 months = 1.02 [0.83-1.26]; OR24 months = 0.90 [0.73-1.10]; OR4 years = 0.88 [0.71-1.07]; OR5 years = 0.91 [0.74-1.13]. CONCLUSION: Patients in care of specialists were most likely to receive a treatment other than OB. Primary adherence was highest in the GPP, whereas short- and long-term persistence was similar for up to 5 years whether treated by a specialist or a GP.

Newborn body composition after maternal bariatric surgery.

INTRODUCTION: In pregnancy after Roux-en-Y gastric bypass (RYGB), there is increased risk of low birthweight in the offspring. The present study examined how offspring body composition was affected by RYGB. MATERIAL AND METHODS: Mother-newborn dyads, where the mothers had undergone RYGB were included. Main outcome measure was neonatal body composition. Neonatal body composition was assessed by dual-energy X-ray absorptiometry scanning (DXA) within 48 hours after birth. In a statistical model offspring born after RYGB were compared with a reference material of offspring and analyses were made to estimate the effect of maternal pre-pregnancy body mass index (BMI), gestational weight gain, parity, gestational age at birth and newborn sex on newborn body composition. Analyses were made to estimate the impact of maternal weight loss before pregnancy and of other effects of bariatric surgery respectively. The study was performed at a university hospital between October 2012 and December 2013. RESULTS: We included 25 mother-newborn dyads where the mothers had undergone RYGB and compared them to a reference material of 311 mother-newborn dyads with comparable pre-pregnancy BMI. Offspring born by mothers after RYGB had lower birthweight (335g, p<0.001), fat-free mass (268g, p<0.001) and fat% (2.8%, p<0.001) compared with reference material. Only 2% of the average reduction in newborn fat free mass could be attributed to maternal pre-pregnancy weight loss whereas other effects of RYGB accounted for 98%. Regarding reduction in fat mass 52% was attributed to weight loss and 47% to other effects of surgery. CONCLUSION: Offspring born after maternal bariatric surgery, had lower birthweight, fat-free mass and fat percentage when compared with a reference material. RYGB itself and not the pre-pregnancy weight loss seems to have had the greatest impact on fetal growth.