No Clinical Efficacy of Adipose-Derived Regenerative Cells and Lipotransfer in Breast Cancer-Related Lymphedema: A double-blinded placebo-controlled phase-II trial.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is a debilitating sequela affecting up to one in three breast cancer survivors. Current treatments are palliative and does not address the underlying lymphatic injury. Recently, preclinical and non-randomized studies have shown promising results using Adipose-Derived Regenerative Cells (ADRCs) and lipotransfer in alleviating BCRL through regeneration of lymphatic tissue. However no randomized controlled trial has been performed in an attempt to eliminate a placebo effect. METHODS: This randomized, double-blinded, placebo-controlled trial included patients with no-option, persistent disabling unilateral BCRL. Patients were randomly assigned in a 1:1 ratio to receive either autologous ADRCs (4.20x10 7±1.75x10 7 cells) and 30cc lipotransfer or placebo (saline) to the axilla. The primary outcome was a change in BCRL volume one year after treatment. Secondary outcomes included changes in the quality of life, indocyanine green lymphangiography stage, bioimpedance, and safety. RESULTS: Eighty patients were included, of which 39 were allocated to ADRCs and lipotransfer treatment and 41 to placebo treatment. Baseline characteristics were similar in both groups. One year after treatment, no objective improvements were observed in the treatment or placebo groups. In contrast, significant subjective improvements were noted for both the treatment and placebo groups. CONCLUSION: This trial failed to confirm a benefit of ADRCs and lipotransfer in the treatment of BCRL. These non-confirmatory results suggest that ADRC and lipotransfer should not be recommended for alleviating BCRL at this time. However, we cannot exclude that repeated treatments or higher doses of ADRCs or lipotransfer could yield a clinical effect.

Exercise in newly diagnosed patients with multiple myeloma: A randomized controlled trial of effects on physical function, physical activity, lean body mass, bone mineral density, pain, and quality of life.

Reduced physical function caused by bone destruction, pain, anemia, infections, and weight loss is common in multiple myeloma (MM). Myeloma bone disease challenges physical exercise. Knowledge on the effects and safety of physical exercise in newly diagnosed patients with MM is limited. In a randomized, controlled trial, we studied the effect of a 10-week individualized physical exercise program on physical function, physical activity, lean body mass (LBM), bone mineral density (BMD), quality of life (QoL), and pain in patients newly diagnosed with MM. Lytic bone disease was assessed, and exercise was adjusted accordingly. Primary outcome: knee extension strength. Secondary outcomes: Six-Minute-Walk-Test, 30-s Sit-to-Stand-Test (SST), grip strength, level of physical activity, LBM, BMD, QoL, and pain. Measurements were conducted pre- and post-intervention, and after 6 and 12 months. We included 100 patients, 86 were evaluable; 44 in the intervention group (IG) and 42 in the control group (CG). No statistically significant differences between groups were observed. Knee extension strength declined in the IG (p = .02). SST, aerobic capacity, and global QoL improved in both groups. Pain decreased consistently in the IG regardless of pain outcome. No significant safety concerns of physical exercise in newly diagnosed patients with MM were observed.

Ten-year follow-up of fracture risk in a systematic population-based screening program: the risk-stratified osteoporosis strategy evaluation (ROSE) randomised trial.

Background: Osteoporotic fractures pose a growing public health concern. Osteoporosis is underdiagnosed and undertreated, highlighting the necessity of systematic screening programs. We aimed to evaluate the effectiveness of a two-step population-based osteoporotic screening program. Methods: This ten-year follow-up of the Risk-stratified Osteoporosis Strategy Evaluation (ROSE) randomized trial tested the effectiveness of a screening program utilizing the Fracture Risk Assessment Tool (FRAX) for major osteoporotic fractures (MOF) to select women for dual-energy x-ray absorptiometry (DXA) scan following standard osteoporosis treatment. Women residing in the Region of Southern Denmark, aged 65-80, were randomised (single masked) into a screening or a control group by a computer program prior to inclusion and subsequently approached with a mailed questionnaire. Based on the questionnaire data, women in the screening group with a FRAX value ≥15% were invited for DXA scanning. The primary outcome was MOF derived from nationwide registers. ClinicalTrials.gov: NCT01388244, status: Completed. Findings: All randomised women were included February 4, 2010-January 8, 2011, the same day as approached to participate. During follow-up, 7355 MOFs were observed. No differences in incidences of MOF were identified, comparing the 17,072 women in the screening group with the 17,157 controls in the intention-to-treat analysis (IRR 1.01, 0.95; 1.06). However, per-protocol, women DXA-scanned exhibited a 14% lower incidence of MOF (IRR 0.86, 0.78; 0.94) than controls with a FRAX value ≥15%. Similar trends were observed for hip fractures, all fractures, and mortality. Interpretation: While the ROSE program had no overall effect on osteoporotic fracture incidence or mortality it showed a preventive effect for women at moderate to high risk who underwent DXA scans. Hence the overall effect might have been diluted by those who were not at an intervention level threshold risk or those who did not show up for DXA. Using self-administered questionnaires as screening tools may be inefficient for systematic screening due to the low and differential screening uptake. Funding: INTERREG and the Region of Southern Denmark.

Accelerated loss of lean body mass in head and neck cancer patients during cisplatin-based chemoradiation.

BACKGROUND: This study investigated changes in body weight, lean body mass (LBM), fat mass (FM), muscle strength and functional performance during radiation treatment in head and neck cancer (HNSCC) patients. Secondly, it investigated the impact of cisplatin-based chemoradiation (CCRT) on LBM loss compared with radiation alone. METHODS: 48 patients (all tumor sites) received either 6 weeks of radiation alone (n = 16) with 66-68 Gy in 33-34 Fx, 5-6 Fx/week or CCRT, adding weekly cisplatin or carboplatin (n = 32). LBM and FM was evaluated using Dual-energy X-ray Absorptiometry bi-weekly from pre- to two weeks post-treatment. Maximal muscle strength (knee extension, leg - and chest press) and functional performance (stair climb, chair rise, and arm curl) were assessed pre- and post-treatment. RESULTS: Body weight and LBM had declined significantly already week 2 into treatment and declined significantly further through week 4 and 6 before leveling off after week 6. Bi-weekly, from treatment start to week 2, 2-4, and 4-6, LBM declined 1.2 ± 0.4 kg (p = .002; 95% CI: 0.4;2.0), 2.0 ± 0.4 kg (p < .0001; 1.2;2.8) and 1.4 ± 0.4 kg (p = .001; 0.6;2.2). With a two-week delay, FM declined significantly from week 2-8. All measures of muscle strength declined significantly from pre- to post-treatment. Functional performance was unchanged. LBM loss from pre- to post-treatment was significantly associated with impaired muscle strength (R2 = 0.3-0.5). CCRT patients lost 3.1 ± 0.8 kg of LBM (p = .0001; 1.5;4.7) more from pre- to post-treatment compared with patients receiving radiation alone. Analyses adjusting for nimorazole, tumor stage, baseline BMI, mean radiation dose to constrictor muscles and oral cavity confirmed this. CONCLUSION: Accelerated and substantial LBM loss was already initiated within the first two weeks of treatment - before the onset of radiation-induced mucositis. LBM loss was associated with muscle strength impairment. Patients receiving CCRT experienced significantly larger LBM loss than patients receiving radiation alone. Registered on clinincaltrials.gov (Identifier: NCT05890859).

Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 2A in Denmark 1930­2021: A Nationwide Population-Based Retrospective Study

Studies of primary hyperparathyroidism (PHPT) in multiple endocrine neoplasia type 2A (MEN 2A) shows divergence in frequency, disease definition, reporting of clinical characteristics and traces of selection bias. This is a nationwide population-based retrospective study of PHPT in MEN 2A, suggesting a representative frequency, with complete reporting and a strict PHPT definition. The Danish MEN 2A cohort 1930-2021 was used. Of 204 MEN 2A cases, 16 had PHPT, resulting in a frequency of 8% (CI, 5-12). Age-related penetrance at 50 years was 8% (CI, 4-15). PHPT was seen in the American Thyroid Association moderate (ATA-MOD) and high (ATA-H) risk groups in 62% and 38% of carriers, respectively. Median age at PHPT diagnosis was 45 years (range, 21-79). A total of 75% were asymptomatic and 25% were symptomatic. Thirteen underwent parathyroid surgery, resulting in a cure of 69%, persistence in 8% and recurrence in 23%. In this first study with a clear PHPT definition and no selection bias, we found a lower frequency of PHPT and age-related penetrance, but a higher age at PHPT diagnosis than often cited. This might be affected by the Danish RET p.Cys611Tyr founder effect. Our study corroborates that PHPT in MEN 2A is often mild, asymptomatic and is associated with both ATA-MOD and ATA-H variants. Likelihood of cure is high, but recurrence is not infrequent and can occur decades after surgery.

Zoledronic Acid for prevention of bone and muscle loss after BAriatric Surgery (ZABAS)-a study protocol for a randomized controlled trial.

BACKGROUND: Bariatric surgery has adverse effects on the muscular-skeletal system with loss of bone mass and muscle mass and an increase in the risk of fracture. Zoledronic acid is widely used in osteoporosis and prevents bone loss and fracture. Bisphosphonates may also have positive effects on skeletal muscle. The aim of this study is to investigate the effects of zoledronic acid for the prevention of bone and muscle loss after bariatric surgery.  METHODS/DESIGN: This is a randomized double-blind placebo-controlled study. Sixty women and men with obesity aged 35 years or older will complete baseline assessments before randomization to either zoledronic acid (5 mg in 100 ml isotonic saline) or placebo (100 ml isotonic saline only) 3 weeks before surgery with Roux-en-Y-gastric bypass (RYGB) or sleeve gastrectomy (SG). Follow-up assessments are performed 12 and 24 months after surgery. The primary outcome is changes in lumbar spine volumetric bone mineral density (vBMD) assessed by quantitative computed tomography (QCT). Secondary bone outcomes are changes in proximal femur vBMD assessed by QCT. Changes in cortical and trabecular bone microarchitecture and estimated bone strength will be assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT). Cortical material bone strength at the mid-tibia diaphysis will be assessed using microindentation and fasting blood samples will be obtained to assess biochemical markers of bone turnover and calcium metabolism.  Secondary muscle outcomes include whole body lean mass assessed using dual-energy X-ray absorptiometry. Dynamometers will be used to assess handgrip, shoulder, ankle, and knee muscle strength. Short Physical Performance Battery, 7.6-m walking tests, 2-min walking test, and a stair climb test will be assessed as biomarkers of physical function. Self-reported physical activity level is assessed using International Physical Activity Questionnaire (IPAQ). DISCUSSION: Results from this study will be instrumental for the evidence-based care of patients undergoing bariatric surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT04742010. Registered on 5 February 2021.

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.

Multiple Focal Brown Tumors (Osteitis Fibrosa Cystica) in a Renal Transplant Recipient.

Brown tumors (BTs) are manifestations of osteitis fibrosa cystica that develops due to increased osteoclast activity secondary to hyperparathyroidism (HPTH). The name comes from its characteristic brown color due to high hemosiderin level and hemorrhage surrounded by osteoclastic giant cells, fibrous tissue, and bone fragments. Presentation can be either unifocal or rarely multifocal. Misdiagnosis of BT compared to malignant giant cell tumor is not uncommon. Early diagnosis and intervention may prevent destructive bone changes. Treatment of BTs due to chronic renal failure should be aimed primarily at its prevention with phosphate binders, vitamin D (analogues), calcimimetics, and prolonged dialysis sessions. Parathyroidectomy can be the option in nonresponsive cases. In this report, we present an unusual case of multiple brown tumors in a 54-year-old female renal transplant patient involving the spine, jaw, and scapula, initially misdiagnosed as giant cell tumor. Five years later, the patient was diagnosed with BT because of the medical history, morphology, and negative p63 staining in combination with secondary/tertiary hyperparathyroidism. The patient subsequently underwent subtotal parathyroidectomy.

Effects of a 6-month, low-carbohydrate diet on glycaemic control, body composition, and cardiovascular risk factors in patients with type 2 diabetes: An open-label randomized controlled trial.

AIM: To investigate the efficacy and safety of a non-calorie-restricted low-carbohydrate diet (LCD) on glycaemic control, body composition, and cardiovascular risk factors in patients with type 2 diabetes (T2D) instructed to maintain their non-insulin antidiabetic medication and physical activity. MATERIALS AND METHODS: In an open-label randomized controlled trial, patients with T2D were randomized 2:1 to either a LCD with a maximum of 20 E% (percentage of total energy intake) from carbohydrates (n = 49) or a control diet with 50-60 E% from carbohydrates (n = 22) for 6 months. Examinations at enrolment and after 3 and 6 months included blood sample analyses, anthropometrics, blood pressure, accelerometer-based assessment of physical activity, and food diaries. Total fat mass and lean mass were determined by dual-energy x-ray absorptiometry scan. The mean difference in change between groups from baseline are reported. RESULTS: The LCD group decreased carbohydrate intake to 13.4 E% and increased fat intake to 63.2 E%, which was -30.5 ± 2.2 E% lower for carbohydrates and 30.6 ± 2.2 E% higher for fat, respectively, compared with the control group (all P < .001). The LCD reduced HbA1c after 3 months (-8.9 ± 1.7 mmol/mol; P < .0001), and this was maintained after 6 months (-7.5 ± 1.8 mmol/mol; P < .0001) compared with the control diet. The LCD also reduced weight (-3.9 ± 1.0 kg), body mass index (-1.4 ± 0.4 kg/m2 ), and waist circumference (-4.9 ± 1.3 cm) compared with the control diet (all P < .01), accompanied by reductions in total fat mass (-2.2 ± 1.0 kg; P = .027) and lean mass (-1.3 ± 0.6 kg; P = .017). No changes in blood lipids or blood pressure were seen after 6 months. The level of physical activity was maintained, and there were no episodes of severe hypoglycaemia. CONCLUSION: A non-calorie-restricted LCD high in fat has significant beneficial effects on glycaemic control and body composition, and does not adversely affect cardiovascular risk factors in patients with T2D. Reducing carbohydrate intake to 10-25 E% appears to be an effective and safe nutritional approach with respect to classical cardiovascular risk factors and hypoglycaemia.

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.

Indocyanine green lymphangiography is superior to clinical staging in breast cancer-related lymphedema.

Precise staging of breast cancer-related lymphedema (BCRL) is important to guide treatment-decision making. Recent studies have suggested staging of BCRL using indocyanine green lymphangiography (ICG-L) based on the extent of lymphatic injury and dermal backflow patterns. Currently, the benefits of ICG-L compared to conventional clinical staging are unknown. For this study, we included 200 patients with unilateral BCRL. All BCRL patients were staged using ICG-L and clinical exam. The amounts of excess arm volume, fat mass and lean mass were compared between stages using Dual Energy X-Ray Absorptiometry. Multivariate regression models were used to adjust for confounders. For each increase in the patient's ICG-L stage, the excess arm volume, fat mass and lean mass was increased by 8, 12 and 6.5 percentage points respectively (P < 0.001). For each increase in the patient's clinical ISL stage, the volume was increased by 3.5 percentage points (P < 0.05), however no statistically significant difference in the lean and fat mass content of the arm was observed for ascending stages. However, the residual plots showed a high degree of variance for both ICG-L and clinical staging. This study found that ICG-L staging of BCRL was superior to clinical staging in forecasting BCRL excess arm volume, fat mass, and lean mass. However, there was a high degree of variance in excess arm volume, fat mass, and lean mass within each staging system, and neither the ICG-L nor clinical staging forecasted perfectly.

Cellulitis Is Associated with Severe Breast Cancer-Related Lymphedema: An Observational Study of Tissue Composition.

Cellulitis is a common complication in Breast Cancer-Related Lymphedema (BCRL). The excess amount of fat and lean mass in BCRL is a vital factor in patient stratification, prognosis, and treatments. However, it is not known whether cellulitis is associated with the excess fat and lean mass in BCRL. Therefore, this prospective observational study was designed to fundamentally understand the heterogonous biocomposition of BCRL. For this study, we consecutively enrolled 206 patients with unilateral BCRL between January 2019 and February 2020. All patients underwent Dual-Energy X-Ray Absorptiometry scans, bioimpedance spectroscopy, indocyanine green lymphangiography comprehensive history of potential risk factors, and a clinical exam. Multivariate linear and beta regression models were used to determine the strength of association and margins effect. Sixty-nine patients (33%) had at least one previous episode of cellulitis. Notably, a previous episode of cellulitis was associated with 20 percentage points more excess fat and 10 percentage points more excess lean mass compared to patients without cellulitis (p < 0.05). Moreover, each 1 increase in the patients BMI was associated with a 0.03 unit increase in the fat mass proportion of the lymphedema arm. Cellulitis was associated with more excess fat and lean arm mass in BCRL. In addition, patients BMI affect the proportion of fat mass in the arm.

Prognostic impacts of glucocorticoid treatment in patients with polymyalgia rheumatica and giant cell arteritis.

Identifying comorbidities in polymyalgia rheumatica/giant cell arteritis (PMR/GCA) is crucial for patients' outcomes. The present study aimed to evaluate the impact of the inflammatory process and glucocorticoid treatment on aortic arterial stiffness and body composition in PMR/GCA. 77 patients with newly diagnosed PMR/GCA were treated with oral glucocorticoids and followed for 40 weeks. Aortic pulse wave velocity (PWV) was measured at baseline and during the follow-up period and compared to the results of temporal artery biopsy (TAB) and 18F-FDG PET/CT. Body composition was assessed by total body DXA at baseline and the end of the study. Of 77 patients (49 (63.6%) female, mean of age: (71.8 ± 8.0)), 64 (83.1%) had pure PMR, 10 (13.0%) concomitant PMR and GCA, and 3 (3.9%) pure GCA. Compared to baseline values, aortic PWV was initially decreased at week 16 (p = 0.010) and remained lower than baseline at week 28 (p = 0.002) and week 40 (p < 0.001), with no association with results of TAB and 18F-FDG PET/CT. Aortic PWV was significantly associated with age, male gender, left systolic and diastolic blood pressure, right diastolic blood pressure, and CRP. Total bone mineral content (BMC) was decreased in both genders (p < 0.001), while fat mass (FM) was significantly increased (p < 0.001). However, lean body mass did not significantly change during the study. Changes in FM were correlated with cumulative prednisolone dose (rho: 0.26, p = 0.031). Glucocorticoid treatment of patients with PMR/GCA had several prognostic impacts. Arterial stiffness was decreased due either to the treatment or a reduction in the inflammatory load. Additionally, treatment led to changes in body composition, including a decrease in BMC and FM excess.

The gap between women's needs when diagnosed with asymptomatic osteoporosis and what is provided by the healthcare system: A qualitative study.

OBJECTIVES: Women diagnosed with asymptomatic osteoporosis need better support to understand the implications of the condition and how to practice self-management in their daily lives. In contrast, physicians report that asymptomatic osteoporosis is not a serious chronic condition and do not pay much attention to the condition compared to other chronic conditions. Therefore, the aim of this study was to investigate the gap between women's needs, when diagnosed with asymptomatic osteoporosis, and what is provided by the healthcare system. METHODS: A secondary analysis of semi-structured interviews with 17 women newly diagnosed with asymptomatic osteoporosis was conducted and combined with semi-structured interviews with six physicians. Giorgi's descriptive phenomenological method was used in the analysis. RESULTS: Two overall themes were identified: different perceptions of asymptomatic osteoporosis and discrepancies in the osteoporosis consultation. Habermas was used as a theoretical approach to discuss the findings. DISCUSSION: We discuss that physicians pay too much attention to the objective world and highlight that there is a need for better inclusion of women's subjective and social worlds, to enable mutual understanding and communicative action in the osteoporosis consultation. This would lead to treatment decisions based on women's needs and support women in their self-management of osteoporosis.

Consequences of Hyperthyroidism and Its Treatment for Bone Microarchitecture Assessed by High-Resolution Peripheral Quantitative Computed Tomography.

Background: Hyperthyroidism is associated with bone mass reduction and increased fracture risk, but the effects on other important bone parameters have been sparsely examined. Therefore, we investigated bone microarchitecture and estimated bone strength by high-resolution peripheral quantitative computed tomography (HR-pQCT) in hyperthyroid patients at diagnosis and after being euthyroid for at least one year. Methods: Two approaches were used: (A) a case-control study comparing 61 hyperthyroid women with 61 euthyroid women matched for age and menopause status; (B) a follow-up study, in which 46 of the 61 women were re-examined after having been euthyroid for one year. HR-pQCT of the distal radius and tibia, and dual-energy X-ray absorptiometry (DXA) of the lumbar spine and the hip were performed. Results: In analysis A: In the radius, compared with the healthy controls, hyperthyroid patients had higher total area (16.9% ± 29.5%; p < 0.001), trabecular area (28.6% ± 45.7%; p < 0.001), and lower cortical area (-11.7% ± 23.2%; p < 0.001). Total volumetric bone mineral density (vBMD) (-13.9% ± 26.5%; p < 0.001), cortical vBMD (-5.8% ± 7.9%; p < 0.001), cortical thickness (-16.7% ± 26.0%; p < 0.001), and estimated bone strength (-6.6% ± 19.5%; p < 0.01) were lower. No significant differences were found in the tibia or in the DXA parameters. In analysis B: In the radius, significant improvements were observed in the cortical area (2.1% ± 4.6%; p < 0.01), cortical thickness (2.5% ± 5.1%; p < 0.001), and total vBMD (0.8% ± 3.0%; p < 0.05). Trabecular area decreased (-0.5% ± 1.0%; p < 0.01) and trabecular separation increased (2.0% ± 8.3%; p < 0.05). In the tibia, cortical area (3.6% ± 7.3%; p < 0.01) and cortical thickness (3.8% ± 7.6%; p < 0.01) increased, and trabecular area decreased (-0.5% ± 1.1%; p < 0.01). Areal BMD, measured by DXA, increased in the spine (1.1% ± 3.4%; p < 0.05) and in the hip (2.0% ± 3.8%; p < 0.01). Conclusions: Compared with the healthy control group, hyperthyroid women had lower vBMD, lower estimated bone strength, and compromised cortical microarchitecture in the radius. After restoration of euthyroidism, significant improvements in vBMD and cortical microarchitecture were observed, highlighting the importance of achieving and maintaining euthyroidism.

Restoration of euthyroidism in women with Hashimoto's thyroiditis changes bone microarchitecture but not estimated bone strength.

PURPOSE: Fracture risk in hypothyroid patients is debated, and since the effects of hypothyroidism on bone microarchitecture and strength are unclarified, we investigated these characteristics by high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: Two approaches were used: a cross-sectional control study, comparing 32 hypothyroid women (mean age; 47 ± 12 years) suffering from Hashimoto's thyroiditis with 32 sex-, age-, and menopause-matched healthy controls; a prospective study, where 27 of the women were reexamined 1 year after restoration of euthyroidism. HR-pQCT of the distal radius and tibia, and dual-energy X-ray absorptiometry (DXA) of the spine and hip were performed. Bone strength was estimated using a finite element analysis (FEA). RESULTS: Cross-sectional control study: in the radius, total (mean 14.6 ± 29.3% (SD); p = 0.04) and trabecular bone areas (19.8 ± 37.1%, p = 0.04) were higher, and cortical volumetric bone mineral density (vBMD) lower (-2.2 ± 6.5%, p = 0.032) in hypothyroid patients than in controls. All indices of tibia cortical and trabecular vBMD, microarchitecture, and estimated bone strength were similar between groups, as was hip and spine areal BMD (aBMD). Prospective study: in the radius, mean cortical (-0.9 ± 1.8%, p = 0.02) and trabecular (-1.5 ± 4.6%, p = 0.02) vBMD decreased, and cortical porosity increased (18.9 ± 32.7%, p = 0.02). In the tibia, mean total vBMD (-1.1 ± 1.9%, p = 0.01) and cortical vBMD (-0.8 ± 1.4%, p = 0.01) decreased, while cortical porosity (8.2 ± 11.5%, p = 0.002) and trabecular area (0.2 ± 0.6%, p = 0.047) increased. No changes in FEA were detected. Lumbar spine aBMD decreased (-1.3 ± 3.0%, p = 0.04). CONCLUSIONS: Hypothyroidism was associated with an increased trabecular bone area and a lower mineral density of cortical bone in the radius, as assessed by HR-pQCT. Restoration of euthyroidism mainly increased cortical porosity, while estimated bone strength was unaffected.

Osteoporosis after adjuvant treatment for early-stage breast cancer.

INTRODUCTION: Adjuvant treatment of early-stage breast cancer has been associated with bone loss in randomised trials, but evidence from unselected populations is needed. In a single-center study, we assessed the annual percentage change in bone mineral density (∆BMDt) and risk of osteoporosis from two to five years after adjuvant chemotherapy in patients with oestrogen-receptor-positive and oestrogen-receptor-negative tumours. METHODS: Dual energy X-ray absorptiometry (DXA) was performed in 241 recurrence-free Danish breast cancer patients, among whom 157 had a prior DXA scan within two years of chemotherapy ("early"). Linear regression was used to assess ∆BMDt in spine and hip according to age, different health-related variables and time since early DXA. RESULTS: Based on 157 patients, we observed annual decreases in spine BMD of 1.73% (95% confidence interval (CI): -2.01--1.44, p less than 0.001) and hip BMD of 1.30% (95% CI: -1.51--1.09, p less than 0.001). Patients aged less than 50 years at diagnosis had a significant decrease in mean spine BMD of 2.23% (95% CI: -2.78--1.68), whereas the decline was more limited in patients aged 50-59 years and patients aged 60 years or older with a mean spine BMD of 1.70% (95% CI: -2.07--1.34) and 0.81% (95% CI: -1.42--0.20), respectively. The results persisted in multivariable analyses. Osteoporosis was diagnosed in 9% of patients, all postmenopausal. CONCLUSIONS: Adjuvant anthracycline-taxane-based chemotherapy followed by endocrine therapy caused bone loss, especially in younger compared with older patients with early-stage breast cancer, confirming the results from randomised trials. FUNDING: This work was supported by the Region of Southern Denmark (grant number 13/7078); the University of Southern Denmark (grant number 00-101-000); the Danish Cancer Society (grant number R90-A6210-14-52); the Department of Oncology and Department of Endocrinology, Odense University Hospital; and the Consultant Council Scholarship, Odense University Hospital. TRIAL REGISTRATION: The study was approved by the Ethics Committee in Region of Southern Denmark (Project ID S-20140142) and the Danish Data Protection Board (ID 2008-58-0035).

Lower estimated bone strength and impaired bone microarchitecture in children with type 1 diabetes.

INTRODUCTION: Patients with type 1 diabetes has an increased risk of fracture. We wished to evaluate estimated bone strength in children and adolescents with type 1 diabetes and assess peripheral bone geometry, volumetric bone mineral density (vBMD) and microarchitecture. RESEARCH DESIGN AND METHODS: In a cross-sectional study, high-resolution peripheral quantitative CT (HR-pQCT) was performed of the radius and tibia in 84 children with type 1 diabetes and 55 healthy sibling controls. Estimated bone strength was assessed using a microfinite element analysis solver. Multivariate regression analyses were performed adjusting for age, sex, height and body mass index. RESULTS: The median age was 13.0 years in the diabetes group vs 11.5 years in healthy sibling controls. The median (range) diabetes duration was 4.2 (0.4-15.9) years; median (range) latest year Hb1Ac was 7.8 (5.9-11.8) % (61.8 (41-106) mmol/mol). In adjusted analyses, patients with type 1 diabetes had reduced estimated bone strength in both radius, ß -390.6 (-621.2 to -159.9) N, p=0.001, and tibia, ß -891.9 (-1321 to -462.9) N, p<0.001. In the radius and tibia, children with type 1 diabetes had reduced cortical area, trabecular vBMD, trabecular number and trabecular bone volume fraction and increased trabecular inhomogeneity, adjusted p<0.05 for all. Latest year HbA1c was negatively correlated with bone microarchitecture (radius and tibia), trabecular vBMD and estimated bone strength (tibia). CONCLUSION: Children with type 1 diabetes had reduced estimated bone strength. This reduced bone strength could partly be explained by reduced trabecular bone mineral density, adverse microarchitecture and reduced cortical area. We also found increasing latest year HbA1c to be associated with several adverse changes in bone parameters. HR-pQCT holds potential to identify early adverse bone changes and to explain the increased fracture risk in young patients with type 1 diabetes.

Oral Bisphosphonate use Reduces Cardiovascular Events in a Cohort of Danish Patients Referred for Bone Mineral Density.

CONTEXT: The cardiovascular (CV) safety of oral bisphosphonates (oBPs) is uncertain. OBJECTIVE: Determine the risk of CV events in oBP users referred for bone mineral density (BMD) testing compared with matched controls. DESIGN: Cohort study. SETTING: Danish national prescription registry enriched with local hospital data from Odense. PARTICIPANTS: Individuals aged ≥45 years referred for BMD testing. EXPOSURE: oBP. OUTCOMES: Hospitalization for any CV event. Secondary study outcomes were specific CV events. Negative (inguinal hernia surgery and ingrown toenail) and positive (fragility fracture) control outcomes assessed systemic bias. Cox proportional hazards models were fitted to estimate hazard ratio (HR) and 95% confidence intervals. RESULTS: There were 2565 oBP users (82.6% women) and 4568 (82.3% women) propensity score-matched controls. Alendronate accounted for 96% of oBP prescription. A total of 406 (15.8%) CV events occurred in oBP users (rate = 73.48 [66.67-80.98]); rate = events divided by person-time; and 837 (18.3%) events in controls (rate = 104.73 [97.87-112.07]) with an adjusted HR of 0.68 (95% CI 0.60-0.77). Additional adjustment for BMD did not attenuate estimates (HR 0.67; 95% CI 0.58-0.78]. Similar results were seen for secondary outcomes where risk reductions were seen regarding atrial fibrillation, stroke, heart failure, and aneurysms. Positive and negative control outcome analyses identified minimal residual confounding. CONCLUSION: Oral BP users experienced a 33% reduced risk of CV events. This observational real-world study adds to a growing body of evidence for cardioprotection by oBP that warrants testing in a randomized setting.

Variability in Medullary Thyroid Carcinoma in RET L790F Carriers: A Case Comparison Study of Index Patients.

Background: Previous studies have suggested that the variability in age of onset and aggressiveness of medullary thyroid carcinoma (MTC) in patients with multiple endocrine neoplasia type 2A (MEN 2A) carrying the same REarranged during Transfection (RET) mutation may be caused by additional RET germline variants or somatic variants. Methods: This study was a retrospective case comparison study of all MEN 2A index patients (n = 2) with the RET L790F germline mutation in Denmark. Whole blood and MTC tissue were analyzed for RET germline variants and other somatic variants (>500), respectively. Results: Patient 1 presented with MTC (T1aN1bM0) at age 14 years, while patient 2 presented with MTC (T1bN0M0) at age 70 years. No germline RET germline variants nor other variants were found to explain this MTC variability. Conclusions: We could not confirm the previously reported finding of a somatic RET variant as likely responsible for the early onset and aggressiveness of MTC in a RET germline mutation carrier. Also, we found no RET germline variants that could explain the MTC variability among our index patients. We did, however, identify a somatic FLT3 R387Q variant with an unknown potential as genetic modifier. Further large-scale studies are needed to investigate genetic modifiers in RET L790F carriers.