The Role of Sex and Gender in Transgender Bone and Other Musculoskeletal Health.

ABSTRACT: Musculoskeletal changes occur with gender-affirming hormonal therapy (GAHT) and gender-affirming surgery (GAS) used in the care of transgender adolescents and adults. Survey results have shown that orthopaedic surgeons desire to care for transgender individuals but express concern over a knowledge deficit. This article reviews the physiology and pathophysiology that may occur with GAHT and GAS. Transgender women have lower bone mineral density (BMD) prior to GAHT than cisgender men. Limited fracture data would suggest that transgender women >50 years of age have fracture rates similar to those of cisgender women. Transgender men have normal BMD prior to GAHT and are not at an increased risk for fracture compared with cisgender women. The use of puberty-blocking medications in the care of transgender youth does result in a decline in BMD, which returns to baseline with GAHT, but the effect of delaying puberty on maximal BMD and the lifetime fracture risk are unknown. At present, dual x-ray absorptiometry (DXA) is used to measure BMD and assess fracture risk. Attention should be paid to using the appropriate reference group in the interpretation of DXA for transgender individuals. Promote musculoskeletal health by ensuring appropriate calcium, vitamin D, weight-bearing activity, and a healthy lifestyle. Adherence to GAHT needs to be encouraged to avoid bone loss. Data with regard to therapy for osteoporosis in transgender patients have been lacking, but, at present, use of available therapies is expected to be effective. Information with regard to differences in other musculoskeletal health issues such as joint injuries has been lacking in transgender individuals.

CGM patterns in adults with cystic fibrosis-related diabetes before and after elexacaftor-tezacaftor-ivacaftor therapy.

Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis that is associated with worse outcomes and higher mortality rates. CF transmembrane conductance regulator gene (CFTR) modulators have shown favorable effects on lung function, pulmonary exacerbations, and nutrition status. However, data regarding effects of CFTR modulators on glycemic control among those with CFRD is lacking. In this retrospective study, CGM data was analyzed to determine effect of elexacaftortezacaftor- ivacaftor therapy (ETI), a CFTR modulator, on glucose control among patients with CFRD. No difference was seen in glucose patterns after 3- and 6- months of starting ETI.

DXA Scan Variants in Transgender Patients.

Transgender and gender non-conforming (TGNC) individuals face numerous barriers to healthcare, which contribute to many health disparities. TGNC persons may choose gender-affirming therapies with surgery and/or hormone replacement therapy (HRT) to manage gender incongruence. Despite the expanding use of HRT, the long-term outcomes on bone health and metabolism, are still relatively unknown in the TGNC population. In 2019, the International Society of Clinical Densitometry (ISCD) released an official position statement on the appropriate use of dual energy x-ray absorptiometry (DXA) to measure bone density in the TGNC population. In this study, we reviewed which "sex" is currently utilized among providers when performing DXA scans to calculate T- and Z-scores for TGNC persons and how this compares to the positions published by the ISCD. A retrospective analysis was performed utilizing HERON queries and subsequent chart review. HERON is a type of Informatics for Integrating Biology and the Bedside software that was utilized to find sets of patients of interest from electronic medical record data while preserving patient privacy through a query interface tool. Project specific sets including patient demographics, medications, gonadectomy, and DXA scan information was created in HERON to make this highly detailed data of specific patients available to the investigators on the platform, as reviewed and retrieved by the Institutional Review Board. The qualitative DXA data obtained from chart review was determined as "correct" or "incorrect" based on positions provided from the ISCD. 10 DXA scans that met inclusion criteria were obtained between 9 TGNC patients. In total, 18 T-scores and Z-scores of the 10 DXAs were reviewed and scored. Based on ISCD positions, 67% of the T-score and Z-scores were calculated incorrectly; using the erroneous "sex" based standard to compare scores. Like DXA scans, many current healthcare standards and protocols are based on a patient's sex or gender, which may cause confusion amongst healthcare personnel who have not received proper training regarding the TGNC population. In this study, 67% of T-scores and Z-scores were calculated incorrectly based on ISCD recommendations. An additional prospective research design is required to determine the consequences of incorrectly calculated DXA scans for TGNC patients. Furthermore, future research is needed to determine HRT's effects on bone mineral density in the TGNC population in the United States.

Romosozumab used to treat a patient with cystic fibrosis-related osteoporosis.

Bone disease is a known complication of cystic fibrosis (CF). To date, there have been no reports on the effectiveness of romosozumab, monoclonal antibody to sclerostin, to treat CF-related bone disease. We report a case of a 46-year-old premenopausal female with CF-related bone disease and multiple fractures who was treated with romosozumab. After one year of therapy with romosozumab, the patient tolerated therapy and bone mineral density (BMD) significantly improved. Of the currently available anti-resorptive or anabolic osteoporosis medications, only bisphosphonates have been studied in individuals with CF. This report highlights that romosozumab may be an effective alternative treatment modality in selected patients with CF at high risk for fractures. Further studies are warranted to evaluate the efficacy and safety profile of romosozumab in people with CF.

Ral signaling pathway in health and cancer.

The Ral (Ras-Like) signaling pathway plays an important role in the biology of cells. A plethora of effects is regulated by this signaling pathway and its prooncogenic effectors. Our team has demonstrated the overactivation of the RalA signaling pathway in a number of human malignancies including cancers of the liver, ovary, lung, brain, and malignant peripheral nerve sheath tumors. Additionally, we have shown that the activation of RalA in cancer stem cells is higher in comparison with differentiated cancer cells. In this article, we review the role of Ral signaling in health and disease with a focus on the role of this multifunctional protein in the generation of therapies for cancer. An improved understanding of this pathway can lead to development of a novel class of anticancer therapies that functions on the basis of intervention with RalA or its downstream effectors.

Osteoporosis management in older patients who experienced a fracture.

BACKGROUND: Fractures in older patients are common, morbid, and associated with increased risk of subsequent fractures. Inpatient and outpatient management and treatment of fractures can be costly. With more emphasis placed on quality care for Medicare beneficiaries, we studied if patients were receiving proper screening for osteoporosis and treatment after diagnosis of fracture. This study aims to determine if adequate screening and treatment for osteoporosis occurs in the postfracture period. METHODS: A retrospective analysis of Medicare beneficiaries aged 67 years or older was gathered from a single institution in both inpatient and outpatient visits. Based on International Classification of Diseases ninth revision codes, primary diagnosis of fractures of neck and trunk, upper limb, and lower limb were obtained in addition to current procedural terminology codes for fracture procedures. We studied patients who had been screened for osteoporosis with a bone mineral study or received osteoporosis treatment after their fracture. RESULTS: Medicare beneficiaries totaling 1,375 patients were determined to have an inclusion fracture between June 1, 2013 and November 30, 2014. At the time of our analysis on December 1, 2014, 1,219 patients were living and included in the analysis. Of these patients, 256 (21.0%) either received osteoporosis testing with bone mineral density or received treatment for osteoporosis. On sex breakdown, 208/820 (25.4%) females received proper evaluation or treatment of osteoporosis in comparison to 48/399 (12.0%) males. This is in comparison to the Centers for Medicare and Medicaid Services' national average of 19.1% for osteoporosis management in females. CONCLUSION: A minority of studied patients received evaluation or treatment for osteoporosis after their fracture. Postfracture investigation and treatment for osteoporosis in Medicare beneficiaries is inadequate. If improved, Medicare costs could be reduced by prevention of future fractures. Future studies could determine how best to ensure this intervention occurs.

Effect of exendin (exenatide)--GLP 1 receptor agonist on the thyroid and parathyroid gland in a rat model.

Exenatide or Exendin-4 is a 39-amino acid agonist of the glucagon like peptide (GLP-1) receptor approved for the adjunctive treatment for type 2 diabetes. Recent reports suggest that GLP-1 agonists may also have distant effects including C-cell thyroid hyperplasia. The aim of this study was to evaluate the effect of exendin-4 on the thyroid and parathyroid cells in a rat model. Rat thyroids were stained for calcitonin, H&E and for carcinoembryonic antigen (CEA). Thyroid C-cell hyperplasia was graded on H&E stained slides using cell size and secretory granule numbers, morphological features of the parathyroid glands and the serum calcium concentrations of the rats were also evaluated. Counts of stained cells/high power field and intensity of staining were recorded by two pathologists. Data were analyzed by ANOVA/post-tests. C cell hypertrophy was elevated in exenatide-treated vs. untreated animals (22.5 ± 8.7 vs. 10.5 ± 2.7 cells/HPF). CEA staining failed to show effects by exendin. Calcitonin staining was significantly elevated in exenatide treated controls (P<0.001). Parathyroid glands were histologically normal in both groups, and serum calcium levels were within normal range in all animals. In summary, exenatide was associated with C cell hyperplasia and increased calcitonin staining of thyroids, but was unrelated to CEA levels. These data raise important concerns about the effects of exenatide which, given its wide clinical use, should be clarified with urgency.

Prophylactic use of zoledronic acid to prevent early bone loss is safe and feasible in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation.

Osteopenia and osteoporosis are well-known consequences of allogeneic stem cell transplantation (allo-SCT). The role of prophylactic zoledronic acid on bone turnover following allo-SCT has not been well characterized. We prospectively studied the role of prophylactic use of zoledronic acid on bone metabolism in 17 patients with acute myeloid leukemia (AML) undergoing allo-SCT over a period of three yr (2006-2009). We measured bone mineral density using dual energy X-ray absorptiometry (DXA) scanning and the markers of bone turnover by urinary N-terminal telopeptide (uNTX) and serum osteocalcin levels prior to and serially following transplantation. All patients received 4 mg of zoledronic acid (Zometa, Novartis Pharmaceuticals Corp., Basel, Switzerland) intravenously prior to starting conditioning regimen and at six months after SCT. DXA scores did not change significantly in any patient over time (p > 0.05). uNTX progressively decreased over time (p < 0.001) and serum osteocalcin stabilized after six months. No patient developed osteonecrosis of the jaw. In conclusion, in this prospective pilot study, prophylactic use of zoledronic acid to prevent early bone loss was found to be safe and feasible in patients with AML undergoing allo-SCT during the immediate post-transplantation period.