Identification of circulating microRNA patterns in patients in psoriasis and psoriatic arthritis.

OBJECTIVE: miRNAs are small non-coding RNAs that control gene expression. Specific intra- and extracellular miRNA signatures have been identified in various diseases. Whether certain miRNA signatures are associated with psoriasis (PsO) and PsA is currently unknown. We aimed to search for circulating miRNA signatures associated with PsO and PsA patients. METHODS: Expression of miRNAs was analysed by reverse transcription quantitative real-time PCR (RT-qPCR) in the serum of PsA, PsO patients and healthy controls. Demographic and disease-specific characteristics and imaging data from hand MRI were recorded. In the discovery phase, 192 miRNA assays were analysed in 48 samples (PsA, PsO, controls: each N = 16). For validation, 17 selected miRNAs were measured in the total population. RESULTS: A total of 141 patients and controls were analysed (51 PsA, 40 PsO, 50 controls). In the discovery phase 51 miRNAs in PsO and 64 miRNAs in PsA were down- or upregulated compared with controls, with 33 miRNAs being changed in both (adj. P < 0.05). The 17 top candidates from discovery were assessed in the validation phase, 9 of them discriminated PsA and PsO from controls [area under the curve (AUC) ≥0.70, all P < 0.05]. Four miRNAs (miR-19b-3p, miR-21-5p, miR-92a-3p and let-7b-5p) were significantly differently regulated between PsO and PsA. A combination of these miRNAs increased the AUC to 0.92 in multivariate regression model to discriminate PsO and PsA. CONCLUSION: miRNA signatures in PsA and PsO patients differ from controls. Nine miRNAs were differentially regulated in PsA and PsO patients, five of them previously reported to be involved in bone and cartilage metabolism, indicating an intimate association of psoriatic inflammation and bone/cartilage changes.

Chondrosarcoma of the spine-a case report.

CASE: A 73-year-old male patient presented with a 3-month history of back pain. In bone scintigraphy and the FDG PET-CT scan (fluorodeoxyglucose positron-emission computed tomography), highly suspect uptake levels were found in TH12-L1. Accordingly, an osteodestructive process was found on MRI (magnetic resonance imaging). Following a successfully performed biopsy of TH12, histologic analysis of the bone material revealed a chondrosarcoma (G1; T4N2M0). Complete resection of the tumor was successfully performed, since chondrosarcoma are resistant to radiation and chemotherapy. CONCLUSION: As chondrosarcoma is a rare bone neoplasm, it must be considered in the differential diagnosis of lower back pain to initiate adequate treatment.

Treatment of hypophosphatasia.

Hypophosphatasia (HPP) is a rare disorder with perinatal, infantile, childhood, and adult presentations. Severe forms are autosomal recessive with an early onset, whereas milder forms have a later onset. The underlying cause of the disease is a mutation based on a genetic disorder of the tissue non-specific alkaline phosphatase (TNSALP) gene, leading on the one hand to decreased activity of the TNSALP enzyme, and on the other hand to accumulation of TNSALP substrates. Symptoms like non-traumatic and non-healing fractures, musculoskeletal pain, chondrocalcinosis, seizures, premature loss of fully rooted teeth or delayed development of milk teeth, respiratory insufficiency, and calcinosis in muscles, kidneys, and joints occur. Supportive treatment is important for HPP patients, including mechanical ventilation, accurate fracture treatment, physical therapy, dental monitoring, and follow-up care to avoid subsequent problems. A causal enzyme therapy replacement with asfotase-alfa was approved by the Food and Drug Administration (FDA) in 2015. Asfotase-alfa improves respiratory insufficiency, bone mineralization, and long-term survival, and has a very good safety profile.

Less strict intervention thresholds for the FRAX and TBS-adjusted FRAX predict clinical fractures in osteopenic postmenopausal women with no prior fractures.

Little is known about the clinical relevance of treating post-menopausal women with no prior history of fragility fracture and bone mineral densities (BMD) within the osteopenic range. In recent years, in addition to BMD and FRAX fracture probability assessments, a surrogate measure of bone micro-architecture quality, called the trabecular bone score (TBS), has been proven to predict future fragility fractures independently of both BMD and the FRAX. In this retrospective analysis of a follow-up study, we compared three risk assessment instruments-the FRAX, the TBS, and a TBS-adjusted FRAX score-in their ability, to predict future fragility fractures over a minimum of five years of follow-up among post-menopausal osteopenic women with no prior fragility fractures. We also sought to determine if more- versus less-stringent criteria were better when stratifying patients into higher-risk patients warranting osteoporosis-targeted intervention versus lower-risk patients in whom intervention would usually be deemed unnecessary. Over a mean 5.2 years follow-up, 18 clinical fragility fractures were documented among 127 women in the age 50 years and older (mean age = 66.1). On multivariate analysis utilizing regression models and Kaplan-Meier curve analysis, less-stringent criteria for the FRAX and TBS-adjusted FRAX were capable of predicting future fractures (with sensitivity/specificity of 83/31; 39/77 and 78/50% for TBS, FRAX and TBS-adjusted FRAX, respectively), while more-stringent criteria were incapable of doing so (with sensitivity/specificity of 56/60; 39/77 and 39/74 for TBS, FRAX and TBS-adjusted FRAX, respectively). Neither TBS threshold alone was a significant predictor of future fracture in our study. However, hazard ratio analysis revealed slight superiority of the TBS-adjusted FRAX over the FRAX alone (HR = 3.09 vs. 2.79). Adjusting the FRAX tool by incorporating the TBS may be useful to optimize the detection of post-menopausal osteopenic women with no prior fractures who warrant osteoporosis-targeted therapy.

Hypophosphatasia: From Diagnosis to Treatment.

PURPOSE OF REVIEW: Hypophosphatasia (HPP) is a rare genetic disorder caused by mutations of the ALPL gene. ALPL encodes the tissue-non-specific isoenzyme of alkaline phosphatase (TNSALP). Consequently, bone mineralization is decreased leading to fractures, arthralgia, and extra-skeletal manifestations including tissue calcification, respiratory failure, and neurological complications. This review summarizes the most important clinical findings, diagnosis, and treatment options for HPP. RECENT FINDINGS: Asfotase alfa is a recombinant human alkaline phosphatase, used as treatment for the underlying cause of HPP. Asfotase alfa enhances the survival in life-threatening HPP and improves bone mineralization, muscle strength, and pulmonary function. However, discontinuation of asfotase alfa leads to reappearance of bone hypomineralization. Due to its varied manifestations, HPP often mimics rheumatological and other bone diseases, thereby delaying its diagnosis. Asfotase alfa, a recombinant alkaline phosphatase, is available for the long-term enzyme replacement therapy in patients with pediatric-onset HPP to treat the bone manifestations of the disease.

Atypical Femoral Fractures-Ongoing and History of Bone-Specific Therapy, Concomitant Diseases, Medications, and Survival.

Although atypical femoral fractures (AFFs) are generally rare events; several studies have indicated a potential link between AFF and long-term bone-specific therapies (BSTs). The aim of this study was to analyze the frequency of AFF and potential associations with prior or ongoing BST. A total of 8851 Caucasian female and male patients with de novo hip fractures treated in the largest Austrian level 1 trauma center from 2000 to 2013 were selected. Of the total, 194 patients with a de novo low-traumatic subtrochanteric or shaft fractures were identified: 35 atypical and 159 typical fractures. Of these patients, concomitant diseases, medication, previous fractures, and survival data were retrieved and analyzed. Female patients in both groups were significantly older. The median survival was significantly shorter in patients with AFF (9 vs 18 months; p < 0.0001). Cardiovascular disease, sarcopenia, chronic kidney disease, type 2 diabetes, smoking (past or current history), and prevalent fragility fractures were more frequent in AFF patients, as well as the concomitant use of phenprocoumon, furosemide, and sulfonylurea. Although the number of patients with current BST was less in (14.5%) both groups, more patients in the AFF group were previously treated with BST (71% vs 49%; p = 0.016), and they received these therapies for a longer time period. A combination of severe comorbidities, long-term pharmaceutical therapies, and a history of previous or ongoing BST was associated with an increased individual risk for AFF.

High-resolution peripheral quantitative CT imaging: Cortical porosity, poor trabecular bone microarchitecture, and low bone strength in lung transplant recipients.

PURPOSE: To characterize bone microarchitecture and quantify bone strength in lung transplant (LT) recipients by using high-resolution (HR) peripheral quantitative computed tomographic (CT) imaging of the ultradistal radius. MATERIALS AND METHODS: After study approval by the local ethics committee, all participants provided written informed consent. Included were 118 participants (58 LT recipients [mean age, 46.8 years ± 1.9; 30 women, 28 men] and 60 control participants [mean age, 39.9 years ± 1.9; 41 women, 19 men]) between April 2010 and May 2012. HR peripheral quantitative CT of the ultradistal radius was performed and evaluated for bone mineral density and trabecular and cortical bone microarchitecture. Mechanical competence was quantified by microfinite element analysis. Differences between LT recipients and control participants were determined by using two-way factorial analysis of covariance with age adjustment. RESULTS: Total and trabecular bone mineral density were significantly lower (-13.4% and -16.4%, respectively; P = .001) in LT recipients than in healthy control participants. LT recipients had lower trabecular number (-9.7%; P = .004) and lower trabecular thickness (-8.1%; P = .025). Trabecular separation and trabecular network heterogeneity were higher (+24.3% and +63.9%, respectively; P = .007 and P = .012, respectively) in LT recipients. Moreover, there was pronounced cortical porosity (+31.3%; P = .035) and lower cortical thickness (-10.2%, P = .005) after LT. In addition, mechanical competence was impaired, which was reflected by low stiffness (-15.0%; P < .001), low failure force (-14.8%; P < .001), and low bone strength (-14.6%; P < .001). CONCLUSION: Men and women with recent LT showed severe deficits in cortical and trabecular bone microarchitecture. Poor bone microarchitecture and low bone strength are likely to contribute to high fracture susceptibility observed in LT recipients.

Ibandronate increases sclerostin levels and bone strength in male patients with idiopathic osteoporosis.

The pathomechanism of male idiopathic osteoporosis (MIO) differs from postmenopausal osteoporosis with regard to alterations in osteoblast activity. We evaluated intravenous ibandronate (IBN) in 25 MIO patients with fragility fractures in a prospective, monocentric, single-arm, and open-label study for 24 months. The impact and changes of sclerostin (Scl), Dickkopf-1 (DKK-1), CTX, and PINP were examined. Additionally, volumetric cortical, trabecular and areal bone mineral density (BMD), trabecular bone score (TBS), and finite element analyses (FEA) were evaluated. Compared to baseline, median Scl levels were increased after 1 month (Δ 121%, p < 0.0001) and remained elevated for 12 months. DKK-1 decreased (p < 0.001) to a lesser extent until month 9 with values comparable to baseline at study endpoint. Early changes (baseline-month 1) of Scl negatively correlated with early changes of DKK-1 (-0.72), CTX (-0.82), and PINP (-0.55; p < 0.005 for all). The overall changes over the 24 months study period of Scl negatively correlated with decreased CTX (-0.32) and DKK-1 levels (-0.57, p < 0.0001 for both); CTX and PINP changes positively correlated at each time point (p < 0.001). Volumetric hip BMD increased by 12 and 18%, respectively (p < 0.0001 for both). Cross-sectional moment of inertia and section modulus for total hip significantly improved (p < 0.05 for all). Areal BMD at total hip, spine, and TBS increased. FEA displayed an increase in bone strength both in the hip (17%) and vertebrae (13%, all p < 0.0001) at anatomical sites susceptible for fragility fracture. IBN increases Scl and improves cortical and trabecular bone strength with early and ongoing vigorous suppression of bone resorption.

[Cathepsin K antagonists: preclinical and clinical data]. / Cathepsin K-Inhibitoren: präklinische und klinische Daten.

Cathepsin K, a cysteine protease, is an essential enzyme in degradation of collagen type I. Since cathepsin K is relatively specific to osteoclasts, it represents a promising candidate for drug development. In the past decades, efforts have been made in developing highly potent, selective and orally applicable cathepsin K inhibitors. In contrast to balicatib and relacatib, whose drug development programmes were stopped due to cutaneous side-effects related to limited drug specificity, the more specific cathepsin K inhibitors odanacatib (ODN) and ONO-5334 have entered clinical trials. Odanacatib progressively increases bone mineral density (BMD) and decreases bone resorption markers in postmenopausal women with low BMD. Its clinical efficacy and safety was confirmed by several clinical studies but indicates that odanacatib is characterized by a resolution-of-effect with increases in bone resorption and rapid decreases in BMD following treatment discontinuation. A phase III fracture prevention study in postmenopausal women with osteoporosis is currently in the final phase.

Osteogenesis imperfecta type III and hypogonadotropic hypogonadism result in severe bone loss: a case report.

We present the case of a 33-year-old male patient with multiple fractures and typical radiographical and clinical characteristics of osteogenesis imperfecta (OI) type III. Furthermore, the patient has suffered from hypogonadotropic hypogonadism since childhood. On the basis of antiresorptive therapy, no further fractures occurred within several years. Recently, recurrent nontraumatic fractures without bone healing were observed. Decreased bone mineral density was assessed by dual X-ray absorptiometry (DXA). High-resolution peripheral quantitative computed tomography (HR-pQCT) showed impaired trabecular bone structure. Due to recurrent fragility fractures and severe deterioration of bone structure, an osteoanabolic treatment with teriparatide was initiated to potentially stimulate fracture healing and to increase bone formation.

Femoral geometric parameters and BMD measurements by DXA in adult patients with different types of osteogenesis imperfecta.

OBJECTIVES: Osteogenesis imperfecta (OI) is an inherited disorder characterized by increased bone fragility with recurrent fractures that leads to skeletal deformities in severe cases. Consequently, in most OI patients, the hip is the only reliable measuring site for estimating future fracture risk. The aim of the study was to assess the applicability of hip structure analysis (HSA) by DXA in adult patients with osteogenesis imperfecta. MATERIALS AND METHODS: We evaluated bone mineral density (BMD) and hip structure analysis (HSA) by DXA, including cross-sectional area (CSA), cross-sectional moment of inertia (CSMI) and femoral strength index (FSI) in 30 adult patients with different types of OI and 30 age-matched healthy controls (CO). The OI total group (OI-tot) was divided into two subgroups: the mild OI I group (OI-I) and the more severe OI III and IV group (OI-III-IV). RESULTS: The mean neck BMD of OI-I and OI-III-IV were significantly lower compared to CO (-15.9 %, p < 0.005 and -37.5 %, p < 0.001 respectively). Similar results were observed at trochanter and total hip. CSA and the CSMI value were significantly lower for OI-I (-23.2 %, p < 0.001) and OI-III-IV (-45.9 %, p < 0.001) in comparison to CO. In addition, significant differences were found between the mild OI-I and the severe OI-III-IV group (-29.6 %, p < 0.05). FSI was significantly decreased in the OI-III-IV (25.7 %, p < 0.05) in comparison to the CO. Furthermore, significant correlations between BMD and HSA and between HSA and height and weight were found in osteogenesis imperfecta and controls. CONCLUSION: BMD measurement in osteogenesis imperfecta patients is very critical. The combination of BMD and geometric structural measurements at the hip in osteogenesis imperfecta patients may represent an additional helpful means in estimating bone strength and fracture risk.

Circulating miRNAs Respond to Denosumab Treatment After 2 Years in Postmenopausal Women With Osteoporosis-the MiDeTe study.

CONTEXT: MicroRNAs (miRNAs)-short, single-stranded, noncoding RNAs-regulate several biological processes, including bone metabolism. OBJECTIVE: We investigated circulating miRNAs as promising biomarkers for treatment monitoring in women with postmenopausal osteoporosis on denosumab (DMAB) therapy. METHODS: In this prospective, observational, single-center study, 21 postmenopausal women treated with DMAB were included for a longitudinal follow-up of 2 years. Next-generation sequencing (NGS) was performed to screen for serological miRNAs at baseline, month 6, and month 24. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to confirm NGS findings in the entire cohort. Bone turnover markers (BTM) P1NP and CTX, and bone mineral density (BMD) by dual x-ray absorptiometry were assessed and correlated to miRNAs. RESULTS: BMD at the hip (5.5%, P = 0.0006) and lumbar spine significantly increased (11.4%, P = 0.017), and CTX (64.1%, P < 0.0001) and P1NP (69.3%, P < 0.0001) significantly decreased during treatment. NGS analysis revealed significant changes in miRNAs after 2 years of DMAB treatment but not after 6 months. Seven miRNAs were confirmed by RT-qPCR to be significantly changed during a 2-year course of DMAB treatment compared to baseline. Four of these were mainly transcribed in blood cells, including monocytes. Correlation analysis identified significant correlation between change in miRNA and change in BTMs as well as BMD. Based on effect size and correlation strength, miR-454-3p, miR-26b-5p, and miR-584-5p were defined as top biomarker candidates, with the strongest association to the sustained effect of denosumab on bone in osteoporotic patients. CONCLUSION: Two years of DMAB treatment resulted in upregulation of 7 miRNAs, 4 of which are mainly transcribed in monocytes, indicating a potential impact of DMAB on circulating osteoclast precursor cells. These changes were associated to BMD gain and BTM suppression and could therefore be useful for monitoring DMAB treatment response.

Update on denosumab in postmenopausal osteoporosis--recent clinical data.

Denosumab, a fully human monoclonal antibody against the key osteoclastogenic factor RANK ligand, is currently approved for the treatment of postmenopausal osteoporosis. Denosumab differs from bisphosphonates in many aspects, for example, its ability to act in the extracellular compartment and its likelihood to be distributed throughout the skeleton. In contrast, bisphosphonates have to be internalized by osteoclasts and are mainly located across bone surfaces. This could explain why patients with osteoporosis, who are already treated with bisphosphonates, might experience further benefit when switching to denosumab. Head-to-head studies revealed that transition to denosumab resulted in a greater increase of bone mineral density (BMD) and a greater reduction of bone turnover than did continued alendronate. Additional analyses of the phase 3 FREEDOM trial demonstrated that fracture reduction was particularly high in cortical bone, such as the wrist. In addition, denosumab treatment for a 5- and 8-year period showed sustained reduction in fracture risk, increase in BMD and continued to be well tolerated. The 7-year extension study of FREEDOM and a phase 3 trial evaluating denosumab for the treatment of male osteoporosis are still ongoing and will provide supportive data in the near future.

Metabolic Bone Diseases-A Topic of Great Diversity.

The progress in research has improved the understanding of the epidemiology and pathogenesis of osteoporosis and bone disorders in general [...].

Pelvic Fractures-An Underestimated Problem? Incidence and Mortality Risk after Pelvic Fracture in Austria, 2010-2018.

(1) Background: Pelvic fractures (PFs) are related to osteoporosis, and represent a serious individual and socioeconomic burden. (2) Methods: We examined age- and sex-standardised incidence rates (SIRs) of PF, along with rates of all-cause overall and one-year mortality among patients with PF. We compared the mortality rates between PF patients and a matched fracture-free cohort. Patients ≥50 years old in Austria hospitalised with PF in 2010−2018, along with their dates of death, were recorded. (3) Results: We identified 54,975 patients with PF, of whom 70.9% were women. Between 2010 and 2018 the SIR of PF increased in men by 10.0%­from 125.3 (95% Confidence Interval 118.9−132.0) to 137.8 (95% CI 131.8−144.0) per 100,000­and in women by 2.7%­from 218.7 (95% CI 212.0−225.6) to 224.7 (95% CI 218.3−231.3) per 100,000. The one-year post-PF mortality rate was higher in men than in women (13.0% and 11.1%, respectively; p < 0.001). Pelvic fracture patients aged ≥65 had an elevated mortality risk (Hazard Ratio 1.75, 95% CI 1.71−1.79, p < 0.001) compared to controls. (4) Conclusions: There is a clear increase in the incidence of PF in the elderly population, with a greater increase in men over time. Pelvic fracture itself contributes to increased mortality in individuals aged 65 and above.

Dispensing anti-osteoporotic drugs changed during the COVID-19 pandemic.

OBJECTIVES: Caring for osteoporosis patients has proven challenging during the COVID-19 pandemic due to repeated lockdowns in Austria. The distinct possibility of insufficient treatment regimens is therefore a matter of pressing concern. The aim of the study was to assess alterations in dispensing anti-osteoporotic drugs during the COVID-19 pandemic. PATIENTS/METHODS: This study was a nationwide retrospective register-based observational study which included all patients in Austria aged ≥50 who received at least one prescription for anti-osteoporotic medication between January 2016 and November 2020. Pseudonymised individual-level patients' data were obtained from social insurance authorities. Anti-osteoporotic agents were divided into: (i) oral bisphosphonates, (ii) intravenous bisphosphonates, (iii) selective estrogen receptor modulators (SERMs), (iv) teriparatide (TPTD) and (v) denosumab (DMAB). We used interrupted time series analysis with autoregressive integrated moving average models (ARIMA) to predict drug dispensing. RESULTS: There were 2,884,374 dispensations of anti-osteoporotic drugs to 224,598 patients between 2016 and 2020. The mean monthly prescriptions for oral bisphosphonates (-14.5 %) and SERMs (-12.9 %) decreased during the COVID-19 pandemic when compared to the non-COVID-19 period. Dispensing for intravenous bisphosphonates (1.7 %) and teriparatide (9.5 %) increased. Prescriptions for DMAB decreased during the first lock-down, however increased by 29.1 % for the total observation time. The Arima models showed that in March 2020 (beginning of the 1st COVID-19 lockdown), there was a decrease of 778 dispensings, with a further increase of 14 dispensings every month for denosumab; a decrease by 178 dispensings, with a further increase of 23 dispensings every month for zolendronic acid; a decrease by 2950 dispensings, but with a further increase of 236 dispensings every other month for ibandronate and a decrease by 1443 dispensing with a further decrease of 29 dispensings for alendronate than predicted, had the lockdown not occurred. CONCLUSIONS: The total number of prescriptions dispensed to patients treated with anti-osteoporotic medications declined rapidly during first COVID-19 lockdown. The observed decrease of DMAB during the first lockdown rebounded in the following months. Considering the massive treatment gap for osteoporosis, and the related fracture risk, clinicians should continue treatment, even during a pandemic.

Fragility fractures in men with idiopathic osteoporosis are associated with undermineralization of the bone matrix without evidence of increased bone turnover.

The pathogenesis of primary osteoporosis in younger individuals is still elusive. An important determinant of the biomechanical competence of bone is its material quality. In this retrospective study we evaluated bone material quality based on quantitative backscattered electron imaging to assess bone mineralization density distribution (BMDD) in bone biopsies of 25 male patients (aged 18-61 years) who sustained fragility fractures but were otherwise healthy. BMDD of cancellous bone was compared with previously established adult reference data. Complementary information was obtained by bone histomorphometry. The histomorphometric results showed a paucity of osteoblasts and osteoclasts on the bone surface in the majority of patients. BMDD revealed a significant shift to lower mineralization densities for cancellous bone values: CaMean (weighted mean Ca content, -5.9%), CaPeak (mode of the BMDD, -5.6%), and CaHigh (portion of fully mineralized bone, -76.8%) were decreased compared to normative reference; CaWidth (heterogeneity in mineralization, +18.5%) and CaLow (portion of low mineralized bone, +68.8; all P < 0.001) were significantly increased. The shift toward lower mineral content in the bone matrix in combination with reduced indices of bone formation and bone resorption suggests an inherent mineralization defect leading to undermineralized bone matrix, which might contribute to the susceptibility to fragility fractures of the patients. The alteration in bone material might be related to osteoblastic dysfunction and seems fundamentally different from that in high bone turnover osteoporosis with a negative bone balance.

Severe osteoporosis with multiple vertebral fractures after gender reassignment therapy - is it male or female osteoporosis?

OBJECTIVE: We report about a 49-years-old patient with severe osteoporosis and multiple vertebral fractures after male-to-female reassignment therapy. The patient had 12 years of hormone replacement therapy (HRT) with very low serum levels of estradiol and testosterone at the time the fractures occurred. The reasons are currently not known. Most likely the patient seems to be non-compliant with the HRT intake. RESULTS: Bone mineral density (BMD) measurements showed highly decreased T-Scores between -3.5 and -4.5. All routine laboratory parameters, especially the markers of bone turnover, were within the normal range. µ-CT 3D-structural analysis of the bone biopsy showed a highly reduced trabecular connectivity (Conn.Dens.). Bone mineral density distribution (BMDD), measured by quantitative backscattered electron imaging (qBEI), showed a BMDD within normal range, except heterogeneity index (Ca(WIDTH)) and fraction of highly mineralised bone (Ca(HIGH)), which were increased. CONCLUSIONS: We conclude that our patient has a cross-sex hormonal therapy induced total imbalance of bone homeostasis, because of the long lasting under monitored hormone therapy which led to severe interferences in physiological maturities. Male-to-female transsexuals without an adequate estrogen treatment are at increased risk of developing osteoporosis.

Attenuation of COVID-19-induced cytokine storm in a young male patient with severe respiratory and neurological symptoms.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), produces protean manifestations and causes indiscriminate havoc in multiple organ systems. This rapid and vast production of proinflammatory cytokines contributes to a condition termed cytokine storm. A 35-year-old, otherwise healthy, employed, male patient was tested positive for COVID-19. He was admitted to the hospital on disease day 10 due to retarded verbal reactions and progressive delirium. On account of these conditions and the need for noninvasive/invasive ventilation, a combination treatment with baricitinib and remdesivir in conjunction with standard of care was initiated. The cytokine storm was rapidly blocked, leading to a vast pulmonary recovery with retarded recovery of the central nervous system. We conclude that the rapid blockade of the COVID-19-induced cytokine storm should be considered of avail as a principle of careful decision-making for effective recovery.