The 2023 Guidelines for the management and treatment of glucocorticoid-induced osteoporosis.

INTRODUCTION: Although synthetic glucocorticoids (GCs) are commonly used to treat autoimmune and other diseases, GC induced osteoporosis (GIOP) which accounts for 25% of the adverse reactions, causes fractures in 30-50% of patients, and markedly decreases their quality of life. In 2014, the Japanese Society for Bone and Mineral Research (JSBMR) published the revised guidelines for the management and treatment of steroid-induced osteoporosis, providing the treatment criteria based on scores of risk factors, including previous fractures, age, GC doses, and bone mineral density, for patients aged ≥18 years who are receiving GC therapy or scheduled to receive GC therapy for ≥3 months. MATERIALS AND METHODS: The Committee on the revision of the guidelines for the management and treatment of GIOP of the JSBMR prepared 17 clinical questions (CQs) according to the GRADE approach and revised the guidelines for the management and treatment of GIOP through systematic reviews and consensus conferences using the Delphi method. RESULTS: Bisphosphonates (oral and injectable formulations), anti-RANKL antibody teriparatide, eldecalcitol, or selective estrogen receptor modulators are recommended for patients who has received or scheduled for GC therapy with risk factor scores of ≥3. It is recommended that osteoporosis medication is started concomitantly with the GC therapy for the prevention of fragility fractures in elderly patients. CONCLUSION: The 2023 guidelines for the management and treatment of GIOP was developed through systematic reviews and consensus conferences using the Delphi method.

Efficacy of once-weekly teriparatide for primary prevention of glucocorticoid-induced osteoporosis: A post hoc analysis of the TOWER-GO study.

OBJECTIVES: A post hoc analysis of the Teriparatide Once-Weekly Efficacy Research for Glucocorticoid-induced Osteoporosis (TOWER-GO) study was performed to examine the effect of once-weekly administration of 56.5 µg teriparatide on primary prevention of glucocorticoid-induced osteoporosis (GIOP). METHODS: Of the subjects of the TOWER-GO study, 73 were included. The percentage changes from baseline in lumbar spine bone mineral density (BMD) and bone turnover markers were evaluated over 72 weeks with once-weekly teriparatide and once-weekly alendronate. RESULTS: The percentage change of lumbar spine BMD from baseline at 72 weeks was significantly increased in both groups. Bone formation markers were significantly increased by teriparatide administration, although they were slightly decreased by alendronate administration. Bone resorption markers were gradually decreased by teriparatide, whereas alendronate markedly decreased them within 4 weeks. No major safety concerns arose. CONCLUSIONS: In this primary prevention study of GIOP, comparable increases in BMD were observed between alendronate and once-weekly teriparatide. More desirable changes in bone markers were observed with teriparatide administration. These data suggest that once-weekly teriparatide is effective in primary prevention of GIOP.

Efficacy of once-weekly teriparatide in patients with glucocorticoid-induced osteoporosis: the TOWER-GO study.

INTRODUCTION: Bisphosphonates are the standard treatment for glucocorticoid-induced osteoporosis (GIOP) with teriparatide being another option. While daily teriparatide has been shown to be effective in increasing bone mineral density (BMD), the efficacy of once-weekly teriparatide (56.5 µg) has not yet been evaluated. The TOWER-GO study, a 72-week, multicenter, open-label, randomized controlled trial, was conducted in patients with GIOP to compare the effects of once-weekly teriparatide and once-weekly alendronate 35 mg on BMD. MATERIALS AND METHODS: Patients (N = 180) with GIOP for whom drug treatment was indicated according to the 2004 guidelines in Japan were randomized to receive once-weekly teriparatide (n = 89) or once-weekly alendronate (n = 91). The primary endpoint was the non-inferiority of percentage change in lumbar spine BMD at final follow-up. The secondary endpoints were the percentage change in BMD from baseline, incidence of bone fractures, and changes in bone turnover markers. RESULTS: While the non-inferiority of teriparatide to alendronate was not confirmed, BMD increased significantly from baseline with teriparatide and alendronate by 5.09% and 4.04%, respectively (both p < 0.05), at 72 weeks. The incidence of vertebral and non-vertebral fractures was similar in both groups. Bone formation markers increased in the teriparatide group and decreased in the alendronate group. CONCLUSIONS: The non-inferiority of once-weekly teriparatide versus once-weekly alendronate in BMD change at 72 weeks was not shown, but the increase in bone formation markers over time and the increase of BMD in GIOP patients treated with once-weekly teriparatide were confirmed.

[Metabolism of bone and calcium period in perinatal patients treated with glucocorticoids.]

Pregnancy and child birth are possible even in young females with diseases to be treated with glucocorticoid by controlling disease activity and careful follow-up. There is no description about expectant and nursing mothers in the guide lines for glucocorticoid-induced osteoporosis published in many countries. Obtaining informed consent is more important for understanding the benefit and risk of the pregnancy and child birth during the glucocorticoid treatment in the female patients, to whom getting a child is very meaningful.

[Glucocorticoid and Bone. Efficacy and safety of bisphosphonate in treatment of glucocorticoid induced osteoporosis].

Glucocorticoids (GCs) were widely used for the treatment of various disorders. And Osteoporosis is one of the major complications of glucocorticoid therapy. An increased risk of both vertebral and nonvertebral fractures has been reported with dosages of prednisolone or equivalent as low as 2.5-7.5 mg daily. The skeletal effects of glucocorticoids include both direct and indirect actions on bone that result in an early, transient increase in bone resorption accompanied by a decrease in bone formation, which is maintained for the duration of glucocorticoid therapy. Bisphosphonates are the front-line choice for prevention of fracture in glucocorticoid-treated patients and are recommended renewal GIOP guideline from Japan.

Improvement of active salivary gland ultrasonography findings in Sjögren's syndrome in response to short-term glucocorticoid treatment: A case report and review of the literature.

Salivary gland ultrasonography is a non-invasive imaging technique that helps in the diagnosis and assessment of disease activity in Sjögren's syndrome. However, it remains unclear whether the salivary gland ultrasonography findings are reversible in response to treatment. We present a case of a woman in her 20s who presented with parotid swelling and pain lasting for 3 months. The patient was diagnosed with anti-SS-A antibody-positive Sjögren's syndrome with active sialadenitis, and short-term glucocorticoid treatment resulted in resolution of clinical symptoms and improvement of salivary gland ultrasonography findings by the Outcome Measures in Rheumatology Clinical Trials scoring system. Notably, the anechoic/hypoechoic foci and vascular signals in the parotid and submandibular glands were reduced after treatment. Furthermore, peak systolic blood flow velocity of the facial artery entering the submandibular gland was decreased. Our case highlights that the findings of 'inflammatory' structural changes and vascularisation on salivary gland ultrasonography, including the Outcome Measures in Rheumatology Clinical Trials scoring system, reflect the disease active of Sjögren's syndrome and are reversible with treatment. Salivary gland ultrasonography has the potential to be a useful tool for monitoring treatment response and stratifying patients by disease activity in Sjögren's syndrome; therefore, further research is needed on the relationship of salivary gland ultrasonography findings with the pathophysiological mechanisms of sialadenitis and long-term clinical outcomes.

Pre-procedural glucose levels and the risk for contrast-induced acute kidney injury in patients undergoing emergency coronary intervention.

BACKGROUND: The incidence, risk factors, and outcome of contrast-induced acute kidney injury (CI-AKI) in 730 patients with acute coronary syndrome (ACS) undergoing emergency percutaneous coronary intervention (PCI), whose contrast volume was below maximum allowable contrast dose (MACD) was prospectively investigated. METHODS AND RESULTS: MACD was defined as (5ml×body weight [kg]/baseline creatinine [mg/dl]). CI-AKI was defined as a greater than 25% increase in creatinine from the baseline or an absolute increase of ≥0.5mg/dl within 48h after the procedure. CI-AKI occurred in 212 (29%) patients. Patients with CI-AKI had a higher risk for in-hospital mortality (9.4% vs. 1.5%, P<0.001) and a longer stay in the coronary care unit (median, 4.0 vs. 3.0 days, P<0.001) compared with those without CI-AKI. In a multivariate logistic analysis including 20 clinical variables, elevated glucose levels as variables categorized into quartiles were independently (P<0.001) associated with the development of CI-AKI. In addition, this relationship was seen in both the subgroup of patients with known diabetes and that of those without known diabetes. CONCLUSIONS: CI-AKI might occur commonly and could be be associated with a more complicated clinical course in ACS patients undergoing emergency PCI whose contrast volume does not exceed MACD. Elevated pre-procedural glucose might be a powerful and independent risk factor for the development of CI-AKI in this population.

A Susceptible Period of Photic Day-Night Rhythm Loss in Common Marmoset Social Behavior Development.

The prevalence of neurodevelopmental psychiatric disorders such as pervasive developmental disorders is rapidly increasing worldwide. Although these developmental disorders are known to be influenced by an individual's genetic background, the potential biological responses to early life's environmental exposure to both physical and psychological factors must also be considered. Many studies have acknowledged the influence of shorter time for rest at night and the simultaneous occurrence of various kinds of complications involving developmental disorders. In a prior study, we examined how a common marmoset's (Callithrix jacchus) psychosocial development was affected when it was reared under constant daylight from birth and then reared individually by humans nursing them under constant light (LL) during their juvenile development stages. The behaviors of these marmosets were compared with those of normal day-night cycle (LD) marmosets using a multivariate analysis based on principal component analysis (PCA). That study found that LL marmosets relatively elicited egg-like calls (Ecall) and side-to-side shakes of the upper body with rapid head rotation through adulthood frequently. Based on the PCA, these behaviors were interpreted as "alert" or "hyperactive" states. However, we did not clarify susceptible periods of the photic rhythm loss experience and the psychological development output. In this study we summarize the following studies in our model animal colonies involving 30 animals (11 female, 19 males) to further explore critical age states of inquiry about each social behavior profiling. We compared social behaviors of three age stages, juvenile, adolescent and young adult equivalent to one another in four LL experience conditions, LL (postnatal day (P) 0 to around 150), Middle (P60-149, 90 days), Late (P150-239, 90 days), and LD (no experience). In the most representative 1st and 2nd principal component scores, the shifting to higher frequency of alert behaviors developed at the adult stage in LL, Middle, then Late in turn. The no LL experience group, LD, generally featured higher frequency of local preference of high position compared to LL experience present groups, in adulthood. This limited model primate study might inspire different developmental age sensitive mechanisms of neuronal network to control socio-emotional functions by utilizing the multivariate visualization method, BOUQUET. This study could potentially contribute to nurturing educational designs for social developmental disorders.

Factors influencing the prescribed dose of opioid analgesics in cancer patients.

The dose of opioids prescribed for cancer pain does not always correlate with the actual pain severity. However, there is little evidence to explain this observation. In the present study, we sought to determine factors that influence the dose of opioid analgesics. A total of 227 patients who were administered opioids between August 2012 and May 2016 and later expired within the Department of Palliative Care at Ashiya Municipal Hospital were included, and the following variables were examined: age, sex, type of cancer, Verbal Rating Scale before and after the administration of the maximum pre-scribed dose of opioids, type of opioids and route of administration, blood test results, pain severity, and use of adju-vants. Data were analyzed using step-wise multiple linear regression. Median of the maximum prescribed dose of opioids, expressed in oral morphine equivalent, was 68.6, 60.0, and 39.2 mg for patients aged <65, 65-74, and ≥75 years, respectively. Step-wise multiple linear regression analysis further demonstrated that an increase in age by 1 year decreased the maximum prescribed dose of opioids by 0.98-fold (p = 0.006). Other factors that influenced the maximum prescribed dose of opioids included the use of analgesic adjuvants (1.91-fold, p = 0.001), oral administration (0.54-fold, p = 0.016), and elevated level of bilirubin (0.95-fold by 0.1 mg/dL increase, p = 0.013). Opioids examined in the study are metabolized in the liver by cytochromes P450 or by glucuronidation. Thus, if reduced drug metabolism causes the reduction in the maximum prescribed dose of opioids, liver function may contribute to this effect. Based on our findings that old age is associated with a lower prescribed dose of opioids, future studies should examine additional variables included in laboratory tests in more detail and measure hepatic blood flow to determine the cause of this as-sociation.

[Drug selection guide for osteoporosis determined by the clinical staging, pathophysiology and age].

The various therapeutic agents for osteoporosis became currently available and it is significant to select drugs according to disease stage, pathophysiology and age. As markers for bone resorption and bone mineral density can predict the subsequent risk of hip fracture in elderly women, bone resorption inhibitors such as bisphosphonate or raloxifene are appropriate for subjects with high levels of the marker or low bone mineral density. Moreover, bisphosphonate and raloxifene are also recommended for subjects with prevalent fractures, even though disease staging in osteoporosis is complicated. However, these data should be carefully referred in clinical application, since they were obtained in combination with vitamin D and calcium preparation.

[Mechanisms of anti-inflammatory actions of glucocorticoids].

Synthetic glucocorticoids display a consistent anti-inflammatory action which are composite mechanisms through genomic and non-genomic pathways, or different types of cells and molecules. Also a wide range of doses of glucocorticoids can be allowed to show a demanded anti-inflammatory effect in many inflammatory diseases.

[Vitamin K2 as a potential therapeutic agent for glucocorticoid-induced osteoporosis].

In recent years, bone quality is thought to be an important factor in bone strength. Vitamin K(2) (VK(2))drugs inhibit bone fracture, although their effect of increasing bone mineral density (BMD)is lower compared to bisphosphonate. This suggests VK(2) analogs improve bone quality. Glucocorticoid-induced osteoporosis(GIOP)brings about a bone fracture even under the condition of high BMD. VK(2) drugs might be effective to prevent bone fracture in GIOP, because they increase bone strength independently of bone mineral density (BMD).

[Secondary osteoporosis. Guidelines for glucocorticoid-induced osteoporosis].

The first guideline for the prevention and treatment of glucocorticoid-induced osteoporosis was published from American College of Rheumatology in 1996, and then novel guidelines were developed in many countries. These evidence-based guidelines were useful for enlightment of glucocorticoid-induced osteoporosis. The latest guideline was published in our country in 2005. As the special feature of this guideline, a flow chart makes all of physicians in all fields to utilize the guideline. It suggests the significance of the treatment as well as primary prevention and induces an effective drug treatment. Accumulating evidences are improving this guideline with some issues.

Glycine is used as a transmitter by decrementing expiratory neurons of the ventrolateral medulla in the rat.

The medullary respiratory network involves various types of respiratory neurons. The present study focused on possible inhibitory neurons called decrementing expiratory (E-DEC) neurons and aimed to determine whether their transmitter is glycine or GABA. In Nembutal-anesthetized, neuromuscularly blocked, and artificially ventilated rats we labeled E-DEC neurons with Neurobiotin and processed the tissues for detection of mRNA encoding either glycine transporter 2 (GLYT2) as a marker for glycinergic neurons or glutamic acid decarboxylase isoform 67 (GAD67) as a marker for GABAergic neurons, using in situ hybridization. Of 38 E-DEC neurons that were labeled, cranial motoneurons (n = 14), which were labeled as control, were negative for either GLYT2 mRNA (n = 10) or GAD67 mRNA (n = 4). The other E-DEC neurons (n = 24) were non-motoneurons. Sixteen of them were examined for GLYT2 mRNA, and the majority (11 of 16) was GLYT2 mRNA-positive. The remaining E-DEC neurons (n = 8) were examined for GAD67 mRNA, and all of them were GAD67 mRNA-negative. The GLYT2 mRNA-positive E-DEC neurons were located in the ventrolateral medulla spanning the Bötzinger complex (BOT), the rostral ventral respiratory group (VRG), and the caudal VRG. We conclude that not only E-DEC neurons of the BOT but also many E-DEC neurons of the VRG are inhibitory and use glycine as a transmitter. Although the present negative data cannot rule out completely the release of GABA or co-release of glycine and GABA from E-DEC neurons, several lines of evidence suggest that the glycinergic process is primarily responsible for the phasic inhibition of the respiratory network during the expiratory phase.

The olfactory bulb and the number of its glomeruli in the common marmoset (Callithrix jacchus).

The olfactory system has been well studied in mammals such as mice and rats. However, few studies have focused on characterizing this system in diurnal primates that rely on their sense of smell to a lesser extent due to their ecological environment. In the present study, we determined the histological organization of the olfactory bulb in the common marmoset (Callithrix jacchus). We then constructed 3-dimensional models of the glomeruli of the olfactory bulb, and estimated the number of glomeruli. Olfactory glomeruli are the functional units of olfactory processing, and have been investigated in detail using mice. There are approximately 1800 glomeruli in a mouse hemibulb, and olfactory sensory neurons expressing one selected olfactory receptor converge onto one or two glomeruli. Because mice have about 1000 olfactory receptor genes, it is proposed that the number of glomeruli in mammals is nearly double that of olfactory receptor genes. The common marmoset carries only about 400 intact olfactory receptor genes. The present study revealed that the number of glomeruli in a marmoset hemibulb was approximately 1500-1800. This result suggests that the number of glomeruli is not positively correlated with the number of intact olfactory receptor genes in mammals.

The spinal cord of the common marmoset (Callithrix jacchus).

The marmoset spinal cord possesses all the characteristic features of a typical mammalian spinal cord, but with some interesting variation in the levels of origin of the limb nerves. In our study Nissl and ChAT sections of the each segment of the spinal cord in two marmosets (Ma5 and Ma8), we found that the spinal cord can be functionally and anatomically divided into six regions: the prebrachial region (C1 to C3); the brachial region (C4 to C8) - segments supplying the upper limb; the post-brachial region (T1 to L1) - containing the sympathetic outflow, and supplying the hypaxial muscles of the body wall; the crural region (L2 to L5) - segments supplying the lower limb; the postcrural region (L6) - containing the parasympathetic outflow; and the caudal region (L7 to Co4) - supplying the tail. In the rat, mouse, and rhesus monkey, the prebrachial region consists of segments C1 to C4 (with the phrenic nucleus located at the C4 segment), and the brachial region extends from C5 to T1 inclusive. The prefixing of the upper limb outflow in these two marmosets mirrors the finding in the literature that a large C4 contribution to the brachial plexus is common in humans.