Actualisation 2023 des lignes directrices de pratique clinique pour la prise en charge de l'ostéoporose et la prévention des fractures au Canada.

CONTEXTE: Au Canada, plus de 2 millions de personnes vivent avec l'ostéoporose, une maladie qui accroît le risque de fracture, ce qui fait augmenter la morbidité et la mortalité, et entraîne une perte de qualité de vie et d'autonomie. La présente actualisation des lignes directrices vise à accompagner les professionnelles et professionnels de la santé au Canada dans la prestation de soins visant à optimiser la santé osseuse et à prévenir les fractures chez les femmes ménopausées et les hommes de 50 ans et plus. MÉTHODES: Le présent document fournit une actualisation des lignes directrices de pratique clinique de 2010 d'Ostéoporose Canada sur le diagnostic et la prise en charge de l'ostéoporose au pays. Nous avons utilisé l'approche GRADE (Grading of Recommendations Assessment, Development and Evaluation) et effectué l'assurance de la qualité conformément aux normes de qualité et de présentation des rapports de la grille AGREE II (Appraisal of Guidelines for Research & Evaluation). Les médecins de premier recours et les patientes et patients partenaires ont été représentés à tous les niveaux des comités et des groupes ayant participé à l'élaboration des lignes directrices, et ont participé à toutes les étapes du processus pour garantir la pertinence des informations pour les futurs utilisateurs et utilisatrices. Le processus de gestion des intérêts concurrents a été entamé avant l'élaboration des lignes directrices et s'est poursuivi sur toute sa durée, selon les principes du Réseau international en matière de lignes directrices. Dans la formulation des recommandations, nous avons tenu compte des avantages et des risques, des valeurs et préférences de la patientèle, des ressources, de l'équité, de l'acceptabilité et de la faisabilité; la force de chacune des recommandations a été déterminée en fonction du cadre GRADE. RECOMMANDATIONS: Les 25 recommandations et les 10 énoncés de bonne pratique sont répartis en sections : activité physique, alimentation, évaluation du risque de fracture, instauration du traitement, interventions pharmacologiques, durée et séquence du traitement, et monitorage. La prise en charge de l'ostéoporose devrait se fonder sur le risque de fracture, établi au moyen d'une évaluation clinique réalisée avec un outil d'évaluation du risque de fracture validé. L'activité physique, l'alimentation et la pharmacothérapie sont des éléments essentiels à la stratégie de prévention des fractures, qui devraient être personnalisés. INTERPRÉTATION: Les présentes lignes directrices ont pour but d'outiller les professionnelles et professionnels de la santé et la patientèle afin qu'ensemble ils puissent parler de l'importance de la santé osseuse et du risque de fracture tout au long de la vie adulte avancée. La détection et la prise en charge efficace de la fragilité osseuse peuvent contribuer à réduire les fractures et à préserver la mobilité, l'autonomie et la qualité de vie.

Clinical practice guideline for management of osteoporosis and fracture prevention in Canada: 2023 update.

BACKGROUND: In Canada, more than 2 million people live with osteoporosis, a disease that increases the risk for fractures, which result in excess mortality and morbidity, decreased quality of life and loss of autonomy. This guideline update is intended to assist Canadian health care professionals in the delivery of care to optimize skeletal health and prevent fractures in postmenopausal females and in males aged 50 years and older. METHODS: This guideline is an update of the 2010 Osteoporosis Canada clinical practice guideline on the diagnosis and management of osteoporosis in Canada. We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework and quality assurance as per Appraisal of Guidelines for Research and Evaluation (AGREE II) quality and reporting standards. Primary care physicians and patient partners were represented at all levels of the guideline committees and groups, and participated throughout the entire process to ensure relevance to target users. The process for managing competing interests was developed before and continued throughout the guideline development, informed by the Guideline International Network principles. We considered benefits and harms, patient values and preferences, resources, equity, acceptability and feasibility when developing recommendations; the strength of each recommendation was assigned according to the GRADE framework. RECOMMENDATIONS: The 25 recommendations and 10 good practice statements are grouped under the sections of exercise, nutrition, fracture risk assessment and treatment initiation, pharmacologic interventions, duration and sequence of therapy, and monitoring. The management of osteoporosis should be guided by the patient's risk of fracture, based on clinical assessment and using a validated fracture risk assessment tool. Exercise, nutrition and pharmacotherapy are key elements of the management strategy for fracture prevention and should be individualized. INTERPRETATION: The aim of this guideline is to empower health care professionals and patients to have meaningful discussions on the importance of skeletal health and fracture risk throughout older adulthood. Identification and appropriate management of skeletal fragility can reduce fractures, and preserve mobility, autonomy and quality of life.

Pituitary Apoplexy: Results of Surgical and Conservative Management Clinical Series and Review of the Literature.

OBJECTIVE: Pituitary apoplexy is associated with visual, cranial nerve, and endocrine dysfunction. In this article, the results of surgical and conservative management of pituitary apoplexy in a single center are evaluated and a review of the literature is presented. METHODS: A retrospective analysis was made of patients with pituitary apoplexy who underwent surgery or conservative management at our center between January 2007 and June 2017. Surgery was typically selected for patients who presented with acute deterioration of visual status and/or level of consciousness. Patients with no visual field deficit and those who had medical contraindications to undergo a surgical procedure because of previous comorbidities typically had conservative treatment. Baseline characteristics and clinical and radiologic outcomes were reviewed. A review of the literature (1990-2018) was performed according to PRISMA guidelines. Studies comparing the results of conservative and surgical management were identified. Visual, cranial nerve, and endocrine outcomes and tumor recurrence were analyzed. RESULTS: Forty-nine patients (73.1%) were managed surgically and 18 (26.9%) conservatively. After careful case selection, patients underwent surgical or conservative treatment. Patients who underwent conservative treatment had fewer visual deficits. At diagnosis, visual deficit (38.8% vs. 75.5%; P = 0.008) and cranial nerve palsy (27.7% vs. 51%; P = 0.058) were less common in the conservative group. Conservative and surgical treatments had similar visual and cranial nerve improvement rates (75% vs. 58.3%, P = 0.63 and 75% vs. 69.2%, P = 1.0, respectively). In the conservative group, tumor shrinkage was observed in 76.4% of cases. The systematic review retrieved 11 studies. No significant difference between conservative and surgical treatment for clinical outcomes (visual field recovery, odds ratio [OR], 1.45; 95% confidence interval [CI], 0.72-2.92; cranial nerve recovery, OR, 2.30; 95% CI, 0.93-5.65; and hypopituitarism, OR, 1.05; 95% CI, 0.64-1.74) or tumor recurrence (OR, 0.68; 95% CI, 0.20-2.34) was observed. CONCLUSIONS: A tailored approach to pituitary apoplexy, one that does not include an absolute need for surgery, is appropriate. Conservative management is appropriate in selected patients presenting without visual deficits.

PREDICTIVE MARKERS FOR POSTSURGICAL MEDICAL MANAGEMENT OF ACROMEGALY: A SYSTEMATIC REVIEW AND CONSENSUS TREATMENT GUIDELINE.

Objective: To clarify the selection of medical therapy following transsphenoidal surgery in patients with acromegaly, based on growth hormone (GH)/insulin-like growth factor 1 (IGF-1) response and glucometabolic control. Methods: We carried out a systematic literature review on three of the best studied and most practical predictive markers of the response to somatostatin analogues (SSAs): somatostatin receptor (SSTR) expression, tumor morphologic classification, and T2-weighted magnetic resonance imaging (MRI) signal intensity. Additional analyses focused on glucose metabolism in treated patients. Results: The literature survey confirmed significant associations of all three factors with SSA responsiveness. SSTR expression appears necessary for the SSA response; however, it is not sufficient, as approximately half of SSTR2-positive tumors failed to respond clinically to first-generation SSAs. MRI findings (T2-hypo-intensity) and a densely granulated phenotype also correlate with SSA efficacy, and are advantageous as predictive markers relative to SSTR expression alone. Glucometabolic control declines with SSA monotherapy, whereas GH receptor antagonist (GHRA) monotherapy may restore normoglycemia. Conclusion: We propose a decision tree to guide selection among SSAs, dopamine agonists (DAs), and GHRA for medical treatment of acromegaly in the postsurgical setting. This decision tree employs three validated predictive markers and other clinical considerations, to determine whether SSAs are appropriate first-line medical therapy in the postsurgical setting. DA treatment is favored in patients with modest IGF-1 elevation. GHRA treatment should be considered for patients with T2-hyperintense tumors with a sparsely granulated phenotype and/or low SSTR2 staining, and may also be favored for individuals with diabetes. Prospective analyses are required to test the utility of this therapeutic paradigm. Abbreviations: DA = dopamine agonist; DG = densely granulated; GH = growth hormone; GHRA = growth hormone receptor antagonist; HbA1c = glycated hemoglobin; IGF-1 = insulin-like growth factor-1; MRI = magnetic resonance imaging; SG = sparsely granulated; SSA = somatostatin analogue; SSTR = somatostatin receptor.

Hypothalamic Vasopressin-Producing Tumors: Often Inappropriate Diuresis But Occasionally Cushing Disease.

Tumors of hypothalamic neurons that produce vasopressin are rare. We retrieved all cases of vasopressin-positive tumors in the sellar region from the database of the Department of Pathology. Five cases fulfilled the selection criteria, representing the first series of such tumors. Clinical, radiologic, and pathologic features were reviewed. Four tumors classified as neurocytomas were identified in 3 females and 1 male patient; the ages at onset of symptoms ranged from 17 to 40 years. All were large sellar masses with suprasellar extension and/or invasion of the parasellar sinuses. Three patients had the syndrome of inappropriate antidiuresis; in one of these, a 6-year history was initially considered to be idiopathic. One patient died of progressive disease; 3 had incomplete resections and are being followed. In contrast to these patients with neurocytoma, a 65-year-old woman had Cushing disease and a 0.8 cm mass that was completely resected at transsphenoidal surgery; this tumor was a gangliocytoma producing vasopressin associated with corticotroph hyperplasia. We postulate that the small amount of vasopressin secreted by this mature gangliocytic tumor was locally bound to corticotrophs, resulting in hyperplasia and Cushing disease, without sufficient overproduction to cause systemic effects of vasopressin excess. Hypothalamic neurocytoma is a tumor that can mimic pituitary neuroendocrine tumors and olfactory neuroblastoma but is distinguished by positivity for neurofilaments, NeuN, and TTF-1 and negative staining for adenohypophysial biomarkers. Our cases illustrate that neurocytoma and gangliocytoma are 2 variants of tumors of hypothalamic neurons that can produce vasopressin. The morphologic and proliferative features of these 2 tumor types represent 2 ends of a spectrum; their function also can result in divergent clinical manifestations, one characterized by reduced urine output and the other by the more insidious features of glucocorticoid excess.

Silent subtype 3 pituitary adenomas are not always silent and represent poorly differentiated monomorphous plurihormonal Pit-1 lineage adenomas.

Originally classified as a variant of silent corticotroph adenoma, silent subtype 3 adenomas are a distinct histologic variant of pituitary adenoma of unknown cytogenesis. We reviewed the clinical, biochemical, radiological, immunohistochemical and ultrastructural features of 31 silent subtype 3 adenomas to clarify their cellular origin. Among 25 with clinical and/or radiological data, all were macroadenomas; there was cavernous sinus invasion in 30% of cases and involvement of the clivus in 17% of cases. Almost 90% of patients were symptomatic; 67% had mass effect symptoms, 37% were hypogonadal and 8% had secondary adrenal insufficiency. Significant hormonal excess in 29% of cases included hyperthyroidism in 17%, acromegaly in 8% and hyperprolactinemia above 150 µg/l in 4%. Two individuals with hyperprolactinemia who were younger than 30 years had multiple endocrine neoplasia type 1. Immunohistochemically, all 31 tumors were diffusely positive for the pituitary lineage-specific transcription factor Pit-1. Although three only expressed Pit-1, others revealed variable positivity for one or more hormones of Pit-1 cell lineage (growth hormone, prolactin, thyroid-stimulating hormone), as well as alpha-subunit and estrogen receptor. Most tumors exhibited perinuclear reactivity for keratins with the CAM5.2 antibody; scattered fibrous bodies were noted in five (16%) tumors. The mean MIB-1 labeling index was 4% (range, 1-9%). Fourteen cases examined by electron microscopy were composed of a monomorphous population of large polygonal or elongated cells with nuclear spheridia. Sixty-five percent of patients had residual disease after surgery; after a mean follow-up of 48.4 months (median 41.5; range=2-171) disease progression was documented in 53% of those cases. These data identify silent subtype 3 adenomas as aggressive monomorphous plurihormonal adenomas of Pit-1 lineage that may be associated with hyperthyroidism, acromegaly or galactorrhea and amenorrhea. Our findings argue against the use of the nomenclature 'silent' for these tumors. To better reflect the characteristics of these tumors, we propose that they be classified as 'poorly differentiated Pit-1 lineage adenomas'.

Odanacatib for the treatment of osteoporosis.

INTRODUCTION: Osteoporosis and fragility fractures are important public health concerns. Cathepsin K inhibitors, including odanacatib , are a novel class of medications for osteoporosis whose mechanism of action is to directly inhibit bone resorption without killing osteoclasts, thereby permitting the complex coupling between bone resorption and formation to continue. AREAS COVERED: The physiological basis for the mechanism of action of cathepsin K inhibitors is covered in addition to a review of the preclinical, Phase I, Phase II and preliminary Phase III trial data of odanacatib. EXPERT OPINION: Evidence suggests that odanacatib has similar efficacy to bisphosphonates at increasing bone mineral density and decreasing risk of fragility fractures. Although odanacatib may preferentially inhibit bone resorption more than formation, the clinical significance of this difference in mechanism of action is not yet known. A careful analysis of the Phase III trial data is needed with specific attention to adverse events.

Sellar glomangioma.

Glomus tumors of the sellar region are exceedingly rare with only two reported cases in the literature. A case of a sellar glomangioma in a 72-year-old man is described. The tumor had the radiographic and gross appearance of a pituitary adenoma. Microscopically, the tumor was composed of epithelioid cells surrounding prominent small vascular channels. The tumor cells had indistinct cell borders and monotonous nuclei. Histological and immunohistochemical analysis identified the sellar tumor as a glomangioma. Here, we report the clinicopathological features of a third case of a sellar glomus tumor and review the literature.

Male and non-English-speaking patients with fracture have poorer knowledge of osteoporosis.

BACKGROUND: Prior fracture is a strong independent risk factor for subsequent fracture. To date, few studies have examined the level of osteoporosis knowledge specifically in the population of patients who have sustained a fracture. This study was designed to assess the knowledge of osteoporosis among patients who sustained a fracture and who were forty years of age or older, as well as to identify what social factors and health and fracture characteristics determine the level of osteoporosis knowledge in this population. METHODS: Patients who had sustained a fracture and were attending fracture clinics at two Toronto hospitals were identified and invited to fill out a questionnaire during their visit. This questionnaire included questions that could be answered by checking "true," "false," or "don't know" and that were designed to assess the patient's knowledge of osteoporosis. The questionnaire also included questions about the respondent's background. RESULTS: Of 259 patients identified as eligible for the study, 204 (78.8%) agreed to participate. The mean number of correct responses was 16.5 (55%) out of thirty responses. Variables significantly associated with greater numbers of correct responses were female sex, English as a first language, being currently employed, exercising regularly, and having received information from a health-care provider or from a newspaper or magazine. CONCLUSIONS: The level of osteoporosis knowledge was fairly low among the surveyed patients, indicating that more education is needed. This study also highlighted certain characteristics (i.e., male sex, English as a second language, being unemployed, and not exercising) that are associated with a lower level of knowledge. Our results can help target certain groups for osteoporosis educational initiatives, especially ethnic groups whose first language is not English, so as to appropriately reduce the risk of future fractures in this high-risk population.

Retinal arteriolar hemodynamic response to a combined isocapnic hyperoxia and glucose provocation in early sight-threatening diabetic retinopathy.

PURPOSE: To quantify the magnitude of change of retinal arteriolar hemodynamics induced by a combined isocapnic hyperoxia and glucose provocation in diabetic patients with early sight-threatening diabetic retinopathy (DR) and in age-matched control subjects and to compare the response to that of an isocapnic hyperoxia provocation alone. The study hypothesis was that hyperglycemia reduces the retinal vascular reactivity response to a hyperoxic stimulus. METHODS: The sample comprised 17 control subjects (group 1), 15 patients with no clinically visible DR (group 2), 16 patients with mild-to-moderate nonproliferative DR (group 3), and 15 patients with diabetic macular edema (group 4). Retinal hemodynamic measurements were acquired in the subjects, at baseline and 1 hour after consuming a standardized oral glucose load drink while breathing oxygen isocapnic with baseline. RESULTS: Retinal blood velocity and flow significantly decreased in all groups (P < or = 0.001 and P < or = 0.0002, respectively) in response to a combined isocapnic hyperoxia and glucose provocation. The maximum-to-minimum velocity ratio significantly increased (P < or = 0.005), and wall shear rate (WSR) significantly decreased (P < or = 0.0002), in groups 1, 2, and 3, but not in group 4. The vascular reactivity response was not significantly different across the groups. The control group demonstrated a reduced change in flow (P = 0.009) and WSR (P = 0.010) to the combined isocapnic hyperoxia and glucose provocation compared with that of hyperoxia alone. CONCLUSIONS: The vascular reactivity response to a combined isocapnic hyperoxia and glucose provocation produced a pronounced reduction in blood flow. Unlike the response to hyperoxia alone, the vascular reactivity response was not significantly different across the groups. Hyperglycemia reduced the retinal vascular reactivity response to hyperoxia in age-matched control subjects.

A prospective investigation of the relations among cognitive dietary restraint, subclinical ovulatory disturbances, physical activity, and bone mass in healthy young women.

BACKGROUND: Cognitive dietary restraint (CDR) may mediate subclinical ovulatory disturbances, which may result in loss of bone mineral density (BMD). CDR is associated with greater physical activity, which may modify the effect of CDR and ovulatory disturbances on bone mass. OBJECTIVE: We aimed to investigate the relations among CDR, ovulatory disturbances, and physical activity and their effect on BMD in healthy premenopausal women over a 2-y period. DESIGN: In this prospective cohort study, key explanatory factors, important covariates, and BMD were measured at baseline and at 12 and 24 mo; 225 women completed the baseline assessment, and 189 completed the study. CDR was measured with the Three-Factor Eating Questionnaire, and physical activity was measured with the Baecke scale. An average of 9.8 menstrual cycles in 2 y were monitored by using salivary progesterone measurements and urinary ovulation detection kits. Ovulatory disturbances included anovulatory cycles or short luteal phase lengths of <10 d. BMD at the lumbar spine, femoral neck, and total body was measured by using dual-energy X-ray absorptiometry. General linear mixed modeling was used to determine predictors of change in BMD over time. RESULTS: CDR was not associated with ovulatory disturbances or changes in BMD. The average annual rate of change in lumbar spine BMD was decreased by 0.01 g/cm(2) in women who had experienced > or =3 monitored cycles with ovulatory disturbances (P = 0.02). CONCLUSIONS: CDR did not predict bone loss, and there was no relation between CDR and ovulatory disturbances. Ovulatory disturbances had a negative effect on the rate of change at the lumbar spine. The cause of these disturbances is unknown.

Retinal arteriolar hemodynamic response to an acute hyperglycemic provocation in early and sight-threatening diabetic retinopathy.

The aim was to quantify the magnitude of retinal arteriolar vascular reactivity to a hyperglycemic provocation in diabetic patients stratified by severity of retinopathy and in age-matched controls. The sample comprised 20 non-diabetic controls (Group 1), 19 patients with no clinically visible DR (Group 2), 18 patients with mild-to-moderate non-proliferative DR (Group 3) and 18 patients with diabetic macular edema (Group 4). Retinal hemodynamic measurements using the Canon Laser Blood Flowmeter (CLBF-100) were acquired before and 1 h after drinking a standardized oral glucose load drink. The magnitude of the retinal vascular response, as well as max:min velocity ratio and wall shear rate (WSR), was calculated and compared across groups. A significant change in blood glucose level was observed for all groups (p<0.05). The change in blood glucose elevation was significantly less in Group 1 compared to the other groups. No significant change in arteriolar diameter, blood velocity, blood flow, max:min velocity ratio and WSR was found in patients with diabetes and in age-matched subjects without diabetes. The results of this study indicate that retinal arteriolar blood flow is unaffected by acute elevation of blood glucose using an oral glucose load drink in patients with diabetes and in age-matched controls. This lack of a blood flow response to acute hyperglycemia in patients with early sight-threatening DR may be explained by a loss of retinal vascular reactivity.

Alendronate in the treatment of low bone mass in steroid-treated boys with Duchennes muscular dystrophy.

OBJECTIVE: To examine alendronates side-effect profile and effect on bone mineral density (BMD) in deflazacort-treated boys with Duchennes muscular dystrophy (DMD) and low BMD. DESIGN: Before-after trial. SETTING: Neuromuscular clinic at a children's hospital in Canada between 1999 and 2000. PARTICIPANTS: All consenting boys with DMD who had z scores less than -1.00 (spine and/or total body) and in whom BMD testing was feasible. INTERVENTION: Boys received .08 mg.kg(-1) .d(-1) of alendronate orally, with 750 mg of daily calcium and 1000 IU of vitamin D. BMD, height, weight, physical activity, Tanner stage, and adverse effects were followed for 2 years. MAIN OUTCOME MEASURES: BMD z scores at the lumbar spine (L1-4) and total body. RESULTS: Of the 42 eligible boys assessed, 23 had low BMD; for 16 of the 23, future BMD testing was feasible. Mean age was 10.8 years (range, 6.9-15.6 y). Mean baseline z scores at the total body and spine were -0.80 and -1.94, respectively. At 2 years, mean z scores were unchanged. Furthermore, alendronate response varied by baseline age. In multivariable analysis, improvement in total body and spine z scores was associated with younger age at baseline ( P =.01 for both). CONCLUSIONS: In deflazacort-treated boys, alendronate had a positive effect on BMD z scores; the effect was greatest when given early in the course of disease.

The impact of a simple fracture clinic intervention in improving the diagnosis and treatment of osteoporosis in fragility fracture patients.

We examined the effect of a fracture clinic intervention in reducing previously documented undertreatment of osteoporosis (OP) in individuals with fragility fractures. Fragility fracture patients presenting to five community fracture clinics with no prior diagnosis of, or treatment for OP, and whose radiographic appearance was consistent with fragility fracture, were included. These individuals (intervention group) were informed of their OP risk, and advised to follow up with their physician for assessment. A standardized letter, intended for the physician and outlining the same was provided. Three months later, a telephone interview determined whether a physician visit had occurred, and if so, what investigation and treatment recommendations were made. These outcomes were compared with those for an equal number of age- and sex-matched fragility fracture "controls," selected from among fracture clinic attendees in the 6-9 months preceding the intervention. Logistic regression was used to examine the effect of having received the intervention on physician follow-up, bone density testing, and OP treatment recommendations. The mean age of the 278 participants (139 per group) was 66.0 years; 74% were female. Adjusting for age, sex, hospital, and perceived diagnosis of OP, those who received the intervention were more likely to follow up with a physician (adjusted OR 1.85, p=0.02) and to be recommended bone density testing (adjusted OR 5.22, p<0.0001), but were not more likely to receive an OP treatment recommendation (adjusted OR 2.07, p=0.07). It is concluded that a simple fracture clinic intervention increased follow-up and investigation, but not treatment for OP, in fragility fracture patients. Individuals recommended treatment for OP were more likely to perceive themselves as having OP and to have had a previous fragility fracture. Our findings suggest that future interventions should incorporate assessment of patients' OP health beliefs and education about risk factors for fracture, and should be coupled with physician education to achieve optimal results.