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Competing Interests: Intérêts concurrents : Lora Giangregorio déclare avoir reçu des honoraires d’Amgen Inc. pour une conférence donnée sur l’exercice physique, hors du cadre du présent manuscrit, sans mention de médicaments. La Dre Giangregorio est également membre du conseil consultatif scientifique d’Ostéoporose Canada et coresponsable du Groupe d’intérêt spécial sur la fracture vertébrale du Fragility Fracture Network. Sandra Kim déclare qu’Ostéoporose Canada lui a offert le soutien d’une personne spécialiste de la méthodologie GRADE (Grading of Recommendations, Assessment, Development and Evaluations) à l’Université McMaster au cours de l’étude. De 2017 à 2020, la Dre Kim a aussi été membre bénévole du conseil d’administration d’Ostéoporose Canada. Nancy Santesso déclare avoir reçu une rémunération versée à son établissement (Université McMaster) afin d’apporter son expertise de l’outil GRADE à l’élaboration des lignes directrices et à la préparation de contenus au cours de l’étude. La Dre Santesso a aussi reçu du soutien d’Ostéoporose Canada pour se rendre aux réunions sur les lignes directrices. Heather McDonald-Blumer déclare avoir reçu des honoraires de consultation d’Eli Lilly et de Novartis pour sa présence à des conseils consultatifs, sans lien avec les présents travaux. Rowena Ridout est membre du conseil d’administration d’Ostéoporose Canada depuis 2020 (aucune rémunération perçue). Neil Binkley déclare avoir reçu une subvention de recherche (versée à son établissement) de Radius, ainsi que des frais de consultation et des honoraires d’Amgen. Angela Cheung a reçu des honoraires d’Amgen et des Laboratoires Paladin à titre de consultante. La Dre Cheung a aussi été membre du comité des lignes directrices cliniques de l’Endocrine Society, coprésidente du programme de santé postménopause de l’American College of Obstetrics and Gynecology et vice-présidente et coresponsable de la Conférence de prise de position 2023 de la Société internationale de densitométrie clinique. Robert Josse déclare avoir reçu des frais de consultation d’Amgen Canada, des Laboratoires Paladin et d’Alexion, ainsi que des honoraires d’Amgen et d’Alexion. Le Dr Josse a aussi participé à des comités consultatifs pour Amgen, Paladin, Alexion et Ultragenyx. Aliya Khan a reçu des subventions de recherche d’Alexion, d’Amgen Canada, de Takeda, d’Ascendis, de Chugai, de Radius, d’Amolyt et d’Ultragenyx, ainsi que des honoraires de conférencière d’Amgen, d’Alexion, d’Ascendis, de Takeda et d’Ultragenyx. La Dre Khan a également participé à des comités consultatifs pour Amgen Canada, Alexion, Amolyt, Ascendis et Takeda. E. Lynn Izumi Nash déclare que le Collège des médecins de famille de l’Ontario lui a versé des honoraires pour la conception d’ateliers de formation médicale continue sur l’ostéoporose. La Dre Nash est aussi membre du conseil consultatif scientifique d’Ostéoporose Canada (à titre bénévole). Zahra Bardai déclare avoir reçu des honoraires en tant que membre du comité de planification scientifique de Pri-Med Canada depuis 2011 et en tant que créatrice du Programme d’apprentissage basé sur la pratique en petit groupe de la Fondation pour l’éducation médicale continue, à l’Université McMaster. La Dre Bardai est aussi membre bénévole du conseil consultatif scientifique d’Ostéoporose Canada. Suzanne Cadarette déclare avoir reçu des subventions de recherche (versées à son établissement) en tant que cochercheuse principale pour des projets financés par les Instituts de recherche en santé du Canada et les National Institutes of Health. Heather Frame a siégé au conseil d’administration d’Ostéoporose Canada jusqu’en novembre 2020. Kaleen Hayes déclare avoir reçu des subventions de recherche à l’initiative des chercheurs du National Institute on Aging, d’Insight Therapeutics, de Genentech et de Sanofi (versées directement à son établissement), et des honoraires de consultation de l’Agence canadienne des médicaments et des technologies de la santé. Alexandra Papaioannou a fait partie d’un comité consultatif et de services de conférenciers et conférencières et a reçu des honoraires d’Amgen Canada. Christine Thomas a été membre du conseil d’administration d’Ostéoporose Canada à différentes périodes.

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., Competing Interests: Competing interests: Lora Giangregorio reports receiving an honorarium from Amgen Inc. for a lecture on exercise with no mention of medications, outside the current manuscript. Dr. Giangregorio is also a member of the Scientific Advisory Council of Osteoporosis Canada and co-lead of the Vertebral Fracture Special Interest Group, Fragility Fracture Network. Sandra Kim reports receiving support from Osteoporosis Canada for a Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodologist at McMaster University, during the conduct of the study. Dr. Kim was also a volunteer member of the Osteoporosis Canada Board of Directors from 2017 to 2020. Nancy Santesso reports receiving payment to provide GRADE expertise for guideline development and preparation of materials paid to institution (McMaster University), during the conduct of the study. Dr. Santesso has also received support from Osteoporosis Canada for travel to guideline-related meetings. Heather McDonald-Blumer reports receiving consulting fees from Eli Lilly and Novartis, for attendance on advisory boards, outside the submitted work. Rowena Ridout has been a member of the Osteoporosis Canada Board of Directors since 2020 (no payment received). Neil Binkley reports receiving a research grant (paid to institution) from Radius, and consulting fees and honoraria from Amgen. Angela Cheung has received honoraria for consultancy work from Amgen and Paladin Laboratories. Dr. Cheung has also held the following roles: member of the Clinical Guidelines Committee of the Endocrine Society; co-chair of the postmenopausal health pathway, American College of Obstetrics and Gynecology; and vice-president and co-chair of the 2023 Position Development Conference, International Society for Clinical Densitometry. Robert Josse reports receiving consulting fees from Amgen Canada, Paladin Laboratories and Alexion, and honoraria from Amgen and Alexion. Dr. Josse has also participated on advisory boards for Amgen, Paladin, Alexion and Ultragenyx. Aliya Khan has received research grants from Alexion, Amgen Canada, Takeda, Ascendis, Chugai, Radius, Amolyt and Ultragenyx, and speaker honoraria from Amgen, Alexion, Ascendis, Takeda and Ultragenyx. Dr. Khan has also participated on advisory boards for Amgen Canada, Alexion, Amolyt, Ascendis and Takeda. E. Lynn Izumi Nash reports receivin an honorarium from the Ontario College of Family Physicians for designing continuing medical education workshops on osteoporosis. Dr. Nash is also a member of the Scientific Advisory Council for Osteoporosis Canada (voluntary unpaid position). Zahra Bardai reports receiving honoraria as a member of the Pri-Med Canada Scientific Planning Committee (2011–present) and as an author of the Foundation for Medical Practice Education Small Group Practice–Based Learning Program, at McMaster University. Dr. Bardai is also a volunteer member of the Osteoporosis Canada Scientific Advisory Council. Suzanne Cadarette reports receiving research funds (paid to institution) as co–principal investigator on Canadian Institutes of Health Research and National Institutes of Health project grants. Heather Frame is a former member of the Osteoporosis Canada Board of Directors (term ended November 2020). Kaleen Hayes reports receiving researcher-initiated grants from the National Institute on Aging, Insight Therapeutics, Genentech and Sanofi (all paid directly to institution), and consulting fees from the Canadian Agency for Drugs and Technologies in Health. Alexandra Papaioannou has participated on an advisory board and in speakers’ bureaus and received honoraria from Amgen Canada. Christine Thomas has been a member of the Osteoporosis Canada Board of Directors at various time points. Conflict-of-Interest Oversight Committee: Heather McDonald-Blumer (Chair), Larry Funnell, Rowena Ridout., (© 2023 CMA Impact Inc. or its licensors.)

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET-CT) was not met (P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666 ., (© 2023. The Author(s).)

Osteoporosis and resulting osteoporotic fractures are responsible for significant morbidity, excess mortality, and health care costs in the developed world. Medical therapy for osteoporosis has been shown in multiple randomized controlled trials to reduce the risk of vertebral and non-vertebral fractures and hip fractures, and in some studies bisphosphonate medications have been associated with improved survival. Although the overall benefit to risk ratio of osteoporosis medications remains favorable, there have been concerns raised about the long-term safety of these treatments. Atypical femur fracture, which is a rare type of fracture that has been associated with the long-term use of potent antiresorptive bone medications, is a potentially devastating consequence of osteoporosis treatment. This paper reviews our current understanding of atypical femur fractures, their relationship to antiresorptive osteoporosis medications, and proposed strategies for management, in order to inform clinical decision making about the optimal use and duration of medical therapy for the treatment of patients with osteoporosis or at high risk for osteoporotic fractures., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

In this report, we describe 6 children with osteogenesis imperfecta with unusual stress femoral fractures. All children were on long-term cyclic pamidronate treatment. All fractures occurred without trauma or with minimal trauma and were located in the subtrochanteric or the diaphyseal regions of the femur over preexisting intramedullary rods. These fractures have very similar features to the reported minimal trauma atypical femoral fractures in adults on long-term bisphosphonate treatment. These fractures raise concerns about the role of prolonged remodeling suppression and microdamage accumulation and the risk of increased bone fragility.

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.

Background: Exemestane can prevent breast cancer in postmenopausal women. Because of potential widespread use, we examined the safety of exemestane on bone health., Methods: In this nested safety substudy of the MAP.3 trial (a randomised, placebo-controlled, double-blind trial of exemestane 25 mg a day for the primary prevention of breast cancer), we included postmenopausal women from five centres who were eligible to participate in MAP.3, not osteoporotic, not receiving drugs for bone-related disorders, with baseline lumbar spine, total hip, and femoral neck T-scores above -2·0. The primary endpoint was percent change from baseline to 2 years in total volumetric bone mineral density (BMD) at the distal radius by high-resolution peripheral quantitative CT. The primary analysis was per protocol using a non-inferiority margin. This analysis was done earlier than originally planned because of the impending announcement of MAP.3 results and subsequent unmasking of patients to treatment assignment. This study is registered with ClinicalTrials.gov, number NCT01144468, and has been extended to 5 years of unmasked follow-up., Findings: 351 women (176 given exemestane, 175 given placebo; median age 61·3 years [IQR 59·2-64·9]) met our inclusion criteria and completed baseline assessment. At the time of clinical cutoff, 242 women had completed 2-year follow-up (124 given exemestane, 118 given placebo). From baseline to 2 years, the mean percent change in total volumetric BMD at the distal radius was -6·1% (95% CI -7·0 to -5·2) in the exemestane group and -1·8% (-2·4 to -1·2) in the placebo group (difference -4·3%, 95% CI -5·3 to -3·2; p<0·0001). The lower limit of the 95% CI was lower than our non-inferiority margin of negative 4% (one-sided test for non-inferiority p=0·70), meaning the hypothesis that exemestane was inferior could not be rejected. At the distal tibia, the mean percent change in total volumetric BMD from baseline to 2 years was -5·0% (95% CI -5·5 to -4·4) in the exemestane group and -1·3% (-1·7 to -1·0) in the placebo group (difference -3·7%, 95% CI -4·3 to -3·0; p<0·0001). The mean percent change in cortical thickness was -7·9% (SD 7·3) in the exemestane group and -1·1% (5·7) in the placebo group at the distal radius (difference -6·8%, 95% CI -8·5 to -5·0; p<0·0001) and -7·6% (SD 5·9) in the exemestane group and -0·7% (4·9) in the placebo group at the distal tibia (difference -6·9%, -8·4 to -5·5; p<0·0001). Decline in areal BMD, as measured by dual-energy x-ray absorptiometry, in the exemestane group compared with the placebo group occurred at the lumbar spine (-2·4% [95% CI -3·1 to -1·7] exemestane vs -0·5% [-1·1 to 0·2] placebo; difference -1·9%, 95% CI -2·9 to -1·0; p<0·0001), total hip (-1·8% [-2·3 to -1·2] exemestane vs -0·6% [-1·1 to -0·1] placebo; difference -1·2%, -1·9 to -0·4; p=0·004), and femoral neck (-2·4% [-3·2 to -1·7] exemestane vs -0·8% [-1·5 to 0·1] placebo; difference -1·6%, -2·7 to -0·6; p=0·002)., Interpretation: 2 years of treatment with exemestane worsens age-related bone loss in postmenopausal women despite calcium and vitamin D supplementation. Women considering exemestane for the primary prevention of breast cancer should weigh their individual risks and benefits. For women taking exemestane, regular bone monitoring plus adequate calcium and vitamin D supplementation are important. To assess the effect of our findings on fracture risk, long-term follow-up is needed., Funding: Canadian Breast Cancer Research Alliance (Canadian Institutes of Health Research/Canadian Cancer Society)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Vitamin K has been widely promoted as a supplement for decreasing bone loss in postmenopausal women, but the long-term benefits and potential harms are unknown. This study was conducted to determine whether daily high-dose vitamin K1 supplementation safely reduces bone loss, bone turnover, and fractures., Methods and Findings: This single-center study was designed as a 2-y randomized, placebo-controlled, double-blind trial, extended for earlier participants for up to an additional 2 y because of interest in long-term safety and fractures. A total of 440 postmenopausal women with osteopenia were randomized to either 5 mg of vitamin K1 or placebo daily. Primary outcomes were changes in BMD at the lumbar spine and total hip at 2 y. Secondary outcomes included changes in BMD at other sites and other time points, bone turnover markers, height, fractures, adverse effects, and health-related quality of life. This study has a power of 90% to detect 3% differences in BMD between the two groups. The women in this study were vitamin D replete, with a mean serum 25-hydroxyvitamin D level of 77 nmol/l at baseline. Over 2 y, BMD decreased by -1.28% and -1.22% (p = 0.84) (difference of -0.06%; 95% confidence interval [CI] -0.67% to 0.54%) at the lumbar spine and -0.69% and -0.88% (p = 0.51) (difference of 0.19%; 95% CI -0.37% to 0.75%) at the total hip in the vitamin K and placebo groups, respectively. There were no significant differences in changes in BMD at any site between the two groups over the 2- to 4-y period. Daily vitamin K1 supplementation increased serum vitamin K1 levels by 10-fold, and decreased the percentage of undercarboxylated osteocalcin and total osteocalcin levels (bone formation marker). However, C-telopeptide levels (bone resorption marker) were not significantly different between the two groups. Fewer women in the vitamin K group had clinical fractures (nine versus 20, p = 0.04) and fewer had cancers (three versus 12, p = 0.02). Vitamin K supplements were well-tolerated over the 4-y period. There were no significant differences in adverse effects or health-related quality of life between the two groups. The study was not powered to examine fractures or cancers, and their numbers were small., Conclusions: Daily 5 mg of vitamin K1 supplementation for 2 to 4 y does not protect against age-related decline in BMD, but may protect against fractures and cancers in postmenopausal women with osteopenia. More studies are needed to further examine the effect of vitamin K on fractures and cancers., Trial Registration: ClinicalTrials.gov (#NCT00150969) and Current Controlled Trials (#ISRCTN61708241).