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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.

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. 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. 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. 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.

A 40-year-old man was referred to our internal medicine clinic for assessment of a 3-month history of unintentional weight loss and daily night sweats with subjective fevers. He had been treated for rectal chlamydia infection 1 month prior. Given the patient's symptoms, CT findings of proctitis, and risk factors, we made a presumptive diagnosis of lymphogranuloma venereum (LGV) as the cause for his ongoing weight loss. About 1 month after his initial presentation, results from repeat urine and rectal chlamydia and gonorrhea testing were negative, but we prescribed a 3-week course of empiric oral doxycycline 100 mg twice daily and also referred him to a gastroenterologist for endoscopic evaluation because of his persistent symptoms. In light of the initial endoscopic findings, the gastroenterologist considered the patient's presentation to be most consistent with an STI (LGV), with a low likelihood for gastrointestinal disease.

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 . In the LUMINA-1 trial for fibrodysplasia ossificans progressiva, garetosmab, an activin A monoclonal antibody, did not lead to significant changes in heterotopic ossification lesion activity in pre-existing lesions in period 1. Garetosmab prevented the formation of new lesions in both periods 1 and 2.

Background Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic bone disease that is characterized by progressive heterotopic ossification of the thoracic cavity. Prognosis is poor with cardiopulmonary complications being the main cause of death. Spirometry is a well-established metric of functional exercise capacity and prognosis in lung diseases but its use is limited in this population. Accuracy and validity of spirometry is dependent on forced expiratory maneuvers which are difficult to perform for individuals with FOP. Oscillometry is an effort-independent pulmonary function test that is highly sensitive to changes in respiratory mechanics. Little is known about oscillometry in individuals with FOP. The purpose of this paper is to characterize FOP using oscillometry. Results Eight participants with FOP were recruited for oscillometry prior to spirometry. Cumulative Analogue Joint Involvement Scale (CAJIS) scores were used to evaluate total body and regional FOP burden. Spirometry showed a uniform pattern of restrictive physiology in all eight participants with no significant difference amongst the group. Oscillometry revealed significant diversity in respiratory mechanics and chest wall involvement from normal, airway obstruction and ventilatory inhomogeneity to extra-thoracic airflow obstruction. We compared individuals with normal and abnormal oscillometry and found no statistically significant differences in functional status and clinical parameters. However, there is a tendency for lower CAJIS scores and fewer recent flare-ups in those with more normal respiratory mechanics. The tidal volumes were significantly higher in the group with more normal respiratory mechanics. Two wheelchair-dependent participants exhibited a pattern of high respiratory resistance that increased during both inspiration and expiration, to suggest presence of a fixed extra-thoracic defect. Conclusions Oscillometry provides additional, more detailed information beyond spirometry in individuals with FOP. It is far easier than spirometry to complete and may be useful to help track disease progression and response to therapies in individuals with FOP.

Alkaline phosphatase (ALP) should be measured in older adults presenting with fragility fractures. Hypophosphatasia (HPP) should be suspected in individuals with hypophosphatasemia (low serum ALP). A correct diagnosis allows clinicians to avoid using potent antiresorptive osteoporosis medications, which are contraindicated in patients with HPP.

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. 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. 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. ClinicalTrials.gov (#NCT00150969) and Current Controlled Trials (#ISRCTN61708241).

Exemestane can prevent breast cancer in postmenopausal women. Because of potential widespread use, we examined the safety of exemestane on bone health. 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. 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). 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. Canadian Breast Cancer Research Alliance (Canadian Institutes of Health Research/Canadian Cancer Society).