Opportunistically identifiable vertebral fractures on routine radiological imaging predict mortality: observational cohort study.

In men and women with opportunistically identifiable vertebral fractures (VFs) on routine CT scans including the chest and/or abdomen, the risk of death is 51% higher than in those with no VF on the CT scan, and 325% higher than an age- and sex-matched general population cohort. PURPOSE: There is little knowledge about the risk of death in patients with VFs present on routine radiological imaging. We evaluated the risk of death in men and women aged 50 years or older with opportunistically identifiable VFs on routine CT scans and not treated with osteoporosis medications. METHODS: Thoracic and lumbar VFs were identified through a blinded, two-step approach on CT scans performed as part of normal clinical care in a Danish hospital in 2010 or later. Subjects with VF were matched on age and sex against those with no VF (1:2-ratio) and a general population cohort (1:3-ratio), respectively, and followed for up to 7 years through the national Danish registers. Subjects treated with an osteoporosis medication in the year prior to baseline were excluded. RESULTS: Subjects with VF had a significantly higher risk of death during follow-up as compared to subjects with no VF on the CT scan (adjusted hazard ratio [HR] 1.51 [95% confidence interval 1.27-1.79; p < 0.001]) and even more so when compared to the general population cohort (HR 4.25 [3.53-5.12; p < 0.001]). In subjects with versus without VF on the CT scan, the risk was higher in those with moderate or severe VF, in those with no malignancy prior to baseline, and in those with a lower Charlson comorbidity index score. CONCLUSION: Subjects with VF available for identification on routine CT scans face a substantially increased risk of death. Opportunistic identification and reporting of VF is important to identify these patients to allow intervention if indicated.

Race-specific FRAX models are evidence-based and support equitable care: a response to the ASBMR Task Force report on Clinical Algorithms for Fracture Risk.

Task Force on 'Clinical Algorithms for Fracture Risk' commissioned by the American Society for Bone and Mineral Research (ASBMR) Professional Practice Committee has recommended that FRAX® models in the US do not include adjustment for race and ethnicity. This position paper finds that an agnostic model would unfairly discriminate against the Black, Asian and Hispanic communities and recommends the retention of ethnic and race-specific FRAX models for the US, preferably with updated data on fracture and death hazards. In contrast, the use of intervention thresholds based on a fixed bone mineral density unfairly discriminates against the Black, Asian and Hispanic communities in the US. This position of the Working Group on Epidemiology and Quality of Life of the International Osteoporosis Foundation (IOF) is endorsed both by the IOF and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).

Global guidance for the recognition, diagnosis, and management of tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with progressive bone pain, muscle weakness, and fragility fractures. TIO is characterized by hypophosphatemia, excess renal phosphate excretion, and low/inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH)2 D) levels. Rarity and enigmatic clinical presentation of TIO contribute to limited awareness among the medical community. Accordingly, appropriate diagnostic tests may not be requested, leading to delayed diagnosis and poorer patient outcomes. We have developed a global guidance document to improve the knowledge of TIO in the medical community, enabling the recognition of patients with TIO and appropriate referral. We provide recommendations aiding diagnosis, referral, and treatment, helping promote a global standard of patient management. We reviewed the literature and conducted a three-round Delphi survey of TIO experts. Statements were drafted based on published evidence and expert opinions (≥70% consensus required for final recommendations). Serum phosphate should be measured in patients presenting with chronic muscle pain or weakness, fragility fractures, or bone pain. Physical examination should establish features of myopathy and identify masses that could be causative tumors. Priority laboratory evaluations should include urine/serum phosphate and creatinine to assess renal tubular reabsorption of phosphate and TmP/GFR, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25(OH)2 D, and FGF23. Patients with the clinical/biochemical suspicion of TIO should be referred to a specialist for diagnosis confirmation, and functional imaging should be used to localize causative tumor(s). Recommended treatment is tumor resection or, with unresectable/unidentifiable tumors, phosphate salts plus active vitamin D, or burosumab.

Primary hyperparathyroidism and fracture probability.

The incidence of hip and major osteoporotic fracture was increased in patients with primary hyperparathyroidism even in patients not referred for parathyroidectomy. The risk of death was also increased which attenuated an effect on fracture probabilities. The findings argue for widening the indications for parathyroidectomy in mild primary hyperparathyroidism. INTRODUCTION: Primary hyperparathyroidism (PHPT) is associated with an increase in the risk of fracture. In FRAX, the increase in risk is assumed to be mediated by low bone mineral density (BMD). However, the risk of death is also increased and its effect on fracture probability is not known. OBJECTIVE: The aim of this study was to determine whether PHPT affects hip fracture and major osteoporotic fracture risk independently of bone mineral density (BMD) and whether this and any increase in mortality affects the assessment of fracture probability. METHODS: A register-based survey of patients with PHPT and matched controls in Denmark were identified from hospital registers. The incidence of death, hip fracture, and major osteoporotic fracture were determined for computing fracture probabilities excluding time after parathyroidectomy. The gradient of risk for fracture for differences in BMD was determined in a subset of patients and in BMD controls. The severity of disease was based on serum calcium and parathyroid hormone levels. RESULTS: We identified 6884 patients with biochemically confirmed PHPT and 68,665 matched population controls. On follow-up, excluding time after parathyroidectomy in those undergoing surgery, patients with PHPT had a higher risk of death (+52%), hip fracture (+48%), and major osteoporotic fracture (+36%) than population controls. At any given age, average 10-year probabilities of fracture were higher in patients with PHPT than population controls. The gradient of fracture risk with differences in BMD was similar in cases and controls. Results were similar when confined to patients not undergoing parathyroidectomy. Fracture probability decreased with the severity of disease due to an increase in mortality rather than fracture risk. CONCLUSION: The risk of hip and other major osteoporotic fracture is increased in PHPT irrespective of the disease severity. Fracture probability was attenuated due to the competing effect of mortality. The increased fracture risk in patients treated conservatively argues for widening the indications for parathyroidectomy in mild PHPT.

Epidemiology of Tumor-Induced Osteomalacia in Germany Based on Real World Data.

Tumor-induced osteomalacia (TIO) is an ultra-rare disease caused mostly by benign tumors that secrete fibroblast growth factor-23. Because of nonspecific symptoms, the diagnostic delay is long, and therapy can be challenging. Moreover, epidemiological data on TIO are scarce owing to its rarity. Therefore, this study aimed to quantify TIO's incidence rates and prevalence in Germany. Retrospective longitudinal and cross-sectional analyses were conducted using anonymized German claims data from the statutory health insurance (SHI) database. This database, which comprises the data of approximately 5 million insurants, is a representative sample of the German population and supports national projections. As there is no unique International Statistical Classification of Diseases and Related Health Problems (ICD) code for TIO, operational categories based on different surrogates were defined to determine the prevalence and incidence rates of TIO among probable patients. This study showed that TIO has a prevalence of (documented code, advanced imaging, medication, or tumor removal) 0.187 per 100,000 persons and an incidence rate of ≤ 0.094 per 100,000 person years. This analysis provides the first epidemiological insight into German patients with TIO. Despite the general limitations associated with the analysis of SHI claims data of ultra-rare diseases, we believe that this analysis provides a sound basis for further analysis, particularly with regard to the care situation of patients with TIO.

Osteoporosis epidemiology using international cohorts.

PURPOSE OF REVIEW: To provide an update on the most important new cohort studies within osteoporosis and their bearing on clinical management and directions for future research. RECENT FINDINGS: We identified a collection of new observational cohort studies - including new reports from already established large cohorts - and intervention studies providing new insights into osteoporosis pathophysiology, risk finding, intervention, and treatment barriers. SUMMARY: Recent cohort studies in osteoporosis highlight the importance of timely identification and treatment of people who are at high risk of suffering osteoporotic fractures. Physical performance is a strong indicator of fracture risk and one that is tightly linked to a number of chronic conditions, not least inflammatory conditions like rheumatoid arthritis. Advances in case finding may involve opportunistic screening for low bone mineral density and vertebral fractures of radiology images obtained for other purposes, polygenic risk scores, and routinely collected medication and comorbidity information.

One- and 2-year incidence of osteoporotic fracture: a multi-cohort observational study using routinely collected real-world data.

We estimated and characterized the imminent fracture risk (1-2 years) of high-risk fracture patients through a multinational (UK, Spain, Denmark) cohort study. Older individuals with newly diagnosed osteoporosis and individuals who had a fracture while on treatment with a bisphosphonate were at a high risk of imminent fracture. PURPOSE: To characterize and estimate 1- to 2-year fracture risk in high-risk fracture patients. METHODS: Multi-cohort study in (database/study period) UK (CPRD/1995-2017), Spain (SIDIAP/2006-2016) and Denmark (DHR/1995-2016) including individuals ≥ 50 years old in NDO (newly diagnosed osteoporosis), OFx (incident osteoporotic fracture), BP (incident oral bisphosphonates use) or FWOT (fracture while on treatment with bisphosphonates). Outcomes (ICD-10/READ): hip, clinical spine, non-hip, non-spine and hip/humerus/distal forearm fracture. FOLLOW-UP: from cohort entry until death, migration/transfer or end of the study. STATISTICS: baseline characteristics and incidence rate (IR per 1000 persons). RESULTS (1-YEAR IR): NDO included 69,899 (UK), 37,901 (Spain) and 158,191 (Denmark) individuals. Spanish-IR was lowest for hip (4.7), clinical spine (2.5) and major osteoporotic fracture (MOF) (17.3) and highest in Denmark (74.2, 26.0 and 120.1, respectively). OFx included 83,514 (UK), 51,044 (Spain) and 509,551 (Denmark) individuals. IR in Denmark was highest for hip (24.1) and MOF (47.2), in Spain was highest for the clinical spine (9.4) and lowest for hip (9.5) and in the UK was lowest for the clinical spine (2.8) and MOF (20.7). BP included 148,507 (UK), 52,037 (Spain) and 204,010 (Denmark) individuals. Spanish-IR was lowest for hip (5.0) and MOF (21.1) and highest in Denmark (20.3 and 48.6, respectively). FWOT included 28,930 (UK), 1,865 (Spain) and 31,882 (Denmark) individuals. Clinical spine-IR was highest for Spain (12.0). Hip-IR was lowest for Spain (7.6) and highest for Denmark (33.6). Comparing young subjects, those who have FWOT started with an increased fracture rate. CONCLUSION: OFx and FWOT individuals experience higher re-fracture incidence rates than those with osteoporosis with or without treatment.

FREM predicts 10-year incident fracture risk independent of FRAX® probability: a registry-based cohort study.

The Danish Fracture Risk Evaluation Model (FREM) was found to predict fracture risk independent of 10-year fracture probability derived with the FRAX® tool including bone mineral density from DXA. INTRODUCTION: FREM was developed from Danish public health registers without DXA information to identify high imminent risk of major osteoporotic fracture (MOF) and hip fracture (HF), while FRAX® estimates 10-year fracture probability from clinical risk factors and femoral neck bone mineral density (BMD) from DXA. The FREM algorithm showed significant 1- and 2-year fracture risk stratification when applied to a clinical population from Manitoba, Canada. We examined whether FREM predicts 10-year fracture risk independent of 10-year FRAX probability computed with BMD. METHODS: Using the Manitoba BMD Program registry, we identified women and men aged ≥ 45 years undergoing baseline BMD assessment. We calculated FREM and FRAX scores, and identified incident fractures over 10 years. Hazard ratios (HRs) for incident fracture were estimated according to FREM quintile, adjusted for FRAX probability. We compared predicted with observed 10-year cumulative fracture probability estimated with competing mortality. RESULTS: The study population comprised 74,446 women, mean age 65.2 years; 7945 men, mean age 67.5 years. There were 7957 and 646 incident MOF and 2554 and 294 incident HF in women and men, respectively. Higher FREM scores were associated with increased risk for MOF (highest vs middle quintile HRs 1.49 women, 2.06 men) and HF (highest vs middle quintile HRs 2.15 women, 2.20 men) even when adjusted for FRAX. Greater mortality with higher FREM scores attenuated its effect on 10-year fracture probability. In the highest FREM quintile, observed slightly exceeded predicted 10-year probability for MOF (ratios 1.05 in women, 1.49 in men) and HF (ratios 1.29 in women, 1.34 in men). CONCLUSIONS: Higher FREM scores identified women and men at increased fracture risk even when adjusted for FRAX probability that included BMD; hence, FREM provides additional predictive information to FRAX. FRAX slightly underestimated 10-year fracture probability in those falling within the highest FREM quintile.

Prediction of imminent fracture risk in Canadian women and men aged 45 years or older: external validation of the Fracture Risk Evaluation Model (FREM).

The Fracture Risk Evaluation Model (FREM) identifies individuals at high imminent risk of major osteoporotic fractures. We validated FREM on 74,828 individuals from Manitoba, Canada, and found significant fracture risk stratification for all FREM scores. FREM performed better than age alone but not as well as FRAX® with BMD. INTRODUCTION: The FREM is a tool developed from Danish public health registers (hospital diagnoses) to identify individuals over age 45 years at high imminent risk of major osteoporotic fractures (MOF) and hip fracture (HF). In this study, our aim was to examine the ability of FREM to identify individuals at high imminent fracture risk in women and men from Manitoba, Canada. METHODS: We used the population-based Manitoba Bone Mineral Density (BMD) Program registry, and identified women and men aged 45 years or older undergoing baseline BMD assessment with 2 years of follow-up data. From linked population-based data sources, we constructed FREM scores using up to 10 years of prior healthcare information. RESULTS: The study population comprised 74,828 subjects, and during the 2 years of observation, 1612 incident MOF and 299 incident HF occurred. We found significant fracture risk stratification for all FREM scores, with AUC estimates of 0.63-0.66 for MOF for both sexes and 0.84 for women and 0.65-0.67 for men for HF. FREM performed better than age alone but not as well as FRAX® with BMD. The inclusion of physician claims data gave slightly better performance than hospitalization data alone. Overall calibration for 1-year MOF prediction was reasonable, but HF prediction was overestimated. CONCLUSION: In conclusion, the FREM algorithm shows significant fracture risk stratification when applied to an independent clinical population from Manitoba, Canada. Overall calibration for MOF prediction was good, but hip fracture risk was systematically overestimated indicating the need for recalibration.

Newly Diagnosed Celiac Disease and Bone Health in Young Adults: A Systematic Literature Review.

Celiac disease (CD), a gluten-induced autoimmune disease, is associated with low bone mineral density (BMD) among children. Unfortunately, it is often diagnosed in adulthood, which may lead to an increased risk of fragile bones. The aim of this systematic review was to report on BMD status among young adults newly diagnosed with CD, and to examine the effect of a gluten-free diet (GFD), nutritional supplements, such as vitamin D, or antiresorptive medications on BMD recovery. Databases searched were Medline, Embase, and Cochrane Library up to July 2nd, 2020. Both observational studies and clinical trials were considered, if patients were newly diagnosed and between 20 and 35 years of age and reported on BMD. We critically appraised the identified studies using ROBINS-I and summarized the findings narratively. Out of 3991 references, we identified 3 eligible studies: one cross-sectional study and two longitudinal studies. In total, 188 patients were included, and the study population consisted primarily of women with an age range between 29 and 37 years old. Compared to healthy controls, our target population had lower BMD. Moreover, a strict GFD may increase BMD during a follow-up period of up to 5 years. Newly diagnosed CD patients aged 20-35 years are at risk of lower BMD. Therefore, it may be crucial to assess BMD at time of diagnosis in young women. Whether the results can be extrapolated to young men is unknown. While strict GFD may improve BMD over time, there is a lack of robust evidence to demonstrate that nutritional supplements or antiresorptive agents are beneficial in the prevention of fragile bones in this age group.

The effect of parathyroidectomy compared to non-surgical surveillance on kidney function in primary hyperparathyroidism: a nationwide historic cohort study.

BACKGROUND: Patients with primary hyperparathyroidism (pHPT) and impaired kidney function (estimated glomerular filtration rate (eGFR) < 60 mL/min) are offered parathyroidectomy (PTX) to protect them from further complications. Surprisingly, two recent uncontrolled cohort studies have suggested a further decrease in kidney function following PTX. We aimed to examine the effects of PTX compared to non-surgical surveillance on kidney function in pHPT patients. METHODS: Historic cohort study. From the Danish National Patient Registry (NPR) and major medical biochemistry laboratories in Denmark, we identified 3585 patients with biochemically confirmed pHPT among whom n = 1977 (55%) were treated with PTX (PTX-group) whereas n = 1608 (45%) were followed without surgery (non-PTX group). Baseline was defined as time of diagnosis and kidney function was re-assessed 9-15 months after PTX (PTX group) or 9-15 months after diagnosis (non-PTX group). RESULTS: At follow-up, eGFR had decreased significantly in the PTX- compared to the non-PTX-group (median - 4% vs. - 1%, p < 0.01). Stratification by baseline eGFR showed that the decrease was significant for those with a baseline eGFR value of 80-89 and > 90 mL/min, but not for those with lower eGFR values. Findings did not differ between patients with mild compared to moderate/severe hypercalcemia. However, after mutual adjustments, we identified baseline levels of calcium, PTH, and eGFR as well as age and treatment (PTX vs. no-PTX) as independent predictors for changes in kidney function. CONCLUSION: Compared to non-surgical surveillance, PTX is associated with a small but significant decrease in kidney function in pHPT patients with an initial normal kidney function.

Epidemiology of Tumor-Induced Osteomalacia in Denmark.

Tumor-induced osteomalacia (TIO) is a rare, acquired condition of phosphate wasting due to phosphaturic mesenchymal tumors. Because the incidence and prevalence of TIO is unknown, we conducted an observational cohort study using national Danish health registers for the period 2008 to 2018 to obtain such information. The study also aimed to describe the demographics of the TIO population and the prognosis. The operational definition was based on hypophosphatemia or adult osteomalacia diagnoses, combined with prescriptions used in the initial management and procedures consistent with advanced imaging used for locating tumors. The incidence of TIO in Denmark was found to be below 0.13 per 100,000 person years for the total population of the country and 0.10 per 100,000 in adult-onset disease. The prevalence of TIO was estimated to be no more than 0.70 per 100,000 persons for the total population and 0.43 per 100,000 in adults. In 2018, there were a maximum of nine new cases of TIO in Danish adults. Mortality was low but few patients fulfilled the protocol cure criterion during the observation period. TIO has no ICD-10 code and limitations to the study include lack of information on serum biochemistry and on the use of phosphate supplements. Strengths include the use of long-term longitudinal, national hospital and prescription data from a country with universal healthcare. Given the very small patient population with TIO and the known delay to diagnosis and cure, management of patients with suspected TIO should be centralized.

Bisphosphonate Drug Holidays in Primary Care: When and What to Do Next?

PURPOSE OF REVIEW: This review describes the rational for bisphosphonate holidays, summaries key evidence to support the concept, and provides a roadmap to help clinicians initiate, monitor, and discontinue a bisphosphonate drug holiday. RECENT FINDINGS: Randomized trials and data from large observational studies are available to determine the short and long-term bisphosphonate benefits (prevention of fracture) and harms (principally atypical femoral fractures and osteonecrosis of the jaw). Mounting evidence points towards a causal relationship between bisphosphonate use and AFF and ONJ, particularly with > 5 years of use. Multiple studies now confirm the risk of AFF falls rapidly after BPs are discontinued. Osteoporosis patients without previous hip, vertebral, or multiple non-spine fractures who are successfully treated with oral bisphosphonates for 5 years (3 years if intravenous), should be offered a 3-5 year drug holiday, particularly if hip BMD T-score is > - 2.5. Bisphosphonates should only be continued beyond 10 years (6 years if parenteral) in patients at very high risk of fracture.

The Latest Evidence from Vitamin D Intervention Trials for Skeletal and Non-skeletal Outcomes.

Vitamin D has long been considered a central part of the treatment paradigm for osteoporosis. Initial studies in high-risk populations with widespread vitamin D deficiency found a reduction of both vertebral and non-vertebral fractures. Subsequent studies in the general population have yielded mixed but mostly disappointing results both for skeletal and especially non-skeletal outcomes. Recent sequential trial meta-analyses suggest that future studies are likely to be futile given the overall disappointing result. However, mega-trials are still in progress, and additional results have been released. This narrative review aims to evaluate new literature to determine if there has been any substantial change in the message. In conclusion, there is no longer a strong case for initiating vitamin D alone trials in the general adult population, irrespective of age and gender, for significant health outcomes such as fractures, cardiovascular disease and cancer. New studies should focus on risk groups and take directions from the Heaney criteria for evaluation of threshold nutrients. Indeed, real benefits may still be reaped by directing vitamin D supplementation to persons with proven or likely vitamin D deficiency. Further, the role of dietary calcium as a critical co-nutrient remains controversial and could contribute to the discrepancy between studies in terms of cancer outcomes and possibly falls and fractures.

Hiding in plain sight-unreported osteoporotic vertebral fractures.

KEY POINTS: • Reporting of vertebral fractures has important clinical consequences and can be improved by routinely performing sagittal reformating and by the use of a standard nomenclature and classification.

Assessment of fracture risk in women with eating disorders: The utility of dual-energy x-ray absorptiometry (DXA)-Clinical cohort study.

OBJECTIVE: Eating disorders (EDs) are associated with decreased bone mineral density (BMD) and increased fracture risk. The association between BMD and fracture risk in EDs is not well elucidated. We aimed to assess BMD in an ED cohort of patients with active disease and patients in remission, and to assess the predictive value of BMD on incidence of fractures. METHOD: We included 344 female patients (median age 19, IQR 16; 24) referred to ED treatment. Later, patients were invited to follow-up including assessment of remission status and a dual-energy x-ray absorptiometry (DXA)-scan. Information on fractures was obtained through the Danish National Registry of Patients. RESULTS: Patients with current anorexia nervosa (AN) had significantly lower BMD compared to controls at lumbar spine (16% lower, p < .0001), femoral neck (18% lower, p < .0001), and total hip (23% lower, p < .0001). Recovered AN patients had higher BMD compared to those with current disease (p < .0001 for all measures), but lower BMD compared to controls at lumbar spine (p < .01) and hip (p < .001). BMD did not differ between BN patients and controls. In patients with active eating disorders not otherwise specified, BMD was lower only at the total hip (p < .005). We found no association between BMD and fracture risk. CONCLUSION: We confirm that AN is associated with low BMD, whereas BN is not. Remission is associated with higher BMD compared to patients with active AN, but a deficit remains. We found no significant association between BMD and fracture risk, challenging the benefit of the widespread use of DXA scans in young women with ED. CLINICAL TRIAL REGISTRATION: The study is registered in ClinicalTrials.gov, number NCT00267228.

Fractures in women with eating disorders-Incidence, predictive factors, and the impact of disease remission: Cohort study with background population controls.

OBJECTIVE: Malnutrition and low weight in eating disorders (EDs) are associated with increased fracture risk compared to the general population. In a cohort study, we aimed to determine fracture rates compared to age and gender matched controls (ratio 5:1), assess the impact of disease remission on fracture risk, and establish predictive factors for fractures. METHOD: Of note, 803 ED patients referred to specialized ED treatment between 1994 and 2004 were included. In 2016, data on fractures were obtained through the Danish National Registry of Patients. RESULTS: Fracture risk was increased in anorexia nervosa (AN; IRR 2.2 [CI 99%: 1.6-3.0]) but not in bulimia nervosa (BN; IRR 1.3, ns) or other specified feeding or eating disorders (OSFED; IRR 1.8, ns). IRR in the AN group were increased for vertebral fractures (IRR 3.8 [CI 99%: 1.4-10.3]), upper arm (IRR 3.0 (CI 99% 1.6-5.5) and hip (IRR 6.6 [CI 99%: 2.6-18.0]). Disease remission in AN is associated to lower fracture risk compared to active disease, but higher fracture risk compared to controls (IRR 1.7 [CI 99%: 1.1-2.7]). In regression analysis, age at debut of disease, nadir BMI and duration of disease before referral to treatment, independently predicted fracture. DISCUSSION: We confirm increased fracture risk in AN, and show significant differences in fracture risk between patients in disease remission and patients with active disease. Furthermore, we show that age at debut of disease and duration of disease before referral to treatment is positively correlated to fracture risk, whereas nadir BMI is negatively correlated to fracture risk.

Side effects of drugs for osteoporosis and metastatic bone disease.

Osteoporosis is a common condition that leads to substantial morbidity and mortality and affects an increasing number of persons worldwide. Several pharmacological therapies that inhibit bone resorption, promote bone formation, or both, are available for the treatment of osteoporosis. The osteoanabolic treatment spectrum was recently expanded by the introduction of a novel bone-forming agent in the United States, and clinical trials indicate that a new class of bone anabolic therapy may become available. Both antiresorptive and bone anabolic therapies are associated with common and rare adverse effects, which are particularly important to address as these drugs are used for long-term treatment in numerous patients with a large proportion being elderly and/or having multimorbidity. In addition, antiresorptive drugs are used to inhibit bone resorption in patients with malignant hypercalcaemia or to prevent skeletal events in cancer patients, and bisphosphonates have been repurposed as a cancer preventive therapy. However, therapeutic doses are generally higher when antiresorptive drugs are used in the oncological setting, which influence the prevalence of adverse effects significantly. This review highlights key issues and controversies regarding adverse effects of currently available and emerging drugs used for osteoporosis and metastatic bone diseases.

Excess mortality following hip fracture in patients with diabetes according to age: a nationwide population-based cohort study of 154,047 hip fracture patients.

OBJECTIVE: to test the hypothesis that excess mortality conferred by diabetes following hip fracture decreases with advancing age. METHODS: a nationwide population-based cohort study including 154,047 patients who were admitted with a hip fracture in Denmark from 1996 to 2012. Information on hip fracture diagnosis, diabetes, other comorbidities, and the primary outcome all-cause mortality was collected using the national Danish health registries. The association between diabetes and all-cause mortality according to age was assessed using Cox proportional hazards regression in the age categories: <50, 50-59, 60-69, 70-79, 80-89 and ≥90 years. RESULTS: during a median follow-up of 3 years (interquartile range: 1-6 years, 603,091 person-years) 114,990 died from any cause. In total, 8% (n = 12,158) of the patients had diabetes at baseline and had unadjusted, and age, sex and Charlson Comorbidity Index adjusted hazard ratios for all-cause mortality of 1.19 (95% confidence interval: 1.16-1.21) and 1.14 (1.12-1.17) as compared to patients without diabetes. The sex and Charlson Comorbidity Index adjusted hazard ratios according to age were 1.64 (1.34-2.02) for patients <50 years, 1.26 (1.12-1.40) for patients 50-59 years, 1.21 (1.13-1.29) for patients 60-69 years, 1.11 (1.07-1.16) for patients 70-79 years, 1.10 (1.07-1.14) for patients 80-89 years and 1.09 (1.02-1.16) for patients ≥90 years. There was a statistically significant interaction between diabetes and age (P < 0.001). CONCLUSIONS: diabetes is associated with excess mortality following hip fracture across all ages, but the excess mortality decreases with advancing age.

Socioeconomic status in Danish women with polycystic ovary syndrome: A register-based cohort study.

INTRODUCTION: Low socioeconomic status (SES) may be associated with increased risk of polycystic ovary syndrome (PCOS) and vice versa. Possible associations between SES, obesity and ethnicity in PCOS are undetermined. MATERIAL AND METHODS: National register-based study including women with PCOS aged 25 years or above (PCOS Denmark and an embedded cohort; PCOS Odense University Hospital [OUH]) and one control population. PCOS Denmark (n = 13 891) included women with PCOS in the Danish National Patient Register. Women in PCOS OUH underwent clinical examination (n = 814). Three age-matched controls were included per patient (n = 41 584). The main outcome measure was SES (personal income, occupational status and education). RESULTS: The median (Q1; Q3) age of women in PCOS Denmark and controls was 33 (29; 39) years. Women with personal income in the lower tertile had a higher probability of a PCOS diagnosis than women in the high-income tertile (adjusted odds ratio [aOR] 1.5, 95% confidence interval [CI] 1.4-1.6). Women who were unemployed or on welfare payment (aOR 1.5, 95% CI 1.4-1.6), or who retired early (OR 1.8, 95% CI 1.7-2.0) had a higher probability of a PCOS diagnosis than women affiliated to the labor market. Women originating from the Middle East more often had PCOS (aOR 3.2, 95% CI 2.8-3.7) compared with women originating from Europe. In PCOS OUH, SES was lower in obese than in normal weight women. CONCLUSIONS: A diagnosis of PCOS was associated with lower SES. In PCOS, women of foreign origin and women with obesity more often had low SES.