Ethel S. Siris

Randomized trials have not been performed, and may never be, to determine if osteoporosis treatment prevents hip fracture in men. Addressing that evidence gap, we analyzed data from an observational study of new hip fractures in a large integrated healthcare system to compare the reduction in hip fractures associated with standard-of-care osteoporosis treatment in men versus women. Sampling from 271,389 patients aged ≥ 65 who had a hip-containing CT scan during care between 2005 and 2018, we selected all who subsequently had a first hip fracture (cases) after the CT scan (start of observation) and a sex-matched equal number of randomly selected patients. From those, we analyzed all who tested positive for osteoporosis (DXA-equivalent hip BMD T-score ≤ −2.5, measured from the CT scan using VirtuOst). We defined “treated” as at least six months of any osteoporosis medication by prescription fill data during follow-up; “not-treated” was no prescription fill. Sex-specific odds ratios of hip fracture for treated vs not-treated patients were calculated by logistic regression; adjustments included age, BMD T-score, BMD-treatment interaction, BMD, race/ethnicity, and seven baseline clinical risk factors. At two-year follow-up, 33.9% of the women (750/2,211 patients) and 24.0% of the men (175/728 patients) were treated primarily with alendronate; 51.3% and 66.3%, respectively, were not-treated; and 721 and 269, respectively, had a first hip fracture since the CT scan. Odds ratio of hip fracture for treated vs not-treated was 0.26 (95% confidence interval: 0.21–0.33) for women and 0.21 (0.13–0.34) for men; the ratio of these odds ratios (men:women) was 0.81 (0.47–1.37), indicating no significant sex effect. Various sensitivity and stratified analyses confirmed these trends, including results at five-year follow-up. Given these results and considering the relevant literature, we conclude that osteoporosis treatment prevents hip fracture similarly in both sexes.

Osteoporosis is the most common metabolic bone disease in the USA and the world. It is a subclinical condition until complicated by fracture(s). These fractures place an enormous medical and personal burden on individuals who suffer from them and take a significant economic toll. Any new fracture in an adult aged 50 years or older signifies imminent elevated risk for subsequent fractures, particularly in the year following the initial fracture. What a patient perceives as an unfortunate accident may be seen as a sentinel event indicative of bone fragility and increased future fracture risk even when the result of considerable trauma. Clinical or subclinical vertebral fractures, the most common type of osteoporotic fractures, are associated with a 5-fold increased risk for additional vertebral fractures and a 2- to 3-fold increased risk for fractures at other sites. Untreated osteoporosis can lead to a vicious cycle of recurrent fracture(s), often resulting in disability and premature death. In appropriate patients, treatment with effective antifracture medication prevents fractures and improves outcomes. Primary care providers and medical specialists are critical gatekeepers who can identify fractures and initiate proven osteoporosis interventions. Osteoporosis detection, diagnosis, and treatment should be routine practice in all adult healthcare settings. The Bone Health and Osteoporosis Foundation (BHOF) – formerly the National Osteoporosis Foundation – first published the Clinician’s Guide in 1999 to provide accurate information on osteoporosis prevention and treatment. Since that time, significant improvements have been made in diagnostic technologies and treatments for osteoporosis. Despite these advances, a disturbing gap persists in patient care. At-risk patients are often not screened to establish fracture probability and not educated about fracture prevention. Most concerning, the majority of highest risk women and men who have a fracture(s) are not diagnosed and do not receive effective, FDA-approved therapies. Even those prescribed appropriate therapy are unlikely to take the medication as prescribed. The Clinician’s Guide offers concise recommendations regarding prevention, risk assessment, diagnosis, and treatment of osteoporosis in postmenopausal women and men aged 50 years and older. It includes indications for bone densitometry as well as fracture risk thresholds for pharmacologic intervention. Current medications build bone and/or decrease bone breakdown and dramatically reduce incident fractures. All antifracture therapeutics treat but do not cure the disease. Skeletal deterioration resumes sooner or later when a medication is discontinued—sooner for nonbisphosphonates and later for bisphosphonates. Even if normal BMD is achieved, osteoporosis and elevated risk for fracture are still present. The diagnosis of osteoporosis persists even if subsequent DXA T-scores are above − 2.5. Ongoing monitoring and strategic interventions will be necessary if fractures are to be avoided. In addition to pharmacotherapy, adequate intake of calcium and vitamin D, avoidance of smoking and excessive alcohol intake, weight-bearing and resistance-training exercise, and fall prevention are included in the fracture prevention armamentarium. Where possible, recommendations in this guide are based on evidence from RCTs; however, relevant published data and guidance from expert clinical experience provides the basis for recommendations in those areas where RCT evidence is currently deficient or not applicable to the many osteoporosis patients not considered for RCT participation due to age and morbidity.

The 3‐year placebo‐controlled FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial established the antifracture efficacy of denosumab in postmenopausal women with osteoporosis. The 7‐year open‐label extension demonstrated that denosumab treatment for up to 10 years was associated with low rates of adverse events and low fracture incidence. The extension lacked a long‐term control group, thus limiting the ability to fully evaluate long‐term efficacy. This analysis provides a quantitative estimate of the long‐term antifracture efficacy of denosumab based on two approaches: comparison with FRAX®‐ (Fracture Risk Assessment Tool‐) and virtual twin‐estimated 10‐year fracture rates. Subjects who were randomized to denosumab in the FREEDOM trial, continued into the Extension study, completed the 10‐year visit, and missed ≤1 dose in the FREEDOM trial and ≤1 dose in the Extension (n = 1278) were included in the analysis. The 10‐year observed cumulative incidence of major osteoporotic fracture (MOF) and hip fractures was compared with the 10‐year fracture probability predicted at baseline by FRAX, a computer‐based fracture risk algorithm, and with that estimated for a hypothetical cohort of 10‐year placebo controls (virtual twins). The observed 10‐year fracture incidence was lower than the 10‐year probability predicted by FRAX for both MOF (10.75% [95% CI, 9.05 to 12.46] versus 15.63% [95% CI, 15.08 to 16.18], respectively), and hip fractures (1.17% [95% CI, 0.58 to 1.76] versus 5.62% [95% CI, 5.28 to 5.97], respectively). The observed fracture incidence was also lower than the fracture rate estimated in a hypothetical cohort of 10‐year placebo controls for MOF (23.13% [95% CI, 17.76 to 28.87]; relative risk 0.49 [95% CI, 0.36 to 0.64]). These data support the long‐term efficacy of denosumab in reducing MOF and hip fractures in postmenopausal women with osteoporosis. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

We evaluated the prevalence of osteoporosis using the osteoporosis diagnostic criteria developed by the National Bone Health Alliance (NBHA), which includes qualified fractures, FRAX score in addition to BMD. The expanded definition increases the prevalence compared to BMD alone definitions; however, it may better identify those at elevated fracture risk. Recently an NBHA working Group published a paper in OI with recommendations for expanding the criteria that would constitute an osteoporosis diagnosis in postmenopausal women and in men over age 50 for use in the US – Siris et al., Osteoporosis International 25(%): 1439–1443, 2014. The recommendations have now been endorsed by NOF, ASBMR and a number of professional medical groups and appear in the NOF Clinician’s Guide. The new diagnostic criteria continue to include a T-score by DXA of spine or hip that is less than or equal to −2.5, but alternatively also include a hip fracture with or without BMD testing or a vertebral, pelvis, proximal humerus and in some cases a distal forearm fracture in a person with low bone mass, or a FRAX score that meets or exceeds the NOF Guide osteoporosis treatment cut point.

Background and Objectives: The extent to which greater frailty among American compared with European women reflects individual-level characteristics has not been well studied. To test the hypothesis that cardiometabolic conditions and depression and anxiety confound the relationship between region and incident prefrailty and frailty in American compared with European women. Materials and Methods: The Global Longitudinal Study of Osteoporosis in Women (GLOW) is a 5-year observational cohort study of women aged ≥55 years. A total of 19,674 participants from the United States and Europe were nonfrail at baseline and provided information on characteristics, including body mass index, depression and anxiety, and cardiovascular disease. We used multivariable Cox proportional hazards models to examine the relationship between region and incident frailty and prefrailty. Results: Over 40% of respondents became prefrail or frail during follow-up. Adjusting for age, body mass index, depression and anxiety, cardiovascular disease, and other health-related characteristics, European respondents had a decreased risk of developing prefrailty (2-year hazard ratio [HR]: 0.78, 95% confidence interval [CI]: 0.73–0.84; 3-year HR: 0.74, 95% CI: 0.67–0.81) and frailty (2-year HR: 0.65, 95% CI: 0.56–0.76; 3-year HR: 0.82, 95% CI: 0.68–0.99) compared with American respondents. Risk of incident frailty and prefrailty did not vary by region at 5 years of follow-up. Conclusions: Cardiometabolic conditions and depression and anxiety did not account for increased frailty and prefrailty onset among American compared with European women. Differences in smaller regions and environmental characteristics may contribute to frailty and prefrailty.

We evaluated the prevalence of osteoporosis using the osteoporosis diagnostic criteria developed by the National Bone Health Alliance (NBHA), which includes qualified fractures, FRAX score in addition to bone mineral density (BMD). The expanded definition increases the prevalence compared to BMD alone definitions; however, it may better identify those at elevated fracture risk.

Summary Osteoporosis causes an elevated fracture risk. We propose the continued use of T-scores as one means for diagnosis but recommend that, alternatively, hip fracture; osteopenia-associated vertebral, proximal humerus, pelvis, or some wrist fractures; or FRAX scores with ≥3 % (hip) or 20 % (major) 10-year fracture risk also confer an osteoporosis diagnosis. Introduction Osteoporosis is a common disorder of reduced bone strength that predisposes to an increased risk for fractures in older individuals. In the USA, the standard criterion for the diagnosis of osteoporosis in postmenopausal women and older men is a T-score of ≤ −2.5 at the lumbar spine, femur neck, or total hip by bone mineral density testing. Methods Under the direction of the National Bone Health Alliance, 17 clinicians and clinical scientists were appointed to a working group charged to determine the appropriate expansion of the criteria by which osteoporosis can be diagnosed. Results The group recommends that postmenopausal women and men aged 50 years should be diagnosed with osteoporosis if they have a demonstrable elevated risk for future fractures. This includes having a T-score of less than or equal to −2.5 at the spine or hip as one method for diagnosis but also permits a diagnosis for individuals in this population who have experienced a hip fracture with or without bone mineral density (BMD) testing and for those who have osteopenia by BMD who sustain a vertebral, proximal humeral, pelvic, or, in some cases, distal forearm fracture. Finally, the term osteoporosis should be used to diagnose individuals with an elevated fracture risk based on the World Health Organization Fracture Risk Algorithm, FRAX. Conclusions As new ICD-10 codes become available, it is our hope that this new understanding of what osteoporosis represents will allow for an appropriate diagnosis when older individuals are recognized as being at an elevated risk for fracture.

In the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) study, women with incident clinical fractures reported significant declines in health-related quality of life (HRQoL). The largest declines were observed when the assessment was <3 months post fracture. The largest impact of incident clinical fractures was on physical function, and that of incident clinical vertebral fractures was on back pain. In the FREEDOM trial, denosumab significantly reduced the risk of new vertebral, hip, and nonvertebral fractures. We evaluated the effect of denosumab on HRQoL and the association between incident clinical fractures and HRQoL. The FREEDOM trial enrolled 7,868 women aged 60–90 years with a total hip and/or lumbar spine BMD T-score <−2.5 and not <−4.0 at either site. Women were randomized to receive denosumab 60 mg or placebo every 6 months, in addition to daily calcium and vitamin D. HRQoL was assessed with the Osteoporosis Assessment Questionnaire-Short Version (OPAQ-SV) at baseline and every 6 months for 36 months. The OPAQ-SV assesses physical function, emotional status, and back pain. Higher scores indicate better health status. No statistically significant differences in mean change in HRQoL from baseline to end of study were found when comparing treatment groups. Compared with women without any incident fractures during the study, women with incident clinical fractures reported significant declines in physical function (−4.0 vs. −0.5) and emotional status (−5.0 vs. −0.8) at month 36 (P < 0.001 for both). Importantly, time-dependent covariate analyses demonstrated that the largest declines were observed when the assessment was <3 months post fracture. The largest impact of incident clinical fractures was on physical function, and that of incident clinical vertebral fractures was on back pain. These findings not only demonstrate that incident clinical fractures impact HRQoL but also contribute new information regarding the impact of these fracture events on HRQoL over time.