Abaloparatide Effects on Cortical Volumetric BMD and Estimated Strength Indices of Hip Subregions by 3D-DXA in Women With Postmenopausal Osteoporosis.

In ACTIVE, abaloparatide increased areal BMD (aBMD) of the hip and femoral neck vs teriparatide and placebo in women with osteoporosis. Previously, 3D-processing of dual X-ray absorptiometry (DXA) scans of a subgroup of ACTIVE subjects showed similar increases in trabecular volumetric BMD (Tb.vBMD) and greater increases in cortical vBMD (Ct.vBMD) of the total hip with abaloparatide vs teriparatide. The current analyses from this subgroup describe 2D- and 3D-DXA data for hip subregions. Randomly selected subjects from ACTIVE (n = 250/treatment group) who received 18 mo of placebo, abaloparatide 80 µg, or open-label teriparatide 20 µg by daily subcutaneous injection underwent hip DXA at baseline, and mo 6 and 18 of treatment. Areal BMD of the femoral neck, trochanter, and femoral shaft was determined using standard 2D-DXA and 3D-SHAPER software to retrospectively evaluate changes from baseline in volumetric parameters of these 3 hip subregions, including trabecular and cortical segmentation. Changes in biomechanical parameters cross-sectional moment of inertia (CSMI), section modulus (Z), and buckling ratio were also evaluated. Femoral neck, trochanter, and shaft aBMD increased in the abaloparatide and teriparatide groups at mo 6 and 18 vs placebo, with greater increases for abaloparatide vs teriparatide at the femoral neck at mo 6 and the shaft at mo 6 and 18. All 3 subregions showed similar significant increases in Tb.vBMD with abaloparatide and teriparatide vs placebo, whereas Ct.vBMD of all 3 subregions showed greater increases after 18 mo of abaloparatide vs teriparatide. Biomechanical parameters improved in all subregions with abaloparatide and teriparatide vs placebo, with greater improvements in CSMI and Z of the femoral neck and lower shaft after 6 and 18 mo of abaloparatide vs teriparatide. Differential femoral neck and shaft Ct.vBMD responses may explain the greater increases in CSMI and Z of those subregions with abaloparatide vs teriparatide.

Outcomes post fragility fracture among members of an integrated healthcare organization.

This study highlights an unmet need in osteoporosis management, suggesting that beyond bone mineral density and fracture history, gender, fracture type, and age should be considered for fracture risk assessment. Following fragility fracture, men, patients with a spine or hip fracture, and those aged ≥ 65 have a higher disease burden. INTRODUCTION: The objective of this study was to characterize osteoporosis-related fracture incidence and identify predictors of subsequent fractures and mortality. METHODS: This retrospective cohort study, conducted within Kaiser Permanente Southern California, included patients aged ≥ 50 years with qualifying fractures from 1/1/2007 to 12/31/2016, identified from diagnosis/procedure codes. Rates for fracture incidence, mortality, and resource utilization in the year post-fracture are reported. Associations between index fracture types and demographic/clinical characteristics, and mortality, subsequent fracture, and rehospitalization outcomes were estimated. RESULTS: Of 63,755 eligible patients, 66.7% were ≥ 65 years and 69.1% female. Index fractures included nonhip/nonspine (64.4%), hip (25.3%), and spine (10.3%). Age-adjusted subsequent fracture rate/100 person-years was higher for those with an index spine (14.5) versus hip fracture (6.3). Hospitalization rate/100 person-years was highest for patients ≥ 65 (31.8) and for spine fractures (43.5). Men (vs women) had higher age-adjusted rates of hospitalization (19.4; 17.7), emergency room visits (73.8; 66.3), and use of rehabilitation services (31.7; 27.2). The 30-day age-adjusted mortality rate/100 person-years was 46.7, 32.4, and 15.5 for spine, hip, and nonspine/nonhip fractures. The 1-year age-adjusted mortality rate/100 person-years was 14.7 for spine and 15.6 for hip fractures. In multivariable analyses, spine and hip fractures (vs nonhip/nonspine fractures) were significant predictors of 1-year mortality, all-cause and osteoporosis-related hospitalization, and nursing home use (all P-values < 0.0001). CONCLUSION: Morbidity is high in the year following a fragility fracture and men, patients with a spine or hip fracture, and those aged ≥ 65 have a greater disease burden.

Development and validation of a one year predictive model for secondary fractures in osteoporosis.

The number of osteoporosis-related fractures in the United States is no longer declining. Existing risk-based assessment tools focus on long-term risk. Payers and prescribers need additional tools to identify patients at risk for imminent fracture. We developed and validated a predictive model for secondary osteoporosis fractures in the year following an index fracture using administrative medical and pharmacy claims from the Optum Research Database and Symphony Health, PatientSource. Patients ≥50 years with a case-qualifying fracture identified using a validated claims-based algorithm were included. Logistic regression models were created with binary outcome of a second fracture versus no second fracture within a year of index fracture, with the goal of predicting second fracture occurrence. In the Optum Research Database, 197,104 patients were identified with a case-qualifying fracture (43% commercial, 57% Medicare Advantage). Using Symphony data, 1,852,818 met the inclusion/exclusion criteria. Average patient age was 70.09 (SD = 11.09) and 71.28 (SD = 14.24) years in the Optum Research Database and Symphony data, respectively. With the exception of history of falls (41.26% vs 18.74%) and opioid use (62.80% vs 46.78%), which were both higher in the Optum Research Database, the two populations were mostly comparable. A history of falls and steroid use, which were previously associated with increased fracture risk, continue to play an important role in secondary fractures. Conditions associated with bone health (liver disease), or those requiring medications that impact bone health (respiratory disease), and cardiovascular disease and stroke-which may share etiology or risk factors with osteoporosis fractures-were also predictors of imminent fractures. The model highlights the importance of assessment of patient characteristics beyond bone density, including patient comorbidities and concomitant medications associated with increased fall and fracture risk, in alignment with recently issued clinical guidelines for osteoporosis treatment.

Gender Disparities in Osteoporosis Screening and Management Among Older Adults.

INTRODUCTION: One in two women and one in four men experience an osteoporosis-related fracture in their lifetime. Related morbidity and mortality rates are higher in men versus women. Current guidelines are inconsistent in the screening recommendations for osteoporosis in men. Examination of gender disparities in the management of osteoporosis-related fractures among Medicare enrollees is currently lacking. METHODS: In this retrospective cohort study using 5% National Medicare claims data from January 1, 2012 through December 31, 2016, eligible patients who were at least 65 years of age on the date of a new fracture episode were classified into two mutually exclusive cohorts on the basis of whether they received testing and/or treatment for osteoporosis in the 6-month period after the new fracture episode. The cohorts were defined on the basis of the National Committee for Quality Assurance (NCQA) quality measure "osteoporosis management in women who had a fracture." Patients were followed to identify the occurrence of subsequent fracture, all-cause mortality, and a composite outcome-defined as the first occurrence of either subsequent fracture or mortality. Logistic regression models were carried out to identify predictors of testing and/or treatment and time-varying survival analysis to identify the relationship between the presence of testing and/or treatment and patient outcomes. RESULTS: Of the 35,774 eligible patients, only 10.2% (12.1% women and 5.7% men) received osteoporosis testing and/or treatment within 6 months after a fracture. The interaction between gender and fragility fracture was significant (P < 0.0001). Fragility fracture had greater adjusted odds of testing and/or treatment among men (adjusted odds ratio [AOR] 3.47; 95% CI 2.94-4.10) than women (AOR 1.65; 95% CI 1.53-1.79). Of patients who were eligible for the outcome assessment, 27.5% experienced a subsequent fracture, 23.2% died, and 44.3% experienced a composite outcome during follow-up. Patients who received testing and/or treatment had a significantly lower hazard of all-cause mortality (hazard ratio [HR] 0.57; 95% CI 0.50-0.65; P < 0.0001) and the composite outcome (HR 0.42; 95% CI 0.39-0.45; P < 0.0001), but no difference in the risk of subsequent fracture (HR 1.02; 95% CI 0.94-1.11; P = 0.6083). Men were found to have a significantly lower hazard of subsequent fracture (HR 0.69; 95% CI 0.64-0.73; P < 0.0001), all-cause mortality (HR 0.67; 95% CI 0.61-0.72; P < 0.0001), and the composite outcome (HR 0.69; 95% CI 0.65-0.73; P < 0.0001). CONCLUSION: Testing and/or treatment for osteoporosis among older adults with a fracture is poor in the Medicare fee-for-service population overall and worse for men compared to women. Receiving appropriate testing and/or treatment was associated with reduced mortality and the risk of composite outcome. Improving osteoporosis testing and/or treatment and reducing health disparities are essential for managing the clinical and economic burden of osteoporosis in the USA.

Risk Factors for Incident Fracture in Older Adults With Type 2 Diabetes: The Framingham Heart Study.

OBJECTIVE: To identify risk factors for fracture in type 2 diabetes. RESEARCH DESIGN AND METHODS: This prospective study included members of the Framingham Original and Offspring Cohorts. Type 2 diabetes was defined as fasting plasma glucose >125 mg/dL or use of type 2 diabetes therapy. We used repeated-measures Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% CIs for associations between potential predictors and incidence of fragility fracture. RESULTS: Participants included 793 individuals with type 2 diabetes. Mean ± SD age was 70 ± 10 years; 45% were women. A total of 106 incident fractures occurred over 1,437 observation follow-up intervals. Fracture incidence increased with age (adjusted HRs 1.00, 1.44 [95% CI 0.65, 3.16], and 2.40 [1.14, 5.04] for <60, 60-70, and >70 years, respectively; P trend = 0.02), female sex (2.23 [1.26, 3.95]), HbA1c (1.00, 2.10 [1.17, 3.75], and 1.29 [0.69, 2.41] for 4.45-6.46% [25-47 mmol/mol], 6.50-7.49% [48-58 mmol/mol], and 7.50-13.86% [58-128 mmol/mol]; P trend =0.03), falls in past year (1.00, 1.87 [0.82, 4.28], and 3.29 [1.34, 8.09] for no falls, one fall, and two or more falls; P trend =0.03), fracture history (2.05 [1.34, 3.12]), and lower grip strength (0.82 [0.69, 0.99] per 5-kg increase). Femoral neck bone mineral density, BMI, smoking, physical function, chronic diseases, medications, and physical function were not associated with fracture incidence. CONCLUSIONS: Prior falls, fractures, low grip strength, and elevated HbA1c are risk factors for fractures in older adults with type 2 diabetes. Evaluation of these factors may improve opportunities for early intervention and reduce fractures in this high-risk group.

Phase 1b Evaluation of Abaloparatide Solid Microstructured Transdermal System (Abaloparatide-sMTS) in Postmenopausal Women with Low Bone Mineral Density.

BACKGROUND AND OBJECTIVE: Abaloparatide, an anabolic osteoporosis treatment administered by subcutaneous (SC) injection, increases bone mineral density (BMD) and reduces fracture risk in postmenopausal women with osteoporosis. The abaloparatide-solid Microstructured Transdermal System [abaloparatide-sMTS (Kindeva, St Paul, MN, USA)], which delivers abaloparatide intradermally, is in development to provide an alternative method for abaloparatide delivery. The objective of this study was to evaluate the ability of subjects to self-administer abaloparatide-sMTS, based on pharmacokinetic and pharmacodynamic markers. METHODS: In this single-arm, open-label, Phase 1b study, 22 healthy postmenopausal women aged 50-85 years with low BMD were trained to self-administer abaloparatide-sMTS 300 µg once daily to the thigh for 5 min for 29 days. The primary endpoint was systemic exposure to abaloparatide. Secondary endpoints included percent change from baseline in serum procollagen type I N-terminal propeptide (s-PINP), patient experience, and safety. RESULTS: All 22 subjects completed the study. At baseline, mean age was 65.2 years, mean total hip T-score was - 1.32, and mean lumbar spine T-score was - 1.98. On Day 1, the median time to reach maximum concentration (Tmax) for abaloparatide-sMTS was 0.33 h and geometric mean (CV %) maximum concentration (Cmax) and area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-t) were 447 (38.0) pg/mL and 678 (45.3) pg·h/mL, respectively; the pharmacokinetic profile was similar on Days 15 and 29. Median percentage change in s-PINP was 45.4% and 64.4% at Days 15 and 29, respectively. The most common adverse events (AEs) were application site erythema, pain, and swelling, which were mostly of mild or moderate severity. No AEs led to study drug withdrawal and no serious AEs were reported. The success rate for self-administration at first application was 99.7%, and subject acceptability was high (~ 4.5 on a 5-point Likert Scale). CONCLUSIONS: Subjects successfully self-administered abaloparatide-sMTS, which provided a consistent pharmacokinetic profile over 29 days and produced s-PINP increases from baseline similar to that observed in the pivotal trial with abaloparatide-SC. Observed patient experience along with the clinical data support continued clinical development of abaloparatide-sMTS. TRIAL REGISTRATION NUMBER: NCT04366726, Date of registration 04/29/2020, retrospectively registered.

Osteoporosis is a serious health condition that causes more than 2 million fractures in the USA annually. Treatment options for osteoporosis include drugs that prevent bone resorption and anabolic agents that build new bone. Bone anabolic agents, such as abaloparatide, have been shown to increase bone mineral density and reduce the risk of fracture in postmenopausal women with osteoporosis. Currently, all bone anabolic agents are delivered by subcutaneous injection. However, some patients do not like injectable treatments, which can negatively impact patients' adherence to prescribed medication. In this study, we describe a novel mode of administration, the abaloparatide-solid Microstructured Transdermal System (abaloparatide-sMTS), which is applied to the thigh for 5 min and delivers abaloparatide intradermally. The study showed that this new method delivered abaloparatide into the blood as effectively as subcutaneous injections and demonstrated signs of activity in the body. Study participants were satisfied with abaloparatide-sMTS and found it easy to use. The most common side effects were skin related, including redness, pain, and swelling, which resolved shortly after dosing.

Effect of Abaloparatide on Bone Mineral Density and Fracture Incidence in a Subset of Younger Postmenopausal Women with Osteoporosis at High Risk for Fracture.

PURPOSE: Current treatment guidelines recommend treatment for postmenopausal women with a T score <2.5 regardless of age. This subgroup analysis evaluated the efficacy and safety of abaloparatide in younger postmenopausal women considered to be at high risk for fracture. METHODS: Subgroup analysis of women in the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial who were <65 years old and met modified utilization management criteria (baseline T score ≤-2.5 [any site] and ≥1 prevalent vertebral and/or ≥1 prior clinical fracture within 5 years of randomization). FINDINGS: A total of 296 women (age range, 49-64 years) were included. Significant increases in bone mineral density from baseline were observed for abaloparatide versus placebo at all 3 sites at 6 months (p < 0.01 for total hip and femoral neck; p < 0.0001 for lumbar spine), 12 months (p < 0.0001 at all 3 sites), and 18 months (p < 0.0001 at all 3 sites). Fracture rates were numerically lower for abaloparatide versus placebo, consistent with the overall trial results, although the differences were not statistically significant. The number needed to treat to prevent 1 additional vertebral fracture after 18 months of treatment versus placebo was 18 for abaloparatide and 21 for teriparatide. The number needed to treat had nonsignificant trends toward lower values with abaloparatide versus teriparatide for nonvertebral fractures (23 vs 40) and clinical fractures (16 vs 73) and similar for major osteoporotic fractures (24 vs 27). The safety profile was consistent with the overall ACTIVE population. IMPLICATIONS: Findings of this subgroup (post hoc) analysis are consistent with the overall ACTIVE population. Abaloparatide appears to be effective and well tolerated in this subgroup of younger postmenopausal women. ClinicalTrials.gov identifier: NCT01343004.

Economic burden of osteoporotic fractures in US managed care enrollees.

OBJECTIVES: To examine healthcare resource utilization (HRU) and costs in a population of managed care enrollees who experienced an osteoporotic fracture. STUDY DESIGN: Retrospective cohort study using the Optum Research Database (January 2007 to May 2017). METHODS: All-cause and osteoporosis-related HRU and costs were analyzed in patients 50 years and older with a qualifying index fracture and continuous enrollment with medical and pharmacy benefits for 12 months preindex (baseline period). RESULTS: Of 1,841,263 patients with fractures during the identification period, 302,772 met eligibility criteria. Two-thirds (66.6%) were 65 years and older, 71.6% were women, and 41.2% were commercial (not Medicare Advantage) enrollees. The most common fracture sites were spine (21.9%), radius/ulna (19.5%), and hip (13.7%). Mean (SD) total all-cause healthcare cost was $34,855 ($56,094), with most paid by health plans ($31,863 [$55,025]) versus patients ($2992 [$2935]). Most healthcare costs were for medical ($31,766 [$54,943]) versus pharmacy ($3089 [$6799]) services. Approximately 75% of patients received rehabilitation services (mean [SD] cost = $18,025 [$41,318]). Diagnosis of index fracture during an inpatient stay versus an outpatient visit (cost ratio, 2.16; 95% CI, 2.13-2.19) and fractures at multiple sites (cost ratio, 1.23; 95% CI, 1.21-1.26) were the leading predictors of cost. Kaplan-Meier estimated cumulative second-fracture rates were 6.6% at 1 year, 12.3% at 2 years, 16.9% at 3 years, and 20.9% at 4 years after index fracture. CONCLUSIONS: These findings suggest a significant economic burden associated with fractures, including a high total all-cause cost of care. Early identification and treatment of patients at high risk of fractures are of paramount importance to reduce fracture risk and associated healthcare costs.

Impact of fractures on quality of life in patients with osteoporosis: a US cross-sectional survey.

Objective: To evaluate the impact of osteoporosis-related fractures on health-related quality of life (HRQoL). Methods: Data were obtained from the 2016 Adelphi US Osteoporosis Disease Specific Programme™, a cross-sectional survey of physicians and their male and female patients with osteoporosis. Patient-reported outcomes (PRO) measures included the European Quality of Life 5 Domains (EQ-5D), European Quality of Life Visual Analog Scale (EQ-VAS), and Osteoporosis Assessment Questionnaire short-version (OPAQ-SV; physical, emotional, and symptom domains). Associations between PRO scores and the number and site of fractures were evaluated using ANOVA. Multivariate analyses were conducted using linear regression. Results: Physicians provided records for 1848 patients with osteoporosis. Of these, 981 (53.1%) completed the patient survey, data for the number of fractures were available for 935/981 (95.3%), and 185/935 (19.8%) had a history of fracture. Experiencing fractures significantly influenced scores on all PRO measures (p < .0001). Hip and spine fractures were associated with the greatest reduction in most PRO scores. The number of fractures, age, body mass index, and Charlson Comorbidity Index (CCI) were significantly associated with PRO measures (p < .05) in multivariate analyses. In patients with a fracture, fracture site, CCI, gender (EQ-5D and EQ-VAS), and age (OPAQ-SV physical only) were significantly associated with PRO measures. Conclusions: In patients with osteoporosis, fractures are associated with lower HRQoL and lower overall health status. Fracture history, fracture site, age, and comorbidity burden significantly influence HRQoL in individuals with osteoporosis. These data suggest the need for interventions to reduce the risk of fractures in patients with osteoporosis.