Dexamethasone Suppression Testing in a Contemporary Cohort with Adrenal Incidentalomas in Two U.S. Integrated Healthcare Systems.

Autonomous cortisol secretion (ACS) from an adrenal adenoma can increase the risk for comorbidities and mortality. The dexamethasone suppression test (DST) is the standard method to diagnose ACS. A multi-site, retrospective cohort of adults with diagnosed adrenal tumors was used to understand patient characteristics associated with DST completion and ACS. Time to DST completion was defined using the lab value and result date; follow-up time was from the adrenal adenoma diagnosis to the time of completion or censoring. ACS was defined by a DST > 1.8 µg/dL (50 nmol/L). The Cox proportional hazards regression model assessed associations between DST completion and patient characteristics. In patients completing a DST, a logistic regression model evaluated relationships between elevated ACS and covariates. We included 24,259 adults, with a mean age of 63.1 years, 48.1% obese, and 28.7% with a Charlson comorbidity index ≥ 4. Approximately 7% (n = 1768) completed a DST with a completion rate of 2.36 (95% CI 2.35, 2.37) per 100 person-years. Fully adjusted models reported that male sex and an increased Charlson comorbidity index were associated with a lower likelihood of DST completion. Current or former smoking status and an increased Charlson comorbidity index had higher odds of a DST > 1.8 µg/dL. In conclusion, clinical policies are needed to improve DST completion and the management of adrenal adenomas.

Fracture Risk and Association With TDF Use Among People With HIV in Large Integrated Health Systems.

BACKGROUND: Greater decline in bone health among people with HIV (PWH) has been documented but fracture risk and the impact of specific antiretroviral therapy (ART) regimens remain unclear. SETTING: Retrospective analyses of electronic health record data from 3 US integrated health care systems. METHODS: Fracture incidence was compared between PWH aged 40 years or older without prior fracture and demographically matched people without HIV (PWoH), stratified by age, sex, and race/ethnicity. Multivariable Cox proportional hazards models were used to estimate fracture risk associated with HIV infection. The association of tenofovir disoproxil fumarate (TDF) use and fracture risk was evaluated in a subset of PWH initiating ART. RESULTS: Incidence of fracture was higher in PWH [13.6/1000 person-years, 95% confidence interval (CI): 13.0 to 14.3, n = 24,308] compared with PWoH (9.5, 95% CI: 9.4 to 9.7, n = 247,313). Compared with PWoH, the adjusted hazard ratio (aHR) for fracture among PWH was 1.24 (95% CI: 1.18 to 1.31). The association between HIV infection and fracture risk increased with age, with the lowest aHR (1.17, 95% CI: 1.10 to 1.25) among those aged 40-49 years and the highest aHR (1.89, 95% CI: 1.30 to 2.76) among those aged 70 years or older. Among PWH initiating ART (n = 6504), TDF was not associated with significant increase in fracture risk compared with non-TDF regimens (aHR: 1.18, 95% CI: 0.89 to 1.58). CONCLUSIONS: Among people aged 40 years or older, HIV infection is associated with increased risk of fractures. Bone health screening from the age of 40 years may be beneficial for PWH. Large cohort studies with longer follow-up are needed to evaluate TDF effect and the potential benefit of early screening.

Long-term effects of primary hyperparathyroidism and parathyroidectomy on kidney function.

IMPORTANCE: Limited evidence supports kidney dysfunction as an indication for parathyroidectomy in asymptomatic primary hyperparathyroidism (PHPT). OBJECTIVE: To investigate the natural history of kidney function in PHPT and whether parathyroidectomy alters renal outcomes. DESIGN: Matched control study. SETTING: A vertically integrated health care system serving 4.6 million patients in Southern California. PARTICIPANTS: 6058 subjects with PHPT and 16 388 matched controls, studied from 2000 to 2016. EXPOSURES: Biochemically confirmed PHPT with varying serum calcium levels. MAIN OUTCOMES: Estimated glomerular filtration rate (eGFR) trajectories were compared over 10 years, with cases subdivided by severity of hypercalcemia: serum calcium 2.62-2.74 mmol/L (10.5-11 mg/dL), 2.75-2.87 (11.1-11.5), 2.88-2.99 (11.6-12), and >2.99 (>12). Interrupted time series analysis was conducted among propensity-score-matched PHPT patients with and without parathyroidectomy to compare eGFR trajectories postoperatively. RESULTS: Modest rates of eGFR decline were observed in PHPT patients with serum calcium 2.62-2.74 mmol/L (−1.0 mL/min/1.73 m2/year) and 2.75-2.87 mmol/L (−1.1 mL/min/1.73 m2/year), comprising 56% and 28% of cases, respectively. Compared with the control rate of −1.0 mL/min/1.73 m2/year, accelerated rates of eGFR decline were observed in patients with serum calcium 2.88-2.99 mmol/L (−1.5 mL/min/1.73 m2/year, P < .001) and >2.99 mmol/L (−2.1 mL/min/1.73 m2/year, P < .001), comprising 9% and 7% of cases, respectively. In the propensity score­matched population, patients with serum calcium >2.87 mmol/L exhibited mitigation of eGFR decline after parathyroidectomy (−2.0 [95% CI: −2.6 to −1.5] to −0.9 [95% CI: −1.5 to 0.4] mL/min/1.73 m2/year). CONCLUSIONS AND RELEVANCE: Compared with matched controls, accelerated eGFR decline was observed in the minority of PHPT patients with serum calcium >2.87 mmol/L (11.5 mg/dL). Parathyroidectomy was associated with mitigation of eGFR decline in patients with serum calcium >2.87 mmol/L.

Increased risks of vertebral fracture and reoperation in primary spinal fusion patients who test positive for osteoporosis by Biomechanical Computed Tomography analysis.

BACKGROUND CONTEXT: While osteoporosis is a risk factor for adverse outcomes in spinal fusion patients, diagnosing osteoporosis reliably in this population has been challenging due to degenerative changes and spinal deformities. Addressing that challenge, biomechanical computed tomography analysis (BCT) is a CT-based diagnostic test for osteoporosis that measures both bone mineral density and bone strength (using finite element analysis) at the spine; CT scans taken for spinal evaluation or previous care can be repurposed for the analysis. PURPOSE: Assess the effectiveness of BCT for preoperatively identifying spinal fusion patients with osteoporosis who are at high risk of reoperation or vertebral fracture. STUDY DESIGN: Observational cohort study in a multi-center integrated managed care system using existing data from patient medical records and imaging archives. PATIENT SAMPLE: We studied a randomly sampled subset of all adult patients who had any type of primary thoracic (T4 or below) or lumbar fusion between 2005 and 2018. For inclusion, patients with accessible study data needed a preop CT scan without intravenous contrast that contained images (before any instrumentation) of the upper instrumented vertebral level. OUTCOME MEASURES: Reoperation for any reason (primary outcome) or a newly documented vertebral fracture (secondary outcome) occurring up to 5 years after the primary surgery. METHODS: All study data were extracted using available coded information and CT scans from the medical records. BCT was performed at a centralized lab blinded to the clinical outcomes; patients could test positive for osteoporosis based on either low values of bone strength (vertebral strength ≤ 4,500 N women or 6,500 N men) and/or bone mineral density (vertebral trabecular bone mineral density ≤ 80 mg/cm3 both sexes). Cox proportional hazard ratios were adjusted by age, presence of obesity, and whether the fusion was long (four or more levels fused) or short (3 or fewer levels fused); Kaplan-Meier survival was compared by the log rank test. This project was funded by NIH (R44AR064613) and all physician co-authors and author 1 received salary support from their respective departments. Author 6 is employed by, and author 1 has equity in and consults for, the company that provides the BCT test; the other authors declare no conflicts of interest. RESULTS: For the 469 patients analyzed (298 women, 171 men), median follow-up time was 44.4 months, 11.1% had a reoperation (median time 14.5 months), and 7.7% had a vertebral fracture (median time 2.0 months). Overall, 25.8% of patients tested positive for osteoporosis and no patients under age 50 tested positive. Compared to patients without osteoporosis, those testing positive were at almost five-fold higher risk for vertebral fracture (adjusted hazard ratio 4.7, 95% confidence interval = 2.2-9.7; p<.0001 Kaplan-Meier survival). Of those positive-testing patients, those who tested positive concurrently for low values of both bone strength and bone mineral density (12.6% of patients overall) were at almost four-fold higher risk for reoperation (3.7, 1.9-7.2; Kaplan-Meier survival p<.0001); the remaining positive-testing patients (those who tested positive for low values of either bone strength or bone mineral density but not both) were not at significantly higher risk for reoperation (1.6, 0.7-3.7) but were for vertebral fracture (4.3, 1.9-10.2). For both clinical outcomes, risk remained high for patients who underwent short or long fusion. CONCLUSION: In a real-world clinical setting, BCT was effective in identifying primary spinal fusion patients aged 50 or older with osteoporosis who were at elevated risks of reoperation and vertebral fracture.

Clinical Outcomes of Telehealth in Patients With Coronary Artery Disease and Heart Failure During the COVID-19 Pandemic.

The COVID-19 pandemic necessitated a rapid adoption of telehealth (TH); however, its safety in subspecialty clinical practice remains uncertain. To assess the clinical outcomes associated with TH use in patients with coronary artery disease and/or heart failure during the initial phase of the COVID-19 pandemic, eligible adult patients who saw cardiologists from March 1, 2020, to August 31, 2020 (TH period) were identified. Patients were divided into two 3-month subcohorts (TH1, TH2) and compared with corresponding 2019 prepandemic subcohorts. The primary outcome was cardiovascular (CV) events within 3 months after index visits. Secondary analysis was CV events in patients aged ≥75 years within 3-month follow-up associated with TH use. Multivariable logistic regression was used to evaluate the association between TH use and CV outcomes. The study cohort included 6,485 TH and 7,557 prepandemic patients. The mean age was 70 years, with 40% of patients aged ≥75 years and 35% women. TH visits accounted for 0% of visits during the prepandemic period, compared with 68% during the TH period. Telephone visits comprised ≥92% of all TH encounters. Compared with the prepandemic period, patients seen during the TH period had fewer overall CV events (adjusted odds ratio 0.78, 95% confidence interval 0.67 to 0.90). Patients aged ≥75 years had similar findings (adjusted odds ratio 0.70, 95% confidence interval 0.55 to 0.89). Additional analysis of CV outcome events within 6 months after index visits showed similar findings. In conclusion, TH largely by way of telephone encounters can be safely incorporated into the ambulatory cardiology practice regardless of age.

Creating a Safety Net Process to Improve Colon Cancer Diagnosis in Patients With Rectal Bleeding.

Background Failure to follow up on patients with rectal bleeding is common and may result in a delay in diagnosis of colorectal cancer or in missing high-risk adenomas. The authors' purpose was to create an electronic patient safety net for those diagnosed with rectal bleeding but who did not have colonoscopy to ensure proper detection of colonic abnormalities, including colon cancer. Methods In an integrated health delivery system serving < 4.6 million patients in Southern California, from 2014 to 2019, the authors electronically identified patients with rectal bleeding aged 45 to 80 years but with no recently documented colonoscopy. These cases were reviewed by a gastroenterologist to determine if colonoscopy was appropriate. The physician looked for known documentation as to the cause of rectal bleeding and verified no contraindications to the procedure; if indicated, testing was offered. Results Using the authors' safety net program, 1430 patients with rectal bleeding who needed and completed a colonoscopy were identified. Of those patients, 7.5% had an advanced adenoma or cancer, with a total of 20 cancers, and 34% had findings that warranted more frequent colonoscopy. Conclusions The authors designed a safety net system that was able to capture information on patients with rectal bleeding who had not had a colonoscopy and detected in 34% colonic pathology that would have otherwise gone undetected. The program did not require many resources to implement and had the ability to potentially prevent harm from reaching patients whose rectal bleeding did not get prompt workup. Other health systems and practices should consider implementing a similar system.

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.

Bisphosphonates and the risk of atypical femur fractures.

Bisphosphonates are effective in reducing hip and other fractures. However, concerns about atypical femur fractures (AFFs) have contributed to substantially decreased bisphosphonate use, and hip fracture rates may be increasing. Despite this impact, important uncertainties remain regarding AFF risks including the association between bisphosphonate use and other risk factors such as BMD, age, weight, and race. To address this evidence gap, a cohort study of 196,129 women ≥50 years of age in the Southern California Kaiser Permanente HMO women (with ≥1 bisphosphonate prescription) were studied; the primary outcome was radiographically-adjudicated AFF between 2007 and 2017. Risk factors including bisphosphonate use and race were obtained from electronic health records. Multivariable Cox models were used for analysis. Benefit-risk was modeled for 1-10 years of bisphosphonates to compare fractures prevented vs. AFFs associated. Among 196,129 women, 277 (0.1%) sustained AFFs. After multivariable adjustment, AFF risk increased with longer bisphosphonate duration: hazard ratio (HR) increased from HR = 8.9 (95%CI: 2.8,28) for 3-5 years to HR = 43.5 (13.7138.1) for >8 years. Hip BMD, surprisingly, was not associated with AFF risk. Other risk factors included Asian ancestry (HR = 4.8 (3.6, 6.6)), short stature, overweight, and glucocorticoid use. Bisphosphonate discontinuation was associated with rapid decrease in AFF risk. Decreases in osteoporotic and hip fractures risk during 1-10 years of bisphosphonates far outweighed the increase AFF risk in Caucasians, but less so in Asians. In Caucasians, after 3 years 149 hip fractures were prevented with 2 AFFs associated compared to 91 and 8 in Asians. The evidence for several potential mechanisms is summarized with femoral geometry being the most likely to explain AFF risk differences between Asians and Caucasians. The results from this new study add to the evidence base for AFF risk factors and will help inform clinical decision-making for individual patients about initiation and duration of bisphosphonate therapy and drug holidays.

Bisphosphonate Treatment Beyond 5 Years and Hip Fracture Risk in Older Women.

Importance: Clinical trials have demonstrated the antifracture efficacy of bisphosphonate drugs for the first 3 to 5 years of therapy. However, the efficacy of continuing bisphosphonate for as long as 10 years is uncertain. Objective: To examine the association of discontinuing bisphosphonate at study entry, discontinuing at 2 years, and continuing for 5 additional years with the risk of hip fracture among women who had completed 5 years of bisphosphonate treatment at study entry. Design, Setting, and Participants: This cohort study included women who were members of Kaiser Permanente Northern and Southern California, 2 integrated health care delivery systems, and who had initiated oral bisphosphonate and completed 5 years of treatment by January 1, 2002, to September 30, 2014. Data analysis was conducted from January 2018 to August 2020. Exposure: Discontinuation of bisphosphonate at study entry (within a 6-month grace period), discontinuation at 2 years (within a 6-month grace period), and continuation for 5 additional years. Main Outcomes and Measures: The outcome was hip fracture determined by principal hospital discharge diagnoses. Demographic, clinical, and pharmacological data were ascertained from electronic health records. Results: Among 29 685 women (median [interquartile range] age, 71 [64-77] years; 17 778 [60%] non-Hispanic White individuals), 507 incident hip fractures were identified. Compared with bisphosphonate discontinuation at study entry, there were no differences in the cumulative incidence (ie, risk) of hip fracture if women remained on therapy for 2 additional years (5-year risk difference [RD], -2.2 per 1000 individuals; 95% CI, -20.3 to 15.9 per 1000 individuals) or if women continued therapy for 5 additional years (5-year RD, 3.8 per 1000 individuals; 95% CI, -7.4 to 15.0 per 1000 individuals). While 5-year differences in hip fracture risk comparing continuation for 5 additional years with discontinuation at 2 additional years were not statistically significant (5-year RD, 6.0 per 1000 individuals; 95% CI, -9.9 to 22.0 per 1000 individuals), interim hip fracture risk appeared lower if women discontinued after 2 additional years (3-year RD, 2.8 per 1000 individuals; 95% CI, 1.3 to 4.3 per 1000 individuals; 4-year RD, 9.3 per 1000 individuals; 95% CI, 6.3 to 12.3 per 1000 individuals) but not without a 6-month grace period to define discontinuation. Conclusions and Relevance: In this study of women treated with bisphosphonate for 5 years, hip fracture risk did not differ if they discontinued treatment compared with continuing treatment for 5 additional years. If women continued for 2 additional years and then discontinued, their risk appeared lower than continuing for 5 additional years. Discontinuation at other times and fracture rates during intervening years should be further studied.

Does Knee Arthroscopy for Treatment of Meniscal Damage with Osteoarthritis Delay Knee Replacement Compared to Physical Therapy Alone?

BACKGROUD: To determine patient factors that lead to treatment of meniscal tears with osteoarthritis (OA) with knee arthroscopy (KA) or physical therapy only (PT-only); and to assess differences in clinical outcomes including the time to knee arthroplasty. METHODS: Patients aged ≥ 45 years with OA at meniscal tear diagnosis were followed up from the date of surgery (KA) or first PT visit (PT-only) until partial/total knee replacement surgery, death, disenrollment, or end of study. Demographic and clinical characteristics were compared and used to derive propensity scores. A Cox proportional hazards model was used to estimate the risk of knee replacement surgery and greater healthcare utilization associated with KA vs. PT-only. RESULTS: Among 7,026 patients (KA, 69%; PT-only, 31%), 27% had partial or total knee replacement surgery during follow-up. PT-only patients were older and more likely to be women and had more comorbidities. After accounting for differences between groups, the cumulative incidence of knee replacement was modestly but significantly higher for those who received KA than those who underwent PT-only (hazard ratio, 1.30; 95% confidence interval, 1.17-1.44; p < 0.001), although there was no significant difference in health service utilization, narcotic medication dispenses, or knee injections after initiating treatment. CONCLUSIONS: For patients with meniscal damage complicated by OA, those who underwent KA were 30% more likely to have partial or total knee replacement surgery at any given time than those who had PT alone.

Atypical Femur Fracture Risk versus Fragility Fracture Prevention with Bisphosphonates.

BACKGROUND: Bisphosphonates are effective in reducing hip and osteoporotic fractures. However, concerns about atypical femur fractures have contributed to substantially decreased bisphosphonate use, and the incidence of hip fractures may be increasing. Important uncertainties remain regarding the association between atypical femur fractures and bisphosphonates and other risk factors. METHODS: We studied women 50 years of age or older who were receiving bisphosphonates and who were enrolled in the Kaiser Permanente Southern California health care system; women were followed from January 1, 2007, to November 30, 2017. The primary outcome was atypical femur fracture. Data on risk factors, including bisphosphonate use, were obtained from electronic health records. Fractures were radiographically adjudicated. Multivariable Cox models were used. The risk-benefit profile was modeled for 1 to 10 years of bisphosphonate use to compare associated atypical fractures with other fractures prevented. RESULTS: Among 196,129 women, 277 atypical femur fractures occurred. After multivariable adjustment, the risk of atypical fracture increased with longer duration of bisphosphonate use: the hazard ratio as compared with less than 3 months increased from 8.86 (95% confidence interval [CI], 2.79 to 28.20) for 3 years to less than 5 years to 43.51 (95% CI, 13.70 to 138.15) for 8 years or more. Other risk factors included race (hazard ratio for Asians vs. Whites, 4.84; 95% CI, 3.57 to 6.56), height, weight, and glucocorticoid use. Bisphosphonate discontinuation was associated with a rapid decrease in the risk of atypical fracture. Decreases in the risk of osteoporotic and hip fractures during 1 to 10 years of bisphosphonate use far outweighed the increased risk of atypical fracture among Whites but less so among Asians. After 3 years, 149 hip fractures were prevented and 2 bisphosphonate-associated atypical fractures occurred in Whites, as compared with 91 and 8, respectively, in Asians. CONCLUSIONS: The risk of atypical femur fracture increased with longer duration of bisphosphonate use and rapidly decreased after bisphosphonate discontinuation. Asians had a higher risk than Whites. The absolute risk of atypical femur fracture remained very low as compared with reductions in the risk of hip and other fractures with bisphosphonate treatment. (Funded by Kaiser Permanente and others.).

Determinants of Oral Bisphosphonate Use Beyond 5 Years.

BACKGROUND: Few studies have examined factors that determine bisphosphonate (BP) continuation beyond 5 years in clinical practice. OBJECTIVE: To investigate factors associated with BP continuation among women who completed 5 years of BP therapy. METHODS: Women who received 5 consecutive years of oral BP treatment entered the cohort during 2002-2014 and were followed up to 5 additional years. Multivariable logistic regression was used to evaluate the association of demographic and clinical factors with adherent treatment continuation. RESULTS: The cohort included 19,091 women with a median age of 72 years. Baseline and time-varying factors associated with increased odds of BP continuation after 5 years were (a) most recent bone mineral density (BMD) T-score -2 to -2.4 (OR = 1.31, 95% CI = 1.25-1.38), T-score -2.5 to -2.9 (OR = 1.48, 95% CI = 1.39-1.57), and T-score ≤ -3.0 (OR = 1.57, 95% CI = 1.47-1.68) versus T-scores above -2.0; (b) index date before 2008 (OR =1.35, 95% CI = 1.29-1.41); and (c) diabetes mellitus (OR = 1.08, 95% CI = 1.01-1.16). In contrast, factors associated with decreased odds of BP continuation were (a) recent hip (OR = 0.61, 95% CI = 0.52-0.71) or humerus (OR = 0.79, 95% CI = 0.66-0.94) fracture or fracture other than hip, wrist, spine, or humerus (OR = 0.90, 95% CI = 0.84-0.97); (b) Charlson Comorbidity Index score > 2 (OR = 0.91, 95% CI = 0.84-0.98); (c) history of rheumatoid arthritis (OR = 0.89, 95% CI = 0.80-0.99); (d) Hispanic (OR = 0.89, 95% CI=0.85-0.94) or Asian (OR = 0.90, 95% CI = 0.85-0.94) race/ethnicity; and (e) use of proton pump inhibitors (OR = 0.65, 95% CI = 0.59-0.71). Patient age and fracture before BP initiation were not associated with treatment continuation. CONCLUSIONS: Clinical factors predicting continued BP treatment beyond 5 years include low BMD T-score, absence of recent fracture, and earlier era of treatment. Use of proton pump inhibitors was associated with lower likelihood of BP continuation. Other clinical and demographic factors were also noted to have variable effects on BP treatment continuation. DISCLOSURES: This study was supported by a grant from the National Institute on Aging and National Institute of Arthritis, Musculoskeletal and Skin Diseases at the National Institutes of Health (NIH; R01AG047230, S1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or Kaiser Permanente. Lo has received previous research funding from Amgen and Sanofi, unrelated to the current study. Adams has received previous research funding from Merck, Amgen, Otsuka, and Radius Health, unrelated to the current study. Ettinger has served as an expert witness for Teva Pharmaceuticals, unrelated to the current study. Ott previously attended a scientific advisory meeting for Amgen but declined the honorarium. The other authors have nothing to disclose. These data were presented at the 2018 Annual Meeting of the American Society of Bone and Mineral Research (ASBMR), September 28-October 1, 2018, Montreal, Quebec, Canada.

Skeletal effects of combined medical and surgical management of primary hyperparathyroidism.

BACKGROUND: Parathyroidectomy (PTX) increases bone mineral density and decreases fracture risk in patients with primary hyperparathyroidism. This study examined the effect of adding bisphosphonates either before or after PTX on skeletal outcomes. METHODS: A retrospective cohort study of bisphosphonate-naïve patients (1995-2016) with osteoporosis and primary hyperparathyroidism (calcium >10.5 mg/dL; PTH >65) was performed. Time-varying Cox regression was used to estimate an adjusted risk of any fracture in 5 comparison groups: observation, bisphosphonates alone, PTX alone, bisphosphonates then PTX, and PTX then bisphosphonates. The secondary outcome was change in bone mineral density of the hip. RESULTS: The cohort comprised 1,737 patients, of whom 303 underwent PTX (17%), 433 received bisphosphonates only (25%), 125 had bisphosphonates then PTX (7%), and 69 had PTX then bisphosphonates (4%). PTX was associated with a decrease in fracture risk (HR 0.55, 95% CI 0.35-0.84), as was bisphosphonates then PTX (HR 0.46, 95% CI 0.25-0.83). In contrast, the fracture risks associated with PTX then bisphosphonates (HR 1.09, 95% CI 0.65-1.81) and bisphosphonates alone (HR 0.82, 95% CI 0.62-1.08) were similar to observation. Hip bone mineral density increased after both PTX (5.50%, 95% CI 3.39-7.61) and PTX then bisphosphonates (6.30%, 95% CI 2.53-10.07). CONCLUSION: Bisphosphonate initiation after PTX may interfere with the beneficial effects of PTX on fracture risk in osteoporotic patients with primary hyperparathyroidism.

Sub-acute hyponatraemia more than chronic hyponatraemia is associated with serious falls and hip fractures.

BACKGROUND: Falls and hip fractures among older people are associated with high morbidity and mortality. Hyponatraemia may be a risk for falls/hip fractures, but the effect of hyponatraemia duration is not well understood. AIMS: To evaluate individuals with periods of sub-acute and chronic hyponatraemia on subsequent risk for serious falls and/or hip fractures. METHODS: Retrospective cohort study in the period 1 January 1998 to 14 June 2016 within an integrated health system of individuals aged ≥55 years with ≥2 outpatient serum sodium measurements. Hyponatraemia was defined as sodium <135 mEq/L with sub-acute (<30 days) and chronic (≥30 days) analysed as a time-dependent exposure. Multivariable Cox proportional-hazards modelling was used to estimate hazard ratios (HR) for serious falls/hip fractures based on sodium category. RESULTS: Among 1 062 647 individuals totalling 9 762 305 sodium measurements, 96 096 serious falls/hip fracture events occurred. Incidence (per-1000-person-years) of serious falls/hip fractures were 11.5, 27.9 and 19.8 for normonatraemia, sub-acute and chronic hyponatraemia. Any hyponatraemia duration compared to normonatraemia had a serious falls/hip fractures HR (95%CI) of 1.18 (1.15, 1.22), with sub-acute and chronic hyponatraemia having HR of 1.38 (1.33, 1.42) and 0.91 (0.87, 0.95), respectively. Examined separately, the serious falls HR was 1.37 (1.32, 1.42) and 0.92 (0.88, 0.96) in sub-acute and chronic hyponatraemia, respectively. Hip fracture HR were 1.52 (1.42, 1.62) and 1.00 (0.92, 1.08) for sub-acute and chronic hyponatraemia, respectively, compared to normonatraemia. CONCLUSIONS: Our findings suggest that early/sub-acute hyponatraemia appears more vulnerable and associated with serious falls/hip fractures. Whether hyponatraemia is a marker of frailty or a modifiable risk factor for falls remains to be determined.

Using Pharmacy Data and Adherence to Define Long-Term Bisphosphonate Exposure in Women.

BACKGROUND: Assigning drug exposure is a necessary first step in examining bisphosphonate (BP) treatment in observational studies using pharmacy data. OBJECTIVE: To determine whether the choice of adherence level using the proportion of days covered (PDC) affected BP exposure assignment. METHODS: 10,381 female health plan members who initiated oral BP therapy between 2002 and 2010 and had received 5 consecutive years of treatment were identified and subsequently followed up to 5 additional years. In each 90-day interval of follow-up, a woman was considered "on treatment" if she received the drug for more than a predetermined PDC based on pharmacy days supply and "off treatment" if she received the drug for less than that PDC. Women who continued on therapy above the PDC threshold during follow-up were considered continuously on therapy. Women who were off treatment during the first 90-days of follow-up were classified as off therapy and were followed to determine if they remained continuously off treatment. This study evaluated the extent to which varying the PDC threshold (≥ 0.5, ≥ 0.6, and ≥ 0.7) affected the proportion of women classified as "continuously on" or "continuously off" BP during follow-up. RESULTS: Under PDC thresholds of 0.5, 0.6, and 0.7, 48%, 43%, and 36% of women who remained on follow-up were categorized as continuously on treatment at year 2 of follow-up, and 18%, 14%, and 12% were categorized as continuously on treatment by the end of follow-up. Using these same PDC thresholds, 9%, 12%, and 15% of women were categorized as off therapy during the first quarter of follow-up and were highly likely to remain off therapy: 4%, 5%, and 5% were classified as continuously off therapy at year 2, and 4% of women were classified as such by the end of follow-up for all 3 thresholds. CONCLUSIONS: A PDC of 0.6 was chosen as a practical threshold for drug adherence. Varying the PDC to 0.5 or 0.7 resulted in modest changes in the proportions of women considered continuously on BP therapy. DISCLOSURES: This study was supported by a grant from the National Institute of Aging and National Institute of Arthritis, Musculoskeletal and Skin Diseases at the National Institutes of Health (R01AG047230, S1). Lo has received previous research funding from Amgen and Sanofi, outside of the current study. Chandra has received previous research funding from Amgen outside of the current study. Adams has received previous research funding from Merck, Amgen, Otsuka, and Radius Health, outside of the current study. Ott previously attended a scientific advisory meeting for Amgen but declined the honorarium. Ettinger previously served as an expert witness for Teva Pharmaceuticals.

BIOCHEMICAL DYNAMICS OF UNTREATED PRIMARY HYPERPARATHYROIDISM: AN OBSERVATIONAL STUDY.

Objective: The natural biochemical history of untreated primary hyperparathyroidism (PHPT) is poorly understood. The purpose of this study was to determine the extent of biochemical fluctuations in patients with PHPT. Methods: Retrospective cohort study from January 1, 1995, to December 31, 2014. Serum calcium and parathyroid hormone (PTH) levels in patients with classic (Ca >10.5 mg/dL, PTH >65 pg/mL) and nonclassic (Ca >10.5 mg/dL, PTH 40 to 65 pg/mL) PHPT were followed longitudinally at 1, 2, and 5 years. Biochemical profiles in follow-up were ranked in descending biochemical severity as classic PHPT, nonclassic PHPT, normal calcium with elevated PTH (Ca <10.5 mg/dL, PTH >65 pg/mL), possible PHPT (Ca >10.5 mg/dL, PTH 21 to 40 pg/mL), or absent PHPT (Ca >10.5 mg/dL, PTH <21 pg/mL or Ca <10.5 mg/dL, PTH <65 pg/mL). Results: Of 10,598 patients, 1,570 were treated with parathyroidectomy (n = 1,433) or medications (n = 137), and 4,367 were censored due to study closure, disenrollment, or death. In the remaining 4,661 untreated patients with 5 years of follow-up, 235 (5.0%) progressed to a state of increased biochemical severity, whereas 972 (20.8%) remained the same, and 3,454 (74.1%) regressed to milder biochemical states. In 2,522 untreated patients with classic PHPT, patients most frequently transitioned to the normal calcium with elevated PTH group (n = 1,257, 49.8%). In 2,139 untreated patients with nonclassic PHPT, patients most frequently transitioned to the absent PHPT group (n = 1,354, 63.3%). Conclusion: PHPT is a biochemically dynamic disease with significant numbers of patients exhibiting both increases and decreases in biochemical severity. Abbreviations: IQR = interquartile range; KPSC = Kaiser Permanente Southern California; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone; PTx = parathyroidectomy.

End-organ effects of primary hyperparathyroidism: A population-based study.

BACKGROUND: Patients with primary hyperparathyroidism are at risk for skeletal and renal end-organ damage. METHODS: We studied patients with biochemically confirmed primary hyperparathyroidism from 1995-2014 and quantified the frequency of osteoporosis, nephrolithiasis, hypercalciuria, and decrease in renal function. RESULTS: The cohort comprised 9,485 patients. In total, 3,303 (35%) had preexisting end-organ effects (osteoporosis, 24%; nephrolithiasis, 10%; hypercalciuria, 5%). Of 6,182 remaining patients, 1,769 (29%) exhibited progression to 1 or more end-organ effects over a median 3.7 years. Among patients with classic primary hyperparathyroidism (calcium and parathyroid hormone increased), progression was unrelated to the degree of hypercalcemia (calcium >11.5 mg/dL, hazard ratio 1.03, 95% confidence interval 0.85-1.25; 11.1-11.5 mg/dL, HR 1.07, 95% confidence interval 0.93-1.23; 10.5-11.0 mg/dL = reference). Patients with nonclassic primary hyperparathyroidism (calcium increased, parathyroid hormone 40-65 pg/mL) had a lesser risk of progression (calcium >11.5 mg/dL, hazard ratio 0.68, 95% confidence interval 0.50-0.94; 11.1-11.5 mg/dL, hazard ratio 0.68, 95% confidence interval 0.56-0.82; 10.5-11.0 mg/dL, hazard ratio 0.66, 95% confidence interval 0.59-0.74). End-organ damage developed before or within 5 years of diagnosis for 62% of patients. CONCLUSION: End-organ manifestations of primary hyperparathyroidism develop before biochemical diagnosis or within 5 years in most patients. End-organ damage occurred more frequently in patients with classic primary hyperparathyroidism versus nonclassic primary hyperparathyroidism, regardless of severity of hypercalcemia.

Osteoporosis and Hip Fracture Risk From Routine Computed Tomography Scans: The Fracture, Osteoporosis, and CT Utilization Study (FOCUS).

Methods now exist for analyzing previously taken clinical computed tomography (CT) scans to measure a dual-energy X-ray absorptiometry (DXA)-equivalent bone mineral density (BMD) at the hip and a finite element analysis-derived femoral strength. We assessed the efficacy of this "biomechanical CT" (BCT) approach for identifying patients at high risk of incident hip fracture in a large clinical setting. Using a case-cohort design sampled from 111,694 women and men aged 65 or older who had a prior hip CT scan, a DXA within 3 years of the CT, and no prior hip fracture, we compared those with subsequent hip fracture (n = 1959) with randomly selected sex-stratified controls (n = 1979) and analyzed their CT scans blinded to all other data. We found that the age-, race-, and body mass index (BMI)-adjusted hazard ratio (HR; per standard deviation) for femoral strength was significant before (women: HR = 2.8, 95% confidence interval [CI] 2.2-3.5; men: 2.8, 2.1-3.7) and after adjusting also for the (lowest) hip BMD T-score by BCT (women: 2.1, 1.4-3.2; men: 2.7, 1.6-4.6). The hazard ratio for the hip BMD T-score was similar between BCT and DXA for both sexes (women: 2.1, 1.8-2.5 BCT versus 2.1, 1.7-2.5 DXA; men: 2.8, 2.1-3.8 BCT versus 2.5, 2.0-3.2 DXA) and was higher than for the (lowest) spine/hip BMD T-score by DXA (women: 1.6, 1.4-1.9; men: 2.1, 1.6-2.7). Compared with the latter as a clinical-practice reference and using both femoral strength and the hip BMD T-score from BCT, sensitivity for predicting hip fracture was higher for BCT (women: 0.66 versus 0.59; men: 0.56 versus 0.48), with comparable respective specificity (women: 0.66 versus 0.67; men: 0.76 versus 0.78). We conclude that BCT analysis of previously acquired routine abdominal or pelvic CT scans is at least as effective as DXA testing for identifying patients at high risk of hip fracture. © 2018 American Society for Bone and Mineral Research.