Association of prior treatment with nitrogen-containing bisphosphonates on outcomes of COVID-19 positive patients.

COVID-19 infection has resulted in significant morbidity and mortality globally, especially among older adults. Repurposed drugs have demonstrated activity in respiratory illnesses, including nitrogen-containing bisphosphonates. In this retrospective longitudinal study at 4 academic medical centers, we show no benefit of nitrogen-containing bisphosphonates regarding ICU admission, ventilator use, and mortality among older adults with COVID-19 infection. We specifically evaluated the intravenous bisphosphonate zoledronic acid and found no difference compared to oral bisphosphonates. BACKGROUND: Widely used in osteoporosis treatment, nitrogen-containing bisphosphonates (N-BP) have been associated with reduced mortality and morbidity among older adults. Based on prior studies, we hypothesized that prior treatment with N-BP might reduce intensive care unit (ICU) admission, ventilator use, and death among older adults diagnosed with COVID-19. METHODS: This retrospective analysis of the PCORnet Common Data Model across 4 academic medical centers through 1 September 2021 identified individuals age >50 years with a diagnosis of COVID-19. The composite outcome included ICU admission, ventilator use, or death within 15, 30, and 180 days of COVID-19 diagnosis. Use of N-BP was defined as a prescription within 3 years prior. ICU admission and ventilator use were determined using administrative codes. Death included both in-hospital and out-of-hospital events. Patients treated with N-BP were matched 1:1 by propensity score to patients without prior N-BP use. Secondary analysis compared outcomes among those prescribed zoledronic acid (ZOL) to those prescribed oral N-BPs. RESULTS: Of 76,223 COVID-19 patients identified, 1,853 were previously prescribed N-BP, among whom 559 were prescribed ZOL. After propensity score matching, there were no significant differences in the composite outcome at 15 days (HR 1.22, 95% CI: 0.89-1.67), 30 days (HR 1.24, 95% CI: 0.93-1.66), or 180 days (HR 1.17, 95% CI: 0.93-1.48), comparing those prescribed and not prescribed N-BP. Compared to those prescribed oral N-BP, there were no significant differences in outcomes among those prescribed ZOL. CONCLUSION: Among older COVID-19 patients, prior exposure to N-BP including ZOL was not associated with a reduction in ICU admission, ventilator use, or death.

Zoledronic acid reduces the rate of clinical fractures after surgical repair of a hip fracture regardless of the Pretreatment bone mineral density.

In patients with surgical repair of a low-trauma hip fracture, zoledronic acid (ZA) reduced the risk of subsequent fractures regardless of pretreatment femoral neck and total hip bone mineral density (BMD). INTRODUCTION: Zoledronic acid reduces the risk of subsequent fractures after repair of a hip fracture. It is still unclear whether the benefits in fracture reduction with ZA depend upon hip bone mineral density at the time of fracture. METHODS: We preformed additional post hoc analyses of data from the HORIZON Recurrent Fracture Trial to determine if ZA treatment reduced the risk of new clinical fractures regardless of pretreatment BMD. We modeled femoral neck and total hip BMD as both continuous and dichotomous variables (BMD T-score above and below -2.5). RESULTS: There are no evidence that baseline femoral neck and total hip BMD modified the anti-fracture efficacy of ZA when pretreatment BMD was analyzed as a continuous or a dichotomous variable (interaction p-values > 0.20). The clinical fracture efficacy of ZA was similar among patients with pretreatment femoral neck BMD values above and below -2.5 (relative hazards = 0.60 and 0.67, respectively, interaction p-value = 0.95). A similar result was obtained using pretreatment total hip BMD values (relative hazards = 0.72 and 0.57, respectively, interaction p-value = 0.41). CONCLUSION: There data should provide more comfort in prescribing ZA after surgical repair of a hip fracture, regardless of pretreatment BMD.

Paget's disease of bone: an endocrine society clinical practice guideline

OBJECTIVE: The aim of this guideline was to formulate practice guidelines for the diagnosis and treatment of Paget's disease of the bone. PARTICIPANTS: The guideline was developed by an Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize supporting evidence. CONCLUSIONS: We recommend that plain radiographs be obtained of the pertinent regions of the skeleton in patients with suspected Paget's disease. If the diagnosis is confirmed, we suggest that a radionucleotide bone scan be done to determine the extent of the disease. After diagnosis of Paget's disease, we recommend measurement of serum total alkaline phosphatase or, when warranted, a more specific marker of bone formation or bone resorption to assess the response to treatment or evolution of the disease in untreated patients. We suggest treatment with a bisphosphonate for most patients with active Paget's disease who are at risk for future complications. We suggest a single 5-mg dose of iv zoledronate as the treatment of choice in patients who have no contraindication. In patients with monostotic disease who have a normal serum total alkaline phosphatase, we suggest that a specific marker of bone formation and bone resorption be measured, although these may still be normal. Serial radionuclide bone scans may determine the response to treatment if the markers are normal. We suggest that bisphosphonate treatment may be effective in preventing or slowing the progress of hearing loss and osteoarthritis in joints adjacent to Paget's disease and may reverse paraplegia associated with spinal Paget's disease. We suggest treatment with a bisphosphonate before surgery on pagetic bone.(AU)

Fracture prevention in patients with cognitive impairment presenting with a hip fracture: secondary analysis of data from the HORIZON Recurrent Fracture Trial.

UNLABELLED: Patients with cognitive impairment (CI) often do not receive secondary fracture prevention. Use of zoledronic acid led to a similar reduction in re-fracture risk but the survival benefit was limited to those without CI. INTRODUCTION: We tested whether the effects of zoledronic acid (Zol) on re-fracture and mortality differed in patients presenting with a hip fracture by cognitive status. METHODS: We used data from the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Recurrent Fracture Trial, of yearly intravenous 5 mg Zol vs. placebo in patients presenting with a hip fracture. Primary outcome was new fracture and secondary outcome mortality. Short Portable Mental Status Questionnaire (SPMSQ) with a cut-point of >2 was used to identify CI. Fine-Gray models for competing events were fitted to study the effect of Zol on re-fracture and Cox regression for death. A multiplicative term was introduced to study a potential interaction between treatment and cognitive status on outcomes. RESULTS: Baseline SPMSQ of 1,966/2,127 (92.4%) patients was measured. Three hundred fifty (17.8%) had CI, balanced between treatment arms. In the placebo arm, there was similar fracture incidence between those with and without CI (15.4 vs. 12.3%, p = 0.26). There was no significant interaction for the effect of CI on Zol and re-fracture (p = 0.66). CI was associated with higher 1-year mortality (12.6 vs. 4.3%, p < 0.001) and the interaction was bordering significance (interaction, p = 0.066). Zol prolonged survival only in patients with normal cognitive status [HR 0.56 (95% CI 0.40-0.80)] and not in those with CI [HR 0.90 (95% CI 0.59-1.38)]. CONCLUSIONS: While these results require confirmation, the findings support the use of bisphosphonates in patients with osteoporotic fracture and CI expected to live for more than 6 months.

Reduction in the risk of clinical fractures after a single dose of zoledronic Acid 5 milligrams.

CONTEXT: Annual infusions of zoledronic acid 5 mg over 3 years have been shown to reduce fracture incidence. There is now evidence that the effects of a single dose of zoledronic acid on bone mineral density and bone turnover last for much more than a year. Whether this is associated with sustained fracture prevention is not known. OBJECTIVE: The objective of the study was to assess fracture incidence after only 1 infusion of zoledronic acid. DESIGN: The design of the study included post hoc analysis of subgroups of subjects from 2 trials, who received only 1 study infusion. SETTING: The study included multicenter, randomized controlled trials. PARTICIPANTS: A total of 1367 subjects from HORIZON-PFT and HORIZON-RFT studies who received only 1 of the planned annual infusions participated in the study. INTERVENTION: The intervention of the study consisted of 1 infusion of zoledronic acid or placebo. MAIN OUTCOME MEASURE: Clinical fracture was the main outcome measure of the study. RESULTS: Mean follow-up period was 1.5 years. In patients who received only a single infusion, there was a 32% reduction in clinical fracture comparing zoledronic acid with placebo over 3 years of follow-up (95% confidence interval 2-53%, P = .04), comparable with the fracture reduction seen in those who had 3 or more annual infusions (34%; 95% confidence interval, 23-43%, P < .0001). New morphometric vertebral fractures were reduced by 68% in the single-infusion group (P = .004). The between-group differences in total hip bone mineral density at 3 years were 3.8% in those receiving 1 infusion and 6.2% in those receiving 3 infusions. CONCLUSIONS: In this post hoc analysis based on postrandomization subgroups, fracture risk appears to be reduced for more than 1 year after a single infusion of zoledronic acid. Prospective studies designed to assess this possibility are now warranted.

Zoledronic acid results in better health-related quality of life following hip fracture: the HORIZON-Recurrent Fracture Trial.

UNLABELLED: This study evaluated the benefits of ZOL versus placebo on health-related quality of life (HRQoL) among patients from HORIZON-RFT. At month 24 and end of the study visit, ZOL significantly improved patients' overall health state compared to placebo as assessed by the EQ-5D VAS. INTRODUCTION: To evaluate the benefits of zoledronic acid (ZOL) versus placebo on health-related quality of life (HRQoL) among patients from The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial (HORIZON-RFT). METHODS: In this randomized, double-blind, placebo-controlled trial, 2,127 patients were randomized to receive annual infusion of ZOL 5 mg (n = 1,065) or placebo (n = 1,062) within 90 days after surgical repair of low-trauma hip fracture. HRQoL was measured using EQ-5D Visual Analogue Scale (VAS) and utility scores (EuroQol instrument) at months 6, 12, 24, 36, and end of the study visit. Analysis of covariance model included baseline EQ-5D value, region, and treatment as explanatory variables. RESULTS: At baseline, patients (mean age 75 years; 24% men and 76% women) were well matched between treatment groups with mean EQ-5D VAS of 65.82 in ZOL and 65.70 in placebo group. At the end of the study, mean change from baseline in EQ-5D VAS was greater for ZOL vs. placebo in all patients (7.67 ± 0.56 vs. 5.42 ± 0.56), and in subgroups of patients experiencing clinical vertebral fractures (8.86 ± 4.91 vs. -1.69 ± 3.42), non-vertebral fractures (5.03 ± 2.48 vs. -1.07 ± 2.16), and clinical fractures (5.19 ± 2.25 vs. -0.72 ± 1.82) with treatment difference significantly in favor of ZOL. EQ-5D utility scores were comparable for ZOL and placebo groups, but more patients on placebo consistently had extreme difficulty in mobility (1.74% for ZOL vs. 2.13% for placebo; p = 0.6238), self-care (4.92% vs. 6.69%; p = 0.1013), and usual activities (10.28% vs. 12.91%; p = 0.0775). CONCLUSION: ZOL significantly improves HRQoL in patients with low-trauma hip fracture.

Association between timing of zoledronic acid infusion and hip fracture healing.

UNLABELLED: Patients in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Recurrent Fracture Trial were assessed for evidence of delayed hip fracture healing. No association was observed between zoledronic acid (ZOL) and delayed healing. We conclude that ZOL has no clinically evident effect on fracture healing, even when the drug is infused in the immediate postoperative period. INTRODUCTION: Intravenous zoledronic acid 5 mg (ZOL) given after a hip fracture reduces secondary fracture rates and mortality. It has been postulated that bisphosphonates may affect healing if given soon after a fracture. We sought to determine whether the timing of ZOL infusion affected the risk of delayed hip fracture healing. METHODS: In the HORIZON Recurrent Fracture Trial, patients were randomized within 90 days of a low-trauma hip fracture to receive either once-yearly ZOL (n = 1,065) or placebo (n = 1,062). Clinical symptoms of delayed hip fracture healing were sought at randomization, 6 months and 12 months after fracture; if present, a central adjudication committee blinded to treatment assignment reviewed radiographs and clinical records. Median follow-up was 1.9 years. RESULTS: The overall incidence of delayed healing was 3.2% (ZOL) and 2.7% (placebo; odds ratio [OR], 1.17; 95% confidence interval [CI], 0.72-1.90; p = 0.61). Logistic regression models revealed no association between ZOL and delayed healing even after adjusting for other risk factors (OR, 1.21; 95% CI, 0.74-1.99; p = 0.44). There was no interaction by timing of infusion, and nonunion rates were similar even when ZOL was given within 2 weeks of hip fracture repair. NSAID use was significantly associated with delayed fracture healing (OR, 2.55; 95% CI, 1.49-4.39; p < 0.001). CONCLUSIONS: ZOL has no clinically evident effect on fracture healing, even when the drug is infused in the immediate postoperative period.

Hip and other osteoporotic fractures increase the risk of subsequent fractures in nursing home residents.

UNLABELLED: Nursing home residents with a history of hip fractures or prior osteoporotic fractures were found to have an increased risk of another osteoporotic fracture over the ensuing two years when compared to nursing home residents with no fracture history. INTRODUCTION: Because of the high prevalence of osteoporosis and fall risk factors in nursing home residents, it is possible that the importance of previous fracture as a marker for subsequent fracture risk may be diminished. We tested whether a history of prior osteoporotic fractures would identify residents at increased risk of additional fractures after nursing home admission. METHODS: We identified all Medicare enrollees aged 50 and older who were in a nursing home in North Carolina in 2000 (n=30,655). We examined Medicare hospitalization claims to determine which enrollees had been hospitalized in the preceding 4 years for a hip fracture (n=7,257) or other fracture (n=663). We followed participants from nursing home entry until the end of 2002 using Medicare hospital claims to determine which participants were hospitalized with a subsequent fracture (n=3,381). RESULTS: Among residents with no recent fracture history, 6.8% had a hospital claim for a subsequent fracture, while 15.1% of those with a prior non-hip fracture and 23.9% of participants with a prior hip fracture sustained subsequent fractures. Multivariate proportional hazards models of time to fracture indicated that persons with prior hip fractures are at three times higher risk (HR=2.99, 95% CI: 2.78, 3.21) and those hospitalized with other non-hip fractures are at 1.8 times higher risk of subsequent fractures (HR=1.84, 95% CI: 1.50, 2.25). CONCLUSION: Nursing home residents hospitalized with a prior osteoporotic fracture are at increased risk of a fracture.

Prevalence and predictors of osteoporosis treatment in nursing home residents with known osteoporosis or recent fracture.

SUMMARY: We studied nursing home residents with osteoporosis or recent fracture to determine the frequency and predictors of osteoporosis treatment. There was wide variation in performance, and both clinical and systems variables predicted use. This study shows that improvement in osteoporosis care is possible and important for many nursing homes. INTRODUCTION: We determined the prevalence and predictors of osteoporosis evaluation and treatment in high-risk nursing home residents. METHODS: We identified 67 nursing facilities in North Carolina and Arizona with > 10 residents with osteoporosis or recent hip fracture. Medical records (n=895) were abstracted for osteoporosis evaluation [dual-energy X-ray absorptiometry (DXA), vitamin D level, serum calcium), treatment (calcium, vitamin D, osteoporosis medication, hip protectors), clinical, and systems covariates. Data were analyzed at the facility level using mixed models to account for the complex nesting of residents within providers and nursing facilities. RESULTS: Calcium and vitamin D was prescribed for 69% of residents, bisphosphonates for 19%, calcitonin for 14%, other pharmacologic therapies for 6%, and hip protectors for 2%. Overall, 36% received any bone protection (medication or hip protectors), with wide variation among facilities (0-85%). Factors significantly associated with any bone protection included female gender [odds ratio (OR) 2.4, (1.5-3.7)] and nonurban/suburban location [1.5, (1.1-2.2)]. Residents with esophagitis, peptic ulcer disease (PUD), or dysphagia [0.6, (0.4-0.9)] and alcohol abuse [0.2, (0.0-0.9)] were less likely to receive treatment. CONCLUSIONS: There is substantial variation in the quality of osteoporosis treatment across nursing homes. Interventions that improve osteoporosis quality of care are needed.

Guías para el diagnóstico y tratamiento de la enfermedad ósea de paget / Guidelines for the diagnosis and therapy of Paget's disease of the bone

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Expert physician recommendations and current practice patterns for evaluating and treating men with osteoporotic hip fracture.

OBJECTIVES: To develop recommendations for the evaluation and the treatment of men with osteoporotic hip fracture from expert publications in the field of male osteoporosis, and to define the current practice patterns in a tertiary care VA Medical Center in Durham, North Carolina. DESIGN: Survey research; a retrospective cohort study. SETTING: Tertiary care VA Medical Center in Durham, North Carolina. PARTICIPANTS: (1) US physicians who published on the subject of male osteoporosis in the peer-reviewed literature between 1993 and 1997 identified by MEDLINE database search. (2) All 119 men admitted to the Durham VA Medical Center with ICD9 code for hip fracture between 1994 and 1998. OUTCOME MEASURES: (1) Osteoporosis evaluation and treatment recommendations of published physicians obtained by survey instrument. (2) Actual osteoporosis evaluation completed and therapy prescribed during index hospitalization in a cohort of men with hip fractures, determined by chart and database review. RESULTS: (1) Forty-three physician-researchers were surveyed with an 84% response rate. For an osteoporosis evaluation, 89% of respondents recommended measuring serum testosterone, 85% serum calcium, 75% 25-OH vitamin D levels, 73% myeloma screen, and 61% serum thyroid-stimulating hormone (TSH). Dual Energy X-ray Absorptiometry would be obtained by 92%. More than 70% recommended calcium, vitamin D, and bisphosphonates for men with a normal metabolic evaluation, and 60% suggested weight-bearing exercise. (2) In the cohort of men admitted with hip fractures, 50% had a serum calcium level and 3% had a serum TSH level measured. Vitamin D was prescribed to 25% of patients in the form of a multivitamin, and 4% received calcium. There was no bisphosphonate, testosterone, or calcitonin use. CONCLUSIONS: Physicians who have published on osteoporosis recommended metabolic evaluation and osteoporosis therapy after hip fracture. Only minimal evaluation and treatment occurred in a cohort of men with osteoporotic hip fractures.

Heterogeneity in Paget disease of the bone.

Paget disease of the bone is a common skeletal disorder. Recently, a gene for Paget disease was localized to 18q with subsequent evidence for linkage heterogeneity. We report the identification and clinical characterization of a large pedigree of Paget disease and demonstrate that the Paget disease gene in this pedigree is not linked to the region on 18q, thus confirming linkage heterogeneity.

Timed loaded standing: a measure of combined trunk and arm endurance suitable for people with vertebral osteoporosis.

Chronic back tiredness or fatigue is a common complaint of people who have a history of osteoporotic vertebral fracture. Trunk muscle endurance has not been studied in people with vertebral osteoporosis, partly due to the lack of assessment tools. We developed a measure of combined trunk and arm endurance suitable for people with vertebral osteoporosis, timed loaded standing (TLS). TLS measures the time a person can stand while holding a two-pound dumbbell in each hand with the arms at 90 degrees of shoulder flexion and the elbows extended. Intraclass correlation coefficients (ICCs) for same day inter-trial and six to ten day test-retest reliability were 0.89 (lower bound 95% confidence interval [LB 95% CI] 0.79) and 0.84 (LB 95% CI 0.68), respectively, in a sample of 21 older women with no known osteoporosis. In 127 women with vertebral fractures, the ICC for same day inter-trial reliability was 0.81 (LB 95% CI 0.75). In a sub-sample of 30 of these women with vertebral fractures, the six to ten day test-retest reliability was 0.85 (LB 95% CI 0.75). Moderately strong and statistically significant (p < or = 0.05) correlations were found between TLS and sixteen of eighteen measures of physical impairment and function. Functional reach distance, gait velocity, MOS-36 Physical Function Subscale, shoulder flexion strength, and six minute walk distance were most strongly associated with TLS time. Women with vertebral fractures who endorsed having back tiredness when standing and working with the arms in front of the body, sitting to rest because of back tiredness or pain, and planning rest periods because of back tiredness or pain had significantly lower TLS times. TLS is a simple, safe physical performance measure of combined trunk and arm endurance that demonstrates acceptable reliability (inter-trial and test- retest) and concurrent validity.

Spinal deformity and mobility self-confidence among women with osteoporosis and vertebral fractures.

This study evaluated the direct and indirect effects of spinal deformity on confidence in mobility among 185 older women with osteoporosis and vertebral fractures. We administered multidimensional tests of physical and psychosocial impairment and function to female residents of continuing care retirement communities, and used path analytic regression methods to delineate relationships between spinal deformity, pain, function and mobility self-confidence. No direct effect of spinal deformity on confidence in mobility was observed. However, important indirect paths mediated by functional limitations were confirmed. A pattern of indirect effects was observed for a broad array of impairment-level constructs. These results support current models of the disablement process that propose functional limitations as the major pathway to disability. However, they also suggest that the impact of impairment-level constructs might be overlooked unless we evaluate indirect, as well as direct effects, on disability.

Factors associated with self-rated health in patients with Paget's disease of bone.

Multiple studies show that poor self-rated health (SRH) increases the risk of mortality up to 5-fold when compared to excellent SRH. This powerful association remains even with objective health status and risk factors controlled. However, few studies have examined the determinants of SRH, especially as they relate to specific chronic diseases. Here we identify personal characteristics and disease-related attributes that are strongly associated with SRH in a sample of patients with Paget's disease of bone to determine whether any factors can be modified. Two thousand people randomly selected from the Paget Foundation mailing list received a survey asking for information on demographics, general health and functioning, and the impact of Paget's disease. Nine hundred and fifty-eight PD patients returned the completed survey and answered the question, "How would you rate your overall health?" Answers ranged from excellent (1) to poor (5). Ordinary least squares regression was used, with SRH as the dependent variable, to identify those variables significantly associated with SRH. The overall regression model was significant (p = 0.0001; R2 = 0.44). Age (p = 0. 005), satisfaction with family help (p = 0.0001), number of comorbid conditions (p = 0.0001), functional limitations (p = 0.0003), disease impact (p = 0.0002), health compared to 5 years ago (p = 0. 0001), and depressive symptoms (p = 0.012) were significant predictors. Of these, satisfaction with family help, functional limitations, disease impact, and depressive symptoms are potentially modifiable with appropriate interventions. Future longitudinal studies should examine the effectiveness of such interventions in improving SRH.