Oral Bisphosphonates Research Articles

Comparative effectiveness of denosumab vs alendronate among postmenopausal women with osteoporosis.

Although clinical trials have shown that denosumab significantly increases bone mineral density at key skeletal sites more than oral bisphosphonates, evidence is lacking from head-to-head randomized trials evaluating fracture outcomes. This retrospective cohort study uses administrative claims data from Medicare fee-for service beneficiaries to evaluate the comparative effectiveness of denosumab vs alendronate in reducing fracture risk among women with PMO in the US. Women with PMO ≥ 66yr of age with no prior history of osteoporosis treatment, who initiated denosumab (n = 89 115) or alendronate (n = 389 536) from 2012 to 2018, were followed from treatment initiation until the first of a specific fracture outcome, treatment discontinuation or switch, end of study (December 31, 2019), or other censoring criteria. A doubly robust inverse-probability of treatment and censoring weighted function was used to estimate the risk ratio associated with the use of denosumab compared with alendronate for hip, nonvertebral (NV; includes hip, humerus, pelvis, radius/ulna, other femur), non-hip nonvertebral (NHNV), hospitalized vertebral (HV), and major osteoporotic (MOP; consisting of NV and HV) fractures. Overall, denosumab reduced the risk of MOP by 39%, hip by 36%, NV by 43%, NHNV by 50%, and HV fractures by 30% compared with alendronate. Denosumab reduced the risk of MOP fractures by 9% at year 1, 12% at year 2, 18% at year 3, and 31% at year 5. An increase in the magnitude of fracture risk reduction with increasing duration of exposure was also observed for other NV fracture outcomes. In this cohort of almost half-a-million treatment-naive women with PMO, we observed clinically significant reductions in the risk of MOP, hip, NV, NHNV, and HV fractures for patients on denosumab compared with alendronate. Patients who remained on denosumab for longer periods of time experienced greater reductions in fracture risk.

Three-year effect of bisphosphonates on bone mineral density after denosumab withdrawal: observations from a real-world study.

Data on long-term treatment regimens for preventing bone mineral density (BMD) loss that occurs after denosumab (Dmab) withdrawal are scarce. Our aim was to evaluate the long-term changes (12-36months) in BMD and bone turnover markers in a group of postmenopausal women who had been treated with Dmab and received subsequent treatment with bisphosphonates. Secondary objectives were to evaluate factors associated with BMD loss, to compare the BMD change in patients who received oral vs intravenous bisphosphonates, and to assess the frequency of fragility fractures after Dmab discontinuation. The clinical data of 54 patients, 26 of whom had clinical and DXA assessments at 36months, were analyzed. After 12months, the mean LS BMD had decreased by 2.8% (±5.0), FN BMD by 1.9% (±5.8), and TH BMD by 1.9% (±3.7). After 36months, LS BMD had decreased by 3.7% (±6.7), FN BMD by 2.5% (±7.1), and TH BMD by 3.6% (±5.2). C-terminal cross-linked telopeptide of type I collagen significantly increased during the first 12months after Dmab withdrawal but then decreased at 36months. BMD loss at 12months was higher in patients with more than 30months of Dmab treatment, but this difference was only statistically significant at FN (-3.3% vs -0.3%, P = .252 at LS, -3.3% vs 0.3%, P = .033 at FN, and -2.1% vs 0.9, P = .091 at TH). There were no statistically significant differences regarding the change in BMD at 12 and 36months between oral and intravenous treatment. Seven patients suffered incidental vertebral fractures (clinical vertebral fractures: n = 6, morphometric fractures: n = 1) three of which were multiple. None of these patients were treated following international or institutional guidelines or recommendations. In summary, our study suggests that bisphosphonates can help maintain BMD for 36months after Dmab discontinuation.

E020 Osteoporosis service improvement audit

Abstract Background/Aims Osteoporosis referrals are sent to rheumatology departments for consideration of parenteral treatments in those who are unable to tolerate oral bisphosphonates or have failed treatment. The rheumatology services at Croydon University Hospital (CUH) are oversubscribed which results in long waiting times for appointments and increased workload on clinicians. The aim of this audit is to identify the scope of osteoporosis workload, the source of referrals, to improve distribution of the osteoporosis workload in CUH and redesign the pathway for osteoporosis referrals. A secondary aim is to identify patients that could be managed without referral enabling more consultation slots within the rheumatology department for patients that present with early inflammatory arthritis. Methods Data was collected retrospectively from all the patients that had been referred to the rheumatology department, either internally or externally and offered a new osteoporosis appointment from June to mid-September 2022 (104 patients in total). A data collection sheet was created from electronic patient records. The data included the patients’ hospital number, age, sex, height, weight, BMI, race, source of referral, reason for referral, fractures sustained, admissions for fracture, prior treatment with IV/ oral bisphosphonates, which oral bisphosphonate treatment and reasons for stopping, co-prescription of calcium/ vitamin D and the follow up plan. Results Among patients who were surveyed, 33 were internal referrals. Referring departments were as follows: 18 from fracture liaison service (FLS), 7 from care of the elderly (COTE), 3 from orthopaedics, 1 from rheumatology, 1 from nephrology, 1 from endocrinology, 1 from haematology and 1 from respiratory. In the GP cohort (71 patients), many were intolerant to oral bisphosphonates due to gastrointestinal upset. Reasons for referral were as follows: 36 for intolerance to oral medication, 14 for declining BMD, 11 for restarting medication after drug holding, 9 for complexity of cases (including young age/ male/ anorexia/ osteogenesis imperfecta), 8 unspecified, 7 had sustained a fracture on treatment, 6 received breast cancer treatment, 6 had renal impairment, 6 for a second opinion and 1 for considering a drug holiday. Conclusion This audit highlights the issues associated with osteoporosis workload and suggests improvements for managing the referrals both internally and externally. GP education is important for managing patients not tolerating oral bisphosphonates before accepting referrals. We have started recommending GP to try alternative oral bisphosphonates or effervescent alendronic acid prior to referral. Some internal workload can be managed by the referring team with advice being provided by the rheumatology team in order to reallocate rheumatology appointments for other conditions. The rheumatology department at Croydon University Hospital met with stakeholders from COTE and FLS and discussed the audit results. The COTE team agreed to initiate and continue IV zoledronate to reduce the osteoporosis burden on the rheumatology department. Disclosure S. Taheri: None. R. Suresh: None. J. Burton: None. S. Adil: None. T. Ahmed: None. N. Horwood: None. R. Sathananthan: None.

Effect of Oral Bisphosphonate Drug Holiday on Mortality Following Hip Fracture.

Current clinical guidelines recommend a drug holiday after extended use of oral bisphosphonates. However, no studies have investigated the effect of drug holidays before hip fractures on postfracture mortality. This work aimed to investigate the effect of a drug holiday on postfracture mortality in patients with extended use of oral bisphosphonates. This retrospective, population-based cohort study took place among all patients with hip fractures in Victoria, Australia, from 2014 to 2018. Patients were adherent to oral alendronate or risedronate for 5 years or more prior to hip fracture. Group-based trajectory modeling categorized patients into different bisphosphonate usage after 5-year good adherence. The main outcome measure was postfracture mortality. We identified 365 patients with good adherence (medication possession ratio ≥80%) to oral alendronate/risedronate for 5 years or more. Most patients (69%) continued to use oral bisphosphonates until admission for hip fracture; 17% had discontinued for 1 year and 14% had discontinued for 2 years. Postfracture mortality was higher in patients who had discontinued risedronate for 1 year (hazard ratio [HR] 2.37; 95% CI, 1.24-4.53) and 2 years (HR 3.08; 95% CI, 1.48-6.41) prior to hip fracture. No increase or decrease in postfracture mortality was observed in patients who had discontinued alendronate for 1 year (HR 0.59; 95% CI, 0.29-1.18) or 2 years (HR 1.05; 95% CI, 0.57-1.93) prior to hip fracture. Postfracture mortality is higher in people who discontinue risedronate, but not alendronate, for 1 or 2 years after being adherent to treatment for at least 5 years. The type of bisphosphonate may be a factor to consider when planning drug holidays.

The cost-effectiveness of osteoporosis medications for preventing periprosthetic fractures following femoral neck fracture indicated hip arthroplasty: a break-even analysis.

Osteoporosis treatment following arthroplasty for femoral neck fracture (FNF) is associated with lower rates of periprosthetic fracture (PPF). Although cost-effective in reducing the rate of secondary fragility fracture, the economic viability of osteoporosis treatment in preventing PPF has not been evaluated. Therefore, the purpose of this study is to use a break-even analysis to determine whether and which current osteoporosis medications are cost-effective in preventing PPF following arthroplasty for FNFs. Three-year average cost of osteoporosis medication (oral bisphosphonates, estrogen hormonal therapy, intravenous (IV) bisphosphonates, denosumab, teriparatide, and abaloparatide), costs of PPF care, and PPF rates in patients who underwent hip arthroplasty for FNFs without osteoporosis treatment were used to perform a break-even analysis. The absolute risk reduction (ARR) related to osteoporosis treatment and sensitivity analyses were used to evaluate the cost-effectiveness of this intervention and break-even PPF rates. Oral bisphosphonate therapy following arthroplasty for hip fractures would be economically justified if it prevents one out of 56 PPFs (ARR, 1.8%). Given the current cost and incidence of PPF, overall treatment can only be economically viable for PPF prophylaxis if the 3-year costs of these agents are less than $1500. The utilization of lower cost osteoporosis medications such as oral bisphosphonates and estrogen hormonal therapy as PPF prophylaxis in this patient population would be economically viable if they reduce the PPF rate by 1.8% and 1.5%, respectively. For IV bisphosphonates and newer agents to be economically viable as PPF prophylaxis in the USA, their costs need to be significantly reduced.

Evaluating the comparability of osteoporosis treatments using propensity score and negative control outcome methods in UK and Denmark electronic health record databases.

Evidence on the comparative effectiveness of osteoporosis treatments is heterogeneous. This may be attributed to different populations and clinical practice, but also to differing methodologies ensuring comparability of treatment groups before treatment effect estimation and the amount of residual confounding by indication. This study assessed the comparability of denosumab vs oral bisphosphonate (OBP) groups using propensity score (PS) methods and negative control outcome (NCO) analysis. A total of 280 288 women aged ≥50yr initiating denosumab or OBP in 2011-2018 were included from the UK Clinical Practice Research Datalink (CPRD) and the Danish National Registries (DNR). Balance of observed covariates was assessed using absolute standardized mean difference (ASMD) before and after PS weighting, matching, and stratification, with ASMD >0.1 indicating imbalance. Residual confounding was assessed using NCOs with ≥100 events. Hazard ratio (HR) and 95%CI between treatment and NCO were estimated using Cox models. Presence of residual confounding was evaluated with 2 approaches (1) >5% of NCOs with 95% CI excluding 1, (2) >5% of NCOs with an upper CI <0.75 or lower CI >1.3. The number of imbalanced covariates before adjustment (CPRD 22/87; DNR 18/83) decreased, with 2%-11% imbalance remaining after weighting, matching, or stratification. Using approach 1, residual confounding was present for all PS methods in both databases (≥8% of NCOs), except for stratification in DNR (3.8%). Using approach 2, residual confounding was present in CPRD with PS matching (5.3%) and stratification (6.4%), but not with weighting (4.3%). Within DNR, no NCOs had HR estimates with upper or lower CI limits beyond the specified bounds indicating residual confounding for any PS method. Achievement of covariate balance and determination of residual bias were dependent upon several factors including the population under study, PS method, prevalence of NCO, and the threshold indicating residual confounding.

Safe prescribing of oral alendronic acid following hip fracture

In the UK, physiotherapists can train as independent prescribers and are working in increasing numbers as advanced clinical practitioners. This case study examines the safe prescribing of oral bisphosphonates following a fragility fracture of the hip and considers this process in the context of the Royal Pharmaceutical Society's competencies (2021) , which were adopted by the Health and Care Professions Council in 2016. Despite these medications being around since the 1960s, their utilisation in the treatment of osteoporosis remains limited, and low levels of patient adherence continues to present a problem. This case study will look at the ways in which these issues can be addressed and identifies areas for future development. It will also describe the process of bone health assessment, offering non-pharmacological approaches as a way to reduce fracture and falls risks. The shared care nature of osteoporosis management will also be considered, with communication and partnership between primary care and secondary care being key in the provision of this treatment.

Osteoporosis

Osteoporosis is a progressive skeletal disorder that is characterised by compromised bone strength that leads to an increased susceptibility to fractures. With an ageing population in the UK and a prevalence rate of 34% in people over the age of 50 years, the health and financial burden of the disease is significant. Osteoporosis develops due to an imbalance in bone remodelling, leading to a decrease in bone mineral density and alterations in the micro-architecture of bone. Diagnosis of osteoporosis involves a thorough assessment to identify patients at risk of developing osteoporosis, as it is often asymptomatic. Bone density measurements through dual-energy x-ray absorptiometry (DXA) scans are the gold-standard diagnostic modality. Treatment of osteoporosis is guided by the symptomatology of patients in addition to their T-score from the DXA scan. Oral bisphosphonates are the first-line therapy in addition to oral calcium and vitamin D supplementation to halt bone resorption and reduce fracture risk.

Cancer treatment-induced bone loss.

Cancer treatment-induced bone loss (CTBL) is associated with anti-tumor treatments, including endocrine therapies, chemotherapeutic treatments, radiotherapy, glucocorticoids, and tyrosine kinase inhibitors. Osteoporosis, characterized by the loss of bone mass, can increase the risk of fractures, leading to mortality and long-term disability, even after cancer remission. Cancer and osteoporosis have marked clinical and pathogenetic similarities. Both have a multifactorial etiology, affect the geriatric population, and markedly influence quality of life. Lifestyle management, including calcium and vitamin D supplementation, is recommended but the supporting evidence is limited. Oral and injectable bisphosphonates are effective for osteoporosis and malignant bone disease. Bisphosphonates increase bone mineral density (BMD) in patients with CTBL. Denosumab is also used in the management of CTBL; in clinical trials, it improved BMD and reduced the risk of fracture. Currently, there are no bone anabolic therapies for patients with cancer. Appropriate therapies are necessary to maintain optimal bone health, particularly in patients at heightened risk.

Targeted Coaching to Improve Osteoporosis Therapy Adherence: A Single Arm Variation of the C-STOP Study.

In this pre-planned variation of the Comparing Strategies Targeting Osteoporosis to Prevent Fractures After an Upper Extremity Fracture (C-STOP) trial, we investigated whether adherence-specific coaching by the case manager (CM) further improved the adherence and persistence rates compared to those seen in the C-STOP trial. We conducted a prospective observational cohort study of community-dwelling adults 50 years or older who suffered an upper-extremity fracture and were not previously treated with osteoporosis medications, to assess whether a well-trained CM can partner with patients to improve adherence to and persistence with oral bisphosphonate intake. The primary outcome was adherence (taking > 80% of prescribed doses) to oral bisphosphonate intake at 12 months after study enrollment. Secondary outcomes included primary adherence to and 12-month persistence with oral bisphosphonate and calcium and vitamin D supplement intake at 12 months. The study cohort consisted of 84 participants, of which 30 were prescribed an oral bisphosphonate. Twenty-two (73.3%) started treatment within 3 months. The adherence rate at 12 months was 77.3%. The persistence rate at 12 months was 95.5%. Of those not prescribed an oral bisphosphonate, 62.8% were taking supplemental calcium and 93.0% were taking supplemental vitamin D at 12 months. Depression was a significant predictor of 12-month non-adherence (adjusted odds ratio, 9.8; 95% confidence interval, 1.2-81.5). Adherence-specific coaching by a CM did not further improve the level of medication adherence achieved in the original C-STOP study. Importantly, these results can inform adherence in future intervention studies.

Comparison of bone mineral density of osteoporotic and osteopenia menopausal women treated with oral bisphosphonates before stopping the treatment and 1year after drug holiday period.

Osteoporosis is a skeletal and bone disorder characterized by bone fractures and decreased bone mineral density (BMD). Bisphosphonates have a great tendency to bind to minerals, and their long-term use can increase the risk of bone fragility in patients. Stopping bisphosphonates after a period of time is called a drug holiday (DH). Recent evidence has shown that patients' BMD may decrease again during DH. However, few studies have been done in this regard. In the present study, we compared the BMD of postmenopausal women during bisphosphonates treatment and 1year after DH. A total of 202 patients were selected with osteopenia (n = 95) and osteoporosis (n = 107); they had been treated with alendronate for 5years (a rheumatologist confirmed the diagnosis of osteopenia and osteoporosis) and had undergone DH for 1year. At the arrival of all patients, BMD was checked with the DXA (dual-energy X-ray absorptiometry) method using the 2007 American Explorer model Hologic device based on the Caucasian race. One year later, patients were reassessed for BMD by the same device. The analysis of femoral neck (FN) and lumbar spine (LS) T-score indices in the osteopenia and the osteoporosis groups showed reduction after DH, and the difference was statistically significant in both groups (p = 0.001). After 1year of stopping bisphosphonate treatment, the average of FN and LS BMD decreased in both groups (p = 0.001). In general, it can be said that DH can reduce FN and LS T-scores. The results indicated a significant reduction in BMD after the DH period for both the osteoporosis and osteopenia groups in the early months. Also, the effect of DH in osteoporosis patients was more compared to the osteopenia individuals, which could have implications for their treatment approach, and also its effect on bone health. Key Points • The DH can reduce FN and LS T-scores • The BMD reduced after the DH period for both the osteoporosis and osteopenia groups • After 1 year of stopping bisphosphonate treatment, the average of FN and LS BMD decreased in both groups.

The implications of competing risks and direct treatment disutility in cardiovascular disease and osteoporotic fracture: risk prediction and cost effectiveness analysis.

Clinical guidelines commonly recommend preventative treatments for people above a risk threshold. Therefore, decision-makers must have faith in risk prediction tools and model-based cost-effectiveness analyses for people at different levels of risk. Two problems that arise are inadequate handling of competing risks of death and failing to account for direct treatment disutility (i.e. the hassle of taking treatments). We explored these issues using two case studies: primary prevention of cardiovascular disease using statins and osteoporotic fracture using bisphosphonates. Externally validate three risk prediction tools [QRISK®3, QRISK®-Lifetime, QFracture-2012 (ClinRisk Ltd, Leeds, UK)]; derive and internally validate new risk prediction tools for cardiovascular disease [competing mortality risk model with Charlson Comorbidity Index (CRISK-CCI)] and fracture (CFracture), accounting for competing-cause death; quantify direct treatment disutility for statins and bisphosphonates; and examine the effect of competing risks and direct treatment disutility on the cost-effectiveness of preventative treatments. Discrimination and calibration of risk prediction models (Clinical Practice Research Datalink participants: aged 25-84 years for cardiovascular disease and aged 30-99 years for fractures); direct treatment disutility was elicited in online stated-preference surveys (people with/people without experience of statins/bisphosphonates); costs and quality-adjusted life-years were determined from decision-analytic modelling (updated models used in National Institute for Health and Care Excellence decision-making). CRISK-CCI has excellent discrimination, similar to that of QRISK3 (Harrell's c = 0.864 vs. 0.865, respectively, for women; and 0.819 vs. 0.834, respectively, for men). CRISK-CCI has systematically better calibration, although both models overpredict in high-risk subgroups. People recommended for treatment (10-year risk of ≥ 10%) are younger when using QRISK-Lifetime than when using QRISK3, and have fewer observed events in a 10-year follow-up (4.0% vs. 11.9%, respectively, for women; and 4.3% vs. 10.8%, respectively, for men). QFracture-2012 underpredicts fractures, owing to under-ascertainment of events in its derivation. However, there is major overprediction among people aged 85-99 years and/or with multiple long-term conditions. CFracture is better calibrated, although it also overpredicts among older people. In a time trade-off exercise (n = 879), statins exhibited direct treatment disutility of 0.034; for bisphosphonates, it was greater, at 0.067. Inconvenience also influenced preferences in best-worst scaling (n = 631). Updated cost-effectiveness analysis generates more quality-adjusted life-years among people with below-average cardiovascular risk and fewer among people with above-average risk. If people experience disutility when taking statins, the cardiovascular risk threshold at which benefits outweigh harms rises with age (≥ 8% 10-year risk at 40 years of age; ≥ 38% 10-year risk at 80 years of age). Assuming that everyone experiences population-average direct treatment disutility with oral bisphosphonates, treatment is net harmful at all levels of risk. Treating data as missing at random is a strong assumption in risk prediction model derivation. Disentangling the effect of statins from secular trends in cardiovascular disease in the previous two decades is challenging. Validating lifetime risk prediction is impossible without using very historical data. Respondents to our stated-preference survey may not be representative of the population. There is no consensus on which direct treatment disutilities should be used for cost-effectiveness analyses. Not all the inputs to the cost-effectiveness models could be updated. Ignoring competing mortality in risk prediction overestimates the risk of cardiovascular events and fracture, especially among older people and those with multimorbidity. Adjustment for competing risk does not meaningfully alter cost-effectiveness of these preventative interventions, but direct treatment disutility is measurable and has the potential to alter the balance of benefits and harms. We argue that this is best addressed in individual-level shared decision-making. This study is registered as PROSPERO CRD42021249959. This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 15/12/22) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 4. See the NIHR Funding and Awards website for further award information.

Patient preference, efficacy, and compliance with zoledronic acid for glucocorticoid-induced osteoporosis in patients with autoimmune diseases.

We evaluated the preference, patient satisfaction, and efficacy of zoledronic acid compared with oral bisphosphonates (BPs) for glucocorticoid-induced osteoporosis (GIOP) in patients with autoimmune diseases. We enrolled 50 patients with new fractures or osteoporosis detected on follow-up bone densitometry after at least 1year of oral BP use among patients diagnosed with GIOP during treatment for autoimmune diseases. After 1year of zoledronic acid treatment, patients completed a survey for preference and satisfaction assessment. Treatment efficacy was analysed by comparing bone mineral density changes and fractures with those in a control group of patients who continued oral BP use. Age, sex, treatment duration, and medication history did not differ significantly between the two groups. Among the participants, 86.7% preferred and were more satisfied with intravenous zoledronic acid than with oral BPs, primarily because of the convenience of its administration interval. Only two patients (4%) reported infusion-related adverse events with zoledronic acid. Furthermore, no significant differences were observed in the annualized percentage change in the bone mineral density of the lumbar spine, femur neck, and hip between patients receiving zoledronic acid and those receiving oral BPs. The occurrence of new fractures was consistent across both groups, with two cases in each, showing no significant differences. Patients showed a preference for and greater satisfaction with zoledronic acid, and its efficacy in treating osteoporosis was comparable to that of oral BPs. Therefore, zoledronic acid is a suitable treatment option for GIOP in patients with autoimmune diseases.

Severe Hypocalcemia With Denosumab Among Older Female Dialysis-Dependent Patients

Dialysis-dependent patients experience high rates of morbidity from fractures, yet little evidence is available on optimal treatment strategies. Chronic kidney disease-mineral and bone disorder is nearly universal in dialysis-dependent patients, complicating diagnosis and treatment of skeletal fragility. To examine the incidence and comparative risk of severe hypocalcemia with denosumab compared with oral bisphosphonates among dialysis-dependent patients treated for osteoporosis. Retrospective cohort study of female dialysis-dependent Medicare patients aged 65 years or older who initiated treatment with denosumab or oral bisphosphonates from 2013 to 2020. Clinical performance measures including monthly serum calcium were obtained through linkage to the Consolidated Renal Operations in a Web-Enabled Network database. Denosumab, 60 mg, or oral bisphosphonates. Severe hypocalcemia was defined as total albumin-corrected serum calcium below 7.5 mg/dL (1.88 mmol/L) or a primary hospital or emergency department hypocalcemia diagnosis (emergent care). Very severe hypocalcemia (serum calcium below 6.5 mg/dL [1.63 mmol/L] or emergent care) was also assessed. Inverse probability of treatment-weighted cumulative incidence, weighted risk differences, and weighted risk ratios were calculated during the first 12 treatment weeks. In the unweighted cohorts, 607 of 1523 denosumab-treated patients and 23 of 1281 oral bisphosphonate-treated patients developed severe hypocalcemia. The 12-week weighted cumulative incidence of severe hypocalcemia was 41.1% with denosumab vs 2.0% with oral bisphosphonates (weighted risk difference, 39.1% [95% CI, 36.3%-41.9%]; weighted risk ratio, 20.7 [95% CI, 13.2-41.2]). The 12-week weighted cumulative incidence of very severe hypocalcemia was also increased with denosumab (10.9%) vs oral bisphosphonates (0.4%) (weighted risk difference, 10.5% [95% CI, 8.8%-12.0%]; weighted risk ratio, 26.4 [95% CI, 9.7-449.5]). Denosumab was associated with a markedly higher incidence of severe and very severe hypocalcemia in female dialysis-dependent patients aged 65 years or older compared with oral bisphosphonates. Given the complexity of diagnosing the underlying bone pathophysiology in dialysis-dependent patients, the high risk posed by denosumab in this population, and the complex strategies required to monitor and treat severe hypocalcemia, denosumab should be administered after careful patient selection and with plans for frequent monitoring.

Trajectories of oral bisphosphonate use after hip fractures: a population-based cohort study

SummaryBisphosphonates prevent future hip fractures. However, we found that one in six patients with hip fractures had a delay in bisphosphonate initiation and another one-sixth discontinued treatment within 12 months after discharge. Our results highlight the need to address hesitancy in treatment initiation and continuous monitoring.PurposeSuboptimal antiresorptive use is not well understood. This study investigated trajectories of oral bisphosphonate use following first hip fractures and factors associated with different adherence and persistence trajectories.MethodsWe conducted a retrospective study of all patients aged ≥ 50 years dispensed two or more bisphosphonate prescriptions following first hip fracture in Victoria, Australia, from 2012 to 2017. Twelve-month trajectories of bisphosphonate use were categorized using group-based trajectory modeling. Factors associated with different trajectories compared to the persistent adherence trajectory were assessed using multivariate multinomial logistic regression.ResultsWe identified four patterns of oral bisphosphonate use in 1811 patients: persistent adherence (66%); delayed dispensing (17%); early discontinuation (9%); and late discontinuation (9%). Pre-admission bisphosphonate use was associated with a lower risk of delayed dispensing in both sexes (relative risk [RR] 0.28, 95% confidence interval [CI] 0.21–0.39). Older patients (≥\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\ge$$\\end{document} 85 years old versus 50–64 years old, RR 0.38, 95% CI 0.22–0.64) had a lower risk of delayed dispensing. Males with anxiety (RR 9.80, 95% CI 2.24–42.9) and females with previous falls had increased risk of early discontinuation (RR 1.80, 95% CI 1.16–2.78).ConclusionTwo-thirds of patients demonstrated good adherence to oral bisphosphonates over 12 months following hip fracture. Efforts to further increase post-discharge antiresorptive use should be sex-specific and address possible persistent uncertainty around delaying treatment initiation.

Bioavailability of Orally Administered Drugs After Bariatric Surgery.

Oral drug absorption after bariatric surgery is likely to be altered, but the impact of different bariatric surgery procedures on individual drugs is not uniform. The aim of this article is to describe factors influencing the bioavailability of orally administered drugs after bariatric surgery and to provide readers with practical recommendations for drug dosing. We also discuss the medications that may be harmful after bariatric surgery. The fundamental factors for enteral drug absorption are the production of gastric acid; the preserved length of the intestine, i.e., the size of the absorption surface and/or the preserved enterohepatic circulation; and the length of common loop where food and drugs are mixed with digestive enzymes and bile acids. Bypassing of metabolizing enzymes or efflux pumps and changes in intestinal motility can also play an important role. Significant changes of drug absorption early after the anatomic alteration may also be gradually ameliorated due to gradual intestinal adaptation. The most affected drugs are those with low or variable bioavailability and those undergoing enterohepatic circulation. Attention should also be paid to oral drug formulations, especially in the early postoperative period, when immediate-release and liquid formulations are preferred. The changes in oral bioavailability are especially clinically meaningful in patients treated with drugs possessing narrow therapeutic index (e.g., oral anticoagulants, levothyroxine, and anticonvulsants) or in acute conditions (e.g., anti-infectives); nevertheless, it may also influence the therapeutic value of chronic therapy (e.g., antidepressants. antihypertensives, antiplatelets, statins, PPIs, contraceptives, and analgesics); therapeutic effect of chronic therapy is further influenced by pharmacokinetic alterations resulting from weight loss. Therapeutic drug monitoring, periodical clinical evaluation, and adequate dose adjustments are necessary. Due to safety reasons, patients should avoid oral bisphosphonates, regular use of non-steroidal anti-inflammatory drugs, and, if possible, corticosteroids after bariatric surgery.

Reducing Fracture Risk in Postmenopausal Osteoporosis: a Review of Effective and Safe Pharmacological Therapy Providing Adherence to Treatment

INTRODUCTION. Postmenopausal osteoporosis (PMO) accounts for up to 85 % of all cases of osteoporosis, complications of which — pathological fractures — lead to a decrease in quality of life and functionality, pain, severe psycho-emotional disorders, loss of ability to self-care, disability and an increased risk of death. Timely prescribed pathogenetic therapy for osteoporosis, including in patients undergoing medical rehabilitation, helps reduce the risk of developing osteoporotic fractures and prevent complications associated with them.&#x0D; MAIN CONTENT OF THE REVIEW. The literature review analyzes 5 domestic and 47 foreign literary sources, on the basis of which a description of modern methods of treating PMO is made in order to reduce the risk of developing pathological fractures. Poor patient adherence to osteoporosis therapy is associated with low effectiveness of PMО treatment and an increased financial burden on the healthcare system — increased hospitalization rates and treatment costs. The infrequent dosing frequency and good tolerability of therapy help to increase adherence to oral supplements.&#x0D; CONCLUSION. The review focused on the effectiveness and safety of the oral bisphosphonate ibandronic acid 150 mg once a month, the administration of which to women with PMO demonstrated good tolerability, ease of use and high efficiency, both in reducing the risk of fractures and in increasing bone mineral density, including long-term treatment periods — 5 years.

Difficulties in decision making on a long standing, complicated case of osteoporosis – a real challenge for functional rehabilitation

We aim was to present a case of severe osteoporosis with concern to an adult female who was under specific medication against the condition while she experienced inexplicable weight loss in association with an incidental fracture inconsistent with DXA changes. Challenges of the case management and decision making are further on explained. Real-life-medicine poses multiple issues that require an individual decision while respecting the standard protocols. That is why a generalized decision is rather impractical. Here we introduce the clinical case of a lady in her late 60s with a known 6-year history of osteoporosis that required several difficult decisions along surveillance: at first, zoledronic acid represented an available solution, yet after one year, BMD decreased and adjustment was done by initiating a second sequence according to the teriparatide protocol. DXA-BMD, as well as the spectrum of bone turnover markers, qualified the patient as responsive and she further continued with oral bisphosphonates while being monitored via telemedicine amid COVID-19 pandemic. After 24 more months, a second decision of zoledronic acid was done, despite prior partial response, but digestive complains restricted the oral administration of anti-osteoporotic drugs. After one more year, denosumab was initiated and consecutive follow-up is essential. At this point, another challenging aspect was revealed: the discordance between DXA – based scores increase and the presence of an incidental fracture. A supplementary investigation was considered useful (Tc- whole body scintigraphy) noting the clinical presentation with local pain, dysfunctionality, and mild weight loss that also required rehabilitation management.

Low screening rates and high prevalence of osteoporosis in cirrhosis: A real-world retrospective analysis.

Patients with cirrhosis are at increased risk for osteoporosis, and those who suffer a fracture are at high risk for mortality. Despite this, osteoporosis is often overlooked and undertreated. This study aimed to evaluate osteoporosis screening, management, and adverse osteoporosis medication events in patients with cirrhosis. We performed a retrospective chart review of adult outpatients with compensated and decompensated cirrhosis seen in single health system over a 6-year period. Patient demographics, liver and bone health comorbidities, DEXA scan results, and medications were abstracted. In total, 5398 patients met criteria. The cohort was predominately white (79.1%) and older (age 59). 44.4% were female. 64.6% had decompensated cirrhosis. Median MELD-Na score was 12.8. 23.5% had a DEXA scan ordered, approximately 50% completed this test. Patients who were older, female, white, with more severe liver disease, and other osteoporosis risk factors were more likely to have a DEXA scan ordered. 48.5% of patients had osteopenia and 30.2% had osteoporosis on DEXA scan. Only 22.6% of patients with osteoporosis received treatment, most commonly oral bisphosphonates. Oral bisphosphonate prescription was not associated with variceal bleeding (8.4% without vs. 4.8% with, p = 0.487). A minority of patients with cirrhosis were screened for osteoporosis. The majority screened had osteopenia or osteoporosis on DEXA scan. Less than a quarter of patients with osteoporosis were started on treatment. Real-world experience of oral bisphosphonate use did not reveal higher rates of gastrointestinal bleeding. There is room for improvement in all aspects of bone health care in cirrhosis.

Denosumab and Mortality in a Real-World Setting: A Comparative Study.

Denosumab (Dmab) is increasingly prescribed worldwide. Unlike bisphosphonates (BPs), its effect on mortality has yet to be well explored. This study examined the association between Dmab and all-cause mortality compared with no treatment in subjects with a fracture and BPs in subjects without a fracture. The study population was from the Sax Institute's 45 and Up Study (n = 267,357), a prospective population-based cohort with questionnaire data linked to hospital admissions (Admitted Patients Data Collection [APDC] data were linked by the Centre for Health Record Linkage), medication records (Pharmaceutical Benefits Scheme [PBS] provided by Services Australia), and stored securely (secure data access was provided through the Sax Institute's Secure Unified Research Environment [SURE]). The new-user cohort design with propensity-score (PS) matching was implemented. In the fracture cohort, Dmab and oral BP users were matched 1:2 to no treatment (Dmab: 617 women, 154 men; oral BPs: 615 women, 266 men). In the no-fracture cohort, Dmab users were matched 1:1 with oral BPs and zoledronic acid (Zol) users (Dmab:oral BPs: 479 men, 1534 women; Dmab:Zol: 280 men, 625 women). Mortality risk was measured using sex-specific pairwise multivariable Cox models. In the fracture cohort, compared with no treatment, Dmab was associated with 48% lower mortality in women (hazard ratio [HR] = 0.52, 95% confidence interval [CI] 0.36-0.72) but not in men. Oral BPs were associated with 44% lower mortality in both sexes (women HR = 0.56, 95% CI 0.42-0.77; men HR = 0.56, 95% CI 0.40-0.78). In the no-fracture cohort, compared with BPs, Dmab was associated with 1.5- to 2.5-fold higher mortality than oral BPs (women HR = 1.49, 95% CI 1.13-1.98; men HR = 2.74; 95% CI 1.82-4.11) but similar mortality to Zol. Dmab in women and oral BPs were associated with lower post-fracture mortality than no treatment. However, Dmab users had generally higher mortality than oral BP users in those without fractures. © 2023 American Society for Bone and Mineral Research (ASBMR).