Current evidence on the impact of medication optimization or pharmacological interventions on frailty or aspects of frailty: a systematic review of randomized controlled trials.

BACKGROUND: Frailty and adverse drug effects are linked in the fact that polypharmacy is correlated with the severity of frailty; however, a causal relation has not been proven in older people with clinically manifest frailty. METHODS: A literature search was performed in Medline to detect prospective randomized controlled trials (RCTs) testing the effects of pharmacological interventions or medication optimization in older frail adults on comprehensive frailty scores or partial aspects of frailty that were published from January 1998 to October 2019. RESULTS: Twenty-five studies were identified, 4 on comprehensive frailty scores and 21 on aspects of frailty. Two trials on comprehensive frailty scores showed positive results on frailty although the contribution of medication review in a multidimensional approach was unclear. In the studies on aspects related to frailty, ten individual drug interventions showed improvement in physical performance, muscle strength or body composition utilizing alfacalcidol, teriparatide, piroxicam, testosterone, recombinant human chorionic gonadotropin, or capromorelin. There were no studies examining negative effects of drugs on frailty. CONCLUSION: So far, data on a causal relationship between drugs and frailty are inconclusive or related to single-drug interventions on partial aspects of frailty. There is a clear need for RCTs on this topic that should be based on a comprehensive, internationally consistent and thus reproducible concept of frailty assessment.

STOPPFall (Screening Tool of Older Persons Prescriptions in older adults with high fall risk): a Delphi study by the EuGMS Task and Finish Group on Fall-Risk-Increasing Drugs.

BACKGROUND: Healthcare professionals are often reluctant to deprescribe fall-risk-increasing drugs (FRIDs). Lack of knowledge and skills form a significant barrier and furthermore, there is no consensus on which medications are considered as FRIDs despite several systematic reviews. To support clinicians in the management of FRIDs and to facilitate the deprescribing process, STOPPFall (Screening Tool of Older Persons Prescriptions in older adults with high fall risk) and a deprescribing tool were developed by a European expert group. METHODS: STOPPFall was created by two facilitators based on evidence from recent meta-analyses and national fall prevention guidelines in Europe. Twenty-four panellists chose their level of agreement on a Likert scale with the items in the STOPPFall in three Delphi panel rounds. A threshold of 70% was selected for consensus a priori. The panellists were asked whether some agents are more fall-risk-increasing than others within the same pharmacological class. In an additional questionnaire, panellists were asked in which cases deprescribing of FRIDs should be considered and how it should be performed. RESULTS: The panellists agreed on 14 medication classes to be included in the STOPPFall. They were mostly psychotropic medications. The panellists indicated 18 differences between pharmacological subclasses with regard to fall-risk-increasing properties. Practical deprescribing guidance was developed for STOPPFall medication classes. CONCLUSION: STOPPFall was created using an expert Delphi consensus process and combined with a practical deprescribing tool designed to optimise medication review. The effectiveness of these tools in falls prevention should be further evaluated in intervention studies.

Is kidney function associated with cognition and mood in late life? : The Screening for CKD among Older People across Europe (SCOPE) study.

BACKGROUND: Chronic kidney disease (CKD), cognitive impairment and depression share common risk factors. Previous studies did not investigate the possible association between kidney function and cognitive and mood disorders in older persons in a broad range of kidney function. The present study explored associations between kidney function, cognition and mood in outpatients of 75 years and over. METHODS: Baseline data of 2252 participants of the SCOPE study, an international multicenter cohort observational study,were used in which community-dwelling persons of 75 years and over were enrolled to screen for CKD Kidney function was estimated with the BIS1-eGFR equation, cognition was assessed with the Mini-Mental State Examination (MMSE) and mood with the Geriatric Depression Scale 15 items (GDS-15). Characteristics were compared across stages of CKD. Mean eGFR values were also compared across categories of MMSE (< 24, 24-26, ≥27) and between groups with high and low score on the GDS-15 (> 5/≤5). RESULTS: In total, 63% of the population had an eGFR < 60 mL/min. In advanced stages of CKD, participants were older and more often men than in earlier stages (p < 0.001). Cardiovascular diseases and diabetes mellitus were more often found in those in advanced stages of CKD (p < 0.001), and also cumulative comorbidity scores were higher than in those in earlier stages (p < 0.001). Median MMSE was 29 in CKD stage 1-2 and 3, and 30 in CKD stage 4, whereas median GDS-15 score was 2 in all stages of CKD. Mean values of eGFR did not differ across categories of MMSE or between groups with high and low score on the GDS-15. Stratification for albuminuria did not change these results. CONCLUSIONS: Older persons in more advanced stages of CKD did not have lower cognitive scores or higher rates of depressive symptoms than older persons in earlier stages. Future longitudinal studies might give information on the possible effect of kidney function on cognition and mood in late life. TRIAL REGISTRATION: This study was registered prospectively on 25th February 2016 at clinicaltrials.gov ( NCT02691546 ).

Use of Selective Serotonin Reuptake Inhibitors and Bone Mineral Density Change: A Population-Based Longitudinal Study in Middle-Aged and Elderly Individuals.

BACKGROUND: Longitudinal studies showed conflicting results regarding the association between use of selective serotonin reuptake inhibitors (SSRIs) and bone mineral density (BMD). Therefore, we investigate the association between-duration of-SSRI use and BMD, and change in BMD ([INCREMENT]BMD). METHODS: Data from the population-based Rotterdam Study cohort (1991-2008) were used. In total, 4915 men and 5831 postmenopausal women, aged 45 years and older, were included, having measurement visits at 4- to 5-year intervals. Multivariable linear mixed models were applied to examine the association between SSRI use, based on pharmacy records, duration of SSRI use, and repeated measures of BMD, and changes in BMD, compared with nonuse. Femoral neck BMD (grams per centimeters squared) was measured at 4 visits, comprising 19,861 BMD measurements. Three [INCREMENT]BMD periods were examined, comprising 7897 [INCREMENT]BMD values. Change in BMD was expressed in the annual percentage [INCREMENT]BMD between 2 consecutive visits. RESULTS: In men and women, we observed no association between SSRI and BMD when compared with nonuse (women: mean difference, 0.007 g/cm; 95% confidence interval, -0.002 to 0.017; P = 0.123). We did not find an association between duration of SSRI use and [INCREMENT]BMD (women: annual percentage change, -0.081; 95% confidence interval, -0.196 to 0.033; P = 0.164). CONCLUSIONS: In conclusion, use of SSRIs is not associated with BMD or [INCREMENT]BMD, after taking duration of treatment into account, in middle-aged and elderly individuals. Therefore, our results question previously raised concerns on the adverse effects of SSRIs on BMD.

Neopterin: a potential biomarker for delirium in elderly patients.

BACKGROUND/AIMS: The diagnosis of delirium is not supported by specific biomarkers. In a previous study, high neopterin levels were found in patients with a postoperative delirium. In the present study, we investigated levels of neopterin, interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1) in acutely ill admitted elderly patients with and without a delirium. METHODS: Plasma/serum levels of neopterin, IL-6 and IGF-1 were determined in patients aged ≥65 years admitted to the wards of Internal Medicine and Geriatrics. Differences in biomarker levels between patients with and without a delirium were investigated by the analysis of variance in models adjusted for age, gender, comorbidities and eGFR (when appropriate). RESULTS: Eighty-six patients were included; 23 of them with a delirium. In adjusted models, higher mean levels of neopterin (70.5 vs. 45.9 nmol/l, p = 0.009) and IL-6 (43.1 vs. 18.5 pg/ml, p = 0.034) and lower mean levels of IGF-1 (6.3 vs. 9.3 nmol/l, p = 0.007) were found in patients with a delirium compared to those without. CONCLUSIONS: The findings of this study suggest that neopterin might be a potential biomarker for delirium which, through oxidative stress and activation of the immune system, may play a role in the pathophysiology of delirium.

Adverse outcomes of frailty in the elderly: the Rotterdam Study.

To investigate the prevalence of frailty in a Dutch elderly population and to identify adverse health outcomes associated with the frailty phenotype independent of the comorbidities. Cross-sectional and longitudinal analyses within the Rotterdam Study (the Netherlands), a prospective population-based cohort study in persons aged ≥55 years. Frailty was defined as meeting three or more of five established criteria for frailty, evaluating nutritional status, physical activity, mobility, grip strength and exhaustion. Intermediate frailty was defined as meeting one or two frailty criteria. Comorbidities were objectively measured. Health outcomes were assessed by means of questionnaires, physical examinations and continuous follow-up through general practitioners and municipal health authorities for mortality. Of 2,833 participants (median age 74.0 years, inter quartile range 9) with sufficiently evaluated frailty criteria, 163 (5.8 %) participants were frail and 1,454 (51.3 %) intermediate frail. Frail elderly were more likely to be older and female, to have an impaired quality of life and to have fallen or to have been hospitalized. 108 (72.0 %) frail participants had ≥2 comorbidities, compared to 777 (54.4 %) intermediate frail and 522 (44.8 %) non-frail participants. Adjusted for age, sex and comorbidities, frail elderly had a significantly increased risk of dying within 3 years (HR 3.4; 95 % CI 1.9-6.4), compared to the non-frail elderly. This study in a general Dutch population of community-dwelling elderly able to perform the frailty tests, demonstrates that frailty is common and that frail elderly are at increased risk of death independent of comorbidities.

The influence of lithium on calcium homeostasis in older patients in daily clinical practice.

BACKGROUND: Lithium can influence calcium homeostasis resulting in changes in parathormone set point and renal calcium handling. The clinical significance of these changes in older patients is unknown. The objective of this study was to investigate the possible association between duration of lithium treatment and corrected calcium, parathormone and 24-h urinary calcium excretion in older psychiatric patients corrected for renal function and vitamin 25OH D and also to estimate the point prevalence of hypercalcemia and raised parathormone. METHODS: A cross-sectional study of psychiatric outpatients visiting a specialized facility for older patients treated with lithium was performed. Patients underwent a comprehensive assessment and blood and urine testing. Potential confounders of calcium homeostasis were recorded. On the basis of the duration of lithium treatment, patients were divided into four groups. RESULTS: One hundred eleven patients were included, mean age 75.2 years. There was no significant association between the duration of lithium treatment and corrected calcium, parathormone and 24-h urinary calcium excretion. The point prevalence of hypercalcemia was 2.7% and 47.8% for raised parathormone. There was an unexpected but significant negative association between the duration of lithium treatment and vitamin 25OH D, with 76.9% vitamin 25OH D deficiency (<50 nmol/L) in the group using lithium for more than 10 years. CONCLUSIONS: No association was found between duration of lithium treatment and calcium parameters in older psychiatric outpatients, but there was a high prevalence of raised parathormone and an unexpected negative association between duration of lithium treatment and 25OH D.

Frailty in Non-geriatric Patients With Head and Neck cancer.

OBJECTIVE: Patients with head and neck cancer (HNC) are characterized by a poor lifestyle and comorbidity. The Geriatric 8 (G8) is an established screening tool to identify frail older patients with cancer. However, studies evaluating frailty in younger HNC patients are lacking. The aim of this study is to evaluate if the G8 can identify frailty and if it is related to mortality in younger HNC patients. STUDY DESIGN: Case-control study design. SETTING: Tertiary cancer center. METHODS: We studied patients <70 years with HNC. Patients with G8 ≤ 14 were considered frail. Patients were matched to nonfrail (G8 > 14) control patients. Patients were matched according to sex, age, smoking, tumor location, and period of first consultation. Baseline health characteristics were compared between frail patients and nonfrail controls. Second, the treatment plan and adverse outcomes were compared. RESULTS: Forty-five patients with G8 ≤ 14 were included and matched to 90 nonfrail controls. The median follow-up time was 357 days. Frail patients had a significantly lower body mass index and level of education, a worse World Health Organization performance status, and reported lower experienced overall health. 28.9% of the frail patients died after 1 year versus 10% of the nonfrail control patients (hazard ratio: 3.87 [95% confidence interval: 1.32-11.36], p = 0.014). CONCLUSION: The G8 is a valid screening tool to identify frail patients in younger HNC patients.

Dose-response relationship between selective serotonin re-uptake inhibitors and injurious falls: a study in nursing home residents with dementia.

AIM: The contribution of selective serotonin re-uptake inhibitors (SSRIs) to injurious fall risk in patients with dementia has not been quantified precisely until now. Our objective was to determine whether a dose-response relationship exists for the use of SSRIs and injurious falls in a population of nursing home residents with dementia. METHODS: Daily drug use and daily falls were recorded in 248 nursing home residents with dementia from 1 January 2006 until 1 January 2008. For each resident and for each day of the study period, data on drug use were abstracted from the prescription database, and information on falls and subsequent injuries was retrieved from a standardized incident report system, resulting in a dataset of 85,074 person-days. RESULTS: We found a significant dose-response relationship between injurious falls and the use of SSRIs. The risk of an injurious fall increased significantly with 31% at 0.25 of the Defined Daily Dose (DDD) of a SSRI, 73% at 0.50 DDD, and 198% at 1.00 DDD (Hazard ratio = 2.98; 95% confidence interval 1.94, 4.57). The risk increased further in combination with a hypnotic or sedative. CONCLUSIONS: Even at low doses, SSRIs are associated with increased risk of an injurious fall in nursing home residents with dementia. Higher doses increase the risk further with a three-fold risk at 1.00 DDD. New treatment protocols might be needed that take into account the dose-response relationship between SSRIs and injurious falls.

Methods of data collection and definitions of cardiac outcomes in the Rotterdam Study.

The prevalence of cardiovascular diseases is rising. Therefore, adequate risk prediction and identification of its determinants is increasingly important. The Rotterdam Study is a prospective population-based cohort study ongoing since 1990 in the city of Rotterdam, The Netherlands. One of the main targets of the Rotterdam Study is to identify the determinants and prognosis of cardiovascular diseases. Case finding in epidemiological studies is strongly depending on various sources of follow-up and clear outcome definitions. The sources used for collection of data in the Rotterdam Study are diverse and the definitions of outcomes in the Rotterdam Study have changed due to the introduction of novel diagnostics and therapeutic interventions. This article gives the methods for data collection and the up-to-date definitions of the cardiac outcomes based on international guidelines, including the recently adopted cardiovascular disease mortality definitions. In all, detailed description of cardiac outcome definitions enhances the possibility to make comparisons with other studies in the field of cardiovascular research and may increase the strength of collaborations.

A Systematic Review of the Current Evidence from Randomised Controlled Trials on the Impact of Medication Optimisation or Pharmacological Interventions on Quantitative Measures of Cognitive Function in Geriatric Patients.

BACKGROUND: Cognitive decline is common in older people. Numerous studies point to the detrimental impact of polypharmacy and inappropriate medication on older people's cognitive function. Here we aim to systematically review evidence on the impact of medication optimisation and drug interventions on cognitive function in older adults. METHODS: A systematic review was performed using MEDLINE and Web of Science on May 2021. Only randomised controlled trials (RCTs) addressing the impact of medication optimisation or pharmacological interventions on quantitative measures of cognitive function in older adults (aged > 65 years) were included. Single-drug interventions (e.g., on drugs for dementia) were excluded. The quality of the studies was assessed by using the Jadad score. RESULTS: Thirteen studies met the inclusion criteria. In five studies a positive impact of the intervention on metric measures of cognitive function was observed. Only one study showed a significant improvement of cognitive function by medication optimisation. The remaining four positive studies tested methylphenidate, selective oestrogen receptor modulators, folic acid and antipsychotics. The mean Jadad score was low (2.7). CONCLUSION: This systematic review identified a small number of heterogenous RCTs investigating the impact of medication optimisation or pharmacological interventions on cognitive function. Five trials showed a positive impact on at least one aspect of cognitive function, with comprehensive medication optimisation not being more successful than focused drug interventions. More prospective trials are needed to specifically assess ways of limiting the negative impact of certain medication in particular and polypharmacy in general on cognitive function in older patients.

[Cost] effectiveness of withdrawal of fall-risk increasing drugs versus conservative treatment in older fallers: design of a multicenter randomized controlled trial (IMPROveFALL-study).

BACKGROUND: Fall incidents represent an increasing public health problem in aging societies worldwide. A major risk factor for falls is the use of fall-risk increasing drugs. The primary aim of the study is to compare the effect of a structured medication assessment including the withdrawal of fall-risk increasing drugs on the number of new falls versus 'care as usual' in older adults presenting at the Emergency Department after a fall. METHODS/DESIGN: A prospective, multi-center, randomized controlled trial will be conducted in hospitals in the Netherlands. Persons aged ≥65 years who visit the Emergency Department due to a fall are invited to participate in this trial. All patients receive a full geriatric assessment at the research outpatient clinic. Patients are randomized between a structured medication assessment including withdrawal of fall-risk increasing drugs and 'care as usual'. A 3-monthly falls calendar is used for assessing the number of falls, fallers and associated injuries over a one-year follow-up period. Measurements will be at three, six, nine, and twelve months and include functional outcome, healthcare consumption, socio-demographic characteristics, and clinical information. After twelve months a second visit to the research outpatient clinic will be performed, and adherence to the new medication regimen in the intervention group will be measured. The primary outcome will be the incidence of new falls. Secondary outcome measurements are possible health effects of medication withdrawal, health-related quality of life (Short Form-12 and EuroQol-5D), costs, and cost-effectiveness of the intervention. Data will be analyzed using an intention-to-treat analysis. DISCUSSION: The successful completion of this trial will provide evidence on the effectiveness of withdrawal of fall-risk increasing drugs in older patients as a method for falls reduction. TRIAL REGISTRATION: The trial is registered in the Netherlands Trial Register (NTR1593).

Antipsychotics and Lorazepam During Delirium: Are We Harming Older Patients? A Real-Life Data Study.

BACKGROUND: Delirium affects approximately one out of three older hospitalized patients and is associated with poor clinical outcomes. Approaches used to manage delirium consist of non-pharmacological and pharmacological interventions. Antipsychotics and lorazepam are commonly used to treat symptoms of delirium, but conflicting data exist on the effect of these drugs on the outcomes of delirium. OBJECTIVE: The aim of this study was to investigate whether the use of antipsychotics, with or without lorazepam, increases the risk of prolonged hospital stay, post-discharge institutionalization, and in-hospital mortality in older patients with delirium. METHODS: In this retrospective chart review study, we included acutely ill patients aged ≥ 65 years who were admitted to a geriatric ward and diagnosed with delirium. Patients were stratified into three groups based on whether or not they received antipsychotics and lorazepam to manage delirium: (0) no antipsychotics; (1) antipsychotics only; and (2) antipsychotics plus lorazepam. Length of hospital stay (LOS) and frequencies of post-discharge institutionalization and in-hospital mortality were compared. RESULTS: In total, 212 patients with delirium were included (mean age 81.9 ± 5.6 years); 40 did not receive antipsychotics (18.9%), 123 received antipsychotics only (58.0%) and 49 received antipsychotics and lorazepam (23.1%). There was a trend to a longer LOS in patients who received both antipsychotics and lorazepam (median LOS group 0 = 8.0 days, group 1 = 10.0 days, and group 2 = 12.0 days). Furthermore, trends to a higher incidence of post-discharge institutionalization and in-hospital mortality were observed in patients who received both treatments (institutionalization group 0 = 45.0%, group 1 = 59.3%, group 2 = 81.6%; and in-hospital mortality group 0 = 7.5%, group 1 = 10.6%, group 2 = 16.3%). CONCLUSION: The use of antipsychotics, with or without lorazepam, during delirium is associated with increased risks of poor outcomes. These findings suggest that clinicians should be cautious about routine prescribing of these drugs to older patients with delirium. Further investigation is needed to clarify this association.

Anticholinergic Drug Burden and Delirium: A Systematic Review.

OBJECTIVES: To investigate the association between anticholinergic drug burden (ADB), measured with anticholinergic drug scales, and delirium and delirium severity. DESIGN: Systematic review. SETTING AND PARTICIPANTS: All available studies. METHODS: A systematic literature search was performed in Medline, Embase, PsycINFO, Web of Science, CINAHL, Cochrane library, and Google Scholar. Studies evaluating the association between ADB (measured as a total score) and delirium or delirium severity, published in English, were eligible for inclusion. RESULTS: Sixteen studies, including 148,756 persons, were included. Fifteen studies investigated delirium. ADB was measured with the Anticholinergic Risk Scale (ARS, n = 5), the Anticholinergic Cognitive Burden Scale (ACB, n = 6), the list of Chew (n = 1), the Anticholinergic Drug Scale (ADS, n = 5), a modified version of the ARS (n = 1), and a modified version of the ACB (n = 1). A high ADB, measured with the ARS, was associated with delirium (5/5). Also with the modified version of the ARS and ACB, an association was found between a high ADB and delirium during 3-month (1/1) and 1-year follow-up (1/1), respectively. When ADB was assessed with other scales, the results were inconclusive, with only 1 positive association for the ACB (1/6) and ADS (1/5) each. The possible association between ADB and delirium severity has also been investigated (ADS n = 2, Summers Drug Risk Number n = 1). One study found an association between a high ADB, measured with the ADS, and an increase in severity of delirium. CONCLUSIONS AND IMPLICATIONS: ADB assessed with the ARS is consistently associated with delirium. The association found between the modified versions of the ARS and ACB and delirium needs confirmation. When ADB was assessed with other scales, the findings were inconclusive. The current findings suggest that the ARS might be a useful tool to identify patients at increased risk for delirium.

Delirium: A Frequent Manifestation in COVID-19 Older Patients.

The authors report a high prevalence of delirium in COVID-19 old patients admitted in an academic hospital. During the recent COVID-19 period, delirium was present in 38% of old patients admitted with delirium at the COVID ward of the Erasmus MC University Medical Center of Rotterdam. We do not know in which patients COVID-19 can cause delirium; however, considering the high prevalence of delirium in COVID-19 old patients and the potential serious consequences, attention is needed in order to reduce disability and mortality in this vulnerable category of patients.

The Possible Impact of Aortic Stiffness on Quality of Late Life: An Exploratory Study.

PURPOSE: Aortic stiffness (AS) is associated with cardiovascular events and all-cause mortality in the older population. AS might also influence the health-related quality of life (HRQOL) as a result of the negative effects of AS on cognitive and physical morbidity. We aimed to investigate the possible association between AS and HRQOL in people aged 75 years and over. PATIENTS AND METHODS: This cross-sectional study was part of the SCOPE study, an international multicenter cohort observational study. The indicators for AS were aortic pulse wave velocity (aPWV) and central pulse pressure (cPP). HRQOL was assessed using the EQ-5D index and the EQ-5D visual analog scale (VAS). ANCOVA and multivariate regression models were used to investigate possible associations. RESULTS: We included 280 Dutch participants of the SCOPE study. Median age was 79 years (IQR 76-83) and 42.1% were women. Participants reporting any problem on the EQ-5D index (n=214) had higher values of aPWV (12.6 vs 12.2 m/s, p = 0.024) than participants not experiencing any problem (n=66) and comparable values of cPP (44.4 vs 42.0 mmHg, p = 0.119). Estimates only slightly changed after adjustments. No association was found between indicators of AS and EQ-5D VAS. CONCLUSION: Aortic stiffness was associated with impaired quality of late life. This association could be mediated by subclinical vascular pathology affecting mental and physical health.

Prevalence and Risk Factors for Delirium in Elderly Patients With Severe Burns: A Retrospective Cohort Study.

Little is known about delirium in elderly burn center patients. The aim of this study is to provide information on the prevalence of delirium and risk factors contributing to the onset of delirium. All patients aged 70 years or older admitted with burn injuries to the Burn Center, Maasstad Hospital, in 2011 to 2017 were eligible for inclusion. We retrospectively collected data regarding the presence of delirium, potential risk factors contributing to the onset of delirium and outcome after delirium. We included elderly 90 patients in this study. The prevalence of delirium in our population was 13% (N = 12). Risk factors for delirium were advanced age, increased American Society for Anesthesiologists score, physical impairment and the use of anticholinergic drugs during admission. Patients with delirium had a poorer outcome, with prolonged hospital stay and increased mortality 6 and 12 months after discharge. Delirium is diagnosed in 13% of the elderly patients admitted to our burn center. Risk factors for delirium found in this study are advanced age, poor physical health status, physical impairment, and the use of anticholinergic drugs. Delirium is related to poor outcomes, including prolonged hospital stay and mortality after discharge.

Association of polypharmacy and hyperpolypharmacy with frailty states: a systematic review and meta-analysis.

PURPOSE: To investigate: (1) the cross-sectional association between polypharmacy, hyperpolypharmacy and presence of prefrailty or frailty; (2) the risk of incident prefrailty or frailty in persons with polypharmacy, and vice versa. METHODS: A systematic review and meta-analysis was performed according to PRISMA guidelines. We searched PubMed, Web of Science, and Embase from 01/01/1998 to 5/2/2018. Pooled estimates were obtained through random effect models and Mantel-Haenszel weighting. Homogeneity was assessed with the I2 statistic and publication bias with Egger's and Begg's tests. RESULTS: Thirty-seven studies were included. The pooled proportion of polypharmacy in persons with prefrailty and frailty was 47% (95% CI 33-61) and 59% (95% CI 42-76), respectively. Increased odds ratio of polypharmacy were seen for prefrail (pooled OR = 1.52; 95% CI 1.32-1.79) and frail persons (pooled OR = 2.62, 95% CI 1.81-3.79). Hyperpolypharmacy was also increased in prefrail (OR = 1.95; 95% CI 1.41-2.70) and frail (OR = 6.57; 95% CI 9.57-10.48) persons compared to robust persons. Only seven longitudinal studies reported data on the risk of either incident prefrailty or frailty in persons with baseline polypharmacy. A significant higher odds of developing prefrailty was found in robust persons with polypharmacy (pooled OR = 1.30; 95% CI 1.12-1.51). We found no papers investigating polypharmacy incidence in persons with prefrailty/frailty. CONCLUSIONS: Polypharmacy is common in prefrail and frail persons, and these individuals are also more likely to be on extreme drug regimens, i.e. hyperpolypharmacy, than robust older persons. More research is needed to investigate the causal relationship between polypharmacy and frailty syndromes, thereby identifying ways to jointly reduce drug burden and prefrailty/frailty in these individuals. PROSPERO REGISTRATION NUMBER: CRD42018104756.

Selective serotonin reuptake inhibiting antidepressants are associated with an increased risk of nonvertebral fractures.

BACKGROUND: Fractures related to osteoporosis and falling constitute a major health problem in the elderly population. Exposure to antidepressants is associated with an increased risk of falls and fractures, but most previous studies incriminate tricyclic antidepressants (TCAs) rather than selective serotonin reuptake inhibitors (SSRIs). OBJECTIVE: To examine the association between antidepressants, including TCAs, SSRIs, and other antidepressants and the risk of nonvertebral fractures in elderly. DESIGN: Prospective population-based cohort study. SETTING: The Rotterdam Study, consisting of 7983 individuals aged 55 years and older. PARTICIPANTS: All persons from the Rotterdam Study. RESULTS: One thousand two hundred nineteen persons experienced a nonvertebral fracture, 25 during TCA use and 18 during SSRI use. After adjustment for age, sex, lower-limb disability, and depression, the risk of nonvertebral fracture was 2.35 (95% confidence interval, 1.32-4.18) for current users of SSRIs compared with nonusers of antidepressants. Multiple adjusting for many possible risk factors did not affect the association. To deal with potential confounding by indication, we subsequently restricted the analysis to antidepressant users (n = 1217). Compared with past users of TCAs or SSRIs, current users of SSRIs had a 2.07-fold (95% confidence interval, 1.23-3.50) increased risk of fracture, which further increased with prolonged use. In this analysis, depressive state at baseline and during follow-up did not play a role, suggesting absence of confounding by indication. The use of TCAs was associated with an increased fracture risk that decreased with prolonged use. CONCLUSIONS: Not only users of TCAs but also of SSRIs have a significantly increased risk of nonvertebral fractures, in SSRI users especially after prolonged use. Despite fewer early adverse effects of SSRIs, physicians treating elderly depressive patients should be aware of the unfavorable long-term consequence of SSRIs on fracture risk.