JAMDA 14 (2013) 860e876

JAMDA journal homepage: www.jamda.com

Updates from the AMDA Meeting

Clinical Update on Nursing Home Medicine: 2013 Barbara J. Messinger-Rapport MD, PhD, FACP, CMD a, Julie K. Gammack MD b, David R. Thomas MD, FACP, AGSF, FGSA, CMD b, John E. Morley MB, BCh b, * a b

Cleveland Clinic, Section of Geriatric Medicine, Cleveland, OH Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, MO

a b s t r a c t Keywords: Antiresorptive drugs bisphosphonates hip fracture hypertension orthostatic hypotension depression undernutrition anorexia cachexia sarcopenia exercise pain behavioral symptoms psychological symptoms dementia

This is the seventh article in the series of Clinical Updates on Nursing Home Care. The topics covered are antiresorptive drugs, hip fracture, hypertension, orthostatic hypotension, depression, undernutrition, anorexia, cachexia, sarcopenia, exercise, pain, and behavioral and psychological symptoms of dementia. Copyright Ó 2013 - American Medical Directors Association, Inc.

Antiresorptive Drugs: Do Older Adults Need a Holiday? The 2 drug classes with the strongest evidence for hip fracture reduction are the bisphosphonate (specifically intravenous [IV] zoledronic acid) and the Receptor Activator of Nuclear Factor (RANKL, specifically denosumab) classes.1 The relatively good safety profiles and progressively lower cost of these drugs (particularly of generic oral bisphosphonates) have resulted in widespread use of these drugs in the middle-age and young-old population, with some use in frail elders, including use in the nursing home. Bone density increases rapidly with bisphosphonates, and the fracture efficacy begins within 12 months.2 The Horizon Recurrent Fracture Trial, enrolling elders within 90 days of a hip fracture, demonstrated not only a 35% reduction in new clinical fracture but also a 28% reduction in all-cause death over 3 years.3 Systematic review of fracture efficiency of bisphosphonates demonstrates a number needed to treat (NNT) of 10e21 to prevent vertebral fracture, and a NNT of about 90 to prevent hip fracture.4 Denosumab has a NNT of 21 for vertebral fracture and 334 for hip fracture.4 These drugs would not likely provide a clinical

The authors declare no conflicts of interest. * Address correspondence to John E. Morley, MB, BCh, Division of Geriatric Medicine, Saint Louis University School of Medicine, 1402 S Grand Blvd, M238, St. Louis, MO 63104. E-mail address: [email protected] (J.E. Morley).

benefit to elders with less than 1 year of life expectancy, but might provide a clinical benefit to elders with a life expectancy greater than 3 years, typical of about one-third of nursing home residents living in a facility longer than 3 months.5 Considerations of either initiating or suspending an osteoporosis drug in long term care may include a greater emphasis on the high absolute risks of hip fractures, the lower life expectancy, and potentially the greater incidence of dental problems, dysphagia, impaired mobility, and chronic kidney disease (CKD) in this cohort compared with individuals enrolled in the seminal randomized controlled trials of these drugs. The understanding of the risks of bisphosphonates has evolved since the Food and Drug Administration (FDA) approved the first bisphosphonate, alendronate. Initially approved for treating osteoporosis for 3 years, duration expanded to 5 years and indications expanded to prevention of osteoporosis. As the bisphosphonates reached a broader population, warnings emerged regarding musculoskeletal problems, osteonecrosis, and atypical fractures.6 Most recently, the FDA, based on extensive review,7 recommended that prescribers consider discontinuation of the bisphosphonates after 3e5 years. The antiresorptive drug denosumab is particularly attractive for older adults with chronic kidney disease (CKD) because the drug is cleared by a nonrenal mechanism, although efficacy in CKD is not proven.8 Although not incorporated as avidly into bone as the bisphosphonates, denosumab does bind to high turnover-rate areas

1525-8610/$ - see front matter Copyright Ó 2013 - American Medical Directors Association, Inc. http://dx.doi.org/10.1016/j.jamda.2013.09.015

B.J. Messinger-Rapport et al. / JAMDA 14 (2013) 860e876

such as the jaw. The risk of osteonecrosis of the jaw from denosumab is about the same as from the bisphosphonates.9 Denosumab also increases the risk of atypical femoral fractures10 and received an FDA warning in 2012. Denosumab has been associated with an increase in serious infections and possibly an increased cancer risk.11 Atypical fractures, a risk for both denosumab and the bisphosphonates, are relatively uncommon, perhaps occurring in 3e50 cases per 100,000 patient-years.10 The mechanism is likely an imbalance between bone resorption and bone deposition caused by the drug. No definitive sex, age, or clinical characteristic is implicated, but retrospective reviews suggest that atypical fractures are associated with prodromal symptoms; suboptimal serum 25-hydroxy Vitamin D levels, relatively long durations for therapy (9 years), relatively young age (67 years), and bone density in the nonosteoporotic range.12 The risk of an atypical fracture is incurred as early as the first year of therapy but may decline rapidly when the drug is discontinued.13 The study of a bisphosphonate holiday has been built into 2 major trialsdthe Fracture Intervention Trial Long Term Extension (FIT/FLEX) study14 and the extension of the Horizon study.15 The findings of the FIT/FLEX have been subject to much interpretation. In women randomized to alendronate for 5 years then randomized to alendronate or placebo, bone density (the primary outcome of the extension study) declined in the hip and spine in the placebo group, and bone turnover markers rose, although not to pretreatment values.14 Monomorphic vertebral fracture frequency, the adjucated clinical outcome (albeit an exploratory outcome of the extension) was the same in the alendronate and the placebo group at the 10-year point. Although a larger “clinical” vertebral fracture risk was found in the placebo group at the 10-year point,16 we cannot consider this a true finding of the study. More than one-quarter of “clinical” fractures found outside the study could not be verified by the study radiologists as monomorphic fractures.17 There was also a report of a reduction in nonvertebral fractures in those women with low bone density with a pre-existing fracture on alendronate compared with placebo in the extension arm.14,16 However, the large number of subgroups makes this finding less meaningful. Additionally, women with very low bone density, T < 3.5, or whose hip bone density was lower at the end of the Fracture Intervention Trial (FIT) study than at baseline, were not allowed to enter the extension of the trial, limiting the generalizability of bisphosphonate holidays.14 In the Horizon trial, 2629 women were randomized to zoledronic acid (ZA) or placebo. At the 3-year point, those on ZA were randomized either to placebo or to continue another 3 years of ZA, with a primary endpoint of bone density and a secondary endpoint of fracture.15 No women over 93 years old were offered a bisphosphonate holiday; again, generalization to the very aged is limited. In the extension study, bone density was higher in the femoral neck and lumbar spine in women on ZA for 6 years compared with 3 years.15 There was a 50% reduction in risk for the adjucated endpoint, a monomorphic vertebral fracture in the ZA arm compared with the placebo arm.15 Atypical fractures did not occur during these studies; the rate is low enough that we only have case series and large database data to analyze. There is no trial data to guide the timing of a safe resumption of bisphosphonates once a holiday is offered, although clinical metabolic markers such as urinary collagen type 1 cross-linked Ntelopeptide (NTx) and/or urinary/serum collagen type 1 cross-linked C-telopeptide (CTx) are used empirically.18 There is no research data at this time to help assess the advantages of a drug holiday on dental complications, nor disadvantages to resuming the drug after a holiday, although empiric guidelines exist.19 The clinical implications from these studies suggest that bisphosphonates should be used cautiously, if at all, for preventing osteoporosis. However, for those frail elders with both a high fall risk and a high fracture risk (for

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example, an elder with severe osteoporosis and a neurodegenerative disease such as Parkinson’s disease or dementia), a holiday of therapy could mean a new debilitating vertebral fracture. In summary, clinicians may consider initiating antiresorptive drug therapy for those frail elders with a life expectancy of at least 3 years who are mobile and receptive to another medication. Those with dysphagia may be safer with the intravenous rather than oral bisphosphonate. The intravenous route may also be safer and more effective in those persons with cognitive impairment and inadequate supervision of medication. Elders with osteoporosis and CKD may be offered denosumab, although the efficacy in CKD has not been proven. Suspending drug therapy after 5 years of oral bisphosphonate therapy, 3 years of IV zoledronic acid, or 3 years of subcutaneous denosumab would be reasonable in all but the highest risk individuals, such as those with a T score < 3.5 standard deviation (SD). Rise in clinical markers such as NTx may signal a need to resume the drug. Consideration of adjunct interventions to reduce injurious fall risk is also important. Aggressive fracture risk reduction may involve interventions with level A and B evidence such as environmental modifications by a professional, exercise prescription possibly including physical therapy, vision assessment and potential cataract surgery, use of vitamin D 800 U daily, and polypharmacy reduction.20 Polypharmacy is particularly important in long term care because more than one-half of elders are prescribed 9 or more medications.21 But it might be reasonable to specifically reassess drugs commonly prescribed to frail elders that lower bone density or raise the risk for falls or fracture. Proton pump inhibitors are associated with an increased risk for hip fracture22 and may attenuate the benefits of alendronate.23 Selective serotonin reuptake inhibitors are associated with an increased risk of lower bone density24,25 and hip fracture.26 There is conflicting evidence for a reduced impact of newer vs older anti-epileptic drug use on bone density in adults.27 Cholinesterase inhibitors are associated with an increased risk of syncope, although the effect on fracture rate is unclear.28,29 Falls may be more likely with aggressive insulin management of diabetes.30 Aggressive targets of hypertension treatment may be a problem for older adults given the high prevalence of orthostatic hypotension, particularly in the dementia population.31 Identifying a Treatment Blood Pressure Target for Frail Elders The Systolic Hypertension in the Elderly Program (SHEP), 32 Systolic Hypertension in Europe (Syst-Eur),33 and Hypertension in the Very Elderly Trial (HYVET)34 studies demonstrated a reduced risk of stroke of 30%e42% compared with placebo; a reduction in cardiovascular events of 26%e34% compared with placebo, and (in the SHEP and HYVET studies), a reduction in the incidence of heart failure by 54% and 64%, respectively. Most studies have a very limited number of very old adults (age >75 or 80 years). Additionally, in the only large and multinational hypertension study specifically recruiting elders 80 years and over,34 potential subjects with heart failure, CKD, and dementia were excluded, as were those residents of nursing homes. Thus, it may be a leap of faith to extend results of hypertension studies to the frail elders who are often the recipients of drugs tested on a much healthier population. The target of hypertension treatment in the US, based on the Seventh Joint National Commission recommends treating to a target of

Clinical update on nursing home medicine: 2013.

This is the seventh article in the series of Clinical Updates on Nursing Home Care. The topics covered are antiresorptive drugs, hip fracture, hyperte...
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