American Geriatrics Society (AGS) 2011 Annual Scientific Meeting
May 11-14, 2011; National Harbor, MD
Cognitive Impairment Observed in Elderly Persons With Low Vitamin D Levels
National Harbor, MD—Global cognitive function appears to decline more rapidly in elderly persons with low vitamin D levels, according to a subanalysis from the Health ABC (Dynamics of Health, Aging, and Body Composition) study presented at the AGS annual scientific meeting. This study was a Presidential Poster Awardee for outstanding research in epidemiology.
Health ABC is a longitudinal study initiated in 1996 to evaluate physical and mental changes in ~3000 healthy community-dwelling black and white adults 70 to 79 years old. Ancillary studies are ongoing, including one examining the relationship between vitamin D levels and falls, factures, and function.
Investigators reviewed data for 2786 well-functioning Health ABC enrollees. At years 1 and 5, researchers administered the Digit Symbol Substitution Test (DSST) and the Modified Mini-Mental State Examination (3MSE), which assesses global cognition. In year 2, they tested serum 25-hydroxyvitamin D levels. Approximately 33% (916) of study participants had levels <20 ng/mL, indicating vitamin D deficiency; ~35% (982) had levels between 20 and 30 ng/mL, which was suboptimal; and the remaining 888 participants had vitamin D levels ≥30 ng/mL, considered sufficient.
Comparing 1-year 3MSE scores with vitamin D levels revealed the lowest adjusted mean scores in vitamin D-deficient patients (88.9); patients with suboptimal levels were in the middle (88.9), and patients with normal vitamin D levels scored highest (90.8; P = .02). DSST results followed the same pattern, with a mean score of 35.3 for deficient patients as compared with 35.8 for the suboptimal group and 37.0 for the sufficient group (P = .01).
At 5 years’ follow-up, study author Kaycee M. Sink, MD, MAS, Director, Kulynych Memory Assessment Clinic, and Associate Professor of Medicine, Section of Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston Salem, NC, said in an interview with Clinical Geriatrics that they found “Vitamin D deficiency was associated with greater declines in [3MSE scores]. However, change in performance on [the DSST], a test of speed of processing and working memory, was not correlated with vitamin D level.” For the vitamin D-deficient group, 3MSE scores dropped by a lower adjusted mean of -1.05, as compared with -0.75 for the suboptimal group and -0.23 for the sufficient group (P = 0.05). “One of the strengths of the study is that we measured cognition several times, so we can say that people who were low in vitamin D were more likely to have cognitive decline over the next several years than those with normal vitamin D levels,” Dr. Sink explained. She said that because “this study is observational…we cannot draw the conclusion that having a low vitamin D level causes cognitive decline.” She added, “Nor do we know if the people who declined were still low in vitamin D at the follow-up testing.”
Dr. Sink suggested screening vitamin D levels in all older adults at risk of deficiency and treating patients with low levels, although “whether taking vitamin D will improve cognition in someone with memory loss or other cognitive impairment is still unknown.” The authors said that this is something future studies should investigate.
This research was supported in part by the Intramural Research Program of the NIH, NIA and contracts N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106. Grant R01 AG029364 also contributed.
Advance Directives Important for Geriatric Patients
National Harbor, MD—Nearly two-thirds of geriatric patients hospitalized for cancer at Mount Sinai Medical Center in New York from 2006-2010 completed an advance directive, which is markedly higher than the typical ~21% completion rate reported in previous studies. Samantha Zuckerman, a rising third-year medical student at Mount Sinai School of Medicine, and colleagues presented their quality analysis on advance directive use in elderly patients receiving palliative care for cancer in a poster session at the recent AGS annual scientific meeting. The study was a Presidential Poster award winner for outstanding research concerning ethics.
The researchers identified charts of hospitalized patients >65 years of age who received a palliative care consult for cancer at Mount Sinai. They randomly selected 205 for analysis, of which 60% (123) had an advance directive. They examined data for correlations between completion of an advance directive and patient demographics, cancer diagnosis and treatment preferences, comorbidities, and reason for the consultation. A multivariate analysis found that patients were significantly more likely to have an advance directive if they had requested a consultation to establish a plan of care (odds ratio [OR], 2.664; P = .045).
“Our study indicated that Hispanic patients and/or patients who were diagnosed with cancer within a year of hospitalization but not during hospitalization were least likely to have an advance directive,” said Zuckerman in an interview with Clinical Geriatrics (OR, 0.319; P = .0403; and OR, 0.293; P = .0012, respectively). The study was not designed to determine why Hispanic patients completed an advance directive less often, but Zuckerman said the research team conjectured that it might be because of “language barriers, obstacles to accessing medical care, and cultural differences.”
The poster abstract noted that the study’s sample size was too small to draw statistically significant conclusions for each data set analyzed. The investigators did observe nonsignificant correlations between advance directive completion and age, discharge site, cancer type, Karnofsky Performance Status, and history of dementia and delirium.
Zuckerman said that one reason for the substantially higher advance directive completion rate seen in their study might be the narrow range of patients included. “This specific population may have a higher rate of advance directive completion because they have a serious diagnosis, may be near the end of life, and may have started to have conversations about their wishes at the end of life,” she explained.
Although all patients should discuss advance directives with their physician and their families, Zuckerman said, “It is especially important to have these conversations in the population we studied—hospitalized geriatric patients with a primary diagnosis of cancer.” She noted that such patients “are at high risk for medical complications and limited prognosis.” Zuckerman said that their study also shows the need for more research to determine why Hispanic patients with cancer and patients who received a diagnosis <1 year earlier appear less likely to have an advance directive.
Supported by the MSTAR Program at Mount Sinai School of Medicine; Patricia S Levinson Fellowship Grant at Mount Sinai School of Medicine.
Fidaxomicin Reduces Risk of Recurrence in Patients With Clostridium difficile
National Harbor, MD—In patients older than 40 years, the effectiveness of fidaxomicin and vancomycin therapies for Clostridium difficile infection (CDI) appears to decline parallel to increasing age, with the worst treatment responses observed in those age 71 to 80 years reported authors of a poster session presented at the recent AGS annual scientific meeting. fidaxomicin was significantly better than vancomycin at preventing CDI recurrence regardless of age.
The study randomized 999 patients age 18 to 94 years with CDI to 10 days of oral vancomycin 125 mg 4 times daily (n = 518) or fidaxomicin 200 mg twice daily plus placebo twice daily (n = 481). Study participants had a new diagnosis of CDI or an initial recurrence that was first diagnosed no more than 90 days prior to randomization. All patients had failed on an initial therapy regimen comprising ≥3 days of metronidazole and received no other prior medication for CDI. For analysis purposes, patients were grouped by age: 18 to 40 years (n = 143); 40 to 50 years (n = 122); 51 to 60 years (n = 168); 61 to 70 years (n = 192); 71 to 80 years (n = 209); and 81 to 94 years (n = 165).
The likelihood of cure was greatest in patients age 18 to 40 years and poorest for those age 81 to 94 years. Clinical cure rates were similar with both treatments regardless of age. In patients older than 40 years, the odds ratio for cure declined and the time to resolution of diarrhea symptoms increased progressively with age. “Each decade above age 40 was associated with an ~17% decrement in clinical cure of CDI,” the authors wrote.
Recurrence is common in older patients treated for CDI, and this investigation showed that treatment failure and recurrence rates increased in accordance with age starting at 40 years. The researchers observed a significant 64% reduction in the rate of recurrence at 4 weeks among patients treated with fidaxomicin compared with those given vancomycin (P <.001) and a 54% reduction in recurrence overall with fidaxomicin (P <.001). Fidaxomicin was associated with declines in recurrence across all age groups except the 81-to-94 age bracket, which had a similar rate of recurrence with both treatments. Overall, fidaxomicin was associated with a 1.9-fold increased probability of cure without recurrence (P <.001).
A subanalysis of patients positive for the seemingly more virulent BI/027 strain of C. difficile showed that its prevalence increased with age, with nearly double the rate of BI/027-positive CDI found in adults age >60 years versus adults ≤60 years (P <.001). The subgroup of cured patients with stool samples positive for the BI/027 strain were 74% more likely to experience recurrence than those who tested negative (P = .013), although the reasons for this were unclear.
In concluding, the investigators noted that “fidaxomicin treatment was associated with a significant benefit over vancomycin for the outcome of recurrence across all age groups.” They said that their findings indicate the need for a broad assessment of CDI prevention and treatment strategies, particularly in elderly patients, who typically have more severe disease and an increased risk of mortality.
Research sponsored by Optimer Pharmaceuticals, Inc.
Workshop Helps Medical Students Identify Elder Mistreatment
National Harbor, MD—Elder abuse is a common yet underreported problem. Researchers at the Montefiore Medical Center in Bronx, NY, developed a workshop designed to help medical students identify elderly patients who are mistreated and to document their observations. Lead author Karin Ouchida, MD, who was affiliated with Montefiore while the study was conducted but is now an Assistant Professor of Medicine, Division of Geriatrics and Gerontology, Weill Cornell Medical Center/New York Presbyterian Hospital, and associates enrolled 378 medical students in the workshop between 2008 and 2010 and presented their data at the AGS annual scientific meeting for the 157 students who were enrolled in 2009-2010. The study was a Presidential Poster Awardee for outstanding research in geriatrics education.
In an interview with Clinical Geriatrics, Ouchida said that the majority of participants considered the session beneficial on multiple levels. “In year 2 of the workshop, 94% of participants agreed or strongly agreed that the training increased their ability to interview victims and 92% agreed or strongly agreed it helped them to interview caregivers.”
The 2.5-hour workshop was administered during a 2-week Geriatrics clerkship. It included a didactic lecture followed by two simulations in which students practiced assessing elderly patients for mistreatment, documenting the exchanges; in one scenario, participants discussed their concerns with caregivers. Ouchida described the simulated patient scenarios as critical. “They allow students to practice asking sensitive and difficult questions in a safe environment,” she explained. “Students also receive immediate feedback on their communication skills from the people playing the roles of the patient/caregiver and from a geriatric psychiatrist and geriatrician.”
The facilitators also reviewed the quality of the students’ documentation. “We made it a goal of the workshop to train these future physicians to appropriately document their elder mistreatment assessments,” said Ouchida. She said that documentation is especially important when patients transition between providers because it makes the new provider aware of mistreatment concerns.
Using a 1-5 scale, the research team had students assess 11 specific aspects of the course and the extent to which they felt each one had improved their ability to evaluate geriatric patients for abuse. Regarding the didactic lecture, a substantial majority of students agreed or strongly agreed that it had improved their ability to define elder abuse and neglect (98%; mean score [MS], 4.53), taught them to identify red flags for abuse and neglect (99%; MS, 4.53), helped them to appreciate the physician’s role in assessing elders for mistreatment and documenting their observations (95%; MS, 4.42), and showed them how to document an assessment (88%; MS, 4.26).
The red flags for abuse and neglect discussed in the workshop include “frequent hospitalizations or use of the emergency department; nonadherence to medical advice or medication regimens; weight loss or malnutrition; evidence of dehydration; sudden changes in advance directives, such as the healthcare proxy; injuries that are inconsistent with a given history; and a caregiver who is reluctant to leave the older adult alone for an interview or exam,” said Ouchida. “An effective training program for medical students should cover all of the red flags,” she noted. Although the program was targeted to future physicians, Ouchida said that Montefiore has also made it available to its hospitalists and emergency medicine physicians.
Supported by the United Jewish Appeal-Federation.
New Advances in Osteoporosis Therapy in the Very Elderly, Frail Elderly, and Institutionalized Elderly
National Harbor, MD—A symposia at the recent AGS annual scientific meeting reviewed the etiology of osteoporosis, the effects of aging on bone health, and recent advances in osteoporosis therapy for high-risk groups of elderly patients (ie, the very old, the frail, and the institutionalized elderly).
The World Health Organization (WHO) defines osteoporosis as a bone mineral density (BMD) score 2.5 or more standard deviations lower than the bone mass of an average young adult. However, “Bone mineral densitometry is not the whole story,” said moderator Bruce R. Troen, MD, Interim Chief, Division of Gerontology and Geriatric Medicine, University of Miami Miller School of Medicine, FL. Advancing age contributes greatly to BMD loss, explained Dr. Troen. Statistics show that the rate of osteoporosis in women age ≥80 years is 10 times the rate seen in women age 50 to 59 years (44% vs 4%, respectively). Although BMD declines more slowly over time in men, their risk for osteoporosis also increases significantly with age.
The Bone Remodeling Process
Bones continually undergo remodeling, said Dr. Troen, with osteoclasts responsible for the resorption of old bone and osteoblasts facilitating the formation of new bone. Interactions between osteoblasts and osteoclasts are critical to maintaining the balance between resorption and formation. Bone turnover accelerates in women following menopause and in men with decreased androgen production. Calcium and vitamin D deficiencies and elevated levels of parathyroid hormone and local resorbing factors also stimulate greater resorption. Age-related changes such as increased fat accumulation in the bone marrow and decreases in local and systemic growth factors can inhibit replenishment of osteoblasts, which delays the rate at which new bone forms. Receptor activator of nuclear factor-кB ligand (RANKL) plays a pivotal role in regulating osteoclast activity. Binding of RANKL to the RANK receptor on osteoclastic precursors mediates these cells’ differentiation, proliferation, and survival. In addition, several stimulatory and inhibitory cytokines and growth factors act as critical mediators of osteoblast-osteoclast formation and coupling. When bone resorption outpaces bone replacement, BMD declines; bones become thinner, develop abnormalities in their microarchitecture, and become more likely to crack or break. Bisphosphonates can be used to treat the loss in BMD because they inhibit osteoclast formation and function, thereby restoring—at least in part—the balance between bone formation and bone resorption. Denosumab, which is a monoclonal antibody that binds RANKL, acts similarly to maintain BMD by inhibiting osteoclastogenesis and subsequent bone resorption.
In summary, bone remodeling depends on critical osteoblast and osteoclast interactions in the bone metabolic unit. Osteoblast-osteoclast coupling is mediated by both stimulatory and inhibitory cytokines and growth factors, including RANKL, M-CSF, BMP, FGF, IGF, and PDGF. Interestingly, vitamin D and parathyroid hormone mediate the early stages of both osteoclast and osteoblast formation, said Dr. Troen.
Osteoporosis accounts for >1.5 million fractures annually, typically involving the vertebrae, hip, distal forearm, pelvis, and ribs, said Dr. Troen. One-third of women and one-sixth of men suffer a hip fracture by age 90 and 50% of these patients will require long-term care. In his presentation on clinical trials with zoledronic acid (ZA) and denosumab, Kenneth W. Lyles, MD, Professor of Medicine, Duke University, Durham, NC, noted that women >80 years of age account for >30% of fragility fractures and 60% of hip fractures. Hip fractures cause serious morbidity and mortality, with a 15% to 25% increase in mortality rate in the first year, he said.
Cathleen Colón-Emeric, MD, MHS, Associate Professor of Medicine, Duke University Medical Center, Durham, NC, spoke on the challenges of managing osteoporosis in geriatric patients. Those residing in nursing homes; with renal or cognitive impairment; with comorbidities such as Parkinson’s disease, prostate cancer, or stroke; or who have vitamin D deficiency have an increased relative risk (RR) of fracture. Guidelines from the National Osteoporosis Foundation (NOF) and the American Association of Clinical Endocrinologists (AACE) on managing postmenopausal osteoporosis base treatment recommendations on fracture risk. After inputting data on average life expectancy, body mass index, sex, race, country, and bone-related risk factors, the WHO FRAX tool () calculates the 10-year risk of hip fracture and major osteoporotic fracture. FRAX can be used with or without BMD. The Garvan Institute nomogram (www.garvan.org.au/bone-fracture-risk) calculates 5- and 10-year risks of fracture based on BMD, age, and history of fractures and falls. Dr. Colón-Emeric said that fracture prediction models might underestimate fracture risk for older patients if they do not weigh the likelihood of falls, comorbidities, functional status, and environment. Algorithms that do not consider the elderly patient’s life expectancy or race might overestimate risk. The bottom line is that fracture prediction models are useful in discussions with patients, but they need a “geriatric adjustment” (up based on additional risk factors and down based on race and low life expectancy for their age). In addition, it is unclear whether persons with osteopenia who are at high risk of fracture benefit to the same extent as those with lower BMD.
Preventing Fractures and Treating Osteoporosis
Dr. Troen said that calcium and vitamin D supplementation have been found to reduce the rate of hip fractures among elderly patients in the community and in institutions. For very elderly or frail elderly patients with osteoporosis, he encouraged interventions that enhance or maintain mobility, prevent falls and fractures, and preserve quality of life.
Dr. Colón-Emeric noted that the NOF and AACE guidelines suggest drug treatment for patients whose 10-year risk of major fracture >20% or with a 10-year risk of hip fracture >3%. She cautioned against presuming that very old patients benefit less from treatment because of their shorter life expectancies. Given their high absolute risk of fracture, treatment is reasonable in ambulatory patients with a life expectancy ≥2 years.
Several drugs are approved by the US Food and Drug Administration (FDA) to treat osteoporosis. Dr. Lyles divided them into antiresorptive agents (eg, bisphosphonates, denosumab, raloxifene, estrogen) and anabolic agents (eg, teriparatide). Antiresorptive agents decrease bone resorption and overall bone remodeling, which results in stabilization or improvement in BMD. Anabolic agents stimulate production of bone tissue. Teriparatide is the only FDA-approved agent in this class.
Alendronate, risedronate, and ZA have been found to decrease the risk of fracture in elderly patients with osteoporosis as compared with placebo. In one study of postmenopausal women, alendronate reduced the RR of hip fracture by 53%, clinical vertebral fracture by 45%, and wrist fracture by 31%. Risedronate has been shown to prevent fractures in women with osteoporosis age ≥80 years. A post hoc analysis of three randomized controlled trials found that it significantly reduced the risk of new vertebral fractures at 1 (P <.001) and 3 years (P <.003) as compared with placebo.
The HORIZON Pivotal Fracture Trial compared a yearly dose of ZA (5 mg, infused) with placebo in women 65 to 89 years old with osteoporosis. At 3 years, patients treated with ZA had a 77% reduction in risk of clinical vertebral fracture (P <.001); a 25% reduced risk of nonvertebral fracture (P = .002); and a 41% lower risk of hip fracture (P = .0024). The HORIZON-Recurrent Fracture Trial compared ZA with placebo in 2127 men and women age ≥50 years who underwent surgical repair of a hip fracture. ZA reduced the 3-year clinical fracture risk by 35% and all-cause mortality by 28%. Adverse events were similar in both arms. A post hoc analysis of the female osteoporosis patients age ≥75 years found significantly lower rates of clinical vertebral and nonvertebral fracture among those taking ZA.
Dr. Lyles said that ZA causes acute-phase reactions in 1.5 to 4 of every 10 patients and osteonecrosis of the jaw (ONJ) in 20 of every 100,000 patients. In addition, atypical subtrochanteric femur fractures occur in 2 of 100,000 patients treated with any bisphosphonate for 2 years and in 78 of 100,000 patients treated with any bisphosphonate for 8 years.
Future research with ZA should focus on whether the gains in spine and hip BMD seen with the concomitant administration of teriparatide and ZA result in further reduction in fracture rates, as well as whether the effect on mortality reduction in patients with surgical repair of a hip fracture with ZA and an oral bisphosphonate can be developed into a therapy for patients with osteoporosis or possibly other frail patients, said Dr. Lyles.
The phase 3 FREEDOM trial randomized 7868 postmenopausal women age 60 to 90 years (mean, 72.3+5.2 years) with osteoporosis to denosumab (60 mg, subcutaneous) or placebo every 6 months for 36 months. Patients in both groups received calcium and vitamin D supplements. At 3 years, denosumab reduced the rate of new vertebral fractures (RR, 0.32; P <.001), the rate of new hip fractures (RR, 0.60; P = .0362), and the rate of new nonvertebral fractures (RR, 0.80; P = .0106). Denosumab also delayed the time to first nonvertebral fracture and to first hip fracture. A subgroup analysis found no significant differences in rates of nonvertebral fractures or new vertebral fractures between patients <75 years and patients >75 years. In the FREEDOM trial, similar rates of adverse events were observed between the two arms, although denosumab was associated with a higher rate of eczema versus placebo (3.0% vs 1.7%, respectively; P <.001). Dr. Lyles said that 3 of 1000 patients experience skin infections and 1 of 100,000 develop ONJ with denosumab use.
Regarding future research with denosumab should focus on whether further investigations will explain the reductions in the rate of concussions with denosumab and allow it to become a potential therapy to preventing falls and whether concomitant administration of denosumab with teriparatide could increase BMD in the spine and hip and reduce fracture rates. In addition, since denosumab has a more rapid offset of action when it is discontinued as compared with oral alendronate, Dr. Lyles asked whether this could be capitalized upon in a time when clinicians are reconsidering long-term bisphosphonate therapy.
In summary, Dr. Lyles told the audience that alendronate, risedronate, ZA, and denosumab reduce vertebral fracture rates in older postmenopausal women with osteoporosis, and that alendronate, ZA, and denosumab reduce other fracture rates in this group. Additional studies of osteoporosis therapies in elderly patients may reduce the burden of this illness and its associated morbidity and mortality.
Other Treatment Considerations
According to Dr. Colón-Emeric, only 20% of female nursing home residents receive osteoporosis medication. Approximately 70% with osteoporosis or hip fracture take calcium/vitamin D; 19% receive bisphosphonates; and 36% are given medication or hip protectors. Wide variation (0%-85%) in treatment exists between facilities, with medical directors citing costs and comorbidities as barriers. Multiple comorbidities, however, do not affect the efficacy or safety of osteoporosis therapy. Poor compliance is another obstacle, said Dr. Colón-Emeric, and is associated with a 46% increase in fracture rate. Patients with gastrointestinal symptoms are 50% more likely to discontinue osteoporosis medication.
Studies show that bisphosphonates increase BMD and may reduce the rate of hip fracture in patients with Parkinson’s disease; increase BMD and reduce hip fracture in patients who suffer from stroke; and increase BMD in patients with dementia. In men receiving androgen deprivation therapy for prostate cancer, small trials suggest that bisphosphonates preserve BMD and reduce skeletal complications. For renally compromised patients, she noted that denosumab is not renally cleared, and its label has no restrictions based on renal function. Bisphosphonates should only be given in patients with a glomerular filtration rate of >30-35 mL/min; in those with moderate renal impairment, intravenous bisphosphonates sometimes cause transient increases in creatinine levels but have no long-term renal effects.
AACE guidelines call for stopping treatment after 5 years in patients with a good BMD response, low fracture risk, and no additional fractures and to reassess them after 2 years off therapy. For patients with a high risk of fracture or who experienced a fracture while receiving therapy, said Dr. Colón-Emeric, AACE recommends 5 additional years of therapy. Clinicians should also consider stopping treatment when patients are no longer ambulatory, in those with a life expectancy <2 years, and if it is no longer consistent with their goals of care.
In summary, Dr. Colón-Emeric said that the presence of multimorbidity often indicates higher fracture risk and does not appear to impact treatment efficacy or harms. Regarding osteoporosis treatment in nursing homes, patients are at higher fracture risk and have the potential for greater benefit. The evidence base is incomplete, but supports treatment safety and efficacy. Treatment should be considered in this group for ambulatory or transfer-independent patients with a 2-year life expectancy, and treatment should include calcium, vitamin D, and fall prevention. It is important to balance the risks and benefits of treatment, although the benefits of fracture reduction outweigh the small risk of harm in most patients.
This activity was supported by an educational grant from Amgen.