Chapter 23. Geriatric Endocrinology

• ADA American Diabetes Association
• BG Blood glucose
• BMD Bone mineral density
• BMI Body mass index
• CHF Congestive heart failure
• CRH Corticotropin-releasing hormone
• CVD Cardiovascular disease
• DHEA Dehydroepiandrosterone
• DPP IV Dipeptidyl peptidase IV
• FFA Free fatty acids
• GFR Glomerular filtration rate
• GIP Glucose insulinotropic peptide
• GLP1 Glucagon-like peptide 1
• GLUT Glucose transporter
• HHNS Hyperglycemic hyperosmolar nonketotic syndrome
• IGT Impaired glucose tolerance
• LH Luteinizing hormone
• LHRH Luteinizing hormone–releasing hormone
• NHANES National Health and Nutrition Examination Survey
• NPH Neutral protamine Hagedorn
• NSAIDS Nonsteroidal anti-inflammatory drugs
• OGTT Oral glucose tolerance test
• PTH Parathyroid hormone
• RANK-L Receptor activator of nuclear factor kappa B ligand
• SERM Selective estrogen receptor modulator
• SIADH Syndrome of inappropriate antidiuretic hormone
• T3 Triiodothyronine
• T4 Thyroxine
• TLI Therapeutic lifestyle intervention
• TSH Thyroid-stimulating hormone
• UKPDS United Kingdom Prospective Diabetes Study

Individuals over age 65 comprise the fastest-growing segment of the United States population; each day this group increases by more than 1000 people. This increase has led to a remarkable situation—of all the people who have ever lived to the age of 65, more than two-thirds are still alive. Thus, it is becoming increasingly important for the endocrinologist to understand how endocrine physiology and disease may differ in the elderly.

Before considering specific endocrinologic conditions in the elderly, however, it is worthwhile to review some general principles that account for many of the age-related changes in disease presentation in the elderly. First, aging itself—in the absence of disease—is associated with only a gradual and linear decline in the physiologic reserve of each organ system (Figure 23–1). Because the reserve capacity of each system is substantial, age-related declines have little effect on baseline function and do not significantly interfere with the individual's response to stress until the eighth or ninth decade. Second, because each organ system's function declines at a different physiologic rate and because 75% of the elderly have at least one disease, endocrine dysfunction in the elderly often presents disparately, with initial symptoms derived from the most compromised organ system. For example, hyperthyroidism in an elderly patient with preexisting coronary and conduction system disease may present with atrial fibrillation and a slow ventricular response, whereas in another equally hyperthyroid patient with a prior stroke, it may present with confusion or depression; neither patient may tolerate hyperthyroidism long enough for the classic thyroid-related manifestations (eg, goiter) to become apparent. Third, elderly patients often have multiple diseases and take many medications that may mimic or mask the usual presentation of endocrine disease.

The prevalence of thyroid disease in the elderly is approximately twice that in younger individuals, with hypothyroidism ranging from 2% to 7% and hyperthyroidism affecting up to 2% of older individuals. The Whickham Survey of 21,000 adults in Great Britain and its follow-up study, conducted between 1972 and 1993, reported that the incidence of overt hypothyroidism was increased 10-fold in women age 75 and older when compared to women in their twenties. In the NHANES 1999 to 2002 survey (N=4392) the overall prevalence of hypothyroidism was 3.7% (includes overt and mild) including a prevalence of 5.5% for individuals age 50 to 79 years and 12.1% for those age 80 and older. Individuals age 80 and older had five times greater probability for developing hypothyroidism (OR=5.0, p =0.0002) compared to those 12 to 49 years of age. In addition, some studies suggest that up to 9% of hospitalized elderly patients have overt thyroid disease. Subclinical hypothyroidism—normal serum levels of thyroid hormones (thyroxine, T4; triiodothyronine, T3) with an elevated level of thyroid-stimulating hormone (thyrotropin) (TSH)—is more prevalent, with estimates of 6% to 13% in the elderly (Figure 23–2), and is higher in women than in men. The NHANES III data (N=16,533) suggests that the distribution of TSH shifts to a higher concentration with age and therefore the prevalence of subclinical hypothyroidism may be overshadowed (see Figure 23–3). In the elderly, the progression from subclinical to overt hypothyroidism is roughly 2% to 5% per year. Subclinical hyperthyroidism—normal serum thyroxine with suppressed serum TSH levels—may be found in approximately 2% of elderly subjects (Figure 23–2). The rate of progression to overt hyperthyroidism is less clear. Finally, the overall prevalence of thyroid hormone use in older adults is approximately 7% (10% in women and 2% in men).

There are few major age-related changes in the physiology of the hypothalamic-pituitary-thyroid axis (Chapters 4 and 7). There are slight age-related increases in serum TSH levels (see Figure 23–3) and decreases in total T4. TSH release remains pulsatile, although the nocturnal rise in serum TSH appears to be blunted with age. There is a slight age-related decline in serum T3, but values usually remain within normal limits. The effect of age on the release of TSH by thyrotropin-releasing hormone is less clear, but most recent studies show little clinically relevant change in either sex. The 24-hour radioiodine uptake is also not significantly altered with age. Thyroid antibodies are common in older women (prevalence up to 25%, Figure 23–4), but their presence does not serve as a specific screening test for thyroid disease. The presence of thyroid antibodies (occult thyroid dysfunction) may skew the upper limit of TSH in the African American, Caucasian, and Mexican American ethnic groups (see Figure 23–4).

The United States Preventive Services Task Force concluded that there was insufficient evidence to recommend routine screening for thyroid disease in adults. Furthermore, there is no consensus regarding screening in the elderly. A scientific review panel suggests case finding for screening older patients at high risk (eg, family history, personal history, radiation, and other risk factors). The American Thyroid Association recommends that adults be screened by serum TSH determination every 5 years. A consensus statement from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society recommends routine screening for subclinical thyroid dysfunction in adults. However, it is reasonable to measure TSH at any time in older individuals who present with atypical symptoms of thyroid disease such as exacerbation of cardiac symptoms, change in mental status, falling, or onset of depression. Despite the sensitivity of the TSH assay, further evaluation with a free T4 or total T4 is often required because up to 98% of elderly subjects with mildly suppressed TSH levels do not have thyrotoxicosis.

Hyperthyroidism

Clinical Features

With age, the prevalence of Graves disease decreases (although it remains the most common cause of hyperthyroidism), and the prevalence of multinodular goiter and toxic nodules increases. Elderly hyperthyroid patients tend to present with symptoms or complications related to the most vulnerable organ system—usually the cardiovascular system (atrial fibrillation, congestive heart failure, angina, and acute myocardial infarction) or the central nervous system (apathy, depression, confusion, or lassitude). The hypercatabolic state also causes muscle wasting, particularly of the quadriceps, thereby increasing the risk of falls. Occasionally, hyperthyroid elderly patients present with gastrointestinal symptoms, but these differ from those seen in younger patients because they include constipation, failure to thrive, anorexia, and weight loss. Because of degeneration of the sinus node and fibrotic changes in the cardiac conduction system, older patients are less likely than younger ones to present with palpitations (Table 23–1). However, a very low serum TSH concentration is associated with a threefold higher risk of atrial fibrillation in the subsequent decade. Hyperthyroidism is also associated with bone loss and fractures.

The physical signs of hyperthyroidism also differ in the elderly (see Table 23–1). Sinus tachycardia is less frequent; the thyroid feels normal in size or is not palpable in two-thirds of patients; and lid lag is uncommon. Ophthalmopathy is less common, not only because Graves disease occurs less often, but also because, even with Graves disease, ophthalmopathy occurs less frequently in the elderly. However, although they are less common in the elderly, some findings appear to be highly suggestive of hyperthyroidism. These include increased frequency of bowel movements, weight loss despite increased appetite, fine finger tremor, eyelid retraction, and increased perspiration. Lid lag is uncommon but if found, it is highly suggestive of hyperthyroidism (specific).

Diagnosis

As in younger patients (Chapter 7), the diagnosis is usually confirmed by standard thyroid function tests, beginning with a depressed TSH level as measured by a sensitive immunoradiometric or chemiluminescent assay. There are potential pitfalls, however. Hospitalized elderly patients who are acutely ill (but euthyroid) may have a suppressed serum TSH. Further, other thyroid function tests should help rule out hyperthyroidism. T3 toxicosis may be more difficult evaluation to diagnose because concomitant nonthyroidal illness is common and can depress serum T3.

Furthermore, iodide-induced hyperthyroidism, reflecting the Jod-Basedow phenomenon (see Chapter 7), is becoming more common in elderly patients with multinodular goiter because of increased exposure to radiocontrast studies; the resultant hyperthyroidism is generally transient.

Finally, because of screening tests with sensitive TSH assays, subclinical hyperthyroidism (normal T4, T3, free T4 with a suppressed TSH) is being recognized more commonly. This is often found in older subjects with autonomous function of a multinodular goiter or nodule. Osteoporosis and atrial fibrillation are complications of subclinical hyperthyroidism that may be an indication for treatment. Recent studies suggest a possible increase in all-cause mortality in patients with subclinical hyperthyroidism with an increase beyond the age of 60, especially in aging men (Figure 23–5). If patients are not treated, careful follow-up is recommended.

Treatment

Beta-blocking agents are useful in alleviating symptoms, but radioactive iodine is the therapy of choice in elderly patients because it is efficient, uncomplicated, and inexpensive. Antithyroid drugs can be used prior to radioactive iodine treatment to render the patient euthyroid and to avoid radiation-induced thyroiditis, but they are not definitive treatment and are more toxic in this age group. Surgery has a more limited role because of its increased morbidity.

Following radioactive iodine treatment, patients become euthyroid over a period of 6 to 12 weeks. They should receive careful follow-up, because hypothyroidism develops in 80% or more of patients who have been adequately treated. Once hyperthyroidism has abated, the metabolic clearance rate of other medications may decrease, and doses may require readjustment. Older patients with subclinical hyperthyroidism require follow-up, especially if presented with an iodine load.

Hypothyroidism

Hypothyroidism in the elderly is most often due to Hashimoto thyroiditis, prior thyroid surgery, or radioactive iodine ablative therapy. Medications, including amiodarone, lithium, and interferon-α, can lead to hypothyroidism. The risk of developing hypothyroidism is significantly increased in older women when serum antithyroid antibodies or serum TSH are elevated.

Clinical Features

It is easy to overlook hypothyroidism in an older person, because many euthyroid elderly patients have the same symptoms. Moreover, elderly patients with hypothyroidism are more likely than younger patients to present with cardiovascular symptoms (eg, congestive heart failure or angina) or neurologic findings (eg, cognitive impairment, confusion, depression, paresthesias, deafness, psychosis, or coma). Finally, in the older hypothyroid patient, the physical findings are frequently nonspecific, although puffy face, delayed deep tendon reflexes, and myoedema support the diagnosis.

Diagnosis

Serum TSH is the most sensitive indicator of primary hypothyroidism and should be checked first. The diagnosis should then be confirmed with a low serum T4 or free T4. Measurement of serum T3 is unnecessary and potentially misleading, because T3 is the thyroid hormone most likely to decrease in nonthyroidal illness. Serum TSH should not be used alone to diagnose hypothyroidism because it does not always differentiate symptomatic from subclinical hypothyroidism. Furthermore, levels of TSH may be higher at night as a result of the nocturnal rise in serum TSH. Moreover, the pulsatile nature of TSH, resulting in serum TSH slightly above the normal ranges, may lead to a diagnosis of subclinical hypothyroidism in a euthyroid subject. Finally, in hypothyroid patients, serum TSH levels can be reduced to within the normal range by treatment with dopaminergic drugs and corticosteroids. In such patients, determination of free T4 may help differentiate those with true hypothyroidism from those with nonthyroidal illness (Chapter 7).

Treatment

The doses of thyroid hormone required for adequate replacement decrease with age. Elderly patients should be started on approximately 25 to 50 μg of levothyroxine, and the dose should be increased by approximately 25 μg every 4 to 6 weeks until the serum TSH comes into the normal range. In patients with cardiovascular disease, even lower initial doses can be used (12.5 μg) and increased at a slower rate. Desiccated thyroid hormone and preparations containing T3 should be avoided, because T3 is rapidly absorbed and cleared and may be cardiotoxic. The metabolic clearance of other drugs changes as hypothyroidism is corrected, and their dosages may require readjustment. On average, the dose of levothyroxine in the elderly is roughly 1 μg/kg/d compared with 1.7 μg/kg/d in young adults. Overtreatment documented by a suppressed serum TSH should be avoided because of the potential adverse effects to the skeleton and cardiovascular system.

It is still not known whether treating subclinical hypothyroidism is beneficial. A Cochrane review of 12 small trials that included treatment of subclinical hypothyroidism with thyroid hormone did not find improved survival, decreased cardiac morbidity, or differences in quality of life or symptoms. Two-thirds of patients with subclinical hypothyroidism were chemically euthyroid for at least 4 years, and the absence of antimicrosomal antibodies may identify patients at lowest risk of progression. The presence of antithyroperoxidase antibodies is associated with a higher risk of progression to overt hypothyroidism of 4.3%/year versus 2.6%/year in antibody-negative patients.

If patients are not treated, they need to be followed closely for progression of disease. Elderly patients previously treated with radioactive iodine are more likely to progress to overt hypothyroidism.

Multinodular Goiter

The prevalence of multinodular goiter increases with age. However, if swallowing and breathing are not compromised and thyroid function tests are normal, the goiter can be observed without treatment. Levothyroxine therapy rarely shrinks the gland, and although it may prevent further enlargement, the risk of inducing iatrogenic hyperthyroidism is significant. This is compounded by the fact that multinodular goiters may independently develop areas of autonomous function.

Thyroid Nodules and Cancer

Thyroid nodules are more common in the elderly. The prevalence of nodules increases with age and is generally higher in women than in men. Furthermore, the prevalence of thyroid nodules detected by ultrasound may be as high as 40% in older women. Ninety percent of these nodules are benign, but the prognosis for elderly patients with malignant nodules may be worse than that for younger patients with malignant nodules. The approach is similar to the workup in a younger patient. The prognosis correlates with the size of the tumor. The outcome in elderly patients may therefore be substantially improved by early evaluation of nodules in patients who are good surgical candidates.

Papillary carcinoma is more common in young and middle-aged patients. However, it has a poorer prognosis in the elderly, possibly because it is detected at a more advanced stage. Follicular carcinoma accounts for 15% of thyroid cancers and usually occurs in middle-aged and older patients. Anaplastic thyroid carcinoma is found almost exclusively in middle-aged and older patients. It presents as a rapidly growing hard mass that is locally invasive, often associated with metastatic lesions, and has a very poor prognosis (Chapter 7).

Introduction

Diabetes is an important health condition for the aging population. More than 20% of individuals over the age of 60 years have diabetes, and another 14% have impaired glucose tolerance (IGT). It is anticipated that these numbers will continue to increase in the coming decades. It is therefore almost certain that those involved in the care of patients in this age group will encounter those with some disorder of glucose tolerance.

Both IGT and diabetes are associated with enhanced morbidity and mortality due to macrovascular and cardiovascular disease (CVD); an increase in risk for microvascular complications (retinopathy, neuropathy) that impair the ability to maintain independence; changes in cognitive function; and depression. Older individuals with diabetes have more functional disability and coexisting illnesses such as hypertension, coronary heart disease (CHD), and stroke than those without diabetes. Older adults with diabetes are also at greater risk for urinary incontinence, injurious falls, and issues related to polypharmacy.

Early diagnosis and appropriate intervention can help to avoid some of the adverse consequences of hyperglycemia, while also improving health-related quality of life (HRQL) in this age group. In 2003, the American Geriatric Society published guidelines that are useful in guiding the care of the older person with diabetes. These recommendations are now included as part of the standards of care published annually by the American Diabetes Association.

Aging and the Physiology of Carbohydrate Intolerance

Normal aging is associated with a gradual increase in both fasting (1 mg/dL [0.6 mmol/L] per decade) and glucose-stimulated blood glucose (BG) (5 mg/dL [0.28 mmol/L] per decade) levels, even in lean, physically active individuals with normal body weight. Normoglycemic elderly subjects have higher glucose and insulin levels during an oral glucose tolerance test (OGTT) than body mass index (BMI)-matched young subjects. These changes in BG are more profound in those who have risk factors for abnormal glucose tolerance.

Type 2 diabetes is characterized by defects in both insulin secretion and sensitivity. Although the majority of people with type 2 diabetes are insulin-resistant, insulin resistance by itself is not sufficient to lead to hyperglycemia. Age-related impairments in beta cell function that include reduced conversion of proinsulin to insulin and abnormal insulin secretion are important contributors to the development of hyperglycemia in elderly individuals. Lean elderly patients with type 2 diabetes have a greater impairment in insulin secretion than insulin sensitivity while obese patients have both impaired insulin secretion and sensitivity in muscle and liver (Figure 23–6).

Several abnormalities of beta cell function contribute to the decline in insulin secretory capacity with advancing age. These include an accumulation of intracellular lipid within the beta cell; a decrease in glucose transporter (GLUT) 2 number; and a reduced sensitivity to the incretin hormones, glucagon-like peptide 1 (GLP1), and glucose insulinotropic peptide (GIP) that acts to augment the postprandial insulin response. Genetic susceptibility also plays a role. In individuals without diabetes who carry five or more risk alleles that are associated with development of diabetes, impairments in insulin secretion are observed at an earlier age than those with fewer alleles. Evidence of autoimmunity with antibodies directed against beta cell proteins has been demonstrated as a cause of impaired insulin secretion in up to 12% of elderly individuals.

These impairments in beta cell function can be unmasked by an increase in insulin resistance that occurs with normal aging. The insulin resistance that accompanies aging is associated with the accumulation of intracellular fat and a progressive decline in the number and function of mitochondria resulting in reduced oxidative glucose metabolism and phosphorylation activity. Insulin resistance is augmented by weight gain; reductions in lean body mass and increases in fat mass; physical inactivity; and use of some medications (ie, glucocorticoids and atypical antipsychotics). Insulin resistance occurs in muscle, where there is a reduction in insulin-mediated glucose uptake following a meal; in adipose tissue where impaired regulation of hormone-sensitive lipase results in increases in circulating levels of free fatty acids (FFA); and liver where there is overproduction of glucose in the fasting state and failure to adequately suppress glucose production after a meal.

Metabolic Syndrome

The metabolic syndrome refers to a clustering of metabolic abnormalities outlined in Table 23–2 that are associated with an increase in risk for type 2 diabetes and CVD. This syndrome is more common in the elderly, increasing from approximately 7% of the population in the third decade to 44% in the seventh decade. Lifestyle interventions targeting modifications in dietary intake, regular exercise, and weight reduction are effective in reducing the progression to overt type 2 diabetes among individuals above age 60 years.

Establishing the Diagnosis of Diabetes Mellitus

Diagnostic Criteria

The majority of elderly individuals with diabetes will have type 2 diabetes. The typical symptoms usually associated with hyperglycemia may either not be present or may have developed so gradually that they may not be perceived as being abnormal. The use of diuretics can mask polyuria and polydipsia as manifestations of hyperglycemia. An age–related decrease in thirst may blunt these usual symptoms. It is therefore important that laboratory measurement of BG be performed on at least an annual basis in individuals above the age of 60.

A diagnosis of diabetes can be established by one of three established criteria outlined in Table 23–3. Oral glucose tolerance testing is performed infrequently in clinical practice and is not required to establish the diagnosis, particularly in elderly individuals. Measurement of an A1c is now accepted as an alternative tool in establishing a diagnosis of diabetes, with values ≥6.5% consistent with a diagnosis of diabetes. A1c values of 6.0% to 6.4% identify those at high risk for development of type 2 diabetes. A reasonable approach would be to measure an A1c in any elderly person with abnormal glucose values.

Glycemic Goals

Both the ADA and the American Geriatrics Society recommend that functional, cognitively intact older adults who have significant anticipated life expectancy be treated to similar glycemic goals as younger adults. This means guiding therapy to achieve HbA1c of <7% for the majority of people with diabetes. Achieving this level requires that fasting glucose levels be maintained between 80 and 130 mg/dL, and 2-hour postprandial BG at <180 mg/dL. These recommendations are not absolute. While the goal is to maintain an A1c values as close to normal (<6%) as possible, this goal can be modified in patients who are at high risk for hypoglycemia, who are older, who have comorbid conditions that limit life expectancies. These contingencies have particular relevance to the elderly population who may experience variability in appetite or food intake, or often have other medical problems requiring medications (eg, beta blockers, anxiolytics) that can increase vulnerability to hypoglycemia. On the other hand, uncontrolled diabetes is also associated with undesirable effects in elderly individuals, including fluid and electrolyte abnormalities, problems with urinary incontinence and cognitive function, indicating the need for a reasonable degree of glycemic control even with advanced age. Efforts to achieve A1c levels of <7% are reasonable in some elderly patients, provided that the risk for weight gain and hypoglycemia is minimized. Therapy can be modified to achieve A1c targets of 8% in others as a way of minimizing risk for treatment-associated concerns. However, symptomatic hyperglycemia that can increase risk for an acute hyperglycemic crisis should be avoided in all patients.

Glycemic Control and Complications

Because the complications of diabetes mellitus are related to the duration of disease, elderly patients who live long enough suffer the same complications of nephropathy, neuropathy, and retinopathy as their younger counterparts. The United Kingdom Prospective Diabetes Study (UKPDS) examined the relationship between improved glycemic control and the prevention of complications in 3067 patients with type 2 diabetes (mean age 54 years) assigned to intensive (goal of fasting blood glucose <108 mg/dL) or conventional therapy. After a median follow-up of 10 years, the incidence of microvascular complications (retinopathy, neuropathy, and nephropathy) was reduced by 25% with intensive treatment. There was no difference in the incidence of macrovascular complications, but there was a tendency for fewer myocardial infarctions in the intensive therapy group. A 10-year follow-up report from the UKPDS demonstrated a significant favorable legacy effect of early intensive therapy in preventing both microvascular and macrovascular complications.

Elderly diabetic patients have an impaired counterregulatory response to hypoglycemia which can interfere with recovery from a hypoglycemic event. In addition, the ability to sense hypoglycemia declines, as does the ability to take corrective action. Coupled with the diminished cortical reserve due to the higher prevalence of age-associated conditions such as stroke, lacunar infarction, amyloid angiopathy, and Alzheimer disease, the older brain is less able to recover fully from hypoglycemic insult.

Cardiovascular Disease

CVD is a major cause of morbidity and mortality in elderly people with diabetes. For this reason, interventions recommended for the secondary prevention of recurrent coronary events in individuals without diabetes are recommended for all individuals with diabetes independent of known heart disease. This includes control of blood pressure, treatment of hyperlipidemia, and use of low-dose aspirin therapy in those without contraindications. While tight glycemic control has been demonstrated to reduce the risk for microvascular and neuropathic complications, the role of tight glycemic control for prevention of macrovascular disease and CVD has been addressed in several recent clinical trials.

Three recent large, randomized, prospective clinical trials with relevance to an elderly population were conducted in an effort to define the effect of lowering A1c to levels lower than those currently recommended by the ADA on cardiovascular outcomes in patients with type 2 diabetes. The average age of these subjects, all of whom had a history of a CVD event or were at high risk for an event, ranged from 60 to 66 years.

In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, the goal of intensive glycemic therapy was to achieve an A1c <6% versus <8% with conventional treatment. The glycemic control study was stopped 18 months early due to the observation of a 22% increase in the relative risk for CVD death with intensive therapy. In the Action in Diabetes and Vascular Disease (ADVANCE) study, the goal of intensive therapy was to achieve an A1c <6.5% using the sulfonylurea, gliclazide (not available in the United States). A reduction in microvascular complications, primarily risk for proteinuria, was observed with intensive therapy, but there were no group differences for CVD events. In the Veterans Affairs Diabetes Trial (VADT), the goal of intensive therapy was to achieve an A1c <6%. There were no significant group differences in the composite outcome of CVD events; however, there were more CVD deaths (36 vs 29) and more sudden deaths in intensively treated subjects (11 vs 4) (p = NS). Severe hypoglycemia within the preceding 90 days was a predictor of CVD events and mortality.

What do these results mean to the practicing physician? It is important to note that all three trials included participants with long-standing type 2 diabetes and varying degrees of established atherosclerosis at time of study entry. In addition, the glycemic targets in these trials were well below what is recommended by the ADA (7%) and may not be appropriate in elderly individuals where the risk for hypoglycemia and related adverse sequellae is greater. Other CVD risk factors (eg, hypertension and hyperlipidemia) were treated to a moderate or high degree, resulting in rates of CVD events that were lower than predicted with standard therapy. This places emphasis on the importance of treating nonglycemic CVD risk factors in patients with diabetes.

Treatment Strategies for Achieving Glycemic Goals in the Elderly

The therapeutic goals for any patient with diabetes, including the elderly, are to avoid symptoms of hyperglycemia and hypoglycemia, to minimize risk for acute and chronic diabetes-related complications, and to achieve an optimal health-related quality of life. While the majority of newly diagnosed elderly individuals will have type 2 diabetes, many individuals with type 1 diabetes are enjoying longer survival, making it likely that these patients will require care during advancing years. Insulin therapy, either alone or in combination with oral agents, is often required to maintain desired glycemic control in the face of progressive beta cell dysfunction in those with type 2 diabetes. For these reasons, knowledge of insulin and noninsulin injectable medications is as important as that of the five different classes or oral hypoglycemic agents (Table 23–4) indicated for the treatment of type 2 diabetes.

Therapeutic Lifestyle Intervention

The essential components of therapeutic lifestyle intervention (TLI) include dietary modifications and exercise. Weight reduction is recommended for overweight and obese individuals. Recommendations to obtain an adequate amount of sleep as either one uninterrupted sleep cycle or with daily naps may help reduce risk for progression to overt diabetes in those with impairments in glucose intolerance.

Dietary interventions for treatment of diabetes promote appropriate dietary caloric intake with an appropriate distribution of calories among carbohydrates, protein, and fat. There is contradictory information in the literature regarding the optimal diet that should be recommended for patients with diabetes. Studies comparing different diets for achieving weight loss have yielded inconsistent results. In general, obese patients can be encouraged to follow a weight reduction regimen that is most acceptable to their taste, as this is more likely to result in a reasonable degree of compliance.

The Mediterranean diet which emphasizes the intake of fresh fruits and vegetables, whole grains, beans, nuts, and olive oil, may have some advantages over traditional low-fat diets in the elderly population. In one European study of more than 2000 subjects aged 70 to 90 years, the integration of a Mediterranean style diet with other healthy lifestyle interventions reduced all-cause mortality by more than 50%. The Mediterranean diet not only promotes weight loss, but also has demonstrated favorable effects on circulating lipids and BG levels.

In the ongoing Look AHEAD Study, subjects with type 2 diabetes between the ages of 45 and 74 years were able to achieve a 9% weight loss and 21% increase in fitness level with 30 minutes of exercise and 1200 to 1800 calorie intake each day. Exercise prescriptions and encouragement to maintain a reasonable level of physical activity are as important in the elderly as in the younger population. There is no longer a requirement to perform cardiac stress testing before recommending an exercise program. To optimize compliance with exercise prescriptions, it is important to encourage activities that are enjoyed, that can be performed safely, and that can be incorporated into a daily routine. Some insurance companies now provide health club memberships as a way of encouraging activity. Many elderly individuals have difficulty with aerobic activity as a form of exercise. For those who are housebound or who have difficulty walking for any distance due to presence of spinal stenosis, peripheral neuropathy, claudication or other medical problems, stationary bicycling, arm lifts with weights, or leg lifts can be encouraged. Progressive resistance training has been proposed as a more reasonable and beneficial form of exercise in these patients.

Pharmacologic Therapy

TLI is rarely adequate at achieving and maintaining glycemic control without pharmacologic therapy in the majority of patients with type 2 diabetes, including the elderly. This means that some form of pharmacologic therapy will almost always be required. While there is no absolute contraindication to use of any of the oral or injectable agents available for treating diabetes, there are special considerations for prescribing and monitoring of these agents in older adults. As a general rule, medications should be started at the lowest dose and gradually titrated upward as tolerated until glycemic targets are reached. In some cases, it becomes necessary to add on a second agent before maximal doses are reached with one agent as a way of minimizing adverse reactions. For example, the incidence of gastrointestinal side-effects increases with increasing doses of the biguanide, metformin. There are many patients who may be unable to tolerate the maximal dose of 2 g of metformin each day, but who are able to tolerate 1 to 1.5 g/d. In these instances, it may be desirable to continue metformin at a lower dose and add an insulin secretogogue to achieve the desired level of glycemic control. A discussion of pharmacologic therapy in this review is presented with consideration of this strategy in an elderly population (see Table 23–4).

Initiation of metformin together with TLI is recommended at the time of diagnosis of type 2 diabetes. Side-effects with use of metformin that have particular relevance to elderly patients include anorexia, nausea, abdominal cramping, and diarrhea that preclude the use of this drug in approximately 5% of all individuals. Reductions in vitamin B12 levels have also been observed. Given the high prevalence of vitamin B12 deficiency in the elderly population, it is reasonable to monitor its levels and/or recommend vitamin B12 supplementation at a dose of 50 μg/d or more.

The most feared complication of therapy with metformin is lactic acidosis. This can be avoided by following prescribing guidelines that recommend against use of metformin in those with renal insufficiency, defined as a serum creatinine ≥1.5 mg/dL in men, ≥1.4 mg/dL in women; or a creatinine clearance of <60 mL/min. The observed age-related decline in glomerular filtration rate (GFR), as a measure of creatinine clearance, raises concerns for using metformin in the elderly; however, the formulas used to estimate GFR (eGFR) do not always provide accurate results in this population. When there is doubt as to whether metformin can be initiated or continued in a patient with a normal serum creatinine but a reduced eGFR, measurement of a creatinine clearance with 24-hour urine collections can provide a more accurate measure of renal function. In patients assessed as having normal renal function at the time metformin is started; renal function needs to be reassessed with changes in clinical status. Caution is suggested in patients >80 years of age, although there are no data demonstrating a higher incidence of lactic acidosis in this population, provided that renal function is normal.

There may in fact be advantages to metformin therapy. In a study of patients age 72 years with type 2 diabetes and congestive heart failure (CHF), those treated with metformin experienced lower morbidity and mortality when compared to those treated with sulfonylurea monotherapy. There are also epidemiologic data that suggest that treatment with metformin is associated with a lower incidence of cancer and cancer-related deaths.

Alternative or additional pharmacologic therapy is required for patients for whom metformin therapy is contraindicated, who do not tolerate the medication, or who do not achieve the desired level of glycemic control. Insulin secretogogues include long-acting sulfonylureas and shorter-acting meglitinides, which have similar efficacy in lowering A1c levels by 1.5%. The sulfonylureas reduce both fasting and postprandial glucose levels while the shorter-acting meglitinides reduce postprandial glucose excursions. Both renal insufficiency and increasing age are risk factors for hypoglycemia with use of these agents in the elderly when used as either monotherapy or combination therapy. Glipizide and glimepiride are less likely to cause prolonged hypoglycemia in the elderly than glyburide, which has active metabolites. The shorter- acting meglitinides administered immediately prior to a meal can be useful in reducing the risk for hypoglycemia in the elderly who experience variability in appetite or the timing of meals.

When insulin secretogogues are prescribed, it is important that patients and their family members be educated in how to both recognize and treat a low-BG reaction (Table 23–5). Many individuals are unaware of what these symptoms are and can mistake this for simple fatigue or a cardiac event, resulting in potentially dangerous delays in therapy. It is important that patients be instructed to carry a glucose source with them at all times. This can be in the form of hard candy or glucose tablets.

The two thiazolidinediones available for clinical use are pioglitazone and rosiglitazone. Both agents reduce HA1c levels by 0.8% to 1.5%, with pioglitazone having more favorable effects on circulating triglycerides. Caution is warranted when using this class of medications in elderly individuals due to their potential to cause weight gain, edema, CHF, and reductions in bone mineral density (BMD) with increased fracture risk. In one report investigating outcomes with glitazones in individuals age >65, treatment with rosiglitazone was associated with a 60% increased risk of new-onset CHF, a 40% increased risk for MI, and a 29% increase in mortality. As both the incidence and prevalence CHF increase with age in those with diabetes, caution is required when using these agents in elderly patients. If a decision is made to use these agents, close monitoring for onset of edema, weight gain, and shortness of breath is important. Regular monitoring of 25-hydroxyvitamin D levels and BMD measurements is also indicated to address fracture risk.

The alpha-glucosidase inhibitors, acarbose and miglitol, delay absorption of carbohydrate from the small intestine by inhibiting the enzymes that convert carbohydrates into monosaccharides. This results in a reduction in postprandial glucose excursions, with reductions in A1c of 0.5% to 0.8% when used alone or in combination with other oral agents or insulin. The main limitation to the use of these agents is the high incidence of GI side effects that are directly related to their mechanism of action. Abdominal bloating and distension, diarrhea, and cramping occur in approximately 50% of patients. Initiating therapy at a low dose of 25 mg once a day given with the main meal and allowing gradual upward titration can improve compliance with this group of medications. It is important that patients be instructed to use glucose tablets to treat hypoglycemia that may occur when taking this class of medications with sulfonylureas or insulin, as there can be delayed absorption of glucose from food sources.

There are now two relatively new classes of medications that address the role of the incretin hormone, GLP1, in glucose homeostasis: injectable GLP1 analogs and orally administered dipeptidyl peptidase IV inhibitors (DPP IV). GLP1 is a hormone that is normally secreted by L cells in the distal ileum in response to a meal (Figure 23–7). GLP1 acts directly on beta cells to enhance endogenous insulin secretion, and on alpha cells to reduce glucagon levels. Endogenously secreted GLP1 is degraded by the DPP IV, which contributes to its short circulating half-life. Exenatide is the first GLP1 mimetic approved for clinical use. Liraglutide is another agent in this class that has recently been approved for use. Sustained reductions in A1c of approximately 1% have been observed with use of these agents. The major side- effects include anorexia, nausea and vomiting, abdominal pain, diarrhea, and weight loss. However, these side-effects often abate over time and with exenatide are minimized by starting with doses of 5 μg administered twice a day for a month before increasing to 10 μg twice a day. Hypoglycemia is possible when used in combination with a sulfonylurea. There are at least 36 postmarketing reports of acute pancreatitis with use of exenatide, but the incidence of this disorder does not appear to be greater than in the general population with type 2 diabetes. Nevertheless, a high index of suspicion is recommended in patients who report abdominal pain with use of these agents. It is anticipated that a once- weekly preparation of exenatide will become available for clinical use in the next 1 to 2 years.

There are two DPP IV inhibitors available for clinical use, sitagliptin and saxagliptin. By prolonging the duration of action of endogenously secreted GLP1, these agents reduce A1c by 0.6% to 0.9%. The DPP IV inhibitors are weight neutral and do not cause hypoglycemia when used as monotherapy. The major side-effects of these agents are an increase in upper respiratory and lower urinary tract infections, headache, skin rash, sinusitis, and back pain. The higher incidence of infectious complications may have significance in the elderly population who are more likely to have asymptomatic bacteriuria. However, there is no absolute contraindication to use of these agents in the elderly. Dose adjustments are required in the presence of renal insufficiency with each of the available agents. The relatively benign side-effect profile can make them attractive for use; however, these agents are expensive and may have effects that are currently unknown. DPP IV is a ubiquitous enzyme that is also expressed in lymphocytes, raising concern for alterations in immune function.

When glycemic targets cannot be achieved with the agents discussed earlier, insulin therapy becomes necessary. In patients with isolated morning hyperglycemia, the addition of a bedtime dose of neutral protamine Hagedorn (NPH) can be effective in controlling fasting glucose levels. When both fasting and daytime BG levels are elevated, a long-acting insulin administered once daily can be more effective in lowering glucose levels throughout the day (Table 23–6). When BG levels remain elevated despite the use of basal insulin alone, premeal doses of a short- or rapid-acting insulin can be added.

When adding NPH insulin at bedtime to oral agents, a low starting dose of 5 to 10 U allows an elderly patient to become accustomed to insulin injections with a low risk for hypoglycemia. The dose can then be titrated gradually over a period of several weeks until glucose levels are in the desired range. A commonly used strategy is to advise patients to increase by 1 or 2 U every 4 days until they achieve a fasting glucose of less than 140 mg/dL.

When initiating basal/bolus insulin, the starting dose of insulin can be calculated as 0.2 to 0.3 U/kg/d, with 50% of the dose administered as basal insulin and 50% as premeal insulin in divided doses prior to meals. For patients already receiving basal insulin who require the addition of premeal insulin, the dose of premeal insulin can be calculated as follows:

• If the BG is mildly elevated with the majority of readings below 200 mg/dL, the dose of basal insulin can be reduced by 50% with distribution of the remaining 50% into three premeal insulin doses.
• If the majority of BG levels are >200 mg/dL, premeal insulin doses can be started as approximately 25% to 30% of the current basal dose given before each meal. For example, if a patient is receiving 24 U of glargine or NPH each day, the starting dose of regular or humalog before each meal would be 6 to 8 U.

Many elderly individuals can be given instructions in how to advance their insulin doses or how to adjust the dose of insulin according to results of BG measurements. Correction insulin refers to the administration of supplemental doses of short or rapid-acting insulin when BG exceeds glycemic targets. A reasonable glycemic target may be to maintain all BG between 100 and 150 mg/dL. In these cases, the individual patient can be instructed to reduce their premeal insulin dose by 1 to 2 U if their BG is <100 mg/dL, and to increase by 1 U for every 50 mg/dL above 150 mg/dL.

There will be a minority of elderly patients who are unable to achieve adequate control of postprandial glucose excursions with insulin alone. Pramlintide, a synthetic analog of the beta cell hormone amylin, is effective at reducing postprandial BG levels when used in combination with insulin. This injectable medication is approved for use in combination with insulin for patients with both type 1 and type 2 diabetes. Side-effects of pramlintide include nausea and vomiting, which are more common in people with type 1 diabetes, and hypoglycemia. Nausea and vomiting can be minimized by starting at doses of 15 μg before each meal with gradual upward titration to 60 for people with type 1 diabetes. Those with type 2 diabetes can be started at a dose of 60 μg and titrated to 120 μg before meals. The risk for hypoglycemia can be reduced by reducing prandial insulin doses by 50% when pramlintide is initiated.

In summary, there are five classes of oral agents and two noninsulin injectable therapies, in addition to insulin, that are effective at achieving glycemic control as monotherapy or as part of combination therapy. The side-effect profile, risk for hypoglycemia, and cost need to be considered when choosing a regimen for an individual patient.

Screening for Diabetes-Related Complications in the Elderly

The care of older adults with diabetes is complicated by their clinical and functional heterogeneity. Some older individuals developed diabetes years earlier and may have significant complications. Others may be newly diagnosed but may already have complications related to the disease. Some older adults with diabetes are frail with limited physical or cognitive abilities due to the presence of other underlying chronic conditions. Life expectancies are highly variable for this population, but often longer than clinicians realize. Providers caring for older adults with diabetes must take this heterogeneity into consideration when setting and prioritizing treatment goals.

Screening for microvascular diabetes-related complications is as important in older adults as it is in younger individuals, with attention directed to complications that can result in functional impairments if these remain untreated. While the natural history of diabetic retinopathy is different in those above age 70, recommendations for periodic eye examinations to detect not only changes related to diabetic retinopathy, but also for cataracts, macular degeneration, or glaucoma are important in allowing for early detection of disorders that can progress to cause visual impairment.

Annual measurement of serum creatinine and urine microalbumin allow for identification of nephropathy and chronic kidney disease due to other causes that can have their progression modified by dietary interventions and use of medications to lower blood pressure. Annual measurement of a lipid profile with interventions to treat those identified as having dyslipidemia can modify risk for cardiovascular events, which are associated with morbidity, decreased quality of life, and mortality.

Regular foot examinations with identification of anatomic abnormalities and sensory deficits that can reduce mobility are recommended. Medicare will cover the cost of special shoe wear for individuals with diabetes complicated by neuropathy or foot deformity. Pedorthic shoe wear is characterized by increased depth with a wider toe box that reduces pressure points that predispose to ulcer formation. Many prescriptions for shoe wear also include orthotics that allow for more even pressure distribution, thus improving the ability to walk without concern for foot injury.

Acute Hyperglycemic Complications

Hyperglycemic hyperosmolar nonketotic syndrome (HHNS) is more common in elderly patients than diabetic ketoacidosis (DKA). HHNS can occur in patients with and without a history of type 2 diabetes. It is characterized by severe elevations in BG (>600-800 mg/dL), plasma hyperosmolarity (>320 mOsm/L), severe dehydration, and absent to mild acidosis. The development of HHNS in the elderly population can be attributed, in part, to an impaired thirst mechanism and an age-related increase in the renal threshold for reabsorption of glucose leading to an osmotic diuresis and intravascular volume contraction. Predisposing factors include myocardial infarction, pneumonia, infections, use of certain medications (eg, diuretics, phenytoin, glucocorticoids), or any acute medical illnesses. Patients often present with an altered mental status (lethargy, coma), marked volume depletion, orthostatic hypotension, and prerenal azotemia. Urine and serum ketones can be mildly elevated but usually not to the degree observed with diabetic ketoacidosis.

HHNS is a life-threatening disorder that requires prompt therapy with intravenous fluids and close monitoring of cardiac status. In addition to therapy directed toward treatment of the precipitating event (if known), extracellular fluid volume deficits, which can be profound, are replaced initially with normal saline followed by half-normal (0.45%) saline. Half of the fluid and electrolyte deficits can be replaced in the first 24 hours and the remainder over the next 48 hours.

Once volume replacement is addressed, low-dose intravenous infusions of insulin (5 U bolus followed by 1-5 U/h) can be initiated. The administration of insulin prior to volume correction can exacerbate intravascular fluid depletion and further compromise renal function as glucose shifts to the intracellular compartment. Potassium deficits can be addressed once urine output is established. Following resolution of the hyperglycemia, patients require careful evaluation of the cause of the deterioration as well as attention to the need for ongoing management of hyperglycemia with insulin or oral agents.

Care of the Elderly Patient with Diabetes in the Hospital

Hyperglycemia frequently accompanies acute illnesses that prompt hospitalization in patients with and without a history of diabetes. Newly recognized hyperglycemia adversely affects patient outcomes to a greater extent than established diabetes, with longer hospital length of stay, higher mortality, and increased likelihood of discharge to an extended care or rehabilitation facility. For these reasons, attention to glycemic control is as important during periods of hospitalization as it is in the outpatient setting.

The ability to achieve tight glycemic control in the hospital is hampered by rapid changes in clinical status, as well as by hospital routines that can increase risk for undetected hypoglycemic events that are associated with adverse patient outcomes. Current guidelines suggest glycemic targets of 140 to 180 mg/dL in both critically ill and non-critically ill-hospitalized patients. In critical care settings, this can be achieved with validated IV insulin infusion protocols. In non-critically ill patients, scheduled subcutaneous basal-bolus insulin is preferred. Less stringent glycemic targets may be appropriate for patients who have multiple comorbidities and reduced life expectancy, but in general, glucose levels should be maintained at values below 200 mg/dL to minimize fluid and electrolyte abnormalities, reduce renal complications, and avoid infections.

The practice of using sliding scale insulin as the only glycemic management strategy in hospitalized patients is discouraged. These regimens are associated with both hypoglycemia and hyperglycemia as they encourage reaction to a single BG value rather than a rational management strategy. Oral and injectable noninsulin glucose-lowering agents have a limited role for hospital use but may be appropriate for selected non-critically ill patients.

Osteoporosis

Despite the high prevalence, severe morbidity, and expense of osteoporosis, until recently most of our knowledge was derived from studies of younger postmenopausal women. Yet it is the older woman who typically experiences the ravages of the disease. Twenty-five percent of women have vertebral fractures by age 70; by age 80, the figure is closer to 50%. More than 90% of hip fractures occur in patients over age 70, and by age 90, one woman in three will have sustained such a fracture. Hip fractures are associated with significant morbidity, an increased risk of institutionalization, and an up to 20% increase in mortality rates. Despite the significant differences between perimenopausal and older women, diagnostic and therapeutic approaches for older women are derived largely from studies of newly postmenopausal women. The relevance of such studies for older women has only recently been questioned.

Definition and Risk of Fracture

The definition of osteoporosis has changed over the years. In 1991, a consensus development conference defined osteoporosis as "a disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk." The World Health Organization issued classification criteria for postmenopausal women based on measurements of BMD or bone mineral content. Osteoporosis is defined as a BMD T-score of −2.5 standard deviations below the young adult mean value (Table 23–7). This permits numerical standardization of the definition. In 2008 the World Health Organization developed the FRAX algorithm that estimates the likelihood for a patient to sustain a hip or a major osteoporotic fracture (clinical spine, forearm, hip, or shoulder) over the next 10 years. The model is designed to include men and women, age 40 to 90, who have not previously been treated with medications for osteoporosis. FRAX uses population-based cohorts for Europe, North America, Asia, and Australia, and for the United States risk assessments are available for Caucasian, African American, Hispanic, and Asian groups. In addition to specific risk factors (Table 23–8), the model uses age, gender, height, weight, and femoral neck BMD or T-scores.

Risk Factors for Osteoporosis and Fractures

Multiple factors contributed to the risk of low bone mass, osteoporosis, or fractures. Lifestyle factors include low calcium or vitamin D intake, high caffeine or salt intake, alcohol, smoking, falls, thin/frail habitus, and inactivity. Common endocrine disorders in the elderly include hyperthyroidism, hyperparathyroidism, and diabetes. Multiple myeloma and lymphoma can present with fractures. Emphysema, congestive heart failure, depression, end-stage renal disease, and malabsorption also contribute to it. Medications in the elderly that contribute to bone loss include glucocorticoids (≥5 mg/d of prednisone or equivalent for ≥3 months), anticonvulsants, aromatase inhibitors, androgen deprivation therapy, excess thyroid hormone, lithium, antirejection drugs, and heparin. By age 70, approximately 80% of women have a hip BMD that is osteopenic or osteoporotic, compared with 40% of women in their fifties (Figure 23–8).

Falling is often cited as a major risk factor for hip fracture in older women. Although more than one-third of elderly women fall annually, however, fewer than 5% of falls result in fracture. A fall to the side, a low hip BMD, low BMI (lean body habitus), and high-fall energy have been shown to be significant independent risk factors for hip fracture in community-dwelling elderly. In nursing home subjects, a fall to the side, low hip BMD, and impaired mobility were independent risk factors. Other factors, including a maternal history of hip fracture, previous hyperthyroidism, inability to rise from a chair, poor depth perception, poor contrast vision, and use of anticonvulsants or long-acting benzodiazepines are also associated with hip fractures in elderly women. Furthermore, with multiple risk factors, the risk of hip fracture increases significantly.

Factors Affecting Bone Physiology

There are significant physiologic differences between newly postmenopausal and older women with respect to maintenance of skeletal integrity. Although calcium intake is often inadequate in both age groups, calcium absorption declines with age despite an age-related increase in serum levels of parathyroid hormone (PTH). This increase is not due solely to a decrease in renal reabsorption of calcium but may represent secondary hyperparathyroidism from vitamin D insufficiency. When PTH levels are assessed in elderly community dwelling women, PTH levels increase as vitamin D levels fall below roughly 30 ng/mL (75 nmol/L) (Figure 23–9), similar to what has been observed in younger cohorts.

Vitamin D

Vitamin D deficiency is common in the elderly, and vitamin D metabolism changes with age. Up to 15% of healthy elderly residents of communities in the sunny southwestern United States have frank vitamin D deficiency; still more have subclinical vitamin D deficiency; and up to 50% of elderly nursing home residents are deficient in vitamin D. This occurs because elderly individuals have decreased sun exposure and an impaired ability to form vitamin D precursors in the skin, a decreased dietary intake of vitamin D, and (possibly) an age-related decline in vitamin D receptors in the duodenum. In addition, the ability to convert vitamin D to its active moiety (1,25[OH]2-D3) is impaired with age. Certain vitamin D receptor polymorphisms have been associated with lower BMD and bone loss in some populations, although further investigations of vitamin D metabolism are needed in the elderly in the United States. Finally optimal vitamin D levels of ≥30 ng/mL (75 nmol/L) have been associated with higher BMD, decreased fracture risk, improved lower extremity function, and decreased risk of colon cancer (Figure 23–10).

Evaluation

Screening older patients by obtaining a BMD measurement is a comfortable, painless, noninvasive, rapid technique for determining an individual's bone mass and relative fracture risk. In general, the relative risk of spine or hip fracture roughly doubles for every standard deviation decrease in BMD below young, gender-matched mean values. Patients may remain dressed and lie on a padded table. Although several methods are available, currently the best technique uses dual-energy x-ray absorptiometry (DXA) of the hip or spine (Figures 23–13 and 23–14). The National Osteoporosis Foundation suggests obtaining a bone mass assessment in all women age 65 or older and all men age 70 or older regardless of risk factors. In addition, younger postmenopausal women and men age 50 to 69 with risk factors (see Risk Factors for Osteoporosis), adults who fracture after age 50, and those with a condition or medication causing bone loss should receive a bone mass measurement. For most elderly women, the hip is the single most useful measurement because nonspecific calcifications can lead to falsely elevated measurements in the posteroanterior view of spine.

Similar to the evaluation in a younger individual who presents with bone loss or fracture, the workup in an older patient can be designed to exclude secondary causes of osteoporosis. Hyperthyroidism and hyperparathyroidism are both more common in older women, can cause bone loss, and can be clinically silent in older individuals. Because 10% of women over age 65 are receiving thyroid hormone replacement therapy and because thyroid hormone overreplacement results in bone loss in postmenopausal women, true physiologic replacement with a normal serum TSH (if possible) should be the goal of treatment. Osteomalacia, vitamin D deficiency, and insufficiency may present as nonspecific muscle or skeletal discomfort and is more common in the elderly. This can best be assessed by checking a 25 hydroxyvitamin D level that should be ≥30 ng/mL or 75 nmol/L. In addition, metastatic carcinoma, multiple myeloma, hepatic and renal disease, and malabsorption (especially secondary to gastrectomy) should be excluded. Hypogonadism in men can be evaluated with a testosterone level. Medications (listed under Risk Factors) can cause bone loss.

Biochemical markers of bone turnover reflect bone formation and resorption. Although these markers are associated with the rate of bone turnover even in elderly women, they cannot be used in lieu of a BMD measurement to assess bone mass or to make a diagnosis. Because factors outside the skeleton contribute to fracture risk in the elderly, however, the search for correctable factors must extend beyond those that affect BMD. Particular attention should be devoted to the patient's home environment and medication use.

Patients who have sustained a fragility fracture as an adult have clinical osteoporosis and require evaluation and treatment. Because two-thirds of vertebral fractures are asymptomatic, patients with 1.5 to 2 in of height loss may need a lateral radiograph to look for vertebral deformities or compression fractures. Older patients presenting with skeletal discomfort should be evaluated by radiography to rule out a fracture. Vertebral osteoporosis usually presents with anterior wedging, involvement of more than one vertebra, prominent vertebral trabeculae, and vertebral deformities usually occurring below T6 (Figure 23–15). Worrisome signs suggesting that skeletal involvement is not due to osteoporosis alone include nerve root compression, posterior wedging, isolated vertebral involvement (especially above T4), and pedicle destruction. Furthermore, older individuals may complain of persistent groin pain with weight-bearing, while plain radiographs of the hip reveal no fracture. A bone scan may be necessary to confirm the diagnosis of hip fracture. Vertebral fractures can also be assessed with DXA technology by Vertebral Fracture Assessment. Because this can be done at the same point of care when a patient is having a DXA scan, this is convenient for older patients.

Treatment

Because the factors that affect bone physiology—the rate of bone loss, the structure of remaining bone, and the risk of fracture—are substantially different in newly postmenopausal and elderly women, interventions appropriate for younger women may be inappropriate for elderly women. Studies of older individuals that use BMD—or preferably fracture—as an end-point provide the best data.

Calcium

Controversy surrounds the use of calcium supplementation by itself in postmenopausal women, and few data are available regarding its use in older women. Theoretically, calcium supplementation seems appropriate because calcium intake in the elderly is low, and the ability to adapt to a low calcium diet declines with age. Calcium supplementation reduces the rate of bone loss. A meta-analysis of prospective cohort studies and randomized controlled trials concluded that calcium intake by itself was not associated with hip fracture risk and was neutral for nonvertebral fractures. However, a reduction in hip fractures and improvement in BMD has been demonstrated in very elderly women (mean age 84) treated with vitamin D (800 IU daily) and calcium (1200 mg daily). The National Academy of Sciences recommends 1200 mg/d of elemental calcium in divided doses. In addition to dairy products, many foods (eg, orange juice, cereals, and nutritional bars) are now fortified with calcium. Calcium carbonate supplements should be given in divided doses with meals to improve absorption in the elderly, who may suffer from achlorhydria. Calcium citrate can be used as an alternative in such patients. A potential problem with prescribing high doses of calcium in the elderly includes inducing or exacerbating constipation. In addition, because compliance with other drug regimens decreases as the number of drugs increases, calcium tablets may be taken at the therapeutic expense of more important medications. Finally, because supplementary calcium does interfere with absorption of zinc, elderly patients receiving calcium supplementation should be encouraged to take a multivitamin containing zinc. Calcium absorption is not impaired by psyllium.

Vitamin D

Vitamin D deficiency is common in the elderly, and vitamin D is needed for calcium absorption, mineralization of bone, and improvement in muscle strength. The current recommendation from the National Osteoporosis Foundation is 800 to 1000 IU/d. Vitamin D can be administered as a pure supplement of cholecalciferol (available as 400-2000 U tablets), in a daily multivitamin (400-800 IU) or calcium supplement (200-500 IU/tablet). A Cochrane review of 45 trials involving 84,585 participants comparing vitamin D alone or with calcium versus placebo reported vitamin D alone was not effective, but when combined with calcium, did result in hip fracture reduction in institutionalized elderly. Another meta-analysis of randomized controlled trials concluded that 700 to 800 IU/d of vitamin D, but not 400 IU/d of vitamin D, reduced the risk of hip and nonvertebral fractures in elderly patients. Clinical trials utilizing calcitriol (1,25-dihydroxy vitamin D3) as a therapeutic option for osteoporosis have reported conflicting results. Given that the complications of hypercalcemia are increased, this form of vitamin D should probably be avoided.

Exercise

Although the rationale for exercise therapy is sound, few data are available on results of exercise in elderly women. One study prescribed exercise for older women and found that forearm bone mineral content increased in those who continued exercising during a 3-year trial. Middle-aged women (mean age 60) participating in high-intensity strength training for 1 year had improvements in femoral bone mass, muscle strength, balance, and activity level compared with controls. A Cochrane review of 111 trials (55,303 participants in the community) reported that multiple component group exercise reduced the rate of falls and risk of falling, as did TaiChi. Walking—generally 30 minutes three times a week—is often suggested for frail individuals.

Bisphosphonates

Bisphosphonates—nonhormonal agents that inhibit bone resorption—effectively prevent and treat osteoporosis. Bisphosphonates are the mainstay of therapy in the elderly. The aminobisphosphonates, alendronate, risedronate, ibandronate, and zoledronic acid have been shown to increase BMD at the spine (5%-8%) and hip (3%-6%) over 3 years in prospective clinical trials in postmenopausal women. Fractures of the spine were reduced by approximately 40% to 70%. Alendronate, risedronate, and zoledronic acid have reduced nonvertebral fractures (25%-40%), including hip fractures (40%-60%), in women with osteoporosis. Improvements following treatment with alendronate and risedronate have also been demonstrated in older women residing in long-term care facilities. Furthermore zoledronic acid has been shown to reduce clinical fracture 35% and reduce all-cause mortality by 28% in patients following a hip fracture. When taken properly, the oral medications are well–tolerated—an important factor in choosing therapeutic alternatives for the elderly. Moreover the oral medications are available as a daily, weekly (alendronate, risedronate), and once monthly (risedronate, ibandronate) medication and the IV therapies can be given every 3 or 12 months (ibandronate and zoledronic acid respectively). The oral medications have been associated with nausea, heartburn, and epigastric distress. Both the IV and oral bisphosphonates have been associated with arthromyalgias and myalgias which is an important clinical consideration in this age group. Theses agents should not be used in elderly patients with an estimated GFR &le;35 mL/min. Osteonecrosis of the jaw is a rare event in patients using these agents at a dose for osteoporosis. For men, alendronate, risedronate, and zoledronic acid are approved. For glucocorticoid-induced bone loss, alendronate, risedronate, and zoledronic acid are approved for treatment, risedronate is approved for prevention.

Estrogen and Selective Estrogen Receptor Modulators

There is considerable evidence that estrogen therapy, if initiated at menopause, slows bone loss, temporarily increases bone mass, and may prevent osteoporotic vertebral and hip fractures. If therapy is continued, its efficacy is sustained at least until age 70. In addition, some studies have shown that estrogen increases vertebral and femoral bone mass. However, the Women's Health Initiative found an increased risk of cardiovascular disease, breast cancer, and thromboembolic events along with a significant reduction in hip fractures and other osteoporotic fractures in women receiving conjugated estrogen plus medroxyprogesterone. Because of the increased risks, hormone therapy is currently not recommended as a treatment for osteoporosis because there are other available and effective therapies.

Selective estrogen receptor modulators (SERMs) have estrogen agonist and antagonist actions. Raloxifene has been approved for the prevention and treatment of postmenopausal osteoporosis. Although improvements in BMD are less with raloxifene than estrogen therapy, studies demonstrate a reduction of approximately 50% in vertebral fractures with no mastalgia, vaginal bleeding, or increased endometrial thickness. Studies demonstrated a reduction in cholesterol and raloxifene is also approved for the reduction in the risk of invasive breast cancer in postmenpausal women with osteoporosis. Because there is an increase in venous thromboembolic events, raloxifene should not be used in immobilized elderly or those with clotting abnormalities. Raloxifene has not been shown to reduce nonvertebral or hip fractures.

Other Therapeutic Options

Although calcitonin is an approved therapy for osteoporosis in postmenopausal women, few data are available about its effect on the incidence of fractures. It is expensive and when given by injection is poorly tolerated by the elderly. Nasal calcitonin has been shown to reduce fractures of the spine—but not of the hip—with no improvement in hip bone density. Calcitonin may reduce acute pain associated with vertebral fractures.

Teriparatide, PTH (1-34), the first anabolic agent, has been shown to significantly increase bone density (9.7% for spine bone density in 18 months) and reduce vertebral and nonvertebral fractures in postmenopausal osteoporotic women. Teriparatide is approved for postmenopausal women and men at high risk for fracture and for patients with glucocorticoid-induced osteoporosis. There are little data in the frail elderly. This is given as a subcutaneous daily injection for 2 years only.

Denosumab, an antiresorptive agent, that is a fully monoclonal antibody to receptor activator of nuclear factor kappa B ligand (RANK-L) inhibits binding to RANK and the formation and activation of osteoclasts. Denosumab has been shown to increase BMD at the spine by 9.2% and at the hip by 6.0% over 3 years compared to placebo in a clinical trial in women with an average age of 72 years. Denosumab reduced vertebral fractures by 68%, hip fractures by 40%, and nonvertebral fractures by 20% (all p<0.05). This is given as a subcutaneous injection every 6 months and is still under evaluation by the FDA. There are little data in the elderly.

Although results regarding the efficacy of hip protectors for hip fracture reduction in elderly patients have been mixed, hip protectors represent a relatively inexpensive option in frail elders. Poor compliance has been a key component in the lack of efficacy. Furthermore the type and design of the hip pad may also play a role in its efficacy.

Vertebroplasty and kyphoplasty are interventions in which polymethylmethacrylate (vertebroplasty) or polymethylmethacrylate in a balloon (kyphoplasty) are placed in compressed vertebrae for patients with intractable pain from vertebral fractures. There are few trials with these interventions, and it is not known whether the procedures strengthen or weaken adjacent vertebrae. Recent randomized trials with sham-operated controls suggest that vertebroplasty was similar to the control group for pain and pain-related disability associated with an osteoporotic compression fracture.

Summary of Management Recommendations

In summary, there is ample reason to question the validity of extrapolating data from studies of newly postmenopausal women when formulating a treatment plan for older women. However, given the prevalence of the problem, it is reasonable to recommend an adequate daily intake of vitamin D (800-1000 IU), an adequate daily intake of calcium (totaling 1200 mg), and judicious participation in an individually tailored exercise program. The use of bisphosphonates, SERMs, teriparatide (PTH) (1-34), or other treatments needs to be individually considered in elderly women. For elderly men, the use of alendronate, risedronate, zoledronic acid, and teriparatide are available for treatment.

Perhaps more importantly, the risk of falls should be addressed. The risk can be reduced by reviewing medications (including nonprescription agents) and discontinuing (when possible) those with adverse effects on cognition, balance, or blood pressure. Common offenders include long-acting benzodiazepines, tricyclic antidepressants, antipsychotics, antihypertensives, and agents with anticholinergic side-effects. It is also important to correct reversible sensory losses and medical conditions and to educate patients about hazards in their environment, such as throw rugs, extension cords, and poorly illuminated stairways, which could lead to falls and fractures. For patients with gait disorders, physical therapy should be considered.

Patients who have recently sustained a hip fracture should receive the same evaluation and consideration as those without a fracture. Because a hip fracture places the patient at a more than double the risk for a future fracture, and bisphosphonate therapy will reduce that risk, a hip fracture should not serve as a reason to omit evaluation or treatment (see also Chapter 8).

Hyperparathyroidism

Clinical Features

The prevalence of hyperparathyroidism increases with age. Although its incidence is less than 10 per 100,000 in women under age 40, the incidence increases to 190 per 100,000 in women over age 60. As a result, more than half of all cases of hyperparathyroidism occur in individuals over the age of 65. Most cases are mild. Detection is by routine screening of serum calcium, and few or no symptoms are present. However, with relatively minor elevations of serum calcium (up to 11-12 mg/dL [2.8-3 mmol/L]), some elderly subjects may experience weakness, fatigue, depression, and confusion. Failure to thrive and constipation are commonly seen; renal, gastrointestinal, and skeletal complications occur less often. Other causes of hypercalcemia in the elderly—especially multiple myeloma, malignancy, vitamin D intoxication, and thiazide diuretics—must be considered in the differential diagnosis (see Chapter 8). Familial benign hypocalciuric hypercalcemia, an autosomal dominant disease, can generally be ruled out with a urinary calcium creatinine clearance ratio of less than 0.01. Other causes of secondary hyperparathyroidism due to vitamin D deficiency (common in the elderly) such as malabsorption and chronic kidney disease should also be excluded.

Treatment

For symptomatic patients and those with serum calcium levels 1 mg/dL above the upper limit of normal, parathyroidectomy may be recommended according to current guidelines (see Chapters 8 and 26). Parathyroidectomy is well tolerated in the elderly and is the treatment of choice. Minimally invasive parathyroidectomy uses preoperative localization by neck ultrasound and sestamibi scan and intraoperative measurement of PTH rather than the conventional approach of visualization of all glands. This not only improves the success rate but simplifies the surgical procedure as well. Parathyroidectomy procedures in elderly patients have similar outcomes compared with younger patients with respect to cure rate, morbidity, mortality, and patient satisfaction. For those with more modest elevations, treatment recommendations are less simply stated because it is difficult to differentiate symptoms and signs due to the disease from those seen in older individuals without hyperparathyroidism. Moreover, asymptomatic individuals—especially those with levels of serum calcium under 11 mg/dL (2.8 mmol/L)—have been known to remain asymptomatic for more than a decade. An observational study of 116 patients followed up to 15 years, reported that one-third of subjects had disease progression meeting surgical criteria. Until more data become available, the decision to treat asymptomatic individuals surgically should be made on an individual basis.

In older patients who are not surgical candidates, cinacalcet (a calcimimetic that binds to the calcium-sensing receptor on the cells of the parathyroid gland) can rapidly normalize serum calcium and reduce PTH in patients with primary hyperparathyroidism. Short-term studies demonstrate normalization of serum calcium, a small decrease in serum PTH without a significant impact on BMD. In women, a course of estrogen may be effective. Ethinyl estradiol (30-50 μg/d) or conjugated estrogens (0.625-1.25 mg/d) reduce serum calcium by an average of 0.8 mg/dL (0.2 mmol/L), diminish urinary calcium excretion, and antagonize the skeletal effects of PTH. However, the risks of estrogen (discussed earlier) make this an undesirable choice. In men and women with higher elevations of serum calcium, oral phosphates can be used, but they are less well tolerated in the elderly because of their gastrointestinal side-effects and the potential for ectopic calcification. Furosemide is a less satisfactory alternative in frail elderly patients because it increases the risk of dehydration and resultant hypercalcemia.

Changes in Water Balance

With age, major changes in renal function and homeostatic mechanisms result in significant changes in water balance. Renal blood flow, cortical mass, the number of glomeruli, and tubular function all decline with age, though medullary mass is preserved. On average, the glomerular filtration rate decreases at a rate of 10 mL/min per decade from age 30 onward. Clinically, however, the most relevant change is the age-related decline in creatinine clearance, which is largely due to relative hypertension in the elderly. Because of the decrease in muscle mass associated with aging, however, serum creatinine levels are unchanged and may not accurately reflect the extent of renal functional impairment.

Extrarenal modulators of water balance also change significantly with age. Although there are no changes in the basal level, half-life, volume of distribution, or metabolic clearance of vasopressin, the stimulated responses of vasopressin are significantly altered. Hyperosmolar stimuli increase serum vasopressin levels in older subjects to five times those achieved in younger subjects. This exaggerated antidiuretic hormone response makes elderly patients more susceptible to hyponatremia. On the other hand, the normal vasopressin increase observed in response to overnight dehydration and postural change is impaired in the elderly. Additionally, basal and stimulated levels of serum renin and aldosterone decline with age. In contrast, basal levels of atrial natriuretic peptide are three times higher in healthy elderly individuals than in young controls. These elevated levels of atrial natriuretic peptide may help identify patients at risk for the development of CHF. Finally, the thirst sensation appears to be somewhat impaired in healthy elderly individuals and is more impaired in those who are frail.

In addition to physiologic changes, many diseases and drugs further increase the vulnerability of the elderly to changes in water balance. These include kidney disease, hypertension, and congestive heart failure as well as medications that alter water balance (eg, narcotics, diuretics, lithium, carbamazepine, amphotericin B, intravenous hypotonic fluids, and hypertonic contrast agents).

Hypernatremia

Clinical Features

The incidence of hypernatremia in elderly patients admitted to the hospital ranges from 1% to 3% and is higher for institutionalized elderly patients. Signs and symptoms are usually nonspecific (eg, lethargy, weakness, confusion, depression, failure to thrive). The cause is usually multifactorial, including impaired thirst mechanism, renal disease, sedative-induced confusion, use of restraints, reduced access to free water intake, excess water loss due to fever, and decreased response to vasopressin. Medications can cause nephrogenic diabetes insipidus; these include lithium, foscarnet, diuretics, amphotericin B, and demeclocycline. Central diabetes insipidus can result from CNS trauma, malignancy, infection, or it may be idiopathic.

Treatment

As in younger patients, initial therapy involves correcting the volume deficit with isotonic saline and then correcting the water deficit with half-normal (0.45%) saline. Roughly 30% of the deficit should be corrected within 24 hours and the remainder within the next 24 to 48 hours (see also Chapter 5).

Hyponatremia

Clinical Features

The prevalence of hyponatremia is approximately 2.5% in the general hospital setting—higher in geriatric units—and rises to 25% in nursing home settings. Hyponatremia can be classified by the total body sodium as hypovolemic hyponatremia (decrease in total body sodium, eg, after diarrhea, vomiting, diuretic use), euvolemic hyponatremia (normal total body sodium, as seen with syndrome of inappropriate antidiuretic hormone [SIADH]), hypothyroidism, adrenal insufficiency, and medications) or hypervolemic hyponatremia (excess total body sodium, as seen with CHF or cirrhosis). Presenting symptoms and signs of euvolemic hyponatremia are often nonspecific and include lethargy, weakness, and confusion. The mechanisms predisposing to hyponatremia include the exuberant response of vasopressin to osmolar stimuli, a decreased ability to excrete a water load, and the sodium-wasting tendency of the older kidney. Furthermore, elderly patients often use medications and have diseases that impair free water excretion. Drugs that can cause hyponatremia include tricyclic antidepressants, phenothiazines, serotonin reuptake inhibitors, angiotensin-converting enzyme inhibitors, morphine, antiseizure medications, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen. Common hyponatremic syndromes in the elderly include SIADH and thiazide-induced hyponatremia. In the geriatric rehabilitation hospital, approximately half of patients with hyponatremia have SIADH (see Chapters 5 and 21).

Treatment

The treatment of hyponatremia in the elderly depends on the type of hyponatremia. The treatment of euvolemic hyponatremia does not differ from that in younger patients (Chapters 5 and 24). Vasopressin receptor antagonists lead to an increase in electrolyte-free water diuresis, and an increase in serum sodium levels in patients with SIADH and hypervolemic hyponatremia from CHF or cirrhosis. Additional studies are needed, but these agents may become the mainstay of treatment.

Hyporeninemic Hypoaldosteronism

Hyporeninemic hypoaldosteronism usually occurs in elderly patients with diabetes and mild renal insufficiency. Patients are usually asymptomatic. Hyperkalemia and metabolic acidosis are found on routine screening. Symptoms of hyperkalemia (eg, heart block) may be provoked by administration of a beta-adrenergic blocking agent, which further compromises extrarenal regulation of potassium homeostasis. After other causes of persistent hyperkalemia are ruled out, patients respond well to administration of small doses of fludrocortisone (0.05 mg/d) or furosemide combined with restriction of dietary potassium.

Glucocorticoids and Stress

Cortisol levels increase 20% to 50% with age. There is an increase in the nocturnal level of cortisol, an age-related morning increase in cortisol in women (not men), and an advancement in the circadian rhythm (Figure 23–16). Aging is associated with an increase in the cortisol production rate, independent of weight, and this accounts for the increased daily urinary free cortisol levels in older individuals. Dehydroepiandrosterone (DHEA) secretion declines with age and can be partially restored by mineralocorticoid antagonism, but in healthy elders, trials do not support supplementation with DHEA.

In healthy elderly individuals, dynamic testing of the hypothalamic–pituitary-adrenal axis is normal; expected responses to insulin-induced hypoglycemia, metyrapone, dexamethasone, adrenocorticotropic hormone, and corticotropin-releasing hormone (CRH) are preserved (Figure 23–17).

Disorders of the Hypothalamic-Pituitary-Adrenal Axis

Abnormal Response to Stress

In contrast to the normal responses in the elderly to dynamic testing of the hypothalamic-pituitary-adrenal axis, increased stress elicits abnormal responses. For example, although serum cortisol levels increase to the same extent in young and old patients undergoing elective surgery, the increase may be protracted in the elderly. Compared to younger, physically fit women, older physically fit women have greater cortisol production in the recovery period after a physical exercise challenge. Patients with diabetes mellitus and hypertension have also been found to have an exaggerated and prolonged response to corticotropin-releasing hormone (CRH) stimulation. Older patients with Alzheimer disease may also have a delayed and prolonged response to CRH stimulation. It is not known if these elevated cortisol levels contribute to the increased hypertension, glucose intolerance, muscle atrophy, and impaired immune function observed in the elderly. However, an elevated urinary free cortisol level is an independent predictor of osteoporotic fractures in the elderly.

Adrenal Hypersecretion

Although adrenal hypersecretion (Cushing syndrome) is uncommon in the elderly, it is easily overlooked because it mimics normal aging processes. Signs such as hypertension, glucose intolerance, weight gain, and osteoporosis are less specific in elderly than in younger patients, but as in younger patients the diagnosis is established or excluded using the usual criteria (Chapter 9).

Adrenal Insufficiency

Symptoms of adrenal insufficiency in younger patients (eg, failure to thrive, weakness, weight loss, confusion, and arthralgias) are common complaints in adrenally intact elderly patients; the most specific sign of adrenal insufficiency in the elderly is hyperpigmentation. The laboratory findings of adrenal insufficiency are similar to those in younger patients and include azotemia, hypoglycemia, hyponatremia, hyperkalemia, and eosinophilia. Because the metabolic clearance rate of cortisol decreases with age, older patients generally require lower replacement doses of cortisol (Chapter 9). For critically ill patients, the routine use of glucocorticoids should be reserved for patients diagnosed with adrenal insufficiency or those with hypotension, sepsis, acute respiratory distress syndrome, or lack of responsiveness to standard supportive care. Treatment doses of hydrocortisone (200 mg/d IV in four divided doses) should be weaned as soon as possible.

Changes in Reproductive Function in Men

Overall, while sexual activity decreases with age, there are conflicting reports about the physiologic changes in the hypothalamic-pituitary-testicular axis. Longitudinal studies demonstrate an age-related decrease in testosterone and free testosterone and a higher frequency of hypogonadal values (Figures 23–18 and 23–19). Some studies suggest that circulating testosterone and bioavailable testosterone fall with age by 40% to 65% and are even lower in institutionalized elderly. A decrease in the number or responsiveness of testicular Leydig cells is likely because serum follicle-stimulating hormone and luteinizing hormone (LH) increase with age, and the testosterone response to human chorionic gonadotropin decreases. In addition, there is probably an age-related decrease in the ratio of circulating bioactive to immunoreactive LH. Finally, age-related alterations in pituitary function are suggested by a decreased gonadotropin response to luteinizing hormone–releasing hormone (LHRH) stimulation.

Epidemiologic studies suggest that the declining levels of testosterone are associated with decreased muscle mass and strength, decreased bone mass, increased fat, and insulin resistance. The benefit of testosterone replacement in older hypogonadal men is less clear. Potential adverse events of testosterone replacement include disordered sleep and polycythemia. The clinical impact on the cardiovascular system and prostate disease are also concerns. Androgen supplementation is currently not recommended in healthy older men. Clinical trials are needed to establish a clear benefit and document the safety of testosterone supplementation in elderly men.

The correlation between sexual activity and the age-related hormonal changes described is weak. There are decreased concentrations of spermatozoa in the ejaculate of older men, sperm motility and the volume of ejaculate decrease with age, and the proportion of abnormal spermatozoa also increases. DHEA and DHEA sulfate are steroids of adrenal origin that decrease with age. Levels do not correlate with cognitive function or decline, and DHEA supplementation has not been shown to be beneficial. However, studies in the elderly are ongoing.

Erectile dysfunction (impotence) becomes more prevalent with age, but an endocrinologic cause becomes less likely. The prevalence of erectile dysfunction in men under age 45 is 5%; the prevalence in men over age 75 is 50%. However, more than 90% of men in the latter group have coexistent medical conditions or are taking medications that contribute to the problem. Furthermore, up to 30% of men over age 76 develop erectile dysfunction following prostatectomy, compared with 3% to 11% in younger age groups. Often there are multiple overlapping causes of erectile dysfunction—psychosocial, neurovascular, metabolic (diabetes mellitus), medication-related, and vascular—in the same individual.

The evaluation of erectile dysfunction in the elderly is similar to that in younger individuals (Chapter 12), although more emphasis must be placed on the effects of drugs (both prescribed and nonprescribed) and vascular causes, and a search for multiple causative factors should be undertaken. Medications associated with erectile dysfunction include diuretics (thiazides, spironolactone); antihypertensives (calcium channel blockers, beta blockers, clonidine), cardiac and cholesterol-lowering drugs, antidepressants (SSRI, tricyclic antidepressants, lithium), phenothiazines, H2 blockers, hormones (GnRH agonists, 5 alpha-reductase inhibitors, glucocorticoids), anticholinergic agents, and cytotoxic agents. Excess alcohol and smoking also contribute to it. Therapies include phosphodiesterase type 5 inhibitors that relax vascular smooth muscle cells. Because these medications can result in hypotension and increase the risk of myocardial infarction, if used with nitrates, the use must be carefully considered in elderly men with coronary artery disease.

Thyroid Function and Disease

Carbohydrate Intolerance and Diabetes Mellitus

Osteoporosis and Calcium Homeostasis

Changes in Water Balance

Glucocorticoids and Stress

Reproductive Function in Men