Aging and endocrinology

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CHAPTER 56

Aging and endocrinology

1. What effect does aging have on body weight?

Aging is associated with important changes in body composition that may be influenced by the endocrine milieu and can have important endocrine and metabolic consequences (Table 56-1). In cross-sectional studies, body weight increases until about age 55 years and then declines. This may be the result of a “die-off” effect in the heaviest patients during middle age. Prospective studies suggest that weight actually declines after age 65 to 70 years. This reduction in body weight, whether intentional or unintentional, appears to be associated with an increase in mortality, morbidity, and disability. Indeed, there is a well-described obesity paradox in older patients, so that the weight with the lowest overall mortality is shifted upward. The explanation for this is not clear, but it is possible that any sustained weight loss may, in fact, be unintentional, given that intentional weight loss is difficult to maintain. Weight loss in the presence of illness or disease that raises cytokine levels may predispose to a disproportionate loss of weight as lean mass (muscle mass), thereby exacerbating age-related “sarcopenia” and leading to a catabolic state. It is also possible that the apparent obesity paradox of aging results from the heterogeneity of obesity in older patients; obesity beginning in young or middle age is associated with untoward consequences, and obesity beginning in older age is less dangerous. Interventions in these two potentially heterogeneous groups may also be expected to produce different effects, but this has not been studied.

TABLE 56-1.

BODY COMPOSITION CHANGES WITH AGING

  CHANGE
Fat mass
Lean mass
Muscle mass
Bone mass

2. What changes in lean body mass occur with aging?

There is an inevitable loss of lean body mass, mostly skeletal muscle, with aging. The aging-associated loss of muscle has been termed sarcopenia and has been blamed for much, but not all, of the age-related decline in muscle strength and power (dynopenia). In cross-sectional studies, a 20% to 30% loss of lean mass has been detected between ages 30 and 80 years. The decline in strength is even greater, with longitudinal studies finding up to a 60% loss from age 30 to 80 years. Furthermore, the loss of strength and power is not as linear as the loss of muscle mass and seems to accelerate at older ages. A 25% decline in strength has been detected between 70 and 75 years of age. Power (work per unit time) may decline at double the rate of strength. These changes in lean mass, muscle mass, strength, and power have complex but important functional consequences for older people. Of greatest clinical importance are the relationships among muscle mass, strength or power, and functional ability. These relationships are complex and probably nonlinear, and in general they have been difficult to demonstrate clearly. An example is the consistent association of testosterone supplementation with increases in lean mass but inconsistent associations with improvements in strength or function.

A more recent concept, sarcopenic obesity, considers the degree of adiposity relative to lean mass. Currently, because consensus is lacking on how sarcopenic obesity should be defined, the prevalence and clinical relevance have not been established. One contributing factor in sarcopenic obesity could be weight cycling, with loss of lean and fat mass followed by regain of fat mass only. This may be more likely in older patients who are less anabolic and generally less active. The loss of lean mass with aging can have a profound effect on resting metabolic rate and thus can predispose to further accretion of fat mass if caloric intake is not reduced.

3. What changes in bone mass and density occur with aging?

Prospective data indicate that peak bone mass occurs during the late teen years in women and about a decade later in men. Because of the intimate structural and functional link between muscle and bone, the occurrence of peak bone mass likely corresponds to peak skeletal muscle development. It is generally thought that bone mass is maintained, or decreases slowly (< 0.2% per year), at least through age 40 years in women and age 50 years in men. Intuitively, a decline in physical activity during middle age may be expected to induce an even faster rate of bone loss. However, the increase in body weight that typically also occurs during middle age may counter this to a large extent, by increasing mechanical loading forces acting on the skeleton during weight-bearing activity. The inevitable loss of bone mass in old age increases the risk of osteoporosis in elderly men and augments the risk of osteoporosis in postmenopausal women. In elderly women and men, the decrease in bone mineral at the hip appears to be accelerated (∼1% per year) relative to the changes at the spine, which may increase in advanced age. Vertebral compression fractures and the development of extravertebral osteophytes lead to an increase in bone mineral density (BMD) that does not reflect increased vertebral bone strength. The utility of spine BMD for the diagnosis of osteoporosis in elderly persons is therefore compromised.

4. Does menopause have an independent effect on bone mass?

5. Can weight-bearing exercise prevent the menopause-related loss of bone mineral in women?

6. Do sex hormones influence the skeletal response to exercise?

Although the direct effects of estrogens on bone metabolism are well known, growing evidence indicates that the responses of bone cells to mechanical stress involve activation of estrogen receptor alpha. The effects of age-related sex hormone deficiency on receptor density and/or function in bone remain unknown. In animal models, the effects of mechanical stress in the presence of estrogens (in females) or androgens (in males) on the bone proliferative response have been found to be either additive or synergistic (i.e., more than additive). There is also evidence for additive or synergistic effects of exercise and estrogens on BMD in postmenopausal women. More recent studies of laboratory animals suggest that estrogen receptor alpha may facilitate the effects of mechanical loading on bone, whereas estrogen receptor beta may inhibit such effects.

7. What criteria are used to determine who should be treated for low bone density?

Dual-energy x-ray absorptiometry (DXA) scans are the best means of following changes in bone density in the elderly population. T-scores higher than −1.0 indicate normal bone density, whereas T-scores lower than −1.0 but higher than −2.5 indicate osteopenia, and T-scores lower than −2.5 indicate osteoporosis. Pharmacotherapy for low bone density is not only reserved for those with osteoporosis. The World Health Organization (WHO) developed the FRAX score, which gives an individual’s 10-year probability of fracture and can identify those patients with osteopenia who would benefit from treatment. The recommendation in the United States is to consider treatment if the 10-year probability of a major osteoporosis-related fracture is at least 20% or at least 3% for a hip fracture. Additionally, anyone with a fragility fracture regardless of BMD should be considered for treatment. A FRAX score may be calculated without DXA.

8. What pharmacologic agents are available for use in elderly patients with low bone density?

Following the supplementation of calcium and vitamin D, bisphosphonates are the first-line drug class for the improvement of bone density and fracture prevention. Their antiresorptive properties have been shown to be efficacious in improving BMD and preventing fractures at all major sites. There have been reports of rare side effects such as osteonecrosis of the jaw, as well as concerns about an association between long-term use (> 3–5 years) of bisphosphonates and atypical fractures of the thigh, known as subtrochanteric and diaphyseal femur fractures. Recommendations are to consider periodic reevaluation of the need for continued bisphosphonate therapy, particularly in patients who have been treated for more than 5 years, and always to ask about symptoms such as new thigh or groin pain.

Denosumab is an antiresorptive osteoporosis drug, approved by the Food and Drug Administration (FDA) in 2010, that is a human monoclonal antibody functioning as a RANK ligand (RANKL) inhibitor. This drug has the net effect of preventing the maturation of osteoclasts, decreasing bone resorption with increased BMD in women and men, and reducing the risk of fracture (better fracture data in women). Use of this agent could be considered in patients who have been unresponsive to or are intolerant of other available osteoporosis therapies and in patients with renal insufficiency. No dose adjustment is necessary in patients with renal impairment, although they may be at more risk for hypocalcemia, particularly if they are not receiving adequate calcium and vitamin D. Additionally, because RANKL functions within the immune system, long-term monitoring is needed to assess increased risk for serious infections and neoplasms.

The only FDA-approved anabolic drug is teriparatide, which is recombinant human parathyroid hormone (PTH[1–34]). It improves BMD and prevents fractures. This drug is administered via daily subcutaneous injection, an important consideration in elderly patients who may not have the functional capacity or appropriate assistance to do so.

9. Does fat mass increase and/or become redistributed with aging?

There is an increase in total adiposity and shift toward more abdominal fat distribution with advancing age. The increase in central adiposity begins in young men who gain excess fat, but this does not appear to occur in women until around the time of the menopausal transition. Although the loss of lean mass was once thought to be the primary determinant of physical disability in old age, more recent studies indicate that increased adiposity is an independent, and perhaps stronger, predictor of disability in older individuals. The increase in abdominal visceral adiposity (along with the decline in physical activity) plays an important role in the age-associated increase in insulin resistance and probably contributes to the high incidence and prevalence of type 2 diabetes mellitus and metabolic syndrome in old age.

10. Does the menopause trigger an increase in abdominal obesity in women?

Cross-sectional comparisons of women across the age spectrum suggest that waist size increases more rapidly in women aged 50 years and older than in younger women. Prospective studies indicate that increases in waist circumference are related to both chronologic and ovarian age, with the most rapid increases in waist girth occurring in perimenopausal women. Premenopausal women treated with gonadotropin-releasing hormone agonists to suppress sex hormones gain 1 to 2 kg of fat mass in 4 to 6 months, with a disproportionate increase in central body regions. Several randomized, controlled trials provided evidence that postmenopausal women who took hormone therapy gained less weight and had less increase in waist size than did placebo-treated women. The effects seemed to be slightly larger with unopposed estrogens. It has not yet been determined whether estrogens specifically prevent or attenuate intraabdominal fat accumulation.

11. What are the results of prospective studies of voluntary weight loss (through lifestyle or weight loss surgery) in elderly persons?

Obesity in older adults is a mounting public health concern, given its increasing incidence and its association with loss of functional independence and frailty. Hypocaloric diets have been effective in reducing total and visceral fat and improving glucose tolerance, insulin sensitivity, blood pressure, and pulmonary function. Obese elderly adults are capable of participating and adhering to rigorous interventions such as diet, exercise, or diet plus exercise. Such studies have found that diet alone and exercise alone both reduce frailty, but the combination of diet and exercise generates the greatest objective functional and subjective benefits.

Intentional weight loss typically results in a loss of lean mass (muscle and bone), which may exacerbate sarcopenia and the risk of osteoporosis. This could have adverse effects in elderly adults who are already at risk for osteoporosis. The addition of exercise training to diet in older obese adults prevented the weight-loss-induced increase in bone turnover and attenuated, but did not prevent, the decline in BMD.

Some prospective observational studies have suggested that weight loss in older adults may be associated with increased mortality, despite a decrease in comorbidities such as cardiovascular disease and type 2 diabetes. In randomized controlled weight loss interventions, weight loss did not increase mortality in older adults over 8 to 12 years of follow-up. In fact, secondary analyses from one trial suggested that intentional weight loss may reduce mortality risk in this population. Additional trials of intentional weight loss in older adults are needed to confirm whether it does, indeed, reduce mortality risk and whether the risk-to-benefit profile is similar in older adults who became obese earlier versus later in life.

Weight loss surgery is effective at reducing medical comorbidities in elderly persons. The sparse available data do not suggest increased mortality. In fact, mortality rate may be decreased compared with matched obese cohorts.

12. Why is vitamin D status important in older adults?

Vitamin D supplementation has been found to reduce the incidence of osteoporotic fractures in elderly persons. This may occur via increased bone mineralization and/or improved muscle function and reduction in falls. Vitamin D deficiency is defined as a 25-hydroxyvitamin D (25-OHD) level of less than 20 ng/mL (50 nmol/L). It has been estimated that more than 40% of community-dwelling older women and men in the United States are vitamin D deficient, and the prevalence is even higher in nursing home residents. There are multiple causes of vitamin D deficiency in older adults, including the following: decreased skin synthesis; decreased sun exposure; decreased intake; impaired absorption, transport, or liver hydroxylation of oral vitamin D; medications altering vitamin D metabolism; chronic illnesses associated with malabsorption; and liver and kidney disease.

BMD is adversely affected when serum 25-OHD is less than 30 ng/mL. Vitamin D3 supplementation of 700 to 800 IU/day or 100,000 IU every 4 months has been found to raise serum 25-OHD to more than 30 ng/mL and reduce the incidence of fractures. There is currently no evidence for antifracture efficacy of vitamin D2 supplementation.

Vitamin D deficiency also causes muscle weakness. Proximal muscle strength is linearly related with serum 25-OHD when levels are less than 30 ng/mL. Vitamin D supplementation has been associated with a 22% reduction in falls. Nursing home residents randomized to receive 800 IU/day of vitamin D2 plus calcium had a 72% reduction in falls.

In addition to its important role in muscle and bone metabolism, vitamin D deficiency is postulated to influence immune function, cancer risk, PTH and renin production, and insulin secretion. Epidemiologic studies demonstrate higher mortality in patients with insufficient or deficient levels of 25-OHD.

13. What are the recommendations for vitamin D supplementation in older adults?

The recommendations for vitamin D supplementation in older adults differs among professional societies. However, it is agreed that daily supplementation is best achieved with vitamin D3. In 2010, the National Osteoporosis Foundation (NOF) recommended that older adults should have a serum 25-OHD level of 30 ng/mL (75 nmol/L) to reduce risk for falls and fractures. Supplementation doses up to 800 to 1000 IU/day were recommended because of the lack of evidence for the efficacy of higher doses.

In 2012, the United States Preventive Services Task Force (USPSTF) reported that supplementation of 400 IU/day vitamin D in combination with 1000 mg/day calcium does not reduce fracture risk in noninstitutionalized, community-dwelling, asymptomatic adults without a previous history of fractures. It was further noted that evidence regarding the effectiveness of higher doses of vitamin D and calcium on incident fracture is lacking.

The current Institute of Medicine recommendations for vitamin D supplementation are set at 600 IU/day for men and women aged 51 to 70 years and 800 IU/day for older individuals.

14. What interventions have been associated with increased longevity, and have they been shown to work in humans?

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