Compiler: He Jieyu, Cai Jing, Liu Youshuo, Institute of Aging and Geriatric Diseases, Central South University.
Introduction: In June 2023, the International Conference on Endocrinology was held in Chicago, USA, where well-known experts and scholars in the field of endocrinology gathered to discuss the cutting-edge progress and hot issues in the field of endocrinology. Among them, the debut of the "Scientific Statement on Hormones and Aging" undoubtedly "filled" everyone's expectations directly - the conference announced the "Scientific Statement of Hormones and Aging" of the American Endocrine Society for the first time. Experts focused on the effects of aging on the endocrine system, including aging and the hypothalamic-pituitary axis (growth hormone, adrenal glands, gonads (divided into ovaries and **) and thyroids), osteoporosis, vitamin D deficiency, diabetes, and water metabolism.
Original text: Hormones and aging: An Endocrine Society Scientific Statement the journal of clinical endocrinology & metabolism. 2023, 00, 1–40
advance access publication 16 june 2023
Preface. Hormones are important substances that regulate the body's functions. As we age, our body functions and cognitive functions decline. The extent to which age-related changes in hormonal regulation and increased prevalence of endocrine disorders affect physical and cognitive decline is unclear. In the context of the global trend of population ageing, the importance of articulating these issues cannot be overstated. The current** shows that the population aged 65 and over will increase from 70.3 billion (1 in 11 people) to 1.5 billion people (1 in 6 people) by 2050 (1). The purpose of this scientific statement is to summarize the current state of research on multiple hormonal axes in aging and to identify areas where future research is needed. Each section is summarized from physiological alterations and monitoring data, feasible interventions, clinical trial data on efficacy and safety in the elderly population, key points, and unresolved scientific questions. There are no guidelines for how hormonal changes with age are defined as "physiological aging" or "endocrine disease", depending in part on the current indication. This scientific statement will develop from the topics of 4 categories of hypothalamic-pituitary axis [growth hormone, adrenal glands, gonads (divided into ovaries and **) and thyroid], osteoporosis, vitamin D deficiency, diabetes mellitus, and water metabolism. Aging science is a research method that studies the biological mechanisms of aging and its interaction with comorbidities, and finally, we will summarize the top research directions to be addressed and the need for research methods in aging science.
Osteoporosis. Physiological changes in the elderly population monitoring data.
Osteoporosis is a chronic bone disease that causes progressive bone loss in postmenopausal women as well as in older adults (235). This bone loss will progressively destroy bone microstructure, reduce bone strength, and increase the risk of fractures. Evidence-based guidelines for the management of osteoporosis, including how to effectively identify people at high risk of fracture and intervention strategies to reduce the risk of fracture (235-237), have been published.
Bone mineral density (BMD) t-value at the lumbar spine or femoral neck -25 is defined as osteoporosis. The prevalence of osteoporosis ranges from 6 in women aged 50-59 years8 to 70 among women aged 79 -257, 34 in 80-year-old women9％（238）。Osteoporosis accounts for 5% of men aged 70 -79 years and 10% of men aged 80 years9%。In addition, about half of adults aged 70 and older have low bone mineral density, which, combined with other risk factors, puts them at high risk of developing fractures.
The incidence and severity of fractures increase exponentially with age; Vertebral (spine) and hip fractures account for 24 of all fractures in women aged 60 to 69 years, but up to 67 (239) in women aged 80 years (Figure 7). About half of women and 20 of men will experience a fracture due to osteoporosis in their lifetime; Two-thirds of these fractures occur after the age of 75 (240). More than 2 million osteoporotic fractures occur in the United States each year, including 700,000 vertebral (vertebral) fractures and 300,000 hip fractures, resulting in more than 500,000 hospitalizations (241).
Figure 7: Prevalence of hip, spine, and all fractures in women aged 60-69, 70-79, and 80 years in the Dubbo study. The combination of hip and spine fractures accounted for 24% of all fractures between 60-69 years, 44% between 70-79 years, and 67% at 80 years (239).
There is a high incidence of hip and vertebral fractures and a high mortality rate (242-245). The average age at which hip fractures occur is 82 years, and hip fractures have higher healthcare costs and disability rates than other types of fractures (246). Although this knowledge and effective methods have become widespread, most elderly patients with fractures do not accept osteoporosis. Less than 15% of Medicare patients (average age 80.)9 years of age) began osteoporosis** within one year of the fracture, and more than 60% of them had a hip or spine fracture (247). In the United States, age-adjusted rates for hip fractures began to decline after 1997, but recent data suggest that these rates are rising again due to the widening gap (248).
Most fractures occur after a fall. Osteoporosis and sarcopenia are risk factors for falls and often co-occur in older adults (249). At least one-third of women over the age of 65 will experience a fall, and the risk of falls increases with age (250).
The strongest risk factors for fracture include older age, low bone mineral density, and a history of previous fractures or falls, all of which interact with each other. Older women have a higher risk than younger women with the same t-score and may have a higher risk of fracture when bone mineral density values are not significantly reduced (251) (Figure 8). A history of past fractures doubles the risk of future fractures, which is particularly high in the first two years after an accidental fracture (252). In addition, recurrent fractures in older adults are more likely to be severe fractures (253).
Figure 8: Female femoral neck t-values are < 1 and < 2., respectively5, the relationship between age and hip fracture risk (251).
The U.S. Preventive Services Task Force (USPSTF) and social guidelines recommend bone density testing for all women 65 years of age (254-256). Bone density tests for men are recommended starting at age 70 (257). Evaluation of secondary causes of osteoporosis is necessary, including endogenous and exogenous Cushing syndrome, male hypogonadism, clinical hyperthyroidism, and severe vitamin D deficiency. In FRAX, a validated fracture risk algorithm, BMD results can be combined with other risk factors to estimate fracture probability in individual patients (258). FRAX underestimated fracture risk in patients who had recently fractured or fallen.
Available interventions.
The primary intervention strategy to reduce the risk of fracture is to minimise risk factors, including nutritional support, smoking cessation, and regular physical activity. A multidisciplinary approach to fall risk prevention includes exercises to promote strength and balance, correction of visual deficits, minimization of drugs associated with fall risk, such as thiazide diuretics, sedatives, and receptor blockers, elimination of risk factors in the home environment, and appropriate use of assistive devices. However, none of these methods have been evaluated in studies large enough or long enough, and there is insufficient evidence for reducing the risk of fracture. These general measures and strategies to prevent falls are recommended as primary prevention in all older adults, and medications are recommended in patients at high risk of fracture** (235).
A variety of drugs with different mechanisms of action have been approved for osteoporosis (237) (Table 3). All medications reduce the risk of vertebral fractures in postmenopausal osteoporosis women. With the exception of raloxifene and ibandronate, all drugs reduce the risk of nonvertebral fractures. Alendronate, risedronate, zoledronic acid, denosumab, and romosumab have been shown to reduce the risk of hip fracture. Anti-bone remodeling drugs reduce bone turnover and increase bone density and strength, but do not repair the microstructural damage of osteoporosis. Enhancement of bone metabolism or osteogenic agents can promote bone formation and improve trabecular bone structure. Compared with oral bisphosphonates, bone metabolism enhancers are more effective in improving bone mineral density and reducing fracture risk in older adults (259). Osteogenesis drugs are indicated for patients at very high risk of fracture (t-score -3 in the absence of fragile fractures0；In the presence of fragile fractures, the t-value is -25；Patients with severe or multiple vertebral fractures) (236,256,260). Detailed information on the efficacy, safety, and use of individual drugs can be found in the Endocrine Society's clinical practice guidelines and their guideline updates (235,236).
Table 3Approved in the United States for the use of ** osteoporosis.
Abbreviations: EAA, estrogen agonist antagonist; iv, intravenous; PTH, parathyroid hormone; sq. m., subcutaneous.
Recent data suggest a strong relationship between **-associated changes in bone mineral density and reduced risk of fracture (261). This has given rise to an emerging concept of goal-orientation, which uses total hip bone mineral density as a "target" to guide initial selection and subsequent decision-making (262).
Raloxifene is an estrogen agonist antagonist, a weak anti-bone remodeling drug that reduces the risk of vertebral fractures but not other fractures.
Salmon calcitonin is a weaker inhibitor of bone resorption that may reduce the risk of vertebral fractures. Due to the possible carcinogenic risk of salmon calcitonin**, the drug is no longer approved in Europe. Short-term** may be considered to relieve pain after acute vertebral fracture (263).
Bisphosphonates are the most commonly used medication for osteoporosis. In addition to ibandronate sodium, approved bisphosphonates reduce the risk of vertebral, non-vertebral, and hip fractures. Although long-term use of bisphosphonates** has been shown to be associated with osteonecrosis of the jaw and atypical femoral shaft fractures, the benefit-risk profile remains favourable for 10 years in patients at high fracture risk. Moreover, bisphosphonate use for more than 5 years does not result in additional bone density increases or decreases fracture risk. Guidelines recommend reassessing fracture risk after 3 to 5 years of bisphosphonate**. For patients who remain at high risk of fracture after 5 years of bisphosphonate**, sequential to denosumab or osteogenesis agents may be considered (235).
Denosumab is a human monoclonal antibody that is injected subcutaneously every 6 months and reduces the risk of vertebral, non-vertebral, and hip fractures. Over the course of 10 years**, bone mineral density gradually increased, the risk of fracture was reduced or maintained, and no major safety concerns were identified. While there is no time limit for denosumab**, discontinuation leads to a rapid loss of markers of bone metabolism**, bone mineral density, and vertebral fracture protection, and an increased risk of multiple fractures. Alendronate or zoledronic acid should be given at the time of discontinuation of denosumab to slow these effects (264).
Teriparatide and abaparatide are parathyroid hormone receptor agonists that activate bone formation but have a lesser effect on bone resorption. Both drugs have been shown to reduce vertebral and non-vertebral fractures, but they have not been shown to reduce hip fracture risk in pivotal clinical trials. These drugs are administered by daily subcutaneous injection, which usually takes 18 -24 months because their anabolic effects diminish with longer use. A course of these drugs is recommended to be followed by antiresorptive drugs to consolidate the benefits.
Romolimab is an anti-osteoscleroscleropin antibody that activates bone formation and inhibits bone resorption and is injected subcutaneously once a month for 12 months, followed by bisphosphonates or denosumab. Compared with placebo and alendronate, these courses were associated with a greater increase in bone mineral density and a greater reduction in fracture risk over 12 months. There was an increased cardiovascular risk compared to alendronate, but not placebo (265).
Clinical trial data on efficacy and safety.
IOM (now the National College of Medicine) recommends a total daily calcium intake of 1200 mg (266) for older adults based on inconsistent data. Too much daily calcium intake is not beneficial and can be harmful. The role of vitamin D supplementation in older adults is more uncertain, which we will discuss in more detail in the next section. Based on the available evidence, it is recommended that older adults consume 1 to 1 per kilogram of body weight per day2 g protein (267). High protein intake slows muscle loss and reduces the frequency of falls (268).
Weight-bearing exercise does not typically increase bone mineral density in older adults, whereas regular walking can reduce bone loss in sedentary older adults (269). A multicomponent exercise program targeting balance, gait, and muscle strength can reduce the frequency of falls and possible fractures in older adults (250). Correcting cataracts and limiting the use of neuroactive sedatives may reduce the risk of falls. Hip protectors may be considered in patients at high risk of falling, particularly in a supervised setting (270). The Centers for Disease Control and Prevention provides useful tools for assessing and managing fall risk, based on published guidance (271). For older patients who have experienced fractures, an individualized plan is helpful (272,273). Intensive exercises for the back improve symptoms and reduce the risk of subsequent fractures in patients with vertebral fractures (274).
The average age of participants in clinical trials of fracture drugs was between 65 and 75 years; Some even recruited participants as young as 100 years old. Subgroup analyses of responses to 3 bisphosphonates (alendronate, risedronate, and zoledronate), denosumab, teriparatide, and abaloparatide in a subset of older participants enrolled in pivotal trials have been published (275-280). These analyses showed that the efficacy, safety, and tolerability of ** in the elderly subgroup were generally similar to the response in the overall study cohort. Importantly, in older patients, the risk of fracture is significantly reduced 6 months after the start**.
Because neither raloxifene nor calcitonin-salmon reduces the risk of nonvertebral or hip fractures, it is not recommended for older patients with osteoporosis. Bisphosphonates should be used with caution in patients with severely impaired renal function. When oral bisphosphonates are difficult to use due to dosing rules and too many other medications, annual or biennial zoledronate infusions are an option (281). In a randomized controlled trial of patients (mean age 74 years) who received ** within 3 months of hip fracture, zoledronate reduced fracture risk (35%) and mortality (28%) compared with placebo (282). For older patients who take multiple drugs orally, twice-yearly subcutaneous denosumab is preferred. Denosumab can be used in patients with impaired renal function, but these patients are at high risk of hypocalcemia. Denosumab reduced the risk of hip fracture by 62% compared with placebo in patients aged 75 years and older (277). Teriparatide and abaparatide may be associated with palpitations and orthostatic hypotension and are not recommended for patients at increased risk of osteosarcoma, including those with a history of bone radiation**. Romosumab is not appropriate in patients with very high cardiovascular risk.
Essentials. l Osteoporosis-related fractures are a common and serious problem in older adults.
Older patients at high risk of fracture are easily identified, especially those with recent fractures.
Ensuring good nutrition and encouraging regular physical activity can help promote bone health.
Drugs that reduce the risk of fracture are effective and well tolerated in older patients and should be considered in all older patients with osteoporosis, particularly those with a history of previous fractures.
Research on unsolved scientific questions.
Fractures are not usually associated with osteoporosis. As a result, most elderly patients with fractures do not receive osteoporosis**. Research evaluation strategies will be helpful in educating patients and clinicians about the importance and benefits of osteoporosis.
Studies comparing the efficacy and safety of osteoporosis drugs in older patients are needed. There is a lack of studies assessing the effects of measures used to reduce fall risk on fracture risk. Studies evaluating the effects of anti-aging** on preventing the effects of aging by selectively inducing senescent cell death should include bone outcomes as an indicator.
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