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 * 1) Lead Section:

Osteosarcopenia is a newly recognized medical syndrome characterized by the simultaneous presence of two age-related chronic musculoskeletal conditions: osteoporosis and sarcopenia. This condition represents a hazardous combination of compromised bone and muscle health. Osteoporosis refers to the progressive loss of bone mass, bone mineral density, and the deterioration of bone tissue through structural changes, leading to heightened bone fragility and susceptibility to fractures. Contrarily, sarcopenia entails the gradual decline in muscle mass, strength, and functionality that occurs with aging and/or immobility. As a multifactorial condition, osteosarcopenia etiology encompasses comorbidities, bone-to-muscle homeostatic communications via paracrine and endocrine mechanisms, genetics, biochemistry, and lifestyle factors, among others.

Individuals affected by osteosarcopenia, primarily a frail subset of the elderly population, experience a decline in both bone density and muscle mass, through mechanisms like age-associated adipogenesis and muscle-fat infiltration-driven cellular dysfunction, posing significant challenges to physical function, mobility, and overall quality of life. The synergistic effects of osteosarcopenia, combining the sarcopenic increased risk of falls and the osteoporotic heightened bone vulnerability, amplifies the likelihood, greater than that of osteoporosis or sarcopenia alone, of experiencing falls, fractures, and patient institutionalization, and incurs significant socioeconomic costs in an aging society.

Addressing osteosarcopenia requires a comprehensive approach involving exercise, nutrition, pharmacological therapies, and appropriate medical interventions. Early detection, public awareness, and research on bone-muscle mechanical and biochemical interactions (known as bone-muscle crosstalk) are crucial for the prevention and management of the condition.


 * 1) Etymology

Osteosarcopenia is derived from combining two words, ‘osteoporosis’ and ‘sarcopenia’. All the meanings are derived from Greek, where ‘osteo’ means bone, ‘sarco’ means muscle, and ‘penia’ means loss. The term osteosarcopenia has risen as the prevalence of cases where ‘osteoporosis’ and ‘sarcopenia’ coexist, which was discovered in the early 2000s. It has been said that it is likely for the bone and the muscle health to interplay, causing the coexistence.


 * 1) Signs & Symptoms

The hallmark signs and symptoms of osteosarcopenia manifest in various ways, primarily encompassing a gradual loss of muscle mass, mobility, strength, and endurance (known as muscle atrophy), decreased bone density and an increased incidence of fractures resulting from falls, which sum to generalized weakness and decreased physical performance. These manifestations reflect the synergistic effects of bone and muscle deterioration.

Defining early or late indicators of osteosarcopenia is challenging due to the possible background influence of obesity, fat mass, or edema on measurements like changes in weight, limb circumference, or waist circumference, degrading indicator accuracy. Indictors can be derived from individual markers of sarcopenia, including upper-body hypertrophy as an early indicator, and osteoporosis, including changes in natural posture, though osteoporosis typically remains asymptomatic until a fracture occurs.

Common symptoms of osteosarcopenia include challenges in performing daily activities, such as walking, climbing stairs, or lifting objects, which can ultimately affect overall quality of life by decreasing independence and physical functionality. The progressive severity of these symptoms as a gradual process varies among individuals and is influenced by various factors, underscoring the essentiality of a comprehensive medical evaluation for accurate diagnosis, including the determination of disease criteria, and the designing of a suitable management and prevention plan.


 * 1) Causes & Pathophysiology

Multiple hypotheses exist to explain the mechanism behind the development of osteosarcopenia, including mechanical, biochemical, and lifestyle factors. Osteosarcopenia is a combination of two different illnesses: osteoporosis and sarcopenia. Such two different illnesses have different pathophysiologies, yet they interplay among themselves to develop the condition of osteosarcopenia.

Age-related immunological changes, such as hormonal imbalance and oxidative stress, cause sarcopenia. The imbalance of hormones, such as testosterone, growth hormone (GH) and estrogen, declines as an individual ages, leading to decreased muscle protein synthesis and muscle strength.

Imbalance in protein turnover is another possible mechanism that contributes to sarcopenia. With imbalance in protein turnover, there is more protein that is degraded than is synthesized in the body, which causes gradual loss of proteins. One possible cause of this phenomenon is due to mitochondrial dysfunction, which leads to reduced energy available for protein synthesis and increased production of reactive oxygen species, which can lead to oxidative stress.

Oxidative stress leads to muscle protein degradation. Oxidative stress increases the activation of the proteolytic system, such as the ubiquitin-proteasome pathway, which is responsible for the degradation of damaged or misfolded proteins. Therefore, the proteolytic system overactivates due to oxidative stress, which leads to excessive breakdown of muscle proteins, contributing to muscle atrophy.


 * 1) Prevention & Management Methods

There is no specific cure for osteosarcopenia as it is primarily an age-related phenomenon; management strategies, aimed at slowing down the progression of the condition and improving overall bone and muscle health, can be divided into a combination of exercise, nutrition, and pharmacotherapic interventions.

Exercise

Physical activity is a key to prevention and management. Exercise offers a wide array of health benefits, particularly for the older population. Multi-modal exercise programs that incorporate traditional and high-velocity resistance training, weight-bearing aerobic training, and balance/mobility activities are recommended to enhance muscle strength and promote bone health or, in other words, decrease bone loss. A mechanism that exemplifies the benefits of exercise involves the enhancement or preservation of protein synthesis in aging skeletal muscles, a site-specific increase in bone mineral density, as well as an increase in cellular mitochondria quantity and adiposity, thereby amplifying metabolic energy supply. There has also been evidence that resistance exercise can improve multiple musculoskeletal health outcomes, hence the quality of life.

A meta-analysis has shown that exercise reduces overall fracture risk by 51% in adults aged 45 and above. Additionally, a separate meta-analysis found that combined resistance and balance training programs decreased the risk of falls in frailer elderly individuals by 29%. Translating research findings into a standardized exercise prescription (including type, duration, and intensity) for osteosarcopenia is still being studied.

Nutrition

In managing osteosarcopenia, optimal nutrition targets include vitamin D, calcium, and protein consumption. An adequate and well-balanced diet, rich in essential nutrients, is crucial for supporting bone and muscle health and facilitating their biosynthesis. Vitamin D supplementation contributes to increased muscle strength, functional mobility, and stability, as well as the prevention of adipogenesis in intramuscular tissue, through its metabolic role in calcium absorption. The recommended daily vitamin D intake for older adults is generally 800-2000 IU. For bone health, the recommended daily calcium intake is 700-1200 mg. Although vitamin D and calcium are considered micronutrients, they play significant roles in delaying osteoporosis by different mechanisms, such as the influence of calcium in maintaining bone density and strength and intramuscular metabolism. Given the age-related decline in protein synthesis and processing, higher protein quantities are necessary to prevent muscle atrophy and preserve muscle mass. However, according to the PROT-AGE expert group, patients with severe chronic kidney disease are advised to limit their protein intake. Experts advise a daily protein consumption of 1.0-1.2 g/kg of body weight, with a focus on consuming at least 20-25g of high-quality protein per meal and post-exercise for older age groups.

Pharmacotherapy

Current pharmacotherapies for osteosarcopenia primarily target bone tissue. In some cases, medications such as bisphosphonates (including alendronate, risedronate, and zoledronate) or hormone replacement therapy, which influence bone-density signaling pathways and the apoptosis or death of bone-degrading osteoclasts, may be prescribed as first-line treatments for managing osteosarcopenia. Other pharmacological therapies for the osteoporosis aspect of osteosarcopenia include denosumab (a receptor activator of nuclear factor-κB ligand inhibitor that improves muscle and bone mass and enhance muscular strength and balance), selective estrogen receptor modulators, and anabolic agents (aids the inhibition of the synthesis and mechanisms of osteoclasts). Newly developed therapies, such as selective androgen receptor modulators with anabolic effects on muscle and bone, as well as activin signaling pathway inhibitors and testosterone therapy for enhanced muscle mass, are being explored in order to take into account the sarcopenia aspect of the condition.


 * 1) Diagnosis

The diagnosis of sarcopenia involves separate diagnosis of osteoporosis and sarcopenia, as currently there are no screening tools available for osteoporosis itself.

The diagnosis of osteoporosis can be done by measuring the Bone Mineral Density (BMD). BMD can be measured by Dual-energy X-ray Absorptiometry (DXA). A patient is diagnosed with osteoporosis when the T-score is 2.5 or lower standard deviation (SD) lower than the mean BMD of the same-sex reference population.

The diagnosis of sarcopenia includes measuring the muscle strength, which is typically measured by the hand grip strength using hand-held dynamometer and walking speed. A person may be diagnosed with sarcopenia when the muscle mass of a patient is at least two standard deviations below the relevant population mean. The European Working Group on Sarcopenia in Older People (EWGSOP) launched a broader clinical definition for sarcopenia, which is the presence of low muscle mass and either low muscular strength or low physical performance.


 * 1) Epidemiology & Prognosis

The prevalence, impact, and public health concerns associated with osteosarcopenia are most prominent in the aging population, though prevalence depends on the study and its specific epidemiological design. While specific epidemiological data on osteosarcopenia is still emerging, studies considering a history of falls as a criterion indicate a high prevalence among older adults, especially those in advanced age groups. The prevalence rates vary across different study samples or populations, with estimates ranging from 5% to 40% in community-dwelling older adults and higher rates in institutionalized individuals. A meta-analysis examining roughly 15,000 patients affected by fractures revealed an overall prevalence rate of 21% for osteosarcopenia. Independent epidemiological studies on osteoporosis and sarcopenia provide valuable insights into the prevalence rate of osteosarcopenia.

Osteosarcopenia exhibits a higher prevalence in women compared to men, and its occurrence tends to increase alongside age in direct correlation. Furthermore, osteosarcopenia is strongly associated with a notable increase in mortality rates. A study revealed that individuals with osteosarcopenia had a one-year mortality rate of 15.1%, surpassing the rates observed in those with osteoporosis (5.1%) or sarcopenia (10.3%) alone.

Key risk factors for osteosarcopenia include a sedentary lifestyle, inadequate nutrition, chronic diseases, hormonal changes, and certain pharmacological side effects, with the dominant factors being female, advanced in age, and having a history of fractures.


 * 1) Public Health Impact

Osteosarcopenia is an emerging condition with a projected increase in prevalence over time. Despite the absence of specific medications for osteosarcopenia, the development of targeted drugs through clinical trials is crucial for addressing the needs of affected individuals. The condition often results in reduced quality of life for patients, as restricted movements and pain can contribute to psychological distress. Furthermore, caregivers may experience increased burden due to the challenges in assisting with movement limitations, which could potentially lead to a greater demand for social healthcare services.


 * 1) Research Directions

Osteosarcopenia is a relatively newly discovered syndrome, and there are various ways that can bring an understanding of the disease. As of 2024, there are currently no approved pharmacological agents specifically for treating osteosarcopenia. However, denosumab, a drug commonly used for osteoporosis, shows potential for treating osteosarcopenia. Further research and clinical trials are necessary to validate its effectiveness in this context.

Establishing the mechanism driving the development of osteosarcopenia is another crucial aspect to be emphasized. A comprehensive understanding of the actual mechanisms, especially the interplay between the muscle and bone systems, will aid in identifying risk factors and developing targeted personalized treatments for affected individuals. This area of research holds great promise for improving the management of osteosarcopenia.