Draft:Osteosarcopenia

Osteosarcopenia is a newly recognized medical syndrome characterized by the simultaneous presence of two age-related chronic musculoskeletal conditions: Osteoporosis and Sarcopenia. Representing a hazardous combination of compromised bone and muscle health, the term “osteosarcopenia” was created. Osteoporosis refers to the grades-variant deterioration and progressive loss of bone mass and bone mineral density, through bone structural changes, resulting in heightened bone fragility and increased susceptibility to fractures. Contrarily, sarcopenia entails the gradual decline in skeletal muscle mass, strength, and functionality that is varyingly accompanied by aging and/or immobility. Overall, osteosarcopenia presents significant challenges to physical function, mobility, and overall quality of life, compromising survival.

Osteosarcopenia primarily affects a frail subset of the elderly population. Being a multifactorial condition, it involves various factors in its etiology, including patient status, comorbidities, bone-to-muscle homeostatic communications through cellular signaling, encompassing paracrine and endocrine mechanisms, genetics, biochemistry, pathological conditions, lifestyle factors, and others. Pathological mechanisms include age-associated adipogenesis and muscular fat-infiltration-driven cellular dysfunction.

The synergistic effects of osteosarcopenia, which combine the sarcopenic increased risk of falls and osteoporotic heightened bone vulnerability, result in a greater epidemiological likelihood, compared to osteoporosis or sarcopenia alone, of experiencing falls, fractures, patient institutionalization, and significant socioeconomic costs in an aging society.

Addressing osteosarcopenia necessitates a comprehensive approach involving exercise, nutrition, pharmacological therapies, and appropriate medical interventions. It is crucial to prioritize early detection, raise public awareness, and conduct research on the mechanical and biochemical interactions between bone and muscle, known as bone-muscle crosstalk, to effectively prevent and manage this condition.

Etymology
The term osteosarcopenia is derived from the combination of “osteoporosis” and “sarcopenia,” with “osteo” referring to bone, “sarco” referring to muscle, and “penia” denoting loss, all derived from Greek. The term osteosarcopenia emerged to describe the prevalent coexistence of osteoporosis and sarcopenia, which was recognized through medical cases involving bone fractures accompanied by significant muscle loss that were discovered in the early 2000s. It highlights the likelihood of interplay between bone and muscle health, leading to their simultaneous presence.

Signs  and 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), along with decreased bone density and an increased incidence of fractures resulting from falls. These manifestations reflect the synergistic effects of bone and muscle deteriorating, collectively contributing to generalized frailty and decreased physical performance.

Determining early or late indicators of osteosarcopenia is a complex task, as measurements such as changes in weight, limb circumference, or waist circumference can be influenced by factors like body composition, obesity, body fat percentage, or the accumulation of fluid in the body tissues (known as edema), which can compromise the accuracy of these indicators and cause diagnostic predictions to be somewhat arbitrary. However, certain markers of sarcopenia and osteoporosis can be used as potential indicators to standardize the diagnostic criteria. One potential sarcopenia-derived early indicator of osteosarcopenia is an imbalanced upper-body muscle hypertrophy. Contrarily, osteoporosis is typically asymptomatic until a fracture occurs. Though apparent changes may not manifest until the condition has progressed drastically, changes in natural posture, such as a stooped or hunched back, can be indicative of advanced osteoporosis and provide insights into the progression of osteosarcopenia.

Overall, osteosarcopenia is characterized by indicatory symptoms including challenges in performing daily activities, such as walking, climbing stairs, or lifting objects, which can ultimately impact quality of life by reducing independence and physical functionality. The severity of these symptoms progresses gradually and varies among individuals, influenced by various factors. Therefore, a comprehensive medical evaluation is essential for an accurate diagnosis, involving the determination of disease criteria and the designing of a suitable management and prevention plan.

Causes and pathophysiology
Multiple hypotheses have been proposed to elucidate the underlying mechanisms contributing to the development of osteosarcopenia, encompassing mechanical, biochemical, and lifestyle factors, among others. Understanding osteosarcopenia requires further consideration of the individual pathophysiological mechanisms associated with both sarcopenia and osteosarcopenia.

Sarcopenic etiology
In the progression and development of sarcopenia, age-related immunological changes, encompassing hormonal imbalance and oxidative stress, are key contributors. With physiological aging, there is a decline in the balance of hormones, such as testosterone, growth hormone(GH), and estrogen, which leads to a decrease in muscle protein synthesis and a consequent diminishment of muscle strength.

Another probable mechanism contributing to sarcopenia is an imbalance in protein turnover, which refers to the physiological continuous cycle of protein synthesis and degradation. This imbalance occurs when the rate of protein degradation exceeds the rate of protein synthesis in the body, resulting in a gradual loss of proteins. One possible factor behind this phenomenon is mitochondrial dysfunction, which decreases the energy supply available for protein synthesis and increases the production of reactive oxygen species, potentially resulting in detrimental oxidative stress.

Consequently, oxidative stress triggers muscle protein degradation through its over-activation of the ubiquitin-proteasome pathway, a protein-degrading system responsible for the breakdown of damaged or mis-folded proteins, resulting in the excessive breakdown of muscle proteins and contributing to muscle atrophy.

Osteoporotic etiology
In the progression and development of osteoporosis, various risk factors independent of bone mineral density are involved. These contributing factors encompass patient characteristics such as age and gender, with the elderly and women being at higher risk for osteoporosis, as well as body mass index, genetic susceptibility to fractures, smoking, menopause, age- and sex-related steroid deficiency, oral glucocorticoid use, alcohol intake, and history of falls.

Osteoporosis is characterized by the deterioration and loss of bone tissue, where bone loss occurs when the rate of bone resorption, which is the process where osteoclasts break down bone tissue into reusable calcium and minerals, exceeds the rate of osteoblast-mediated bone synthesis. With the bone remodeling cycle imbalance, adipogenesis – the formation of fat deposits – is favored over osteogenesis – the formation of bone tissue, inducing bone fragility. Osteoporosis can be classified into two main groups: primary osteoporosis, which includes postmenopausal (type I) and age-related (type II) osteoporosis affecting cortical and trabecular bone, and secondary osteoporosis, which is associated with different disease, medications, and lifestyle influences.

The endocrine etiology of osteoporosis is characterized by hormonal mechanisms, including estrogen deficiencies that can worsen with menopause, leading to secondary hyperparathyroidism, as well as inadequate intake of vitamin D and calcium, which are consequential factors in the development of the condition. Decreased estrogen levels stimulate increased osteoclast activity and decreased osteoblast activity, resulting in an upregulation of bone resorption signals.

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

The diagnosis of osteoporosis can be conducted by assessing the Bone Mineral Density (BMD), which is typically measured using Dual-energy X-ray Absorptiometry (DXA). A diagnosis of osteoporosis is given when the standardized osteoporotic BMD T-score is 2.5 or more standard deviations (SD) below the mean BMD of the same-sex reference population.

Contrarily, the diagnosis of sarcopenia involves assessing muscle strength, which is measured by hand grip strength using a hand-held dynamometer, as well as walking speed. A diagnosis of sarcopenia is given when a patient’s muscle mass is at minimum two standard deviations below the relevant population mean. The European Working Group on Sarcopenia in Older People has launched a broader clinical definition for sarcopenia, which encompasses low muscle mass and either low muscular strength or low physical performance.

Prevention and management methods
As osteosarcopenia is predominantly an age-related phenomenon, there is currently no specific cure for the condition. However, management strategies, aimed at slowing down its progression and enhancing overall bone and muscle health, have been devised and typically involve exercise, nutrition, and pharmacotherapeutic interventions.

Exercise
Physical activity is a key component in prevention and managing osteosarcopenia. Particularly for the elderly or women of postmenopausal age, multi-modal exercise programs that incorporate moderate-to-vigorous resistance training, balance/mobility activities, and weight-bearing aerobic exercises are recommended to enhance muscle strength, promote musculoskeletal health, and increase bone formation and mineral density potentially through the release mechanisms of anti-inflammatory cytokines and growth hormone alongside the increased expression of bone-generating genes. Additionally, exercise has been shown to improve protein synthesis in aging skeletal muscles and increase cellular mitochondria quantity, contributing to metabolic energy supply.

Several meta-analyses have shown that exercise can also reduce the overall fracture risk by 51% in adults aged 45 and above, and combined resistance and balance training programs have been found to decrease the risk of falls in frailer elderly individuals by 29%. However, establishing a standardized exercise prescription, including the type, duration, and intensity, specifically for osteosarcopenia, is an ongoing area of study.

Nutrition
In managing osteosarcopenia, optimal nutrition targets include vitamin D, calcium, and protein intake for supporting musculoskeletal health and biosynthesis.

Vitamin D supplementation supports muscle strength, mobility, functionality, and stability, while also preventing adipogenesis in intramuscular tissue by aiding calcium absorption. On the other hand, calcium helps maintain bone density, strength, and intramuscular metabolism. Given the age-related decline in protein synthesis and processing, higher protein quantities are necessary to prevent muscle atrophy. However, individuals suffering from severe chronic kidney disease are advised by PROT-AGE to restrict their protein consumption.

Daily intake recommendations for older adults include 800-2000 IU of vitamin D, 700-1200 mg of calcium, and 1.0-1.2 g/kg of body weight for protein, with a focus on consuming at least 20-25 g of high-quality protein per meal and post-exercise.

Pharmacotherapy
Current pharmacotherapies for osteosarcopenia primarily target bone tissue. Medications like bisphosphonates (such as alendronate, risedronate, and zoledronate) and hormone replacement therapy, which influence bone-density signaling pathways and promote the death of osteoclasts, are commonly prescribed. Other options include denosumab, selective estrogen receptor modulators, and anabolic agents. Denosumab is a receptor activator of nuclear factor- κB ligand inhibitors that improves skeletomuscular mass and enhances muscular strength and balance. Emerging therapies, such as selective androgen receptor modulators and activin signaling pathway inhibitors, are being explored to simultaneously address the bone and muscle aspects of osteosarcopenia.

Epidemiology and prognosis
Though the specific epidemiological data on osteosarcopenia is still emerging, studies that consider a history of falls as a criterion indicate that osteosarcopenia is most prevalent and impactful among the aging population, particularly in older adults with a history of falls. Prevalence rates vary but range from 5% to 40% in community-dwelling older adults and are higher in institutionalized individuals. A meta-analysis of roughly 15,000 patients affected by fractures revealed an overall osteosarcopenia prevalence rate of 21%.

Osteosarcopenia is more common in women and its prevalence increases with age as well as the extent of a sedentary lifestyle. It is associated with a higher mortality rate compared to osteoporosis (5.1%) or sarcopenia (10.3%) alone, with a one-year mortality rate of 15.1%. Half of women and one-fifth of men over 50 will sustain an osteoporotic fracture in their lifetime.

Public health impact
Osteosarcopenia is an emerging condition expected with a projected increase in prevalence. Although specific medications for osteosarcopenia are currently unavailable, the development of targeted drugs through clinical trials is essential in meeting the needs of affected individuals. Osteosarcopenia often reduces patients’ quality of life, as restricted movements and pain can contribute to psychological distress, and incur high healthcare costs. Furthermore, caregivers may experience increased burden due to the challenges of assisting with mobility limitations, potentially resulting in a greater demand for social healthcare services.

Research directions
Osteosarcopenia, a newly discovered syndrome, presents multiple research avenues for better understanding the disease and developing targeted treatments. Currently, there are no approved pharmacological agents specifically for osteosarcopenia, but denosumab shows potential. Further research and clinical trials are necessary to confirm its effectiveness in this context.

Understanding the underlying mechanism and systemic interplay, particularly involving the muscle-bone unit, behind the development of osteosarcopenia is crucial for identifying risk factors and improving management and prevention.