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Musculoskeletal Disease

OSTEOPOROSIS is the most common reason for a broken bone among the elderly; bones may weaken gradually and painlessly to such a degree that fracture may occur spontaneously or in response to minor stress. About 15% of Caucasians in their 50s and 70% of those over 80 are affected, with more women suffering the disease than men. According to the National Osteoporosis Foundation, about 54 million Americans have osteoporosis and low bone mass, placing them at increased risk for osteoporosis. Studies suggest that approximately one in two women and up to one in four men age 50 and older will break a bone due to osteoporosis.

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Osteoporosis is frequently found in individuals who have been treated with glucocorticoids for an extended time —usually for conditions such as asthma, rheumatoid arthritis, systemic lupus erythematosus and other inflammatory/immune/autoimmune disorders. In addition, there are many health problems and a few medical procedures that increase the likelihood of osteoporosis. These include among others hematologic/blood disorders/cancer such as leukemia, lymphoma, multiple myeloma, sickle cell disease, thalassemia, breast cancer, prostate cancer, diabetes, weight loss surgery, ad kidney failure.

In Europe, the prevalence — defined by radiological criteria — increases with age in both sexes and is almost as high in men as in women —about 12%. In women over 45 years of age, osteoporosis accounts for more days in hospital than many other diseases, including diabetes, myocardial infarction and breast cancer.

On account of its global prevalence, osteoporosis is considered a serious public health concern. The International Osteoporosis Foundation (IOF) estimates that over 200 million people worldwide suffer from this disease; approximately 30% of all postmenopausal women have osteoporosis in the USA and in Europe.  Importantly, one in three women over 50 will experience osteoporosis fractures, as will one in five men.

By 2050, the worldwide incidence of hip fracture is projected by the IOF to increase by 240% in women and 310% in men. The estimated number of hip fractures worldwide will increase almost four times, from 1.66 million in 1990 to 6.26 million in 2050.

In osteoporosis there is usually imbalance between the rates of bone formation by osteoblasts and bone resorption by osteoclasts; two mechanisms by which osteoporosis develops are excessive bone resorption and inadequate formation of new bone during remodeling, likely due to inhibition of mesenchymal stem cell differentiation into osteoblasts.

Excessive bone resorption during bone turnover is a result of osteoclast activation and it depends on stimulation of RANK (receptor activator of nuclear factor-kappa-beta) by nuclear transcription factor Nf-kappa-beta. Previously, NF-Kb activity had been described as the key to inflammatory responses and is considered a potent mediator of inflammatory osteolysis.

PERIODONTAL DISEASE, also known as gum disease, is a set of inflammatory conditions that affect the tissues surrounding the teeth: in its early stage it is called gingivitis, and it may progress into its more serious form — called periodontitis — in which the gums recede from the tooth, bone may be lost and the teeth may loosen or fall out.

Periodontitis is very common, being widely regarded as the second most common dental disease worldwide, after dental decay. Chronic periodontitis affected about 750 million people (about 10.8% of the world population) in 2010. In the USA it affects about 40% of the population. It is estimated that lost productivity due to severe periodontitis costs the global economy about 54 billion USD each year.

Periodontal disease is the most common cause of tooth loss in humans; it is initiated by oral microbial biofilm and it is associated with a painful condition. Periodontitis is characterized by accumulation of bacteria — called plaque — which induces an inflammatory response in the host; the subsequent chronic inflammatory process causes structural damage to the area between the tooth and the supporting bone.

OSTEOARTHRITIS is a joint disease resulting from degradation of both joint connective tissue (cartilage) and underlying bone. The most common symptoms are joint pain and stiffness, and they progress slowly over the years; these and other symptoms can interfere with work and normal daily activities.  Osteoarthritis is the cause of about 2% of years lived with disability.

As of 2010, about 250 million people globally had osteoarthritis of the knee (3.6% of the population or 9,000,000 people); hip osteoarthritis affects about 0.85% of the population (1,742,500 people). Together, hip and knee osteoarthritis had a ranking for disability globally of 11th among the 291 disease conditions assessed in 2010 by Cross et al.

As of 2012, osteoarthritis affected 52.5 million people in the USA, approximately 50% of whom were 65 years old or older. It is estimated that 80% of the population have radiographic evidence of osteoarthritis by age 65 and that the rate of osteoarthritis in the USA will be 78 million adults by 2040.

In the USA, there were about 964,000 hospitalizations for osteoarthritis in 2011, a rate of 31 stays per 10,000 population. With an aggregate cost of 14.8 billion USD (15,400 USD per stay), it was the second-most expensive condition seen in USA hospital stays in 2011. By payer, it was the second-most costly condition billed to Medicare and private insurance.

According to an analysis of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, the worldwide prevalence of hip and knee osteoarthritis was approximately 303.1 million with the highest prevalence estimate in the US at 6,128.1 per 100,000 people. Based on an official population of 328,239,523 in 2019, this translates into 201,148,462 people suffering of hip and knee osteoarthritis in the US.

SARCOPENIA is a kind of muscle atrophy that occurs with aging and/or immobility. It is characterized by loss of skeletal muscle mass, quality and strength, and may lead to reduced quality of life and disability.

Sarcopenia is emerging as a major public health concern on account of the increased longevity of the population and the growing geriatric population. Furthermore, sarcopenia is a predictor of many adverse outcomes including increased disability, falls and mortality. Loss of lean body mass is also associated with increased risk of infection and poor wound healing.

The prevalence of sarcopenia depends on the definition used in each epidemiological study. Estimated prevalence in 60-70-year-old people is 5-13% and increases to 11-50% in people over 80 years of age. This equates to over than 50 million people and is projected to affect more than 200 million in the next 40 years.

CACHEXIA is associated with an underlying illness causing muscle loss that is not entirely reversed by nutritional supplementation. Most commonly, cachexia is caused by congestive heart failure, chronic obstructive pulmonary disease, chronic kidney disease, end-stage cancer, AIDS and other conditions related to systemic inflammation/oxidative stress.

In contrast to weight loss from inadequate caloric intake, cachexia causes mostly muscle loss instead of fat loss. Cachexia is associated with increased mortality and poor quality of life.

Accurate epidemiological data on the prevalence of cachexia is lacking due to changing diagnostic criteria and under-identification of people with the disorder. It is estimated that cachexia from any disease affects more than 5 million people in the USA. The prevalence of cachexia is growing and is estimated to affect about 1% of the population.

The most frequent cachexia-associated diseases in the US are COPD (chronic obstructive pulmonary disease), heart failure, cancer, and chronic kidney disease. Cachexia contributes to significant loss of function and healthcare system utilization. Estimates using the National Inpatient Sample in the USA suggest that cachexia accounted for 177,640 hospital stays in 2016. Cachexia is considered the immediate cause of death of numerous people with cancer, estimated between 22 and 30%.

 

SG1002 provides great effective therapeutic potential for the above-mentioned diseases because it safely delivers H2S in vivo and H2S is proven to have beneficial therapeutic effects in said diseases.

Mounting interest in understanding and clinically exploiting the opposing roles of H2S and oxidative stress in the musculoskeletal system is clearly evidenced by the increasing number of research articles and reviews dealing with such subjects that have been published over the last decade (Xu 2011, Burguera 2012, Abu-Amer 2013, Sieghart 2013, Gambari 2014, Sieghart 2014, Yang 2014, Blanco-Garcia 2015, Takeno 2015, Jiang 2016, Yang 2016, Jiang 2017, Liu 2017, Lv 2017, Pellegrini 2017, Wallace 2017, Yan 2017, Zhang 2017, Behera 2018 a,b, Bitar 2018, Burguera 2018, Gugliandolo 2018, Magro 2018, Majumber 2018, Raggio 2018, Vaamonde-Garcia 2018, Xu 2018, Batallè 2019, Behera 2019, Gambari 2019, Ma 2019, Wang 2019, Zhai 2019, Liao 2020, Nasi 2020, Sunzini 2020, Wegner 2020).

In a review titled “Role of H2S in the musculoskeletal system” and published in 2019, Behera et al. state that:

  • Several studies have previously provided evidence showing the essential regulatory action of H2S in skeletal homeostasis. In this review, we have emphasized the novel function of H2S in both bone and skeletal muscle anabolism;

  • H2S is known to regulate bone marrow mesenchymal stem cells (BMMSCs) and skeletal muscle function. H2S is important for BMMSCs function in that it maintains cell proliferation and differentiation;

  • Cystathionine-β-synthase (CBS) deficiency causes bone loss and administration of H2S via an H2S donor (NaHS or GYY4137) can restore normal bone homeostasis;

  • In the past decades, the advancement of research on mesenchymal stem cell (MSC) transplantation has brought milestones in regenerative medicine, as it has been found that MSCs have a high potential for tissue regeneration;

  • Recent studies reported that exogenous H2S promotes bone fracture healing;

  • Postmenopausal osteoporosis is a common skeletal disease associated with the declining level of estrogen, leading to bone loss and increased risk of fracture. In a mice ovariectomy model to mimic postmenopausal osteoporosis, treatment with an H2S donor (GYY4137) increased bone formation and completely prevented both trabecular and cortical bone loss caused by ovariectomy;

  • It has also been demonstrated that H2S functions as an antioxidant and anti-inflammatory molecule, as well as balancing redox homeostasis and inducing antioxidant transcription factor Nrf2;

  • H2S is required for periodontal tissue homeostasis and has potential therapeutic value in orthodontic treatments;

  • H2S has demonstrated benefits for tissue regeneration;

  • H2S may have the potential to reverse skeletal muscle myopathy and dysfunction.

Furthermore, they discuss the crucial osteoprotective role played by H2S in cell proliferation and differentiation of BMMSCs in the hyperhomomocysteinemia (HHcy) mouse model: administration of an H2S donor prevented the HHcy-induced oxidative damage and bone loss. In fact, the authors point out that recent studies demonstrate that administration of H2S could potentiate MSC proliferation and survival by preventing multiple forms of stress (low oxygen, oxidative damage, or serum deprivation).

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