Osteoporosis: Bone Formation and Resorption Imbalance in Post-Menopause - Research Paper

Lay Person Summary

Osteoporosis is a condition that leads to weak and fragile bones that are at an increased risk of sudden fractures. Such bones have more sponge growing as well as larger pores that weaken the internal structure of the bone. It is caused by an imbalance of molecular activity on the bone regarding formation and resorption. In human life, bone is continually formed to replace the older one that is regenerated. Therefore, increased activity of bone degeneration compared to bone formation causes an imbalance that leads to reduced bone strength. Several factors such as estrogen hormone have been noted to affect the processes of bone degeneration. Therefore, post-menopause women, who have reduced estrogen levels are at higher risk of osteoporosis. In this regard, this study sought to examine how estrogen supplementation can manage bone degeneration thereby helping in management of the condition. It is anticipated that a drug therapy that supplements estrogen in post-menopause women will help in balancing bone formation and resorption, thus helping to treat osteoporosis.

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Background Information

Osteoporosis

Osteoporosis is a medical condition that weakens the bones, thereby leading to an increased risk of sudden fractures. Bone mineral density reduces significantly, thus leading to the deterioration of bone micro-architecture. As a result, the bones are fragile, hence being predisposed to easy breaking. Bones that are weakened by osteoporosis are characterized by holes in the sponge growing larger and becoming more prevalent thereby weakening the bone's internal structure (Gambacciani & Levancini, 2014). Besides, in this condition, the outer shell of the cortical or the dense bone encases trabecular bone, a sponge-like bone that is adversely affected when the pores increase. The decline in the functions of the body that builds the bones can lead to decreased muscle density, which increases the possibility of fractures. WHO has identified osteoporosis as one of the significant conditions that need to deal with to improve the overall quality of life, considering that osteoporotic fractures lead to considerable mortality and morbidity among a productive population (Han, You, Xing, Zhang, & Zou, 2018). Therefore, there has been an increased need to develop treatment measures that depict more efficacy in osteoporosis treatment, as the condition predisposes people with such fractures to even more fractures.

Bone Formation and Repair

Skeletal bone is developed continually throughout the lifespan of an individual. This process of bone repair is called remodeling, which is characterized by the resorption of the mature damaged bone, which is replaced with the newly formed bone. In this regard, the bone present in a person depends on the amount of bone that is formed, and the one that is resorbed. In case the process is not balanced, then the bone formed has weaknesses and cannot function normally. When more bone is resorbed than it is created then the process leads to a net bone loss (Gambacciani & Levancini, 2014). Bone formation is facilitated by cells called osteoblasts. On the other hand, bone-resorbing is facilitated by important cells called osteoclasts. It should be noted that osteoblasts constitute about 5% of the bone cells. These cells differentiate the mesenchymal stem cells thereby facilitating the formation of the terminally-differentiated osteocytes that represent about 90% of the overall bone cells (Gambacciani & Levancini, 2014). In this regard, treatment therapies of osteoporosis function in two mechanisms either by blocking the osteoclast formation or stimulating osteoblast formation. Therefore, researchers have been investigating the development of bone remodeling mechanisms that can enhance effectiveness of the results in long-term management of the condition.

Osteoporosis in Post-Menopause Women

Menopause has been noted to predispose women to osteoporosis globally. Osteoporosis is a global health concern among women who are past menopause. Concerning the increased risks of the condition in this population, increased efforts have been noted in studies regarding the bone formation in women, to understand how the risk factors can be mitigated and the condition managed properly (Riggs, 2000). In the post-menopause age of women, estrogen levels are significantly reduced. This significant reduction is associated with the risk of increased trabecular bone loss that can lead to multiple fractures of a woman's bone. Deficiency of estrogen levels is associated with the massive increases in the bone resorption that is caused by increased osteoclast numbers which result from the increased osteoclast activity. Besides, reduced estrogen leads to reduced osteoclast formation. Studies have shown that up to 7.2% of post menopause women have undiagnosed osteoporosis conditions, who have increased levels of bone fractures compared with the ones diagnosed with the disease (Gambacciani & Levancini, 2014). Besides, bone fractures among the post-menopause women due to the reduced estrogen levels cause disability of women to about two thirds and even increases the mortality during the diagnosis year by about 20%. In this regard, bone loss prevention, as well as timely diagnosis, are imperative in decreasing the risk of disability in this population.

Diagnosis and Treatment of Osteoporosis

The determination of osteoporosis mainly depends on the examination of the bone mineral density (BMD) that is examined by a dual X-ray absorptiometry (DXA). This is expressed as a T-Score and/ or the presence of the fragility fractures. According to the World Health Organization, a fragility fracture is a fracture that is caused by an injury, that under normal bone conditions cannot produce a fracture (Gambacciani & Levancini, 2014). In clinical applications, this fragility fracture can result from minimal trauma including falling from standing height or even less, or even no identifiable trauma. In such patients, there is an increased possibility of low bone mass. Although both men and women are at an increased predisposition of osteoporosis with age, post-menopause women show a higher prevalence due to the risk of reduced estrogen levels.

In this regard, the treatment approaches that have been developed in treating this condition are unique on women, especially in post-menopause women. The treatment approaches could be pharmacological interventions or physical and dietary supplementations (Riggs, 2000). The pharmacological interventions that have been commonly utilized and approved include hormone replacement therapy, SERMS, bisphosphonates, and Denosumab. Studies have shown that hormone replacement therapy has the ability to preserve and even increase the BMD in all the skeletal sites, including the femoral neck, lumbar spine, as well as the forearm in the post-menopausal women (Riggs, 2000). Additionally, the administration of various identified and approved drugs, including low doses of oral contraceptives, can reverse the deleterious effects of hypoestrogenism in younger women (Katoh, 2005). Administering oral contraceptives in post-menopause women has indicated success in restoring bone turnover.

Research Hypothesis and Aims

Despite the availability of several procedures that can be used in maintaining osteoporosis, medical practitioners have illustrated significant challenges in its treatment and management. For example, many patients are not comfortable in taking medications and treatments for long-terms, especially with the medication side effects that are prevalent. Some treatments can lead to atypical femoral fracture and even osteonecrosis (Moverare-Skrtic et al. 2014). Although there have been multiple therapies that help in the management of the condition, osteoporosis does not have a single treatment method that facilitates full recovery on its own. Therefore, researchers have suggested various techniques that can improve treatment effectiveness. GWAS studies have identified a strong correlation between WNT16 with fracture risk and bone mineral density. Further studies have evaluated the role of WNT16 in the etiology of osteoporosis through experiments that use mouse manipulation techniques (Zheng et al. 2012). These studies have identified that WNT16 is a primary regulator of bone homeostasis.

Aims

The aim of this study is to investigate and suggest novel drug therapies that can improve the efficacy in osteoporosis treatment in post-menopause women. The study will evaluate the relationship between estrogen and bone density, particularly in post-menopause women, to suggest the benefits of estrogen treatment therapies.

Preliminary Data

Experiment 1

For this experiment, 6 out of the 12 C57BL/6J adult female mice with low bone density had undergone ovariectomy, which involves the removal of the ovaries as a treatment group. The remaining 6 had a sham operation to serve as the control, leaving them with functioning ovaries. All of the mice were on a phytoestrogen-free diet. Each group was further divided into groups of 3, receiving subcutaneous injections of either estrogen(E2) or vehicle (no estrogen) over five days. After 20 days, the mice were euthanized, and the mRNA present in the femur was extracted. Using qRT-PCR, the mRNA in the femur was converted to cDNA. Subsequent quantitative analysis was used to analyze the expression levels of Wnt16 and osteoprotegerin (Opg). To prevent errors due to a difference in the initial number of cells present in the femur, the researchers analyzed the expression levels of TATA-binding proteins (Tbp) and normalized the Wnt16 and Opg expression levels to the Tbp expression level.

The experiment aims to understand estrogen's effect on bone density, particularly in females who have experienced a decline in ovarian function due to disease or me...