Senesence and Osteoporosis - Term Paper Example

# 6449 # 6449 March 28th, 2008 SENESENCE AND OSTEOPOROSIS INTRODUCTION: Osteoporosis is a condition characterized by low bone mass along with increased bone fragility, leading to an increased risk of fractures, which are major causes of morbidity substantially in older people. The bone mass peaks at an average age of 25 years. After that, it remains stable in both the sexes until the age of about 40-45 years. This is the age of accelerated bone loss in women, and a comparatively gradual bone loss in men. This leads to a loss of about 25-30% bone mass in women, over a period of 5-10 years. This is followed by a slower phase with a stable bone loss of about 0.5-1% per year. In contrast, men only have a stable bone loss. FACTORS AFFECTING BONE LOSS: According to some recent studies, both the sexes undergo an accelerated bone loss at later stages. The exact mechanisms are still not much understood, but several factors related to age-dependant changes have been implicated. Some of these are: 1. Estrogen deficiency, 2. Reduced osteoprotegerin levels, 3. Reduced calcium and vitamin D intake, 4. Impaired calcium and vitamin D absorption, 5. Increased Interleukin-1 and Interleukin-6 levels, 6. Tumor necrosis factor-alpha, 7. Increased bone resorption and turn over, 8. Impaired osteoblast function, 9. Decreased insulin-like growth factor secretion, 10. Decreased transforming growth factor-beta secretion and 11. Reduced core-binding factor-1 levels. ROLE OF GENDER DIFFERENCE: In addition to old age, gender difference plays a major role in determination of this disease. Osteoporosis in females is directly related to the hormonal changes in the body. Menopause occurs at an age of about 50-52 years, following which, levels of circulating estradiol and estrol significantly decrease by about 25% and 75% respectively. Among several theories, the most accepted one is the one describing direct action of the estradiol on avian osteoclasts. Bone resorption is the unique function of osteoclasts. In the avian model, there is a direct action of estradiol in decreasing the development and function of osteoclasts and increasing the activity of osteoblasts. Estrogen deficiency enhances the activity of osteoclasts, leading to the perforation of bone trabeculae, thus increasing the fracture risk. The life span of functional osteoclasts may also increase following the estrogen deficiency. Another useful effect of estrogen has been described, that they may decrease the osteoclast activity by promoting apoptosis, thus limiting the life span of osteoclasts. Osteoprotegerin is an inhibitor of osteoclast differentiation. Estrogen has also been shown to regulate its secretion. Another clear evidence is that women undergoing early menopause, or oophorectomy have an accelerated bone loss and show a higher incidence of bone fractures. Women experiencing early menopause usually have prolonged periods of oligomenorrhea, a trait that has a strong genetic predisposition. Thus these patients are exposed to repeated periods of increased bone loss and low bone mass. GROWTH HORMONE DEFICIENCY: Growth hormone is important in the regulation of the longitudinal bone growth. Its role in the regulation of bone metabolism in human is not completely understood yet. However, its importance in both bone formation and bone resorption is proven by many in vivo and in vitro studies. There are two ways by which the growth hormone increases the bone formation: 1. Via a direct interaction with the growth hormone receptors on osteoblasts, and 2. By an induction of endocrine and autocrine IGF-1. Growth hormone deficiency leads to a reduction in bone mass, both in humans, and in experimental animals. Research has shown that a long term treatment of patients with the Growth Hormone Deficiency disease, resulted in an increased bone mass. Recent clinical studies have also demonstrated that treating the people with normal Growth Hormone secretion with Growth Hormone, increases the biochemical markers for both bone formation and bone resorption. According to the studies, a ‘biphasic model’ of Growth Hormone has been proposed. According to this model, Growth Hormone initially increases the bone resorption with a concomitant bone loss that is followed by a phase of increased bone formation. After the moment when bone formation is stimulated more that bone resorption (transition point), bone mass is increased. However, a net gain of bone mass caused by Growth Hormone may take some time as the initial decrease in the bone mass must first be replaced. This ‘transition point’ occurs approximately after 6 months and a net increase in the bone mass is seen after 12-18 months of Growth Hormone treatment. (1) In adults, the osteoporosis is the result of chronic excess of resorption of bone by osteoclasts, as compared to the amount of bone deposited by osteoblasts. The prime cause of this imbalance between the bone resorption and deposition seems to be the changes in hormone levels with age, as described above. These changes include the deficiency of estrogens in females, and testosterone in males. But this fact can’t be denied that senescence of osteoblasts and that of the osteoprogenitor cells also plays a major role. Research studies have shown a reduction in the density of lacunae for osteocytes with age in the human cortical bone. With the decrease in number of osteocytes, microcracks accumulate and graduallay weaken the bone, and may also lead to osteocyte apoptosis. (2) The osteoblasts and osteoclasts are derived from the progenitors originating in the bone marrow, while the process of bone remodeling by the growth factors and cytokines, controlling the birth and death of these cells. So, the basic mechanism involved is an imbalance between the production of both of these types of cells, i.e. the osteoclasts and osteoblasts. According to the research so far, an overproduction of osteoclasts relative to the need of remodeling and an underproduction of the osteoblasts relative to the need of cavity repair, represents the basic pathophysiologic changes in the post-menopausal and the age-related osteopenia, respectively. According to this research, the osteoporosis caused by an excess glucocorticoid is also the result of the changes in the birth and death of the osteocytes. Not to forget, a decrease in the osteoblastogenesis in the bone marrow, along with an increased rate of osteoblasts and osteocyte apoptosis. (5) CELLULAR AGING: For a better understanding of the mechanisms involved, three pathogenic mechanisms need to be considered: 1. Cellular aging, 2. Impairment of systemic stimulation of bone formation by decreasing hormone levels, and 3. Lower cellular effectiveness of growth hormones and cytokines. By cellular senescence, we mean both replicative and post-mitotic senescence. In replicative senescence, the number of cell cycles is limited, while the post-mitotic aging is influenced by the endogenous and exogenous factors. This results in certain genetic alterations, known as ‘delayed persistent genomic instability’. Another result is an increasing impairment of the specific cellular functions. The post-mitotic phase consists of the ostopenia caused by a decrease of systemically available sexual hormones. But research is still being carried out on this point. Ostopenia caused by a decreased activity of locally effective cytokines and growth factors is becoming increasingly understood. We can thus conclude that the cellular senescence is considered to be one of the major elements in the development of bone loss. Potential therapeutic targets are likely to open up an additional path in the treatment of local and systemic osteopenias. (4) VERTEBRAL SIZE AND FRACTURES: The role of the gender difference in the frequency of osteoporosis can be understood by considering the vertebral size in elderly women with osteoporosis. In the elder population, the bone density reduction is a major determinant for the development of vertebral fractures. Although, the spinal bone densities in men and women are comparable, yet women have a greater incidence of fractures. According to the recent studies, women have 20-25% smaller vertebrae than men, after taking into account the differences in body size. (6) However, the bone density reduction alone is not just sufficient to explain the vertebral fractures in women; many women with low spinal bone density do not experience the vertebral fractures, and there is a substantial overlap in bone density between women with and without the radiographic evidence of vertebral compression. So, in order to understand this point, certain other factors contributing to the bone strength are taken into account. One of these is the quality of bone material and its three-dimensional arrangement. Other few studies, however, have also taken into account the role of bone size as a possible determinant for vertebral fractures in osteoporosis. (7) The degree to which the gender differences in vertebral size contribute to the greater incidence of fractures in women remains to be determined. Nevertheless, differences in vertebral cross-sectional area have important biochemical implications with respect to the loading capacity of the spine and they could account for variations in fracture incidences that are not attributable to reductions in cellulous vertebral bone density. According to a detailed study carried out in California, the small vertebral size contributes to the development of vertebral fractures in women, already at a risk for developing fractures. The cross-sectional area of the vertebral bodies was smaller in women with osteoporosis and vertebral fractures than in women of the same age without fractures. These differences were found from measurements obtained solely from the un-fractured vertebral bodies, thus the results cannot be ascribed to the deformities arising from the vertebral compressions. This study also proved that the vertebral fractures in elderly women may result from the insufficient bone acquisition during childhood and a relatively low peak bone mass. The amount of bone gained during growth is largely genetically regulated. Recent studies in children and adults also indicate that the variations in vertebral size and not vertebral density account for gender difference in vertebral peak bone mass.(7) CONCLUSION: So, to conclude, we can say that we can stress upon three basic factors directly affecting the frequency and occurrence of osteoporosis. The most important among them is the gender difference, as females have to undergo many hormonal changes in their bodies, after menopause, leading to an increased susceptibility for this disease. Next is the growth hormone deficiency which shows a direct relationship with the development of osteoporosis. The third important factor, being studied yet is the cellular aging/senescence, contributing to the development of osteoporosis in the form of both, replicative and post-mitotic senescence. Although there are other factors as well, like reduced calcium and vitamin D intake, impaired calcium and vitamin D absorption and other factors, already listed above, but the above mentioned three factors play a key role in making an individual more susceptible for developing osteoporosis. BIBLIOGRAPHY 1. Claes Ohlsson, Bengt-Ake Bengtsson, Olle G.P. Isaksson, Troels T. Andreassen and Maria C. Slootweg. Growth Hormone and Bones. [online]. 1998. [cited April 5, 2008]. Available from: http://edrv.endojournals.org/cgi/content/full/19/1/55 2. Osbjorn M. Pearson and Daniel E. Lieberman. The aging of Wolf’s Law: Ontogeny and Responses to Mechanical Loading in Cortical Bone. [online]. 2004. [cited April 5, 2008]. Available from: http://www.fas.harvard.edu/~skeleton/pdfs/2004f.pdf 3. Donald W. Reynolds Department of Geriatics-Cellular and Molecular Biology of Aging. [online] [cited April 5, 2008]. Available from: http://www.geriatrics.uams.edu/research/research_biology.asp 4. Battmann A; Schulz A; Stahl U. Cellular senescence: a mechanism of development of osteoporosis. 2001. [cited April 5, 2008]. Available from: http://www.medscape.com/medline/abstract/11515177 5. Manolagas SC. Cellular and molecular mechanism of osteoporosis. [online] 1998. [cited April 5, 2008]. Available from: http://www.medscape.com/medline/abstract/9801728 6. V Gilsanz, M L Loro, T F Roe, J Sayre, R Gilsanz and E E Schulz. Vertebral size in elderly women with osteoporosis. [online] 1995. [cited April 5, 2008]. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=295847 7. Vicente Gilsanz, M. Lulza Loro, Thomas F. Roe, James Sayre, Ramon Gilsanz and Eloy E. Schulz. Vertebral size in elderly women with osteoporosis. [online] 1995. [cited April 5, 2008]. Available from: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=295847&blobtype=pdf Read More