Biology Assignment !
Fahad Algaly
heatherdrew_geroscience_paper_3.docxThe Mechanisms of Treatments for Osteoporosis
Heather Drew
05/19/12
The Mechanisms of Treatments for Osteoporosis
Heather Drew
05/19/12
Introduction
The cost of aging is one debt that we all share. Advances in the fields of healthcare and biomedical research have allowed us to extend our lives as much as is currently possible and yet we still battle with many age-related illnesses. Age is a major risk factor for detrimental morphological changes that the body undergoes as well as the onset of cancer or degenerative diseases (Kohlmeier, Lynn Kohlmeier, 1998). One set of collective physical markers that are indicative of the aging process, frailty, is characterized by the loss and dysfunction of skeletal bone and muscle (Lauretani F et al, 2003). Frailty not only increases the risk of both acute and chronic disease but is also a predictor of mortality. Osteoporosis itself is the manifestation of altered cellular senescence and other age-related factors and contributes greatly to frailty and increased risk of bone fracture. By studying the molecular mechanisms that dictate the cycle of bone formation and resorption, scientists have been able to identify novel methods that may used to counter frailty and ultimately osteoporosis.
Background
Osteoporosis is an age-related disease of the bone that is characterized by reduced bone mineral density, disruption of the microarchitecture of osseous tissue, and alterations in bone-related proteins (Raisz L, 2005). These changes lead to frailty of the bones and increase the risk of disease and mortality. Osteoporosis occurs when there is a disruption of bone tissue homeostasis, or, the balance between bone resorption and bone formation (Poole KE, Compston JE, 2006). As seen in Figure 1 and Figure 2, this balance largely depends on the development of osteoblasts and osteoclasts. Both cell types are derived from bone marrow progenitors; osteoblasts differentiating from mesenchymal lineage and osteoclasts from hematopoietic cells. The production of such progenitor cells has been shown to be regulated by cytokines (such as interleukin-6 and interleukin-11) as well as sex steroids (such as estrogen). This indicates that both inflammatory response as well as hormonal changes such as menopause may lead to an increased risk of osteoporosis (Raisz L, 2005). In regards to the affect of aging on this cycle, cellular senescence may decrease the ability of the bone marrow to form osteoblast precursors leading to a loss in bone formation and increase in fractures. The large amount and variety of regulatory factors that play key rolls in the homeostasis of bone formation has led to multiple drug targets and therapies that may possibly be able to combat the detrimental effects of osteoporosis.
Lining Cells
Osteoclasts
Osteoblasts
Osteocytes
Mononuclear Cells
Mesenchymal Stem Cells
Hematopoietic Stem Cells
Fig. 1. Schematic outline of the bone remodeling system. In the bone tissue, osteoclasts play a major role in bone resorption while osteoblasts are integral directors of bone formation thus proving to be key counter components of the bone formation cycle. The first step of this process involves the mechanically and biochemically stimulated retraction of cells lining the bone mineral and matrix. Next, fusion and activation of the osteoclast takes place followed by digestion of the underlying bone. Once this step is completed mononuclear cells prepare the resorbed surface for osteoblasts in the remaining bone cavity and deposit newly synthesized matrix. Matrix mineralization and differentiation of some osteoblasts into osteocytes completes the remodeling cycle.
Promising Treatments for Osteoporosis
One very promising drug target that has been utilized already by multiple companies is the introduction of bisphosphonates into the cellular milieu of the osseous tissue. Along with Type I collagen, calcium hydroxylapatite constitutes the majority of the bone matrix and is protected by a group of molecules called pyrophosphates. Unfortunately, pyrophosphates are subject to degradation by pyrophosphatases leaving the bone matrix susceptible to resorption via osteoclasts. Bisphosphonates (analogues of pyrophosphates as seen in Figure 3) however are resistant to pyrophosphatases and can provide protection to the bone matrix where pyrophosphates cannot. Bisphosphonates have also been shown to encourage osteoclasts to undergo apoptosis by creating a nonfunctional ATP-like molecules within cell, which directly competes with ATP and disrupts cellular energy metabolism (Whitaker et al., 2012). By instigating apoptosis an overall decrease in the resorption of the bone is observed (Poole KE, Compston JE, 2006). As molecules that not only provide protection from bone matrix resorption but also initiate apoptosis of osteoclasts, bisphosphonates provide an effective treatment for combating osteoporosis.
P
P
O
O
O
OH
OH
OH
OH
||
—
||
—
|
|
|
|
Pyrophosphate
|
|
P
P
C
O
O
OH
OH
OH
OH
||
—
||
—
|
|
|
|
R1
R2
Bisphosphonate
Figure 3: The Analogues Pyrophosphate and Bisphosphonate
Normal Bone
Osteoporosis
Bone Formation
=
Bone Resorption
Bone Formation
<
Bone Resorption
Fig 2. Balance of bone formation and resorption. Osteoporosis is brought about by the imbalance of bone formation and bone resorption regulators (osteoclasts are more prevalent in osteoporosis) leading to great structural changes within the bone tissue. For example, an increase in pyrophosphatases (which increase bone matrix susceptibility to resorption by osteoclasts) may be a contributing factor to the manifestation of osteoporosis.
The hormone calcitonin is also a suitable therapy possibility for osteoporosis. Calcitonin has been shown to be a key component in calcium and phosphorus metabolism and has the ability to decrease blood calcium levels (Kerstetter JE et al., 2003). With this and the knowledge that osteoclasts release calcium and phosphorus into the blood upon resorption, it was further found that calcitonin actually suppresses resorption by inhibiting the activity of osteoclasts (Raisz L, 2005). Calcitonin accomplishes this by binding to cell surface receptors of the osteoclasts, which leads to disruption of the cell’s cytoskeletal organization and polarity, causing the cell to shrink and cease functioning (Raisz L, 2005). Another hormone that may provide the bone matrix with protection from osteoclasts is estrogen. Estrogen, like bisphosphonates, also has a multi-fold affect on bone resorption. The hormone not only plays a role in blocking the osteoblast’s synthesis of interleukin-6 (a potent stimulator of bone resorption) but also regulates osteoclasts apoptosis. It has been shown that when estrogen is deficient in the system, osteoclasts live longer thereby resorbing more bone matrix (Nieves JW, 2005). Estrogen has also been found to directly target osteoclasts by inhibiting osteoclastogenesis through a decrease in osteoclast precursor’s response to the tumor necrosis factor-related factor, RANKL (receptor activator of NF-κB ligand is a potent inducer of the differentiation of monocytes to osteoclasts) (Davis A et al., 2010). Because estrogen disrupts the synthesis of molecules that induce resorption, induces osteoclast apoptosis as well as prevents its differentiation, the hormone has widely been used as a therapy for chronic bone loss.
Conclusions
The treatments described in this paper only represent a small selection of osteoporosis and bone-related studies that are currently being conducted. In regards to osteoporosis researchers are also looking into what role chronic inflammation plays, whether or not testosterone may be a viable treatment for men, and even how well regular exercise and vitamin/calcium supplements may help to stave off onset of the disease. But one outcome that can be agreed upon is that such a complex disease with perhaps several roots will need to be treated on multiple levels.
Davis A, Goeckeritz B, Oliver A (2010). "Approved treatments for osteoporosis and what's in the pipeline". Drug Benefit Trends 22 (4): 121–124.
Kerstetter JE, O'Brien KO, Insogna KL (2003). "Dietary protein, calcium metabolism, and skeletal homeostasis revisited". Am. J. Clin. Nutr. 78 (3 Suppl): 584S–592S.
Kohlmeier, Kohlmeier L (1998). "Osteoporosis - Risk Factors, Screening, and Treatment". Medscape Portals. Retrieved 2008-05-11.
Lauretani F et al. (2003). J Appl Physiol; 95: 1851-1860
Raisz L (2005). "Pathogenesis of osteoporosis: concepts, conflicts, and prospects". J Clin Invest 115 (12): 3318–25.
Nieves JW (2005). "Osteoporosis: the role of micronutrients". Am J Clin Nutr 81 (5): 1232S–1239S.
Poole KE, Compston JE (2006). "Osteoporosis and its management". BMJ 333 (7581): 1251–6.
Whitaker, Marcea; Guo, Jia, Kehoe, Theresa, Benson, George (9 May 2012). "Bisphosphonates for Osteoporosis — Where Do We Go from Here?".New England Journal of Medicine
Resting Bone
Living Cells Retract
Osteoclast Fusion
Osteoblasts Enter Cavity/Reversal
Digestion/Resorption
New Ostoid and Mineralization
6
5
