The 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 ...

1. The 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

2. 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

3. 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

4. OH
||
—
||
—
|
|
|
|
Pyrophosphate
|
|
P
P
C
O
O
OH
OH
OH
OH
||
—
||
—
|
|
|
|
R1
R2
Bisphosphonate
Figure 3: The Analogues Pyrophosphate and Bisphosphonate
Normal Bone

5. 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

6. 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.
References
Davis A, Goeckeritz B, Oliver A (2010). "Approved treatments
for osteoporosis and what's in the pipeline". Drug Benefit
Trends22 (4): 121–124.
Kerstetter JE, O'Brien KO, Insogna KL (2003). "Dietary
protein, calcium metabolism, and skeletal homeostasis

7. 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 Invest115 (12): 3318–25.
Nieves JW (2005). "Osteoporosis: the role of
micronutrients". Am J Clin Nutr81 (5): 1232S–1239S.
Poole KE, Compston JE (2006). "Osteoporosis and its
management". BMJ333 (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

8. Osteoblasts Enter Cavity/Reversal
Digestion/Resorption
New Ostoid and Mineralization
6
5