is an ever-prevalent condition, with over 40 million men and women suffer from
osteoporosis in the United States alone. The most serious concern that
accompanies this condition is the high risk for fractures, especially in the
spine and hip area leading to increased morbidity and mortality. The care for
patients who have sustained such fractures is expensive, with the spending
reaching the billions in each year (McClung 2007). Osteoporosis occurs when the
rate of bone remodeling is not at equilibrium, that is, the bone is being
resorbed much faster than the new bone being formed leading to a deficit in
bone mass. It has been found that osteoporosis is consistently under-diagnosed
and under-treated throughout the population (Liewicki 2), in addition to lack
of successful treatments because persistence with continuing therapy is low.

This leads to a demand for a therapy that will allow for longer time periods
between doses to allow for lower commitment, while still retaining the
effectiveness of the treatment.             Denosumab is a fully human
monoclonal antibody that can bind to the receptor activator of nuclear factor
kappa B Ligand (RANKL), which is a tumor necrosis factor, preventing the RANKL
from binding to the RANK receptors. RANK receptors are expressed on the surface
of pre-osteoclasts, which are the precursors to osteoclasts. Osteoclasts resorb
bone and osteoblasts form new bone in a process called bone remodeling. This
treatment was primarily developed for low bone mineral density (BMD) resulting
from osteoporosis, however, several studies have found that it can also be used
to successfully treat low BMD resulting from metastases in the bones or from
cell tumor of the bone (GCTB).  GCTB is
an aggressive but benign osteolytic tumor that can lead to significant
destruction of bone; currently, no chemotherapy exists to treat it, but rather
it is usually treated surgically. These tumors have the potential to
metastasize to the lungs but have not been noted as leading to mortality. The
most common outcome is morbidity due to surgical resection of the tumor. The
success of denosumab in treating this disease allows those patients with
surgically untreatable GCTB to use it to slow down the rapid destruction of
bone and keep the disease progression under control.              Currently, another type of drug,
called bisphosphonates, can also treat the same conditions with a different
mechanism of action. However, studies have proven that denosumab is the
preferable treatment where its outcomes have fewer side effects and are more
long lasting. Therefore, denosumab has an exciting future where research can
lead it to be able to treat even more bone-related conditions.             In the process of remodeling of
bone, the bone is constantly being resorbed and formed by way of osteoblasts
and osteoclasts. One of the major regulators of this pathway is the
RANKL/RANK/OPG pathway (Fig. 2). RANKL is a transmembrane protein that is
expressed by the osteoblasts and binds to the RANK receptors, which are on the
surface of the pre-osteoclasts (precursor to osteoclasts). When RANKL binds to
the receptors, the pre-osteoclasts turns into an osteoclast, which then can
resorb bone. These precursors require a specific growth factor called
macrophage colony stimulating factor (MCS-F) for their growth and for inducing
RANK. In addition, for development into an osteoclast, the transcription
factors c-fos, NFATc1/NFAT2, and NF-kappa-beta p50 and p52 (Fig. 1). These
transcription factors are necessary for the development of osteoclast gens such
as tartrate-resistant acid (TRAP), cathepsin-K, calcitonin receptor, and c-myc
for the proliferation of osteoclasts. The binding of RANKL to RANK also
stimulates the activation of src-dependent pathways, which plays a role in the
bone- resorbing capability of osteoclasts. Figure 1: The binding of RANKL to
RANK on the pre-osteoclasts leads to the activation of critical transcription
factors to express genes necessary for osteoclast development.  Osteoprotegerin
(OPG) is a “decoy receptor” for the RANKL, because it can bind to the RANKL and
inhibit it from binding to RANK, preventing osteoclasts from forming and
resorbing bone. It is a naturally occurring inhibitor produced by the
osteoblasts, and is mediated by the voltage-dependent calcium channel CaV2.

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When there is an imbalance in the rate at which the bone is being resorbed
versus the rate at which the bone is being formed, that is when osteoporosis
occurs, which can also be signaled by the decrease of the OPG to RANKL ratio
(Kostenuik 2005). RANKL proteins, which are expressed by osteoblasts, are also
regulated by simulators such as the parathyroid hormone (PTH) (Boyce and Xing
2007).  Teriparatide is a treatment that
is a recombinant fragment of the PTH, which stimulates bone formation through
osteoblasts (Hanley et. al. 2012). As women reach menopause, their hormones
will be out of balance, and with an imbalance of estrogen the likelihood that
there is a decrease in BMD. This leads to many of the osteoporosis cases
deriving from the female post-menopausal population. Denosumab, like OPG, acts by inhibiting the
binding of RANKL to RANK, which then prevents the osteoclasts from forming and
resorbing the bone. This fully human monoclonal antibody was developed to
specifically bind to RANKL anywhere in the bones, with a longer half-life that
will allow patients to have lower commitment to the drug with the same
effectiveness (Fig. 3). With this treatment, patients can maintain lower rates
of bone being resorbed for up to 6 months. This medication is also administered
through a subcutaneous injection as opposed to other common options that are
administered intravenously, which makes the ease of receiving treatment much
more attractive option for patients. In addition, several studies have found
denosumab to have superior and long-lasting effects when compared to the other
possible treatments available.   Figure 2: The OPG/RANKL/RANK pathway helps to regulate the bone remodeling
process. (Kostenuik
2005)             In a study done by Cummings et. al.

(2009) on 7868 post-menopausal women with low BMD, they tested the effects of
using either 60mg of denosumab or placebo every 6 months for 36 months. During
the treatment, it was reported that denosumab was able to increase BMD at the
hip by 9% and at the lumbar spine by 6%. In addition, it also lowered the rate
of bone resorption by around 86% at the one-month marker, which has previously
been shown to be correlated with deceased risk of fracture. Moreover, this
trial reported no incidences of increased cancer or infections, in comparison
to the placebo group. The researchers concluded that denosumab could provide an
alternative treatment for osteoporosis, with the observed benefits.   Figure 3: Mechanism of action of both denosumab and bisphosphonates
(an alternative) in the RANKL/RANK pathway. Estrogen therapy is also used to
interfere with osteoblast produced factors that activate osteoclasts. (Hanley
et. al. 2012)             In a similar study done by McClung
et. al. (2006), he used a randomized placebo-controlled environment to evaluate
the efficacy and safety of denosumab in 412 post-menopausal women with low BMD.

Every 3 months, each woman would receive either denosumab subcutaneously 6, 14,
or 30 mg Q3M, or 14, 60, 100, or 210 mg Q6M, or oral alendronate 70 mg a week,
or a placebo, for 12 months. It was observed that after 12 months, denosumab
increased lumbar spine BMD by 3.0-6.7%, and after 48 months, denosumab
increased lumbar spine BMD by 9.4-11.8%. The study also found that denosumab
effects were dose-dependent, rapid, sustained, and reversible. Additionally, no
significant adverse effects were reported in the study.             More recently, denosumab has also
been used in studies as a treatment for GCTB and other cancers involving
metastases in the bone. In a study conducted by Thomas et. al. (2010),  37 patients with recurrent or unresectable
GCTB received denosumab 120 mg every month, with loading doses on days 8 and 15
of the month. They found that 30 of the 35 patients (2 patients had insufficient
histology or radiology data for efficacy) had a 90% elimination of giant cells
or no radiological progression up to the week 25. The authors concluded that
denosumab would be a possibility as a therapeutic option for treatment of GCTB.

Histological tests showed that nearly all of the giant cells were eliminated,
along with rapid and sustained bone turnover suppression. Because of its
effectiveness, the authors suggested that denosumab may be the ideal treatment
for surgically unresectable GCTB.             In order to further test the
specific physiological effects of denosumab on patients with GCTB, a study was
done on patients with recurrent or unresectable GCTB (Branstetter 2012). The
study had a similar model to the one done by Thomas et. al. in that they administered
120 mg denosumab every month with loading doses on days 8 and 15. These
researchers noted that the signaling by RANKL on the tumor cells activates RANK
on the pre-osteoclasts, which then activates giant cell formation and
destructive osteolysis of GCTB. The study showed results that all subjects had
at least a 90% decrease in tumor giant cells and tumor stromal cells. In
addition, thirteen out of twenty patients had an increase in new woven bone,
which replaced the RANKL-positive stromal cells. Denosumab was effective in
reducing the RANKL-positive tumor giant cells and replacing tumor cells with
new woven bone.             In 2013, Chawla et. al. performed an
international, parallel-group, open-label study on patients with GCTB in order
to test for the safety and efficacy of denosumab as a treatment. The authors
separated them into three cohorts, those with surgically unresectable GCTB,
those with resectable surgery with less than ideal predicted outcomes, and
those who came from a previous denosumab GCTB study. The first and second
cohorts received 120 mg of denosumab every month with loading doses on days 8
and 15, and cohort three received the same regimen that they had carried over
from their previous study. The authors found that in 281 patients, only fifteen
had hypocalcaemia, which is low blood calcium levels, and only three had
osteonecrosis of the jaw, which is death of the bone tissue due to the lack of
blood supply in the jaw. In a review by Thomas et. al., they make a point to
say that osteonecrosis of the jaw has been put under special surveillance in
all of these studies in order to ensure patient safety (Thomas et. al. 2010). As
for adverse events, they observed rare occasions of hypophosphatemia, which is
a low phosphate level in the blood, anemia, and back pain. 74 of the patients
did not need to undergo surgery, and in the 26 who did have surgery, 16 of them
underwent a less morbid surgery than had been planned. The study had some
limitations, because the one-year study period might be too short to reliably
to prove efficacy in all cases of GCTB (Balke 2013).             Denosumab was first approved by the
FDA under the trade name ProliaTM June 1, 2010 for post-menopausal
women with osteoporosis at high risk of fracture. The suggested dosage was 60
mg every six months through subcutaneous injection. Later that year, on
November 18, 2010, denosumab was approved under the name XgevaTM made
by Amgen Inc. for prevention of skeletal-related events for patients with bone
metastases in solid tumors. On September 16, 2011, the FDA approved denosumab
under then name Prolia ® made by Amgen, Inc. to treat patients at high risk of
fracture from androgen deprivation therapy for nonmetastatic prostate cancer or
adjuvant aromatase inhibitor therapy for breast cancer, to increase bone mass.

Most recently, on June 13, 2013, the FDA approved denosumab under the name
Xgeva ® made by Amgen, Inc. for treatment of GCTB where surgical resection is
impossible or would result in severe morbidity in adults and adolescents by way
of subcutaneous injection.             The
main concern with denosumab is its potential for interactions with the immune
system due to its targeting of the RANKL/RANK pathway. RANKL is expressed by
helper T cells in the immune system, which could lead to the concern of
increase infections. There were concerns that denosumab would bind to the RANK
receptors on T cells instead of the RANK receptors on the pre-osteoclasts,
inhibiting immune response. However, all of the studies testing denosumab have
found minimal incidences of increase infection due to the use of denosumab.

Actually, the existence of the pathway between RANK-RANKL and the immune system
leads to potential research involving bone-related immune diseases, such as
autoimmune arthritis. A limitation is that most of the studies required its
patients to be taking calcium and vitamin D supplements in addition to the
denosumab injections, which makes it important to discuss whether this
treatment would be effective in individuals who do not maintain a constant intake
of these supplements. Rather, this treatment may be dependent on consuming
supplements. Nevertheless, all of the current treatments available for treating
osteoporosis are not very effective without constant intake of vitamin D and
calcium.             The other popular treatment option
for both osteoporosis and GCTB are the bisphosphonates. Bisphosphonates are
very similar in structure to a naturally occurring byproduct of metabolism
called pyrophosphate. They are absorbed by the osteoclasts, and through various
mechanism of action, can inhibit bone resorption. Most of the version will
induce osteoclast apoptosis, but a few versions will inhibit pathways necessary
for osteoclast bone resorption abilities. In a study comparing the use of
bisphosphonates and the inhibition of RANKL to treat hypercalcemia (Morony
2005), they tested the use of OPG as an inhibitor against the bisphosphonates
pamidronate or zoledronic acid. In order to be effective, bisphosphonates need
to bind directly to the bone matrix and either be consumed or liberated by
osteoclasts to be able to suppress bone resorption. Thus, they saw a more rapid
reversal of hypercalcemia, greater reductions in osteoclast surface and bone
resorption markers (serum TRAP-5b), with the use of OPG rather than the
bisphosphonates. The authors concluded that OPG created a more rapid and
complete inhibition of hypercalcemia and bone resorption compared to the
bisphosphonates.             Another study directly compared the
effectiveness of denosumab versus the bisphosphonate zoledronic acid on the
delaying or preventing skeletal-related events in breast cancer patients with
bone metises (Stopeck 2010).  The
patients were randomly assigned to receive either intravenous zoledronic acid 4
mg and subcutaneous placebo or subcutaneous denosumab 120 mg and intravenous
placebo every 4 weeks. The results showed that denosumab was more effective in
delaying time to the first skeletal related event and the time to subsequent
skeletal related events. Denosumab also showed greater reduction in bone
turnover markers. However, hypocalcemia did occur more frequently with the use
of denosumab. The study concluded that since denosumab was superior in delaying
the skeletal related events and was much more convenient in the subcutaneous
administration it will potentially be the more popular option when treating
breast cancer patients with bone metastases. In a study comparing the cost
effectiveness of different bisphosphonates and denosumab (Parthan 2013), they
found that denosumab had a good value and most cost effective in comparison to
the bisphosphonates, especially in high-risk subgroups. For example, in
high-risk subgroups, total lifetime cost would be around $70,800 for denosumab
and then $76,900 for ibandronate. Therefore, not only is denosumab an effective
treatment, but it is also a cost effective option for patients, especially in
high-risk subgroups. In the other populations, it might be important to weigh
the pros and cons of which medication is most appropriate for the specific
condition that is being treated.             It is evident that this mechanism of
action of inhibiting the RANKL in the pathway is one of the most effective ways
of preventing further bone damage in current medication. As research continues
to proceed, it is clear that denosumab should be able to play an effective role
in any disease that compromises bone density, and is not just limited to the
most obvious bone diseases like osteoporosis. Already this has been proven by
its use and approval in treatment of different cancers that have metastases in
the bone. Current research is still trying to reduce its possibility for side effects;
however, even now the research has shown that the side effects that are likely
to happen are not very serious. An extension to the use of this drug that could
be explored is in the immune system, since the RANKL are expressed on cells in
the immune system. Though, it is unknown how this could be of medical benefit
in the body. Most likely, future research will be focused on finding even
better treatments that take advantage of this pathway to cause the bone
remodeling to be stabilized.  


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