Current
and Future Trends of Drugs Used in Osteoporosis
Radhakrishna B., Ashok M.,
Harish P.L., Veera Jyothsna M. and Shivalinge Gowda K.P.*
Department of Pharmacology,
P.E.S. College of Pharmacy, Hanumanthanagara, Bangalore-560050
ABSTRACT:
Osteoporosis
represents a weakening of bone tissue due to an imbalance in the dynamic
processes of bone formation and bone resorption that are continually ongoing
within bone tissue. Most currently available osteoporosis therapies are
antiresorptive agents. Promising new
drugs are currently under investigation by the FDA for the treatment of
osteoporosis. Majority of the drugs
used in osteoporosis are antiresorptive agents. These drugs act by inhibiting
osteoclastic bone resorption and thus slowing the loss of bone mass. However
these drugs do not stimulate new drug formation and does not increase true bone
mass. The only FDA approved bone anabolic agent is PTH. It is the most
beneficial agent for the patients with very low bone mass. Clinical trials are
undergoing for denosumab. One of the new
drug strontium ranelate acts by stimulating the bone formation and inhibiting
bone resorption. More recent research
indicates that dietary sources of phytoestrogens may increase osteoprotegerin
production and help prevent bone loss and bone resorption; however, rigorous
data are needed before clinical recommendations can be made. This
review discusses the use of currently available agents as well as highlighting
emerging agents expected to bring significant changes to the approach to
osteoporosis therapy in the near future.
KEY-WORDS: Bone resorption, antiresorptive
agent, bone anabolic agent, osteoprotegerin.
INTRODUCTION:
Osteoporosis
is the area of interest since it affects the age old people and particularly
the postmenopausal women because of estrogen deficiency after cessation of
menopause. Osteoporosis is a
condition of low bone mass and micro architectural disruption that results in
fracture with minimal trauma. Characteristic sites of fracture include
vertebral bodies, distal radius, and the proximal femur, but the osteoporotic
individuals have generalized skeletal fragility, and fractures at other sites
such as ribs and long bones, also are common. The main reason behind the
osteoporosis is being depletion of the hormone estrogen1. The direct
health care costs related to osteoporosis are estimated to be 38 million
dollars per day; comparable with the costs attributed to congestive heart
failure (CHF) or asthma. The disability, mortality, and cost of hip and
vertebral fractures are substantial in the rapidly growing, aging population so
that prevention of osteoporosis is a major public health concern.
Postmenopausal osteoporosis is characterized by an increase in bone resorption
relative to bone formation, in conjunction with an increased rate of bone
turnover. The progressive decrease in bone mass leads to an increased susceptibility
to fractures, which result in morbidity and mortality. Vertebral fractures are
important not only because they can cause pain, kyphosis and height loss but
also because they predict subsequent, non vertebral fractures independently of
bone mineral density2.
A sharp decrease in ovarian estrogen
production is the predominant cause of rapid, hormone-related bone loss during
the first decade after menopause3. Menopause, aging and hereditary
factors, inadequate calcium intake and absorption, lack of exercise, prolonged
steroid administration, excessive alcohol intake, and cigarette smoking are the
major risk factors that predispose osteoporosis. The pharmacological agents
used to manage osteoporosis act by decreasing the rate of bone resorption, thereby
slowing the rate of bone loss, or by promoting bone formation. Many synthetic
agents such as calcium, calcitonin, hormones, bisphosphonates and selective
estrogen receptor modulators (SERMs) such as Raloxifen and Droloxifene have
been developed to treat osteoporosis, but are associated with side effects such
as hypercalcemia, hypercalciuria, increased risk of endometrial and breast
cancer, breast tenderness, menstruation, thromboembolic events, vaginal
bleeding, hot flashes, dyspepsia and GI ulcers2.
Figure 1: (a) Normal bone, (b) Osteoporotic bone
Types
of Osteoporosis:
There
are two main types of osteoporosis Type I (postmenopausal) and Type II
(senile).
Type I: Type I osteoporosis is characterized by an increased bone breakdown,
mainly affecting Trabecular bone. Fractures associated with Type I osteoporosis
usually occur in the vertebrae, distal radius, and other areas high in
trabecular bone.
Type
I osteoporosis primarily occurs among women, and directly relates to decreased
estrogen production resulting from menopause. Decreased production of estrogen
results in increased bone breakdown and decreased calcium absorption. Type I
osteoporosis usually occurs within 10 to 15 years after menopause
Type II: Type II osteoporosis results from
a gradual loss of both trabecular and cortical bone. Many factors related to
aging are felt to contribute to Type II osteoporosis including inadequate
calcium intake, decreased calcium absorption, decreased synthesis of vitamin D,
and decreased physical activity. These factors lead to a situation in which
bone breaks down but never fully reforms. Fractures associated with Type II
osteoporosis usually occur in the hip. Type II osteoporosis occurs in both
males and females after 70 years of age4.
Secondary causes
of osteoporosis should especially be excluded when:
·
Suggestive
symptoms or signs of a secondary process are present
·
BMD is
low relative to age- and weight-matched controls (Z-score < –2)
·
BMD
declines at a more rapid rate than expected for age or fails to respond to
appropriate therapy.
The fracture results from an increase in activation
frequency of bone remodeling units and an imbalance between osteoclatic bone
resorption and osteoblastic bone formation leading to cancellous bone loss5.
In addition, excessive osteoclastic activity during the early postmenopausal
period results in perforation of trabeculae and loss of trabecular connectivity.
Although there are several risk factors for fractures, reduced bone
mineral density is the strongest predictor. Thus, the ultimate goal of
pharmacological treatment in women with postmenopausal osteoporosis is to
reduce the risk of fractures by increasing bone mass of normal quality 6.
Pathophysiology
of osteoporosis:
To understand the
pathophysiology of osteoporosis, it is necessary to review normal bone
physiology. Bone is living tissue and its strength depends upon the normal
functioning of 3 key bone cells: osteoclasts, osteoblasts, and osteocytes.
Osteoclasts and osteoblasts compose the bone multicellular unit (BMU), where
bone remodeling and reconstruction occur. At the BMU, a small packet of old or
damaged bone tissue is removed by the osteoclast in a process known as bone
resorption. Osteoblasts are then recruited to the excavated site to fill it in
with new, young, healthy bone tissue (bone formation).This occurs continuously
throughout the skeleton and is critical for normal bone strength. Osteoclast
and osteoblast functions are well coordinated or coupled. Osteocytes, the most
numerous and longest-lived bone cells act as the mechanosensors for the
skeleton and are actually derived from senescent osteoblasts. They form an
intricate communication network with each other and with the outer bone
surface, and, in response to mechanical and structural demands, they direct
where and when bone remodeling will occur7.
Figure 2: Figure showing the interaction of RANKL and its receptor RANK
and activation or inhibition of osteoclast calcium resorption activity 8.
Since the time
needed for osteoclasts to resorb bone is short (weeks), while the time needed
for osteoblasts to form bone is long (months), any process in adults that
increases the rate of bone remodeling will result in a net loss of bone.
Additionally, as the number of unfilled excavation pits increases, they form
stress risers, which are vulnerable sites that can easily perforate and result
in micro fractures. During childhood and puberty, high rates of bone resorption
are accompanied by even higher rates of bone formation. But with aging, for
unknown reasons, the osteoblastic response to bone resorption is inadequate and
resorption outstrips formation. This osteoblastic failure is a major factor in
the pathogenesis of osteoporosis.
A key cytokine,
called RANKL (receptor activator of nuclear factor-κβ ligand), is
produced by osteoblasts and activated T cells within the bone marrow and plays
a major role in the intercellular communication network. RANKL binds to the
receptor activator of nuclear factor κβ (RANK) receptor, which is
expressed on the surface of osteoclasts and osteoclast precursors. When RANKL
binds to RANK, it promotes the differentiation of osteoclast precursors from an
early stage of maturation into fully mature, multinucleated, and functional
osteoclasts. RANKL can also activate mature osteoclasts, stimulating these
cells to begin resorbing bone. In addition, RANKL binds to osteoprotegerin
(OPG), a soluble decoy receptor produced by numerous hematopoietic cells. OPG,
by sequestering RANKL and preventing its binding to RANK, functions as a potent
antiresorptive cytokine. The RANKL/RANK/OPG system appears to be the final
common pathway through which all processes that stimulate bone resorption must
go9.
Prevention and treatment of
osteoporosis:
Pharmacological agents used to manage osteoporosis act
by decreasing the rate of bone resorption, thereby slowing the rate of bone
loss, or by promoting bone formation. The only drugs currently approved in the
United States for use in osteoporosis are those that decrease resorption. Drugs
used in treating osteoporosis includes,
·
Antiresorptive
agents(calcium)
·
Vitamin
D and its analogs
·
Estrogen
·
Calcitocin
·
Bisphosphonates
·
Thiazide
diuretics
·
Bone
forming agents(fluoride)
·
Androgen
·
Parathyroid
Harmone.
Antiresorptive agents: By far the major sources of calcium in the
diet are milk and milk products, which are also major sources of phosphate, but
phosphate is also present in many other dietary foods, including the meats.
Calcium is poorly absorbed from the intestinal tract because of the relative
insolubility of many of its compounds and also because bivalent cations are
poorly absorbed through the intestinal mucosa. On the other hand, phosphate is
absorbed exceedingly well most of the time except when excess calcium is in the
diet; the calcium tends to form almost insoluble calcium phosphate compounds in
the intestines that fail to be absorbed but instead pass on through the bowels
to be excreted in the feces. In the other words, the major problem in the
absorption of calcium and phosphate is actually a problem of calcium absorption
alone, for if this is absorbed, phosphate will also be absorbed.
Vitamin D and its analogues: Vitamin D has a potent effect in increasing
calcium absorption from the intestinal tract; it also has important effects on
both bone deposition and bone resorption. However, vitamin D itself is not the
active substance that actually causes these effects. Instead, the vitamin D
must first be converted through a succession of reactions in the liver and the
kidney to the final active product, 1, 25-dihydroxycholecalciferol. Several
different compounds derived from sterols belong to the vitamin D family, and
they all perform more or less the same functions. The most important of them is
cholecalciferol, called vitamin D3. Most of this
substance is formed in the skin is a result of irradiation of
7-dehydrocholesterol by ultraviolet light from the sun. Consequently,
appropriate exposure to the sun prevents vitamin deficiency.
Calcitocin: About 30years ago, a new hormone that has a
weak effect on blood calcium opposite to those of parathyroid hormone was
discovered. This hormone was named calcitonin, because it reduces the blood
calcium ion concentration. In the human being, it is secreted not by the
parathyroid gland but instead by the thyroid gland, by parafollicular cells, or
C cells. Calcitonin is a large polypeptide with a molecular weight of
approximately 3400; it has a chain of 32 amino acids. In young animals,
calcitonin decreases blood calcium ion concentration very rapidly, beginning
with minutes after injection of the calcitonin. Thus the effect of calcitonin
on blood calcium ion concentration is exactly opposite that of parathyroid
hormone, and it occurs several times as rapidly.
Calcitonin reduces plasma
calcium concentration in at least two separate ways:
1. The immediate effect is to decrease the absorptive
activities of the osteoclast and probably also the osteolytic activity of the
osteocytic membrane throughout the bone, thus shifting the balance in favor of
deposition of calcium in the rapidly exchangeable pool of bone calcium salts.
2. The second and more prolonged effect is to prevent
formation of new osteoclasts. Calcitonin has a weak effect on plasma calcium
concentration in the adult human being. The reason for this is simply that the
daily rates of bone absorption and deposition of calcium are small, and the
stimulatory effect of calcitonin cannot alter the rates enough to make much
difference.
Parathyroid Hormone: For many years it has been known that
increased activity of the parathyroid gland causes rapid absorption of calcium
salts from the bones with resultant hypercalcemia in the extracellular fluid;
conversely, hypofunction of the parathyroid glands causes hypocalcemia, often
with resultant tetany. Also this hormone is important in phosphate and calcium
metabolism. Parathyroid hormone seems to
have two separate effects on bone in causing absorption of calcium and
phosphate.. The second phase is a much slower one, requiring several days or
even weeks to become fully developed, and it results from the proliferation of
osteoclasts, followed by greatly increased osteoclastic reabsorption of the
bone itself, not merely absorption of calcium phosphate salts from the bone10.
Estrogen: Estradiol is the major estrogen secreted by
the ovary. It is synthesized in the graffian follicles, corpus luteum and
placenta from cholesterol. They are important in maintaining bone mass
primarily by retarding osteoclast activity. Osteoclast pit formation is
inhibited and there is increased expression of bone matrix proteins such as
osteonectin, osteocalcin, collagen and alkaline phosphatase. They promote
positive calcium balance, partly by inducing renal hydroxylase enzyme which
generates active form of vitamin D3. Both osteoblasts and osteoclasts
express estrogen receptors (ERs). The major action of estrogens is to reduce
maturation and activity of osteoclasts by modifying regulatory cytokine signals
from osteoblasts. The direct action on osteoclasts is to accelerate their
apoptosis11.
Bisphosphonates: Bisphosphonates are the pharmacological
agents, which are not only used in the treatment of osteoporosis, but also in
the pathological conditions characterized by an increased bone resorption, such
as Paget’s disease of bone, malignant hypocalcemia during myeloma, osteolytic
bone metastatis and fibrous displasia of bone. The rationale of current
treatment strategy is to provide sufficient drug to inhibit resorption,
followed by a sustained interval off medication to permit normal mineralization12.
Mechanism of action of
bisphosphonates:
Bisphosphonates core structure consists of
phosphate-carbon-phosphate backbone that results in tight binding of
bisphosphonates to the major bone mineral, hydroxyapatite. The side chains will
influence the pharmacological activity of bisphosphonates. The R1
influences binding to bone; a –OH group at this position results in enhanced
binding and is present in the most commonly used bisphosphonates. The R2
group determines antiresorptive potency and also has effects on hydroxyapatite
binding. Non-N-containing
bisphosphonates:
Disruption of the HMG CoA-reductase pathway
at the level of FPPS prevents the formation of two metabolites (farnesol and geranylgeraniol) that are essential for connecting some
small proteins to the cell membrane. This phenomenon is known as prenylation, and is
important for proper sub-cellular protein trafficking. While inhibition of
protein prenylation may affect many proteins found in an osteoclast, disruption to the lipid modification of Ras, Rho, Rac proteins has been speculated to underlay the effects of
bisphosphonates. These proteins can affect osteoclastogenesis, cell survival,
and cytoskeletal dynamics. In particular, the cytoskeleton is vital for
maintaining the "ruffled border" that is required for contact between
a resorbing osteoclast and a bone surface14.
Bone anabolic agents: Teriparatide: Increasing their activity. It is used mostly
for patients with established has been shown to be effective in osteoporosis.
It acts like parathyroid hormone and stimulates osteoblasts, thus fractured),
have particularly low BMD or several risk factors for fracture or cannot
tolerate the oral bisphosphonates. It is given as a daily injection with the
use of a pen-type injection device.
Future Trends in
Osteoporosis Management:
Promising new drugs are currently under
investigation by the FDA for the treatment of osteoporosis. Recombinant human
parathyroid hormone shows promise as the first anabolic drug to positively
affect bone mineral density and bone markers. This treatment is currently under
review by the FDA. In February 2002, the FDA approved zoledronic acid (Zometa),
a new member of the bisphosphonate family of drugs, for the treatment of bone
metastases in cancer patients. This powerful bisphosphonate is effective in
preventing and treating osteoporosis.9 Zoledronic acid is administered
by intravenous injection over a 15-minute period once every 12 months. Denosumab is a RANKL (Receptor activator of
nuclear factor kappa B ligand) inhibitor. It is human monoclonal antibody
recently (June 2010) approved by USFDA for the use in osteoporosis of post
menopausal women. Clinical trials are
going on for its other indications. Strontium ranelate is the only
antiosteoporotic agent which both increases bone formation and reduces bone
resorption. Strontium ranelate is registered as a
prescription drug in more than 70 countries for the treatment of
post-menopausal osteoporosis to reduce the risk of vertebral and hip fractures.
In the United States, Strontium ranelate is not approved by the FDA.
One of the newest scientific advances is
the identification of osteoprotegerin. Osteoprotegerin is a glycoprotein member
of the tumor necrosis factor receptor family. This protein acts as a decoy
receptor and binds to one of the enzymes responsible for osteoclast
differentiation, thereby preventing osteoclast formation and then bone
reabsorption. Early studies have
indicated that osteoprotegerin levels rise in the presence of 17
beta-estradiol. More recent research indicates that dietary sources of
phytoestrogens may increase osteoprotegerin production and help prevent bone
loss and bone resorption; however, rigorous data are needed before clinical
recommendations can be made.15
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Received on 07.08.2011
Accepted on 31.08.2011
© A&V Publication all right reserved
Research J. Pharmacology and
Pharmacodynamics. 3(6): Nov.-Dec., 2011, 329-333