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Restoring Aging Bones

The bone decay of osteoporosis can cripple, but an improved
understanding of how the body builds and loses bone is leading to ever
better prevention and treatment options

By Clifford J. Rosen

Late last year a new patient, 72-year-old Maxine LaLiberte, limped
into my office. She said she had always been very active. She baby-sat
frequently for her nine grandchildren and had been looking forward to
a long-planned cross-country motor home trip with her husband. But now
the excruciating pain between her shoulder blades was curtailing her
movements and making her feel old. I was all too familiar with those
symptoms in people my patient's age. Even without examining her, I was
reasonably sure that one or more of her vertebrae had fractured as a
result of osteoporosis, a disorder characterized by bone loss so
severe that fractures occur spontaneously or from even minor bumps

Osteoporosis afflicts about 10 million Americans, especially women
past menopause. Fully half of all postmenopausal women will incur an
osteoporosis-related fracture during their lives. Fortunately, the
outlook for people with osteoporosis has never been better. Drugs are
now available that can restore lost bone and thereby greatly reduce
the risk of additional breaks. Furthermore, recent insights into the
cellular and molecular bases of osteoporosis have generated exciting
ideas for new and even more effective therapies. Just a decade ago
the****utic options for osteoporosis consisted mainly of calcium
supplements, painkillers and, for women past menopause, estrogen
replacement therapy--helpful treatments, but imperfect. Estrogen
replacement therapy, for instance, increases the risk for heart
attack, stroke, breast cancer and blood clots. Today, in contrast,
pharmacies stock several drugs that reduce the likelihood of new
fractures by as much as 70 percent in the first year of treatment.

Similarly dramatic improvements have taken place in diagnosis. Not
long ago a fracture often was the only tip-off that someone had
osteoporosis. But physicians are now using a sophisticated in-office
tool called dual-energy x-ray absorptiometry (DEXA) to measure bone
mineral density at sites especially susceptible to fracture. DEXA is
allowing doctors to diagnose osteoporosis much earlier--in time to
initiate drug treatment that can keep bones intact and prevent
fractures from occurring. In addition, DEXA can be a useful screening
tool to predict the likelihood of future breaks at any site.

Recent research has also yielded a new appreciation for heredity's
role in osteoporosis. The disorder was long considered a "traumatic"
condition, in which decades of skeletal wear and tear culminate in
fractures and pain. Genetic investigations have now revealed, however,
that genes influence bone density and, hence, the risk of fractures.
These studies indicate that genetic differences account for up to 70
percent of human variability in bone mass, although such factors as
diet and exercise play a part, too. Apparently, many different genes
influence propensity. As specific osteoporosis-promoting gene variants
are found, they could form the basis for tests to detect
susceptibility and could also lead to drugs able to counteract their
effects.

Reversing Silent Thievery The need for better preventive and
the****utic options is urgent. Osteoporosis, which literally means
"porous bones," is the underlying cause of virtually all broken bones
in people older than 65. The vertebrae, hips and wrists are
particularly susceptible to osteoporotic fractures. These broken bones
can cause chronic, disabling pain and--in the case of the hip--often
usher in a series of events that can lead to death: of the 275,000
older Americans who suffer a broken hip every year, 20 percent die
within a year of the episode from blood clots, infections or
undernutrition. In addition to the 10 million Americans with existing
osteoporosis, another 18 million have low bone mass (osteopenia), a
condition that does not qualify as osteoporosis but heightens their
risk for eventually developing the disorder.

Medicines introduced in the past 10 years are designed to alleviate
the suffering of osteoporosis by interfering with a process known as
bone remodeling, or turnover. Seemingly inert when viewed from the
outside, bone is a living tissue that ceaselessly destroys and
rebuilds itself throughout adult life. This remodeling essentially
replaces the entire skeleton every 10 years--dissolving, or resorbing,
old bone and completely replacing it with new. Remodeling undoubtedly
serves some useful functions, such as freeing calcium from bone for
use by various tissues and repairing microfractures. But defective
remodeling underlies the development of osteoporosis.

During childhood and adolescence, bone formation proceeds at a faster
rate than resorption, causing bone density to increase until young
adults attain their peak bone mass at around age 18. Density stays
constant throughout young adulthood as bone formation and resorption
proceed at the same rate. But around age 40, everyone begins to
experience some age-related bone thinning as resorption begins to
outpace bone formation. For several reasons, however, the risk of
osteoporosis is much greater in women, who account for 80 percent of
cases.

The average woman attains a peak bone mass that is generally about 5
percent below that of a man's, so women have a bit less bone density
"in the bank" when age-related bone loss begins. In addition, women
lose an important bone protector--estrogen--at menopause. As a result,
bone loss in women can increase sharply for some four to seven years
after the shutoff of estrogen at menopause.

Two types of bone cells carry out remodeling--bone-forming osteoblasts
and large, bone-resorbing osteoclasts. Both cell types come together
in three milllion to four million remodeling sites, termed basic
multicellular units (BMUs) of bone remodeling, that are scattered
throughout the skeleton. Remodeling always occurs in the same
sequence: a rapid (two- to three-week) bone resorption phase followed
by a slower (two- to three-month) bone formation phase. Resorption
begins when the osteoclasts attach to a microscopic section of bone
surface and release substances that degrade the structural parts of
bone--calcium, other minerals and the protein collagen. This degrading
activity forms an indentation in bone called a resorption pit, after
which the osteoclasts disappear, probably as a consequence of
programmed cell death (also called apoptosis, or cell suicide).
Remodeling's bone formation phase begins when osteoblasts--perhaps
attracted by growth factors released during bone resorption--converge
on the resorption pit, filling it with new bone by synthesizing and
secreting collagen and other bone proteins. Calcium, phosphorus and
other minerals then crystallize around the collagen matrix to form
hydroxyapatite, the hard, mineralized part of bone that accounts for
90 percent of its mass.

Until late last year, all drugs approved for treating osteoporosis
were considered antiresorptives, because they slow resorption more
than they promote formation (although in truth, anything that affects
one process also affects the other to some degree). Drugs of one
antiresorptive class in particular--the bisphosphonates--have
transformed osteoporosis treatment over the past decade and are now
the first choice for both men and women with osteoporosis. These oral
agents slow bone remodeling by attaching readily to the mineral part
of bone, where they sit in wait for osteoclasts to bind to the bone's
surface. Once that happens, the bisphosphonates diffuse into the
osteoclasts and induce those cells to self-destruct.

Large-scale, randomized clinical trials have shown unequivocally that
the most potent bisphosphonates--alendronate (Fosamax) and risedronate
(Actonel)--not only prevent further bone loss but can also increase
bone density in most patients by 5 to 10 percent over three years.
That bone buildup may seem modest, but it is enough to reduce the risk
of spine, hip and wrist fractures by as much as 50 percent at three
years, with more significant fracture reduction evident in the first
year of therapy. The bisphosphonates need to be taken just once a week
and seem exceptionally safe: aside from heartburn, side effects are
rare. These drugs have been in use for only a decade, however, so
their long-term safety beyond 10 years remains to be demonstrated.

Seeking New Drug Targets Motivated in part by a desire for more
effective osteoporosis drugs, scientists are now intensively studying
how bone remodeling is regulated so that those controls can be
manipulated to encourage bone formation. In the past two years they
have made progress in teasing out the features that regulate
osteoclastogenesis--the birth and maturation of osteoclasts, the
bone-dissolving cells.

Osteoblasts and osteoclasts both arise through the differentiation of
predecessor cells in bone marrow (which also houses the body's
blood-producing cells). So-called stromal cells mature into
osteoblasts, and macrophages (a type of white blood cell)
differentiate into osteoclasts. Recently biologists have learned that
stromal cells and their offspring, the osteoblasts, govern the
production of the bone-degrading osteoclasts; they do so by secreting
three different signaling molecules--two that promote osteoclast
development and one that suppresses it.

Early on, for instance, osteoblasts secrete a signaling molecule
called macrophage colony-stimulating factor that binds to a receptor
on macrophages, inducing them to multiply. A second chemical, RANKL,
secreted by osteoblasts, binds to a different receptor on macrophages,
inducing the cells to differentiate into osteoclasts. The third
osteoblast product, however, osteoprotegerin, can block osteoclast
formation by acting as a decoy receptor--latching onto RANKL and
preventing it from coming into contact with its intended receptor on
macrophages.

In theory, anything that interferes with osteoclast formation--and
thus with bone resorption--should enhance bone density. Research
involving one intervention based on the new molecular
understanding--delivery of osteoprotegerin--is ongoing. In human
trials, injections of the molecule have slowed the rate of bone
resorption by at least 60 percent. Biologists have also identified
nearly a dozen other chemical signals involved in coordinating bone
formation and resorption--among them estrogen, parathyroid hormone and
insulinlike growth factor-1. Study of these substances has suggested
additional strategies for preventing and treating osteoporosis.
Circulating estrogen exerts its differing influences in the body by
teaming up with estrogen receptors present in various tissues,
including the uterus, breast, colon, muscle and bone. Doctors have
known for 50 years that estrogen helps to preserve bone density, but
the molecular mechanisms have long been a mystery. It is now clear
that one of estrogen's functions is to interfere with the creation of
osteoclasts.

More specifically, estrogen binds to osteoblasts in bone and induces
them to increase their output of osteoprotegerin and to suppress their
RANKL production--a combination of signals that suppresses osteoclast
formation, keeping bone loss in check. The reduction of estrogen that
accompanies menopause thus contributes to bone loss largely by
removing an important brake on osteoclast formation and activity. In
addition, estrogen appears to prolong the lives of osteoblasts while
simultaneously promoting the suicide of osteoclasts. So the decline of
estrogen at menopause hits women with a triple whammy: shorter-lived
osteoblasts must contend with more osteoclasts that have longer life
spans.

Until last year, physicians routinely urged their female patients to
take hormone replacement therapy (usually estrogen combined with
progestin, a form of progesterone) at menopause, not only to protect
against osteoporosis but to ward off other age-related health problems
for which estrogen was considered useful, including heart disease and
dementia. The health benefits of hormone replacement therapy were
thought to outweigh any possible dangers.

So women and their doctors were stunned last July when medical
authorities overseeing the federally sponsored Women's Health
Initiative determined that hormone replacement therapy caused small
increases in breast cancer, heart attack, stroke and blood clots and
that the risks of the therapy outweighed its modest benefits, which
included small decreases in the risks for hip fractures and colon
cancer. Three months later, after reviewing results from this and
similar studies, the influential U.S. Preventive Services Task Force
recommended against the use of combined estrogen and progestin therapy
for preventing cardiovascular disease and other chronic conditions,
such as osteoporosis in postmenopausal women. For now, the best
estrogen alternatives for bone health are the bisphosphonates. In a
meta-****ysis that our group recently completed, combining data from
many studies, the bisphosphonates proved slightly better than estrogen
therapy at increasing bone mineral density and preventing fractures.

Drugs known as selective estrogen receptor modulators (SERMs) may also
be useful for the long-term treatment of women fearful about breast
cancer. SERMs act like estrogen in some tissues (bone, for example)
while at the same time blocking estrogen's effects in other tissues,
such as the breast. So far the only SERM approved for the treatment
and prevention of osteoporosis is raloxifene (Evista), but others are
being tested. Raloxifene is not as effective as estrogen in increasing
bone mineral density and preventing fractures, and it can cause hot
flashes; however, studies involving women being treated for
osteoporosis have found that raloxifene reduced their risk for breast
cancer.

Controlling the Controllers But an even better answer may be on the
way. In a few years, scientists may begin human testing of synthetic
estrogens that offer all of estrogen's bone benefits and none of the
risks--and help men as well as women. Work on those agents began in
response to a radical hypothesis proposed a few years ago by Stavros
C. Manolagas of the University of Arkansas for Medical Sciences.

Manolagas proposed that estrogen exerts its effects on cells in two
separate ways. One is the well-established mechanism by which estrogen
influences all its target tissues in females, reproductive and
nonreproductive alike: After estrogen crosses a cell's outer membrane
and cytoplasm, it enters the nucleus and binds to its receptor. This
estrogen/receptor duo (along with other nuclear proteins known as
co-activators) directly interacts with specific sequences of DNA to
induce certain genes to give rise to specific proteins needed for
cellular activities. But this "genotropic" pathway (so named because
of estrogen's direct contact with genes) could not explain all of
estrogen's numerous effects on cells. So Manolagas hypothesized that
estrogen also acts through a different mechanism that influences bone
and other nonreproductive tissues in both males and females and has no
effect on reproductive tissues. In this scenario, estrogen still binds
to receptors in cells, but then the hormone and its receptor induce
cellular changes by acting on kinases, enzymes that reside outside the
nucleus, in the cytoplasm. (In the case of bone tissue, these kinases
exist in the cytoplasm of osteoblasts and osteoclasts.) The activated
kinases then migrate to the nucleus, where they help to regulate the
expression of genes.

Manolagas and his colleagues synthesized an estrogenlike hormone,
dubbed estren, designed to act exclusively through the nongenotropic
pathway. Last October in Science, Manolagas and his team reported on
mouse studies comparing estren with estrogen. Estren was even more
effective than estrogen in rebuilding bone in female mice whose
ovaries had been removed to simulate menopause. Just as important,
estren did not increase the weight of mice uteri, confirming the
drug's lack of effect on reproductive tissue. Similar results were
observed in male mice: estren proved just as good as testosterone in
rebuilding lost bone in mice whose testes had been removed, and,
unlike testosterone, it had no effect on the weight of seminal
vesicles in male mice.

The findings indicate that estren could become the first of a new
class of osteoporosis drugs that Manolagas has named ANGELS
(activators of nongenomic estrogenlike signaling). These agents might
work even better than estrogen in building bone without causing
estrogen's unwanted effects on reproductive tissue, such as uterine
and breast cancer.

In the Driver's Seat Much as estrogen defends against bone loss by
limiting osteoclast development, parathyroid hormone (PTH) can be
considered the engine that "drives" osteoporosis, because it promotes
the action of osteoclasts. PTH triggers osteoclast formation
indirectly, by binding to osteoblasts and prompting them to increase
RANKL output and decrease osteoprotegerin production--precisely
opposite to the way estrogen regulates RANKL and osteoprotegerin to
block osteoclast formation and preserve bone. Paradoxically, however,
the notoriously "resorptive" PTH was recently approved as the first
bone-building agent, as opposed to the antiresorptives, and some data
suggest that it could be the best of all osteoporosis treatments.

Although the body's own PTH promotes bone loss when elevated over long
periods, intermittent injections turn out to elicit quite a different
response. The first inkling that PTH could build bone emerged in 1928,
when researchers noted that PTH injections increased bone density in
dogs. But the finding was ignored until the 1970s, when researchers at
Massachusetts General Hospital and at the University of Cambridge
began independently experimenting with delivering natural, and later
recombinant, PTH. Over the past 25 years, experiments in humans have
shown that intermittently administered PTH has an amazing ability to
increase bone density (especially in the vertebrae), enhance the
structural integrity of bone, and prevent fractures in both men and
postmenopausal women. Typically, daily PTH injections result in
bone-density increases of 8 to 10 percent after one year, with the
risk of fracture reduced by an impressive 60 percent. Injectable PTH,
under the brand name Forteo, was approved in late 2002 by the U.S.
Food and Drug Administration for the treatment and prevention of
osteoporosis in both men and women.

Why does the body's own PTH cause bone thinning, whereas PTH "pulses"
have a bone-building effect? The intermittent doses seem to direct
osteoblast precursors to mature into osteoblasts while simultaneously
preventing established osteoblasts from dying, resulting in much
greater numbers of bone-forming osteoblasts that function for longer
periods. One particular molecule activated by intermittent PTH
treatment is insulinlike growth factor-1 (IGF-1), which stimulates
stromal cells to differentiate into bone-forming osteoblasts. It also
circulates in high concentrations in the blood. Healthy adults have
wide differences in their serum IGF-1 levels--and these can have
important implications for bone density. For example, an evaluation of
women in the Framingham Heart Study found that women in the highest
quartile for serum IGF-1 had the highest bone density in the spine,
hip and wrist.

Although diet has some influence over IGF-1 (malnutrition can cause
steep declines), levels of IGF-1 are largely genetically determined.
Over the past decade my laboratory in Bar Harbor, Me., has studied the
genetic regulation of IGF-1 using two strains of mice that exhibit
major differences in bone mineral density. Our research has shown that
60 percent or more of IGF-1 is genetically determined--a significant
finding, because emerging evidence suggests that the "high normal"
IGF-1 levels that protect against osteoporosis also correlate with an
increased risk for breast cancer, prostate cancer and, perhaps, colon
cancer. In the future, measuring IGF-1 levels in people may serve as a
useful risk predictor, with high levels indicating a low risk for
osteoporosis but an elevated risk for certain types of cancer. In the
end, the DEXA scan of Maxine's spine confirmed my suspicions. She had
suffered a recent fracture of her eighth thoracic (T8) vertebra, near
her shoulder blades, and her vertebral bone mineral density was more
than 2.5 standard deviations below that of a 35-year-old woman. Either
finding alone was sufficient for a diagnosis of osteoporosis, yet her
prognosis was good. I told her that the back pain would diminish over
the next several weeks. And I prescribed a bisphosphonate drug that
would restore 5 to 10 percent of her bone density and reduce by 70
percent the likelihood that she would experience a fracture within the
next year. The news cheered her. With more grandchildren on the way,
her baby-sitting responsibilities were about to increase.

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CLIFFORD J. ROSEN is executive director of the Maine Center for
Osteoporosis Research and Education in Bangor, Me., and is adjunct
staff scientist at the Jackson Laboratory in Bar Harbor, Me. He
obtained his M.D. at the State University of New York at Syracuse,
Upstate Medical Center, in 1975 and has been associate clinical
professor at Boston University Medical Center since 1993. He currently
serves as president of the American Society for Bone and Mineral

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