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INSIDEthis issueBBoonnee BBuuiillddeerrss::

The DiscoveriesBehind Preventing

and TreatingOsteoporosis

3Mysteries

of bone growthWhat Makes

Women Prone toPostmenopausal

Osteoporosis?

4A revolutionary

hypothesis

5The ins and

outs of calcium

7New drugs for

osteoporosisaccidentally

discovered

8ABCs and Dsof nutrition

Explosion ofresearch

9

Breakthroughs in Bioscience 2 www.faseb.org/opar

Acknowledgments Margie Patlak, Elkins Park, PA authored the article and

Steven Teitelbaum, MD, Washington School of Medicine,

St. Louis, MO, was the scientific advisor. They are grate-

ful to the FASEB Breakthroughs in Bioscience Committee

members for their guidance in develping the article as well

as to the scientists who reviewed it. The article was edited

by Elia Ben-Ari, Arlington, VA.

BREAKTHROUGHS IN BIOSCIENCE COMMITTEE

Fred Naider, PhD, Chair, College of Staten Island, CUNY

David Brautigan, PhD, University of Virginia, Charlottesville

John Grossman, MD, PhD, MPH, Society for Gynecologic

Investigation

Tony Hugli, PhD, La Jolla Institute for Molecular Medicine

Richard Lynch, MD, University of Iowa College of Medicine

Margaret Saha, PhD, College of William and Mary

SCIENTIFIC REVIEWERS

Robert Marcus, MD, Veterans Affairs Medical Center

Gregory R. Mundy, MD, University of Texas Health Science Center

B. Lawrence Riggs, MD, Mayo Clinic

BREAKTHROUGHS IN BIOSCIENCE PRODUCTION TEAM

Director, Tamara R. Zemlo, PhD, MPH, Associate Director

of Science Policy, Office of Public Affairs, FASEB.

Editorial Coordinator, Paulette Walker Campbell, Science

Writer/Editor, Office of Public Affairs, FASEB.

COVER IMAGE: Shown on the cover are

reproductions of two scanning electron

micrographs of osteporotic and normal

human cancellous bone. (Colorization

added for effect.)

Image © 2001, David W. Dempster, PhD.

Ask an actress to portray anold woman and chancesare she’ll start by stooping

over so she appears to have acurved spine, or “dowager’shump.” Until recently, such aposture was thought to be a fre-quent and inevitable consequenceof a woman’s aging. Thisassumption is evident in literatureand art, which often depictwomen bent over with age. “Herchest had dropped, so that shestooped,” noted Charles Dickens

in his description of the elderlyMiss Havisham in his novel GreatExpectations. A striking exampleof a dowager’s hump also appearsin a painting of an old woman bythe fifteenth century artistVittore Carpaccio (fig. 1). Andeverything from Greek myths toclassic fairy tales are peopledwith stooped older women.

More often than not, these depic-tions are probably of women witha bone-thinning disease known asosteoporosis. This disease willultimately afflict about half of allwomen who reach the age ofsixty-five, and frequently causesthe bones in the spineto collapse. Suchspinal collapses causewomen to be perpetu-ally hunched over and,in severe cases, causethem to lose as muchas a foot in height (fig.2). Osteoporosis alsoaffects as many as twoout of every ten menover the age of seven-ty.

Osteoporosis makesthe bones so fragilethat the simplest thingscan cause them tobreak: stepping off acurb, a sneeze, a hug.The disease often caus-es such pain and dis-ability that people afflicted by itmust spend their last days in anursing home. Hip fractures dueto osteoporosis are especially dis-abling and can even be deadly.One out of five elderly peoplewho break a hip die within a yearfrom complications of the frac-

ture. The annual costs of osteo-porosis exceed fourteen billiondollars in this country, accordingto the National OsteoporosisFoundation.

Osteoporosis has haunted womensince the dawn of history—Egyptian mummies from 4,000years ago have been found withthe telltale dowager’s hump. Butthere is now hope that mostyoung women today can expectto spend their old age standing asstraight and tall as they everwere, thanks to recent dramaticimprovements in the diagnosis,prevention, and treatment of

osteoporosis. A better under-standing of what puts people atrisk of developing osteoporosishas armed women with strategiesto help prevent the disorder (see“What Makes Women Prone toPostmenopausal Osteoporosis?”on page 4). New diagnostic tools

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CALCIUMBone Builders: The Discoveries Behind Preventing and Treating Osteoporosis

Figure A curved spine or “dowager’shump ” can be seen in the elderly womandepicted in this painting by fifteenthcentury artist Vittore Carpaccio Suchdeformity is caused by osteoporosis

Figure Women with postmenopausal osteoporosistend to experience numerous fractures in the bones intheir spine (vertebrae) as they age Eventually these vertebrae can collapse causing the spine to curve Such curvature causes loss of height a tilted rib cage a dowager’shump and a protruding abdomen Designed by Corporate

AGE 40 AGE 60 AGE 70

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allow doctors to detect osteoporo-sis in its early stages, before itcauses widespread harm to theskeleton. And a fuller picture ofwhat causes osteoporosis has ledto effective treatments that canstave off bone fractures. Many ofthese improvements stem notfrom targeted research on the dis-ease but from more basicresearch aimed at answering suchfundamental questions as, how dobones grow, why do femalepigeons have more massive bonesthan males, and how does thebody maintain the delicate bal-ance of calcium it needs to runsmoothly?

Mysteries of bone growthAn early medical pioneer, theeighteenth century English sur-geon John Hunter, described him-self as one who “pestered peoplewith questions about whatnobody knew or cared anythingabout.” One of those questionswas, how does bone grow anddevelop over time? Hunter’sexperiments on animals, alongwith observations of changes inthe human jaw, led him to a sur-prising discovery: As new bone islaid down in the body, old bone isdestroyed, or resorbed. This dis-covery that bone is constantly

being remodeled predated wide-spread use of the microscope andthe notion of cells as the work-horses of the body. So Hunterwas unable to find out whatcaused such striking bone remod-eling.

It took a hundred more years of

observations and experiments bymany basic scientists to discoverthat lodged in living bone arelarge ruffle-edged cells known asosteoclasts, which break downbone. Close on the heels ofosteoclasts are bone-buildingcells known as osteoblasts (fig.

What Makes Women Prone to Postmenopausal Osteoporosis?

Figure Osteoclasts (oc) which are stained red in this section of bone (B) areresponsible for the degradation of bone and cartilage Their multiple nuclei appear asdarkly stained bodies within the cell Osteoblasts (ob) are the rectangular shaped cellseach with a single prominent nucleus lining the surface of the bone These cells appeardark in color due to the presence of numerous ribosomes which are structures in cellsthat synthesize protein The catabolic and anabolic activities of osteoclasts andosteoblasts respectively are coupled under physiological conditions to maintain bonehomeostasis (the balance between bone growth and degradation) Courtesy ofJonathan Lam Washington University School of Medicine St Louis MO

The basic understanding of osteoporosis that emerged during the last half of the twentieth century not only led tonew treatments but also set some investigators on a research path aimed at uncovering why some postmenopausalwomen suffer from osteoporosis while others are virtually untouched by the disease. These scientists, known as epi-demiologists, searched for the risk factors that make women susceptible to postmenopausal osteoporosis, hoping thatsome of these factors could be modified.

Thanks to the basic research on bone biology that had been done over the past century or two, epidemiologists had anumber of clues to follow. The most obvious clue was calcium in the diet. Basic research showed that calcium is themain component of bone, and that insufficient blood levels of calcium can trigger the erosion of this mineral frombones. Epidemiologists therefore hypothesized that low levels of calcium in the diet might boost a woman’s risk ofdeveloping postmenopausal osteoporosis.

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3). Because of the industry ofboth types of cell, the entire adulthuman skeleton is completelyreplaced about every ten years.Such bone remodeling, whichHunter first discovered in the1770s , was later shown to play acritical role in osteoporosis.

For more than a hundred yearsafter Hunter died, however, osteo-porosis wasn’t even a recognizeddisease. A step toward suchrecognition was made in the1830s by the French pathologistJean Georges Chretien FredericMartin Lobstein. He noticed thatsome patients’ bones were riddledwith larger than normal holes,and he coined the term osteo-porosis (porous bone) to describesuch deteriorated human bone.But Lobstein didn’t pursue thequestion of what might be caus-ing these holes to form in bone,or even whether they might be asymptom of disease.

We now know that bone consistsof a matrix of fibers of the toughprotein collagen, hardened withcalcium and other minerals. Theoutside portion of every bone is atough dense rind called corticalbone. Inside is a honeycomb net-work made up of intersectingplates, or trabeculae.Osteoporosis eats away at bothcortical and trabecular bone,

resulting in large holes such asLobstein saw (see cover picture).These holes weaken the skeleton.Like a building without supportbeams, bone without enough cor-tex and trabeculae easily cracksor collapses when it is knockedor compressed.

But what caused such bone dete-rioration? Early in the last centu-ry, doctors assumed it was a natu-ral consequence of age or immo-bility, but one astute clinicalresearcher in the 1930s was puz-zled by the fact that so many ofhis patients with osteoporosiswere older women who had gonethrough menopause. A few of hispatients were in their thirties orforties, but these women sharedsomething with the older womenwith osteoporosis—they, too,were in effect postmenopausal,because their ovaries had beenremoved. Intrigued by thisobservation, and being an imagi-native man who believed thatevery clinical problem has anexplanation, Fuller Albright ofMassachusetts General Hospitalcouldn’t help but ponder what itwas about being postmenopausalthat made women particularlysusceptible to having frail bones.

A piece that helped Albrightsolve this puzzle came from apair of anatomists who noticed, in

1934, that the bones of ovulatingfemale pigeons were much moremassive than those of malepigeons. Could the hormoneestrogen, which is producedchiefly by the ovaries, be causingthe difference in bone mass?Researchers at Yale Universityexplored this possibility. Whenthey injected estrogen into malepigeons, the birds’ bone massincreased dramatically, reachinglevels found in female birds.

A revolutionaryhypothesisPrompted by the findings inpigeons, in 1940 Albright pro-posed his revolutionary hypothe-sis: Estrogen triggers the buildupof calcium reserves in bone, fromwhich calcium can be releasedinto the bloodstream during preg-nancy and lactation to serve theneeds of the fetus and newborn.The sharp reduction in estrogenthat occurs with menopause caus-es a loss of bone, he suggested,by enabling more bone to be bro-ken down than is subsequentlybuilt up. Women whose skeletonslong outlive the functioning oftheir ovaries often reach the pointof having too little bone, whichmakes them susceptible to bone

Studies have shown that women with osteoporosis tend to consume less calcium than women without the disorder,and that they absorb it less efficiently from the foods they eat. But there have been conflicting findings as to whethera greater calcium intake is linked to an increase in bone mass or bone density or a decrease in fractures. Becausemost studies show a positive relationship between increased calcium intake and bone health, the National Academyof Sciences in 1997 boosted the amount of daily calcium intake recommended for post-menopausal women.

Research reveals that a woman’s bone mass peaks at about age thirty, after which more bone is lost than formed. Aswith money in a retirement account, the more bone deposited in the “bone bank” before age thirty, the more that willremain later in life. Studies indicate that adolescent girls and young women often do not have adequate amounts ofcalcium in their diets, and thus may not build as much bone as possible. However, researchers have shown that ifgrowing girls increase their calcium intake they are more likely to build denser bones. Such increased bone densityshould theoretically translate into less susceptibility to bone fractures in later years.

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fractures. Albright named theresulting condition post-menopausal osteoporosis. He wasthe first to suggest that loss ofbone was what caused the painfulfractures and spinal collapse thatwere driving older women to theclinic in droves.

To support his hypothesis,Albright cited his laboratoryfindings, which showed that post-menopausal women excrete morecalcium and phosphate—themajor components of bone min-eral—in their urine, blood, andstools than they consume in theirdiet. He also showed that regularinjections of estrogen reversedthis calcium imbalance, boostingthe amount of calcium retained inthe body, presumably in thebones.

Not only did Albright identify anew disease, postmenopausalosteoporosis, but he also offeredthe first treatment for the condi-tion. Numerous studies havesince shown the effectiveness ofestrogen replacement therapy atstaving off osteoporosis inwomen. Interestingly, researchershave recently shown that estrogenprevents osteoporosis in men too.

If given to women when theyfirst enter menopause, estrogencan prevent height loss and slashthe chances of breaking a boneby more than half. But estrogentherapy can only prevent damageto the skeleton by stemming boneloss. The hormone cannot replace

lost bone. Consequently, to beeffective, estrogen therapy needsto be started before serious boneloss occurs.

That was easier said than done inthe 1940s. Osteoporosis is calleda silent disease because by thetime it causes symptoms it hasalready extensively damaged theskeleton. Standard X rays can’tdetect the minimal bone loss seenin the early stages of the disease.Albright solved this dilemma bygiving estrogen therapy to allpostmenopausal women whocame to his clinic. But researchshows that only one in four post-menopausal women is likely todevelop severe osteoporosis. Toavoid unnecessary treatment,doctors needed a way to identifythose postmenopausal womenmost prone to severe conse-quences of the disorder.

Fortunately, starting in the1960s, researchers developedmore sensitive devices for detect-ing bone loss, including densito-meters, which can determinebone density by measuringchanges in the absorption ofenergy passing through bones inthe hand, spine, hip, or otherbody part. This technique enablesphysicians to detect osteoporosisin its early stages, well beforefractures occur. Densitometerscan detect as little as a 1 percentchange in bone density betweensuccessive measurements.Ultrasound, magnetic resonanceimaging (MRI), and computer-

ized tomography (CT scans) canalso be used to assess bone densi-ty or bone strength. (See the MRIarticle in the Breakthroughs inBioscience series.)

In addition, basic research hasuncovered several specific com-pounds that are released into thebloodstream or urine when boneis broken down. Doctors can useblood or urine tests for thesecompounds to assess how rapidlybone is being lost and whetherbone loss is due to osteoporosisor another disorder. The testsguide a doctor’s choice of therapyand can help determine whether atreatment is effective.

The end result of these new testsand imaging tools is that nowdoctors can, as part of routinecheckups, assess whether post-menopausal women are losingsignificant amounts of bone dueto osteoporosis. If this is the case,doctors can begin treatmentbefore the disease robs the bonesof minerals and makes themprone to fractures.

Although estrogen is a highlyeffective treatment for post-menopausal osteoporosis, it is notright for every woman. It cancause side effects such as breasttenderness and vaginal bleedingthat some women find intolera-ble. And because some studieshave linked estrogen therapy toan increased risk of breast cancer,women with a family history ofsuch cancers may not be ideal

Several studies have found that premenopausal women, particularly those younger than thirty, can also stem their riskof developing osteoporosis through regular weight-bearing exercise such as jogging, walking, or tennis. Such exercisebuilds more massive bones, and evidence suggests that even small increases in peak bone mass translate into a signif-icantly reduced risk of fracture later in life.

There is conflicting evidence on whether exercise by postmenopausal women significantly reduces their risk of devel-oping osteoporosis. What is certain is that bed rest and other situations that strongly hamper a woman’s mobilityincrease her risk of developing the disease.

Findings by both epidemiologists and basic scientists also suggest that a woman can stem her chances of developing

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candidates for estrogen therapy.

But thanks to the striking find-ings of researchers conductingexperiments on mice and rats inthe 1960s, women can now lowertheir risk of developing bothosteoporosis and breast cancer.The researchers were searchingfor an anti-estrogen drug thatcould be used to prevent or treatbreast cancer, which may be fos-tered by exposure to estrogen.They tested a novel compound onrodents to assess how well itcountered the effects of estrogenin the body, and found that thecompound did indeed stem thegrowth of breast tumors but, sur-prisingly, it could also triggercells in the uterus to divide. Thediscovery that a compound couldhave anti-estrogen effects in onepart of the body (the breast) andsimultaneously have estrogen-likeeffects in another part (theuterus) led other researchers todevelop what are known as selec-tive estrogen receptor modulator(SERM) drugs.

One of these drugs, raloxifene(Evista), has been on the marketsince 1998 to prevent post-menopausal osteoporosis.Although it does not preservebone density as much as estrogendoes, studies indicate that it canstem the risk of fractures in thespine by as much as 45 percent.Raloxifene does not cause vagi-nal bleeding and, most important,preliminary results indicate that itmay also dramatically reduce

women’s risk of breast cancer,slashing the risk by as much asthree-quarters.

The ins and outs of calcium

Four drugs other than estrogenand raloxifene have also proveneffective for postmenopausalosteoporosis, and several othersare on the horizon. The discover-ies that led to the development ofthese drugs were not made byresearchers searching for anosteoporosis cure, but rather byscientists curious about what con-trols muscle contractions, whyabnormalities in certain glandsaffect the strength of bones andteeth, and why cows experiencemalnutrition on some diets.

In 1900, a Rockefeller Universitybiologist wondered what wouldhappen if he changed the compo-sition of an animal’s body fluids.He found that when he took amuscle from a living frog and putit in a solution of water and tablesalt, the muscle contracted rhyth-mically. But when he added calci-um, the muscle stopped contract-ing. He concluded that calcium inthe blood prevents our musclesfrom continuously twitching.

At about the same time,Albright’s mentor, the Viennesepathologist Jacob Erdheim, notedthat the parathyroid glands—pea-sized glands in the neck—were

enlarged in three patients with acondition known as osteomalacia.In this condition, the bones aresoftened because they lack ade-quate calcium and phosphorus.Always trying to find the causeof the abnormalities he observed,Erdheim conducted a series ofexperiments and showed in 1906that when he removed theparathyroid glands in rats, theirteeth lost calcium. These findingssuggested that the parathyroidsmight affect the amount of calci-um lodged in the skeleton.

Building on those findings, in1909 a pathologist and chemistresearch duo at Johns HopkinsUniversity in Baltimore showedthat when they removed theparathyroids from dogs the ani-mals began to convulse. But ifthey gave these same animals cal-cium salts, the convulsionsstopped.

These experiments strongly indi-cated that the parathyroid glandsplay a role in governing the fluxof calcium in the body, andlaunched a quest by scientists topinpoint the compound secretedby the parathyroids that has thisaction. One of these scientistswas Adolph Hanson, a small-town doctor from Minnesota whoconducted his experiments in amakeshift lab in the basement ofhis home. Hanson reported in1923 that, using cattle parathy-roid glands he had collected froma slaughterhouse, he had isolatedthe active compound from the

osteoporosis if she refrains from smoking or consuming large amounts of alcohol on a regular basis. Investigatorshave found evidence suggesting that cigarette smoking lowers levels of estrogen in the bloodstream, interferes withcalcium absorption, and inhibits the growth of bone-building osteoblasts. They have also shown that alcohol inhibitsthe absorption of calcium in the intestines and the activation of vitamin D.

The end result of all this research on risk factors for postmenopausal osteoporosis is that women now have strategiesfor reducing their chances of developing the disorder, particularly if they implement those strategies early in life.Indeed, osteoporosis has been described as an adolescent disease with a geriatric onset, highlighting the importanceof beginning to take steps early in life, through exercise and diet, to reduce its disabling impact in later years.

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parathyroids that can prevent theconvulsions that occur whenthese glands are removed fromdogs. The renowned Canadianbiochemist James B. Collip inde-pendently isolated the sameactive extract in 1925 and showedthat it boosted the level of calci-um in the blood. These extractswere then purified and the activecompound was named parathy-roid hormone. This work led tothe hypothesis that when bloodlevels of calcium are low,parathyroid hormone stimulatesbones to release calcium into thebloodstream. It is now knownthat calcium is a vital mineral inthe body that not only plays a keyrole in muscle contraction,including heartbeat, but also isessential for nerve transmission,blood clotting, and other func-tions. To work properly, the bodymust keep the blood level of cal-cium within a narrow range.When the blood supply of thismineral drops too low, parathy-roid hormone fosters its replen-ishment by triggering the bonesto release calcium into the blood-stream (fig. 4). The skeleton isthe storehouse for the body’s cal-cium; of the two to four poundsof calcium in the body, more than99 percent is in the teeth andbones.

The parathyroids also boost bloodsupplies of calcium by increasingthe amount of this mineral that isabsorbed from the intestines anddecreasing the amount that ispassed in the urine. Although reg-ular large doses of parathyroidhormone foster bone resorption,researchers in the 1930s discov-ered that when they regularlygave rats small doses of this hor-mone, bone formation actuallyincreased. Recent tests of thisapproach in postmenopausalwomen have shown that itprompts impressive gains in bone

density and substantially lowersthe risk of fractures. Althougheasier means of delivering thehormone (for example, via nose

sprays or inhalants rather thaninjections) and additional safetytests are needed, parathyroid hor-mone holds substantial promise

1770s—John Hunter discovers that as new bone is formed, old bone is destroyed (resorbed).1922—Elmer McCollum discovers vitamin D.

1923-1925—Parathyroid hormone is independently isolatedby Adolph Hanson and James Collip and shown to boost levels of calcium in the blood.

1930s—Hans Selye shows that small doses of parathyroid hormone foster bone formation in rats.

1930s and 1940s—Fuller Albright defines postmenopausal osteoporosis and begins treating women with the condition with estrogen.

1960s—Herbert Fleisch discovers compounds known as bis-phosphonates, which inhibit bone resorption.

1960s—Researchers discover that compounds known as selective estrogen receptor modulators (SERMs ) can simultaneously block breast tumors and trigger the growth of uterine cells.

1970s—Researchers discover that osteoclasts and white blood cells come from the same parent cells in the bone marrow.

1970s—Researchers discover compounds called cytokines, which are generated by white blood cells and influence the cells’ own development and activity.

1980s and 1990s—Researchers discover cytokines that influence the development and activity of osteoclasts.

1990s—The bisphosphonates alendronate and risedronate enter the market as anti-osteoporosis drugs.

1990s—Researchers discover some of the molecules that enable osteoclasts to break down bone.

1990s—Researchers uncover growth factors and other compounds that stimulate the production and activity of osteoblasts.

1998—The selective estrogen receptor modulator drug raloxifene enters the market as a drug to treat and prevent postmenopausal osteoporosis.

Photos courtesy of the National Library of Medicine

ElmerMcCollum

John Hunter

FullerAlbright

T I M E L I N E

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as a drug that can prompt boneformation in women sufferingfrom postmenopausal osteoporosis.

New drugs for osteoporosis accidentally discoveredIn the 1960s, a Swiss physiolo-gist by the name of HerbertFleisch wanted to know exactlywhat causes calcium to bedeposited in or removed frombone. Through his experiments,he identified a new compound inhuman blood and urine that pre-vented the formation of calciumsalts in laboratory experiments.The compound, a pyrophosphate,was remarkably similar to com-pounds that have been used forover a century to prevent thebuildup of scale (calciumdeposits) in water boilers.Curious as to how this compoundoperated, Fleisch conducted aseries of experiments that led him

to discover that thepyrophosphate avidlylatches onto calcium(one of the principalcomponents in bone).This finding suggestedthat the compoundcould affect the flowof calcium into and outof the skeleton.

Fleisch was quick tosee the potential use-fulness of pyrophos-phates in treating vari-ous bone disorders,including osteoporosis.But pyrophosphatesare quickly brokendown in the body, soFleisch worked withpharmaceutical com-panies to developlonger-lasting synthet-ic versions of the com-pound he had discov-

ered. Some of these pyrophos-phate-mimicking drugs, known asbisphosphonates, were shown tosuppress bone resorption, appar-ently by inhibiting the capacity ofosteoclasts to break down bone.Two of these drugs, alendronate(Fosamax) and risedronate(Actonel), have been on the mar-ket since 1996 and 2000, respec-tively, as treatments for post-menopausal osteoporosis. Studiesshow that these drugs can cut therisk of bone fracture nearly inhalf in women with the disorder.

ABCs and Dsof nutritionAnother compound used to pre-vent and treat postmenopausalosteoporosis was discovered by aresearcher bent on uncoveringwhy cows were failing to thrivewhen fed certain diets. In 1907,biochemist Elmer McCollumcame to the University ofWisconsin to study what causes

the malnutrition seen in cows fedsingle- grain diets—only corn,only wheat, or only oats.Something vital was missing fromthese animals’ diets, andMcCollum set out to find outwhat it was by conducting a seriesof experiments in rats.

McCollum reasoned that ratswould be easier to work with thancows because they had a shorterlife span. The small animals alsoate little, so they required lessresources during an experiment.But because of the vigorousobjections of his superiors, whothought rats were farm pests notworthy of experimentation,McCollum was unable to getfunding for his research. He hadto use his own resources to sup-port a series of experiments inwhich he systematically supple-mented the rats’ single-grain dietswith various foods to see whichfoods could counter the malnutri-tion these animals experienced.From these experiments he dis-covered vitamin A. His successalso established the much-maligned rat as a useful animalmodel for nutrition studies.

At the time, children often suf-fered from a bone-deforming dis-ease known as rickets, andresearchers had shown that codliver oil could prevent the disease.To determine whether vitamin Ain cod liver oil was responsiblefor this effect, McCollumdestroyed the vitamin A in a sam-ple of the oil and then fed the oilto rats. The animals did not devel-op rickets, suggesting that anothervitamin besides vitamin A lurkedin cod liver oil. McCollum calledthis essential nutrient vitamin D.

McCollum’s findings, which hereported in 1922, triggered a flur-ry of basic research aimed at pin-pointing the chemical structure ofvitamin D and its active forms as

Low concentration of calcium in blood

Increased concentration of calcium in blood

Release of parathyroid hormone

Release of calciumfrom bone to the blood

Decreased loss ofcalcium in urine

Enhanced absorption ofcalcium from intestines

Vitamin Dkidney

Figure Low concentrations of calcium in the bloodstream trigger the release of parathyroid hormone Thishormone boosts calcium levels in blood by promptingbones to release some of their calcium stores into theblood and by inducing the kidneys to stem the loss of calcium in urine Parathyroid hormone in conjunction withvitamin D activated by bodily exposure to sunlight alsoenhances the absorption of calcium from the intestinesDesigned by Corporate Press

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well as the role vitamin D playsin the body. These investigationsrevealed that vitamin D is a hor-mone activated by sunlight.Vitamin D boosts calcium levelsin the body by fostering the abili-ty of intestines to absorb calciumfrom the diet. A lack of vitaminD triggers a cascade of reactionsresulting in increased boneresorption.

Once this basic research hadrevealed the nature of vitamin D,clinical researchers began toyingwith the idea that the compoundmight prove beneficial to womensuffering from postmenopausalosteoporosis. The elderly, in gen-eral, tend to be prone to vitaminD deficiency, studies show. Somestudies also show that dietarysupplements of vitamin D andcalcium given to elderly womencan reduce their risk of hip frac-ture. For these reasons, doctorsoften prescribe vitamin D supple-ments to women with post-menopausal osteoporosis, espe-cially elderly women not exposedto much sun.

Explosion ofresearchThe repertoire of drugs doctorshave at their disposal to preventor treat osteoporosis is likely toexpand greatly in the near futureas a result of the explosion inbasic research on bone biologythat has been fostered by theavailability of a variety of newresearch tools. These tools, whichinclude antibodies designed toseek out and bind to specific pro-teins, genetic probes, cell culturesof osteoblasts and osteoclasts,and rodents whose ovaries havebeen removed as well as geneti-cally engineered animal models,have enabled researchers to fine-tune their explorations of whatexactly controls bone remodeling.Hormones such as estrogen,

parathyroid hormone, and vita-min D may be the kingpins inbone remodeling, but they cannotaffect this process without the aidof other molecules that operate inthe vicinity of bone to control itsresorption or formation.

But what are those molecules?Insight into this mystery came inthe 1960s, from researchers atCornell and Harvard Universitieswho were conducting basicanatomy studies on the newt.These scientists used radioactivetracers to show that cells thatbecome bone-eating osteoclastsstart out as white blood cells inthe bone marrow. Building onthis finding, Donald Walker ofJohns Hopkins University inBaltimore showed in the 1970sthat he could cure mice of a bonedisease caused by faulty osteo-

clasts by giving them bone mar-row transplants. Apparentlyosteoclasts that developed fromthe bone marrow restored boneresorption in these animals. Thisindicated that in mice the osteo-clast shares its origins with whiteblood cells; they both developfrom parent cells in the bonemarrow. Shortly after Walker’sdiscovery, other researchersfound that human osteoclasts alsooriginate from marrow cells.

At the time these discoverieswere made, other basicresearchers discovered that cellsof the immune system (whichinclude white blood cells andtheir parent cells) secrete a vari-ety of substances, calledcytokines, that influence thesecells’ own development andactivity. Could these same

C.

A.

B.

white blood cells

cytokines

osteoclastosteoblast

integrins

BONE

BONE

Figure In addition to circulating hormones a number of factorscontrol bone resorption Cytokines propel white blood cells (A) to fusetogether and develop into osteoclasts The integrin proteins that jut outfrom the surface of the osteoclast anchor the cell to bone (B) Onceanchored acids and enzymes released by the osteoclast dissolve a cavity in bone (C) Designed by Corporate Press

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cytokines also be influencing thedevelopment and activity ofosteoclasts?

A number of investigators set outto answer this question and dis-covered that several cytokines doindeed propel immature whiteblood cells to become bone-eat-ing osteoclasts (fig. 5). One ofthese cytokines also increases thelife span of each osteoclastformed. Other researchersshowed that estrogen plays amajor role in reining in the pro-duction of these cytokines, whichexplains why postmenopausalwomen, who lack the hormone,have elevated numbers of osteo-clasts. This population explosionof long-lived osteoclasts tips thebalance away from bone forma-tion and toward bone resorptionsuch that more bone is lost thanformed.

The discovery of cytokines thatpromote bone resorption offersnew targets for anti-osteoporosisdrugs, which researchers areavidly pursuing. Investigators arealso dissecting the biochemical

pathways that these cytokinesinfluence, and have uncoveredseveral key compounds that couldalso serve as drug targets.Another recently discovered ther-apeutic target is the molecule thatanchors osteoclasts to bone. Suchanchoring is a necessary firststep in bone resorption, so drugsthat can prevent anchoring maybe effective anti-osteoporosisdrugs of the future.

Researchers are also beginning touncover some of the compoundsthat stimulate the production andactivity of bone-formingosteoblasts. This research offersthe possibility that, in the future,doctors will be able to use drugsto restore and not just preventbone loss. Although parathyroidhormone, a compound known toprompt bone formation, is likelyto be used as an osteoporosisdrug in the near future, all thedrugs currently used to treatosteoporosis work by stemmingbone resorption.

Even without these potential newdrugs to counter postmenopausal

osteoporosis, the disorder hasalready undergone a remarkabletransformation from an acceptedand inevitable consequence of awoman’s aging to a preventableand treatable disease. All of thiswould not have been possiblewithout the efforts of a cadre ofresearchers over the past 250years from fields as disparate asanatomy, biochemistry, pathology,and physiology. These investiga-tors pursued such basic questionsas, how does bone grow, whatrole does estrogen play in boneremodeling and in breast cancer,how does the body maintain itsdelicate calcium balance, why aresome diets insufficient, and whatcells give rise to osteoclasts?Without the curiosity of these sci-entists fueling basic insights intobone biology, drugs for osteo-porosis would never have beendiscovered—and many womenwould continue to have no optionbut to enter their golden yearsstooped over and in pain.

BiographiesMargie Patlak writes about biomedical research and health from the Philadelphiaregion. She has written for Discover, Glamour, Physician’s Weekly, Consumer Reports onHealth, The Washington Post, the Los Angeles Times, the Dallas Morning News, andnumerous other publications. She also writes frequently for the National Institutes ofHealth and the National Academy of Sciences.

Steven L. Teitelbaum, M.D., is the Wilma and Roswell Messing Professor ofPathology at Washington University School of Medicine and a Past-President of theAmerican Society for Bone and Mineral Research.

ReferencesGordan, G.S. 1981. Fuller Albright and postmenopausal osteoporosis: A personal appreci-ation. Perspectives in Biology and Medicine: 24:547-560.

Kalu, D.N. 1995. Evolution of the pathogenesis of postmenopausal bone loss. Bone 17(Supplement 1):135S-144S. Li, Alison. 1992. J.B. Collip, A.M. Hanson, and the isolation of the parathyroid hormone,or endocrines and enterprise. Journal of the History of Medicine and Allied Sciences 47:405-438.

Manolagas, S.C. 2000. Birth and death of bone cells: Basic regulatory mechanisms andimplications for the pathogenesis and treatment of osteoporosis. Endocrine Reviews21:115-137.

Murray, C.M. 1997. Control mechanisms in bone resorption: 240 years after John Hunter.Am R Coll Surg Engl 79:20-27.

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