63 Conferences and Reviews Overview of Osteoporosis B. LAWRENCE RIGGS, MD, Rochester, Minnesota Osteoporosis is defined as an absolute decrease in the boneandperhaps5to 10yearsearlierfortrabecularboneand amount ofbone to a level below that required for me- continuesintoextremeoldage.13 Therateofslowboneloss chanicalsupportor, asFullerAlbrightsuccinctlyputitmany duetothisprocessprobablyissimilarinmenandwomenand years ago, "There is too little bone" (Figure 1). The bone results in losses ofsimilar amounts ofcortical bone and of that is present is normal chemically and histologically. trabecular bone.1 3'5 In women, a third process, a transient acceleratedpostmenopausal phaseofbonelossduetoestro- Epidemiology gen deficiency, is superimposed on the slow phase ofbone Osteoporosis is a major public health problem"2 In the lossandresultsinlossofdisproportionately moretrabecular United States, about 1.5 million fractures are attributable bonethan ofcortical bone.1'367' The amount ofbone that is to osteoporosis each year. The sites of these fractures are lost over life with each ofthese phases is not well defined. the vertebrae (650,000), the hip (250,000), the distal fore- However, a reasonable estimate is that the slow phase pro- arm (Colles' fracture, 200,000), and other skeletal sites ducesalossofabout25% fromthecorticalcompartmentand (400,000).Onethirdofwomenoverage65atsometimewill about 25% from the trabecular compartment in both sexes. suffervertebral fractures; thelifetime riskforhipfracturein During the accelerated phase, postmenopausal women lose whitewomen, 15%,approximatesthatofthecombinedrisks an additional 10% from the cortical compartment and 25% ofbreast, endometrial, andovariancancer. Thelifetime risk fromthetrabecularcompartment. Thus,overall,womenlose ofhip fracture in men, 5%, approximates thatofthe riskof about 35% of cortical bone and 50% of trabecular bone prostatecancer. Thedirectandindirectcostsofosteoporosis during their lifetime, whereas men lose about two thirds of in the United States have been estimated to be $7 billion to these amounts.5 8 $10 billion annually. Much of this expense relates to hip Age-Related Changes inBoneRemodeling. Bone forma- fracture. This catastrophic type ofinjury is fatal in 12% to tion andbone resorption occurat anatomically discrete foci 20% ofcases. Halfofthesurvivors areunabletowalkunas- called bone remodeling units.1 4 At the beginning of each sisted, and 25% are confined tolong-term care in a nursing remodeling cycle, through a mechanism yet to be defined, home. flattened lining cells are activated and retract to expose the underlying bone.9 Osteoclastprecursor cells in marrow are Pathophysiology recruitedandmigratetotheexposedareaofbone. Thesefuse Age-Related Bone Loss. It is convenient to divide the to form osteoclasts and, over a period of 1 to 3 weeks, the skeleton into two compartments consisting ofcortical bone osteoclastsconstructatunnelincorticalboneoralacunaon and trabecular bone. Cortical bone predominates in the the surface of trabecular bone. The osteoclasts disappear shafts oflong bones; trabecular bone is concentrated in the during a reversal phase and are replaced by osteoblasts, vertebrae, inthepelvisandotherflatbones, andattheendof whichthenfillintheresorptioncavityoveraperiodof3to4 long bones. Trabecular bone is metabolically much more months to create a new structural unit ofbone (Figure 3). active than cortical bone, probably because of its greater The maindeterminantofthe rate ofboneturnover is the surface area, and is more responsive to changes in mineral frequency ofactivation ofnew bone remodeling units.4"0 In homeostasis. normal young adults, the processes ofbone resorption and Three distinct phases ofchanges inbone mass over life bone formation are tightly coupled so that bone balance is canberecognized, twoofwhichoccurinboth sexesandone maintained.However,duringage-relatedboneloss,thereisa thirdofwhichoccurs only inwomen3'4 (Figure2). The first remodelingimbalancewitharelativeorabsoluteincreasein processleadstoattainmentofpeakbonemassandrepresents resorption over formation.4" 0 Because ofthis imbalance at the summation ofgrowth (90% to 95%) and consolidation each bone remodeling unit, an increase in bone turnover (5% to 10%).4 Peak bone mass is attained both by linear (i.e., an increase in the number ofbone remodeling units) growth due to mineralization of the endochondrial growth leads to increased bone loss. platesandbyradialgrowthduetoarateofperiostealapposi- Theslowandacceleratedphases ofbone loss areassoci- tionthatexceedsthatforendosteal resorption. Afterclosure ated with two different abnormalities of bone remodeling ofthegrowthplateaboutage20,theradialgrowthcontinues (Figure4). Intheslow, age-dependentphase,theosteoclasts for another 10to 15 years. construct resorption cavities of normal depth, or even de- The second process consists of a slow, age-dependent creased depth, but the osteoblasts fail to refill them com- phase ofbone loss. This begins around age 40 for cortical pletely.1'4'5Thisleadstoagradualthinningofthetrabeculae, (RiggsBL: Overviewofosteoporosis. WestJ Med 1991 Jan; 154:63-77) MayoClinicandMayoMedicalSchool,Rochester. DrRiggsisConsultant,DivisionofEndocrinologyandMetabolism,MayoClinic,andPurvisandRobertaTaborProfessorofMedicalResearch,MayoMedicalSchool,Rochester, MN55905. This work has been previously published as an update to the CECIL TEXTBOOK OF MEDICINE, WB Saunders, Philadelphia, Pennsylvania, and sponsored by Key Pharmaceuticals,makersofNORMODYNE(labetalolHCI)tablets. ReprintrequeststoB. LawrenceRiggs,MD,DepartmentofMedicine,MayoClinic,Rochester,MN55905. 64 OVERVIEWOFOSTEOPOROSIS but their connectivity is maintained.1 In contrast, the ac- whenanexponential increaseleads toavery high incidence celerated, postmenopausal phase ofbone loss is associated offracture. Fracturesoftheshaftsofthelimbbone, whichis with a high rate of bone turnover; there is an increase in predominantly corticalbone, donotincreasewithagingand osteoclast number and the osteoclasts create a resorption often are associated with severe trauma; therefore, they do cavityofincreaseddepth (Figure4). Theseprocessesleadto not seem to be directly related to osteoporosis. trabecular perforation and loss ofstructural trabeculae and trabecular connectivity. Etiology Age-RelatedFractures. Whentheincidenceoffracturesis The modernconcept is that osteoporosis is amultifacto- plottedasafunctionofage, twodistinctpatternsemerge.'12 rial disorder. Figure 6 gives a model forthe main groups of (Figure 5). The first pattern involves fractures at sites con- these factors and how they interact. The morbid event in taining large amounts oftrabecular bone, such as the distal osteoporosis is fracture. This results fromtheinteraction of forearm (Colles' fracture) and vertebrae. These fractures lowbonedensity andtrauma. Lowbonedensity laterin life increase in women soon after menopause; for Colles' frac- canoccurbecausetheamountofpeakbonemassachievedby ture, theincidencecontinuestoincreaseuntilage65 whenit young adulthood is inadequate or because there is an in- reaches a plateau, whereas the incidence ofvertebral frac- creasedrateofboneloss. The majorgroupsoffactors caus- tures continues to rise. The second pattern involves sites ingincreasedbonelosscanbesubsumedunderthecategories containing similar amounts ofcortical and trabecularbone. ofaging, menopause, localfactors regulatingboneturnover, Althoughthemostimportantfractureofthistypeinvolvesthe and sporadic factors occurring in some but not other mem- hip, asimilarpatternisfollowedbyfracturesoftheproximal bers ofthe population. humerus, proximaltibia, andpelvis. The incidence ofthese fractures increases quite slowly with aging until late in life, LowBone Density A decrease in bone mass clearly is the most important cause of fractures in osteoporosis. Eighty per cent of the variance incompressive strength ofthe trabecularbone and 90% ofthat in cortical bonecan be accounted forby differ- ences in bone density.3 In the absence of severe trauma, fracturesdonotoccuruntilbonedensityhasfallenbelowthe 1. QUIESCENCE 2. ACTIVATION Figure 1.-Transverse and coronal sections or vertebrae from normal and osteoporoticsubjects.(From RiggsBL:Osteoporosis. InDeGrootUetal(Eds): 3.RESORPTION Textbook of Endocrinology. 2nd Ed. Philadelphia, W. B. Saunders Company, 1989, pp 1188-1207.) 1,500 (f 4. REVERSAL .E _.f OB C I ' 1,000 1 5. FORMATION 0) CD' co C6 I 0 6. QUIESCENCE m 0 0 0 20 40 60 80 100 OLD BONE Age, yr Figure3.-Illustrationofthedifferentstagesofboneremodeling.Seetextfor Figure2.-Changesin bonemasswith growth andaging in men and women details. (From ParfittAM: Bone remodeling: Relationship tothe amountand showingthreedistinctphases.Seetextfordetails.(FromRiggsBL:Involutional structureofbone,andthepathogenesisand prevention offractures. InRiggs osteoporosis. In Williams TF, Evans JG (Eds): Oxford Textbook of Geriatric BL, Melton U (Eds): Osteoporosis: Etiology, Diagnosis, and Management. III Medicine. London,Oxford UniversityPress, in press.) NewYork, Raven Press, 1988, pp45-94.) THTEWEWSTERENHJJOSURNOATLUOFOEEMREMDIECRNINDEFAINCo*LIJJAANNNUUEAARRYY 11999911 *, 115544 *o 11 6655~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ values found in young adults.' This fracture threshold has fracturesincreases. Thus,thelowerthelevelofbonedensity, beenempirically setatabout 1.0gmpersqcmfortheverte- thegreatertheriskoffracture. Theseincreases,however,are brae, 1.0gmpersqcm fortheproximal femur, and0.4 gm not linear, which suggests that osteoporosis may lead to per sq cm for the ultradistal radius."3,4 With further de- qualitative changes in bone that may weaken the skeleton. creases in bone density below the fracture threshold, the Possible qualitative changes include loss of structural ele- incidence ofhip fractures, vertebral fractures, and Colles' ments andtrabecularconnectivity, accumulation oftrabecu- larmicrofractures, and, in someelderly subjects, histologic NORMAL-FOCAL osteomalacia.15 BONE BALANCE Trauma Thepropensityoftheelderlytofallisanindependentrisk OSTEC)BLAST- MEDIATED factorforfractures.16,17Themostcommoncauseoffractures BONE LOSS 7 amongelderlypersonsisasimplefallfromastandingheight orless, althoughafewhipfracturesmaybespontaneousand OSTEC'CLAST- vertebral fractures oftenresultfromlifting orstraining. The MEDIATED riskoffalling increases with aging, and at least one third of BON LOSS O B n community-dwelling elderly persons fall at least once each Old Bone =Z New Bone rE year. Fallsaremorefrequentintheelderlybecauseoffailing Figure4.-Two mechanismsforremodeling imbalance in trabecularbone. In vision, neurologic diseases andtheir sequelae orarthritisof healthyyoungadults(upperpanel),theosteoblasts completely refill the re- the lower limb joints, and the use of sedatives and other sorption cavityconstructed bythe osteoclasts. In osteoclast-mediated bone drugs. loss (middle panel), a resorption cavity ofexcessive depth isshown that is Also, theelderly have increasedtrauma in their falls be- incompletelyrefilledbyanormalamountofnewbone.Inosteoblast-mediated bone loss(lowerpanel),there isa resorption cavityofnormal depth that is causeimpairedcoordinationandslowedreflexesreducetheir incompletely filled by a subnormal amount ofnew bone. (From Parfitt AM: ability to breakthe impact ofa fall. In addition, the type of Boneremodeling:Relationshiptotheamountandstructureofbone,andthe fall may determine the site offracture."718 Forward falls in pathogenesis and prevention of fractures, In Riggs BL, Melton U Ill (Eds): which the impact is broken by the outstretched hands are Osteoporosis: Etiology, Diagnosis, and Management. New York, Raven Press, morelikelytoresultindistalforearm(Colles') fracture, and 1988, pp45-94.) abackward fall landing on thebuttocks orwithalateral fall landingonthehiparemorelikelytoresultinproximalfemur fracture. Although the elderly fall frequently, only 6% of their falls result in fracture.'9 Inadequate PeakBoneMass Insufficientaccumulation ofboneduring skeletalgrowth andconsolidationpredisposestofractureslaterinlifeasage- relatedbonelossensues. Differencesinpeakbonemassmay explain inpartracial andsexualdifferences inthe incidence Black rC Whi$ Figure5.-Thetwomajorage-related fracture patterns, asillustrated bythe incidenceofColles'fractureand hipfracture asafunction ofagein women residing in Rochester, MN. (From Riggs BL, Melton U IlIl: Evidence for two (j) distinctsyndromes ofinvolutional osteoporosis.AmJ Med 1983;75:899.) 1) -o 0 co Level of fracture 0 20 40 60 80 Age in years Figure7.-Effectofsexandraceonpeakbonemasscanexplainsusceptibility to osteoporosis as age-related bone lossensues. Individual values about re- gression lines(forwhitewomenthisisgiven byatop-shapedfigure).Thus,a whitewoman inthe lowerpartofthe normal distribution inyoung adultlife wouldbeatincreasedriskforfractureslaterinlife.(FromRiggsBL:Osteoporo- Figure6.-Modelforetiologyofosteoporosisshowingvariousgroupsoffac- sWisB,ISnaDuenGdreorostCUo,mpeatnayl,(E1ds9)8:9,Tepxptb1o1o8k8o-f12E0n7d.o)crinology, 2ndEd.Philadelphia, torscausing fractures and theirinteraction. 66 OVERVIEWOFOSTEOPOROSIS 66 OVERVIEW OFOSTEOPOROSIS ofosteoporosis.20 White women have the lightest skeletons [25(OH)D] lat-hydroxylase, which is responsible for the and black men have the heaviest; white men and black conversion of25(OH)D to 1,25(OH)2D3, is impaired with women have skeletons of intermediate density (Figure 7). aging.34'40Thisabnormalitymayresultfromatrophyofrenal This rankordercorresponds totherankorderfortheoccur- parenchymal tissue with aging and probably decreases the renceoffractures. Women ofshortstatureand northern Eu- productionof1,25(OH)2D3intheelderly, especiallyinthose ropean extraction tend toward a more gracile skeleton and whose glomerular filtration rate is <40 mL per min. This alsohaveanincreased incidenceofosteoporosislaterinlife. late-occurring defect aggravates the impairment in calcium Moreover, iftherateofbonelosswithageisconstant, those absorption caused by intestinal resistance to 1,25(OH)2D3. white womenwiththelowestpeakbone mass areatgreatest risk for fractures later in life2" (Figure 7). 1.8 Although the determinants of differences in peak bone cmE mass among individuals have not been adequately defined, c0 cm two important factors appear to be heredity and the level of .C dietarycalciumconsumptionduringgrowth. Peakbonemass 1.4 has stronggeneticdeterminants, andstudies inmonozygotic and dizygotic twins have found a heritability index ofabout 0 0.8522.23 (Figure 8). This may explain the trend for familial aggregation ofosteoporosis.24 It is obvious that insufficient 3: 1.0 " calciumintakewillberatelimitingforaccumulationofskele- n tal mass; this is consistent with epidemiologic findings.25 E -j IncreasedBoneLoss 0.6 Age-RelatedFactors. By farthe mostpowerful predictor co A ofbonemassinagivenindividual isage. Forexample, ifthe 1.8 age ofa healthy woman is known, the bone density ofher cEm lumbar spine or femoral neck can be predicted with a stan- m C.) darddeviationofonly 10%5(Figure9). Thedecreaseinbone C\i 0 density with age probably reflects the aggregate effects ofa C number ofage-related factors. One important factor is decreased osteoblast function. 0 0 Thisabnormality, whichcanbeassessedbymeasurementof m a wall thickness of trabecular packets, begins in middle life andbecomesprogressively moresevereasage increases.4.27 c" 1.0 .0 Although impaired osteoblast function could be caused by E senescence, fracture healing in the elderly is not delayed, -j indicatingthatosteoblastsdorespondtoappropriatestimuli. More likely, the regulation ofosteoblastactivity is impaired byalteredproductionofsystemicorlocalgrowthfactors. For 0.6 1.0 1.4 example, circulating levels ofgrowth hormone and insulin- B Lumbar BMD twin 1-g/cm2 likegrowthfactorI(IGF-I,somatomedinC),whichmediates the effect of growth hormone in bone and cartilage, both Figure8.-Relationshipbetweendensityoflumbarspinein monozygous(up- decreasebyalmostonehalfwithaging.27'28 Moreover, bone perpanel)anddizygous(lowerpanel)twin pairs. Diagonal representslineof cellssynthesizeandrespondtoanumberofregulatorsofcell identity.Notethatagreementismuchbetterforthemonozygoustwins.(From PocockNA,etal:Geneticdeterminantsofbonemassinadults.Atwinstudy.J proliferation-especially IGF-I, IGF-II, and transforming Clin Invest 1987; 80:706.) growthfactor,.29.30Theproductionoforresponsetooneor more ofthese growth factors could decrease with aging. A second age-related factor is a decrease in intestinal 1.6 g LUMBAR SPINE transportofcalciumwhichoccurs inbothsexes,particularly afterage 7031.32 (Figure 10). The main regulatorofcalcium absorption is the physiologically active metabolite of vita- E4' 01..28 _ N0*a minD, 1,25-dihydroxyvitamin D [1,25(OH)2D3]. Bothade- creaseintheresponsiveness oftheintestineto 1,25(OH)2D3 mD 0.40 and a decrease in the production rate of 1,25(OH)2D3 may contribute to the decrease in calcium absorption. Although available data are conflicting, the largest study showed that serum 1,25(OH)2D3concentrationincreaseduntilage65and C0.O4 thendecreased.33Anincreaseinserum 1,25(OH)2D3associ- atedwithaconcomitantdecreaseincalciumabsorptionsug- 20 40 60 80 gests a primary impairment in intestinal responsivess to Age, yr 1,25(OH)2D3 action. In experimental animals, the concen- tration of 1,25(OH)2D3 receptors inboth intestine and bone Figure9.-Relationship between ageand densityofthe lumbarspine in 105 normal women. (From Riggs BL, et al: Differential changes in bone mineral cells decreases with aging. density of the appendicular and axial skeleton with aging: Relationship to The activity of the renal enzyme 25-hydroxyvitamin D spinal osteoporosis.J Clin Invest 1981; 67:328.) THEWESTERNJOURNALOFMEDICINE * JANUARY 1991 * 154 * 1 67 Thus, because they absorb calcium pooirly, elderly indi- resorption and formation due to impaired osteoblast func- viduals should consume more calcium to nnaintain calcium tion, this leads to increased bone loss. balance,butinfacttheyconsumeless.AlthoiughtheRDAfor A third factor is an age-related decrease in serum calciumis800mgperday,therecentNHANESsurveybythe 25(OH)D.4° Aging decreases absorption ofvitamin D from US Public Health Service showedthattwotthirds ofmiddle- the intestine and the dermal synthesis ofvitamin D follow- agedandelderly women surveyedhadanintake ofonly 550 ing solar exposure.4" In addition, many of the elderly are mg per day, and one third had an intake oIf <400 mg per housebound and poorly nourished. A relative or absolute day.32 deficiency of vitamin D could contribute to impaired If the decrease in calcium absorption iin the elderly is calcium absorption and to bone loss. Indeed, about 10% of physiologically important, it should induce a compensatory elderly American patients havingbone biopsy atthetime of secondary hyperparathyroidism and incregased bone loss. orthopedic surgery following hip fracture have histologic There is evidence that both of these event:s occur. Serum osteomalacia.42 immunoreactiveparathyroidhormone(iPTH[)increaseswith Menopause. Surgical menopause accelerates bone loss, aging: increased circulating intact PTH in the elderly has andestrogen replacementprevents orslowsthisloss inboth now been convincingly demonstrated by NH2-terminal- the appendicular and axial skeletons6"6 (Figure 11). Post- specific radioimmunoassay,36 byPTHbioasssay,3" andby im- menopausal administration ofestrogen decreases theoccur- munoradiometric assay (unpublished data). Further, incon- rence of subsequent vertebral or hip fractures by about trast to the older belief that bone turnover decreases with 50%.4 Women who have undergone oophorectomy in aging,dataobtainedwithbiochemicalmarkersforboneturn- youngadulthoodhavelowerbonedensityinlaterlifethando over, such as serum osteocalcin and serunn bone alkaline non-oophorectomized premenopausal women of the same phosphatase,38 and with tetracycline-based bone histo- age.45 Thus, estrogen deficiency atthe menopause is anun- morphometry39 showthat itincreases. The iincrease inbone equivocal cause of bone loss and subsequent fractures in turnoverresults inan increasednumberofb)one remodeling women. Although men do not undergo the equivalent of units, and because of the remodeling imb)alance between menopause, male hypogonadism is often associated with osteoporosis.46 Theacceleratedphaseofpostmenopausal bone loss lasts c 1.2 0 I0 Osteoporosis forabout5to 10years,6butacomponentofbonelossupto20 4 0- 1.0 years after menopause may be related to estrogen defi- o cc ciency.4'Normalhumanbonecellscontainsexsteroidrecep- 0.6 H Normal range tors and respond directly totreatment with these steroids.48 - . Sporadic Factors. A variety ofbehavioral and environ- mental factors may increase the rate ofbone loss in a given c'06 . individual. Smokingandhighalcoholconsumption increase 0.4 H * the risk for developing osteoporosis by twofold, and their I .1% effectsareadditive.49 Ethanol istoxic to osteoblasts.50 Obe- 0.2 c H t sity is protective,49 possibly because of increased loading LL stress tothe spine and, in postmenopausal women, because 0.0 I. * i S ofincreasedconversion(infattissue)ofadrenalandrogensto 2C 40 60 80 100 estrogens. Age, yr Skeletalloadingfromweightbearingandskeletalstresses Figure 10.-Shaded area shows age-adjusted normal ra3nge for calcium ab- frommusclecontractionstimulateosteoblastfunction. Mus- sorption (assessed with45Caand20mgcalcium carrier) inwomen and closed clemassandbonemassaredirectlyrelated.51 Amongamen- circlesindicateosteoporoticwomen. Notethestriking re years.(FromNordinBEC:Clinicalsignificanceandpathog3enesisofosteoporo- sis. BrMedJ 1971; 1:571.) TABLE 1.-Classification ofClinical TypesofOsteoporosis Primaryosteoporosis Bonemarrowdisorders Juvenile Multiple myelomaand Idiopathic(youngadults) relateddisorders Involutional osteoporosis Systemicmastocytosis Disseminated carcinoma Endocrinediseases Hypogonadism Connectivetissuediseases Ovarian agenesis Osteogenesis imperfecta Hyperadrenocorticism Homocystinuria Hyperthyroidism Ehlers-Danlossyndrome Hyperparathyroidism Marfan'ssyndrome Diabetesmellitus(?) Miscellaneouscauses Gastrointestinal diseases Immobilization Subtotalgastrectomy Chronicobstructive pulmonarydisease Malabsorption syndromes Chronicalcoholism Chronicobstructivejaundice Chronicheparin Primarybiliarycirrhosis administration oFoigpuhroerec1t1o.m-yE.ffe(cFtromofLiensdtsraoygeRn, oert apll:acPreebvoenttrieoantmoefntspionnalboosnteeoploorsossiasfteinr ASleavcetraesimaalnutrition Rheumatoidarthritis(t) oophorectomised women. Lancet 1980; 2:1151.) 68 OVERVIEWOFOSTEOPOROSIS orrheic anorexic women, thosewhoare morephysically ac- TABLE 2.-The Two Clinical Typesof tive have denser bones than those who are sedentary.52 InvolutionalOsteoporosis Regular exercise programs retard bone loss in postmeno- pausal women.53 TypeI TypeI/ Nutritional factorsalsomaybeimportant, althoughthere Age,yr........... 51-75 >70 is considerable controversy regarding this. Inadequate cal- Sex ratio, F:M :......:1 2:1 cium intake may be particularly important during skeletal Typeofbone loss.....NlMainlytrabecular Trabecularandcortical growth inobtaining themaximal bonemassand, because of Rateofbone loss..A.c. eilerated Notaccelerated inadequatecalciumabsorption, inmaintainingbonemassin Main fracturesites ... Vrtaenbdradlist(aclrush) Verwteebdrgael a(mnudlthiippl)e theelderly. Inastudy ofoldermenand women, the level of radius(Clles') calcium intake at entry was found to be inversely related to Main causes..... Factorsrelatedto Factorsrelated to. the occurrence of hip fractures when the group was reas- menopause aging sessed after 14 years.54 Nonetheless, a community-based longitudinal study"5 failed to demonstrate a relationship be- salsarecommon. Inseverelyaffectedpatients, theremaybe tween dietary calcium intake and rates ofbone loss. Thus, unilateral or bilateral hip fractures. there is considerable uncertainty whether calcium intake Serum values for calcium, phosphorus, and alkaline pfolraytshomsuecwhitohfaverroylelionwyionutnagkeosr(m<i4d0dl0e-maggepderaddualtys),. except pmhoonsphaantdaseisaraessnoocrimaatle.d Hwyiptehrcanlocrimuarliaviaslureelsatifvoerlysceormu-m Clinical Spectrum 1,25(OH)2D3.5 Bone histomorphometry after tetracycline double labeling has shownboth high andlow boneturnover A classification of the clinical types of osteoporosis is forms. giveninTable 1. Osteoporosiscanbeeitherprimary orsec- ondary, depending ontheabsenceorpresenceofconcurrent Involutional Osteoporosis mkendoiwcnaltodbieseaassseosc,iastuerdgiwciatlh opsrtoecoepdourroesiss,. oSruchmesdeiccoantdiaornsy Involutionalosteoporosiscanbedividedintotwodistinc- causes canbe identified in 20% ofwomen and40% ofmen thiovremsoynnadlrocmheasngoens,thaenbdastisheofredliaftfieornesnhciepsionfctlhienidcailsefaesaeturpeast,- presenting with vertebral fractures' and should always be searched for. ternstoageandmenopause.1,58Thisconceptmayprovehelp- ful in clinical assessment, in examining the pathogenesis of IdiopathicJuvenile Osteoporosis the disease, and in evaluating therapy (Table 2). Arare, self-limitedprimaryformofthediseaseoccursin Type I (Postmenopausal) Osteoporosis. This syndrome boysandgirls, usuallybetweentheagesof8and 14years.56 characteristically affects women within 15 to 20years after Thediseaserunsanacutecourse,usuallyoveraperiodof2to menopause and results from an exaggeration of the post- 4 years, and then remits. During the active phase of the menopausalphaseofacceleratedboneloss. Althoughaclini- disease, thereisgrowtharrestandmultipleaxialandappen- cally similar form ofosteoporosis may occur in men ofthe dicular fractures. The clinical severity ofthe osteoporosis sameage, this may representthe sameprocess diagnosed in runs the spectrum from mild to severe. The most striking younger men as idiopathic osteoporosis but occurring at an feature of the disease is its almost invariable spontaneous older age. Type I osteoporosis is characterized by a dispro- remission with resumption ofnormal linearand radial bone portionate loss oftrabecularbone which results in fractures growth. atskeletalsiteswithahighconcentrationoftrabecularbone, The etiology ofthis condition is obscure. Although the especially in the vertebrae, at the distal forearm (Colles' close relationship ofthe disease to puberty has led some to fracture), and at the distal ankle. The vertebral fractures speculate that hormonal factors are important, there have usuallyarethe "crush" typeandareassociatedwithconsid- beendocumentedcasesofonsetandremissionofthedisease erable deformation and with pain. well before puberty. The rate oftrabecular bone loss in patients with type I Diagnostically, itis importanttoexclude othercauses of osteoporosis is two to four times greater than that ofpost- osteopeniainchildren, includingCushing'ssyndrome, acute menopausal women ofthe same age without fractures, but leukemia, and osteogenesis imperfecta. therateofcorticalbonelossisonly slightlygreater. Thereis somecontroversy regardingthecharacteristics ofboneturn- Idiopathic Osteoporosis in YoungAdults over, whichhas variously been reportedtobehigh, normal, This is much more common than idiopathicjuvenile os- orlowfollowing analysis oftetracycline-labeled iliacbiopsy teoporosis but still is much less frequent than involutional samples. Inalargerecentseriesthatemployedhistomorpho- osteoporosis. Incontrasttoinvolutionalosteoporosis, which metricmethodsallowingtheassessmentofbothboneforma- occurspredominantlyinwomen, idiopathicosteoporosisoc- tionandboneresorptionrate,boneturnoverwasincreasedin curs inboth sexes withequal frequency. Undoubtedly, idio- onethirdofpatientsbutwas normal inthe remainder.59 The pathicosteoporosisrepresentsacompositeofseveraletiolog- increase in bone formation, however, was less than the in- ically distinct disorders. The clinical spectrum varies creaseinboneresorption, leadingtoaremodelingimbalance widely: sometimesitismildandisclinicallymanifestedbya andboneloss. Thisremodelingimbalanceisconsistentwith singleoronlyafewvertebralfractures,evenintheabsenceof anosteoblastdefect, which wasdemonstratedhistologically treatment. Morecommonly, however,therearemultiplever- by a decrease in wall thickness. There was a continuum in tebralfracturesoccurringoveraperiodof5to 10yearswith changes inboneturnoverbetweenthenormal andhighbone associated loss of height of up to 6 inches. In contrast to turnover patients rather than a bimodal distribution. Al- involutional osteoporosis, fractures ofthe ribs and metatar- thoughthepossibilityofsubtypesexists, itismorelikelythat THEWESTERNJOURNALOFMEDICINE * JANUARY 1991 * 154 * 1 69 someosteoporotic patients havepassedthrough ahighturn- increasing number of them will have bone density values overstageandhave reachedastageofnormal boneturnover below the fracture threshold.2" The two most important of in which further loss oftrabecular bone will be small. these age-related factors are decreased osteoblast function Type I osteoporosis appears to be caused by factors that and decreased calcium absorption with secondary hyper- arecloselyrelatedtoorareexacerbatedbymenopause. This parathyroidism. leads to the following cascade: accelerated bone loss, de- creased secretion ofparathyroid hormone and increased se- Secondary Osteoporosis cretion of calcitonin, and functional impairment in 25- Endocrine Diseases. Osteoporosis may be associated hydroxyvitamin D [25(OH)D] la-hydroxylase activity with with anumberofsyndromes ofendocrine dysfunction. Hy- decreased production of 1,25(OH)2D3, therefore leading to pogonadism in either sex increases the incidence of os- decreasedcalciumabsorption. Thedefectincalciumabsorp- teoporosis. Hypogonadism is probably the main cause of tion may further aggravate bone loss. osteoporosisassociatedwithovarianagenesis(Turner'ssyn- Allwomenareestrogendeficientaftermenopause, how- drome), although agenetic abnormality ofbone maturation ever, and serum levels of sex steroids are similar in post- probablyalsoispresent. Functionalhypogonadisminfemale menopausal women with and without type I osteoporosis.60 distance runners maybeassociatedwithdecreasedvertebral Thus, otherfactors mustaugmentthe rateortheduration of density.65 Endogenous or exogenous hyperadrenocorticism theacceleratedphaseofboneloss: thesefactorsinteractwith bothdecreasesboneformationandincreasesboneresorption estrogen efficiency to determine individual susceptibility. withrapidboneloss. Thedecreaseinboneformationresults Onepossiblemechanismisdefectiveregulationofosteoblast from inhibition of collagen biosynthesis. The increase in function thatcouldaccount forthe impairedboneformation bone resorption may be indirectly mediated, possibly by an detectedby histomorphometry.59 Thus, when bone turnover increased sensitivity of bone to parathyroid hormone. Pa- increases as aconsequenceofthe menopause, those women tientswithglucocorticoidexcessalsohaveimpairedcalcium whoaredestined todevelop typeIosteoporosis compensate absorption, and this can be reversed by administering vita- less well for the increase in bone resorption by increasing minDoritsactivemetabolite.Aneffectofcorticosteroidson boneformation. Anotherpossiblemechanismislocalelabo- vitamin D metabolism, however, has not been conclusively ration ofa factorthatpotentiates theeffect ofestrogen defi- established. ciency on increasing bone resorption. Patients with type I Hyperthyroidism consistently increases bone turnover, osteoporosis andhighboneturnoverhave increasedproduc- but in most patients formation and resorption remain cou- tion ofinterleukin-1 by stimulated monocytes as compared pled. Symptomatic osteoporosis associated with hyperthy- with age-matched controls.6' This increase can be normal- roidism, therefore, is relatively unusual and, whenpresent, ized by treatment with estrogen.62 On a motor basis, generallyoccursinpostmenopausalwomen. Osteitisfibrosa interleukin-1 is the most potent factor known to increase isthecharacteristic skeletalabnormalityassociatedwithhy- bone resorption. Another possible mechanism is increased perparathyroidism; nevertheless about 5% of patients, sensitivity of bone to circulating PTH, although a recent mostlypostmenopausalwomen,presentwithosteopeniaand studyinfusingPTHintonormalandosteoporotic postmeno- vertebralcompressionfractures. Incontrast, mildhyperpar- pausal women could not document this.63 A final possible athyroidism in youngersubjects is not associated with bone mechanism is that those persons entering the menopause loss.66 Patients with eitherjuvenile- or adult-onset diabetes with low-normal values for bone density may be the first mellitusmayhaveanincreasedriskforosteoporosis, butthis whosevalues fallbelowthe fracturethreshold aspostmeno- has not been clearly established. Osteoporosis associated pausal bone loss ensues. This is unlikely to be the major withacromegaly isbelievedtoberareand, whenpresent, is mechanism, however, because compared with age-matched the resultofconcomitanthypogonadism. Infact, becauseof postmenopausal controls, most patients with type I os- the anabolic effect ofgrowth hormone excess on the skele- teoporosis have increased rates of bone loss.64 Obviously, ton, mostpatients withacromegaly haveanincreaseinboth these possibilities are not mutually exclusive. trabecular and cortical bone mass. Type II (Age-Related) Osteoporosis. This syndrome oc- Gastrointestinal Diseases. These conditions can cause cursinbothmenandwomenage70andolderbutistwiceas eitherosteoporosisorosteomalacia, andtheygenerallypro- commoninwomen. Itresults fromslowbonelossoperating duce a mixture ofboth. About 5% ofpatients with subtotal overaperiodofseveraldecades.Themainmanifestationsare gastrectomy, particularlythosewiththeBillrothIItype, sub- fractures of the hip and vertebral fractures, although sequently develop bone disease. Malabsorption syndromes fracturesoftheproximalhumerus,proximaltibia,andpelvis impair absorption of calcium and vitamin D; usually this are common. The vertebral fractures are often ofthe mul- resultsinosteomalacia. However, ifthisismild,thepredom- tiple wedge type, leading to dorsal kyphosis ("dowager's inant lesion may be osteoporosis. Chronic obstructivejaun- hump"). Trabecularthinningassociatedwithslowboneloss dicemaybeassociatedwithbonediseasebecausetheentero- is responsible forthe gradual and usually painless vertebral hepatic circulation of active vitamin D metabolites is deformation. IntypeIIosteoporosis, bonedensityvaluesfor impaired. Thismechanismmayplayaroleintheosteomala- theproximal femur, vertebrae, and sites intheappendicular cia associated with primary biliary cirrhosis. In the United skeleton are usually in the lower part ofthe normal range States,however, osteoporosisassociatedwithaprofoundde- (adjustedforageandsex). Thissuggestsproportionatelosses pression inbone formation isthetypical finding.6" Its etiol- ofcortical andtrabecularboneandarateoflossthatis only ogy isunknown. Severemalnutritioninvolvingbothprotein slightly higher than the mean for age-matched peers. Thus, andcalciumdeficiency-ashasbeenobservedinprisonersof theage-relatedprocessescausingtypeIIosteoporosisappear war-maycauseosteoporosis. Womenwithanorexianervosa to affect virtually the entire population of aging men and often have osteoporosis, with functional amenorrhea also women, and, as the slow phase ofbone loss progresses, an possibly contributing totheboneloss. Finally, alactasiahas 70 OVERVIEWOFOSTEOPOROSIS 70 OVERVIEW OF been reported in up to 30% of osteoporotic subjects. This subjects ofsimilarage. Long-termtherapywithheparinhas disorder may be a risk factor for osteoporosis because it been reported tocause severeloss ofbone and spontaneous producesintolerancetomilkandthusisassociatedwithalow fractures. Heparin decreases thestability oflysosomes, and calcium intake. release of collagenase and other lysosomal enzymes may Bone Marrow Disorders. Multiple myeloma produces be responsible for the bone loss. Whereas it has been sug- diffuse osteoporosis in about 10% of patients and other gested that osteoporosis may be a complication ofrheuma- myeloproliferative disorders may do soless frequently. This toid arthritis, most of the bone loss in these patients can abnormality ismediatedbyanincreasedlocalproduction of probably be accounted for by use ofcorticosteroids and by lymphotoxin, interleukin-1, orothercytokinesbybonemar- immobilization. rowcells.Diffuseosteoporosisalsomayoccurwhendissem- inated carcinoma involves the bone marrow. Clinical Presentation Connective TissueDiseases. Anunusuallysevereformof Osteoporosis is manifested by backpain, loss ofheight, osteoporosismayoccurinosteogenesisimperfecta. Thisdis- spinal deformity (especially kyphosis), and fractures ofthe easeisusuallyinheritedasanautosomaldominanttraitandis vertebrae, hips, wrists, and, less frequently, other bones. associatedwithbluesclera,deafness,thinskin,andimpaired Themostcharacteristicsymptomofosteoporosisisbackpain biosynthesisoftypeIcollagen. Severaltypesofmutationsor causedbyvertebralcompression. Typically, awomanwithin deletions ofthe gene for type I procollagen have been de- 20yearsaftermenopausedevelopsacutelumbarorthoracic scribedinpatients withthisphenotype. Although onsetusu- backpainaftersomeordinaryactivity suchasraisingawin- ally is in childhood, some patients present with premature dow orlifting a sack ofgroceries. The pain may be mild or spinal osteoporosis in the absence ofa history oflimbbone severe, and it may be localized or radiate to the flank. It fracture.TheMarfanandEhlers-Danlossyndromesalsomay remitsindaysorweeksbutthenrecurswiththeoccurrenceof be associated with spinal osteopenia but less frequently in- new fractures. After several episodes ofacute, intermittent cludevertebral fractures. Osteoporosis commonly occurs in pain, achronicmechanicalbackachemaydevelopasaresult patients withhomocystinuria, anautosomal recessive disor- ofspinal deformity (Figure 12). In untreated or unsuccess- dercausedby deficient cystathionine synthase activity. The fully treated patients, severe kyphosis may develop with a resultant increase in homocysteine and other metabolites in loss of4 to 8 inches in height. In severe cases, the rib cage the circulation interferes with cross-linking ofcollagen. comes to rest on the pelvic brim, The frequency ofoccur- Miscellaneous Causes. Totalimmobilization, suchasoc- renceofvertebral fractures andthenumberoffractures that cursintraumaticquadriplegia, resultsinalossofupto 1% of eventuallyoccurvarywidelyamongpatients,buttheaverage bonepermonth,especiallyinthetrabecularboneoftheaxial isoneperyearinthe initialphaseofthedisease. Ingeneral, skeleton. Afterloss of40% to 50% ofbone from the spinal progressionisslowerinelderlywomen, andcommonlysub- column, a new steady state is reached and bone mass is stantialdorsal kyphosis andcervical lordosis-the so-called maintained. Bonelossisassociatedwithbothdepressed.bone dowager's hump-develops in the absence of significant formation and enhanced bone resorption. Significant bone pain. Halfofthehipfracturesinelderlymenandwomenare loss also occurs during total bed rest among nonparalyzed spontaneous and halfare associated with falls. individualsandinastronautsduringgravitationalweightless- ness. If immobilization is transient, replacement of bone Diagnosis massoccursonremobilization, providedthattherehasbeen onlythinningofbonetrabeculae ratherthanlossoftrabecu- GeneralMedicalExamination lae and other structural elements. All patients with newly discovered osteoporosis should Notinfrequently, osteoporosisisassociatedwithchronic have a general medical evaluation to assess severity and to obstructivepulmonarydisease. Whetherthisisrelatedtothe excludesecondarydiseasesthatmaycausetheosteoporosis. consumptionoftobacco,whichisbelievedtobeabonetoxin, Thereshouldbehistoricaldocumentationofthechronology or to thepulmonary disease itselfis unknown. Young alco- and location of fractures, previous treatment, age at onset holicsalsohavebeenshowntohavethinnerbonesthanother and type of menopause (natural or surgical), presence of fracturesorosteoporosis inotherfamilymembers, presence ofrisk factors such as use ofalcohol and tobacco, previous F gastrointestinalsurgery,anduseofcorticosteroids. Systemic E0-1-05 symptoms of abnormal physical findings suggest the pres- I enceofanunderlyingdisease. Evensevereosteoporosisgen- C, erally does not result in weakness or loss ofweight. IL~__. The physical examination should include an accurate C0 measurementofheightandasearchforfindingssuggestiveof 0 0 systemicdisease. Bluesclera,thinskin,andlaxjointsmaybe a indicative of osteogenesis imperfecta or a related collagen 'E disorder. Characteristic physical findings ofCushing's syn- Residual pain drome or hyperthyroidism should be sought for. The pres- enceofsplenomegalyorhepatomegalysuggeststhepresence 5 10 15 oflymphoma or other malignancy. Time, years All patients should have a complete blood cell count, Figure 12.-Clinical courseofanuntreated orunsuccessfullytreated patient determination oferythrocyte sedimentation rate, multichan- with osteoporosis. Upper panel showscontinued lossofheight. Lower panel nelserumchemistryanalyses,andurinalysis. Serumcalcium showsoccurrenceofbackpainwhichisatfirstacuteandintermittentbutlater chronic. and phosphorus levels are normal in primary osteoporosis. THEWESTERNJOURNALOFMEDICINE * JANUARY 1991 * 154 * 1 71 Serumalkalinephosphataselevelsalsoarenormalexceptfor the end plates resulting from pressure of the intervetebral transient elevations during healing of vertebral fractures. disk, usually occurring inthelumbar spinal column). Also, Sustainedelevations ofthealkalinephosphataselevel, inthe the nucleus pulposus may herniate locally into the vertebral absence of liver disease, suggest osteomalacia or skeletal body (Schmorl's nodes). The severity of the osteoporosis metastases. may be defined as follows:68 two Grade I fractures, mild Multiplemyelomamaybepresentwithoutsymptomsand osteoporosis; three to five Grade I or one or two Grade II with a normal hematogram and erythrocyte sedimentation fractures, moderateosteoporosis; andmorethanthis, severe rate. Although most cases can be diagnosed by serum and osteoporosis (Figure 13). Aradiograph ofthespinalcolumn urineproteinelectrophoresis, bonemarrowexaminationmay inatypicalpatientwithosteoporosisisshowninFigure 14B. be required toestablish the diagnosis. Bone marrow exami- Osteoporosisduetoglucocorticoidexcessshouldbecon- nationissometimesalsonecessary todiagnosethepresence sidered when there is associated osteoporosis of the skull, ofdisseminated carcinoma. fracturesoftheribsandpelvicrami,andprominentpartially mineralized callus at the site offracture. In the absence of Radiologic Findings pseudofractures, osteomalaciamaybedifficulttodistinguish Radiographs ofthe spinal column should be obtained in from osteoporosis, but it often has a radiographic "ground all patients to diagnosevertebral fracture as acause ofback glass" appearance rather than the characteristic "clear pain, to evaluate severity ofthe underlying osteoporosis, to glass" appearance of osteoporosis. Posterior wedging of a provideabaselineforassessingtheeffectoftherapyonfuture vertebra (exceptforL-5) suggests adestructive lesionrather fractureoccurrence, andtosearchforevidenceofsecondary than osteoporosis. diseases thatmay have produced the osteoporosis. General- ized osteopenia is suggested bythe findings ofaccentuation BoneDensitometry ofthevertebralendplates,prominenceoftheweight-bearing Recent development ofmethods that allow precise mea- vertical trabeculae (due to disappearance of the horizontal surementofbonemineraldensityintheaxialskeletonatsites trabeculae), andlossofcontrastinradiodensity betweenthe subjectto fracture represents a majoradvance in thecareof interior ofthe vertebral body and the adjacent soft tissue. osteoporotic patients.6970 These measurements have three Vertebraldeformitymaytaketheformofcollapse(reduction principal uses: (1) to confirmthediagnosis ofosteoporosis, ofanterior and posterior height), anterior wedging (reduc- (2)toestimatetheseverityofboneloss, and(3)todetermine tioninanteriorheight, usuallyoccurring inthethoracic spi- whetherthe patient is responding to treatment. The charac- nal column), or "ballooning" (by concave compression of teristics of the available three techniques are compared in Table 3. Single-energy quantitative computed tomography (QCT) can be performed using commercially available CT Wedge deformity Grade 1 Grade 2 scannersandacalibrationphantom. Reproducibility issatis- C7 a < 85 ,.a_ iXCl.75 factorybutaccuracy ispoor (mainly becauseofaconfound- ingeffectofmarrowfat), andradiationexposureisrelatively I.. high.Betteraccuracycanbeobtainedwithdual-energyQCT, A. '1t -- defor.!m.i.a but atthe price ofpoor reproducibility and higher radiation -,* : I exposure. Nonetheless, the method is quite sensitive (be- cause ofits ability to measure exclusively the metabolically activetrabecularboneinthecenterofthevertebralbody)and Bioconcavitydeformity specific (because distortion by extravertebral artifacts is G;rade 1 Grade 2 avoided). Dual-photonabsorptiometry (DPA)usestransmis- ,f, 0;75 sion scanning with a 153Gd sourcethatemitstwophotoelec- .r .. i .. _ 'V - IrJ.I. fr_ ,.1V ,,,.,,, r .- t B Normal Compression * deformity r compreSSeahp 85% normalhp Figure 13.-Method forstaging severity ofvertebral fractures. See text for Fiogulred1^4.w-oRamdinog.r'apBhs.ofthespinal column.A.Normal boneina 60-year- details. (From Eastell R, Riggs BL: Diagnostic evaluation of osteoporosis, In ertebrl osteporosisin a 6-year-ld womn. Thereis a YoungWF,KleeGG(Eds):Endocrinol MetabClin NorthAm. Philadelphia, WB decrease in bonedensity with high-gradecollapsefracturesofT-12 and L-1 SaundersCompany, 1988, pp 547-571.) and ballooning (expansion ofthe intervertebral discs)ofL-2 and L-3. 72 OVERVIEWOFOSTEOPOROSIS 72 OVERVIEW OFOSTEOPOROSIS late well withbonehistomorphometry-based measurements TABLE 3.-MjorMethodsforMeasuring BoneMineral of bone formation. Unfortunately, a sensitive measure for Densit oftheAxialSkeleton boneresorptionisnotavailable. Urinaryhydroxyprolineex- OCT DPA DEX4 cretion is relatively insensitive and difficultto measure and Reproducibilit %.. 3-5 2-4 1-2 requires dietary control to obtain reliable results. Recent A;curacy,9b ..... .. 5-15 4 4 reports, however, suggest that urinary excretion ofspecific Raiation, mreMs ......3.........00,500 5-10 <5 pyridiniumcrosslinks maybeahighly specificandsensitive Scantime,miws.......10 30 0 measure ofbone collagen breakdown."3 . A diagnostic algorithm for investigation of the patient with osteoporosis is shown in Figure 15. tric peaks, thereby allowing bone density to be measured independently ofsofttissuethickness andcomposition. The Treatment methodhasgoodreproducibilityandaccuracyandlowradia- tion exposure, but it measures the entire vertebra, which is General TherapeuticMeasures only 70% trabecular bone, and results are affected by the Acutebackpainrespondstoanalgesics,heat,andgeneral presenceofdystrophiccalcification, osteoarthritisofthespi- massagetoalleviatemusclespasm. Sometimesabriefperiod nal column, and vertebral compression fractures within the ofbedrestis required. Chronicbackpainofteniscausedby scanning area. The most recently developed technique is spinal deformity and thus is difficult to relieve completely. dual-energy x-ray absorptiometry (DEXA), which also uti- Instruction in posture and gait training and institution of lizes dual-energy transmission scanning but generates pho- regular back extension exercises to strengthen the flabby tonsfromanx-raytuberatherthanfromanisotopesource.7 perivertebralmusclesaregenerallybeneficial. Occasionally, ThenewmethodhasseveralimportantadvantagesoverDPA, useofanorthopedicbackbraceisrequired. Allpatientswith includingbetterreproducibility, shorterscantime,andascan osteoporosis should have a diet adequate in calcium, pro- image approaching thatofa standard skeletal radiograph in teins, andvitamins, shouldbe reasonably activephysically, quality.IncontrasttoQCT,bothDPAandDEXAarecapable and should take precautions to prevent falls. ofmeasuring mineral density ofthe proximal femur and of the total skeleton. Bone density ofthe appendicular skeleton can be mea- Historyconsistentwithvertebralfracture sured by single-photon absorptiometry using transmission I scanning with a 125I source. Although the method has good AP and lateral radiographsofthoracolumbarspine N-v reproducibility (1% to3%), thecorrelationbetweendensity L X fvrratcetburraels of the lumbar spine and the radius or os calcis is too low Vertebral fractures (r=0.5 to 0.8) for vertebral density to be predicted accu- I present ratelyinindividualpatients. Thus,theseoldermethodsgrad- ually are being replaced by QCT, DPA, and DEXA. LS-BMD AbAobovveesffrraaccttuurree Rtercauomnas,idjeurvesnielveere threshold epiphysitis Assessment ofBone Turnover Below fracturethreshold Measurementofboneturnoverishelpful inmanagement ofthe osteoporotic patient in two ways. First, as discussed Testforhematologicand malabsorptive Present later,itmaybehelpfulindecidingwhichtypeoftreatmentto diseases-e.g., bloodcellcount, ESR, _ Furthertests proteinelectrophoresis. For employ. Osteoporotic patients with high bone turnover are primaryhyperparathyroidism and likely to have a good response to antiresorptive therapy osteomalacia, s-Ca,s-phos, ALP, u-Ca whereasthosewithlowturnoverarenot.Thisdistinctionwill becomeincreasingly moreimportantaseffectiveformation- I Selectedpatients stimulating regimens are developed. Second, it is useful in following the course oftherapy. Assessboneturnover-e.g., s-BGP, s-BAP, u-OHPro, bone biopsy Iliactrephinebiopsymaybeusefulinselectedpatientsfor thispurposeandalsomaybeusedtoexcludeosteomalacia.4 Biopsy specimens should be obtained after the patient has I receivedtetracyclinedouble-labeling. (Tetracycline is selec- tivelydepositedinareaswherethereisboneformation,andit Lowturnover HitutrInover fluoresces when the bone section is transilluminated with ultraviolet light). The biopsy specimen shouldbeprocessed by an experienced laboratory that will provide quantitative Mayconsider Good response likely information. formation-stimulating toantiresorptive therapy-e.g., NaF therapy Theotherway toassess boneturnoverisby biochemical markers.72Alkalinephosphatase isproducedbyosteoblasts. Figure 15.-Diagnostic algorithm for investigation of the patient with os- Although total serum alkaline phosphatase is relatively in- teophorosis. ALP=alkaline phosphatase; AP=anteroposterior; S-BAP=serum sensitive, measurement ofthe specific isoenzyme of bone bone specific alkaline phosphatase; S-BGP=serum bone Gla-protein; S- maybehelpful. Anothermarkerreflectingboneformationis Ca=serum calcium; u-Ca=urinary calcium; ESR=erythrocyte sedimentation serum bone Gla-protein (BGP, osteocalcin). BGP is a non- rate;uOHPro=urinaryhydroxyproline; LS-BMD=dual-photon absorptiometry ofthe lumbarspine. (From Eastell R, Riggs BL: Diagnostic evaluation ofos- collagenousproteinfoundonlyinboneanddentin. Circulat- teoporosis, InYoung WF, Klee GG (Eds): Endocrinol Metabol Clin North Am. inglevelscanbemeasuredby radioimmunoassay andcorre- Philadelphia, WB SaundersCompany, 1988, pp 547-571.)