Decreased Bone Density in Splenectomized Gaucher Patients Receiving Enzyme Replacement Therapy

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Blood Cells, Molecules, and Diseases (2002)28(2) Mar/Apr: 288–296 Schiffmannet al.doi:10.1006/bcmd.2002.0517, available online at http://www.idealibrary.com on

Decreased Bone Density in Splenectomized Gaucher PatientsReceiving Enzyme Replacement TherapySubmitted 03/21/02; revised 03/27/02(Communicated by E. Beutler, M.D., 03/28/02)

Raphael Schiffmann,1 Henry Mankin,2 James M. Dambrosia,3 Ramnik J. Xavier,4 Constance Kreps,1

Suvimol C. Hill,5 Norman W. Barton,1 and Daniel I. Rosenthal6

ABSTRACT: Little is known about the effect of enzyme replacement therapy (ERT) on the bone abnormin Gaucher disease. Splenectomized Gaucher patients tend to suffer the most severe skeletal complichypothesized that vitamin D supplementation would act synergistically with glucocerebrosidase infuincrease bone density in splenectomized Gaucher patients. In a 24-month study, 29 splenectomizedpatients were randomized to three groups: Group 1, calcitriol (1,25-dihydroxyvitamin D3; 0.25–3.0�g/day) alonefor the first 6 months with the addition of ceredase/cerezyme at 60 IU/kg every 2 weeks during monthGroup 2, calcitriol together with ceredase/cerezyme at 60 IU/kg every 2 weeks during months 1–6; andenzyme only at 60 IU/kg body wt every 2 weeks. In all three groups, enzyme dose was halved after thmonths of therapy. The primary outcome measure was bone mineral density of the lumbar spine measingle-energy quantitative CT. Bone density by single-energy CT (P � 0.001) and by dual-energy CT (P � 0.06)declined overall, but there was no significant difference between the groups. Calcitriol had no significantbone density. Fat fraction in lumbar spine increased (P � 0.000) and skeletal MRI scores improved. Bone-spealkaline phosphatase (P � 0.002) and serum osteocalcin increased (P � 0.008), while blood cyclic AMP anurinary deoxypyridinoline did not change appreciably. Hemoglobin, platelet counts, and liver volume signimproved. We conclude that ERT alone, or in combination with calcitriol, cannot repair the bone compossplenectomized adult Gaucher patients. Alternatively, measuring trabecular bone density may be an in

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INTRODUCTION

Gaucher disease is the most prevalent oflysosomal storage disorders. As a consequendeficient glucocerebrosidase activity, accumtion of undegraded glucocerebroside withinlysosomes of macrophages produces a multtem disease that includes progressive visceralargement and replacement of bone marrowdistinctive lipid-laden macrophages. Symptoatic anemia, coagulation abnormalities, viscenlargement and skeletal deterioration occur

Correspondence and reprint requests to: Raphael Schiffmann, Natio20892-1260. Fax: 301-480-8354. E-mail: [email protected] Developmental and Metabolic Branch, National Institute of Neurolo2 Orthopaedic Service, Massachusetts General Hospital, Boston, M3 Biostatistics Branch, National Institute of Neurological Disorders a4 Department of Medicine and Molecular Biology, Massachusetts G5 Diagnostic Radiology Department, W. G. Magnuson Clinical Cente

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ing the course of the illness in most patientsminority of patients develop progressive neulogical deterioration (1).

Skeletal complications are particularly debtating in Gaucher disease (2, 3). They includeacute episodes of excruciatingly painful cortimedullary bone infarction that may be recurr(the so-called “Gaucher bone crisis”); (ii) collapof the articular surfaces of major joints asconsequence of osteonecrosis; (iii) an increincidence of osteomyelitis; and (iv) osteopeleading to an increased incidence of pathol

titutes of Health, Building 10, Room 3D03, 9000 Rockville Pike, BeMD

isorders and Stroke, National Institutes of Health, Bethesda, Maryla0892.usetts 02114.ke, National Institutes of Health, Bethesda, Maryland 20892.Hospital, Boston, Massachusetts 02114.onal Institutes of Health, Bethesda, Maryland 20892.

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cal fractures of the vertebral bodies and longbones.

Skeletal morbidity is cumulative and appearsto be accelerated by splenectomy (4–6). Patientswith aggressive disease are often disabled andnon-ambulatory by mid-adulthood. The precisemechanism by which Gaucher cell infiltrationproduces these complications is not understood,but severity is proportional, in general, to theextent of local abnormalities such as replacementof the bone marrow compartment by storage cells(7). The mineral phase of the skeleton appears tobe affected secondarily (8). Generalized osteope-nia may be due to a combination of marrowreplacement and debility.

Enzyme replacement therapy (ERT) is nowthe standard medical therapy for Gaucher disease(9, 10). Repeated intravenous infusions of mac-rophage-targeted glucocerebrosidase in the dos-age range of 15–60 IU/kg body wt every 2 weeksresults in complete or partial reversal of anemia,thrombocytopenia, and visceral enlargement after9–12 months of therapy in patients with type 1,nonneuronopathic Gaucher disease (9, 11, 12).

Accurate, noninvasive assessment of the ex-tent of skeletal and marrow involvement is nowpossible in patients with Gaucher disease (13, 14).However, limited information is available on theskeletal response to ERT (10, 15–17). Such ther-apy clears Gaucher cells from the bone marrowand increases bone density, particularly in chil-dren in whom early therapy can prevent skeletalcomplications (7, 10). Measurable improvementin the skeleton develops slowly compared withthe hematologic and visceral responses (10). Ingeneral, the bone marrow tends to respond beforeimprovements in the mineral phase of the skeletonare noted.

Patients with type 1 Gaucher disease whohave undergone prior splenectomy may have asubstantial burden of skeletal pathology despiteimproved hematological parameters. In the inter-vals between acute episodes, the skeletal diseaseis clinically silent. Therefore such patients maynot be given ERT, partly because health careproviders are unaware of the potential severity ofskeletal disease and because of the lack of cleartherapeutic guidelines. Since initiation of ERT

represents an important life style and economicdecision, more data are needed regarding the fac-tors which determine response, and whether theeffectiveness of ERT can be augmented by adju-vant treatments.

We studied the skeletal response to repeatedinfusions of macrophage-targeted glucocerebrosi-dase (Ceredase or Cerezyme) in splenectomizedadult patients, and compared the responses inpatients given only enzyme to a group whosetreatment was supplemented with 1,25-dihy-droxyvitamin D3 (calcitriol). Calcitriol plays animportant role in bone development and mainte-nance (14). Supplementation with pharmacologicdoses of calcitriol can be accomplished with min-imum clinical risk (18). We hypothesized thatERT would increase bone density and that calcit-riol might further enhance the skeletal responsesto this therapy.

PATIENTS AND METHODS

Patients

Selection criteria. Patients of either sex be-tween 18 and 60 years of age, who underwentcomplete splenectomy prior to 1993 (approxi-mately 1 year prior to initiation of this study) andnaı̈ve to ERT were potential candidates for thisinvestigation. Patients were recruited over 3years. All patients had to be ambulatory at thetime of entry into the study. Patients who werebedridden or wheelchair-bound for two or moreconsecutive months in the year prior to study wereexcluded. Patients with estrogen or testosteronedeficiency as a consequence of premature gonadalfailure were excluded. Women over 45 years ofage had a determination of premenopausal folliclestimulating hormone level to enter the study.

Patients who took medications that modifiedcalcium and bone metabolism within 6 months ofthe study were excluded. Examples of such med-ications included: anticonvulsants, bisphospho-nates, calcitonin, cholestyramine, corticosteroids,diuretics, insulin, lithium, estrogen, fluoride, andvitamin D supplements. Patients with associatedpathologies such as acromegaly, alcoholism, cir-rhosis (symptomatic), Cushing’s syndrome, hy-

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doi:10.1006/bcmd.2002.0517, available online at http://www.idealibrary.com on

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perparathyroidism, hypoparathyroidism, hyper-thyroidism, hypothyroidism, insulin-dependentdiabetes, malignancy, or chronic progressive car-diopulmonary, renal or infectious disease wereexcluded. Patients with a history of drug abuse orrecurrent renal calculi were also excluded.

The trabecular bone density of the lumbarspine measured by quantitative CT (QCT) had tobe between 101 and 200 mg/cm3 (normal range �1 SD is 180 � 20 mg/cm3). The risk of vertebralcompression fractures rises rapidly as density fallsbelow 100 mg/cm3. The relative degree of hepaticenlargement measured by quantitative MR couldnot exceed five times the normal value calculatedaccording to the formula relative enlargement �hepatic volume in cm3/(body weight in kilo-grams � 25) (19). All patients entering this studyhad to have access to macrophage-targeted gluco-cerebrosidase (ceredase or later cerezyme, Gen-zyme Corp., Cambridge, MA) through theirhealth insurance organization.

Treatment Groups

Group 1 (n � 9). Calcitriol (0.25–3.0 �g/dayand dietary calcium content adjusted to 600 mg/day) alone for the first 6 months with the additionof ceredase/cerezyme at 60 IU/kg every 2 weeksduring months 7–12. The enzyme dosage wasreduced to 30 IU/kg every 2 weeks for month13–24. The group was designed to isolate the neteffect of calcitriol.

Group 2 (n � 10). Calcitriol (0.25–3.0 �g/dayand dietary calcium content adjusted to 600 mg/day) taken together with ceredase/cerezyme at 60IU/kg every 2 weeks during months 1–6. Enzymedosage was reduced to 30 IU/kg every 2 weeks formonths 7–24.

Group 3 (n � 10). Enzyme only at 60 IU/kgbody wt every 2 weeks for the first 6 months thenenzyme at half the dose (30 IU/kg body wt every2 weeks; 7 to 24 months). Patients in that groupwere kept on a diet of 1000 mg of calcium/day.The Institutional Review Board of the NationalInstitute of Neurological Disorders and Strokeand of the Massachusetts General Hospital ap-

proved the study and all patients gave their writ-ten and informed consent.

Monitoring of Therapy

Body weight, serum calcium concentration,and 24-h urine calcium and creatinine excretionwere monitored every 2 weeks during the studyperiod in these patients. The dose of calcitriol wasadjusted to achieve a urinary calcium excretion inthe upper limit of normal (4 mg/kg/day). Patientswere encouraged to ingest at least 30 ml of liquidper kilogram of body weight daily to reduce therisk of renal stone formation. Drug compliancewas monitored by pill counts at the time of eachclinic visit. Dietary compliance was monitored byanalysis of periodic food logs by a certified die-titian.

Hypothesis Testing and Randomization

Based on previous data (10), we hypothesizedthat bone density, as measured by single energyQCT (SEQCT), would increase on average by10% during the 24 months of treatment (primaryoutcome measure). A secondary hypothesis wasthat bone density would increase on calcitriol andERT significantly more than on ERT alone. Pa-tients who fulfilled the selection criteria andelected to participate in the study were assigned toone of three treatment groups by block random-ization. Randomization was based on gender,liver size (1.1 to 3.0 times enlarged versus 3.1 to5.0 times enlarged) and bone density of the lum-bar spine (101 to 145 mg/cm3 versus 146 to 200mg/cm3). Balance within blocks was not forced.Randomization was computer-generated prior tostudy initiation and the code was available only tothe statistician of the study (J.M.D.).

QCT

SEQCT scans were performed using conven-tional methods. The scans were calibrated againstan internal phantom containing serial dilutions ofK2HPO4, as previously noted (13, 20). Becauseour earlier work demonstrated increased marrowfat fraction as a result of treatment, dual-energyscans (DEQCT) were also obtained for corrobo-

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ration (20). Cortical femoral bone thickness wasdetermined as previously described (10). Thegroup assignment of each patient was masked tothe investigators who generated these data.

MRI Score

As in our previous work, T1-weighted coronalspin-echo images of the pelvis and both lowerextremities were obtained (10), and 11 anatomicalregions were scored for evidence of abnormalitiescaused by Gaucher disease. Each patient was as-signed a score based upon the maximum numberof sites in which involvement was demonstrated.One radiologist (S.C.H.) scored all studies.

MRI Fat Fraction

The fat fraction was also evaluated as previ-ously described (10, 14). Briefly, in-and-out-of-phase images were obtained of a single midsagit-tal section of the lumbar spine. Regions of interestwere selected from the anterior portion of eachvertebral body (to avoid the asymmetry intro-duced around the basivertebral veins); the averagefat fraction was calculated for L1–L4.

Skeletal Biochemical Markers

Bone-specific alkaline phosphatase was mea-sured with enzyme immunoassay (pyrilinks D andalkphase B, Metra Biosystems, Mountain View,CA). Osteocalcin in blood was measured using animmunoradiometric method (Quest Diagnostics/Nichols Institute, San Juan Capistrano, CA). Uri-nary deoxypyridinoline and cyclic AMP were per-formed using an HPLC method developed by theMayo Clinic Laboratory (Rochester, MN).

Statistical Analysis

The preplanned analysis consisted of thechange over time of the primary outcome measureand was analyzed by univariate and multivariaterepeated-measures techniques using all availabledata on the randomized patients on an intent-to-treat basis. P � 0.05 was considered significant.

RESULTS

Patient Baseline Characteristics

The trial profile is described in Fig. 1. Forty-nine patients were screened and 19 were ex-cluded. Five patients refused to participate, onepatient had prior spine irradiation, 6 patients weretoo mildly affected, one patient had prior historyof ERT, 2 had pulmonary hypertension, and 4were judged to be too ill to participate with lum-bar spine bone density below 100 mg/cm3. Wewere not able to recruit the preplanned number ofpatients within a reasonable period of time. Atotal of 29 patients participated in this study. Theclinical characteristics of the patients are listed inTable 1. The mean values of the three treatmentgroups were well balanced. All patients had nor-mal 25-dihydroxyvitamin D3, 1,25-dihydroxyvi-tamin D3, and parathormone blood levels at alltime points.

Quantitative Imaging

Over the 2-year period, there was a significantreduction in bone density by SEQCT (P � 0.001,Fig. 2A) and a nonsignificant reduction in densityby DEQCT (Fig. 2B). When we pooled the pa-tients from the three groups, the total mean reduc-tion of bone density by DEQCT was 8.76 � 17.66mg/cm3, P � 0.06. In Group 1, onset of bone losswas delayed by 6 months. The largest reduction inbone density occurred in the first 6 months oftherapy on 60 IU/kg every 2 weeks. Looking atthe entire patient population, the mean bone den-sity decline on SEQCT was 6.5 mg/cm3 vs anincrease in density of 0.023 mg/cm3 in the fol-lowing 6 months of therapy on 30 IU/kg every 2weeks (P � 0.04). On DEQCT, the mean declinein the first 6 months of therapy was 7.25 mg/cm3

vs a 2.6 mg/cm3 increase in bone density in thefollowing 6 months (P � 0.26).

Ten patients returned for a follow up evalua-tion at 36–60 months. Their mean bone densityby SEQCT continued to decline at mean rate of2.5% per year. These patients were on a doseranging from 26 IU/kg to 74 IU/kg body wt ad-ministered every 2 weeks. Adequate cortical bone



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thickness data were available in 13 patients only(four in Group 1, six in Group 2 and three inGroup 3). At the end of the 2-year trial, corticalbone thickness decreased in six patients, in-creased in three and remained unchanged in four.

Fat Fraction

There was a robust increase in fat fraction thatwas almost maximal after 6 months of ERT (60IU/body wt) (P � 0.000, Fig. 2C). As expected, inGroup 1 the improvement in fat fraction was

delayed by 6 months, pending inclusion of ERTinto the treatment regimen. This improvement infat fraction was mirrored by a reduced MRI bonescore in 50–60% of the patients in each treatmentgroup. Adjustment for age or sex of the patient didnot affect the outcome of any of the parametersstudied.

Biochemical Skeletal Markers

There was a significant increase in bone-spe-cific alkaline phosphatase (P � 0.002, Fig. 2D)

FIG. 1. Trial profile.

TABLE 1

Baseline Patient Characteristics

Treatment groupparameter

Vitamin D alone for 6 months,then � ERTa Vitamin D � ERT ERT only

Number (M/F) 9 (5/4) 10 (7/3) 10 (4/6)Age (years) 38.3 � 10.2 36.2 � 8.5 34.8 � 6.3Liver volume (ml) 3446 � 505 3716 � 1969 3412 � 1016Bone density (SEQCT, mg/cm3) 151.1 � 23.4 151.8 � 18.4 150.1 � 19Infarcts on plain X-ray films (mean and range) 1.1 (0–4) 2 (0–5) 1.7 (0–3)MRI bone score (mean and range) 10 (6–11) 7.3 (5–11) 7.4 (4–11)

a ERT, enzyme replacement therapy.


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and serum osteocalcin (P � 0.008, Fig. 2E) overtime by repeated measures ANOVA. Cyclic AMPand deoxypyridinoline did not change signifi-

cantly (Fig. 2F). Groups 2 and 3 saw a divergencein the values of cyclic AMP and deoxypyridino-line by the 12-month time point, with a return to

FIG. 2. The effect of ERT on bone composition and turnover. (A) Single-energy quantitative CT (SEQCT; P � 0.001).(B) Dual-energy quantitative CT. Normal values: 180 � 20 mg/cm3. (C) Fat fraction (P � 0.000). Normal values: 15–20%.(D) Bone-specific alkaline phosphatase (P � 0.002). Normal values: 12.6–20.4 U/L. (E) Serum osteocalcin (P � 0.008)Normal values: 2–15 �g/L. (F) Cyclic AMP (P � 0.34). Normal values: 0.8–7.5 �mol/L. (G) Deoxypyridinoline (P � 0.21).Normal values: Males 18–40 �mol/mol creatinine; females 20–62 �mol/mol creatinine. Group 1, solid circles; Group 2, opencircles; Group 3, solid triangles. Values are means � standard deviation.



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baseline values after 24 months of therapy. He-moglobin (P � 0.001, Fig. 3A) and platelets sig-nificantly increased in all three treatment groups(P � 0.000, Fig. 3B), and liver volume decreased(P � 0.000, Fig. 3C). The onset of improvementwas delayed by 6 months in Group 1, consistentwith the interpretation that ERT is the effectiveagent. Body weight of the patients tended to in-crease over time (P � 0.05, not shown).

Side Effects and Complications

One patient in Group 3 (enzyme only) andanother in Group 1 developed pulmonary hyper-tension. The latter patient and a third patient (inGroup 3) suffered osteonecrosis of the hip whileon cerezyme at a dose of 30 IU/kg every 2 weeks.One patient developed vitamin B12 deficiency.Seven patients had one to three bone crises during

the 2-year study (3 in Group 1; 2 in Group 2; and2 in Group 3). These complications occurredthroughout the 2-year study period. No patientfractured a bone during the study period but twopatients developed fractures during the post-studyperiod.

DISCUSSION

In this study we found that, contrary to ourinitial hypothesis, ERT was associated with pro-gressive reduction in bone density in splenecto-mized adult Gaucher patients. Calcitriol had noeffect on bone density. The role of ERT in reduc-ing the trabecular bone density is underscored bythe fact that bone density remained stable duringthe 6 months of therapy with only calcitriol. Theoverall annual mean rate of decline in bone den-sity in the enzyme-treated patients was about7.8%. The extent of bone density reduction wasmuch greater than that which is seen in healthypopulations. Cross-sectional and longitudinaldata, using QCT or dual energy X-ray absorpti-ometry, showed an almost complete stability ofbone mineral density in the lumbar spine of adultmales between age 30 and 55 years (21) and onlysmall decline in pre- and perimenopausal (2–4%)and postmenopausal women (21–24). However,such natural history data are not available onuntreated type 1 Gaucher patients.

The alteration of bone density observed usingQCT was confirmed in 10 patients who also haddual energy X-ray absorbtiometry of five otherskeletal sites (not shown). Nevertheless, since westudied sequentially only the lumbar vertebralbodies, we do not know whether the decrease inbone density was limited to that skeletal region.Although ERT dose was halved after the first 6months of treatment, our study provides little ev-idence that the outcome would have been differ-ent with a higher enzyme dose. The greater re-duction in bone density seen in the first 6 monthsof the study may be related to the dose sequencerather than to enzyme dose per se, and possiblyalso to the increase in fat fraction over that periodof time. The fact that the DEQCT also declinedindicated bone loss suggests that increasing fatfraction does not account for the entirety of the

FIG. 3. Effect of ERT on systemic parameters. (A)Hemoglobin (P � 0.001). (B) Platelets (P � 0.000). (C)Liver volume (P � 0.000). Group 1, solid circles; Group 2,open circles; Group 3, solid triangles. Values are means �standard deviation.


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phenomenon that we have observed. These find-ings significantly differ from the increased bonedensity observed in type 1 and type 3 Gaucherchildren (10, 25, 26). The decline in trabecularbone density is especially surprising in view ofthe marked improvement in lumbar spine fat frac-tion and the significant improvement of hemato-logic parameters and liver volume. These indicateeffective systemic and skeletal clearance of stor-age material as observed in previous studies (10).However, skeletal fat fraction in our patients lev-eled at, or just below, the lower limit of normal,not excluding the possibility that the enzyme doseadministered in the latter part of the study wassuboptimal. Although there was no indication thatthe decline in trabecular bone density was com-pensated by an increase in bone cortical thickness,this cannot be completely excluded since the datawere incomplete.

The mechanism of bone density reductionwith ERT is unclear. Gaucher disease is associ-ated with relative paucity of osteoclasts and osteo-clastic activity, either to compensate for lack ofosteoblastic activity (27), or because of lack ofdifferentiation of monocytes into osteoclasts (28).We observed a significant increase in osteocalcinand bone-specific alkaline phosphatase, osteo-blastic markers, with no overall change in deoxy-pyridinoline, an osteoclastic marker. Although af-ter a 1-year treatment regimen, deoxypyridinolinesignificantly increased in the ERT-only group, itreturned to baseline levels after 2 years. The in-creased levels of biochemical markers of boneturnover observed in our study can be contrastedwith a decline of osteoblastic and osteoclasticbone markers seen with other medical treatmentsthat lead to increased bone density (29–31). Sig-nificant decline in biochemical bone markers wasalso seen when ERT was supplemented with pam-idronate or alendronate in adult Gaucher patients(32, 33). In the study of Westrup et al., the vastmajority of patients had intact spleens and theirbone density remained unchanged on ERT alonewhile it significantly increased when ERT andalendronate therapy were combined (33). In Cienaand Bembi’s study, significant increase in bonedensity by DEQCT was obtained with pamidro-nate alone. It is possible that ERT, which is tar-

geted mostly to macrophages, led to increasedbone turnover with a sustained elevation of osteo-blastic activity but only transient elevation ofosteoclastic activity and resultant bone loss.Therefore, for optimal effect on bone repair, bet-ter targeting of the infused glucocerebrosidase fordirect delivery to osteoblasts and osteoclasts maybe needed, although the latter do express the man-nose lectin receptor (34).

A previous study showed a significant in-crease in skeletal mass in patients treated withERT (10). However, our patient population differsin two important respects. The previous patientshad intact spleens, and 8 of the 12 were children.In fact, increases in skeletal mass occurred largelyin the younger patients. It is possible that this wasdue to a secondary effect of improved generalhealth (growth resumption, greater activity level,etc.) which was superimposed upon the otherwisebone-wasting features or enzyme treatment. Sple-nectomy may be a marker for severely damagedskeleton (8) that is poorly vascularized and cannotbe repaired, at least in the short-term. The rapiddecline in bone density may portend an increasingfracture risk later in life in splenectomized pa-tients despite ERT (8).

The rate of bone loss in untreated Gaucherpatients has never been determined. More impor-tantly, the frequency of skeletal complicationssuch as pain, bone crisis, bone infarcts or fracturesis highly variable, and therefore, we cannot com-pare our splenectomized Gaucher patients withthe natural history of this disease with regard tothese outcomes. It is our clinical impression thatthe incidence of bone crises and fractures hasmarkedly declined in Gaucher patients on ERT. Ifso, in an analogous manner to the effect of fluo-ride-calcium on the skeleton (35), bone mineraldensity may not be an adequate clinical outcomemeasure to evaluate the effect of therapy on theskeleton in Gaucher disease patients.

ACKNOWLEDGMENTS

The authors thank the patients for their participationand Devera G. Schoenberg, M.S., for editorial assistance.We thank Nancy Sebring for expert nutrition educationand monitoring.



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