http://france.elsevier.com/direct/BONSOI/

Joint Bone Spine 73 (2006) 733–735

Original article

Bone mineral density in Marfan syndrome. A large case-control study

Bertrand Mouraa, Florence Tubacha, Moana Sulpicea, Catherine Boileaub, Guillaume Jondeauc,Christine Mutib, Bertrand Chevallierd, Yasmine Ounnoughenee, Jean-Marie Le Parca,*,

Multidisciplinary Marfan Syndrome Clinic GroupaRheumatology Department, Ambroise-Paré Teaching Hospital, 9, avenue Charles-de-Gaulle, 92100 Boulogne-Billancourt, France

bGenetics Department, Ambroise-Paré Teaching Hospital, 9, avenue Charles-de-Gaulle, 92100 Boulogne-Billancourt, FrancecCardiology Department, Ambroise-Paré Teaching Hospital, 9, avenue Charles-de-Gaulle, 92100 Boulogne-Billancourt, FrancedPediatrics Department, Ambroise-Paré Teaching Hospital, 9, avenue Charles-de-Gaulle, 92100 Boulogne-Billancourt, France

eOphthalmology Department, Ambroise-Paré Teaching Hospital, 9, avenue Charles-de-Gaulle, 92100 Boulogne-Billancourt, France

Received 26 July 2005; accepted 30 January 2006Available online 14 September 2006

Abstract

Objective: To measure bone mineral density (BMD) in a group of patients meeting Gand criteria for Marfan syndrome, comparatively with agroup of healthy controls.

Methods: Dual-energy X-ray absorptiometry (DEXA) was used to measure BMD at the hip and wrist in 130 patients seen at the Multidisci-plinary Marfan Clinic, Paris, France. Results were compared to values in the database of the absorptiometry machine (Hologic QDR100) and tovalues in 72 healthy height-matched controls including 35 whose body mass index (BMI) values were similar to those in the patients.

Results: A history of fractures was noted in 32 (24.6%) patients. Z-score values were significantly decreased in the patients compared to theHologic database values at the femoral neck (−1.190 ± 0.098, P < 0.0001) and wrist (−1.403 ± 1.06; P < 0.001). Patients had significantly lowerBMD values at the femoral neck compared to the height-matched controls (0.841 ± 0.15 versus 1.010 ± 0.017; P < 0.0001). BMD values werealso significantly lower in the patients compared to the controls of similar height and BMI. BMD values did not correlate with history of fracturesor acetabular protrusion. In the patients, BMD values lower than −2.5 correlated with presence of dural ectasia.

Conclusion: Men and women with Marfan syndrome have significant osteopenia independent from BMI.© 2006 Elsevier Masson SAS. All rights reserved.

Keywords: Marfan syndrome; Bone mineral density; Body mass index

1. Introduction

Marfan syndrome is an autosomal dominant condition dueto mutations in the fibrillin gene located on chromosome 15.About 4 to 6/10,000 live born infants are affected. Abnormal-ities involve the musculoskeletal, cardiovascular, ocular, andneurological systems. Diagnostic criteria were published in1988 and revised at the Gand Conference in 1996. Earlier diag-nosis of Marfan syndrome has led to substantial improvementsin the prevention and treatment of disease-related events, viaboth pharmacological and surgical means. Most notably, pro-

* Corresponding author. Tel.: +33 1 49 09 56 75; fax: +33 1 49 09 58 65.E-mail address: jean-marie.leparc@apr.aphp.fr (J.-M. Le Parc).

1297-319X/$ - see front matter © 2006 Elsevier Masson SAS. All rights reserved.doi:10.1016/j.jbspin.2006.01.026

gress has been made in preventing sudden death due to ruptureof the aorta.

The major clinical impact of musculoskeletal abnormalitiesin Marfan syndrome has been established by clinical and radi-ological studies. An increase in the fracture risk and a decreasein bone mineral density (BMD) values have been documentedin most patients with Marfan syndrome, raising questionsabout the relationships between the disease and bone mass.

In January 1995, a multidisciplinary clinic for Marfan syn-drome patients was created at the Ambroise-Paré TeachingHospital in Boulogne-Billancourt, France. In a study of clinicalfeatures and BMD values in 70 patients meeting Gand criteriafor Marfan syndrome, we found significant osteopenia con-trasting with a relatively low prevalence of fractures [1].Here, we expand these findings by reporting data in a larger

Table 2BMD at the hip in patients with Marfan syndrome and in controls

BMD (mean ± S.D.) Marfan (N = 130) Controls (N = 72) P valueFemur 0.841 ± 0.15 1.010 ± 0.17 0.0001Neck 0.781 ± 0.13 0.876 ± 0.16 0.0003Ward triangle 0.606 ± 0.13 0.725 ± 0.15 0.0001Trochanter 0.620 ± 0.12 0.765 ± 0.14 0.0001

Table 3BMD at the hip in males with Marfan syndrome and in control males matchedon BMI

BMD values Patients(N = 36)

Controls(N = 45)

P value

Mean (kg/m2 ± S.D.) 24.2 ± 2.3 23.1 ± 2.14 < 0.05Total hip (g/cm2 ± S.D.) 0.913 ± 0.8 1.062 ± 0.4 0.0001Femoral neck (g/cm2 ± S.D.) 0.830 ± 0.7 0.895 ± 0.6 0.02Ward triangle (g/cm2 ± S.D.) 0.617 ± 0.5 0.723 ± 0.5 0.0007BMD: bone mineral density.

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number of patients and comparing them to values in healthycontrols.

2. Methods

We included 130 adult patients seen consecutively at ourMultidisciplinary Marfan Syndrome Clinic and meeting Gandcriteria [2]. Patients were evaluated once a week as describedelsewhere [3]. Body mass index (BMI) was computed in eachpatient. BMD values were measured at the hip and wrist bydual-energy X-ray absorptiometry (DEXA) using a HologicQRD 1000 machine (Hologic, Waltham, MA). All BMD mea-surements were obtained by the same highly experiencedinvestigator, and the results were reported in g/cm2. The coef-ficient of variation computed from repeated measurements ofthe phantom supplied by Hologic was 0.34% ± 3%. Becausemany patients had severe scoliosis or a history of spinal sur-gery, we did not measure BMD at the spine.

BMD values in the patients were expressed as Z-scores andcompared to those in the Hologic database. Then, we comparedBMD values in the patients to those in 72 controls, including27 young height-matched adults, 15 women and 12 men,recruited among hospital students and staff members who con-sented to the study and 45 adult men for whom BMD measure-ments at the hip were available (data supplied by ChristianRoux, MD, Cochin Teaching Hospital, Paris, France). Becausedural ectasia is common in patients with Marfan syndrome andmay be related to BMD, we conducted separate analyses inMarfan patients with and without dural ectasia.

2.1. Statistical analysis

Clinical features in cases and controls were compared usingchi-square (χ2) and Student’s t tests. Correlation coefficientswere computed between BMI and BMD, with the alpha riskset at 5%. BMD values were expressed as mean ± standarddeviation (S.D.) and compared using Student’s t tests. Forcomparisons of BMD values in patients and in the Hologicdatabase, we used the Z-score adjusted to 0 with the univariateStudent’s test. BMD values in g/cm2 were compared betweencases and healthy controls. Statistical tests were run using Stat-View 1.0 (Abacus Concept, Berkeley, CA).

3. Results

Table 1 reports the main clinical characteristics in thepatients and controls. Among the patients, 24.6% had a historyof trauma-related or low-impact fractures, 85% had scoliosis,

Table 1Clinical features of patients with Marfan syndrome and healthy controls

Total MalesN = 130 N = 50

Age (years) 34.7 (10.7) 35.5 (10.2)Height (cm) 180.5 (9.7) 188.4* (7.4)BMI (kg/cm2) 20.9** (± 3.5) 20.5 (3.5)BMI: body mass index. *P < 0.0001; **P < 0.001.

17.7% had spondylolisthesis, 59.3% had grade II or higheracetabular protrusion, and 55.4% had dural ectasia.

Z-scores at both the hip and wrist were significantlydecreased in the patients compared to the Hologic database(total femoral neck, −1.190 ± 0.98 and total wrist,−1.404 ± 1.06 (P < 0.0001). Table 2 shows that BMD (g/cm2)at the femoral neck was significantly lower in the patients thanin the height-matched controls with higher BMI values.

We then compared femoral neck BMD values in patientswhose BMI was 20 or higher and in 45 controls matched onBMI (mean BMI, 24.2 ± 2.3 in the patients and 23.1 ± 2.1 inthe controls). As shown in Table 3, BMD values remained sig-nificantly lower in the patients. As expected, BMD correlatedwith BMI in our overall patient population, both at the wrist(r = 0.33, P < 0.0001) and at the hip (r = 0.36, P < 0.0001).Finally, patients with dural ectasia had significantly lowerfemoral neck BMD values than patients without dural ectasia(0.810 ± 0.14 g/cm2 and 0.865 ± 0.14 g/cm2, P = 0.017).

4. Discussion

This is the first study comparing BMD values in over onehundred patients meeting Gand criteria for Marfan syndromeand in healthy controls. The results confirm that both menand women with Marfan syndrome have osteopenia at thewrist and hip. Bone mass was decreased compared to valuesin the Hologic database and to measurements made in height-matched healthy adults. To evaluate the hypothesis that duralectasia in Marfan syndrome is related to decreased bonestrength, we compared BMD values in patients with and with-out dural ectasia. Dural ectasia was more common in patientswith osteoporosis defined as hip BMD lower than −2.5 S.D.

Females Controls Tall malesN = 70 N = 72 N = 1534.1 (11) 35.7 (9.8) 41.2 (6.4)175 (7.2) 180.9 (6.9) 182.9 (3.6)20.5 (3.5) 23.2** (2.8) 24.2** (2.3)

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than in the other patients. However, the small number of casesin this comparison precludes definitive conclusions.

As expected, BMD correlated with BMI in our patients.BMD correlates with BMI in the general population. However,when we compared a patient subgroup characterized by normalBMI values to controls matched on BMI, we found signifi-cantly lower BMD values at the hip in the patients, suggestingan association between Marfan syndrome and osteopenia. Ourresults agree with data reported by Kohlmeier et al. [4,5] butdiverge from findings by Tobias et al. [6], Gray et al. [7] and,more recently, Giampietro et al. [8]. The patient selection cri-teria used in these studies differed from those used in our ear-lier study [1]. The clinical impact of our findings challengesthe notion that Marfan syndrome is associated with a high frac-ture risk. A history of fractures was noted in 10% of thepatients in our earlier study [1] and 24.6% in the study reportedhere. This higher prevalence is similar to that reported by Gra-hame and Pyeritz [9]. We did not separate trauma-related frac-tures from low-impact fractures, and we do not have epidemio-logical data on the prevalences of the various fracture types inthe normal population in France. Methodological limitations ofour study include the cross-sectional design, young patient age,and limited number of patients, particularly in each age group.In normal adults, BMD shows a close positive correlation withheight, so that BMD values in populations of tall individualsare overestimated. This would be expected to lead to highBMD values in populations of patients with Marfan syndrome.To control for this source of bias, apparent BMD can be com-puted. Using this method, Kohlmeier et al. documented osteo-penia in patients with Marfan syndrome [10].

Longitudinal studies would provide information on the rele-vance and impact of osteopenia in patients with Marfan syn-drome. Peak acquired bone mass in adolescents with Marfan

syndrome deserves to be determined in order to assess bonemass changes during growth.

In conclusion, in a group of 130 patients meeting Gand cri-teria for Marfan syndrome, we found significant osteopeniaand a fairly high prevalence of fractures. The clinical impactof osteopenia in Marfan syndrome deserves to be evaluated inlongitudinal studies. Currently available data are not sufficientto establish recommendations for preventing or treating boneloss in patients with Marfan syndrome.

References

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