Bone mineral density in adults with Marfan syndrome

N. Carter, E. Duncan and P. Wordsworth

Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Headington, Oxford OX3 7BN, UK


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives.Reduced bone mineral density (BMD) has been reported in pre-menopausal women and children with Marfan syndrome (MFS). The bone mineral status of adult men with MFS is unknown. The objective of this study was to determine the BMD of adult men and women with MFS.

Methods.BMD (g/cm2) was measured by dual-energy X-ray absorptiometry (DXA) of the lumbar spine (L1–L4), femoral neck and total hip in 25 adults (12 male) who fulfilled the 1996 MFS diagnostic criteria. The results were compared with age- and sex-matched controls and expressed as S.D. from the population mean (z score).

Results.Overall, BMD was significantly reduced in the lumbar spine (z = -0.42 ± 0.97, P < 0.05), total hip (z = -0.57 ± 0.88, P < 0.005) and femoral neck (z = -0.51 ± 0.88, P < 0.005). In women alone, BMD was reduced at the femoral neck (z = -0.53 ± 0.95, P < 0.05) and at the hip (z = -0.64 ± 0.77, P < 0.005). In men, BMD was reduced at the femoral neck (z = -0.48 ± 0.84, P < 0.05) with a non-significant trend to lower BMD at the hip (z = -0.49 ± 1.01, P = 0.054) and lumbar spine (z = -0.59 ± 1.02, P = 0.09).

Conclusion.Axial BMD is lower than normal in Marfan adults. This reduction may contribute to fractures seen in the Marfan population.

KEY WORDS: Marfan syndrome, Bone mineral density.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Marfan syndrome (MFS) is an autosomal dominant disorder characterized by musculoskeletal, ocular and cardiac abnormalities [1]. It is caused by mutations of the fibrillin-1 gene on the long arm of chromosome 15 [2]. Fibrillin has been identified in bone and may be involved in binding calcium [3]. It is possible that abnormal fibrillin could play a role in altering the distribution of mechanically induced strain or in affecting the mineralization of bone [4]. Bone mineral density (BMD) studies in children with MFS have demonstrated reductions at the femoral neck, and in women with MFS, BMD was reduced in the lumbar spine and at the total hip [4]. Other studies, however, have reported normal BMD at the distal forearm, lumbar spine and hip with reduced BMD only at the greater trochanter [55, 6]. Previous fractures and other musculoskeletal symptoms, such as spinal pain, have been suggested in adults with MFS [7]. The bone mineral status of adult men with MFS has not been studied. In this study we measured the BMD of adult men and women who fulfilled the 1996 revised diagnostic criteria for MFS [8].


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Twenty-five adults (12 men and 13 women) over 18 yr old, living in the south of England and satisfying the 1996 revised diagnostic criteria for MFS were studied. Exclusion criteria included conditions or medications known to have an effect on bone (e.g. rheumatoid arthritis, hyperthyroidism, corticosteroid use). After consent, age, height, weight and menopause status were recorded. BMD was assessed with dual-energy X-ray absorptiometry (DXA; Hologic QDR 1000, Hologic Corp., Waltham, MA, USA) of the lumbar spine (L1–L4), total hip and femoral neck. Two subjects with previous spinal fusion had only hip and femoral neck BMD measured. BMD was recorded as g/cm2, as T scores (S.D. from mean BMD of young adults) and Z scores (S.D. from mean BMD of age- and sex-matched controls) calculated against the manufacturer's database for the spine and against the third National Health Nutrition Examination Survey (NHANES III 1988–1991) database for the hip [9]. Differences between mean MFS Z scores and controls at each site were assessed by two-tailed Student's t-test. Statistics were calculated using a data analysis tool pack for Microsoft Excel.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The mean age was 38 ± 12 (S.D.) yr. The mean age for males was 33 ± 9 yr (range 19–47). The mean age for females was 43 ± 13 yr (range 19–67). The mean body mass index (BMI) for the whole group was 23.0 ± 3.4 (males 23.7 ± 4.1 and females 22.2 ± 2.5). Only one male had a BMI below the WHO recommended healthy range [14]. Regression of BMD on BMI did not show a significant correlation. However, the numbers in this group were small.

The results of BMD and Z scores are summarized in Table 1Go. Overall, BMD was lower than in age- and sex-matched controls (z score) at the lumbar spine (P < 0.05), femoral neck (P < 0.005) and total hip (P < 0.005). When considered separately for sex, BMD was reduced significantly at the femoral neck in both men (P < 0.05) and women (P < 0.05) and at the total hip in women (P < 0.005). There was a trend for reduced BMD in the spine (P = 0.054) and total hip (P = 0.09) in men, but this did not reach statistical significance.


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TABLE 1. BMD and z scores at the lumbar spine, total hip and femoral neck in adult males and females with MFS

 


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
These results add weight to the evidence that Marfan adults have lower axial BMD compared with the general population. In addition, they show that adult men as well as women with MFS have reduced BMD. Kohlmeier et al. [10] initially reported lower than normal BMD at the hip in 17 adult Marfan women with preserved BMD at the lumbar spine. After extending that series to 32 women, BMD was also found to be reduced in the lumbar spine [4]. Kohlmeier et al. [4] also reported BMD data in 16 Marfan children who were found to have lower femoral neck BMD and a trend to reduced BMD of the lumbar spine.

Tobias et al. [5] found that BMD was similar to the reference population at the hip and lumbar spine in post-menopausal Marfan women. It has therefore been suggested that osteopenia in MFS was due to the failure of attainment of peak bone mass, but a lower subsequent rate of post-menopausal bone loss reduced the prevalence of low BMD compared with age-matched controls in older female patients [4]. No longitudinal studies of bone loss have been performed to test this hypothesis.

The present study is the first to assess the bone mineral status of Marfan adults who fulfilled the revised 1996 diagnostic criteria of MFS. Criticisms of the 1986 Berlin nosology diagnosis of MFS [11] include over-diagnosis in relatives. The 1996 criteria now include the potential contribution of molecular analysis and more stringent requirements for the diagnosis of MFS in relatives of an affected individual. The subjects in this study may more accurately represent those with true MFS than with allied phenotypes. These differences in disease definition may explain the differences between the results of others and our own results.

The molecular explanation for the lower peak bone mass achieved in MFS patients is unknown. Fibrillin has been identified in bone [12]. A mutation in one of the epidermal growth factor (EGF)-like repeats of fibrillin has a consensus sequence analogous to the first EGF-like domain on factor IX [3]. In the factor IX gene, this area is known to bind calcium and it has been suggested that mutation at this site may disrupt calcium binding. It is possible that a mutation at this EGF-like site in fibrillin may alter its biomechanical properties in bone [4]. This may lead to a reduction in the acquisition of peak BMD. Studies of specific mutations of fibrillin in osteoporotic individuals with MFS have yet to be performed.

Important factors in the acquisition of bone mass include exercise and calcium intake [13]. In children and young adults with MFS, the presence of musculoskeletal pain and advice to avoid contact sports (risk of aortic rupture) may reduce the exercise undertaken and thus reduce mechanical loading of the skeleton. This aspect has not been addressed formally in studies so far, although at least 2 h/week recreational activity was reported in women and children with MFS. None, however, was involved in vigorous or competitive sport [4]. The effects of this form of exercise on the attainment of adequate bone mass in Marfan children are not known.

At present the relevance of these factors to fracture risk has not been fully evaluated in MFS. Fracture data in MFS are limited; fractures have been reported in 16/48 (33%) of Marfan adults [7]. The site and cause of these fractures were not documented and were, in fact, attributed to joint laxity. Kohlmeier et al. [4] stated that no Marfan adults sustained non-traumatic fractures, although 50% of pre-menopausal women and 12.5% of children sustained peripheral traumatic fractures. Further work is required to determine the fracture risk to the MFS population and to elucidate the cause of the underlying osteopenia. Until then it would be appropriate to encourage site-specific loading exercise of the hip and lumbar spine and to ensure an adequate calcium intake in MFS patients.

In summary, we have demonstrated reduced axial BMD in men and women with MFS. This may be due to mutations of the fibrillin gene or to environmental issues such as reduced exercise leading to sub-optimal peak bone mass.


    Acknowledgments
 
We thank Dorothy Halliday and Anne Roberts for their work with the Marfan database, John Shipman and Ian Smith for their technical expertise in bone densitometry and Matthew Brown for statistical analysis.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 13 May 1999; revised version accepted 7 October 1999.