Dr Atul A Deodhar MD MRCP Division of Arthritis and Rheumatic Diseases (L329A). The Oregon Health Sciences University
Ehlers-Danlos syndrome (EDS) is an inherited disorder of connective tissue that shows extreme variations in its clinical presentations. The most common symptoms are loose skin and hypermobility of the joints. The serious manifestation of dilatation of the blood vessels is fortunately rare. Bone is an important member of the connective tissue group, but very little is known about bone involvement in EDS. Osteoporosis is the most common disease that affects bones. This article argues that people with EDS are likely to be genetically susceptible to osteoporosis and hence need to learn more about this very important health issue. It also suggests preventive strategies by modifying the important environmental factors that are known to accelerate bone loss and development of osteoporosis.
Osteoporosis can be defined as a reduction in bone mass that leads to increased risk of fractures. It is an enormous public health problem for most societies in terms of disability, pain and socio-economic costs. With the aging of these communities, these costs can only increase. We have only recently become aware of the magnitude of the problem. In the United States for a white woman above the age of 50, the lifetime risk of any hip, vertebral or distal forearm fracture is 40 percent and for a man it is13 percent. In England and Wales, approximately 50,000 hip fractures occur every year. As a result, half of these patients cannot walk independently and 30 percent of them become totally dependent. A fifth of 70-year-old women have a vertebral fracture causing considerable disability, pain and loss of quality of life. The problem of forearm fractures is underestimated even though it results in prolonged pain and impaired function. The overall hospital cost of osteoporotic fractures to the National Health Service in UK is estimated to be £615 million per year and is rising.
Bone is a living tissue, continually re-modeling and renewing itself throughout life, to respond to physical stresses. Bone grows from birth through puberty to reach its maximum around the age of thirty-five. This phase in life when we have the best possible bone strength is termed the peak bone mass. Bone mass then begins to decline due to the imbalance of formation and reabsorption. This loss is particularly rapid in women in the first 10 years after menopause because of the lack of female sex hormone, oestrogen. Osteoporosis therefore is the end result of an inadequate attainment of peak bone mass, or a subsequent rapid loss, or a combination of both. Evidence suggests that there is a strong genetic influence on peak bone mass.
The level of peak bone mass is also modified by environmental factors like hormones, nutrition and exercise. The environmental influences on bone are well known. For instance, a life long high intake of calcium is associated with greater bone mass; there is a positive effect of physical activity on bone observed in athletic individuals and there is a loss of bone mass following prolonged immobility. The use of certain medications like heparin and corticosteroids are also known to cause rapid bone loss. The other very important factors are the sex hormones; oestrogen and testosterone. Lack of these sex hormones for instance in delayed puberty, prolonged absence of menstrual periods or early menopause can influence bone mass adversely.
Let us now consider the genetic influence on bone strength. A number of family and twin studies have demonstrated that genetic factors play a very important role in the development of osteoporosis by influencing peak bone mass.
Identical twins, who share 100% of their genes, have remarkably similar bone density. In family studies, daughters of women with prior vertebral fractures have been shown to have low bone density. Collagen is the main protein constituent of bone. Genetic defects in the formation of collagen can cause osteoporosis. Osteogenesis Imperfecta is a good example of this.
Osteogenesis Imperfecta (OI) is a genetic connective tissue disease, characterised by increased fragility of bones. Affected persons may have multiple fractures with minimal trauma. Some patients with Ol have a very severe form of osteoporosis while mild cases with Ol can present late in life, and can be mistaken for 'post-menopausal osteoporosis'. Ol has been associated with defects in the structure or synthesis of type I collagen. Type I collagen not only plays a crucial scaffolding role in bone, it is also an important protein in the skin. In some types of EDS, the defects at the molecular level have been identified and include similar abnormalities in the synthesis and processing of types I and 3 collagens. EDS and Ol are therefore closely related and are known to co-exist. Theoretically, we can postulate that some forms of EDS with type 1 collagen defects could have osteoporosis.
Clinical evidence to suggest that patients with EDS also have osteoporosis is limited. The scientific literature contains only two small bone density studies in patients with EDS. Coelho and colleagues from Portugal assessed bone density in 4 patients with type I EDS. They were 3 males and 1 female with ages ranging from 16 to 25 years. None of these patients had any other significant risk factors for low bone mass and none had a clinical or radiological evidence of fractures. All patients had low bone density in the lumbar spine but not in the hip. We measured bone density in five female and two male patients with EDS in Cornwall. Six had type 2 and one patient had type 3 EDS. They were between the ages of 16 to 70 and were referred by their family physicians for assessment of bone density. They did not have any predisposing factor for osteoporosis. We found that four out of seven patients had significantly reduced bone mass both in the hip and in the lumbar spine, two had significantly reduced bone mass in the hip only and the 16 year old had moderately reduced bone density in the spine. They were thus at increased risk of developing fractures. We hypothesise that the abnormality of the collagen framework in EDS may lead to faulty deposition of calcium in the bones', with resultant reduced bone mass.
The presence of osteoporosis can be suggested by history and physical examination but the only way to diagnose osteoporosis with certainty is by a bone density measurement. This test usually takes 10 to 15 minutes to perform, is painless and uses very small quantities of x-rays. Generally a repeat measurement is carried out a year or so later to check for the rate of loss of bone mass. If you are worried about the possibility of osteoporosis, speak to your family physician and ask for a bone density measurement test. If you are found to be osteoporotic what can be done?
As we cannot change our genetic background, management of osteoporosis in the setting of Ehlers-Danlos syndrome will depend on awareness of the problem and modifying the environmental factors. As a general measure, every person with EDS should have adequate calcium intake (I to 1.5 grams per day) in their diet. A pint of skimmed milk or equivalent amount of dairy products per day will provide one gram of calcium. If for some reason, the person is unable to tolerate dairy products the diet should be supplemented with tablets of calcium. For those above the age of 65, it may be worth considering vitamin D supplements (800 international units per day) too. Increased physical activity in the form of regular weight bearing exercises like brisk walking, have beneficial effects on bone mass. The majority of osteoporotic fractures are associated with falls. The risk factors for falling are numerous, but are mainly related to advanced age or ill health. A general improvement in fitness has the greatest effect in reducing the risk of falling.
There are no studies in patients with EDS looking at the benefits of different medication in treatment of osteoporosis. However, till such studies become available, there is no reason to deny patients with EDS and osteoporosis the benefits of currently available therapies. Women with EDS at menopause should consider the use of hormone replacement therapy (H RT) for at least ten years unless there is an absolute contraindication. HRT has been shown to prevent loss of bone and halve the risk of myocardial infarction and stroke. For these reasons, it may be worth considering HRT in every woman with EDS at menopause. In the last few years, many other treatments have become available to treat pre-existing osteoporosis.
Intra-nasal calcitonin, oral slow release fluoride and newer bisphosphonates such as alendronate have been shown to be effective in halting the bone loss and in some cases reducing fracture risks. These treatments can be very potent and need to be used under careful monitoring by a specialist. With the present resurgence of interest in osteoporosis, new hormonal and non-hormonal agents are undergoing clinical trials. The next decade promises to be very exciting in the development of novel therapies to treat osteoporosis.
Ehlers Danlos syndrome and Osteoporosis (Letter) A.A. Deodhar, A. D. Woolf.
Annals of the Rheumatic Diseases. 53(12):841-2. I994 Dec.
Osteoporosis and Ehlers Danlos Syndrome (Letter) P. C. CoeIho, R. A. Santos, J. A. Gomes Annals of the Rheumatic Diseases. 53(3):212-3. I994 Mar.
Collagens and their abnormalities in a wide spectrum of diseases. (Review) I. Kivirikko
Annals of Medicine. 25(2):l 13-26, 1993 Apr.
For more information on Osteoporosis, contact:
National Osteoporosis Society P0 Box 10, Radstock Bath BA3 3YB
The views expressed are those of the author(s) and should not be construed to represent the opinions or policy of the Ehlers-Danlos Support UK or its Trustees.