University Department of Medicine and 1Rheumatic Disease Unit, Ninewells Hospital and Medical School, Dundee, UK.
Correspondence to:
T. Pullar, Rheumatic Diseases Unit, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. E-mail: thomas.pullar{at}tuht.scot.nhs.uk
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. Forty premenopausal women with fibromyalgia and 37 age-matched female controls were studied. Broadband ultrasound attenuation (BUA) and velocity of sound (VOS) were measured at the calcaneum and bone mineral density was measured at the forearm and lumbar spine using dual-energy X-ray absorptiometry. Serum calcium, alkaline phosphatase, -glutamyl transferase, 25-hydroxyvitamin D and plasma viscosity were measured in all subjects and parathyroid hormone was measured in subjects recruited in the latter part of the study.
Results. Seventeen patients with fibromyalgia syndrome and seven controls had 25-hydroxyvitamin D concentrations <20 nmol/l (P < 0.015) and in three FMS patients serum parathyroid hormone was raised. Bone density in fibromyalgia patients was slightly lower at the mid-distal forearm but comparable to that in controls at other sites.
Conclusions. There is no reason to recommend routine bone densitometry in fibromyalgia patients. However, vitamin D subnutrition is common in these patients and this should be sought.
KEY WORDS: Fibromyalgia, Bone density, Vitamin D, Osteoporosis.
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
As patients with FMS have impaired mobility, we postulated that they may be at increased risk of developing osteoporosis. Studies of bone mineral density (BMD) in FMS have, to date, shown conflicting results [4, 5]. We therefore aimed to assess bone density using various techniques in patients with FMS and also to look for secondary causes of osteopenia. In addition, as these patients might be less mobile and therefore get less sunlight exposure, we also looked for evidence of osteomalacia.
![]() |
Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
General practitioners were sent details of the study with respect to each patient. Unless the general practitioner contacted us within 2 weeks to say that the study was not suitable for the patient, each patient was contacted by post with details of the study and invited to participate, provided that she was premenopausal, was not pregnant and did not have other conditions known to affect bone metabolism.
Eighty-five suitable patients were identified. Three general practitioners replied to say that their patients were not suitable for the study. Eighty-two FMS patients were contacted. Ten failed to respond even after a reminder letter, giving a response rate of 88%. Five patients responded indicating no interest in the study. Twenty-six FMS patients were excluded from the study; 15 were on hormone replacement therapy, eight were postmenopausal, one was found to have rheumatoid arthritis, one was taking tamoxifen for breast cancer and one was on bisphosphonate treatment. There were no patients on regular corticosteroid therapy, with hyperthyroidism, inflammatory bowel disease, primary biliary cirrhosis or known alcohol abuse.
Controls
Forty-two age-matched premenopausal female controls were recruited. Ten were recruited from friends and relatives of the patients, and 32 from friends and colleagues of controls and also from hospital and medical school employees. One control subject was later found to have had two raised plasma viscosity results (1.72 mPa/s) and was excluded from the data analysis. Four controls were excluded from the analysis because they had six or more tender fibromyalgia sites.
No controls needed to be excluded because of a Stanford Health Assessment Questionnaire (HAQ) score of 0.25 or more. Thirteen control subjects had a Fibromyalgia Impact Questionnaire (FIQ) score greater than 1. Scores for these subjects ranged from 1.04 to 4.0 out of a possible 10. Most of the score derived from questions on general aspects, such as tiredness or anxiety. All the control subjects were working and we felt that working women could well be tired, tense and perhaps a little depressed. There was little contribution to the score from questions on pain or stiffness or the ability to carry out everyday tasks. These control subjects were not excluded from the data analysis.
Study visit
The same researcher (PAM) saw all subjects, performed all the bone density measurements and the fibromyalgia tender spot counts. Only one study visit was required for each subject. During the visit, informed consent was obtained, the study was explained and any questions were answered. A structured history was taken with details of weight, height, age at menarche, alcohol and smoking habits, medications including any past use of steroids, calcium intake, family history of osteoporosis, other medical problems and, for FMS patients, the time since fibromyalgia was diagnosed. Alcohol status was assessed in three categories: regular alcohol consumption (114 units per week), occasional drinks only, and never drinks alcohol. The smoking status was assessed in three categories: current smokers, past smokers, and never smoked.
Functional ability and mobility assessment
The functional ability and mobility of each subject was assessed by four methods in order to get results that were as accurate as possible. Participants were classified into one of four functional classes: 1 was normal, 2 represented normal function despite handicap, 3 reflected the ability to carry out few or none of the duties of the usual occupation or self-care, and 4 was total or almost total incapacity, bedridden or confined to a wheelchair. We also used the modified Stanford HAQ [7], the McAlpine mobility score [8] and the FIQ [9]. Although HAQ is validated only for patients with rheumatoid arthritis, we felt it offered useful additional information on the activities of daily living of the subjects. Using 10-point visual analogue scales, the FMS patients assessed their pain and the perceived activity of their fibromyalgia over the preceding 7 days. The number of fibromyalgia tender points was assessed in each participant, as indicated in the ACR criteria for the diagnosis of FMS, with the total possible score of 18 tender points [6].
Laboratory investigations
All participants had blood taken for measurement of plasma viscosity and serum calcium, alkaline phosphatase, -glumyltransferase (GGT) and 25-hydroxyvitamin D (25-OH vitamin D). Midway through the study we found that there was a significant number of patients with low levels of serum 25-OH vitamin D. All the subsequent subjects included in the study had the serum parathyroid hormone level assessed routinely.
Bone densitometry
CUBAClinical ultrasound
All the quantitative ultrasound measurements of the calcaneum were carried out with the McCue CUBAClinical dry system according to the manufacturers instructions (McCue Plc, Winchester, UK). Broadband, single-element, flat (unfocused) immersion-type transducers are used in this system. Centre frequency was 1.0 MHz and acoustic intensity was 0.28 W/cm2. Broadband ultrasound attenuation (BUA) was reported in dB/MHz and velocity of sound (VOS) was reported in m/s. The measurement error coefficient of variation of the BUA was found to be 3.5% and that of VOS 0.5%. Quality assurance and quality control checks were carried out each day. The non-dominant heel was measured unless it was the site of a previous fracture or was unsuitable.
Dual-energy X-ray absorptiometry: Lunar DPX Alpha
For the measurements of BMD and bone mineral content (BMC) of the posterioranterior lumbar spine, we used the Lunar DPX Alpha (Lunar Corp., Madison, WI, USA) with software version 1.15. Photon energies were 38 and 70 kev and voltage 76 kVp. The machine was calibrated before scanning each day and the Lunar spine aluminium phantom was scanned to monitor any drift. The measurement error coefficient of variation (based on 10 subjects, each having two lumbar spine scans with repositioning between scans) for L2L4 was 1.54% for BMC and 1.38% for BMD. Patient results are expressed as BMC (g) and as BMD (g/cm2).
Subjects were scanned in indoor clothing with no metal objects at the scan site and the recommended Lunar scanning procedure was used. Medium scan mode was used for all subjects and current was 750 or 3000 µA depending on the body mass index (BMI) of the subject.
Dual-energy X-ray absorptiometry: Osteoscan pDXA
For the peripheral scanning at the radius we used the Osteoscan pDXA (NIM S.r.1., Verona, Italy, supplied by Vertec Scientific, Reading, UK) [10] with software version 2.1x. Photon energies were 27 and 52 kev. The machine was calibrated prior to scanning and the supplied phantom was scanned. Average measurement error coefficient of variation was 2.6% for ultradistal BMC and 1.8% for ultradistal BMD, and 2.1% for mid-distal BMD and 1.9% for mid-distal BMD. The non-dominant wrist was measured unless there had been a fracture, and the manufacturers recommended procedure was followed. Results were expressed as BMC (mg) and as standardised BMD (mg/cm2).
Statistics
We calculated the number needed to be studied on the basis that it should permit the detection of a difference in bone density at the lumbar spine of one standard deviation or more between the FMS patients and the control group. A P value of 0.05 or less was taken as statistically significant with a power of 90%. On this basis, a minimum of 23 subjects would be needed in each group. We preferred to recruit as many patients as practical as only a limited number of fibromyalgia patients fulfilled our inclusion criteria, with the object of detecting an even smaller difference. We stored and analysed all the data using SPSS version 10 (SPSS, Chicago, IL, USA). Normality was tested using the KolmogorovSmirnov test. Normally distributed data were analysed using the t-test for two independent samples, while the non-normally distributed data were analysed using the MannWhitney test. Bone density was compared using analysis of covariance with BMI and age as covariates. We used the 2 test to assess frequency differences between the groups.
Ethics
The study protocol was approved by the Tayside Committee on Medical Research Ethics.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
As expected, patients with FMS had significant mobility and functional impairment as assessed by the McAlpine scale, functional class, HAQ score and FIQ score (P for all < 0.001). FMS patients also had significantly more tender FMS points and sleep disturbance (P < 0.001).
Seventeen FMS patients and seven controls had 25-OH vitamin D concentrations <20 nmol/l (2 = 5.93, P < 0.015). Although all the other laboratory findings were within normal limits, we found that patients with FMS had significantly higher plasma viscosity, serum GGT and serum alkaline phosphatase than controls (P = 0.001, 0.017 and 0.02 respectively). Three of 23 FMS patients (16.7% of those with low serum 25-OH vitamin D, 7.5% of all the FMS patients) and one of 31 control subjects were regarded as having biochemical osteomalacia, as defined by raised serum parathyroid hormone in the absence of hypercalcaemia.
Apart from the BMD in the mid-distal radius, which was significantly lower in the FMS patients compared with controls (P = 0.023), no significant difference was found in measures of BMD (Table 2). Three patients with FMS and two controls had a T score below 1.5 at least one site; one of these controls had a T score below 2.5 at the mid-distal radius.
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Bone densitometry showed a difference in density only at the mid-distal site in the radius. This site mainly reflects cortical bone and indicates long-term rather than short-term bone loss. Ideally, we would also have measured BMD at the hip. A pilot study [4] suggested lower spine BMD in FMS, and this was the primary reason for concentrating on the spine. Although the precision of BMD measurement is greater at the spine, measurements at the hip may have provided further useful information.
No significant differences in disease or lifestyle parameters were apparent between fibromyalgia patients who had high and those who had low serum 25-OH vitamin D levels. However, as a group, the FMS patients were much more likely to be smokers, to have had a previous fracture, to have used steroids, to have a family history of osteoporosis and to be less physically active than controls (paradoxically, alcohol intake was lower in FMS patients). Some of these may represent separate risk factors for osteoporosis; most are possibly a direct consequence of fibromyalgia or, in the case of fractures, perhaps a cause [12].
It would appear, therefore, that although this study failed to demonstrate conclusive evidence of reduced bone density in premenopausal women with fibromyalgia, there are definite indicators, in terms of both lifestyle and low serum 25-OH vitamin D, that these patients had a likelihood of poorer bone health in the future. A follow-up study in postmenopausal patients is indicated to test this hypothesis. These patients were specifically excluded from our current study.
An interesting but unexpected finding was the significantly higher plasma viscosity (although still within the normal range) in FMS patients. This may represent low-grade inflammation as part of their clinical condition, or may reflect a higher degree of cardiovascular risk, perhaps related to their smoking. Recent work has suggested that patients with widespread pain syndromes have a higher overall mortality rate. Serum alkaline phosphatase and GGT levels were also raised, and again may represent low-grade inflammation or may be related to smoking. Again, further work in these areas would be justified.
Symptoms in patients with low serum 25-OH vitamin D did not differ significantly from those in patients with higher levels. Following the study, 18 FMS patients and two controls with serum 25-OH vitamin D concentrations less than 19 nmol/l were given a single injection of calciferol 300 000 units. Eight patients and no controls felt subjective improvement, and in three improvement persisted at 3 months. Those who had initial symptomatic benefit had a mean (S.D.) serum parathyroid hormone concentration of 5.3 (3.04) pmol/l compared with 3.46 (2.4) pmol/l in those who showed no response. Three months after the injection there was no change in HAQ or FIQ scores following calciferol, and serum alkaline phosphatase paradoxically rose, although this rise was confined to those who claimed no symptomatic relief.
It is conceivable that patients with FMS who have an abnormality identified and are given an injection for this may well have a marked placebo response; further controlled studies are again indicated, although there might be an ethical problem in denying treatment in patients with low serum 25-OH vitamin D in a control group. In the meantime, we draw attention to the frequency with which we found vitamin D subnutrition in fibromyalgia patients.
![]() |
Acknowledgments |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|