Bone turnover in untreated polymyalgia rheumatica

T. C. Barnes1, A. Daroszewska1,2, W. D. Fraser2 and R. C Bucknall1

1Departments of Rheumatology and 2Clinical Chemistry, Royal Liverpool University Hospital, Liverpool, UK.

Correspondence to: T. Barnes, Department of Rheumatology, Link 7C, Royal Liverpool University Hospital, Prescot Street, Liverpool, L7 8XP, UK. E-mail: tbarnes{at}doctors.org.uk


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Polymyalgia rheumatica (PMR) is a common condition in the elderly. A previous study demonstrated that it is associated with an increase in bone resorption. This effect was ameliorated by steroids, implying that inflammation is the cause of increased bone resorption and that this can be reduced by steroids. This is in keeping with accumulating evidence that systemic inflammation is associated with bone resorption and bone loss. We studied bone formation and resorption markers in 53 patients with PMR prior to any therapeutic intervention.

Methods. Bone resorption was measured by estimating urinary free pyridinoline (fPYD) and deoxypyridinoline (fDPD). Bone formation was estimated by measuring serum concentrations of procollagen type 1 N-terminal propeptide (P1NP). Disease activity was assessed using inflammatory markers (erythrocyte sedimentation rate and C-reactive protein). Patients had a baseline dual-energy X-ray absorptiometer scan to assess bone mineral density.

Results. Bone resorption markers were significantly increased and bone formation markers significantly decreased in PMR patients prior to treatment, compared with a control population matched for gender and age.

Conclusions. This implies that bone turnover is uncoupled in PMR. This may lead to a decrease in skeletal mass in the long term due to the disease process alone. However, no significant loss of bone mineral density was detected. It is possible that, due to the acute onset of PMR, increased bone resorption is not present long enough to result in a detectable decrease in bone mineral density. The effects of steroid treatment on bone metabolism and the subsequent long-term outcome need to be investigated.

KEY WORDS: Polymyalgia rheumatica, Bone turnover, Osteoporosis.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Polymyalgia rheumatica (PMR) is a condition which is common in elderly Caucasians (12.7–68.3/100 000 population aged over 50 yr). The male:female ratio is 1:3. It is an inflammatory disease characterized by pain and stiffness affecting the shoulder and pelvic girdle muscles. It is associated with a profound inflammatory response. Patients have morning stiffness, weight loss, fatigue and an acute-phase response [elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)]. Treatment is with steroids and the response is usually rapid, but long-term steroids are needed to maintain remission. This cohort of patients has multiple risk factors for osteoporosis. It consists predominantly of elderly, postmenopausal women who are then exposed to steroids.

Accumulating evidence suggests that inflammatory conditions are associated with an increase in bone turnover. This has been demonstrated in rheumatoid arthritis and ankylosing spondylitis [14]. PMR has a sudden onset of symptoms, which come on over a period of days, and it is not organ-specific. It is therefore a good condition in which to further define the effects of a specific inflammatory process on bone turnover. This study aimed to define the bone turnover in patients with PMR prior to any treatment and how this may translate into detectable changes in bone mineral density.

A recent study demonstrated that the bone resorption markers pyridinoline and deoxypyridinoline were increased at diagnosis in patients with PMR [5]. The increase in bone resorption markers correlated with the initial ESR. This study demonstrated that bone resorption markers were reduced and bone formation markers were increased following treatment with steroids for 6 months. A significant decrease in bone mineral density was observed after 6 and 12 months of treatment. This was found to correlate with ESR at diagnosis but not with the mean ESR at 6 or 12 months. There was no correlation with total steroid dose, which was interpreted as showing that the initial inflammation and its effect on bone turnover was a more potent risk factor for the development of osteoporosis than the treatment with steroids [5].

A study of patients with late-onset rheumatoid arthritis and PMR found that untreated patients at diagnosis had normal concentrations of the bone formation markers serum osteocalcin, alkaline phosphatase and ostase, and normal bone mineral density, measured by dual-energy X-ray absorptiometer scanning [6].

In this study the patients were recruited at diagnosis of PMR, prior to starting any treatment. Biochemical markers of bone turnover were measured at baseline. Bone formation was assessed by measuring the N-terminal propeptide of type 1 procollagen (P1NP), which is cleaved from procollagen during the formation of mature collagen in bone. Bone resorption was assessed by measuring urinary free pyridinoline (fPYD) and deoxypyridinoline (fDPD). These are collagen cross-links which are liberated during bone resorption. Urinary concentrations were measured and corrected for creatinine excretion. PYD is present in both type 2 collagen of cartilage and type 1 collagen of bone. DPD is found almost exclusively in mature bone. Both have been shown to be useful markers of bone resorption in metabolic and rheumatic diseases [711].


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Fifty-three patients with PMR were recruited from the Mersey region according to the criteria shown in Table 1. All patients gave informed written consent. Ethical approval was given by the Liverpool Adult Research Ethics Committee. Details of the study group are summarized in Table 2.


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TABLE 1. Recruitment criteria

 

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TABLE 2. Patient characteristics

 
Disability was measured using the alternative disability index derived from a subset of the Health Assessment Questionnaire (HAQ) [12]. Pain was assessed using a visual analogue score (VAS). Disease activity was assessed using the Global Disease Activity Score (GDAS), another VAS [13]. Objective disease activity was assessed using the ESR (mm/h) using the Westergren method, and the CRP concentration (mg/l) was measured using standard methods on a Hitachi analyser (Roche, Lewes, UK).

Composite measurements of bone mineral density at L1–4 and total hip, using a Hologic 1000 QDR (Bedford, MA, USA) in performance mode, were taken at baseline. Measurements were expressed as t and Z scores of hip and spine.

The bone formation marker P1NP (µg/l) was measured using the Orion Diagnostica (Espoo, Finland) radioimmunoassay (the interassay coefficient of variation is <8.3% across the normal working range of the assay). The bone resorption markers fPYD and fDPD (nmol/mmol creatinine) were measured in 2-h fasted urine samples. The method used to measure free cross-links in urine was a modification of the high-performance liquid chromatography (HPLC) method described by Black et al. [14]. Acidified urine was applied to microgranular cellulose (CC31) in butanol (1/4) and washed before elution with heptafluorobutyric acid (0.1%). The eluent was then analysed by ion-pair reverse-phase HPLC using fluorescence detection. Acetylated PYD (Metra Biosystems, Oxford, UK) was used as an internal standard. Creatinine was measured in the urine by standard automated techniques (Roche, Lewes, UK) and results were expressed as fPYD/creatinine and fDPD/creatinine (nmol/mmol). The interassay CV for both methods was <5.5% across the working range of the assays.

Mean bone turnover markers were compared with mean levels in the reference population using the Z test. Differences in means were expressed as 95% percent confidence intervals. The reference data were derived from a north-west UK control population known to have normal bone mineral density. Where possible, comparisons were made with age- and sex-matched controls. The controls were not matched for smoking/alcohol exposure and other known risk factors for osteoporosis. However, due to the large number of patients in the control population (760), bias was reduced to a minimum and the population met the IFCC (International Federation for Clinical Chemistry and Laboratory Medicine) criteria for a reference population for clinical biochemical analysis. Linear correlations were assessed using the Pearson coefficient and significance was assessed using a two-tailed test.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The patients with PMR had increased mean concentrations of the bone resorption markers urine free fPYD (Fig. 1) and fDPD (Fig. 2) compared with the reference population. In addition, the patients with PMR had decreased mean levels of the bone formation marker P1NP (Fig. 3). The 95% confidence intervals for the difference in means between the PMR patients and the reference population are shown in Table 3.



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FIG. 1. fPYD concentrations compared.

 


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FIG. 2. fDPD concentrations compared.

 


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FIG. 3. P1NP concentrations in PMR patients. The horizontal lines show the reference range.

 

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TABLE 3. Difference in mean bone turnover markers compared with the reference

 
There was no significant correlation between the bone turnover markers and inflammatory markers (Table 4), and no correlation between the VAS or GDAS and the bone turnover markers.


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TABLE 4. Pearson linear correlation coefficients of bone turnover and inflammatory markers

 
Eleven of the patients had established osteoporosis (t score less than -2.5). However, the average Z score was greater than 0 (0.21 for hip and 0.88 for spine) and fewer than 2.5% of patients had a Z score less than -1.96, implying that osteoporosis was not more prevalent than in the general population.

The 11 patients with osteoporosis did not have significantly longer disease duration at presentation (P = 0.6), and time to presentation did not correlate with the t score at presentation (r = -0.12). Only one patient, with greater than average time to presentation, had established osteoporosis at diagnosis (104 weeks).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In this study we demonstrated that patients with untreated PMR had elevated concentrations of the bone resorption markers fPYD and fDPD compared with controls. This is consistent with other studies which show an increase in bone resorption in PMR and other inflammatory conditions prior to treatment [15]. This implies that the inflammation itself is important in inducing bone resorption.

We have demonstrated that untreated patients with PMR had decreased serum concentrations of the bone formation marker P1NP compared with controls. This reached statistical significance among women but not among men. This is probably due to the very small number of men in our sample (11 men) or may reflect the additional postmenopausal effect on bone turnover in women. This is in contrast to a previous study in PMR patients which found no difference in procollagen type 1 C terminal propeptide (P1CP) levels at diagnosis compared with controls [5]. We demonstrated that bone turnover was uncoupled in PMR, with resorption predominating over formation.

P1NP was used in this study because it is a marker of collagen formation; it reflects formation but does not reflect all aspects of osteoblast function. Measures such as alkaline phosphatase, which reflect osteoblast cellular function, are subject to other influences and the liver fraction is often raised in PMR [15].

An increase in bone resorption would usually be accompanied by an increase in bone formation due to the close interrelationship between osteoclasts and osteoblasts during the process of bone remodelling. However, in these PMR patients there was no such increase in bone formation. Previous studies have demonstrated this uncoupling of bone turnover in rheumatoid arthritis [4].

Osteoclasts are derived from haemopoietic stem cells, which also give rise to the monocyte/macrophage lineage. Differentiation into osteoclasts is mediated by interaction of receptor activator of nuclear factor {kappa}B ligand (RANKL) with its receptor, receptor activator of nuclear factor {kappa}B (RANK), which is expressed on osteoclast progenitor cells. RANKL is a 317-amino acid peptide which can be membrane-associated on osteoblasts or secreted in a soluble form. There is also a soluble regulatory decoy receptor for RANKL, called osteoprotegerin (OPG), which binds RANKL and interferes with signal transduction and hence osteoclastogenesis. Many proinflammatory cytokines have been shown to affect the expression of both RANKL and OPG. Tumour necrosis factor {alpha} (TNF-{alpha}) and interleukin (IL) 1 increase OPG. IL-1, IL-6 and TNF-{alpha} increase RANKL expression [16]. We did not measure serum concentrations of inflammatory cytokines in these patients, but a previous study has demonstrated an increase in serum IL-6 production in PMR patients [5]. Studies have suggested that TNF, IL-1 and other inflammatory cytokines can increase osteoclastogenesis and bone resorption in vitro and in vivo [1722]. Of note, activated T cells express RANKL on their cell membranes and are capable of inducing osteoclastogenesis [23, 24]. This may explain why, in inflammatory conditions such as PMR, bone resorption is apparently switched on in the absence of an increase in osteoblastic activity.

Uncoupling could also be explained by direct action of cytokines on the osteoblasts themselves. Indeed, previous studies have indicated that TNF-{alpha} and IL-1 have an inhibitory effect on osteoblasts in vivo and in vitro [2527].

The uncoupling of bone turnover is not translated into a detectable loss of bone mineral density at diagnosis. This is presumably because the effect on bone turnover is acute, as a consequence of the acute inflammation seen in patients with PMR. Patients in this study were assessed at a median of 8 weeks from first symptoms (range 2–104 weeks). This supports the presumption that it is the inflammatory process seen in PMR that affects bone turnover.

It would appear from the data that bone resorption markers are not so elevated in younger women with PMR at diagnosis. In fact, PYD concentrations in women aged 55–64 yr with PMR are not significantly different from those in controls. Some of these women may not have been postmenopausal at the time of diagnosis and therefore may still have been exposed to the protective effects of oestrogens. However, most of these women would have been expected to be postmenopausal, and women usually have an accelerated rate of bone loss in the years immediately following the menopause, so the lower increase in bone resorption is not what would be expected. Perhaps younger women are less susceptible to the effects of inflammation on bone turnover than older women. This might also be linked to the observed fact that PMR rarely occurs before the age of 50. Alternatively, it may be that the number of patients in this group (6) was insufficient to reach statistical significance.

In this study we were not able to demonstrate a correlation between inflammatory markers and bone turnover markers. A previous study demonstrated a correlation between ESR and fPYD but not between ESR and fDPD or P1CP [5]. This may be because the ESR is not a direct measure of inflammation. It is dependent on the production of fibrinogen and immunoglobulins [28]. The ESR is increased in anaemia and hypoalbuminaemia, which were common in our population. In addition, the median age of our patients was 72 yr compared with 68 yr in the previous study, and it is well recognized that interpretation of the ESR is more difficult in the elderly. There is conflicting evidence, but studies in apparently well elderly patients revealed an ESR above 20 mm/h in 20% of them. On further investigation, there was a definable cause in all but 6.6% of patients. This was because there is a large amount of occult disease, including anaemia and hypoalbuminaemia, in elderly populations [18]. The previous study of bone turnover in PMR states that, although HAQ scores were not measured, all the patients in the study were mobile. This was certainly not the case in our study. Many of the patients had high HAQ scores (median 1.8, range 0.5–3) and had limited mobility at diagnosis. This may have affected bone turnover independently of ESR [2931]. However, there was no significant correlation between HAQ scores and bone turnover.

Clinical disease activity and bone turnover have been correlated with IL-6 in PMR [5]. In addition, CRP has been correlated with clinical disease activity but not, as far as we are aware, with bone turnover in PMR. CRP is known to correlate well with IL-6 concentrations in many inflammatory conditions and the acute-phase response. However, in PMR one study showed no correlation between CRP, ESR and various proinflammatory cytokines, including IL-6 [32]. This is probably due to the fact that many different cytokines are involved in the induction of CRP. This may explain in part why CRP did not correlate with bone turnover in our patients. We did not measure IL-6 in our patients and therefore are unable to comment directly on any relationships between IL-6, CRP and bone turnover in this population. Bone resorption is initiated and controlled by a network of cytokines interacting in a positive and negative function at the bone surface. Some of these cytokines are released from the bone and its associated tissues. This may explain why systemic markers of inflammation, such as CRP and ESR, do not correlate with bone turnover markers.

The important remaining issue to be resolved is the effect that the addition of steroid therapy will have in these patients. Steroids in isolation are known to increase bone turnover transiently by increasing bone resorption and decreasing bone formation. In the long term, a greater effect is observed on bone formation. However, in these patients steroids would presumably reduce inflammation and therefore decrease the effects of inflammatory cytokines on bone turnover, so disease modification may be beneficial to the bone in the initial stages of treatment.

The authors have declared no conflicts of interest.


    Acknowledgments
 
We wish to thank Frances Brennan, our research secretary, and MSD for supporting this study.


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
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Submitted 22 March 2003; Accepted 13 October 2003





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