Evidence of altered bone turnover, vitamin D and calcium regulation with knee osteoarthritis in female twins

D. J. Hunter1,2, D. Hart2, H. Snieder2,4, P. Bettica5, R. Swaminathan3 and T. D. Spector2

1Rheumatology Department, Royal North Shore Hospital, Sydney, Australia, 2Twin Research and Genetic Epidemiology Unit and 3Department of Chemical Pathology, St Thomas’ Hospital, London, UK4Georgia Prevention Institute, Medical College of Georgia, Augusta, GA, USA and 5European R&D, P&G Pharmaceutical, Staines, UK.

Correspondence to: T. D. Spector, Twin Research and Genetic Epidemiology Unit, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK. E-mail: tim.spector{at}kcl.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. Osteoarthritis (OA) is a disorder of the whole synovial joint organ. There is growing evidence of the importance of bone turnover in OA, and human studies have demonstrated that the subchondral bone is metabolically active in OA. The aim of this study was to assess the relationships of radiographic knee OA with altered bone turnover and calcium regulation.

Methods. We performed a matched and unmatched case–control study using twins assessed for OA. The subjects were 1644 female Caucasian twin pairs (266 monozygotic and 556 dizygotic) aged 24–79 yr from the St Thomas’ UK Adult Twin Registry. Assays for measures of bone turnover [bone-specific alkaline phosphatase, osteocalcin and urinary deoxypyridinoline (DPD)] and calcium regulation [serum parathyroid hormone (PTH), 25-hydroxyvitamin D, serum calcium, serum magnesium and serum phosphate] were performed. The radiological features of knee OA were graded on a four-point scale (0–3) for osteophytes and a five-point scale (0–4) for Kellgren and Lawrence classification. Adjustment for age, body mass index (BMI) and relatedness was made. Conditional logistic regression analysis was also used to estimate the odds ratio (OR) and 95% confidence intervals (CI) for having radiological features of knee OA per standardized unit difference of serum variable between twins.

Results. Of the 1644 women studied, 474 (28.8%) had radiological evidence of knee osteophytes. There was evidence of increased bone turnover, increased PTH levels and decreased vitamin D levels in this group compared with those without osteophytes. No association was seen with joint space loss. After adjusting for age, BMI and relatedness, all of the differences disappeared except for a significant increase 10% in urinary DPD (P = 0.04). Discordant twin pair analysis (performed on a subgroup of 229 pairs) confirmed modest increases in bone resorption indicated by urinary DPD (OR 1.67, 95% CI 0.88–3.16) and a significant decrease in serum magnesium (OR 0.65, 95% CI 0.46–0.92) in the co-twins with OA.

Conclusion. Bone resorption is increased in women with knee OA, consistent with metabolically active subchondral bone. However, bone formation, vitamin D and calcium regulation were not different after adjusting for age and BMI. The results suggest that bone resorption is increased in the presence of OA. Although we cannot clearly differentiate a cause or effect relationship, these results suggest that this is related to disease mechanisms and point to potential diagnostic or therapeutic avenues for bone resorption in OA.

KEY WORDS: Osteoarthritis, Bone turnover


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Osteoarthritis (OA) is a disorder of the whole synovial joint organ, not just the cartilage [1]. Although cartilage pathology is traditionally thought to be the primary mechanism behind OA, the role of subchondral bone changes is also important. A number of studies have highlighted this fact. Radin and Rose [2] suggested that subchondral bone changes may have a role in the initiation and progression of cartilage damage and suggested that OA may initially be a bone disease rather than a cartilage disease. Subchondral bone stiffness may be part of a generalized inherited increase in bone mineral density (BMD). Once cartilage damage is initiated, the stiffness of the subchondral bone may contribute further to progression and chondrocyte dysfunction [3]. Higher bone density may increase and osteoporotic bone may decrease the peak mechanical stress on cartilage during impact loading. Once OA is established, it could in turn influence bone remodelling.

Nevitt et al. [4] suggested a number of mechanisms for the changes in bone remodelling secondary to OA, such as altered distribution of mechanical stresses, reduced area and shock-absorbing capacity of cartilage, stiffening and increased vascularization of periarticular bone, and changes in musculature and weight-bearing through the joint. However, Li and Aspden [5] found subchondral bone of surgically removed femoral heads from age- and sex-matched patients with osteoporosis (OP) to be less stiff than that from normal controls. However, there was a 72% increase in the volume of trabecular bone in the OA group compared with a loss of about 20% in the OP group. This increased apparent density of the OA trabecular bone resulted in greater stiffness, yield strength and energy absorbed to yield, whereas the same properties of OP bone were not significantly lower than normal. They postulated that subchondral bone by itself could not explain both the preservation of the overlying cartilage in OP and the destruction in OA.

Bone scintigraphy has been shown to predict the outcome of OA of the knee joint [6]. Only patients with positive bone scans at baseline showed progression to surgery or radiographic changes of OA. The positive bone scans were felt to reflect increased subchondral bone remodelling.

Thus, there is growing evidence of the importance of bone turnover, and a number of studies have demonstrated that subchondral bone is metabolically more active in OA. We have previously shown in twins strong genetic influences of markers of bone turnover and calcium and vitamin D metabolism [7]. Previous research has also suggested that low serum levels of vitamin D appear to be associated with an increased risk of progression of OA of the knee [8]. With this in mind, we performed a case–control study using twins discordant for OA to assess the relationship between radiographic knee OA and both bone turnover and calcium regulation. Twin studies provide a unique opportunity to examine risk factors in twin pairs discordant for this disease trait. The main advantage of using twins is that both monozygotic (MZ) and dizygotic (DZ) twins are closely matched for age as well as genetic and environmental factors, which markedly reduces the effects of confounding and error variables [9, 10].


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study population
The subjects were 882 female Caucasian twin pairs aged 24–79 yr who had knee X-rays and a biochemical marker assayed, from the St Thomas’ UK Adult Twin Registry, a volunteer sample recruited through a national media campaign in the UK [11]. The subjects used for the matched case–control study were 229 female Caucasian twin pairs (66 MZ and 163 DZ) discordant for knee OA. None of the study subjects was aware of the hypothesis under test. Ethics approval was obtained from the hospital ethics committee and full informed written consent was obtained from all subjects. Zygosity was determined with a standardized questionnaire, and DNA fingerprinting was used for confirmation [12].

Data ascertainment
Demographic information was obtained by a standardized nurse-administered questionnaire. Height and weight were measured and body mass index (BMI; kg/m2) was calculated.

Blood and second voided urine samples were collected in the early morning (at the same time and place for both twins of the pair) after an overnight fast, and stored at –20°C until assayed. Twenty-four-hour urine collection was commenced on the same day, and returned the following day. All twin pair samples were measured in duplicate in the same assay. The measures of calcium regulation included parathyroid hormone, vitamin D and 24-h urinary calcium. Measures of bone formation were osteocalcin and alkaline phosphatase (ALP), and the measure of bone resorption was urinary deoxypyridinoline (DPD).

Assays
Serum intact parathyroid hormone (PTH) was measured using a two-site chemiluminometric immunoassay (MagicLite Intact PTH; Chiron Diagnostics, Emeryville, CA, USA). The sensitivity was 1.4 ng/l, and the intra- and interassay coefficient of variation (CV) at 40 ng/l was less than 10%.

Serum 25-hydroxyvitamin D (25-OH-D) was measured with a specific radioimmunoassay (25-hydroxyvitamin D RIA kit; Incstar, Stillwater, MN, USA) after extraction of serum with acetonitrile. The sensitivity was 3 µg/l and the intra- and interassay precision at 30 ng/ml was 6.1 and 15.6% respectively.

Assays for serum calcium, magnesium and phosphate were performed using standard laboratory procedures. These tests were performed on a 950 Vitros analyser (Ortho-Clinical Diagnostics, Johnson and Johnson, Rochester, NY, USA). The analyser uses dry chemistry slide technology and reflection spectrophotometry. The interassay CVs for serum calcium were 1.2 and 0.9% at 2.1 and 2.9 mmol/l respectively, those for serum magnesium were 1.3 and 1.2% at 1.0 and 2.0 mmol/l respectively, and those for serum phosphate were 1.1 and 0.7% at 1.10 and 2.40 mmol/l respectively.

Serum total osteocalcin was measured with a competitive immunoassay (NovoCalcin; Metra Biosystems, Mountain View, CA, USA). This monoclonal antibody is believed to recognize only intact osteocalcin. The sensitivity was 0.45 µg/l and the intra- and interassay CVs were 8 and 10% respectively at 8 µg/ml.

Serum total alkaline phosphatase was measured using an automated analyser (Vitros ALKP Slides; Johnson and Johnson). The sensitivity was 20 U/l and the intra- and interassay precision was below 5.2 and 7.4% respectively.

Bone-specific alkaline phosphatase (BSAP) was measured with a monoclonal antibody that demonstrates specificity for BSAP (Alkphase-B; Metra Biosystems), thus providing a quantitative measure of BSAP activity in serum as a measure of osteoblastic activity. The sensitivity was 0.7 U/l and the intra- and interassay CVs at 28 U/l were 3.3 and 7.9% respectively.

Urinary DPD cross-links were measured on non-hydrolysed urine samples using a competitive enzyme immunoassay (Pyrilinks-D; Metra Biosystems), and corrected for urinary creatinine concentration. The monoclonal antibody had less than 1% cross-reactivity with free pyridinoline and no significant interaction with cross-linked peptides. The minimum detection limit was 1.1 nmol/l and the intra- and interassay CVs at 30 and 80 nmol/l were less than 10%.

Radiographs
Radiographs of the knees were obtained with a weight-bearing anteroposterior view in full extension. All radiographs were assessed by two trained observers (DJH, DH), who were blind to the pairings, zygosity and clinical findings. Using an atlas of individual features [13], the radiological features of knee OA in the tibiofemoral joint were graded on a four-point scale (0–3) for osteophytes and joint space narrowing. Grade 1 disease on our scale, which indicated a definite feature, was equivalent to the grade 2 score of the original Kellgren and Lawrence classification [14].

The inter-observer reproducibility, tested on a subgroup of 100 of the twins, was estimated using a weighted {kappa} statistic and found to be very satisfactory, ranging from 0.62 to 0.81 for different radiological features of knee OA. The intra-observer agreement ranged from 0.74 to 0.85.

Statistical analysis
The aims of the analysis were twofold: (i) to examine the association of radiographic knee OA with biomarkers of bone turnover and calcium regulation in the whole population; and (ii) to examine differences in these markers in a matched case–control design of twin pairs discordant for OA.

Firstly, association of altered bone turnover/calcium regulation with radiographic knee OA was tested in the whole population after adjusting for age, BMI and relatedness using the generalized estimating equation (GEE) method and a binary outcome.

For the matched analysis of markers and radiographic OA, the informative twins were only the pairs discordant for the disease trait. These were used to examine whether there was a difference in the serum variable in the twin with disease compared with the co-twin without disease. To improve power, MZ and DZ twins were combined in the analyses. Paired analyses were then performed in a way analogous to a case–control study, the twin with the disease being treated as the case and the co-twin as the control. Conditional logistic regression analysis was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for having radiological features of knee OA per standardized unit difference of the serum variable. The standardized variable reflects a normal distribution with a mean of 0 and standard deviation of 1. The BMI was used as a continuous confounding variable for adjustment. Where a significant association was found between OA and the serum variable, this was used in a stepwise conditional logistic regression with backward elimination.

There was no correlation between radiographic grade and physical activity, so this was not included in the analyses. Menopause status was highly concordant between twin pairs, and after adjusting for age no further effect was found by further adjusting for menopause status.

The third part of the analysis was performed to assess the relation between the severity of radiographic knee OA and the DPD level. In addition, the effect of generalized disease on DPD level was assessed. A generalized OA score was computed from three sites: knee, hip and hand (0, no site affected; 1, one site affected; 2, two sites affected; 3, three sites affected).

The analysis was carried out using the statistical software package STATA (Stata Corporation, College Station, TX, USA).


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Knee X-rays of 1764 women were assessed for features of knee OA. To simplify the analysis, only twin pairs who both had assays were included. Both a knee X-ray and at least one assay measure were available for 1644 individuals. The basic characteristics of the study population are shown in Table 1. The subjects with knee osteophytes were on average 5 yr older and 5 kg heavier than subjects without knee osteophytes. The notable findings are higher unadjusted values of DPD, total ALP, BSAP, osteocalcin and PTH and lower 25-OH-D in the knee osteophyte group compared with the other subjects. No difference was seen for calcium, magnesium and phosphate. The demographics of the population were similar for each measure obtained.


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TABLE 1. Basic characteristics of the subjects: mean (S.D.) [number of individuals]

 
The differences in the biochemical variables for knee osteophytes after adjusting for the potential confounding influences of age and BMI using GEE are demonstrated in Table 2. Women with OA had increased bone resorption, as indicated by a 10% higher DPD level. None of the other variables remained significant, and there was no relationship seen with joint space narrowing.


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TABLE 2. Difference in bone markers for knee osteophyte, adjusting for age, BMI and relatedness (GEE)

 
For the discordant twin OA analysis, the mean and standard deviation for the MZ and DZ twin pairs studied were similar. When MZ and DZ pairs were analysed as separate groups, the magnitude and direction of the effects obtained were similar to the combined analyses, although with reduced power.

Table 3 shows the estimates for the OR and 95% CI of the co-twin having radiological features of knee OA per standardized unit difference of serum variable after adjusting for BMI. This analysis was conducted on up to 229 twin pairs (66 MZ and 163 DZ) discordant for OA. For DPD the OR was increased but the confidence limits included unity (OR 1.67, 95% CI 0.88–3.16). When DPD quartiles were assessed, the OR comparing those in the lowest quartile with the highest quartile was 1.39 (95% CI 1.00–1.96). Magnesium levels were lower in OA twins. There were only modest differences for the other variables. There was no clear evidence of interaction between BMI and any of the markers.


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TABLE 3. Odds ratio for knee OA per standard deviation of biochemical variable after adjusting for BMI

 
Further analyses of DPD to see whether this is influenced by disease severity in the knee and/or the extent of disease in other joint areas are presented in Tables 4A and B. These data demonstrate an increase in bone turnover with increasing knee OA severity and increasing number of joints involved in a generalized OA process.


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TABLE 4A. Urinary DPD level by degree of radiographic severity (Kellgren and Lawrence grade): mean (S.D.) [n]

 

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TABLE 4B. Urinary DPD level by extent of radiographic involvement (generalized OA score; GOA): mean (S.D.) [n]

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This is the first study to assess in a large, well-described population the variation of bone biomarkers and measures of calcium regulation with knee OA. Bone involvement is a major feature in the pathophysiological process of OA, and quantification of bone turnover is likely to add important information to our understanding of this disease.

Our data show that bone resorption, as measured by urinary DPD, is increased by about 10% in women with knee OA, which is consistent with metabolically active subchondral bone. However, differences in other markers of bone turnover and calcium regulation between OA patients and controls were largely accounted for by age and BMI, which are major OA risk factors. The localized nature of the bone remodelling in OA may not be reflected in these systemic measures, although the effects of obesity on markers may be of further interest. The discordant twin pair analysis revealed a significant reduction in the risk of having OA with higher magnesium levels, although this was not confirmed in the unpaired analysis, which suggests we should be cautious in our interpretation.

Previous studies have suggested that early OA is characterized by significant changes in bone turnover. This has been recorded by scintigraphy [6] and measurement of osteocalcin [15, 16]. The previous studies of osteocalcin were generally of small sample size and inconsistent, and suggested a reduction in osteocalcin in early OA, and an increase in established OA. Our data show an increase in osteocalcin in subjects with OA when unadjusted. However, after adjusting for age and BMI the effect disappeared, suggesting that in the mild OA cases in our cohort bone formation is not a major factor.

There are a number of type-1 collagen cross-link immunoassays that have been used in evaluating changes in bone turnover in joint disease. This work was pioneered by Robins et al. [17] and suggested that OA is associated with increases in urinary DPD. Our data support this with an increase in DPD of 10% in those with knee osteophytes. The discordant twin pair analysis confirmed a trend in this direction, which was significant when quartiles were compared. The wider confidence intervals resulted from the much smaller size of the sample and the fact that a large proportion of the variance in DPD is under genetic influence [7]. It is likely that, if we had taken samples of DPD at multiple time points, our results would have been even clearer. The difference is not explained by menopause status, as twins are well matched for menopause status [18].

The vitamin D level was lower in subjects with OA, as was previously suggested by McAlindon et al. [8]. This finding was also suggested in another study, which showed low serum levels of 25-vitamin D may be associated with incident changes in radiographic hip OA characterized by joint space narrowing [19]. In our study, after adjusting for the confounders age and BMI, this trend was no longer significant. Again, this may be explained by the fact that a large proportion of the variance of vitamin D is under genetic influence, which has not been adjusted for in previous studies [7].

The discordant twin pair analysis revealed a significant reduction in the risk of having OA with higher magnesium levels, or conversely an increased risk with lower magnesium levels. If true, these results are not easy to explain. Previous research has suggested that OA is associated with thickening of the subchondral bone with an abnormally low mineralization pattern, such that lower levels of magnesium may predispose to the development of OA. Another explanation may lie in lower levels representing deposition within the magnesium whitlockite crystals frequently seen in OA.

Despite the large number of twins included, there are a number of limitations of this study which are worth mentioning. As with all surveys of OA, disease classification remains a problem. There is no absolute clinical, radiological or pathological standard against which the epidemiology of OA can be tested [20]. To avoid systematic misclassification of OA, the women were classified as having disease on the basis of radiographs.

The number of discordant pairs was comparatively small, especially for MZ twins, due to the strong genetic influences on the disease. Therefore, we pooled MZ and DZ twin pairs, and the results remained essentially similar to those for DZ pairs alone.

Potential limitations associated with twin studies generally include discussion on the generalizability of the study. The prevalence of radiological OA, symptoms and risk factors in our twin population-based cohort was similar to that of the Chingford general population [21].

It is not possible to conclude from this cross-sectional study whether these metabolic abnormalities are responsible for incident disease or the progression of OA, or whether they are a consequence of the disease. As most of the variables are under strong genetic control, evidence of no difference within matched pairs may imply that the variable is important in susceptibility to disease rather than that it is a secondary phenomenon. Finding a difference, however, suggests that it is a result of the disease, implying that bone resorption may be secondary and part of the disease process.

In conclusion, this study demonstrates that subjects with radiographic OA have increased bone resorption, as manifested by urinary DPD levels. Furthermore, our data suggest that this is a result of the disease rather than inherited susceptibility. However, other biomarkers of bone turnover, vitamin D and calcium regulation were no different from those in controls after adjusting for confounders. In an era when structure-modifying agents are being developed, this finding has important implications for the planning of clinical trials using bone biomarkers as clinical end-points, and suggests the diagnostic and therapeutic potential of bone resorption in OA.


    Acknowledgments
 
DH is sponsored by Ramsay Health. The study was supported by funding from the British Heart Foundation, the Arthritis Research Campaign, Gemini Genomics and Proctor & Gamble. We would like to thank the staff of the Twin Research Unit, the technical staff of the Department of Chemical Pathology, St Thomas’ Hospital, and the twins themselves for their participation.

Conflict of interest

The authors have declared no conflicts of interest.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 22 April 2002; Accepted 26 March 2003





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