Incidence of total hip or knee replacement due to osteoarthritis in relation to thyroid function: a prospective cohort study (The Nord-Trøndelag Health Study)

Osteoarthritis in the hip and knee is a major health problem and leads to significant morbidity [1]. Several drugs have been evaluated, but so far only exercise has been found to effectively prevent or delay the onset of osteoarthritis [2, 3]. This finding emphasizes the importance of identifying modifiable risk factors. Thyroid hormones play a role in the remodelling and maintenance of bone, and recent studies also indicate the potential importance of thyroid hormones in joints and articular cartilage [4]. Genetic studies have suggested that deiodinase-regulated local availability of the active thyroid hormone triiodothyronine (T3) plays an important role in cartilage maintenance and repair [5]. Further data have indicated that increased intracellular T3 availability increases the risk of osteoarthritis, leading to the hypothesis that reduced tissue T3 availability protects joints from development of osteoarthritis [6]. A phase III clinical trial investigating the use of eprotirome, a thyroid receptor β-agonist, for treatment of hypercholesterolemia [7], was terminated due to indications of dose related articular cartilage damage in dogs which had been treated with eprotirome for 12 months [8]. This was surprising, as eprotirome is a liver-specific thyroid receptor β-agonist, but it indicates that thyroid hormones influence cartilage [9] and could play a role in the pathogenesis of osteoarthritis.

No prospective population studies have investigated the association between thyroid function and osteoarthritis. An older cross-sectional study did not find any association between radiological knee osteoarthritis and thyroid status measured by thyroid stimulating hormone (TSH) [10]. In this prospective cohort study of 37 891 individuals without previously known thyroid disease, the aim was to assess whether thyroid function was associated with subsequent risk of hip or knee replacement due to primary osteoarthritis.

In the Nord-Trøndelag Health Study (HUNT) all inhabitants of Nord-Trøndelag county ≥ 20 years of age were invited to participate in three surveys: HUNT1 (1984–1986), HUNT2 (1995–1997) and HUNT3 (2006–2008) [11]. This study only included data from the HUNT2 and HUNT3 surveys, as the HUNT1 study did not collect blood samples. HUNT2 had 65 237 participants (69.5% of those invited), and HUNT3 had 50 807 participants (54.1% of those invited) [12].

In HUNT2, TSH was measured in 35 269 persons; in all women over 40 years old, in a random 50% sample of men over 40 years old and in a random 5% sample of participants aged 20–40 years. In HUNT3, TSH was measured in all 49 179 participants. We included 35 269 participants from HUNT2 and 13 132 new participants with TSH measurements from HUNT3. In persons that participated in both HUNT2 and HUNT3, baseline measurements from HUNT2 were used in the main analyses. Among these 48 401 individuals, 10 510 were excluded from analysis (Fig. 1). The exclusion criteria included self-reported thyroid disease (hypothyroidism, hyperthyroidism, goitre, other thyroid disease, use of levothyroxine, carbimazole, previous thyroid surgery or radioiodine therapy) (n = 3895), missing information on BMI (n = 364), missing information on smoking (n = 962), previous THR or TKR (n = 644), missing date of operation (n = 99), emigration during baseline measurements period (n = 1) or self-reported osteoarthritis at baseline (n = 4545). Thus, a total of 37 891 people (22 714 women and 15 177 men) were eligible for follow-up in this study. Each participant contributed person-years from baseline (either between August 1995 and June 1997 or between October 2006 and June 2008) until a THR or TKR due to osteoarthritis, THR or TKR due to other causes, migration, death or end of follow-up (December 31, 2013), whichever occurred first.

Of the 37 891 participants, 908 (2.4%) had low TSH (<0.50 mU/l) indicating hyperthyroid function, and 2307 (6.1%) had high TSH (≥3.6 mU/l) indicating hypothyroid function (Table 1). Among the women, 6.9% had high TSH, compared to 4.8% of men. Participants with high TSH were generally older and were less likely to be current smokers than participants in the reference group (TSH 1.5–2.4 mU/l). No clear trend was seen in relation to physical activity.

In total, 978 received THR and 538 received TKR during a median follow-up time of 15.7 years (mean 12.3 years). At baseline, the mean age was 50.7 years (SD 15.8), and the mean ages at THR and TKR were 69.5 years (SD 8.9) and 69.4 years (SD 8.4), respectively.

TSH level did not influence the risk of THR or TKR in the unadjusted analysis or the analysis adjusted for gender, age, BMI and smoking (Table 2). Neither additional adjustment for physical activity and diabetes (Table 2), nor collapsing the outcome variable into total joint replacement (TJR) (Table 3), altered these results. Analyses using TSH as a continuous variable did not show any association between TSH and THR or TKR (Fig. 2). Additional log-transformation of TSH as a continuous variable did not significantly change these results (data not shown).

In a separate analysis studying the change in TSH (delta-TSH) during the time between HUNT2 and HUNT3, 11 657 participants were included. Of these, 200 received THR and 102 received TKR during a mean follow-up time of 6.1 years. No association was seen between changes in TSH and risk of THR or TKR (Fig. 3). Additional adjustment for baseline TSH did not substantially alter these results. The same sub-population was also used to identify persons with no thyroid disease or treatment at baseline in HUNT2 who still had no thyroid disease or treatment at HUNT3. However, no association between TSH and THR (HR 1.00, 95% CI 0.97–1.02) or TKR (HR 0.98, 95% CI 0.94–1.03) was found.

In a sensitivity analysis neither overt hypo- nor hyperthyroid function was found to influence the risk of THR or TKR, (HR 0.91, 95% CI 0.40–2.04) and (HR 2.01, 95% CI 0.75–5.4) respectively. Also, no association was found between overt hypothyroid function and TKR (HR 1.03, 95% CI 0.38–2.78). There were no cases of TKR amongst the overtly hyperthyroid, so no analysis could be performed in this subgroup.

In additional analyses on the baseline population, there was no association between TSH levels and self-reported osteoarthritis at baseline (data not shown). Those with self-reported thyroid disease at baseline had an incidence rate of 0.0027 THR per person-year and 0.0015 TKR per person-year. Our main study population (excluding those with self-reported thyroid disease) had an incidence rate of 0.0021 THR per person-year and 0.0012 TKR per person-year. This gave and incidence rate ratio of 1.28 (95% CI 1.04–1.56) for THR, and 1.27 (95% CI 0.95–1.95) for TKR, and indicated a slightly higher incidence rate for THR in those with self-reported thyroid disease, but no significant difference in the incidence rate for TKR, compared to participants without self-reported thyroid disease.

In this large prospective study we did not find any association between thyroid function and the risk of THR or TKR due to osteoarthritis. Neither were changes in TSH over time, or overt hypo- or hyperthyroidism, associated with incidence of THR or TKR.

Few previous population studies have investigated the association of thyroid function with risk of osteoarthritis. In 1996, a cross-sectional study of 577 men and 798 women found no evidence of a significant association between current thyroid status and either chondrocalcinosis or osteoarthritis [10]. However, that study only investigated prevalent osteoarthritis with a concurrent serum TSH concentration and could not take into account development in TSH or later treatment for abnormal thyroid function. Since our study could use data from both the second and third waves of the HUNT-survey, we were able to investigate the development of TSH over a median time of 11.2 years (SD 0.6). Change in TSH over time was however not associated with osteoarthritis development resulting in the need for joint replacement.

Previous or current thyroid disease at baseline was an exclusion criterion in our study. Nonetheless, all participants with TSH levels suggesting hypothyroid or hyperthyroid function may have received medical treatment for thyroid disease during the follow-up period, as participants with biochemical indication of pathological thyroid function were recommended to contact their general practitioners [22]. This could have weakened any association between TSH and osteoarthritis. We therefore did a sub-analysis of persons that participated in both HUNT2 and HUNT3, and excluded participants that reported use of thyroid medication or thyroid disease in HUNT3. This did not significantly alter the results.

Our findings must be interpreted in relation to recent genetic studies on intracellular T3 availability in joint cartilage. There has been an increased interest in the effect of deiodinase polymorphisms on osteoarthritis [5]. Iodothyronine deiodinases represent a family of proteins involved in local homeostasis of thyroxine (T4) and triiodothyronine (T3). Three deiodinases have been described and, of these, the deiodinase type 2 (D2) and deiodinase type 3 (D3) are detected in bone and cartilage. D2 plays a major role in conversion of T4 to biologically active T3 [23] and thus upregulates local T3 levels. Deiodinase type 3 (D3) is the main T3-inactivating enzyme and consequently downregulates the local T3 levels. T3 is considered an important regulator of chondrocyte cell growth and differentiation in the endochondral growth plate [24]. Local T3 availability, regulated by the opposite functions of D2 and D3, may be a determinant of osteoarthritis development. D2 has been reported to be upregulated in the cartilage of joints affected by osteoarthritis compared to joints unaffected by osteoarthritis [25, 26]. However, it is not known if this is a result of the ongoing osteoarthritis process, or a reflection of the underlying disease pathway. Taken together, these findings suggest that deiodinase regulated local availability of T3 in chondrocytes is a possible factor in the pathophysiology of osteoarthritis [27, 28]. Since our study did not find any association between circulating TSH, T3/T4 levels and osteoarthritis, it is conceivable that the serum thyroid hormone levels may be independent of local intracellular T3 levels in joints. Another possible explanation could be that polymorphism in the gene coding for D2 creates a predisposition for non-optimal bone shape [29, 30], leading to increased risk of osteoarthritis independent of local thyroid hormone levels.

In this prospective study of 37 891 participants without previously known thyroid disease, we did not find that thyroid function was associated with risk of hip or knee joint replacement due to osteoarthritis. Neither did we find any association between TSH development over time and risk of hip or knee joint replacement due to osteoarthritis.