Pain syndrome in women with osteoarthritis against the background of overweight and hypothyroidism

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Introduction

Osteoarthritis (OA) is recognized as the most common joint disease and is one of the main reasons for limiting physical activity among people over 40 years of age, which is associated with pain syndrome [1]. Pain leads to impaired mobility, worsens quality of life, contributes to disability and is a significant predictor of the risk of early mortality [2].

Pain syndrome in OA occurs as a result of pathological changes in periarticular tissues: trabecular microfractures, bone venous congestion, intramedullary hypertension, increased pressure on the subchondral bone, spasm of periarticular muscles, changes in intraarticular ligaments and irritation of surrounding tissues by osteophytes. Classically, the pain syndrome in OA is nociceptive. Chronic inflammation in OA promotes an increase in the number of Na+ channels in nerve fibers, accompanied by an increase in the frequency of nerve impulses, as a result of which pain control and modulation are disrupted. Increased excitability of peripheral nociceptors leads to stimulation of angiogenesis and the growth of new sensory fibers in joint tissue and the development of peripheral sensitization. Long-term peripheral sensitization leads to the development of central sensitization as a result of spontaneous excitability of central pain neurons (in neurons of the brainstem, anterior cingulate cortex, right dorsolateral prefrontal cortex, left middle frontal gyrus, and left lateral occipital region). The presence of neuropathic pain may be associated not only with central sensitization, but also with injury to the sensitive nerve fibers innervating the joint by the damaged subchondral bone plate [3]. Thus, the genesis of pain in OA is mixed and is the most common and pronounced symptom, in addition to morning stiffness, decreased range of motion, swelling, crunching and instability of the joints.

Obesity is one of the main risk factors for the development and more rapid progression of OA [1]. An increase in body mass index (BMI) by every 5 units increases the risk of developing knee OA by 35% [4], which is also confirmed by the data of the Rotterdam cohort study (3585 people over 6 years), where it was found that a BMI of more than 27 kg/m² is significantly associated with the progression of radiographic manifestations of gonarthrosis in the form of a narrowing of the joint space by 1.5 mm [5].

According to M. Cakir et al. (2008), musculoskeletal disorders are often detected in patients with hypothyroidism [6]. The prevalence of hypothyroidism ranges from 0.1 to 10 % [7]. The results of a study by Turkish scientists show a negative effect of uncompensated hypothyroidism on the thickness of the distal cartilage of the femur according to ultrasonography [8]. There are very few works devoted to the analysis of the effect of a compensated thyroid state on the course of OA.

The prevalence of comorbidity between OA, overweight and hypothyroidism may reach 2–4 % in the population and requires more thorough study.

The aim of the study is to evaluate pain syndrome and its relationship with clinical, laboratory and functional changes in women with OA against the background of excess body weight and hypothyroidism.

Materials and Methods

The study included 43 women with an established diagnosis of OA, with a BMI ≥ 27 kg/m² and aged from 40 to 65 years. The patients were divided into two groups according to thyroid function: group 1 – 18 women (mean age 52.6 ± 7.6 years) with primary drug-compensated hypothyroidism (TSH = 1.75 ± 0.96 μIU/ml) and group 2 – 25 patients (mean age 52.7 ± 7.8 years) without thyroid pathology (TSH = 1.8 ± 0.9 μIU/ml). The diagnosis of hypothyroidism was established based on anamnestic data (strumectomy, presence of autoimmune thyroiditis), the initial TSH level ˃ 4.0 μIU/ml.

All patients underwent physical and laboratory examination: assessment of thyroid status (TSH, free (free T₄), free T₃ (free T₃), thyroid peroxidase antibodies (Ab to TPO). In addition, the work took into account the parameters of phosphorus-calcium metabolism: total calcium, ionized calcium, phosphorus, parathyroid hormone, B-crosslaps; as well as parameters of non-specific inflammation: C-reactive protein (CRP), complete blood count (CBC).

The presence of OA and its severity were confirmed by radiography of the affected joints in two projections. The severity of the pain syndrome was determined using the visual analogue scale (VAS) [9], using the Leken algofunctional index, and the McGill questionnaire. The McGill questionnaire is a tool for not only quantitative but also qualitative pain assessment, allowing for a more complete picture of pain sensations.

The questionnaire includes three scales: sensory (list of pain sensations, consists of the first 13 sections containing 52 descriptor words), affective (impact of pain on emotional state, consists of the following six sections containing 16 descriptor words) and evaluative (assessment of pain intensity, corresponds to the 20th section and includes five characteristics). The analysis included the assessment of three indicators on scales: index of the number of selected descriptors (INSD) – the total number of selected verbal characteristics; pain rank index (PRI) – the sum of the ordinal numbers of descriptors in each section; pain intensity – assessment on the pain intensity scale [10].

The study did not include women over 65 years of age, with diabetes mellitus, severe concomitant pathology: liver failure, cancer, heart failure, unstable angina, rhythm and conduction disorders, myocarditis, respiratory failure, sepsis, pregnancy.

Statistical processing of the obtained data was carried out using the integrated package for statistical analysis Statistica 10. The normality of distribution was tested using the Shapiro-Wilk criterion. The results are presented as the mean and its error (M ± SD), as well as as the median Me (Q1–Q3). The reliability of differences (p) between the observation groups was assessed using nonparametric methods of comparison for quantitative (Mann-Whitney criterion (U-criterion), t-criterion) and qualitative characteristics (Pearson criterion (χ²)). For correlation analysis, the Spearman criterion (R) was used. Differences in indicators were considered reliable at a significance level of p ˂ 0.05.

Statistical processing of the obtained data was carried out using the integrated package for statistical analysis Statistica 10. The normality of distribution was tested using the Shapiro-Wilk criterion. The results are presented as the mean and its error (M ± SD), as well as the median Me (Q1–Q3). The reliability of differences (p) between the observation groups was assessed using nonparametric comparison methods for quantitative (Mann-Whitney criterion (U-criterion), t-criterion) and qualitative characteristics (Pearson criterion (χ²)). Spearman's R-test was used for correlation analysis. Differences in indicators were considered significant at a significance level of p ˂ 0.05.

Results and Discussion

Patients in both groups did not differ in terms of objective examination data (Table 1) and duration of OA (Fig. 1).

Table 1

Objective examination data by groups

Parameter	Group 1, n = 18	Group 2, n = 25	Р
Weight, kg	99.8 ± 20.7	94.9 ± 11.3	0.703
Waist circumference (WC), cm	106.3 ± 11.5	103.1 ± 10.5	0.490
Hip circumference (HC), cm	122.1 ± 11.7	117.5 ± 7.7	0.276
BMI, kg/m2	36.9 ± 6.6	36.1 ± 4.5	0.872

 

Fig. 1. Distribution of OA duration by groups

 

The majority of patients in both groups suffered from gonathrosis (67 % (n = 12) in group 1 and 84 % (n = 21) in group 2), less often from coxarthrosis (22 % (n = 4) of patients in group 1, 12 % (n = 3) in group 2), isolated cases of OA of the ankle and shoulder joints were determined. When assessing the severity of radiographic changes in OA in both groups, stage 1 according to Kellgren-Lawrence prevailed (72 % (n = 13) in group 1 and 60 % (n = 15) in group 2 (c² = 0.688; p = 0.407)).

The second radiological stage was recorded more often in patients of the 2nd group (36 % (n = 9)) while it was present in only one patient of the 1st group (2 = 13.361; p ˂ 0.001). The second radiological stage was recorded more often in patients of the 2nd group (36 % (n = 9)) while it was present in only one patient of the 1st group (c² = 13.361; p ˂ 0.001). The third radiographic stage according to Kellgren-Lawrence was detected in 22 % (n = 4) in the 1st group, and in the 2nd only in one case (c² = 3.382; p = 0.05). A relationship was found between the degree of obesity and the radiographic stage of OA (R = 0.502; p = 0.02) in the 2nd group. A significant relationship was noted between the duration of OA and the level of free T₄ in patients of the 1st group (R = –0.815; p = 0.01), which confirms the negative impact of thyroid hormone deficiency on the course of OA.

A comparison of non-specific inflammation indicators in patients of both groups was conducted and is presented in Table 2.

 

Table 2

Indicators of nonspecific inflammation by study group

Parameter	Group 1, n = 18	Group 1, n = 25	Р
CRP, mg/L	4.6 ± 2.5	3.7 ± 2.9	0.094
ESR, mm/h	14 (10–23)	13 (7–25)	0.523
Leukocytes, ×10⁹/L	6.3 ± 1.3	6 ± 1.9	0.241
Neutrophils, %	53.9 ± 8.4	51 ± 7.8	0.255

 

Markers of nonspecific inflammation were associated with the clinical and functional manifestations of OA. In Group 1, the ESR level showed a direct correlation with the radiographic stage of OA (R = 0.613; p = 0.02).

An interesting finding was the association between CRP levels and thyroid peroxidase antibodies (anti-TPO antibodies) (R = 0.633; p = 0.036) in patients with compensated hypothyroidism and OA. The anti-TPO antibody level in Group 1 was 121.9 (0.7–281.7) IU/mL, compared with 0.54 (0.2–2.78) IU/mL in Group 2.

Analysis of phosphorus-calcium metabolism in both groups revealed vitamin D deficiency in 72 % of patients.

Secondary hyperparathyroidism was detected in 56 % of patients (n = 11) in Group 1 and in 20 % (n = 5) in Group 2 (χ² = 7.750; p = 0.006). Parathyroid hormone levels were significantly higher in Group 1 despite comparable mean calcium and vitamin D concentrations (Table 3).

 

Table 3

Parameters of phosphorus-calcium metabolism by study group

Parameter	Group 1, n = 18	Group 2, n = 25	Р
Total calcium, mmol/L	2.39 ± 0.11	2.34 ± 0.09	0.259
Ionized calcium, mmol/L	1.18 ± 0.08	1.21 ± 0.07	0.166
Phosphorus, mmol/L	1.17 ± 0.13	1.15 ± 0.19	0.347
Parathyroid hormone, pg/mL	79.3 ± 35.6	56.1 ± 20.4	0.027
Vitamin D, ng/mL	24.1 ± 9.1	27.1 ± 15.4	0.614
β-crosslaps, ng/mL	0.489 ± 0.261	0.514 ± 0.2	0.389

 

The study also demonstrated a negative correlation between vitamin D levels and anti-TPO antibodies in Group 1 (R = –0.539; p = 0.046). The level of the bone resorption marker β-crosslaps correlated with the radiographic stage of OA (R = 0.613; p = 0.039) and with anti-TPO antibody levels (R = 0.666; p = 0.018) in Group 1.

The mean Lequesne algofunctional index was 8.44 ± 4.24 and 7.24 ± 3.37 points in Groups 1 and 2, respectively, corresponding to a severe degree of clinical and functional impairment due to OA in both groups.

A negative correlation between the Lequesne index and vitamin D levels was observed in both groups (R = –0.642, p = 0.004; R = –0.424, p = 0.03, respectively).

In Group 1, the Lequesne index was positively correlated with ESR (R = 0.574; p = 0.03) and waist circumference (R = 0.629; p = 0.005). In Group 2, laboratory and functional analysis demonstrated significant positive correlations between the Lequesne index and the radiographic stage of OA (R = 0.468; p = 0.04) as well as the degree of obesity (R = 0.484; p = 0.003), while significant negative correlations were found with total calcium (R = –0.712; p = 0.0001) and ionized calcium (R = –0.476; p = 0.02).

Pain severity assessed by the VAS was higher in women in Group 1 than in Group 2 (6.05 ± 1.8 vs. 5.1 ± 1.7 points, p = 0.09). In Group 1, VAS scores showed a direct correlation with ESR (R = 0.613; p = 0.015). In Group 2, the duration of OA was positively associated with VAS scores (R = 0.418; p = 0.02).

Analysis of the McGill Pain Questionnaire demonstrated greater pain severity in patients with compensated hypothyroidism (Table 4).

 

Table 4

Results of the McGill pain questionnaire

Parameter		Group 1	Group 2	р
Sensory scale	INSD	6.33 ± 1.94	5.56 ± 1.95	0,192
	PRI	10.3 ± 4.25	8 ± 3.38	0,06
Affective scale	INSD	1.78 ± 1.26	1.32 ± 0.95	0,247
	PRI	3 (2–4)	1 (1–3)	0,124
Evaluative scale	INSD	1.83 ± 0.99	1.36 ± 0.49	0,161
	PRI	3.17 ± 1.04	2.12 ± 1.2	0,008
Pain Intensity (PI), points		2,44 ± 0,51	1.92 ± 0.4	0.009

 

The greatest differences were observed in the PRI values of the sensory and evaluative scales. Patients with hypothyroidism selected a greater number of descriptors characterizing pain (e.g., stabbing, burning, etc.) and reported greater pain severity.

In Group 1, significant associations were identified for the principal McGill Pain Questionnaire scales. The sensory scale showed positive correlations with OA duration (R = 0.512; p = 0.03) and ESR (R = 0.518; p = 0.047). The sensory scale PRI was directly correlated with the duration of hypothyroidism (R = 0.586; p = 0.04), whereas lower free T3 levels were associated with higher affective scale INSD values (R = –0.673; p = 0.046) and greater pain intensity (R = –0.866; p = 0.002).

The affective scale indices (INSD and PRI) in Group 1 were directly associated with β-crosslaps levels (R = 0.528; p = 0.02 and R = 0.684; p = 0.003, respectively), while the affective scale PRI correlated with parathyroid hormone levels (R = 0.589; p = 0.01).

The INSD and PRI values of the sensory scale also correlated with parathyroid hormone levels (R = 0.780, p = 0.0001 and R = 0.698, p = 0.001, respectively).

In the present study, pain severity assessed by the VAS, the Lequesne algofunctional index, and the McGill Pain Questionnaire was high in both groups. However, pain scores were higher in women with compensated hypothyroidism and correlated with markers of nonspecific inflammation as well as with the duration of hypothyroidism, indicating a substantial contribution of impaired thyroid function to the severity of clinical and functional changes in OA.

Secondary hyperparathyroidism associated with vitamin D deficiency was significantly more common in patients in Group 1. These findings were accompanied by higher scores on the principal pain assessment scales. Several studies have demonstrated that low serum vitamin D levels are associated with an increased risk of knee OA progression [11]. Vitamin D deficiency plays an important role in impaired bone metabolism, as it reduces intestinal calcium absorption, thereby contributing to elevated parathyroid hormone levels and increased bone resorption. A positive association was also found between the bone resorption marker β-crosslaps and pain sensitivity in patients with compensated hypothyroidism.

Another noteworthy finding was the inverse relationship between vitamin D levels and anti-thyroid peroxidase antibodies (anti-TPO antibodies), which may reflect the extraskeletal effects of vitamin D [12]. One of the most common causes of hypothyroidism is autoimmune thyroiditis, which is characterized not only by the production of autoantibodies against thyroid tissue but also by increased production of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), FasL, and TRAIL, leading to persistent impairment of thyroid function [13].

Thyroid hormones have been shown to play an important role in the regulation of chondrogenesis and bone mineralization [8]. The observed inverse relationships between OA duration and free T4 levels, as well as between pain intensity and free T3 levels, may indicate an unfavorable effect of hypothyroidism on the course of OA despite adequate pharmacological compensation.

Conclusions

1. In women with osteoarthritis and overweight, the severity of pain syndrome is directly associated with the duration of osteoarthritis, markers of nonspecific inflammation, radiographic stage of the disease, and vitamin D deficiency.
2. Despite pharmacological compensation of hypothyroidism, patients with osteoarthritis and overweight exhibit more pronounced clinical, laboratory, and functional changes, manifested by increased pain intensity and a reduced pain sensitivity threshold. Pain intensity correlated with lower free T4 and free T3 levels, as well as with the duration of hypothyroidism. In patients with osteoarthritis and obesity with pharmacologically compensated hypothyroidism, the bone resorption marker β-crosslaps was positively associated with both the radiographic stage of osteoarthritis and the affective scale of the McGill Pain Questionnaire. This finding may indicate the presence of structural changes in the subchondral bone that contribute to increased pain intensity and the progression of osteoarthritis.

About the authors

Ya. V. Koroleva

E.A. Vagner Perm State Medical University

Author for correspondence.
Email: yana_sun85@mail.ru
ORCID iD: 0009-0006-0996-9426

Assistant of the Department of Endocrinology and Clinical Pharmacology

Russian Federation, Perm

N. S. Tarbeeva

E.A. Vagner Perm State Medical University

Email: yana_sun85@mail.ru
ORCID iD: 0009-0009-4505-7610

PhD (Medicine), Associate Professor of the Department of Endocrinology and Clinical Pharmacology

Russian Federation, Perm

E. N. Smirnova

E.A. Vagner Perm State Medical University

Email: yana_sun85@mail.ru
ORCID iD: 0000-0003-2727-5226

DSc (Medicine), Professor, Head of the Department of Endocrinology and Clinical Pharmacology

Russian Federation, Perm

N. V. Selyanina

E.A. Vagner Perm State Medical University

Email: yana_sun85@mail.ru
ORCID iD: 0000-0002-2317-7808

DSc (Medicine), Professor of the Department of Neurology and Medical Genetics

Russian Federation, Perm

References

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