Baseline characteristics

As of 29 February 2024, the study population consisted of 101 patients with chronic HypoPT: 18 (18%) men and 83 (82%) women, of whom 35 (42%) were premenopausal and 48 (58%) were postmenopausal women. This study included patients treated with both conventional therapy and PTH (1–34) (teriparatide). Our analysis specifically focused on those receiving conventional therapy. We also conducted a sensitivity analysis, which showed no significant differences between the group receiving conventional therapy and the group receiving PTH (1–34) therapy. Therefore, all patients remained in the final analysis. Baseline characteristics for the study population and by subgroups are presented in Table 1.

Table 1 Baseline characteristics of study participants by etiology (N = 101)

As expected, the most common etiology was postsurgical, reported in 74.3% of patients (n = 75). Of these, 46 cases (61.3%) were associated with surgery for thyroid cancer, while 29 cases (38.7%) were related to surgery for benign thyroid or parathyroid disease. A non-surgical etiology was reported in 25.7% (n = 26) of patients, with 57.7% (n = 15) being idiopathic and 42.3% (n = 11) associated with genetic variants including CaSR, GATA3, GCM2, PTHR, and TBX1 genes. An autoimmune etiology (AIRE gene variant) was identified in one patient (9.1%, n = 1/11).

The most commonly reported symptoms were paresthesia in 44.6% of patients (n = 45), numbness in 39.6% of patients (n = 40), and muscle cramps in 33.7% of patients (n = 34). Fatigue and muscle spasm were reported in 16.8% of patients (n = 17). There was no significant difference in serum calcium levels among participants with and without paresthesia or numbness (see supplementary Tables 1 and 2). Less frequent symptoms were confusion (10%, n = 10), seizure (9%, n = 9), depressed mood (3.0%, n = 3), and laryngospasm (1.0%, n = 1).

Regarding comorbidities, hypothyroidism was the most frequent (66%, n = 67) followed by hypertension (31.7%, n = 32). Chronic kidney disease and cardiovascular disease were reported in 12% (n = 12) and 9% (n = 9) patients, respectively. Less frequent comorbidities were osteoarthritis (4.0%, n = 4), chronic obstructive pulmonary disease (1.0%, n = 1), and hyperthyroidism (1.0%, n = 1).

The majority of patients with chronic HypoPT were receiving oral calcium supplements (89%; mean (SD) dose 2080 (1828) mg/day), calcitriol (80%; mean (SD) dose 0.7 (0.7) µg/day), LT4 (synthroid/levothyroxine) was administered in 66.3% of patients (n = 67) at a mean (SD) dose of 134.0 (89.0) µg/day, and oral magnesium supplement was administered to 24.8% of patients (n = 25) at a mean (SD) dose of 968.4 (1135.4) mg/day. Cholecalciferol supplementation was taken by 65.4% of patients at a mean (SD) dose of 2119.9 (1553.1) IU/day. In total, 11% of patients (n = 11) received PTH (1–34) (teriparatide) at a mean (SD) dose of 18.9 (8.0) µg/day. Only postmenopausal women were on antiresorptive therapy for concomitant osteoporosis. Seven were on bisphosphonate therapy (alendronate) (14.5%, 7/48), and 3 were on denosumab (6%, 3/48).

Biochemical profile according to menopausal status

The biochemical profile of premenopausal and postmenopausal women with chronic HypoPT is shown in Table 2. Total and corrected calcium, alkaline phosphatase (ALP), and 25(OH)D were significantly higher in postmenopausal compared to premenopausal women, whereas eGFR and TSH were significantly lower in postmenopausal than in premenopausal women. We found no statistically significant difference in serum calcium levels, phosphorus, magnesium, and 25(OH)D levels among men and postmenopausal women (see supplementary Tables 3 and 4). The bone biomarkers CTX and P1NP were higher in postmenopausal women; however, this was not statistically significant in comparison to premenopausal women.

Table 2 Biochemical variables and bone markers among premenopausal and postmenopausal women

Hypercalciuria (> 7.5 mmol/day) was observed in 19 patients (18.8%), including 4 men, 6 premenopausal women, and 9 postmenopausal women. The incidence of nephrolithiasis was 16.7% in the study population (n = 10/60), mostly affecting postsurgical chronic HypoPT and postmenopausal women. The incidence of nephrocalcinosis was 8.3% (n = 5/60), and the majority of cases (n = 4/5) were postmenopausal women.

Further subgroup analyses by sex (women vs. men) and etiology (non-surgical vs. postsurgical chronic HypoPT) revealed a similar biochemical profile among subgroups, with few statistically significant differences between subgroups (Supplementary Tables 5 and 6). Creatinine was significantly lower among women in comparison to men, likely due to sex-related variations, as men typically have higher creatinine levels than women [27,28,29]. Men and women had comparable eGFR, whereas 1,25(OH)2D was significantly higher in women. Corrected serum calcium level was significantly higher in patients with postsurgical compared with non-surgical chronic HypoPT.

Skeletal health status (BMD and TBS)

In this study population of 101 patients with chronic HypoPT, mean (SD) BMD values were as follows: 1.212 (0.225) gm/cm2 at L1–L4 (n = 85), 0.987 (0.192) gm/cm2 at femoral neck (n = 88), 1.054 (0.207) gm/cm2 at total hip (n = 87), and 0.840 (0.134) gm/cm2 at 1/3 radius (n = 80). The TBS was within the normal range, with a mean (SD) of 1.33 (0.15) (n = 69) (TBS classification: NR in postmenopausal women > 1.350, partially degraded (1.200 < TBS < 1.350), or degraded TBS ≤ 1.200) [30, 31].

A correlation analysis of BMD and TBS among premenopausal and postmenopausal women with chronic HypoPT is presented in Table 3. Total hip, L1–L4, and femoral neck BMD were significantly lower in postmenopausal than in premenopausal women, whereas BMD values at 1/3 radius were similar between subgroups. TBS was significantly lower in postmenopausal than premenopausal women (1.29 (0.16) vs. 1.41 (0.10); p = 0.001). For a comprehensive evaluation of skeletal health status in this patient population, Z-scores and T-scores were also assessed in premenopausal and postmenopausal women, respectively (Table 3).

Table 3 BMD and TBS by menopausal status

Additionally, subgroup analyses of BMD and TBS by sex (women vs. men) and etiology (non-surgical vs. postsurgical chronic HypoPT) were performed (supplementary Tables 7 and 8). Statistically significant differences were observed between men and women with chronic HypoPT in BMD values at total hip, femoral neck, and 1/3 radius; these values were consistently lower in women than in men. The analysis of patients with non-surgical and postsurgical chronic HypoPT revealed comparable BMD values at all sites between subgroups, but a significantly lower TBS in postsurgical than in non-surgical patients.

Low BMD, osteoporosis, and fragility fractures

Overall, 11.9% of patients (n = 12/101) reported a history of fragility fractures, most of whom were postmenopausal women (83.3%, n = 10/12). The other 2 patients were men ≥ 50 years (16.7%, n = 2/12). Location of fracture was reported in 12 patients, including hip (n = 4), vertebrae (n = 2), ribs (n = 2), wrist (n = 1), humerus (n = 1), and clavicle (n = 2). The prevalence of fragility fractures in postmenopausal women was 20.8% (n = 10/48), and it was 22.2% (n = 2/9) in men ≥ 50 years. No fragility fractures were reported in premenopausal women or men under age 50 years.

Low BMD was confirmed by T-score < − 1.0 and > − 2.5 at any site in postmenopausal women and men ≥ 50 years, and by Z-score ≤ − 2 at any site in premenopausal women and men < 50 years. Overall, 12 patients (11.9%, n = 101) showed low BMD, all of whom were postmenopausal women. The prevalence of low BMD in postmenopausal women was 25.0% (n = 12/48). Low BMD was not present in premenopausal women or men in this cohort.

In total, 15 postmenopausal women (31.3%, n = 48) and 2 men ≥ 50 years (22.2%, n = 9) showed osteoporotic T-scores (≤ − 2.5) at any site. The distribution of patients with low BMD and osteoporosis is presented in Fig. 3. The correlation between the duration of disease and BMD variables has been evaluated. The results indicate statistically significant positive correlations between the duration of disease and the absolute BMD in gm/cm2 at the following sites: L1–L4 BMD (r = 0.317, p = 0.0034), femoral neck BMD (r = 0.272, p = 0.0107), and total hip BMD (r = 0.280, p = 0.0090) (Table 4). There was no correlation at the 1/3 radial site.

Fig. 3

Distribution of postmenopausal women with low BMD or osteoporosis. Low BMD is defined as a T-score > −2.5 and lower < −1.0 or osteoporosis as defined by a T-score ≤ − 2.5 at any one of the following sites: lumbar spine, femoral neck, total hip or 1/3 radial site

Table 4 Correlation analysis between duration of disease and BMD

We further analyzed the proportion of patients with an osteoporotic T-score at any site and/or fragility fracture. In total, 19.8% of patients (n = 20/101; 17 postmenopausal women and 3 men ≥ 50 years) had an osteoporotic T-score or fragility fracture(s), whereas 4.0% patients (n = 4/101; all postmenopausal women) had both. Overall, 35% of postmenopausal women had osteoporosis by BMD or fragility fracture, and 4% had both. Three men over ≥ 50 years had osteoporosis by BMD or fragility fracture (33.3%, n = 3/9).

None of the men under age 50 years had osteoporosis or a prior fragility fracture.

Subgroup analysis of PTH (1–34) users versus non-PTH users

The majority of the PTH (1–34) users were postmenopausal women (80%), with an average age of 64 ± 16.2 years. The primary etiology was postsurgical HypoPT (63.6%), and the average duration of chronic HypoPT was 17.1 ± 11.3 years. All patients were treated with PTH (1–34). Dosage regimens varied, with 36.4% receiving 20 mcg daily, and others receiving less frequent doses in combination with conventional therapy. In these patients the dose of PTH (1–34) varied between 20 mcg 4–6 times per week and one patient was only taking 10 mcg three times per week (9.1%). Additional details are provided in Supplementary Table 9. There were no significant differences in BMD values at the lumbar spine (L1–L4) between PTH (1–34) users and those solely on conventional therapy (p = 0.511). However, femoral neck (p = 0.050), total hip (p = 0.044), and 1/3 radius (p = 0.050) BMD values were lower in PTH (1–34) users compared to non-PTH users. Regarding serum calcium levels, Tables 5, 6 indicates no significant differences in serum corrected calcium or ionized calcium between PTH (1–34) users and non-PTH users.

Table 5 Comparison of BMD values between PTH (1–34) Users and Non-PTH usersTable 6 Comparison of serum calcium (total, corrected, and ionized) levels between PTH (1–34) users and non-PTH users