Primary hyperparathyroidism (PHPT) is an endocrine disease caused by excessive secretion of parathyroid hormone (PTH) from one or more of the four parathyroid glands, manifesting elevated or normal serum calcium levels. Classical PHPT presents with a symptomatic, multiple system dysfunction, especially skeletal and renal damages. However, the clinical profile of PHPT has gradually changed from symptomatic to asymptomatic, due to multichannel examinations (1). Routine blood tests for serum PTH and calcium, frequent neck ultrasonography, as well as various imaging methods can by employed to identify asymptomatic PHPT (2). In China, the incidence of asymptomatic PHPT has increased from <21% in 2000-2006 to 42.4% to 52.5% in 2007-2010 (3).

Conventionally, parathyroidectomy (PTX) is the only definitive treatment for PHPT. Patients who do not meet the surgical indications or refuse surgery can choose medical treatment or just be observed. Nevertheless, PTX may bring about more blood loss and longer surgical time (4). Medications often present a limited clinical efficacy. As one of the commonly used calcimimetics, cinacalcet is unable to significantly improve bone mineral density (BMD) and urinary calcium excretion, although it does lower serum calcium level (5). Moreover, it often induces adverse events like headache, nausea and vomiting. Observations may be a good choice for asymptomatic patients with stable condition, but previous studies have shown that kidney stones and/or nephrocalcinosis present in 21% to 55% of patients with asymptomatic PHPT (6, 7). PHPT patients had higher a risk of fracture compared with healthy controls, especially in the forearm and spine sites. The risks of vertebral fractures were more than four times higher in PHPT patients than in those without skeletal and renal damages (8). Therefore, an early intervention of PHPT, even in mild condition (serum calcium <12mg/dL and associated with nonspecific symptoms), is still commonly required (5).

In the past few years, microwave ablation (MWA) has been considered as an alternative for PHPT patients, and its efficacy and safety have been initially clarified. Through literature review on PubMed, a total of 427 PHPT cases treated with thermal ablation have been reported since 2011, including 248 cases treated with MWA. The total success rate of thermal ablation to treat PHPT was 69.1% ( Table 1 ). However, these studies did not assess the skeletal and renal involvement in PHPT patients before and after MWA. In the present study, we aimed to investigate the changes in PTH, serum calcium and volume of ablated lesions in PHPT patients, as well as evaluate skeletal and renal functions to further evaluate the efficacy and safety of ultrasound-guided MWA in the treatment of PHPT.

Thermal ablations have been used to treat primary hyperparathyroidism for a decade, including high-intensity focused ultrasound (HIFU) (9, 11), laser ablation (LA) (10, 12, 17), radiofrequency ablation (RFA) (14, 18) and MWA (13, 15, 19, 21). Although their mechanisms to produce heat vary a lot, thermal ablation techniques produce heat to ablate lesions through a mechanism of tissue necrosis. Currently, MWA is the most widely used type of thermal ablation in PHPT treatment, and the cure rate was 80.0%~100.0%, which was comparable to surgery (4). However, few studies reported the therapeutic effect on target organs of bone and kidney. Only one study presented BMD improvement after 2 years’ MWA in PHPT patients (16). To our knowledge, this is the first study to evaluate the bone metabolic profiles and renal function of PHPT patients treated with MWA.

In the present study, the median level of 25(OH)D increased from 13.1 ng/mL to 18.5 ng/mL post ablation. Compared with healthy people, PHPT patients are more likely to complicate with vitamin D deficiency or insufficiency (5). Although most patients recruited in our study had a slight increase in 25(OH)D level, their vitamin D levels were not in the normal range. The American Association of Endocrine Surgeons recommended a short-term supplementation of calcium and/or vitamin D in postoperative PHPT patients, which may favor patients treated with MWA (22). In this study, all patients received vitamin D supplementation after ablation to avoid numbness or tetany. A meta-analysis reported that vitamin D supplementation in patients with PHPT and vitamin D deficiency could significantly reduce PTH levels without causing hypercalcemia and hypercalciuria (24), indicating it is an effective and safety treatment in PHPT condition.

The levels of bone turnover markers rise in PHPT, reflecting accelerated bone remodeling cycle. Bone resorption is always coupled with bone formation. Chronically increased PTH favors osteoclast to increase resorption, followed by the release of a number of growth factors from bone matrix to stimulate osteoblast migration, differentiation, and function (25). Hence, bone formation speeds up, resulting in rapid release of cell-derived bone turnover markers detected in the circulation (26). Although the effects of PTH on bones are still obscure, decreased BMD and increased bone turnover markers have been observed in PHPT patients. A study reported that MWA improved BMD in PHPT patients after 2 years’ follow-up (16). As bone turnover markers act as more sensitive indicators to reflect the fine changes in bone condition, it is meaningful to evaluate them before and after MWA.

We observed that the level of osteocalcin decreased significantly after ablation. Osteocalcin regulates the regulation of bone resorption, but also the mineralization of the matrix and differentiation of osteoblasts, a mechanism that maintains the normal mineralization of bone, inhibits the mineralization of cartilage and the abnormal hydroxyapatite crystal formation of bone. A study from Poland found that the osteocalcin levels of 17 PHPT patients returned to normal at six months after surgery (27). In our study, although osteocalcin did not fall into normal ranges in all patients, the median level of osteocalcin significantly decreased from 35 ng/mL to 22 ng/mL, indicating the improvement of bone turnover status. Another bone formation marker ALP also significantly dropped from 89 U/L before MWA to 72 U/L at the final examination. The lower bone formation rate after ablation was consistent with those in other studies on thermal ablation in the treatment of PHPT (19).

Serum P1NP, a specific and sensitive index of new bone formation, reflects the ability of osteoblasts to synthesize collagen, while β-CTX is a marker of bone resorption reflecting the bone resorption activity of osteoclasts. We observed total P1NP significantly decreased from 89.46 ng/mL to 61.85 ng/mL and β-CTX lowered from 1099.00 pg/mL to 372.30 pg/mL, which was comparable to the response after surgery (28). To be noted, the levels of β-CTX in 13 patients altogether fell into the reference intervals at the last follow-up. Costa AG et al. (29) found that the levels of bone resorption markers dropped most rapidly after surgical removal of parathyroid glands, providing a ‘‘window’’ when bone formation is accelerated due to the initial and preferential reduction in bone resorption after PTX. In patients treated with MWA, β-CTX is also a sensitive index to track the influence of hyperparathyroidism on bone.

Nine healthy subjects were included as the control group. There were no significant differences in 25(OH)D, ALP, total P1NP and β-CTX between PHPT patients after MWA and the control group, indicating that MWA can lower some certain bone turnover markers of PHPT patients to those of healthy controls. Abnormally high levels of bone turnover markers in PHPT patients indicate the potential bone loss and osteoporosis, which may further increase the risk of osteoporotic fractures. Furthermore, a retrospective study from Brazil demonstrated minimum preoperative values of 0.684 ng/mL for β-CTX and 76.0 ng/mL for P1NP in PHPT patients were associated with a ≥4% increase in BMD (30), making biochemical bone markers a surrogate tool to monitor the progression of PHPT.

Renal dysfunction due to or followed by nephrolithiasis, is a severe complication of PHPT. Approximately 12% (31) to 30.4% (32) PHPT patients are combined with impaired renal function (eGFR less than 60 mL/min/1.73 m²). Liang CC et al. (33) reported that PTX could slow the decline of eGFR, but another study did not find PTX could reverse renal dysfunction (32). Scarce data were available to evaluate the renal function of PHPT patients after treatment. In this study, marginal increase in creatinine and eGFR levels were observed, but the differences did not show statistical significance, perhaps due to our relatively small sample size, short follow-up duration and selection bias of retrospective study. Although the relationship between PHPT and renal function has not been clarified, chronic increase in PTH level may serve as a risk factor for kidney function impairment by accelerating endothelial injury and subsequent organ fibrosis (34). Further research is needed to assess the association of renal function with PHPT in patients treated with different options.

After 6-12 months of follow-up, two patients failed to show normal PTH or calcium levels. A multicenter study reported that the 7 out of 114 patients had recurrent PHPT during a follow-up period of 18.1 months (20). They found that a maximum diameter less than 0.6 cm resulted in missed ablation. In this study, we found that pre-MWA serum PTH, lesion volume, maximum diameter of lesion and ablation time were significantly different between the two groups, a finding that is consistent with those reported in other studies (35). Besides, another two patients had PTH slightly exceeding the upper limit of normal range. In PHPT treatment, normocalcemic parathormone elevation (NPE), characterized by a normal range of serum calcium with elevated PTH levels, has been detected in PHPT patients treated with PTX (36). During a short-term follow-up of 3-18 months and a long-term follow-up of 10 years after surgery, 11% (37) to 44% (38) of PHPT patients developed NPE, respectively. It is speculated that peripheral resistance to PTH may exist in PHPT patients, and adaptive compensation of serum PTH fails to restore calcium homeostasis after treatment of PHPT, leading to abnormal PTH after surgery (38). In addition, this abnormality can also be attributed to differences in baseline PTH, serum calcium level, vitamin D status, lesion volume (35, 39), follow-up durations (40) and clinical experiences. Interestingly, with the prolongation of observation after operation, the proportion of NPE decreased gradually, and NPE was not correlated with the recurrence of PHPT (37, 40). No major complications occurred during the process of MWA and follow-ups, verifying that MWA is a safe therapy for PHPT. In this study, three patients experienced with hoarseness, partly due to the heat produced by thermal ablation stimulating the recurrent laryngeal nerves. Therefore, the recurrent laryngeal nerves should be protected during thermal ablation.

A limitation of our study is a relatively low success rate compared with other studies of MWA, but this rate was parallel with that of HIFU (9). Nevertheless, from post-ablation 1 month to 12 months, the clinical success rate gradually raised. We supposed during a longer follow-up, a higher success rate may be observed. Shadowed by COVID-19 outbreak, the relatively short observation duration, incomplete data as well as small simple size potentially influenced the final success rate.

In conclusion, this study verified that MWA is a reasonable option in the treatment of PHPT, especially asymptomatic PHPT patients with potential target organ damage or a mild condition. We provided evidence that ultrasound-guided MWA effectively decreases levels of abnormal bone turnover markers and thus improve bone health of PHPT patients. In the future, perspective studies with large samples are required to identify the long-term efficacy and safety of thermal ablation for PHPT, and its long-term effects on bone health and renal function in PHPT patients.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

WN and YY developed the research questionnaire and wrote the protocol for this study. WN, XH, and SX were responsible for the original study design and data collection together with the other authors. WN and YY analyzed the data. SX, JL, XW, and JW participated the diagnosis and treatment of PHPT. XC, GC, and SX interpreted the results. WN and YY wrote the article. CL and SX revised it critically for important intellectual content. All authors agreed to take responsibility for the integrity of the data and the accuracy of the data analysis. All authors have approved the final version of the manuscript.

Design and data collection were supported by the grant supports of Jiangsu Provincial Key Research and Development Program (BE2020726) and the Medical Scientific Research Foundation of Jiangsu Province of China (Surface project) (M2020102).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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