Challenges in the management of bone metastases: focus on differentiated thyroid cancer and neuroendocrine tumors.

Bone metastases are frequently associated with skeletal related events (SREs), including pathological fractures, bone pain, hypercalcemia, and spinal cord compression. These complications can significantly impair a patient's quality of life [ 1 ]. Bone-modifying agents (BMAs), including bisphosphonates and denosumab, have been shown to reduce the incidence of SREs in the setting of metastatic cancer [ 2 , 3 ]. However, there is limited data regarding the optimal timing for initiation, appropriate dosing frequency, and clear criteria for discontinuation. While current guidelines advocate for the aggressive treatment of bone metastases [ 4 ], endocrinologists often treat malignancies with a favorable prognoses and excellent long-term survival. Therefore, the treatment strategies used in other cancer types may not be directly applicable to these patient populations.

Differentiated thyroid cancer

The incidence of differentiated thyroid cancer (DTC) is rising with the majority of cases classified as low-risk and associated with an excellent prognosis [ 5 , 6 ]. However, survival outcomes are significantly worse in patients with distant metastatic disease [ 7 ]. Bone is the second most common site of distant metastases, occurring in approximately 1% to 4% of patients with DTC [ 8 ]. Bone metastases are an independent predictor of poor prognosis and metastatic disease in the lungs has a better response rate and higher remission rate when compared to metastatic disease in the bone [ 8-10 ]. When bone metastases are present, the 10-year survival rates drop significantly, ranging from 14% to 53% [ 11 , 12 ]. Older age and larger tumor size are associated with decreased overall survival [ 13 , 14 ]. Bone metastases are more commonly seen in patients over the age of 65 [ 8 ]. This is older than the average age of diagnosis for DTC and may reflect a more aggressive disease course in an older population. Compared to papillary thyroid cancer, patients with follicular thyroid cancers are approximately twice as likely to develop bone metastases and more likely to have an SRE [ 8 ]. Despite this, the overall survival is thought to be similar between the histologic subtypes even in the setting of bone metastases [ 15 ].

Bone metastases from DTC will typically be lytic lesions. Radioactive iodine (RAI) is used to detect small or symptomatic metastases while [ 18 F]-fluorodeoxyglucose positron emission tomography (FDG-PET) and cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI) can be used to detect RAI-refractory disease. The axial skeleton is the most common site of involvement, particularly the spine and pelvis, making vertebral compression fractures the most common fracture type [ 16 , 17 ]. These patients represent a high risk population and 34% to 78% of patients will either present with or develop an SRE [ 8 , 17 ]. Among those who experience an initial SRE, 65% of patients will develop a second SRE [ 17 ]. The high rates of SRE in patients with thyroid cancer, even with just 1 or 2 bone metastases, are comparable to the rates seen in breast and prostate cancer [ 18 ].

Despite the significant clinical implications, the evidence examining the treatment and outcomes of bone metastases in differentiated thyroid cancer is limited.

Case # 1

A 51-year-old male with progressive dysphagia symptoms was found to have 5.9-cm mixed cystic solid left thyroid nodule on ultrasound ( Fig. 1 ). The thyroid nodule was biopsied twice with benign pathology (Bethesda II). However, because of continued growth of the thyroid nodule and the patient's compressive symptoms, he elected to proceed with a left thyroid lobectomy. Surgical pathology was notable for a 7.5-cm encapsulated follicular thyroid carcinoma with extensive vascular invasion. Given the extensive vascular invasion, the patient was classified as high risk for recurrence. He underwent a completion right hemithyroidectomy with benign pathology and was treated with a 72 mCi dose of 131 I using Thyrogen stimulation. The patient's posttherapy whole-body scan showed uptake in the thyroid bed with 3 additional foci of activity in the left superior calvarium, right shoulder girdle region, and right anterior hemithorax ( Fig. 2 ). There was an additional focus of uptake in the central lower pelvis that was thought to be bladder. Stimulated thyroglobulin (TG) level was 188 ng/mL with negative thyroglobulin antibodies. A CT head and CT chest did not identify any structural correlate for the RAI-avid bone lesions. The patient was asymptomatic from his bone disease.

The patient was kept on TSH suppression and did not receive BMAs. The suppressed TG reached a nadir of 3.5 ng/mL. One year after his initial RAI treatment, patient underwent an RAI-whole body scan after thyroid hormone withdrawal. The RAI whole-body scan showed focal uptake in the left superior calvarium and right sixth rib. He was treated with 152 mCi dose of 131 I. Posttherapy whole-body scan with single-photon emission CT with integrated CT was significant for uptake in the left superior calvarium, right sixth rib, and left superior pubic ramus ( Fig. 3 ). This was consistent with persistent RAI uptake in the osseous metastases that were present on the posttherapy whole-body scan from 1 year prior. The previously seen focal uptake in the right shoulder girdle had resolved. Stimulated TG level was 11.8 ng/mL with negative TG antibodies. The patient continues to be on TSH suppression with close follow up.

Case #1 discussion: the role of RAI and the treatment of bone metastases without a structural correlate

There are no prospective, randomized clinical studies that have evaluated the role of RAI therapy for the treatment of bone metastases. However, RAI therapy remains an important part of thyroid cancer management and is recommended for iodine-avid bone metastases [ 6 ]. RAI avidity and treatment have been consistently associated with improved survival outcomes [ 6 , 10 , 16 , 19 , 20 ]. In a retrospective study of 444 patients with distant metastatic disease, those who achieved negative imaging studies after RAI treatment, including negative RAI whole-body scan and negative conventional radiographs, had significantly improved overall survival compared to those who did not (92% vs 19%) [ 10 ]. When combined with other modalities such as external beam radiation, Cyberknife, systemic therapies, or arterial embolization, RAI treatment is associated with an increase in overall survival compared to patients treated with RAI alone [ 21 ]. In about one third of patients with bone metastases from DTC, RAI treatment alone or in conjunction with localized treatment can lead to a complete response in the bone [ 22 ]. Unfortunately, approximately 20% of bone metastases lack RAI avidity on the initial RAI whole-body scan, and RAI-refractory bone disease has a worse prognosis [ 10 ]. Age is an important prognostic factor, and patients with RAI-avid bone metastases that are younger have higher rates of complete response and better overall survival [ 12 , 20 , 23 ]. Patients with bone metastases diagnosed prior to RAI therapy have a worse prognosis which could be due to a larger tumor burden, more symptomatic disease, or development of SREs at the time of initial diagnosis [ 15 ]. RAI has also demonstrated palliative benefits with approximately one third of symptomatic patients experiencing complete relief from bone pain after RAI therapy for iodine-avid bone lesions [ 24 ].

Patients with RAI-avid bone metastases without a corresponding structural lesion on imaging appear to represent a distinct subgroup with more favorable clinical outcomes. In these patients, the complete response rate increases significantly from 46% to 82% [ 12 ]. Additional studies have shown that these patients rarely develop SREs [ 17 , 25 ]. This favorable long-term prognosis suggests that either early detection of microscopic disease allows for more effective RAI therapy, or that these lesions represent a less aggressive tumor type. However, long-term mortality data in this population are limited, and it remains unclear whether these patients should be classified as having advanced thyroid cancer.

Case #1 highlights that RAI can be an effective treatment in patients with bone metastases. The patient demonstrated a significant decline in his stimulated TG following the first dose of RAI, consistent with a biochemical response to therapy. Although the patient is older than 45 years old, which was the age cutoff used in earlier studies evaluating age as a prognostic factor, the patient's asymptomatic presentation, the persistent RAI avidity of the bone metastases, and the absence of structural correlates for his RAI-avid bone lesions suggest that he will likely have a favorable prognosis and lower risk of developing SREs.

Case #2

A 47-year-old male presented with an enlarging palpable right neck mass. Neck ultrasound was notable for a 6.1-cm right neck mass lateral to the thyroid. The patient underwent a biopsy of the right thyroid nodule, which was suspicious for a follicular neoplasm (Bethesda IV); a biopsy of a right neck mass was notable for thyroid parenchyma with macrofollicular architecture and mild nuclear atypia. The patient underwent a total thyroidectomy with bilateral central and lateral neck dissection. Surgical pathology was notable for multifocal follicular-variant papillary thyroid carcinoma with positive margins, lymphatic invasion, and multiple positive lymph nodes in the central and lateral neck compartments with extranodal extension.

Because the patient was considered high risk for recurrence, he was treated with 127 mCi of 131 I after thyroid hormone withdrawal. The patient's posttherapy whole-body scan was completed 7 days after treatment and was notable for uptake in the bilateral thyroid bed, bilateral iliac bones, left rib, and the T8/L1 vertebrae region ( Fig. 4 ). Stimulated thyroglobulin level was 999.6 ng/mL with negative thyroglobulin antibodies. An MRI scan of the thoracic spine and pelvis was obtained to evaluate for a structural correlate and establish a baseline for monitoring interval changes in size and treatment response. There were no structural lesions in the pelvis but MRI of the thoracic spine showed a T1 hypointense lesion in the inferior endplate of the T8 vertebral body and an expansile enhancement in the posterior left rib ( Fig. 5 ). Given the presence of bone metastases and concern that small pulmonary metastases may be below the threshold to be seen on an RAI whole body scan, a CT scan of the chest was also obtained and demonstrated bilateral solid pulmonary nodules measuring up to 3 mm, suspicious for pulmonary metastases.

The patient was kept on TSH suppression and his suppressed TG reached a nadir of 14.3 ng/mL 3 months after RAI treatment. The patient had a physically demanding job and was concerned about the risk of SREs related to his bone metastases. After multidisciplinary discussion, given multiple sites of bone metastases including at the spine and hip, patient was started on zoledronic acid 4 mg every 3 months. His TG continued to rise with a doubling time of approximately 6 months. An MRI scan of the thoracic spine obtained about 6 months after RAI treatment showed stable but persistent bone lesion in the T8 vertebral body. A CT of the chest showed new and enlarging pulmonary nodules. One year after RAI treatment, patient had a repeat RAI whole-body scan after thyroid hormone withdrawal. The scan showed uptake in the left 9th rib and T8 vertebral body. The patient was treated with 203mCi 131 I. A posttherapy whole-body scan conducted 7 days after RAI treatment demonstrated similar uptake in the left 9th rib and T8 vertebral body but also new uptake in the sternum. Stimulated TG level was 916.4 ng/mL with negative TG antibodies. Follow-up MRI scans of the spine continued to show stable disease and repeat RAI whole-body scan was negative. Therefore, zoledronic acid was discontinued after 2 years of treatment.

Case #2 discussion: the role of BMAs in bone metastases from thyroid cancer

BMAs, such as bisphosphonates or denosumab, have been shown to effectively prevent or delay SREs in patients with solid tumors [ 26 ]. Bisphosphonates bind to the bone matrix and are taken up by osteoclasts, ultimately leading to their apoptosis and decreased bone resorption [ 27 ]. Denosumab, a monoclonal antibody, functions by binding to receptor activator of nuclear factor kappa-B ligand, thereby inhibiting osteoclast activity and reducing bone resorption [ 28 ]. The data on the use of BMAs in thyroid cancer are limited. The optimal timing for initiation, dosing intervals, and treatment duration remains unclear in this patient population.

Studies evaluating the use of BMAs in thyroid cancer are limited and primarily consist of retrospective, single-center studies with small sizes, variable treatment protocols, and heterogenous patient populations ( Table 1 ). Treatment with zoledronic acid has also been shown to significantly delay the onset of skeletal complications, demonstrating greater efficacy than other treatment modalities, including surgery, RAI, or external beam radiation therapy [ 30 ]. It may also reduce the incidence and delay the onset of metastatic spinal cord compression, one of the most severe consequences of bone metastases [ 31 ]. Although denosumab has been shown to be more effective than zoledronic acid in delaying SREs in patients with solid tumors, patients with thyroid cancer were limited in these studies [ 33 ]. Among patients with thyroid cancer who received BMAs for their bone metastases, 75% had already experienced at least 1 clinical SRE at the time of treatment initiation [ 34 ]. Despite the high incidence of SREs in patients with bone metastases from thyroid cancer, treatment rates remain low, with only 22.4% of patients being treated [ 34 ]. This is a potential missed opportunity for earlier intervention. Further research is needed to identify patients at the highest risk for SREs who would derive the greatest benefits from BMA treatment.

Bone-directed treatment can also decrease bone pain and improve quality of life. In a prospective study of 10 patients with thyroid cancer that had undergone extensive treatment with surgery, RAI, external radiotherapy, and chemotherapy but continued to have painful bone metastases, pamidronate was shown to significantly reduce bone pain ( P = .0052) and improve performance status ( P = .051) [ 29 ]. Zoledronic acid has also been show to decrease pain scores and reduce analgesic agents in almost one third of patients with bone metastases from DTC [ 31 ].

The optimal treatment dosing frequency of BMAs in patients with DTC remains unclear. Although most thyroid cancer studies have used zoledronic acid at 4 mg every 4 weeks, emerging evidence suggests that extending the dosing interval to every 12 weeks can still be effective and safe. This approach has been extrapolated from studies in breast cancer, prostate cancer, and multiple myeloma, which have shown that a 12-week doing schedule does not increase SREs but may decrease treatment-related toxicities [ 35 , 36 ]. The American Thyroid Association has endorsed the 12-week dosing schedule, although it acknowledges there are limited data within thyroid cancer supporting this recommendation [ 6 ]. Larger, prospective trials are needed to better determine the optimal dosing strategies and schedule.

The selection of BMA should be guided by individual patient factors including risk of SRE, status of overall tumor control, cost, and patient preference. Denosumab may be more effective at reducing SREs and can be used in patients with reduced renal function. However, abrupt cessation of denosumab is associated with rapid rebound bone loss and risk of multiple vertebral fractures [ 37 , 38 ], and dosing regimens other than monthly administration have not been tested. Intravenous bisphosphonate may be more cost effective, are not associated with rebound bone loss on cessation and can be administered either monthly or every 3 months.

Although BMAs offer clear benefits in reducing SREs and alleviating bone pain, their long-term use needs to be carefully considered in patients with thyroid cancer who can have long life expectancies, even in the setting of metastatic disease. With prolonged antiresorptive therapy, patients are at risk for rare side effects including osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF). ONJ is rare but the risk is dose-dependent and the majority of cases been reported in oncology patients [ 39 ]. Although the incidence of ONJ in patients with thyroid cancer is poorly defined, the reported rates are alarmingly high. In small retrospective studies, ONJ occurred in up to 9% of patients treated with monthly zoledronic acid and in up to 26% of patients treated with denosumab [ 30 , 40 ]. These rates are substantially higher than the 1.7% incidence observed in a meta-analysis of randomized controlled trials, which primarily included patients with breast cancer, prostate cancer, and myeloma [ 41 ]. Patients with thyroid cancer may be at a higher risk for ONJ if patients receive external beam radiation therapy to the neck, which can be used in patients with advanced disease. Furthermore, the use of tyrosine kinase inhibitors as systemic therapy can further elevate this risk [ 42 , 43 ]. Given these considerations, the frequency and duration of BMAs in patients with advanced thyroid cancer should be guided by a multidisciplinary team. Therapy should be tailored to the patient's individual risk profile to maximize therapeutic benefit but minimize complications.

Adjuvant bisphosphonate use has been associated with improved overall and disease-specific survival in postmenopausal women with early breast cancer [ 44 ]. However, the potential impact of BMAs on survival outcomes in DTC has not been seen. Retrospective studies have suggested a trend toward improved overall survival in patients treated with zoledronic acid, and a longer median survival in patients receiving denosumab [ 21 , 32 ]. These findings are based on small patient cohorts, and multivariate analysis has not identified use of BMAs as an independent prognostic factor for improved survival [ 34 ]. Larger, prospective studies are needed but there is currently insufficient evidence to suggest a direct survival benefit from BMA therapy in this population.

Bone-modifying agents reduce skeletal-related events and bone pain in patients with thyroid cancer and bone metastases. However, the available data are limited to small, retrospective studies and their use in patients with thyroid cancer is largely underexplored. Critical questions remain regarding optimal timing, dosing schedule, and long-term safety. Further prospective studies are needed to clarify how to best optimize the use of BMAs in thyroid cancer to guide evidence-based recommendations.

Case #2 highlights the complexities involved in deciding whether to initiate BMAs, as well as the importance of multidisciplinary care and shared decision-making. There is insufficient evidence that adjuvant BMAs use improves overall or disease specific survival in patients with thyroid cancer. In this patient, the TG level continued to rise despite initiation of zoledronic acid, which was likely driven by progression of nonosseous disease. This case also underscores the importance of de-escalation therapy, especially when bone disease remains stable and is not progressing.

Neuroendocrine tumors

Case #3

A 64-year-old female underwent wedge resection of the right middle lobe of the lung for a 3.4-cm pleural-based mass. Pathology revealed intermediate-grade neuroendocrine tumor. She received 6 cycles of carboplatin/etoposide and 50 Gy of external beam radiation therapy. MRI of the abdomen revealed hepatic masses, core needle biopsy confirmed a metastatic neuroendocrine tumor (NET), and she was started on everolimus and monthly octreotide and underwent transarterial embolization of the liver. No bone lesions were noted on an octreotide scan nor on serial chest CT and abdominal MRI scans over the next year. Twenty-two months after her surgical resection, a 68 Ga-DOTATATE PET scan revealed 3 hypermetabolic foci in the liver and numerous foci in the bones, including the left anterior first rib, posterior element of T5, 8th rib, L2, right anterior iliac wing, and right inferior sacrum ( Fig. 6 ). She was started on zoledronic acid 4 mg every 3 months.

Case #3 discussion: the role of BMAs in bone metastases from neuroendocrine tumors

Neuroendocrine tumors arise from neuroendocrine cells, most often in the gastrointestinal or respiratory tracts. Bone metastases have been reported in 4% to 20% of patients with a NET [ 45-54 ]. Bone metastases in NETs most commonly arise from primary tumors in the small intestine, pancreas, and lung [ 47 , 48 , 50 , 55 ], and are synchronous (diagnosed at the same time as the primary tumor) in approximately one third to one half of cases [ 45 , 48 , 50 , 52 , 53 ]. With the introduction of 68 Ga-DOTA-peptide PET/CT scans, the incidence has increased because of improved detection [ 56 , 57 ]. In a small autopsy study, bone metastases were noted in 42% of subjects with carcinoid tumors, suggesting that bone metastases may still be underdetected [ 58 ].

More than half of patients with NET bone metastases are symptomatic, with pain as the most common symptom, as well as other skeletal-related events including spinal cord compression, fracture, and hypercalcemia [ 45 , 48 , 52 , 57 ]. Median overall survival is significantly shorter with bone metastases (40-60 months), compared to 84 to 100 months without bone metastases [ 45 , 46 , 48 , 52 , 56 ].

Management options for NET bone metastases include chemotherapy, peptide receptor radionuclide therapy, external beam radiation, surgery, and BMAs [ 59 ]. Despite the risk of SREs, only 25% to 50% of patients with NET bone metastases are treated with bisphosphonates or denosumab [ 45 , 46 , 52 , 53 ]. There are no randomized controlled trials or prospective studies of BMAs in NET bone metastases.

As with differentiated thyroid cancer, the optimal timing, dosage, and duration of BMA therapy remains to be determined in NET bone metastases. The increased identification of bone metastases by 68 Ga-DOTA-peptide PET/CT scans suggests that bone metastases previously went unrecognized and therefore may be asymptomatic for some time. However, because SREs are common in NET bone metastases, it is reasonable to initiate BMA at the time of diagnosis.

There are no studies investigating the optimal duration of BMA therapy. The duration of follow-up in studies demonstrating the efficacy of BMAs in reducing SREs is typically less than 3 years. In patients with NETs, even with bone metastases, median survival may exceed 3 to 5 years [ 45 , 46 , 48 , 52 , 56 ]. Because bisphosphonates have a prolonged half-life in bone, our current practice is to initiate IV zoledronic acid every 3 months in patients with newly identified bone metastases. If imaging studies reveal stability of bone metastases over 1 to 2 years, after discussion with the patient and the oncology team, we will consider reducing the frequency to every 6 months, and if stable for another year or 2, even to every 12 months. At any time, if imaging studies reveal progression of bone lesions the dosing frequency can be increased back to every 3 months.

Because prolonged exposure to bisphosphonates increases the risk of ONJ and AFF, in patients treated with bisphosphonates for osteoporosis, consideration of a drug holiday is recommended after 5 years on oral bisphosphonates or 3 years on IV bisphosphonates for individuals not at high risk of fracture [ 60 ]. The risk of atypical fracture is rapidly reduced on cessation of bisphosphonates [ 61 ]. The role of drug holidays in the management of bone metastases is unknown. Because bone metastases are incurable, guidelines have generally recommended indefinite use of BMAs until no longer consistent with goals of care [ 4 , 62 ], However, in a patient with stable bone disease treated for several years with bisphosphonates, it may be reasonable to consider a drug holiday after discussion of risk and benefits.

It is currently unknown whether adjuvant bisphosphonate therapy extends overall survival in patients with NETs [ 63 ]. To date. retrospective studies have not demonstrated improved overall survival with bisphosphonates [ 46 , 48 ].

Case #3 highlights the changing landscape of the management of NET with bone metastases, as newer imaging modalities have revealed that bone metastases may be more common than previously appreciated. Although bone metastases are associated with increased SREs and reduced overall survival, the optimal timing, dose, and duration of BMA therapy in patients with bone metastases from NET remains uncertain. With median survival measured in years, again the importance of multidisciplinary care and shared decision-making must be emphasized to maximize benefit while minimizing risk.

Conclusion

The management of bone metastases in patients with DTC and NETs remains a significant clinical challenge because of the lack of prospective, disease-specific studies to guide management. Although these patients are at risk for SREs that significantly impact morbidity and quality of life, optimal strategies for prevention and management are understudied. Current recommendations remain extrapolated from more aggressive cancers and there is a need for research in these more indolent cancers.

Targeted imaging and treatment, including RAI and 68 Ga-DOTA-peptide PET/CT scans, have improved the detection and prognosis in patients with bone metastases. BMAs, such as bisphosphonates and denosumab, have been shown to reduce SREs, prolong the time until a subsequent SRE, and decrease pain. Despite these benefits, BMAs have not made a significant impact on overall survival. However, further studies are still needed to determine the optimal timing for initiation of BMAs, the most effective dosing interval, and the overall duration of therapy. It is currently unknown whether treatment should be continued indefinitely in patients with bone metastases from DTC or NETS but with stable bone disease. In addition, in patients anticipated to have a long life expectancy, the risks of treatment-related complications such as ONJ and AFF need to be considered.

A multidisciplinary, individualized approach is essential to optimize outcomes and balance efficacy with safety. Future prospective studies focused on DTC and NETs are needed to establish evidence-based guidelines to improve long-terms outcomes and quality of life for these patients.

Funding

None.

Disclosure

No conflicts of interest to declare.

Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

References

1 Rajeswaran T , Wong HCY , Zhang E , et al Quality of life issues in patients with bone metastases: a systematic review . Support Care Cancer . 2024 ; 32 : 1 ‐ 13 . 10.1007/s00520-023-08241-0 38091116

2 Wang Z , Qiao D , Lu Y , et al Systematic literature review and network meta-analysis comparing bone-targeted agents for the prevention of Skeletal-related events in cancer patients with bone metastasis . Oncologist . 2015 ; 20 ( 4 ): 440 ‐ 449 . 25732263 10.1634/theoncologist.2014-0328 PMC4391764

3 Wajda BG , Ferrie LE , Abbott AG , et al Denosumab vs. Zoledronic acid for metastatic bone disease: a comprehensive systematic review and meta-analysis of randomized controlled trials . Cancers (Basel) . 2025 ; 17 ( 3 ): 388 . 39941757 10.3390/cancers17030388 PMC11816125

4 Van Poznak C , Somerfield MR , Barlow WE , et al Role of bone-modifying agents in metastatic breast cancer: an American society of clinical oncology–cancer care Ontario focused guideline update . J Clin Oncol . 2017 ; 35 ( 35 ): 3978 ‐ 3986 . 29035643 10.1200/JCO.2017.75.4614

5 Lim H , Devesa SS , Sosa JA , Check D , Kitahara CM . Trends in thyroid cancer incidence and mortality in the United States, 1974-2013 . JAMA . 2017 ; 317 ( 13 ): 1338 . 28362912 10.1001/jama.2017.2719 PMC8216772

6 Ringel MD , Sosa JA , Baloch Z , et al 2025 American thyroid association management guidelines for adult patients with differentiated thyroid cancer . Thyroid . 2025 ; 35 ( 8 ): 841 ‐ 985 . 40844370 10.1177/10507256251363120 PMC13090833

7 Wilhelm A , Conroy PC , Calthorpe L , et al Disease-specific survival trends for patients presenting with differentiated thyroid cancer and distant metastases in the United States, 1992–2018 . Thyroid . 2023 ; 33 ( 1 ): 63 ‐ 73 . 36413032 10.1089/thy.2022.0353 PMC9885538

8 Choksi P , Papaleontiou M , Guo C , Worden F , Banerjee M , Haymart M . Skeletal complications and mortality in thyroid cancer: a population-based study . J Clin Endocrinol Metab . 2017 ; 102 ( 4 ): 1254 ‐ 1260 . 28324052 10.1210/jc.2016-3906 PMC5460727

9 Khired ZA , Hussein M , Jishu J , et al Osseous metastases in thyroid cancer: unveiling risk factors, disease outcomes, and treatment impact . Cancers (Basel) . 2023 ; 15 ( 14 ): 3557 . 37509220 10.3390/cancers15143557 PMC10377410

10 Durante C , Haddy N , Baudin E , et al Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy . J Clin Endocrinol Metab . 2006 ; 91 ( 8 ): 2892 ‐ 2899 . 16684830 10.1210/jc.2005-2838

11 Wu K , Hou S-M , Huang T-S , Yang R-S . Thyroid carcinoma with bone metastases: a prognostic factor study . Clin Med Oncol . 2008 ; 2 : 129 ‐ 134 . 21892275 10.4137/cmo.s333 PMC3161655

12 Schlumberger M , Challeton C , De Vathaire F , et al Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma . J Nucl Med . 1996 ; 37 : 598 ‐ 605 . 8691248

13 Zhao H , Tang X-Z , Wang D-P , et al Prognostic factors and survival outcomes in thyroid cancer patients with bone metastasis: insights from a population-based cohort study . Endocr Pract . 2025 ; 31 ( 10 ): 1274 ‐ 1285 . 40680835 10.1016/j.eprac.2025.07.010

14 Chen DW , Carr G , Worden FP , Veenstra CM , Haymart MR , Banerjee M . Survival prognostication in patients with differentiated thyroid cancer and distant metastases: a SEER population-based study . Thyroid . 2024 ; 34 ( 7 ): 837 ‐ 845 . 38757633 10.1089/thy.2023.0709 PMC11295792

15 Choi YM , Kim WG , Kwon H , et al Early prognostic factors at the time of diagnosis of bone metastasis in patients with bone metastases of differentiated thyroid carcinoma . Eur J Endocrinol . 2016 ; 175 ( 3 ): 165 ‐ 172 . 27272238 10.1530/EJE-16-0237

16 Osorio M , Moubayed SP , Su H , Urken ML . Systematic review of site distribution of bone metastases in differentiated thyroid cancer . Head Neck . 2017 ; 39 ( 4 ): 812 ‐ 818 . 28079945 10.1002/hed.24655

17 Farooki A , Leung V , Tala H , Tuttle RM . Skeletal-related events due to bone metastases from differentiated thyroid cancer . J Clin Endocrinol Metab . 2012 ; 97 ( 7 ): 2433 ‐ 2439 . 22564664 10.1210/jc.2012-1169

18 Oster G , Lamerato L , Glass AG , et al Natural history of skeletal-related events in patients with breast, lung, or prostate cancer and metastases to bone: a 15-year study in two large US health systems . Support Care Cancer . 2013 ; 21 ( 12 ): 3279 ‐ 3286 . 23884473 10.1007/s00520-013-1887-3

19 Kondraciuk JD , Rice SL , Zhou X , et al Thyroid cancer bone metastasis: survival and genomic characteristics of a large tertiary care cohort . Clin Nucl Med . 2019 ; 44 ( 8 ): e465 ‐ e471 . 31274625 10.1097/RLU.0000000000002626 PMC6621602

20 Bernier M-O , Leenhardt L , Hoang C , et al Survival and therapeutic modalities in patients with bone metastases of differentiated thyroid carcinomas . J Clin Endocrinol Metab . 2001 ; 86 ( 4 ): 1569 ‐ 1573 . 10.1210/jcem.86.4.7390 11297585

21 Wu D , Gomes Lima CJ , Moreau SL , et al Improved survival after multimodal approach with 131I treatment in patients with bone metastases secondary to differentiated thyroid cancer . Thyroid . 2019 ; 29 ( 7 ): 971 ‐ 978 . 31017051 10.1089/thy.2018.0582

22 Jannin A , Lamartina L , Moutarde C , et al Bone metastases from differentiated thyroid carcinoma: heterogenous tumor response to radioactive Iodine therapy and overall survival . Eur J Nucl Med Mol Imaging . 2022 ; 49 ( 7 ): 2401 ‐ 2413 . 35149914 10.1007/s00259-022-05697-w PMC9165254

23 Petrich T , Widjaja A , Musholt TJ , et al Outcome after radioiodine therapy in 107 patients with differentiated thyroid carcinoma and initial bone metastases: side-effects and influence of age . Eur J Nucl Med . 2001 ; 28 ( 2 ): 203 ‐ 208 . 11303891 10.1007/s002590000420

24 Qiu Z-L , Song H-J , Xu Y-H , Luo Q-Y . Efficacy and survival analysis of 131 I therapy for bone metastases from differentiated thyroid cancer . J Clin Endocrinol Metab . 2011 ; 96 ( 10 ): 3078 ‐ 3086 . 21795449 10.1210/jc.2011-0093

25 Robenshtok E , Farooki A , Grewal RK , Tuttle RM . Natural history of small radioiodine-avid bone metastases that have no structural correlate on imaging studies . Endocrine . 2014 ; 47 ( 1 ): 266 ‐ 272 . 24366637 10.1007/s12020-013-0123-8

26 von Moos R , Costa L , Gonzalez-Suarez E , Terpos E , Niepel D , Body J–J . Management of bone health in solid tumours: from bisphosphonates to a monoclonal antibody . Cancer Treat Rev . 2019 ; 76 : 57 ‐ 67 . 31136850 10.1016/j.ctrv.2019.05.003

27 Schwartz E , Reichert Z , Van Poznak C . Pharmacologic management of metastatic bone disease . Bone . 2022 ; 158 : 115735 . 33171313 10.1016/j.bone.2020.115735

28 Hanley DA , Adachi JD , Bell A , Brown V . Denosumab: mechanism of action and clinical outcomes . Int J Clin Pract . 2012 ; 66 ( 12 ): 1139 ‐ 1146 . 22967310 10.1111/ijcp.12022 PMC3549483

29 Vitale G , Fonderico F , Martignetti A , et al Pamidronate improves the quality of life and induces clinical remission of bone metastases in patients with thyroid cancer . Br J Cancer . 2001 ; 84 ( 12 ): 1586 ‐ 1590 . 11401309 10.1054/bjoc.2001.1832 PMC2363684

30 Orita Y , Sugitani I , Toda K , Manabe J , Fujimoto Y . Zoledronic acid in the treatment of bone metastases from differentiated thyroid carcinoma . Thyroid . 2011 ; 21 ( 1 ): 31 ‐ 35 . 21058881 10.1089/thy.2010.0169

31 Orita Y , Sugitani I , Takao S , Toda K , Manabe J , Miyata S . Prospective evaluation of Zoledronic acid in the treatment of bone metastases from differentiated thyroid carcinoma . Ann Surg Oncol . 2015 ; 22 ( 12 ): 4008 ‐ 4013 . 25762482 10.1245/s10434-015-4497-0

32 Andrade F , Probstner D , Decnop M , et al The impact of Zoledronic acid and radioactive iodine therapy on Morbi-mortality of patients with bone metastases of thyroid cancer derived from follicular cells . Eur Thyroid J . 2019 ; 8 ( 1 ): 46 ‐ 55 . 30800641 10.1159/000493190 PMC6381918

33 Zheng GZ , Chang B , Lin FX , et al Meta-analysis comparing denosumab and zoledronic acid for treatment of bone metastases in patients with advanced solid tumours . Eur J Cancer Care (Engl) . 2017 ; 26 : e12541 . 10.1111/ecc.12541 27430483

34 Mazziotti G , Formenti AM , Panarotto MB , et al Real-life management and outcome of thyroid carcinoma-related bone metastases: results from a nationwide multicenter experience . Endocrine . 2018 ; 59 ( 1 ): 90 ‐ 101 . 29110129 10.1007/s12020-017-1455-6

35 Cao L , Yang Y-J , Diao J-D , et al Systematic review and meta-analysis comparing zoledronic acid administered at 12-week and 4-week intervals in patients with bone metastasis . Oncotarget . 2017 ; 8 ( 52 ): 90308 ‐ 90314 . 29163830 10.18632/oncotarget.19856 PMC5685751

36 Himelstein AL , Foster JC , Khatcheressian JL , et al Effect of Longer-interval vs standard dosing of Zoledronic acid on skeletal events in patients with bone metastases: a randomized clinical trial . JAMA . 2017 ; 317 ( 1 ): 48 . 28030702 10.1001/jama.2016.19425 PMC5321662

37 Bone HG , Bolognese MA , Yuen CK , et al Effects of Denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass . J Clin Endocrinol Metab . 2011 ; 96 ( 4 ): 972 ‐ 980 . 21289258 10.1210/jc.2010-1502

38 Cummings SR , Ferrari S , Eastell R , et al Vertebral fractures after discontinuation of Denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension . J Bone Miner Res . 2018 ; 33 ( 2 ): 190 ‐ 198 . 29105841 10.1002/jbmr.3337

39 Khan AA , Morrison A , Hanley DA , et al Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus . J Bone Miner Res . 2015 ; 30 ( 1 ): 3 ‐ 23 . 25414052 10.1002/jbmr.2405

40 Wassermann J , Mathy E , Lescaille G , et al Safety of denosumab in patients with refractory differentiated thyroid cancer and advanced medullary thyroid cancer . J Clin Oncol . 2019 ; 37 ( 15_suppl ): e17578 ‐ e17578 .

41 Qi W-X , Tang L-N , He A-N , Yao Y , Shen Z . Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of seven randomized controlled trials . Int J Clin Oncol . 2014 ; 19 ( 2 ): 403 ‐ 410 . 23605142 10.1007/s10147-013-0561-6

42 Lorusso L , Pieruzzi L , Gabriele M , et al Osteonecrosis of the jaw: a rare but possible side effect in thyroid cancer patients treated with tyrosine-kinase inhibitors and bisphosphonates . J Endocrinol Invest . 2021 ; 44 ( 12 ): 2557 ‐ 2566 . 34291429 10.1007/s40618-021-01634-0 PMC8572199

43 Mauceri R , Panzarella V , Morreale I , Campisi G . Medication-related osteonecrosis of the jaw in a cancer patient receiving lenvatinib . Int J Oral Maxillofac Surg . 2019 ; 48 ( 12 ): 1530 ‐ 1532 . 31378564 10.1016/j.ijom.2019.07.010

44 O’Carrigan B , Wong MHF , Willson ML , Stockler MR , Pavlakis N , Goodwin A . Bisphosphonates and other bone agents for breast cancer . Cochrane Database Syst Rev . 2017 ; 10 ( 10 ): CD003474 . 29082518 10.1002/14651858.CD003474.pub4 PMC6485886

45 Van Loon K , Zhang L , Keiser J , et al Bone metastases and skeletal-related events from neuroendocrine tumors . Endocr Connect . 2015 ; 4 ( 1 ): 9 ‐ 17 . 25430999 10.1530/EC-14-0119 PMC4285767

46 Kavecansky J , Wei L , Caronia L , Ramirez M-T , Bloomston M , Shah MH . Bone metastases in well-to-moderately differentiated neuroendocrine tumors: a single institutional review from the Ohio state university medical center . Pancreas . 2015 ; 44 ( 2 ): 198 ‐ 203 . 25411805 10.1097/MPA.0000000000000267

47 Riihimäki M , Hemminki A , Sundquist K , Sundquist J , Hemminki K . The epidemiology of metastases in neuroendocrine tumors . Int J Cancer . 2016 ; 139 ( 12 ): 2679 ‐ 2686 . 27553864 10.1002/ijc.30400

48 Scharf M , Petry V , Daniel H , Rinke A , Gress TM . Bone metastases in patients with neuroendocrine neoplasm: frequency and clinical, therapeutic, and prognostic relevance . Neuroendocrinology . 2018 ; 106 ( 1 ): 30 ‐ 37 . 28152537 10.1159/000457954

49 Song L , Zhai X , Yu S , et al Clinical analysis of 547 patients with neuroendocrine tumors in a Chinese population: a single-center study . Cancer Med . 2019 ; 8 ( 8 ): 3729 ‐ 3737 . 31127690 10.1002/cam4.2259 PMC6639184

50 Lim KHJ , Raja H , D’Arienzo P , et al Identification of areas for improvement in the management of bone metastases in patients with neuroendocrine neoplasms . Neuroendocrinology . 2020 ; 110 ( 7-8 ): 688 ‐ 696 . 31639796 10.1159/000504256

51 Trikalinos NA , Tan BR , Amin M , Liu J , Govindan R , Morgensztern D . Effect of metastatic site on survival in patients with neuroendocrine neoplasms (NENs). an analysis of SEER data from 2010 to 2014 . BMC Endocr Disord . 2020 ; 20 ( 1 ): 44 . 32245472 10.1186/s12902-020-0525-6 PMC7126407

52 Garcia-Torralba E , Spada F , Lim KHJ , et al Knowns and unknowns of bone metastases in patients with neuroendocrine neoplasms: a systematic review and meta-analysis . Cancer Treat Rev . 2021 ; 94 : 102168 . 33730627 10.1016/j.ctrv.2021.102168

53 Scopel M , De Carlo E , Bergamo F , et al Bone metastases from neuroendocrine tumors: clinical and biological considerations . Endocr Connect . 2022 ; 11 ( 7 ): e210568 . 35671272 10.1530/EC-21-0568 PMC9254287

54 Dong S-C , Tang Q-Y , Wang L , et al Characteristics and risk differences of different tumor sizes on distant metastases of pancreatic neuroendocrine tumors: a retrospective study in the SEER database . Hepatobiliary Pancreat Dis Int . 2025 ; 24 ( 2 ): 188 ‐ 196 . 39019667 10.1016/j.hbpd.2024.07.001

55 Alexandraki KI , Pizanias M , Uri I , et al The prognosis and management of neuroendocrine neoplasms-related metastatic bone disease: lessons from clinical practice . Endocrine . 2019 ; 64 ( 3 ): 690 ‐ 701 . 30635793 10.1007/s12020-019-01838-8

56 Skoura E , Michopoulou S , Mohmaduvesh M , et al The impact of 68 Ga-DOTATATE PET/CT imaging on management of patients with neuroendocrine tumors: experience from a national referral center in the United Kingdom . J Nucl Med . 2016 ; 57 ( 1 ): 34 ‐ 40 . 26471695 10.2967/jnumed.115.166017

57 Wedin M , Janson ET , Wallin G , Sundin A , Daskalakis K . Impact on symptoms and survival of bone metastases in patients with small-intestinal neuroendocrine tumours . J Neuroendocrinol . 2025 ; 37 ( 10 ): e70073 . 40778558 10.1111/jne.70073 PMC12488365

58 Ross EM , Roberts WC . The carcinoid syndrome: comparison of 21 necropsy subjects with carcinoid heart disease to 15 necropsy subjects without carcinoid heart disease . Am J Med . 1985 ; 79 ( 3 ): 339 ‐ 354 . 4036985 10.1016/0002-9343(85)90313-4

59 Lacalle-González C , Estrella Santos A , Landaeta Kancev LC , et al Management of non-hepatic distant metastases in neuroendocrine neoplasms . Best Pract Res Clin Endocrinol Metab . 2023 ; 37 ( 5 ): 101784 . 37270333 10.1016/j.beem.2023.101784

60 Adler RA , El-Hajj Fuleihan G , Bauer DC , et al Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American society for bone and mineral research . J Bone Miner Res . 2016 ; 31 ( 1 ): 16 ‐ 35 . 26350171 10.1002/jbmr.2708 PMC4906542

61 Black DM , Geiger EJ , Eastell R , et al Atypical femur fracture risk versus fragility fracture prevention with Bisphosphonates . N Engl J Med . 2020 ; 383 ( 8 ): 743 ‐ 753 . 32813950 10.1056/NEJMoa1916525 PMC9632334

62 Coleman R , Hadji P , Body J-J , et al Bone health in cancer: ESMO clinical practice guidelines† . Ann Oncol . 2020 ; 31 ( 12 ): 1650 ‐ 1663 . 32801018 10.1016/j.annonc.2020.07.019

63 Cives M , Pellè E , Rinzivillo M , et al Bone metastases in neuroendocrine tumors: molecular pathogenesis and implications in clinical practice . Neuroendocrinology . 2021 ; 111 ( 3 ): 207 ‐ 216 . 32403104 10.1159/000508633

Abbreviations

atypical femoral fracture

bone-modifying agent

computed tomography

differentiated thyroid cancer

magnetic resonance imaging

neuroendocrine tumor

osteonecrosis of the jaw

radioactive iodine

skeletal-related event

thyroglobulin