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– Borderline resectable oral cavity cancer is a surgical dilemma
Can chemo-immunotherapy increase operability?

A new Phase II trial suggests yes

🧪 NeoLOCUS trial (Lancet Regional Health SE Asia)

Regimen:
Carboplatin + nab-paclitaxel + low-dose nivolumab
•oral metronomic therapy (methotrexate + celecoxib + erlotinib)

🎯 Population
Borderline resectable OSCC
n = 34

📊 Key results

• ORR: 66.6%
• R0 resection after 2 cycles: 75.7%
• Overall surgical conversion: 90.3%
• Major pathological response: 41%
• pCR: 13.8%

🧬 Interesting biology
Good responders showed reduction in FOXP3+ Tregs, suggesting immune-microenvironment modulation.

⚠️ Safety
Grade ≥3 toxicity: 14.7%
No treatment-related deaths.

💡 Why this matters

Borderline OSCC often fails surgery after standard NACT.
This low-dose IO + metronomic + chemo strategy may offer an affordable outpatient approach in LMIC settings.

But this is single-arm Phase II → randomized validation needed.

Abstract

Context: Patients with elevated parathyroid hormone (PTH) and consistently normal serum calcium levels, in whom secondary causes of hyperparathyroidism have been excluded, may represent the earliest presentation of primary hyperparathyroidism (PHPT).

Objective: The objective of the study was to characterize patients with normocalcemic PHPT referred to a bone disease unit.

Design: This was a longitudinal cohort study.

Setting: Ambulatory patients were referred to the metabolic bone disease unit.

Patients: The study population included 37 patients [aged 58 yr, range 32–78; 95% female; serum calcium, 9.4 ± 0.1 (SEM) mg/dl (2.3 ± 0.02 mmol/liter), reference range, 8.5–10.4 (2.1–2.6 mmol/liter); PTH, 93 ± 5 pg/ml].

Interventions: Interventions included yearly (median 3 yr; range 1–8 yr) physical examination, biochemical indices, and bone mineral density (BMD).

Main Outcome Measures: We measured the development of features of PHPT.

Results: Evaluation for classical features of PHPT revealed a history of kidney stones in five (14%), fragility fractures in four (11%), and osteoporosis in 57% [spine (34%), hip (38%), and/or distal one third radius (28%)]. BMD did not show preferential bone loss at the distal one third radius (T scores: spine, −2.00 ± 0.25; hip, −1.84 ± 0.18; one third radius, −1.74 ± 0.22). Further signs of PHPT developed in 40% (seven hypercalcemia; one kidney stone; one fracture; two marked hypercalciuria; six had >10% BMD loss at one or more site(s) including four patients developing World Health Organization criteria for osteoporosis). Seven patients (three hypercalcemic, four persistently normocalcemic) underwent successful parathyroidectomy.

Conclusions: Patients seen in a referral center with normocalcemic hyperparathyroidism have more substantial skeletal involvement than is typical in PHPT and develop more features and complications over time. These patients may represent the earliest form of symptomatic, rather than asymptomatic, PHPT.

Lowe, Hyesoo et al. “Normocalcemic primary hyperparathyroidism: further characterization of a new clinical phenotype.” The Journal of clinical endocrinology and metabolism 92 8 (2007): 3001-5 .

#Arrangoiz #ParathyroidSurgeon #ParathyroidExpert #Hyperparathyroidism #PrimaryHyperparathyroidism #CancerSurgeon #EndocrineSurgery #Teacher #Surgeon #HeadandNeckSurgeon #SurgicalOncologist #ParathyroidAdenoma #Hypercalcemia #ElevatedCalciumLevels #Miami #MountSinaiMedicalCenter #MSMC #Mexico #Hialeah

• Differential Diagnosis of Hypercalcemia:
  • Primary hyperparathyroidism:
    • Solitary adenoma:
      • 85% to 90% of the cases
    • Multigland Disease:
      • Multigland hyperplasia:
        • 3% of the cases
      • Doble adenoma:
        • 6% to 9% of the cases
      • Triple adenoma:
        • 0.3% of the cases
  • Secondary hyperparathyroidism
  • Tertiary hyperparathyroidism
  • Familial hypocalciuric hypercalcemia
  • Medications:
    • Lithium
    • Hydrochlorothiazide
  • Malignancy:
    • Parathyroid carcinoma
    • Multiple myeloma
    • Tumors producing PTH-related peptide:
      • Ovarian cancer
      • Lung cancer
    • Acute or chronic leukemia
  • Granulomatous diseases:
    • Sarcoidosis, histioplasmosis, tuberculosis
  • Thyrotoxicosis
  • Paget disease
  • Increased intake:
    • Milk-alkali syndrome
    • Vitamin A toxicity
    • Vitamin D toxicity

• Primary hyperparathyroidism (PHPT):
  • Is caused by an inappropriate, autonomous  secretion of parathyroid hormone (PTH) by the parathyroid gland(s):
    • Which leads to an elevated serum calcium concentration or wide variations of the serum calcium concentration
  • Single gland disease:
    • Caused by a single, enlarged, overactive gland, is found in 85% to 90% of cases
  • Multiple gland disease occurs in 10% to 15% of the cases:
    • Multiple gland disease may consist of:
      • Double adenomas (6% to 9% of the cases)
      • Four-gland hyperplasia (3% of the cases)
      • Three enlarged and one normal appearing gland (0.3% of the cases).
        • Because asymmetric hyperplasia is common, it is difficult to distinguish between multiple adenomas and hyperplasia and the term multiple gland disease is preferred
  • PHPT in the United States usually presents quite early:
    • Often when hypercalcemia is noted during routine laboratory testing
  • Signs may include:
    • Nephrolithiasis, decreased bone density, and fragility fractures, and subjective symptoms may include fatigue, cognitive changes, depression, constipation and other gastrointestinal complaints, musculoskeletal pain, nocturia, and rarely pruritus:
      • Many patients may appear asymptomatic:
        • A detailed history often uncovers symptoms:
          • 95% of the cases have symptoms when appropriate history is taken:
            • The recently revised guidelines for asymptomatic PHPT include a more extensive evaluation of the skeletal and renal systems
  • A family history of endocrine disorders should be investigated:
    • As hyperparathyroidism alone can be familial or can present as a component of multiple endocrine neoplasia (MEN) types 1 and 2A

👉Hyperparathyroidism is associated with a wide array of symptoms related to neurocognitive and psychiatric function

👉Patients often report difficulties with memory and concentration, “brain fog”, mood related problems including depression, anxiety and irritability

👉They may also report weakness, general fatigue, sleep disturbance, joint and muscle pain

👉While the specific etiology of these symptoms is not clearly defined, they have been noted with increased frequency in this population

👉Read more at:

👉https://www.jscimedcentral.com/jounal-article-pdf/JSM-Head-and-Neck-Cancer-Cases-and-Reviews/headneck-1-1002.pdf

• Intraoperative rapid PTH does not itself define cure:
  • It is an intraoperative predictor of adequacy of resection
• Formal cure after parathyroidectomy:
  • Is still biochemical eucalcemia lasting at least 6 months
• Rapid PTH works:
  • Because intact PTH has a short half-life:
    • Roughly 3 to 5 minutes:
      • So levels should fall quickly after all hyperfunctioning tissue is removed
• The AAES guidelines:
  • Recommend intraoperative PTH monitoring with a reliable protocol for minimally invasive parathyroidectomy:
    • They note cure rates of about 97% to 99% in selected patients when adjunctive IPM is used
• Core concept:
  • The practical question in the OR is:
    • “Has all hypersecreting parathyroid tissue been removed?”
      • Rapid PTH helps answer that in real time
• Most protocols use a baseline sample before incision and / or immediately before excision:
  • Then a post-excision level at 10 minutes, with an additional 20-minute sample when the decline is borderline or delayed
• The most common reason the curve is misleading:
  • Is a PTH spike from gland manipulation:
    • Which is why many surgeons rely on the highest pre-incision or pre-excision value rather than only the pre-incision sample 
• Main intraoperative PTH protocols
  • The classic comparative study of 260 patients with concordant imaging:
    • Found overall accuracy of:
      • 97.3% for Miami, 92.3% for Vienna, 83.8% for Rome, and 65% for Halle criteria
    • In that same study:
      • Miami criteria was the best-balanced criterion for predicting cure:
        • Whereas Rome and Halle were somewhat better for detecting multigland disease but at the cost of more negative conversions to bilateral exploration
• The Miami criterion:
  • Is the most widely used:
    • A > 50% fall from the highest pre-incision or pre-excision PTH level, measured 10 minutes after excision of the abnormal gland
  • In the major Miami experience and subsequent reviews:
    • This approach achieved about 97% to 98% sensitivity, 97% specificity, ~99% PPV, and ~97% to 98% overall accuracy for postoperative eucalcemia
  • Long-term follow-up from the Miami group also showed durable outcomes with very low recurrence after focused surgery guided by intraoperative rapid PTH
  • This is why, in everyday endocrine surgery practice, the Miami criterion is usually the most useful protocol:
    • It is easy to remember, fast, reproducible, and has the best overall balance between avoiding persistent disease and avoiding unnecessary wider exploration
  • A 2024 network meta-analysis including 72 studies and 19,072 patients found that among conventional criteria:
    • The Miami criterion had the best diagnostic properties overall
• Vienna criterion:
  • The Vienna criterion also uses a > 50% drop at 10 minutes:
    • But the reference is the defined pre-incision baseline rather than the highest pre-excision value
  • It was designed to standardize interpretation and improve identification of multigland disease
  • In the comparative dataset above:
    • Vienna performed well, with 92.3% overall accuracy:
      • But still not as well as Miami for routine prediction of cure
    • In practical terms, Vienna is reasonable if your team insists on a strict, fixed baseline, but it is less forgiving when pre-excision manipulation creates a spike:
      • That is one reason many high-volume groups prefer Miami’s use of the highest available baseline
• Halle criterion:
  • Is much stricter:
    • Success is called only when PTH drops into the low-normal range:
      • Classically around 35 pg/mL:
        • Shortly after excision
  • This gives excellent specificity, but it performs poorly as a routine stopping rule because many successfully treated patients still have PTH levels above that threshold intraoperatively:
    • Especially if starting levels are high or clearance is delayed
  • In the Barczyński comparison, Halle had 100% specificity but only 65% overall accuracy:
    • Meaning it would trigger many unnecessary further explorations
  • For that reason, Halle is usually not the best default criterion for standard sporadic PHPT with concordant imaging:
    • It is too strict for routine use
• Rome criterion:
  • Is a more complex, stricter protocol
  • In one description, it requires a > 50% fall from the highest pre-excision level and / or a value within the normal range and / or an additional fall by 20 minutes
  • The point of Rome is to improve detection of persistence and multigland disease:
    • Especially when the early curve is ambiguous
  • A 2022 study evaluating the Rome approach found that the 20-minute / baseline ratio:
    • Had the highest diagnostic significance and suggested the 20-minute sample is particularly informative
  • Rome can be useful when the 10-minute value is borderline, when preoperative localization is less reliable, or when multigland disease is a real concern:
    • But as a standard protocol for all focused cases, it adds complexity and tends to increase exploration without clearly outperforming Miami for overall cure prediction
• What do meta-analyses say about using ioPTH at all?
  • Beyond comparing criteria, the broader question is whether using ioPTH improves outcomes
  • A 2021 systematic review / meta-analysis of 28 studies and 13,323 patients found operative failure rates of 3.2% with ioPTH versus 5.8% without ioPTH:
    • With a significant reduction in persistent / recurrent PHPT when ioPTH was used
  • Another 2021 systematic review / meta-analysis focused on minimally invasive parathyroidectomy included 12 studies and 2,290 patients and found that ioPTH use was associated with higher cure rates (OR 3.88, 95% CI 2.12–7.10) and a lower need for reoperation:
    • It did increase conversion to bilateral exploration, but without higher morbidity
  • So the evidence supports the value of ioPTH, especially when doing focused or minimally invasive surgery and when multigland disease is a concern
• Are stricter cutoffs better?
  • Usually, not enough to justify routine adoption
  • Newer work continues to test stricter thresholds:
    • A 2025 ROC analysis found that a 60% drop gave the best balance of sensitivity and specificity in that cohort, outperforming 50% and 70% on AUC, but the authors also cautioned that stricter thresholds may cause overtreatment and unnecessary exploration
    • Similarly, a 2025 two-center study suggested that combining the Miami rule with normalization to the reference range may help in selected cases, but the overall literature still favors the Miami criterion as the best general-purpose rule, which is consistent with the large network meta-analysis
• Practical interpretation in the OR
  • A resident-friendly approach is:
    • Draw pre-incision and pre-excision PTH
    • Remove the suspected gland
    • Check 10-minute PTH
    • If > 50% drop from the highest baseline → likely cure, stop if anatomy and clinical context fit
    • If borderline or not adequate → wait for 20-minute level and continue exploration if still not satisfactory
    • That approach handles the common real-life issues:
      • Manipulation spikes, delayed clearance, and occult multigland disease
• When rapid PTH is especially helpful:
  • Rapid PTH is most helpful in:
    • Focused / minimally invasive parathyroidectomy
    • Discordant or equivocal localization
    • Suspicion for multigland disease
    • Reoperative surgery
    • Cases where confirmation of adequacy of excision will determine whether you stop or proceed to wider exploration
• Bottom line: which protocol is most useful?
  • For most sporadic PHPT cases, especially with focused surgery:
    • The Miami criterion is the most useful protocol:
      • It has the best combination of simplicity, speed, evidence base, and diagnostic performance, and it remains the most widely adopted and best-supported criterion in comparative studies and network meta-analysis
• Key references:
  • Wilhelm SM, et al. AAES Guidelines for Definitive Management of Primary Hyperparathyroidism. JAMA Surg. 2016. 
  • Barczyński M, et al. Evaluation of Halle, Miami, Rome, and Vienna intraoperative iPTH assay criteria. Langenbecks Arch Surg. 2009. 
  • Khan ZF, et al. Intraoperative Parathyroid Hormone Monitoring in the Surgical Management of Sporadic PHPT. Endocrinol Metab. 2019. 
  • Quinn AJ, et al. Systematic review/meta-analysis of ioPTH in MIP. JAMA Otolaryngol Head Neck Surg. 2021. 
  • Medas F, et al. Systematic review/meta-analysis of rapid ioPTH. Int J Surg. 2021. 
  • Staibano P, et al. Network meta-analysis of diagnostic test accuracy. JAMA Otolaryngol Head Neck Surg. 2024/2025 indexing. 

• Prevalence of PHPT during pregnancy:
  • Is reported to be between 0.15% and 1.4%
• PHPT during pregnancy may have serious consequences to the mother and to the fetus:
  • If it remains unrecognized or untreated:
    • In up to 80% of patients, it is not recognized due to physiological changes during pregnancy that mask gestational PHPT, such as:
      • Hemodilution:
        • Related to intravascular fluid expansion
      • Hypoalbuminemia
      • Increased glomerular filtration rate:
        • Resulting in hypercalciuria
      • Transplacental transfer of calcium
  • Clinical presentation of PHPT durign pregnagncy may range from:
    • Hyperemesis, lethargy, hypertension, thirst, abdominal pain, depression, constipation, bone fracture, maternal heart rhythm disorders, maternal hypertension to preeclampsia, nephrolithiasis, pancreatitis, hyperemesis gravidarum, and hypercalcemic crisis:
      • Because the understanding of this concept and standard monitoring of all pregnant patients in developed countries:
        • The presentation of PHPT during pregnancy is very mild:
          • It is diagnosed in earlier stages
  • Sestamibi scan is contraindicated during pregnancy:
    • Due to radiation exposure risk to the fetus:
      • Ultrasound is the only diagnostic option since it carries no risk of radiation exposure and is easy to perform
  • Management of PHPT during pregnancy:
    • Should be individualized based on symptoms and severity of hypercalcemia:
      • Parathyroidectomy is indicated in symptomatic patients and patients with severe hypercalcemia:
        • When calcium level is elevated above 11 mg/dL (2.74 mmol/L)
      • Parathyroidectomy should be performed only in the second trimester:
        • To prevent miscarriage and anesthetic drugs exposure in the first trimester or spontaneous delivery in the third trimester
      • Mild form of PHPT causes low risk of maternal and obstetrical complications:
        • Therefore the patients can be managed conservatively, and parathyroidectomy can be deferred until after the delivery
      • Some medications, such as bisphosphonates, are contraindicated during pregnancy
      • Calcitonin:
        • Showed limited data and poor effectiveness:
          • But it does not cross the placenta and appears to be safe
      • Cinacalcet:
        • Has shown good results in several studies:
          • Although safety data are limited
      • Recent paper published by Rigg et al. retrospectively reviewed data of 28 pregnant patients with PHPT (22 managed medically and 6 surgically by elective parathyroidectomies):
        • Showed that 30% of those who were managed medically developed preeclampsia, and 66% managed medically had preterm deliveries

Consensus Recommendations – Early Breast Cancer

• ER-Positive / HER2-Negative Disease:
  • Genomic Testing:
    • Strong support for multigene assays (Oncotype DX, MammaPrint, etc.) in:
    • Node-negative disease
    • 1 to 3 positive nodes:
      • Especially postmenopausal:
        • In premenopausal patients with 1 to 3 nodes → chemotherapy often still favored even with low genomic risk
• Chemotherapy:
  • Postmenopausal:
    • N1 (1 to 3 nodes), low genomic risk:
      • Chemotherapy can be omitted
  • Premenopausal:
    • N1 disease:
      • Chemotherapy generally recommended:
        • Ovarian suppression contribution acknowledged but not universally accepted as replacement
• Ovarian Function Suppression (OFS):
  • Recommended in:
    • High-risk premenopausal patients
    • Node-positive disease AI + OFS preferred over tamoxifen alone in higher-risk settings
• CDK4/6 Inhibitors:
  • Abemaciclib recommended in:
    • High-risk node-positive (monarchE-like criteria)
  • Ribociclib:
    • Data discussed but not yet fully standard globally
• HER2-Positive Early Breast Cancer:
  • Neoadjuvant Therapy:
    • Standard for:
      • Tumors ≥ 2 cm
      • Node-positive disease
    • Preferred regimen:
      • Taxane + dual anti-HER2 (trastuzumab + pertuzumab)
  • Residual Disease After Neoadjuvant Therapy:
    • T-DM1 (KATHERINE data) remains standard
  • Duration of Trastuzumab:
    • 12 months remains consensus standard
    • 6 months acceptable only in select lower-risk or toxicity cases
  • De-escalation:
    • Small node-negative HER2+ (< 2 cm):
      • TH regimen acceptable (APT-like approach)
      • Ongoing interest in response-adapted therapy
• Triple-Negative Breast Cancer (TNBC):
  • Neoadjuvant Therapy:
    • Standard:
      • Anthracycline + taxane backbone
      • Addition of pembrolizumab:
        • Supported in stage II to III
  • Residual Disease:
    • Continue pembrolizumab:
      • KEYNOTE-522 strategy
    • Capecitabine considered if no prior immunotherapy
  • BRCA-Mutated:
    • Adjuvant olaparib recommended:
      • OlympiA criteria
• Axillary Management:
  • Clinically Node-Negative:
    • Sentinel lymph node biopsy (SLNB) standard
    • 1 to 2 Positive Sentinel Nodes (Upfront Surgery):
      • Omission of ALND supported if:
        • Undergoing breast-conserving therapy Whole-breast RT planned – ACOSOG Z0011 principles upheld
  • After Neoadjuvant Therapy:
    • If cN+:
      • ycN0:
        • SLNB acceptable if ≥ 3 nodes retrieved + dual tracer
        • Residual nodal disease → ALND still recommended in most settings
• Radiation Therapy:
  • Hypofractionation:
    • Standard for most patients
  • Ultra-hypofractionation (FAST-Forward-like) widely accepted
  • Omission of RT:
    • May be considered in:
      • Age ≥ 70
      • Small ER+ tumors
      • Planned endocrine therapy
• Regional Nodal Irradiation:
  • Recommended in:
    • Node-positive disease
    • High-risk biology
• De-escalation Themes:
  • Avoid overtreatment in:
    • Low-risk luminal A disease
    • Elderly / frail patients
    • Tailor treatment based on:
      • Biology > anatomy alone
      • Genomic profiling
      • Patient preference
• Liquid Biopsy & MRD:
  • ctDNA promising but:
    • Not yet standard for treatment decision:
      • Still investigational for escalation / de-escalation
• Germline Mutation Carriers
  • BRCA1/2:
    • Consider bilateral mastectomy (case-dependent)
    • Adjuvant olaparib in high-risk early disease
    • PALB2 increasingly treated similarly to BRCA in high-risk scenarios
• Artificial Intelligence and Imaging:
  • MRI not routine for all early-stage patients
  • PET-CT not recommended for stage I routine staging
  • AI emerging for:
    • Risk stratification
    • Imaging interpretation
    • Treatment personalization
• Key Global Themes of St. Gallen 2025:
  • Precision > escalation Biology-driven treatment
  • Safe de-escalation when supported by data
  • Increased use of CDK4/6 inhibitors and immunotherapy in early disease
  • Continued minimization of axillary surgery

• What was the primary research question of the INSEMA trial?
  • Answer:
    • To determine whether sentinel lymph node biopsy (SLNB) can be safely omitted in patients with clinically node-negative early-stage breast cancer undergoing breast-conserving surgery and whole breast radiation, without compromising invasive disease-free survival (iDFS)
• What type of study was this, and how was it designed?
  • Answer:
    • It was a prospective, randomized, multicenter, non-inferiority trial conducted in Germany and Austria
    • Patients were randomized in a 4:1 ratio to no SLNB vs. SLNB
• What were the eligibility criteria for patients to be included in the trial?
  • Answer:
    • Female patients
    • Clinically node-negative (cN0) invasive breast cancer
    • Tumor size cT1 to cT2 (≤ 5 cm)
    • Candidates for breast-conserving surgery and whole-breast irradiation
    • No prior axillary surgery, neoadjuvant therapy, or mastectomy
• What was the primary endpoint, and what was the non-inferiority margin?
  • Answer:
    • Primary endpoint:
      • 5-year invasive disease-free survival (iDFS)
    • Non-inferiority margin:
      • Hazard Ratio upper limit of 1.271 and ≥ 85% iDFS in the no-SLNB arm
• What were the main results regarding iDFS
  • Answer:
    • iDFS: 91.9% (no-SLNB) vs. 91.7% (SLNB)
    • HR: 0.91 (95% CI, 0.73–1.14) → Non-inferiority was met
• Was there a difference in overall survival (OS)
  • Answer:
    • Yes, but it favored no-SLNB slightly:
      • 5-year OS: 98.2% (no-SLNB) vs. 96.9% (SLNB):
        • Difference was not statistically significant
• What was the axillary recurrence rate in both groups?
  • Answer:
    • No-SLNB: 1.0%
    • SLNB: 0.3%
      • While slightly higher in the no-SLNB group:
        • Both rates were very low and clinically acceptable
• What secondary outcomes were assessed?
  • Answer:
    • Lymphedema incidence
    • Arm / shoulder function and pain
    • Quality of life
      • All significantly favored the no-SLNB group
• What are the main clinical implications of this study?
  • Answer:
    • In selected low-risk patients:
      • SLNB may be safely omitted:
        • Reducing surgical morbidity and improving quality of life without compromising survival
• Which subgroup of patients benefits most from SLNB omission based on this trial?
  • Answer:
    • Women ≥ 50 years old with T1, grade 1 to grade 2, hormone receptor-positive, HER2-negative tumors undergoing lumpectomy with whole breast radiation
• Can we apply the findings of this trial to patients undergoing mastectomy or partial-breast irradiation?
  • Answer:
    • No:
      • Those patients were excluded, so the results cannot be extrapolated to those scenarios
• How might omitting SLNB affect adjuvant therapy decisions?
  • Answer:
    • Without nodal staging, decisions about chemotherapy or genomic testing might become more challenging:
      • Multidisciplinary evaluation is essential
• How do these findings compare to axillary de-escalation trends seen in trials like ACOSOG Z0011 or SOUND?
  • Answer:
    • Similar direction:
      • All support less axillary surgery in low-risk, clinically node-negative patients
    • INSEMA takes it a step further by testing omission of SLNB itself
• What are some limitations of the INSEMA trial
  • Answer:
    • Limited generalizability:
      • Mostly postmenopausal, low-risk tumors
    • Exclusion of higher-risk patients:
      • HER2+, triple-negative, T2 > 3 cm
    • Lack of data in mastectomy or neoadjuvant settings
• If one of your patients meets criteria from this trial, how would you counsel them on omitting SLNB?
  • Answer:
    • Explain that in select low-risk early-stage breast cancer, omitting SLNB does not affect survival, reduces the risk of complications like lymphedema, and improves quality of life:
      • However, thorough discussion with oncology and radiation teams is important to individualize care

• Increased Bone Turnover (Primary Mechanism)

• Thyroid hormones (T3 and T4):
  • Stimulate bone remodeling:
    • But they disproportionately increase:
      • Osteoclastic bone resorption
    • Mechanism:
      • Thyroid hormone increases osteoblast activity:
        • Which in turn stimulates osteoclasts:
          • Via the RANKL pathway
    • This results in:
      • ↑ osteoclast-mediated bone resorption
      • ↑ release of calcium and phosphate from bone
    • Key physiologic effects:
      • Accelerated bone turnover
      • Net bone loss
      • Calcium release into circulation
    • This explains why hyperthyroidism
    • is associated with:
      • Hypercalcemia (usually mild)
      • Hypercalciuria
      • Osteopenia / osteoporosis
  • Increased Sensitivity to Catecholamines:
    • Thyroid hormone enhances β-adrenergic activity:
      • Which further stimulates bone turnover
    • This contributes to:
      • Increased osteoclast activity
      • Further calcium mobilization from bone
  • Suppressed Parathyroid Hormone (PTH):
    • Because calcium increases, the body responds physiologically:
      • Serum calcium rises
      • PTH becomes suppressed
  • Increased Renal Calcium Excretion:
    • Because of the higher filtered calcium load:
      • Hypercalciuria develops
      • Patients may occasionally develop nephrolithiasis:
        • However, stones are much less common than in primary hyperparathyroidism.
  • Increased IL-6 and Cytokine Activity:
    • Hyperthyroidism may increase cytokine signaling such as:
      • IL-6
      • TNF-α
    • These cytokines stimulate osteoclast differentiation and further promote bone resorption
• Typical laboratory pattern:

Test	Finding
Calcium	Mildly ↑
PTH	Suppressed
Phosphate	Normal or mildly ↑
1,25-Vitamin D	Normal
Urinary calcium	↑

This helps differentiate thyrotoxicosis-related hypercalcemia from primary hyperparathyroidism.

• Clinical Characteristics:
  • Typical hypercalcemia seen in hyperthyroidism:
    • Once thyrotoxicosis is treated, calcium levels usually normalize

Characteristic	Feature
Frequency	~15–20% of patients with hyperthyroidism
Severity	Usually mild (Ca 10.5–11.5 mg/dL)
Mechanism	Increased bone resorption
PTH	Suppressed
Treatment	Correction of hyperthyroidism

• Important Surgical Teaching Point:
  • When evaluating hypercalcemia with suppressed PTH, consider:
    • Differential diagnosis
      • Malignancy
      • Hyperthyroidism
      • Vitamin D intoxication
      • Granulomatous disease (sarcoidosis)
      • Medications (thiazides)
  • Thus, thyroid function tests should be obtained in unexplained hypercalcemia
• Key References:
  • Mosekilde L. Hyperthyroidism and bone metabolism. Endocrinol Metab Clin North Am. 1990.
  • Ross DS et al. 2022 American Thyroid Association Guidelines for Thyrotoxicosis. Thyroid. 2022.
  • Mundy GR, Martin TJ. The hypercalcemia of malignancy and endocrine disorders. Metabolism. 1982.
  • Bilezikian JP et al. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. ASBMR.
• Teaching pearl for residents:
  • If you see hypercalcemia with suppressed PTH and symptoms of thyrotoxicosis, always check TSH before assuming malignancy