HYPERPARATHYROIDISM
Parathyroid Hormone Excess | Hypercalcemia | Brown Tumors | Renal Stones
HYPERPARATHYROIDISM TYPES
Critical Must-Knows
- Primary HPT: Elevated calcium AND elevated/inappropriately normal PTH (adenoma 85%)
- Bone effects: Osteitis fibrosa cystica, brown tumors (lytic lesions), subperiosteal resorption
- Classic triad: Bones (brown tumors), stones (renal calculi), groans (abdominal pain)
- Surgical indications: Age under 50, calcium over 2.85 mmol/L, renal impairment, osteoporosis, brown tumors
- Secondary HPT: Normal/low calcium with elevated PTH (renal failure most common)
Examiner's Pearls
- "Elevated calcium WITH elevated PTH distinguishes primary HPT from malignancy
- "Brown tumors are osteoclastic giant cell lesions (not malignant despite name)
- "Subperiosteal resorption on hand X-rays is pathognomonic for hyperparathyroidism
- "Secondary HPT causes renal osteodystrophy with mixed bone disease patterns
Clinical Imaging
Imaging Gallery
Clinical Imaging
Brown Tumors - Imaging Findings
Critical Hyperparathyroidism Exam Points
Biochemical Diagnosis Is Key
Primary HPT: Elevated calcium (over 2.55 mmol/L) AND elevated PTH (or inappropriately normal PTH). If calcium elevated but PTH suppressed, think malignancy or other causes. Check phosphate (usually low in primary HPT).
Brown Tumors Are Not Cancer
Brown tumors are lytic bone lesions caused by osteoclast hyperactivity. They are benign reactive lesions containing giant cells and hemosiderin (brown color). Mimic metastases on imaging. Resolve after parathyroidectomy.
Distinguish Primary vs Secondary HPT
Primary: High calcium, high PTH (adenoma). Secondary: Low/normal calcium, high PTH (renal failure, vitamin D deficiency). Tertiary: High calcium, high PTH (autonomous after chronic secondary). Treatment differs completely.
Surgical Indications Are Specific
Operate on primary HPT if: Age under 50, calcium over 2.85 mmol/L, GFR under 60, T-score under -2.5, brown tumors, renal stones. Otherwise can observe asymptomatic mild disease with monitoring.
At a Glance
Hyperparathyroidism presents in three forms: Primary (autonomous PTH secretion, usually from a single adenoma in 85% of cases), Secondary (compensatory PTH elevation from chronic renal failure or vitamin D deficiency), and Tertiary (autonomous hyperfunction after chronic secondary HPT). The classic clinical triad "Bones, Stones, Groans" describes skeletal manifestations (osteitis fibrosa cystica, brown tumors, subperiosteal resorption), renal calculi from hypercalciuria, and abdominal pain. Brown tumors are benign osteoclastic giant cell lesions (not malignant despite the name) that mimic metastases on imaging but resolve after parathyroidectomy. Biochemical diagnosis is key: elevated calcium WITH elevated PTH confirms primary HPT (malignancy causes elevated calcium with suppressed PTH). Surgical indications for primary HPT include: age under 50, calcium greater than 2.85 mmol/L, GFR less than 60, T-score less than -2.5, brown tumors, or renal stones—asymptomatic mild disease can be observed with monitoring.
BONES STONES GROANSBONES STONES GROANS - Classic Primary HPT Triad
Memory Hook:BONES (skeletal), STONES (renal), GROANS (GI) - plus psychiatric moans and overtones!
KIDNEY BONEPTH EFFECTS - Actions of Parathyroid Hormone
Memory Hook:KIDNEY regulates calcium and phosphate, BONE releases calcium stores - PTH raises calcium!
Overview and Epidemiology
Hyperparathyroidism is a disorder of excessive parathyroid hormone (PTH) secretion, leading to dysregulation of calcium and phosphate homeostasis. The condition is classified into three types based on mechanism.
Types:
- Primary HPT: Autonomous PTH secretion from parathyroid adenoma (85%), hyperplasia (10-15%), or rarely carcinoma (under 1%)
- Secondary HPT: Compensatory PTH elevation in response to chronic hypocalcemia (renal failure, vitamin D deficiency, malabsorption)
- Tertiary HPT: Autonomous PTH secretion developing after prolonged secondary HPT (typically post-renal transplant)
Why HPT Matters to Orthopaedics
Hyperparathyroidism causes brown tumors (lytic bone lesions that mimic metastases), pathological fractures, and generalized bone loss. Secondary HPT in renal failure leads to renal osteodystrophy with complex bone disease. Preoperative recognition prevents misdiagnosis of malignancy and guides appropriate medical vs surgical management.
Physiology and Pathophysiology
Parathyroid Hormone Physiology
PTH actions on calcium homeostasis:
PTH Effects on Target Organs
| Organ | Action | Result | Mechanism |
|---|---|---|---|
| Bone | Increases osteoclast activity | Bone resorption, calcium release | RANKL upregulation via osteoblasts |
| Kidney (proximal tubule) | Decreases phosphate reabsorption | Phosphaturia, low serum phosphate | Inhibits sodium-phosphate cotransporter |
| Kidney (distal tubule) | Increases calcium reabsorption | Reduced calcium excretion | Activates calcium channels (TRPV5) |
| Kidney (1-alpha hydroxylase) | Activates vitamin D | Increased intestinal calcium absorption | Converts 25-OH to 1,25-dihydroxy vitamin D |
Net result: Elevated serum calcium, reduced serum phosphate
Primary Hyperparathyroidism Pathogenesis
Parathyroid Adenoma (85%)
- Single gland enlargement (usually inferior glands)
- Loss of normal calcium-sensing feedback
- Autonomous PTH secretion regardless of calcium level
- Surgical cure with targeted adenomectomy
Parathyroid Hyperplasia (10-15%)
- Multiple gland involvement (all 4 glands)
- Associated with MEN syndromes (MEN1, MEN2A)
- Familial hypocalciuric hypercalcemia (FHH) differential
- Requires subtotal or total parathyroidectomy
Familial Hypocalciuric Hypercalcemia Mimic
FHH is a benign genetic condition mimicking primary HPT (elevated calcium, normal/high PTH). Key difference: urine calcium is LOW (calcium/creatinine clearance ratio under 0.01). FHH does NOT require surgery. Always check 24-hour urine calcium before parathyroidectomy.
Secondary Hyperparathyroidism
Mechanism: Chronic hypocalcemia stimulates parathyroid glands to increase PTH secretion
Causes:
- Chronic kidney disease (most common): Reduced phosphate excretion and impaired 1-alpha hydroxylase (low active vitamin D)
- Vitamin D deficiency: Reduced intestinal calcium absorption
- Malabsorption (celiac, Crohn's): Inadequate calcium absorption
- Chronic loop diuretic use: Renal calcium wasting
Result: Normal or LOW calcium with elevated PTH (appropriate response)
Tertiary Hyperparathyroidism
Mechanism: After prolonged secondary HPT, parathyroid glands become autonomous (no longer responsive to calcium feedback)
Typical scenario: Renal transplant patient with previously high PTH now develops hypercalcemia post-transplant (glands continue secreting PTH autonomously)
Treatment: Requires parathyroidectomy (medical management ineffective)
Clinical Assessment
Primary Hyperparathyroidism Presentation
Asymptomatic Primary HPT (Most Common Today)
70-80% of cases detected incidentally on routine blood tests (automated chemistry panels)
Findings:
- Mildly elevated calcium (2.6-2.8 mmol/L)
- Elevated PTH (1.5-2x upper limit normal)
- No bone or renal symptoms
- Often detected during health screening
Management: Assess for surgical indications (age, calcium level, bone density, renal function). If no indications: monitor calcium, bone density, and renal function annually. Maintain hydration and avoid thiazide diuretics.
Brown Tumors - Orthopaedic Manifestation
Definition: Osteoclastic giant cell lesions (osteitis fibrosa cystica) appearing as lytic bone lesions
Pathophysiology:
- Excessive PTH drives osteoclast activity
- Focal areas of bone resorption replaced by fibrous tissue and giant cells
- Hemorrhage within lesions produces hemosiderin (brown color grossly)
Clinical features:
- Lytic expansile lesions on X-ray (mimic metastases, myeloma, giant cell tumor)
- Most common sites: Jaw (mandible), ribs, pelvis, long bones
- Usually painless unless pathological fracture occurs
- May present as palpable bony swelling
Key point: Brown tumors are BENIGN and resolve after parathyroidectomy
Brown Tumor vs Giant Cell Tumor Differential
Brown tumors occur in setting of elevated PTH and hypercalcemia, are often multiple, and regress after parathyroidectomy. Giant cell tumors are true neoplasms (benign but locally aggressive), occur in young adults (20-40 years), are typically solitary at metaphysis-diaphysis junction, and require surgical excision. Check calcium and PTH to differentiate.
Biochemical and Imaging Investigations
Biochemistry
Biochemical Profiles in Hyperparathyroidism
| Type | Calcium | PTH | Phosphate | Clinical Context |
|---|---|---|---|---|
| Primary HPT | Elevated (over 2.55) | Elevated (or inappropriately normal) | Low/normal | Adenoma, hyperplasia, carcinoma |
| Secondary HPT | Low or normal | Elevated (appropriate) | Elevated (if renal failure) | CKD, vitamin D deficiency |
| Tertiary HPT | Elevated | Elevated (autonomous) | Variable | Post-renal transplant, chronic secondary |
| Malignancy (PTHrP) | Elevated | Suppressed (low) | Low/normal | Lung, breast, renal cancer |
Additional tests:
- 25-OH vitamin D: Rule out vitamin D deficiency (causes secondary HPT)
- 24-hour urine calcium: Distinguish FHH (low) from primary HPT (high)
- Creatinine/eGFR: Assess renal function (surgical indication if impaired)
- Alkaline phosphatase: May be elevated with bone turnover
Inappropriately Normal PTH in Hypercalcemia
If calcium is elevated, PTH should be suppressed (low). If PTH is in the normal range with elevated calcium, this is inappropriate and indicates primary HPT. The calcium-PTH relationship is key to diagnosis.
Radiology
Plain X-rays show characteristic features:
Pathognomonic Findings
- Subperiosteal resorption: Radial side of middle phalanges (hand X-ray)
- Salt and pepper skull: Granular decalcification
- Brown tumors: Lytic expansile lesions (jaw, ribs, pelvis)
- Bone cysts: Multiple lytic lesions
General Findings
- Osteopenia: Generalized bone density loss
- Loss of lamina dura: Around teeth (dental X-rays)
- Rugger jersey spine: Dense endplates (secondary HPT with renal osteodystrophy)
- Chondrocalcinosis: Calcium pyrophosphate deposition
DEXA scan:
- Assess bone mineral density (T-score)
- Osteoporosis (T-score under -2.5) is a surgical indication
- Primary HPT preferentially affects cortical bone (distal radius most affected)
Parathyroid Imaging (Preoperative Localization)
Sestamibi scan (Tc-99m sestamibi):
- Nuclear medicine imaging to locate adenoma preoperatively
- Sensitivity 70-90% for single adenomas
- Less sensitive for hyperplasia (multiple glands)
Ultrasound:
- Identifies enlarged parathyroid glands
- Operator-dependent
- Combined with sestamibi improves localization
4D CT or MRI:
- Reserved for reoperative cases or ectopic glands
- High sensitivity for localization
Medical and Surgical Management
Primary Hyperparathyroidism - Surgical Indications
Indications for Parathyroidectomy in Primary HPT
| Criterion | Threshold | Rationale |
|---|---|---|
| Age | Under 50 years | Long-term risk of bone loss and renal stones |
| Serum calcium | Over 2.85 mmol/L | Increased risk of symptoms and complications |
| Renal function | eGFR under 60 mL/min | Prevent progressive renal impairment |
| Bone density | T-score under -2.5 (any site) | Osteoporosis increases fracture risk |
| 24-hour urine calcium | Over 400 mg/day | High risk of nephrolithiasis |
| Presence of complications | Nephrolithiasis, fracture, brown tumors | Direct disease-related complications |
| Patient preference | Unable to comply with monitoring | Surgery curative, avoids lifelong surveillance |
Surgical Options
Minimally Invasive Parathyroidectomy (MIP)
Indications:
- Single adenoma localized on imaging
- Concordant sestamibi and ultrasound
Technique:
- Small incision (2-3 cm)
- Targeted removal of identified adenoma
- Intraoperative PTH monitoring (drop over 50% confirms cure)
- Faster recovery, lower morbidity
Success rate: 95-98% in experienced hands
This is now the preferred approach when imaging is concordant.
Hungry Bone Syndrome Post-Parathyroidectomy
After successful parathyroidectomy, rapid bone remineralization can cause severe hypocalcemia (hungry bone syndrome). Risk factors: High preop PTH, large adenoma, brown tumors, renal impairment. Requires aggressive calcium and calcitriol supplementation postoperatively. Monitor calcium daily initially.
Medical Management
For asymptomatic patients not meeting surgical criteria:
Monitoring:
- Serum calcium every 6-12 months
- eGFR annually
- DEXA scan every 1-2 years
- 24-hour urine calcium if nephrolithiasis develops
Conservative measures:
- Adequate hydration (2-3 L/day)
- Avoid thiazide diuretics (increase calcium)
- Maintain vitamin D sufficiency (25-OH vitamin D 50-75 nmol/L)
- Weight-bearing exercise
Pharmacological (if surgery declined):
- Calcimimetics (cinacalcet): Activates calcium-sensing receptor, lowers PTH and calcium
- Bisphosphonates: Prevent bone loss, do not treat hypercalcemia
- Not curative, only symptom control
Secondary Hyperparathyroidism Management
Treat underlying cause:
- CKD: Phosphate binders, activated vitamin D (calcitriol), calcimimetics
- Vitamin D deficiency: Vitamin D supplementation (cholecalciferol 50,000 IU weekly until replete)
- Malabsorption: Treat GI condition, oral or IV calcium/vitamin D
Renal osteodystrophy management:
- Control phosphate (under 1.5 mmol/L with binders)
- Maintain calcium (2.2-2.5 mmol/L)
- Suppress PTH (target 2-9x upper limit normal for CKD stage)
- Monitor for vascular calcification
Complications
Complications of Hyperparathyroidism
| Complication | Mechanism | Presentation | Management |
|---|---|---|---|
| Pathological fracture | Brown tumors, osteoporosis | Fracture with minimal trauma | Fixation if needed, parathyroidectomy to heal lesions |
| Nephrolithiasis | Hypercalciuria, calcium stones | Renal colic, hematuria | Hydration, treat stones, parathyroidectomy prevents recurrence |
| Nephrocalcinosis | Calcium deposition in kidney | Progressive renal impairment | Parathyroidectomy to prevent progression |
| Hypercalcemic crisis | Severe hypercalcemia (over 3.5 mmol/L) | Confusion, nausea, dehydration, arrhythmias | IV fluids, calcitonin, bisphosphonates, urgent parathyroidectomy |
| Parathyroid carcinoma | Rare (under 1%) | Very high calcium (over 3.5), palpable neck mass | En bloc resection with ipsilateral thyroid lobe |
Evidence Base and Key Studies
Surgery vs Observation in Asymptomatic Primary HPT
- Prospective study: 121 patients with asymptomatic primary HPT randomized to surgery vs observation
- Surgery group: Significant improvement in bone mineral density (lumbar spine +12%, femoral neck +6%)
- Observation group: Continued bone loss and no improvement in quality of life
- 15-year follow-up: Surgery group had lower fracture rate
Minimally Invasive vs Bilateral Exploration
- Retrospective cohort: 1650 parathyroidectomies
- MIP with intraoperative PTH: 97% cure rate, shorter operative time, less morbidity
- Bilateral exploration: 96% cure rate, longer OR time, higher complication rate
- MIP requires concordant preoperative imaging (sestamibi + ultrasound)
PTH Effects on Bone and Fracture Risk
- Meta-analysis of studies examining fracture risk in primary HPT
- Overall fracture risk increased 1.5-2x compared to age-matched controls
- Vertebral and forearm fractures most increased
- Bone mineral density significantly reduced at cortical sites
Exam Viva Scenarios
Practice these scenarios to excel in your viva examination
Scenario 1: Lytic Bone Lesion Workup
"A 58-year-old woman presents with a painless swelling of her jaw. X-ray shows a lytic expansile lesion of the mandible. Blood tests reveal calcium 2.9 mmol/L (normal 2.2-2.5) and PTH 150 pg/mL (normal 10-65). How do you approach this case?"
Scenario 2: Renal Osteodystrophy
"A 45-year-old man with end-stage renal disease on hemodialysis for 10 years presents with diffuse bone pain and muscle weakness. Blood tests show calcium 2.0 mmol/L, phosphate 2.5 mmol/L (elevated), PTH 850 pg/mL (markedly elevated). How do you assess and manage this patient?"
MCQ Practice Points
Biochemical Diagnosis Question
Q: A patient has serum calcium 2.9 mmol/L and PTH 120 pg/mL. What is the most likely diagnosis? A: Primary hyperparathyroidism. Elevated calcium with elevated (or inappropriately normal) PTH indicates autonomous PTH secretion. In hypercalcemia, PTH should be suppressed; if it's normal or high, that's inappropriate and diagnostic of primary HPT.
Brown Tumor Nature Question
Q: What is the histological composition of a brown tumor in hyperparathyroidism? A: Osteoclastic giant cells and hemosiderin-laden macrophages within fibrous tissue. Brown tumors are benign reactive lesions (not malignant) caused by excessive osteoclast activity. The brown color comes from hemosiderin from chronic hemorrhage.
FHH Differential Question
Q: How do you differentiate familial hypocalciuric hypercalcemia from primary hyperparathyroidism? A: 24-hour urine calcium measurement. FHH has LOW urine calcium (calcium/creatinine clearance ratio under 0.01) despite hypercalcemia, due to increased renal calcium reabsorption from calcium-sensing receptor mutation. Primary HPT has HIGH urine calcium. FHH does not require surgery.
Surgical Indication Question
Q: A 62-year-old asymptomatic patient with primary HPT has calcium 2.7 mmol/L, normal renal function, and DEXA T-score -2.3. Is surgery indicated? A: No, observation is appropriate. Surgical indications include age under 50, calcium over 2.85 mmol/L, eGFR under 60, or T-score under -2.5. This patient meets none of these criteria and can be monitored with annual calcium, renal function, and DEXA scans.
Orthopaedic Fracture Risk
Q: Which fracture sites are most associated with primary hyperparathyroidism? A: Vertebral compression fractures and distal forearm (Colles) fractures are most common. Cortical bone is preferentially affected due to increased remodeling. Hip fractures are also increased (2-3x risk). Fractures may occur at lower trauma thresholds. Brown tumors are rare but can cause pathologic fractures, particularly in long bone diaphyses.
Australian Context
Australian Epidemiology
Primary hyperparathyroidism has a prevalence of approximately 1-3 per 1000 in Australia, with higher rates in postmenopausal women. The condition is often detected incidentally during routine blood tests. Parathyroid surgery is performed in major metropolitan hospitals by endocrine surgeons, with minimally invasive techniques increasingly utilized when preoperative localization is successful.
Clinical Practice Considerations
Management follows international guidelines with surgical referral for patients meeting operative criteria. Cinacalcet may be used for secondary hyperparathyroidism in dialysis patients. Bone health assessment and fracture prevention are important components of management, particularly for those with reduced bone density.
HYPERPARATHYROIDISM
High-Yield Exam Summary
Key Biochemistry
- •Primary HPT: High Ca, High PTH (or inappropriately normal PTH)
- •Secondary HPT: Low/Normal Ca, High PTH (appropriate response)
- •Tertiary HPT: High Ca, High PTH (autonomous after chronic secondary)
- •Malignancy (PTHrP): High Ca, Low PTH (suppressed)
PTH Actions
- •Bone: Increases osteoclast activity (via RANKL) - releases calcium
- •Kidney DCT: Increases calcium reabsorption
- •Kidney PT: Decreases phosphate reabsorption (phosphaturia)
- •Kidney 1-alpha hydroxylase: Activates vitamin D (increases gut Ca absorption)
Brown Tumors
- •Osteoclastic giant cell lesions (osteitis fibrosa cystica)
- •Lytic expansile lesions on X-ray (jaw, ribs, pelvis, long bones)
- •BENIGN - regress after parathyroidectomy
- •Differentiate from GCT: multiple lesions, elevated Ca/PTH
Surgical Indications (Primary HPT)
- •Age under 50 years
- •Calcium over 2.85 mmol/L
- •eGFR under 60 mL/min
- •T-score under -2.5 (osteoporosis)
- •Urine calcium over 400 mg/24hr OR nephrolithiasis, fracture, brown tumors
Complications
- •Pathological fracture (brown tumors, osteoporosis)
- •Nephrolithiasis (20% of primary HPT)
- •Hungry bone syndrome (post-parathyroidectomy hypocalcemia)
- •Hypercalcemic crisis (Ca over 3.5, needs urgent treatment)
Secondary HPT Management
- •Phosphate binders (calcium-based or sevelamer)
- •Activated vitamin D (calcitriol) to suppress PTH
- •Calcimimetics (cinacalcet) for refractory cases
- •Parathyroidectomy if medical management fails (PTH over 800-1000)