Calcium and Bone Disorders — Clinical Case

DCE Long Case

Patient profile

Mrs M is a 68-year-old retired teacher presenting to the endocrine outpatient clinic with a 3-month history of progressive fatigue, polyuria, nocturia, and diffuse bone pain. She fractured her left distal radius 18 months ago after a fall from a standing height and has stage 3b CKD (eGFR 42 mL/min). [1]

Presenting concern: For three months she has felt increasingly tired and thirsty, passing urine four to five times nightly, and has developed a deep aching pain in her lower back, ribs, and thighs. She has lost 3 kg unintentionally. She fractured her left distal radius in her garden 18 months ago and was told her bone density was low. [1]

Past medical history: Hypertension (on amlodipine 5 mg for 10 years), stage 3b CKD (eGFR 42, attributed to hypertensive nephrosclerosis), distal radial fracture 18 months ago (managed in a cast), cholecystectomy. Menopause at age 52, no hormone replacement. No prior thyroid or parathyroid surgery. [1]

Medications: amlodipine 5 mg daily, occasional paracetamol for bone pain. No calcium supplements, no thiazides, no glucocorticoids. [1]

Family history: Mother had kidney stones and osteoporosis; sister has type 2 diabetes. No known MEN syndrome. [1]

Social: Retired teacher, lives with husband. Non-smoker, alcohol 4 standard drinks per week. Walking 30 minutes daily (reduced due to bone pain). [1]

Examination:

• Alert, oriented, no acute distress. Temperature 36.8. Pulse 78 regular. Blood pressure 144/88. Respiratory rate 16. SpO2 98% room air.
• Weight 62 kg, height 160 cm (BMI 24.2). Mild thoracic kyphosis.
• Cardiovascular: normal heart sounds, no murmurs.
• Abdomen: soft, non-tender, no masses. Cholecystectomy scar.
• Neurological: normal; no Chvostek or Trousseau sign.
• Musculoskeletal: diffuse bony tenderness over the lower thoracic and lumbar spine and the anterior tibial shins. Kyphosis at the thoracolumbar junction. No joint swelling or deformity.
• No neck mass, no lymphadenopathy. [1]

Investigations:

• Corrected calcium 2.85 mmol/L (reference 2.15 to 2.55). Albumin 38 g/L.
• Phosphate 0.78 mmol/L (reference 0.8 to 1.5).
• Magnesium 0.8 mmol/L (reference 0.7 to 1.0). Normal.
• ALP 165 U/L (reference 30 to 120). Gamma-GT 55 U/L (slightly elevated, consistent with bone origin).
• Intact PTH 8.5 pmol/L (reference 1.6 to 6.9).
• 25-hydroxyvitamin D 32 nmol/L (reference above 75).
• Renal function: creatinine 130 micromol/L (baseline 90 two years ago), eGFR 42 mL/min. Electrolytes otherwise normal.
• 24-hour urinary calcium: 310 mg (reference below 250 women; threshold for surgery above 250 women per Fifth Workshop).
• Calcium-to-creatinine clearance ratio: 0.024 (consistent with PHPT, excludes FHH).
• TFTs normal. TSH 2.1 mIU/L.
• Serum protein electrophoresis: no paraprotein. Urine Bence-Jones negative.
• Tissue transglutaminase IgA negative. Total IgA normal.
• DEXA: T-score -2.8 lumbar spine (L1 to L4), -2.6 femoral neck, -2.9 distal third radius. (Baseline 3 years ago: -2.3 spine, -2.1 femoral neck — deterioration.)
• Lateral thoracolumbar spine X-ray: mild anterior wedge deformity at T12 (15% height loss, previously unrecognised).
• Renal ultrasound: normal-sized kidneys, 5 mm non-obstructing stone in the right renal pelvis. No nephrocalcinosis.
• Parathyroid sestamibi SPECT-CT: focal increased uptake at the inferior aspect of the right thyroid lobe, consistent with a right inferior parathyroid adenoma.
• Neck ultrasound: 1.5 cm hypoechoic nodule posterior to the right thyroid lower pole, consistent with a parathyroid adenoma. No suspicious thyroid nodules. [1]

Candidate's opening statement (SASPOP)

"This is Mrs M, a 68-year-old retired teacher presenting with a 3-month history of symptomatic hypercalcaemia — fatigue, polyuria, and bone pain — on a background of severe multi-site osteoporosis with a prior distal radial fragility fracture and a newly recognised T12 wedge deformity, stage 3b CKD, and an incidental right renal stone. The biochemical picture of hypercalcaemia with an inappropriately elevated PTH, hypophosphataemia, and elevated ALP is diagnostic of primary hyperparathyroidism, and the sestamibi SPECT-CT localises a right inferior parathyroid adenoma. Her main problems are the autonomous PTH secretion driving the hypercalcaemia and bone loss, the severe osteoporosis with a vertebral and distal radial fracture putting her at very high re-fracture risk, the CKD that constrains bisphosphonate dosing, the nephrolithiasis, and the vitamin D deficiency that worsens her parathyroid disease. My priorities are to offer parathyroidectomy as the definitive cure — she meets four Fifth Workshop surgical criteria — to manage the anticipated post-operative hungry bone syndrome, to initiate osteoporosis pharmacotherapy after surgery, and to replete her vitamin D deficiency. I will engage her in a shared decision on surgery and outline the monitoring plan." [1]

Structured problem list (numbered, prioritised)

1. Primary hyperparathyroidism — right inferior parathyroid adenoma on sestamibi; meets four surgical criteria (calcium 0.3 above ULN, T-score below -2.5 with fracture, eGFR below 60, 24-hour urinary calcium above threshold with nephrolithiasis).
2. Severe osteoporosis with prior fractures — distal radial fracture and T12 wedge deformity; T-scores below -2.5 at all three sites.
3. CKD stage 3b — eGFR 42; constrains bisphosphonate dosing and independently meets a surgical criterion.
4. Nephrolithiasis — 5 mm right renal stone; another surgical criterion.
5. Vitamin D deficiency — 25-hydroxyvitamin D 32 nmol/L; worsens PHPT.
6. Symptomatic hypercalcaemia — fatigue, polyuria, bone pain.
7. Hypertension — on amlodipine, well-controlled. [1]

Integrated management plan

Step 1 — Confirm the diagnosis and localise: [1]

The diagnosis is confirmed — the sestamibi SPECT-CT and neck ultrasound both localise a right inferior parathyroid adenoma, concordant in 85 to 90% of single-gland disease [1]. The calcium-to-creatinine clearance ratio of 0.024 excludes FHH. The myeloma screen and coeliac serology are negative, excluding alternative causes of bone disease.

Step 2 — Offer parathyroidectomy (shared decision): [1]

She meets four of the Fifth International Workshop (2022) criteria for parathyroidectomy [1]:

• Corrected calcium 2.85 mmol/L (0.3 above ULN; criterion is above 0.25).
• T-score below -2.5 at all sites with a prior distal radial fracture and T12 wedge deformity.
• eGFR 42 (criterion is below 60).
• 24-hour urinary calcium 310 mg (above the 250 mg threshold for women) plus nephrolithiasis on ultrasound.

I would refer to an experienced endocrine surgeon for a focused (minimally invasive) parathyroidectomy, given the concordant localisation. Intra-operative PTH monitoring would confirm cure (a drop of more than 50% at 10 minutes post-excision). The cure rate is above 95% for single adenoma in high-volume centres. [1]

Step 3 — Pre-operative optimisation: [1]

• Replete vitamin D deficiency cautiously with colecalciferol 1000 to 2000 IU daily (not high-dose loading, which can raise calcium further in PHPT).
• Ensure adequate hydration (3 L water daily).
• Check vocal cord function pre-operatively as a baseline for recurrent laryngeal nerve assessment.
• Continue amlodipine; anaesthetic review given the CKD. [1]

Step 4 — Post-operative management (hungry bone syndrome prevention): [1]

After parathyroidectomy, I anticipate hungry bone syndrome — she has severe PHPT with high bone turnover (ALP 165, T-scores below -2.5, vertebral wedge), which predisposes to profound post-operative hypocalcaemia from rapid calcium uptake into demineralised bone [4]. I would:

• Check corrected calcium within 6 hours post-op, then every 6 to 12 hours for 48 hours.
• Start oral calcium carbonate 1 to 2 g three times daily and calcitriol 0.5 to 1 microgram daily immediately post-operatively.
• Give IV calcium gluconate for symptomatic or severe hypocalcaemia (corrected calcium below 1.9 mmol/L or symptoms: perioral tingling, carpopedal spasm, prolonged QT).
• Monitor phosphate (also falls with hungry bone) and magnesium.

Step 5 — Osteoporosis pharmacotherapy: [1]

After surgery once calcium stabilises, I would initiate antiresorptive therapy for her severe osteoporosis:

• Oral alendronate 70 mg weekly — acceptable above CrCl 35 (her eGFR is 42). Counsel on the empty-stomach, upright-for-30-minutes, water-only regimen. Contraindicated if she has oesophageal disease.
• Alternative: IV zoledronic acid 3.5 mg (dose-reduced for CrCl 35 to 60) annually if oral therapy is not tolerated.
• Calcium 1000 to 1200 mg elemental daily and vitamin D to maintain 25-hydroxyvitamin D above 50 nmol/L.
• I would NOT start osteoporosis pharmacotherapy before surgery — bisphosphonates persist in bone for years and could blunt the post-operative bone recovery. The exception is if surgery is delayed. [1]

Step 6 — Monitoring and follow-up: [1]

• Post-operative review at 2 to 4 weeks: confirm biochemical cure (calcium and PTH normal), assess wound, review calcium and calcitriol dosing (begin weaning as tolerated).
• 6-month review: DEXA to assess early bone recovery; calcium, PTH, renal function, 25-hydroxyvitamin D.
• Annual biochemistry and DEXA every 2 years.
• Nephrology follow-up for the CKD. [1]

Step 7 — Communication, safety, and shared decision: [1]

I would frame the consultation around the fact that her PHPT meets clear surgical criteria, that parathyroidectomy is the only definitive cure, and that surgery will address the hypercalcaemia, slow the bone loss, and reduce her stone risk. I would present the surgical risk honestly — cure rate above 95% in experienced hands, risk of permanent hypoparathyroidism 1 to 5%, risk of recurrent laryngeal nerve injury 1 to 2%, and the certainty of transient hypocalcaemia requiring temporary calcium and calcitriol. I would document her decision, arrange the surgical referral, and plan a post-operative review. [1]

Probing questions the examiner would ask

Q: What are the Fifth International Workshop (2022) criteria for parathyroidectomy in asymptomatic primary hyperparathyroidism, and how do they differ from the Fourth Workshop? [1]

A: "The 2022 criteria are: serum calcium more than 0.25 mmol/L above the ULN; skeletal involvement (T-score below -2.5 at any site, vertebral fracture by imaging, or prior fragility fracture); renal involvement (eGFR below 60, 24-hour urinary calcium above 250 mg for women or 300 mg for men, nephrocalcinosis or nephrolithiasis on imaging, or history of kidney stones); and age below 50. The principal change from the Fourth Workshop (2014) is the renal criterion — the 24-hour urinary calcium threshold was updated to above 250 mg for women and above 300 mg for men, and the workshop explicitly recognises nephrolithiasis and nephrocalcinosis on imaging as surgical indications, even if the urinary calcium does not meet the threshold. The message is that the kidney is a target organ in PHPT and any renal manifestation is a criterion for surgery [1]."

Q: How would you manage this patient if she firmly declined surgery? [1]

A: "If she declined surgery after full counselling, I would respect her autonomy and offer medical management. First, cinacalcet 30 mg twice daily to lower the serum calcium — it sensitises the calcium-sensing receptor and suppresses PTH, controlling the calcium within days. However, cinacalcet does not improve bone density, so the bone disease continues. Second, oral alendronate 70 mg weekly to protect the skeleton — bisphosphonates improve bone density in PHPT even without surgery, though the effect on the hypercalcaemia is modest. Third, replete the vitamin D deficiency and ensure adequate calcium intake. Fourth, monitor closely — annual biochemistry (calcium, renal function), DEXA every 1 to 2 years, and renal imaging. I would revisit the surgical option at each visit, as her bone disease and CKD are progressive. I would document the shared decision and her understanding of the trade-offs." [1]

Q: She is found to have a serum calcium of 2.6 mmol/L, PTH 6.5 pmol/L, and a calcium-to-creatinine clearance ratio of 0.008. What does this change? [1]

A: "The low clearance ratio (0.008, below 0.01) suggests familial hypocalciuric hypercalcaemia (FHH) rather than primary hyperparathyroidism. FHH is an autosomal dominant loss-of-function mutation of the calcium-sensing receptor — the parathyroid glands and renal tubules perceive calcium as lower than it is, so PTH remains mildly elevated and the kidney avidly reabsorbs calcium, producing a low urinary calcium. The condition is benign — patients do not develop the complications of PHPT (stones, bone disease, CKD) and do not benefit from parathyroidectomy. If I operated, the hypercalcaemia would persist. The management is reassurance and monitoring — no surgery, no pharmacotherapy. I would screen first-degree relatives (it is autosomal dominant). The key lesson is to always calculate the calcium-to-creatinine clearance ratio before recommending surgery in mild PHPT [1]."

Q: How would your management differ if she presented with a corrected calcium of 3.6 mmol/L and confusion? [1]

A: "This is severe symptomatic hypercalcaemia — a medical emergency. I would manage it simultaneously with the diagnostic workup. The sequence is: aggressive IV normal saline 3 to 6 L over 24 hours to restore volume and promote calciuresis; IV zoledronic acid (dose-reduced for her CrCl 42 — 3.5 mg) to inhibit osteoclast-mediated bone resorption (effect at 2 to 4 days, nadir 4 to 7 days); calcitonin 4 to 8 IU per kg subcutaneously every 12 hours as a bridge for the first 48 hours while the bisphosphonate works; and once she is stabilised and the diagnosis is confirmed (PTH high), proceed to parathyroidectomy. Glucocorticoids are ineffective in PHPT hypercalcaemia. I would not give furosemide routinely and never before volume repletion [3]."

Q: She develops severe hypocalcaemia (corrected calcium 1.5 mmol/L) with carpopedal spasm on day 2 post-parathyroidectomy. How do you manage this? [1]

A: "This is hungry bone syndrome with severe symptomatic hypocalcaemia. Immediate management is IV calcium gluconate 10% — 10 to 20 mL (1 to 2 g) over 10 minutes with cardiac monitoring, followed by a continuous calcium infusion (calcium gluconate 100 mL of 10% in 1 L normal saline at 50 mL per hour, titrated to symptoms and serial calcium). I would check magnesium and replete if low (IV magnesium sulfate 2 to 4 g). I would maximise oral calcium (2 g elemental three times daily) and calcitriol (1 to 2 micrograms daily). I would also check phosphate (often low in hungry bone) and replace if severe. The hypocalcaemia can last weeks to months — the patient is gradually weaned from IV to oral therapy as bone remineralises and the parathyroid glands (if any were suppressed by the adenoma) recover function. I would warn the patient that this is an expected consequence of successful surgery in severe disease, and that full recovery of calcium homeostasis takes time [4]."

Communication and shared decision-making

"I would frame Mrs M's primary hyperparathyroidism as a common, treatable condition where the single parathyroid adenoma — already localised on imaging — can be removed by a focused operation in experienced hands. I would present the evidence honestly: her biochemistry meets four of the Fifth International Workshop's surgical criteria, the cure rate for a single adenoma is above 95% in a high-volume centre, and the operation will address both the hypercalcaemia and the ongoing bone loss. I would explain that her CKD makes the decision more urgent, not less, because her bone disease will progress faster and her medical options are constrained by her renal function. I would acknowledge the risks — transient hypocalcaemia is expected and manageable with calcium and calcitriol, permanent hypoparathyroidism is rare (1 to 5%), and recurrent laryngeal nerve injury is 1 to 2% — and set against them the substantial benefit of cure. I would give her written information about the condition and the operation, arrange a surgical referral to a high-volume endocrine surgeon, and document the shared decision. If she declined surgery after full counselling, I would respect her autonomy, offer cinacalcet for calcium control and a bisphosphonate for bone protection, and arrange close monitoring with annual biochemistry and DEXA, revisiting the surgical option at each visit." [1]

DCE Short Case — DEXA Interpretation and Osteoporosis Management

Instruction

"Interpret this DEXA result and outline your osteoporosis management." [1]

Key data the patient demonstrates (for this case)

• T-score -2.8 at the lumbar spine (L1 to L4), -2.6 at the femoral neck, -2.9 at the distal third radius — all below -2.5, osteoporosis at all three sites.
• Prior distal radial fragility fracture 18 months ago; newly recognised T12 wedge deformity (15% height loss).
• Primary hyperparathyroidism as the secondary cause (PTH 8.5 pmol/L, corrected calcium 2.85 mmol/L).
• CKD stage 3b (eGFR 42 mL/min) constraining bisphosphonate dosing.
• Vitamin D deficiency (25-hydroxyvitamin D 32 nmol/L).
• FRAX 10-year hip fracture probability above 3%, major osteoporotic fracture probability above 20%. [1]

Presentation template

"I have reviewed Mrs M's DEXA scan. The T-score is -2.8 at the lumbar spine, -2.6 at the femoral neck, and -2.9 at the distal third radius — all three sites are below -2.5, consistent with osteoporosis. The distal third radius is the cortical site most affected by primary hyperparathyroidism and is the key site in parathyroid bone disease. She has a prior distal radial fragility fracture and a newly recognised T12 wedge deformity, making this severe (established) osteoporosis. Her FRAX 10-year hip fracture probability, incorporating her age, prior fracture, and secondary cause (PHPT), is above 3%, and her major osteoporotic fracture probability is above 20% — both above treatment thresholds. The management is integrated: first, cure the primary hyperparathyroidism by parathyroidectomy, which will improve bone density over 1 to 3 years; second, initiate antiresorptive therapy — oral alendronate 70 mg weekly (acceptable above CrCl 35) — once the post-operative calcium stabilises; and third, supplement calcium and vitamin D to maintain 25-hydroxyvitamin D above 50 nmol/L. I would repeat the DEXA at 2 years to assess response." [1]

Discussion questions

Q: Why is the distal third radius disproportionately affected in primary hyperparathyroidism? [1]

A: "The distal third radius is predominantly cortical bone. Primary hyperparathyroidism preferentially causes cortical bone loss — the chronic excess of PTH accelerates cortical osteoclast-mediated resorption at endocortical surfaces. The lumbar spine, which is predominantly trabecular bone, is relatively spared. This is why the DEXA in PHPT should always include the distal third radius — without it, the cortical bone loss can be missed. After parathyroidectomy, cortical bone density recovers preferentially at the radius over 1 to 3 years [1]."

Q: What secondary causes of osteoporosis would you screen for in this patient? [1]

A: "Beyond the established PHPT, I would screen for: thyroid dysfunction (TSH — already normal at 2.1), vitamin D deficiency (already identified at 32 nmol/L — replete), coeliac disease (tissue transglutaminase IgA — already negative), myeloma (serum protein electrophoresis and urine Bence-Jones — already negative), hypogonadism (she is postmenopausal, confirmed), chronic glucocorticoid use (none), excess alcohol (within safe limits), and premature menopause (she was 52, within the normal range). I would also review her medication list for bone-toxic drugs — aromatase inhibitors, anti-epileptics, proton pump inhibitors (long-term), and excess thyroid hormone replacement. In this case, the PHPT is the dominant secondary cause, and the CKD contributes through secondary mineral and bone disorder." [1]

Q: How would you manage her osteoporosis if her eGFR were 25 mL/min and she could not take bisphosphonates? [1]

A: "At eGFR 25, bisphosphonates are contraindicated or require extreme caution — zoledronic acid is not recommended below CrCl 35, and alendronate is contraindicated below CrCl 35 in many formularies. The alternative antiresorptive is denosumab 60 mg subcutaneously every 6 months, which is not renally excreted and is safe in CKD. The critical caveat is the rebound bone loss on cessation — denosumab must not be stopped without a transition to an alternative agent (typically an oral bisphosphonate, but this is constrained in advanced CKD). For very high-risk osteoporosis in advanced CKD, I would also consider teriparatide (no renal adjustment, though more expensive and reserved for very high risk) and would involve a nephrologist to evaluate for CKD-mineral and bone disorder (high or low bone turnover, secondary hyperparathyroidism, adynamic bone disease) with a bone biopsy if the diagnosis is uncertain [5]."

Q: What are the rare complications of bisphosphonate therapy and how do you counsel the patient? [1]

A: "Two rare but important complications. First, atypical femoral fracture — a transverse or short-oblique fracture of the subtrochanteric or diaphyseal femur, often preceded by weeks to months of prodromal thigh or groin pain. It is bilateral in up to 25% of cases. If a patient on a bisphosphonate reports thigh pain, I image both femurs with a plain X-ray (and MRI or bone scan if equivocal) and stop the bisphosphonate. Second, osteonecrosis of the jaw — exposed necrotic bone in the mandible or maxilla persisting for more than 8 weeks, particularly after dental extraction. I advise a dental review before starting therapy and good oral hygiene. Both are rare — approximately 1 per 10 000 to 1 per 100 000 patient-years for atypical fracture in osteoporosis-dose therapy — but the risk increases with duration. I counsel the patient with the actual numbers, framing the substantial fracture-reduction benefit (hip fracture relative risk reduction of approximately 40%, vertebral approximately 50 to 70%) against the very small absolute risk of these complications." [1]

Q: How do you decide whether to use an anabolic agent (teriparatide) first versus an antiresorptive? [1]

A: "The 2020 AACE/ACE guidelines introduce a high-risk vs very-high-risk stratification. For very-high-risk patients — T-score below -3.5, multiple or recent fractures, or fractures while on antiresorptive therapy — the guideline supports an anabolic-first approach (teriparatide for 2 years followed by an antiresorptive to preserve the bone gained). The rationale is that anabolic therapy builds new bone first, and the subsequent antiresorptive preserves it — this sequence produces greater bone density gains than antiresorptive-first in very high-risk patients. For this patient, she is very high risk (T-score below -2.5 at all sites with fractures), but the priority is curing her PHPT first, which itself improves bone density. If she fractures or loses bone density despite parathyroidectomy and antiresorptive therapy, I would escalate to teriparatide. I would not start teriparatide before parathyroidectomy because the high PTH state complicates the response [5]."