Calcium and Bone Disorders — Viva Defence

Long Case Viva Defence

The scenario

A 68-year-old woman is referred to the endocrine clinic with a 3-month history of fatigue, polyuria, and bone pain. She has stage 3b CKD (eGFR 42 mL/min), hypertension, and a distal radial fracture 18 months ago. Corrected calcium is 2.85 mmol/L, phosphate 0.78 mmol/L, intact PTH 8.5 pmol/L (reference 1.6 to 6.9), ALP 165 U/L, 25-hydroxyvitamin D 32 nmol/L. DEXA shows T-scores of -2.8 at the lumbar spine, -2.6 at the femoral neck, and -2.9 at the distal third radius. 24-hour urinary calcium is 310 mg. Renal ultrasound shows a 5 mm non-obstructing right renal stone. [1]

Opening statement (SASPOP)

"This is Mrs M, a 68-year-old retired teacher presenting with a 3-month history of symptomatic hypercalcaemia, complicated by severe multi-site osteoporosis with a prior distal radial fragility fracture, stage 3b CKD, and an incidentally found renal stone. The biochemical picture — hypercalcaemia with an inappropriately elevated PTH, hypophosphataemia, and elevated ALP — is diagnostic of primary hyperparathyroidism. Her main problems are the autonomous PTH secretion driving the hypercalcaemia and bone loss, the severe osteoporosis with a prior fracture that puts her at very high re-fracture risk, the CKD that constrains my bisphosphonate dosing, the nephrolithiasis, and the vitamin D deficiency that worsens her parathyroid disease. My priorities are to confirm the diagnosis and localise the adenoma, to offer parathyroidectomy as the definitive cure since she meets four Fifth Workshop criteria, to manage the 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]

Problem list (numbered, prioritised)

1. Primary hyperparathyroidism — meets surgical criteria (calcium, bone, renal, urinary calcium, stones).
2. Severe osteoporosis with prior fragility fracture — T-score below -2.5 at all three sites.
3. CKD stage 3b — 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. [1]

Integrated management plan

Pillar 1 — Confirm the diagnosis and localise the adenoma: "The biochemical pattern is diagnostic of primary hyperparathyroidism. I have excluded familial hypocalciuric hypercalcaemia — the 24-hour urinary calcium is 310 mg and the calcium-to-creatinine clearance ratio is well above 0.01, confirming calciuric PHPT [1]. I would arrange a parathyroid sestamibi SPECT-CT scan and a high-resolution neck ultrasound to localise the adenoma for the surgeon. I would check a serum protein electrophoresis and urine Bence-Jones to exclude coexisting myeloma given her bone pain and fracture, and screen for MEN1 if there is any family history of endocrine tumours."

Pillar 2 — Offer parathyroidectomy: "She meets four of the Fifth International Workshop (2022) criteria for parathyroidectomy — calcium 0.3 above the ULN, T-score below -2.5 at all sites with a prior fracture, eGFR below 60, and urinary calcium above the threshold with nephrolithiasis [1]. Parathyroidectomy is the only definitive cure and will address the hypercalcaemia, slow the bone loss, and reduce her stone risk. I would refer to an experienced endocrine surgeon. The cure rate for single adenoma is above 95% in high-volume centres."

Pillar 3 — Pre-operative optimisation: "I would replete the vitamin D deficiency cautiously with colecalciferol 1000 to 2000 IU daily — not high-dose loading, as that can raise calcium further in PHPT. I would ensure she is well hydrated and check vocal cord function pre-operatively as a baseline for recurrent laryngeal nerve assessment [6]."

Pillar 4 — Post-operative hypocalcaemia prevention (hungry bone syndrome): "After parathyroidectomy, the sudden withdrawal of PTH causes rapid osteoblast-mediated calcium uptake into the demineralised bone — hungry bone syndrome. I would check calcium within 6 hours, then every 6 to 12 hours for 48 hours, start oral calcium and calcitriol prophylactically, and give IV calcium gluconate for symptomatic or severe hypocalcaemia." [1]

Pillar 5 — Osteoporosis pharmacotherapy: "Her osteoporosis is severe with a prior fracture. The primary treatment is cure of the PHPT, which improves bone density over 1 to 3 years. But given her very high risk, I would also initiate antiresorptive therapy after surgery once calcium stabilises. Given her CKD (eGFR 42), I would use oral alendronate (acceptable above CrCl 35) or dose-reduced IV zoledronic acid (3.5 mg for CrCl 35 to 60). I would supplement calcium and vitamin D to maintain 25-hydroxyvitamin D above 50 nmol/L [6][7]."

Pillar 6 — Monitoring and follow-up: "I would review at 2 to 4 weeks post-surgery to confirm biochemical cure (calcium and PTH in the normal range), then at 6 months with a DEXA. Annual biochemistry and DEXA every 2 years thereafter." [1]

Probing questions the examiner would ask

Q: How do you distinguish familial hypocalciuric hypercalcaemia from mild primary hyperparathyroidism, and why does it matter? [1]

A: "FHH is an autosomal dominant loss-of-function mutation of the calcium-sensing receptor. The parathyroid glands and renal tubules both perceive calcium as lower than it is, so PTH remains mildly elevated and the kidney avidly reabsorbs calcium. The result is lifelong mild hypercalcaemia with low urinary calcium excretion. The discriminator is the calcium-to-creatinine clearance ratio — below 0.01 in FHH, above 0.02 in PHPT. The 24-hour urinary calcium is low (below 100 mg) in FHH and elevated in PHPT. It matters because FHH is benign — patients do not develop complications and do not benefit from parathyroidectomy. If you operate, the hypercalcaemia persists. So any patient with mild PHPT should have the clearance ratio checked before surgery is recommended [1]."

Q: How would your osteoporosis management differ if her eGFR were 25 mL/min? [1]

A: "At eGFR 25, oral and IV 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 caveat is the rebound bone loss on cessation — denosumab must not be stopped without a transition to an alternative agent. For very high-risk osteoporosis in advanced CKD, I would also consider teriparatide (no renal adjustment needed, though it is more expensive) and investigate for CKD-mineral and bone disorder (CKD-MBD) — secondary or tertiary hyperparathyroidism, which may require a calcimimetic or parathyroidectomy in its own right. I would involve a renal physician." [1]

Q: What is hungry bone syndrome and how do you manage it? [1]

A: "Hungry bone syndrome is profound and prolonged hypocalcaemia after parathyroidectomy, caused by the rapid uptake of calcium and phosphate into demineralised bone once the chronic PTH excess is removed. It is more common in patients with severe PHPT, high bone turnover (elevated ALP), and longstanding disease — as in this patient with her ALP of 165 and severe bone disease. Management is anticipatory — start oral calcium (1 to 2 g elemental three times daily) and calcitriol (0.5 to 1 microgram daily) immediately post-operatively, monitor calcium every 6 to 12 hours, and give IV calcium gluconate for symptomatic or severe hypocalcaemia. Phosphate also falls and may need replacement. The syndrome can last weeks to months; the patient is gradually weaned from supplementation as bone remineralises [5]."

Q: She asks whether she can avoid surgery and just take a tablet. What is the role of cinacalcet? [1]

A: "Cinacalcet is a calcimimetic that allosterically sensitises the calcium-sensing receptor on parathyroid chief cells, suppressing PTH secretion and lowering serum calcium. The dose is 30 mg orally twice daily, titrated. It is effective at lowering calcium within days to weeks. However, it does not improve bone mineral density — the bone loss continues. It is indicated for patients who are not surgical candidates (comorbidity, patient refusal, persistent post-surgical disease) or who have severe hypercalcaemia that needs rapid control while awaiting surgery. For this patient, who meets clear surgical criteria and has severe bone disease, cinacalcet would control the calcium but not the underlying bone loss, so surgery is preferred. If she truly refused surgery after full counselling, I would combine cinacalcet (for calcium control) with an antiresorptive (for bone protection) and monitor closely [1]."

Q: How would you investigate for secondary causes of her osteoporosis beyond the PHPT? [1]

A: "Even though PHPT is a clear secondary cause, I would screen for the other common contributors: thyroid function (exclude hyperthyroidism), 25-hydroxyvitamin D (already low at 32 nmol/L — replete), coeliac serology (tissue transglutaminase IgA with total IgA), testosterone or gonadal status if male (she is female, so I would check FSH and oestradiol if premature menopause is suspected), serum protein electrophoresis and urine Bence-Jones (exclude myeloma), 24-hour urinary free cortisol if clinical features of Cushing, and a review of drug history (glucocorticoids, aromatase inhibitors, anti-epileptics, excess thyroid hormone replacement). I would calculate her FRAX 10-year fracture probability incorporating the clinical risk factors, with and without the femoral neck BMD, to quantify and communicate her risk [6]."

Communication and shared decision-making

"I would frame Mrs M's primary hyperparathyroidism as a common, treatable condition where the single adenoma can be cured by a focused operation in experienced hands. I would present the evidence honestly — her biochemistry meets four surgical criteria, the cure rate is above 95%, and the operation will address both the hypercalcaemia and the ongoing bone loss. I would acknowledge that the CKD makes the decision more urgent, not less, because her bone disease will progress faster and the medical options are constrained by her renal function. I would explain the surgical risk — 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%. I would give her written information, arrange the surgical referral, and document the shared decision. If she declined surgery, I would respect her autonomy, offer cinacalcet for calcium control plus an antiresorptive for bone protection, and arrange close monitoring." [1]

Short Case Discussion — DEXA Interpretation and Osteoporosis Management

Instruction: "Interpret this patient's DEXA scan and outline your osteoporosis management." [1]

Systematic interpretation routine

1. Identify the patient and indication — confirm the scan belongs to the patient and establish why it was ordered (screening, fracture risk assessment, monitoring therapy).
2. Report the T-score at each site — lumbar spine (L1 to L4), femoral neck, total hip, and the distal third radius (1/3 radius) if performed. State the category at each site: normal (above -1.0), osteopenia (-1.0 to -2.5), osteoporosis (below -2.5).
3. Report the Z-score if the patient is premenopausal or under 50 — a Z-score below -2.0 is below the expected range for age and prompts a search for secondary causes.
4. Apply FRAX — integrate the clinical risk factors with or without the femoral neck BMD to estimate the 10-year probability of major osteoporotic and hip fracture.
5. Exclude secondary causes — thyroid, parathyroid, gonadal function, coeliac serology, vitamin D, myeloma screen, drug history.
6. Recommend treatment or monitoring — based on the T-score, FRAX, prior fracture, and secondary cause profile. [1]

Presentation template

"This is the DEXA scan of Mrs M, a 68-year-old woman. 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 had a distal radial fragility fracture 18 months ago, making this severe (established) osteoporosis. Her FRAX 10-year hip fracture probability, incorporating her age, low BMI, 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 threefold: first, cure the primary hyperparathyroidism by parathyroidectomy; second, initiate antiresorptive therapy with oral alendronate or dose-reduced IV zoledronic acid 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 (80% cortical, 20% trabecular). 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 that is the hallmark of parathyroid bone disease can be missed. After parathyroidectomy, cortical bone density recovers preferentially at the radius over 1 to 3 years [1]."

Q: How do you decide when to offer a bisphosphonate drug holiday? [1]

A: "After 5 years of oral bisphosphonate therapy (or 3 years of IV zoledronic acid), I reassess the fracture risk. For patients at low to moderate risk — stable or improved T-score, no fracture during therapy, no new risk factors — a drug holiday of 1 to 2 years is reasonable because bisphosphonates persist in the skeleton with antiresorptive activity for years. During the holiday, I monitor bone turnover markers and repeat the DEXA at 1 to 2 years, resuming therapy if bone loss occurs or a fracture supervenes. For patients at high risk — prior fracture, very low T-score below -2.5, on glucocorticoids — I continue therapy or switch agents rather than take a holiday. For this patient, given her severe osteoporosis and prior fracture, I would not take a holiday after the initial 5-year course; I would continue antiresorptive therapy or reassess with the DEXA [6]."

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 if the X-ray is 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 patients to have a dental review before starting therapy and to maintain good oral hygiene. Both complications are rare — approximately 1 per 10 000 to 1 per 100 000 patient-years for atypical fracture, and below 1 per 1000 for osteonecrosis in osteoporosis-dose therapy — but the risk increases with duration. I counsel the patient with the actual numbers, framing the substantial fracture-reduction benefit against the very small absolute risk of these complications, to enable an informed shared decision." [1]

Q: What is the role of teriparatide and when do you choose it over an antiresorptive? [1]

A: "Teriparatide is recombinant PTH (1-34), given as 20 micrograms subcutaneously daily for a maximum of 2 years. It is paradoxically anabolic — intermittent low-dose PTH stimulates osteoblast activity and new bone formation, in contrast to the catabolic effect of continuous endogenous PTH in hyperparathyroidism. I choose it for very high-risk patients — those with a T-score below -3.5, multiple vertebral fractures, or fractures sustained while on antiresorptive therapy. After the 2-year course, the patient must transition to an antiresorptive to preserve the bone gained; otherwise the benefit is lost. For this patient, I would start with an antiresorptive first (alendronate or zoledronic acid) and reserve teriparatide for progression or further fracture despite antiresorptive therapy [6]."