1. Mrs AG

2. Presenting complaint Mrs AG Mrs AG 75 years old 75 years old Admitted 19/9/07 Admitted 19/9/07 5 day history 5 day history Uncontrolled shaking Uncontrolled shaking Nausea Nausea Poor appetite Poor appetite Feeling ‘lousy’ Feeling ‘lousy’

3. History of presenting complaint Previous cancer of the breast Previous cancer of the breast Had mastectomy and radiotherapy Apr 2006 Had mastectomy and radiotherapy Apr 2006 Diagnosed with bony metastatic disease Summer 2007 Diagnosed with bony metastatic disease Summer 2007

4. History of presenting complaint Commenced on sodium clodronate 1.6grams/day in August 2007 Commenced on sodium clodronate 1.6grams/day in August 2007 Stopped after 2 days due to diarrhoea Stopped after 2 days due to diarrhoea Restarted 3 rd Sept 2007 at 400mg/day Restarted 3 rd Sept 2007 at 400mg/day Stopped on the 14 th Sept due to diarrhoea Stopped on the 14 th Sept due to diarrhoea

5. History of presenting complaint Then developed Then developed Nausea Nausea Poor appetite Poor appetite Uncontrollable shaking Uncontrollable shaking Paraesthesiae in hands and legs Paraesthesiae in hands and legs Muscle cramps Muscle cramps Unable to mobilise Unable to mobilise

6. Past medical history Metastatic Ca. breast Metastatic Ca. breast Hypertension Hypertension Hypercholesterolaemia Hypercholesterolaemia

7. Drug history Allergies Allergies Penicillin and Erythromycin Penicillin and Erythromycin Aspirin 75mg OD Atorvastatin 10mg ON Lisinopril 20mg OD Allopurinol 100mg OD Anastrazole 1mg OD Frusemide 40mg OD Esomeprazole 20mg OD

8. Social and Family History Lives with husband Lives with husband Independent in all ADL’s normally Independent in all ADL’s normally Non-smoker, moderate alcohol Non-smoker, moderate alcohol No family history of note No family history of note

9. On examination Tremulous Tremulous Tachycardic Tachycardic BP 160/86 BP 160/86 Afebrile Afebrile RR 20, Sats 97% on air RR 20, Sats 97% on air

10. On examination Clear chest Clear chest Abdo soft and non-tender Abdo soft and non-tender Marked resting and action tremor Marked resting and action tremor Peripheral paraesthesiae Peripheral paraesthesiae No signs of DVT No signs of DVT

11. Investigations ECG – Sinus tachycardia, normal QT ECG – Sinus tachycardia, normal QT CXR – Some areas of shadowing right and left lung fields ??mets CXR – Some areas of shadowing right and left lung fields ??mets Previous CT abdo/pelvis – widespread sclerotic bony lesions, ?lung mets Previous CT abdo/pelvis – widespread sclerotic bony lesions, ?lung mets

12. Investigations Bloods on admission Bloods on admission WCC 8.5, Hb 12.8 WCC 8.5, Hb 12.8 Na 145, K 3.8, Urea 5.5, Creat 71 Na 145, K 3.8, Urea 5.5, Creat 71 Corr Ca 2+ 1.36, PO 4 1.60 Corr Ca 2+ 1.36, PO 4 1.60 LFT’s normal except Alk phos 166 LFT’s normal except Alk phos 166 TSH and haematinics normal TSH and haematinics normal

13. Impression Profound hypocalcaemia secondary to bisphosphonate therapy and frusemide Profound hypocalcaemia secondary to bisphosphonate therapy and frusemide

14. Treatment Commenced on Calcichew D3 Forte 2 tabs OD Commenced on Calcichew D3 Forte 2 tabs OD Given 10mls of 10% calcium gluconate Given 10mls of 10% calcium gluconate Further 100mls of 10% calcium gluconate * 2 Further 100mls of 10% calcium gluconate * 2 Magnesium 5 grams infused (Mg level 0.15 prior to infusion) Magnesium 5 grams infused (Mg level 0.15 prior to infusion) Frusemide stopped Frusemide stopped

15. Further tests Short synacthen test – normal response Short synacthen test – normal response PTH 5.5 (1.6 – 6.9) PTH 5.5 (1.6 – 6.9) PTH appears low for degree of hypocalcaemia, this may be due to hypomagnesaemia which can interfere with physiological release of PTH in hypocalcaemia PTH appears low for degree of hypocalcaemia, this may be due to hypomagnesaemia which can interfere with physiological release of PTH in hypocalcaemia

16. Further tests Vitamin D level Vitamin D level 15.3 15.3 <10 – deficiency <10 – deficiency 10-20 – may indicate deficiency 10-20 – may indicate deficiency >20 - adequate >20 - adequate

17. Patient progress 24/9/07 24/9/07 Feeling much better. No longer shaking as much, no paraesthesia, no cramps Feeling much better. No longer shaking as much, no paraesthesia, no cramps Mobile with zimmer frame Mobile with zimmer frame Ca 2+ 2.11, Mg 0.53 Ca 2+ 2.11, Mg 0.53 25/9/07 25/9/07 Mobile independently on ward – discharged home Mobile independently on ward – discharged home

18. Hypocalcaemia Hypocalcaemia Hypocalcaemia occurs when calcium is lost from the extra cellular fluid in greater quantities than can be replaced by the intestine or bone. Hypocalcaemia occurs when calcium is lost from the extra cellular fluid in greater quantities than can be replaced by the intestine or bone.

19. Symptoms/signs of hypocalcaemia Paraesthesiae of distal extremities and circumoral area Paraesthesiae of distal extremities and circumoral area Chvostek and Trousseau signs Chvostek and Trousseau signs Muscle cramps Muscle cramps Laryngospasm Laryngospasm Tetany Tetany Seizures Seizures Prolonged QT interval which can progress to VF or heart block Prolonged QT interval which can progress to VF or heart block

20. Causes of hypocalcaemia Vitamin D deficiency Vitamin D deficiency Hypomagnesaemia Hypomagnesaemia Loop diuretics Loop diuretics Hypoparathyroidism Hypoparathyroidism Pseudohypoparathyroidis m Pseudohypoparathyroidis m Chronic renal failure Chronic renal failure Post parathyroidectomy Rhabdomyolysis Malignant disease Acute pancreatitis Septic shock

21. Causes of hypocalcaemia Hypoparathyroidism Hypoparathyroidism Deficiency of PTH leads to increased renal calcium excretion and decreased intestinal calcium absorption (secondary to reduced 1,25(OH) 2 D 3 production) Deficiency of PTH leads to increased renal calcium excretion and decreased intestinal calcium absorption (secondary to reduced 1,25(OH) 2 D 3 production) (Note: PTH stimulates renal hydroxylation of 25(OH)D 3 to 1,25(OH) 2 D 3 ) (Note: PTH stimulates renal hydroxylation of 25(OH)D 3 to 1,25(OH) 2 D 3 )

22. Causes of hypocalcaemia Pseudohypoparathyroidism Pseudohypoparathyroidism Rare hereditary disorder Rare hereditary disorder Affects target-cell response to PTH Affects target-cell response to PTH PTH is raised PTH is raised Patients can have shortened metacarpals and metatarsals along with short stature. Patients can have shortened metacarpals and metatarsals along with short stature.

23. Causes of hypocalcaemia Malignancy Malignancy Prostate and breast can cause increased osteoblastic activity leading to increased bone formation and hypocalcaemia. Prostate and breast can cause increased osteoblastic activity leading to increased bone formation and hypocalcaemia. Rapid cell destruction secondary to chemotherapy increases serum phosphorus. This complexes with serum calcium leading to hypocalcaemia. Rapid cell destruction secondary to chemotherapy increases serum phosphorus. This complexes with serum calcium leading to hypocalcaemia.

24. Causes of hypocalcaemia Rhabdomyolysis Rhabdomyolysis Release of cellular phosphorus, again binding to serum calcium causing hypocalcaemia. Release of cellular phosphorus, again binding to serum calcium causing hypocalcaemia.

25. Causes of hypocalcaemia Renal failure Renal failure Reduced phosphorus excretion with continued intestinal phosphorus absorption leads to hyperphosphataemia Reduced phosphorus excretion with continued intestinal phosphorus absorption leads to hyperphosphataemia This leads to decreased conversion of 25(OH)D 3 to 1,25(OH) 2 D 3 This leads to decreased conversion of 25(OH)D 3 to 1,25(OH) 2 D 3 This leads to decreased intestinal calcium absorption. This leads to decreased intestinal calcium absorption.

26. Causes of hypocalcaemia Hypocalcaemia and hypomagnesaemia often co- exist Hypocalcaemia and hypomagnesaemia often co- exist Can be due to decreased absorption or poor dietary intake. Can be due to decreased absorption or poor dietary intake. Hypomagnesaemia impairs PTH secretion and can interfere with its peripheral action. Hypomagnesaemia impairs PTH secretion and can interfere with its peripheral action.

27. Causes of hypocalcaemia Pancreatitis Pancreatitis Release of pancreatic lipase causing degradation of retroperitoneal omental fat Release of pancreatic lipase causing degradation of retroperitoneal omental fat Binding of calcium in the peritoneum resulting in hypocalcaemia. Binding of calcium in the peritoneum resulting in hypocalcaemia. Septic shock Septic shock Unknown mechanism Unknown mechanism

28. Discussion There are a number of reports of symptomatic hypocalcaemia following intravenous bisphosphonate therapy. However, this is uncommon with oral therapy. There are a number of reports of symptomatic hypocalcaemia following intravenous bisphosphonate therapy. However, this is uncommon with oral therapy. Usually, compensatory mechanisms, i.e. increase in PTH secretion act to correct calcium levels. Usually, compensatory mechanisms, i.e. increase in PTH secretion act to correct calcium levels.

29. Discussion Newer, more potent bisphosphonates may reduce the effects of PTH on bone resorption. Newer, more potent bisphosphonates may reduce the effects of PTH on bone resorption. Hypomagnesaemia can impair the compensatory increase in PTH secretion. Hypomagnesaemia can impair the compensatory increase in PTH secretion. Patients should have calcium and vitamin D status checked along with magnesium, phosphate and renal function levels prior to commencing potent bisphosphonate therapy. Patients should have calcium and vitamin D status checked along with magnesium, phosphate and renal function levels prior to commencing potent bisphosphonate therapy.