E8- Disorders of calcium metabolism

describe calcium homeostasis

- very stable in the extracellular space

- input: gut

- excretion: kidney

- storage: bone

what are the fractions of serum calcium

- bound to proteins: albumin, globulins (47%)

- ultrafiltrable: ionised, complex bound (53%)

- serum level correction always happens through the ionised fraction (active)

which systems are affected by hypercalcaemia syndrome?

- CV

- GI

- renal

- neurological

- general

What are the CV symptoms of hypercalcemia syndrome

- hypertension

- bradycardia, I. AV block

- extrasystole, ventricular tachycardia

What are the GI symptoms of hypercalcemia syndrome

- loss of appetite

- nausea, vomiting

- constipation

- polydipsia

- rarely: acute pancreatitis

What are the renal symptoms of hypercalcemia syndrome

- polyuria due to hypercalciuria

- renal stones

What are the neurological symptoms of hypercalcemia syndrome

- decreased concentration

- anxiety, confusion

- personality disturbances

- depression

- somnolence, coma

What are the general symptoms of hypercalcemia syndrome

- muscle weakness

- exsiccosis

what are frequent causes of hypercalcaemia

1) primary/tertiary hyperparathyroidism

2) malignancies

• ectopic PTH production (rare)

• ectopic PTHrP production (common)

• osteoclast activation

• direct osteolysis

• ectopic calcitriol production

which tumours produce PTHrP?

- lung

- kidney

- ovarium

- bladder

which tumours produce calcitriol?

- granulomatous tumours

- lymphomas, Hodgkin disease

What cancers cause local stimulation of bone resorption by tumour

• Myeloma multiplex

• Breast

What cancer causes direct osteolysis

Bone metastasis

what are less frequent causes of hypercalcaemia

1. granulomatous

   1. sarcoidosis

2. drugs:

   1. vit D and derivatives

   2. thiazide diuretics

3. endocrine: thyrotoxicosis

4. immobilisation, long term parenteral feeding

what are symptoms of hypercalcaemia

- vast range

- fatigue, weakness

- poor appetite

- polyuria, exsiccosis

- constipation

- QT shortening

what are treatment methods of hypercalcaemia

• General

  • solve underlying cause!

  • low calcium diet

  • avoid drugs known to increase serum calcium

• stimulate urinary calcium excretion:

  • fluid and electrolyte substitution

  • salt diuresis

  • furosemide

  • dialysis

what is the treatment order of hypercalcaemic patient

1) fluids as these patients are usually dehydrated from polyuria

2) FSD

3) bisphosphonates (in good kidney function)/denosumab/corticosteroids (in haematological disease)

how do you inhibit of bone resorption

• treatment of underlying disease

/+

• mobilisation

• calcitonin (fast acting so first few days)

• antiresorptives:

  • bisphosphonates- clodronate, zoledronate

  • anti-RANKL (slow!)- denosumab

• glucocorticoids (in calcitriol excess)

Describe primary hyperparathyroidism

• autonomous hyper function → hypercalcemia

• Primary hyperplasia of all parathyroid gland

  • In young age, as a part of multiple endocrine adenomatosis, rare

• Autonomous tumour in one or more parathyroid gland

  • Adenoma, carcinoma- very rare

Describe secondary hyperparathyroidism

• regulatory hyperfunction= compensatory process against hypocalcmia of any reason- always hyperplasia

• Normocalcemia

• Chronic renal failure

• Malabsorption

• Renal hypercalciuria

Describe tertiary hyperparathyroidism

• in long term secondary hyperparathyroidism the regulatory hyperfunction can be transformed to an autonomous process

• Resulting even more PTH production

  • Mostly adenoma or microadenoma

what are clinical symptoms of primary hyperparathyroidism

- osteopenia, osteoporosis

- bone pain, increased fragility

what are typical X-ray findings of primary hyperparathyroidism

• cysts in long bones

• Osteolysis

What is the renal form of hyperparathyroidism

• calcium oxalate stone production in the urinary tract

• Clinical manifestations

  • Recurrent and bilateral calcium stones in the kidney

  • Nephrocalcinosis

  • Idiopathic microhaematuria (in children)

What is the GI form of hyperparathyroidism

• GI symptoms due to hypercalcaemia itself

• Rarely

  • Peptic ulcer, acute pancreatitis

What is the neurogenic/ psychiatric forms of hyperparathyroidism

• hypertension

• Neuropathy, polyneuritis

• Anxiety, depression

What is the dominant- asymptomatic form of hyperparathyroidism

• “Chemical HPT” or “subtle HPT”

• No clinical symptoms

• No pathological findings on X ray

• Only moderate hypercalcemia

  • Serum Ca 2.6-2.85mmol/l

• Increased risk of CV and cognitive diseases

what is the localisation of parathyroid adenoma

- neck and thyroid US

- parathyroid scintigraphy

- neck and mediastinum CT

what are the indications for surgery in primary HPT

• renal complications

  • Stones, calcinosis, decreasing GFR

• low bone mass, fragility fractures

  • Or progression in the bone and kidney problems

• serum calcium > 2.85mmol

• suspicion of thyroid cancer

• patient <50yrs

what to do if primary HPT patient is not eligible for surgery?

• Prevention of bone loss

  • oestradiol

  • bisphosphonate

- calcimimetics

*all moderate and transient, and don't affect kidney stones

what are the complications of parathyroid surgery

transient complications:

• post op hypocalcaemia

• recalcification tetany

  • atrophy of remaining glands

  • hungry bone syndrome

long-term:

• final hypoparathyroidism

• hypothyroidism

• vocal cord injury

what is hungry bone syndrome?

- prolonged hypocalcaemia after successful parathyroidectomy

- due to rapid calcium influx into the bones

describe secondary hyperparathyroidism

- compensation of hypocalcaemia of any reason

- e.g. chronic renal failure

- malabsorption

- renal hypercalciuria

describe tertiary hyperparathyroidism

- long term secondary hyperparathyroidism: regulatory function is converted into autonomous hyperfunction

- usually due to adenoma/microadenoma

Wha are

what are the causes of hypocalcaemia

- increased renal calcium loss

- decreased absorption (vit D deficiency)

- inhibited release from bone (hypoparathyroidism, hungry bone, osteoblastic metastasis)

- acute pancreatitis, large amounts of IV lactate/citrate

what are the symptoms of hypocalcaemia

- typical:

- myopathy, muscle spasm, twitches

- tetaniform seizures

- emotional instability

- prolonged QT: sudden cardiac arrhythmias

describe hyperventilation caused "hypocalcaemia"

- hyperventilation:

-> respiratory alkalosis

-> H+ dissociation from albumin

-> Ca2+ association to albumin, decreased [ionised Ca2+]

- do not treat with Ca2+! resolve underlying psychiatric/respiratory issue

what are the ways to identify hypocalcaemia

Chvostek: tapping face

Trousseau: hand sign with inflated cuff

*if patient is Chvostek positive, you never do Trousseau because it can produce generalised tetany

what are the lab values of hypocalcaemia

albumin-adjusted Ca2+ is <2.25mmol/L

what is the treatment of hypocalcemia

- eliminate underlying cause

- treatment of hypoparathyroidism

- oral calcium supplementation

- Vit D and magnesium supplementation

why is osteoporosis significant as a medical issue?

-> fractures

-> surgery

-> pain, risks

-> expensive

-> immobilisation

-> imminent fracture

-> death

in Europe: 10 fractures per minute

define osteoporosis

- generalised disease of the skeleton characterised by a progressive bone loss and deterioration of microstructure, followed by increased bone fragility

- i.e. even minor trauma can cause bone fractures

most common fractures in osteoporosis

- hip

- femur

- humerus

- vertebrae

What are the typical findings of osteoporosis

• typical physcial findings = late iagnosis

• no early symptoms, clincal signs

• after years → fractures by small injury= low trauma fractures

Why do fractures occur

• power effect- falling

• +

• mechnical competence decreases

  • loss of bone mass

  • loss of microstructure

  • decrease in bone quality

lab alterations in osteoporosis

none, especially in the early phases, no early symptoms

physical status of advanced osteoporosis

- shorter spine: cervical kyphosis, lumbar lordosis

- belly falls forward

- porotic leatherwood

- Christmas tree sign

possible clinical complaints in osteoporosis

- chronic musculoskeletal pain

- increasing spine curvature

- progressive loss of height

- fractures in minor trauma/fractures not explained by other causes

- abdominal complaints not explained by other causes

- muscle weakness, kidney stones

immobilisation related diseases

- venous thrombosis

- pulmonary embolism

- pneumonia

- decubitus

what is imminent fracture?

- refracture after first fracture

- there is a significant risk for this in the first two years

- influenced by site of fracture (e.g. hip has higher risk)

What are the risk factors for osteoporotic fractures

• age

• BMD

• other

  • low body mass

  • previous low trauma fracture

  • porotic fracture of parents

  • smoking

  • long term steroid treatment

  • alcohol

  • rheumatoid arthritis

rate of bone loss

- bone mass peaks at age 25-30

- starts decreasing after menopause/age50-60 in men

- women have two phases of bone loss: rapid (menopause related) and slower (age-related)

factors contributing to osteoporosis other than hormonal changes

- hypomobility in society

- decreased Vit D and calcium intake

diseases that can accelerate osteoporosis ("secondary osteoporosis")

OP in diseases of other organs

• liver- D deficiency

• GI- malabsorption

• inflammatory- bone resorbing cytokines

• renal insufficiency- D activation, PTH excess

• haematologic malignancies- bone resorbing disease, cytokines, cytostatics

• immobilisation

• endocrine- more thyroxine, steroire, less sex hormones

What is the treatment for preventing osteoporotic fractures

• inhibit bone resorption

  • estradiol

  • bisphosphonates- alendronate, zolendronate

  • denosumab- RANK ligand antibody

• stimulating bone formation

  • PTH analogues

• Basis therapy

  • calcium and vitamin D supplements

What are the methods to measure bone mass

• radiologic

  • X ray

  • radiogrammetry

• Photon absorption- bone densitometry- ODM

  • radiographic absorptiometry

  • single or dual photon absorptiometry

  • quantitative CT

What is the use of measuring bone mass

photon absorption (osteo)densitometry

- can calculate bone mineral density

- can calculate fracture risk over the next decade

scoring of bone mass density (DEXA)

Z score

- compared to healthy individuals of same sex and age

- bewteen +2 and -2

- less than -2.5: osteoporosis

T score

- compared to healthy individuals age 30 and same sex

• Normal

  • T score > -1

• osteopenia

  • T score between -1 + -2.5

• osteoporosis

  • T score < -2.5

What is the differential diagnosis of calcipenic osteopathies

who do we need to screen for osteoporosis?

- post-menopausal women

- men over 65

- family history of osteoporosis

- exogenous glucocorticoid treated patients/Cushing patients

- people with pathological fractures

drugs accelerating osteoporosis

- glucocorticoids

- anti-oestrogen therapies (breast tumours)

- anti-androgens (prostate carcinoma)

Describe bisphosphonate treatment

• increases bone density

• by 50-60% reduces rate of new fractures

• PO daily/ weekly/ monthly or IV 4x/year

• PO side effect- erosion/ ulcer in stomach/ oesophagus

  • rare- aseptic osteonecrosis in jaw

Describe denosumab treatment

• IM injection

• similar or more expressed cortcial bone

• SE- infection, jaw osteonecrosis

describe PTH treatment in osteoporosis

Teriparatid

• dramatic + quick increases spine density

• reduces 70% of fractures

• less effective in peripheral bone- small increase in density + smaller decrease in fracture rate

• few SE- hypercalcemia, hypercalciuria, vertigo

• limited to 18 month treatment