Endocrinology

Metabolic bone disease

Anatomy and Physiology

  • Calcium
    • Total body calcium 1 Kg and 99% is contained within bone
    • Carried either in ionised active form or protein (albumin) bound inactive.
    • Labs only measure total (bound + ionised) calcium
  • Parathormone (PTH)
    • Parathyroid gland secrete PTH when Ionised Calcium levels fall detected by calcium sensing receptors
    • PTH raises Calcium by stimulating osteoclasts, increases distal tubule calcium reuptake, stimulating renal hydroxylation of Vitamin D,
    • Increases renal phosphate excretion
  • Vitamin D
    • Ergocalciferol in diet and 7 dehydrocholesterol to cholecalciferol (D3) in skin
    • 25-hydroxlation in liver can be affected by drugs and liver disease
    • 1- Hydroxylation in kidneys regulated by PTH
    • Active form 1,25(OH)2 D3 increases small intestine calcium uptake
    • Inactive form is 24, 25(OH) D3
  • Hypercalcaemia

    Causes

    • Primary Hyperparathyroidism (PHP)
    • Malignancy
    • Sarcoidosis
    • Excess Vitamin D
    • Familial Hypocalciuric hypercalcaemia - resembles PHP but PTH normal.

    Clinical

    • Renal stones, Renal tubular defects, impaired concentrating with polyuria and polydipsia, Interstitial nephritis, Chronic kidney disease
    • Constipation, Peptic ulcer disease, pancreatitis, anorexia
    • Muscle weakness, lethargy even coma and reduced reflexes
    • Apathy, depression, psychosis
    • Band keratopathy of eye from corneal deposits

    Investigations

    • ECG - Shortened QTc
    • Digoxin sensitivity

    Management

    • Treat a level greater than 3.2- 3.5 mmol/l by rehydration with 0.9% Saline and then repeat levels which may then have fallen.
    • Use IV Bisphosphonates for higher levels or those that fail to low with rehydration but this takes a few days to act.
    • Rehydration is the key
    • Patients may need up to 6 Litres of 0.9% saline over 24 hours and careful fluid balance management.
    • Furosemide 20 mg bd is sometimes used once hydrated as it promotes calcium loss in urine

    Primary Hyperparathyroidism

    Introduction

    • Commonest cause usually detected in the over 50s
    • Prognosis is typically excellent.

    Causes

    • Parathyroid adenoma (85%)
    • Diffuse Hyperplasia of all 4 glands
    • Parathyroid carcinoma (1%)

    Clinical

    • Usually clinical well and often asymptomatic the raised calcium picked up incidentally
    • Hypercalcaemia Symptoms and nephrolithiasis
    • Bone pain - osteitis fibrosa cystica bone cysts, fractures and brown tumours

    Investigations

    • Elevated serum and urinary calcium (stones) and reduced phosphate
    • PTH normal or elevated (should be undetectable with hypercalcaemia)
    • Alkaline phosphatase may be elevated

    Management

    • Medical in mild cases with mild asymptomatic hypercalcaemia or frail elderly
    • Adenoma - surgical removal
    • Hyperplasia - 3 glands removed and fourth left or transplanted to forearm
    • Beware hungry bones syndrome post surgical treatment
    • Bone have been starved of calcium suddenly increase calcium demand now that PTH is normal
    • There is calcium and phosphate deposition with low phosphate temporary in first month post surgery. Give replacement.

    Hypercalcaemia of malignancy

    Causes

    • Tumours secreting PTH related peptide which mimics PTH - squamous cell tumours of head, neck lung, oesophagus, renal cell carcinoma and breast cancer
    • Haematological secrete osteoclast activating cytokines e.g. myeloma, lymphoma

    Clinical

    • Hypercalcaemia
    • Symptoms and nephrolithiasis
    • Symptoms of malignancy - weight loss, cachexia

    Investigations

    • Elevated calcium
    • PTH normal or low

    Management

    • Is as for severe hypercalcaemia and to find and treat cause

    Hypocalcaemia

    Introduction

    • Is usually due to a lack of Parathyroid hormone or Vitamin D

    Causes

    • Hypoparathyroidism - surgical, autoimmune, low magnesium
    • Renal failure, Osteomalacia, Pseudohypoparathyroidism (PHP) PTH resistance
  • Symptoms and signs:

    • Acute - tetany and positive chvostek signs (tap VII nerve)
    • Trousseau's sign - carpopedal spasm on inflating BP cough), stridor, seizure
    • Chronic - negative inotropy with Heart failure, poor dentition, paraesthesia, cramps, seizures, cataract, papilloedema, optic neuritis

    Investigations

    • Low calcium and check for low magnesium
    • Low phosphate suggests Vitamin D deficiency
    • High phosphate suggests PTH deficiency or resistance or renal failure
    • PTH level usually high but low with primary hypoparathyroidism
    • 25(OH)D3 level low with OM
    • ECG - long QTc , CT brain scan - basal ganglia calcification
    • Giving PTH to those with Pseudohypoparathyroidism fails to increase urinary phosphate or cAMP

    Management

    • IV calcium gluconate if severe
    • Correct any low magnesium
    • Give Oral calcium and Vitamin D
  • Hypoparathyroidsim

    Causes

    • Autoimmune
    • Thyroid Surgery (not seen with radioactive iodine treatment to thyroid as highly resistant)

    Clinical

    • Acute - tetany and positive chvostek signs (tap VII nerve, Trousseau's sign - carpopedal spasm on inflating BP cough), stridor, seizure
    • Chronic - negative inotropy with Heart failure, poor dentition, paraesthesia, cramps, seizures, cataract, papilloedema, optic neuritis

    Investigations

    • Low calcium, high phosphate, low PTH, ECG long QT

    Management

    • IV calcium gluconate and long term Calcium and Vitamin D replacement

    Osteomalacia

    Aetiology

    • Soft bones due to defective mineralisation usually due to a lack of Vitamin D
    • There may be a lack of Vitamin D3 from skin or diet (fat soluble)
    • Failure of the process of 1 alpha hydroxylation with Chronic renal failure
    • End organ insensitivity to the action of 1,25(OH)D3 (Vitamin D resistant rickets Types 1 and 2)
    • low phosphate which prevents bone mineralisation (Hypophosphataemic rickets)
    • Increased breakdown of Vitamin D metabolites e.g. Phenytoin and Phenobarbitone
  • High risk groups
    • Impaired dietary intake of Fat soluble vitamin - Vitamin D e.g
    • Vegans, malnutrition, Malabsorption
    • Dark skinned - less sunlight exposure such as Asian immigrants in the North of England who lead a very domestic existence with little sun exposure to activate 7-dehydrocholesterol.
    • Fair skinned people need 15 minutes of sunshine 3 times a week to synthesis enough Vitamin D
    • Dark skinned or those who do not reveal a lot of skin need even more sunlight.
    • Malabsorption of fat soluble vitamins due to liver disease (e.g. PBC) or gut Malabsorption e.g. Crohn's of small intestine, Coeliac
    • Chronic renal failure leads to impaired 1-alpha hydroxylation with low levels of 1,25(OH)D3 which leads to hypocalcaemia and secondary hyperparathyroidism
    • Long term Phenytoin and Phenobarbitone therapy affects Vitamin D metabolism through liver enzyme induction
    • Vitamin D resistant rickets Types 1 and 2 - Insensitivity to 1,25(OH)D3
    • Low phosphate - Hypophosphataemic rickets

    Clinical

    • Soft uncalcified bones
    • Bone pain and tender bones and Pathological fracture
    • Muscle pains and Proximal myopathy and waddling gait
    • Looser's zones and Pseudofracture seen at stress points on X-Ray which may cause pain
    • Rickets - dental problems, Bowed legs, soft bones leading to skeletal and rib deformities
    • Widened non-calcified epiphyses, rickety rosary ribs.

    Investigations

    • A raised alkaline phosphatase is a marker of osteoblast activity
    • Serum calcium and phosphate are low but may be normal due to
    • Raised PTH boosting the calcium
    • Plain X-Rays show Looser's zones and deformities - Looser's zones - These are also known as pseudo fractures and may be tender with overlying redness
    • Looser's zones are incomplete stress fractures which heal with callus which is lacking in calcium due to poor mineralisation
    • They can be seen as translucent bands perpendicular to the bone cortical surface
    • Usual sites for Looser's zones are at points of stress such as the pubic rami, Humeral neck, femoral neck, Lateral borders of scapulae
    • Bone biopsy - show widened osteoid seams but rarely done now with 25(OH)D3 assay
    • DEXA scan for bone mineral density is typically normal

    Management

    • Vitamin D deficiency - Vitamin D2 400 U daily
    • Malabsorption - Vitamin D2 40,000-100,000 U daily
    • Renal failure - 1 alpha hydroxycholecalciferol (Alphacalcidol) or 1,25 dihydrocholecalciferol D3 (calcitrol)
  • Osteoporosis

    Introduction

    • Osteoporosis is a bone disease characterised by decreased bone mass and deterioration of bony microarchitecture leading to an increased risk of fractures.
  • Classification
    • Compares BMD to that of an average 25-year-old woman (T-score):
    • Normal: T-score of ?1 SD or more
    • Osteopenia : T-score between ?1 and ?2.5 SD
    • Osteoporosis : T-score below ?2.5 SD
    • Established osteoporosis: T-score below ?2.5 SD, with one or more associated fragility fractures.

    Clinical

    • Possibly clinically and biochemically silent until fracture Vertebral fractures : Back pain, Loss of height, Kyphosis, Appearance of abdominal swelling as collapse of lumbar vertebrae
    • Other fractures - Neck of Femur, Colles, Humerus
  • Risk factors for Osteoporosis
    • Female, Increasing Age Caucasian, Smoking Low exposure to Oestrogen - late menarche and early menopause
    • Malabsorption - Coeliac Steroid usage - COPD, Cushing syndrome Hyperthyroidism Hyperparathyroidism
    • Family history of osteoporosis Alcoholism Chronic heparin injection Methotrexate ? Diabetes mellitus
    • Immobilisation, Gaucher's disease, Myeloma, Mastocytosis,
    • Obesity is not a risk factor

    Investigations

    • Blood Investigations typically normal
    • Bone biopsy - not practical
    • DEXA scan - BMD T-scores can vary by site and method of measurement
    • Reference standards have been published for the different measurement sites
    • The prediction of fracture risk is usually based on BMD measurements at the femoral neck
    • Look for underlying cause in younger person

    Management

    • All patients should be replete with calcium and vitamin D
    • Bisphosphonates e.g. Alendronate, Risedronate : Currently the most used drugs are Alendronate and Risedronate and they increase BMD and reduce hip and vertebral fractures in a once daily or weekly formulation and reduce fractures by about 50% in post menopausal OP
    • They can be given daily or by a once weekly medication
    • They require that patient can stand and has no problems swallowing.
    • Strontium ranelate stimulates bone growth and reduce bone resorption Raloxifene is a selective oestrogen receptor modulator as it has different effects at the ER in different tissues
    • It reduces bone resorption by osteoclasts but has some side effects - hot flushes, VTE, muscle cramps but reduces breast cancer and has no effect on stroke or heart disease
    • It is not first line and has no evidence of benefit on non vertebral fractures
    • Teriparatide : recombinant form of parathyroid hormone, used in the treatment of advanced osteoporosis
    • Usually in those with very high risk of fracture and T score less than < -4 SD
  • Paget's disease

    Introduction

    • Overactive bone metabolism can lead to deformity and fractures

    Aetiology

    • There is an increased turnover of bone with increased osteoclastic bone resorption and fibrosis which is reputed to occur in 5% of the older population in the UK
    • Environmental possibly, Viral - Osteoclasts contain inclusion bodies Incidence is probably decreasing

    Clinical

    • Bone involved feels warm from increased activity - there is increased bone turnover maybe 5 or 10 fold
    • Affects mainly axial skeleton - skull, spine, vertebrae, lower limbs Changes in bone structure cause deformity and enlargement
    • Skull - Headache, Deafness - Skull X-Ray - "Cotton wool appearance"
    • Damage to Weight supporting femur, tibia - long bone fractures
    • Spinal stenosis/cord compression
    • Cranial nerve lesions due to compression are rare but can occur
    • Platybasia - Softening of skull base which leads to deformity - even hydrocephalus if ventricular system involved
    • Cardiac - High output cardiac failure is documented but very rare
    • Deafness - May be conduction due to involvement of middle ear ossicles and skull or sensorineural due to compression of VIII nerve in internal auditory meatus
    • Cancer - Risk of developing osteosarcoma

    Investigations

    • Alkaline phosphatase is high due to osteoblast activity but can be normal when one bone involved and normal Calcium (maybe elevated with immobilisation) and Phosphate is normal
    • Calcium can be elevated if immobile.
    • Raised urinary hydroxyproline Increased urinary excretion of pyridinoline cross links is a more specific and sensitive marker

    Management

    • Bisphosphonates + Calcitonin + Surgery to pin fractures

    Renal Osteodystropy

  • A particular form of bone disease seen with chronic kidney disease because
  • Phosphate retention causes secondary hyperparathyroidism
  • Low calcium due to reduced 1 alpha hydroxylation with secondary hyperparathyroidism
  • Tertiary hyperparathyroidism - autonomous PTH secretion

    Clinical

    • Rickets and osteomalacia
    • Delayed closure of epiphysis in children and young adults
    • Osteitis fibrosa cystica and Osteosclerosis

    Management

    • Phosphate binders and then once phosphate normal start 1 alpha hydroxylated vitamin D supplements
    • Renal replacement therapy
    • Subtotal parathyroidectomy for Tertiary hyperparathyroidism