300 CALCIUM METABOLISM
Pharmacokinetics
Bisphosphonates are incompletely absorbed ( 10%) and food
and antacids further reduce absorption. They disappear rap-
idly from the blood, distributing to bone, where their effects
are long lived. Within 24 hours, approximately 50% of the
absorbed dose is excreted unchanged in the urine, but the
remainder is excreted over many weeks.
CALCITONIN
This is a 32-amino-acid polypeptide hormone secreted by thy-
roid parafollicular C-cells. Secretion is determined mainly by
the plasma Ca^2 concentration.
Uses
Synthetic or recombinant salmon calcitonin (salcatonin) is
used to lower the plasma calcium concentration in hypercal-
caemia, especially from malignancy, and in the treatment of
pain and some of the neurological complications (e.g. deaf-
ness due to VIII nerve compression) of severe Paget’s disease
and for post-menopausal osteoporosis (together with calcium
and vitamin D supplements, if diet is inadequate). Calcitonin
is given by subcutaneous or intramuscular injection, or as
a nasal spray. Plasma calcium, phosphate, alkaline phos-
phatase and if possible urine hydroxyproline excretion are
monitored.
Mechanism of action
The main action of calcitoninis on bone; it inhibits bone
resorption by binding to a specific receptor on osteoclasts
inhibiting their action. In the kidney, it decreases the reabsorp-
tion of both Ca^2 and phosphate in the proximal tubules.
Adverse effects
Adverse effects include the following:
- pain at the injection site;
2.nausea and diarrhoea;
3.flushing.
STRONTIUM RANELATE
Strontium is a bone-seeking element; it was widely used for
osteoporosis in the 1950s, but there were concerns that it
inhibited calcitriol synthesis and might cause defective bone
mineralization. These adverse effects may have reflected a
calcium-deficient diet and incorrect dosing. Recent evidence
indicates that strontium ranelatereduces bone reabsorption
and increases bone formation, and reduces vertebral and hip
fractures in women with post-menopausal osteoporosis. It is
given by mouth at night to older women with osteoporosis
and a history of bone fracture when bisphosphonates are
contraindicated or not tolerated. It causes gastro-intestinal
adverse effects.
TERIPARATIDE
Teriparatideis a PTH agonist. It is a recombinant fragment of
PTH, used by experts in metabolic bone disease for the treat-
ment of post-menopausal osteoporosis. It is contraindicated in
patients with other metabolic bone diseases, including hyper-
parathyroidism, Paget’s disease or previous radiation therapy
to the skeleton and used with caution if there is renal impair-
ment or cardiac disease. It is given daily by subcutaneous injec-
tion for periods up to 18 months, monitoring serum calcium,
phosphate, alkaline phosphatase, creatinine and electrolytes.CINACALCET
Cinacalcetis a calcimimetic drug which enhances signalling
through the calcium sensing receptor (CaSR). It is an allosteric
activator of CaSR and reduces secretion of PTH. This is accom-
panied by a modest reduction in plasma calcium and phos-
phate. It also reduces expression of the PTH gene (and hence
the synthesis of PTH) and diminishes parathyroid hyperpla-
sia. It is given by mouth for secondary hyperparathyroidism
in patients on dialysis for end-stage renal disease and for
hypercalcaemia caused by parathyroid carcinoma, with mon-
itoring of serum calcium and PTH.Case history
A 52-year-old woman has had epilepsy since childhood,
treated with phenytoin 300 mg/day and her fits have been
well controlled. Since the loss of her job and the death of her
husband she has become an alcoholic. At the age of 54 years,
she is seen by her local GP because of weakness in her legs,
difficulty in climbing stairs and getting out of her chair. She
has no sensory symptoms in her limbs and no sphincter prob-
lems. Neurological examination of her legs is normal apart
from signs of thigh and hip muscle weakness and slight wast-
ing. Clinical investigations reveal that haemoglobin, white
blood and platelets are normal, but her erythrocyte sedi-
mentation rate is 30 mm per hour, her blood glucose level is
5.4 mM, sodium is 136 mM, K is 4.6 mM, urea is 10 mM and
creatinine is 80μM. Liver function tests are all normal,
except for an elevated alkaline phosphatase of 600 IU/L, and
bilirubin is normal. A chest x-ray is normal. Further biochem-
ical investigation reveals a plasma calcium concentration of
1.8 mM and a phosphate concentration of 0.6 mM.
Question
What is the likely cause of her metabolic disturbance and
leg weakness, and how would you treat it?
Answer
This patient has hypocalcaemia with hypophosphataemia
and a raised alkaline phosphatase, but no evidence of renal
dysfunction. This is the clinical picture of a patient with osteo-
malacia. The aetiology is secondary to her chronic phenytoin
therapy. The mechanism of these effects is complex and
relates to several actions of the drug. Phenytoin is a potent
inducer of hepatic drug metabolizing enzyme systems,
including the enzymes involved in vitamin D metabolism,
specifically metabolism of calciferol to 25-hydroxycholecal-
ciferol by the liver, and its further metabolism to inactive
products. It also impairs the absorption of vitamin D from the
gut. Treatment of this form of drug-induced osteomalacia
consists of giving the patient oral Ca^2 supplements together
with low-dose 1-α-hydroxy vitamin D (0.5μg per day), and
continuing the phenytoin if necessary.