DRUGS USED FOR TREATMENT OF

THYROID AND BONE DISEASE

A. Tuthill
INTRODUCTION

• Thyroid
- Normal
- Overactivity
- Underactivity

• Bone
- Normal
- Osteopenia / Osteoporosis
- Pagets
Thyroid Function

• Thyroxine (T4), tri-iodothyronine (T3), Calcitonin

• Iodine – ingested as iodide: Na+/I- symporter

• Thyroid peroxidase catalyses iodination of tyrosine residues
on thyroglobulin in thyroid follicles

• T4 and T3 actions :
- stimulates metabolism (↑ O2 consumption, ↑ metabolic rate)
- regulates growth and development
Thyroid Function

• Feedback control of hypothalamus / pituitary

• Thyrotrophin releasing hormone stimulates release of TSH
• TSH :
- Trophic effects
- Uptake of iodide (transcription)
- Synthesis and secretion of thyroglobulin
- Generation of H2O2 and iodination
- Endocytosis and Secretion of T4 and T3
- Blood flow
• Iodide
Thyroid Function

• Thyroxine binding globulin 75%

• Thyroxine Binding Pre-albumin 15-20%

• 0.05% free T4, 0.5% free T3

• T4 t1/2 7-9 days

• T3 t1/2 2 days

• Nuclear receptor (TRα, TRβ)

Hyperthyroidism
• V. Common
• Clinical / subclinical
• Causes:
- Antibody-mediated (Graves’ Disease)
- Nodules (single toxic adenoma / multinodular goitre)

- Thyroiditis (drug-related, post-partum)

• Symptoms : sweating, weight loss, palpitations, loose bowel

motions, irregular menses, anxiety, tremor
• Signs : Thyroid enlargement, eye signs, tachycardia
Hyperthyroidism : Treatment

• Anti-thyroid Drugs (Carbimazole, propylthiouracil)

• Surgery
• Radio-active Iodine (I131)

• Thioureylenes:
- Inhibit the thyroperoxidase reactions involved in thyroid
hormone synthesis
- PTU inhibits deiodination of T4 to T3 in peripheral tissues

- Agranulocytosis (0.1-1%), rash, teratogenesis

Hyperthyroidism : Treatment

• Other drugs:
- Iodide/iodine (pre-operatively)
- Beta blockers
- Steroids

• Selenium
• Orbital decompression / radiotherapy

• Avoiding smoking / stressful life events

Hypothyroidism

• Causes:
- Iatrogenic
- Antibodies

• Symptoms: tiredness, constipation, changes in hair,

menstrual irregularities, cold intolerance
• Signs: bradycardia, periorbital oedema, slow-relaxing
reflexes, goitre
Hypothyroidism : Treatment

• Thyroid hormone replacement

- T4
- T3
Thyroid Cancer
• Accounts for 1.5% of all cancers in the US

• Most common endocrine malignancy (95%)

• 22,000 cases per year and estimated 500 – 1000 patients die
annually; incidence increasing

• 90% of thyroid cancer cases have favourable prognosis

Thyroid Cancer
Follicular cell origin
• Differentiated
– Papillary 80%
– Follicular 10%
– Hurthle cell 3-5%

• Undifferentiated
– Anaplastic 1-2%

Parafollicular cell origin

– Medullary 5%
Thyroid Cancer : Treatment

• Surgery
• Radio-active Iodine ablation
• TSH suppression

• Thyroglobulin used as tumour marker

- Basal
- Stimulated (Recombinant human TSH)

• Tyrosine Kinase Inhibitors

• MEK inhibitors
Bone Disease
Bone Disease
• Human skeleton 80% cortical bone, 20% trabecular bone
• Calcium, phosphate
• Osteoblasts (bone formation)
• Osteoclasts (bone resorption)
• Osteocytes (derived from osteoblasts)

• Remodelling:
- Hormones (PTH, Vitamin D, Oestrogen, Growth hormone,
Glucocorticoids, Calcitonin)
- Cytokines (IGF1, TGF-β, BMPs, Interleukins, TNF, NFκB)
- Diet, exercise
 Bone Remodeling – A Coupled Control
System
Osteoprogenitor
Osteoblasts
cells
• Osteoblasts have receptors
for osteolytic agents
• Osteoclasts in culture are
activated by stimulating
osteoblasts
• Osteoblasts deposit factors
in newly formed matrix
Mononuclear
progenitor cells
Osteoclasts
• Osteoclasts produce factors
that recruit and activate
osteoblasts
• Factors released as
osteoclasts age and die
(apoptosis)
Bone Turnover
•Bone Turnover Relative to Development

•Formation
•Resorption

•Male
•Female

•Formation > Resorption •Formation = Resorption •Formation < •Formation < Resorption
•High Turnover •Resorption •Low Turnover
Parathyroid Hormone
• Single-chain polypeptide of 84 amino acids
• Acts on PTH receptors on bone, kidney, GI tract, to maintain
plasma calcium
• Stimulates synthesis of 1,25, dihydroxyvitamin D3
• Promotes phosphate excretion
• Feedback from ionised calcium concentration (Ca2+sensing G
protein coupled surface receptor) controls levels

• High levels inhibit osteoblast activity (1o Hyperparathyroidism)

• Low doses stimulate osteoblast activity and enhance bone
formation
Vitamin D
• Two sources
• - Dietary ergocalciferol (D2)
• - Cholecalciferol (D3) : synthesised in skin under action of
UV irradiation on 7-dehydrocholesterol
• Cholecalciferol is converted to 25 hydroxyvitamin D3 in liver,
and to 1,25 dihydroxyvitamin D3 (calcitriol) in kidney under
influence of PTH

• Calcitriol stimulates absorption of calcium and phosphate in

intestine, calcium reabsorption in kidneys and mobilises
calcium from bone.
Oestrogens

• Inhibit cytokines which recruit osteoclasts and increase

osteoblast proliferation
• Oppose bone-resorbing actions of PTH

• Rapid bone loss at/after menopause

Calcitonin

• Effect to decrease plasma Ca2+ concentration – decrease

renal reabsorption and inhibits bone resorption
Osteoporosis
Reduction in bone mass
with distortion in
microarchitecture;
Increased risk of fracture
Osteoporosis

• Causes:
- Oestrogen deficiency
- Thyrotoxicosis
- Glucocorticoids
- Coeliac disease
- Testosterone deficiency
- Alcohol excess
- Smoking
 Costs of Osteoporosis
• 10,000,000 cases in U.S. alone
• Affects 1 in 2 women and 1 in 8 men > 50 years old

• Causes 1.5 million fractures/year - 700,000 spine, 300,000 hip

and 300,000 wrist, 25,000 deaths from complications

• Menopause is the biggest risk factor for disease

• Disease often not diagnosed until after 1 or more fractures

have occurred
• Psychological and social effects of disease are immense
Osteoporosis : Treatment
• 1. Anti-resorptive
- Bisphosphonates
- Calcitonin
- Selective Oestrogen Receptor Modulators
- Strontium ranelate
- Denosumab

• 2. Increase bone formation

- PTH
- Strontium Ranelate
Bisphosphonates

• Stable analogues of pyrophosphate resistant to metabolism

• Inhibit bone resorption by promoting osteoclast apoptosis or
preventing osteoclast attachment

• PO / IV
• 50% accumulates in bone; renal excretion
• GI side-effects
• Atypical femoral shaft fractures : drug holiday after 5 years

• Uses: Osteoporosis, malignancy, Paget’s disease

Oestrogens / SERMS

• HRT
• SERMS eg Raloxifene (agonist activity on bone and
cardiovascular system; antagonist at breast and uterus)

• Side-effects: Flushing, cramps, thromboembolism, oedema

• Post-menopausal women who cannot tolerate

bisphosphonates
Strontium Ranelate

• Can substitute for calcium in hydroxyapatite

• Weak anti-resorptive

• No longer recommended for use due to increased incidence

of cardiovascular events
Parathyroid Hormone

• High levels inhibit osteoblast activity (1o

Hyperparathyroidism)
• Low doses stimulate osteoblast activity and enhance bone
formation
• Teriparatide 1-34 peptide fragment of recombinant PTH
• SC injection daily
• Reduces pain of vertebral fracture

• Side-effects: hypercalcaemia, headache

• Use for max. 24 months
Calcium and Vitamin D

• Vitamin D
- Vitamin D deficiency,
- Renal Failure (activated)
- Hypoparathyroidism (activated)

• Building blocks of bone, support other therapies

• Malabsorption
• Osteomalacia
Denosumab

• A human monoclonal antibody to RANKL

• Inhibits Osteoclast development
• SC injection q 6/12 (Compliance)
• Ensure adequate intake of Calcium and Vitamin D
• More potent and longer half-life than osteoprotegerin
• Not eliminated in urine therefore may be appropriate in
patients with eGFR < 30 ml/min

• Effectiveness only lasts for duration of therapy

• Osteonecrosis of the jaw / atypical fractures
 Mechanism of Action for Denosumab
Osteoclast Activation Osteoclast Formation, Function
and Survival Inhibited
Denosumab
CFU-M
OPG
RANKL
Pre-Fusion
RANK Osteoclast

Growth Factors Multinucleated

Hormones Osteoclast
Cytokines

Mature
Osteoclast

Bone

Adapted from Boyle WJ, et al. Nature. 2003;423:337-42.

Paget’s Disease

• Excessive breakdown and formation of bone, followed by

disorganized bone remodelling.
• This causes affected bone to weaken, resulting in pain,
misshapen bones, fractures and arthritis in the joints near
the affected bones

• Elevated Bone Alkaline Phosphatase / Xray

• Bisphosphonates
Summary

• Thyroid – excess or deficiency

• Osteoporosis– secondary causes

• Safety

• Quality of life