comprehensive description of mechanism of osteoporosis and the various drugs used to treat them

1. Osteoporotic Drugs
Dr. Sairamakrishnan S

2. • Osteoporosis is defined as a bone mineral
density of 2.5 standard deviations below that
of a young adult.
• Dual-energy X-ray absorptiometry (DXA) is
considered the gold standard for the diagnosis
of osteoporosis

3. Category T-score
Normal ≥ −1.0
Osteopenia −2.5 to −1.0
Osteoporosis ≤ −2.5
Severe osteoporosis ≤ −2.5 with fragility
fractures

4. • Osteoporosis is a silent thief which robs us of
our bone strength
• Osteoporosis is age dependant
• Around 15% of people aged 50 years and 70%
of people aged over 80 years suffer from
osteoporosis.
• It affects women more than men.
• 1 out of 3 # in women and 1 out of 5 # in men
aged 50 years is attributable to osteoporosis.

5. Risk factors of Osteoporosis
• Non modifiable
– Female sex
– Oestrogen deficiency following early menopause
or hysterectomy
– European or Asian ancestry
– Family history of fractures attributable to
osteoporosis (~30 genes have been identified)
– Small stature

6. • Modifiable risk factors
– Vitamin D deficiency
– Calcium deficiency
– Malnutrition
– Tobacco use
– Excessive Alcoholism (small quantities of alcohol
has been proven to be beneficial)
– Soft drinks (phosphoric acid)
– Prolonged exposure to heavy metals (eg.:lead,
cadmium)
– Prolonged immobilization

7. • Medical conditions
– Hypogonadism (eg.:Turners, Klinefelters)
– Endocrine disorders
• Cushing's syndrome
• Hyperparathyroidism
• Hyperthyroidism
• Hypothyroidism
• Diabetes mellitus
• Acromegaly
• Adrenal insufficiency

8. – Malabsorption states
• Crohn’s disease
• Ulcerative colitis
• Cystic fibrosis
• Post GI surgeries
• Liver diseases
– Connective tissue diseases (eg.:Marfans)
– Renal disorders
– Autoimmune connective tissue disorders (eg.:SLE)
– Hematologic disorders and malignancies
– Parkinson's disease

9. • Drugs
– Steroids
– Antiepileptics
– Thyroxine
– Anticoagulants (both heparin and warfarin)
– Proton pump inhibitors
– Thiozolidindiones
– Lithium therapy

10. • These risk factors predispose for osteoporosis
by altering one of the following
– Calcium metabolism
– Bone formation and resorption

11. Calcium metabolism
• Calcium metabolism is mediated by
– Vitamin D
– Parathyroid hormone
– Calcitonin
• These control the absorption of calcium from
the gut, deposition or resorption of calcium
from the bone and calcium excretion through
the kidneys.

12. Vitamin D

13. Parathyroid hormone

14. Calcitonin

15. Bone formation and resorption
• In normal bone, matrix remodeling of bone is
constant; up to 10% of all bone mass may be
undergoing remodeling at any point in time.
• The three main mechanisms by which
osteoporosis develops are an inadequate peak
bone mass, excessive bone resorption, and
inadequate formation of new bone during
remodeling.

16. • Oestrogen through its alpha receptor
stimulates osteoblasts and inhibits osteoclasts
and its deficiency increases bone resorption
leading to osteoporosis in postmenopausal
women
• Osteoclasts are activated through many
molecular pathways of which RANK - RANKL –
Osteoprotegerin(OPG) pathway is well
established

17. • RANKL is produced by osteoblasts (and
inflammatory cells) which bind to RANK on
osteoclasts and activates them.
• OPG acts as a decoy receptor and binds to
RANKL before it binds to RANK and prevents it
from activating the osteoclasts
• Expression of OPG by mesenchymal cells is
increased by oestrogen.
• This pathway is the target of newer
osteoporotic drugs

18. • Vitamin K2 is a cofactor in gamma
carboxylation which is needed for osteocalcin
secretion. It also inhibits the expression of
RANK by the osteoclasts and thus prevents
their activation.
• Thus vitamin K2 not only increases bone
formation it also decreases bone resorption
thus helps in the prevention of osteoporosis.

19. • Osteoporotic fractures commonly involve
around the cancellous bone regions as they
are associated with high rate of bone turnover
compared to the cortical bone.
• # NOF and IT # > Vertebral # > Distal radius # >
Rib #

20. Prevention
• Taking diet rich in Calcium and vitamin D
• Regular physical activities
• Avoiding Tobacco use
• Avoiding excessive alcohol consumption
• Avoiding prolonged immobilization

21. Pharmacotherapy
• Vitamin D
• Calcium suplimentation
• Vitamin K2
• Hormone replacement therapy
• Bisphosphonates
• Teriparatide
• Calcitonin

22. • Newer drugs
– Strontium ranelate
– Raloxifene (selective oestrogen receptor agonists)
– Denosumab

23. Vitamin D
• Vitamin D is the antirachitic substances
synthesized in the body and found in foods
activated by uv radiation
• D3-cholecalciferol-synthesized in the skin
under the influence of uv rays
• D2-calciferol-present in irradiated food-
yeasts,fungi,bread.milk
• D1-mixture of antirachitic substances found in
food

24. ACTIONS
• CALCITRIOL-enhances absorption of calcium
and phosphate from intestine,brought about
by increasing synthesis of calcium channels
and a carrier protien for ca2+ called calcium
binding protein or calbindin
• Calcitriol enhances resorption of calcium and
phosphate from bone
• Calcitriol enhances tubular resorption of
calcium and phosphate in kidney

25. PHARMACOKINETICS
• Vitamin D is well absorbed from the intestine
in the presence of bile salts,mainly through
lymphatics
• In the circulation it is bound to a specific alpha
globulin and is stored in the adipose tissue
• Metabolites of vit D are excreted mainly in bile

26. PREPARATIONS
• DOSE :PROPHYLAXIS:400IU/DAY,TREATMENT
3000-4000IU/DAY.Alternatively 300000-
600000IU can be given orally or im once in 2-
6months
• CALCIFEROL(ergocalciferol,D2) available in
gelatin capsules 25000 and 50000 IU caps
• CHOLECALCIFEROL:arachitol-300000IU(7.5mg)
and 600000IU(15mg)perml inj . CALCIROL-
60000IU in 1g granules

27. • CALCITRIOL-0.25-1 orally daily or alternate
days ,0.5-1 iv on alternate days
• ALFACALCIDOL-it is a 1 alpha-OHD3 prodrug
that is rapidly hydroxylated in the liver to
calcitriol.dose-1-2 /day,children 0.5 /day
• DIHYDROTACHYSTEROL-a synthetic analogue
of vit D2 . Dose 0.25-0.5mg/day

28. INTERACTIONS
• Cholestyramine and chronic use of liquid
paraffin can reduce vit D absorption
• Phenytoin and phenobarbitone reduce the
responsiveness of target tissues to calcitriol

29. CALCIUM
• Plasma calcium level is regulated by 3 hormones
PTH,calcitonin,calcitriol.Normal level 9-11mg/dl
• Physiological roles:ca2 controls excitabiliy of
nerves and muscles and regulates permiability of
cellmembrane.it maintains integrity of cell
membrane and regulates cell adhesion
• Ca2+ ions are essential for excitation and
contraction coupling in all muscles and excitation-
secretion coupling in exocrine and endocrine
glands

30. • Intracellular messenger for
hormones,autocoids and transmitters
• Impulse generation in heart and A-V
conduction
• Coagulation of blood
• Structural function in bone and teeth

31. INCREASE RESORPTION
• CORTICOSTEROIDS
• PARATHARMONE
• THYROXINE
• HYPERVITAMINOSIS D
• PROSTAGLANDINS E2
• INTERLEUKIN 1&6
• ALCOHOLISM
• LOOP DIURETICS
DECREASE RESORPTION
• ANDROGENS/ESTROGENS
• CALCITONIN
• GROWTH HORMONE
• BISPHOSPHONATES
• FLUORIDE
• GALLIUM NITRATE
• MITHRAMYCIN
• THIAZIDE DIURETICS

32. ABSORPTION AND EXCRETION
• Ca2+ is absorbed by facilitated diffusion from
the entire small intestine by a carrier
mediated active transport under the influence
of vit D
• VIT D increases and calcitonin decreases prox
tubular resorption,while PTH increases distal
tubular resorption of ca2+
• Normally 1/3rd of ingested ca2+ is
absorbed,dietary allowance 0.8-1.5g /day

33. PREPARATIONS
• Ca chloride(27%ca)-highly irritating,available
as im,iv and oral forms
• Ca gluconate(9%ca)-availble as 0.5-1g tab
and10% inj,it is the preferred inj salt
• Ca lactate(13%ca)-oral,non irritant and well
tolerated
• Ca diphasic phosohate(23%ca)-is insoluble
reacts with HCL to form soluble chloride,used
orally as an antacid and ca supplementation

34. • Ca carbonate(40%ca)-insoluble,tasteless and
nonreacting
• SIDE EFFECTS:constipation,bloating and excess
gas
• DOSAGE:1-1.5g /day

35. CALCITONIN
• Calcitonin is a hypocalcaemic hormone produced
by parafollicular C cells of thyroid
• PREPARATION-synthetic salmon calcitonin is used
clinically,because it is more potent,human
calcitonin also available
• MIACAlCIN NASAL SPRAY-2200 IU in 2ml,a nasal
formulation delivering 200IU per actuation
• DOSAGE- for osteoporosis 100IU s.c or i.m daily
along with ca and vitD supplementation

36. BISPHOSPHONATES
• FISRT GENERATION BPN-
ETIDRONATE,TILUDRONATE
• 2ND GENERATION-
PAMIDRONATE,ALENDRONATE,IBANDRONATE
• 3RD GENERATION-RISEDRONATE,ZOLEDRONATE
• BISPHOSPHONATES ARE ANALOGUE OF
PYROPHOSPHATE
• CARBON ATOM REPLACING OXYGEN IN P-O-P
SKELETON

37. MECHANISM OF ACTION
• ACCELERATED APOPTOSIS IF OSTEOCLASTS
REDUCING THEIR NUMBER
• DISRUPTION OF CYTOSKELETON AND RUFFLED
BORDER OF OSTEOCLASTS
• 2ND AND 3RD GENERATION HAVE IMP EFFECTS
ON MEVALONATE PATHWAY .THEY INHIBIT
CERTAIN GTP BINDING PROTEINS INVOLVED IN
CYTOSKETAL ORGANISATION,MEMBRANE
RUFFLING

38. • Net effect is inactivation of
osteoclasts,impaired vesicle fusion and
enhanced apoptosis.interference with
mevalonate pathway may also impart
antitumour action on bony metastasis
• SIDE EFFECTS:gi intolerance,esophagitis.
CONTRAINDICATION: in GERD,peptic
ulcer,renal impairment

39. • ETIDRONATE-first BPN to be used clinically
• Route of admistration-oral and iv
• Dosage-5-7.5mg/kg/day
• SF-gastric
irritation,bonepain,headache,metallic
taste,pyrexia,hypersensitivity,prolonged use
wil lead to osteomalacia

40. PAMIDRONATE
• 2ND generation BPN only by iv infusion
• Dosage-60-90mg over 2-4hrs weekly or
monthly
• SF-thrombophlebitis of inj vein,bony
pain,fever,leukopenia,flu like reaction initially
due to cytokine release

41. ALENDRONATE
• Orally effective 2nd generation BPN should be
taken on empty stomach in the morning with
full glass of water and not to lie down or take
food for 30min to prevent contact with
oesophageal mucosa which results in
esophagitis
• Dosage-5-10mg od or 35-70mg/weekly
• Ca,iron,mineral water,tea,coffee,fruit juice
interfere with alendronate absorption

42. • Bioavailability-1%,upto 50% sequestrated in
bone,rest is excreted unchanged mainly in
urine
• Terminal elimination of t1/2 of alendronate is
10.5yrs

43. RISEDRONATE
• Oral 3rd generation BPN more potent than
alendronate
• BIOAVAILABILITY-1% and other features
similar to alendronate
• DOSAGE-35mg/week

44. ZOLEDRONATE
• Parenteral highly potent 3rd generation BPN
• Dosage-4mg diluted in 100ml saline or glucose
solution infused iv over 15min,may be
repeated after 7days and then at 3-4weeks
intervals
• SF-renal toxicity,flu like symptoms
• For hypercalcaemia more effective than
pamidronate and DOC

45. TERIPARATIDE
• It is a recombinant preparation of 1-34 residues of
amino terminal of human PTH
• It duplicates all the actions of human PTH
• DOSE: 20 mcg s/c daily
• Plasma t1/2 is 1hr
• Intermittent exposure to PTH activate osteoblasts more
than osteoclasts
• It is found to be equally or more effective than
oestrogen and BPN in reducing risk of vertebral as well
as non vertebral fractures
• AE-highcost,osteosarcoma

46. Vitamin K2 (menaquinone)
• Vitamin K2 is a cofactor of gamma-
carboxylase, which activates osteocalcin.
• Osteocalcin promotes normal bone
mineralization
• Vitamin K2 also inhibits the expression of the
osteoclast differentiation factor (ODF) and
RANKL
• DOSAGE: 50mcg daily

47. Strontium Ranelate
• Strontium ranelate stimulates calcium sensing
receptors and leads to the differentiation of
pre-osteoblast to osteoblast
• Strontium ranelate also stimulates osteoblasts
to secrete osteoprotegerin in inhibiting
osteoclasts
• DOSAGE: 2g daily
• Side Effects: CVS symptoms, DRESS Syndrome.

48. DENOSUMAB
• DENOSUMAB is a human monoclonal antibody
• MOA-Denosumab is a RANKL inhibitor,which
works by preventing the development of
osteoclasts
• Uses-osteoporosis,treatment induced
boneloss,bony metastasis,GCT
• AE-joint and muscle
pain,cellulitis,hypocalcemia,osteonecrosis of jaw
• Dosage-60mcg sc once every six months

49. RALOXIFENE
• It is a selective estrogen receptor modulator
• It is an estrogen partial agonist in bone and
cvs,but an antagonist in endometrium and
breast.it has affinity for both estrogen alpha
and beta receptors
• Dose-60mg/day orally
• T1/2-28hrs ,major route of excretion is faeces

50. • It is a first line drug in treatment and
prevention of osteoporosis in postmenopausal
women,ca and vitD supplements enhance the
benefit
• It has no use in men