Drugs for stronger bone

1. Pharmacotherapy of osteoporosis
Dr. Sourav Chakrabarty
PGT
Dept of Pharmacology
B.S.M.C

2. Overview
• Introduction
• Bone modeling & remodeling physiology
• Calcium homeostasis & its control
• Primary and secondary osteoporosis
• Drugs for osteoporosis management
• Future prospects
• Conclusion

3. Introduction
• Osteoporosis: A Progressive condition of low bone mass and micro-
architectural disruption that results in increased fragility and
susceptibility to fractures.
• WHO definition- Bone mineral density that falls 2.5 SD below the
mean for young healthy adults of the same sex(T score)
• A global pandemic- 10 million affected in USA
• Hip and vertebral fractures are most common

4. Incidence of fractures according to age

5. Bone modeling
• Bone modeling- during growth, skeleton size by linear
growth and by apposition of new bone tissue on cortex.
• Sex hormone at puberty contributes in modeling
• Also nutrition, lifestyle and genetic factors
• Vit D receptor, type I collagen, ER, IL-6 IGF-1.

7. Hormonal control of bone resorption. A. Proresorptive and
calcitropic factors; B. Anabolic and antiosteoclastic factors. RANKL
expression is induced in osteoblasts, activated T cells, synovial
fibroblasts, and bone marrow stromal cells. It binds to membrane-
bound receptor RANK to promote osteoclast differentiation,
activation, and survival. Conversely, osteoprotegerin (OPG)
expression is induced by factors that block bone catabolism and
promote anabolic effects. OPG binds and neutralizes RANKL, leading
to a block in osteoclastogenesis and decreased survival of preexisting
osteoclasts. RANKL, receptor activator of nuclear factor NFB; PTH,
parathyroid hormone; PGE2, prostaglandin E2; TNF, tumor necrosis
factor; LIF, leukemia inhibitory factor; TPO, thrombospondin; PDGF,
platelet-derived growth factor; OPG-L, osteoprotegerin-ligand; IL,
interleukin; TGF-β, transforming growth factor β

8. Hormonal control of bone resorption. A.
Proresorptive and calcitropic factors; B. Anabolic
and antiosteoclastic factors. RANKL expression is
induced in osteoblasts, activated T cells, synovial
fibroblasts, and bone marrow stromal cells. It
binds to membrane-bound receptor RANK to
promote osteoclast differentiation, activation, and
survival. Conversely, osteoprotegerin (OPG)
expression is induced by factors that block bone
catabolism and promote anabolic effects. OPG
binds and neutralizes RANKL, leading to a block in
osteoclastogenesis and decreased survival of
preexisting osteoclasts. RANKL, receptor activator
of nuclear factor NFB; PTH, parathyroid hormone;
PGE2, prostaglandin E2; TNF, tumor necrosis
factor; LIF, leukemia inhibitory factor; TPO,
thrombospondin; PDGF, platelet-derived growth
factor; OPG-L, osteoprotegerin-ligand; IL,
interleukin; TGF-β, transforming growth factor β

9. The hormonal interactions controlling bone mineral homeostasis. In the body
(A), 1,25(OH)2D is produced by the kidney under the control of parathyroid
hormone (PTH), which stimulates its production, and fibroblast growth factor
23 (FGF23), which inhibits its production. 1,25(OH)2D in turn inhibits the
production of PTH by the parathyroid glands and stimulates FGF23 release
from bone. 1,25(OH)2D is the principal regulator of intestinal Ca and
phosphate absorption. At the level of the bone (B), both PTH and 1,25(OH)2D
regulate bone formation and resorption, with each capable of stimulating
both processes. This is accomplished by their stimulation of preosteoblast
proliferation and differentiation into osteoblasts, the bone forming cell. PTH
and 1,25(OH)2D stimulate the expression of RANKL by the osteoblast, which,
with MCSF, stimulates the differentiation and subsequent activation of
osteoclasts, the bone resorbing cell. FGF23 in excess leads to osteomalacia by
inhibiting 1,25(OH)2D3 production and lowering phosphate levels. MCSF,
macrophage colony-stimulating factor; OPG, osteoprotegerin; RANKL, ligand
for receptor for activation of nuclear factor-B.

11. Calcium homeostasis & its control
Primary (principal): Parathyroid hormone
(PTH), Vitamin D (metabolites), Fibroblast
growth factor 23 (FGF23)
Secondary: Calcitonin, Glucocorticoids,
Sex steroids (estrogen), Prolactin, growth
hormone, Insulin, thyroid hormone

12. • PTH is the most important stimulator for renal production of the active
metabolite of vitamin D, 1,25(OH)2D.
• PTH promote both bone formation and resorption by stimulating the
osteoblasts and osteoclasts.
• Enhances renal retention of Ca and Mg.
• Promotes renal phosphate excretion and also that of amino acids,
bicarbonate, Na, Cl, and sulfate.
Parathyroid Hormone(PTH)

13. Parathyroid Hormone (Cont’d)
• Ca is the principal regulator of PTH secretion.
• It binds to the Ca sensing receptor (CaR) and links changes in
intracellular Ca to changes in extracellular Ca.
• Phosphate regulates PTH secretion directly and indirectly by
forming complexes with Ca.
• Excess PTH is to increase bone resorption.
• PTH in low and intermittent doses increases bone formation.

15. • Stimulates intestinal absorption of Ca and phosphate.
• Promotes both bone formation and resorption by stimulating the
osteoblasts and osteoclasts.
• Enhances renal retention of Ca.
• It regulates PTH, and insulin secretion, cytokine production, and
differentiation of cancer cells.
• 25(OH)D is the major metabolite regulating Ca flux and
contractility in muscle.
Vitamin D (metabolites) Cont’d

16. Actions
• Enhancement of absorption of Ca and PO4 from intestine
– By increasing the synthesis of calcium channels and a carrier “calcium
binding protein (CaBP)” or calbindin
– Analogous to stroid hormones – binds to cytoplasmic vit D receptor
(VDR)-translocation-increased synthesis of mRNA-regulation of protein
synthesis
• Calcitriol also enhances recruitment and differentiation of osteoclast precursor
for remodelling - resorption of Calcium and PO4 from bone
– Mature osteoclasts lack VDR, induces “receptor for acivaton of nuclear
factor-kB-ligand (RAANKL)” in osteoblasts and activates osteoclasts
indirectly
– Laying down and mineralization of osteoids
• Also enhances tubular reabsorption of Calcium

17. Fibroblast Growth Factor 23
• Fibroblast growth factor 23 (FGF23) is the most important
inhibitor for renal production of 1,25(OH)2D.
• It stimulates P excretion in the kidney.
• This leads to hypophosphatemia and low levels of 1,25(OH)2D3.
• Osteoblasts and osteocytes in bone are its primary site of
production.

18. Calcitonin
• It lowers Ca and P and inhibits osteoclastic bone resorption.
• Human calcitonin (HL-10 min).
• Salmon calcitonin (as nasal spray) half-life- 43 min,
• At first bone formation is not impaired, but with time both
formation and resorption of bone are reduced.
• Calcitonin in pharmacologic amounts decreases gastrin secretion
and reduces gastric acid.
• used in Paget's disease, osteoporosis and hypercalcemia.

19. Osteoporosis

20. Primary osteoporosis
• Due to menopausal estrogen loss and aging.
• Type I - loss of trabecular bone owing to estrogen lack at
menopause
• Type II- loss of cortical/trabecular bone due to long-term
remodeling inefficiency, dietary inadequacy and activation of the
parathyroid axis with age.

21. Secondary Osteoporosis
 Acromegaly
 Addison’s disease
 Amyloidosis
 Anorexia
 COPD
 Hemochromatosis
 Hyperparathyroidism
 Lymphoma and leukemia
 Malabsorption states
 Multiple myeloma
 Multiple sclerosis
 Rheumatoid arthritis
 Sarcoidosis
 Severe liver disease(PBC)
 Thalessemia
 Thyrotoxicosis
 Drugs:
• Aluminum
• Anticonvulsants
• Excessive thyroxine
• Glucocorticoids
• GnRH agonists
• Heparin
• Lithium

22. Early warning signs
•History of broken bones as an adult
•Unexplained back pain – subsides after a couple of weeks
•Loss of height
•Stooped posture
(Dowager’s Hump)

23. BMD assessment
• Dual energy x-ray absorptiometry (DEXA) is the best current test
to measure bone density
• Quantitative CT vertebral scanning
• Single photon and dual photon absorptiometry

24. Laboratory markers
Bone resorption markers
– Pyridinoline (PYR)
– Deoxy pyridinoline (DPD)
– N-telopeptides of type 1
collagen (NTX)
– C-telopeptides of type 1
collagen (CTX)
Bone formation markers
– Osteocalcin (OC)
– Bone specific alkaline
phosphatase (bone ALP)
– Procollagen type 1 N-
terminal propeptide
(P1NP)
– Procollagen type 1 C-
terminal propeptide
(P1CP)

26. Osteoporosis drugs used
Anabolic Agent Antiresorptive Agents
Function Forms new bone Suppresses bone resorption
Mechanism ↑ osteoblast activity ↓ osteoclast activity
Bone turnover Accelerates turnover Slows turnover
BMD effect Forms new bone
↑ bone volume
↑ mineralization of existing
bone
Drugs Teriparatide , Fluoride,
Androgens
Bisphosphonates Calcitonin ,
ERT, SERMs, Calcium,VitD
,Thiazides
Dual action bone agent :Strontium ranelate

27. Calcium
Preparations
• Calcium chloride (27% Ca): freely water soluble, but irritant - tissue necrosis on
IM or IV (extravasation). Orally also irritant
• Calcium gluconate (9 % Ca): 0.5 gm/1 gm tabs and 10% injections – non irritant
(preferred)
• Calcium lactate: orally non irritant
• Calcium dibasic phosphate (23% Ca): Insoluble, but with HCl form soluble salts
- antacids and replacement
• Calcium carbonate: Insoluble and no irritant – antacids

28. Calcium
• The rationale for using supplemental calcium to protect bone varies
with time of life
.
• Preteens and adolescents require adequate calcium for bone
accretion.
• Higher intake during 3rd decade is related to final phase of bone
acquisition.
• In the elderly supplemental calcium suppresses bone turnover,
improves BMD, and decreases the incidents of fractures.
• Calcium supplementation causes reduction in cortical bone loss.

29. Pharmacokinetics
• Absorbed from entire small intestine including duodenum – carrier
mediated active transport under the influence of Vit.D
• Phytates, phosphates, oxalates and tetracycline – reduces
absorption
– Glucocorticoides and Phenytoin reduces Ca absorption
• Filtered through glomerulus but mostly reabsorbed
• Vit. D increases and Calcitonin decreases reabsorption in proximal
tuule
• PTH increases distal tubular reabsorption
• 300 mg is excreted daily in urine and faeces
• Daily requirement: 800 -1500 mg per day (1/3rd absorbed)

30. Vitamin D
• 1mcg of Cholecalciferol = 40 IU of vit.D
• Calciferol (D2): oily solutions in gelatin capsules –
25000/50000 IU caps
• Cholecalciferol (D3): oral and IM injections – given 3 to 4
weeks intervals
• Calcitriol: 0.25 to 1 mcg orally on altenate days
• Alfacalcidol: Prodrug – rapidly hydrolysed to calcitriol in
liver. Equally active to calitriol on long term use. Dose – 1-2
mcg/day

31. Pharmacokinetics
• Absorbed fro intestine in presence of Bile salts mainly by
lymphatics
• D3 is better absorbed than D2
• Binds to alpha-globulin and stored in fatty tissues for many months
• Half life varies from 1 – 18 days

32. Bisphosphonates
• Bisphosphonates (also called di-phosphonates) are a class of drugs that
prevent the loss of bone mass
• Inhibits osteoclastic activity
• Also useful in metastatic bone disease

33. • Minimally modified side chains (R1
R2) contain a chlorophenyl group.
• Metabolized into a non-hydrolyzable
ATP analog that accumulates within
osteoclasts and induces apoptosis.
which account for its antiresorptive
effect.
• Least potent.
Etidronate
Medronate
Clodronate
Tiludronate

34. • Contains nitrogen group (amino terminal) in
the side chain.
• Primarily inhibits bone resorption.
• Antiresorptive activity involves inhibition of
multiple steps in the pathway from mevalonate
to cholesterol and isoprenoid lipids that are
required for the prenylation of proteins that are
important for osteoclast function.
• They are 10-100 times more potent than 1st
generation BPs.
Alendronate
Pamidronate
Ibandronate

35. • Contain nitrogen atom within a
heterocyclic ring.
• These are upto 10,000 times more
potent than 1st generation.
Risedronate,
Zoledronate

36. Mechanisms of action
• There are 2 classes of BPs which have different mechanisms of
action:
• Non nitrogen containing BPs are taken up by the osteoclast and
cause cell apoptosis through activation of caspase pathway.
• Nitrogen containing BPs are not metabolized and affect protein
prenylation of osteoclast by inhibiting farnesyl diphosphate (FPP)
synthase, a key enzyme of the mevalonate pathway .

39. • Inverse relation exists between pharmacologic activity and oral
bioavailability
• Absorption by passive diffusion from gut
• Milk and other dairy products, orange juice, coffee and calcium and iron
products reduce absorption (Form insoluble complexes)
• Bound to plasma proteins
• 20-80% of the absorbed dose is rapidly taken up by bone.
• Remainder is rapidly excreted in urine
• Long skeletal retention (half life up to 10 years)

40. • Upset stomach
• Inflammation/erosions of esophagus
• Fever/flu-like symptoms
• Slight increased risk for electrolyte disturbance
• Uveitis
• Musculoskeletal joint pain
• Bisphosphonate related osteonecrosis of jaw (BRONJ)

41. Osteonecrosis of the right mandible after
tooth extraction in a patient taking
zoledronic acid for metastatic breast cancer.
Osteonecrosis of the palatal torus in a
patient with osteoporosis taking
alendronate.

42. Contraindications
• Renal failure
• Esophageal erosions
– GERD, benign strictures, most benign GI problems are NOT a
contraindication
– Concern for esophageal irritation/erosions from direct
irritation, recommendations to drink water after and not lie
down at least 30 minutes
– Reality: no increased GI side effects compared to placebo
group in multiple studies

43. Estrogen Replacement Therapy (ERT)
Indication: Used to prevent and treat osteoporosis (FDA
indication is for prevention)
Mechanism:
↓ osteoclast activity,
Acts on osteoblast to ↓ production of IL- 6
↑ production of osteoprotegerin,there by interfering with
recruitment of osteoclast precursors.
Dose: Estrogen: 0.625mg od, Progesterone 2.5mg qd (if
uterus present)

44.  Advantages
Increases bone density (1-
5%) and decreases risk of
fracture (25%)
Relief of hot flashes, vaginal
dryness
Decreases LDL, increases
HDL
?Prevention of Alzheimer’s
disease
Relatively inexpensive
 Disadvantages
↑ bone loss after stopping
↑ risk of uterine ca
↑ risk of thromboembolic
events
Possible ↑ risk of breast
cancer
Side effects:
 breast tenderness,
breakthrough bleeding
↑ risk of coronary events in
women with known CAD in
first year of use (HERS trial)

45. Selective Estrogen Receptor Modulators
(SERMs)
Raloxifene: Non-steroidal benzothiopene .
• Partial agonist in bone and CVS but an antagonist in
endometrium and breast.
• Dose: 60mg OD
• 2.6%  BMD compared to placebo
• Significant reduction in incidence of breast CA
Tamoxifen: antagonist in breast carcinoma cells, blood vessels but
agonist in uterus, bone, liver and pituitary
Also Bazedoxifene may be used.

46.  Advantages
Increases bone density
(2%) and decreases
fracture risk (30%)
No stimulation of breast or
endometrial tissue
No need for progestin in
women with uterus
Decrease LDL
 Disadvantages
Increased risk of
thromboembolic events
Doesn’t treat post-
menopausal sx
May increase hot flashes

47. Calcitonin-salmon
• Synthetic polypeptide of 32 amino acids
• Used as nasal spray(200 IU/day)
• Mechanism of action:
• causes inhibition of osteoclast function with loss of the ruffled
osteoclast border responsible for resorption of bone.
• t 1/2 - 43 mins
 Advantage – May provide analgesic effect on bone pain associated
with fractures
 Disadvantage – Inconsistent effects on BMD and fracture risk

48. Thiazide diuretics
• Reduce urinary calcium excretion and constrain bone loss
in patients with hypercalciuria.
• Dosage :
Hydrochlorothiazide – 25 mg once or twice daily.

49. rParathyroid hormone [rPTH(1-34), teriparatide]
Stimulates new bone formation on trabecular and cortical bone
surfaces by preferential stimulation of osteoblastic activity over
osteoclastic activity.
• Approved for :
– Osteoporosis in postmenopausal women
– Idiopathic and hypogonadal osteoporosis in men
– Glucocorticoid induced osteoprorosis
• Daily SC injections of 40mcg of rPTH for 12-18 months
• Increased BMD by 9-13% and decreased risk of vertebral fractures by
65 to 69 %
– Side effects: muscle pain, weakness, dizziness, headache, and
nausea
• In Rodents-osteogenic sarcoma

50. Strontium ranelate
• “Dual action bone agents" (DABAs).
• Mechanism of action: Stimulates the calcium sensing
receptors and leads to the differentiation of pre-osteoblast to
osteoblast which increases the bone formation.
• Stimulates osteoblasts to secrete osteoprotegerin in
inhibiting osteoclasts formed from pre-osteoclasts in
relation to the RANKL system, which leads to the decrease
of bone resorption.
• Dosage : 2 g oral suspension daily
• Adverse effects : thromboembolism

51. Androgens
• Testosterone replacement therapy increases BMD in
Hypogonadal men.
• Androgens may improve BMD in osteoporotic women but
therapy is limited by virilizing side effects.
• Nandrolone decanoate - 50mg by injection every 3 weeks
.
• Androgenic progestrin( Norethisterone acetate)- acts
synergistically with estrogen to increase BMD in
osteoporotic women.

52. Denosumab
• Human monoclonal antibody to the receptor activator of nuclear
factor- kB ligand (RANKL)
• Blocks its binding to RANK, inhibiting the development and
activity of osteoclasts, decreasing bone resorption , and increasing
bone density
• Dose- 60 mg s.c twice yearly for 36 months
12/13/2016 53

53. Future prospects
• Ospemifene, Lasofoxifene ,Bazedoxifene,Arzoxifene
• Anti-sclerostin antibodies: Blosozumab
• Sclerostin -a protein produced by osteocytes in bone acts by
antagonizing the anabolic Wnt signaling system on osteoblasts, thus
leading to anti-anabolic effect on bone.
• The binding of Wnt proteins to the LRP5/6-Frizzled co-receptor on the
cell membrane of osteoblasts
• Regulate gene transcription that promotes osteoblastic bone formation

54. Cathepsin K inhibitors
• Cathepsin K is a protease expressed in osteoclasts.
• Degrades type 1 collagen in organic bone.
• Cathepsin K inhibitors (e.g., odanicatib) inhibit matrix dissolution,
decrease bone resorption, and thus improve BMD in postmenopausal
women.
• Several cathepsin K inhibitors have been developed, while the
development was blocked in one of them because of serious side effects
(scleroderma-like changes in the skin).

55. Statins
• Enhance bone morphogenetic protein-2 gene expression and bone
formation in vivo.
• Increase of osteoblast number and promotion of osteoblastic
differentiation, leading onto increased bone formation by
simvastatin has been seen in animal models.
• Thus, there is a need to develop potent and preferably bone-
specific statin-related molecules.
• Echistatin, a potential new drug for
osteoporosis.." Endocrinology”

56. C-src kinase inhibitors
• The non-receptor tyrosine kinase c-src is required for the
development of the osteoclast ruffled border, one of the final stages
in the maturation of osteoclasts.
• Functional sealing zone and resorptive surface.
• Saracatinib is a novel orally available competitive inhibitor of Src
kinase shown to inhibit bone resorption in vitro.
Hannon RA, JBMR 2010

57. Calcilytics
• Calcium-sensing receptor antagonists (calcilytics) are a new drug
class of orally administered agents that stimulate endogenous PTH
release and have bone forming action.
• JTT-305/MK-5442 and SB-423557 are two calcilytics that were
shown to increase bone formation and prevent bone loss in
ovariectomised rats.
• ATF 936 and ronacaleret are still under clinical trials for the
establishment of their role in the treatment of osteoporosis.

58. Conclusion
• So ,Our aim should be
• 1. increase knowledge of bone physiology and
osteoporosis
• 2.raise the awareness of major risk factors and
•
• 3.provide information on possibilities of primary
and secondary prevention and management of
the disease

59. Thank You.