Prevention & treatment of osteoporosis
Osteoporosis =
systemic disease of skeleton characterized by low bone density
and by increase of bone fragility and its predisposition to
fractures
•the highest occurency in postmenopausal women
•frequent cause of fractures in elderly people
 assoc. prof. PharmDr. Oldřich Farsa, Ph.D., FPh UVPS Brno 2019
OC = osteoclast; OB = osteoblast; GH = growth hormon; IL = interleukins; E2 =
oestrogens; PTH = parathormon; RANK L = receptor activator of nuclear factor
kappa beta ligand (osteoprotegerin ligand); RANK = receptor for RANK L; M-CSF
= macrophage colony stimulating factor etc.
„remodeling“ of 10 – 25 % bone matter per year (women in fertile age)
bone resorption > bone fromation  osteoporosis
Medicines for osteoporosis
Prevention
•Fluorides
•Calcium compounds
•Vitamine(s) D
Treatment
•Bisphosphonates
•Compounds acting on sex hormone receptors
•Parathormon, teriparatide
•Calcitonin
•Monoclonal antibodies: denosumab
•Strontium ranelate
Fluorides
NaF
Na2PO3F sodium monofluophosphate – 50%  of incidence of vertebral fractures
Fluocalcic®
tbl. eff. (+ CaCO3)
Calcium compounds
•CaCO3
•cheeses, dairy products, milk
•bioavailability almost the same; from plant resources poor (phytates)
Vitamins D
active formVigantol ® gtt.
Alendronic acid /
Vitamin D3
Teva
Calciferol Biotika Forte ®
Bisphosphonates
= mainly sodium salts of monotopic bisphosphonic acids
•analogues of calcium pyrophosphate which forms the most of
inorganic matter of bone
•act directly in „remodelation“; incorporated into osteoclasts
•also complexes or salts with 99
Tc, 186
Re for nuclear diagnostic
P
O
P
O
–
O
–
O
–
O
–
O
OCa
2+
Ca
2+
P P
O
–
OH
OH
O
–
O
O
Na
+
Na
+
calcium pyrophosphate medronate
Na
+
Na
+
OH
P P
OH
O
O
O
O
OH
CH3
disodium dihydrogen-1-
hydroxyethyl-1,1-
bis(phosphonate)
etidronate
Re-bone®
inj. (+ 186
Re)
P
P
Cl
Cl
O
OH O
OH
O
O
Na
+
Na
+
disodium dihydrogen-1,1-
dichlormethan-1,1-
bis(phosphonate)
clodronate
Bonefos®
, Lodronat®
1st
generation“
•interfere with ATP
Bisphophonates of 1st
generation continued
Na
+
Na
+
P
CH
OH
O
O
P
S
OH
O
O Cl
disodium dihydrogen-1-(4-
chlorfenylsulfanyl)methan-1,1-
bis(phosphonate)
tiludronate
P
C
H2
O
O
OH
P
OH
O
ONa
+
Na
+
disodium
dihydrogenmethan-
1,1-bis(phosphonate)
medronate
Amerscam®
(+ 99
Tc)
Bisphosphonates
2nd
generation = aminobisphosphonates
•inhibit the last step of cholesterol synthesis   activity of osteoclasts
 formation of osteoclasts
 apoptosis of asteoclasts
Compounds with primary amino grop
P
P
OH
O
O
OH
O
O
OH
NH2
Na
+
Na
+
disodiumdihydrogen-4-amino-1-
hydroxybutan-1,1-
bis(phosphonate)
alendronate
Fosamax®
, Lindron®
P
P
OH
O
O
OH
O
O
OH
NH2
Na
+
Na
+
disodium dihydrogen-4-amino-1-
hydroxypropan-1,1-
bis(phosphonate)
pamidronate
Aredia®
, Pamifos®
Bisphosphonates
2nd
generation - aminobisphosphonates
with aliphtic or heterocyclic tertiary amino
group
P
P
OH
OH
OH
O
OH
O
O
N
Na
+
sodium trihydrogen-1-hydroxy-3-
methyl(pentyl)amino-propan-
1,1-bis(phosphonate)
ibandronate
Bondromat®
N
N
OH
P
P
O
O
OH
OH
O
O
Na
+
Na
+
disodium dihydrogen-1-hydroxy-
2-[(1H)imidazol-1-yl]ethan-1,1-
bis(phosphonate)
zolendronate
Zometa®
Bisphosphonates
2nd
generation - aminobisphosphonates
with heterocyclic tertiary amino group
•pyridine derivatives
P POH
OH
O
OH
O
O
N
Na
+
sodium trihydrogen-2-(pyridin-2-
yl)ethan-1,1-bis(phosphonate)
piridronate
N
OHP
P
OH
OH
O
O
OH
O Na
+
sodium trihydrogen-1-hydroxy-2-(pyridin-3-
yl)ethan-1,1-bis(phosphonate)
risendronate
Actonel®
Compounds interacting with estrogenic receptors: selective estrogen receptors
modulators (SERM)
S
O
OH
OH
O
N
O
N
CH3
CH3
CH3
tamoxifene
•rather anti-cancer / estrogen antagonist
Tamoxifeni citras PhB
raloxifene
•SERM
OH
CH3
OH
CH3
diethylstilbestrol
SERM
Mechanism of action of raloxifene
•2 types of receptor proteins: ER,
ER
•ER is activated by binding of
estradiol but inhibited by activated
ER
•genes transcription under estrogenic
control then proceeds in nonreproductive
tissue only
Sex hormones and their synthetic analogues
Estrogens
•2nd
line prevention and treatment of o. in women in and after
menopause
 risk of cancer of uterus  usually with gestagens (subfysiol.
dose)
•often TTS CH3
OH
OH
H
H
H
1
2
3
4
5
6
7
8
910
11
12
13
14
15
16
17
18
estra-1,3,5(10)-trien-3,17-diol
estradiol
Avaden®
, Climara®
emp., Dermestril ®
TTS emp.,
Oestrogel®
Estrogen analogues
CH3
CH3 C
OH
CH
O
HH
17-hydroxy-6-methyl-19-norpregn-5(10)en-20-in-3-on
tibolon
Ladybon®
, Livial®
• evidence for increse of bone matter during one year of
treatment
•no action in endometrium
Androgens
•in men with o. caused by hypogonadism only
17-hydroxyandrost-4-en-3-on
testosterone
Sustanon®
inj. sol. (mixture of propionate, isocapronate,
phenylpropionate and decanoate of testosteronu)
Understore ®
cps. (undecanoate)
CH3
CH3
OH
O
H
H
H
1 9
Calcitonin
N
N
N
H
N
H O
NH2O
O
NH
N
H
N
H
N
H
N
H
S
S
N
H
NH2
O
O O
O
OH
O
OH
O
O
NH2
OH
N
H
N
HO
O
N
H
O
N
H
O
NH2
O N
H NH
O
OH
ONH
NH2
O
O
NH
O
N
H
O
N
H
N
H O
N
NH
O
NH2
O
N
H
OH
N
H
O
OH
O
O
N
H
O
NH
NH
NH2
O N
H
NH
OH
N
H
N
H
N
H
NH2
O
O
OH
O
O
OH
N
H
N
HO
O
OH
O
ONH2
OH
Calcitoninum salmonis EP = salmon´s calcitonin (syntetic; AA sequence
identical with salmon´s hormone; 32 AA)
Miacalcic®
inj., nasal; Osteodon®
; Tonocalcin®
withdrawn due to increase of
incidence of nasal septum cancer after administration
Calcitonin
•peptide of 32 AA (salmon´s – Onchorhyncus kisutch; human 139 AA)
•secreted from C-cells of thyroid gland ( = parafolicular cells – Baber
1876), in lower vertebrates by ultimobranchial bodies originated from
5th gills slot
•receptors on osteoclasts (but also kidneys, brain)
 excretion of Ca2+
from bone (  calcemia)
 osteoclasts formation
•applied together with Ca2+
Parathyroid hormone
•
•produced in parathyroidal bodies
•protein of 84 AA
•evidence for anabolic efect in bone but continous aplication causes
bone destruction
•therapeutic usage limited, new drug forms???
•N-terminal sequence 1 – 34 of parathyroid hormone
•produced by a recombination technology
•intermitent aplication preferably stimulates new bone formation by osteoblasts
•used in postmenopausal women when a previous treatment lasting at least 2 years failed
Teriparatide
denosumab
•completely human monoclonal antibody
•IgG2
•against RANKL = receptor activator of nuclear factor kappa beta ligand (or
osteoprotegerin ligand)
•binds to RANKL specifcally and blocks its binding to RANK  inhibition of
osteoclast formation  decrease of bone resorption
•10years treatment keeps low incidency of both vertebral and non-vertebral
fractures
•Prolia ®, Xgeva ®
Strontium ranelate
S
O
O
O
O
O
O
O
O N
N
Sr
2+
2
• Sr2+
is the active part, ranelic acid is not absorbed
•incorporation of traces of Sr2+
into bone phosphates  density and strength
•used in postmenopausal women in whom other drugs are contraindicated or intolerated
•evidence for decrease of fractures