Drugs affecting bone

mineral
homeostasis
 Topic learning outcomes
1. Mechanism of absorption,MOA & role
of minerals on
bones.
2. Diagnosis and symptoms of bone
mineral homeostasis related
disorders.
3. Drugs for bone disorders with
MOA at receptor level, side
effects.
4. Pharmacotherapeutics for bone
 Calcium
Ø Ca2+ is vital for muscle contraction
Ø Ca2+ is vital for fusion, and release of storage
vesicles.
Ø intracellular Ca2+ acts as a critical second
messenger
Ø promote blood coagulation
Ø support the formation and continuous
remodeling of the skeleton.
Ø Cross-linking of structural proteins in bone
matrix.
Ø In adult men ~1300g and 1000g in women,
Ø 99% is in bone and teeth.
Ø Normal serum calcium con. 8.5-10.4
mg/dL Ø ionized (50%),
Ø protein-bound (40%)-(Albumin accounts for some 90%) Ø
complexed (10%).
 Calcium
The steady-state content of calcium in bone reflects
the net effect of bone resorption and bone formation
A labile pool of bone Ca2+ exchanges readily with
interstitial fluid.
This exchange is modulated by hormones, vitamins,
drugs, and other factors that directly alter bone
turnover or that influence the Ca2+ level in
interstitial fluid.
a diet low in calcium leads to a compensatory
increase in fractional absorption owing partly to
activation of vitamin D.
drugs such as glucocorticoids and phenytoin depress
intestinal Ca2+ transport.
 Calcium Absorption
~75% of calcium is from milk
and dairy products.
The adequate intake is 1300
mg/day in adolescents and
1000 mg/day in adults.
After age 50, the adequate
intake is 1200 mg/day.
Active vitamin D–dependent

Ca2+ enters the body only

through the intestine.
Active vitamin D–dependent
transport occurs in the
proximal duodenum,
 Urinary Ca2+ excretion
About 9 g of Ca2+ are filtered each day.
Tubular reabsorption >98%
Reabsorption is regulated by parathyroid
hormone (PTH)
loop of Henle Diuretics (e.g., furosemide)
increase calcium excretion.
By contrast, thiazide diuretics diminishing
calcium excretion
 Phosphate
Essential component of all body tissues,
present in plasma, extracellular fluid, cell
membrane phospholipids, intracellular
fluid, collagen, and bone tissue.
> 80% of body phosphorus is in
bone, and
~15% is in soft tissue
phosphate roles:
– energy metabolism
– key regulator of enzyme activity when
transferred by protein kinases from ATP to
phosphorylatable serine, threonine, and
tyrosine residues.
Hormonal Interactions Controlling Bone
Mineral Homeostasis
 Hormonal Regulation Of Calcium And
Phosphate Homeostasis

parathyroid hormone
(PTH)
1,25-dihydroxy
vitamin D (calcitriol),:
which regulate
mineral homeostasis
by effects on:
– Kidney
– Intestine
– bone
 Parathyroid
Hormone
(PTH)Ca2+ by
PTH regulate plasma
affecting:
– Bone resorption/formation
– Renal Ca2+
excretion/reabsorption
– Calcitriol synthesis (thus GI Ca2+
absorption).
 PTH CHEMISTRY

PTH - single polypeptide chains of 84

amino acids with molecular masses
of ~9500 Da.
Biological activity is associated
binding to the PTH receptor.
signaling pathways: CAMP or
IP3–Ca2+.
PTH Regulation of Secretion

At LOW Ca2+ PTH secretion increases.

hypocalcemia induces parathyroid hypertrophy
and hyperplasia.
Ca2+ itself appears to regulate parathyroid gland
growth as well as hormone synthesis and
secretion.
Adrenergic receptor agonists and dopamine
increase parathyroid cell cyclic AMP levels, and
increase PTH secretion,
 PTH Effects on Bone
PTH enhances bone resorption and
thereby increases Ca2+ delivery to the
extracellular fluid,
The primary skeletal target cell for PTH is
the osteoclast,
PTH also recruits osteoblast precursor cells
to form new bone remodeling units.
PTH in vivo reflects not only hormone
action on individual cells but also the
increased total number of active
osteoblasts, owing to initiation of new
remodeling units.
 Vitamin D
Vitamin D permit efficient absorption of
dietary calcium and to allow full
expression of the actions of PTH.
Vitamin D is actually a hormone rather
than a vitamin;
synthesized in mammals and, under ideal
conditions, probably is not required in the
diet.
Receptors for the activated form of
vitamin D are expressed in many cells:
lymphocytes, epidermal cells, hair follicles,
adipose tissue, pancreatic islets, muscle,
and neurons.
 Bone homeostasis
1.It involves multiplebut coordinated cellular
and molecular events. Two main types of cells are
responsible for bone metabolism: osteoblasts (which
secrete new bone), and osteoclasts (which break
bone down).
2.The structureof bones aswell as
adequate supply of calcium requires close
cooperation between these two cell types.
3.Bone metabolism relies on complex
signaling pathways and control mechanisms to
achieve proper rates of growth and differentiation.
4.These controls include the action of several
hormones, including parathyroidhormone (PTH),
vitamin D, growth hormone, steroids, and
calcitonin,as well as several bone marrow-derived
membraneand soluble cytokines and growthfactors.
 Bone remodeling unit

Subsequent to appropriate signaling, osteoclasts

move to resorb the surface of the bone, followed by
deposition of bone by osteoblasts.

Together, the cells that are responsible for bone

remodeling are known as the basic multicellular unit
(BMU), and the temporal duration (i.e. lifespan) of
the BMU is referred to as the bone remodeling
period.
 Bone remodeling
Bone remodeling (or bone metabolism) is
a lifelong process where mature
bone tissue is removed from
the skeleton (a process called bone
resorption) and new bone tissue is formed
(a process called ossification or new bone
formation).
These processes also control the
reshaping or replacement of bone
following injuries like fractures
but also micro- damage (normal
activity).
In the first year of life, almost
100% of the skeleton is replaced. In
adults,remodeling proceeds at about 10%
[
 Osteoporosis
Osteoporosis is a disease of the skeleton in which bones
become "thin" and prone to fracture.
In other words, the bone loses calcium and density. At
age 65, about 30% of women have osteoporosis, and
nearly all of them are unaware of their condition. After
age 80, up to 70% of women develop osteoporosis.
Osteoporosis is a major risk factor for fracture in the
spine and hip. The decrease in bone density can also
lead to bone loss in the jaw and subsequent tooth decay.
Over 2 million osteoporosis-related fractures occur in the
United States annually, with an estimated cost of $17
billion
The prevalence of osteoporosis may be on the rise, in
part, due to a decrease in the overall routine utilization
of hormone replacement therapy (HRT) for most
postmenopausal women.
Also, while osteoporosis is less prevalent in men than
women, men account for almost 30% of low bone
mass
related (fragility) fractures 18
COMPILED BY: PROF. ANWAR BAIG
 Secondary Hormonal Regulators
of Bone Mineral Homeostasis
Calcitonin: secreted by thyroid, T1/2= 10 min, lower
serum calcium and phosphate by actions on bone
and kidney.
Glucocorticoids alter bone mineral homeostasis by
antagonizing vitamin D-stimulated intestinal
calcium transport, by stimulating renal calcium
excretion, and by blocking bone formation.
Estrogens, prevent accelerated bone loss by:
– reduce bone-resorbing action of PTH.
– increased 1,25(OH)2D level in blood
May increased risk of breast cancer from continued
estrogen use
 Drugs for osteoporosis

1. Calcitriol and
Analouges
2. Bisphosphon
ates
3. Calcimimetics:
Cinacalcet
4. Calcitonin
5. Estrogen
6. Calcium
1- Calcitriol and Analouges
s
Available for oral
administration or
injection.
I.V high doses of
calcitriol or one of
its derivatives.
predominant
used for patients
with chronic
kidney disease
and end-stage
kidney disease.
 Therapeutic Indications for
Vitamin D
The major therapeutic uses of
vitamin D may be divided into four
categories:

– Prophylaxis and cure of nutritional

rickets (softening of bones in children)
– treatment of metabolic rickets and
osteomalacia, particularly in the
setting of chronic renal failure
– prevention and treatment of
osteoporosis
Adverse Effects of Vitamin D Therapy

Hypercalcemia, with or without

hyperphosphatemia, may limit its
use at doses that effectively
suppress PTH secretion.
Hypervitaminosis D is treated by:
– immediate withdrawal of the
vitamin
– low-calcium diet
– administration of glucocorticoids
– loop diuretics is also useful.
 2.Bisphosphonates
First-generation (MCET):
– Medronate; clodronate;
etidronate and tiludronate.
Second-generation (AP)
aminobisphosphonates:
– Alendronate and pamidronate,
contain a nitrogen group in
the side chain.
– 10-100 times more potent
than first-generation
compounds.
Third-generation (RZ):
risedronate and zoledronate)
contain a nitrogen atom within a
heterocyclic ring and are up to
10,000 times more potent than
first-generation agents.
 Bisphosphonates- MOA
concentrate at sites of active remodeling
Incorporated into the bone matrix
Analogue of pyrophosphate
Accelerate apoptosis of osteoclast reducing their
number
Disruption of cytoskeletal of osteoclast
Inhibit differentiation of osteoclast precursor
Inactivation of osteoclast by disturbing
mevalonate pathway (lipid synthesis)
 Uses of Bisphosphonates

Osteoporosis: Alendronate,risedronate are more

effective than calctonin
Pagets disease: (Honey comb like bone)
Alendronate,risedronate,Pamidronate,zolendronate
are cheaper than calctonin.
Hypercalcaemia of malignancy:
Pamidronate or zoledronate
Combine with calcitonin
 Bisphosphonates
Absorption, Fate, and Excretion

All oral, very poorly absorbed from the intestine,

low bioavailability (<1% [alendronate,
risedronate] to 6% [etidronate, tiludronate]).
Food reduces absorption: Should be
administered with a full glass of water following
an overnight FAST and at least 30 minutes
before breakfast.
Oral bisphosphonates HAVE NOT BEEN used
widely in CHILDREN or adolescents because of
uncertainty of long-term effects of
bisphosphonates on the growing skeleton.
Excreted by kidneys.
 Bisphosphonates
Absorption, Fate, and Excretion
Pamidronate is not available as an oral
preparation because it causes gastric
irritation
However, with the possible exception of
etidronate, all currently available
bisphosphonates have this complication.
~50% of absorbed drug accumulates in bone;
rest excreted unchanged in the urine.
Contraindications: esophageal motility
disorders, peptic ulcer renal failure
disease
 Bisphosphonates Adverse Effects

Very safe
At higher doses: gastric (etidronate) and
esophageal (pamidronate& alendronate)
irritation
Irritation minimized by taking the drug
with glass of water and remaining upright
for 30 minutes.
Rare, OSTEONECROSIS of the jaw (ONJ),
1/100,000 with I.V doses of zoledronate
are used to control bone metastases and
cancer-induced hypercalcemia.
 3- Calcimimetics: Cinacalcet
Cinacalcet: Cinacalcet blocks PTH secretion
a new class of drugs that activates the calcium sensing
receptor (CaR).
CaR is widely distributed but has its greatest concentration in the
parathyroid gland.
Mechanism of action
Cinacalcet is a drug that acts as a calcimimetic by allosteric
activation of the calcium-sensing receptor . The calcium-sensing
receptors on the surface of the chief cell of the parathyroid gland
is the principal regulator of parathyroid hormone secretion (PTH).
Cinacalcet increases the sensitivity of calcium receptors on
parathyroid cells to reduce parathyroid hormone (PTH) levels and
thus decrease serum calcium levels. As receptors are already
block from the calcimimetic (Cinacalcet) the native rise and fall
of Ca levels now interact with the remaining receptors, effectively
lowering the threshold for activation of feedback on the
parathyroid chief cells.
Approved for the treatment of secondary hyperparathyroidism
in chronic kidney diseaCOsMePILaEnD dBY:fPoRrOFt.hANeWtArReBaAItGment of
4- CALCITONIN
4- CALCITONIN
Calcitonin lowers plasma Ca2+ and phosphate
concentrations in patients with hypercalcemia;
by DECREASED BONE RESORPTION.
Although calcitonin is effective for up to 6 hours
in the initial treatment of hypercalcemia, LESS
ACTIVE after a few days due to receptor
downregulation.
Development of antibodies with prolonged
therapy.
Salmon calcitonin is available as a NASAL
SPRAY, introduced for once-daily treatment of
postmenopausal osteoporosis.
Side effects: Nausea, hand swelling, urticaria,
rarely, intestinal cramping.
 5- Estrogen
Helping to maintain a normal bone
resorption rate.
SUPPRESSES THE PROLIFERATIO N
AND DIFFERENTIATION OF
OSTEOCLASTS
Increases osteoclast apoptosis.
Decreases the production of several
cytokines that are potent stimulators
of osteoclasts (IL-1. IL-6, TNF)
Decreases the production of RANKL
and increases the production of OPG;
both of which reduce
osteoclastogenesis.
 Estrogen
Postmenopausal or estrogen
deficiency increases risk for
osteoporosis
Estrogen replacement effective in
conservation of bone and protection
against osteoporotic fracture after
menopause
Side effects: increased risks of heart
disease and breast cancer were
found in chronic treatment
 RALOXIFENE (Evista)
Selective estrogen receptor
modulator
Decrease bone resorption
60mg 1Xday
Side effects:
– Hot flushes
– leg cramps
– Thrombolism
Contraindic
– Pregnancy/lactation
atin:
– Pulmonary CO
eMPmILEDbBoY:lPiRsOmF 35
 6- Calcium
There is controversy about the role of calcium
during the early years after menopause, when
the primary basis for bone loss is estrogen
withdrawal.

Patients who are unable or unwilling to increase

calcium by dietary means alone may choose
from many palatable, low-cost calcium
preparations.
ORAL CALCIUM CARBONATE, which should
be taken with meals to facilitate dissolution and
absorption.
Traditional dosing of calcium is ~1000 mg/day,
nearly the amount present in a quart of milk.
Adults >50 years of age need 1200 mg of
calcium daily. COMPILED BY: PROF. ANWAR BAIG 36
 7- Parathyroid hormone:
TERIPARITIDE (Forteo)
ACTS AS PARATHYROID HORMONE (PTH)
Increase bone formation by stimulation of
Osteoblasts
Increase renal reabsorption of calcium
20mg 1xday

Side effects:
– Orthostatic hypotension
– Hypercalcemia

Contraindication:
– Hypercalcemia
– Hypersinsitivity
THE END