calcium aand vitamin D abnormaities leads to bone diseases

1. CALCIUM HOMEOSTASIS AND DISORDERS
BY
Mohie-Aldien A Sherif
Professor of Pharmacology, Faculty of Medicine, Benha
University, Benha, Egypt

3. Porous/Cancellous/Trabecular/ spongy Compact Bone
*Low mineral & high collagen) → flexible
→ Shock absorption ( change shape) e.g.,
vertebrae
*metabolically active
*High mineral & low collagen) → Stiffer →
Withstanding stress in high loads areas e.g. Long
bones( has some trabecular bone- near to the marrow)
* Less metabolically active

4. Osteoblast Ostycte Osteoclast
Func-tion *Bone forming cells.
*differentiated to osteocyte
*Secrete type I collagen, alkaline
phosphatase+ ,regulate osteoclast•
*Responsible for Ca+2
exchange with extra-
cellular fluid
*Bone resorption cells.
* Synthesize bone acid phosphatase
Stimu-
lated
IGF, vit. D (small dose ,Ca deficiency),
PGE2, fluride
PTH P.T.H.  osteoblasts  ↑osteoclasts , vit. D
(high dose) , IL1,6, heparin., RANK legend,
Inhibited glucocorticoid Calcitonin ,Estrogen, PGE2, ,
Bisphosphonate. OPG
1-produce RANK ligand → bind to RANK receptor
membrane/ free cytoplasmic) → ↑ cells differentiation
to osteoclasts ,
2-produce osteoprotegrin (OPG) is free RANK receptor
binds RANKL → prevent osteoclasts overstimulation . + a
marker of bone turnover, it ↑ in pts w/ a fracture or w/ lytic
bone lesions; ¾ comes from liver and ¼ comes from bone
so bone-specific alk phos is a better marker of bone
turnover

5. 2-6
weeks
~2-6
months
Mineralized extracellular matrix
Non-mineralized
extracellular matrix (osteoid)
1. 2. 3. 4. 5.
Stages of BONE REMODELING
Occurs at periosteal & endosteal surfaces

6. Gut
(dudon
um)
Vit.D
PO4 (3mg/dl): 78% is free (+) PTH
(+) calcitonin,
(-) PTH , Vit. D
Total calcium (9-11mg/dl):
*47% ionised (4-4.9mg/dl, by acidosis)
* 13% Anion-bound (PO4,citrate) ca:  by alkalosis)
Protein bound ca: 40% ( 80-90% to albumin. It is
affected by Na& ph.
(+) Vit.D, PTH
.
(-) Phytate, oxalate,
cholecystokinin,
oil
(+) Vit.D
500mg/d(+) PTH (continous), IL-6
, IL-1 , TGF-B , Vit D (high dose),
glucocorticoid , heparin
(-) calcitonin(Miacalcic),
Bisphosphonate, PgE2,
androgen, Estrogen , NO
Bone accretion (500mg/d):
Passive as a concentration in
extracellular fluid of bone is less
than that in serum.
pH 7. 45
pH 7.35
Alkalosis: increased calcium binding to protein;
decreased ionized fraction
Acidosis: decreased calcium binding to protein;
increased ionized fraction
Each 0.1 decrease in pH increases ionized calcium by 0.05 mmol/L
Hydroxyapatite (98.9% = 31 mol= 1250g)
1% of which is available as an exchangeable pool
Ca intake (1000mg/d)
Cytosolic Ca(100 nmol/l)
*10000 fold lower than extracellular
calcium
*This steep gradient maintained by
plasma membrane Ca++ ATPase (PMCA)

8. (PTH) 1.25 dihydroxy chol-calciferol Calcitonin
Serum Ca (hypercalcaemic agent) (bone turnover agent)  (hypocalcaemic)
G.IT * ↑ Ca+2 absorption *↑ Ca+2 /P absorption * ↑Ca+2 absorption
Kidney * ↑ Ca+2 re-absorption
*↑ Po4 excretion (phosphaturia)
* ↑α1,25 dihydroxylase
* ↑Ca+2 reabsorption *↑ Ca+2 reabsorption
Bone * at low conc./intermittent →↑
osteoblasts →↑bone deposition
* High conc./ continuous → indirect ↑
Osteoclast (↑ bone resorption)
* Small dose/ ca+2 deficiency → ↑
osteoblast → bone mineralization and
proteins (such as osteocalcin)
*High dose → ↑ osteoclast &↓PTH
* ↓osteocllast →↑ bone
formation
* Ca deposition in bone
Mechanism *↑ Gs adenylcyclase
C.A.M.P.
* Nuclear receptor → ↑transcription
→↑carrier.
* ↑ C.A.M.P.
Uses Acute tetany (I.M) repeated injecton
→ Antibody resistance
Oral: 1)chronic hypocalcaemia
(dihydr/otachysterl (AT10)
2) Rickets, osteomalacia, osteoporosis
S.C:1) osteoporosis.
2) paget’s disease.
(with ca+2 supplement)

9. The VDR regulates gene transcription by homo-dimerization and by heterodimerization to a retinoic acid X receptor (RXR). The complex binds
to target DNA sequences and regulates the transcription of several genes important in mediating vitamin D’s effects on calcium and skeletal
metabolism and its diverse biological effects.

10. Systemic Factor Osteoclast (bone Erosion) Osteoblast (bone forming) Bone Serum Ca
PTH ↑ (High conc./ continuous) ↑ (low conc./ intermittent) Variable ↑
Vit D ↑ ( High dose) ↑ (low conc./↓ Ca) Variable ↑
Calcitonin ↓ → ↑ ↓
IL1,6/TNFα,β/TGFB ↑ ↓ ↓ ↑
glucocorticoid ↑ ↓ ↓ ↑
T3/T4 ↑ → ↓ ↑
Estrogen/ Testosterone ↓ ↑ ↑ ↓
Mechanical load ↓ ↑ ↑ →
Heparin ↑ → ↓ ↑
Miacalcic,PgE2 , Bisphos-
phonate, Na fluoride ,GH;
↓ ↑ ↑ ↓

11. Local OB OC
Wnt (wingless-type mouse mammary tumor virus integration site)-↑ by PgE2 ;NO. ATP) (OB) ↑ ↔
Sclerostin (SOS) ; DDK( Dickkopf-related protein1) ; sFRP (soluble frizzled-related protein) ;
WIF-1 (Wnt-inhibitory factor-1) →↓wnt (osteocyte)
↓ ↔
RANK legand (Receptor activator for nuclear factor κB) ( osteocyte) ↔ ↑
OPG (Osteoprotegerin) ;NO →↓ RANK-RANKL interaction) ↔ ↓
FGF (bone marrow; OB; lineage cells) ↑ ↔
PDGF (inflammatory cells) ↑ ↔
TGFB (bone matrix) ↑ ↔
M-CSF (OB) ↔ ↑
IGF (OB; bone mtrix) ↑ ↔
BMP (bone marrow) →↑ OPG → ↑OB ↑ ↔
Osteocalcin → mineralization (OB ) ↑ →
PThrP (PTH related protein) by OB precursor) ↑ →
Leukemic inhibitory Factor (bone marrow) ↓ ↑
IL1,6/TNF/TGFB ↓ ↑
TNF-a = Tumor necrosis factor ;
GM-CSF = Granulocyte –macrophage stimulating factor
SOST= Sclerostin
NPT2a = sodium-dependent phosphate co-transporters ;
BMPs =Bone Morphogenic proteins →↑ OPG → ↑OB
; bone matrix).. OC releases cathepsin (Cp),
MMP =matrix metalloproteinase- Col1= collagenous
OCN = osteocalcin
OSP osteopontin ;
OSN= osteonectin ,
BSP =bone sialoprotein
BMP= ,bone morphogenetic proteins .
Osteocytes (Ot)

13. PThrP (PTH related
protein
PGE2
NO;
ATP
(-)
WINT,Osteocalcin

14. Hypoxia-inducible factor 1-α
Figure 1
Sclerostin/
DDK1(↓wint)
Lipocalin-2 (LCN2)
↑Insulin secretion
↑ Insulin senstivity
↑ glucose tolerance
↓ apetite(feeding)

15. ↑ bone
resorption
*Osteitis-fibrosa-cystica (↑PTH → focal resorption &reactive fibrosis + ↑ serum Ca →
ectopic Ca deposition. e.g. Kidney. (nephro lithiasis& nephrocalcinosis ;BV
*paget ( huge multi-nucleated OC→ intense bone resorption &vascular hypertrophy +
irregularly shaped trabecular bone
↓ bone
formation
↓ mineralization of matrix : *Adult →Osteomalacia
* Children → Rickets
↓ matrix – Osteogenesis Imperfecta ( often have blue sclera)
 in both matrix & mineral : Osteoporosis

16. Table 2.
Pathophysiology of
commonest causes
of osteoporosis.
DOI: (10.1177/0004563218759371)

17. ↑ bone resor-ption *Osteitis-fibrosa-cystica (↑PTH → focal resorption &reactive fibrosis + ↑ serum Ca → ectopic Ca deposition. e.g.
Kidney. (nephro lithiasis& nephrocalcinosis ;BV
*paget ( huge multi-nucleated OC→ intense bone resorption &vascular hypertrophy + irregularly shaped trabecular bone
↓ bone form-ation ↓ mineralization of matrix : *Adult →Osteomalacia
* Children → Rickets
↓ matrix – Osteogenesis Imperfecta ( often have blue sclera)
 in both matrix & mineral : Osteoporosis

18. Osteoporotic Bone Loss
• A skeletal disorder characterized by
compromised bone strength
predisposing to an increased risk of
fracture. Bone Strength:
• Bone Density: Grams of mineral per
area or volume (70% bone strength)
• Bone Quality:
– Architecture
– Turnover
– Damage accumulation
– Mineralization
Normal Bone
Osteoporosis

19. Z-score is used to compare your bone density to the
average values for a person of your same age and
gender.

20. Selected
Medications
Associated with
Increased Bone
Loss and/or
Fracture Risk

21. Cholcalciferol (vit. D3) 25 OH-cholcolciferel(Calcidiol )*** Serum Level 1.25 dihydrotycholcalciferol (calcitril)
*Delayed onset (1week).
* Activated in kidney, liver.
* Long duration (stored in fat).
* Narrow theapeutic range.
* Delayed onset.
*Activated in kidney only.
* Short duration.
* wide therapeutic range.
* Rapide onset (2-4 d).
* Active form.
* Short duration.
* wide therapeutic range.
(hpercalcaemia, hyperclacuria, wide spread ectopic calcification
e.g. kidney)
Vit. D Supplementation (2,000- 4,000 IU/Day)
decrease: All cause mortality.IHD; cancers; Depression;
fractures. Relative Contraindications : Sarcoid Tuberculosis
Lymphoma 1ry Hyperparathyroidism ? Renal Calculi

24. Osteoclasts matured from bone marrow hematopoietic stem cells (BMMs) with the stimulation of two critical factors, M-CSF (activator of nuclear factor kappa-B ligand
(RANKL). When binding to its specific receptors [CSF-1R and receptor activatCSF-1) and receptor or of nuclear factor kappa-B (RANK)] on BMMs membrane, a series of
cascades are activated, and BMMs were then differentiated into matured osteoclast. Realizing the importance of M-CSF and RANKL in osteoclast differentiation, inhibitors
to CSF-1R and RANKL were considered as available strategy to suppress over-activated osteoclasts. Bisphosphonates, a widely used anti-osteoporosis agent, can be
absorbed by osteoclast and induce osteoclast apoptosis. Additionally, it has been indicated that GLP-2 is a negative regulator of osteoclast differentiation, thus, the exact
mechanisms are still unclear. Bone resorption is demonstrated as specific function of osteoclast, and bone matrix degradation is induced by the release of cathepsin K, as
well as H+, and the release of H+ is enabled by V-ATPase on the membrane of matured osteoclast. So that, cathepsin K and V-ATPase are considered as another two targets
to impair osteoclast function, especially, inhibitors of cathepsin K, such as Odanacatib, Balicatib are undergoing clinical trials. Front. Med., 20 December 2017
Biological procedures of osteoclast differentiation, bone resorption, and mechanisms of current or future
marrow
hemato
poietic
stem
cells

25. (romosozumab ; blosozumab)
Parathyroid Hormone Related-
Protein, PTHrP) analoge
Stimulate OB (Anticresorptive) Abaloparatide
Calcimitic (tt .hyper-parathroidism)
Calcilytic (
• CaR. agonist/ Alosteric activation →↓PTH release
• CaR. Antagonist→↑PTH ((Anticresorptive))
• Cinacalcet , etelcalcetide.
• No efficacy in trial for osteoporosis
SERMs Stimulate OB ((Anticresorptive) Lasofoxifene, Bazedoxifene

27. Drug (Brand,
Manufacturer)
Treatment of PMO Prevention of
PMO
Treatment
(men)
Treatment of
GIO
Prevention of
GIO
Alendronate x x x x x
Alendronate/cholecalciferol x x
Alendronate effervescent x x
Risedronate IR x x x x x
Risedronate DR x
Ibandronate injection x
Ibandronate tablets x x
Zoledronic acid x x x x x
Denosumab x x
Raloxifene x x
Conjugated estrogens/ bazedoxifene x
Teriparatide x
c
x
Abaloparatide x
Calcitonin-salmon
d
x
Food and Drug Administration-Approved Indications for Osteoporosis Treatments4
aAlso indicated to increase bone mass in women and men at high risk of fracture without osteoporosis.
bTreatment only for those at high risk of fracture.
cIncreases bone mass in men with primary or hypogonadal osteoporosis at high risk of fracture.
dMiacalcin injection (Novartis) is indicated for the treatment of PMO in women more than five years postmenopause when alternative treatments are not suitable.
GIO = glucocorticoid-induced osteoporosis; PMO = postmenopausal osteoporosis.

30. High bone turn over( Paget’s
disease; Multiple myeloma
Fluid & diuretics(Forced diuresis, Loop diuretic)
Oral supplement: bisphosphate or calcitonine
Glucocorticoids,
Dialysis
Hg ,EDTA
excessive Mg
IV: gluconate or chloride with EKG change
Oral calcium with vitamin D

34. Thank you

36. BONE ANABOLIC AGENTS
TERIPARATIDE
BISPHOSPHONATES
ESTROGEN ANALOGES
ANDROGEN ANALOGES
SERMS
CALCITONIN
RANKL INHIBITORS STRONTIUM
TREATMENT OF OSTEOPOROSIS
Replace what is missing….Ca, Vit D, Na fluoride
Reset back the balance of remodeling
ANTIRESORPTIVE AGENTS






Used to enhance the strength by the formation of fluorapatite.
Is considered only when trabecular bone is  in presence of normal cortical bones
Others; Thiazide diuretics, statins

37. Infections; urinary & respiratory
Eczema & skin rash
Constipation
Cataract
Joint pains
DENOSUMAB
Brain Uterus Vagina Breast Bone CVS
Estradiol ++ ++ ++ ++ ++ ++
Raloxifene — — — — + +
Synthetic steroid  estrogen, androgen & progestin properties Can be used without CVS risks
Teriparatide: 1-34 fragment of recombinant PTH - anabolic on the bone
↑ bone mass, structural integrity and strength, number and activity of Obs,
↓ OB apoptosis - acts via G-protein-coupled PTH-1 receptors (AC and PL activation)
-well-tolerated , nausea, dizziness, headache, joint pain, mild hypercalcaemia, orthostatic hypotension, headache might occur
- s.c. injection once a day - Clinical use: osteoporosis; prevention and treatment of pathological fractures

38. Recommended
Dietary
Allowances and
Upper Limits of
Calcium and
Vitamin D

40. a) Cholcalciferot (vit. D3) b) 1. Hydrexy-cholcolciferel
(alcidol)
c) 1.25 is dihydrotychol-
calciferol (calcitril)
*Delayed onset (1week).
* Activated in kidney, liver.
* Long duration (stored in fat).
* Narrow theapeutic range.
* Delayed onset.
*Activated in kidney only.
* Short duration.
* wide therapeutic range.
* Rapide onset (2-4 days).
* Active form.
* short duration.
* wide theropeutic range.
(hper calcaemia, hyperclacuria, wide spread ectopic alcification e.g. kidney)
•Vit. D Preparations: oral administration

41. Table 1. Specialized bone cells involved in the bone remodelling process.

44. Factor control bone remodling OB OC
Intermittent /low concentration PTH ↑ ↓
Vit D low conc./ Ca deficient ↑ ↓
Calcitonin → ↓
Estrogen/ Testosterone (↑OPG) ↑ ↓
Mechanical load →↑ osteocyte ↑ ↓
PTH related protein (PThrP )(OB precursor) ↑ →
FGF(bone marrow; OB; lineage cells) ↑ ↔
PDGF (inflammatory cells) ↑ ↔
TGFB (bone matrix) ↑ ↔
IGF (OB;bone mtrix) ↑ ↔
Ephrin (osteoclast) ↑ ↓
Wnt (wingless-type mouse mammary tumor virus integration site)-
↑ by PgE2 ;NO. ATP (OB)
↑ ↔
Osteoprotegerin (OPG//NO (OB)→↓ RANK-RANKL interaction) → ↓
Bone Morphogenetic Proteins (bone marrow) →↑ OPG → ↑OB ↑ ↔
Osteocalcin→ mineralization (OB );↑insulin secreation ↑ →
Osteonectin (OB) → binds ca →initiating mineralization in
bone and collagen.+ angiogenesis, proliferation and migration
↑ →
Leptin ↑ →
Sema4D (osteoclast) ↓ →
Leukemic inhibitory Factor (bone marrow) ↓ ↑
Receptor activator for nuclear factor κB RANK L.( osteocyte) → ↑
Osteopontin anchor OC to mineralized matrix →bone
remodling
→ ↑
Pg →↑RANKL/↓OPG (osteocyte) ↑ ↔
T3/T4 → ↑
Glucocorticoid (↑RANKl;↓↓ OPG) → ↑↑
IL1,6/TNF/TGFB/M-csf ↓ ↑
Sclerostin (SOS) & DDK(Dickkopf-related protein1) ; sFRP-1
(soluble frizzled-related protein) ; WIF-1 (Wnt-inhibitory factor-1)
(OC) →↓wnt → ↓ wnt (osteocyte)
↓ →
Heparin → ↑
Osteoclast
(Bone resor-
ption cells)
Osteoblast
(Bone forming
cells)
Ostycte
(bone
maintaining)
Function * Synthesize
bone acid
phosphatase
*Secrete type I
collagen, alkaline
phosphatase+ ,
regulate OC
Ca+2
exchange
with
extracellular
fluid;
Stimu-
lated
by
P.T.H.(High
conc./continuous
) ; vit. D ( High
dose) ; cortisone
; T3/T4 ;
IL1,6/TNF /
TGFB ; heparin.,
RANK legend,
PTH (low conc/
intermittent);vit. D
(low conc/↓ Ca in
bone), PGE2, fluride
; IGF ; Estrogen,
testosterone;
mechanical load;
GH , Osteocalcin
Bispho. Na;
PTH
Inhibite
d
by
Calcitonin ,
Estrogen,
testosterone;
PgE2; GH;
mechanical load;
fluoride, OPG;
Bisphos.
RANK legand.
Glucocorticoid;
IL1,6/TNF/TGFB;
cortisone;
Sclerostin (from
osteocyte)
-

45. Daily dietary calcium requirements
National Health and Medical Research Council. (2006) Executive Summary of Nutrient Reference Values for
Australia and New Zealand Including Recommended Dietary Intakes.
Commonwealth Department of Health and Aging, Australia, Ministry of Health, New Zealand.
40 mg = 1 mmol