Osteoporosis is a disease of bone that leads to an increased risk of fracture. In osteoporosis the bone mineral density (BMD) is reduced, bone micro architecture is disrupted, and the amount and variety of proteins in bone is altered. Osteoporosis is defined by the World Health Organization (WHO) in women as a bone mineral density 2.5 standard deviations below peak bone mass (20-year-old healthy female average) as measured by DXA; the term "established osteoporosis" includes the presence of a fragility fracture.

1. Metabolic bone diseases
Osteoporosis
Part 1
Dr. Fathi Neana, MD
Chief of Orthopaedics
Dr. Fakhry & Alrajhy Hospital
Saudi Arabia
March 7, 2017

3. 3
1- Cardiac Dysfunction, Hypertrophy and Failure.
The leading cause of mortality in the developed
world
2- Essential for blood clotting.
3- Stabilizes blood pressure.
4- Contributes to normal brain function.
5- Critical for communicating essential
information among cells.
6- Helps insulin open cells to glucose
6- Chemicals that transmit a signal from a nerve
cell to a target cell
(for example, when a nerve tells a muscle to
move)
7- Facilitates the actual process of contraction of
the muscle cell
8- Assists the movement of sperm to fertilize the
egg
Calcium extra skeletal functions
only 1 percent of the calcium in the body is found outside the bone
This form of calcium is critical for many functions in the body

4. Calcium
extra
skeletal
functions

5. Calcium Homeostasis
Calcium - Vit D – PTH – Calcitonin

6. Figure 1.
Signal transduction by voltage-gated
Ca2+
channels. Ca2+
entering cells initiates
numerous intracellular events, including
contraction, secretion, synaptic
transmission, enzyme regulation,
protein phosphorylation /
dephosphorylation, gene transcription.
(Inset) Subunit structure of voltage-
gated Ca2+
channels. The five-subunit
complex that forms high-voltage-
activated Ca2+
channels is illustrated with
a central pore-forming α1 subunit, a
disulfide-linked glycoprotein dimer of α2
and δ subunits, an intracellular β
subunit, and a transmembrane
glycoprotein γ subunit (in some
Ca2+
channel subtypes). As described in
the text, this model is updated from the
original description of the subunit
structure of skeletal muscle
Ca2+
channels. (Adapted from
Takahashi et al. 1987).
Voltage-Gated Calcium Channels

7. Bone is constantly being remodeled.
Remodeling is triggered and controlled by
1- Need for calcium in the extracellular
fluid
2- As a response to mechanical stresses
on the bone tissue
3- Other factors like, (Growth factors –
Hormones - Cytokines)
Bone remodeling is well balanced otherwise
pathological problems may occur
Bone remodeling & metabolism
Bone may seem to be stable and unchanging
But in fact bone metabolism is a dynamic process that balances bone formation and bone
resorption (Bone remodeling)

8. OPG (Osteoprotegerin) RANKL inhibitor
(estrogen - Prolia)
also known as osteoclastogenesis inhibitory factor(OCIF),
or tumor necrosis factor receptor superfamily member
11B (TNFRSF11B), is a protein that in humans is encoded by
theTNFRSF11B gene.[3]
Osteoprotegerin is a cytokine
receptor, and a member of the tumoro necrosis factor (TNF)
receptor superfamily.
RANK (Receptor activator of nuclear
factor Kappa B
RANKL (Receptor activator of nuclear
factor Kappa B ligand.
(PTH in malignancy)
Osteoprotegerin is a decoy receptor for the receptor
activator of nuclear factor Kappa B ligand. By binding
RANKL, OPG prevents RANK-mediated nuclear factor kappa
B (NF-kB) activation which is a central and rapid acting
transcription factor for immune-related genes, and a key
regulator of inflammation, innate immunity, and cell survival
and differentiation
Abbreviations
The ratio of OPG:RANKL produced by
osteoblasts
will determine the extent of bone
resorption.

9. What is the Osteoclast
(Calcium - Vit D – PTH – Calcitonin) -> Osteoblast

10. Macrophage of the
universe
Black holes
Black hole of the body
Macrophage
‫ا اا ا‬‫ا ا‬‫ا اا ا‬‫ا ا‬‫ا ا‬‫ا اا ا‬‫ا اا ا‬‫ا اا ا‬ ‫ا اا ا‬‫ا اا ا‬‫ا اا اا ا‬‫ا ا‬‫ا ا‬‫ا اا اا ا‬‫ا ا‬ ‫ا ا‬‫ا اا ا‬‫ا ا‬
‫ا ا‬‫ا اا ا‬‫ا ا‬‫ا اا اا ا‬ ‫ا ا‬‫ا اا اا ا‬‫ا اا ا‬‫ا اا ا‬‫ا اا ا‬‫ا ا‬‫ا ا‬‫ا اا ا‬‫ا اا ا‬‫ا اا ا‬‫ا اا ا‬‫ا اا ا‬‫ا ا‬ ‫ا ا‬‫ا اا ا‬‫ا ا‬‫ا اا اا ا‬
‫ا اا اا ا‬‫ا اا ا‬‫ا اا ا‬‫ا ا‬‫ا اا ا‬‫ا ا‬‫ا اا ا‬‫ا ا‬ ‫ا ا‬‫ا اا ا‬‫ا اا ا‬‫ا اا ا‬‫ا اا ا‬ ‫ا ا‬‫ا ا‬‫ا اا ا‬‫ا ا‬
22 ‫ا اا اا اا اا اا اا اا ا‬ ‫ا اا اا اا ا‬
(22) If there were, in the heavens
and the earth, other gods besides
Allah, there would have been
confusion in both! but glory to Allah,
the Lord of the Throne: (High is He)
above what they attribute to Him!

11. Cell Name Anatomical Location
Adipose tissue macrophages Adipose tissue
Monocytes Bone marrow/blood
Kupffer cells Liver
Sinus histiocytes Lymph nodes
Alveolar macrophages (dust
cells)
Pulmonary alveoli of lungs
Tissue macrophages
(histiocytes) leading to
giant cells
Connective tissue
Langerhans cells Skin and mucosa
Microglia Central nervous system
Hofbauer cells Placenta
Intraglomerular mesangial
cells
Kidney
Osteoclasts Bone
Epithelioid cells Granulomas
Red pulp
macrophages (Sinusoidallini
ng cells)
Red pulp of spleen
Peritoneal macrophages Peritoneal cavity
LysoMac [33]
Peyer's patch
Each type of macrophage, determined by
its location, has a specific name
fixed macrophages, stay at strategic
locations such as the lungs, liver, neural
tissue, one, spleen and connective tissue,
ingesting foreign materials
and recruiting additional macrophages if
needed
Functions
Phagocytosis
Role in adaptive immunity
Role in muscle regeneration
Role in wound healing
Role in limb regeneration
Role in iron homeostasis

13. Osteoblasts
are related to fibroblasts
and other connective tissue
cells
Osteoclasts
are descended from stem
cells in the bone marrow
that give rise to monocytes
(macrophages).

15. The Osteoblast
is the gait through which most Osteoclastic activity & bone remodeling is
controlled
(The ratio of OPG : RANKL will determine the extent of bone resorption)
Estrogen vs PTH (in diseases as in PT adenoma – bone malignancy)
Bone remodeling is
triggered and controlled
by
1- Need for calcium in the
extracellular fluid
2- As a response to
mechanical stresses on the
bone tissue.
3- Other factors like,
Growth factors
Hormones
Cytokines

16. Rule of PTH

17. OPG (Osteoprotegerin) production is
stimulated in vivo by the female sex
hormone estrogen,[7
as well as the osteoporosis
drug, strontium. Denosumab is a
pharmacologic agent that in essence acts like
Osteoprotegerin as a decoy receptor for
osteoblastic RANKL.
Rule of Oestrogen

18. Metabolic Bone Diseases
• Generalized
• Bone turnover
affected
• Not infections
• Not primary bone
neoplastic disease
• Mineralization defect;
Osteomalacia /Rickets
• Low bone mass - mineral content;
Osteoporosis
• High bone mass - mineral content;
Osteopetrosis; Bisphosphonate;
Benign High bone mass, Fluorosis
• High bone turnover;
Pagets; Hyperparathyroidism
• Low bone turnover;
Adynamic disease

19. Bone Remodeling
Formation vs Resorption
(Turnover )
Rate of Turnover
Matrix vs mineral content

20. Bone
Remodeling
Formation
vs
Resorption
Osteoporosis
vs
Osteopetrosis

21. Osteoporosis
is a disease of bone that leads to an
increased risk of fracture. In
osteoporosis the bone mineral
density (BMD) is reduced, bone micro
architecture is disrupted, and the
amount and variety of proteins in
bone is altered. Osteoporosis is
defined by the World Health
Organization (WHO) in women as a
bone mineral density 2.5 standard
deviations below peak bone mass
(20-year-old healthy female average)
as measured by DXA; the term
"established osteoporosis" includes
the presence of a fragility
fracture.[1]

22. Osteopetrosis
Albers-Sc honberg Disease, Generalized Congenital
Osteosclerosis, Ivory Bones, Marble Bones,
Osteosclerosis Fragilis Generalisata
Osteopetrosis is a congenital defective Osteoclast
function. Osteoclasts are the cells responsible for bone
resorption. They are necessary for the formation of
bone marrow. In people with Osteopetrosis,
Osteoclasts do not function normally and the cavity for
bone marrow does not form.
This causes bones that appear dense on x-ray and
cannot resist average stressors and therefore break
easily.
The condition is quite rare; incidences have been
reported at 1 in 20,000-500,000 for the dominant form
and 1 in 200,000 for the recessive form

24. Bone Remodeling
Rate of Turnover
Bone turnover is a term used
to describe the rate of bone
formation and resorption
Bone resorption is coupled to
bone formation
During growth, turnover
high, formation> resorption,
net bone gain
During adulthood, turnover
moderate, formation<
resorption, net bone loss

25. Diseases of bone turnover
• High bone turnover
Pagets
Hyperparathyroidism
Osteomalacia and rickets
Thyrotoxicosis
Hypogonadism
• Low bone turnover
Adynamic bone disease
Hypophosphatasia
Pagets

27. Diseases of bone turnover
• High bone turnover
Pagets
Hyperparathyroidism
Osteomalacia and rickets
Thyrotoxicosis
Hypogonadism
• Low bone turnover
Adynamic bone disease
Hypophosphatasia
Hyperparathyroidism

28. • High bone turnover
Pagets
Hyperparathyroidism
Osteomalacia and rickets
Thyrotoxicosis
Hypogonadism
• Low bone turnover
Adynamic bone disease
Hypophosphatasia
Osteomalacia and rickets
Diseases of bone turnover

29. • High bone turnover
Pagets
Hyperparathyroidism
Osteomalacia and rickets
Thyrotoxicosis
Hypogonadism
• Low bone turnover
Adynamic bone disease
Hypophosphatasia
Thyrotoxicosis
Diseases of bone turnover

30. Bone Remodeling
Matrix vs mineral
content
Osteogenesis
Imperfecta
(OI)
is a group of genetic
diseases of collagen in
which the bones are
formed improperly,
making them fragile and
prone to breaking.
Osteogenesis Imperfecta

31. Type I Collagen, Osteogenesis Imperfecta and the Genetics of Osteoporosis
collagen
“blue” eyes in OI
fractures in OI
Collagen is the major protein of bone
• Proteins encoded by COLIA1 and
COLIA2 genes
• Collagen genes produce alpha 1 and
alpha 2 chains
• Chains assemble to form collagen fibres
Mutations in collagen coding regions
cause extreme bone fragility and severe
Osteoporosis
•“Brittle bone disease”
• Osteogenesis Imperfecta (OI)
Osteogenesis Imperfecta
Blue sclera

32. Metabolic bone diseases
Osteoporosis

33. Osteoporosis
Low (mineralized bone) mass (Resorption > Formation)
Decreased volume of mineralized bone tissue per unit
of bone
Cortical thinning and increased porosity
Decreased number and thickness of trabeculae
Decreased bone strength Increased risk of fracture
Osteoporosis is one of the most devastating disorders associated with aging.
Osteoporosis-related fractures result in significant morbidity and mortality.
Characterized by qualitatively normal but quantitatively deficient bone.
Generalized decrease in bone mass is seen.
Bone is normal structurally as determined by histological and chemical analysis
Radiographs in patients with osteoporosis reveal increased radiolucency of bone
(Osteopenia)
Osteopenia occurs when bone resorption exceeds bone formation.

34. "Micro architectural deterioration" refers to the thinning of the
trabeculae and the loss of intertrabecular connections in bone

35. Osteoporosis Risk
factors
• Age-related
• Hypogonadism: estrogen
&testosterone
• Calcium deficiency and
insufficiency
• Vitamin D deficiency and
insufficiency
• Corticosteroid Treatment and
Cushing’s Disease
• Immobilization
• Antiepileptic Drugs
• Myeloma
• Thyrotoxicosis
• Idiopathic
• Osteogenesis Imperfecta:
COLA1,A2
• Phosphate Deficiency
• Homocystinuria: cystathionine
synthase
• Heparin
• Pseudoganglioma syndrome:
LRP 5
Major risk factors
-Age > 65 years
-Systemic glucocorticoid therapy of >3
months duration
-Mal-absorption syndrome
-Primary hyper parathyroidism
-Propensity to fall
-Osteopenia apparent on X-ray film
-Hypo-gonadism
-Early menopause (before age 45)
-Family history of osteoporotic fracture
(especially maternal hip fracture)
Minor risk factors
Rheumatoid arthritis
- Past history of clinical hyperthyroidism
- Chronic anticonvulsant therapy
- Low dietary calcium intake
- Smoker
- Excessive alcohol intake
- Excessive caffeine intake
- Weight <57 kg
- Weight loss >10% of weight at age 25
- Chronic heparin therapy

36. 1. Primary osteoporosis
Involutional (most common)
- osteoporosis in which no
underlying cause can be
identified.
oType I
(postmenopausal)
oType II (aging related)
oIdiopathic
oJuvenile
oAdult
2. Secondary osteoporosis -
osteoporosis in which there is
an underlying cause.
CLASSIFICATIONS OF OSTEOPOROSIS
• Generalized
Cortical
Trabecular
. . Regional
(involving one segment of the
skeleton)
• Localized
rheumatoid arthritis
• Bone marrow disease
(single multiple focal areas of
osteoporosis)
myeloma
secondary cancer
lymphoma and leukemia
Mastocytosis histiocytosis

37. 0.4
0.6
0.8
1.0
1.2
1.4
0 10 20 30 40 50 60 70 80
0.4
0.6
0.8
1.0
1.2
1.4
0 10 20 30 40 50 60 70 80
BMD, g/cm2
0.4
0.6
0.8
1.0
1.2
1.4
0 10 20 30 40 50 60 70 80
Age
TOTAL BODY FEMORAL NECK LUMBAR SPINE
Change in BMD (mean ± 1SD) with age in
healthy male (--) and female (--)(DPX, Lunar)

38. 0.50
0.60
0.70
0.80
0.90
1.00
1.10
1.20
55-59 60-64 65-69 70-74 75-79 80-84 85-89
Female
Male
0
500
1000
1500
2000
2500
65-69 70- 74 75-79 80- 84 85- 89
250
0
0
500
1000
1500
2000
Femoral Neck BMD and Hip Fracture
Age (years)
BMD, g/cm2
Fractures/100,000/year
Kellie et al, AM J Pub Health 1990; 80:326

39. Hip Fractures/100,000/year
0
500
1000
1500
2000
2500
3000
3500
65-69 70-74 75-79 80-84 85-89 90-94 95-99
White American Female
Black American Female
Japanese Female
Age (years)
Kellie et al, AM J Pub Health 1990; 80:326-328
Orimo et al, Osteoporosis 1990: Osteoporosis pp 56-61

43. )()(
4(
(4) Praying: "O my Lord! infirm indeed are my bones, and the hair of my head doth glisten
with grey: but never am I unblest, O my Lord, in my prayer to Thee!
Chapter 30 The Romans ‫ةةةة‬
‫ةةةةة‬ - Ar-Room: Verse 54
‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬ ‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬ ‫فف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬ ‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫فف‬
‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬ ‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬ ‫ف‬‫ف‬‫ف‬‫ف‬ ‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬ ‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬
‫فف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬ ‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬ ‫ف‬‫ف‬‫ف‬‫ف‬ ‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬ ‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬
‫ف‬‫ف‬‫ف‬‫فف‬‫ف‬‫ف‬‫ف‬‫فف‬‫ف‬ ‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬ ‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬
‫ف‬‫ف‬‫فف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬ ‫ف‬‫ف‬‫فف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬ ‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬‫ف‬
It is Allah Who created you in a state
of (helpless) weakness, then gave
(you) strength after weakness, then,
after strength, gave (you weakness
and a hoary head: He creates as He
wills, and it is He Who has all
knowledge and power
(Senility - Flamed head - Bone weakness -
General weakness)

44. ‘Menopause” VS ”Andropause”
Hormonal changes ( Sex Hormones – Growth hormone etc)
Bone weakness is not alone
Senility
Flamed head
(Grey hair)
Bone weakness
The strongest tissue weakened
General weakness
(All systems – skin -
Musculoskeletal –
Neuromuscular – CV - Renal –
Respiratory – Psychological -
Coordination – Balance -
Vision – Hearing – Reactions
etc)
Special care is needed
Slippery stairs & floor
Illumination
Obstacles & furniture
Exercises (Power + ROM)
Healthy diet – Sunshine
Psychological
23

45. Hype about hip fractures?
Not a myth but exaggeration of a fact to pay attention
Published in The New York Times, May 10, 2010,
Company With Osteoporosis Treatment Wins the ‘Super Bowl’ By LORA KOLODNY
Courtesy of McCombs School of Business, Texas Venture Labs
Biologics MD team competing at Global Moot Corp.

46. ‘Menopause” VS ”Andropause”
Fracture neck femur in the elderly
Elderly >75y
Non operative treatment (financial vs medical causes)

51. 1997 Khazna

55. Treatment
1- Life style
(Exercises – Ca, Vit D rich diet)
2- Anti resorptive agents
3- Bone forming agents

56. Treatment
Life style
Nutrition
Calcium, Vitamin D
Exercises
It acts like parathyroid hormone small doses by
stimulating Osteoblasts
(Ratio of OPG > RANKL)
Exercise with its anabolic effect, may at the
same time stop or reverse osteoporosis.

57. Osteoblasts
Respond well to increased stresses on bones
Weight bearing activities stimulate
Osteoblasts
Walk vs. Brisk Walk 4-6 hours a week
1- Cardiovascular function
2- D.M. Reduce insulin resistance
3- Fracture incidence less by 65%
4- Even reduce cancer by 18%
5- Metabolic Syndrome if combined
with intermittent fasting (IF)
WT bearing is the best
Antiresorptive bone forming agent

58. Bone Mass and Activity
80
85
90
95
100
105
110
115
%SedentaryControl
Row Volleyball Basketball Swim Run Weights
Sports

59. 1- Anti resorptive agents
Bisphosphonate, Estrogen analogs, Raloxifene SERMs, Calcitonin
2- Bone anabolic agents
Teriparatide (Forteo, recombinant PTH)
Calcium salts, Sodium fluoride
3- Other agents (RANKL inhibitors)
1- Denosumab (marketed as Prolia®) was approved for the treatment
of osteoporosis in June 2010 fully human monoclonal antobody that
mimics the activity of OPG (osyeoprotegerin).
2- Strontium ranelate (Protelos) Oral strontium ranelate is an
alternative oral treatment, belonging to a class of drugs called "dual
action bone agents" (DABAs)
Treatment
Medicines

60. The Citric acid cycle - Krebs cycle - TCA cycle
Bisphosphonate and Statin block Mevalonic acid pathway
The citric acid cycle is a key metabolic pathway that unifies
carbohydrate, fat, and protein metabolism. The reactions of the
cycle are carried out by 8 enzymes that completely oxidize acetate,
in the form of Acetyl CoA
BISPHOSPHANATE

61. Bisphosphonates (drugs such as Fosamax, Actonel, and Boniva) .
Like statins
They block very important metabolic pathways (Mevalonate pathway)
Nitrogenous Bisphosphonates begin their action on bone metabolism by blocking the enzyme farnesyl
diphosphate synthase (FPPS) which is involved in the mevalonate pathway (also called the HMG-CoA reductase
pathway). Statins disrupt the mevalonate pathway to stop cholesterol synthesis, they do not bind to bone
surfaces.
Bisphosphonates inhibited steps of the mevalonate pathway result
in Osteoclasts that lack a ruffled border and are therefore unable
to resorb bone.
They are “potent inhibitors of FPPS” which catalyzes the synthesis
of farnesyl disphosphate (FPP), an important precursor of sterols,
dolichols, ubiquinones, and prenylated proteins
Benefits of CoQ10 ranging from positive results on cardiac health and endurance training, cancer, diabetes,
periodontal disease, and neurological conditions
A higher risk of developing atrial fibrillation (irregular and rapid heartbeat) is a possible side effect of
Bisphosphonates – and low levels of CoQ10 caused by the drugs.
The highest concentrations of CoQ10 in the body are found in organs that require the most energy to function
properly such as the heart, the lungs, the kidneys, and the liver. Unfortunately, normal ubiquinone production
decreases with age.
Foods rich in ubiquinone – mainly fish, fish oils, organ meats and whole grains

62. 1-Bisphosphonate Interactions
interact with several common medications. Some make the drug less effective, while others can
increase the risk of side effects. These include:
•Aspirin and NSAIDs drugs (ibuprofen, naproxen and anaprox): causes increased stomach
irritation.
•Iron supplements and magnesium products: prevents absorption.
•Antacids: makes it less effective.
2- FDA Recalls and Warnings
Warning letter for “overstating the benefits while minimizing the risks
Femur Fractures
Osteonecrosis of the Jaw
Barrett’s esophagus, dysphagia and gastritis esophageal cancer
Incapacitating bone, joint and muscle pains
Irregular heartbeat
Painful eye disorders that cause inflammation and distorted vision.
3-Cases Against Fosamax Increase
Court cases against Merck began in 2004 once research proved that Fosamax causes Osteonecrosis
of the jaw. Patients with side effects such as femur fractures, Dead Jaw Syndrome, esophagus
problems and musculoskeletal pain have filed lawsuits against Merck. Thousands of patients have
filed in a multidistrict litigation (MDL) in New York and New Jersey. With MDL cases, pre-trial
proceedings are heard together; however, each case has a separate trial
Bisphosphonate side effects

63. Video OPG RANK RANKL pathwaym4a