Metabolic bone diseases

OsteoporosisPart 1Dr. Fathi Neana, MD

Chief of OrthopaedicsDr. Fakhry & Alrajhy Hospital

Saudi ArabiaMarch 7, 2017

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 glucose6- 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 cell8- Assists the movement of sperm to

fertilize the egg

Calcium extra skeletal functionsonly 1 percent of the calcium in the body is found outside the

boneThis form of calcium is critical for many functions in the body

Calcium extra

skeletal functions

Calcium HomeostasisCalcium - Vit D – PTH – Calcitonin

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

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 tissue3- Other factors like, (Growth factors –Hormones - Cytokines)

Bone remodeling is well balanced otherwise pathological problems may occur

Bone remodeling & metabolismBone 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)

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.

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

Macrophage of the universe

Black holes

Black hole of the bodyMacrophage

رب ه الل فسبحان لفسدتا ه الل ا ل إ� آلهة فيهما كان لويصفون ا عم العرش

الأنبياء 22 سورة(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!

Cell Name Anatomical LocationAdipose tissue macrophages

Adipose tissueMonocytes Bone marrow/bloodKupffer cells LiverSinus histiocytes Lymph nodesAlveolar macrophages (dust cells)

Pulmonary alveoli of lungs

Tissue macrophages (histiocytes) leading to giant cells

Connective tissue

Langerhans cells Skin and mucosaMicroglia Central nervous systemHofbauer cells PlacentaIntraglomerular mesangial cells Kidney

Osteoclasts BoneEpithelioid cells GranulomasRed pulp macrophages (Sinusoidallining 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

FunctionsPhagocytosis

Role in adaptive immunityRole in muscle regeneration

Role in wound healingRole in limb regenerationRole in iron homeostasis

Osteoblastsare related to fibroblasts and other connective tissue cells

Osteoclasts are descended from stem cells in the bone marrow that give rise to monocytes (macrophages).

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

HormonesCytokines

Rule of PTH

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

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

Bone RemodelingFormation vs Resorption

(Turnover )

Rate of Turnover

Matrix vs mineral content

Bone Remodeling

Formation

vsResorption

Osteoporosisvs

Osteopetrosis

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]

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

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

Diseases of bone turnover

• High bone turnoverPagets

HyperparathyroidismOsteomalacia and rickets

ThyrotoxicosisHypogonadism

• Low bone turnoverAdynamic bone disease

Hypophosphatasia

Pagets

Diseases of bone turnover

• High bone turnoverPagets

HyperparathyroidismOsteomalacia and rickets

ThyrotoxicosisHypogonadism

• Low bone turnoverAdynamic bone disease

Hypophosphatasia

Hyperparathyroidism

• High bone turnover

Pagets Hyperparathyroidism

Osteomalacia and ricketsThyrotoxicosisHypogonadism

• Low bone turnoverAdynamic bone disease

Hypophosphatasia

Osteomalacia and rickets

Diseases of bone turnover

• High bone turnoverPagets

HyperparathyroidismOsteomalacia and rickets

ThyrotoxicosisHypogonadism

• Low bone turnoverAdynamic bone disease

Hypophosphatasia

Thyrotoxicosis

Diseases of bone turnover

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

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 regionscause extreme bone fragility and severeOsteoporosis•“Brittle bone disease” • Osteogenesis Imperfecta (OI)

Osteogenesis Imperfecta

Blue sclera

Metabolic bone diseasesOsteoporosis

OsteoporosisLow (mineralized bone) mass (Resorption > Formation)

Decreased volume of mineralized bone tissue per unit of bone

Cortical thinning and increased porosityDecreased 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 analysisRadiographs in patients with osteoporosis reveal increased radiolucency of bone (Osteopenia)Osteopenia occurs when bone resorption exceeds bone formation.

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

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 factorsRheumatoid 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

1. Primary osteoporosis Involutional (most common) - osteoporosis in which no underlying cause can be identified.

oType I (postmenopausal)oType II (aging related)oIdiopathicoJuvenileoAdult

2. Secondary osteoporosis - osteoporosis in which there is an underlying cause.

CLASSIFICATIONS OF OSTEOPOROSIS

• GeneralizedCorticalTrabecular

. . Regional (involving one segment of the

skeleton)

• Localizedrheumatoid arthritis

• Bone marrow disease (single multiple focal areas of

osteoporosis)myelomasecondary cancerlymphoma and leukemiaMastocytosis histiocytosis

0.4

0.6

0.8

1.0

1.2

1.4

0 10 20 30 40 50 60 70 800.4

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)

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

FemaleMale

0

500

1000

1500

2000

2500

65- 69 70- 74 75-79 80- 84 85-89

2500

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

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 FemaleBlack American FemaleJapanese Female

Age (years)

Kellie et al, AM J Pub Health 1990; 80:326-328Orimo et al, Osteoporosis 1990: Osteoporosis pp 56-61

: تعالى الله ي يقول ]ن إ رب م]ني )قال العظم اشتعل )و (وهنأس ولم (شيبا الر

ا ) شق]ي رب ]ك ]دعائ ب مريم ( 4أكن سورة)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 سورة الروم - Ar-Room: Verse 54

ذ]ي خلقكم م]ن ضعف ثم جعل م]ن بعد] ه ال الل �ضعف قوة ثم جعل م]ن بعد] قوة ضعفا وشيبة ]يم القد]ير �يخلق ما يشاء وهو العلIt 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)

‘Menopause” VS  ”Andropause”Hormonal changes ( Sex Hormones – Growth hormone etc)

Bone weakness is not alone

Senility

Flamed head(Grey hair)

Bone weaknessThe 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 & floorIllumination

Obstacles & furniture

Exercises (Power + ROM)

Healthy diet – Sunshine

Psychological

ا عندك يبلغن ا لكبرإمتقل فال كالهما أو أحدهماوقل تنهرهما وال أف لهما

كريما ( قوال ) 23لهما اإلسراء

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.

‘Menopause” VS  ”Andropause”Fracture neck femur in the elderly

Elderly >75y Non operative treatment (financial vs medical causes)

1997 Khazna

Treatment

1- Life style(Exercises – Ca, Vit D rich diet)

2- Anti resorptive agents

3- Bone forming agents

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.

OsteoblastsRespond 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

Bone Mass and Activity

80

85

90

95

100

105

110

115

% S

eden

tary

Con

trol

Row Volleyball Basketball Swim Run Weights

Sports

1- Anti resorptive agentsBisphosphonate, Estrogen analogs, Raloxifene SERMs, Calcitonin

2- Bone anabolic agentsTeriparatide (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

The Citric acid cycle - Krebs cycle - TCA cycleBisphosphonate 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

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

1 -Bisphosphonate Interactionsinteract 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 WarningsWarning letter for “overstating the benefits while minimizing the risksFemur FracturesOsteonecrosis of the JawBarrett’s esophagus, dysphagia and gastritis esophageal cancerIncapacitating bone, joint and muscle painsIrregular heartbeatPainful eye disorders that cause inflammation and distorted vision.

3 -Cases Against Fosamax IncreaseCourt 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

Video OPG RANK RANKL pathwaym4a