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Metabolic Bone Diseases Current Concept
 

Metabolic Bone Diseases Current Concept

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Vitamin D, PTH, Bisphosphonate, RANK, Osteoprotegrin, osteoporosis, osteocytes, osteoclasts, space age disease,

Vitamin D, PTH, Bisphosphonate, RANK, Osteoprotegrin, osteoporosis, osteocytes, osteoclasts, space age disease,

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  • more infrmative ,in detail,no need for further book reading on this topic
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  • 2012 Annual Meeting News
    Tuesday through Friday, February 7 – 10, 2012.
    http://www.aaos.org/news/acadnews/2012/AAOS3_2_7.asp
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  • Both Estrogen (E) and testosterone (T) are key regulators of skeletal growth and maturation, and E, together with GH and IGF-I, initiate a 3- to 4-yr pubertal growth spurt that doubles skeletal mass.

    Although E is required for the attainment of maximal peak bone mass in both sexes, the additional action of T on stimulating periosteal apposition accounts for the larger size and thicker cortices of the adult male skeleton.

    Aging women undergo two phases of bone loss, whereas aging men undergo only one.

    In women, the menopause initiates an accelerated phase of predominantly cancellous bone loss that declines rapidly over 4-8 yr to become asymptotic with a subsequent slow phase that continues indefinitely. The accelerated phase results from the loss of the direct restraining effects of E on bone turnover, an action mediated by E receptors in both osteoblasts and osteoclasts. In the ensuing slow phase, the rate of cancellous bone loss is reduced, but the rate of cortical bone loss is unchanged or increased. This phase is mediated largely by secondary hyperparathyroidism that results from the loss of E actions on extraskeletal calcium metabolism. The resultant external calcium losses increase the level of dietary calcium intake that is required to maintain bone balance. Impaired osteoblast function due to E deficiency, aging, or both also contributes to the slow phase of bone loss. Although both serum bioavailable (Bio) E and Bio T decline in aging men, Bio E is the major predictor of their bone loss. Thus, both sex steroids are important for developing peak bone mass, but E deficiency is the major determinant of age-related bone loss in both sexes.

    Endocr Rev. 2002 Jun;23(3):279-302. : Sex steroids and the construction and conservation of the adult skeleton. : Riggs BL, Khosla S, Melton LJ 3rd.
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    Metabolic Bone Diseases Current Concept Metabolic Bone Diseases Current Concept Presentation Transcript

    • Metabolic Bone Diseases Vinod Naneria Consultant orthopaedic surgeon Choithram Hospital & Research Centre Indore , India
    • Skeleton • Structural integrity + strength to body • Protect vital organs • Blood cell formation • Storage of essential minerals, calcium, phosphate, magnesium, and sodium. • Largest organ systems in the body. • 10% cardiac out-put. • Frequent site for deposition of abnormal cells. 1 – 2 kg calcium, 1 kg phosphates
    • Skeleton • Maximum strength with minimal minerals • Metabolically very active organ. • Trabecular bone is > cortical. • Remodelling increases with age. • 25% cancellous & 3% cortical bone / annum • 50% of trabecular & 30% of cortical bone in lifetime in female • 18% of total skeleton deposited or removed/year.
    • Without minerals Without Collagen
    • Osteocytes • Osteocytes - terminally differentiated bone-forming long lived most abundant cells in bone. • Stimulated by calcitonin; inhibited by PTH • Osteocytes- actively involved in bone turnover; • Osteocyte network is through its large cell-matrix contact surface involved in ion exchange; • Osteocytes are the mechanosensory cells of bone, play a pivotal role in functional adaptation of bone. • Periosteocytic space filled with Extracellular fluid. • Sensation of mechanical load is perceived as fluid shear stress on bone surface. • apoptosis of osteocytes may generate signals that activate osteoclast resorption
    • •Periosteocytic space filled with Extracellular fluid. •Sensation of mechanical load is perceived as fluid shear stress on bone surface. •Apoptosis of osteocytes may generate signals that activate osteoclast resorption Osteocyte with Cytoplasmic Extensions
    • Osteoblasts • Synthesize organic components of matrix (collagen type I, proteoglycans, glycoproteins.) • Collagen forms osteoids: strands of spiral fibers that form matrix • Influence deposit of Ca++, PO4. • Active vs inactive osteoblasts • Estrogen, PTH stimulate activity • Mesenchymal linage
    • Osteoclasts • Derived from monocytes; engulf bony material • Active osteoblasts stimulate osteoclast activity • Large, branched, motile cells • Secrete enzymes that digest matrix • Heamopiotic linage.
    • Osteogenic cells
    • Bone Resorption
    • Importance • Past : Deficiency disease • Present : Disabling disease • Future : Space age disease
    • Metabolic Bone Diseases • Mineralization; osteomalacia/rickets • Low bone mineral content; osteoporoses; OI • High bone mineral content; osteopetrosis; bisphosphonate; benign high bone mass • High bone turnover; pagets; hyperparathyroidism • Low bone turnover; adynamic disease
    • Defect • Osteoblasts - PTH, Estrogen • Osteoclast - Estrogen, anti resorptive agents(Bisphosphonate), • Mineralization - Calcium, Phosphorus, Fluorine, Magnesium, Lithium, heavy metals. Vitamin D + Calcitonin • Remodelling - Osteoporosis, Osteopetrosis, Paget’s disease • Type 1 collagen - Hereditary- OI, Mucopolysacharoidosis
    • Key-words • Osteocytes - Mechano-sensor • Osteoblasts - Bone forming • Osteoclast - Bone absorbing • Mineralization - Calcium, phosphate • Osteoid - Type 1 collagen • Remodelling - BMU
    • Key-players • Calcium & Phosphates • Parathyroid hormone (PTH). • Cholecalciferol and Calcitriol (Vit.D3). • Estrogen and other Sex hormones. • SERMs - Reloxiphen, Phyto-estrogen • Calcitonin. • Bisphosphonate ( anti resorptive agents)
    • Target Organs Kidney G.I.Tract Bone
    • Army Recruitment Osteoblasts Osteoclasts
    • Battle field BMU‘S Bone Metabolic Unit Bone multi-cellular Unit • Bone turn-over is tightly coupled with osteoclast mediated bone resorption followed by osteoblast stimulated bone formation. • This delicate balance in bone remodelling results in no net change in skeletal mass. • Basic Six steps are responsible for remodelling
    • BMU- steps • Activation: Osteoclasts • Resorption: Bone matrix • Reversal: pre-osteoblasts • Formation: osteoid formation • Mineralization: • Quiescence Blue – the lining resting cell layer, Red – newly deposited osteoid, Green- mineralized bone, Dark green – old mature bone.
    • Remodelling
    • BMU One BMU lasts about 11 seconds and represents about 6 months of real time. A micro-crack starts the process, the osteocytes sense damage and send signals into the marrow space. Preosteoclasts turn into multi-nucleated osteoclasts and start resorption, meanwhile preosteoblasts turn into osteoblasts and start forming osteoid (orange) which then mineralizes (green). One remodeling cycle takes between about 3 and 6 months, and approximately 10% to 20% of the cancellous bone surface at any one time will be undergoing some stage of bone remodeling.
    • Calcium • Human body is very sensitive to “Calcium” • Cardiovascular and Nervous systems need calcium for – Conductivity contractility irritability • 99% stored in bones
    • • The irritability and conductivity of nerve and the irritability and contractility of smooth and skeletal muscle are inversely proportional to the concentration of Ca. • The irritability and contractility of cardiac muscle are directly proportional to the concentration of Ca. • When the serum calcium concentration is low, the patient becomes hypertonic and hyper-reflexic, convulses, and dies in diastole. • When the serum Ca is elevated, the reverse is seen - that is, there is hypotonicity, hyporeflexia, obtundation, and coma, and death occurs in systole.
    • Calcium cannot cross a cell barrier without a transport system. The first and principal of these components is 1,25- dihydroxyvitamin D, which acts to enhance the mRNA to increase synthesis of one or several calcium-binding proteins (calbindin or cholecalcin), which transport the calcium across the cell barrier to the extracellular space. A second component is the cytosolic concentration of phosphate, which, if above a critical level, may “turn off” transport. A third, less important, component is parathyroid hormone, which enhances the production of 1,25-dihydroxyvitamin D in the kidneys. The parathyroid hormone molecule binds to a receptor on the cell membrane and, through the action of adenyl cyclase and cyclic adenosine monophosphate, the hormone enhances the entry of calcium into the cell and may also activate the release of calcium by the mitochondria.
    • • Calcium stored – Hydroxyapatite Ca((PO4)6(OH)2 • A small proportion is in circulation • To maintain the critical level of calcium in blood -- Hormones like – Parathyroid, Vit.-D Calcitonin, Sex steroids, Thyroid & Glucocorticoid.. • Disorders of key-players will cause a metabolic bone disease.
    • Calcium metabolism • PTH and calcitonin • Vitamin D • Calcium absorption defects: – ↓ Dietary intake – ↑ Renal excretion – Calcium substitution by fluorine.
    • Osteomalacia • Reduced mineralization of bone matrix due to calcium deficiency. Calcium deficiency Osteomalacia results when the osteoid does not have mineral.
    • Vitamin D The active hormone is 1,25(OH)2D3 responsible for the absorption of calcium from gut. Probably it acts indirectly by increasing serum calcium level thus reducing the effect of PTH on bone. Synthesized in Skin + Liver + Kidney
    • Vitamin D- calcitriol Physiologic and Pharmaco-dynamic Effects • Bone -- will increase bone resorption, thus increasing the loss of bone calcium and phosphorus to the serum. • Kidney -- increases calcium and phosphorus reabsorption passively, by decreasing their secretion. • Intestine -- will increase the intestinal absorption of dietary calcium and phosphorus. • The net effect of the calcitriol form of vitamin D is to increase serum levels of both calcium and phosphorus. • Involved with PTH release, insulin secretion, cytokine production, and cell proliferation.
    • The actions of 1,25-dihydroxyvitamin D are somewhat broader than simply stimulation of calcium-binding proteins; they include activities that have an effect on osteocalcin production, osteoclastic resorption, monocytic maturation, myelocytic differentiation, skin growth, and insulin secretion.
    • Vitamin D analog • 25-dihydrovitamin D (calcifediol) • Secalcifediol – 24,25-dihydroxyvitamin D • Paricalcitol • Dihydrotachysterol (DHT) • Calcipotriene (calcipotriol) • Ergocalciferol • Calcitriol -- the 1,25 dihydroxyvitamin D
    • Vitamin D • Vitamin D Deficiency • Impaired 25 OH Vitamin D production • Impaired 1,25 OH2 Vitamin D production • Defective Vitamin D receptor
    • Vitamin D Deficiency • Environmental housebound; frail elderly; immigrant from low to high latitude; gastrectomy; malabsorption • Genetic dark skin pigmentation • Biochemistry D low; 25D low; 1,25D low to normal ; Ca low; PTH high; Alk Ph high; P low
    • Impaired 25D production • Environmental hepatic failure; drugs affecting CYP liver enzymes • Genetic mutations in 25Dhydroxylase: not described • Biochemistry D normal; 25D low; 1,25 D low to normal; Ca low; PTH high; Alk ph high; P low
    • Impaired 1,25 D production • Environmental chronic renal failure • Genetic mutations in 25D 1 alpha hydroxylase (D dependent rickets type 1) • Biochemistry D normal; 25D normal; 1,25D low; Ca low; PTH high; Alk Ph high; P high in CRF and low in D dependent rickets
    • Defective D receptor (VDR) • Environmental non described • Genetic mutations in VDR ( D dependent rickets type 2) • Biochemistry D normal; 25D normal; 1,25D high; Ca low; PTH high; Alk Ph high; P low
    • Deficiency of Vit. D • Dietary lack of the vitamin • Insufficient ultraviolet skin exposure • Malabsorption of fats and fat-soluble vitamins- A, D, E, & K. • Abnormal metabolism of vitamin D chronic renal failure. Disease of Affluent class
    • Vitamin D Resistant Rickets • In the renal tubular disorders, rickets and osteomalacia develop in the presence of normal intestinal function and are not cured by normal doses of vitamin D. • Resistant or refractory rickets. Defective final conversion of Vit. D in to active form.
    • Effect at growth end plate • Inadequate growth plate mineralization. • Defective calcification in the interstitial regions of the hypertrophic zone. • The growth plate increases in thickness. • The columns of cartilage cells are disorganized. • Cupping of the epiphyses. • Bones incapable of withstanding mechanical stresses and lead to bowing deformities. • Eventual length of the long bones is diminished. ( short stature) •
    • Genu valgus Tri radiate pelvis Wrist widening Wrist cupping Looser’s zones Wide metaphysis
    • Phosphate • Environmental dietary phosphate depletion; prematurity in neonates; mesenchymal tumors; renal tubule disease • Genetic mutations in PHEX; mutations in FGF
    • The principal control mechanism for phosphate is renal, in that there is not only a tubular maximum (and hence a so-called spill) and tubular secretion but a very finely tuned tubular reabsorption mechanism for phosphate. This mechanism is affected by a number of factors but is principally under the control of parathyroid hormones. Thus, conditions such as rickets, osteomalacia, or renal osteodystrophy, which cause an increase in parathyroid hormone release (principally in response to a lowered Caı concentration), cause a simultaneous decline in the percentage of tubular resorption of phosphate and a resultant hyperphosphatunia and hypophosphatemia’. Such a mechanism is clearly protective since, if both the ionic calcium and the phosphate concentrations rise, we are dangerously close to turning to stone!
    • Phosphate: Fanconi Syndrome • Disease of the renal tubule can be genetic or acquired • Biochemistry P low; TmP low; aminoaciduria; glycosuria; Ca normal; PTH normal; Alk Ph normal; D normal; 25D normal; 1,25D normal
    • Renal Osteodystrophy • Kidney - homeostasis of Ca, PO4 and metabolism of vitamin D • CKD  disturbances in this homeostasis  abnormalities of PTH and vitamin D systems • A spectrum of bone disorders: – Osteitis Fibrosa – Osteomalacia – Mixed Osteodystrophy – Adynamic Bone Disease – Cystic Disease (occurs in DRA)
    • Renal bone disease • Osteitis fibrosa cystica • ↓ GRF. • ↑ Phosphate excretion •  serum phosphate - ↓ serum Ca. •  turn over of bone → Secondary Hyper Parathyroidism • Osteomalacia •  Demineralized bone ( osteoid) •  Aluminum deposition • ↓ Vitamin D active metabolites
    • Adynamic Bone Disease • Profound  in number of active remodelling sites  in number of osteoblasts and osteoclasts  bone formation and mineralization • Bone structure predominantly lamellar  mineralizing surfaces • Reduced trabecular bone formation and resorption • Unlike osteomalacia – no increase in osteoid formation or unmineralised bone • The relationship between osteoid seam thickness and adjusted apposition rate is normal - osteoid seam thickness not increased
    • Adynamic Bone Disease • Low PTH levels (state of relative hypoparathyroidism) • More common in older patients • Patients with DM • Patients on PD • Overtreatment with vit D, aluminum intoxication, steroids, low sexual and thyroid hormone levels • ?cytokines and other related factors • Originally associated with excess aluminum • Emergence of idiopathic of ABD unrelated to aluminum in dialysis patients.
    • Renal Osteodystrophy • Adynamic Bone disease: – → Peritoneal + Hemodialysis patients. – ↓ Bone turn over. – ↑ Osteoid formation. – ↑ Aluminum deposition. – ↓ PTH activity due to use of Vit.D + calcium. – ↓ Vit. K – carboxylation of matrix.
    • Normal Bone Female, age 30 years
    • Moderate Osteoporosis Female, age 88 years
    • architecture in the 3rd lumbar vertebra of a 30 year old woman
    • bone architecture in the 3rd lumbar vertebra of a 71 year old woman
    • extensive pitting and fragility of the bone
    • pitting of the bone ‘stalagmite’
    • Menopausal Osteoporosis • Reduced bone mineral mass • Normal mineral to matrix ratio. Estrogen deficiency The resorption cavities go a little deeper and resorption lasts a little longer, and the bone formation increases but doesn't quite match the higher resorption rate.
    • Estrogen • Estrogen receptors (ERs) in both osteoclasts and osteoblasts. • Two iso-forms of ERs – ER-alpha and ER-beta. – Synthetic estrogens and selective estrogen receptor modulators (SERMs) act on these iso-forms differently and produce different clinical outcomes. Reloxiphen selectively on bone & not on breast
    • Estrogen • In bone cells to regulate the process of programmed cell death, called apoptosis. • Accelerates the death of osteoclasts, while prolonging the life of osteoblasts. • ↑ intestinal absorption of calcium • ↑ reabsorption of calcium from the renal tubule. positive calcium balance.
    • Estrogen effects may be mediated in part by growth factors and interleukins. For example, interleukin 6 is a potent stimulator of bone resorption, and estrogen blocks the osteoblast's synthesis of interleukin 6. Estrogen may also antagonize the interleukin 6 receptors. Estrogen has multiple other effects that relate to the skeleton. For example, enhanced intestinal calcium absorption can be beneficial to bones. Estrogen protects the bone from the resorptive effects of PTH. Estrogens may interact with mechanical forces to build bone. There are different effects on the endocortical surfaces and the periosteal surfaces that result in different shapes of bones in men compared to women.
    • RELOXIPHEN This movie shows the effect of Raloxifene in women with osteoporosis.
    • Bisphosphonates • Interfere with osteoclast cytoskeleton. • Inhibit mevalonate pathway enzymes. • Decrease protein-tyrosine phosphatases. • Stimulate apoptosis of osteoclasts. • Inhibit osteoclast attachment to bone. • Inhibit proton pump of osteoclasts. Anti osteoclast → Anti resorptive
    • Bisphosphonates • Negative charges on the two phosphate groups of the bisphosphonate nucleus gave these compounds a high affinity for the surface of bone. After binding to mineralized bone surface, they are taken up by osteoclasts during bone resorption. Within these cells, they inhibit the enzyme farnesyl pyrophosphate synthase. This is a key enzyme in the mevalonate pathway, which leads to the synthesis of cholesterol. This ultimately leads to the death of Osteoclast.
    • After the estrogen deficiency in the first 6 months show high turnover; then the little blue diamonds representing a bisphosphonate start to attach to the bone; resorption stops suddenly and formation stops after a few months. The bone continues to become more mineralized (darker), and only a few BMU's are still active.
    • Paget’s Disease • Increase rates of bone turn-over with development of disorganized woven bone. Plicamycin (Mithramycin), • uncontrolled Biphosphonates, Calcitonin osteoclastic bone resorption.
    • Steroid induced bone disease • Osteoblastic activity • ↑ Rate of bone resorption • ↓ BMU • ↑ Hypercalciuria • ↓ Collagen synthesis • ? Secondary hyper parathyroidism
    • Steroid Induced osteoporosis Corticosteroids increase the bone resorption rate and depth, similar to menopause. The steroids block action of osteoblasts, so the bone formation does not increase.
    • Osteopetrosis • Failure of osteoclastic and chondroclastic resorption. • Failure of remodelling Genetic disorder
    • Osteopetrosis • Defiency of carbonic anhydrase in osteoclasts. • Defective hydrogen ion pumping by osteoclasts and this in turn causes defective bone resorption by osteoclasts. • acidic environment is needed for dissociation of calcium hydroxyapatite from bone matrix and its release into blood circulation. • Hence, bone resorption fails while its formation persists. Excessive bone is formed
    • Fluorosis • Abnormal matrix mineralization. • Crystals of fluoroapatite replace calcium phosphate crystals of hydroxyapatite. Endemic in India Iatrogenic fluorosis
    • Fluoride • Mechanism of Action -- In the prevention of dental caries, fluoride stabilises hydroxyapatite crystals. The cellular mechanism of action of fluoride in increasing bone density is not known. However, it is known that fluoride induces osteoblastic mitogenesis. Moreover, it is ineffective unless the patient also takes calcium supplements. • Pharmacodynamic Effect -- Fluoride with calcium supplementation will increase bone mineral density and volume.
    • PTH • Change of shape of osteoblast • ↑ secretion of neutral collagenase by osteoblast cells. • Collagenase digests the protective layer of matrix exposing the bone surface for osteoclastic resorption. PTH is to increase PTH serum calcium and receptors decrease serum only on phosphate levels Osteoblasts
    • PTH on Bone • Bone -- High doses of PTH will increase the number and activity of osteoclasts, resulting in bone resorption (breakdown). This effect may be secondary to PTH-induced stimulation of osteoblasts (bone forming cells) which then stimulates osteoclastic activity. Osteoblast activity resulting from PTH action has been linked with intracellular increases in both cAMP and calcium. Despite the activity of osteoblasts, the net effect of high dose PTH is bone resorption and loss of calcium to the serum. At low doses, PTH may stimulate bone formation (osteoblast action alone) and no calcium is lost.
    • PTH on Kidney • Kidney -- PTH increases calcium and magnesium reabsorption and decreases the reabsorption of phosphate, amino acids, bicarbonate, sodium, chloride, and sulphate. PTH will also cause the formation of the calcitriol form of vitamin D. • Intestine -- PTH increases the absorption of dietary calcium and phosphate. This action is secondary to vitamin D formation and activity. • The net effect of PTH on these systems is to increase serum calcium and decrease serum phosphate levels.
    • PTH in response -> hypocalcemia • mobilize calcium from bone – blood • ↓ renal clearance of calcium • ↑ calcium absorption - intestine Calcium homeostasis
    • Diagram showing the mechanism of the development of the biochemical and osseous findings of primary hyperparathyroidism. PTH = parathyroid hormone. GI gastrointestinal. and TR tubular resorption.
    • Disease of Stone & Bone • Hyper calcemia • Hypo phoshphatemia • Hyper calciuria • High alk.phosphatase level • PTH immune assay • Ultrasosnography of neck.
    • PTH animation
    • Calcitonin • Secreted by Thyroid C cells in response to elevations in circulating calcium concentrations, thus provides a fine tuning of the calcium homeostasis and retain the dietary calcium in skeleton. • Potent inhibitor of osteoclastic activity, & osteoclast generation. • Osteoclast have calcitonin receptors 300,000/ cell. Anti – PTH, Anti – Vit D3
    • Calcitonin • Bone --↓ osteoclastic activity in bone to decrease calcium and phosphate loss into circulation. • Kidney -- ↑ renal loss of calcium and phosphorus by inhibiting their reabsorption. • Other effects -- ↓ gastric acid and gastrin secretion and increases the secretion of sodium, potassium, chloride, and water into the intestine.
    • Bone Markers • To diagnose a metabolic bone disease • To assess the effect of anti-resorptive agents at earliest. • Can be used within 3 – 6 months • BMD assessments takes more than a year.
    • Bone Markers To assess bone formation: • Serum immunoassays for osteocalcin. • Alkaline phosphatase – both types • N-terminal extension peptide (PINP) of type I collagen. To assess bone resorption: • Immunoassays for the type I collagen pyridinoline crosslink and related peptides.
    • FORMATION- Osteoblast RESORPTION- Osteoclast Serum Plasma/Serum Tartrate-resistant acid Osteocalcin phosphatase (Bone GlaProtein) Free pyridinoline and Total and bone specific alkaline deoxypyridinoline phosphatase Type I collagen N and C- Procollagen I carboxy (PICP) telopeptide breakdown products and N-terminal (PINP) extension peptides Urine Pyridinoline and deoxpyridinoline (collagen crosslinks) Bone Markers Type I collagen N and C- telopeptide breakdown products Fasting calcium and hydroxyproline Hydroxylysine glycosides
    • Vitamin –K Bone mineralization • Three vitamin-K dependent proteins have been isolated in bone: osteocalcin, matrix Gla protein (MGP), and protein S. • The synthesis of osteocalcin by osteoblasts is regulated by the active form of vitamin D - 1,25(OH)2D3 . • The mineral-binding capacity of osteocalcin requires vitamin K-dependent gamma-carboxylation of three glutamic acid residues. • MGP prevents the calcification of soft tissue and cartilage, while facilitating normal bone growth and development. • The vitamin K-dependent anticoagulant protein S is synthesized by osteoblasts, • Protein S deficiency suffer complications related to increased blood clotting as well as decreased bone density .
    • Plicamycin (Mithramycin) • antineoplastic antibiotic that decreases protein synthesis. • Its mechanism of action that accounts for efficacy in bone loss is not known, but is presumed to be mediated by decreased protein synthesis. • Pharmacodynamic Effect -- Plicamycin reduces bone resorption, thus increasing bone density. • Therapeutic Uses -- Paget's disease and hypercalcæmia
    • Calcium and Bone Modulators • Biphosphonates • Plicamycin (Mithramycin) • Fluoride Phosphorus Modulators •Aluminium hydroxide •Sevelamer hydrochloride
    • Selected Clinical Aspects of Bone Homeostasis saline diuresis, biphosphonates, calcitonin, gallium nitrate, plicamycin, phosphate, and glucocorticoids. • Hypercalcæmia • Hypocalcæmia calcium supplementation with vitamin D • Hyperphosphotæmia aluminium hydroxide antacids • Rickets & Osteomalasia vitamin D + Calcium supplementation • Chronic Renal Failure phosphate retention, • Paget's Disease ↓vitamin D, ↓free calcium, ↓ calcium absorption, hyperparathyroidism. uncontrolled osteoclastic bone resorption. Bisphosphonate, Calcitonin
    • Summary
    • Space age bone disease • Cosmonauts and astronauts who spent many months on space station Mir revealed that space travelers can lose (on average) 1 to 2 percent of bone mass each month. • 5 – 20% ↓ in bone mineral mass in 6 months. • Journey to Mars is 2 years. • The gravity on the Red Planet is about one half of that found on Earth.
    • Space age bone disease • Weightlessness in “Zero G”. • Minimal mechanical stress on bone. • ↓ numbers of osteoblasts. • Osteoclast number – normal. • NASA projects – hPTH(1-31) as potent osteoblastic agent under extensive study. – Effect of exercises in “Zero G”.
    • Current Thinking • Recent advancement on – Osteoporosis – Co-relation with Coronary disease – Molecular manipulation for osteogenesis – Co-relation with Obesity – Fracture prevention – Space age osteoporosis
    • paracrine communication • paracrine communication, where the products of cells diffuses in the ECF to affect neighboring cells that may be some distance away. • Paracrine system is essential to bone metabolism • Mediators are 1. molecules RANK = receptor activator for nuclear factor kb ,RANK ligand (RANKL) 2. Osteoprotegrin ( OPG)
    • RANK =Receptor activator for nuclear factor kb • RANK is a member of TNF family of receptors expressed mainly on cells of macrophages / monocytes lineage such as preosteoclasts • When this receptor binds its specific ligand (RANKL) through cell- cell contact , osteoclastogenesis is initiated • RANKL is produced by and expressed on the cell membranes of osteoblast & marrow stromal cells • Its major role is stimulation of osteoclast formation , fusion, differentiation, activation , survival
    • ligand –In chemistry, a ligand is either an atom, ion, or molecule (functional group) that binds to a central metal to produce a coordination complex. – The bonding between the metal and ligand generally involves formal donation of one or more of the ligand's electrons. – The metal-ligand bonding ranges from covalent to more ionic. Furthermore, the metal-ligand bond order can range from one to three. Ligands are viewed as Lewis bases, although rare cases are known involving Lewis acidic "ligands."
    • OPG • Osteoprotegrin is a soluble protein member of TNF family • Produced by bone , hematopoetic marrow , immune cells • OPG blocks action of RANKL , inhibits osteoclastogenesis by acting as a decoy receptor that binds to RANKL , thus preventing interaction between RANK & RANKL • Therefore interplay between bone cells & these molecules permits osteoblasts and stromal cells to control osteoclasts development
    • OPG • OPG an important role in vascular biology. In fact, OPG could represent the long sought-after molecular link between arterial calcification and bone resorption, which underlies the clinical coincidence of vascular disease and osteoporosis, which are most prevalent in postmenopausal women and elderly people.
    • Sclerostin • Sclerostin produced by the osteocytes blocks the mineralization at the later stages. • osteocytes main source of sclerostin. • osteocytes play a major role in regulating bone remodeling. • Defects in the SOST gene -absence or reduced production of sclerostin, causes Sclerosteosis and van Buchem diseases, hypertrophic bones which are fracture resistant. • sclerostin binds to LRP5 and antagonizes the Wnt pathway,
    • Osteoclast : target organ • Blocked of RANK ligend by human antibody to RANK ligand, Denosumab • Cathepsin K- deficiency: Picnodisostosis • Corbonic anhydrase deficiency: – Osteopetrosis • RANKL decoy by Osteoprotegrin: ↓ Osteoclastosis. • Over production of RANKL by parathyroid harmones: ↑ osteoclastosis – brown lesions. • Sclerostatin by osteocytes : prevents extra new bone formation.
    • RANK Ligand and Osteoprotegerin. Paracrine Regulators of Bone Metabolism and Vascular Function • Receptor activator of nuclear factor (NF-kappaB) ligand (RANKL), its cellular receptor, receptor activator of NF-kappaB (RANK), and the decoy receptor osteoprotegerin (OPG) constitute a novel cytokine system. RANKL produced by osteoblastic lineage cells and activated T lymphocytes is the essential factor for osteoclast formation, fusion, activation, and survival, thus resulting in bone resorption and bone loss. RANKL activates its specific receptor, RANK located on osteoclasts and dendritic cells, and its signaling cascade involves stimulation of the c-jun, NF-kappaB, and serine/threonine kinase PKB/Akt pathways..
    • • The effects of RANKL are counteracted by OPG which acts as a soluble neutralizing receptor. RANKL and OPG are regulated by various hormones (glucocorticoids, vitamin D, estrogen), cytokines (tumor necrosis factor alpha, interleukins 1, 4, 6, 11, and 17), and various mesenchymal transcription factors (such as cbfa-1, peroxisome proliferator-activated receptor gamma, and Indian hedgehog). Transgenic and knock-out mice with excessive or defective production of RANKL, RANK, and OPG display the extremes of skeletal phenotypes, osteoporosis and osteopetrosis
    • Abnormalities of the RANKL/OPG system have been implicated in the pathogenesis of postmenopausal osteoporosis, rheumatoid arthritis, Paget's disease, periodontal disease, benign and malignant bone tumors, bone metastases, and hypercalcemia of malignancy, while administration of OPG has been demonstrated to prevent or mitigate these disorders in animal models.
    • RANKL and OPG are also important regulators of vascular biology and calcification and of the development of a lactating mammary gland during pregnancy, indicating a crucial role for this system in extraskeletal calcium handling. The discovery and characterization of RANKL, RANK, and OPG and subsequent studies have changed the concepts of bone and calcium metabolism, have led to a detailed understanding of the pathogenesis of metabolic bone diseases, and may form the basis of innovative therapeutic strategies.
    • The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. – The recent identification of the receptor activator of nuclear factor kappaB ligand (RANKL), its cognate receptor RANK, and its decoy receptor osteoprotegerin (OPG) has led to a new molecular perspective on osteoclast biology and bone homeostasis. Specifically, the interaction between RANKL and RANK has been shown to be required for osteoclast differentiation. The third protagonist, OPG, acts as a soluble receptor antagonist for RANKL that prevents it from binding to and activating RANK. Any dysregulation of their respective expression leads to pathological conditions such as bone tumor-associated osteolysis, immune disease, or cardiovascular pathology. In this context, the OPG/RANK/RANKL triad opens novel therapeutic areas in diseases characterized by excessive bone resorption.
    • Role of osteoprotegerin and its ligands and competing receptors in atherosclerotic calcification. Vascular calcification significantly impairs cardiovascular physiology, and its mechanism is under investigation. Many of the same factors that modulate bone osteogenesis, including cytokines, hormones, and lipids, also modulate vascular calcification, acting through many of the same transcription factors. In some cases, such as for lipids and cytokines, the net effect on calcification is positive in the artery wall and negative in bone. The mechanism for this reciprocal relation is not established.
    • • A recent series of reports points to the possibility that two bone regulatory factors, receptor activator of NF-kappaB ligand (RANKL) and its soluble decoy receptor, osteoprotegerin (OPG), govern vascular calcification and may explain the phenomenon. Both RANKL and OPG are widely accepted as the final common pathway for most factors and processes affecting bone resorption. Binding of RANKL to its cognate receptor RANK induces NF-kappaB signaling, which stimulates osteoclastic differentiation in preosteoclasts and induces bone morphogenetic protein (BMP-2) expression in chondrocytes.
    • • A role for RANKL and its receptors in vascular calcification is spported by several findings: a vascular calcification phenotype in mice genetically deficient in OPG; an increase in expression of RANKL, and a decrease in expression of OPG, in calcified arteries; clinical associations between coronary disease and serum OPG and RANKL levels; and RANKL induction of calcification and osteoblastic differentiation in valvular myofibroblasts.
    • Associations between coronary disease and serum OPG and RANKL levels
    • Obesity and Osteoporosis • It has been proposed that increases in adipose tissue, with increasing BMI in postmenopausal women, results in increased estrogen production, osteoclast suppression, and a resultant increase in bone mass. • Obesity has been associated with insulin resistance, characterized by high plasma levels of insulin. High plasma insulin levels may contribute to a variety of abnormalities, including androgen and estrogen overproduction in the ovary, and reduced production of sex hormone-binding globulin by the liver. These changes may result in elevated sex hormone levels, leading to increased bone mass due to reduced osteoclast activity and possibly increased osteoblast activity .
    • Obesity • M/F ratio of Coronary artery disease 4/1 • F/M average age F 3 years > M • Obesity increases Bone mineral mass • Extra production of Estrogen by adipose tissues • Perimenopausal Hypothyroidism ↑ body weight.
    • Fat cell targets for skeletal health • Adipocytes are derived from a mesenchymal precursor stem cell that also gives rise to osteoblasts, chondroblasts, myoblasts, and fibroblasts. An osteoblast can be transformed to an adipocyte if Pparγ2 (peroxisome proliferator-activated receptor γ2) is expressed, while an adipocyte can be converted to an osteoblast if Runx2 is expressed.
    • • Emerging evidence points to a critical role for the skeleton in several homeostatic processes, including energy balance. The connection between fuel utilization and skeletal remodeling begins in the bone marrow with lineage allocation of mesenchymal stem cells to adipocytes or osteoblasts. • Mature bone cells secrete factors that influence insulin sensitivity, and fat cells synthesize cytokines that regulate osteoblast differentiation; thus, these two pathways are closely linked. The emerging importance of the bone–fat interaction suggests that novel molecules could be used as targets to enhance bone formation and possibly prevent fractures.
    • Three pathways that could be pharmacologically targeted for the ultimate goal of enhancing bone mass and reducing osteoporotic fracture risk: the leptin, peroxisome proliferator- activated receptor gamma and osteocalcin pathways. Not surprisingly, because of the complex interactions across homeostatic networks, other pathways will probably be activated by this targeting, which could prove to be beneficial or detrimental for the organism. Hence, a more complete picture of energy utilization and skeletal remodeling will be required to bring any potential agents into the future clinical armamentarium.
    • How is the close pairing of the osteoclast and osteoblast activity regulated? • Osteoblasts regulate osteoclast formation via the RANKL– RANK and the M-CSF–OPG mechanism, but there is no known direct feedback of osteoclasts on osteoblasts. • Instead, the whole bone remodeling process is primarily under endocrine control. • Parathyroid hormone accelerates bone resorption and estrogens slow bone resorption by inhibiting the production of bone-eroding cytokines. • An interesting new observation is that intracerebroventricular but not intravenous leptin decreases bone formation. This finding is consistent with the observations that obesity protects against bone loss and that most obese humans are resistant to the effects of leptin on appetite). Thus, there may be neuroendocrine regulation of bone mass via leptin.
    • Bone Remodeling. The remodeling process of bone comprises the coupled activity of bone resorbing osteoclasts and bone forming osteoblasts. This system is tightly controlled by a number of soluble regulatory factors and through cellular interactions within the bone microenvironment.
    • Resorbed bone is nearly precisely replaced in location and amount by new bone. Bone loss through osteoclast-mediated bone resorption and bone replacement through osteoblast-mediated bone formation are tightly coupled processes. Osteoblasts direct osteoclast differentiation. Key questions remain, however, as to how osteoblasts are recruited to the resorption site and how the amount of bone produced is so precisely controlled. Osteoclasts play a crucial role in the promotion of bone formation. Osteoclast conditioned medium stimulates human mesenchymal stem (hMS) cell migration and differentiation toward the osteoblast lineage as measured by mineralized nodule formation in vitro.
    • Induction of sphingosine kinase 1 (SPHK1), which catalyzes the phosphorylation of sphingosine to form sphingosine 1- phosphate (S1P), in mature multinucleated osteoclasts as compared with preosteoclasts. S1P induces osteoblast precursor recruitment and promotes mature cell survival. Wnt10b and BMP6 also were significantly increased in mature osteoclasts, whereas sclerostin levels decreased during differentiation. Stimulation of hMS cell nodule formation by osteoclast conditioned media was attenuated by the Wnt antagonist Dkk1, a BMP6-neutralizing antibody, and by a S1P antagonist. BMP6 antibodies and the S1P antagonist, but not Dkk1, reduced osteoclast conditioned media-induced hMS chemokinesis..
    • Obesity and Osteoporosis • Extensive epidemiological data show that high body weight or BMI is correlated with high bone mass, and that reductions in body weight may cause bone loss . The basic mechanisms underlying this observed obesity: bone mass correlation remain unclear, though several explanations have been proposed. It is generally accepted that a larger body mass imposes a greater mechanical loading on bone, and that bone mass increases to accommodate the greater load. Further, adipocytes are important sources of estrogen production in postmenopausal women, and estrogen is known to inhibit bone resorption by osteoclasts.
    • Animated summary Of Bone multi-cellular unit
    • DISCLAIMER • Information contained and transmitted by this presentation is based on personal experience and collection of cases at Choithram Hospital & Research centre, Indore, India, during past 30 years. • It is intended for use only by the students of orthopaedic surgery. •Many GIF files are taken from Internet. • Views and opinion expressed in this presentation are personal opinion. • Depending upon the x-rays and clinical presentations viewers can make their own opinion. • For any confusion please contact the sole author for clarification. • Every body is allowed to copy or download and use the material best suited to him. I am not responsible for any controversies arise out of this presentation. • For any correction or suggestion please contact naneria@yahoo.com All animation slides are taken from , Osteoporosis and Bone Physiology” web site, 1999 - 2006 http://courses.washington.edu/bonephys of Dr. Susan Marie Ott, MD. Medical staff of University of Washington Medical Center.
    • Bon Voyage