TREATMENT OF

OSTEOPOROSIS

Prof. Riad Agbaria

Physiology of Calcium

Calcium is essential: In intracellular fluid – micromolecular and macroscopic biological functions.

– Ca2+, is an important of current flow across excitable membranes.

– Ca2+ is vital for muscle contraction – Ca2+ is vital for fusion, and release of storage vesicles.

– intracellular Ca2+ acts as a critical second messenger In extracellular fluid, – promote blood coagulation –

support the formation and continuous remodeling of the skeleton

.

– Cross-linking of structural proteins in bone matrix.

Body content of calcium

In adult men ~1300g and 1000g in women, 99% is in bone and teeth . Normal serum calcium con. 8.5-10.4 mg/dL – ionized (50%), – protein-bound (40%) (Albumin accounts for some 90%) – complexed (10%).

Calcium Stores

The skeleton contains 99% of total body calcium in a crystalline form resembling the mineral hydroxyapatite [Ca10(PO4)6(OH)2]; other ions, including Na+, K+, Mg2+, and F-, also are present in the crystal lattice.

The steady-state content of calcium in bone reflects the net effect of bone resorption and bone formation A labile pool of bone Ca2+ exchanges readily with interstitial fluid. This exchange is modulated by hormones, vitamins, drugs, and other factors that directly alter bone turnover or that influence the Ca2+ level in interstitial fluid.

Calcium Absorption and Excretion

~75% of calcium is from milk and dairy products . The adequate intake is 1300 mg/day in adolescents and 1000 mg/day in adults. After age 50, the adequate intake is 1200 mg/day.

Active vitamin D –dependent Ca2+ enters the body only through the intestine . Active vitamin D duodenum, –dependent transport occurs in the proximal

Efficiency Of Intestinal Ca2+ Absorption a diet low in calcium leads to a compensatory increase in fractional absorption owing partly to activation of vitamin D . Disease associated with diarrhea, BID or chronic malabsorption promote fecal loss of calcium, drugs such as glucocorticoids and phenytoin depress intestinal Ca2+ transport .

Urinary Ca

2+

excretion

About 9 g of Ca2+ are filtered each day.

Tubular reabsorption >98% Reabsorption is regulated by parathyroid hormone (PTH) loop of Henle Diuretics (e.g., furosemide ) increase calcium excretion.

By contrast, thiazide diuretics diminishing calcium excretion

Phosphate

Essential component of all body tissues, present in plasma, extracellular fluid, cell membrane phospholipids , intracellular fluid, collagen, and bone tissue .

> 80% of body phosphorus is in bone , and ~15% is in soft tissue phosphate roles: – energy metabolism – key regulator of enzyme activity when transferred by protein kinases from ATP to phosphorylatable serine, threonine, and tyrosine residues.

Hormonal Regulation Of Calcium And Phosphate Homeostasis

parathyroid hormone (PTH) 1,25-dihydroxy vitamin D (calcitriol),: which regulate mineral homeostasis by effects on: – Kidney – Intestine – bone

Hormonal Interactions Controlling Bone Mineral Homeostasis

FGF23 is a recently discovered hormone that stimulates renal phosphate excretion and inhibits renal production of 1,25(OH

Mechanisms of Bone Mineral Homeostasis 1,25(OH)2D3 (D), Parathyroid hormone (PTH), Calcitonin (CT). Fibroblast Growth Factor 23 (FGF23)

MCSF, macrophage colony-stimulating factor; OPG, osteoprotegerin; RANKL, ligand for receptor for activation of nuclear factor -B

Osteoclasts function

Osteoclasts move to areas of microfracture in the bone by chemotaxis. Osteoclasts lie in a small cavity called Howship's lacunae, Attachment to the bone matrix is facilitated by integrin receptors The osteoclast releases hydrogen ions through the action of carbonic anhydrase (H2O + CO2 → HCO3- + H+) through the ruffled border into the resorptive cavity, acidifying and aiding dissolution of the mineralized bone matrix into Ca2+, H3PO4, H2CO3, water and other substances. Hydrogen ions are pumped against a high concentration gradient by proton pump vacuolar-ATPase. This enzyme has been targeted in the prevention of osteoporosis. In addition, several hydrolytic enzymes, such as members of the cathepsin and matrix metalloprotease(MMP) these hydrolytic enzymes, cathepsin K groups , are released to digest the organic components of the matrix. These enzymes are released into the compartment by lysosomes. Of is of most importance.

Parathyroid Hormone (PTH)

PTH regulate plasma Ca2+ by affecting: – Bone resorption/formation – Renal Ca2+ excretion/reabsorption – Calcitriol synthesis (thus GI Ca2+ absorption).

PTH

CHEMISTRY

PTH single polypeptide chains of 84 amino acids with molecular masses of ~9500 Da.

Biological activity is associated binding to the PTH receptor .

signaling pathways: CAMP or IP3 –Ca2+.

PTH Physiological Functions

PTH affects a variety of tissues: – vascular smooth muscle, placenta, liver, pancreatic islets, brain, dermal fibroblasts, and lymphocytes. BY TWO RECEPTORS: PTH1 & PTH2

PTH Regulation of Secretion

At LOW Ca2+ PTH secretion increases . hypocalcemia hyperplasia. induces parathyroid hypertrophy and Ca2+ itself appears to regulate parathyroid gland growth as well as hormone synthesis and secretion.

Adrenergic receptor agonists and dopamine increase parathyroid cell cyclic AMP levels, and increase PTH secretion, Active vitamin D metabolite, 1,25-dihydroxyvitamin D (calcitriol), directly suppresses PTH gene expression.

PTH Effects on Bone

PTH enhances bone

resorption

and thereby increases Ca2+ delivery to the extracellular fluid, The primary skeletal target cell for PTH is the osteoblast , PTH also recruits osteoclast precursor cells to form new bone remodeling units. PTH

in vivo

reflects not only hormone action on individual cells but also the increased total number of active osteoblasts, owing to initiation of new remodeling units.

Vitamin D

Vitamin D permit efficient absorption of dietary calcium and to allow full expression of the actions of PTH. Vitamin D is actually a vitamin; hormone rather than a synthesized in mammals and , under ideal conditions, probably is not required in the diet. Receptors for the activated form of vitamin D are expressed in many cells: lymphocytes , epidermal cells, hair follicles , adipose tissue , pancreatic islets, muscle, and neurons.

Calcitriol Synthesis

The final step in the activation of vitamin D to calcitriol kidney proximal tubule cells. occurs in Pi, PTH, and Ca2+: govern the enzymatic activity of the 25 hydroxyvitamin D3-1-hydroxylase that catalyzes this step Reduced circulating or tissue phosphate content rapidly calcitriol production , whereas hyperphosphatemia or increases hypercalcemia suppresses it. PTH powerfully stimulates calcitriol synthesis . Thus, when hypocalcemia causes a rise in PTH concentration, both the PTH-dependent lowering of circulating Pi and a more direct effect of the hormone on the 1-hydroxylase lead to increased circulating concentrations of calcitriol.

Osteoporosis

Disease of the skeleton marked low bone mass and microarchitectural degeneration of bone tissue, Over 2 million United States annually, with an estimated cost of $17 billion osteoporosis-related fractures occur in the The prevalence of osteoporosismay be on the hormone replacement therapy postmenopausal women. (HRT) for most rise , in part, due to a decrease in the overall routine utilization of Also, while osteoporosis is less prevalent in men than women, men account for almost 30% of low bone mass related (fragility) fractures

Common Risk Factors for Osteoporosis Estrogen deficiency (a result of menopause) Amenorrhea (absence of menstrual periods) Advanced age Family history of osteoporosis History of prior fracture (after age 50) Alcoholism Calcium and/or vitamin D deficiency Cushing syndrome Hypogonadism (low testosterone in men) Anorexia/eating disorders Inflammatory bowel disease (IBD) Hyperparathyroidism Hyperthyroidism Rheumatoid arthritis (RA)

1- VITAMIN D

Vitamin D

Globulin binds V-D, 25(OH)D and 24,25(OH)2D T1/2 of calcifediol = 23 days,in anephric subjects= 42 days.

Liver is principal organ for clearance. Excess vitamin D is stored in adipose tissue . Calcitriol T1/2= hours. 1,25(OH)2D analogs are bound poorly by the vitamin D-binding protein. So clearance is very rapid , T1/2= minutes .

Calcitriol; 1,25(OH)2D

Calcitriol; 1,25(OH)2D The most potent agent stimulates: – intestinal calcium and phosphate transport – in intestine induce: synthesis of calcium-binding protein and TRPV6, an intestinal calcium channel … – Like PTH, calcitriol can induce RANK ligand in osteoblasts and proteins such as osteocalcin, which may regulate the mineralization process. Calcitriol Act on the Specific receptors for 1,25(OH)2D exist in target tissues. 25(OH)D appears to be more potent than stimulating renal reabsorption 1,25(OH)2D in of calcium and phosphate

Calcitriol; 1,25(OH)2D

Calcitriol receptor found in and involves: – PTH secretion from parathyroid gland – insulin secretion from the pancreas – cytokine production by macrophages and T cells – proliferation and differentiation of a large number of cells, including cancer cells. – Thus, the clinical utility of 1,25(OH)2D and its analogs is likely to expand.

Secondary Hormonal Regulators of Bone Mineral Homeostasis

Calcitonin : secreted by thyroid, T 1/2 = 10 min, calcium and phosphate by actions on lower serum bone and kidney Glucocorticoids alter bone mineral homeostasis by antagonizing vitamin D-stimulated intestinal calcium transport, by stimulating renal calcium excretion, and by blocking bone formation.

Estrogens, period by: prevent accelerated bone loss – reduce bone-resorbing action of PTH.

– increased 1,25(OH)2D level in blood postmenopausal – May increased risk of breast cancer from continued estrogen use

TREATMENT OF OSTEOPOROSIS

Drugs for osteoporosis

1.

2.

3.

4.

5.

6.

7.

Calcitriol and Analouges Bisphosphonates Calcimimetics: Cinacalcet Calcitonin Estrogen Calcium Parathyroid hormone

Hormonal Interactions Controlling Bone Mineral Homeostasis

FGF23 is a recently discovered hormone that stimulates renal phosphate excretion and inhibits renal production of 1,25(OH

1- Calcitriol and Analouges

Available for injection .

oral administration or I.V high disease doses of calcitriol or one of its derivatives. predominant used for patients with chronic kidney and end stage kidney disease.

Therapeutic Indications for Vitamin D

The major therapeutic uses of vitamin D may be divided into four categories: – Prophylaxis and cure of nutritional rickets (softening of bones in children) – treatment of metabolic rickets and osteomalacia, particularly in the setting of chronic renal failure – prevention and treatment of osteoporosis

Adverse Effects of Vitamin D Therapy Hypercalcemia , with or without hyperphosphatemia, may limit its use at doses that effectively suppress PTH secretion.

Hypervitaminosis D is treated by: – immediate withdrawal of the vitamin – low-calcium diet – administration of glucocorticoids – loop diuretics is also useful.

Drugs for osteoporosis

1.

Calcitriol and Analouges 2.

Bisphosphonates 3.

Calcimimetics: Cinacalcet 4.

Calcitonin 5.

Estrogen 6.

Calcium

2- Bisphosphonates MA

concentrate at sites of active remodeling Incorporated into the bone matrix Remain in the matrix until the bone is remodeled and then are released in the acid environment of the resorption lacunae beneath the osteoclast as the overlying mineral matrix is dissolved.

Induce osteoclast apoptosis

Bisphosphonates other Cellular Effects

inhibition of 1,25(OH)2D production inhibition of intestinal calcium transport metabolic changes in bone cells such as inhibition of glycolysis inhibition of cell growth Changes in acid and alkaline phosphatase.

2- Bisphosphonates

First-generation (MCET)

and tiludronate. : – Medronate; clodronate; etidronate

Second-generation (AP)

aminobisphosphonates: – Alendronate and pamidronate, contain a nitrogen group in the side chain. – 10-100 times more potent generation compounds.

than first-

Third-generation (RZ)

: risedronate and zoledronate) contain a nitrogen atom within a heterocyclic ring and are up to 10,000 times more potent than first-generation agents.

Bisphosphonates Absorption, Fate, and Excretion

All oral , very poorly absorbed from the intestine, low bioavailability (<1% [alendronate, risedronate] to 6% [etidronate, tiludronate]).

Food a reduces absorption: Should be administered with full glass of water following an overnight at least 30 minutes before breakfast.

FAST

and Oral bisphosphonates

HAVE NOT BEEN

used widely in

CHILDREN

or adolescents because of uncertainty of long-term effects of bisphosphonates on the growing skeleton .

Excreted by kidneys.

Bisphosphonates Absorption, Fate, and Excretion

Pamidronate is not available as an oral preparation because it causes gastric irritation However, with the possible exception of etidronate , all currently available bisphosphonates have this complication .

~50% of absorbed drug accumulates in bone ; rest excreted unchanged in the urine.

Contraindications

: esophageal motility disorders, peptic ulcer renal failer disease The portion bound to bone is retained for months , depending on the turnover of bone itself.

Bisphosphonates Adverse Effects

Very safe At higher doses : gastric (etidronate) and esophageal (pamidronate& alendronate) irritation Irritation minimized of water by taking the drug with and remaining upright for 30 glass minutes. Rare,

OSTEONECROSIS

induced hypercalcemia.

of the jaw ( ONJ ), 1/100,000 with I.V

doses of zoledronate are used to control bone metastases and cancer-

Drugs for osteoporosis

1.

2.

3.

4.

5.

6.

Calcitriol and Analouges

Bisphosphonates Calcimimetics: Cinacalcet Calcitonin Estrogen Calcium

3- Calcimimetics: Cinacalcet

Cinacalcet:

Cinacalcet blocks PTH secretion

a new class of drugs that activates the calcium sensing receptor (CaR).

CaR is widely distributed but has its greatest concentration in the parathyroid gland. Approved for the treatment of secondary

hyperparathyroidism

in chronic kidney disease and for the treatment of parathyroid carcinoma .

Drugs for osteoporosis

1.

2.

3.

4.

5.

6.

7.

Calcitriol and Analouges

Bisphosphonates Calcimimetics: Cinacalcet Calcitonin Estrogen Calcium Parathyroid hormone

4- CALCITONIN

Hormonal Interactions Controlling Bone Mineral Homeostasis

FGF23 is a recently discovered hormone that stimulates renal phosphate excretion and inhibits renal production of 1,25(OH

4- CALCITONIN

Calcitonin lowers plasma Ca2+ and phosphate concentrations in patients with hypercalcemia; by

DECREASED BONE RESORPTION

. Although calcitonin is effective for up to 6 hours in the initial treatment of hypercalcemia,

LESS ACTIVE

after a few days due to receptor downregulation.

Development of

antibodies

with prolonged therapy.

Salmon calcitonin is available as a

NASAL SPRAY

, introduced for once-daily treatment of

postmenopausal

osteoporosis.

Side effects

: Nausea, hand swelling, urticaria, rarely, intestinal cramping.

Drugs for osteoporosis

1.

2.

3.

4.

5.

6.

7.

Calcitriol and Analouges

Bisphosphonates Calcimimetics: Cinacalcet Calcitonin Estrogen Calcium Parathyroid hormone

5- Estrogen

Helping to maintain a normal bone resorption rate.

SUPPRESSES THE PROLIFERATION AND DIFFERENTIATION OF OSTEOCLASTS

Increases osteoclast apoptosis .

Decreases the production of several cytokines that are potent stimulators of osteoclasts (IL-1. IL-6, TNF) Decreases the production of RANKL and increases the production of OPG; both of which reduce osteoclastogenesis .

Estrogen

Postmenopausal or estrogen deficiency increases risk for osteoporosis Estrogen replacement effective in conservation of bone and protection against osteoporotic fracture after menopause Side effects: increased risks of heart disease and breast cancer were found in chronic treatment

RALOXIFINE (Evista)

Selective estrogen receptor modulator

Decrease bone resorption

60mg 1Xday Side effects

: – Hot flushes – leg cramps – Thrombolism (monitor INR)

Contraindicatin:

– Pregnancy/lactation – Pulmonary embolism & DVT

Drugs for osteoporosis

1.

2.

3.

4.

5.

6.

7.

Calcitriol and Analouges Bisphosphonates Calcimimetics: Cinacalcet Calcitonin Estrogen Calcium Parathyroid hormone

6- Calcium

There is controversy about the role of calcium during the early years after menopause, when the primary basis for bone loss is estrogen withdrawal. Patients who are calcium by dietary means alone may choose from many palatable, unable or unwilling to increase low-cost calcium preparations .

ORAL CALCIUM CARBONATE

, which should be taken with meals to facilitate dissolution and absorption. Traditional dosing of calcium is ~1000 mg/day of age need 1200 mg of calcium daily. , nearly the amount present in a quart of milk. Adults >50 years

Drugs for osteoporosis

1.

2.

3.

4.

5.

6.

7.

Calcitriol and Analouges Bisphosphonates Calcimimetics: Cinacalcet Calcitonin Estrogen Calcium Parathyroid hormone

7- Parathyroid hormone:

TERIPATIDE (Forteo)

ACTS AS PARATHYROID HORMONE (PTH)

Increase bone formation by stimulation of Osteoblasts Increase renal reabsorption of calcium 20mg 1xday

Side effects

: – Orthostatic hypotension – Hypercalcemia

Contraindication :

– Hypercalcemia – Hypersinsitivity

THE END