Drugs used in the treatment of Osteoporosis

• Osteoporosis is a systemic disease of the skeleton in which the amount of bone is decreased and the structure integrity of trabecular bone is impaired. Cortical bone becomes more porous and thinner. This makes bones weaker and more likely to fracture.

2 3 Classification of osteoporosis Osteoporosis may be of primary or secondary type. There are two types of primary osteoporosis: type 1 – postmenopausal, age 50 – 75 and type 2 – senile osteoporosis, age 70 and above.

Type I of primary osteoporosis • Regarding gender differences, type 1 osteoporosis occurs 6 times as often in females as in males. In this type of osteoporosis, an increased rate of bone loss (2-3% per year) is observed as a result of and the increased activity of osteoclasts at the beginning of menopause.

• In this form of the disease the loss of trabecular bone is three times greater than the loss of cortical bone. Typical fracture site: vertebrae, distal radius. 4 Classification of osteoporosis

Type II of primary osteoporosis (senile osteoporosis)

In type 2 osteoporosis, occurring in old age, the loss of trabecular and cortical bone is similar and is caused by the decreased osteoblast activity and bone formation, and decreased GI Ca absorption.

Typical fracture site: femoral, neck, hip.

Rate of bone loss: 0,3-0,5% per year.

5 Classification of osteoporosis

Secondary osteoporosis (type III) accompanies certain diseases in which bone creation is decreased or resorption is increased or both dysfunctions appear together.

Secondary osteoporose (type III) Typical age of diagnosis: any age Gender ratio: 1:1 vomen/men Bone morphology: decreased cortical bone Typical fracture site: vertebrae, hip, extremities.

Rate of bone loss: variable.

6 Risk factors for osteoporosis

The following factors increase the risk of osteoporosis:

• lifestyle (smoking cigarettes, lack of exercise, long-term low- consumption, vegetarian diet, excessive consumption of coffee, alcohol and protein, and products increasing calcium elimination, insufficient supply of ) • genetic factors (white or yellow race, gender, mother’s osteoporosis, low body mass, slight body frame, early menopause, lack of the enzyme which decomposes lactose).

7 Causes of secondary (type III) osteoporosis

The following factors are recognized to cause secondary osteoporosis: • endocrinologic disorders (hypophysis, hyperthyroidism, hyperparathyroidism, adrenal gland diseases, gonad hypofunction) • gastroenterologic disorders (malabsorption syndromes, liver diseases, states after resection of the gastrointestinal tract, amyloidosis) • kidney disorders (uremia, hypercalciuria, renal failure) • rheumatologic disorders (rheumatiod arthritis, ankylosing spondylitis, systemic lupus) • hematologic and oncologic disorders (leukemia, lymphoma, multiple myeloma, breast carcinoma, sarcoidosis, pernicious and hemolytic anemia, hemophilia) • eating disorders (anorexia, bulimia) • long-term use of certain drugs, such as glucocorticoids, preparations of thyroid, anticoagulants, anticonvulsants, oncologic drugs, drugs binding phosphates and drugs with aluminium) 8 • metal ion poisoning (cadmium poisoning). Quantification of bone mineral density (BMD) Recomended method DEX (priviously DEXA) - Dual energy X- ray absorptiometry Two X-ray beams with differing energy levels are aimed at the patient's bones. When soft tissue absorption is subtracted out, the BMD can be determined from the absorption of each beam by bone. Dual energy X-ray absorptiometry is the most widely used and most thoroughly studied bone density measurement technology.

The recomended site of the test: the neck of the femoral bone.

9 T-score

The T-score is a comparison of a patient's BMD to that of a healthy thirty-year-old of the same sex and ethnicity. This value is used in post-menopausal women and men over aged 50 because it better predicts risk of future fracture.

The criteria of the WHO are:

Normal is a T-score of -1.0 or higher Osteopenia is defined as less than -1.0 and greater than -2.5 Osteoporosis is defined as -2.5 or lower, meaning a bone density that is two and a half standard deviations below the mean of a thirty year old woman.

10 Remodeling of bone tissue

• Bone tissue, like any living tissue, undergoes permanent remodeling. Part of bone tissue is resorbed and in its place new bone tissue is created. In the remodeling of bone tissue an important role is played by osteoclasts (bone cells responsible for bone resorption), osteoblasts (cells creating new bone stroma) and osteocytes (crucial for the rapid and accurate exchange of mineral ingredients between blood and bone). • In young individuals the process of creating new bone tissue dominates, while in older people the process of bone loss prevails. • The bone tissue that participates in bone remodeling is subject to endocrine, paracrine and autocrine regulation.

11 Contrôle du remodelage osseux par le système OPG/RANKL. La liaison de RANKL à son récepteur RANK sur les précurseurs des ostéoclastes induit la différenciation ostéoclastique et la survie des ostéoclastes. L’OPG produite par les ostéoblastes se lie au RANKL, antagonise sa liaison à RANK et inhibe l’ostéoclastogenèse. Les hormones et facteurs régulateurs du remodelage osseux agissent en contrôlant positivement ou négativement la production d’OPG et de RANKL par les ostéoblastes. RANK = Receptor Activator for Nuclear Factor . 12 RANKL = RANK ligand; OPG = Osteoprotegerin Endocrinology Vol. 142, No. 12 5050-5055 Biomed. Papers 145(2), 61–64 (2001) 61 PTH-CALCITONIN-VITAMIN D-BONE OSTEOPROTEGERIN, RANK, RANKL Minireview: The OPG/RANKL/RANK System David Stejskala, Josef Bartekb, Radmila Sundeep Khosla Pastorkováa, Viktor Růžičkaa, Ivo Orala, Dalimil Horalíka

RANKL, expressed on the surface of preosteoblastic/stromal cells, binds to RANK on the osteoclastic precursor cells. M-CSF, which binds to its receptor, \ c-Fms, on preosteoclastic cells, appears to be necessary for osteoclast development because it is the primary determinant of the pool of these precursor cells. RANKL, however, is critical for the differentiation, fusion into multinucleated cells, activation, and survival of osteoclastic cells. OPG puts a brake on the entire system13 by blocking the effects of RANKL. A number of proresorptive cytokines, such as TNF- and IL-1, modulate this system primarily by stimulating M-CSF production (thereby increasing the pool of preosteoclastic cells) and by directly increasing RANKL expression. In addition, a number of other cytokines and hormones, such as TGF-ß (increased OPG production), PTH (increased RANKL/decreased OPG production), 1,25- dihydroxyvitamin D3 (increased RANKL production), glucocorticoids (increased RANKL/decreased OPG production), and estrogen (increased OPG production) exert their effects on osteoclastogenesis by regulating osteoblastic/stromal cell production of OPG and RANKL. 14 However, not all regulation of the osteoclast is exclusively via the osteoblast because calcitonin acts directly on osteoclastic cells, and estrogen has been shown to induce apoptosis of osteoclasts as well as inhibit osteoclast differentiation by interfering with RANK signaling, principally RANKL-induced JNK activation and c-Jun activity and expression. Moreover, TGF-ß can also stimulate RANK expression on preosteoclastic cells, and thus enhance osteoclastic sensitivity to RANKL. 15 Hormones participating in bone tissue remodelling • The main hormones that participate in the metabolism and remodeling of bone tissue are parathormone (PTH; parathyroid hormone), calcitonin (CT), vitamin D, estrogens, glucocorticoids, the growth hormone, insulin and the thyroid gland hormone.

• PTH, CT and vitamin D maintain at a constant level the concentration of calcium ions in plasma and of phosphates in the extracellular fluid.

• PTH is released as a result of the low level of calcium in plasma and has an opposite effect to calcitonin. PTH decreases renal elimination of calcium, indirectly stimulates absorption of calcium in the intestines, together with active vitamin D stimulates the resorption of calcium from bone tissue and stimulates the transformation of

25(OH)D3 to 1,25(OH)2D3 in the kidneys. 16 17 • Parathormone is a one-chain polypeptide which contains 84 amino acids. • The sequence that causes the full activity of PTH has 27 amino acids. • PTH is synthesized in the cells of the parathyroid gland and stored in its vesicles. • The principal factor controlling PTH secretion is the reverse relationship between hormone concentration and the concentration of ionized calcium and magnesium in plasma. • There is a relationship between the amount of released PTH and the concentration of cAMP (cyclic adenosine monophosphate) in the parathyroid glands.

18 • Protein membrane receptors participate in the mechanism of action of PTH. They are present in the cells of bone and in the kidneys. • The interaction of PTH with receptors initiates a typical cascade reaction: the activation of adenyl cyclase (leads to an) → increase in the intracellular concentration of cAMP → an increase in the intracellular concentration of calcium → phosphorylation of specific proteins by kinases → activation of intracellular enzymes or proteins. • The reaction complex induced by PTH, similarly to other peptide hormones, leads to a decrease in the number of receptors (down regulation of receptor number) and in the concentration of effector hormones. 19 • Parathormone (PTH) is an important physiological regulator of calcium metabolism. • The calcium balance in the physiological range depends on the long- lasting influence of the hormone on intestinal absorption, with the participation of calcitriol. • Parathormone intensifies bone dissolution (osteolysis) and influences the organic and non-organic constituents of bone tissue. The released calcium ions are translocated to the aqual extracellural space. • PTH decreases calcium elimination by the kidneys or, in other words, influences the kidney clearance of calcium and increases the concentration of these ions in the extracellural fluid. • PTH also intensifies the absorption of calcium by the intestines and stimulates the synthesis of calcitriol in the kidneys. • PTH influences the homeostasis of phosphates. The osteolysis

induced by PTH increases calcium concentration and decreases 20 phosphate concentration in the extracellural fluid. Calcitonin

• Calcitonin is a hormone secreted by specialized ‘C’ cells found in the thyroid follicles in response to the increased concentration of calcium in plasma.

• Calcitonin decreases calcium concentration in plasma by stimulating calcium and phosphate elimination in urine. It also prevents calcium resorption from bone tissue and inhibits calcium absorption from the intestines.

21 • Calcitonin is an antagonist for PTH. CT is a polypeptide created by the specialized parafollicular cells of the thyroid (C cells). • A molecule of CT consists of 32 amino acids. • For the biological activity of CT the following is necessary: a disulphide bond, created by cysteine at position 1 and 7 and the carboxyterminal rest of prolinamide. • There are significant differences in the sequence of amino acids between the CT of mammals, for example human and porcinal (from pigs) CT have only 14 common amino acids out of the general number of 32 amino acids.

S S Cys-Gly-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Glu-Asp-Phe-Asn- Lys-Phe-His-Thr-Phe-Pro-Glu-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro-NH2 Human calcitonin 22 • Calcitonin acts after binding with specific receptors of effector cells. The highest density of receptors (approx. 1 million) is observed in osteoclasts. • Calcitonin recptors are present in the adrenal cortex, the cns, lymphocytes and neoplastic cells. • The interaction of calcitonin with a specific membrane receptor, which is connected with G-protein, activates adenyl cyclase. It leads to an increase in the intracellular concentration of cAMP. cAMP, as the intracellular second messenger, affects different cell functions. In osteoclasts it considerably reduces the actively resorbing cell surface, which leads to a decrease in the osteolytic activity of osteoclasts. • In the GI tract CT inhibits the secretion of gastrin and the production of gastric juice, influences the resorption of water and electrolytes from the intestines, inhibits gastrointestinal peristalsis, decreases the secretion of pancreas enzymes and the release of insulin. 23 Estrogens and Glucocorticoids

• Estrogens play an important role in the maintenance of bone integrity. They inhibit the cytokines that activate osteoclasts and oppose the bone-resorbing, Ca2+-mobilising action of PTH.

• At physiological concentration glucocorticoids are required for osteoblast differentiation. • Excessive pharmacological concentrations inhibit bone formation by inhibiting osteoblast differentiation and activity.

24 25 The pharmacological treatment of osteoporosis Therapy is aimed at decreasing or inhibiting the loss of bone mass, preventing fractures, decreasing pain and increasing motor activity.

Agents used in the treatment and prevention of osteoporosis are categorized as:

. antiresorptive agents, or . bone-forming agents

depending on the primary mechanism of action.

26  Antiresorptive agents (Anticatabolic drugs):  ERT (Estrogen replacement therapy)  Selective Estrogen Receptor Modulators (SERM) - Raloxifene   Calcitonin 

 Bone-forming agents (Anabolic drugs): (recombinant human PTH 1-34)  Antiresorptive and bone-forming agents:

 Appropriate intake of calcium, vitamin D3, magnesium and protein 27 Antiresorptive agents Estrogen replacement therapy

• Estrogens – natural inhibitors of bone resorption – by binding with specific receptors in osteoblasts extend the time of their life and activity and accelerate the apoptosis of osteoclasts. • They protect indirectly bone tissue from PTH. They improve calcium absorption, activate biosynthesis of calcitonin and increase the number of vitamin D receptors in osteoclasts. • Estrogens are irreplaceable in the treatment of postmenopausal genital prolapse. • They diminish the rate of bone remodeling and postmenopasusal bone loss. • Premature menopause (before age 45), the increased risk of osteoporosis or postmenopasusal osteoporosis are the main

therapeutic indications for the use of ERT. 28 Estrogen replacement therapy • Using ERT is safe if patients for this therapy are qualified individually, the drug chosen is suitable, the treatment is monitored and the time of estrogen administration is respected (generally 5 years).

• ERT should not be used more than for 10 years.

• The following illnesses are contraindications for the use of ERT: breast carcinoma, endometrium carcinoma, melanoma, acute thrombosis of deep blood vessels, acute liver failure.

OH O OH CH !7 !7 !7 !7

HO HO HO

17-Estradiol Estrone 17-Ethinyl-17-estradiol 29 Selective Estrogen Receptor Modulators (SERM)

• Although SERM show antiestrogen action towards the tissue of the mammary glands, they act as estrogens on bone tissue, plasma lipids and the endometrium. • This selective action means that the selectivity factor does not increase the risk of endometrium and breast carcinomas. • That risk is observed in the case of estrogen therapy. • SERM do not prevent hot flushes and other menopausal symptoms.

30 • Raloxifene, the first selective modulator of estrogen receptors (SERM selective estrogen receptor modulator), has been approved for the prevention of osteoporosis in women after menopause. • Raloxifene with oral calcium supplementation prevents the loss of bone tissue of the spine and the hip joint and promotes bone creation. It also has a beneficial influence on the lipid profile.

HO S OH Raloxifene, EVISTA

O N O In clinical trials there are the SERM of the second generation:

Lasofoxifene (phase III)

Ospemifene – metabolite of toremifene (phase II/III) 31 Bazedoxifene Bisphosphonates • Bisphosphonates are analogues of pyrophosphate, which is a natural ingredient of bone tissue and inhibits bone tissue mineralization. • The structure P-O-P, characteristic of pyrophosphate, was replaced by the structure P-C-P in bisphosphonates, which is not hydrolysed.

2- R2 PO3 R1 OH – the most, H, Cl 2- R – Cl, alkil, aminoalkil, dialkiloaminoalkil, R1 PO 2 3 heteroalkil, cycloalkiloamino

• Clodronate disodium, Etidronate disodium, Tiludronate disodium, Alendronate disodium, Pamidronate disodium, Ibadronic acid, Risedronate disodium and are the most often used bisphosphonates. 32 PO H 3 2 H N PO3HNa H2N 2 HO PO HNa 3 HO PO3HNa

Alendronate sodium; FOSAMAX i inne Disodium pamidronate; AREDIA, PAMIFOS

PO HNa PO HNa H3C 3 Cl 3 Cl PO HNa HO PO3HNa 3

Etidronate disodium; DIFOSFEN, OSTEDRON Clodronate disodium; BONEFOS OH N OH PO3H2 PO3H2 PO3H2 PO3HNa N N

Risedronate sodium; ACTONEL Zoledronic acid ; ZOMETA

CH3 S PO3HNa N PO3H2 H3C PO3HNa Cl HO PO3H2 Tiludronate disodium; SKELID Ibadronic acid; BONDRONAT

33 2- R2 PO3 2- R1 PO3 Structure-activity realationship

• The hydroxyl constituent (R1) increases the affinity of for hydroxyapatite and improves the antiresorptive action of the compound.

• The R2 constituent has a significant influence on the activity of bisphosphonates.

• R2-aminoalkil substituted bisphosphonates (pamidronate, alendronate, neridronate) are more active than etidronate and clodronate.

PO HNa PO HNa PO3H2 H3C 3 Cl 3 H N Cl PO HNa 2 HO PO3HNa 3 HO PO3HNa 34 Structure-activity realationship

. The length of the alkil chain is also very important for the activity of bisphosphonates (alendronate  pamidronate and neridronate).

. The substitution of the amino group by alkil and the introduction of a heterocyclic or alicyclic constituent connected with the central carbon atom by means of different bonds improves the activity of

these compounds (activity: NH  CH2  S  O).

. The activity of bisphosphonates can be presented in the following increasing order: etidronate – tiludronate – pamidronate – alendronate – risedronate (1:10:100:1000:1000-5000).

CH3 N OH S PO3HNa N PO3H2 PO3H2 H C PO HNa 3 Cl 3 HO PO3H2 PO3HNa 35 • Those bisphosphonates which contain the amino group (alendronate, pamidronate, neridronate) permeate osteoclasts and inhibit the activity of farnezil diphosphate synthetase. The deficiency of this enzyme in the osteoclasts leads to the lack of farnezil pyrophosphate and geranylgeranyl pyrophosphate which are necessary for the prenylation of cytoplasmatic proteins Ras, Rho and Rac. These proteins bind GTP (guanosine triphosphate/diphosphate) and GDP and determine the basic functions of osteoclasts. The lack of protein prenylation inhibits resorptive activity and causes the apoptosis of osteoclasts. • While mevalonate reduces the action of bisphosphonates, lovastatin intensifies it. These bisphosphonates which do not have the amino group inhibit the resynthesis of ATP (adenosine triphosphate) in osteoclasts as a result of interference with aminoacyl-tRNA synthetase and involve bisphosphonates instead pyrophosphates in this process. Because bisphosphonates are not hydrolyzed they inhibit cell metabolism, which leads to the apoptosis of osteoclasts.

36 Acetoacetyl-CoA

HMG-CoA

HMG-CoA-reductase HMG-CoA-reductase inhibitors

Mevalonate

Isopentyl-PP

Geranyl-PP

Farnesyl-PP-synthetase Bisphosphonates

CH3 CH3 CH3 Squalene FT Farnesyl Farnesyl-PP H3C CH2 Ras GGT I Cholesterol CH3 CH3 CH3 CH3 Rho DNA Geranylogeranyl H3C CH2 Rac Osteoclast

Prenylation of cytoplasmatic proteins in osteoclasts. 37 Pharmacokinetics • In addition to their direct influence on metabolic processes in osteoclasts, bisphosphonates enter the structure of hydroxyapatite and inhibit its resorption, inhibit the adhesion of osteoclasts to bone tissue and their maturation and suppress their resorption activity. • Bisphosphonates are administered orally. Their absorption from the intestines is poor (1 – 5%). It is caused by the polar character of these compounds, which limits intracellural penetration. • Up to 50% of the absorbed dose accumulates in the place of bone mineralization within 4-6 hours and remains there for months or even years. The rest is eliminated unchanged in urine. • The absorption of bisphosphonates is impaired by food, particularly by milk, so these drugs should be administered on an empty stomach, half an hour before breakfast and the patient should drink one glass of

water. 38 Therapeutic application

Indications for the use bisphosphonates are as follows: • postmenopausal and posteroidal osteoporosis (etidronate, alendronate, risedronate) • Paget’s disease (etidronate, pamidronate, tiludronate, risedronate) • the treatment of hypercalcemia during neoplastic disease (clodronate, pamidronate, tiludronate, risedronate) • the treatment of symptoms connected with the increased activity of osteoclasts such as neoplastic metastasis to bone tissue, multiple myeloma • the prevention and treatment of heteroatopic ossification focus caused by damage to the spinal cord or a surgical replacement of the tarsal joint. 39 Adverse effects

Bisphosphonates have an adverse effect on the mucosa of the gastrointestinal tract.

They may cause its inflammation and even ulceration of the esophagus, stomach or duodenum.

Unwanted effects are observed when bisphosphonates with a free amino group are used.

40 Calcitonin The preparations available for clinical use are – human (CIBACALCIN) – salmon (CALSYNAR) and – porcinal (CALCITONIN). • Porcinal (natural), salmon and human calcitonins (synthetic) are administered intranasally, subcutaneously or intramuscularly. • Preparations of calcitonin have different chemical structures and pharmacokinetic properties. Salmon calcitonin acts approx. 50 times more strongly and longer than human CT and approx. 30 times more strongly than porcinal CT. • Old age and postmenopausal osteoporosis, Paget’s disease, Sudeck’s disease, the prevention of renal calculosis, the treatment of bone tissue destruction caused by neoplastic metastases are the main therapeutic indications for the use of CT. 41 Bone-forming agents- Teriparatide

In 2002, the U.S FDA approved teriparatide for the treatment of postmenopausal osteoporosis in patients who have a high risk of fracture as well as to increase bone mass in men with primary or hypogonodal osteoporosis who have a high risk of fracture. Teriparatide (Forteo) is a recombinant human PTH 1-34, the biologically active portion of the endogenously produced preprohormone. It is manufactured and marketed by Eli Lilly and Company. Teriparatide is the first approved bone-forming agent. Bone formation is possible because of the ability of this agent to increase the number of osteoblasts. 42 Although teriparatide enhances the function of both osteoclasts and osteoblasts, the exposure incidence dictates its effect on the skeleton. If administered once daily or intermittently, teriparatide preferentially enhances osteoblastic function, and bone formation occurs. Continuous exposure to endogenous PTH may result in poor skeletal composition because of enhanced osteoclast-mediated bone resorption. After 18 months of treatment, lumbar BMD increased up to 12% in postmenopausal women. After 10 months of treatment, 53% of men had an increase of 5% or greater in spine BMD. The risk for developing new vertebral fractures was reduced by 65% after 21 months of treatment, and the number of nonvertebral fragility fractures was reduced by 53%. 43 Treatment for longer than 2 years is not recomended. Administration Teriparatide is administered by injection once a day in the thigh or abdomen. The recommended dose is 20 μg per day. Contraindications Teriparatide should not be prescribed to: . patients who are predisposed to hypercalcemia (temporary, teriparatide increases in serum calcium levels) . patients who are at increased risks for osteosarcoma . patients with Paget's disease . patients who have received skeletal radiation therapy because of an increased incidence of osteosarcoma (malignant bone tumors) . children, young adults, women who are pregnant or nursing

Adverse effects. Dizziness and leg cramps are the most commonly reported adverse side effects. 44 Denosumab

Denosumab is a fully human monoclonal antibody. Denosumab inhibits the maturation of osteoclasts by binding to RANKL, protecting the bone from degradation and thus from osteoporosis. The drug therefore mimics the endogenous effects of osteoprotegerin, another protein produced by osteoblasts which acts as an alternate receptor for RANKL, modulating the RANK/RANKL induced osteoclast activity. It was approved for use in the treatment of osteoporosis by the European Commission on May 28, 2010 and by the United States FDA on June 2, 2010. 45 46 Indications

It was approved by FDA for use in postmenopausal women with risk of osteoporosis in June 2010, becoming the first RANKL inhibitor to be approved by the FDA.

Contraindications and interactions

The drug is contraindicated in patients with hypocalcaemia.

Sufficient calcium and vitamin D levels must be reached before starting a denosumab therapy.

47 Adverse effects

The most common side effects include infections of the urinary and respiratory tract, cataract, constipation, rashes and joint pain.

A small study found a slightly increased risk of cancer and severe infections, but these results did not reach statistical significance.

Another trial showed significantly increased rates of eczema and hospitalisation due to infections of the skin.

It has been proposed that the increase in infections under denosumab treatment might be connected to the role of RANKL in the immune system. It is expressed by T helper cells and thought to be involved in dendritic cell maturation. 48 Antiresorptive and a bone-forming agents Strontium ranelate

Strontium ranelate, a strontium(II) salt of ranelic acid, is a for osteoporosis marketed as Protelos or Protos by Servier.

It is unusual in the sense that it both increases deposition of new bone osteoblasts and reduces the resorption of bone by osteoclasts.

It is therefore promoted as a "dual action bone agent" (DABA). 49 Mode of action

Strontium ranelate is the only antiosteoporotic agent which both increases bone formation and reduces bone resorption, resulting in a rebalance of bone turnover in favor of bone formation. Strontium ranelate stimulates the calcium sensing receptors and leads to the differentiation of pre-osteoblast to osteoblast which increases the bone formation. Strontium ranelate also stimulates osteoblasts to secrete osteoprotegerin in inhibiting osteoclasts formed from pre-osteoclasts in relation to the RANKL system, which leads to the decrease of bone resorption. Strontium ranelate is unusual in that the cation (strontium) is responsible for the pharmacological effect, whereas in most modern it is the base (anion) that is the active ingredient.

50 Nouvelle stratégie anti-ostéoporotique ciblant le système OPG/RANKL. Le ranélate de strontium augmente l’expression d’OPG (Osteoprotegerin) et diminue celle de RANKL, et, par ailleurs, stimule la réplication des ostéoblastes. Cette stratégie vise à rééquilibrer le rapport OPG/RANKL et le métabolisme osseux et à prévenir la perte osseuse dans l’ostéoporose. 51 Indications Strontium ranelate is registered in more than 70 countries for the treatment of post-menopausal osteoporosis to reduce the risk of vertebral and hip fractures.

Strontium ranelate shows antifracture efficacy in very old elderly and osteopenic patients. It is generally well tolerated.

Dosage One sachet, containing 2 grams of strontium ranelate, daily at bedtime diluted in a glass of water.

52 Contraindications Strontium ranelate is contraindicated in hypersensitivity to the active substance or to any of the excipients. It is not recommended in patients with severe renal disease, i.e. creatinine clearance below 30 mL/min due to lack of data. Precaution is advised in patients at increased risk of venous thromboembolism (VTE), including patients with a past history of VTE. Precaution is advised in patients with phenylketonuria, as strontium ranelate contains phenylalanine.

Precaution as it interferes with colorimetric measurements of calcium in blood and urine. 53 Interactions . According to the manufacturer, strontium ranelate should be taken 2 hours apart from food, milk and derivative products, and medicinal products containing calcium. . Should be taken 2 hours before antacids. . Treatment should be suspended while taking oral tetracycline and quinolone antibiotics, as these chelate the active substance.

Side effects The most common side effects include nausea, diarrhea, headache and eczema, but with only 2–4% increase compared with placebo group. However, most of the side effect will be tolerated in 3 months. 54 Appropriate intake of calcium, vitamin D3, magnesium and protein

Calcium salts

Appropriate intake of calcium during childhood, adolescence, and early adulthood increases peak BMD and may reduce the overall risk of developing osteoporosis. For those who are at low risk of developing osteoporosis and have adequate BMD, consumption of the recommended amounts of calcium . 1,200-1,500 mg of elemental calcium per day for teenegers, . 1,000 mg/day for premenopausal women and men . up to 1,500 mg/day for postmenopausal women not taking ERT, . 1,000 mg/day for postmenopausal women taking ERT typically is sufficient to prevent bone loss. 55 Absorption of calcium from the GI tract (25-40%) improves under acidic condition; therefore, those medications that change the acidic environment of the stomach (e.g., H2 antagonists and proton-pump inhibitors) have an adverse effect on calcium absorption.

The more water soluble and, therefore, more easily absorbed salts (e.g., citrate, lactate, and gluconate) are less dependent on the acidic environment for appropriate absorption and would be appropriate alternatives for patients who produce low levels of acid.

Calcium salts (lactate, gluconate) are used orally together with estrogens and calcitonin in the treatment of postmenopausal osteoporosis or in the treatment of osteoporosis caused by GK (glucocorticoids), together with calcitriol and calcitonin.

56 Vitamin D

• Vitamin D2 (ergocalciferol), -calcidiol and calcitriol are used in the treatment of: – osteodystrophy caused by the decreased production of calcitriol that accompanies chronic renal failure (calcitriol, -calcidiol) – hypocalcemia connected with hypoparathyroidism (ergocalciferol) – rickets – Osteomalacia – D hypovitaminosis caused by malabsorption and liver disease and to prevent these states (ergocalciferol) • During therapy with vitamin D, the level of calcium in plasma should be determined once weekly to avoid toxicity due to overdosage.

57 Ossopan and Osteogon – osseinhydroxyapatite complexes

• The ossein part contains collagen, non-collagen proteins, including osteocalcin, and the bone growth factor. • The hydroxyapatite part contains calcium and magnesium. It is a biologically active complex of the mineral and organic ingredients of bone tissue. • Growth factors inhibit the action of osteoclasts and stimulates the activity of osteoblasts. • Fractures, bone injury, intensive body growth, regulation of calcium-magnesium metabolism in pregnancy and lactation are indications for the use of ossein-hydroxyapatite complexes. 58 Other drugs used in the treatment of osteoporosis Sodium fluoride Sodium fluoride (NaF) promotes the proliferation and activity of osteoblasts and is classified as a nonhormonal bone-forming agent. Because treatment with NaF induces bone formation, it is essential that this therapy be coupled with oral calcium (1000 mg/day) and vitamin D supplementation to ansure correct calcification of bone tissue. Additionally, NaF exhibits moderate antiresorptive activity, because it inhibits osteoclastic activity when it is absorbed into the bone matrix.

59 To obtain a desired effect, the dosage of NaF should be precisely calculated because the therapeutic window for NaF is fairly narrow: . doses less than 45 mg/day are subtherapeutic, and . doses in excess of 75 mg/day impair home mineralization. In addition, the bone that is formed in the presence of NaF is neither as well mineralized nor as strong as normal bone tissue.

By using NaF, a large increase in bone density and the mass of the skeleton is achieved without increasing the risk of fracture.

During therapy with NaF, preparations of calcium and vitamin D should be administered to ansure correct calcification of bone tissue.

60 61 Recomended time of the treatment

• Alendronate – 10–12 years • Risedronate – 7 years • Raloxifene – 8 years • Strontium ranelate – 5 years • Teriparatide – 2 years

62 Experimental agents for treatment of osteoporosis

Various classes of drugs, such as thiazide diuretics, proton-pump inhibitors, androgens, statins and human monoclonal antibody, have been shown to have beneficial effects in treatment of diseases associated with abnormal calcium homeostasis through various mechanisms.

63 Experimental agents for treatment of osteoporosis

Osteoprotegerin (phase II of clinical trial)

Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor (OCIF), is a cytokine, which can inhibit the production of osteoclasts. It is a member of the tumor necrosis factor (TNF) receptor superfamily. It is a basic glycoprotein comprising 401 amino acid residues arranged into 7 structural domains. It is found as either a 60 kDa monomer or 120 kDa dimer linked by disulfide bonds.

Osteoprotegerin inhibits the differentiation of osteoclast precursors (Osteoclasts are related to monocyte/macrophage cells and are derived from granulocyte/macrophage-forming colony units (CFU-GM)) into osteoclasts and also regulates the resorption of osteoclasts in vitro and in vivo. 64 Osteoprotegerin is a RANK homolog, and works by binding to RANKL ligand on osteoblast/stromal cells, thus blocking the RANK- RANK ligand interaction between osteoblast/stromal cells and osteoclast precursors. This has the effect of inhibiting the differentiation of the osteoclast precursor into a mature osteoclast. Recombinant human osteoprotegerin specifically acts on bone, increasing bone mineral density and bone volume. Osteoprotegerin has been used experimentally to decrease bone resorption in women with postmenopausal and in patients with lytic bone metastases, osteoporosis. Osteoprotegerin production is stimulated in vivo by the female sex hormone estrogen, as well as the experimental osteoporosis drug, strontium ranelate.

65 inhibitor ( SB-357114; phase I of clinical trial)

Cathepsin K, also known as CTSK is an enzyme which in humans is encoded by the CTSK gene. The protein encoded by this gene is a lysosomal cysteine protease involved in bone remodeling and resorption. This protein, which is a member of the peptidase C1 protein family, is predominantly expressed in osteoclasts. Cathepsin K is a protease, which is defined by its high specificity for kinins, that is involved in bone resorption. The enzyme's ability to catabolize elastin, collagen, and gelatin allow it to break down bone and cartilage. This catabolic activity is also partially responsible for the loss of lung elasticity and recoil in emphysema. Cathepsin K inhibitors, such as odanacatib, show great potential in the treatment of osteoporosis.

Cathepsin K expression is stimulated by inflammatory cytokines that66 are released after tissue injury. . Nitroflurbiprofen (phase II of clinical trial) – decreases bone resorption

. Protein tyrosine kinase Src inhibitor (CGP-7765; preclinical trial) – decreases osteoclast mediated bone resorption

. αvβ3 integrin receptor antagonist (SB-265123; preclinical trial)

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