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cations cations of that concept by summarizing the or more osteoporotic fractures in Common their sites lifetime. of fracture include the bodies, vertebral distal radius, proximal proximalhumerus. femur and the Etiology: The most common cause of osteoporosis from arises estrogen deficiency that begins some years before the time of comprises menopause. approximately The 20% skeleton trabecular and bone 80% cortical continual process bone of resorption and and governed by formation, undergoes the activity of a bone cells remodellingunits. in Estrogen deficiency bone accelerates the normal of bone tissue, but the net activity of bone resorbing cells (osteoclasts) is greater than that of bone forming cells (osteoblasts). This gives rise to thinning of the cortices of bones, thinning of trabecular bone and loss of trabecular elements. (Figure-1) noncommercialprovided use, properly is work original the | July-September 2013 | Vol. 5 | Issue 3 | ISSN 0975-9344 | 0975-9344 ISSN | 3 Issue | 5 Vol. | 2013 July-September | Int.Drug J. Dev. Res.,& July-September 2013, 12 5(3): Aminobiphosphonate, Osteoporosis, Pyrophosphates,
Osteoporosis is a disease of great social impact, in recent years
lisher and licensee IYPF. licensee and lisher is This Access Open an article w
bstract: eywords: we we explore the potential appli bone diseases and candidate proteins will that benefit from the proposed bone delivery approach. A selective synopsis of BP synthesis is presented to highlight proteins. to attachment the synthesis of functional BPs K suitable for Osteoclast,Osteoblast. covalent A has assumed increasing importance, due to the progressive ageing of the population and the consequent increase of its femoral complications, first and of vertebral al fractures. Various employed treatment strategies to has overcome, been Aminobiphosphonate represents a is major advance in the treatment of one musculoskeletal disorders of them and & they are they now amongst the most commonly practice. used Bisphosphonates are analogues and of are inorganic pyrophosphate inhibitors developed for the of treatment of enhanced bone resorption. In this review, bone resorption. Many derivatives have been . . Theydeveloped were , , as well as mineralization in-vivo in-vitro © 2013 © Nadim M. et R. Chhipa pub al,
ntroduction
and used in the treatment of bone diseases.bone of treatment the usedin and Osteoporosis is described by the Organization World as Health a ‘progressive systemic skeletal disease characterized by low bone micro mass architectural deterioration and of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture’. More than one-third of adult women and one in five men will sustain one Osteoporosis: Osteoporosis: I Bisphosphonates are pyrophosphate analogues in which the oxygen bridge has been replaced by a carbon with various side compounds chains have been P-C-P. known These to since the the chemist 19th century, the first synthesis back dating to 1865. After discovering effectively that control they calcium phosphate can formation and dissolution and bone resorptionbone and PharmaceuticalChemistry, Shri SarvajanikPharmacy College, GujaratTechnological University, ArvindBaug, Mehsana-384001,Gujarat, India Authors: Corresponding Nadim M. R. Chhipa Email: [email protected] of Department Nadim M. R. Chhipa Chhipa R. M. Nadim Sen Jyoti Dr.Dhrubo Prof. CoveredEmbase,&Scopus in Elsevier
AminobiphosphonatesOsteoporosis: in A Review
Page 120 Secondary osteoporosis Secondary osteoporosis has the same symptoms as primary osteoporosis. But it occurs as a result of having certain medical conditions, such as hyperparathyroidism, hyperthyroidism, or leukaemia. It may also occur as a result of taking medicines known to cause bone breakdown,
such as oral or high-dose inhaled corticosteroids (if Figure-1: Comparison of structure of trabecular bone in health (left panel) and osteoporosis used for more than 6 months), too high a dose of (right), illustrating the architectural damage thyroid replacement, or aromatase inhibitors including trabecular thinning and perforation (used to treat breast cancer). Secondary Diagnosis of Osteoporosis: osteoporosis can occur at any age. rosis: A Review rosis:Review A The diagnosis of osteoporosis relies on the Osteogenesis imperfecta quantitative assessment of bone mineral density Osteogenesis imperfecta is a rare form of (BMD), usually by central dual energy X-ray osteoporosis that is present at birth. absorptiometry (DXA). BMD at the femoral neck Osteogenesisimperfecta causes bones to break provides the reference site. It is defined as a value for no apparent reason.
for BMD 2.5 standard deviations (SD) or more Idiopathic juvenile osteoporosis 121 Page below the young female adult mean (T-score less Idiopathic juvenile osteoporosis is rare. It occurs in than or equal to –2.5 SD). Severe osteoporosis children between the ages of 8 and 14 or during (established osteoporosis) describes osteoporosis times of rapid growth. There is no known cause for in the presence of 1 or more fragility fractures. 1 this type of osteoporosis, in which there is too little bone formation or excessive bone loss. This Classifications of Osteoporosis : condition increases the risk of fractures. 2 The Four types of Osteoporosis Primary osteoporosis Treatment of Osteoporosis: 3 Primary osteoporosis is the most common type of Treatment for osteoporosis may involve: osteoporosis. It is more common in women than a. Lifestyle changes, such as diet and men. A person reaches peak bone mass (density) exercise at about age 30; after that, the rate of bone loss b. Taking calcium and vitamin D slowly increases, while the rate of bone building c. Using medications decreases. Medicines used to treat osteoporosis include: In women, accelerated bone loss usually begins a. Bisphosphonates (the main drugs used to after monthly menstrual periods stop, when a prevent and treat osteoporosis in Nadim M. R. Chhipa et al; Aminobiphosphonates in Osteopo in Aminobiphosphonates al; et Chhipa NadimR. M. woman's production of estrogen slows down postmenopausal women) (usually between the ages of 45 and 55). In men, b. Estrogens, teriparatide, raloxifene and gradual bone thinning typically starts at about 45 calcitonin to 50 years of age, when a man's production of testosterone slows down.
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There are two surgeries used to treat severe, one to incorporate additional functionalities to the disabling pain from spinal fractures due BPs. Bisphosphonates have been developed to osteoporosis: primarily as potent inhibitors of osteoclast- a. Kyphoplasty mediated bone resorption. This bioactivity largely b. Vertebroplasty results from their P–C–P bond and C-bound lateral Exercise plays a key role in preserving bone chain R. Both P–C–P structure and C–OH density in older adults. Some of the exercises substituent are responsible for bisphosphonate recommended to reduce your chance of a binding to the mineralized bone matrix, whereas fracture include: the R-substituting group determines their a. Weight-bearing exercises -- walking, capability of inhibiting osteoplastic bone jogging, playing tennis, dancing resorption. 4, 5
b. Free weights, weight machines, stretch The P-C-P moiety is responsible for the strong affinity for calcium ions bands OH O O OH c. Balance exercises -- tai chi, yoga P OH P OH OH OH d. Rowing machines O PO PO R OH 1 OH R2 Calcium ions are chelated more Review effectively when R 1 is an -OH Aminobiphosphonates: group The R 2 side chain determines potency
Page 122 Page Introduction : The structure of pyrophosphoric acid and a Bisphosphonates are analogues of inorganic geminal BP. Common members of the BP family
pyrophosphate and are inhibitors of bone Aminobiphosphonate R1 R2 Paper resorption. Bisphosphonates are pyrophosphate Non-Nitrogen Containing analogues in which the oxygen bridge has been Etidronate -OH -CH 3 Clodronate -Cl -Cl replaced by a carbon with various side chains P- Nitrogen Containing Pamidronate -OH (-CH 2)2-NH 2
C-P. Bisphosphonates (BPs), which exhibits a strong Alendronate -OH (-CH 2)3-NH 2 affinity to bone mineral under physiological Neridronate -OH (-CH 2)5-NH 2 -N conditions. Systemic administration of BPs Incadronate -H commonly results in 20–50% deposition of the
molecules at bone tissues, with minimal Olpadronate -OH (-CH 2)2-N-NH 2 -H2C accumulation at other sites. Bisphosphonates are Riserdronate -OH known to inhibit biochemical markers of bone N CH - formation in-vivo , but it is unclear to what extent N N 2 Zelodronate -OH this is a consequence of osteoclast inhibition or a
direct inhibitory effect on cells of the osteoblast Table1: Aminobiphosphonates lineage. Depending on the structural details of a BP it is BPs are structurally analogous to the endogenous possible to increase the bone affinity of BPs (e.g., – inorganic phosphate, pyrophosphoric acid. OH on the central C), to impart a variety of Replacement of the central oxygen (O) atom in pharmacological activities to BPs and to enhance the pyrophosphatewith a carbon (C) in BPs allows
Covered in Scopus & Embase, Elsevier Int. J. Drug Dev. & Res., July-September 2013, 5 (3): 120-132 © 2013 Nadim M. R. Chhipa et al, publisher and licensee IYPF. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. the potency of the main pharmacological activity CH3 CH3 CH 3 O of BPs, namely the inhibition of osteoclast- O O O O PO NH 2 P O H + OH + N CH3 mediated bone resorption. O CH 3 O P O CH3 O O CH3 CH3 diethyl hydrogen (diethoxymeth phosphate CH Structure-Activity Relationships (SAR): N-benzyl-1-phen oxy)ethane 3 ylmethanamine Bisphosphonate moiety is essential for Pd/C hydroxyapatite affinity. The CH3
O monophosphonates are not active! OH O OH PO P O aq. HCl 1 2 2NH CH3 Side chain (R and R groups): responsible 2NH P O P OH OH O CH for inhibition of resorption. A single carbon O O 3
atom between phosphate residues required CH3
Dichloro (clodronate) and hydroxy-alkyl rosis: A Review rosis:Review A 7 (etidronate) derivatives (first generation Synthesis of Aminobiphosphonates
agents): Inhibit bone mineralization (at Mechanism of Action: higher doses) and resorption (see mechanism below) The Mechanism of aminobiphosphonates can Incorporation of an OH at C1 optimizes explain from its action on osteoporotic bone via its
affinity for hydroxyapatite and increases action on osteoclast & bone resorption process. 123 Page anti-resorptive activity (increases both It involve following steps: components of activity). Uptake of aminobiphophonates by osteoclast: Incorporation of a 4-chlorothiophenyl The mechanism behind the uptake of substituent at C1 (tiludronate): 10X more aminobiphosphonates from surface of the bone active than etidronate into the osteoclast cytoplasm is found to be Incorporation of an aminoalkyl side chain at different for different aminobiphosphonates. C1 increases anti-resorptivepotency 10-fold, Uptake of the Non-nitrogen containing allows for separation between antiresorptive aminobiphosphonates occur through active and bone mineralization effects (see reabsorption process in which acid secreted onto mechanism below). the bone surface could release the bound state Length of carbon chain important: 2-5 is aminobiphosphonates which can be uptake tolerated and 3 Cs is optimal as in through the ruffled border adjacent to the alendronate. Alendronate is about 1000X resorption lacunae. more potent than etidronate and Incadronate doesn’t require active bone pamidronate is 100X more active than reabsorption as it affect osteoclast bone etidronate. attachment and this was studied in in-vivo study in Nadim M. R. Chhipa et al; Aminobiphosphonates in Osteopo in Aminobiphosphonates al; et Chhipa NadimR. M. Incorporation of a nitrogen heterocycle the oc/oc mouse. (pyridine) at C1 further enhances anti- Earlier studies which involve the resorptive potency (Third generation agents: administration of pharmacological relevant dose Risedronate): Risedornate is as much as of highly potent aminobiphosphonates like 5000X more potent than etidronate. 6 alendronate having uptake mechanism for
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through the plasma membrane. Osteoclasts isoprenoid could be involved to form squalene gather through the ruffled border the content of and ultimately cholesterol, but the critical step for the resorption lacunae and by the process of the N-BPs suppression of osteoclastic bone transcytosis translocate it through the cell. resorption is its conversion to GGPP. Physically located internalized vesicles within the Isoprenylation is the process which involves cytoplasm, derived from the membrane of the the transfer of a lipid group of farnesyl ruffled border, by the vesicular border remain (farnesylation) or geranyl-geranyl (geranyl- separated from the cytoplasmic content. Passive geranylation) onto an amino acid residue diffusion could be one process for crossing these (cysteine) in characteristic carboxy-terminal motifs membrane, although active or facilitated (eg, Cys-Ala-Ala-X). Suppression of FPP synthase transport may involve as suggested by recent by the N-BPs results into decline in the levels of evidences. both FPP and subsequently of GGPP. The Recently, by combining alendronate with consequent loss of protein geranyl-geranylation increasing dose of clodronate, the suppressed followed by osteoclast inactivation. This effect has effects of alendronate were found on its target been demonstrated by alendronate, ibandronate intracellular pathway within the osteoclast, which or risedronate in the inhibitory concentrarion of Review have its independent mechanism to work. This above aminobiphosphonate. suggest a participation of a structure specific Furthermore, HMG-CoA (3-hydroxy-3- Page 124 Page process, which showed that there was a methylglutaryl coenzyme A) reductase inhibitors, competition for entry mechanism into the lovastatin and mevastatin also mimicked the
cytoplasm. action of N-BP (upstream of FPP synthase), which Paper Molecular Target of the Nitrogen-containing can be also blocked by the addition of geranyl- Bisphosphonates: Farnesyl Diphosphate Synthase geraniol. FPP synthase identify as the relevant The signalling pathways are remains to be
molecular target by the Number of studies that determined which are involve geranyl- suggest that this enzyme have upstream in the geranylated small GTPases which are affected by pathway controlling both synthesis of cholesterol bisphosphonates and finally lead to osteoclast and isoprenylation, so it become the critical apoptosis. Most proximal to the GTPases is, the target of the N-BPs in the osteoclast. Recently, one mTOR (mammalian target of rapamycin) or from the in-vivo studies of the several N-BPs, another one is S6K (ribosomal protein S6 kinase) including alendronate, risedronate and signalling pathway. When geranyl-geranylation is ibandronate, but not for the simple blocked in the osteoclast, signalling through this bisphosphonates, clodronate and etidronate this path is suppressed. Downstream significance of N- molecular action has been confirmed. BP or rapamycin therapy include activation of In the cholesterol biosynthetic pathway caspases, pro-apoptotic kinase, and MST1 (Figure-2) farnesyl diphosphate (FPP) synthase is (mammalian sterile-zo-like kinase). MST1 was an enzyme that is responsible for producing the activated during apoptosis caused by NBPs, isoprenoid lipids FPP (15 carbon) and geranyl- lovastatin, and clodronate, which was identified geranyl diphosphate (GGPP; 20 carbon). FPP as a pro-apoptotic signalling intermediate
Covered in Scopus & Embase, Elsevier Int. J. Drug Dev. & Res., July-September 2013, 5 (3): 120-132 © 2013 Nadim M. R. Chhipa et al, publisher and licensee IYPF. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. downstream of the bisphosphonates. MST1 kinase acts as a substrate for caspases 3, 7 and 9 and as an activator of these caspases (Figure-3). The ruffled border acts a hallmark of active osteoclasts, which is a convoluted membrane that faces the bone surface. Disappearance of the ruffled border provides morphologic evidence for mechanism- based osteoclast inactivation and could explain the lack of acid extrusion caused by alendronate in isolated osteoclasts. Ruffled border formation is a process that is highly dependent on cytoskeletal function and strongly regulated by rosis: A Review rosis:Review A geranylgeranylated GTPases, such as Rac and Rho. 8 Figure 3: Schematic for nitrogen-containing bisphosphonate (N-BP) and clodronate molecular actions in suppressing osteoplastic bone resorption. GTPase—guanosine triphosphates; IPP—isopentenyldiphosphate; DMAPP—
dimethylallyl diphosphate. 125 Page
Classification of Aminobiphosphonates 9: 1) 1st Generation A) ETIDRONATE 6, 10-14
(1-hydroxy-1-phosphonoethyl) phosphonic acid
Molecular Formula: C2H8O7P2, Molecular Weight: 206.028244 Da The drug had been approved by FDA on 1 September 1977 for PROCTOR AND GAMBLE under the brand name DIDRONEL. Figure 2: Schematic of the cholesterol biosynthetic Brand Names : Cintichem, Technetium 99m, pathway. Sites of inhibition for the nitrogen- Hedspa, Dequest 2010, Didronel, Ferrofos 510, containing bisphosphonates (N-BPs;
Nadim M. R. Chhipa et al; Aminobiphosphonates in Osteopo in Aminobiphosphonates al; et Chhipa NadimR. M. farnesyldiphosphate [FPP] synthase) and statins (3- Osteoscan. hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] Physico-chemical Properties: reductase) are indicated. The basic structures of FPP and geranyl-geranyldiphosphate (GGPP) are Appearance: light beige powder also shown. DMAPP—dimethyl allyl diphosphate; Stability: Stable. Incompatible with strong oxidizing GTPase—guanosine triphosphate; IPP— isopentenyldiphosphate. agents
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Specific Gravity: 1.45 State: Solid Melting Point: 199°C Melting Point: 250ºC Log P: -3.8 Water Solubility: 395mg/ml Water solubility : 1.15e+01g/l Log P: -2.4 Pharmacokinetic Summary : Density: 2.306 g/cm 3 Oral Bioavailability : 1.6% Pharmacokinetic Summary: Volume of distribution : 1.4 L/kg Absorption: Around 1-3% from GIT
Terminal t 1/2 : >90 days Volume of distribution: 20 L Plasma Clearance : 6 hrs. Protein Binding: 2%-36%
Targets & Action: Terminal t 1/2 : 13 hours 1. Hydroxyapatite - Antagonist Targets & Action: 2. Receptor-type tyrosine-protein phosphatase S 1) ADP/ATP translocase 1: Inhibitor - Inhibitor 2) ADP/ATP translocase2: Inhibitor 3. V-type proton ATPase catalytic subunit A - 3) ADP/ATP translocase3: Inhibitor Inhibitor 4) Hydroxyapatite : Antagonist Indications: Indications: Review Paget’s disease Malignancy-related hypercalcemia Heterotopic Ossification Osteolytic bone metastases Page 126 Page Adverse Reactions: Gastrointestinal Complaints Adverse Reactions: Hypersensitivity, Rashes, (Diarrhoea, Nausea), Increased or Recurrent Bone Hypocalcaemia, Increased Parathyroid, Hormone
Pain at Pagetic Sites Level Paper Drug Interaction: Warfarin, Aluminium, Sucralfate. Drug Interaction: Antacid (calcium, iron, magnesium or aluminium-containing B) CLODRONATE 15-19 preparations), Aminoglycosides, Estramustine and
Calcium lowering agents.
10, 20-23 C) TILUDRONATE [Dichloro (phosphono) methyl] phosphonic acid
Molecular Formula: CH 4Cl 2O6P2, Molecular Weight: 244.892384 Da [(4-chlorophenyl) sulfanyl-phosphonomethyl] The Drug has not been approved by FDA still. The phosphonic acid
application had been filled by BERLEX Molecular Formula: C7H9ClO 6P2S, Molecular LABORATORIES under the name BONEFOS, FDA Weight: 318.608284 Da declared further trail awaited report for this drug The drug had been approved by FDA on 7 March on 11 May 2005. 1997 for SANOFI AVENTIS US under the brand Brand Names: Acidum Clodronicum [INN-Latin], name SKELID. Bonefos, Clasteon, Loron, Ostac Brand name: Skelid. Physico-Chemical Properties:
Covered in Scopus & Embase, Elsevier Int. J. Drug Dev. & Res., July-September 2013, 5 (3): 120-132 © 2013 Nadim M. R. Chhipa et al, publisher and licensee IYPF. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Physico-Chemical Properties: Log P: -4.7 State: Solid Solubility: In water and in 2N sodium hydroxide, Log P: -0.6 sparingly soluble in 0.1N hydrochloric acid and in Water solubility: 6.97e+00 g/l 0.1N acetic acid Density: 1.827 g/cm 3 Water solubility: 1.58e+01 g/l Pharmacokinetic Summary: Density: 1.999 g/cm 3 Oral bioavailability: 6% Pharmacokinetic Summary: Protein binding: Approx. 90% Absorption: Rapid after IV administration
T1/2 : 150 hours Protein binding: Approx. 54% to human serum Targets & Action: protein 1. Hydroxyapatite : Antagonist Metabolism &Excretion: Not metabolized but
rosis: A Review rosis:Review A 2. V-type proton ATPase catalytic subunit A : eliminated though renal excretion
Inhibitor T1/2 : mean ± SD elimination half-life is 28 ± 7 hours 3. Tyrosine-protein phosphatase non-receptor Renal Clearance: 49 ± 28 mL/min type 1 : Inhibitor Indications: Paget's disease Target & Action: Adverse Reactions: Painful or difficult swallowing, 1. Farnesyl pyrophosphate synthetase : Inhibitor
Severe Heartburn, Diarrhea, Joint Pain, Rashes. 2. Hydroxyapatite : Antagonist 127 Page Drug Interactions : Indomethacin, Warfarin, Indications: Diclofenac, Calcium. Hypercalcemia of Malignancy Paget’s disease 2) 2nd Generation: Osteolytic Bone Metastases of Breast Cancer A) PAMIDRONATE 10, 24-27 Osteolytic Lesions of Multiple Myeloma Adverse reactions: Fluid overload, Hypertension, Abdominal pain, Bone pain, Urinary Tract Infection. Drug Interactions: Loop diuretic, potentially
(3-Amino-1-hydroxy-1, 1-propanediyl) bis nephrotoxic drug, Thalidomoide (phosphonic acid)
B) ALEDRONATE 10, 28-31 Molecular Formula: C3H11 NO 7P2, Molecular Weight: 235.069504 Da The drug had been approved by FDA on 31 October 1991 for NOVARTIS under the brand
Nadim M. R. Chhipa et al; Aminobiphosphonates in Osteopo in Aminobiphosphonates al; et Chhipa NadimR. M. name AREDIA. (4-amino-1-hydroxy-1-phosphonobutyl) Brand names: Aredia, Amidronate, Aminomux phosphonic acid
Physico-Chemical Properties: Molecular Formula: C4H13 NO 7P2, Molecular Weight: State: Solid powder 249.096044 Color: White to practically white
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The drug had been approved by FDA on 29 Paget's disease. September 1995 for MERCK AND CO INC. under Adverse Reactions: Gastrointestinal Complaints the brand name FOSAMAX. (Diarrhea, Nausea), Abdominal pain, Brand names: Adronat, Alendros, Arendal, Musculoskeletal pain, Headache, Taste Fosamax, Fosamax Plus D, Onclast. prevention. Physico-Chemical Properties: Drug Interaction: Calcium supplements, Antacids, State: Solid Other multivalent Cations, Hormone Replacement Color& Nature: White, Crystalline & non- Therapy hygroscopic powder C) IBANDRONATE 10, 32-36 Solubility: soluble in water, very slightly soluble in alcohol, and practically insoluble in chloroform. Melting Point: 234ºC Water solubility: 1mg/m Log P: -4.3 pKa: 2.72(at 25°C)
Density: 1.857 gm/cm 3 {1-Hydroxy-3-[methyl (pentyl) amino]-1, 1-
propanediyl} bis (phosphonic acid) Review Pharmacokinetic summary: Molecular Formula: C9H23 NO 7P2, Molecular Weight: Mean oral bioavailability: 0.64% for doses 5 to 70 Page 128 Page 319.229004 Da mg in women The drug had been approved by FDA on 16 May Volume of distribution: 28 L 2003 for HOFFMANN LA ROCHE under the brand
Protein Binding: Approx. 78%
name BONIVA. Paper Metabolism: Not metabolized Brand names: Bondronate, Boniva, Bonviva Clearance: Renal (71 mL/min), Systemic (<200 Physico-Chemical Properties: mL/min) State: Solid
Target & Actions: Color& nature: White to off white powder
1. Farnesyl pyrophosphate synthetase : Inhibitor Solubility: Freely soluble in water, practically
2. Hydroxyapatite : Antagonist insoluble in organic solvents.
3. Tyrosine-protein phosphatase non-receptor Log P: -2.1 type 4 : Inhibitor Density: 1.45 g/cm 3
4. Receptor-type tyrosine-protein phosphatase Water solubility: 1.34e+01 g/l S: Inhibitor Pharmacokinetic Summary:
5. Receptor-type tyrosine-protein phosphatase Oral bioavailability: 0.6%
epsilon : Inhibitor Plasma t 1/2 : 10-60 hr.
6. V-type proton ATPase catalytic subunit A : Protein binding: Approx. 86% Inhibitor Volume of distribution: >90 L Indications: Target & Actions: Osteoporosis in postmenopausal women & 1. Farnesyl pyrophosphate synthetase : Inhibitor men 2. Hydroxyapatite : Antagonist Glucocorticoid-induced osteoporosis
Covered in Scopus & Embase, Elsevier Int. J. Drug Dev. & Res., July-September 2013, 5 (3): 120-132 © 2013 Nadim M. R. Chhipa et al, publisher and licensee IYPF. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Indications: t1/2 : 1.5 hr. Treatment of Postmenopausal Osteoporosis Clearance: 122 mL/min Treatment of osteoporosis is based on clinical Target & Actions: data of one year duration. 1. Farnesyl pyrophosphate synthetase : Inhibitor Adverse Reactions: Hypocalcaemia, 2. Hydroxyapatite : Antagonist Anaphylactic reactions, Renal impairment, Indication: Musculoskeletal Pain, Osteonecrosis of the Jaw Treatment & prevention of osteoporosis in Drug Interaction: Melphalan/Prednisolone, Bone postmenopausal women Imaging Agents, Tamoxifen Treatment of osteoporosis in men Treatment & prevention of glucocorticoid- B) RISEDRONATE 10, 37-40 induced osteoporosis in men & women Paget’s disease rosis: A Review rosis:Review A Adverse Reaction: Abdominal pain, Headache, Dyspepsia, Nausea, Rash, Pertussis, Osteonecrosis
of jaw, musculoskeletal pain (1-hydroxy-1-phosphono-2-pyridin-3-ylethyl) Drug Interaction: Antacids and calcium phosphonic acid Molecular Formula: C7H11 NO 7P2, Molecular Weight: supplements which contain polyvalent cations,
283.112264 Hormone replacement therapy (HRT), H 2-blockers 129 Page The drug had been approved by FDA on 27 and PPIs. March 1998 for WARNER CHILCOTT LLC under the brand name ACTONEL. 3) 3rd Generation: ZOLEDRONATE 10, 41-45 Brand names: Actonel, Benet Physico-Chemical Properties: State: Solid Color& nature: White to off white crystalline powder Solubility: soluble in pH 7.0 potassium phosphate [1-Hydroxy-2-(1H-imidazol-1-yl)-1,1- dibasic solution, 0.1 N sodium hydroxide, and ethanediyl]bis(phosphonic acid) water; very slightly soluble in 0.1 N hydrochloric
acid, practically insoluble in ethanol, and insoluble Molecular Formula: C5H10 N2O7P2, Molecular in isopropanol. Weight: 272.089624 Log P: -3.6 The drug had been approved by FDA on 16 April Density: 1.871 g/cm 3 2007 for NOVARTIS under the brand name Water Solubility: 1.04e+01 g/l RECLAST. Nadim M. R. Chhipa et al; Aminobiphosphonates in Osteopo in Aminobiphosphonates al; et Chhipa NadimR. M. Pharmacokinetic Summary: Physico-Chemical properties: Absorption: ~1 hr after oral dose State: Solid Volume of distribution: 13.8 L/kg Color& nature: White crystalline powder Protein Binding: ~24% Log P: -4.2 Density: 2.136 g/cm 3
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Water solubility: 3.27e+00 g/l need of investigation in this area as the Pharmacokinetic summary: osteoporosis is world-wide distributed disease by Absorption: Approx. 1% oral absorption making the aminobiphosphonate as the marker Protein Binding: ~22% for further investigation.
t1/2 : 146 hrs. Clearance: 3.7 +/- 2.0 L/h References: Target & actions:
1. Farnesyl pyrophosphate synthetase : Inhibitor 1) Kanjis, J. A. "Osteoporosis." Journal of Medical Sciences 3(3), (2010): 124-130. 2. Hydroxyapatite : Antagonist 2) “Classification of Osteoporosis” Orthopaedic 3. Geranyl-geranyl pyrophosphate synthetase : Specialists of North Carolina, OSNC, Web. 22 Mar. Inhibitor 2013 from
Stuart H. Ralston "Aminobisphosphonates Cause
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Covered in Scopus & Embase, Elsevier Int. J. Drug Dev. & Res., July-September 2013, 5 (3): 120-132 © 2013 Nadim M. R. Chhipa et al, publisher and licensee IYPF. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.