Copyright © 2013 By IYPF All rights reserved Open Access Contents Int. J. Drug Dev. & Res . | July-September 2013 | Vol. 5 | Issue 3 | ISSN 0975-9344 | www.ijddr.in Aminobiphosphonates in Osteoporosis: A Review Nadim M. R. Chhipa Abstract: Osteoporosis is a disease of great social impact, in recent years has assumed increasing importance, due to the progressive ageing of the Prof. Dr. Dhrubo Jyoti Sen population and the consequent increase of its complications, first of al l femoral and vertebral fractures. Various treatment strategies has been Department of employed to overcome, Aminobiphosphonate is one of them & they Pharmaceutical Chemistry, Shri represents a major advance in the treatment of musculoskeletal disorders Sarvajanik Pharmacy College, and they are now amongst the most commonly used agents in clinical Gujarat Technological practice. Bisphosphonates are analogues of inorganic pyrophosphate University, Arvind Baug, and are inhibitors of bone resorption. Many derivatives have been Mehsana-384001, Gujarat, developed for the treatment of enhanced bone resorption. In this review, India we explore the potential appli cations of that concept by summarizing the bone diseases and candidate proteins that will benefit from the proposed Corresponding Authors: bone delivery approach. A selective synopsis of BP synthesis is presented Nadim M. R. Chhipa to highlight the synthesis of functional BPs suitable for covalent Email: attachment to proteins. [email protected] Review Page 120 Page 120 Keywords: Aminobiphosphonate, Osteoporosis, Pyrophosphates, Osteoclast, Osteoblast. or more osteoporotic fractures in their lifetime. Introduction Common sites of fracture include the vertebral Paper Bisphosphonates are pyrophosphate analogues in bodies, distal radius, proximal femur and the which the oxygen bridge has been replaced by a proximal humerus. 1 carbon with various side chains P-C-P. These Etiology: compounds have been known to the chemist The most common cause of osteoporosis arises since the 19th century, the first synthesis dating from estrogen deficiency that begins some years back to 1865. After discovering that they can before the time of menopause. The skeleton effectively control calcium phosphate formation comprises approximately 20% trabecular bone and dissolution in-vitro , as well as mineralization and 80% cortical bone and undergoes a and bone resorption in-vivo . They were developed continual process of resorption and formation, and used in the treatment of bone diseases. governed by the activity of bone cells in bone Osteoporosis: remodellingunits. Estrogen deficiency accelerates Osteoporosis is described by the World Health the normal of bone tissue, but the net activity of Organization as a ‘progressive systemic skeletal bone resorbing cells (osteoclasts) is greater than disease characterized by low bone mass and that of bone forming cells (osteoblasts). This gives micro architectural deterioration of bone tissue, rise to thinning of the cortices of bones, thinning of with a consequent increase in bone fragility and trabecular bone and loss of trabecular elements. 1 susceptibility to fracture’. More than one-third of (Figure-1) adult women and one in five men will sustain one Covered in Scopus & Embase, Elsevier Int. J. Drug Dev. & Res., July-September 2013, 5 (3): 120-132 © 2013 Nadim M. R. Chhipa et al, pub lisher and licensee IYPF. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. 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:AReview 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 Page 121 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 et al; Chhipa Nadim R. 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. 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. 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 OH R1 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 122 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.