Bisphosphonates

1. Bisphosphonates

2. Bisphosphonates are pyrophosphate analogues in which the oxygen in p – o – p has been replaced by a carbon, resulting in a metabolically stable p – c – p structure Resistant to enzymatic destruction

3. Bisphosphonates have two side chains: R1 affects binding affinity tobone ; R2 affects antiresorptive capacity and, possibly, Side-effect profile. Bisphosphonates vary in potency Based on these specific side chains.

4. .

5. Generations of Bisphosphonates With each successive generation, there has been increased potency, with more selectivity for inhibition of resorption and less inhibition of bone formation . First-generation bisphosphonates , such as etidronate and clodronate , inhibit bone formation and bone resorption equally.   Second-generation bisphosphonates include pamidronate and alendronate   The third generation includes the highly potent risedronate and zolendronate .

6. Mechanism of action Nitrogenous bisphosphonates act on bone metabolism by binding and blocking the enzyme farnesyl diphosphate synthase (FPPS) in the HMG- coa reductase pathway (also known as the mevalonate pathway)

7. Disruption of the HMG coa-reductase pathway at the level of FPPS prevents the formation of two metabolites ( farnesol and geranylgeraniol ) that are essential for connecting some small proteins to the cell membrane . This phenomenon is known as prenylation , and is important for proper sub-cellular protein trafficking

8. While inhibition proteins can affect osteoclastogenesis , cell survival, and cytoskeletal dynamics. In particular, the cytoskeleton is vital for maintaining the "ruffled border" that is required for contact between a resorbing osteoclast and a bone surface.

9. Non- N -containing bisphosphonates Etidronate , Clodronate , Tiludronate The non-nitrogenous bisphosphonates ( disphosphonates ) are metabolised in the cell to compounds that replace the terminal pyrophosphate of ATP, forming a nonfunctional molecule that competes with ATP in the cellular energy metabolism. The osteoclast initiates apoptosis and dies, leading to an overall decrease in the breakdown of bone

10. Pharmacokinetics Oral bisphosphonates have a very low bioavailability and poor gastrointestinal absorption rates (from < 0.7% alendronate and risedronate to 6% for etidronate ). Oral absorption can be diminished in the presence of mineral water, other liquids,or food in the stomach. Absorbed bisphosphonate r emains in the skeleton for prolonged periods(half-lives of 1.5 to 10 years), whereas nonincorporated drug is excreted in the urine

11. Indications for Use Indications for bisphosphonates include such conditions Postmenopausal Glucocorticoid -induced osteoporosis, Paget’s disease, Osteolytic and osteoblastic bone metastases, Fibrous dysplasia, Heterotopic ossification, Myositis ossificans . Other bisphosphonates , medronate (R 1 , R 2 = H) and oxidronate (R 1 = H, R 2 = OH) are mixed with radioactive technetium and are injected for imaging bone and detecting bone disease

12. Fracture Intervention Trial Here 658 osteoporotic women w ith either vertebral fracture or osteoporosis at femoral neck were treated with alendronate for 3 to 4 Years . There was decreased risk of fracture, with relative risks of 0.47 for hip fracture , 0.52 for radiographic vertebral fracture, 0.55 for clinical vertebral fracture , and 0.70 for all clinical fractures

13. An oral daily dose of risedronate (5 mg) resulted in BMD increases after 6 months of therapy. At 24 months, lumbar spine BMD increased from baseline by 4%, with increases of 1.3% and 2.7% in the femoral neck and femoral trochanter , respectively A single weekly dose is as clinically effective as daily dosage but with lower incidences of dyspepsia,Esophagitis , and gastroesophageal reflux disease (GERD)

14. Thirteen patients who received 30 mg of pamidronate i ntravenously over 3 months had an increased BMD of 6.2 % in the lumbar spine and 4.7% in the hip. Parenteral zolendronate administered at annual intervals showed 4.3 % to 5.1 % increase in BMD in the treatment group f or spine than in the placebo group

15. Bisphosphonates in Metastatic disease They control hypercalcemia , Reduce bone pain, Delay skeletally related events ( sres ), Reduce the number of pathologic fractures, Prolong survival .

16. Intrvenous zolendronate and palmindronate are the ones most useful and should be combined with either chemotherapy or hormonal therapy in women with metastatic bone disease. Zolendronate is the first bisphosphonate shown to be effective in both lytic and blastic metastatic disease

17. Studies suggest the use of bisphosphonates As oral and local adjuvants in total joint arthroplasties increase periimplant bone density or reduce implant migration The effect of soaking morselized allograft in bisphosphonate before impacting it around an experimental implant has been described

18. Drug Interactions Bisphosphonates generally should not be taken with antacids that contain aluminum or magnesium, bottled water containing minerals, or calcium supplements because these agents decrease bisphosphonate absorption . Food renders bisphosphonates ineffective; A 2-hour interval between meals drug is recommended. Aminoglycosides t aken with bisphosphonates may cause severe hypocalcemia .

19. Adverse effects Oral bisphosphonates causes Gastrointestinal complications such as gastritis or esophagitis , abdominal pain, nausea, vomiting, diarrhea, and constipation. To minimize gastrointestinal inflammation And ulcer, patients should remain upright (sitting or standing) for at least 30 minutes after taking the medication

20. BISPHOSPHONATE-RELATED OSTEONECROSIS OF THE JAW AKA Phossy jaw American Academy of Oral and Maxillofacial Surgeons (AAOMS) proposed a definition for bisphosphonate -related ONJ that requires the satisfaction of the following criteria: (1) Current or prior use of bisphosphonate (2) An area of exposed bone within the maxillofacial region without healing for more than 8 weeks (3) Absence of history of radiation to the jaws

21. It has been postulated that reduced bone remodeling associated with bisphosphonate use may lead to an increased risk of developing bone necrosis in select patients. The antiangiogenic effects of bisphosphonates may result in a reduction in the blood supply to the region and contribute to poor wound healing. Infection has also been implicated in the pathogenesis of ONJ

22. STAGES stage 1- were patients with asymptomatic necrotic bone stage 2- accompanied by infection with or without purulent drainage stage 3- patients with necrotic bone accompanied by infection, pain, and at least one of the conditions, including pathologic fractures, extraoral fistula, or osteolysis extending to the inferior border

23. ATYPICAL SUBTROCHANTERIC AND DIAPHYSEAL FRACTURES bisphosphonate may alter the biomechanical properties of bone matrix via its effect on bone collagen and bone mineralization density distribution, resulting in brittle and stiff bones that could fracture with littletrauma . Reduced bone remodeling, coupled with the antiangiogenic effect of bisphosphonates , may further impair the healing of stress fractures, which eventually develop into a complete fracture.