Bisphosphonates

The bisphosphonates (also called diphosphonates) are a group of inorganic compounds that include alendronate (Fosamax), pamidronate (Aredia), and several 

Calcitonin derived from synthetic sources can be administered to mimic the effects of the endogenous hormone. As described previously, endogenous calcitonin decreases blood calcium levels and promotes bone mineralization. Consequently, synthetically derived calcitonin is used to treat hypercalcemia and to 

In the past, calcitonin was administered by injection (intramuscular or subcutaneous), but aerosolized versions of calcitonin are now available that allow delivery in the form of nasal sprays.51,68 Oral delivery of calcitonin is difficult because this hormone is absorbed poorly from the gastrointestinal (GI) tract and because calcitonin is degraded by proteolytic enzymes in the stomach.57 Nonetheless, efforts are being made to overcome these limitations, and an oral form of calcitonin may be available someday.62 

calcitonin has emerged as an effective and easy way to treat a variety of conditions that are characterized by increased bone resorption.59,82 Calcitonin preparations used clinically are either identical to the human form of this hormone (Cibacalcin) or chemically identical to salmon calcitonin (Calcimar, Miacal-cin). Redness and swelling may occur locally when these agents are administered by injection. Other side effects include gastrointestinal disturbances (stomach pain, nausea, vomiting, and diarrhea), loss of appetite, and flushing or redness in the head, hands, and feet. 

Primary drug BISPHOSPHONATES Secondary drug Effect Mechanism Precautions 

ALENDRONATE ANALGESICS-NSAIDs Risk of oesophagitis/peptic ulceration Additive effect Avoid co-administration 

BISPHOSPHONATES ANTACIDS 1 bisphosphonate levels 1 absorption Separate doses by at least 30 minutes 

SODIUM CLODRONATE ANTIBIOTICS -AMINOGLYCOSIDES Risk of symptomatic hypocalcaemia Uncertain Monitor calcium levels closely 

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Chemical Name (1-Hydroxyethylidene)bisphosphonic acid disodium salt Common Name —... 

Bisphosphonates (BP) are today the first line treatment of benign and malignant bone diseases. As pyrophosphate analogues (Fig. 3), BP accumulate in bone and are taken up by osteoclasts. Once in the cell, the nitrogen-containing BP (N-BP) such as Alendronate, Risedronate, Ibandronate and Zoledronate effectively inhibit osteoclast resorption and induce cell... 

Bisphosphonates have been shown to be highly effective in osteoporosis, cancer bone metastasis, multiple myeloma, and Paget s disease of bone. While generally very well tolerated, these drugs do have potential adverse effects. Recently, the association of long-term high dose bisphosphonate treatment with osteonecrosis of the jaw has been described. This is a potentially serious side effect seen mostly in patients with multiple myeloma or... 

Bone Metabolism. Figure 3 Chemical structure of pyrophosphate (a) and the bisphosphonates etidronate (b), clodronate (c), pamidronate (d), ibandronate (e). alendronate (f), risedronate (g), zoledronate (h). 

Bone Metabolism. Figure 4 The mevalonate pathway. Interferences by statins and N-containing bisphosphonates are shown. 

The bisphosphonates are drags used to treat musculoskeletal disorders such as osteoporosis and Fhget s disease. This chapter will discuss the use of these drugs in the treatment of osteoporosis. 

The bisphosphonates are used to treat osteoporosis in postmenopausal women, Paget s disease of the bone, and postoperative treatment after total hip replacement (etidronate). 

Adverse reactions with the bisphosphonates include nausea, diarrhea, increased or recurrent bone pain, headache, dyspepsia, acid regurgitation, dysphagia, and abdominal pain. 

These dragp are contraindicated in patients who are hypersensitive to the bisphosphonates. Alendronate and risedronate are contraindicated in patients with hypocalcemia Alendronate is a pregnancy Category C drug and is contraindicated during pregnancy. These drugp are contraindicated in patients with renal impairment with serum creatinine less than 5 mg/dL. Concurrent use of these dm with hormone replacement therapy is not recommended. 

When administered with ranitidine, alendronate bioavailability is increased. When calcium supplements or antacids are administered with risedronate or alendronate, absorption of the bisphosphonates is decreased, hi addition, risedronate absorption is inhibited when the drug is administered with magnesium and aluminum. There is an increased risk of gastrointestinal... 

BISPHOSPHONATES. When administering alendronate or risedronate the nurse gives the drug orally in the morning before the first food or drink of the day. Risedronate and etidronate are administered once daily. Etidronate is not administered within 2 hours of food, vitamin and mineral supplements, or antacids. 

ISPHOSPHONATES The nurse monitors the patient taking the bisphosphonates for any adverse reactions such as nausea, diarrhea, increased or recurrent bone pain, headache dyspepsia, acid regurgitation, dysphagia, and abdominal pain. Analgesic maybe administered for headache Notify the primary health care provider of adverse reactions such as the return of bone pain or severe diarrhea... 

CN [ 1 -hydroxy-3-(methylpentylaniino)propylidene]bisphosphonic acid monosodium salt monohydrate anhydrous... 

G)H2Cl7N20 86567-35-0) see Apraclonidine (dichloromethylene)bisphosphonic acid tetrakis(l-methyl-ethyl) ester... 

The bisphosphonate - upon reduction with lithiumaluminum hydride in ether at 0°C - produced the amide functionalized primary bisphosphine (1) in good yields [45]. This reaction proceeded to reduce the amide group in 1 to produce the amine functionaUzed primary bisphosphine (2) in <5% yields. The amido bisprimary phosphine 1 is an air stable crystalline solid whereas the amine compound 2 is an oxidatively stable liquid. Separation of 1 and 2 in pure forms was achieved using coliunn chromatography. The amidic bisprimary phosphine 1 was crystallized from chloroform and exhibits remarkable stability not only in the solid state but also in solution as well. The crystal structure of the air stable primary his-phosphine 1 as shown in Fig. 1 is unprecedented to date. 

The thioether functionalized bisphosphonates, 7 and 8, upon reduction with LiAlH4 produced the corresponding S2P2 and S3P2 primary bisphosphine frameworks 9 and 10 respectively in good yields (Scheme 4) [47,48]. 

The Wittig-Horner procedure, starting from bisphosphonate or aromatic bisphosphine oxide monomers, allows for AA/BB-coupling of the PO-activated bismethylene monomers, not only with aromatic dialdehydes but also with aromatic diketones to the corresponding PPV derivatives (76), and for the selfcondensation of AB-type aromatic starting compounds containing both alde-hyde/keto and PO-activated methylene functions [101]. 

BRENCKMANN 0 and PAPAIOANNOU A (2001) Bisphosphonates for osteoporosis in people with cystic fibrosis. Cochrane Database Syst Rev. 4 CD002010. 

TERONEN O, HEIKKILA P, KONTTINEN Y T, LAITINEN M, SALO T, HANEMAAIJER R, TERONEN A, MAISI p and SORSA t (1999) MMP inhibition and downregulation by bisphosphonates. Ann NYAcadSci. SIS 453-65. 

R (2002) Novel antiangiogenic effects of the bisphosphonate compoimd zoledronic acid. J Pharmacol Exp Then 302 (3) 1055-61. 

Bisphosphonic acids and their salts are analogs of pyrophosphate where the P-O-P linkage of the latter has been replaced by P-C-P. Bisphosphonates are known to inhibit bone resorption, and have attracted much attention as potential therapeutic agents. Bisphosphonates do not absorb or fluoresce, and sample matrix interferences can make detection difficult, especially in biological samples. Successful applications of IEC to bisphosphonate analysis have been described.173174... 

Lovdahl, M. J. and Pietrzyk, D. J., Anion-exchange separation and determination of bisphosphonates and related analytes by post-column indirect fluorescence detection,. Chromatogr A, 850, 143, 1999. 

May be superior to bisphosphonates for humoral hypercalcemia of malignancy (PTHrp)... 

Patients with IBD, particularly those with CD, are also at risk for bone loss. This may be a function of malabsorption or an effect of repeated courses of corticosteroids. Patients with IBD should receive a baseline bone density measurement prior to receiving corticosteroids. Vitamin D and calcium supplementation should be used in all patients receiving long-term corticosteroids. Oral bisphosphonate therapy may also be considered in patients receiving prolonged courses of corticosteroids or in those with osteopenia or osteoporosis. 

Central bone mineral density testing to evaluate the need for preventive or therapeutic bisphosphonate therapy ... 

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