Bisphosphonates administration

It is important to note that normalisation of serum calcium may take 3-4 days following bisphosphonate administration so further dosing should not occur before this time. 

Adami, S., Bhalla, A.K., Dorizzi, R., Montesanti, F., Rosini, S., Salvagno, G., and Lo Cascio, V. (1987). The acute-phase response after bisphosphonate administration. Calcif Tissue Int 41 326-331. 

I Administration. Even under optimal conditions, all bisphosphonates are poorly absorbed (bioavailabihty = 1% to 5%). Bisphosphonates must be administered carefully to optimize the chnical benefit and minimize the risk of adverse G1 effects. Each oral tablet should be taken with at least 4 ounces of plain tap water (not coffee, juice, mineral water, or milk) at least 30 minutes before consuming any food or any other supplement or medication. The weekly oral solution needs to be taken with only 2 ounces of water. The patient should remain upright (either sitting or standing) for at least 30 minutes after bisphosphonate administration. When calcium and vitamin D dietary consumption are insufficient, supplementation is needed to ensme the beneficial effects of bisphosphonates. 

Most patients prefer once-weekly bisphosphonate administration (see Table 88-6). This dosing schedule lowers G1 tract drug exposure. Because the turnover rate of the cells lining the G1 tract is about 5 days, any cells damaged during drug exposure are theoretically replaced before the next week s dose is taken. Once-weekly alendronate administration achieved similar BMD results, had similar GI adverse effects, and did not impair mineralization, compared with daily doses of 10 mg. ... 

Proper drug administration is important for optimal absorption and prevention of adverse effects. Oral bisphosphonates... 

Bone disease is a common manifestation of multiple myeloma. Bisphosphonates should be initiated in symptomatic patients with bone lesions to slow osteopenia and reduce the fracture risk associated with the disease. Pamidronate and zolendronic acid have equivalent efficacy in the management of osteolytic lesions, but because of relative ease of administration, zolendronic acid is used most frequently.43 The use of zolendronic acid decreases pain and bone-related complications and improves quality of life. The suggestion that bisphosphonates have direct antimyeloma activity, based on the ability to inhibit NF-kB signaling, remains controversial. Recent cases of osteonecrosis of the jaw have been a major concern. Risk factors are unclear, but osteonecrosis of the jaw is more common in patients receiving intravenous administration of bisphosphonates and having dental procedures performed. It is recommended that patients... 

In other studies, bisphosphonate-pamidronate or alendronate were linked to the terminal carboxylic acid of the stabilized dipeptide Pro-Phe to improve the bioavailability of bisphosphonates by hPepTl-mediated absorption. In-situ single-pass perfused rat intestine studies revealed competitive inhibition of transport by Pro-Phe, suggesting carrier-mediated transport. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration to rats. The authors suggested that oral bioavailability of bisphosphonates may be improved by PepTl-mediated absorption when administered as peptidyl prodrugs [53]. Future mechanistic studies may prove if hPepTl is involved in the absorption process. 

The most common bisphosphonate adverse effects are nausea, abdominal pain, and dyspepsia. Esophageal, gastric, or duodenal irritation, perforation, ulceration, or bleeding may occur when administration directions are not followed or when bisphosphonates are prescribed for patients with contraindications. The most common adverse effects of IV bisphosphonates include fever, flu-like symptoms, and local injection-site reactions. Osteonecrosis of the jaw occurs rarely if it develops, oral chlorhexidine washes, systemic antibiotics, and systemic analgesics are used based on severity. 

Bonviva consists of ibandronic acid, a bisphosphonate and is available as 150 mg tablets and 1 mg/mL injection. Patients receiving the oral formulation for the treatment of postmenopausal osteoporosis are advised to take one tablet once a month. Absorption of bisphosphonates from the gastrointestinal tract may be effected by food or other administered drugs. Therefore patients are advised to take the Bonviva 150 mg tablet at least 1 hour before breakfast or another oral medicine and to continue standing or sitting upright for at least 1 hour after administration. 

AP23451 administration to mice inoculated with MDA-231 breast cancer cells effectively prevents metastasis-induced osteolysis similar to bisphosphonate zoledronic (Zometa ). However, it also significantly reduces the volirme of tumor cells inside the bone marrow cavities of the mice as opposed to a lack of inhibitory effect on tirmor cell volume in mice treated with zoledronic acid. AP23588 is also a bone-targeted Src kinase inhibitor which has been determined to possess both anti-resorptive and anabohc properties in vitro with respect to reducing osteoclast activity and stimulating osteoblast activity, respectively. 

Asthma (zoledronic acid) While not observed in clinical trials with zoledronic acid, administration of other bisphosphonates has been associated with bronchoconstriction in aspirin-sensitive asthmatic patients. Use zoledronic acid with caution in patients with aspirin-sensitive asthma. 

Agents include etidronic acid, pamidronic acid, clodronic acid, alendronic acid, ibandronic acid, rise-dronic acid, zoledronic acid and tiludronic acid. Formulations of clodronic acid and pamidronic acid are available for intravenous administration. The indications for the use of bisphosphonates include treatment of postmenopausal osteoporosis, hypercal-caemia of malignancy and Paget s disease. 

Alternatives to steroid hormone therapy for osteoporosis include raloxifene, bisphosphonates, sodium fluoride, vitamin D and calcium supplementation, calcitonin, and parathyroid hormone. Tamoxifen has estrogenic effects on bone and delays bone loss in postmenopausal women. However as a result of estrogenic activity in the uterus, long-term tamoxifen administration has been associated with an increased risk of... 

Calcitonin is also effective in reducing serum calcium levels in life-threatening hypercalcemia however, it is not as rapid or as effective as the bisphosphonates. Subcutaneous administration of salmon (Calcimar) or human (Cibacalcin) calcitonin reduces serum calcium levels within 3 to 5 days in 75 to 90% of malignant hypercalcemias. 

With the exception of the possible development of a hypervitaminosis associated with high-dose administration of vitamin D2 or D3, the compounds discussed in this chapter are relatively safe. Allergic reactions to the injection of calcitonin and PTH have occurred and chronic use of some bisphosphonates has been associated with the development of osteomalacia. The principal side effects of intravenous bisphosphonates are mild and include low-grade fever and transient increases in serum creatinine and phosphate levels. Oral bisphosphonates are poorly absorbed and can cause esophageal and gastric ulceration. They should be taken on an empty stomach the individual must remain upright for 30 minutes after ingestion. 

Mechanism of Action A bisphosphonate that inhibits normal and abnormal bone resorption, without retarding mineralization. Therapeutic Effect Leads to significantly increased bone mineral density reverses the progression of osteoporosis. Pharmacokinetics Poorly absorbed after oral administration. Protein binding 78%. After oral administration, rapidly taken into bone, with uptake greatest at sites of active bone turnover. Excreted in urine. Terminal half-life Greater than lOyr (reflects release from skeleton as bone is resorbed). 

A detailed account of the biochemistry of the bisphosphonates has recently appeared elsewhere170). Briefly, the bis-phosphonates inhibit soft tissue calcification. Bis-phospho-nates, such as HEBP inhibit the mineralization of cartilage, bone and dentine. Prolonged administration of HEBP to man at oral doses of 10 mg-1 kg-1 for more than one month affects the mineralization of hard tissues. Slight changes in the substituents on the gemi-... 

The treatment of Mrs CR s hypercalcaemia is urgent and requires immediate administration of bisphosphonate therapy, the first choice therapy in cases of severe hypercalcaemia. Currently four bisphosphonates are available in the UK for the treatment of malignant hypercalcaemia - sodium clodronate, disodium pamidronate, zoledronic acid and ibandronic acid. The choice of which bisphosphonate to recommend will depend on which one is on the local hospital formulary. 

Continued treatment with bisphosphonate may also be appropriate to not only reduce the likelihood of recurrent hypercalcaemia but also to manage Mrs CR s bone metastases. Many guidelines (including the NICE Improving outcomes guidance for breast cancer, 2002a) recommend the use of bisphos-phonates to reduce the onset of skeletal complications such as skeletal fractures. An appropriate suggestion would be to continue one of the bisphosphonates previously outlined at three-weekly intervals (to coincide with chemotherapy administration). 

First, Mrs TY should be advised that teriparatide is only available as an injection and, therefore, Mrs TY may not find this an acceptable route of administration. Second, the NICE guidelines state that teriparatide should only be used in postmenopausal women who are unable to take bisphosphonates or strontium or who have had an unsatisfactory response bisphosphonates. They must also have experienced more than two fractures and have a T-score which fits into the range specified in the NICE guidance (NICE 2008). 

Q9 The hypercalcaemia which occurs in hyperparathyroidism may be reduced by administration of a loop diuretic such as furosemide, which helps calcium excretion. Bisphosphonates, which prevent bone resorption and so reduce calcium release from bone, can be used to treat hypercalcaemia associated with malignancies. Calcitonin may also be useful in treating the hypercalcaemia associated with cancer, as it reduces calcium levels both by attenuating its renal reabsorption and by increasing calcium deposition in bone. 

Bisphosphonates, regardless of route of administration, have also been associated with hallucinations (auditory and olfactory) (106) and visual disturbances (107). 

Other bisphosphonates, such as etidronate and pamidro-nate, have caused both reversible and irreversible auditory, visual, and olfactory hallucinations beginning 2 hours to 1 week after drug administration. The mechanism of these adverse effects is unknown but is thought to be independent of calcium homeostasis. 

NS AIDs BISPHOSPHONATES -ALENDRONATE Risk of oesophagitis/peptic ulceration Additive effect Avoid co-administration... 

The development of bisphosphonates for clinical purposes began with the discovery that inorganic pyrophosphate is present in blood and urine and inhibits the precipitation of calcium and phosphate (1). Derivatives of pyrophosphate had been widely used for industrial purposes, because they inhibit the precipitation of calcium carbonate. Their principal use was as antiscaling additives in washing powders, water, and oil brines, to prevent deposition of calcium carbonate scale. It was then found that pyrophosphate binds strongly to calcium phosphate, prevents both the formation and dissolution of calcium phosphate crystals, and inhibits calcification in vitro. The bisphosphonates are used to treat bone diseases characterized by increased osteoclastic bone resorption (2). Long-term administration of low doses of oral bisphosphonates is considered to be valuable in patients with postmenopausal osteoporosis (3,4). 

Pamidronate in the disodium form, a second-generation bisphosphonate, has an intermediate antiresorptive activity its continuous administration produces rapid suppression of bone resorption. Unlike etidronate, it does not impair bone mineralization at therapeutic dosages in patients with Paget s disease. Pamidronate inhibits osteoclast activity primarily by binding with hydroxyapatite crystals in the bone matrix, preventing the attachment of osteoclast precursor cells. Other mechanisms of action of matrix-bound pamidronate may include direct... 

Calcitonin inhibits osteoclastic bone resorption, increases the urinary excretion of calcium and phosphate, and reduces serum calcium. It is established in the treatment of disorders of high bone turnover, including Paget s disease and postmenopausal osteoporosis, but is less effective than the bisphosphonates. Calcitonin is less effective than other therapeutic measures in the treatment of acute hypercalcemia. Long-term administration of calcitonin reduces morbidity in cases of osteogenesis imperfecta... 

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