Bisphosphonates dosing

The nephrotoxic potential of bisphosphonates has been well documented in numerous preclinical and clinical studies, but the molecular mechanism remains elusive. The observed effects on kidney cells in clinical biopsies are reminiscent of those reported in osteoclasts namely, the inhibition of FTPS and reduced prenylation of key signalling proteins, thereby impairing normal intracellular metabolism and inducing apoptosis [94]. Moreover, mitochondrial changes revealed by electron microscopy of renal biopsies also resemble those associated with bisphosphonate-induced inhibition of the mevalonate pathway [89, 97]. This hypothesis is supported by the fact that the fraction of a bisphosphonate dose that does not bind bone is exclusively cleared by renal excretion, thus exposing the kidney to high drug levels. 

Cramer JA, Amonkar MM, Hebborn A, Altman R. Compliance and persistence with bisphosphonate dosing regimens among women with postmenopausal osteoporosis. Curr Med ResOpin 2005 21 1453-1460. 

Baran D Osteoporosis. Efficacy and safety of a bisphosphonate dosed once weekly. Geriatrics... 

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... 

Hormone-replacement therapy is also indicated for the prevention of osteoporosis but is not recommended for longterm use. Alternatives such as bisphosphonates or raloxifene should be considered as first-line therapy for the prevention of osteoporosis, in addition to appropriate doses of calcium and vitamin D. 

BMD will increase and the risk of fractures will decrease in women taking HRT. However, when therapy is discontinued, a decline in BMD will resume at the same rate as in women not on HRT. Therefore, therapy for osteoporosis prevention should be considered long term. Since HRT should be maintained only for the short term, alternative therapies such as bisphosphonates or raloxifene should be considered as first-line therapy for the prevention of postmenopausal osteoporosis, in addition to appropriate doses of calcium and vitamin D. Because of the risks associated with HRT, it should not be prescribed solely for the prevention of osteoporosis. 

There is considerable interest in using injectable bisphosphonates, such as pamidronate and zoledronic acid, in patients unable to tolerate or absorb oral bisphosphonates. Zoledronic acid in particular has a potential advantage of once-yearly dosing. Currently, neither drug has received FDA approval for this indication. Ibandronate has recently been approved for this indication. 

BMD increases are dose dependent and greatest in the first 6 to 12 months of therapy. Small increases continue over time at the lumbar spine but plateau after 2 to 5 years at the hip. After discontinuation, the increased BMD is sustained for a prolonged period that varies depending on the bisphosphonate used. 

Teriparatide can be used if bisphosphonates are not tolerated or contraindicated. Testosterone replacement therapy should be considered in men, and high-dose hormonal oral contraceptives can be considered for premenopausal women with documented hypogonadism. 

Use caution when bisphosphonates are given to patients with active upper Gl problems (such as dysphagia, esophageal diseases, gastritis, duodenitis, or ulcers). Etidronate therapy has been withheld from patients with enterocolitis because diarrhea is seen in some patients, particularly at higher doses. 

Oral formulations are very poorly absorbed with bioavailability ranging from less than 1-6%. Doses should be taken on an empty stomach to improve absorption. Increasing the dose will lead to gastrointestinal complaints. Of the absorbed dose 20-50% is adsorbed to bone and only very slowly released. Free bisphosphonates are eliminated in the urine with an apparent half-live of about 20 hours. However, the elimination half-life of risedronic acid is more than... 

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. 

Second-generation" bisphosphonate that offers potential advantages over etidronate (as does alendronate) in that it inhibits bone resorption at doses that do not impair bone mineralization, and is less likely than etidronate to produce osteomalacia... 

The goal of treatment is to reduce bone pain and stabilize or prevent other problems such as progressive deformity, hearing loss, high-output cardiac failure, and immobilization hypercalcemia. Calcitonin and bisphosphonates are the first-line agents for this disease. Treatment failures may respond to plicamycin. Calcitonin is administered subcutaneously or intramuscularly in doses of 50-100 MRC (Medical Research Council) units every day or every other day. Nasal inhalation at 200-400 units per day is also effective. Higher or more frequent doses have been advocated when this initial regimen is ineffective. Improvement in bone pain and reduction in serum alkaline phosphatase and urine hydroxyproline levels require weeks to months. Often a patient who responds well initially loses the response to calcitonin. This refractoriness is not correlated with the development of antibodies. 

Corticosteroids are extremely useful in elderly patients who cannot tolerate full doses of NSAIDs. However, they consistently cause a dose- and duration-related increase in osteoporosis, an especially hazardous toxic effect in the elderly. It is not certain whether this drug-induced effect can be reduced by increased calcium and vitamin D intake, but it would be prudent to consider these agents (and bisphosphonates if osteoporosis is already present) and to encourage frequent exercise in any patient taking corticosteroids. 

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-... 

Bisphosphonates are potent inhibitors of bone resorption. They increase bone density and reduce the risk of fractures in the hip, spine, and other locations. Alendronate and risedronate are approved for the treatment of osteoporosis, using either daily dosing schedules alendronate 10 mg/d, risedronate 5 mg/d or weekly schedules alendronate 70 mg/wk, risedronate 35 mg/wk. These drugs are effective in men as well as women and for various causes of osteoporosis. 

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