Bisphosphonates multiple myeloma

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... 

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... 

Metastatic bone disease (MBD) is characterized by very high levels of bone turnover in regions proximal to the tumour [33]. Bone resorption inhibitors such as bisphosphonates represent the current standard of care for the treatment of bone metastases primarily due to breast or prostate cancer and multiple myeloma. It has been proposed that other strong anti-resorptives such as a Cat K inhibitor could be useful in the treatment of bone metastases. Evidence for this has been presented in the form of a preclinical MBD model in which human breast cancer cells are implanted into nude mice. Treatment with a Cat K inhibitor gave a significantly lower area of breast cancer-mediated osteolytic lesions in the tibia [34]. In a separate study, the efficacy of a Cat K inhibitor in the reduction in tumour-induced osteolysis was found to be enhanced in the presence of the bisphosphonate zolendronic acid [35,36]. When prostate cancer cells were injected into the tibia of SCID mice, treatment with a Cat K inhibitor both prevented and diminished the progression of cancer growth in bone [37]. 

Aparicio, A., Gardner, A., Tu, Y., Savage, A., Berenson, J., and Lichtenstein, A. (1998). In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia 12 220-229. 

Davies, F., Morgan, G., Wu, P., Gregory, W., Bell, S.E., Szubert, A., Navarro-Coy, N., Drayson, M., Owen, R.G., Feyler, S., Ashcroft, J., Ross, F., et al. (2011). Are there benefits to long-term bisphosphonate treatment in multiple myeloma (MM) Insights from temporal analyses of zoledronic acid (ZOL) versus clodronate (CLO) in the MRC Myeloma IX trial J Clin Oncol 29(Suppl.) abstr 8011, 506pp. 

Bone pain, including cancer metastases, requires NSAIDs alone and with opioids. Bisphosphonates, e.g. sodium pamidronate, sodium clodronate, relieve pain from osteolytic bone metastases from breast cancer and multiple myeloma. 

Uses. Three bisphosphonates (alendronate, etidronate, risedronate) are currently licensed in the UK for the treatment of osteoporosis (zoledronate is also effective), and the others are used in Paget s disease of bone, and hypercalcaemia due to cancer (pamidronate, clodronate, zoledronate). Bisphosphonates may also provide benefit for neoplastic disease that has spread to bone evidence indicates that clodronate by mouth and pamidronate i.v. are effective in the secondary prevention of bone metastases due to multiple myeloma and breast cancer. 

Bisphosphonates are widely used for the prevention and treatment of osteopenia and osteoporosis and for the reduction of skeletal complications in patients with malignant bone disease. Several oral bisphosphonates, including alendronate, risedronate, and ibandronate, are approved worldwide for the treatment of osteoporosis in postmenopausal women, as are intravenous (i.v.) formulations of ibandronate (3 mg quarterly) and zoledronic acid (5 mg annually). Several i.v. bisphosphonates are available for the treatment of the skeletal complications that frequently occur in malignant disease, such as hypercalcaemia of malignancy (HCM), multiple myeloma, and bone metastases associated with solid tumours. Pamidronate is approved worldwide for the treatment of HCM, multiple myeloma, and breast cancer bone metastases. Although not registered for oncology indications in the United States, i.v. ibandronate is widely available elsewhere for HCM and breast cancer bone metastases. 

Nephrotoxicity of bisphosphonates is a known complication of this compound class, often exacerbated by diseases that compromise renal function, such as multiple myeloma, and by concomitant use of antineo-plastic agents, steroids, and radiation therapy. The first reports of tubulointerstitial damage after treatment with etidronate and clodronate appeared more than 2 decades ago [60]. Subsequently, acute tubular necrosis, focal segmental glomerulosclerosis (FSGS), and granulomatous interstitial nephritis have been reported in renal biopsies from predominantly cancer patients exposed to several bisphosphonates, often at high i.v. doses. 

Osteoporosis is of two forms- primary i.e. idiopathic and secondary. Primary osteoporosis is classified into type I and type II osteoporosis. Type I is referred to post menopausal osteoporosis which is the main type affecting women, characterized by rapid bone loss and affects women after the menopause, mainly in trabecular bone and is associated with vertebrae and distal radio fractures whereas type II also termed as senile osteoporosis occurs due to chronic deficiency of calcium, increase in parathormone activity and decrease in bone formation and is associated with aging. On the other hand secondary type results from inflammatory processes, endocrine changes, multiple myeloma, sedentariness and the use of drugs such as heparin, corticoid and alcohol [3]. Prevention is the main treatment of osteoporosis, for which bone mass peak and the prevention of postmenopausal reabsorption are critical elements. The common treatment of osteoporosis includes calcium consumption as calcium salts, vitamin D supplements, and hormone reposition [4], the use of calcitonin to modulate serum levels of calcium and phosphorous [5], the use of bisphosphonate, mainly alendronates [6], use of ipriflavone and sodium fluoride [7], besides physical activity to strengthen muscles, stimulate osteoblasts formation and prevent reabsorption. 

Sarasquete ME, Garcia-Sanz R, Marin L et al (2008) Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma a genome-wide single nucleotide polymorphism analysis. Blood 112 2709-2712... 

Zoledronic acid is a bisphosphonate that causes inhibition of bone resorption. It is indicated in the treatment of hypercalcemia of malignancy treatment of patients with multiple myeloma and bone metastases from solid tumors in conjunction with standard antineoplastic therapy. 

Pamidronate, a second-generation bisphosphonate, is 100-fold more potent than etidronate (Fig. 35.7) (6). It has been approved for the treatment of hypercalcemia of malignancy, for Paget s disease, and for osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma. When used to treat bone metastases, pamidronate decreases osteoclast recruitment, decreases osteoclast activity and increases osteoclast apoptosis (53). Erosive esophagitis has been reported with the use of pamidronate sodium. 

Osteonecrosis of the jaw Osteonecrosis of the jaw is a well-known adverse reaction to bisphosphonates in patients with multiple myeloma or other malignancies. Its incidence is still undetermined, and only a few cases in patients taking bisphosphonates for non-oncological diseases have been reported. The EIDOS and DoTS descriptions of this reaction are shown in Figure 1. 

Aredia, pamidronate disodium (APD), is a bone-resorption inhibitor used to treat hypercalcemia associated with malignancy and osteolytic bone lesions associated with multiple myeloma, metastatic breast cancer, and moderate to severe Paget s disease of bone. Aredia, a member of the group of chemical compounds known as bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium is designated chemically as phosphonic acid (3-amino-l-hydroxypropylidene) bis-, disodium salt, pentahydrate, (APD). 

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