Amino bisphosphonates such as alendronate and risedronate inhibit farnesyl pyrophosphate synthase, an enzyme in the mevalonate pathway that appears to be critical for osteoclast survival. The cholesterol-lowering statin drugs (eg, lovastatin), which block mevalonate synthesis (see Chapter 35), stimulate bone formation, at least in animal studies. Thus, the mevalonate pathway appears to be important in bone cell function and provides new targets for drug development. The mevalonate pathway effects vary depending on the bisphosphonate used (only amino bisphosphonates have this property) and may account for some of the clinical differences observed in the effects of the various bisphosphonates on bone mineral homeostasis.
With the exception of the induction of a mineralization defect by higher than approved doses of etidronate and gastric and esophageal irritation by the oral bisphosphonates, these drugs have proved to be remarkably free of adverse effects when used at the doses recommended for the treatment of osteoporosis. Esophageal irritation can be minimized by taking the drug with a full glass of water and remaining upright for 30 minutes or by using the intravenous forms of these compounds. The initial infusion of zoledronate is commonly associated with several days of a flu-like syndrome that generally does not recur with subsequent infusions. Of other complications, osteonecrosis of the jaw has received considerable attention but is rare in patients receiving usual doses of bisphosphonates (perhaps 1/100,000 patient-years). This complication is more frequent when high intravenous doses of zoledronate are used to control bone metastases and cancer-induced hypercalcemia. More recently, concern has been raised about over-suppressing bone turnover. This may underlie the occurrence of subtrochanteric femur fractures in patients on longterm bisphosphonate treatment. This complication appears to be rare, comparable to that of osteonecrosis of the jaw, but has led some authorities to recommend a “drug holiday” after 5 years of treatment if the clinical condition warrants it (ie, if the fracture risk of discontinuing the bisphosphonate is not deemed high).
Denosumab is a fully humanized monoclonal antibody that binds to and prevents the action of RANKL. As described earlier, RANKL is produced by osteoblasts and other cells, including T lymphocytes. It stimulates osteoclastogenesis via RANK, the receptor for RANKL that is present on osteoclasts and osteoclast precursors. By interfering with RANKL function, denosumab inhibits osteoclast formation and activity. It is at least as effective as the potent bisphosphonates in inhibiting bone resorption and has been approved for treatment of postmenopausal osteoporosis and some cancers (prostate and breast). The latter application is to limit the development of bone metastases or bone loss resulting from the use of drugs that suppress gonadal function. Denosumab is administered subcutaneously every 6 months. The drug appears to be well tolerated, but three concerns remain. First, a number of cells in the immune system also express RANKL, suggesting that there could be an increased risk of infection associated with the use of denosumab. Second, because the suppression of bone turnover with denosumab is similar to that of the potent bisphosphonates, the potential risk of osteonecrosis of the jaw and subtrochanteric fractures is comparable. Third, denosumab can lead to transient hypocalcemia, especially in patients with marked bone loss (and bone hunger) or compromised calcium regulatory mechanisms, including chronic kidney disease and vitamin D deficiency. That said, denosumab can be used in patients with advanced renal disease, unlike the bisphosphonates, as it is not cleared by the kidney, and it has the advantage over bisphosphonates in that it is readily reversible because it does not deposit in bone.