Bisphosphonates

Bisphosphonates have a structure similar to native pyrophosphate. They bind with high affinity to hydroxyapatite crystals, particularly where bone is being actively resorbed. As osteoclasts resorb that bone, the embedded drug is released and impairs the osteoclast’s ability to continue. On the alendronate label, the drug localizes under osteoclasts, which still adhere to the bone surface but lack the ruffled border of active resorption. Normal bone is then laid down on top of the drug, and while it is buried in the bone matrix it is not pharmacologically active.

The two chemical groups kill osteoclasts in different ways. The nitrogen-containing agents (alendronate, risedronate, ibandronate, pamidronate, zoledronic acid) inhibit farnesyl pyrophosphate synthase, an enzyme of the pathways that make cholesterol and other lipids; although the enzyme is ubiquitous, the resulting apoptosis appears only in osteoclasts. The older non-nitrogen-containing agents (etidronate, clodronate, tiludronate) are metabolized inside the cell into nonfunctional ATP analogs that compete with ATP in energy metabolism, which also triggers osteoclast apoptosis. The nitrogen-containing agents are much more potent; the older ones can inhibit mineralization and cause osteomalacia, so they are no longer in broad use.

In osteoporosis after menopause, bone turnover increases and resorption exceeds formation. Alendronate reduces bone resorption with no direct effect on bone formation, although formation also falls in time because resorption and formation are coupled during bone turnover. All bisphosphonates improve bone mineral density in postmenopausal osteoporosis; alendronate, risedronate and zoledronic acid decrease spine, hip and other nonvertebral fractures, while ibandronate has not consistently been shown to reduce hip fractures.

The drug is incorporated into the bone matrix and released gradually over years, and the amount stored depends on the dose and duration of use; alendronate’s terminal half-life is estimated to exceed 10 years. The optimal duration of treatment has not been determined, and the labels suggest considering stopping after 3 to 5 years in patients at low risk for fracture.

Oral absorption is tiny: alendronate’s bioavailability is about 0.64% after an overnight fast, it is negligible when taken with or up to two hours after breakfast, and coffee or orange juice reduces it by about 60%. So the tablet is taken as the first thing in the morning, with plain water, more than 30 minutes before the first food, any other beverage or any other medication.

The same tablet injures the esophagus. Esophagitis, ulcers and erosions — rarely stricture or perforation — have been reported, and the risk of severe esophageal events is greater in patients who lie down after the dose or do not swallow it with a full glass of water. Patients therefore stay upright for at least 30 minutes and do not chew, suck or crush the tablet. Oral agents are avoided with achalasia, esophageal stricture, Barrett esophagus, varices, Roux-en-Y gastric bypass or inability to sit upright for 30 minutes; IV preparations serve patients who cannot take them.

Osteonecrosis of the jaw is exposed bone in the maxillofacial region that does not heal within 8 weeks, in a patient treated with a bisphosphonate and without radiation to the jaw. Without resorption and new bone formation, old bone survives beyond its lifespan and its capillary network is not maintained; the jaw is affected because it remodels faster than other bones. Most cases occur with high-dose IV bisphosphonates in multiple myeloma and breast cancer; other risk factors are a higher dose and longer exposure, pre-existing dental disease, dental implants, extractions and poorly fitting dentures.

Atypical femur fractures involve the femoral diaphysis or subtrochanteric region and are considered stress fractures, attributed to oversuppressed bone turnover, altered bone quality and impaired fracture repair. Their risk increases with the duration of exposure. Dull, aching thigh or groin pain can precede a complete fracture by weeks to months, and the fractures may be bilateral. A patient who has one should stop the bisphosphonate, because continuing it raises the risk in the other leg.

IV bisphosphonates cause an acute-phase reaction within 1 to 3 days of the infusion — fever, myalgias, arthralgias and headache — which responds to acetaminophen or NSAIDs, is highest after the first infusion and declines with further doses. Hypocalcemia is usually transient but is more common with IV agents and in patients with untreated vitamin D deficiency, hypocalcemia, poor calcium intake or hypoparathyroidism, so calcium and vitamin D deficiency are corrected first.

IV pamidronate and zoledronic acid are also nephrotoxic, which is rare with oral agents; the risk rises with larger doses, shorter infusion times and more frequent dosing, and the commonest lesion with pamidronate is collapsing focal segmental glomerulosclerosis. Serum creatinine is checked before each dose. In hypercalcemia of malignancy, IV normal saline comes first, and IV zoledronic acid or pamidronate is added; bisphosphonates begin working in 2 to 3 days and their effect lasts 2 to 4 weeks. In Paget disease of bone, bisphosphonates are the first-line treatment, and alkaline phosphatase is followed to judge the response.