Bisphosphonates: Mechanisms of Action and Role in Osteoporosis Therapy

Bisphosphonates are the most commonly prescribed treatments for osteoporosis in both postmenopausal women and men. They inhibit bone resorption by osteoclasts and indirectly reduce bone formation coupled to resorption without direct effects on bone formation by osteoblasts. Several of the nitrogen-containing bisphosphonates (N-BP) have been shown to reduce the risk of fractures of the spine, proximal femur and non-vertebral fractures in prospective placebo-controlled studies up to 4 years long. While fracture risk reduction implies improved bone strength and bone strength cannot be measured in individual patients, current models indicate that decreased bone resorption results in both improved bone microarchitecture and greater bone mass, and that both effects contribute to bone strength. All bisphosphonates share the “bisphosphonate” P-C-P structure responsible for their affinity for hydroxyapatite on bone surfaces, while the chemistry of the moiety linked to the central carbon results in their inhibition of osteoclast-mediated bone resorption. The pharmacokinetic profiles of all N-BPs are similar and differ substantially from most other drugs. Oral bioavailability is <1% and they must be administered fasting or via intravenous (IV) infusion. BPs in blood distribute quickly to bone surfaces or are eliminated in urine. The half-life of BPs on bone surfaces is 3–5 weeks, where they inhibit osteoclasts that form resorption lacunae on BP-coated surface. Their long bone-surface half-life allows weekly, monthly and even yearly treatment regimens. BPs are not metabolized and may be incorporated into new bone, where they are not pharmacologically active unless a subsequent round of bone remodeling results in their resorption. When BP treatment is stopped, bone resorption increases in two phases. The first phase occurs over weeks to months as the concentration on the surface of bone decreases. If enough BP has been incorporated into new bone formed during prior treatment, that bisphosphonate may be released and again inhibit bone resorption. The second phase of post-treatment resorption increase occurs gradually as BP within bone decreases (estimated half-life with bone is approximately 5 years). Upper gastrointestinal symptoms are the only common side effects of oral bisphosphonates and may require use of an intravenous formulation. Less common side effects include musculoskeletal pain that begins several months after the start of treatment and resolves when treatment is interrupted. Two rare potential side effects (osteonecrosis of the jaw and atypical femoral fractures) limit broader patient acceptance and lead to the use of a “drug holiday” after 3–5 years of treatment to reduce side effect risk. Controlled clinical trials are required to determine the persistence of both fracture risk reduction and risk of adverse events (including atypical femoral fractures) after long-term (3–5 years) treatment with bisphosphonates is either discontinued, continued at the same dose or continued at a lower dose, to develop an evidence-based approach to the use of drug holidays.