Category:Bisphosphonates

A bisphosphonate is a medicine of the chemical class of pyrophosphate analogues in which the central oxygen atom of pyrophosphate (P-O-P) is replaced by a carbon (P-C-P), giving a molecule resistant to enzymatic hydrolysis. The bisphosphonates bind avidly to hydroxyapatite crystals of bone and, when osteoclasts resorb the bound bone, are taken up and produce osteoclast apoptosis. Their clinical indications are dominated by osteoporosis (post-menopausal and corticosteroid-induced), Paget's disease of bone, multiple myeloma and other bone metastases of solid tumours, the hypercalcemia of malignancy, osteogenesis imperfecta in childhood, and selected fibrodysplastic and metabolic bone diseases.

The history of the bisphosphonates begins with their use as industrial water-softening agents. Pyrophosphate had been known since the 1860s to prevent the precipitation of calcium carbonate from water in textile and detergent industries; the synthetic bisphosphonates were developed as more stable analogues in the 1950s for the same use. The Swiss pediatric endocrinologist Herbert Fleisch in Bern observed in the 1960s that pyrophosphate was present in mammalian extracellular fluid, that it inhibited soft-tissue calcification in vivo, and that it was rapidly hydrolysed by alkaline phosphatase. He hypothesised that synthetic, hydrolysis-resistant bisphosphonates would have the same anticalcification action with longer in-vivo half-life;^[1] the first clinically used bisphosphonate, etidronate disodium (Didronel, Procter & Gamble 1977), was approved for Paget's disease of bone and was later used in heterotopic ossification and hypercalcemia. Etidronate's narrow therapeutic window (continuous high-dose use produces osteomalacia by inhibition of bone mineralisation as well as resorption) limited its osteoporosis use.

The transformative bisphosphonate was alendronate (Fosamax, Merck 1995), the first of the nitrogen-containing "amino-bisphosphonates" whose mechanism is the inhibition of farnesyl pyrophosphate synthase in osteoclasts (rather than the simple cellular ATP-analogue accumulation mechanism of the older non-nitrogen-containing bisphosphonates etidronate, clodronate, and tiludronate). Alendronate reduced vertebral and hip fracture risk in postmenopausal osteoporosis by approximately 50 percent in the FIT-1 and FIT-2 trials and remained the standard first-line osteoporosis medicine for two decades. The longer-half-life risedronate (Actonel, Procter & Gamble 1998), ibandronate (Boniva, Roche 2003), and the intravenous zoledronate (Reclast/Zometa, Novartis 2001 for hypercalcemia of malignancy and bone metastases, 2007 for osteoporosis at once-yearly intravenous dosing) extended the class.

The pharmacology of contemporary bisphosphonate use is, in clinical terms, dominated by three considerations. The first is the very long bone half-life (approximately ten years for alendronate; the medicines bind to mineral and are slowly released as the bone remodels) which produces a sustained antiresorptive effect after treatment cessation; this is the basis of the "medicine holiday" recommendation after three to five years of oral bisphosphonate or three years of annual zoledronate, with continued antiresorptive benefit for several years off-medicine. The second is the osteonecrosis of the jaw (ONJ), an uncommon but characteristic adverse effect dose-related and occurring most frequently with high-dose intravenous bisphosphonate in cancer indications (1-10 percent of myeloma patients on chronic zoledronate) and rarely with osteoporosis-dose bisphosphonate (estimated at 1 per 10,000 to 1 per 100,000 patient-years). Dental health optimisation before initiation and avoidance of invasive dental procedures during therapy reduce the risk. The third is the atypical femoral fracture, a subtrochanteric or shaft femoral fracture with characteristic radiographic appearance occurring at higher rates in patients on more than five years of bisphosphonate therapy; the absolute rate is small (approximately 1 per 1000 patient-years after 5-10 years of use) but is the principal driver of the duration-limited treatment recommendation.

The competing antiresorptive medicines have complicated the bisphosphonate's first-line position. The RANKL monoclonal antibody denosumab (Prolia, Amgen 2010) reduces vertebral and hip fracture risk in osteoporosis comparably to bisphosphonates with a different safety profile; it is administered as a six-monthly subcutaneous injection and is the preferred antiresorptive for patients with renal impairment (where bisphosphonate dosing must be reduced or avoided). The unfortunate complication of denosumab is a rebound of bone resorption with multiple vertebral fractures upon abrupt discontinuation, which has motivated the contemporary recommendation that denosumab not be stopped abruptly without transition to bisphosphonate. The anabolic medicines teriparatide (Forteo, Eli Lilly 2002) and abaloparatide (Tymlos, Radius 2017) stimulate bone formation rather than blocking its resorption; they are used in patients with very high fracture risk or with multiple fragility fractures despite bisphosphonate therapy. The newer sclerostin antibody romosozumab (Evenity, Amgen 2019) combines bone-formation stimulation with antiresorption and is used for one year before transition to a bisphosphonate or denosumab. The contemporary clinical algorithm in postmenopausal osteoporosis is therefore a more nuanced sequence than the bisphosphonate-only era of 1995-2010.

The oncologic and metabolic-bone-disease indications of the bisphosphonates are well established and are the subject of distinct clinical pathways. Intravenous pamidronate or zoledronate is the standard treatment of hypercalcemia of malignancy (along with aggressive saline diuresis); zoledronate (alongside denosumab) reduces skeletal-related events in patients with bone metastases from solid tumours or multiple myeloma; oral or intravenous bisphosphonate is the standard treatment of symptomatic Paget's disease of bone. The pediatric use of intravenous pamidronate or zoledronate in osteogenesis imperfecta has substantially improved long-term outcomes in this disease.

By route and chemistry:

• Non-nitrogen-containing (first-generation):
  • Etidronate (Didronel; Paget's disease, heterotopic ossification, hypercalcemia)
  • Clodronate (Bonefos, Europe; bone metastases, hypercalcemia)
  • Tiludronate (Skelid; Paget's disease)
• Nitrogen-containing (amino-bisphosphonates, more potent; second- and third-generation):
  • Oral once-weekly/monthly: alendronate (Fosamax), risedronate (Actonel, Atelvia delayed-release), ibandronate (Boniva)
  • Intravenous: pamidronate (Aredia; hypercalcemia, bone metastases), zoledronate (Reclast for osteoporosis annual; Zometa for oncologic monthly)
  • Intravenous less common: neridronate (Italy; osteogenesis imperfecta, complex regional pain syndrome)

The closely related but distinct bone-targeted radiopharmaceutical radium-223 (Xofigo, Bayer 2013) for bone-metastatic prostate cancer uses the bone-tropic chemistry of an alpha emitter rather than antiresorption; it is listed at antineoplastics rather than here.

The boundary of this category is "medicine of the bisphosphonate chemical class, used for any of its established indications." The other antiresorptive medicines (denosumab, romosozumab, calcitonin, selective estrogen receptor modulators) act through different mechanisms and are not bisphosphonates; they are cross-listed at osteoporosis medications and antiresorptives when those pages are built. The anabolic bone-forming medicines (teriparatide, abaloparatide) are not antiresorptive in mechanism and are listed under hormones (PTH analogues). The supportive-care medicines used in patients on bisphosphonate therapy (calcium supplements, vitamin D, magnesium supplements in selected cases) are listed under their primary categories.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.