Category:Bisphosphonates: Difference between revisions

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The transformative bisphosphonate was [[wikipedia:Alendronate|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 [[wikipedia:Risedronate|risedronate]] (Actonel, Procter & Gamble 1998), [[wikipedia:Ibandronate|ibandronate]] (Boniva, Roche 2003), and the intravenous [[wikipedia:Zoledronic acid|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 "~~drug~~ 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 [[wikipedia:Osteonecrosis of the jaw|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 [[wikipedia:Atypical femoral fracture|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 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 [[wikipedia:Osteonecrosis of the jaw|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 [[wikipedia:Atypical femoral fracture|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 [[wikipedia:Denosumab|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 [[wikipedia:Teriparatide|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.

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