Bisphosphonates define a class of drugs that are widely indicated since the 1990s to treat osteoporosis both in men and women. Their effectiveness in treating osteoporosis and other conditions is related to their ability to inhibit bone resorption.
Bisphosphonates have a structure similar to native pyrophosphate and divide into two groups: nitrogen-containing and non-nitrogen containing bisphosphonates. Nitrogen-containing bisphosphonates include alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. Non-nitrogen containing bisphosphonates include etidronate, clodronate, and tiludronate. All bisphosphonates inhibit bone resorption by attaching to hydroxyapatite binding sites on the bone, particularly in areas with active resorption. As osteoclasts resorb bone, the bisphosphonate embedded in the bone is released and impairs the osteoclast’s ability to continue bone resorption.
Nitrogen-containing bisphosphonates work by inhibiting farnesyl pyrophosphate synthase, which is important in promoting attachment of the osteoclast to the bone. As a result, the osteoclast detaches from the bone surface, thus inhibiting bone resorption.
Non-nitrogen containing bisphosphonates, on the other hand, are metabolized within the cell to substrates that replace the terminal pyrophosphate moiety of adenosine triphosphate, forming a nonfunctional molecule which competes with adenosine triphosphate in the energy metabolism of the cell. This situation initiates osteoclast apoptosis, which in turn leads to an overall decrease in the bone breakdown.
Nitrogen-containing bisphosphonates are much more potent antiresorptive agents than the non-nitrogen-containing bisphosphonates. Also, non-nitrogen containing bisphosphonates are found to have a high potential to inhibit bone mineralization and can cause osteomalacia. For this reason, they are no longer in broad-based use.
EFFICACY OF BISPHOSPHONATES
All bisphosphonates improve bone mineral density in postmenopausal women with osteoporosis. Alendronate, risedronate, and zoledronic acid decrease the risk of spine, hips as well as other nonvertebral fractures. Ibandronate has not consistently shown to reduce the risk of hip fractures.
Risedronate: Reduces vertebral and nonvertebral fractures by about 40%.
Ibandronate: Reduces vertebral fractures by about 50%. No reduction in risk of nonvertebral fractures.
Alendronate, risedronate, and ibandronate are given orally, most commonly at weekly (alendronate, risedronate) or monthly (risedronate and ibandronate) intervals. The administration of zoledronic acid and pamidronate is intravenous, and there is also an intravenous preparation of ibandronate. Intravenous preparations are beneficial in patients who cannot tolerate oral bisphosphonates or in whom oral bisphosphonates are contraindicated, such as the presence or history of esophageal stricture.
Alendronate is given as 35 mg once weekly for the prophylaxis of osteoporosis in postmenopausal females and as 70 mg once weekly for the treatment of osteoporosis in men and women. For Paget disease of bone in males and females, alendronate is given orally as 40 mg once daily for six months, and risedronate is given 30 mg orally daily for two months. Risedronate is given as 35 mg once weekly and 150 mg once a month. Ibandronate sodium is given as 150 mg orally once a month or 3 mg intravenously every month. Zoledronic acid is given as 4 mg to 5 mg intravenously over at least 15 to 30 minutes every 12 months for the treatment of osteoporosis. Pamidronate is given as 30 mg to 60 mg by slow intravenous infusion every 3 to 6 months for the treatment of hypercalcemia of malignancy, Paget disease, and bone metastasis.
Patients should receive supplemental calcium 1000 to 1200 mg/day and vitamin D 800 to 1000 international units/day if dietary intake is inadequate. Patients should take oral bisphosphonates as the first medication in the morning and more than 30 minutes before the first food intake, beverage (except water), or any other medication. Patients should receive instruction to stay upright, not to lay down for at least thirty minutes or until the first food intake of the day to reduce esophageal irritation/ulceration. Milk and milk products, coffee, orange juice, and food may decrease the absorption of oral bisphosphonates.
Bisphosphonates are generally well tolerated, with most adverse effects being non-severe. Reports exist of some serious adverse effects with bisphosphonate use, but these are extremely rare.
1. Gastrointestinal adverse effects.
All oral bisphosphonates have correlations with upper gastrointestinal adverse effects, including gastrointestinal reflux, esophagitis, esophageal/gastric ulcers, and gastritis. Gastrointestinal side effects are the most common reason for discontinuation of oral bisphosphonates. The risk increases in patients who take concomitant NSAIDs. Proper administration of oral bisphosphonates may help to reduce the risk of these gastrointestinal adverse effects. Clinicians should avoid oral bisphosphonates in patients who are at a higher risk of these gastrointestinal adverse effects including those who are not able to sit upright for at least 30 minutes after taking the bisphosphonate, and patients with esophageal disorders such as achalasia, esophageal stricture, Barrett's esophagus, and esophageal varices and patients who have undergone Roux-en-Y gastric bypass. The risk of upper gastrointestinal adverse effects may be slightly lower with risedronate compared to alendronate. Other gastrointestinal adverse effects include abdominal pain, diarrhea, and constipation, which can occur in up to 5% of patients.
2. Infusion reaction.
Intravenous bisphosphonates have associations with an infusion/acute phase reaction characterized by flu-like symptoms, fevers, myalgias, arthralgias, and headaches within 1 to 3 days of the infusion. The symptoms usually respond to acetaminophen or NSAIDs and resolve within a few days. The risk of the acute phase reaction is highest with the 1st infusion of the intravenous bisphosphonate (up to 30%), and the risk declines significantly with further dosing (less than 7%). This infusion/acute phase reaction is usually mild and self-limiting and does not necessitate discontinuation of the intravenous bisphosphonate therapy.
Transient hypocalcemia is a common issue secondary to bisphosphonate use, and the incidence may be as high as 18%. Severe hypocalcemia, however, is rare. Hypocalcemia is more common, secondary to intravenous bisphosphonates, and in patients who have an underlying untreated vitamin-D deficiency, hypocalcemia, poor calcium intake, and hypoparathyroidism. Calcium and vitamin-D deficiency require correction before initiating bisphosphonates, especially intravenous bisphosphonates.
4. Arthralgia and Myalgia.
Bone, joint, and muscle pain can occur secondary to bisphosphonates. The symptoms are rare, with an incidence of less than 5%. Symptoms are usually mild, although there have been reports of severe pain. Musculoskeletal pain can have onset within days two years after starting bisphosphonates and may not always resolve entirely after discontinuation of bisphosphonates.
5. Ocular adverse effects.
6. Atypical femur fractures.
Another rare but serious adverse effect of bisphosphonates is an atypical femoral fracture, typically involving diaphysis or sub-trochanteric region of the femur. Over suppression of bone turnover, pathophysiological alteration in the bone quality and impairment of fracture repair process, or thought to be responsible for these atypical femur fractures, which are considered stress fractures. The incidence is 3.2 to 50 cases per 100,000 person-years, and the risk increases with the duration of exposure to bisphosphonates. Atypical femur fractures usually not seen within the first five years of treatment of bisphosphonates, with most cases reported with more than seven years of bisphosphonate treatment. Initial symptoms are dull aching pain in the groin. Plain x-rays may reveal cortical thickening. Findings of radiographs, especially if early/mild shall we confirmed by further imaging with magnetic resonance imaging (MRI) or bone scintigraphy. Bisphosphonates shall be discontinued in patients who suffer an atypical femur fracture in one leg; if the drug is not stopped, these patients are at higher risk of developing atypical femur fracture in the other leg. Discontinuation of bisphosphonate is associated with a decline in this risk. A drug holiday shall be considered after prolonged exposure to bisphosphonates when clinically appropriate.
7. Osteonecrosis of the jaw.
One of the most severe adverse effects is bisphosphonate-related osteonecrosis of the jaw (BRONJ). Most cases of BRONJ have occurred in patients with multiple myeloma and breast cancer treated with high doses of intravenous bisphosphonates. It has also been reported in patients taking bisphosphonates for osteoporosis with an incidence of approximately 1 in 10,000 to 1 in 100,000. The risk factors for BRONJ include the use of intravenous bisphosphonates, higher dose and prolonged duration of exposure, pre-existing dental disease, dental implants, dental extraction, and poorly fitting dentures. The use of glucocorticoids and anticancer therapy, history of diabetes, smoking, and cancer may be other risk factors. A diagnosis of BRONJ must meet all the following criteria:
The American Association of Oral and Maxillofacial Surgeons has further defined the stages of Bisphosphonate-related osteonecrosis of the jaw (BRONJ) as follows:
If planning an invasive dental procedure, the recommendation is to delay the initiation of bisphosphonate therapy for a few months to allow healing of the jaw. In patients who have been on bisphosphonates for more than four years and are planning for an invasive dental procedure, recommendations are to stop the bisphosphonate two months before the dental procedure and resume them after jaw healing has been complete. When clinically appropriate, consider a drug holiday after 3 to 5 years of intravenous bisphosphonates and 5 to 10 years of oral bisphosphonates.
Contraindications to bisphosphonates include:
Serum calcium, vitamin D, and renal function requires baseline monitoring before initiating bisphosphonates. In patients with calcium and/or vitamin D deficiency, the recommendation is to correct the deficiency before starting bisphosphonates. The clinician should take a detailed dental history before initiating bisphosphonates, and therapy initiation should delay if planning an invasive dental procedure in the near future. Bone mineral density shall be evaluated 1 to 2 years after initiating therapy and every two years or more frequently in patients deemed high risk. Annual measurements of height, weight, serum calcium, 25- hydroxyvitamin D, and an assessment of back pain for the development of compression fractures is also necessary.
In some circumstances, monitoring of biochemical markers of bone resorption such as N-telopeptide of type-1 collagen, C-terminal telopeptide of type 1-collagen and pyridinoline cross-links, and markers of bone formation such as bone-specific alkaline phosphatase, osteocalcin, and N-terminal propeptide of type 1 procollagen before and three months after bisphosphonate initiation can help monitor the effectiveness of the medication in inhibiting bone resorption and measuring compliance. However, these assays are fraught with significant variability within individual patients and poor standardization, so they are not in routine use.
Bisphosphonates are very efficacious in the prevention of fractures in patients with osteoporosis. They are relatively safe, although they do have correlations with some rare and serious adverse effects. Patient education is crucial to ensure compliance and effective treatment of osteoporosis. Patients shall receive education to eliminate other risk factors associated with osteoporotic fractures, including smoking cessation, weight-bearing exercises, avoiding excessive alcohol intake, and increasing dairy product intake. The nursing team can assist with patient education and ensuring compliance with medications. Primary care physicians play the most important role in identifying individuals with a high-risk for osteoporosis and fractures and ensure primary prevention. Pain control and orthotic devices can assist patients who have already developed fractures. Referral to specialists such as endocrinologists or rheumatologists shall be considered, especially in complicated cases. Early detection, patient education, and an interprofessional team approach can ensure better outcomes and prevention of fractures in high-risk patients. [Level 5]
|||Otto S,Pautke C,Van den Wyngaert T,Niepel D,Schiødt M, Medication-related osteonecrosis of the jaw: Prevention, diagnosis and management in patients with cancer and bone metastases. Cancer treatment reviews. 2018 Jun 18 [PubMed PMID: 30055439]|
|||Farrell KB,Karpeisky A,Thamm DH,Zinnen S, Bisphosphonate conjugation for bone specific drug targeting. Bone reports. 2018 Dec [PubMed PMID: 29992180]|
|||Miller K,Steger GG,Niepel D,Lüftner D, Harnessing the potential of therapeutic agents to safeguard bone health in prostate cancer. Prostate cancer and prostatic diseases. 2018 Jul 9 [PubMed PMID: 29988100]|
|||Frediani B,Giusti A,Bianchi G,Dalle Carbonare L,Malavolta N,Cantarini L,Saviola G,Molfetta L, Clodronate in the management of different musculoskeletal conditions. Minerva medica. 2018 Aug [PubMed PMID: 29947493]|
|||Bernardi S,Di Girolamo M,Necozione S,Continenza MA,Cutilli T, Antiresorptive drug-related osteonecrosis of the jaws, literature review and 5 years of experience. Musculoskeletal surgery. 2018 Jun 14 [PubMed PMID: 29948937]|
|||Cummings SR,Black DM,Thompson DE,Applegate WB,Barrett-Connor E,Musliner TA,Palermo L,Prineas R,Rubin SM,Scott JC,Vogt T,Wallace R,Yates AJ,LaCroix AZ, Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998 Dec 23-30 [PubMed PMID: 9875874]|
|||Black DM,Cummings SR,Karpf DB,Cauley JA,Thompson DE,Nevitt MC,Bauer DC,Genant HK,Haskell WL,Marcus R,Ott SM,Torner JC,Quandt SA,Reiss TF,Ensrud KE, Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet (London, England). 1996 Dec 7 [PubMed PMID: 8950879]|
|||Harris ST,Watts NB,Genant HK,McKeever CD,Hangartner T,Keller M,Chesnut CH 3rd,Brown J,Eriksen EF,Hoseyni MS,Axelrod DW,Miller PD, Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999 Oct 13 [PubMed PMID: 10527181]|
|||Black DM,Delmas PD,Eastell R,Reid IR,Boonen S,Cauley JA,Cosman F,Lakatos P,Leung PC,Man Z,Mautalen C,Mesenbrink P,Hu H,Caminis J,Tong K,Rosario-Jansen T,Krasnow J,Hue TF,Sellmeyer D,Eriksen EF,Cummings SR, Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. The New England journal of medicine. 2007 May 3 [PubMed PMID: 17476007]|
|||Lyles KW,Colón-Emeric CS,Magaziner JS,Adachi JD,Pieper CF,Mautalen C,Hyldstrup L,Recknor C,Nordsletten L,Moore KA,Lavecchia C,Zhang J,Mesenbrink P,Hodgson PK,Abrams K,Orloff JJ,Horowitz Z,Eriksen EF,Boonen S, Zoledronic acid and clinical fractures and mortality after hip fracture. The New England journal of medicine. 2007 Nov 1 [PubMed PMID: 17878149]|
|||Chesnut CH 3rd,Skag A,Christiansen C,Recker R,Stakkestad JA,Hoiseth A,Felsenberg D,Huss H,Gilbride J,Schimmer RC,Delmas PD, Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2004 Aug [PubMed PMID: 15231010]|
|||Curry SJ,Krist AH,Owens DK,Barry MJ,Caughey AB,Davidson KW,Doubeni CA,Epling JW Jr,Kemper AR,Kubik M,Landefeld CS,Mangione CM,Phipps MG,Pignone M,Silverstein M,Simon MA,Tseng CW,Wong JB, Screening for Osteoporosis to Prevent Fractures: US Preventive Services Task Force Recommendation Statement. JAMA. 2018 Jun 26 [PubMed PMID: 29946735]|
|||Viswanathan M,Reddy S,Berkman N,Cullen K,Middleton JC,Nicholson WK,Kahwati LC, Screening to Prevent Osteoporotic Fractures: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2018 Jun 26 [PubMed PMID: 29946734]|
|||Graham DY,Malaty HM, Alendronate and naproxen are synergistic for development of gastric ulcers. Archives of internal medicine. 2001 Jan 8 [PubMed PMID: 11146706]|
|||Schussheim DH,Jacobs TP,Silverberg SJ, Hypocalcemia associated with alendronate. Annals of internal medicine. 1999 Feb 16 [PubMed PMID: 10068397]|
|||Rosen CJ,Brown S, Severe hypocalcemia after intravenous bisphosphonate therapy in occult vitamin D deficiency. The New England journal of medicine. 2003 Apr 10 [PubMed PMID: 12686715]|
|||Wysowski DK,Chang JT, Alendronate and risedronate: reports of severe bone, joint, and muscle pain. Archives of internal medicine. 2005 Feb 14 [PubMed PMID: 15710802]|
|||Pazianas M,Clark EM,Eiken PA,Brixen K,Abrahamsen B, Inflammatory eye reactions in patients treated with bisphosphonates and other osteoporosis medications: cohort analysis using a national prescription database. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2013 Mar [PubMed PMID: 23044864]|
|||Patel DV,Bolland M,Nisa Z,Al-Abuwsi F,Singh M,Horne A,Reid IR,McGhee CN, Incidence of ocular side effects with intravenous zoledronate: secondary analysis of a randomized controlled trial. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2015 Feb [PubMed PMID: 25187119]|
|||Khan AA,Morrison A,Hanley DA,Felsenberg D,McCauley LK,O'Ryan F,Reid IR,Ruggiero SL,Taguchi A,Tetradis S,Watts NB,Brandi ML,Peters E,Guise T,Eastell R,Cheung AM,Morin SN,Masri B,Cooper C,Morgan SL,Obermayer-Pietsch B,Langdahl BL,Al Dabagh R,Davison KS,Kendler DL,Sándor GK,Josse RG,Bhandari M,El Rabbany M,Pierroz DD,Sulimani R,Saunders DP,Brown JP,Compston J, Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2015 Jan [PubMed PMID: 25414052]|
|||Aparecida Cariolatto F,Carelli J,de Campos Moreira T,Pietrobon R,Rodrigues C,Bonilauri Ferreira AP, Recommendations for the Prevention of Bisphosphonate-Related Osteonecrosis of the Jaw: A Systematic Review. The journal of evidence-based dental practice. 2018 Jun [PubMed PMID: 29747794]|
|||Simm PJ,Biggin A,Zacharin MR,Rodda CP,Tham E,Siafarikas A,Jefferies C,Hofman PL,Jensen DE,Woodhead H,Brown J,Wheeler BJ,Brookes D,Lafferty A,Munns CF, Consensus guidelines on the use of bisphosphonate therapy in children and adolescents. Journal of paediatrics and child health. 2018 Mar [PubMed PMID: 29504223]|
|||Albergaria BH,Chalem M,Clark P,Messina OD,Pereira RMR,Vidal LF, Consensus statement: osteoporosis prevention and treatment in Latin America-current structure and future directions. Archives of osteoporosis. 2018 Aug 24 [PubMed PMID: 30143914]|
|||Nuti R,Brandi ML,Checchia G,Di Munno O,Dominguez L,Falaschi P,Fiore CE,Iolascon G,Maggi S,Michieli R,Migliaccio S,Minisola S,Rossini M,Sessa G,Tarantino U,Toselli A,Isaia GC, Guidelines for the management of osteoporosis and fragility fractures. Internal and emergency medicine. 2018 Jun 13 [PubMed PMID: 29948835]|
|||Kim J,Jang SB,Kim SW,Oh JK,Kim TH, Clinical effect of early bisphosphonate treatment for pyogenic vertebral osteomyelitis with osteoporosis: An analysis by the Cox proportional hazard model. The spine journal : official journal of the North American Spine Society. 2018 Aug 30 [PubMed PMID: 30172897]|
|||Rouach V,Goldshtein I,Wolf I,Catane R,Chodick G,Iton A,Stern N,Cohen D, Exposure to alendronate is associated with a lower risk of bone metastases in osteoporotic women with early breast cancer. Journal of bone oncology. 2018 Sep [PubMed PMID: 30148062]|
|||Lou S,Wang L,Wang Y,Jiang Y,Liu J,Wang Y, Combination therapy of anabolic and nonbisphosphonates antiresorptive agents for the treatment of osteoporosis: A meta-analysis. Medicine. 2017 Dec [PubMed PMID: 29384970]|