About Bisphosphonates


October, 2014
By Christine M. Vocke and Sharon F. Terry, PXE International


Bisphosphonates (BPs) are chemically stable analogues of inorganic pyrophosphate (PPi). Studies on the role of inorganic pyrophosphate in the control of soft-tissue and skeletal mineralization resulted in the discovery that these compounds could inhibit calcification. This realization triggered additional studies to determine whether these compounds could inhibit other physiologic processes, such as bone resorption.[1]

As clearly stated in a 2008 publication by Drake et al., bisphosphonates are chemically stable derivatives of inorganic pyrophosphate (PPi), a naturally occurring compound in which two phosphate groups are linked by esterification (the reaction between alcohols and carboxylic acids to make esters).[2] Within humans, PPi is released as a by-product of many of the body’s synthetic reactions; thus, it can be readily detected in many tissues, including blood and urine.[3] Pioneering studies from the 1960s demonstrated that PPi was capable of inhibiting calcification by binding to hydroxyapatite crystals, leading to the hypothesis that regulation of PPi levels could be the mechanism by which bone mineralization is regulated.[4]

A critical feature of the clinical pharmacology of bisphosphonates is their bioavailability (rate of metabolism in circulation to the site of action). As a class, bisphosphonates are very hydrophilic (having a tendency to mix with, dissolve in, or be wetted by water). They are poorly absorbed from the gastrointestinal tract after oral administration (generally with absorption of <1% for an oral dose), instead undergoing intracellular transport because they are not lipophilic (tending to combine with or dissolve in lipids or fats).[5] Only about 50% of the absorbed drug is selectively retained in the skeleton, whereas the remainder is eliminated in the urine without being metabolized. Skeletal uptake and retention are primarily dependent on host factors (renal function, general rate of bone turnover, and binding site availability) and bisphosphonate potency for bone matrix (inner cellular bone tissue). The amount of bisphosphonate retained after either oral or intravenous administration varies widely both between patients and across clinical conditions, and is primarily believed to reflect variations in bone loss.[6] During therapy, bisphosphonates are incorporated into newly formed bone and can persist there for years, through multiple cycles of bone resorption and deposition. Thus, patients continue to be exposed to the pharmacologic effects of bisphosphonate activity long after they stop taking the medication.[7] 
 

What are the different types of bisphosphonates?

Drug Types:

Generic Name

Brand Name

alendronate Fosamax
etidronate Didronel
ibandronate Boniva
pamidronate Aredia
risedronate Actonel, Atelvia
sodium clodronate Bonefos
tiludronate Skelid
zoledronate Reclast, Aclast, Zometa, Zomera

What are possible side effects?

  • Fever (intravenous administration)
  • Vein irritation (mild phlebitis) at site of infusion (intravenous administration). Central infusion is recommended to avoid any leakage of medication around the vein (saline) and reduce chance of phlebitis.
  • General aches and pains
  • Kidney dysfunction (primarily associated with myeloma as it can impact kidney function by elevated blood calcium levels)
  • Osteonecrosis of the jaws (ONJ) (primarily found in patients with myeloma undergoing Aredia and Zometa therapy).
    • 3.5% of patients developed ONJ associated with Zometa, 0.5% with Bonefos. This condition produces pain, swelling, bone damage around the tooth sockets in the jaws. There is bone necrosis or loss of bone, which can lead to loose teeth, sharp edges of exposed bone, bone spurs, and the breaking loose of small bone spicules or dead bone. Symptoms may become more noticeable over time with pain, swelling, numbness, a “heavy jaw feeling” or loosening of teeth.
  • Other side effects include: rash, upset stomach, blurred vision, headache, and shortness of breath. Atypical fractures of the femur (thigh bone) known as subtrochanteric and diaphyseal femur fractures are rare, and associated with five or more years of bisphosphonate treatment. (See FDA safety review announcement in October 2010, which later was added to labels of prescriptions.)

Potential side effects of bisphosphonates administered orally: esophagitis and/or other gastrointestinal complaints, which may preclude their use in patients with pre-existing esophageal or intestinal problems. 

Reports of esophageal cancer with oral bisphosphonate use.

As described in a recent letter from an epidemiologist at the FDA, the use of oral bisphosphonates (alendronate/Fosamax) also appears to be associated with an increased risk of esophageal cancer.[8] From its approval of alendronate (Fosamax) in 1995 through mid-2008, the FDA received reports of 23 patients taking alendronate (Fosamax) who were diagnosed as having esophageal cancer, with a median time from use to diagnosis of 2.1 years. Reports of 31 patients from Europe and Japan showed that, in addition to alendronate (Fosamax), esophageal cancer occurred in patients prescribed risedronate (Actonel and Atelvia), ibandronate (Boniva), and etidronate (Didronel), with a median time to diagnosis of 1.3 years.

Key point: It remains unknown whether esophageal cancer results from nonadherence to prescribing directions, leading to esophageal irritation or erosion, and whether this association will persist after further study. Because several of the affected patients had preexisting Barrett esophagus, it is recommended that physicians avoid prescribing oral bisphosphonates to patients with known esophageal pathology pending further data.[9]

At this time, FDA believes that the benefits of oral bisphosphonate drugs in reducing the risk of serious fractures in people with osteoporosis continue to outweigh their potential risks. FDA's review is ongoing and the Agency has not concluded that patients taking oral bisphosphonate drugs have an increased risk of esophageal cancer. It is also important to note that esophageal cancer is rare, especially in women.[10],[11]  
 

Who should not take bisphosphonates?

  • Patients with pre-existing kidney disease or known elevation in serum creatinine (>3.0 mg/dL) or above normal range.
  • Patients who have allergic reactions or are intolerant to bisphosphonates.

 

Can bisphosphonates be combined with other therapies?

In general, they can be combined safely with most other therapies.

 


[1] Montgomery CO, Bracey JW, Suva LJ. Bisphosphonates: the good, the bad, and the unidentified. AAOS Now. 2011 Dec. Free article at: http://www.aaos.org/news/aaosnow/dec11/clinical9.asp

[2] Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clinic Proceedings. 2008 Sep;83(9), 1032-45). PMID: 18775204

[3] Russell RGG. Bisphosphonates. Annals of the New York Academy of Sciences. 2006 Apr;1068(1), 367-401. PMID: 16831938

[4] Fleisch H, Russell RGG, Straumann F. Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. Nature. 1966 Nov 26;212(5065):901-3. PMID: 4306793

[5] Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone. 18(2), 75-85. PMID: 8833200

[6] Cremers SC, Pillai G, Papapoulos SE. Pharmacokinetics/pharmacodynamics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis. Clin Pharmacokinet. 2005;44(6):551-70. PMID: 15932344

[7] Whitaker M, Guo J, Kehoe T, Benson G. Bisphosphonates for osteoporosis—where do we go from here? N Engl J Med. 2012 May 31;366(22), 2048-51. PMID: 22571168

[8] Wysowski DK. Reports of esophageal cancer with oral bisphosphonate use. N Engl J Med. 2009 Jan 1;360(1), 89-90. PMID: 19118315

[9] Kennel KA, Drake MT. Adverse effects of bisphosphonates: implications for osteoporosis management. Mayo Clinic Proceedings. 2009 Jul;84(7), 632-38. PMID: 19567717

[10] United States Food and Drug Administration. (2011). FDA Drug Safety Communication: Ongoing safety review of oral osteoporosis drugs (bisphosphonates) and potential increased risk of esophageal cancer. Free information provided at: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm263320.htm

[11] United States Food and Drug Administration . (2011). Bisphosphonates (marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax+D, Reclast, Skelid, and Zometa) Information. Free information provided at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm101551.htm

 

Last updated May 18th, 2016