Bisphosphonates are a class of drugs that prevent the loss ofbone density, used to treatosteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis.[1] They are called bisphosphonates because they have twophosphonate (PO(OH)
2) groups. They are thus also calleddiphosphonates (bis- ordi- +phosphonate).
Evidence shows that they reduce the risk of fracture in post-menopausal women with osteoporosis.[2][3][4][5][6]
Bone tissue undergoes constantremodeling and is kept in balance (homeostasis) byosteoblasts creating bone andosteoclasts destroying bone. Bisphosphonates inhibit the digestion of bone by encouraging osteoclasts to undergoapoptosis, or cell death, thereby slowing bone loss.[7]
The uses of bisphosphonates include the prevention and treatment of osteoporosis,Paget's disease of bone,bone metastasis (with or withouthypercalcemia),multiple myeloma,primary hyperparathyroidism,osteogenesis imperfecta,fibrous dysplasia, and other conditions that exhibit bone fragility.
Bisphosphonates are used to treat osteoporosis,osteitis deformans (Paget's disease of the bone), bonemetastasis (with or without hypercalcemia), multiple myeloma, and other conditions involving fragile, breakable bone.
In osteoporosis and Paget's, the most popular first-line bisphosphonate drugs arealendronate andrisedronate. If these are ineffective or if the person develops digestive tract problems, intravenouspamidronate may be used.Strontium ranelate orteriparatide are used for refractory disease. The use of strontium ranelate is restricted because of increased risk ofvenous thromboembolism,pulmonary embolism and serious cardiovascular disorders, includingmyocardial infarction.[8] In postmenopausal women, theselective estrogen receptor modulatorraloxifene is occasionally administered instead of bisphosphonates. Bisphosphonates are beneficial in reducing the risk ofvertebral fracture insteroid induced osteoporosis.[9]
Bisphosphonates are recommended as a first line treatments for post-menopausal osteoporosis.[5][10][11][12]
Long-term treatment with bisphosphonates produces anti-fracture and bone mineral density effects that persist for 3–5 years after an initial 3–5 years of treatment.[2] The bisphosphonate alendronate reduces the risk of hip, vertebral, and wrist fractures by 35-39%; zoledronate reduces the risk of hip fractures by 38% and of vertebral fractures by 62%.[3][4] Risedronate has also been shown to reduce the risk of hip fractures.[5][6]
After five years of medications by mouth or three years of intravenous medication among those at low risk, bisphosphonate treatment can be stopped.[13] In those at higher risk ten years of medication by mouth or six years of intravenous treatment may be used.[13]
Bisphosphonates reduce the risk of fracture and bone pain[14] in people with breast,[15] lung,[16] and other metastatic cancers as well as in people with multiple myeloma.[17] In breast cancer there is mixed evidence regarding whether bisphosphonates improve survival.[15][18][19][20] A 2017 Cochrane review found that for people with early breast cancer, bisphosphonate treatment may reduce the risk of the cancer spreading to the person's bone, however, for people who had advanced breast cancer bisphosphonate treatment did not appear to reduce the risk of the cancer spreading to the bone.[15] Side effects associated with bisphosphonate treatment for people with breast cancer are mild and rare.[15]
Bisphosphonates can also reduce mortality in those with multiple myeloma and prostate cancer.[20]
Evidence suggests that the use of bisphosphonates would be useful in the treatment ofcomplex regional pain syndrome, a neuro-immune problem with high MPQ scores, low treatment efficacy and symptoms which can include regional osteoporosis. In 2009 bisphosphonates were "among the only class of medications that has survived placebo-controlled studies showing statistically significant improvement (in CRPS) with therapy."[21]
There is observational evidence and molecular explanation for some bisphosphonates offering a level of protection againstCOVID-19.[22][23]
Bisphosphonates have been used to reduce fracture rates in children with the diseaseosteogenesis imperfecta[24] and to treatotosclerosis[25] by minimizing bone loss.
Other bisphosphonates, includingmedronate (R1=H, R2=H) andoxidronate (R1=H, R2=OH), are mixed with radioactivetechnetium and injected, as a way to image bone and detect bone disease.
Oral bisphosphonates can cause upsetstomach andinflammation and erosions of theesophagus, which is the main problem of oralN-containing[further explanation needed] preparations, that is ones containing "normal" unbranched chains. This can be prevented by remaining seated upright for 30 to 60 minutes after taking the medication. Intravenous bisphosphonates can give fever andflu-like symptoms after the first infusion, which is thought to occur because of their potential to activate humanγδ T cells.
Bisphosphonates, when administered intravenously for the treatment of cancer, have been associated withosteonecrosis of the jaw (ONJ), with themandible twice as frequently affected as themaxilla and most cases occurring following high-dose intravenous administration used for some cancer patients.Phossy jaw has been described since Victorian times. Some 60% of cases are preceded by a dental surgical procedure (that involves the bone), and it has been suggested that bisphosphonate treatment should be postponed until after any dental work to eliminate potential sites of infection (the use of antibiotics may otherwise be indicated prior to any surgery).[26]
A number of cases of severe bone, joint, or musculoskeletal pain have been reported, prompting labeling changes.[27]
Some studies have identified bisphosphonate use as a risk factor foratrial fibrillation (AF), though meta-analysis of them finds conflicting reports. As of 2008[update], theUS Food and Drug Administration did not recommend any alteration in prescribing of bisphosphonates based on AF concerns.[28] More recent meta-analyses have found strong correlations between bisphosphonate use and development of AF, especially when administered intravenously,[29] but that a significantly increased risk of AF that required hospitalization did not have an attendant increased risk of stroke or cardiovascular mortality.[30]
In large studies, women taking bisphosphonates for osteoporosis have had unusual fractures ("bisphosphonate fractures") in thefemur (thigh bone) in the shaft (diaphysis orsub-trochanteric region) of the bone, rather than at the femoral neck, which is the most common site of fracture. However, these fractures are rare (12 in 14,195 women) compared to the common hip fractures (272 in 14,195 women), and the overall reduction in hip fractures caused by bisphosphonate is more than the increase in unusual shaft fractures.[31][obsolete source] There are concerns that long-term bisphosphonate use can result in over-suppression ofbone turnover. It is hypothesized that micro-cracks in the bone are unable to heal and eventually unite and propagate, resulting in atypical fractures. Such fractures tend to heal poorly and often require some form of bone stimulation, for examplebone grafting as a secondary procedure. This complication is not common, and the benefit of overall fracture reduction still holds.[31][32][non-primary source needed] In cases where there is concern of such fractures occurring,teriparatide is potentially a good alternative because it does not cause as much damage as a bisphosphonate does by suppressing bone turnover.[33]
Three meta analyses have evaluated whether bisphosphonate use is associated with an increased risk of esophageal cancer. Two studies concluded that there was no evidence of increased risk.[34][35][36]
All bisphosphonate drugs share a common phosphorus-carbon-phosphorus "backbone":
The twoPO
3 (phosphonate) groupscovalently linked tocarbon determine both the name "bisphosphonate" and the function of the drugs.Bis refers to the fact that there are two such groups in the molecule.
The longside-chain (R2 in the diagram) determines the chemical properties, the mode of action and the strength of bisphosphonate drugs. The short side-chain (R1), often called the 'hook', mainly influences chemical properties andpharmacokinetics.
See nitrogenous and non-nitrogenous sections inMechanism of action below.
Of the bisphosphonate that is resorbed (from oral preparation) or infused (forintravenous drugs), about 50% is excreted unchanged by the kidney. The remainder has a very high affinity forbone tissue, and is rapidly adsorbed onto the bone surface. Once bisphosphonates are in bone, they have a very long eliminationhalf-life that can exceed ten years.[37]
Bisphosphonates are structurally similar topyrophosphate, but with a central carbon that can have up to twosubstituents (R1 and R2) instead of an oxygen atom. Because a bisphosphonate group mimics the structure of pyrophosphate, it can inhibit activation of enzymes that utilize pyrophosphate.
The specificity of bisphosphonate-based drugs comes from the two phosphonate groups (and possibly a hydroxyl at R1) that work together to coordinate calcium ions. Bisphosphonate molecules preferentially bind tocalcium ions. The largest store of calcium in the human body is in bones, so bisphosphonates accumulate to a high concentration only in bones.
Bisphosphonates, when attached to bone tissue, are released byosteoclasts, the bone cells that break down bone tissue. Bisphosphonate molecules then attach to and enter osteoclasts where they disrupt intracellular enzymatic functions needed forbone resorption.[38]
There are two classes of bisphosphonate compounds: non-nitrogenous (nonitrogen in R2) and nitrogenous (R2 contains nitrogen). The two types of bisphosphonates work differently in inhibiting osteoclasts.
| Class | Name | R1 | R2 | Relative potency (vs Etidronate=1) |
|---|---|---|---|---|
Non-nitrogenous | Etidronate (Didronel) | OH | CH3 | 1 |
| Clodronate (Bonefos, Loron) | Cl | Cl | 10 | |
| Tiludronate (Skelid) | H | p-Chlorophenylthio | 10 | |
Nitrogenous | Pamidronate (APD, Aredia) | OH | [CH2]2NH2 | 100 |
| Neridronate (Nerixia[a]) | OH | [CH2]5NH2 | 100 | |
| Olpadronate | OH | [CH2]2N(CH3)2 | 500 | |
| Alendronate (Fosamax) | OH | [CH2]3NH2 | 500 | |
| Ibandronate (Boniva - US, Bonviva - Asia) | OH | [CH2]2N(CH3)[CH2]4CH3 | 1000 | |
| Risedronate (Actonel) | OH | 3-Pyridylmethyl | 2000 | |
| Zoledronate (Zometa, Aclasta) | OH | 1H-imidazol-1-ylmethyl | 10000 |
The non-nitrogenous bisphosphonates (diphosphonates) aremetabolised in thecell to compounds that replace the terminal pyrophosphate moiety of ATP, forming a non-functional molecule that competes withadenosine triphosphate (ATP) in the cellular energy metabolism. The osteoclast initiatesapoptosis and dies, leading to an overall decrease in the breakdown of bone. This type of bisphosphonate has overall more negative effects than the nitrogen containing group, and is prescribed far less often.[39]
Nitrogenous bisphosphonates act on bone metabolism by binding and blocking the enzymefarnesyl diphosphate synthase (FPPS) in theHMG-CoA reductase pathway (also known as the mevalonate pathway).[40]
Bisphosphonates that containisoprene chains at the R1 or R2 position can impart specificity for inhibition ofGGPS1.[41]
Disruption of the HMG CoA-reductase pathway at the level of FPPS prevents the formation of two metabolites (farnesol andgeranylgeraniol) that are essential for connecting some small proteins to thecell membrane. This phenomenon is known as prenylation, and is important for proper sub-cellular protein trafficking (see "lipid-anchored protein" for the principles of this phenomenon).[42]
While inhibition of protein prenylation may affect many proteins found in anosteoclast, disruption to the lipid modification ofRas,Rho,Rac proteins has been speculated to underlie the effects of bisphosphonates. These proteins can affect both osteoclastogenesis, cell survival, and cytoskeletal dynamics. In particular, the cytoskeleton is vital for maintaining the "ruffled border" that is required for contact between a resorbing osteoclast and a bone surface.
Statins are another class of drugs that inhibit the HMG-CoA reductase pathway. Unlike bisphosphonates, statins do not bind to bone surfaces with high affinity, and thus are not specific for bone. Nevertheless, some studies have reported a decreased rate offracture (an indicator ofosteoporosis) and/or an increasedbone mineral density in statin users. The overall efficacy of statins in the treatment of osteoporosis remains controversial.[43]
Bisphosphonates were developed in the 19th century but were first investigated in the 1960s for use in disorders of bone metabolism. Their non-medical use was to soften water in irrigation systems used in orange groves. The initial rationale for their use in humans was their potential in preventing the dissolution ofhydroxylapatite, the principal bone mineral, thus arresting bone loss. In the 1990s their actual mechanism of action was demonstrated with the initial launch ofalendronate byMerck & Co.[44]
