Bisphosphonates are medications known to decrease bone resorption by inhibiting osteoclastic activity. They are the first-line therapy for the treatment of osteoporosis because a significant body of literature has proved their efficacy in reducing the risk of fracture in the hip, spine and other nonvertebral osseous sites. In addition, the use of bisphosphonates has significantly decreased morbidity and increased survival, and they have also proved to be cost-effective. Unexpected adverse effects have been reported recently, but the benefit of bisphosphonates use outweighs the risks. This article reviews the current use of bisphosphonates in orthopedic surgery.
Key points
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Bisphosphonates are the first line of therapy in most patients with osteoporosis.
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Bisphosphonates decrease the risk of fractures in the hip, the spine, and other nonvertebral sites in patients with osteoporosis.
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Bisphosphonates are cost-effective and effective in decreasing mortality and increasing survival in patients with osteoporosis.
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The protective effect of bisphosphonates continues with long-term therapy in patients with osteoporosis.
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The benefit of bisphosphonate use outweighs the risk of adverse effects, which are uncommon but are becoming more noticeable because of the current widespread use.
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Indications for the use of bisphosphonates are increasing because good results are being obtained when treating orthopedic conditions in which the common denominator is increased osteoclastic activity.
Introduction
There is a significant number of skeletal disorders affecting bone mineral density that are product of increased osteoclastic activity. Some of these are prevalent in the general population, such as osteoporosis and skeletal metastatic disease. Others are less frequent, such Paget disease and osteogenesis imperfecta (OI).
Bisphosphonates are the most clinically important and widely used antiresorptive medication for the treatment of conditions with increased bone resorption caused by osteoclastic activity, including osteoporosis, Paget disease, and metastatic bone disease. These are synthetic, metabolically stable analogues of inorganic pyrophosphate in which the P-O-P bond has been replaced by a nonhydrolyzable P-C-P. The diphosphate configuration of this molecule facilitates the binding of calcium molecules, which is thought to be the main biochemical reason for the high affinity to bone seen with these compounds. Because of this property they were initially used as bone scanning markers when combined with radioisotopes.
In the last decade, this group of medications has been widely researched, especially in osteoporosis. Their efficacy has been proved by many investigations in fracture prevention. Because bisphosphonates are cost-effective and safe to use, their current use is widespread: at least 4 million American women were prescribed bisphosphonates for the treatment of osteoporosis in 2008.
Several bisphosphonates have been approved by the United States Food and Drug Administration (FDA) for the treatment of orthopedic conditions characterized by increased osteoclastic activity and/or decreased bone mineral density ( Table 1 ).
| Generic Name | Commercial Name | Route of Administration | Potency | FDA Approval | FDA Approved Uses |
|---|---|---|---|---|---|
| Etidronate | Didronel | Oral | — | Yes | Osteoporosis |
| Clodronate | Multiple brands (Bonefos) | Oral Intravenous | 1 | Yes | Metastatic osteolysis |
| Tiludronate | Skelid | Oral | 0.8 | Yes | Paget disease |
| Alendronate | Fosamax | Oral | 150 | Yes | Osteoporosis Paget disease |
| Pamidronate | Aredia | Intravenous | 20 | Yes | Paget disease Hypercalcemia of malignancy Metastatic osteolysis |
| Risedronate | Actonel, Optinate | Oral | 700 | Yes | Osteoporosis Paget disease |
| Ibandronate | Bondronat Boniva | Oral Intravenous | 860 | Yes | Osteoporosis |
| Zoledronic acid | Zometa | Intravenous | >10,000 | Yes | Hypercalcemia of Malignancy Metastatic Osteolysis |
Multiple investigations have shown good results with off-label use of these medications in a large and diverse spectrum of conditions. Orthopedic surgeons need to be familiar with the use of bisphosphonates and current indications. This article reviews of the use of bisphosphonates in orthopedic surgery.
Introduction
There is a significant number of skeletal disorders affecting bone mineral density that are product of increased osteoclastic activity. Some of these are prevalent in the general population, such as osteoporosis and skeletal metastatic disease. Others are less frequent, such Paget disease and osteogenesis imperfecta (OI).
Bisphosphonates are the most clinically important and widely used antiresorptive medication for the treatment of conditions with increased bone resorption caused by osteoclastic activity, including osteoporosis, Paget disease, and metastatic bone disease. These are synthetic, metabolically stable analogues of inorganic pyrophosphate in which the P-O-P bond has been replaced by a nonhydrolyzable P-C-P. The diphosphate configuration of this molecule facilitates the binding of calcium molecules, which is thought to be the main biochemical reason for the high affinity to bone seen with these compounds. Because of this property they were initially used as bone scanning markers when combined with radioisotopes.
In the last decade, this group of medications has been widely researched, especially in osteoporosis. Their efficacy has been proved by many investigations in fracture prevention. Because bisphosphonates are cost-effective and safe to use, their current use is widespread: at least 4 million American women were prescribed bisphosphonates for the treatment of osteoporosis in 2008.
Several bisphosphonates have been approved by the United States Food and Drug Administration (FDA) for the treatment of orthopedic conditions characterized by increased osteoclastic activity and/or decreased bone mineral density ( Table 1 ).
| Generic Name | Commercial Name | Route of Administration | Potency | FDA Approval | FDA Approved Uses |
|---|---|---|---|---|---|
| Etidronate | Didronel | Oral | — | Yes | Osteoporosis |
| Clodronate | Multiple brands (Bonefos) | Oral Intravenous | 1 | Yes | Metastatic osteolysis |
| Tiludronate | Skelid | Oral | 0.8 | Yes | Paget disease |
| Alendronate | Fosamax | Oral | 150 | Yes | Osteoporosis Paget disease |
| Pamidronate | Aredia | Intravenous | 20 | Yes | Paget disease Hypercalcemia of malignancy Metastatic osteolysis |
| Risedronate | Actonel, Optinate | Oral | 700 | Yes | Osteoporosis Paget disease |
| Ibandronate | Bondronat Boniva | Oral Intravenous | 860 | Yes | Osteoporosis |
| Zoledronic acid | Zometa | Intravenous | >10,000 | Yes | Hypercalcemia of Malignancy Metastatic Osteolysis |
Multiple investigations have shown good results with off-label use of these medications in a large and diverse spectrum of conditions. Orthopedic surgeons need to be familiar with the use of bisphosphonates and current indications. This article reviews of the use of bisphosphonates in orthopedic surgery.
Mechanism of action
The general effect of bisphosphonates is to inhibit bone resorption. Recent research has helped to clarify the molecular and cellular mechanisms through which this group of compounds works.
Bisphosphonates are classified into 2 major groups according to their chemical structure: nitrogen-containing (NC) and non–nitrogen-containing (NNC) bisphosphonates ( Fig. 1 ). The NNC group includes etidronate, clodronate, and tiludronate, which contain a simple nonnitrogen substitute group such as –OH, –H, or CH 3 that is metabolized into a toxic analogue of adenosine triphosphate (ATP). This analogue prompts inhibition of function and apoptosis in the osteoclast after intracellular accumulation.
The NC group is a newer class in which the radical chain includes amino groups or molecules. These bisphosphonates are more potent (up to 1000-fold) in terms of antiresorptive effect. Bisphosphonates in this group include zoledronic acid, pamidronate, alendronate, and risedronate. Their main mechanism of action is inhibition of the enzyme farnesyl pyrophosphate synthase, an essential enzyme in the mevalonate pathway ( Fig. 2 ) in the osteoclast. This enzyme is key in the process known as protein prenylation (transferring of a lipid on to a cysteine residue of a protein). GTPase is an important signaling protein, the synthesis of which depends on prenylation. The lack of GTPase causes osteoclast dysregulation, characterized by altered membrane trafficking, lack of cellular morphology control, disruption of integrin signaling, loss of membrane ruffling, and ultimately apoptosis.
The NC bisphosphonates effect is not specific to the osteoclast. The mevalonate pathway is present in several cell types. It seems that, because the osteoclast is in intimate contact with the bone surface during resorption, it is exposed to higher concentration of bisphosphonates than other cells. The clinical relevance of the bisphosphonate effect in other cellular groups still needs to be determined.
Indications
There are multiple conditions for which bisphosphonates are used; the common denominator of these is pathologic processes in which bone loss secondary to osteoclastic activity is characteristic.
Osteoporosis
Osteoporosis is one of the first indications for which bisphosphonates received FDA approval for use. This common condition affects 75 million people in Europe, Japan, and the United States. The World Health Organization has defined osteoporosis as a mineral bone density that is 2.5 standard deviations less than the peak of young adults of the same gender and race. This value is expressed as a T score. When the bone density value is compared with normal individuals of the same age and gender, it is expressed as the Z score. A Z score of less than −2, reflects the lowest 2.5%.
Osteoporosis is recognized as the primary independent risk factor for fractures in the elderly that can be treated and effectively risk reduced. Multiple medications, including hormone replacement therapy, selective estrogen receptor modulators (Raloxifene), calcitonin therapy, and bisphosphonates, are available and have been used because of their antiresorptive effect. Bisphosphonates have become the most important antiresorptive because they are the only of such medications that have proved to reduce the risk of hip fracture in large, placebo-controlled, randomized trials (PCRTs).
Most data regarding fracture reduction efficacy and safety of bisphosphonates come from prospective, randomized, placebo-controlled, phase III regulatory trials in postmenopausal women. Average follow-up is up to 3 years with fewer than 50,000 participants in terms of study samples. Only 2 trials testing alendronate were extended to 10 years. There are concerns in terms of the long-term effects of bisphosphonates (as discussed later). Data are scarce and there are no placebo-controlled data beyond the 5-year benchmark.
There are 10 trials that have evaluated the efficacy of the antifracture effect of bisphosphonates in osteoporosis. Table 2 presents a summary of these. The first landmark study is the Fracture Intervention Trial (FIT), which was a multicenter prospective investigation in 3658 women at risk of osteoporotic fractures, who were randomized to receive alendronate or placebo for 3 to 4 years; patients and examiners were blinded to the intervention. The main end point was the presence of a vertebral fracture, defined as clinically evident vertebral fracture or the loss of more than 20% of the lateral radiograph view in a given vertebral body. Of the women treated with alendronate, only 8% presented radiographically evident vertebral fractures versus 15% in the placebo group. Other secondary end points showed a reduction in the risk of developing any type of fracture in the alendronate group (2.3% vs 5%). The overall number of hip and wrist fractures in the alendronate group decreased as well.
| Medication | Trial | Follow-up (y) | Fracture Risk (Absolute Reduction) | Fracture Risk (Relative Risk) | Number of Patients to Treat to Prevent 1 Fracture | Reference | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Hip Fracture (%) | Vertebral Fracture (%) | Nonvertebral Fracture (%) | Hip Fracture (%) | Vertebral Fracture (%) | Nonvertebral Fracture (%) | Hip Fracture (%) | Vertebral Fracture (%) | Nonvertebral Fracture (%) | ||||
| Alendronate | FIT I | 3 | 1.1 | 7.1 | 2.8 | 50.8 | 47.1 | 18.9 | 90 | 14 | 36 | Black et al, 1996 |
| Alendronate | FIT II | 3 | 0.2 | 1.7 | 1.5 | 20.7 | 44.3 | 11.1 | 447 | 60 | 68 | Cummings et al, 1998 |
| Alendronate | MALE | 2 | N/A | 5.0 | N/A | N/A | 62.0 | N/A | N/A | 9 | N/A | Orwoll et al, 2000 |
| Ibandronate | BONE | 3 | N/A | 4.9 | −0.9 | N/A | 62.0 | −11.0 | N/A | 20 | N/A | Chesnut et al, 2004 |
| Risedronate | VERT NA | 3 | 0.4 | 5.0 | 3.2 | 19.7 | 30.7 | 38.1 | 276 | 20 | 31 | Harris et al, 1999 |
| Risedronate | VERT MN | 3 | 0.5 | 10.9 | 5.1 | 18.2 | 37.6 | 31.9 | 203 | 9 | 20 | Reginster et al, 2000 |
| Risedronate | HIP | 3 | 1.1 | N/A | 1.8 | 28.2 | N/A | 16.1 | 91 | N/A | 56 | McClung et al, 2001 |
| Risedronate | GIO | 1 | N/A | 11.0 | N/A | N/A | 70.0 | N/A | N/A | 9 | N/A | Wallach et al, 2000 |
| Zoledronic acid | HORIZON PFT | 3 | 1.1 | 7.6 | 2.7 | 44.0 | 70.0 | 25.2 | 91 | 13 | 37 | Black et al, 2007 |
| Zoledronic acid | HORIZON RFT | 3 | 1.5 | N/A | 3.1 | 42.9 | N/A | 29.0 | 67 | NA | 32 | Lyles et al, 2007 |
The available data from these trials assessing the antifracture effect of bisphosphonates suggest that alendronate, risedronate, and zoledronic acid decrease fracture risk at the spine, nonvertebral sites, and the hip. Ibandronate, a newer bisphosphonate, reduces the risk only in vertebral fractures.
A general observation in all these investigations is that efficacy in fracture risk reduction depends on the patient’s risk profile: patients with higher fracture risk presented a higher absolute risk reduction.
The benefit of bisphosphonates in patients with osteoporosis in the midterm is clear. The incidence of hip fractures in the United States decreased between 1996 and 2007 when osteoporosis treatment with bisphosphonates became widespread after the FIT results. Benefits are also not limited to fracture risk reduction. Other investigations have shown reduction in morbidity, reduced health-care costs, and reduced mortality. The use of bisphosphonates, oral or intravenous, for up to a 3-year period decreased mortality up to 28% in patients who sustained low-energy hip fractures. The adjusted reduction risk of mortality in men and women using bisphosphonates for a period of 5 years is 27%. A recent meta analysis by Bolland and colleagues in 2010 showed that the use of antiresorptive therapies in osteoporosis including bisphosphonates for at least 1 year is associated with decreased mortality in elderly patients at high risk of fracture.
As mentioned earlier, the data for long-term use are scarce. One of the 2 studies is the extension of the FIT to 10 years of use. This investigation showed an increase in mineral density in the lumbar spine (13.7%) and other skeletal sites. A dose of 5 mg showed a modest increase in bone mineral density. This investigation did not compare with placebo but with different dosages. The efficacy of alendronate in terms of fracture reduction risk did not seem to diminish with the 10 years of sustained therapy. This investigation was also useful in showing that a 70-mg weekly dose is therapeutically as effective as 10 mg daily. This weekly dosage has become the standard therapy. This study also confirmed the direct relationship between alendronate use and increased bone mineral density because discontinuation of treatment caused gradual loss of bone density and increased N-telopeptide level.
Osteoporosis in Men and Glucocorticoid Use
Although the disease is more prevalent in women, osteoporosis in men has recently become an area of research focus, because of an increase in hip fractures occurring in men. The high prevalence of hip fractures in men (25%–30% of all hip fractures) is significant because the 1-year mortality doubles after a hip fracture. Two trials focused in the male population showed increased bone mineral density and reduction in both bone turnover serum markers and fracture events. However, difficulties still exist in the treatment of this population, because evidence is scarce and there is lack of agreement about the definition of the disease and the best time to start therapy.
Patients receiving therapy with glucocorticoids are also known to develop osteoporosis as a direct secondary effect of this therapy. Fracture incidence is also 1.3 to 2.6 times higher in this population. The bisphosphonates alendronate and risedronate are also FDA approved for use in this clinical indication. Data are scarce but 2 PCRTs have proved risedronate’s efficacy in these patients, with 70% reduction in vertebral fractures rate. Data for alendronate also come from 2 PCRTs. However, increased bone mineral density and decreased fracture risk are significant only when combining the data from both studies. The recommendation is to start treatment early when using therapy with glucocorticoids as a prevention plan, given that reduction in bone density occurs during the first months of treatment.
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