The Journal of Bone and Joint Surgery (American). 2005;87:1609-1618.
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Current Concepts Review

Bisphosphonates in Orthopaedic Surgery

Carol D. Morris, MD, MS1 and Thomas A. Einhorn, MD2

1 Orthopaedic Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Suite A-342, New York, NY 10021. E-mail address: morrisc{at}mskcc.org
2 Department of Orthopaedic Surgery, Boston University Medical Center, 720 Harrison Avenue, Boston, MA 02116

Investigation performed at Memorial Sloan-Kettering Cancer Center, New York, NY, and Boston University Medical Center, Boston, Massachusetts


   Abstract
Top
 Abstract
Introduction
 Mechanism of Action
 Clinical Measures of...
 Clinical Applications
 Overview
 References
 
Bisphosphonates are the most clinically important class of antiresorptive agents available to treat diseases characterized by osteoclast-mediated bone resorption.

Currently, seven bisphosphonates have the approval of the United States Food and Drug Administration.

The most common adult diseases treated with bisphosphonates include osteoporosis, Paget disease, and metastatic bone disease.

The treatment of pediatric disorders such as osteogenesis imperfecta and fibrous dysplasia with bisphosphonates has gained momentum, and initial investigations have demonstrated an acceptable safety profile.

Currently, there is a lack of long-term follow-up data, which will be necessary for the development of responsible guidelines for therapy.


   Introduction
Top
 Abstract
 Introduction
Mechanism of Action
 Clinical Measures of...
 Clinical Applications
 Overview
 References
 
Bisphosphonates are the most clinically important class of antiresorptive agents available to treat diseases characterized by osteoclast-mediated bone resorption such as osteoporosis, Paget disease, and tumor-associated bone diseases. They are synthetic, metabolically stable analogues of inorganic pyrophosphate in which the P-O-P bond has been replaced with a non-hydrolyzable P-C-P bond (Fig. 1). The diphosphate configuration of both P-O-P and P-C-P contributes to a three-dimensional structure capable of binding divalent ions such as Ca2+ and is the basis for the bone-targeting property of these compounds. This feature led to their use as bone-scanning agents when coupled with a radioisotope such as technetium-991. Because the P-O-P compound is rapidly metabolized, it is safe to label with radioactive isotopes for bone-scanning. However, there is no known enzyme capable of metabolizing the P-C-P bond of bisphosphonates, which allows considerable longevity of these compounds after they are administered.



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  		Fig. 1 Schematic of the bisphosphonate skeleton.

 
More than three decades of research and development have produced a wide range of molecules that vary on the basis of the side-chain substituents (-R1, -R2) attached to the carbon compound; this leads to variable clinical efficacy for a given bone-resorptive condition based on the stereochemistry of that side chain (Table I). Since bisphosphonates were described more than a century ago, more than 1000 have been synthesized and more than a dozen have been investigated in humans. Currently, seven bisphosphonates have been approved by the United States Food and Drug Administration (FDA) for use for various skeletal indications (Table I). As a result of intense clinical interest and a number of compelling preclinical investigations, several bisphosphonates are being used in an off-label fashion for a variety of skeletal disorders. In addition, bisphosphonates that have not yet gained FDA approval are presently under clinical investigation and have shown promise in a number of therapeutic applications.


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  		TABLE I Commonly Used Bisphosphonates

 


   Mechanism of Action
Top
 Abstract
 Introduction
 Mechanism of Action
Clinical Measures of...
 Clinical Applications
 Overview
 References
 
The cellular and molecular mechanisms by which bisphosphonates inhibit bone resorption are only just beginning to become clear. The mechanism of action depends largely on the chemical structure, which can be grouped into two major pharmacological classes: nitrogen-containing and non-nitrogen-containing compounds.

The early compounds such as etidronate and clodronate possess simple, non-nitrogen-containing substituents (-OH, -H, and CH3) and are metabolized into nonhydrolyzable analogues of adenosine triphosphate (ATP). The bisphosphonate preferentially binds to the mineral component of bone exposed by osteoclasts during normal or pathologic bone resorption. Since osteoclasts have high endocytic activity, in the later cycles of bone-remodeling these cells resorb both the bone and the bound bisphosphonate, or the ATP analogue. These cytotoxic ATP analogues are then thought to accumulate intracellularly, inhibiting osteoclast function and inducing apoptosis.

A newer class of bisphosphonates, developed by modifying the R2 side chain to include an amino group, was found to be up to 1000-fold more potent with respect to antiresorptive activity. Further modification of the primary amine led to even more potent bisphosphonates. Collectively, these are called the nitrogen-containing bisphosphonates, and they include the commonly used drugs pamidronate, zoledronic acid, alendronate, and risedronate. They exert their effects by inhibiting components of the intracellular mevalonate pathway (Fig. 2)2. The mevalonate pathway is the biosynthetic pathway responsible for cholesterol production and perhaps is best known as the target of several cholesterol-lowering statin drugs such as lovastatin and mevastatin. The cholesterol precursors farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP) are synthesized along the mevalonate pathway. FPP and GGPP, collectively referred to as isoprenoid lipids, are responsible for transferring their respective lipid group (farnesyl or geranylgeranyl) onto the cysteine residue of a protein. This process is called protein prenylation. GTPase, an important signaling protein, is formed by protein prenylation. The nitrogen-containing bisphosphonates inhibit protein prenylation, and thus GTPase formation, by inhibiting enzymes that have yet to be fully identified. The loss of GTPase prenylation leads to a loss of osteoclast regulation, including control of cell morphology, disruption of integrin signaling, altered membrane-protein trafficking, loss of membrane ruffling and cytoskeleton disruption, and induction of apoptosis3-5. The findings of several basic investigations support the hypothesis that inhibition of protein prenylation is the major molecular mechanism by which the nitrogen-containing bisphosphonates inhibit bone resorption.



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  		Fig. 2 The mevalonate pathway.

 
It is a common misconception that the mechanism of action of the bisphosphonates is specific to the osteoclast. The mevalonate pathway is present in many cell types. Because osteoclasts are in intimate contact with the bone surface during resorption and bound bisphosphonates are released during resorption, osteoclasts are exposed to a very high concentration of the compound and as such are most affected in this setting. Other cells exposed to high concentrations of bisphosphonates in cell culture also have problems with protein prenylation, although the clinical relevance of this observation is unclear at the present time. While there is no doubt, on the basis of our current understanding, that osteoclasts are the obvious target of bisphosphonate therapy, the effect of bisphosphonates on osteogenic and other cells needs further investigation.


   Clinical Measures of Effectiveness
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 Abstract
 Introduction
 Mechanism of Action
 Clinical Measures of...
Clinical Applications
 Overview
 References
 
A number of outcome parameters are used as surrogate markers of bisphosphonate efficacy. Bone mineral density as assessed with dual-energy x-ray absorptiometry (DXA or DEXA) is a measure of clinical efficacy that can be evaluated noninvasively. Its measurement in clinical investigations of bisphosphonate is based on the concept that these drugs protect the skeleton from bone loss and that effect is reflected by stabilization or improvement in bone density. Biochemical markers of bone turnover—namely, calcium-creatinine and hydroxyproline-creatinine ratios as well as measurements of the excretion of the collagen cross links pyridinoline (PYD), deoxypyridinoline (DPD), n-telopeptide (NTX), and serum cross laps (CTX)—are useful for monitoring bisphosphonate therapy6. Of these, urinary excretion of NTX appears to best reflect decreased bone resorption in patients receiving anti-resorptive therapy7. In addition, the plain radiographic appearance of lytic disease, pain, and the need for radiation or surgery are used to indicate therapeutic response.


   Clinical Applications
Top
 Abstract
 Introduction
 Mechanism of Action
 Clinical Measures of...
 Clinical Applications
Overview
 References
 
A number of orthopaedic conditions have the potential to respond to the antiosteoclastic activity induced by bisphosphonates. On the basis of the current knowledge of bisphosphonate action and the results achieved in the treatment of metabolic and metastatic bone diseases, it seems that any skeletal condition in which osteoclast activity plays a dominant role could potentially be affected by bisphosphonates. In this review, the clinical applications of bisphosphonate therapy, including both FDA-approved and off-label uses, are discussed for a variety of diseases.

Metabolic Bone Diseases
The metabolic bone diseases were among the first conditions to be treated with bisphosphonates and were the first indications for which the FDA approved use of these drugs. Postmenopausal osteoporosis and Paget disease are the most common diseases for which bisphosphonates are prescribed. Because of the tremendous success in the treatment of those two metabolic conditions, bisphosphonates are now used to treat secondary osteoporosis due to several conditions, such as extended glucocorticoid therapy and organ transplantation.

Osteoporosis
Osteoporosis affects millions of people worldwide, with an estimated 28 million cases in the United States alone and almost 75 million cases when Europe and Japan are included. For white women over the age of fifty years, the lifetime risk of a vertebral fracture is one in three and the lifetime risk of a hip fracture is one in six. Osteoporosis is the primary risk factor for fractures in the elderly that can be effectively treated to reduce that risk. The World Health Organization has operationally defined osteoporosis as a bone mineral density that is 2.5 standard deviations below the mean peak value in young adults of the same race and sex8, which is expressed as a T-score of -2.5. Bone mineral density compared with the mean value in normal subjects of the same age and sex is represented by the Z-score. A Z-score of less than -1 reflects the lowest 25% of the reference range, and a score of less than -2 represents the lowest 2.5%. While definitions of osteoporosis are largely conceptual, quantitative evaluations of bone density can aid in diagnosis and assist in therapeutic decision-making because bone density is one of the factors with a known correlation to fracture risk.

Therapies that are used to treat osteoporosis act by decreasing bone resorption. They include hormone-replacement therapy, use of the selective estrogen-receptor modulator raloxifene, calcitonin therapy, and bisphosphonates therapy. Bisphosphonates are the most important class of antiresorptive therapies available and are the only medications that have been shown to reduce the risk of hip fracture in large randomized trials. Etidronate, alendronate, and risedronate have been approved by the FDA for the treatment and prevention of osteoporosis, and clodronate, pamidronate, tiludronate, zoledronate, and ibandronate have been evaluated in this clinical setting as well. Etidronate given continuously at high doses can impair mineralization9. This drug is therefore usually administered in an intermittent cyclical fashion at 400 mg/day for two weeks followed by use of supplemental calcium (usually 500 mg) for eleven weeks. This schedule has resulted in a 2% increase in the bone mineral density in the femoral neck, a 4% to 8% increase in the bone mineral density in the lumbar spine, and a decrease in vertebral fracture rates10-12. Because of its potential adverse effects on mineralization, etidronate is rarely used for the management of osteoporosis in the United States.

Alendronate was the first orally active bisphosphonate available in the United States, and its effectiveness as an osteoporosis drug was investigated in a large multi-institutional double-blind randomized trial called the Fracture Intervention Trial (FIT)13. More than 2000 women who had low bone density in the femoral neck, with or without vertebral fracture, were randomized to receive alendronate or a placebo for three years. Both clinically evident vertebral fractures and vertebral fractures evidenced by a 20% decrease in vertebral height as seen on a lateral radiograph served as the primary end points. Eight percent of the women treated with alendronate sustained a radiographically evident vertebral fracture compared with 15% of those treated with the placebo. In addition, the risk of any clinical fracture developing was lower in the alendronate group (2.3%) than in the placebo group (5.0%). The alendronate group had fewer hip and wrist fractures than did the placebo group. In a ten-year extension of the FIT study14, treatment with 10 mg of alendronate daily resulted in a 13.7% increase in bone mineral density in the lumbar spine as well as increased bone mineral density at other skeletal sites. A 5-mg daily dose resulted in a more modest increase in bone mineral density. The efficacy of the drug for preventing fractures did not appear to diminish during the ten-year period of sustained therapy. Furthermore, a once-a-week dose of 70 mg of alendronate demonstrated therapeutic efficacy equivalent to that of a daily dose, and this has become the standard of therapy15. Discontinuation of alendronate therapy resulted in a gradual loss of effect, as demonstrated by measurement of bone mineral density and n-telopeptide (NTX) level.

Special Considerations in Osteoporosis
Osteoporosis in men has gained considerable attention in recent years. Although the disease is less prevalent in men than in women (3% to 6% compared with 13% to 18%), approximately 25% to 30% of all hip fractures occur in men16. Also, male fragility fractures cause the same morbidity, and hip fractures are associated with double the one-year mortality rate. While the best way to diagnose osteoporosis in men is somewhat unclear, as there is a lack of consensus on how the disease should be defined, when treatment is indicated, bisphosphonates are the drugs of choice. Daily treatment with 10 mg of alendronate produced positive effects on bone mineral density, serum markers of bone turnover, and fracture incidence in two large clinical trials17,18.

It has become clear that all patients with early-stage breast cancer (i.e., without evidence of skeletal metastases) are susceptible to the development of osteoporosis. This at-risk population includes not only postmenopausal women receiving aromatase inhibitors (which are known to accelerate bone loss) for estrogen-receptor-positive disease but also premenopausal women who undergo chemotherapy-associated premature menopause from ovarian suppression resulting in bone loss equivalent to that following surgical oophorectomy. Therefore, it is possible that, even in the absence of bone metastases, such patients might benefit from bisphosphonate therapy to preserve bone mineral density. A strong body of evidence suggests the benefits of early detection with subsequent intervention guided by monitoring of bone mineral density, with use of the same criteria employed for otherwise healthy patients. Glucocorticoids are used for the treatment of many chronic diseases, including renal, hepatic, rheumatologic, and pulmonary disorders, as well as an adjuvant to suppressive therapy during organ transplantation19,20.

Osteoporosis occurs in 30% to 50% of patients receiving long-term glucocorticoid therapy (≥7.5 mg/day of prednisone for more than one year). Fracture incidence is estimated to be 1.3 to 2.6 times higher in patients who are receiving glucocorticoids than in those who are not. Bisphosphonates are indicated for the treatment of glucocorticoid-induced osteoporosis, and risedronate and alendronate have been approved by the FDA for this purpose. Two randomized trials have demonstrated the efficacy of risedronate therapy, with a 70% reduction in the rate of vertebral fractures compared with that following use of a placebo21,22. The combined results of two other randomized trials demonstrated an increased bone mineral density and a decrease in vertebral fractures in patients receiving treatment with alendronate compared with those receiving a placebo23. Because most bone loss occurs in the first six months of glucocorticoid use, strong consideration should be given to an osteoporosis prevention plan that incorporates bisphosphonate therapy during the early phases of treatment.

Paget Disease
Paget disease of bone, or osteitis deformans, is characterized by localized accelerated bone resorption followed by deposition of dense chaotic and thus ineffectively mineralized bone matrix. It is estimated to occur in 2% to 3% of the United States population over sixty years old24. The etiology of Paget disease is largely unknown, although decades of research have revealed a possible genetic component25,26. Viral transmission has also been implicated in genetically susceptible individuals27,28. Symptomatic individuals experience a plethora of symptoms including bone pain, arthritic pain, headache, and neurological symptoms. Indications for treatment include those symptoms and the need for elective surgical prophylaxis to decrease perioperative blood loss in this hypervascular condition.

In the United States, physicians can choose among calcitonin and several bisphosphonates, including oral etidronate, alendronate, tiludronate, and risedronate and intravenous pamidronate, for the treatment of Paget disease. The most potent of these, pamidronate, alendronate, and risedronate, have achieved sustained remission and normalization of serum alkaline phosphatase levels in several large clinical trials. Intravenous pamidronate offers the opportunity to titrate the dose to individuals on the basis of the disease severity. The optimal regimen of pamidronate remains controversial. Patients with mild disease may have normalization of the alkaline phosphatase level after a single 60-mg infusion over three to four hours, whereas patients with moderate-to-severe disease may require weekly or biweekly 60-mg infusions with cumulative doses of up to >400 mg29. The recommended regimen of oral alendronate is 40 mg daily for six months followed by reevaluation of clinical indices. With use of this dosing scheme, >60% of patients had normalization of serum alkaline phosphate levels30. Similar observations have been reported with the use of risedronate and tiludronate31,32.

Metastatic Disease
More than 400,000 patients are diagnosed with bone metastases yearly in the United States alone. Skeletal complications of metastatic disease include hypercalcemia of malignancy, bone pain, pathologic fracture, and spinal cord compression. Osseous metastasis is probably the most symptomatic metastatic disease, as there is a tremendous impact on quality of life, mobility, and independence. Bone metastases eventually develop in >80% of patients with carcinoma of the breast, prostate, or kidney. The invasion of malignant cells into the bone microenvironment causes a breakdown in the normal, tightly controlled bone-remodeling process, leading to an un-coupling of cellular function and an excess of osteoclastic over osteoblastic activity. This disruption of bone homeostasis leads to osteolysis, skeletal destruction, and a risk of pathologic fracture33.

Bisphosphonates have been incorporated as part of the management strategy for almost all cancers that exhibit skeletal metastases. The effects of bisphosphonates in patients with cancer are multifold: not only do bisphosphonates inhibit osteoclastic function, but they reduce the local release of factors that stimulate tumor growth and hence even potentially extend overall survival33. In fact, there is a growing body of evidence that bisphosphonates possess direct antitumor activity against a variety of cancers as well as act synergistically when combined with other anticancer agents34,35. It is unclear and probably unlikely that all cancers mediate osteolysis by the same mechanisms. For example, the molecules responsible for the metastatic potential of multiple myeloma may be different from those implicated in metastases of carcinomas. These different molecular pathways may account for the variable efficacy of a given drug when used for different tumor types.

Hypercalcemia
Hypercalcemia of malignancy is the most common life-threatening metabolic complication of advanced cancer, affecting up to 20% of patients, although the incidence varies considerably according to the cancer subtype. It is most frequently observed in patients with multiple myeloma and those with carcinoma of the lung, breast, or kidney, and it is mediated by soluble factors such as parathyroid-related hormone-related peptide (PTHrP) and cytokines secreted by tumor cells and the immune system. Bisphosphonates are the most effective therapy for hypercalcemia of malignancy. The most commonly used drugs are pamidronate and zoledronic acid. Two identical, concurrent, parallel, multicenter, randomized trials were performed to compare the efficacy and safety of pamidronate (90 mg infused over two hours) and zoledronic acid (4 or 8 mg infused over five minutes) for treating this disorder36. The primary end points were a complete response by the tenth day and the duration of the response. Both doses of zoledronic acid were superior to pamidronate with respect to both clinical end points. In the group of 287 patients, 87% of those who had received 8 mg of zoledronate and 70% of those who had received pamidronate had a complete response (p = 0.002). Safety profiles were equivalent for all groups, although the higher dose of zoledronic acid required lengthening of the infusion time to fifteen minutes secondary to renal dysfunction. Although pamidronate has a lengthy track record in this clinical setting, it is likely that zoledronic acid will replace it as the first-line therapy for the treatment of hypercalcemia of malignancy given that it is more effective and has a more convenient dosing schedule.

Pain and Pathologic Fracture
The role of bisphosphonates in treating painful bone metastases and preventing pathologic fracture has been extensively investigated for many cancers. As it is not practical to present the results of all clinical trials of the use of bisphosphonates for metastatic cancer, breast cancer, which is the largest source of symptomatic metastases and has probably been the most extensively investigated in clinical trials, will be highlighted. While the data are specific for patients with breast cancer, some of the principles can be extrapolated to any patient with symptomatic or potentially symptomatic bone metastases.

The American Society of Clinical Oncology publishes evidence-based clinical practice guidelines for a variety of cancer treatments derived from up-to-date reviews of published data, meeting abstracts, and clinical trials and subsequent recommendations by an expert panel based on these reviews. What follows are their guidelines on the role of bisphosphonates in women with breast cancer37. These guidelines can be divided into three clinical scenarios: imaging evidence of bone metastases, evidence of extraskeletal metastases without bone metastases, and adjuvant systemic therapy.

The recommended treatment for patients with evidence of lytic disease on plain radiographs consists of 90 mg of pamidronate delivered intravenously over two hours or 4 mg of zoledronic acid delivered over fifteen minutes every three to four weeks. There is insufficient evidence to support one bisphosphonate over another. It is considered reasonable to begin administering bisphosphonates to women who have an abnormal bone scan and a computed tomography or magnetic resonance imaging scan showing bone destruction but normal findings on plain radiographs. Bisphosphonates are not recommended for women with an abnormal bone scan but no evidence of bone destruction on plain radiographs, computed tomography scans, or magnetic resonance imaging. When bisphosphonates are administered according to the recommended infusion doses, times, and intervals, the risk of renal dysfunction is low and if renal dysfunction does occur it is usually reversible if it is detected early. Biochemical markers of bone resorption have not proved to be as reliable as radiographic evidence for monitoring clinical response and adjusting therapy. Once therapy is initiated, it is recommended that treatment continue until there is a substantial decline in the patient's performance status. There is no evidence to support the use of bisphosphonates alone as a replacement for analgesics or radiation in the setting of bone pain, or even as an adjuvant to these therapies in a patient with refractory pain.

Starting bisphosphonates without evidence of bone metastases in a patient with other, extraskeletal metastases for the purpose of preventing future skeletal events is not recommended. This scenario will likely be the focus of future clinical trials.

The data regarding adjuvant use of bisphosphonates to prevent osseous disease in patients with early breast cancer is evolving and inconsistent. The current recommendations do not support the routine use of bisphosphonates at any stage of nonosseous disease despite the high risk of future bone metastases. Most recently, the results of three phase-III trials of oral clodronate (not approved by the FDA) as adjuvant therapy for patients with either lymph-node-positive disease or positive immunocytochemical evidence (bone marrow aspirate positive for tumor-associated glycoprotein-12) were reported. Two of these trials yielded favorable results, with a decrease in skeletal and nonskeletal metastases as well as improvement in disease-free and overall survival38. In the third trial, clodronate had a negative impact on disease progression and the development of skeletal metastases.

While the above guidelines are specific for patients with breast cancer, bisphosphonate therapy has the potential to have a beneficial effect as a treatment for virtually every cancer that is known to metastasize to bone, and most patients with bone metastases, regardless of the carcinoma subtype, are treated with bisphosphonates. Clinical trials have shown outcomes favoring the use of bisphosphonates for patients with multiple myeloma, renal cancer, prostate cancer, and thyroid cancer39,40. Although the advantage of bisphosphonates with regard to increasing bone mineral density, reducing fracture risk, and alleviating pain varies among different tumors, their beneficial role is clear and will become better defined as more data become available.

Arthroplasty
As the population ages and more total joint replacements are performed, complications related to loosening and periprosthetic fracture are on the rise. The use of bisphosphonate therapy in an effort to sustain and improve the clinical survival of total joint implants has thus generated great interest. Mechanisms causing undesired bone loss following total joint arthroplasty include wear-debris-induced osteolysis, stress-shielding, immobilization, and operative trauma, with the first two mechanisms being the most important. It has been well established that the macrophages that absorb small particles of wear debris cytokinetically signal osteoclasts to resorb bone41. The resultant osteolytic defect has the potential to compromise the surrounding host bone, leading to a variety of problems requiring surgical intervention. The surrounding bone's ability to adjust to the altered mechanical demands (so-called stress-shielding) leads to additional undesired bone loss. Bisphosphonates have been preliminarily shown to intervene in these processes, although the clinical outcomes of such intervention have not been clearly defined. Various routes of administration, including intravenous, oral, and local, have been explored. Bisphosphonates have not been approved by the FDA for the purpose of decreasing osteolytic-associated complications of arthroplasty.

Investigations of both animals and humans have demonstrated an increase in bone mineral density and a reduction in bone loss in the acute postoperative period following total hip and total knee arthroplasty. At least two randomized trials have shown that oral alendronate (10 mg) increases bone mineral density in the distal part of the femur and proximal part of the tibia for up to one year following total knee arthroplasty compared with that measured in the immediate preoperative period42,43. Patients receiving a placebo actually had a decrease in bone mineral density at the same anatomic sites. In a prospective, randomized controlled trial, Wilkinson et al. reported a significant reduction in bone loss in patients who had received a single dose of intravenous pamidronate (90 mg) on the fifth day following total hip arthroplasty compared with patients who had received a placebo44. The pamidronate group had a significant increase in bone mineral density, as measured with dual-energy x-ray absorptiometry, in the proximal part of the femur (p = 0.001) and pelvis (p = 0.01) as well as a reduction of serum and urine biochemical markers for bone turnover, including bone-specific alkaline phosphatase, osteocalcin, and the N-terminal propeptide of type-I collagen45. There were no adverse effects on hip function or self-assessed health. Interestingly, similar amounts of heterotopic ossification were observed in the two treatment groups, supporting the notion that the aminobisphosphonates have great efficacy in inhibiting bone resorption without interfering with bone formation.

The data from the trial reported by Wilkinson et al.44 are compelling enough to warrant a longer study to determine the effectiveness of bisphosphonates in preventing late complications associated with loosening, as the half-life of bisphosphonates is quite long. The use of alendronate has also been shown to effectively inhibit wear-debris-induced osteolysis in a canine hip arthroplasty model46. However, at this time, there are insufficient clinical data to support the use of bisphosphonates to prevent the progression of periprosthetic osteolysis once it has been identified.

While a desired effect of bisphosphonates might be seen in the above scenarios, an undesired effect is a concern in patients being treated with bisphosphonate therapy for osteoporosis who may be candidates for hip replacement without cement. Because bone formation and remodeling are necessary to establish the initial fixation of uncemented implants and as the remodeling process is thought to be initiated by and coupled to osteoclasts, it is prudent to consider the influence of these drugs in this setting. A number of well-designed animal models have been used to investigate the consequences of alendronate administration on host-bone integration with surfaces commonly employed in cementless joint arthroplasty47. The data from the animal studies have consistently shown no substantial discernible effect on radiographic or histologic findings concerning the initial fixation of these implants. These observations ultimately need to be confirmed in a human model.

Pediatric Conditions
Use in skeletally immature individuals is perhaps the most controversial aspect of bisphosphonate treatment. Historically, case reports of bisphosphonate therapy in children reflected sporadic and limited experience48,49. We are aware of only one randomized controlled trial of bisphosphonate use in children, which involved treatment of osteopenia in patients with quadriplegic cerebral palsy who could not walk50. In that study, Henderson et al. demonstrated that pamidronate improved bone mineral density, without any symptomatic adverse effects. The off-label use of bisphosphonates to treat osteolytic and osteoporotic bone conditions in children has gathered a fair amount of momentum in recent years as a result of the positive early outcomes. The controversy involves the possibility of long-term detrimental effects on skeletal development and function, as it has been suggested that prolonged bisphosphonate administration is associated with so-called brittle bones51. This is particularly troubling given the prolonged half-life of these drugs in bone. Intravenous administration of pamidronate in children has been shown to cause substantial increases in vertebral density and elevation of Z-scores52. These scores continue to increase and do not plateau until two to three years after infusion. The resulting stiffness of the treated bone can exceed that of normal bone, lowering its resistance to bending and subsequent fracture. Whyte et al. reported the development of bisphosphonate-induced "osteopetrosis" in a boy who had received 60 mg of pamidronate every three weeks over a 2.5-year period for treatment of a disorder of bone metabolism of uncertain etiology53. This report highlighted the lack of firm end points of therapy for children and the need to monitor therapeutic status, perhaps on the basis of biochemical markers of bone turnover. To our knowledge, no evidence of decreased linear growth has been reported. In addition, the drug's potential teratogenicity, later in life, after it has mobilized from the bone of adolescent girls is largely unknown, although no congenital abnormalities have been reported in the children of the few patients who have received alendronate and subsequently given birth. Studies of animals suggest that bisphosphonates cross the placenta and have similar expected pharmacological effects on both the mother and the fetus54.

In general, bisphosphonates should be used with caution in children. While the described reservations do not preclude a role for bisphosphonates in the treatment of pediatric bone disorders, in the absence of large controlled trials the decision to use bisphosphonate therapy in children requires careful consideration, with weighing of the expected benefits against the risks, and treatment should be administered under the guidance of a clinician who has experience in caring for children with bone disorders. It is imperative to develop responsible guidelines for the use of bisphosphonates in pediatric clinical practice.

Osteogenesis Imperfecta
Severe osteogenesis imperfecta is a disorder that principally affects type-I collagen and is characterized by osteopenia, frequent fractures, progressive deformity, loss of mobility, and chronic bone pain. Four discrete types (I through IV) are commonly distinguished on the basis of clinical and genetic features that vary in the degree of severity. Historically, there was no accepted medical treatment for the condition other than pain relief and surgical correction of deformities.

The medical literature is now replete with case series touting the remarkable success of treating osteogenesis imperfecta with bisphosphonates55. As a result, bisphosphonates are now widely used to treat children, adolescents, and adults with osteogenesis imperfecta. Almost all investigations have involved the use of intravenous pamidronate, with doses ranging from 0.5 to 1.5 mg/kg. The drug was usually administered over three consecutive days every three to four months. The outcomes are almost universal: increased bone mineral density, decreased Z-scores, decreased fracture rates, decreased pain, improved walking, decreased levels of urinary biochemical markers of bone turnover, and increased cortical thickness as seen on plain radiographs. Histologically, these changes are reflected in increased cortical width and cancellous volume due to higher trabecular numbers as opposed to increased trabecular thickness. Such investigations have included patients ranging in age from less than three years old to adulthood, and the results have been consistent regardless of age. While historical controls were used in all studies, all data strongly indicate that the observed changes reflect the drug effect rather than an evolution in the natural history of the disease.

Munns et al. retrospectively reviewed the effects of pamidronate on fracture and osteotomy-site healing in patients with osteogenesis imperfecta56. They found that pamidronate had little effect on fracture-healing, but healing was delayed following osteotomies used for extremity realignment. Older age and tibial location were independent predictors of delayed healing, with odds ratios of 1.25 and 3.5, respectively. Although pamidronate does not alter the genetic defect underlying osteogenesis imperfecta and therefore is not curative, it is a promising modality for symptomatic relief in patients with an otherwise debilitating disease. The optimal therapeutic dose and schedule remain unclear. Other bisphosphonates are currently under clinical investigation to compare their effects with those of pamidronate.

Fibrous Dysplasia
Fibrous dysplasia of bone is characterized by the production of fibrous tissue and woven bone at sites where normal bone should develop. The abnormal bone leaves the skeleton weak and prone to fractures. The fundamental defect is somatic mutation in the gene coding for the alpha subunit of Gs, the G protein that stimulates cAMP formation. Overproduction of cAMP in turn causes overexpression of c-fos, which plays an important role in regulating the interplay of osteoblastic and osteoclastic proliferation and differentiation. The resulting excessive osteoclastic activity is thought to be a potential therapeutic target, and bisphosphonates have been investigated in this regard.

Bisphosphonate therapy for the treatment of fibrous dysplasia has been examined in several clinical series57-62. Intravenous pamidronate was administered in all of those studies, with the exception of the one by Lane et al.60, who combined pamidronate therapy, and then later replaced it, with oral alendronate. Bisphosphonates universally improved pain analogue scores and N-telopeptide values. Cortical thickening and progressive ossification were seen on radiographs of skeletally mature patients. Results in children were less consistent, with most patients lacking evidence of radiographic healing. While the early data are hardly definitive, they are encouraging for a disease for which there have been few gains in treatment options.

Legg-Calvé-Perthes Disease
Legg-Calvé-Perthes disease is a childhood form of osteonecrosis of the femoral head with an incidence of 8.5 to twenty-one per 100,000 children per year63. The most serious sequela of this condition is femoral head deformity leading to premature degenerative arthritis in early adult life. Because osteoclastic resorption of necrotic subchondral bone may lead to mechanical weakening of the femoral head, resulting in collapse, a down-regulation of osteoclastic activity may attenuate or prevent the progression of this disease. Using a model of atraumatic osteonecrosis induced in young rats, Little et al. found preservation of femoral head architecture six weeks after treatment with zoledronic acid64. A more recent study of pigs treated with ibandronate demonstrated similar findings, with preservation of the femoral head epiphyseal quotient (height divided by diameter) in animals treated with prophylactic and moderately high doses of the drug63. While we are not aware of any clinical data regarding the use of bisphosphonates in preventing or slowing the progression of this disease, these results are very encouraging and follow-up studies are currently in progress.

Fracture-Healing
Since osteoclasts are essential to the normal remodeling activities in bone and are involved in bone growth, development, and repair, it is important to recognize situations in which the use of a bisphosphonate may inhibit or impair a normal physiological process. One of the most commonly asked questions is whether bisphosphonates affect fracture-healing. As it is well known that bone formation and resorption are coupled through molecular and metabolic pathways65,66 and as it is also known that the ability of newly formed fracture callus to be remodeled into mechanically competent lamellar bone is osteoclast-mediated67, several investigators have examined the role of bisphosphonates during fracture-healing. An early study on the effects of ethane-1-hydroxy-1, 1-diphosphonate (EHDP), a so-called first-generation bisphosphonate that inhibits mineralization at high doses, showed dose-dependent and reversible inhibition of fracture-healing in mature beagle dogs68. More recent studies of more potent, less toxic bisphosphonates have shown different results. An investigation in which mature beagle dogs were treated with therapeutic doses of alendronate nine weeks preceding a radial osteotomy, sixteen weeks after the osteotomy, or continuously from nine weeks to sixteen weeks after the osteotomy showed no adverse effects on fracture union, strength, or callus mineralization. However, dogs treated with alendronate during the healing period were found to have a delay in callus remodeling compared with the remodeling seen in dogs treated with a placebo69. More recent investigations in which incadronate was used showed similar findings, with high, continuously administered doses delaying the process of fracture-healing but not impairing the ultimate recovery of mechanical integrity of the callus70,71.

Despite the large number of patients treated with bisphosphonates, the effects of these drugs on fracture-healing have not been investigated in humans and thus are not known. One prospective clinical trial was performed to examine bone mineral density in the fracture callus of thirty-two postmenopausal women with a distal radial fracture treated with cast immobilization72. At two months after the fracture, patients treated with bisphosphonates had a 20% increase in bone mineral density at the fracture site compared with that in a placebo group, but this magnitude of difference diminished with time. There was no difference in pain or function between the two groups. On the basis of the evidence available from preclinical investigations, it may be reasonable to suggest that, at doses comparable with those used in the treatment of osteoporosis, administration of a bisphosphonate in the presence of a fracture will not inhibit healing, although the remodeling of the callus may be mildly delayed. Guidelines for patients receiving larger doses, such as those used to treat Paget disease or metastatic bone disease, are more difficult to extrapolate.


   Overview
Top
 Abstract
 Introduction
 Mechanism of Action
 Clinical Measures of...
 Clinical Applications
 Overview
References
 
Bisphosphonates are a fascinating and promising therapeutic entity for the treatment of skeletal disorders characterized by increased osteoclastic activity. Their journey from laboratory bench to clinical practice is a success story. While this review summarized only the most common applications of bisphosphonate therapy, its potential benefits in the treatment of a number of conditions continue to be revealed almost daily. As our understanding of the basic mechanisms of action and the clinical translations of those mechanisms continues to evolve, the benefits and drawbacks of therapy will become clearer. Certainly, there is a lack of long-term follow-up data, which are necessary to develop responsible guidelines for therapy.


   Acknowledgments
 
The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.


   References
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 Abstract
 Introduction
 Mechanism of Action
 Clinical Measures of...
 Clinical Applications
 Overview
 References
 

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