Optimizing Outcomes for Patients With Metabolic Bone Disease

• Introduction
  
  
• The Evolving Management of Osteoporosis: Shortcomings and Solutions
  Author: Steven T. Harris, MD, FACP
  
  
• Optimizing Therapeutic Outcomes for Patients With Paget’s Disease of Bone
  Author: Frederick R. Singer, MD
  
  
• Modifying Treatment Paradigms: Differentiating Attributes of a Novel Bisphosphonate
  Author: Graham Russell, MD, PhD
  
  
• Figures
  
  
• References
  
  

Introduction

Osteoporosis and Paget’s disease of bone have a significant impact on health and quality of life. This monograph will review recent clinical data and outline emerging approaches to the management of these metabolic bone diseases.

Optimal treatment of osteoporosis and Paget’s disease of bone should include interventions that can relieve symptoms and prevent complications while minimizing adverse events. An important barrier to treatment is poor medication compliance, which is somewhat related to the complexity of dosing regimens. Simplifying treatment, while maintaining efficacy, has the potential to improve outcomes.

Antiresorptive medications are central to the management of osteoporosis and Paget’s disease of bone. Chief among these are the bisphosphonates (BPs). Efficacy has improved with successive generations of these agents. Continued development of BPs with unique biochemical structures may yield medications with greater potency and duration of action. However, differences in the structural characteristics, potency, binding affinity, and bone uptake appear to exist across commonly used BPs; this may explain their effects in the clinical setting.

The Evolving Management of Osteoporosis: Shortcomings and Solutions

Author: Steven T. Harris, MD, FACP

The management of osteoporosis remains a complex, imperfect process. Although the field has seen the introduction of many new medications that reduce fracture risk, there are many areas in which current treatment strategies fall short. These represent the unmet needs of patients. First and foremost, osteoporosis is still notably underdiagnosed and undertreated—even after years of discussion in many different medical forums. Even those who do receive treatment can never fully escape the risk of fracture. None of the therapeutic options available are uniformly effective or free from associated adverse effects. Further eroding the impact of therapy is the difficulty in applying research to the “real world.” As in many other areas of medicine, efficacious therapies in clinical trials do not automatically translate into effective treatments in clinical practice. Coexisting health conditions and suboptimal adherence/persistence with treatment limit the extent to which patients can realize the benefits touted in clinical trials. Addressing these unmet needs can lead to better patient outcomes.

Unmet Needs in the Diagnosis and Treatment of Osteoporosis

Analyzing the shortcomings of osteoporosis treatment must first begin with a step back to view the adequacy of diagnosis. A fundamental problem is that many individuals—even those who have already suffered a fracture—are not being diagnosed as having osteoporosis. Elliot-Gibson et al systematically reviewed studies that addressed how frequently patients with fragility fractures underwent investigation for osteoporosis. Of the 16 studies that evaluated diagnosis by dual-energy x-ray absorptiometry (DXA), only 2 found that all patients with fragility fractures underwent DXA. The other 14 studies reported that DXA testing was performed in a median of 8% (range 0.5% to 32%) of patients.¹ Barriers to diagnosis and treatment of osteoporosis include time and costs for diagnosis; cost of therapy; potential adverse effects of medications and doubts regarding their effectiveness; and ambiguity as to which clinician (ie, primary care physician or specialist) should be diagnosing and treating the disease.² It is not surprising that a retrospective analysis of patients participating in 7 health maintenance organizations found that only 21% of women with hip fractures were being treated for osteoporosis.³ A review of other studies revealed similarly low rates of treatment among patients with fractures.⁴

While improving the rates of diagnosis and treatment should be a major focus of our efforts, it is not the only focus. Another hurdle is the issue of compliance with therapy. Clinical trials typically report compliance of greater than 80%. In this setting, therapeutic agents have reduced the risk of vertebral, nonvertebral, and hip fractures in postmenopausal women with osteoporosis. Compliance is maintained in these trials by many factors that are absent in clinical practice. Patients in the “real world” are not as compliant or persistent with their osteoporosis regimens. Compliance has been well studied among patients enrolled in managed care organizations. One study found that 70% of patients were compliant when compliance was defined as the percentage of time a patient filled a prescription for osteoporosis medication.⁵ Retrospective and prospective cohort studies found that less than 25% of patients remained on therapy a year after the medications were prescribed.^6,7 Even those who faithfully remain on osteoporosis medication may not be taking it correctly; that is of particular concern with BP therapy, because fastidious dosing still only allows absorption of roughly 0.5% of the oral dose. In an osteoporosis clinic, Hamilton et al surveyed women who were taking risedronate and assessed their compliance with dosing instructions. Despite receiving verbal and written dosing instructions, 26% of patients did not adhere correctly to instructions.⁸

Clinical effectiveness suffers when compliance is poor. Patients in a managed care organization in California who failed to remain on treatment regimens for at least 1 year had a higher risk of hip and vertebral fractures than those who did persist.⁷ A review of health service databases in Canada sought to correlate fracture risk with compliance in a cohort of more than 11,000 women with osteoporosis. Women who were noncompliant with their regimens were significantly more likely to sustain fractures compared with compliant women (P<.0001).⁹ These relationships are supported by observations that improvements in bone turnover markers¹⁰ and bone mineral density (BMD)⁵ parallel the degree of compliance with medication.

Compliance can be characterized in a variety of ways. In general, an individual who is compliant with a treatment regimen takes the medication as it is prescribed. Thus, compliance encompasses the details involved in taking each dose as well as the long-term pattern of continued use. One tool for defining and measuring compliance is the medication possession ratio, which is the percentage of therapy days that a patient actually has drug on hand. For example, it can be defined as the number of days of supplied medication (assessed by refill information) during the follow-up period divided by the number of days of follow-up.¹¹ A related concept is adherence, or the percentage of prescribed medication that was actually taken. Adherence can also refer to maintenance of the correct dosing regimen. Persistence can be defined as the degree to which patients continue to take prescribed medication on a regular basis and is determined at a certain time.¹² It can be measured, for example, by the number of pills taken within a 2-week period after 1 year of therapy. Or it can be described as the length of time between refills. Although the terminology has been confusing, it appears that the consistency with which patients take their prescribed medications over time can affect the clinical effectiveness of any therapeutic regimen.

Effect of Less Frequent Dosing (weekly versus daily)

Unfortunately, poor compliance and lack of persistence plague all medical treatments, including that for osteoporosis. Studies have documented noncompliance ranging from 20% to 80%.¹³ According to Peterson et al, one third of all prescriptions are never filled.¹⁴ Among those that are filled, more than half are associated with improper administration.¹⁴ In the osteoporosis arena, BPs are now often dosed once a week rather than daily. The weekly formulations were designed to increase patient adherence and provide convenience to patients by lowering dosing frequency.

Several studies investigated the advantages of weekly administration of BPs versus daily. Boccuzzi et al followed osteoporotic women in a managed care organization who were taking weekly (n=7092) or daily (n=1273) BPs. The 12-month medication possession ratio was 62.5% for weekly users and 53.8% for daily users.⁶ Cramer et al also followed a cohort of postmenopausal osteoporotic women on weekly (n=731) or daily (n=2010) BPs for 12 months. The medication possession ratio was 69.2% for those on weekly BPs compared with 57.6% for those on daily BPs.¹¹ Cramer’s study also measured persistence. They found that 44.2% of those on the weekly medication were still taking it after 12 months compared with 31.7% of those on the daily regimen. Although both studies showed that weekly administration is associated with improved adherence/persistence compared with daily administration, the absolute differences were small and of uncertain clinical significance. Furthermore, the level of adherence/persistence with weekly dosing was still suboptimal.¹¹ 

It is also important to investigate the patterns of adherence/persistence in patients who have recently begun therapy for osteoporosis. Ettinger et al collected data on more than 200,000 patients who received prescriptions for daily/weekly BPs, dispensed from 25% of US retail pharmacies. After patients were on therapy for 1 month, the authors monitored patient records for 11 months and compared persistence for each month relative to the initial month. Most patients had previously been treated with an osteoporosis medication. Among treatment-naïve patients, overall persistence for those on daily BPs was 15.7% while it was somewhat greater (31.7%) for those on weekly BPs. Thus, medication persistence remains inadequate, even with weekly BPs.¹⁵

Inadequate compliance compromises clinical benefit. The following sections illustrate how poor compliance/persistence leads to unsatisfactory improvement in BMD and bone turnover markers, as well as suboptimal reduction in fracture risk. These can all increase the risk of hospitalization and associated costs.

Yood et al evaluated the correlation of change in BMD with compliance in 176 women with osteoporosis who were recently started on osteoporosis therapy. All women were enrolled in a large multispecialty group practice associated with a health maintenance organization; the mean age was 63 years. Compliance was defined as the percentage of time a patient filled a prescription for osteoporosis medication. Fifty-three percent of patients received BPs, 53% received estrogen, 5% received calcitonin, and 10% received more than one class of medication. BMD was measured at baseline for all patients and remeasured at least 1 year later (mean 590 days) in 52% of the patients. The overall compliance rate for patients who completed the study was 70.7%. For those whose compliance with therapy was at least 66%, the mean increase in lumbar spine BMD was 3.80% (±2.59) per year compared with 2.11% (±2.64) per year for those with less than 66% compliance. Similarly, the mean increase in hip BMD was 2.64% (±2.27) per year for compliant patients versus 0.80% (±2.41) per year for noncompliant patients.⁵

Another end point related to compliance is change in bone turnover markers. A study conducted by Eastell et al evaluated the effect of compliance with daily risedronate on bone turnover markers and BMD response in 2302 postmenopausal women with osteoporosis.¹⁰ Urinary N-terminal cross-linking telopeptide of type I collagen (uNTX), and serum type I collagen C-telopeptide (sCTX) were measured at baseline and at 10 and 22 weeks while BMD was measured at baseline and at 1 year. Compliance with medication was measured with electronic monitoring caps. The improvements in all parameters were directly related to compliance. For example, at 22 weeks, more than 60% of compliant patients had at least a 50% decrease in sCTX from baseline compared with only 20% of noncompliant patients. These results indicate that compliance with BP therapy correlates positively with changes in bone turnover markers and BMD.¹⁰

While changes in BMD and bone turnover markers are important surrogate end points, reduction in fracture risk is the most clinically relevant outcome for patients. Caro et al analyzed the relationship between compliance and risk of fracture in an actual practice setting. They reviewed the Saskatchewan health services database for demographic, prescription drug utilization, physician services, and hospitalization information pertaining to osteoporotic women. All of the women were taking at least one osteoporosis medication, such as calcitonin, estrogen, or a BP, between 1996 and 2001. Women were deemed highly compliant if they had the medication available during 80% of the duration of the study. The study included 11,249 women with a mean age of 68.4 years at the time of the index prescription. The average follow-up was 2.0 years. Strong risk factors for experiencing a fracture during the follow-up period were: low compliance, older age, history of fracture, prior use of corticosteroids, and prior use of osteoporosis medication. Patients who were highly compliant for the duration of follow-up, regardless of these other factors associated with fracture, had a 25.4% lower fracture rate (P<.0001).⁹

The same group also evaluated this cohort for hospitalization rates and costs associated with fracture. The hospitalization rates were analyzed with a Poisson regression model and log-transformed costs were analyzed using linear regression. Highly compliant women had a lower risk of hospitalization (42.6% vs 54.3%, P<.0001) and lower average monthly costs ($214 vs $245, P<.0001) compared with less compliant women.¹⁶ These studies demonstrate that noncompliance has a substantial impact on BMD outcomes, bone turnover markers, and ultimately, fracture risk.

Patients face several barriers that make it difficult for them to comply with treatment. Because osteoporosis is largely asymptomatic, the goal of treatment is to prevent an event rather than to alleviate troubling symptoms. Patients who fail to view fracture as a credible threat will likely have minimal incentive to take medications to prevent it. In addition, positive reinforcement to encourage adherence to treatment is lacking. Unlike other chronic conditions such as hypertension and diabetes, the nature of the disease precludes giving frequent and meaningful feedback to patients related to the effects of treatment.

Patients still face barriers even if they are motivated to take medications. For example, the oral BPs have fairly rigorous and inconvenient dosing regimens. Ettinger et al explored this issue in a telephone survey of 812 women at the Kaiser Permanente Medical Care Program who were taking alendronate 10 mg daily. The women were asked questions about their adherence with dosing and administration instructions. More than half (55.8%) of the women reported nonadherence with at least 1 instruction. Specifically, 51.7% did not comply with at least 1 absorption-related instruction (eg, no food 30 minutes afterwards), and 13.5% did not comply with at least 1 safety-related instruction (eg, drink at least 6 ounces of water with medication, remain upright 30 minutes afterwards). It is noteworthy that 40% of women did not recall receiving all of the instructions.¹⁷ This is likely due to the failure of physicians to provide instructions, as well as the difficulty patients have remembering them. Regardless, the end result of nonadherence erodes both the effectiveness (poor absorption) and risk-benefit balance (unsafe dosing and administration) of these medications.

For any therapy with reduced dosing frequency, evidence of efficacy must be appraised critically. It is notable that alendronate and risedronate were initially approved for use based on clinical trials that showed significant fracture reduction with daily therapy. However, the subsequent clinical trials of weekly alendronate and weekly risedronate were relatively small, and were only designed to demonstrate that weekly therapy produced changes in BMD and bone turnover markers that were statistically “non-inferior” to those observed with daily therapy.¹⁸ There are no trials showing that fracture risk is reduced with the weekly administration of either alendronate or risedronate.

It is apparent that there are many unmet needs in the treatment of osteoporosis. These include underdiagnosis and undertreatment of the disease as well as poor compliance among those who are treated. The advent of weekly oral BPs has improved adherence/persistence modestly, yet much work remains to be done in this area. The development of agents with even less frequent dosing has the potential to improve adherence/persistence with medication, and therefore, the effectiveness of therapy.

Solutions to the Management of Osteoporosis

Given the central role of adherence in the effectiveness of therapy, it is valuable to discuss strategies that can improve adherence. Behavioral interventions to improve medication adherence target the skills or habits of patients, utilizing items such as alarms or beepers, calendars, reminders, and pill boxes. Educational interventions target the knowledge of patients through verbal, written, or audio-visual channels. A meta-analysis of trials on methods to improve medication adherence (not necessarily related to osteoporosis) estimated that educational and behavioral interventions increase adherence by approximately 4% to 11%.¹⁴ Additional interventions are needed to supplement these behavioral and educational efforts.

Clowes et al studied the effect of nurse monitoring on adherence and persistence with raloxifene among 75 postmenopausal women with osteopenia. The women were randomized to 3 groups: control; monitoring by nurse interaction at 12, 24, and 36 weeks; or monitoring by nurse interaction plus additional feedback on changes in bone turnover markers. Follow-up was for 1 year. The women were considered adherent if they took at least 75% of prescribed pills over the entire year, and were considered persistent if they took more than 50% of tablets during the 2 weeks before the 1-year visit. The results showed a trend toward greater cumulative adherence to therapy (>75% of prescribed pills) in the nurse-monitored and marker-monitored proportion of subjects compared with controls (0.65 vs 0.42). In a similar trend, greater persistence occurred with the proportion of monitored subjects compared with controls (0.84 vs 0.67).¹²

While patient adherence represents an important target for interventions, we should not disregard opportunities to modify the behavior of physicians. Reminders built into electronic medical record (EMR) systems have the potential for improving quality of care across the entire spectrum of clinical medicine. This has also been applied to the management of osteoporosis. Women in the Kaiser Permanente Northwest healthcare system with recent osteoporotic fracture were randomized to 3 groups. The first group received “usual care.” In the second group, physicians received a patient-specific reminder regarding management of osteoporosis via the EMR system. In the third group, physicians received a reminder and patients received reminders and information about osteoporosis through postal mail. At 6 months, patients whose physicians received reminders were more likely to receive osteoporosis medication or undergo BMD measurement than those patients in the usual care group (51% vs 6%). The addition of patient reminders to EMR messages did not improve the likelihood of receiving medication or undergoing a BMD measurement compared with EMR messages alone, but was still superior to usual care (43% vs 6%).¹⁹

Management of osteoporosis is far more complex than simply prescribing a medication. Management involves a series of discrete steps, with failure at any single step compromising the clinical outcome. Novel dosing regimens of BPs may address several problems at once. The moderate effect of weekly dosing on adherence/persistence has already been discussed. Newer medications have even longer treatment intervals with monthly, quarterly, biannual, or yearly dosing, demonstrating the potential for improving adherence/persistence and minimizing gastrointestinal adverse effects. While the monthly dosed BP ibandronate is currently on the market in oral form, the intermittently injectable dosed agents are currently under development.

Clinicians can anticipate the arrival of at least 3 new injectable therapies for the treatment of metabolic bone disease in the near future. Although oral monthly ibandronate is currently on the market, ibandronate will also be offered as a quarterly intravenous (IV) injection. Denosumab (AMG 162) will probably be administered as a subcutaneous injection twice a year. Zoledronic acid will be offered as a once yearly, 15-minute IV infusion. Any agent administered via the IV route allows the clinician to confirm that the patient received the dose. Each of these intermittent injectable medications may facilitate greater adherence and persistence than are observed with daily, weekly, or monthly oral therapies.

Summary

Optimizing Therapeutic Outcomes for Patients With Paget’s Disease of Bone

Paget’s disease of bone is a progressive disorder characterized by localized hypertrophy of the bony skeleton. It commonly affects the skull, spine, pelvis, and long bones. The disturbed bones become softened and enlarged. The initial osteolytic phase features bone resorption and hypervascularity. Extensive remodeling occurs in the mixed phase, with both resorption and formation of bone. Both osteoclasts and osteoblasts are highly active, leading to increased amounts of woven bone. During the final phase, sclerosis dominates.²⁰

Etiology and Pathophysiology of Paget’s Disease of Bone

The etiology of Paget’s disease of bone is not completely understood, but epidemiologic studies have found increased prevalence in first-degree relatives of affected individuals, as well as patterns of prevalence related to migrating ethnic subpopulations.²⁰ The majority of cases are sporadic. Roughly 20% are familial and have autosomal dominant transmission, but penetration appears to be incomplete.²¹ One genetic defect related to Paget’s disease of bone is mutation of the sequestosome 1 or p62 gene. Approximately 46% of familial cases harbor a mutation in this gene. Findings from animal models suggest that this mutation leads to increased osteoclastic activity possibly by affecting ubiquitin binding.²² A mutation in valosin-containing protein, which may affect osteoclast function via the ubiquitin pathway, has been linked to a rare syndrome of Paget’s disease of bone, myopathy, and dementia.²³

Some investigators have postulated that the disease has a viral etiology. Early ultrastructural studies have documented nuclear and cytoplasmic paramyxovirus-like inclusions in the osteoclasts of patients with Paget’s disease of bone. Paramyxoviruses have also been detected with immune electron microscopy, in situ hybridization, and reverse transcriptase polymerase chain reaction. It is thought that the paramyxoviruses induce the increased osteoclast activity observed in Paget’s disease of bone.²⁰ A mouse model of Paget’s disease of bone has been produced by placing measles virus (a paramyxovirus) nucleocapsid protein into osteoclasts.

The pathophysiology of Paget’s disease of bone is best understood by considering the process of bone remodeling, which allows for the continual renewal of the skeleton. Osteoclasts cause resorption of old bone while osteoblasts lay down new bone in the resorbed areas and this later mineralizes. In normal patients, this process is controlled. However in Paget’s disease of bone, an example of osteoclast-mediated disorders, the osteoclasts in the affected areas proliferate and become abnormally large. This is supported by a study in which Meunier et al found a higher concentration of osteoclasts in iliac bone biopsies of Pagetic bone (3.2 ± 2.3 osteoclasts per mm²) compared with non-Pagetic bone (0.3 ± 0.2 osteoclasts per mm²) in the same patients (P<.001).²⁴ The hyperactivity of osteoclasts leads to excessive bone resorption. As bone resorption and formation are still coupled, osteoblasts produce new bone. The end result is a high bone turnover rate and newly formed, yet abnormal, bone.

The accelerated bone turnover results in the formation of woven bone. With its chaotic pattern of collagen deposition, woven bone gradually replaces lamellar bone. Compared to lamellar bone, woven bone has more osteocytes per unit area of matrix, and more variation in size and shape of the osteocytes. Woven bone is structurally weak and disorganized, and thus more susceptible to bowing or fracture.²⁵

A clinical hallmark of Paget’s disease of bone is gross skeletal deformity. Although any bone can be affected, the disease usually manifests in long bones and the axial skeleton. These deformities include bowing of long bones (such as the tibia), increased skull size, enlarged jaw, accentuated dorsal kyphosis, and deformities of the pelvis and clavicles (Figure 1).²⁵ In active Paget’s disease of bone, with increased vascularity of the bone and soft tissue, the temperature of overlying skin may be notably higher than that of unaffected areas. The majority of patients do not experience bone pain, but it will occasionally develop late in the course of the disease. The pain is mild to moderate and can persist even while the patient is at rest.²⁵

Individuals with Paget’s disease of bone can suffer considerable morbidity and reduced quality of life. A major complication is secondary osteoarthritis, usually in the hips, developing adjacent to an affected bone. While less common, pathological fractures do occur.²⁵ Other complications result when the bony deformities compress neighboring nervous structures. For example, hearing loss is associated with Paget’s disease of the temporal bone. Spinal stenosis resulting from vertebral involvement is rare. Neoplastic transformation into osteosarcoma or other sarcomas, while still more common than in the unaffected population, occurs in less than 1% of those with Paget’s disease of bone. Other clinical outcomes include hypercalcemia, usually in immobilized individuals, and high-output heart failure.²⁵

The accelerated bone resorption and remodeling of Paget’s disease of bone are reflected in increased biomarkers of bone turnover.²⁵ These markers are useful for defining and monitoring disease activity. Meunier et al examined the correlation between the findings on radionuclide bone scanning of patients with Paget’s disease of bone and levels of biochemical markers.²⁶ There was a significant linear relationship between the extent of Paget’s disease of bone, as quantified by radionuclide scanning, and levels of urine hydroxyproline and serum alkaline phosphatase (SAP). In general, markers of osteoclastic bone resorption include urinary hydroxyproline and deoxypyridinoline, urinary N-telopeptide of type I collagen (NTX), and serum C-telopeptide of type I collagen (CTX). The telopeptide tests are more specific than hydroxyproline in that they are not affected by dietary intake or by disorders affecting other collagen-containing organs. The primary marker of bone formation in Paget’s disease of bone is the total SAP level. This mirrors osteoblastic activity but can be distorted in the presence of pregnancy or liver disease. Bone-specific alkaline phosphatase is a more specific assay and may be more reliable in patients with monostotic disease.

Management of Paget’s Disease of Bone

As in all chronic conditions, the management of Paget’s disease of bone should be oriented towards clear short-term and long-term goals. A reasonable short-term goal is to alleviate bone pain or pain due to secondary osteoarthritis. Other short-term goals include slowing disease progression and minimizing bleeding in patients undergoing surgery on Pagetic bone by initiating treatment early. The goals of long-term treatment parallel the short-term goals. Sustained pain relief is an important objective, as is controlling the progression of disease, as reflected by bone turnover markers. Another long-term aim is prevention of complications in both symptomatic and asymptomatic disease.²⁷

Pharmacological treatment of Paget’s disease of bone centers on antiresorptive therapy with BPs. Bisphosphonates are generally effective, as illustrated in Figure 2. Before treatment, there is a grossly abnormal Pagetic lesion at the distal femur. After 18 months of treatment with the BP olpadronate, the bone structure has improved radiologically. It is hoped that such improvements will prevent, minimize, or slow the development of complications.

Five BPs have been approved by the Food and Drug Administration for the treatment of patients with Paget’s disease of bone: etidronate, tiludronate, pamidronate, alendronate, and risedronate. All are administered orally except for pamidronate, which is given intravenously over 2 or more hours. Generalizations about their efficacy depend on the precise outcome of interest, such as the percentage of patients with normalized biochemical markers at a certain time point. Adopting a longitudinal view of the developmental timeline of BPs reveals that the newer agents appear to achieve normalization of SAP levels to a greater degree than do older agents (ie, etidronate). Tiludronate, alendronate, and risedronate have all been separately compared with etidronate in randomized controlled trials. To provide a uniform comparison among these treatments, the percentage of patients who had normalized SAP levels at 6 months can be evaluated.

Roux et al compared etidronate 400 mg/day for 6 months, tiludronate 400 mg/day for 6 months, and tiludronate 400 mg/day for 3 months.²⁸ At 6 months, SAP levels had normalized in 24% and 27% of patients in the 3-month and 6-month tiludronate groups, respectively, compared with 11.4% of those in the etidronate group (P<.05).²⁸ In a study by Siris et al that compared alendronate 40 mg/day with etidronate 400 mg/day for 6 months, SAP levels had normalized in 63% and 17% of patients (P<.001), respectively.²⁹ Risedronate 30 mg/day for 2 months was also more effective than etidronate 400 mg/day for 6 months in normalizing SAP levels in 77% and 11% of patients (P<.001), respectively.³⁰ The evidence supports the superior efficacy of tiludronate, alendronate, and risedronate compared to etidronate. However, approximately 10% to 20% of patients exhibited some degree of gastrointestinal toxicity in these clinical trials.^28-30

In an uncontrolled study of pamidronate given as a single IV dose of 60 mg over 12 hours, 78% of patients achieved normalization of SAP levels in 6 months. No gastrointestinal adverse events were reported.³¹

One worrisome phenomenon is possible physiological tolerance to BPs. In the Miller et al trial discussed earlier, risedronate was more effective than etidronate in normalizing SAP levels. Some patients in both groups had previously used etidronate at least 6 months before the study began. Figure 3 demonstrates how those in the etidronate group who had previously used etidronate had a worse response than those who had not previously used etidronate. Prior use of etidronate did not change the efficacy of risedronate during the trial.³⁰

While there has been considerable progress in the treatment of Paget’s disease of bone, there is still room for improvement. It is possible that the efficacy of current oral BPs is approaching a plateau.

Emerging Trends in the Treatment of Paget’s Disease of Bone

Novel agents with distinct biochemical properties may produce effects that are quantitatively and qualitatively different from the current medications. One new molecule is ZA, a novel, heterocyclic, double–nitrogen-containing BP. With enhanced affinity for bone and farnesyl diphosphate synthase, the major pharmacological target of BP,^32,33 ZA offers the potential for prolonged disease control. Zoledronic acid is administered as a single IV dose of 5 mg given over 15 minutes. Given in the office setting, it allows for dosing confirmation (guaranteed delivery) and improved adherence/persistence. The parenteral route also precludes the development of gastrointestinal toxicity.

Zoledronic acid for Paget’s disease of bone was recently compared with risedronate in 2 randomized, placebo-controlled trials with identical protocols by Reid et al.³⁴ The results were pooled in a joint analysis. A total of 357 patients were randomized to receive a single 15-minute IV infusion of ZA 5 mg or daily oral risedronate 30 mg for 60 days. The main outcome was therapeutic response (return of SAP to normal levels or a 75% decrease in the excess over the mid-reference range) at 6 months. Results showed that 96% of the ZA group had a therapeutic response at 6 months compared with 74% of the risedronate group (P<.001). The percentage of patients who achieved normalized SAP levels was also higher in the ZA group than in the risedronate group (89% vs 58%, P<.001). Similar trends were observed at 2 months, with ZA inducing a greater therapeutic response than risedronate (Figure 4).³⁴

The median time to therapeutic response was 64 days in the ZA group compared with 89 days in the risedronate group (P<.001). Overall, a greater and faster reduction in SAP levels was observed in the ZA group (P<.001).³⁴

These trials also confirmed the potential for prolonged remission with ZA. Patients who had a therapeutic response at 6 months were eligible to enter an extended follow-up period. Over a median follow-up of 18 months after first dosing, a much higher percentage of patients treated with ZA maintained their therapeutic response compared with patients treated with risedronate (Figure 5).

Overall, adverse events between the ZA and risedronate groups were similar. Calcium and vitamin D supplementation may help protect patients from hypocalcemia.³⁴ It should be noted that asymptomatic hypocalcemia can occur in patients with high bone turnover and attention should be given to possible underlying disorders of calcium metabolism. Renal function is not significantly affected with the 5-mg IV dose given over 15 minutes.³⁴ In addition, osteonecrosis of the jaw has not been reported in patients with Paget’s disease of bone who were given a single infusion of ZA.

In these studies by Reid et al, ZA was found to have superior efficacy in patients with Paget’s disease of bone compared with risedronate, the current standard of care. Zoledronic acid induced a greater therapeutic response in fewer days. It is also apparent that a single dose of ZA displays potential for long-term remission.³⁴

Summary

Modifying Treatment Paradigms: Differentiating Attributes of a Novel Bisphosphonate

Author: Graham Russell, MD, PhD

Bisphosphonates are simple, stable, synthetic compounds that bind strongly to bone mineral. By inhibiting osteoclast function they reduce bone resorption and turnover. They have been used effectively in the treatment of osteoporosis, Paget’s disease of bone, multiple myeloma, and bone metastases. Despite their long history dating back to the 1800s, new BPs continue to be developed, providing greater efficacy and potency than their predecessors.

At present, there are 5 nitrogen-containing BPs used in clinical practice. Three of them— pamidronate, alendronate, and ibandronate—have alkyl-amino side chains. The side chains of risedronate and ZA are heterocyclic rings, which confer increased potency compared with the simple nitrogen side chains of the earlier BPs (Figure 1).

Early Studies With Bisphosphonates

Decades ago, the theories about BPs focused on their effects on mineral growth and solubility. The BPs were initially analogs of pyrophosphate that were observed to inhibit both growth and dissolution of hydroxyapatite crystals.³⁵ Early experiments demonstrated that BPs could inhibit bone resorption in bone cultures. Oral or injectable formulations reduced bone remodeling in animal experiments. In the Schenk test, inhibition of bone remodeling was linked to greater metaphysial tibia density in growing rats.³⁶

Figure 2 illustrates the relationship between the in vivo and in vitro activity of BPs in inhibiting bone resorption.³⁷ The x axis is the in vivo ability of BPs to block the effects of exogenous parathyroid hormone on thyroparathyroidectomized rats. The y axis is the in vitro activity in calvaria. Preclinical testing reveals that ZA is the most effective BP among those tested.

Effects of Bisphosphonates on Bone

Uptake studies with BPs show very clearly that they localize to sites of new bone mineralization and later also bury deep into bone. Bisphosphonates persist within bone as new bone tissue is laid down over where BPs have been deposited. For example, the autoradiograph in Figure 3 depicts the distribution of ¹⁴C-labelled ZA in a rat skeleton 1 hour and 1 year after IV infusion.

Bisphosphonates bind to bone mineral and concentrate both at sites of bone mineralization and resorption. They are internalized by osteoclasts, possibly via vesicle transport. This leads to a variety of changes within the osteoclast, including detachment, inability to migrate, loss of a ruffled border, failure of resorptive capacity, and ultimately, programmed cell death by apoptosis.

Clinical Actions of Bisphosphonates

The total dose of BP is an important determinant of its effects. Various BPs have different dosing intervals designed to provide a reproducible total dose over a given period of time. This is illustrated by work from Gasser and Green that contributed to the preclinical basis for the use of ZA. Ovariectomized rats were treated with single doses of IV ZA at doses ranging from 0.8 to 500 µg. Sham-operated rats served as controls. Figure 4 displays CT images of the proximal tibial metaphysis, demonstrating that protection from ovariectomy-induced bone loss was directly related to the previous single dose of ZA. Higher doses provided complete protection from bone loss. The 100 µg/kg dose, equivalent with dosing for humans, conferred protection against bone loss for up to 32 weeks.³⁸

Reid et al sought to determine the optimal dose and dosing interval for ZA in a randomized, double-blind, controlled trial. A total of 351 postmenopausal women with low BMD received placebo or IV ZA of varying doses and dosing intervals for 1 year. The main end point was lumbar BMD. All groups receiving ZA achieved greater lumbar and femoral neck BMD compared with placebo. In addition, all ZA groups demonstrated rapid and sustained reductions in urinary N telopeptide to creatinine ratio compared with placebo after 1 year. There were no significant differences among any of the ZA dosing regimens.³⁹

Studies of other BPs demonstrate a gradual loss of effect after discontinuation. Bone et al found that after 5 years of daily alendronate treatment in postmenopausal women with osteoporosis, markers of bone turnover began to return to, but did not reach, pretreatment values.⁴⁰ Similar trends have been documented when stopping risedronate after 3 years of daily therapy.⁴¹ These and other data support the notion that BPs may be classified by their persistence of action after stopping treatment. Etidronate and risedronate have shorter durations of continuing action while alendronate and ZA have longer lasting effects.

Molecular Mechanisms of Action of Bisphosphonates

Explanations for the high magnitude of effect and long duration of action of ZA include its high binding affinity for bone mineral and its potent cellular and molecular effects on osteoclasts via FPP synthase inhibition. Bisphosphonates inhibit farnesyl diphosphate (FPP) synthase within osteoclasts. Separate studies suggest a direct relationship between the ability of BPs to inhibit FPP synthase and their ability to inhibit bone resorption. Dunford et al demonstrated that ZA was a more effective inhibitor of FPP synthase than etidronate, pamidronate, alendronate, ibandronate, and risedronate.³² Work by Green et al also showed that ZA was the most effective inhibitor of calvarial bone resorption.³⁷

The ability to bind hydroxyapatite is also central to the efficacy of BPs. Nancollas et al studied the binding affinity of a variety of BPs for hydroxyapatite and octacalcium phosphate. Zoledronic acid had the highest binding affinity for both crystals, higher than that of clodronate, etidronate, risedronate, ibandronate, and alendronate.³³

Differences in binding of BPs to hydroxyapatite can be confirmed with chromatography studies. When applied to columns of hydroxyapatite, BPs with different binding affinities should elute at different rates. Those with the lowest affinity should come out first while the most strongly bound should emerge last. Lawson et al found that ZA had a slower elution time compared with risedronate.⁴² The differences among BPs in binding to hydroxyapatite may explain the variations in retention and persistence of effects of BPs observed in clinical studies.⁴²

The differential ability of BPs to bind hydroxyapatite may be related to structural differences in their side chains. The nitrogen-containing side chain of alendronate binds hydroxyl residues in hydroxyapatite with more affinity than the side chain of risedronate does. This may partially explain the difference in potency between these agents. A unique feature of ZA is that it has more potential binding sites than the BPs, as depicted in Figure 5.

As an overall model for the interaction between BPs and bone, high-affinity BPs, such as alendronate and ZA become avidly bound to bone mineral. These high-affinity compounds may remain close to the surface instead of diffusing into the bone.

Current Understandings and Future Discoveries With the Use of Bisphosphonates

As in any field, progress depends upon the gradual bridging of the gap between the known and the unknown. Decades of research and clinical practice have taught us much about BPs. The mechanism of action—binding to bone mineral and inhibiting FPP synthase—is established. The total dose delivered greatly influences the overall response, likely explaining the differences in clinical efficacy and duration of action among BPs.

Yet there is also much to be discovered. Future research will hopefully shed light on the following areas: other differences among BPs; the effect of BPs on osteoclast precursor populations, osteoblasts, osteocytes, and T-cells (which give rise to the acute phase response observed with some of the nitrogen-containing BPs); other molecular targets apart from FPP synthase; potential harm from long-term use; and optimal duration of treatment for various conditions. Of course, the design of novel compounds remains a worthy endeavor.

Summary

Bisphosphonates are well accepted as the main class of antiresorptive agents and have many clinical applications. There are important differences between clinically useful BPs regarding their potency and duration of action. The efficacy of BPs is closely related to their affinity for bone mineral and ability to inhibit FPP synthase. The differences among BPs in binding to hydroxyapatite may explain the variations in retention and persistence of effect observed in animal and clinical studies. The advent of newer BPs, with differentiating structural activity properties, may help optimize the clinical management of bone resorptive diseases.