Monitoring Antiresorptive Therapies: Assessing the Way We Evaluate Clinical Efficacy

Are All Bisphosphonates the Same? Review of Efficacy and Tolerability Data

Osteoporosis is a debilitating disease, second only to cardiovascular disease as a leading healthcare problem. Worldwide, about one in three women and one in eight men over the age of 50 are at risk for osteoporotic fracture in their lifetimes (World Health Organ-ization data). “Currently, there are a number of effective treatment options available for persons with osteoporosis, including bisphosphonate therapies,” said Steven T. Harris, MD, FACP, Chief, Osteoporosis Clinic, Clinical Professor of Medicine, University of California, San Francisco. Dr. Harris provided an overview comparing the efficacy and tolerability data among available bisphosphonate agents.

Efficacy and Safety Endpoints
Several bisphosphonates—including alendronate, risedronate, and ibandronate—have been approved by the US Food and Drug Administration (FDA) for the treatment of osteoporosis, but only alendronate and risedronate are currently available for prescription. While numerous studies of bisphosphonate efficacy have been conducted, none has compared these agents directly. In addition, differences in study populations and methodology make it difficult to apply meta-analyses or compare trial results rigorously. In examining current data, tolerability endpoints include so-called “adverse events” associated with therapy during clinical trials. For efficacy, the impact on surrogate markers—such as bone mineral density, biochemical markers of bone turnover, and imaging studies (CT, MRI)—is interesting and important. “Ultimately, however, the most important factor is whether these agents prevent fractures—both vertebral and non-vertebral fractures,” Dr. Harris explained. “Because no head-to-head comparison trials have yet been conducted, clinicians must consider both pivotal study data and clinical judgment when selecting a bisphosphonate therapy for an individual patient.”

Tolerability Considerations
According to Dr. Harris, one of the most common side effects noted with alendronate and risedronate therapy in clinical practice is gastrointestinal upset. However, clinical trials thus far have shown no difference in the nature of and no greater incidence in gastrointestinal adverse events with these agents than in controls who received calcium and vitamin D alone. “In addition, there is a clinical impression that there is no obvious difference in gastrointestinal adverse events between alendronate and risedronate in practice, particularly when using weekly dosing,” Dr. Harris pointed out (Schnitzer et al. Aging (Milano) 2000;12(1):1. Brown et al. Calcif Tissue Int 2002; 71(2):103).

Efficacy Considerations
Clinical trials efficacy data on bisphosphonate therapies focus on evaluating the surrogate markers of disease and incidence of fracture. In terms of surrogate markers alone, alendronate and risedronate show some differences. For example, the suppression of biochemical markers of bone turnover appears to be somewhat greater with currently used doses of alendronate than with risedronate. The bone mineral density increase of the spine and hip also appears greater with alendronate than with risedronate, although head-to-head comparisons in matched populations have not been performed (Black et al. Lancet 1996; 348:1535. Cummings et al. JAMA 1998; 280(24):2077. Harris et al. JAMA 1999; 282(14):1344. Reginster et al. Osteoporos Int 2000; 11(1):83).

“In terms of reduced risk for fracture, alendronate and risedronate both show evidence of an early-onset fracture benefit that cannot be explained simply by a change in bone mineral density,” Dr. Harris said. Both agents show a decrease in vertebral, non-vertebral, and hip fracture risk. In addition, this effect appears to be sustained. “When therapy is stopped, biochemical markers increase and bone mineral density drifts downward; however, there appears to be some sustained effect even after therapy is discontinued,” Dr. Harris said. He noted that available fracture data are from studies of daily bisphosphonate dosing only; the studies of weekly therapy had insufficient statistical power to examine fracture reduction (Black et al. Lancet 1996; 348:1535. Cummings et al. JAMA 1998; 280(24):2077. Harris et al. JAMA 1999; 282(14):1344. Reginster et al. Osteoporos Int 2000; 11(1):83).

Ibandronate, which has been approved by the FDA for daily dosing, has been shown to reduce vertebral fracture risk. Studies of alternate ibandronate dosing regimens—including weekly, monthly, and intermittent intravenous dosing—are underway. Zoledronic acid with annual intravenous dosing, which has shown some promise in improving bone mineral density, is also under study for potential effects on fracture reduction.

In closing, Dr. Harris emphasized that bisphosphonate therapy represents an effective and tolerable treatment option for patients with osteoporosis. “We hope that upcoming trial results will shed further light on how these agents work, how they differ, and which might offer the greatest fracture reduction benefit,” he concluded.

Monitoring Treatment Response and Predicting Fracture Risk: Bone Mineral Density

“As new therapies and new dosing regimens become available for the treatment of osteoporosis, effective monitoring of treatment response will be essential,” said Michael McClung, MD, FACE, Assistant Director, Department of Medical Education, Providence Portland Medical Center and Director, Oregon Osteoporosis Center, in Portland, Oregon. Bone mineral density (BMD) has been the usual test that clinicians have used to follow the response to treatment with osteoporosis drugs. Using BMD in this way has both advantages and weaknesses.

The objectives of monitoring of patients receiving therapy for osteoporosis include: 1) evaluating treatment efficacy, 2) identifying non-responders, 3) improving adherence to therapy, and 4) providing feedback and satisfaction to patients and providers.

BMD and Fracture Risk
“BMD is a valuable tool in predicting fracture risk, especially when that information is combined with other risk factors such as age and previous fracture history,” Dr. McClung said. Treatment with antiresorptive or anabolic agents increases BMD and reduces fracture risk (Cummings et al. NEJM 1993. Delmas. Lancet 2002; 359:2018). However, the increase in BMD that occurs with therapy is not a direct effect of antiresorptive treatment and accounts for only a modest component of fracture risk reduction with these therapies.

Mechanisms of Fracture Risk Reduction
According to Dr. McClung, antiresorptive therapies act not by stimulating new bone growth, but by reducing bone resorption, resulting in several effects by which fracture risk is reduced (McClung. Endocrinol Metab Clin N Am 2003; 32:253). “Reduced bone remodeling sites and increased mineralization can be measured by BMD. However, other important effects of treatment, such as reducing the number of stress risers and maintaining bone mass and structure, are not captured by this test,” Dr. McClung said.

Monitoring Treatment Response
“Fracture risk reduction occurs as early as 6 months after treatment is begun, long before important increases in BMD are seen,” Dr. McClung explained. The results of both meta-regression analyses and studies using individual patient data document that a modest relationship exists between the amount of increase in BMD in response to treatment and the protection from fracture risk with treatment. With the antiresorptive agents bisphosphonates and raloxifene, less than 20% of the protection from spine fractures can be attributed to the increase in BMD (Hochberg et al. Arth Rheum 1999;42:1246. Sarkar et al. J Bone Miner Res 2002;17:1. Watts et al. ISCD 135, 2004).

Identifying Non-Response
In clinical trials, the proportion of patients who do not respond to potent agents like estrogen, bisphosphonates or teriparatide is very small. In clinical practice, perhaps as many as 10% of patients experience significant bone loss while on treatment. Dr. McClung stated, “When bone loss on treatment is seen, whether and how the medicine was taken needs to be reviewed, and a search for medical or metabolic causes of bone loss [such as vitamin D deficiency] is appropriate.”

Quality Control
Any test used to monitor treatment must be performed very carefully and reproducibly, and the least significant change (smallest change that can be detected between two tests) must be determined by each laboratory.

Conclusions
Dr. McClung concluded by saying that bone density is the most important laboratory test used to diagnose osteoporosis and to assess fracture risk. Its value in monitoring treatment response is more limited. There is only weak correlation between how much BMD changes and the protection from fractures afforded by the treatment. “Thus, not seeing an increase in BMD with treatment is not evidence of a poor response. The most important role for monitoring treatment with BMD is to identify those patients who lose bone mass while on therapy, in which case, a review of their clinical status is necessary,” he concluded.

Monitoring Treatment Response and Predicting Fracture Risk: Bone Turnover Markers

In treating persons with osteoporosis, the ability to monitor treatment response is paramount. “While bone mineral density [BMD] testing is a useful determinant of response in untreated patients, bone turnover marker [BTM] changes occur sooner, allow for greater identification of response, and account for a greater proportion of fracture risk reduction with antiresorptive therapy,” said Nelson B. Watts, MD, FACE, Program Chair; Director, University of Cincinnati Bone Health & Osteoporosis Center; Professor of Medicine; University of Cincinnati College of Medicine in Cincinnati, Ohio. According to Dr. Watts, the use of certain BTMs, along with BMD, may provide an optimal approach to monitoring response and predicting fracture risk in individuals receiving antiresorptive therapy.

Markers of Bone Remodeling
Normal bone remodeling occurs when a stimulus activates a remodeling cycle. Osteoclasts resorb the bone for a period of 7 to 10 days, leaving a resorption pit and skeletal instability. This pit is rapidly filled by osteoblasts, which produce bone matrix and facilitate mineralization over a period of 10 to 12 weeks. “However, for each remodeling cycle, more bone is resorbed than is replaced, leaving a bone deficit. The higher the rate of bone turnover, the greater the loss of bone and skeletal integrity,” Dr. Watts explained. A number of elements of bone strength are determined by the rate of bone remodeling, with high bone turnover playing a key role in the pathogenesis of osteoporotic fracture. These elements include low bone mass, undesirable bone geometry, microarchitectural deterioration, proportion of cortical to cancellous bone, presence of stress risers, abnormal matrix properties, and suboptimal mineralization (Watts. ISCD 2004). “In persons receiving antiresorptive therapy for osteoporosis, monitoring of BTMs may be useful in identifying treatment response and predicting fracture reduction,” Dr. Watts said.

The biochemical markers of bone turnover are many, both in the resorption and formation of bone (Table 1). Several factors affect bone remodeling, and therefore BTM measures (Table 2). Thus, in monitoring BTM for antiresorptive treatment response, the timing of the sample is important: clinicians should obtain either a morning fasting blood sample or second-morning fasting urine sample.

Predicting Fracture Reduction
According to Dr. Watts, monitoring antiresorptive treatment response represents a clinical challenge. It is well known that osteoporosis treatments increase BMD, reduce bone turnover, and/or reduce the risk of fracture. However, in individual patients, risk of fracture cannot be directly measured. Rather, BMD and BTM measures can be used as predictive indicators of treatment response and fracture risk. “While not all persons with high BTM levels have osteoporosis, BTMs have been shown to be predictive of loss of hip BMD in untreated patients. In turn, high bone turnover is an independent risk factor for hip fracture,” Dr. Watts explained (Garnero et al. J Bone Mine Res 1996; 11:1531).

Not only do BTM measures show a more rapid response to therapy than BMD, but resorption markers change more quickly than formation markers (maximum effect 2 to 3 months vs 3 to 6 months) (Filton & McTavish. Drug Eval 1991;41:289). In one study, Watts and colleagues measured the change in bone-specific alkaline phosphatase and BMD in patients receiving antiresorptive therapy. The results showed that 81% had a measurable increase in spinal BMD after 3 years, while 90% demonstrated a significant reduction in BTM after 6 months (Watts et al. Osteoporosis Int 2001;12:279). In addition, Bjarnason and colleagues showed that a reduction in bone-specific alkaline phosphatase with raloxifene therapy corre- lates with a reduction in fracture of the femoral neck (Bjarnason et al. Osteoporosis Int 2001;12:922).

Importantly, once maximum therapeutic effect is achieved, continued antiresorptive therapy does not result in continued reduction in bone remodeling (Bone et al. NEJM 2004;350:1189). In one study, patients receiving risedronate were followed to measure 3- to 6-month BTM change and 3-year fracture risk. The results showed a reduced fracture risk until 40% reduction of NTX; therein fracture reduction plateaus regardless of any further reduction in remodeling.

In closing, Dr. Watts emphasized, “BTMs can be used to predict BMD loss and fracture in untreated patients with osteoporosis. BTM measures change more rapidly than BMD, and may be particularly useful in identifying treatment response and accounting for fracture risk reduction in patients receiving antiresorptive therapy.”

The Future of Bone Imaging

“Bone mineral density [BMD] measurement alone is not entirely sufficient in assessing skeletal status and predicting fracture risk in persons with osteoporosis. For this reason, recent advances in the imaging of bone structure may have significant clinical implications for this patient population,” said Harry K. Genant, MD, Professor Emeritus of Radiology, Orthopedic Surgery, Medicine, and Epidemiology, University of California, San Francisco. Dr. Genant provided an overview of the strengths and limitations of new imaging techniques, including high-resolution and volumetric computed tomography (CT), micro CT, and magnetic resonance (MR) microscopy.

According to Dr. Genant, the imaging of bone structure—both macrostructure and microstructure—in persons with osteoporosis may be beneficial in providing information beyond BMD, improving fracture risk prediction, clarifying the pathophysiology of skeletal disease, defining skeletal response to therapy, and assessing biomechanical relationships. Several new macrostructure and microstructure imaging techniques offer the promise of improved assessment and management of osteoporosis (Table 1).

High-Resolution & Volumetric CT Imaging
Using advanced approaches, the volumetric CT scan provides information on important compartments of bone, such as the trabecular bone in isolation, cortical rim, or end plates of the vertebrae. The high-resolution CT scan allows clear imaging at a variety of measurement sites, including the spine and hip. “The strengths of these two techniques include wide availability, the non-invasive and non-destructive nature of the tests, and ability to provide imaging of a variety of sites,” Dr. Genant said. In addition, high-resolution and volumetric CT scanning allows macrostructure and BMD imaging, and in vivo assessment. “The limitations of these technologies involve exposure to ionizing radiation and substantial resolution and threshold dependencies, which may affect the relative accuracy of the measurement,” Dr. Genant explained.

Micro CT Imaging
The micro CT uses special equipment to generate 3D high-resolution images of biopsy specimens in vitro or of laboratory animals in vivo. Thus far, this test has been used primarily in animal models and in specimens. This non-destructive technique offers the opportunity for a biomechanical test and affords highly accurate and precise imaging and automated 2D and 3D evaluation. This technique is still under study in laboratory specimens and animal subjects. Limitations include its invasiveness, as it currently requires a biopsy or specimen, and substantial sampling errors. The test is also expensive and there is limited in availability. “High radiation exposure is also a limiting factor with micro CT, affecting our ability to obtain higher levels of spatial resolution. However, this is not a critical factor in examining animal subjects or specimens,” Dr. Genant said.

High-Resolution & MR Microscopy Imaging
With the recent heightened interest in MR imaging, MR microscopy is an attractive potential test for use in persons with osteoporosis. In vivo applications of this technique have focused on the peripheral skeleton, as it is easier to achieve high signal-to-noise for thinner body parts than for the central skeleton. The strengths of this technique include the non-invasive, non-destructive nature of the scan, lack of ionizing radiation, ability to use with existing equipment, and its moderate precision and accuracy. “The MR microscopy is not as accurate or precise as micro CT imaging due to its lower spatial resolution,” Dr. Genant explained. Limitations involve this technique’s expense, complexity, and its substantial signal, resolution, and threshold effects.

In closing, Dr. Genant emphasized that new imaging techniques hold the promise of exciting new options for the future assessment and management of osteoporosis. “In moving forward, researchers and clinicians need to consider not only what information can be derived from these techniques, but also their technical and clinical implications,” he concluded.