Prevalence of Non-Responders to Both Oral Bisphosphonate Monotherapy and Intravenous Ibandronate in Patients with Postmenopausal Osteoporosis

Objectives: Although bisphosphonates (BPs) are effective for the majority of patients with osteoporosis, some individuals do not adequately respond to these drugs. The objective of this study was to estimate the prevalence of true BP non-responders who showed insufficient response after both oral BPs and intravenous ibandronate. Methods: Among 146 consecutive patients with postmenopausal osteoporosis who received oral BP monotherapy for more than 12 months, insufficient responders to oral BP monotherapy were switched to intravenous ibandronate injection and followed for more than 12 months. Serum N-terminal telopeptide of type I collagen (NTX) and bone alkaline phosphatase (BAP) concentrations were measured. Patients who also showed insufficient response to intravenous ibandronate were defined as true BP non-responders. Insufficient response to BP therapy was evaluated based on the serum NTX reduction cut-off for minimum significant change. Results: Sixty-one patients (41.8%) were diagnosed as oral BP non-responders. Four-teen patients who switched to intravenous ibandronate and had complete data available were used for final analysis. After switching to intravenous ibandronate, both NTX and BAP decreased significantly (p < 0.05). However, at 6 - 12 months after switching, 57.1% - 64.3% of patients still showed insufficient response of


Introduction
Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing a person to increased risk of fracture [1]. Fracture risk in osteoporosis increases with age, particularly among women. The overall 10-year fracture risk at 50 years old is reportedly 9.8% in women and 7.1% in men, compared to 21.7% in women and 8% in men at 80 years old [2]. Anti-osteoporotic pharmacotherapy is the most important and essential option for preventing osteoporotic fractures. Among multiple therapeutic options available for pharmacotherapy against osteoporosis, bisphosphonates (BPs) are the first-line drugs and act strongly to reduce osteoclast-mediated bone resorption [3].
BPs can be administered either orally or intravenously, but are commonly used as oral medication. However, the prevalence of an inadequate response to oral BPs varies widely among different studies, varying from 8% to 60% [4]- [11].
Although the wide variety in methods of evaluation, including poor response in bone turnover markers, ineffectiveness in changing bone mineral density (BMD), or incident osteoporotic fractures, would have contributed to the wide range in prevalence, the evidence suggests that non-responders to oral BPs actually exist.
Treatment non-response to oral BPs could have a number of causes, including non-compliance, non-persistence, some underlying, untreated cause of osteoporosis, an inability to absorb the drug [12], or insufficiency of vitamin D [5] [7] [9] [13]. Upper gastrointestinal adverse events have been reported with oral BPs and are a strong predictor of non-adherence [14]. Studies have shown that maintenance vitamin D status is required for optimal therapeutic efficacy of BPs [5] [15]. However, the most important probable cause of non-response is an extremely low bioavailability via the oral route [3] [16]. Many BPs have a gastrointestinal absorption rate below 1% [3] [16], and this low value may be further reduced by the specific conditions of the individual patient.
Administration of BPs via an intravenous route is thus theoretically preferable.
However, studies have reported that intravenous BPs also have non-responders [4] [5]. The most suspected cause of inadequate response to intravenous BP treatment is vitamin D insufficiency, but the details remain unclear. Bae et al. [4] investigated the effect of intravenous administration of ibandronate in 13 patients with osteoporosis who had shown insufficient response to orally administered BPs. After intravenous ibandronate administration, serum levels of C-terminal telopeptide of type I collagen (CTX), a bone resorption marker, were significantly reduced [4]. However, in that study, because all subjects received supple-  were the licensed doses in Japan.

Subjects
In this study, patients receiving combination therapy with any other antiosteoporosis agents (vitamin D, menatetrenone, teriparatide, etc.) were excluded.
To investigate definitive effects of oral BP, patients with upper gastrointestinal diseases such as reflux esophagitis or delayed esophageal emptying or active gastric/duodenal ulcer and who were unable to maintain an upright position for at least 60 min were excluded.Because bone turnover markers were influenced by metabolic bone diseases and fresh fractures, we also excluded patients with: 1) a history of metabolic bone disease other than primary osteoporosis; 2) malignancy; 3) secondary osteoporosis including diabetes mellitus and glucocorticoid usage; 4) current smoking; 5) any documented fracture within the preceding 1 year prior to starting oral BP therapy; or 6) any fracture after oral BP therapy.
A total of 146 patients with BP monotherapy were divided into oral BP responders and non-responders due to changes in serum NTX levels from baseline.

Measurement of Bone Turnover Markers
Blood was collected before and after treatment in all patients. Serum levels of NTX as a marker for bone resorption and bone-specific alkaline phosphatase (BAP) as a marker for bone formation were measured before and after oral BP treatment. Furthermore, in patients who switched to intravenous ibandronate, NTX and BAP were also measured at 6 and 12 months after switching to intra- of serum NTX and BAP were 6.9% and 3.2%, respectively. Inter-assay CV of serum NTX and BAP were 15.5% and 10.2%, respectively [18].
In this study, reduction of NTX exceeding the minimum significant change (MSC) was used as the criterion for evaluating BP treatment effectiveness. MSC is defined as twice the inter-day variation in the morning in premenopausal women [19]. MSC has been reported as 16.3% for serum NTX, and 9.0% for serum BAP [19]. If the serum NTX level in patients receiving BP therapy showed insufficient changes and did not decrease more than the MSC from baseline, the patient was defined as a BP non-responder.

Statistical Analyses
Results

Rate of Non-Response to Oral Administration of BPs and Patients Who Switched to Intravenous Ibandronate
A flow chart of patient disposition is shown in Figure 1. Among the 146 patients who received oral BP monotherapy for more than 12 months, 61 patients (41.8%) were diagnosed as non-responders based on an insufficient reduction in serum NTX compared to the cut-off of the MSC.

Efficacy of Intravenous Administration of Ibandronate in Oral BP Non-Responders
Changes in bone turnover markers among the 14 oral BP non-responders who switched to intravenous ibandronate are shown in Table 1. Both serum NTX and BAP concentrations changed significantly (p < 0.0001 and p = 0.0003, respectively) throughout the study. Compared to baseline (before oral BP monotherapy), percent changes in NTX and BAP were significant after switching to ibandronate.
We further counted the number of patients for whom changes in bone turnover markers were less than the MSC even after switching to intravenous administration of ibandronate (

Rate of True BP Non-Responders as Estimated by the MSC of Serum NTX
This study attempted to elucidate the prevalence of true BP non-responders.
First, this study revealed the prevalence of non-responders to oral BP monotherapy in postmenopausal osteoporosis using serum NTX as a marker was 41.8%, even though the enrolled patients demonstrated ≥ 80% compliance and did not have secondary osteoporosis. A compliance rate of 70% -80% is widely accepted  This study used bone turnover markers to identify response to BP treatment, because serial concentrations of bone turnover markers may prove more useful than serial BMD for early identification of response to pharmacotherapy. The ability to identify non-responders as early as possible can be beneficial, allowing changes in management strategy. Repeated BMD measurement is commonly used to monitor treatment response, but shows limitations in that changes due to treatment can take longer to become detectable [12], and the National Osteoporosis Foundation recommends a 2-year interval after treatment [24]. However,

Probable Causes of BP Non-Response
Published studies have demonstrated that, in addition to a lack of adequate compliance to the treatment and secondary osteoporosis, vitamin D insufficiency and reduced calcium intake can also be confounding conditions for ineffectiveness of BP therapy [4]- [11] [15] [22]. Peris et al. [9] suggested that maintenance of 25(OH)D levels at > 30 ng/ml is indicated for adequate response to BP treatment.
The present study used ibandronate as an intravenously administrational BP.
Ibandronate is a potent BP for the treatment of osteoporosis and can be used orally or intravenously [25]. However, one study reported that the rate of non-response to intravenous ibandronate (1 mg/month), as evaluated by BMD and urinary CTX from baseline to 1 year, was 6.1% [26]. That study also showed that mean 25(OH)D levels were significantly lower among non-responders than among responders [26]. Thus, 25(OH)D level appears important as an indicator of treatment response with intravenous ibandronate.
In contrast, Cairoli et al. [23] reported that among 97 postmenopausal women with primary osteoporosis, 25.8% responded inadequately to BPs (alendronate or risedronate), despite good compliance to therapy and normal 25(OH)D levels [23]. In that study, treatment failure was defined by incident fragility fractures and/or decreased BMD. In addition, Bourke et al. [27] suggested with the results from a larger population study that dietary calcium intake and baseline vitamin D status had no influence on the effects of zoledronate at 1 year. Reasons for the ineffectiveness of BP independent of vitamin D status remain unclear, but a study by Cairoli et al. [23] concluded that current smoking and bone turnover in the upper part of the normal range were associated with inadequate response to BPs [23]. Moreover, more recent studies have shown that genetic polymorphisms in the genes involved in the main pathways for the mechanisms of BP action influence response to BP therapy [28]. In the present study, no patients were current smokers, but vitamin D status could not be evaluated because 25(OH)D measurements were not covered by the national insurance system in Japan when we performed this study.

Limitations
This study showed strength in estimating the prevalence of true BP non-responders by evaluating serial treatment after oral and intravenous BPs. The study was not randomized, but was conducted in a prospective manner. Our data were obtained from "real-life" practice. However, limitations to this study should also be noted. Because this study attempted to elucidate the effects of BP monotherapy, patients receiving co-therapy with vitamin D were excluded. In clinical settings, drug monotherapy is sometimes preferable according to the medical insurance system. However, our study design lacked information concerning potential con-

Conclusion
Among 146 patients with postmenopausal osteoporosis who received oral BP monotherapy, 41.8% were diagnosed as oral BP non-responders based on a serum NTX reduction below the MSC. Among oral BP non-responders, rates of non-responders to intravenous ibandronate at 6 -12 months after administration were 57.1% -64.3% and 21.4% -35.7% when compared to data from baseline or just before switching to ibandronate, respectively. Based on these results, the prevalence of true BP non-responders in postmenopausal osteoporosis was estimated to be as low as 9% -15% or as high as 24% -27%.