Surrogate markers of fracture risk—bone turnover markers (BTMs) and bone mineral density (BMD)—can be used to monitor treatment response. We assessed whether changes in these markers greater than the least significant change (LSC) were associated with fracture risk reduction and greater adherence. This secondary analysis of the Improving Measurements of Persistence on ACtonel Treatment (IMPACT) study—a multinational prospective, open-label, cluster-randomized study of postmenopausal women on oral risedronate 5 mg/d for 52 weeks—assessed adherence by electronic monitors. Urinary N-terminal cross-linked telopeptide of type 1 collagen (uNTX) and serum C-terminal cross-linked telopeptide of type 1 collagen (sCTX) levels were assessed at baseline and weeks 10 and 22, and BMD at baseline and week 52. Fractures were recorded as adverse events. In 2302 women, responses beyond LSC in BTMs (uNTX and sCTX) and BMD (spine only) were associated with a reduced risk of nonvertebral fractures (NVFs) and all fractures. NVF incidence was about 50% lower in patients with 30% or more of uNTX reduction at week 22 (1.6%) than in those with less than 30% reduction (3.2%, p = .015). NVFs also were reduced in patients with more than 3% spine BMD increase at 52 weeks than those with 3% or less. Responses greater than LSC in BTMs and BMD were associated with greater adherence, but there was no association between adherence and fracture outcomes at 52 weeks. Changes greater than the LSC in BTMs and BMD reflect better treatment adherence, were associated with fracture risk reduction, and identify differences in individual responsiveness to risedronate. © 2011 American Society for Bone and Mineral Research.

Introduction

Osteoporosis is a common disease characterized by low bone mineral density (BMD), increased bone turnover, and deterioration of bone microarchitecture. These features lead to enhanced bone fragility and an increased risk of bone fractures.1 There are many therapies to reduce risk of fractures in patients with osteoporosis; bisphosphonates generally are considered first-line therapy for postmenopausal osteoporosis.

High levels of bone turnover markers (BTMs) are associated with increased fracture risk in postmenopausal women,2-4 and BTMs can be used to monitor response to osteoporosis treatment.5-10 For example, data from two large risedronate studies showed that BTM changes predicted 67% of the fracture risk reduction at 3 years.7, 11 BMD measurements also have been used to monitor response to osteoporosis therapy.12 For example, data from two large risedronate studies showed that BMD changes predicted 17% of the fracture risk reduction at 3 years.13

BMD and BTMs respond differently to therapeutic agents. To show a measurable and reproducible BMD response, 1 to 2 years is required,14 whereas decreases in urinary levels of bone-resorption markers were observed within a month of risedronate therapy.5, 15, 16 Since the short-term (3 to 6 months) changes in BTMs are significantly correlated with long-term (1 to 2 years) increases in BMD,17, 18 both BTMs and BMD can be used to monitor treatment—BTMs for early assessment and BMD in the longer term.

Adherence can be broken in two components: Persistence is the length of time during which the medication is taken, and execution of the dosing regimen (compliance) is the extent to which a patient's actual dosing corresponds to the prescribed dosing regimen while the patient is still engaged with therapy.19, 20 This can be assessed formally by using electronic monitors. In a study of raloxifene, adherence was found to be related to BTMs [urinary N-terminal cross-linked telopeptide of type 1 collagen (uNTX)] and BMD (total-hip BMD).21 However, larger studies are needed to examine this in more detail.

The effectiveness of existing therapies depends on a patient's adherence with therapy.22-25 However, poor adherence with long-term therapy is common in osteoporosis23, 26-31 and other asymptomatic chronic diseases.32-34 Low medication adherence is associated not only with an increased risk of fractures but also with higher rates of all-cause hospitalizations35 and incremental costs.36

The Improving Measurements of Persistence on ACtonel Treatment (IMPACT) study evaluated the effect of a physician's feedback of the biochemical response to risedronate therapy on persistence. Reinforcement using BTMs influenced persistence with treatment in postmenopausal women with osteoporosis depending on the BTM response observed.19 No new safety issues with the use of daily risedronate administration were observed in that study.

The aims of this analysis were to relate changes in BTMs and BMD to fracture risk with risedronate therapy, to relate changes in BTMs and BMD to adherence, and to relate adherence to fracture risk with risedronate therapy.

Methods

Patients and study design

IMPACT was a multinational, multicenter, 1-year prospective study conducted at 171 centers in 21 countries. It enrolled postmenopausal women aged 65 to 80 years who had not been diagnosed previously with osteoporosis. Diagnosis of osteoporosis was based on either a BMD T-score of −2.5 or less at the hip or spine or a BMD T-score of between −1.0 and −2.5 with a clinically documented low-trauma fracture (defined as all fractures, excluding those related to automobile accidents) sustained at or after 45 years of age.

Calcium (500 mg/d) and vitamin D (400 IU/d) supplementation was initiated during the screening period, 2 to 4 weeks (median of 20 days) before baseline (week 0) when risedronate treatment was started, and continued throughout the study period. All patients received oral risedronate 5 mg/d for 1 year. Centers were randomized to either providing reinforcement by showing patients the results of the change in uNTX (RE+) or not providing such reinforcement (RE–). At 13 and 25 weeks, all patients received information about the need to continue treatment. RE+ patients were given reinforcement based on the change from baseline in uNTX according to the following response categories: “good” (>30% decrease), “stable” (−30% to +30% change), or “poor” (>30% increase).19 In this report, we refer to a “good” response as a “greater” response, and a “stable and poor” response as a “lesser” response. Full details of the study design have been reported previously.18 Baseline characteristics of the study are summarized in Table 1.19

Table 1. Baseline Characteristics of Patients in the Intention-to-Treat Analysis (n = 2,302)

Characteristic	RE+ (n = 1189)	RE– (n = 1113)
Age, years, mean ± SD	71.1 ± 4.3	71.5 ± 4.5
Weight, kg, mean ± SD	64.1 ± 11.2	63.2 ± 10.7
Height, cm, mean ± SD	157.0 ± 7.0	157.4 ± 6.8
Spine T-score, mean ± SD	−2.8 ± 1.0	−2.8 ± 1.0
Hip T-score, mean ± SD	−2.0 ± 0.8	−2.0 ± 0.8
Patients with prevalent vertebral fracture, n (%)	359 (30.2%)	330 (29.7%)
Patients with history of maternal hip fracture at age > 50 years, n (%)	133 (11.2%)	146 (13.1%)
Age when menses stopped, years, mean ± SD	47.7 ± 5.7	48.1 ± 5.7
Use of corticosteroids for > 3 months, n (%)	40 (3.4%)	44 (4.0%)
Use of sex hormones, n (%)	225 (18.9%)	204 (18.3%)
History of cigarette smoking, n (%)	366 (30.8%)	351 (31.5%)
Alcohol use, n (%)
None	420 (35.3%)	372 (33.4%)
<3 drinks per week	532 (44.7%)	485 (43.6%)
≥3drinks per week	236 (19.9%)	255 (22.9%)

RE+ = reinforcement; RE– = no reinforcement; SD = standard deviation.
Source: Reproduced with permission from Delmas PD et al.19 © 2007 by The Endocrine Society.

Fractures

Lateral thoracic and lumbar spine X-rays were performed at study entry and again at 12 months. Because the final assessment was an amendment to the original protocol, only 57% (1317 of 2302) of the patients had X-rays evaluable for both time points. Vertebral fractures were assessed by both local radiologists according to the semiquantitative method described by Genant and colleagues37 and were sent to a single central reading facility (Synarc, San Francisco, CA, USA) for confirmation of radiographic quality and blinded assessment of vertebral fractures.38

Nonvertebral fractures were recorded on the electronic case report form as adverse events. Nonvertebral osteoporotic fractures were defined as those occurring at six skeletal sites (ie, clavicle, hip, humerus, leg, pelvis, and wrist)16 not associated with a fall and were confirmed by local X-ray reports or by statements in the patients' records.

Outcome measurements

Adherence

Drug dosing histories were compiled electronically using the Medication Event Monitoring System (MEMS; AARDEX Group, Ltd., Sion, Switzerland). The childproof cover of the MEMS bottle contains a microprocessor that records the date and time of each opening. Patients returned their study medication bottles at weeks 13, 25, and 52. Electronic monitoring allows the reliable compilation of drug dosing histories in ambulatory patients.39

For each patient, adherence was defined as the number and percentage of prescribed doses taken during a specified time interval. An arbitrary threshold of 80% was used to dichotomize the adherence outcome.

BTMs

uNTX and serum C-terminal cross-linked telopeptide of type 1 collagen (sCTX) were measured at baseline and at weeks 10 and 22 after treatment initiation. uNTX was measured by automated analyzer (Vitros Eci, Ortho Clinical Diagnostics, Raritan, NJ, USA), and levels were obtained from the mean values of two second-void morning urine samples collected on consecutive days. Intraassay variation was 1.1% to 6.7%, and interassay variation was 3.5% to 7.8%.19 Response to therapy was considered significant if the change in uNTX was greater than the least significant change (LSC), that is, a decrease of 30% or more from baseline. The LSC was determined in advance of the study using duplicate second-void morning urine samples on consecutive days.

Levels of sCTX from fasting morning blood samples were measured by a two-site immunochemiluminometric assay using human type 1 collagen monoclonal antibodies. Measurements were performed in an automatic analyzer (Elecsys, Roche Diagnostics, Mannheim, Germany). Intraassay variation was less than 3%, and interassay variation was less than 8%. sCTX levels were recorded as the mean concentration from samples obtained after 10 and 22 weeks of treatment. LSC for a single measurement of sCTX was calculated at baseline. Response to therapy was considered significant if the decrease in sCTX levels was 30% or greater.

BMD

BMD screening was performed at baseline and at 1 year. Lumbar spine and hip BMD values were measured in duplicate using dual-energy X-ray absorptiometry (DXA). BMD data were obtained using Lunar, Norland, or Hologic densitometers. T-scores at the hip were calculated based on reference data from the Third National Health and Nutrition Examination Survey.40

Statistical analysis

Analyses were undertaken on the intention-to-treat (ITT) population. This was defined as all patients who received at least one dose of risedronate and returned a functioning MEMS monitor.

The association between BTMs (sCTX and uNTX) or BMD (hip and spine) and adherence was derived using a logistic regression where the proportion of patients with greater response is modeled as a function of the number of doses taken. Time intervals of 22 and 52 weeks were used for BTMs and BMD, respectively. A scatter plot of percentage change in BTM or BMD, against number of doses taken was used to visualize the association. Median change and the percentage of patients with greater response were displayed in five adherence groups for illustration. Any association between greater response in BTM or BMD and fracture (vertebral and nonvertebral) was evaluated using a chi-square test. Any association between adherence (≥80%) and all fractures (vertebral and nonvertebral) was evaluated using a chi-square test.

Results

Patients

A total of 2302 women were included in the ITT population. Of these, 1317 were available for nonvertebral fracture and all-fracture analyses. Vertebral fracture analysis was not examined separately in this study because the number was too low. At baseline, the mean age was 71 years; 98% of women met the T-score criterion for osteoporosis (ie, a BMD T-score of −2.5 or less at the hip and/or lumbar spine) or osteopenia (ie, a BMD T-score of −1.0 or less at the hip and/or lumbar spine) with a low-trauma fracture after age 45 years. The mean (SD) total-hip T-score was −2.11 (0.92) and mean (SD) spine T-score was −2.79 (1.01). The mean (SD) uNTX levels were 52 (27) nmol BCE/mmol of creatinine, and sCTX levels were 0.42 (0.22) ng/mL. Adherence in this population was high and similar for both no reinforcement (RE–) and reinforcement (RE + ) groups. On average, 90% of prescribed doses were taken. At 1 year, persistence with treatment was 79%, and among patients who remained engaged with therapy, 95% executed the dosing regimen daily.19

Fracture incidence and BTM response

Fracture outcomes were related to BTM responses to risedronate therapy (Table 2). The incidences of both nonvertebral (Fig. 1) and all fractures (nonvertebral and vertebral) were lower in patients with more than 30% reduction in uNTX or sCTX levels compared with patients who experienced a 30% or less BTM reduction. At week 22, 3.1% of women (n = 28) with a 30% or greater reduction in uNTX experienced any fractures (nonvertebral and vertebral) compared with 4.7% (n = 18) with a less than 30% reduction (p = .166). Similarly, 2.8% of women (n = 29) with a 30% or greater reduction in sCTX experienced any fractures compared with 8.2% (n = 17) with a less than 30% reduction (p = .0002).

Table 2. The Association Between BTMs and BMD Responses and Fractures

	Greater responseb	Lesser response	p Value χ² test	Greater response	Lesser response	p Value χ² test
	ITT populationa			Subpopulation including patients with adherence ≥ 80%
uNTX response at week 22
Patients with nonvertebral fracture	1.6% (22/1405)	3.2% (20/617)	.015	1.3% (15/1169)	2.9% (14/476)	.020
Patients with vertebral or nonvertebral fractures	3.1% (28/898)	4.7% (18/384)	.166	2.5% (19/758)	4.3% (13/302)	.123
sCTX response at week 22
Patients with nonvertebral fracture	1.7% (28/1632)	4.3% (15/346)	.002	1.3% (18/1353)	4.2% (11/262)	.001
Patients with vertebral or nonvertebral fractures	2.8% (29/1041)	8.2% (17/207)	.0002	2.3% (20/878)	7.5% (12/160)	.0004
Hip response at week 52
Patients with nonvertebral fracture	1.5% (10/682)	2.4% (29/1200)	.164	1.5% (9/590)	2.1% (21/989)	.400
Patients with vertebral or nonvertebral fractures	2.5% (11/444)	4.1% (32/779)	.137	2.6% (10/389)	4.0% (26/658)	.236
Spine response at week 52
Patients with nonvertebral fracture	1.4% (16/1146)	3.1% (23/736)	.010	1.5% (15/1000)	2.6% (15/579)	.126
Patients with vertebral or nonvertebral fractures	2.5% (19/756)	5.1% (24/467)	.015	2.6% (17/665)	5.0% (19/382)	.038

BMD = bone mineral density; BTMs = bone turnover markers; ITT = intent-to-treat; sCTX = serum C-terminal cross-linked telopeptide of type 1 collagen; uNTX = urinary N-terminal cross-linked telopeptide of type 1 collagen.
a Total risedronate ITT population comprises 2302 women; adherence ≥ 80% found in 1733 women; subpopulation for fracture analysis 1317 women; subpopulation for fracture analysis where adherence ≥ 80% 1132 women.
b Greater response for BTM data (uNTX and sCTX): percentage change > 30% reduction; for BMD data (hip and spine): percentage change > 3% increase.

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

Association between nonvertebral fracture incidence and bone turnover marker response (uNTX and sCTX) at week 22 of risedronate therapy. NVF = nonvertebral fracture; sCTX = serum C-terminal cross-linked telopeptide of type 1 collagen; uNTX = urinary N-terminal cross-linked telopeptide of type 1 collagen.

Subgroup analysis of patients with good adherence (≥80%) also indicated that significant BTM response at week 22 was associated with lower nonvertebral fracture rates (uNTX: 1.3% versus 2.9%, respectively, p = .020, and sCTX: 1.3% versus 4.2%, p = .001; Table 2). Among patients with good adherence, the incidence of all fractures (nonvertebral and vertebral) also was higher in lesser responders for sCTX at week 22 compared with greater responders (7.5% versus 2.3%, p = .0004).

Fracture incidence and BMD response

At 52 weeks, percentage change in spine BMD was associated with nonvertebral fracture rate; in the group of patients achieving a more than 3% LSC in spine BMD, nonvertebral fracture incidence was lower than in the group with BMD changes of 3% or less (1.4% versus 3.1%, respectively, p = .010; Fig. 2). However, no association was found between percentage change in hip BMD from baseline and nonvertebral fracture incidence (Table 2). Similarly, the incidence of all fractures (vertebral and nonvertebral) was positively associated with spine BMD change, but it was not associated with hip BMD change. At week 52, the incidence of all fractures was lower in the group of patients with a more than 3% LSC in spine BMD from baseline compared with those in whom BMD change was 3% or less (2.5% versus 5.1%, respectively, p = .015).

Subgroup analysis of patients with good adherence revealed no association between spine or hip BMD change at 52 weeks and nonvertebral fracture incidence, although the incidence of all fractures was lower among those with a more than 3% LSC in spine BMD (2.6% versus 5.0%, p = .038).

Adherence and BTM and BMD response

Adherence was positively associated with BTM change. At week 22 of risedronate treatment, the proportion of patients achieving a significant reduction (≥30%) in uNTX or sCTX levels from baseline was positively related with the number of doses of risedronate taken over that period (p < .0001; Fig. 3). At week 22, the median percentage reduction in uNTX and sCTX levels was associated with increasing adherence. BMD response was associated with adherence for both spine and hip BMD (p < .0001 and p < .020, respectively), with greater median BMD changes being observed among patients who adhered to therapy better (Fig. 4).

Adherence and fracture incidence

At 52 weeks, no association was detected between adherence to therapy and fracture outcomes. This was confirmed when considering both nonvertebral fractures and all fractures (vertebral and nonvertebral). The association between nonvertebral fractures and both adherence groups (<80% or ≥80%) was 1.9% (p = .9650) at 52 weeks. The potential utility of surrogate markers to identify adherent patients, a good response to therapy, and the risk of fracture (nonvertebral and all fractures) is summarized in Table 3.

Table 3. The Potential Utility of Surrogate Markers to Identify Adherent Patients, Response to Therapy, and Risk of Fracture

Parameter	Greater treatment response
	Bone turnover markers		Bone mineral density
	uNTX	sCTX	Spine	Hip
Reduced fracture risk across the spectrum of adherence (ie, in all patients)
Nonvertebral fractures	+	+	+	−
All fractures	−	+	+	−
Reduced fracture risk in adherent patients
Nonvertebral fractures	+	+	−	−
All fractures	−	+	+	−
Good adherence	+	+	+	+

sCTX = serum C-terminal cross-linked telopeptide of type 1 collagen; uNTX = urinary N-terminal cross-linked telopeptide of type 1 collagen.

Discussion

This secondary analysis of the IMPACT study demonstrated relationships between BTM and BMD changes in response to risedronate therapy and fracture risk and adherence that have potential use in the clinic when tailoring therapy for individual patients. Responses in BTMs (uNTX and sCTX) and BMD (spine and hip) greater than the LSC help to identify patients who are adherent to therapy. Across the spectrum of adherence, reductions in BTMs (uNTX and sCTX) and increases in BMD (spine only; >LSC) help to identify patients with a lower risk of all fractures (nonvertebral and vertebral) and nonvertebral fractures only. Patients with reductions greater than the LSC (≥30%) in BTMs (uNTX and sCTX) showed reduced risk of nonvertebral fractures, whereas patients with good reductions in BTMs (sCTX only) and increases in BMD (spine only) greater than the LSC of 3% showed reduced risk of all fractures (nonvertebral and vertebral).

The observation that changes in BTMs relate to fracture risk reduction is consistent with previous studies of antiresorptive drugs for osteoporosis. BTMs (urinary CTX and uNTX) were associated with reduction in vertebral and nonvertebral fracture risk with risedronate.7 Changes in BTMs were associated with reduction in fracture risk with the bisphosphonates alendronate (bone alkaline phosphatase)41 and zoledronic acid (P1NP).42 BTMs (osteocalcin and P1NP) were associated with the vertebral fracture risk reduction with raloxifene.43, 44

Greater changes in BTM and BMD values were associated with lower fracture risk even if patients with poor compliance were excluded. Thus BTM and BMD response is reflecting fracture risk reduction independently of compliance. Nonetheless, greater BTM and BMD changes are also associated with greater compliance, a finding similar to what has been reported in a smaller study of raloxifene.21

We observed at week 52 that better adherence (ie, >80% compliance) was not associated with decreased fracture risk after 1 year of treatment with risedronate. This is in contrast to previous studies that have demonstrated a positive association between patient adherence and fracture risk.22-24, 35, 45-48 In a recent study, patients who were compliant with strontium ranelate experienced a reduction in nonvertebral and hip fractures compared with patients who were noncompliant.45 In another case-control study performed in Canada, a lower risk of nonvertebral fractures was observed in patients who were compliant with alendronate or risedronate therapy compared with those who were noncompliant.46 The lack of association in this analysis is most likely due to the high adherence in this group of patients; it also may have been because of the short-term nature of the study.

Motivation for patients to adhere to therapy, particularly in the absence of a biologic index of treatment response, still remains a challenge.6 One potential solution is to communicate to patients the therapeutic benefits of good adherence with osteoporosis therapy. In the IMPACT study, physician intervention with evidence of efficacy based on positive changes in BTMs improved patient persistence compared with patients who did not receive BTM response feedback.19 Taken together with the results of this analysis, BTMs in the short term and BMD in the longer term are useful to both physicians and patients. Physicians can use BTMs and BMD to assess the risk of fractures (severity/progression of the disease) and monitor the effectiveness of treatment and use them as surrogate markers of adherence. If physicians can identify patients who are nonadherent, they can use BTM and BMD data to provide encouraging treatment feedback or address any specific motivational issues, both of which should help to motivate patients to continuing medication. More detailed information regarding treatment progress also may help the patients feel more involved in the management of their disease, which is likely to improve outcomes. Overall, these factors may help in reducing fracture risk in postmenopausal women with osteoporosis.

The strengths of this study are that it was large and made use of the licensed dose of risedronate (5 mg/d), and this regime had been shown previously to reduce both vertebral and nonvertebral fracture.15, 16, 49 The adherence was estimated using a reliable method—electronic monitoring. The BTMs, BMD, and vertebral fractures all were measured by central laboratories. The limitations of this study are that adherence was high and so not representative of clinical practice. The duration of treatment was only 1 year, and treatment usually is started with the intention of treating longer than this. Also, we did not have vertebral fracture information on all patients.

In summary, risedronate therapy results in decreases in BTMs and increases in BMD. Decreases in BTMs and increases in spine BMD greater than the LSC are associated with lower risk of vertebral and nonvertebral fractures. These surrogate responses also are associated with greater adherence—adherence can be encouraged when a lesser response is observed. The decreases in BTMs greater than 30% and increases in spine BMD greater than 3% are associated with lower risk of vertebral and nonvertebral fractures, even in patients with high adherence, which indicates heterogeneity of responsiveness to treatment. Therefore, changes in BTMs and BMD not only reflect adherence but also identify differences in individual responsiveness to risedronate.

Disclosures

RE is a consultant for and receives research grant funding from Warner Chilcott Pharmaceuticals, Inc., and sanofi-aventis. BV is a full employee of AARDEX Group, Ltd. DLC is a retired employee of and has stock ownership in sanofi-aventis. JDR is a consultant for Warner Chilcott Pharmaceuticals, Inc., and sanofi-aventis. PG has no financial relationship with any sponsor of this study. NBW is a consultant for and received honoraria from Warner Chilcott Pharmaceuticals, Inc., and sanofi-aventis. The authors received no form of compensation related to the development of this article. Warner Chilcott Pharmaceuticals, Inc., and sanofi-aventis were involved in the study design.

Acknowledgements

Funding for this study and editorial/writing support was provided by Warner Chilcott Pharmaceuticals, Inc., and Sanofi-Aventis.

All the authors were involved in the study design and data interpretation. BV had full access to the raw data on behalf of the other authors and provided statistical support. All authors critically reviewed the manuscript and are fully responsible for all content, editorial decisions, and opinions expressed in this manuscript. All authors agreed to and are responsible for the decision to submit the manuscript. Editorial and writing assistance was provided by Tam Vo and a team from Excerpta Medica.

References

1 World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: report of a WHO Study Group. World Health Organ Tech Rep Ser. 1994; 843: 1–129.
2 Garnero P, Hausherr E, Chapuy MC, et al. Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study. J Bone Miner Res. 1996; 11: 1531–1538.
3 Garnero P, Sornay-Rendu E, Claustrat B, Delmas PD. Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J Bone Miner Res. 2000; 15: 1526–1536.
4 Szulc P, Delmas PD. Biochemical markers of bone turnover: potential use in the investigation and management of postmenopausal osteoporosis. Osteoporos Int. 2008; 19: 1683–1704.
5 Delmas PD, Eastell R, Garnero P, Seibel MJ, Stepan J. Committee of Scientific Advisors of the International Osteoporosis Foundation. The use of biochemical markers of bone turnover in osteoporosis. Committee of Scientific Advisors of the International Osteoporosis Foundation. Osteoporos Int. 2000; 11: S2–17.
6 Delmas PD, Hardy P, Garnero P, Dain M. Monitoring individual response to hormone replacement therapy with bone markers. Bone. 2000; 26: 553–560.
7 Eastell R, Barton I, Hannon RA, Chines A, Garnero P, Delmas PD. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res. 2003; 18: 1051–1056.
8 Chesnut CH 3rd, Bell NH, Clark GS, et al. Hormone replacement therapy in postmenopausal women: urinary N-telopeptide of type I collagen monitors therapeutic effect and predicts response of bone mineral density. Am J Med. 1997; 102: 29–37.
9 Fink E, Cormier C, Steinmetz P, Kindermans C, Le Bouc Y, Souberbielle JC. Differences in the capacity of several biochemical bone markers to assess high bone turnover in early menopause and response to alendronate therapy. Osteoporos Int. 2000; 11: 295–303.
10 Garnero P, Shih WJ, Gineyts E, Karpf DB, Delmas PD. Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J Clin Endocrinol Metab. 1994; 79: 1693–1700.
11 Eastell R, Hannon RA, Garnero P, Campbell MJ, Delmas PD. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate: review of statistical analysis. J Bone Miner Res. 2007; 22: 1656–1660.
12 Bonnick SL, Shulman L. Monitoring osteoporosis therapy: bone mineral density, bone turnover markers, or both? Am J Med. 2006; 119 (4 Suppl 1): S25–S31.
13 Watts NB, Cooper C, Lindsay R, et al. Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate: greater increases in bone mineral density do not relate to greater decreases in fracture risk. J Clin Densitom. 2004; 7: 255–261.
14 Deal CL. Using bone densitometry to monitor therapy in treating osteoporosis: pros and cons. Curr Rheumatol Rep. 2001; 3: 233–239.
15 Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999; 282: 1344–1352.
16 Reginster J, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int. 2000; 11: 83–91.
17 Looker AC, Bauer DC, Chesnut CH 3rd, et al. Clinical use of biochemical markers of bone remodeling: current status and future directions. Osteoporosis Int. 2000; 11: 467–480.
18 Bjarnason NH, Christiansen C. Early response in biochemical markers predicts long-term response in bone mass during hormone replacement therapy in early postmenopausal women. Bone. 2000; 26: 561–569.
19 Delmas PD, Vrijens B, Eastell R, et al. Improving Measurements of Persistence on Actonel Treatment (IMPACT) Investigators. Effect of monitoring bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab. 2007; 92: 1296–1304.
20 Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ. 2008; 17: 1114–1117.
21 Clowes JA, Peel NF, Eastell R. The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial. J Clin Endocrinol Metab. 2004; 89: 1117–1123.
22 Caro JJ, Ishak KJ, Huybrechts KF, Raggio G, Naujoks C. The impact of compliance with osteoporosis therapy on fracture rates in actual practice. Osteoporos Int. 2004; 15: 1003–1008.
23 McCombs JS, Thiebaud P, McLaughlin-Miley C, Shi J. Compliance with drug therapies for the treatment and prevention of osteoporosis. Maturitas. 2004; 48: 271–287.
24 Siris ES, Harris ST, Rosen CJ, et al. Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases. Mayo Clin Proc. 2006; 81: 1013–1022.
25 Imaz I, Zegarra P, González-Enríquez J, Rubio B, Alcazar R, Amate JM. Poor bisphosphonate adherence for treatment of osteoporosis increases fracture risk: systematic review and meta-analysis. Osteoporos Int. 2010; 21: 1943–1945.
26 Lombas C, Hakim C, Zanchetta JR. Compliance with alendronate treatment in an osteoporosis clinic [abstract]. J Bone Miner Res. 2001; 16 (Suppl 1): S529.
27 Solomon DH, Avorn J, Katz JN, et al. Compliance with osteoporosis medications. Arch Intern Med. 2005; 165: 2414–2419.
28 Downey TW, Foltz SH, Boccuzzi SJ, Omar MA, Kahler KH. Adherence and persistence associated with the pharmacologic treatment of osteoporosis in a managed care setting. South Med J. 2006; 99: 570–575.
29 Van Staa TP, Leufkens HGM, Cooper C. Is persistence to bisphosphonate therapy related only to dosing regimen? [abstract]. Osteoporos Int. 2006; 17 (Suppl 1): P282.
30 Cramer JA, Gold DT, Silverman SL, Lewiecki EM. A systematic review of persistence and compliance with bisphosphonates for osteoporosis. Osteoporos Int. 2007; 18: 1023–1031.
31 Weycker D, Macarios D, Edelsberg J, Oster G. Compliance with osteoporosis drug therapy and risk of fracture. Osteoporos Int. 2007; 18: 271–277.
32 Miller NH. Compliance with treatment regimens in chronic asymptomatic diseases. Am J Med. 1997; 102: 43–49.
33 Zyczynski TM, Coyne KS. Hypertension and current issues in compliance and patient outcomes. Curr Hypertens Rep. 2000; 2: 510–514.
34 Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther. 2001; 23: 1296–1310.
35 Huybrechts KF, Ishak KJ, Caro JJ. Assessment of compliance with osteoporosis treatment and its consequences in a managed care population. Bone. 2006; 38: 922–928.
36 Sunyecz JA, Mucha L, Baser O, Barr CE, Amonkar MM. Impact of compliance and persistence with bisphosphonate therapy on health care costs and utilization. Osteoporos Int. 2008; 19: 1421–1429.
37 Genant HK, Wu CY, van Kuijk C, Nevitt MC. Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res. 1993; 8: 1137–1148.
38 Delmas PD, van de Langerijt L, Watts NB, et al. IMPACT Study Group. Underdiagnosis of vertebral fractures is a worldwide problem: the IMPACT study. J Bone Miner Res. 2005; 20: 557–563.
39 Vrijens B, Ringe JD, Watts NB. Electronic monitoring of adherence to therapy in postmenopausal osteoporosis: the IMPACT study. Proceedings of the 30th European Symposium on Calcified Tissues 2003, May 8-12, Rome, Italy.
40 Centers for Disease Control and Prevention (CDC). Osteoporosis among estrogen-deficient women—United States, 1988–1994. MMWR Morb Mortal Wkly Rep. 1998; 47: 969–973.
41 Bauer DC, Black DM, Garnero P, et al. Fracture Intervention Trial Study Group. Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated women: the fracture intervention trial. J Bone Miner Res. 2004; 19: 1250–1258.
42 Delmas PD, Munoz F, Black DM, et al. HORIZON-PFT Research Group. Effects of yearly zoledronic acid 5 mg on bone turnover markers and relation of PINP with fracture reduction in postmenopausal women with osteoporosis. J Bone Miner Res. 2009; 24: 1544–1551.
43 Sarkar S, Reginster JY, Crans GG, Diez-Perez A, Pinette KV, Delmas PD. Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk. J Bone Miner Res. 2004; 19: 394–401.
44 Reginster JY, Sarkar S, Zegels B, et al. Reduction in PINP, a marker of bone metabolism, with raloxifene treatment and its relationship with vertebral fracture risk. Bone. 2004; 34: 344–351.
45 Rabenda V, Reginster JY. Positive impact of compliance to strontium ranelate on the risk of nonvertebral osteoporotic fractures. Osteoporos Int. Published online January 16, 2010; DOI: 10.1007/s00198-009-1155-z.
46 Blouin J, Dragomir A, Moride Y, Ste-Marie LG, Fernandes JC, Perreault S. Impact of noncompliance with alendronate and risedronate on the incidence of nonvertebral osteoporotic fractures in elderly women. Br J Clin Pharmacol. 2008; 66: 117–127.
47 Rabenda V, Mertens R, Fabri V, et al. Adherence to bisphosphonates therapy and hip fracture risk in osteoporotic women. Osteoporos Int. 2008; 19: 811–818.
48 Cotté FE, Mercier F, De Pouvourville G. Relationship between compliance and persistence with osteoporosis medications and fracture risk in primary health care in France: a retrospective case-control analysis. Clin Ther. 2008; 30: 2410–2422.
49 McClung MR, Geusens P, Miller PD, et al. Hip Intervention Program Study Group. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med. 2001; 344: 333–340.

Citing Literature

Volume26, Issue7

July 2011

Pages 1662-1669

Bone turnover markers and bone mineral density response with risedronate therapy: Relationship with fracture risk and patient adherence

Abstract

Introduction