Alendronate improves bone mineral density in primary biliary cirrhosis: A randomized placebo-controlled trial

Authors


  • Potential conflict of interest: Nothing to report.

  • This work was presented, in part, at Digestive Disease Week 2004, May 15–20, 2004, New Orleans, LA.

Abstract

Bone loss is a well-recognized complication of primary biliary cirrhosis (PBC). Although it has been suggested that alendronate might improve bone mineral density (BMD) in PBC, no randomized placebo-controlled trial has been conducted. The primary aim of this study was to compare the effects of alendronate versus placebo on BMD and biochemical measurements of bone turnover in patients with PBC-associated bone loss. We conducted a double-blinded, randomized, placebo-controlled trial. Patients with a PBC and BMD t score of less than −1.5 were randomized to receive 70 mg per week of alendronate or placebo over 1 year. BMD of the lumbar spine and proximal femur were measured at entry and at 1 year. Changes from baseline in BMD and biochemical measurements of bone turnover were assessed. Thirty-four patients were enrolled. Seventeen patients were randomized to each arm. After 1 year, a significantly larger improvement (P = .005) in spine BMD was observed in the alendronate group (0.09 ± 0.03 g/cm2 SD from baseline) compared with the placebo group (−0.003 ± 0.02 g/cm2 SD from baseline). A larger improvement (P = .046) was also observed in the femoral BMD of alendronate patients versus placebo. BMD changes were independent of concomitant estrogen therapy. The rate of adverse effects was similar in both groups. In conclusion, in patients with PBC-related bone loss, alendronate significantly improves BMD compared with placebo. Although in this study oral alendronate appears to be well tolerated in patients with PBC, larger studies are needed to formally evaluate safety. (HEPATOLOGY 2005;42:762–771.)

Primary biliary cirrhosis (PBC) is often associated with decreased bone mass and consequent development of osteoporosis.1–5 The rate of bone loss in patients with PBC is approximately twice that of matched controls.3 Approximately 20% to 35% of patients with PBC have significant bone loss by bone mineral density (BMD) measurements.4, 5

The cause of bone loss in PBC is not well understood. Reduced bone formation rates due to decreased osteoblast function have been demonstrated in patients with PBC.6 Increased bone resorption has also been suggested as a contributing mechanism in PBC-related bone disease, as elevations in serum and urinary markers of bone resorption have been found in these patients.7, 8

No specific therapy for PBC-related bone loss has been definitely established. Ursodeoxycholic acid is of no benefit on the BMD of patients with PBC.4, 9 Similarly, studies involving multiple other agents have failed to show any definitive effect in preventing PBC-related bone loss. These studies have included 25-hydroxy vitamin D,10 calcitonin,11 sodium fluoride,12 and etidronate,13 among others. Possible benefits of calcitriol14 and vitamin K215 on the BMD of patients with PBC have been suggested but still require further study. Estrogen replacement therapy has been shown to improve BMD in postmenopausal women with PBC.16 However, because the Heart and Estrogen/progestin Replacement Study and the Women's Health Initiative trials showed an increased risk of venous thromboembolism without any cardioprotective effects in women on hormone therapy,17–19 the use of hormone replacement therapy cannot be recommended.

Biphosphonates are effective agents for the treatment of postmenopausal osteoporosis. These agents are selectively taken up by mineral surfaces in bone and inhibit osteoclast-mediated bone resorption. However, a prospective study comparing the biphosphonate etidronate with placebo did not show a benefit on the BMD of patients with PBC.13 Pamidronate and alendronate are nitrogen-containing biphosphonates and are both more potent than etidronate. Intravenous pamidronate before and after liver transplantation decreased the incidence of symptomatic vertebral fractures in patients with chronic cholestatic liver disease.20 Alendronate improves BMD in postmenopausal women and is safe for long-term use based on a prospective 10-year study.21 However, in patients with PBC, data on the effects of alendronate in BMD are very limited. One study reported statistically significant improvement of BMD in patients with PBC who received alendronate for 1 year compared with etidronate.22 However, that study was not placebo-controlled, and there was no blinding of the therapeutic arms. It is clear that randomized, double-blinded, placebo-controlled trials of alendronate for bone loss in patients with PBC are required.

The primary aim of this study was to compare the efficacy of alendronate with placebo in patients with PBC-associated bone loss. The main end point selected to assess this aim was a significant improvement in BMD. Vertebral fracture rate and measurements of biochemical markers of bone turnover were also assessed. A secondary aim was to describe the rate of adverse events in patients with PBC receiving alendronate compared with placebo.

Abbreviations

PBC, primary biliary cirrhosis; BMD, bone mineral density; NTx, amino telopeptide of type I collagen of bone matrix.

Patients and Methods

Selection of Patients.

Patients were considered for the study if they had a well-established diagnosis of PBC supported by positive antimitochondrial antibodies (≥1:40) and liver biopsy, as well as evidence of bone loss evidenced by a lumbar spine (L2-L4) BMD t score below −1.5.

Other inclusion criteria were (1) an estimated survival based on a Mayo Risk Score23 of more than 80% at 2 years, (2) age between 18 and 70 years, and (3) the ability to give written informed consent. Patients were excluded if they had a history of peptic ulcer disease, known esophageal varices, creatinine levels of more than 1.8 mg/dL, thyroid disease or had used medications known to affect bone metabolism within 6 months of entry into the study (including calcitonin, sodium fluoride, corticosteroids, testosterone, vitamin D in excess of 1,000 IU/d, chronic heparin, diphenyl hydantoin, carbamazepine, or phenobarbital). Patients were excluded if they had started estrogens within 1 year or had stopped estrogens within the previous 6 months. To exclude patients in whom the decreased bone density could be due to osteomalacia, cases with low serum 25-OH vitamin D or elevated parathyroid hormone were excluded. Patients with clinical evidence of decompensated liver disease (ascites, hepatic encephalopathy, or significant coagulopathy indicated by INR > 1.8) were also excluded.

Study Design and Organization.

The study was conducted as a double-blind, randomized, placebo-controlled trial and was approved by the Mayo Clinic and Foundation institutional review board. Written informed consent was obtained from all subjects before enrollment. Enrollment occurred between June 2001 and September 2003. A table with random entries assigned for alendronate or placebo was created in the Clinic's department of statistics; this table was kept by the pharmacy. As the patients were enrolled in the trial, each patient was entered onto a new line and received that particular treatment assignment. The randomization sequence was not concealed from the Pharmacy personnel, but only Pharmacy study personnel had access to the table. The Pharmacy study personnel had minimal contact with the study caregivers, and followed specific precautions so as to not compromise blinding. Patients and study caregivers (physicians or study coordinators) who had contact with the patients or with the database were blinded to the treatment assignment of each patient. Double-blinding was maintained throughout the duration of the randomization phase. The trial was completed in September 2004.

Patients were assigned to one of two study groups. Patients on the treatment group received a standard oral dose of 70 mg/wk of alendronate. To simplify intake and decrease the risk of esophageal side effects as well as improve compliance, a once-weekly 70-mg alendronate formulation was selected for use. This formulation is equivalent to 10 mg alendronate once daily with regard to effects on BMD and biochemical markers of bone turnover.24, 25 In the placebo group, placebo was substituted for the alendronate. Both formulations were white, oblong pills with no markings, no discernible odor, and no difference to taste. All patients received calcium (1,000 mg/d orally) and vitamin D (5,000 U/wk orally).

Patients were contacted every 3 months by the study coordinator. Compliance was assessed by directly asking the patients whether they were taking their medication and, if so, how they were tolerating it.

Clinical history and physical examination were completed in every patient at entry and at 1 year. BMD measurement of the lumbar spine (L2-L4) and proximal femur were obtained at entry and at 1 year, as well as anterior–posterior and lateral thoracic and lumbar spine X-rays. Laboratory studies were also obtained at entry and at 1 year, including chemistry group, complete blood count, calcium, alkaline phosphatase, aminotransferases, albumin, prothrombin time, sensitive thyroid-stimulating hormone, serum 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, parathyroid hormone (PTH), and urinalysis. Markers of bone turnover were measured at entry, at 6 months, and at 1 year. Specifically, osteocalcin levels and urinary excretion of the amino telopeptide of type I collagen of organic bone matrix (NTx) were measured.

Adverse experiences were monitored and recorded throughout the study. On the basis of the adverse event profile of alendronate, the potential for severe esophageal adverse effects was carefully monitored for. Patients considered at risk of having esophageal varices, specifically those with a Mayo risk score above 4.1,26 underwent esophago-gastroduodenoscopy to rule out varices before starting therapy, unless this had been performed within 6 months before enrollment. Repeat upper endoscopy was performed in any patient who developed symptoms suggestive of esophagitis or peptic ulcer disease, or whose Mayo risk score rose >4.1 during the course of the study.

Assessment of Efficacy.

The primary end point was a greater improvement in BMD after 1 year of alendronate therapy compared with placebo. Other efficacy end points included a lesser vertebral fracture rate, as well as a greater decline in markers of bone turnover in the alendronate arm.

Bone Mass and Fracture Assessment.

BMD measurements of the lumbar spine (L2-L4) and proximal femur (neck, greater trochanter, and Ward's triangle) were measured via dual X ray absorptiometry. The scans were analyzed and interpreted by musculoskeletal radiologists. BMD values were obtained as a real density and expressed as grams per centimeters squared.

Lateral radiographs of the thoracic and lumbar spine performed at baseline and at 1 year of treatment were read at the time of performance by general radiologists in accordance with institutional standard procedures. After trial completion, a specialized musculoskeletal radiologist (D. E. W.), blinded to each patient's treatment group, reviewed all spine X rays. This was done with specific attention to evidence of new compression fractures or worsening of previously existent compression fractures at 1 year compared with baseline. Vertebral compression fracture was defined as a reduction of 20% or more in the anterior, middle, or posterior height of the vertebral body.27 Occurrence of peripheral fractures was also noted during the study.

Biochemical Markers of Bone Turnover.

Osteocalcin as an index of bone formation, and urinary NTx as an index of bone resorption, were measured at entry, at 6 months, and at 1 year. High osteocalcin levels are evidence of increased bone turnover in patients with bone loss.28, 29 Similarly, urinary NTx is considered one of the most sensitive biochemical markers of bone resorption and has been successfully used to monitor the effectiveness of osteoporosis therapy.28, 30 Both markers were measured using commercially available and previously validated techniques. Osteocalcin was assessed using the Osteo-Riact kit (CIS Bio International, Bedford, MA). A 24-hour urine collection was performed for quantitative measurement of NTx. For this purpose, the Vitros NTx kit (Ortho-Clinical Diagnostics, Johnson & Johnson, Amersham, Bucks, UK) was used.

Sample Size Calculation and Statistical Analysis.

Sample size calculations were made to detect a clinically important difference between treatment groups regarding BMD change. A SD of 0.061 g/cm2 for BMD over 1 year was estimated from the literature.8, 13, 31 An expected improvement of 0.04 g/cm2 in BMD over 1 year in the treated group and an expected deterioration of −0.02 g/cm2 in the placebo group were assumed. Based on these assumptions, a total sample size of 34 (17 patients per group) would provide 80% power to detect a significant difference (0.06 g/cm2) at 1 year between the BMD change from baseline in the treated group and the BMD change in the placebo group. The alpha level was set at 0.05. To allow for an estimated dropout rate of 15%, a total sample size of 40 patients was projected.

However, study enrollment stopped at 34 patients. This was an indirect result of the publication of the Women's Health Initiative and the Heart and Estrogen/progestin Replacement Study results,17–19, 32 which led to discontinuation of hormone replacement therapy by numerous women. Because patients who had stopped estrogens within 6 months could not be considered for our study per the exclusion criteria, continued accrual was severely hampered and enrollment was subsequently stopped.

The study coordinator entered the data into a spreadsheet program. To protect the double-blind nature of the study, access to the patient database was limited and did not include the principal investigator or the coinvestigators until trial completion. Intention-to-treat analysis was performed. Baseline variables were compared to assess differences between groups. Continuous data were analyzed using the Student t test if normally distributed and using nonparametric tests otherwise. Categorical data were analyzed using the χ2 test or Fisher exact test. Analyses of the efficacy end points were performed using a two-sample t test to assess differences between the placebo and treatment groups and a paired t test to assess changes between time points within each group. The direct estimates of treatment effects were also obtained by calculating the contrast in mean change between treatment groups along with 95% CIs. All statistical tests were two-sided, and an alpha level of 0.05 was chosen to indicate a significant difference. All results are expressed as the mean ± SD.

Results

Patient Characteristics.

Thirty-four patients were enrolled in the study. The average age was 61 years, and 32 (94%) of the patients were women. Seventeen patients were randomly assigned to each group (Fig. 1). In the alendronate group, 15 patients completed the trial and 2 withdrew; in the placebo group, 13 patients completed the trial and 4 withdrew. Among the 2 alendronate-treated patients who withdrew, one did so for unknown reasons after taking 6 months of therapy (severed contact). The other patient was told to stop therapy by the physician after gastritis and antral erosions were found on endoscopy in the setting of anemia. Among the 4 placebo group patients who withdrew, 1 never started therapy for unknown reasons, 2 stopped therapy because of abdominal discomfort and fullness, and 1 stopped after 6 months because of frustration with an inability to collect a 24-hour urine sample.

Figure 1.

Patient flow diagram illustrating the two study groups.

Both groups were comparable at entry regarding demographics and blood tests (Table 1). A higher prevalence of histologically advanced disease (fibrosis stages 3-4) was seen in the alendronate group compared with the placebo group (47% vs. 18%; P = .07). Both groups were comparable regarding lumbar and femoral BMD, biochemical markers of bone turnover, smoking history, and use of estrogen replacement therapy.

Table 1. Baseline Characteristics of 34 Patients With PBC Randomly Assigned to Alendronate or Placebo
Baseline CharacteristicsAlendronate (n = 17)Placebo (n = 17)P Value
  • NOTE. All values are expressed as the mean ± SD unless noted otherwise. Abbreviations: PBC, primary biliary cirrhosis; NTx, amino telopeptide of type I collagen of bone matrix; PTH, parathyroid hormone; sTSH, sensitive thyroid-stimulating hormone; BMD, bone mineral density.

  • *

    History of smoking was defined as a lifetime history of at least 5-pack-years.

Age (yrs)60.9 ± 7.3962 ± 8.22.68
Female sex, n (%)15/17 (88.2)17/17 (100).14
Years since PBC diagnosis10 ± 4.810.3 ± 4.6.86
History of smoking,* n (%)10/17 (59)9/17 (53).73
Postmenopausal (among women), n (%)14/15 (93)16/17 (94).93
Bilirubin (mg/dL)0.57 ± 0.250.6 ± 0.22.70
Albumin (g/L)3.8 ± 0.223.9 ± 0.19.12
Prothrombin time (s)9.2 ± 0.629.5 ± 1.19.40
Aspartate aminotransferase (U/L)50.8 ± 4330.3 ± 6.9.07
Alkaline phosphotase (U/L)450 ± 387360 ± 150.40
Advanced liver fibrosis—stages 3–4, n (%)8/17 (47)3/17 (18).07
Creatinine (mg/dL)1.0 ± 0.141.1 ± 0.21.60
NTx-telopeptide (nmol/mmol Cr)23.7 ± 11.327.7 ± 10.5.30
Osteocalcin (ng/mL)17.8 ± 7.423.7 ± 10.6.09
25-OH vitamin D (ng/mL)28.9 ± 12.227.6 ± 8.9.74
PTH (pmol/L)3.19 ± 1.683.59 ± 3.73.70
sTSH (mIU/L)3.17 ± 2.183.05 ± 2.36.90
Estrogen use, n (%)11/17 (65)10/17 (59).72
Vertebral fractures at baseline, n (%)8/17 (47)5/15 (33.3).43
Lumbar spine BMD (g/cm2)0.92 ± 0.150.94 ± 0.11.78
Proximal femur BMD (g/cm2)0.77 ± 0.070.80 ± 0.09.24

Among the 28 patients who completed the trial (15 in the alendronate group and 13 in the placebo group), most baseline characteristics were also comparable at entry (Table 2). However, similar to the trend observed in the full study group, a higher prevalence of histologically advanced disease was observed in the alendronate group compared with placebo (47% vs. 8%; P = .02).

Table 2. Baseline Characteristics of 28 Patients With PBC Who Completed the Trial After Being Randomly Assigned to Alendronate or Placebo
Baseline CharacteristicsAlendronate (n = 15)Placebo (n = 13)P Value
  • NOTE. All values are expressed as the mean ± SD unless noted otherwise. Abbreviations: PBC, primary biliary cirrhosis; NTx, amino telopeptide of type I collagen of bone matrix; PTH, parathyroid hormone; sTSH, sensitive thyroid-stimulating hormone; BMD, bone mineral density.

  • *

    History of smoking was defined as a lifetime history of at least 5-pack-years.

Age (yrs)59.8 ± 6.9461.9 ± 9.14.49
Female sex, n (%)14/15 (93)13/13 (100).34
Years since PBC diagnosis10.4 ± 4.9810.3 ± 5.3.90
History of smoking,* n (%)9/15 (60)6/13 (46).46
Postmenopausal (among women), n (%)13/14 (93)12/13 (92).96
Bilirubin (mg/dL)0.56 ± 0.260.59 ± 0.23.73
Albumin (g/L)3.9 ± 0.203.9 ± 0.18.35
Prothrombin time (s)9.1 ± 0.69.6 ± 1.3.23
Aspartate aminotransferase (U/L)52.6 ± 45.830.5 ± 7.6.10
Alkaline phosphatase (U/L)475 ± 407368 ± 162.38
Advanced liver fibrosis—stages 3–4, n (%)7/15 (47)1/13 (8).02
Creatinine (mg/dL)1.0 ± 0.121.1 ± 0.22.30
NTx-telopeptide (nmol/mmol Cr)23.5 ± 11.928.8 ± 10.1.21
Osteocalcin (ng/mL)18.2 ± 7.525.7 ± 11.0.07
25-OH vitamin D (ng/mL)29.9 ± 11.928.8 ± 9.5.81
PTH (pmol/L)2.95 ± 1.563.85 ± 4.21.46
sTSH (mlU/L)2.91 ± 1.973.13 ± 2.61.94
Estrogen use, n (%)11/15 (73)6/13 (46.2).14
Vertebral fractures at baseline, n (%)7/15 (46.7)5/13 (38.5).66
Lumbar spine BMD (g/cm2)0.91 ± 0.150.94 ± 0.13.55
Proximal femur BMD (g/cm2)0.77 ± 0.070.80 ± 0.10.37

Efficacy.

The primary end point was a greater improvement in BMD at 1 year in the alendronate group compared with placebo. At 1 year, a significantly greater improvement in both lumbar spine BMD and proximal femur BMD was observed among patients receiving alendronate compared with placebo (Fig. 2). The mean absolute lumbar spine BMD change from baseline (BMD at 1 year − baseline BMD) was 0.09 ± 0.08 g/cm2 in the alendronate group compared with −0.003 ± 0.05 g/cm2 in the placebo arm (P = .005). The direct estimate of treatment effect at the lumbar spine was 0.09 g/cm2 (95% CI: 0.027, 0.15). The mean absolute proximal femur BMD change from baseline was 0.012 ± 0.04 g/cm2 in the alendronate arm, compared with −0.019 ± 0.04 g/cm2 in the placebo arm (P = .046). The direct estimate of treatment effect at the femoral neck was 0.03 g/cm2 (95% CI: 0.00073, 0.06) (Table 3).

Figure 2.

Mean absolute change in BMD after 1 year in patients who received alendronate versus placebo. Standard deviations of the mean absolute changes are presented in Table 3. Change in BMD was calculated via subtraction (BMD at 1 year − baseline BMD). BMD, bone mineral density.

Table 3. Mean Lumbar Spine (L2–L4) and Proximal Femur BMD (g/cm2) at Baseline and at 1 Year in Patients With PBC Who Received Alendronate or Placebo for 1 Year
 Baseline BMD1-Year BMDMean Absolute BMD Change From BaselineMean Percent BMD Change From BaselineDirect Estimate of Treatment Effect (95% CI)
  • NOTE. Mean absolute and mean percentage changes in BMD from baseline are shown. The direct estimate of treatment effect (contrast of mean change in BMD between treatment groups), along with 95% CI, is also shown. Abbreviation: BMD, bone mineral density.

  • *

    A paired t test was used to compare lumbar and proximal femur BMD at the two time points within each group. Lumbar spine BMD within the alendronate group was different at 1 year compared with baseline (P = .003). There was no significant difference in lumbar spine BMD within the placebo group (P = .8). The changes within group in the proximal femur of the alendronate and placebo groups did not reach statistical significance by paired t test (P = .2 and P = .1, respectively).

  • Based on two-sample t tests used to compare means or mean changes between alendronate and placebo groups.

Lumbar spine    0.09 (0.027, 0.15)
 Alendronate0.92 ± 0.15*1.00 ± 0.14*0.09 ± 0.0810.4% 
 Placebo0.94 ± 0.11*0.93 ± 0.1*−0.003 ± 0.05−0.12% 
 P valueNS (P = .78)NS (P = .18).005.005 
Proximal femur    0.03 (0.00073, 0.06)
 Alendronate0.77 ± 0.07*0.79 ± 0.09*0.012 ± 0.041.4% 
 Placebo0.80 ± 0.09*0.79 ± 0.08*−0.019 ± 0.04−2.1% 
 P valueNS (P = .24)NS (P = .98).046.06 

No significant difference was observed in the number of new compression fractures among patients who received alendronate versus placebo. New compression fractures were observed in 1 (7.1%) of 14 alendronate patients and 0 (0%) of 13 placebo patients (P = .3). Among those patients who had vertebral compression fractures at baseline, radiologically evident worsening of already existing compression fractures was observed in 1 (25%) of 4 placebo patients and 0 (0%) of 8 alendronate patients (P = .14). During the study, occurrence of a peripheral fracture (hip) was observed in 1 patient on the placebo arm.

Therapy with alendronate was associated with a more pronounced decrease in biochemical markers of bone turnover compared with placebo. At baseline, there was no significant difference regarding the levels of osteocalcin or NTx between treatment arms. However, at 6 months and at 1 year, statistically significant differences were observed regarding the levels of both markers between the alendronate and placebo groups (Table 4). The change in osteocalcin levels was statistically significant within the alendronate group patients when levels at 1 year were compared with levels at baseline via paired t test analysis (P = .007). The mean percentage change at 1 year in osteocalcin from the baseline level was −21.3% in the alendronate group versus −3% in the placebo group (Fig. 3A). The mean percentage change at 1 year from the baseline level in urinary Ntx was −6.5% in the alendronate group versus 21.1% in the placebo group (Fig. 3B).

Table 4. Mean Values (±SD) of NTx-Telopeptide and Osteocalcin in Patients Who Received Alendronate Versus Those Who Received Placebo Over a 1-Year Period
 Baseline6 Months1 Year
  • NOTE. At baseline, there was no significant difference between the alendronate and placebo group regarding either marker. At 1 year, statistically significant differences were observed in both markers. Abbreviation: NTx, amino telopeptide of type I collagen of bone matrix.

  • *

    Two-sample t test was used to compare mean values between alendronate and placebo groups.

NTx-Telopeptide (nmol/mmol creatinine)   
 Alendronate23.7 ± 11.320.1 ± 11.518.5 ± 8.6
 Placebo27.7 ± 10.527.9 ± 10.134.6 ± 13.8
 P value.3*.06*.003*
Osteocalcin (ng/mL)   
 Alendronate17.8 ± 7.412.5 ± 3.015.0 ± 4.9
 Placebo23.7 ± 10.623.8 ± 9.624.3 ± 8.7
 P value.09*.002*.004*
Figure 3.

(A) Mean percentage changes from baseline observed in osteocalcin (marker of bone formation) levels in patients with PBC receiving alendronate or placebo over a 1-year period. (B) Mean percentage changes from baseline observed in urinary NTx (marker of bone resorption) levels in patients with PBC receiving alendronate or placebo over a 1-year period. NTx, amino telopeptide of type I collagen of bone matrix.

Effects of Estrogen Replacement Therapy.

The proportion of patients on estrogen replacement therapy was similar in both study groups (Table 1). Baseline characteristics of patients on estrogen were not significantly different from those who were not, except for sex in the alendronate group (Table 5). Among patients on estrogen replacement at entry, only one subject (a 67-year-old woman in the alendronate group) discontinued estrogen during the study. Treatment effects remained similar for each outcome of interest after adjusting for concomitant estrogen in multiple linear regression models (Table 6). The P values for treatment effect after adjusting for concomitant estrogen were .005 for spine BMD, .035 for femoral BMD, and .04 for osteocalcin. For NTx, the treatment effect had no statistical significance (P = .09) after adjusting for estrogen therapy.

Table 5. Baseline Characteristics of the Patients in Both Study Groups According to Concomitant Hormone Replacement Therapy Use or Not
Baseline CharacteristicsAlendronate (n = 17)P ValuePlacebo (n = 17)P Value
On HRT (n = 11)No HRT (n = 6)On HRT (n = 10)No HRT (n = 7)
  • NOTE. All values are expressed as the mean ± SD unless noted otherwise. Abbreviation: HRT, hormone replacement therapy. Abbreviations: PBC, primary biliary cirrhosis; NTx, amino telopeptide of type I collagen of bone matrix; PTH, XXX; sTSH, XXX; BMD, bone mineral density.

  • *

    History of smoking was defined as a lifetime history of at least 5-pack-years.

Age (yrs)62.8 ± 4.457.3 ± 10.6.1564.6 ± 6.5958.3 ± 9.4.12
Female sex, n (%)11/11 (100)4/6 (67).0310/10 (100)7/7 (100) 
Years since PBC diagnosis11.5 ± 4.67.2 ± 4.0.0712 ± 4.37.9 ± 4.1.07
History of smoking,* n (%)7/11 (64)3/6 (60).596/10 (60)3/7 (43).49
Postmenopausal (among women), n (%)11/11 (100)3/4 (75).0910/10 (100)6/7 (86).20
Bilirubin (mg/dL)0.57 ± 0.280.57 ± 0.20.960.54 ± 0.190.67 ± 0.25.27
Albumin (g/L)3.8 ± 0.223.9 ± 0.24.853.9 ± 0.233.9 ± 0.14.71
Prothrombin time (s)9.0 ± 0.619.6 ± 0.50.079.7 ± 1.59.2 ± 0.6.41
Aspartate aminotransferase (U/L)51.9 ± 5248.8 ± 26.8932.1 ± 4.928 ± 8.8.25
Alkaline phosphatase (U/L)389 ± 341563 ± 472.39340 ± 73386 ± 219.56
Advanced liver fibrosis—stages 3–4, n (%)5/11 (45)3/6 (50).862/10 (20)1/7 (14).76
Creatinine (mg/dL)1.0 ± 0.131.1 ± 0.16.581.1 ± 0.261.0 ± 0.12.36
NTx-telopeptide (nmol/mmol Cr)22.2 ± 11.926.5 ± 10.3.4625.6 ± 8.130.4 ± 13.1.37
Osteocalcin (ng/mL)16.7 ± 6.220.8 ± 10.6.5120.2 ± 4.728.9 ± 14.9.21
25-OH vitamin D (ng/mL)31.2 ± 12.624.8 ± 11.2.3126.9 ± 7.128.7 ± 11.5.73
PTH (pmol/L)2.85 ± 1.303.82 ± 2.24.273.84 ± 4.63.25 ± 2.6.78
sTSH (mlU/L)3.07 ± 2.263.33 ± 2.26.823.18 ± 1.32.85 ± 3.6.81
Vertebral fractures at baseline, n (%)5/11 (46)3/6 (50).863/8 (37.5)2/7 (28.6).71
Lumbar spine BMD (g/cm2)0.91 ± 0.160.95 ± 0.14.630.93 ± 0.110.95 ± 0.13.73
Proximal femur BMD (g/cm2)0.76 ± 0.080.79 ± 0.06.520.84 ± 0.100.77 ± 0.05.12
Table 6. Results of Multiple Linear Regression Analyses Showing the Significance of the Alendronate Treatment Effect on BMD, NTX, and Osteocalcin After Adjusting for Concomitant Estrogen Use
 βSEP
  1. Abbreviation: BMD, bone mineral density.

Change in spine BMD at 1 year   
 Alendronate0.090.03.005
 Concomitant estrogen therapy−0.030.03.4
Change in femoral BMD at 1 year   
 Alendronate0.030.01.035
 Concomitant estrogen therapy−0.010.02.4
Change in NTx at 1 year   
 Alendronate−10.45.85.09
 Concomitant estrogen therapy3.636.46.58
Change in osteocalcin at 1 year   
 Alendronate−4.632.11.04
 Concomitant estrogen therapy3.542.19.12

Safety and Adverse Events.

The occurrence of adverse experiences was monitored and recorded throughout the study. All patients with adverse events reported gastrointestinal manifestations. An upper endoscopy during the study was performed on any patient who developed symptoms suggestive of esophagitis or peptic ulcer disease. Overall, 4 patients underwent upper endoscopy during the study. All were negative, except for 1 patient who had gastric erosions. Another patient reported concurrent musculoskeletal pain (Table 7). The frequency of adverse events overall was no different in the alendronate group compared with placebo.

Table 7. Reported Adverse Events by Treatment Group
 Alendronate, n (%)Placebo, n (%)P Value
  1. NOTE. A patient may have had more than one symptom within a body system.

Gastrointestinal   
 Any adverse gastrointestinal event3/17 (18)3/16 (19).93
 Abdominal pain1/17 (6)2/16 (13).51
 Nausea0/17 (0)2/16 (13).13
 Abdominal distention1/17 (6)0/16 (0).32
 Heartburn1/17 (6)0/16 (0).32
 Antral erosions and anemia1/17 (6)0/16 (0).32
 Flatulence0/17 (0)1/16 (6).30
Musculoskeletal   
 Bone or joint pain1/17 (6)0/16 (0).32

A 74-year-old man in the alendronate group reported symptoms of fatigue and shortness of breath 3 months after initiating therapy; he was found to have anemia (hemoglobin 7.9 g/dL). An esophago-gastroduodenoscopy demonstrated gastritis with antral erosions. A biopsy for Helicobacter pylori was negative. Besides alendronate, the patient was not on any other medication that could cause gastric mucosal injury; alendronate was discontinued and he recovered satisfactorily. A colonoscopy performed 1 year later for a similar episode of iron deficiency anemia demonstrated a colonic arterio-venous malformation that was treated.

The proportion of patients who discontinued therapy as a result of adverse events (1 patient in the alendronate group, 2 in the placebo group) was no different between treatment groups.

No significant effects regarding clinical and biochemical parameters of liver disease were observed in patients taking alendronate compared with placebo.

Discussion

To date, no definite therapy has been established as proven to prevent bone loss in patients with PBC. This is the first double-blinded, randomized, placebo-controlled trial of alendronate for patients with PBC-related bone loss.

The results of this study clearly demonstrate that alendronate improves BMD in patients with PBC-associated bone loss. The BMD of patients treated with alendronate for 1 year increased significantly at both the lumbar spine and proximal femur compared with placebo. The effects of alendronate on BMD were more pronounced at the lumbar spine, where BMD increased by 10.4%, compared with the proximal femur, where BMD increased only by 1.4%. This concurs with other studies, in both PBC and non-PBC patient populations, in which changes of BMD in patients treated with a biphosphonate were also more evident at the lumbar spine.22, 33

The lumbar BMD improvement in the alendronate arm (10.4%) was better than that observed in other studies of PBC patients treated with daily-dosed alendronate (6%)22 and of postmenopausal patients treated with weekly-dosed alendronate (4%).

The clinical end point of greatest importance in osteoporosis is decrease of fracture risk. To assess this end point directly, very large study populations would be needed. Our study found no difference between the rates of compression fractures in the alendronate group compared with placebo. The antifracture efficacy of alendronate in the postmenopausal population has already been demonstrated in large studies.34, 35 Based on the results of our study regarding BMD and on the established knowledge that an increase in BMD is directly correlated with reduction in vertebral and nonvertebral fractures,36–38 a sufficiently large study would most likely confirm a similar antifracture effect of alendronate in patients with PBC.

As expected, more pronounced decreases in osteocalcin and NTx were seen among patients who received alendronate versus placebo. However, the levels of these markers in the alendronate treatment group did not fall as markedly as we had expected based on the results observed by others.22 It has been shown that in patients with PBC, NTx levels do not accurately correlate with bone turnover.39 Collagen-derived markers of bone turnover are influenced by liver collagen metabolism, and appear to be affected in the setting of extensive liver fibrosis.39 Almost half of the patients in the alendronate group in our study had histologically advanced liver disease (stages 3-4); therefore, the measured markers were probably affected by histological stage and did not adequately reflect changes in bone turnover. Furthermore, it is known that NTx levels are lower in postmenopausal women receiving hormone replacement therapy compared with those not receiving hormones,40 and a large percent of our study patients were on concomitant estrogen therapy.

There was no difference in the rate of adverse events between treatment groups. Gastrointestinal complaints were the main type of adverse event reported. Alendronate has been associated with potentially severe adverse esophageal effects41, 42 in approximately 1.3% of patients.43 To decrease the likelihood of esophageal side effects, a formulation of 70 mg alendronate once weekly was selected for use. No esophageal adverse effects occurred during the study.

One patient in the alendronate group was withdrawn from the study after anemia was discovered and an esophago-gastroduodenoscopy showed gastritis with antral erosions. Therapy was stopped and the patient recovered satisfactorily. Although that patient continued to have episodic iron deficiency anemia during the years following his withdrawal from the study, and this was associated with colonic arterio-venous malformations, we believe that the episode of anemia that occurred during the study was due to gastric mucosal damage secondary to alendronate. Alendronate can be associated with injury of the gastric mucosa.44 The rate of visible gastric mucosal damage caused by alendronate at therapeutic doses ranges between 24% and 38%,45, 46 much less than that observed with aspirin. The rate of potentially clinically significant mucosal damage is lower, ranging from 3% to 25%.46, 47 A trial including 6,459 postmenopausal women recorded the occurrence of severe adverse events (gastroduodenal perforations, ulcers, and bleeding events) and demonstrated a similar rate in the alendronate and placebo groups (1.6% and 1.9%, respectively).48 That study included only female patients. In our study, the only significant adverse event occurred in one man out of 17 patients in the alendronate-treated group (5.8%). Although we have made observations regarding the occurrence of adverse events in the study group and compared observations between treatment groups, larger studies are needed to formally assess the safety of alendronate in patients with PBC. For now, the possibility of severe upper gastrointestinal adverse events is a risk to bear in mind when using alendronate in any patient population.

Because of anecdotal reports of hepatotoxicity caused by alendronate,49, 50 special attention was given to biochemical and clinical parameters of liver disease. No changes of concern occurred in these parameters.

Despite the encouraging results observed regarding the effectiveness of alendronate in patients with PBC-related bone loss, we must also recognize the limitations of the study. One limitation is the relatively small size of the study population. Although a larger sample size was initially calculated as needed to achieve adequate power, the improvement observed in the BMD of the alendronate patients was larger than our original estimate at the time of making sample size calculations. This made achieving statistical significance possible despite a smaller study population.

Another limitation concerns the fact that most of the patients were undergoing concomitant estrogen replacement therapy. This could explain the relatively low rate of bone loss observed in the placebo group, which after 1 year was comparable to that observed in patients with PBC receiving estrogen therapy.16 The high rate of estrogen use likely also influenced the levels of serum markers of bone metabolism. Nevertheless, the proportion of patients on estrogen replacement therapy was comparable in the alendronate and placebo group. In addition, the significantly larger change in BMD in the alendronate group compared with placebo was independent of concomitant estrogen use.

In conclusion, the results of this trial show that alendronate given for 1 year is effective in increasing BMD in patients with PBC-related bone loss. Alendronate appears to be well tolerated in patients with PBC; however, larger studies are needed to formally evaluate safety.

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