Adverse Gastrointestinal Effects of Alendronate Versus Risedronate in Osteoporosis: A Systematic Review and Meta-analysis

Abstract

Bisphosphonates (BPs; alendronate and risedronate) have been approved as a therapy for osteoporosis. While the efficacy of these drugs appears similar, differences in safety and gastrointestinal tract (GIT) adverse effects are lacking. Consequently, a systematic review and a meta-analysis were carried out reporting on the incidence rate of GIT adverse effects and the safety of alendronate versus risedronate. In this study, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used. This study collected articles from Embase, PubMed, Cochrane library, and Web of Science. Only RCTs that focused on the comparison between alendronate and risedronate in treating patients with osteoporosis were included. Risk ratios (RRs), 95% confidence intervals (CIs), and random-effects model were calculated. This meta-analysis identified 2202 studies including 4151 participants. There were six eligible RCTs. The incidence rate of GIT adverse effects in patients who received alendronate was 20.19%, while the incidence rate in patients who received risedronate was 18.30%. The rate of GIT adverse effects was not significantly different with alendronate compared to risedronate (RR: 1.11; 95% CI: 0.86–1.42; P < 0.44). In this review, the incidence rate of alendronate-associated gastrointestinal (GI) adverse effects was slightly higher than the incidence rate of risedronate-associated GI adverse effects. Although the finding is not statistically significant, switching the patient from alendronate to risedronate may nevertheless lower the incidence rate of GI side effects.

INTRODUCTION

Osteoporosis may increase the risk of fracture due to decreased bone mass density (BMD) and bone tissue.[1,2] Disequilibrium between the cells called osteoblasts, which produce bone tissue, and osteoclasts, which are responsible for bone absorption, can lead to arthritis.[3,4] Osteoporosis may be diagnosed when an individual has a bone mass <2.5 standard deviations from the normal value.[1,5] Clinically, most cases are identified by nontraumatic fractures, especially in the forearm, vertebral column, hip, and wrist.[6] Osteoporosis is considered the most common chronic metabolic bone disease.[7] Annually, there are two million cases of fracture that occurs as a consequence of osteoporosis in the United States.[8] Osteoporosis is strongly related to age, occurring more frequently with aging and most often in the elderly.[9,10] In younger women, BMD remains relatively stable until the menopause period, and with the decrease of estrogen, the incidence of osteoporosis will increase.[6,11] Low peak bone mass and progressive bone loss or both are causes of osteoporosis.[1,12] In addition, diet and exercise play a major role in the incidence of osteoporosis.[13,14] Most of the medications used for the treatment of osteoporosis have an essential role in correcting the imbalance of bone formation by osteoblasts and bone resorption by osteoclasts.[6,15] Estrogen, calcitonin, calcitriol, sodium fluoride, and bisphosphonate (BP) treatments have reported an increase in bone mass. Trials of some of these drugs have reported a decrease in vertebral fracture incidence.[16,17] BPs are considered primary drugs used to correct the imbalance in bone formation.[18,19] In Randomized Controlled Trials (RCTs), BP use for the long term showed improvement of BMD and a decrease in the risk of fracture.[20] This study will focus on the BP group, particularly alendronate and risedronate. Alendronate (alendronic acid) is a nitrogen-containing BP, which inhibits bone resorption by osteoclasts by binding to bone surfaces.[21,22] Indeed, a decrease in bone turnover to normal premenopausal levels is one of the beneficial effects of alendronate.[23] Notably, there is evidence of an increase in bone mineral density of the spine, hip, and total body in women with osteoporosis when taking daily treatment with oral alendronate for 3 years.[24,25] In addition, there was an association with lowering the incidence of vertebral fractures, deformities, and loss of height.[26,27] Another study also demonstrated that there was a significant decrease in morphometric, clinical vertebral fractures, and other clinical fractures when women with low bone mass were taking alendronate.[28,29] Some studies stated that there was a 44% decrease in radiographic vertebral fracture when taking alendronate.[30,31] Risedronate, also known as risedronic acid, can inhibit bone absorption by the inhibition of osteoclasts.[32] Risedronate has been reported to decrease fractures in postmenopausal osteoporosis. Risedronate has also been used to treat Paget’s disease and prevents corticosteroid-induced bone loss.[33,34] Notably, risedronate has been reported to drastically increase bone mineral density in the spine and hip within 6 months of use.[35,36] Indeed, risedronate can decrease vertebral fractures by 49% and the nonvertebral fractures by 33% over 3 years.[37,38] Although risedronate and alendronate share similar mechanisms of action, they have several differences. For example, the increase in bone mineral density and decrease in turnover marker levels in patients on alendronate is more marked than those on risedronate.[39] This study highlights the incidence rate of gastrointestinal (GI) adverse effects between the alendronate and risedronate and the safety of those drugs.

METHODOLOGY

Search strategy

PubMed, EMBASE, Cochrane Library, and Web of Science were searched to retrieve all relevant articles until October 2024. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines were used to collect all articles about alendronate and risedronate and their GI adverse effects [Figure 1].[40] Then, the articles that matched with our inclusion and did not match with the exclusion criteria were included in this systematic review and meta-analysis. Searching using the search terms “Alendronate,” “Risedronate,” and “Gastrointestinal Manifestations.” Literature retrieval was restricted to English only, and no restriction was performed on the publication date. Communication with the original authors was done in case of any unclear reported data.

Figure 1.

Flow diagram of the study selection process (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)

Selection criteria

A through literature search was done for studies that compared alendronate versus risedronate on the incidence rate of GI tract (GIT) adverse events. Inclusion criteria were done based on the PICOS (Population, Intervention, Comparison, Outcome, Study design) method.[41] We included only original studies published in English and reporting on GIT adverse effect related to the use of alendronate or risedronate. In this study, the evaluation indicators were GIT adverse events incidence rate related to alendronate and risedronate and the risk ratio (RR). Population: any patients diagnosed with osteoporosis and using alendronate or risedronate for treatment. Intervention/comparison: Alendronate/risedronate. Outcomes: incidence rate of alendronate GIT adverse event compared to risedronate. Study design: Randomized controlled trials (RCTs). The exclusion criteria of the study were as follows: non-English studies. Duplicate studies: Case reports and review articles.

Data extraction

Eligible studies were assessed, and the following information was gathered: author name, year of publication, study location, study design, study title, patient count, and course duration. The data extraction process was carried out independently by two reviewers (H. Karrar and Y. Nouh). Any disagreements were addressed by a third reviewer (R. Alhendi).

Data analysis and risk of bias

Mantel–Haenszel RRs along with 95% confidence intervals (CIs) were calculated using random-effects models. P < 0.05 was considered statistically significant. The quality of each individual study was evaluated using the Cochrane Collaboration’s tool for assessing risk of bias.[42] All these analyses were carried out using Review Manager (RevMan is a program developed by Cochrane Collaboration Company, registered in England and Wales). RevMan is a tool developed by the Cochrane Library for creating and maintaining reviews that encompass language, research characteristics, comparison tables, and study data. It is capable of performing a meta-analysis on the provided data and visually presenting the results.

RESULTS

Results of literature search

A total of 2202 studies were initially identified. A total of 2196 studies were excluded after a screening of titles and abstracts. After thorough review of the remaining articles, the authors decided to include six studies in this systematic review and meta-analysis.[39,44,45,46,47,48] These studies including 4151 patients who met the inclusion criteria for systematic review and meta-analysis. The selection process is shown in Figure 2.

Figure 2.

Quality assessment of the included studies

Study characteristics

The characteristics of the six included studies are summarized in Table 1. The studies were conducted on more than 78 continents. The mean or median patient age ranged from 53 to 72 years. Four studies focused patients who are women with osteoporosis[39,43,44,47] and two studies included any hospitalized patient with osteoporosis.[44,46,48] The duration of drug therapy ranged from 14 days to 24 months. The alendronate dose used was 10 mg/day[45,47] or 70 mg/week,[39,43,44,46,48] and the risedronate dose was 5 mg/day[44,45,47] or 35 mg/week.[39,45,46,48] Table 2 shows the characteristics of patients. The mean age of the included patients was 63.36 years.[39,44,45,46,47,48] The mean age since menopause was 18.5 years.[39,43,44,46,48] 90.7% of the patients were Caucasian.[39,43,44,47] Two studies included patients who consumed alcohol,[45,47] and two studies included patients who were smokers.[45,47]

Table 1.

Summary of the studies meeting the eligibility criteria

Study	Study design	Funding source	Location	Number patient	Patient characteristics	Alendronate versus risedronate	Duration
Bonnick S[43]	Multicenter, RCT, double-blind	Not mention	72 U.S sites	411 versus 414	Women were eligible to enter the extension study if they completed the original 12-months study	70 mg alendronate Once weekly versus risedronate 35 mg once weekly	24 months versus 24 months
Hosking D[39]	Multicenter, RCT, double-blind	Funded by Merck and Co., Inc.	37 sites	219 versus 222	Female, primarily Caucasian (99.5%), with a mean age of 69 years	70 mg alendronate once weekly versus risedronate 5 mg once daily	12 months versus 12 months
Lanza FL[45]	Multicenter, RCT, double-blind	Not mention	10 US sites	231 versus 227	Postmenopausal, nonsmokers, abstain from vitamin or mineral or aspirin during the study	10 mg alendronate once daily versus risedronate 5 mg once daily	15 days versus 15 days
Reid DM[38]	Multicenter, RCT, double-blind	Funded by Merck and Co., Inc.	75 international sites	403 versus 395	Women eligible enter the study in begin treatment within 7 days after their final year 1 study visit	70 mg alendronate once weekly versus risedronate 35 mg once weekly	24 months versus 24 months
Rosen CJ[46]	Multicenter, RCT, double-blind	Merck, NPC, Novartis companies	78 U.S sites	520 versus 533	postmenopausal at 40 years who had low body mass index at least one of four sites	70 mg alendronate once weekly versus risedronate 35 mg once weekly	12 months versus 12 months
Thomson AB[47]	Multicenter, RCT, double-blind	Not mention	7 U.S and Canada sites	317 versus 318	Healthy postmenopausal women at least 40 years of age were had a normal esophageal	10 mg alendronate once daily versus risedronate 5 mg once daily	14 days versus 14 days

RCT=Randomized controlled trial

Table 2.

Patient demographics and baseline characteristics

Study	Bonnick S[43]		Hosking D[39]		Lanza FL[45]		Reid DM[38]		Rosen CJ[46]		Thomson AB[47]
	Alendronate	Risedronate	Alendronate	Risedronate	Alendronate	Risedronate	Alendronate	Risedronate	Alendronate	Risedronate	Alendronate	Risedronate
Age (year), mean	64	64	69.2	68.9	54	53	64.3	63.6	64.2	64.8	54.7	54.8
Years since menopause	20.1	20.1	20.8	20.3	-	-	16.8	16.4	18.3	18.7	-	-
Race (% Caucasian)	95	95	99.1	99.5	-	-	79.7	78.3	-	-	88	86.5
Previous alcohol consumption (%)	-	-	-	-	12.7	14.9	-	-	-	-	40.3	31.4
Hip trochanter	−1.7	−1.7	-	-	-	-	−1.55	−1.60	−1.58	−1.58	-	-
Femoral neck	−2.2	−2.2	-	-	-	-	−1.64	−1.69	−1.76	−1.78	-	-
Total hip	−1.8	−1.8	-	-	-	-	−2.08	−2.14	−2.12	−2.16	-	-
PA lumbar spine	−2.2	−2.2	-	-	-	-	−2.64	−2.65	−2.26	−2.23	-	-
Previous tobacco consumption	-	-	-	-	30.0	37.3	-	-	-	-	40.4	31.4

PA=Posteroanterior

Study outcome

The incidence rate of GIT adverse effects in patients who received alendronate was 20.19%, while the incidence rate in patients who received risedronate was 18.30%. The rate of GIT adverse effects was not significantly different with alendronate than with risedronate (RR: 1.11; 95% CI: 0.86–1.42; P < 0.44) as shown in Figure 3.

Figure 3.

A forest plot illustrating the risk rations for gastrointestinal tract side effects associated with Alendronate in comparison to Risedronate

DISCUSSION

Adverse effects may be gastric or duodenal perforations, ulcers, and bleeding. This meta-analysis of RCTs confirms a little different in rate of GIT adverse effects, occurring in approximately one-fifth of patients treated with alendronate or risedronate regimens. However, individual studies have described incidences ranging from 15% up to 30%. This variability is due to diversity of patient populations, ranges of doses used, duration of the treatments, the differences in severity of the illness, and the presence of potential confounders such as concomitant use of other agents that may cause GIT adverse effects. In addition, we analyzed only studies that were randomized controlled studies. There are several risk factors including advanced age, presence of chronic comorbid conditions, gender, diet, and estrogen level which contributed to risedronate and alendronate-induced GI adverse effects.[6,9] In this study, the mean/median age of patients in most included studies was above 60 years of age, and the average baseline years since menopause was around 20 years. Other patient-specific data were not uniformly reported in the included studies. The risk for GIT adverse effects may also be associated with the duration of risedronate or alendronate therapy. There are several strengths to this analysis. We included only randomized controlled studies. All studies included were double-blinded. In addition, the population was representative of patients from more than 78 continents, and the sample size for each study was large. Several limitations related to this study are worthy of consideration. The RCTs used variable doses for alendronate and risedronate, which can make clinical application challenging. There is a possibility that alendronate or risedronate-associated GIT adverse effects incidence was inflated due to patients’ ages as all were above 60 years of age, consumption of alcohol, and consumption of tobacco. The overall sample size in this analysis was relatively small, and no significant differences were found between the two groups in the percentage of patients who received alendronate and risedronate. Direct comparison between alendronate and risedronate needs further studies to identify. Finally, there was insufficient detail to examine the progression and resolution of GIT adverse effects along a continuum among the individual studies.

CONCLUSION

In this meta-analysis, the incidence rate of alendronate-associated GI adverse effects was found to be slightly higher than the incidence rate of risedronate-associated GI adverse effects. Although the finding is not statistically significant, switching the patient from alendronate to risedronate may nevertheless lower the incidence rate of GI side effects.

Ethical approval

An ethical approval statement is not applicable, because this study is based exclusively on published literature.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.