569594
research-article2015
AOPXXX10.1177/1060028015569594Annals of PharmacotherapyNyandege et al
Review Article
Risk of Fracture and the Concomitant Use of Bisphosphonates With Osteoporosis-Inducing Medications
Annals of Pharmacotherapy 2015, Vol. 49(4) 437–447 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028015569594 aop.sagepub.com
Abner N. Nyandege, PhD1, Patricia W. Slattum, PhD2, and Spencer E. Harpe, PhD3
Abstract Objective: To review the literature on the concomitant use of bisphosphonates and medications that can influence bone metabolism and potentially attenuate bisphosphonate antifracture efficacy. Data Sources: MEDLINE and CINAHL were searched for articles published in English through December 2014 using the following terms: bisphosphonates, bone density conservation agents, acid-suppressive therapy, levothyroxine, thiazolidinediones (TZDs), selective serotonin reuptake inhibitors (SSRIs), bone fractures. Study Selection and Data Extraction: Studies were included if they reported results of concomitant use of any listed medications with bisphosphonates and risk of fractures and focused on women. Articles that focused generally on the use of one of the listed medications and fractures without explicitly examining the potential antifracture efficacy or attenuation of bisphosphonates were excluded. Data Synthesis: A total of 6 relevant studies were identified. Four epidemiological studies reported a statistically significant dose-dependent increase in the risk of fractures when bisphosphonates and acid-suppressive drugs were used together. One post hoc analysis of clinical trial data suggested no attenuation of the antifracture effects of bisphosphonates when used concomitantly with acid-suppressive therapy. One study involving bisphosphonates and SSRIs noted a statistically significant association between fracture risk and SSRI use. No study examining TZDs or levothyroxine with bisphosphonates was identified. Conclusions: Existing research suggests potential attenuation of bisphosphonate antifracture efficacy among patients taking acid-suppressive medications. Based on their pharmacological actions, TZDs, SSRIs, and levothyroxine have similar implications. The paucity of evidence in the literature associating the attenuation of bisphosphonate antifracture efficacy when combined with other medications suggests that further investigation is needed. Keywords osteoporosis, bisphosphonates, drug interactions, pharmacoepidemiology, drug-induced disorders, medication-induced osteoporosis
Introduction The National Osteoporosis Foundation reports that about 80% of the estimated 10 million Americans with osteoporosis are women. In addition, approximately 1 in 2 women 50 years and older will break a bone because of osteoporosis.1 Bisphosphonates are widely prescribed and recommended by the North American Menopause Society as first-line pharmacological treatment in the management of osteoporosis for postmenopausal women.2,3 These agents are characterized by their affinity for bone mineral through binding to hydroxyapatite crystals4 and their inhibitory effects on osteoclasts.5 Chronic conditions, such as diabetes, depression, or inflammatory joint disease, may increase the severity of osteoporosis and affect the management of osteoporosis by increasing the risk of fracture.6 The management of coexisting chronic conditions or multiple chronic conditions (MCCs)
may further increase the risk of fracture. For example, the management of both osteoporosis and chronic inflammatory joint disease may require concomitant use of medications. Care management of MCCs requires heightened coordination of complex medical and psychosocial care and increased management of medications, which is important because concomitant use of medications may increase the potential 1
Market Access Solutions LLC, Raritan, NJ, USA Virginia Commonwealth University School of Pharmacy, Richmond, VA, USA 3 Midwestern University Chicago College of Pharmacy, Downers Grove, IL, USA 2
Corresponding Author: Spencer E. Harpe, Department of Pharmacy Practice, Midwestern University Chicago College of Pharmacy, 555 31st Street, Downers Grove, IL 60515, USA. Email: [email protected]
Downloaded from aop.sagepub.com at DEAKIN UNIV LIBRARY on March 15, 2015
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Annals of Pharmacotherapy 49(4)
Table 1. Bisphosphonate-Drug Interactions and Adverse Drug Events Listed in Package Inserts. Bisphosphonate
Coadministered Drug(s)
Fosamax (alendronate sodium), Boniva (ibandronate sodium), Actonel (risedronate sodium) Fosamax (alendronate sodium), Boniva (ibandronate sodium), Actonel (risedronate sodium) Boniva (ibandronate sodium), Actonel (risedronate sodium) Reclast (zoledronic acid) Reclast (zoledronic acid)
Nephrotoxic drugs Aminoglycosides
Reclast (zoledronic acid)
Loop diuretics
Outcome
Calcium supplements/Antacids
Interference with drug absorption
Aspirin/Nonsteroidal antiinflammatory drugs (NSAIDS)
May worsen gastrointestinal irritation
H2 receptor antagonists and proton pump inhibitors
May affect oral bioavailability, but interactions are not considered to be clinically relevant Renal failure May have additive effect of lowering serum calcium for prolonged periods May increase risk of hypocalcemia
for clinically important interactions and adverse drug events.7 The US Department of Health and Human Services framework to address the population with MCCs highlights the recognition of drug-drug interactions and potential adverse drug events from complex medication regimens as one strategy for medication management.8 Using the 2000-2002 National Ambulatory Medical Care Survey to examine 25 clinically important drug-drug interactions, Aparasu et al9 found that patients older than 44 years, especially older adults, Medicare beneficiaries, and those prescribed multiple medications, were at risk of receiving concomitant medications with the potential for clinically important drug-drug interactions when compared with patients younger than 25 years of age. Moreover, the study showed that the annualized visit rates involving interacting medications were higher among persons older than 64 years when compared with those younger than 64 years, women compared with men, and Caucasian compared with other races.9 Interestingly, none of the combinations of potentially interacting medications examined in the study included osteoporosis treatment agents such as bisphosphonates. Table 1 outlines the drug-drug interactions included in the prescribing information for FDA-approved bisphosphonates. These are primarily pharmacokinetic interactions (eg, decreased bioavailability when used with proton pump inhibitors [PPIs]) or the potential duplication of similar side effects (eg, worsened gastrointestinal irritation when used with nonsteroidal anti-inflammatory agents). The pharmacodynamic effect of bisphosphonates involves the inhibition of bone resorption through the prevention of osteoclast recruitment, differentiation and activity and also by inducing osteoclast apoptosis.5 Medications associated with osteoporosis and an increased risk of fracture, such as glucocorticoids or PPIs, affect bone by inhibiting osteoblast differentiation and activity, bone formation, and/or increasing bone resorption.10,11 Drug-drug interactions between
Table 2. Medications Associated With Increased Risk of Osteoporotic Fracture. Medication Class Oral glucocorticoids Aromatase inhibitors Selective serotonin reuptake inhibitors Proton pump inhibitors H2 receptor antagonists Thiazolidinediones Thyroid hormones Anticoagulants Anticonvulsants Certain mood stabilizers Gonadotropin-releasing hormones Loop diuretics Certain immunosuppresants Antiretroviral agents
Generic Drug Examples Hydrocortisone, prednisone, dexamethasone Letrozole, anastrozole Citalopram, fluoxetine, paroxetine Esomeprazole, omeprazole, lansoprazole Famotidine, ranitidine, cimetidine Rosiglitazone, pioglitazone Levothyroxine Heparin, enoxaparin, warfarin Phenobarbital, oxcarbazepine, valproic acid Lithium Leuprolide, goserelin Furosemide, bumetanide Methotrexate, cyclosporine Abacavir, lamivudine, efavirenz
bisphosphonates and medications that may result in reduced bone strength leading to increased risk of fracture have been hypothesized to be an example of a pharmacodynamic interaction.12 These pharmacodynamic interactions involving medications associated with increased risk of fracture by attenuating or even negating the beneficial effects of bisphosphonates may be clinically relevant, yet they are not included in the approved prescribing information.12,13 Numerous medications have been shown to be associated with osteoporosis in older adults (Table 2).14,15 To narrow the
Downloaded from aop.sagepub.com at DEAKIN UNIV LIBRARY on March 15, 2015
439
Nyandege et al focus when planning this review, those medications with poorly understood pharmacological actions on bone (eg, anticonvulsants)16 and/or with a primary explanation of increased risk of fracture through an increased risk of falling (eg, anticonvulsants17 and benzodiazepines18) were not considered. Acid-suppressive drugs, selective serotonin reuptake inhibitors (SSRIs), thiazolidinediones (TZDs), and levothyroxine were the focus of this review because there is supportive evidence in the literature suggesting that the biological mechanisms of these drug effects can influence bone metabolism and increase the risk of fracture.10-11,19-25 Table 3 briefly outlines the proposed mechanisms of action on bone for these selected medications of interest. Although glucocorticoids are a known risk factor for reduced BMD26 and increased risk of fracture,27-30 they were excluded from this review because bisphosphonates are recommended to reduce the risk of fracture among those receiving long-term glucocorticoid therapy.31,32 Similarly, aromatase inhibitors (AIs) are known to have deleterious effects on bone metabolism during cancer treatment,19 but they were excluded from this review because antiresorptive therapy is recommended during cancer treatment using AIs.33 The association between SSRIs and increased risk of fractures may be fall related, for example, through sedative effects34; however, SSRIs were selected for review because there is evidence that the biological mechanisms of these drug effects can influence bone metabolism.21-24,35 The objective of this review is to examine the literature on the concomitant use of bisphosphonates and medications that can influence bone metabolism and potentially attenuate bisphosphonate antifracture efficacy.
Data Sources MEDLINE and CINAHL searches were performed through December 2014 using the following keywords: (bisphosphonates OR bone density conservation agents) AND (proton pump inhibitors OR histamine H2 receptor antagonists OR levothyroxine OR thiazolidinediones OR selective serotonin reuptake inhibitors) AND (bone fractures OR bone metabolism). The titles and abstracts of all potential articles were reviewed for relevance. Additionally, references of identified articles were reviewed for other relevant articles.
Study Selection and Data Extraction Articles published in English, limited to those including adult women, and relevant primary literature evaluating only concomitant use of bisphosphonates and medications that can influence bone metabolism, where at least one reported study outcome was fracture risk, were included. There were no restrictions placed on study design. The full text of potentially eligible studies was reviewed by one author (ANN) to determine their relevance to the review.
The same individual extracted information about study design, sample size, medications involved, and study results as well as basic information about study strengths and limitations. Any questions regarding the relevance for the current review or study elements for extraction were resolved through discussion with the other 2 authors.
Data Synthesis Search Results After limiting the search results to studies published in English, 208 studies were identified from the search. Only 5 studies were selected for this review after applying our inclusion and exclusion criteria (Figure 1). One additional study was identified by reviewing the references of the 5 selected studies, yielding a total of 6 studies that were included in this review. No studies were identified that examined the concurrent use of TZDs or levothyroxine. The published evidence surrounding the potential interactions between the acid-suppressive drugs or SSRIs and bisphosphonates is reviewed in the following sections. A summary of the identified studies is provided in Table 4.
Acid-Suppressive Medications In a pooled analysis of PPI use, Kwok et al36 showed significant risk for spine fractures (4 studies: OR = 1.50; 95% CI = 1.32-1.72) and hip fractures (10 studies: OR = 1.23; 95% CI = 1.11-1.36). Where duration of follow-up was reported, this ranged from a median of 6.5 weeks to a mean of 7.8 years. Longer duration of exposure (typically >3 years, pooled result of 6 studies) was associated with higher increased risk of fracture (OR = 1.40; 95% CI = 1.14-1.72) when compared with the increased risk of fracture (OR = 1.23; 95% CI = 1.19-1.27) at shorter durations of exposure (
research-article2015
AOPXXX10.1177/1060028015569594Annals of PharmacotherapyNyandege et al
Review Article
Risk of Fracture and the Concomitant Use of Bisphosphonates With Osteoporosis-Inducing Medications
Annals of Pharmacotherapy 2015, Vol. 49(4) 437–447 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028015569594 aop.sagepub.com
Abner N. Nyandege, PhD1, Patricia W. Slattum, PhD2, and Spencer E. Harpe, PhD3
Abstract Objective: To review the literature on the concomitant use of bisphosphonates and medications that can influence bone metabolism and potentially attenuate bisphosphonate antifracture efficacy. Data Sources: MEDLINE and CINAHL were searched for articles published in English through December 2014 using the following terms: bisphosphonates, bone density conservation agents, acid-suppressive therapy, levothyroxine, thiazolidinediones (TZDs), selective serotonin reuptake inhibitors (SSRIs), bone fractures. Study Selection and Data Extraction: Studies were included if they reported results of concomitant use of any listed medications with bisphosphonates and risk of fractures and focused on women. Articles that focused generally on the use of one of the listed medications and fractures without explicitly examining the potential antifracture efficacy or attenuation of bisphosphonates were excluded. Data Synthesis: A total of 6 relevant studies were identified. Four epidemiological studies reported a statistically significant dose-dependent increase in the risk of fractures when bisphosphonates and acid-suppressive drugs were used together. One post hoc analysis of clinical trial data suggested no attenuation of the antifracture effects of bisphosphonates when used concomitantly with acid-suppressive therapy. One study involving bisphosphonates and SSRIs noted a statistically significant association between fracture risk and SSRI use. No study examining TZDs or levothyroxine with bisphosphonates was identified. Conclusions: Existing research suggests potential attenuation of bisphosphonate antifracture efficacy among patients taking acid-suppressive medications. Based on their pharmacological actions, TZDs, SSRIs, and levothyroxine have similar implications. The paucity of evidence in the literature associating the attenuation of bisphosphonate antifracture efficacy when combined with other medications suggests that further investigation is needed. Keywords osteoporosis, bisphosphonates, drug interactions, pharmacoepidemiology, drug-induced disorders, medication-induced osteoporosis
Introduction The National Osteoporosis Foundation reports that about 80% of the estimated 10 million Americans with osteoporosis are women. In addition, approximately 1 in 2 women 50 years and older will break a bone because of osteoporosis.1 Bisphosphonates are widely prescribed and recommended by the North American Menopause Society as first-line pharmacological treatment in the management of osteoporosis for postmenopausal women.2,3 These agents are characterized by their affinity for bone mineral through binding to hydroxyapatite crystals4 and their inhibitory effects on osteoclasts.5 Chronic conditions, such as diabetes, depression, or inflammatory joint disease, may increase the severity of osteoporosis and affect the management of osteoporosis by increasing the risk of fracture.6 The management of coexisting chronic conditions or multiple chronic conditions (MCCs)
may further increase the risk of fracture. For example, the management of both osteoporosis and chronic inflammatory joint disease may require concomitant use of medications. Care management of MCCs requires heightened coordination of complex medical and psychosocial care and increased management of medications, which is important because concomitant use of medications may increase the potential 1
Market Access Solutions LLC, Raritan, NJ, USA Virginia Commonwealth University School of Pharmacy, Richmond, VA, USA 3 Midwestern University Chicago College of Pharmacy, Downers Grove, IL, USA 2
Corresponding Author: Spencer E. Harpe, Department of Pharmacy Practice, Midwestern University Chicago College of Pharmacy, 555 31st Street, Downers Grove, IL 60515, USA. Email: [email protected]
Downloaded from aop.sagepub.com at DEAKIN UNIV LIBRARY on March 15, 2015
438
Annals of Pharmacotherapy 49(4)
Table 1. Bisphosphonate-Drug Interactions and Adverse Drug Events Listed in Package Inserts. Bisphosphonate
Coadministered Drug(s)
Fosamax (alendronate sodium), Boniva (ibandronate sodium), Actonel (risedronate sodium) Fosamax (alendronate sodium), Boniva (ibandronate sodium), Actonel (risedronate sodium) Boniva (ibandronate sodium), Actonel (risedronate sodium) Reclast (zoledronic acid) Reclast (zoledronic acid)
Nephrotoxic drugs Aminoglycosides
Reclast (zoledronic acid)
Loop diuretics
Outcome
Calcium supplements/Antacids
Interference with drug absorption
Aspirin/Nonsteroidal antiinflammatory drugs (NSAIDS)
May worsen gastrointestinal irritation
H2 receptor antagonists and proton pump inhibitors
May affect oral bioavailability, but interactions are not considered to be clinically relevant Renal failure May have additive effect of lowering serum calcium for prolonged periods May increase risk of hypocalcemia
for clinically important interactions and adverse drug events.7 The US Department of Health and Human Services framework to address the population with MCCs highlights the recognition of drug-drug interactions and potential adverse drug events from complex medication regimens as one strategy for medication management.8 Using the 2000-2002 National Ambulatory Medical Care Survey to examine 25 clinically important drug-drug interactions, Aparasu et al9 found that patients older than 44 years, especially older adults, Medicare beneficiaries, and those prescribed multiple medications, were at risk of receiving concomitant medications with the potential for clinically important drug-drug interactions when compared with patients younger than 25 years of age. Moreover, the study showed that the annualized visit rates involving interacting medications were higher among persons older than 64 years when compared with those younger than 64 years, women compared with men, and Caucasian compared with other races.9 Interestingly, none of the combinations of potentially interacting medications examined in the study included osteoporosis treatment agents such as bisphosphonates. Table 1 outlines the drug-drug interactions included in the prescribing information for FDA-approved bisphosphonates. These are primarily pharmacokinetic interactions (eg, decreased bioavailability when used with proton pump inhibitors [PPIs]) or the potential duplication of similar side effects (eg, worsened gastrointestinal irritation when used with nonsteroidal anti-inflammatory agents). The pharmacodynamic effect of bisphosphonates involves the inhibition of bone resorption through the prevention of osteoclast recruitment, differentiation and activity and also by inducing osteoclast apoptosis.5 Medications associated with osteoporosis and an increased risk of fracture, such as glucocorticoids or PPIs, affect bone by inhibiting osteoblast differentiation and activity, bone formation, and/or increasing bone resorption.10,11 Drug-drug interactions between
Table 2. Medications Associated With Increased Risk of Osteoporotic Fracture. Medication Class Oral glucocorticoids Aromatase inhibitors Selective serotonin reuptake inhibitors Proton pump inhibitors H2 receptor antagonists Thiazolidinediones Thyroid hormones Anticoagulants Anticonvulsants Certain mood stabilizers Gonadotropin-releasing hormones Loop diuretics Certain immunosuppresants Antiretroviral agents
Generic Drug Examples Hydrocortisone, prednisone, dexamethasone Letrozole, anastrozole Citalopram, fluoxetine, paroxetine Esomeprazole, omeprazole, lansoprazole Famotidine, ranitidine, cimetidine Rosiglitazone, pioglitazone Levothyroxine Heparin, enoxaparin, warfarin Phenobarbital, oxcarbazepine, valproic acid Lithium Leuprolide, goserelin Furosemide, bumetanide Methotrexate, cyclosporine Abacavir, lamivudine, efavirenz
bisphosphonates and medications that may result in reduced bone strength leading to increased risk of fracture have been hypothesized to be an example of a pharmacodynamic interaction.12 These pharmacodynamic interactions involving medications associated with increased risk of fracture by attenuating or even negating the beneficial effects of bisphosphonates may be clinically relevant, yet they are not included in the approved prescribing information.12,13 Numerous medications have been shown to be associated with osteoporosis in older adults (Table 2).14,15 To narrow the
Downloaded from aop.sagepub.com at DEAKIN UNIV LIBRARY on March 15, 2015
439
Nyandege et al focus when planning this review, those medications with poorly understood pharmacological actions on bone (eg, anticonvulsants)16 and/or with a primary explanation of increased risk of fracture through an increased risk of falling (eg, anticonvulsants17 and benzodiazepines18) were not considered. Acid-suppressive drugs, selective serotonin reuptake inhibitors (SSRIs), thiazolidinediones (TZDs), and levothyroxine were the focus of this review because there is supportive evidence in the literature suggesting that the biological mechanisms of these drug effects can influence bone metabolism and increase the risk of fracture.10-11,19-25 Table 3 briefly outlines the proposed mechanisms of action on bone for these selected medications of interest. Although glucocorticoids are a known risk factor for reduced BMD26 and increased risk of fracture,27-30 they were excluded from this review because bisphosphonates are recommended to reduce the risk of fracture among those receiving long-term glucocorticoid therapy.31,32 Similarly, aromatase inhibitors (AIs) are known to have deleterious effects on bone metabolism during cancer treatment,19 but they were excluded from this review because antiresorptive therapy is recommended during cancer treatment using AIs.33 The association between SSRIs and increased risk of fractures may be fall related, for example, through sedative effects34; however, SSRIs were selected for review because there is evidence that the biological mechanisms of these drug effects can influence bone metabolism.21-24,35 The objective of this review is to examine the literature on the concomitant use of bisphosphonates and medications that can influence bone metabolism and potentially attenuate bisphosphonate antifracture efficacy.
Data Sources MEDLINE and CINAHL searches were performed through December 2014 using the following keywords: (bisphosphonates OR bone density conservation agents) AND (proton pump inhibitors OR histamine H2 receptor antagonists OR levothyroxine OR thiazolidinediones OR selective serotonin reuptake inhibitors) AND (bone fractures OR bone metabolism). The titles and abstracts of all potential articles were reviewed for relevance. Additionally, references of identified articles were reviewed for other relevant articles.
Study Selection and Data Extraction Articles published in English, limited to those including adult women, and relevant primary literature evaluating only concomitant use of bisphosphonates and medications that can influence bone metabolism, where at least one reported study outcome was fracture risk, were included. There were no restrictions placed on study design. The full text of potentially eligible studies was reviewed by one author (ANN) to determine their relevance to the review.
The same individual extracted information about study design, sample size, medications involved, and study results as well as basic information about study strengths and limitations. Any questions regarding the relevance for the current review or study elements for extraction were resolved through discussion with the other 2 authors.
Data Synthesis Search Results After limiting the search results to studies published in English, 208 studies were identified from the search. Only 5 studies were selected for this review after applying our inclusion and exclusion criteria (Figure 1). One additional study was identified by reviewing the references of the 5 selected studies, yielding a total of 6 studies that were included in this review. No studies were identified that examined the concurrent use of TZDs or levothyroxine. The published evidence surrounding the potential interactions between the acid-suppressive drugs or SSRIs and bisphosphonates is reviewed in the following sections. A summary of the identified studies is provided in Table 4.
Acid-Suppressive Medications In a pooled analysis of PPI use, Kwok et al36 showed significant risk for spine fractures (4 studies: OR = 1.50; 95% CI = 1.32-1.72) and hip fractures (10 studies: OR = 1.23; 95% CI = 1.11-1.36). Where duration of follow-up was reported, this ranged from a median of 6.5 weeks to a mean of 7.8 years. Longer duration of exposure (typically >3 years, pooled result of 6 studies) was associated with higher increased risk of fracture (OR = 1.40; 95% CI = 1.14-1.72) when compared with the increased risk of fracture (OR = 1.23; 95% CI = 1.19-1.27) at shorter durations of exposure (
