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Opioids for osteoarthritis? Weighing benefits and risks: A Cochrane Musculoskeletal Group review
Osteoarthritis (OA) affects nearly 27 million Americans, or about 12% of US adults.1 As the average age of the population increases, the prevalence and burden of this debilitating disorder continue to rise.2
The American College of Rheumatology (ACR)’s guidelines for the medical management of OA of the hip and knee, last updated in 2000,3 focus on controlling pain and improving function and health-related quality of life while minimizing the toxic effects of therapy. The guidelines recommend tramadol—an atypical opioid with 2 distinct mechanisms of action4—for moderate-to-severe pain in OA patients who either have contraindications to COX-2 inhibitors and non steroidal anti-inflammatory drugs (NSAIDs) or have failed to respond to previous oral therapy. Patients with severe pain who don’t respond to or are unable to tolerate tramadol may be candidates for more traditional opioid therapy, the guidelines indicate.3
In recent years, however, the use (and abuse) of opioids has skyrocketed. Between 1997 and 2007, US per capita retail purchases of hydrocodone and oxycodone increased 4-fold and 9-fold, respectively.5 In a similar time frame (1996-2006), the number of deaths from opioid overdose more than tripled, going from 4000 to 13,800 annually.6 Not surprisingly, the use of narcotics for noncancer pain remains controversial.7,8 But inadequately treated pain continues to be a serious public health problem, as well.9
This is the third in a series of articles based on the findings of the Cochrane Musculoskeletal Group (CMSG). One of the largest groups in the Cochrane Collaboration, the CMSG synthesizes the results of clinical trials to determine whether interventions for the prevention, treatment, and rehabilitation of musculoskeletal disorders are safe and effective. In this installment, the reviewers use detailed analysis, as well as a case study, to bring their findings to the attention of family physicians in a practical, clinically relevant context.
In 2006 and 2009, respectively, the Cochrane Collaboration published systematic reviews of tramadol (for OA in any joint)10 and other oral and transdermal opioids (for OA of the hip or knee).11 The reviewers’ findings, presented here along with data from more recent trials, can help ensure that you prescribe opioids for patients with OA only when their use is clinically appropriate and evidence-based. We’ve also included a case study (see page 211), so you can assess your knowledge and clinical skills.
CASE Carol J, an active 72-year-old, was diagnosed with OA in her right hip 5 years ago. Now she reports that the pain is getting progressively worse, making it harder and harder to turn over in bed at night or get in and out of the car. The pain is particularly bad at night, Carol says, and she’s had interrupted sleep for months. The patient has taken acetaminophen for the pain since her OA diagnosis, but now finds the analgesic is ineffective, even at the maximum dose of 4 g per day.
Carol has hypertension, which was difficult to manage until she began taking a combination ACE inhibitor/diuretic. She also has moderate renal impairment and mild chronic obstructive pulmonary disease, which limits her exercise tolerance. Nonetheless, she continues to smoke. The patient lives with and cares for her husband, who has Alzheimer’s disease, and worries about her ability to continue to care for him.
What are her treatment options?
Full-dose acetaminophen is no longer helping Carol, and NSAIDs are contraindicated because she takes an ACE inhibitor/diuretic and has moderate renal impairment. Increasing exercise will be a challenge. You strongly encourage her to stop smoking, emphasizing that this is particularly important to reduce the risk involved with any future joint replacement surgery.
Oral dosing options for the patient include:
- prescribing tramadol, starting with a low-dose immediate-release formulation taken one hour before bedtime (The controlled-release formulation is not advisable, given her age and renal function.) or
- adding a traditional opioid, eg, codeine 30 to 60 mg every 6 hours as needed, to her regular acetaminophen regimen.
Codeine and hydrocodone are available in combination preparations with acetaminophen, which may be convenient for some patients. However, hydrocodone was not one of the opioids tested in the trials included in the Cochrane reviews, and evidence of its use in OA is lacking.
Intra-articular corticosteroid injection, performed under imaging guidance, is another option for Carol. You explain that although there have been no studies of intra-articular corticosteroid injections for OA of the hip, these are used occasionally and may provide short-term symptom relief.7
You emphasize that surgery is likely to give her the best long-term outcome. In view of the patient’s circumstances and the need to care for her husband, however, you prescribe tramadol 50 mg at night. (Because of Carol’s age, renal impairment, and the possible adverse effects, it’s wise to start with a low dose and titrate upwards.) You warn her of the risks associated with opioids and advise her to alert your office staff if she experiences any adverse effects.
Before the patient leaves, you arrange an orthopedic consult and schedule a return visit for the following week. At your urging, she agrees to look into respite options for her husband.
Tramadol produces modest results—or none at all
The tramadol review10 included 11 randomized controlled trials (RCTs) with a total of 1019 participants who took tramadol or tramadol/acetaminophen (paracetamol) and 920 controls. In 6 of the 11 studies, the controls received placebo; the remaining 5 trials used “active controls,” with the control group for each RCT receiving a different analgesic. (To learn more about the methodology, see “How the reviews were conducted”.)
Placebo-controlled trials. Compared with patients on placebo, those receiving tramadol had an average absolute reduction in pain of 8.5 mm on a 0-100 mm visual analog scale (VAS) (95% confidence interval [CI], -12.05 to -4.9). That small benefit, however, did not reach the level defined as the minimal perceptible clinical improvement—a reduction of 9.7 mm on Western Ontario and McMaster Universities (WOMAC)’s OA pain subscale.12
Active-controlled trials. In the 5 RCTs comparing tramadol with another active agent, tramadol proved to be no better than the control drug. In fact, in a study of tramadol vs acetaminophen, 500 mg acetaminophen 3 times a day provided more pain relief than 50 mg tramadol 3 times a day.13 Although this was a small (N=20), short-term (7-day) study, this finding is notable because participants took less than the usual acetaminophen dose of 1 g up to 4 times a day.
Nor was tramadol superior to the agents it was compared with in the 4 other active-controlled trials—dihydrocodeine,14 dextropropoxyphene,15 pentazocine,16 and diclofenac17—in reducing pain intensity. It is important to keep in mind, however, that in each of these studies, both the quantity and quality of the evidence was limited. (Two studies did not use numerical scales,14,16 for example; all had methodological issues; and none lasted longer than 28 days.)
The Cochrane Musculoskeletal Group conducted a review of tramadol and a review of other oral opioids and transdermal fentanyl for the treatment of osteoarthritis (OA). Both reviews featured pain, function, and safety as primary outcomes. The tramadol review included randomized controlled trials (RCTs) for OA in any joint, while the oral and transdermal opioid review included randomized and quasi-randomized trials of treatment for OA of the hip or knee. Other parameters follow:
The tramadol review included 11 RCTs, with a total of 1019 participants receiving either tramadol alone or tramadol/acetaminophen (paracetamol) and 920 controls. In 6 of the 11 studies, the controls received placebo; the remaining 5 studies featured “active control.” That is, the control groups received acetaminophen 500 mg 3 times daily, diclofenac (25-50 mg up to 3 times daily on demand), dihydrocodeine 60 mg twice daily, dextropropoxyphene 100 mg 3 times daily, or pentazocine 50 mg 4 times per day. Because each of these agents was used in only one trial, the reviewers could not reach definitive conclusions about tramadol’s performance relative to other medications. The average number of participants in the tramadol and control groups was 91 and 80, respectively. The average length of follow-up was 35 days.
The 11 RCTs included in this review used a variety of pain scales to assess the results of tramadol, active control medications, and placebo. For comparative purposes, the reviewers pooled the results from studies that used numerical scales (0 to 100 and 0 to 10) to assess pain intensity. As a reference, we have used 9.7 and 9.3, respectively, determined by other researchers to be the minimal perceptible clinical improvements on the Western Ontario and McMaster Universities (WOMAC) pain and physical function 0-100 mm visual analog scales.12
The review of oral and transdermal opioids included 10 studies, with a total of 1541 patients receiving opioids and 727 receiving placebo.17 There were 3 trials of codeine (in 2 of the 3, a simple analgesic [acetaminophen 3000 mg/d or ibuprofen 1200 mg/d] was co-administered to both the treatment and control groups); other opioids included in the trials were oxycodone (4 trials), oxymorphone (2 trials), morphine (1 trial), and transdermal fentanyl (1 trial).
A modest boost in well-being
The reviewers measured function in 2 ways, focusing on both global improvement and improvement in physical function.
Global assessment. For the global assessment, the reviewers defined a treatment response as achieving at least a moderate improvement. By that standard, tramadol may improve overall well-being more than placebo. In the placebo-controlled trials, the number needed to treat (NNT) to elicit one treatment response was 6.
Three of the trials with active controls included global/functional assessments, and the results—bearing in mind the reduced quality and quantity of the evidence—were mixed. In a comparison of tramadol with dextropropoxyphene, tramadol increased the likelihood of moderate improvement by 38% (relative risk, 1.38 (95% CI, 1.15-1.67).10 In a trial of tramadol vs pentazocine, tramadol was more effective in reducing the duration of morning stiffness (by about 10 minutes), but not its severity. Tramadol was comparable with pentazocine in the 7 other measures of OA and function.16 In the tramadol-diclofenac study, both drugs were equally effective.17
Physical function. Four of the 6 placebo-controlled tramadol studies included in the Cochrane review used the WOMAC Index score, which included the physical function subscale. The tramadol group had a larger reduction in the score than the placebo group, by 0.34 mm (95% CI, -0.49 to -0.19). While this was equivalent to an 8.5% relative reduction in mean baseline score, it is still small compared with the minimal perceptible clinical improvement level of 9.3 mm on a 0-100 scale needed for the WOMAC physical function subscale. A similar improvement was reported for those taking tramadol compared with diclofenac—the only one of the active-controlled studies to report on physical function.17
Other opioids relieve pain, improve function—but how much?
The review of oral and transdermal opioids for OA11 encompassed 10 trials, with a total of 1541 patients receiving opioids and 727 on placebo. The opioids used in the trials were codeine, oxycodone, oxymorphone, morphine, and transdermal fentanyl. (For more details, see “How the reviews were conducted”.)
Pain. The trials included in the review used a variety of scales to measure pain, so the reviewers gauged results by the proportion of patients responding to treatment. Response was defined as a 50% improvement in pain score.
In the overall analysis, 35% of patients taking opioids responded to treatment, vs 31% of those on placebo—or 4 more patients in 100. That represents an NNT of 25. (A subgroup analysis did not demonstrate any significant differences in effect size among the opioids tested. In addition, the effect size was similar regardless of the potency of the opioid or the administration route.)
Function. Seven of the 10 trials (1794 participants, including both the treatment groups and controls) used validated function scores to measure physical function after 4 weeks of treatment. Here, too, the reviewers defined a treatment response as a 50% improvement in score.
Their finding? Opioids had a greater effect on function compared with placebo, equaling 0.7 on a WOMAC disability scale of 1 to 10. This means that about 3 more patients in 100 responded to treatment with opioids vs placebo—an NNT of 30.
But what about safety?
Opioids, including tramadol, are associated with adverse events (AEs), which may be minor or major. To determine when, or whether, the benefits outweigh the risks for treating patients with OA, both reviews reported on AEs and the number of participants who stopped taking the drug because of AEs.
AEs limit tramadol’s usefulness
While tramadol was more effective than placebo at reducing pain intensity, relieving symptoms, and improving function, the benefits were small—with an overall NNT of 6 (TABLE 1). This is similar to acetaminophen (NNT, 4-16),18 but with a greater downside.
Minor AEs. Four placebo-controlled trials reported on minor AEs.19-22 Those most commonly reported by patients taking tramadol were nausea, vomiting, dizziness, constipation, somnolence, tiredness, and headache.
Overall, 39% of those who received tramadol experienced minor AEs, compared with 18% of patients receiving placebo—an NNH of 5.10 Thus, tramadol’s NNH for minor AEs is equivalent to its NNT for pain relief. In active-controlled studies, there was a higher risk of minor AEs in those receiving tramadol compared with diclofenac or dextropropoxyphene, but a lower risk compared with those taking pentazocine.10
Major AEs. An analysis of the placebo-controlled trials revealed that 21% of those who received tramadol had major AEs—defined as an event that resulted in cessation of treatment—compared with 8% of those taking placebo. By this measure, the NNH was 8: One in 8 patients stopped taking tramadol because of a major AE.10
Among the active-controlled trials, participants taking tramadol were more likely to report a major AE compared with those receiving either diclofenac or dextropropoxyphene (NNH=5), but less likely compared with patients taking pentazocine. In a trial that compared tramadol alone with paracetamol, 2 out of 10 in the tramadol group discontinued treatment; none in the paracetamol group did.13
TABLE 1
Tramadol and other opioids for OA pain: NNT and NNH
| Treatment | NNT | NNH |
|---|---|---|
| Tramadol10 | 6 | 5 |
| Opioids (overall)11 | 25 | 12 |
| NNH, number needed to harm; NNT, number needed to treat; OA, osteoarthritis. | ||
Post-review RCTs provide further evidence
We identified 4 double-blind RCTs of tramadol for the treatment of OA that were of at least 6 weeks’ duration,19-22 published after the 2006 review. The results of these studies (TABLE 2) were broadly consistent with those of the systematic review. Two of the 4 studies had active controls, with one comparing tramadol with diclofenac19 and the other with celecoxib.21 Tramadol and diclofenac were found to be equally effective; celecoxib appeared to be superior in terms of pain relief, global improvement, and physical function, but no statistical comparisons were reported.
TABLE 2
Tramadol for OA: Post-review RCTs are consistent with meta-analysis
| Study duration (N) | Intervention groups | Primary outcome measures | Improvement in | Adverse effects | ||
|---|---|---|---|---|---|---|
| Pain | Global assessment | Function | ||||
| Gana*20 12 wk (1020) | Tramadol ER Placebo | WOMAC OA index (pain and physical function subscales) 100-mm VAS: Subject global disease | Treatment groups, 35% Placebo, 25% | Treatment groups, 32%-36% Placebo, 24% | Treatment groups, 31%-33% Placebo, 22% | ≥1 AE Withdrawals due to AEs |
| Delemos*21 12 wk (1001) | Tramadol ER Placebo | WOMAC OA index (pain and physical function subscales) 100-mm VAS: Subject global disease | Tramadol, 27%-39% Celecoxib, 45% Placebo, 32% | Tramadol, 28%-40% Celecoxib, 44% Placebo, 30% | Tramadol, 26%-35% Celecoxib, 43% Placebo, 28% | ≥1 AE Withdrawals due to AEs |
| Burch†22 12 wk (646) | Tramadol (Contramid OAD) 100 mg titrating to 300 mg Placebo | Pain intensity (11-point numerical scale) Physician/patient global impressions of change (7-point scale) | Treatment group, 40% Placebo, 33% | Treatment group, 80% Placebo, 69% | NA | AEs Placebo: Nausea, 5.6%; constipation, 4.2%; dizziness/vertigo, 3.7%; somnolence, 3.7% Withdrawals due to AEs |
| Beaulieu*19 6 wk (128) | Tramadol CR 200 mg titrating to 400 mg Diclofenac SR 75 mg titrating to 150 mg | WOMAC OA index (pain and physical function subscales) 100-mm VAS: Pain intensity Subject global disease Physician/patient global impressions of change (7-point scale) | Both groups, ~29% | Tramadol, 67%‡ Diclofenac, 54%‡ | Tramadol, 29%‡ Diclofenac, 29%‡ | Withdrawals due to AEs Tramadol, 16% Diclofenac, 15% |
| *Hip or knee osteoarthritis. †Knee osteoarthritis. ‡Not statistically significant. AEs, adverse events; CR, controlled release; ER, extended release; NA, not assessed; OA, osteoarthritis; OAD, once a day; RCTs, randomized controlled trials; SR, sustained release; VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities. | ||||||
Oral and transdermal opioids: Pain relief but high risk
Among the patients with OA of the hip or knee—the study population for the review of oral and transdermal opioids—all the opioids tested were more effective than placebo. The benefits, however, were small to moderate, and were off set by large increases in the risk of AEs and a high dropout rate.
Four of the 10 trials reported the number of patients experiencing any AE: 23% of those taking opioids vs 15% of patients on placebo.11 This represents an NNH of 12 (TABLE 1). All 10 trials reported the number of patients who withdrew due to AEs. Those receiving opioids were 4 times as likely to withdraw due to AEs, compared with those taking placebo. The NNH to cause one additional withdrawal was 19 (95% CI, 13-29).
Bottom line
The data highlight both the limited role of opioids (including tramadol) in OA treatment and—when they are being considered for this patient population—the importance of making patients aware that the risks may outweigh the benefits. Used judiciously and with adequate patient counseling, tramadol may be an option when COX-2-specific inhibitors and NSAIDs fail or cannot be tolerated. Although the small-to-moderate benefits of non-tramadol opioids are generally outweighed by large increases in the risk of AEs, their use may be considered for severe OA pain if tramadol is ineffective or causes intolerable AEs.
CORRESPONDENCE
Faline Howes, BMedSci, MBBS, MPH, FRACGP, Menzies Research Institute Tasmania, Private Bag 23, University of Tasmania, Hobart, Tasmania, Australia 7001; Faline.Howes@ utas.edu.au
1. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58:26-35.
2. Bitton R. The economic burden of osteoarthritis. Am J Manag Care. 2009;15(suppl):S230-S235.
3. Altman RD, Hochberg MC, Moskowitz RW, et al. Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum. 2000;43:1905-1915.
4. Gibson TP. Pharmacokinetics, efficacy, and safety of analgesia with a focus on tramadol HCl. Am J Med. 1996;101(suppl 1A):47S-53S.
5. Hall AJ, Logan JE, Toblin RL, et al. Patterns of abuse among unintentional pharmaceutical overdose fatalities. JAMA. 2008;300:2613-2620.
6. Warner M, Chen LH, Makuc DM. Increase in fatal poisonings involving opioid analgesics in the United States, 1999-2006. NCHS data brief, no 22. Hyattsville, MD: National Center for Health Statistics; 2009.
7. Von Korff M, Deyo RA. Potent opioids for chronic musculoskeletal pain: flying blind? Pain. 2004;109:207-209.
8. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage. 2008;16:137-167.
9. Pletcher MJ, Kertesz SG, Kohn MA, et al. Trends in opioid prescribing by race/ethnicity for patients seeking care in US emergency departments. JAMA. 2008;299:70-78.
10. Cepeda MS, Camargo F, Zea C, et al. Tramadol for osteoarthritis. Cochrane Database Syst Rev. 2006;(3):CD005522.-
11. Nuesch E, Rutjes AW, Husni E, et al. Oral or transdermal opioids for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2009;(4):CD003115.-
12. Ehrich EW, Davies GM, Watson DJ, et al. Minimal perceptible clinical improvement with the Western Ontario and McMaster Universities osteoarthritis index questionnaire and global assessments in patients with osteoarthritis. J Rheumatol. 2000;27:2635-2641.
13. Bianchi M, Broggini M, Balzarini P, et al. Effects of tramadol on synovial fluid concentrations of substance P and interleukin-6 in patients with knee osteoarthritis: comparison with paracetamol. Int Immunopharm. 2003;3:1901-1908.
14. Wilder-Smith C, Hill L, Spargo K, et al. Treatment of severe pain from osteoarthritis with slow-release tramadol or dihydrocodeine in combination with NSAIDs: a randomised study comparing analgesia, antinociception and gastrointestinal effects. Pain. 2001;91:23-31.
15. Jensen E, Ginsberg F. Tramadol versus dextropropoxyphene in the treatment of osteoarthritis: a short-term double-blind study. Drug Invest. 1994;8:211-218.
16. Bird H, Hill J, Stratford M, et al. A double-blind cross-over study comparing the analgesic efficacy of tramadol with pentazocine in patients with osteoarthritis. J Drug Dev Clin Pract. 1995;7:181-188.
17. Pavelka K, Peliskova Z, Stehlikova H, et al. Intraindividual differences in pain relief and functional improvement in osteoarthritis with diclofenac or tramadol. Clin Drug Invest. 1998;16:421-429.
18. Townheed TE, Maxwell L, Judd MG, et al. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev. 2006;(1):CD004257.-
19. Beaulieu AD, Peloso PM, Haraoui B, et al. Once-daily, controlled-release tramadol and sustained-release diclofenac relieve chronic pain due to osteoarthritis: a randomized controlled trial. Pain Res Manag. 2008;13:103-110.
20. Gana TJ, Pascual ML, Fleming RR, et al. Extended-release tramadol in the treatment of osteoarthritis: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Curr Med Res Opin. 2006;22:1391-1401.
21. Delemos BP, Xiang J, Benson C, et al. Tramadol hydrochloride extended-release once-daily in the treatment of osteoarthritis of the knee and/or hip: a double-blind, randomized, dose-ranging trial. Am J Ther. 2010 Mar 3 [Epub ahead of print].
22. Burch F, Fishman R, Messina N, et al. A comparison of the analgesic efficacy of Tramadol Contramid OAD versus placebo in patients with pain due to osteoarthritis. J Pain Symptom Manage. 2007;34:328-338.
Osteoarthritis (OA) affects nearly 27 million Americans, or about 12% of US adults.1 As the average age of the population increases, the prevalence and burden of this debilitating disorder continue to rise.2
The American College of Rheumatology (ACR)’s guidelines for the medical management of OA of the hip and knee, last updated in 2000,3 focus on controlling pain and improving function and health-related quality of life while minimizing the toxic effects of therapy. The guidelines recommend tramadol—an atypical opioid with 2 distinct mechanisms of action4—for moderate-to-severe pain in OA patients who either have contraindications to COX-2 inhibitors and non steroidal anti-inflammatory drugs (NSAIDs) or have failed to respond to previous oral therapy. Patients with severe pain who don’t respond to or are unable to tolerate tramadol may be candidates for more traditional opioid therapy, the guidelines indicate.3
In recent years, however, the use (and abuse) of opioids has skyrocketed. Between 1997 and 2007, US per capita retail purchases of hydrocodone and oxycodone increased 4-fold and 9-fold, respectively.5 In a similar time frame (1996-2006), the number of deaths from opioid overdose more than tripled, going from 4000 to 13,800 annually.6 Not surprisingly, the use of narcotics for noncancer pain remains controversial.7,8 But inadequately treated pain continues to be a serious public health problem, as well.9
This is the third in a series of articles based on the findings of the Cochrane Musculoskeletal Group (CMSG). One of the largest groups in the Cochrane Collaboration, the CMSG synthesizes the results of clinical trials to determine whether interventions for the prevention, treatment, and rehabilitation of musculoskeletal disorders are safe and effective. In this installment, the reviewers use detailed analysis, as well as a case study, to bring their findings to the attention of family physicians in a practical, clinically relevant context.
In 2006 and 2009, respectively, the Cochrane Collaboration published systematic reviews of tramadol (for OA in any joint)10 and other oral and transdermal opioids (for OA of the hip or knee).11 The reviewers’ findings, presented here along with data from more recent trials, can help ensure that you prescribe opioids for patients with OA only when their use is clinically appropriate and evidence-based. We’ve also included a case study (see page 211), so you can assess your knowledge and clinical skills.
CASE Carol J, an active 72-year-old, was diagnosed with OA in her right hip 5 years ago. Now she reports that the pain is getting progressively worse, making it harder and harder to turn over in bed at night or get in and out of the car. The pain is particularly bad at night, Carol says, and she’s had interrupted sleep for months. The patient has taken acetaminophen for the pain since her OA diagnosis, but now finds the analgesic is ineffective, even at the maximum dose of 4 g per day.
Carol has hypertension, which was difficult to manage until she began taking a combination ACE inhibitor/diuretic. She also has moderate renal impairment and mild chronic obstructive pulmonary disease, which limits her exercise tolerance. Nonetheless, she continues to smoke. The patient lives with and cares for her husband, who has Alzheimer’s disease, and worries about her ability to continue to care for him.
What are her treatment options?
Full-dose acetaminophen is no longer helping Carol, and NSAIDs are contraindicated because she takes an ACE inhibitor/diuretic and has moderate renal impairment. Increasing exercise will be a challenge. You strongly encourage her to stop smoking, emphasizing that this is particularly important to reduce the risk involved with any future joint replacement surgery.
Oral dosing options for the patient include:
- prescribing tramadol, starting with a low-dose immediate-release formulation taken one hour before bedtime (The controlled-release formulation is not advisable, given her age and renal function.) or
- adding a traditional opioid, eg, codeine 30 to 60 mg every 6 hours as needed, to her regular acetaminophen regimen.
Codeine and hydrocodone are available in combination preparations with acetaminophen, which may be convenient for some patients. However, hydrocodone was not one of the opioids tested in the trials included in the Cochrane reviews, and evidence of its use in OA is lacking.
Intra-articular corticosteroid injection, performed under imaging guidance, is another option for Carol. You explain that although there have been no studies of intra-articular corticosteroid injections for OA of the hip, these are used occasionally and may provide short-term symptom relief.7
You emphasize that surgery is likely to give her the best long-term outcome. In view of the patient’s circumstances and the need to care for her husband, however, you prescribe tramadol 50 mg at night. (Because of Carol’s age, renal impairment, and the possible adverse effects, it’s wise to start with a low dose and titrate upwards.) You warn her of the risks associated with opioids and advise her to alert your office staff if she experiences any adverse effects.
Before the patient leaves, you arrange an orthopedic consult and schedule a return visit for the following week. At your urging, she agrees to look into respite options for her husband.
Tramadol produces modest results—or none at all
The tramadol review10 included 11 randomized controlled trials (RCTs) with a total of 1019 participants who took tramadol or tramadol/acetaminophen (paracetamol) and 920 controls. In 6 of the 11 studies, the controls received placebo; the remaining 5 trials used “active controls,” with the control group for each RCT receiving a different analgesic. (To learn more about the methodology, see “How the reviews were conducted”.)
Placebo-controlled trials. Compared with patients on placebo, those receiving tramadol had an average absolute reduction in pain of 8.5 mm on a 0-100 mm visual analog scale (VAS) (95% confidence interval [CI], -12.05 to -4.9). That small benefit, however, did not reach the level defined as the minimal perceptible clinical improvement—a reduction of 9.7 mm on Western Ontario and McMaster Universities (WOMAC)’s OA pain subscale.12
Active-controlled trials. In the 5 RCTs comparing tramadol with another active agent, tramadol proved to be no better than the control drug. In fact, in a study of tramadol vs acetaminophen, 500 mg acetaminophen 3 times a day provided more pain relief than 50 mg tramadol 3 times a day.13 Although this was a small (N=20), short-term (7-day) study, this finding is notable because participants took less than the usual acetaminophen dose of 1 g up to 4 times a day.
Nor was tramadol superior to the agents it was compared with in the 4 other active-controlled trials—dihydrocodeine,14 dextropropoxyphene,15 pentazocine,16 and diclofenac17—in reducing pain intensity. It is important to keep in mind, however, that in each of these studies, both the quantity and quality of the evidence was limited. (Two studies did not use numerical scales,14,16 for example; all had methodological issues; and none lasted longer than 28 days.)
The Cochrane Musculoskeletal Group conducted a review of tramadol and a review of other oral opioids and transdermal fentanyl for the treatment of osteoarthritis (OA). Both reviews featured pain, function, and safety as primary outcomes. The tramadol review included randomized controlled trials (RCTs) for OA in any joint, while the oral and transdermal opioid review included randomized and quasi-randomized trials of treatment for OA of the hip or knee. Other parameters follow:
The tramadol review included 11 RCTs, with a total of 1019 participants receiving either tramadol alone or tramadol/acetaminophen (paracetamol) and 920 controls. In 6 of the 11 studies, the controls received placebo; the remaining 5 studies featured “active control.” That is, the control groups received acetaminophen 500 mg 3 times daily, diclofenac (25-50 mg up to 3 times daily on demand), dihydrocodeine 60 mg twice daily, dextropropoxyphene 100 mg 3 times daily, or pentazocine 50 mg 4 times per day. Because each of these agents was used in only one trial, the reviewers could not reach definitive conclusions about tramadol’s performance relative to other medications. The average number of participants in the tramadol and control groups was 91 and 80, respectively. The average length of follow-up was 35 days.
The 11 RCTs included in this review used a variety of pain scales to assess the results of tramadol, active control medications, and placebo. For comparative purposes, the reviewers pooled the results from studies that used numerical scales (0 to 100 and 0 to 10) to assess pain intensity. As a reference, we have used 9.7 and 9.3, respectively, determined by other researchers to be the minimal perceptible clinical improvements on the Western Ontario and McMaster Universities (WOMAC) pain and physical function 0-100 mm visual analog scales.12
The review of oral and transdermal opioids included 10 studies, with a total of 1541 patients receiving opioids and 727 receiving placebo.17 There were 3 trials of codeine (in 2 of the 3, a simple analgesic [acetaminophen 3000 mg/d or ibuprofen 1200 mg/d] was co-administered to both the treatment and control groups); other opioids included in the trials were oxycodone (4 trials), oxymorphone (2 trials), morphine (1 trial), and transdermal fentanyl (1 trial).
A modest boost in well-being
The reviewers measured function in 2 ways, focusing on both global improvement and improvement in physical function.
Global assessment. For the global assessment, the reviewers defined a treatment response as achieving at least a moderate improvement. By that standard, tramadol may improve overall well-being more than placebo. In the placebo-controlled trials, the number needed to treat (NNT) to elicit one treatment response was 6.
Three of the trials with active controls included global/functional assessments, and the results—bearing in mind the reduced quality and quantity of the evidence—were mixed. In a comparison of tramadol with dextropropoxyphene, tramadol increased the likelihood of moderate improvement by 38% (relative risk, 1.38 (95% CI, 1.15-1.67).10 In a trial of tramadol vs pentazocine, tramadol was more effective in reducing the duration of morning stiffness (by about 10 minutes), but not its severity. Tramadol was comparable with pentazocine in the 7 other measures of OA and function.16 In the tramadol-diclofenac study, both drugs were equally effective.17
Physical function. Four of the 6 placebo-controlled tramadol studies included in the Cochrane review used the WOMAC Index score, which included the physical function subscale. The tramadol group had a larger reduction in the score than the placebo group, by 0.34 mm (95% CI, -0.49 to -0.19). While this was equivalent to an 8.5% relative reduction in mean baseline score, it is still small compared with the minimal perceptible clinical improvement level of 9.3 mm on a 0-100 scale needed for the WOMAC physical function subscale. A similar improvement was reported for those taking tramadol compared with diclofenac—the only one of the active-controlled studies to report on physical function.17
Other opioids relieve pain, improve function—but how much?
The review of oral and transdermal opioids for OA11 encompassed 10 trials, with a total of 1541 patients receiving opioids and 727 on placebo. The opioids used in the trials were codeine, oxycodone, oxymorphone, morphine, and transdermal fentanyl. (For more details, see “How the reviews were conducted”.)
Pain. The trials included in the review used a variety of scales to measure pain, so the reviewers gauged results by the proportion of patients responding to treatment. Response was defined as a 50% improvement in pain score.
In the overall analysis, 35% of patients taking opioids responded to treatment, vs 31% of those on placebo—or 4 more patients in 100. That represents an NNT of 25. (A subgroup analysis did not demonstrate any significant differences in effect size among the opioids tested. In addition, the effect size was similar regardless of the potency of the opioid or the administration route.)
Function. Seven of the 10 trials (1794 participants, including both the treatment groups and controls) used validated function scores to measure physical function after 4 weeks of treatment. Here, too, the reviewers defined a treatment response as a 50% improvement in score.
Their finding? Opioids had a greater effect on function compared with placebo, equaling 0.7 on a WOMAC disability scale of 1 to 10. This means that about 3 more patients in 100 responded to treatment with opioids vs placebo—an NNT of 30.
But what about safety?
Opioids, including tramadol, are associated with adverse events (AEs), which may be minor or major. To determine when, or whether, the benefits outweigh the risks for treating patients with OA, both reviews reported on AEs and the number of participants who stopped taking the drug because of AEs.
AEs limit tramadol’s usefulness
While tramadol was more effective than placebo at reducing pain intensity, relieving symptoms, and improving function, the benefits were small—with an overall NNT of 6 (TABLE 1). This is similar to acetaminophen (NNT, 4-16),18 but with a greater downside.
Minor AEs. Four placebo-controlled trials reported on minor AEs.19-22 Those most commonly reported by patients taking tramadol were nausea, vomiting, dizziness, constipation, somnolence, tiredness, and headache.
Overall, 39% of those who received tramadol experienced minor AEs, compared with 18% of patients receiving placebo—an NNH of 5.10 Thus, tramadol’s NNH for minor AEs is equivalent to its NNT for pain relief. In active-controlled studies, there was a higher risk of minor AEs in those receiving tramadol compared with diclofenac or dextropropoxyphene, but a lower risk compared with those taking pentazocine.10
Major AEs. An analysis of the placebo-controlled trials revealed that 21% of those who received tramadol had major AEs—defined as an event that resulted in cessation of treatment—compared with 8% of those taking placebo. By this measure, the NNH was 8: One in 8 patients stopped taking tramadol because of a major AE.10
Among the active-controlled trials, participants taking tramadol were more likely to report a major AE compared with those receiving either diclofenac or dextropropoxyphene (NNH=5), but less likely compared with patients taking pentazocine. In a trial that compared tramadol alone with paracetamol, 2 out of 10 in the tramadol group discontinued treatment; none in the paracetamol group did.13
TABLE 1
Tramadol and other opioids for OA pain: NNT and NNH
| Treatment | NNT | NNH |
|---|---|---|
| Tramadol10 | 6 | 5 |
| Opioids (overall)11 | 25 | 12 |
| NNH, number needed to harm; NNT, number needed to treat; OA, osteoarthritis. | ||
Post-review RCTs provide further evidence
We identified 4 double-blind RCTs of tramadol for the treatment of OA that were of at least 6 weeks’ duration,19-22 published after the 2006 review. The results of these studies (TABLE 2) were broadly consistent with those of the systematic review. Two of the 4 studies had active controls, with one comparing tramadol with diclofenac19 and the other with celecoxib.21 Tramadol and diclofenac were found to be equally effective; celecoxib appeared to be superior in terms of pain relief, global improvement, and physical function, but no statistical comparisons were reported.
TABLE 2
Tramadol for OA: Post-review RCTs are consistent with meta-analysis
| Study duration (N) | Intervention groups | Primary outcome measures | Improvement in | Adverse effects | ||
|---|---|---|---|---|---|---|
| Pain | Global assessment | Function | ||||
| Gana*20 12 wk (1020) | Tramadol ER Placebo | WOMAC OA index (pain and physical function subscales) 100-mm VAS: Subject global disease | Treatment groups, 35% Placebo, 25% | Treatment groups, 32%-36% Placebo, 24% | Treatment groups, 31%-33% Placebo, 22% | ≥1 AE Withdrawals due to AEs |
| Delemos*21 12 wk (1001) | Tramadol ER Placebo | WOMAC OA index (pain and physical function subscales) 100-mm VAS: Subject global disease | Tramadol, 27%-39% Celecoxib, 45% Placebo, 32% | Tramadol, 28%-40% Celecoxib, 44% Placebo, 30% | Tramadol, 26%-35% Celecoxib, 43% Placebo, 28% | ≥1 AE Withdrawals due to AEs |
| Burch†22 12 wk (646) | Tramadol (Contramid OAD) 100 mg titrating to 300 mg Placebo | Pain intensity (11-point numerical scale) Physician/patient global impressions of change (7-point scale) | Treatment group, 40% Placebo, 33% | Treatment group, 80% Placebo, 69% | NA | AEs Placebo: Nausea, 5.6%; constipation, 4.2%; dizziness/vertigo, 3.7%; somnolence, 3.7% Withdrawals due to AEs |
| Beaulieu*19 6 wk (128) | Tramadol CR 200 mg titrating to 400 mg Diclofenac SR 75 mg titrating to 150 mg | WOMAC OA index (pain and physical function subscales) 100-mm VAS: Pain intensity Subject global disease Physician/patient global impressions of change (7-point scale) | Both groups, ~29% | Tramadol, 67%‡ Diclofenac, 54%‡ | Tramadol, 29%‡ Diclofenac, 29%‡ | Withdrawals due to AEs Tramadol, 16% Diclofenac, 15% |
| *Hip or knee osteoarthritis. †Knee osteoarthritis. ‡Not statistically significant. AEs, adverse events; CR, controlled release; ER, extended release; NA, not assessed; OA, osteoarthritis; OAD, once a day; RCTs, randomized controlled trials; SR, sustained release; VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities. | ||||||
Oral and transdermal opioids: Pain relief but high risk
Among the patients with OA of the hip or knee—the study population for the review of oral and transdermal opioids—all the opioids tested were more effective than placebo. The benefits, however, were small to moderate, and were off set by large increases in the risk of AEs and a high dropout rate.
Four of the 10 trials reported the number of patients experiencing any AE: 23% of those taking opioids vs 15% of patients on placebo.11 This represents an NNH of 12 (TABLE 1). All 10 trials reported the number of patients who withdrew due to AEs. Those receiving opioids were 4 times as likely to withdraw due to AEs, compared with those taking placebo. The NNH to cause one additional withdrawal was 19 (95% CI, 13-29).
Bottom line
The data highlight both the limited role of opioids (including tramadol) in OA treatment and—when they are being considered for this patient population—the importance of making patients aware that the risks may outweigh the benefits. Used judiciously and with adequate patient counseling, tramadol may be an option when COX-2-specific inhibitors and NSAIDs fail or cannot be tolerated. Although the small-to-moderate benefits of non-tramadol opioids are generally outweighed by large increases in the risk of AEs, their use may be considered for severe OA pain if tramadol is ineffective or causes intolerable AEs.
CORRESPONDENCE
Faline Howes, BMedSci, MBBS, MPH, FRACGP, Menzies Research Institute Tasmania, Private Bag 23, University of Tasmania, Hobart, Tasmania, Australia 7001; Faline.Howes@ utas.edu.au
Osteoarthritis (OA) affects nearly 27 million Americans, or about 12% of US adults.1 As the average age of the population increases, the prevalence and burden of this debilitating disorder continue to rise.2
The American College of Rheumatology (ACR)’s guidelines for the medical management of OA of the hip and knee, last updated in 2000,3 focus on controlling pain and improving function and health-related quality of life while minimizing the toxic effects of therapy. The guidelines recommend tramadol—an atypical opioid with 2 distinct mechanisms of action4—for moderate-to-severe pain in OA patients who either have contraindications to COX-2 inhibitors and non steroidal anti-inflammatory drugs (NSAIDs) or have failed to respond to previous oral therapy. Patients with severe pain who don’t respond to or are unable to tolerate tramadol may be candidates for more traditional opioid therapy, the guidelines indicate.3
In recent years, however, the use (and abuse) of opioids has skyrocketed. Between 1997 and 2007, US per capita retail purchases of hydrocodone and oxycodone increased 4-fold and 9-fold, respectively.5 In a similar time frame (1996-2006), the number of deaths from opioid overdose more than tripled, going from 4000 to 13,800 annually.6 Not surprisingly, the use of narcotics for noncancer pain remains controversial.7,8 But inadequately treated pain continues to be a serious public health problem, as well.9
This is the third in a series of articles based on the findings of the Cochrane Musculoskeletal Group (CMSG). One of the largest groups in the Cochrane Collaboration, the CMSG synthesizes the results of clinical trials to determine whether interventions for the prevention, treatment, and rehabilitation of musculoskeletal disorders are safe and effective. In this installment, the reviewers use detailed analysis, as well as a case study, to bring their findings to the attention of family physicians in a practical, clinically relevant context.
In 2006 and 2009, respectively, the Cochrane Collaboration published systematic reviews of tramadol (for OA in any joint)10 and other oral and transdermal opioids (for OA of the hip or knee).11 The reviewers’ findings, presented here along with data from more recent trials, can help ensure that you prescribe opioids for patients with OA only when their use is clinically appropriate and evidence-based. We’ve also included a case study (see page 211), so you can assess your knowledge and clinical skills.
CASE Carol J, an active 72-year-old, was diagnosed with OA in her right hip 5 years ago. Now she reports that the pain is getting progressively worse, making it harder and harder to turn over in bed at night or get in and out of the car. The pain is particularly bad at night, Carol says, and she’s had interrupted sleep for months. The patient has taken acetaminophen for the pain since her OA diagnosis, but now finds the analgesic is ineffective, even at the maximum dose of 4 g per day.
Carol has hypertension, which was difficult to manage until she began taking a combination ACE inhibitor/diuretic. She also has moderate renal impairment and mild chronic obstructive pulmonary disease, which limits her exercise tolerance. Nonetheless, she continues to smoke. The patient lives with and cares for her husband, who has Alzheimer’s disease, and worries about her ability to continue to care for him.
What are her treatment options?
Full-dose acetaminophen is no longer helping Carol, and NSAIDs are contraindicated because she takes an ACE inhibitor/diuretic and has moderate renal impairment. Increasing exercise will be a challenge. You strongly encourage her to stop smoking, emphasizing that this is particularly important to reduce the risk involved with any future joint replacement surgery.
Oral dosing options for the patient include:
- prescribing tramadol, starting with a low-dose immediate-release formulation taken one hour before bedtime (The controlled-release formulation is not advisable, given her age and renal function.) or
- adding a traditional opioid, eg, codeine 30 to 60 mg every 6 hours as needed, to her regular acetaminophen regimen.
Codeine and hydrocodone are available in combination preparations with acetaminophen, which may be convenient for some patients. However, hydrocodone was not one of the opioids tested in the trials included in the Cochrane reviews, and evidence of its use in OA is lacking.
Intra-articular corticosteroid injection, performed under imaging guidance, is another option for Carol. You explain that although there have been no studies of intra-articular corticosteroid injections for OA of the hip, these are used occasionally and may provide short-term symptom relief.7
You emphasize that surgery is likely to give her the best long-term outcome. In view of the patient’s circumstances and the need to care for her husband, however, you prescribe tramadol 50 mg at night. (Because of Carol’s age, renal impairment, and the possible adverse effects, it’s wise to start with a low dose and titrate upwards.) You warn her of the risks associated with opioids and advise her to alert your office staff if she experiences any adverse effects.
Before the patient leaves, you arrange an orthopedic consult and schedule a return visit for the following week. At your urging, she agrees to look into respite options for her husband.
Tramadol produces modest results—or none at all
The tramadol review10 included 11 randomized controlled trials (RCTs) with a total of 1019 participants who took tramadol or tramadol/acetaminophen (paracetamol) and 920 controls. In 6 of the 11 studies, the controls received placebo; the remaining 5 trials used “active controls,” with the control group for each RCT receiving a different analgesic. (To learn more about the methodology, see “How the reviews were conducted”.)
Placebo-controlled trials. Compared with patients on placebo, those receiving tramadol had an average absolute reduction in pain of 8.5 mm on a 0-100 mm visual analog scale (VAS) (95% confidence interval [CI], -12.05 to -4.9). That small benefit, however, did not reach the level defined as the minimal perceptible clinical improvement—a reduction of 9.7 mm on Western Ontario and McMaster Universities (WOMAC)’s OA pain subscale.12
Active-controlled trials. In the 5 RCTs comparing tramadol with another active agent, tramadol proved to be no better than the control drug. In fact, in a study of tramadol vs acetaminophen, 500 mg acetaminophen 3 times a day provided more pain relief than 50 mg tramadol 3 times a day.13 Although this was a small (N=20), short-term (7-day) study, this finding is notable because participants took less than the usual acetaminophen dose of 1 g up to 4 times a day.
Nor was tramadol superior to the agents it was compared with in the 4 other active-controlled trials—dihydrocodeine,14 dextropropoxyphene,15 pentazocine,16 and diclofenac17—in reducing pain intensity. It is important to keep in mind, however, that in each of these studies, both the quantity and quality of the evidence was limited. (Two studies did not use numerical scales,14,16 for example; all had methodological issues; and none lasted longer than 28 days.)
The Cochrane Musculoskeletal Group conducted a review of tramadol and a review of other oral opioids and transdermal fentanyl for the treatment of osteoarthritis (OA). Both reviews featured pain, function, and safety as primary outcomes. The tramadol review included randomized controlled trials (RCTs) for OA in any joint, while the oral and transdermal opioid review included randomized and quasi-randomized trials of treatment for OA of the hip or knee. Other parameters follow:
The tramadol review included 11 RCTs, with a total of 1019 participants receiving either tramadol alone or tramadol/acetaminophen (paracetamol) and 920 controls. In 6 of the 11 studies, the controls received placebo; the remaining 5 studies featured “active control.” That is, the control groups received acetaminophen 500 mg 3 times daily, diclofenac (25-50 mg up to 3 times daily on demand), dihydrocodeine 60 mg twice daily, dextropropoxyphene 100 mg 3 times daily, or pentazocine 50 mg 4 times per day. Because each of these agents was used in only one trial, the reviewers could not reach definitive conclusions about tramadol’s performance relative to other medications. The average number of participants in the tramadol and control groups was 91 and 80, respectively. The average length of follow-up was 35 days.
The 11 RCTs included in this review used a variety of pain scales to assess the results of tramadol, active control medications, and placebo. For comparative purposes, the reviewers pooled the results from studies that used numerical scales (0 to 100 and 0 to 10) to assess pain intensity. As a reference, we have used 9.7 and 9.3, respectively, determined by other researchers to be the minimal perceptible clinical improvements on the Western Ontario and McMaster Universities (WOMAC) pain and physical function 0-100 mm visual analog scales.12
The review of oral and transdermal opioids included 10 studies, with a total of 1541 patients receiving opioids and 727 receiving placebo.17 There were 3 trials of codeine (in 2 of the 3, a simple analgesic [acetaminophen 3000 mg/d or ibuprofen 1200 mg/d] was co-administered to both the treatment and control groups); other opioids included in the trials were oxycodone (4 trials), oxymorphone (2 trials), morphine (1 trial), and transdermal fentanyl (1 trial).
A modest boost in well-being
The reviewers measured function in 2 ways, focusing on both global improvement and improvement in physical function.
Global assessment. For the global assessment, the reviewers defined a treatment response as achieving at least a moderate improvement. By that standard, tramadol may improve overall well-being more than placebo. In the placebo-controlled trials, the number needed to treat (NNT) to elicit one treatment response was 6.
Three of the trials with active controls included global/functional assessments, and the results—bearing in mind the reduced quality and quantity of the evidence—were mixed. In a comparison of tramadol with dextropropoxyphene, tramadol increased the likelihood of moderate improvement by 38% (relative risk, 1.38 (95% CI, 1.15-1.67).10 In a trial of tramadol vs pentazocine, tramadol was more effective in reducing the duration of morning stiffness (by about 10 minutes), but not its severity. Tramadol was comparable with pentazocine in the 7 other measures of OA and function.16 In the tramadol-diclofenac study, both drugs were equally effective.17
Physical function. Four of the 6 placebo-controlled tramadol studies included in the Cochrane review used the WOMAC Index score, which included the physical function subscale. The tramadol group had a larger reduction in the score than the placebo group, by 0.34 mm (95% CI, -0.49 to -0.19). While this was equivalent to an 8.5% relative reduction in mean baseline score, it is still small compared with the minimal perceptible clinical improvement level of 9.3 mm on a 0-100 scale needed for the WOMAC physical function subscale. A similar improvement was reported for those taking tramadol compared with diclofenac—the only one of the active-controlled studies to report on physical function.17
Other opioids relieve pain, improve function—but how much?
The review of oral and transdermal opioids for OA11 encompassed 10 trials, with a total of 1541 patients receiving opioids and 727 on placebo. The opioids used in the trials were codeine, oxycodone, oxymorphone, morphine, and transdermal fentanyl. (For more details, see “How the reviews were conducted”.)
Pain. The trials included in the review used a variety of scales to measure pain, so the reviewers gauged results by the proportion of patients responding to treatment. Response was defined as a 50% improvement in pain score.
In the overall analysis, 35% of patients taking opioids responded to treatment, vs 31% of those on placebo—or 4 more patients in 100. That represents an NNT of 25. (A subgroup analysis did not demonstrate any significant differences in effect size among the opioids tested. In addition, the effect size was similar regardless of the potency of the opioid or the administration route.)
Function. Seven of the 10 trials (1794 participants, including both the treatment groups and controls) used validated function scores to measure physical function after 4 weeks of treatment. Here, too, the reviewers defined a treatment response as a 50% improvement in score.
Their finding? Opioids had a greater effect on function compared with placebo, equaling 0.7 on a WOMAC disability scale of 1 to 10. This means that about 3 more patients in 100 responded to treatment with opioids vs placebo—an NNT of 30.
But what about safety?
Opioids, including tramadol, are associated with adverse events (AEs), which may be minor or major. To determine when, or whether, the benefits outweigh the risks for treating patients with OA, both reviews reported on AEs and the number of participants who stopped taking the drug because of AEs.
AEs limit tramadol’s usefulness
While tramadol was more effective than placebo at reducing pain intensity, relieving symptoms, and improving function, the benefits were small—with an overall NNT of 6 (TABLE 1). This is similar to acetaminophen (NNT, 4-16),18 but with a greater downside.
Minor AEs. Four placebo-controlled trials reported on minor AEs.19-22 Those most commonly reported by patients taking tramadol were nausea, vomiting, dizziness, constipation, somnolence, tiredness, and headache.
Overall, 39% of those who received tramadol experienced minor AEs, compared with 18% of patients receiving placebo—an NNH of 5.10 Thus, tramadol’s NNH for minor AEs is equivalent to its NNT for pain relief. In active-controlled studies, there was a higher risk of minor AEs in those receiving tramadol compared with diclofenac or dextropropoxyphene, but a lower risk compared with those taking pentazocine.10
Major AEs. An analysis of the placebo-controlled trials revealed that 21% of those who received tramadol had major AEs—defined as an event that resulted in cessation of treatment—compared with 8% of those taking placebo. By this measure, the NNH was 8: One in 8 patients stopped taking tramadol because of a major AE.10
Among the active-controlled trials, participants taking tramadol were more likely to report a major AE compared with those receiving either diclofenac or dextropropoxyphene (NNH=5), but less likely compared with patients taking pentazocine. In a trial that compared tramadol alone with paracetamol, 2 out of 10 in the tramadol group discontinued treatment; none in the paracetamol group did.13
TABLE 1
Tramadol and other opioids for OA pain: NNT and NNH
| Treatment | NNT | NNH |
|---|---|---|
| Tramadol10 | 6 | 5 |
| Opioids (overall)11 | 25 | 12 |
| NNH, number needed to harm; NNT, number needed to treat; OA, osteoarthritis. | ||
Post-review RCTs provide further evidence
We identified 4 double-blind RCTs of tramadol for the treatment of OA that were of at least 6 weeks’ duration,19-22 published after the 2006 review. The results of these studies (TABLE 2) were broadly consistent with those of the systematic review. Two of the 4 studies had active controls, with one comparing tramadol with diclofenac19 and the other with celecoxib.21 Tramadol and diclofenac were found to be equally effective; celecoxib appeared to be superior in terms of pain relief, global improvement, and physical function, but no statistical comparisons were reported.
TABLE 2
Tramadol for OA: Post-review RCTs are consistent with meta-analysis
| Study duration (N) | Intervention groups | Primary outcome measures | Improvement in | Adverse effects | ||
|---|---|---|---|---|---|---|
| Pain | Global assessment | Function | ||||
| Gana*20 12 wk (1020) | Tramadol ER Placebo | WOMAC OA index (pain and physical function subscales) 100-mm VAS: Subject global disease | Treatment groups, 35% Placebo, 25% | Treatment groups, 32%-36% Placebo, 24% | Treatment groups, 31%-33% Placebo, 22% | ≥1 AE Withdrawals due to AEs |
| Delemos*21 12 wk (1001) | Tramadol ER Placebo | WOMAC OA index (pain and physical function subscales) 100-mm VAS: Subject global disease | Tramadol, 27%-39% Celecoxib, 45% Placebo, 32% | Tramadol, 28%-40% Celecoxib, 44% Placebo, 30% | Tramadol, 26%-35% Celecoxib, 43% Placebo, 28% | ≥1 AE Withdrawals due to AEs |
| Burch†22 12 wk (646) | Tramadol (Contramid OAD) 100 mg titrating to 300 mg Placebo | Pain intensity (11-point numerical scale) Physician/patient global impressions of change (7-point scale) | Treatment group, 40% Placebo, 33% | Treatment group, 80% Placebo, 69% | NA | AEs Placebo: Nausea, 5.6%; constipation, 4.2%; dizziness/vertigo, 3.7%; somnolence, 3.7% Withdrawals due to AEs |
| Beaulieu*19 6 wk (128) | Tramadol CR 200 mg titrating to 400 mg Diclofenac SR 75 mg titrating to 150 mg | WOMAC OA index (pain and physical function subscales) 100-mm VAS: Pain intensity Subject global disease Physician/patient global impressions of change (7-point scale) | Both groups, ~29% | Tramadol, 67%‡ Diclofenac, 54%‡ | Tramadol, 29%‡ Diclofenac, 29%‡ | Withdrawals due to AEs Tramadol, 16% Diclofenac, 15% |
| *Hip or knee osteoarthritis. †Knee osteoarthritis. ‡Not statistically significant. AEs, adverse events; CR, controlled release; ER, extended release; NA, not assessed; OA, osteoarthritis; OAD, once a day; RCTs, randomized controlled trials; SR, sustained release; VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities. | ||||||
Oral and transdermal opioids: Pain relief but high risk
Among the patients with OA of the hip or knee—the study population for the review of oral and transdermal opioids—all the opioids tested were more effective than placebo. The benefits, however, were small to moderate, and were off set by large increases in the risk of AEs and a high dropout rate.
Four of the 10 trials reported the number of patients experiencing any AE: 23% of those taking opioids vs 15% of patients on placebo.11 This represents an NNH of 12 (TABLE 1). All 10 trials reported the number of patients who withdrew due to AEs. Those receiving opioids were 4 times as likely to withdraw due to AEs, compared with those taking placebo. The NNH to cause one additional withdrawal was 19 (95% CI, 13-29).
Bottom line
The data highlight both the limited role of opioids (including tramadol) in OA treatment and—when they are being considered for this patient population—the importance of making patients aware that the risks may outweigh the benefits. Used judiciously and with adequate patient counseling, tramadol may be an option when COX-2-specific inhibitors and NSAIDs fail or cannot be tolerated. Although the small-to-moderate benefits of non-tramadol opioids are generally outweighed by large increases in the risk of AEs, their use may be considered for severe OA pain if tramadol is ineffective or causes intolerable AEs.
CORRESPONDENCE
Faline Howes, BMedSci, MBBS, MPH, FRACGP, Menzies Research Institute Tasmania, Private Bag 23, University of Tasmania, Hobart, Tasmania, Australia 7001; Faline.Howes@ utas.edu.au
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19. Beaulieu AD, Peloso PM, Haraoui B, et al. Once-daily, controlled-release tramadol and sustained-release diclofenac relieve chronic pain due to osteoarthritis: a randomized controlled trial. Pain Res Manag. 2008;13:103-110.
20. Gana TJ, Pascual ML, Fleming RR, et al. Extended-release tramadol in the treatment of osteoarthritis: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Curr Med Res Opin. 2006;22:1391-1401.
21. Delemos BP, Xiang J, Benson C, et al. Tramadol hydrochloride extended-release once-daily in the treatment of osteoarthritis of the knee and/or hip: a double-blind, randomized, dose-ranging trial. Am J Ther. 2010 Mar 3 [Epub ahead of print].
22. Burch F, Fishman R, Messina N, et al. A comparison of the analgesic efficacy of Tramadol Contramid OAD versus placebo in patients with pain due to osteoarthritis. J Pain Symptom Manage. 2007;34:328-338.
1. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58:26-35.
2. Bitton R. The economic burden of osteoarthritis. Am J Manag Care. 2009;15(suppl):S230-S235.
3. Altman RD, Hochberg MC, Moskowitz RW, et al. Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum. 2000;43:1905-1915.
4. Gibson TP. Pharmacokinetics, efficacy, and safety of analgesia with a focus on tramadol HCl. Am J Med. 1996;101(suppl 1A):47S-53S.
5. Hall AJ, Logan JE, Toblin RL, et al. Patterns of abuse among unintentional pharmaceutical overdose fatalities. JAMA. 2008;300:2613-2620.
6. Warner M, Chen LH, Makuc DM. Increase in fatal poisonings involving opioid analgesics in the United States, 1999-2006. NCHS data brief, no 22. Hyattsville, MD: National Center for Health Statistics; 2009.
7. Von Korff M, Deyo RA. Potent opioids for chronic musculoskeletal pain: flying blind? Pain. 2004;109:207-209.
8. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage. 2008;16:137-167.
9. Pletcher MJ, Kertesz SG, Kohn MA, et al. Trends in opioid prescribing by race/ethnicity for patients seeking care in US emergency departments. JAMA. 2008;299:70-78.
10. Cepeda MS, Camargo F, Zea C, et al. Tramadol for osteoarthritis. Cochrane Database Syst Rev. 2006;(3):CD005522.-
11. Nuesch E, Rutjes AW, Husni E, et al. Oral or transdermal opioids for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2009;(4):CD003115.-
12. Ehrich EW, Davies GM, Watson DJ, et al. Minimal perceptible clinical improvement with the Western Ontario and McMaster Universities osteoarthritis index questionnaire and global assessments in patients with osteoarthritis. J Rheumatol. 2000;27:2635-2641.
13. Bianchi M, Broggini M, Balzarini P, et al. Effects of tramadol on synovial fluid concentrations of substance P and interleukin-6 in patients with knee osteoarthritis: comparison with paracetamol. Int Immunopharm. 2003;3:1901-1908.
14. Wilder-Smith C, Hill L, Spargo K, et al. Treatment of severe pain from osteoarthritis with slow-release tramadol or dihydrocodeine in combination with NSAIDs: a randomised study comparing analgesia, antinociception and gastrointestinal effects. Pain. 2001;91:23-31.
15. Jensen E, Ginsberg F. Tramadol versus dextropropoxyphene in the treatment of osteoarthritis: a short-term double-blind study. Drug Invest. 1994;8:211-218.
16. Bird H, Hill J, Stratford M, et al. A double-blind cross-over study comparing the analgesic efficacy of tramadol with pentazocine in patients with osteoarthritis. J Drug Dev Clin Pract. 1995;7:181-188.
17. Pavelka K, Peliskova Z, Stehlikova H, et al. Intraindividual differences in pain relief and functional improvement in osteoarthritis with diclofenac or tramadol. Clin Drug Invest. 1998;16:421-429.
18. Townheed TE, Maxwell L, Judd MG, et al. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev. 2006;(1):CD004257.-
19. Beaulieu AD, Peloso PM, Haraoui B, et al. Once-daily, controlled-release tramadol and sustained-release diclofenac relieve chronic pain due to osteoarthritis: a randomized controlled trial. Pain Res Manag. 2008;13:103-110.
20. Gana TJ, Pascual ML, Fleming RR, et al. Extended-release tramadol in the treatment of osteoarthritis: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Curr Med Res Opin. 2006;22:1391-1401.
21. Delemos BP, Xiang J, Benson C, et al. Tramadol hydrochloride extended-release once-daily in the treatment of osteoarthritis of the knee and/or hip: a double-blind, randomized, dose-ranging trial. Am J Ther. 2010 Mar 3 [Epub ahead of print].
22. Burch F, Fishman R, Messina N, et al. A comparison of the analgesic efficacy of Tramadol Contramid OAD versus placebo in patients with pain due to osteoarthritis. J Pain Symptom Manage. 2007;34:328-338.
When do bisphosphonates make the most sense?
An estimated 10 million US residents, most of them women over the age of 50, suffer from osteoporosis, and another 33 million have low bone mass.1 Together, they incur more than 2 million osteoporotic fractures annually.1,2 In addition to the high cost of a single osteoporotic fracture in terms of morbidity, mortality, and health care spending, individuals who sustain one such fracture are at high risk for another. That risk can be greatly reduced with appropriate treatment.
Bisphosphonates, which act on osteoclasts to inhibit bone resorption, are first-line therapy for prevention of osteoporotic fractures. Four bisphosphonates—alendronate, ibandronate, risedronate, and zoledronic acid—are approved by the US Food and Drug Administration (FDA) for the treatment of postmenopausal osteoporosis.
While menopause itself increases a woman’s risk for osteoporotic fracture, questions remain about when to initiate preventive therapy, which patients are candidates for bisphosphonates, and whether bisphosphonates are effective for primary as well as secondary prevention. This overview from the Cochrane Musculoskeletal Group (CMSG) addresses those questions.
To help you provide optimal treatment for postmenopausal patients, we present the findings of recently conducted systematic reviews of 2 bisphosphonates—alendronate and risedronate—from the Cochrane Database of Systematic Reviews,3,4 in context with the available evidence on the efficacy of ibandronate and zoledronic acid. Cochrane reviews of ibandronate and zoledronic acid are underway, but not yet completed.5,6
This is the second in a series of articles based on the findings of the Cochrane Musculoskeletal Group (CMSG), one of the largest review groups in the Cochrane Collaboration. The CMSG synthesizes the results of high-quality clinical trials to determine whether interventions for the prevention, treatment, and rehabilitation of musculoskeletal disorders are safe and effective. In this article and those that follow, CMSG’s aim is to bring its findings to the attention of family physicians in a context that is relevant to clinical practice.
Alendronate reduces vertebral fracture risk across the board
Wells et al identified 11 RCTs for the alendronate review (3 primary and 8 secondary prevention trials), representing a total of 12,068 women.3 (For definitions of what constituted a primary vs a secondary prevention trial, see the box.)
Doses of alendronate ranged from 1 to 20 mg daily, with most studies using doses of 5 or 10 mg. Treatment duration ranged from 1 to 4 years.
A look at the relative risk (RR) for primary and secondary prevention at different fracture sites (TABLE 1) highlights similarities and differences. The risk reduction for vertebral fractures was statistically significant—and about the same—for women being treated with alendronate for primary and secondary prevention (RR=0.55; 95% confidence interval [CI], 0.38-0.80; RR=0.55; 95% CI, 0.43-0.69, respectively). For all other (nonvertebral) fractures in patients being treated with alendronate, only the outcomes for secondary prevention were statistically significant.
The Cochrane reviewers studied the effects of alendronate and risedronate3,4 for both primary and secondary prevention of osteoporotic fractures in postmenopausal women, using the following definitions (with slight variations in definitions between trials):
Primary prevention. Randomized controlled trials were classified as primary prevention trials if the participants had baseline T-scores >–2.0 or a baseline prevalence of vertebral fracture <20%.
Secondary prevention. Studies were classified as secondary prevention trials if the women had baseline T-scores ≤–2.0 (ie, bone mineral density [BMD] ≥2 standard deviations below peak bone mass) or previous vertebral compression fractures. (In the ibandronate individual patient meta-analysis,14 secondary prevention was defined as lumbar spine T-score <–2.5 or baseline vertebral fracture prevalence >20% or mean age of participants >60 years.)
Age-based criterion. When data on T-scores and/or vertebral compression fractures were unavailable, age was the determinant: Trials were considered secondary prevention if the average age of the participants was >62 years, and primary prevention if the average age was ≤62.
Risedronate is effective only for secondary prevention
Seven RCTs, including 2 primary and 5 secondary prevention trials, were included in the Cochrane review of risedronate, representing a total of 14,049 women.4 Doses ranged from 2.5 to 5 mg daily, but also included cyclical dosing—for example, taking 5 mg/d for the first 2 weeks of every month. Treatment duration ranged from 2 to 3 years.
At doses of 5 mg/d, there were no statistically significant decreases in fracture risk at any site in the primary prevention trials (TABLE 1), although the quality of evidence assessed was low. For secondary prevention, however, the risk reduction for vertebral fracture was significant (RR=0.61; 95% CI, 0.50-0.76), as were the reductions in risk for nonvertebral and hip fractures.
TABLE 1
Fracture risk reduction: How the bisphosphonates compare*
| Study | Vertebral fracture RR (95% CI) | Nonvertebral fracture (hip, wrist, others) RR (95% CI) | Hip fracture RR (95% CI) | Wrist fracture RR (95% CI) |
|---|---|---|---|---|
| Primary prevention | ||||
| Alendronate3 | 0.55 (0.38-0.80) | 0.89 (0.76-1.04) | 0.79 (0.44-1.44) | 1.19 (0.87-1.62) |
| Risedronate4 | 0.97 (0.42-2.25) | 0.81 (0.25-2.58) | N/A | N/A |
| Secondary prevention | ||||
| Alendronate3 | 0.55 (0.43-0.69) | 0.77 (0.64-0.92) | 0.47 (0.26-0.85) | 0.50 (0.34-0.73) |
| Risedronate4 | 0.61 (0.50-0.76) | 0.80 (0.72-0.90) | 0.74 (0.59-0.94) | 0.67 (0.42-1.07)† |
| Ibandronate15,16 Oral daily Oral intermittent | 0.62 (0.42-0.75) 0.50 (0.26-0.66) | No effect)‡ No effect | N/A N/A | N/A N/A |
| Zoledronic acid22 | 0.30 (0.2-0.38) | 0.75)§ (N/A) | 0.59¶ (0.42-0.83) | N/A |
| CI, confidence interval; N/A, not available; RR, relative risk. *Bold type indicates statistical significance (P<.05). †P=.10. ‡RR of nonvertebral fracture was 0.69 (P=.013) for daily oral ibandronate in the subgroup with femoral neck BMD T-score <–3.0. §P<.001. ¶Hazard ratio. | ||||
What are the absolute benefits? A look at number needed to treat
In addition to looking at the RR, the authors of both the alendronate and risedronate reviews calculated the number needed to treat (NNT) to prevent one fracture (TABLE 2) in the trial participants;3,4 they focused on the secondary prevention outcomes, as these were statistically significant. The reviewers also estimated what the NNT would be if the risk reductions achieved with alendronate and risedronate in the reviews occurred when treating community-based samples of women at moderate compared with high fracture risk.
The biggest differences involved hip fracture: For alendronate, if a community-based sample of women at moderate risk of fracture were treated with the drug and the reduction in RR seen in the secondary prevention trials applied, the NNT would be 100. Thus, for every 100 women treated for 5 years with alendronate, 1 hip fracture would be prevented. However, if this same RR reduction were applied to women at high risk of fracture, the NNT would be only 22.3 For risedronate, the estimated NNT to prevent one hip fracture in women at moderate risk was 203, compared with only 45 for women at high risk.4 These estimates indicate that the benefits of bisphosphonate therapy in preventing fractures are greatest in women with a high underlying fracture risk.
TABLE 2
NNT analysis: Women at higher risk are most likely to benefit3,4
| NNT | |||
|---|---|---|---|
| Observed in secondary prevention trials in reviews | Estimated for community-based sample of women with | ||
| High fracture risk* | Moderate fracture risk* | ||
| Alendronate (10 mg/d) | |||
| Vertebral fracture | 19 | 20 | 42 |
| Nonvertebral fracture | 47 | 16 | 27 |
| Hip fracture | 146 | 22 | 100 |
| Wrist fracture | 69 | N/A | N/A |
| Risedronate (5 mg/d) | |||
| Vertebral fracture | 19 | 23 | 49 |
| Nonvertebral fracture | 49 | 19 | 31 |
| Hip fracture | 138 | 45 | 203 |
| Wrist fracture | N/A | N/A | N/A |
| N/A, not available; NNT, number needed to treat. *NNT calculated by applying the relative risk reduction observed in the reviews to published estimates of 5-year fracture risk in a community-based sample of women >50 years of age at moderate and high risk. | |||
Adverse effects do not increase with longer-term treatment
In both the alendronate and risedronate reviews, adverse effects and the risk of discontinuing treatment due to adverse events were similar in the intervention and control groups.3,4 Postmarketing data suggest that there is potential for upper gastrointestinal (GI) problems, however;7 osteonecrosis of the jaw has also been reported infrequently.8,9 More recently, there have been reports of a possible link between bisphosphonates and atypical femoral fractures, which we’ll say more about in a bit.
Some potential adverse events—eg, osteonecrosis of the jaw and atypical femoral fractures—may be related to treatment duration. The maximum duration of the trials included in these meta-analyses was 4 years for alendronate and 3 years for risedronate. However, additional published data do not appear to support a relation between adverse events and treatment duration.
For alendronate, researchers extended the Fracture Incidence Trial (FIT) for a 10-year follow-up,10,11 comparing women who took the drug for the first 5 years with women who took it for 10 years. Adverse effects were similar in both groups.
For risedronate, researchers followed a small subsample (n=164) of the participants in the Vertical Efficacy with Risedronate Therapy (VERT) Study Group for up to 7 years.12,13 For the first 5 years, half of the participants took 5 mg/d risedronate, while the other half took a placebo. During the final 2 years, all participants received 5 mg/d risedronate. The incidence of adverse events among those who took the drug for 7 years was similar to that reported in the first 3 years of the original trial.13
Ibandronate studies focus on dose
Nonvertebral fracture. The Cochrane systematic review examining ibandronate for postmenopausal osteoporosis is not yet completed.5 However, Cranney et al performed a pooled analysis of individual patient data from 8 RCTs to examine the efficacy of different doses of the drug for the secondary prevention of nonvertebral fracture.14 (No studies of the drug for primary prevention have been done.) After 2 years of treatment at higher doses of ibandronate (annual cumulative exposure ≥10.8 mg, equivalent to 150 mg orally/month, 3 mg IV quarterly, or 2 mg IV every 2 months), the hazard ratio was 0.62 (95% CI, 0.396-0.974), compared with those taking lower doses (annual cumulative exposure of 5.5 mg). The individual results of the 2 largest trials did not demonstrate an effect on nonvertebral fracture, except in the subgroup of women with very low femoral neck bone mineral density (BMD) (T-scores <–3.0). 15-17
Vertebral fracture. There is no meta-analysis available with vertebral fracture outcomes for ibandronate, so we present the results of individual secondary prevention trials.
One was a double-blind RCT with 2496 participants, comparing women taking either 2.5 mg/d of ibandronate or 20 mg on alternate days with a group on placebo.15,16 The results? Those in both the daily and the intermittent treatment arms had significant risk reductions (RR=0.62; 95% CI, 0.42-0.75; RR=0.50; 95% CI, 0.26-0.66, respectively), after taking the drug for 3 years (TABLE 1), compared with those on placebo.15,16 The other RCT—a trial in which 2862 women received either quarterly intravenous (IV) injections of 1 or 0.5 mg ibandronate or placebo—did not demonstrate a significant reduction in vertebral fracture.17 This was attributed to an insufficient dose of the drug, a supposition supported by improvements in BMD in patients receiving higher doses of ibandronate.18,19
Oral ibandronate has been well tolerated in clinical trials in terms of GI side effects.20,21 Injection site reactions have been reported in those receiving IV infusions,17 and both IV and monthly oral ibandronate may be associated with mild, self-limiting flu-like symptoms.
Zoledronic acid RCTs show reduced fracture, mortality risk
Black et al studied the efficacy of zoledronic acid in a randomized, double-blind, placebo-controlled trial of 7736 postmenopausal women between the ages of 65 and 89 years.22 The women, all of whom had osteoporosis, received an IV infusion of either zoledronic acid (5 mg) or placebo at baseline, and again at 12 and 24 months. Vertebral and nonvertebral fractures, as well as hip fracture, were significantly reduced in the treatment group compared with placebo (TABLE 1).
In another RCT with 2127 participants, Lyles et al examined the effectiveness of 5 mg zoledronic acid IV given within 90 days of surgical repair of a hip fracture. In the intervention group, there was a 35% risk reduction in new clinical fractures (8.6% vs 13.9% for those on placebo; P=.001); mortality was also lower in the zoledronic acid group (9.6% vs 13.3%; P=.01).23
In both trials, the number of patients who had serious adverse events or dropped out because of an adverse event was similar in the treatment and placebo groups. In both studies, too, a sizeable number of patients treated with zoledronic acid reported flu-like symptoms up to 3 days after receiving an infusion, particularly after the first one. Cardiovascular events were similar across intervention groups in both studies, with one exception: In Black’s study,22 there was an increased incidence of serious atrial fibrillation in the zoledronic acid group (1.3% vs 0.5% for the placebo group).
Other issues to keep in mind
Atypical femoral fractures. Published data suggest an association between bisphosphonate use and atypical femoral fractures, particularly with longer-term use,24 although whether there is a causal link is unclear. Atypical femoral fractures occur with little or no trauma along the femur from just distal to the lesser trochanter to just proximal to the supracondylar flare.
In 2010, the FDA announced requirements for a black box warning about a possible link,25 highlighting the uncertainty about both the optimal duration of bisphosphonate therapy and the cause of these fractures.
While concerns about such a link remain, it is important to note that atypical femoral fractures are very uncommon: Current estimates are that they account for less than 1% of hip/femoral fractures. What’s more, far more fractures are prevented by the use of bisphosphonates than are associated with their use, with an estimated ratio of up to 29:1.24
Dosing schedules. Adherence to treatment is of key importance in maximizing outcomes from osteoporosis treatments, and is frequently low.26,27 One way of improving adherence is to reduce the frequency of dosing required.27 With that in mind, researchers have tested intermittent dosing regimens, using noninferiority or bridging trials.
Such studies have led to a number of approved dosing regimens—70 mg weekly for alendronate; 150 mg monthly and 35 mg weekly for risedronate; and 150 mg PO monthly and 3 mg IV quarterly for ibandronate among them. In making decisions about dosing, family physicians should consider patient preferences, but be aware that there are no direct efficacy data from RCTs to support these dosing regimens.
Calcium and vitamin D. The major fracture prevention trials of bisphosphonates have featured women who are calcium- and vitamin D-replete. In a recent study of 1515 women undergoing treatment with alendronate, risedronate, or raloxifene, however, that wasn’t always the case. 28 After 13 months, 115 participants suffered from a new clinical fracture. The adjusted odds ratio for fractures in women with vitamin D deficiency compared with those with normal levels of vitamin D was 1.77 (95% CI, 1.20-2.59; P=.004), an indication of the importance of maintaining adequate vitamin D levels in patients taking bisphosphonates.
In clinical practice, it is important to ensure that patients being treated with bisphosphonates are not deficient in vitamin D. While direct evidence of poorer outcomes associated with low calcium levels is lacking, it is reasonable to also assess calcium intake and to ensure that patients have adequate intake of both. (For more on calcium and vitamin D requirements, see the Institute of Medicine’s recent report at http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Report-Brief.aspx) and “The IOM’s report on calcium and vitamin D: Should it change the way you practice?”.
“Dietary Reference Intakes for Calcium and Vitamin D,” the consensus report released by the Institute of Medicine (IOM) late last year (http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx) generated a great deal of attention because it concluded that postmenopausal women taking supplements may be getting too much calcium, and that few people need to take vitamin D. These findings, among others, left many physicians wondering how, or if, the IOM’s report should change the way they practice.
The Journal of Family Practice posed that question to Susan Williams, MD, MS, FACN, FACP, an internist at the Cleveland Clinic and a diplomate with the American Board of Physician Nutrition Specialists. Her response: The report probably shouldn’t change the way you practice.
Here, Dr. Williams explains why.
Recommended daily allowances are guidelines. The new dietary reference intakes (DRIs), like the recommended daily allowances (RDAs) they replace, are quantitative estimates of nutrient intakes intended for planning and assessing diets of healthy populations. They were never intended to be applied “across the board,” or used as a benchmark for the dietary adequacy of individual patients.
Testing is still advisable when there is clinical suspicion of a calcium or vitamin D deficiency. Because parathyroid hormone (PTH) compensates for calcium deficiency by drawing calcium from the bones, an adequate serum calcium level alone does not necessarily reflect an adequate calcium intake. In fact, a low serum calcium level is likely to be the result of abnormally low levels of vitamin D. Thus, the best way to get an accurate picture of a patient’s status is to simultaneously test serum calcium, vitamin D, and PTH levels.
Some patients require considerably larger doses of vitamin D than the recommended quantities.1,2 This is particularly true for obese individuals and patients who have undergone bariatric surgery, for example.3-5 The safety of daily dosing of vitamin D in far greater quantities has been established,6,7 and the risks of chronic undersupplementation8-10 outweigh the risks associated with hypervitaminosis D, particularly when D3 (cholecalciferol) supplements are recommended.
Calcium supplementation is safe for postmenopausal women. Many older women have poor dietary intake of calcium, and again, the consequences of a deficiency are far greater than those associated with an excess. The risk of kidney stones in women taking calcium supplements can be averted by advising patients to take calcium citrate, which tends to neutralize urine and has better fractional uptake into the bone than calcium carbonate.
The IOM report serves to remind us that getting adequate calcium and vitamin D is important for everyone. Age and gender-specific recommendations should be emphasized, remembering that in general, the IOM’s DRIs are likely to meet the actual needs of most healthy patients, but may well fall short in the presence of chronic illness and disease.
Remember, too, that while we should always emphasize the importance of eating foods that are rich in calcium and vitamin D, patients’ diets often fall short. In such cases—with the exception of patients with certain conditions (eg, renal failure or hyperparathyroidism)—supplements such as calcium citrate and vitamin D3 can be safely and confidently recommended.
Susan Williams, MD, MS, FACN, FACP, reported no potential conflict of interest relevant to this article.
References
1. Holick MF. The role of vitamin D for bone health and fracture prevention. Curr Osteoporos Rep. 2006;4:96-102.
2. Grant WB, Holick MF. Benefits and requirements of vitamin D for optimal health. Altern Med Rev. 2005;10:94-111.
3. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-281.
4. Bischoff-Ferrari HA, et al. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84:18-28.
5. Flores L, et al. Calcium and vitamin D supplementation after gastric bypass should be individualized to improve or avoid hyperparathyroidism. Obes Surg. 2010;20:738-743.
6. Vieth R, et al. Efficacy and safety of vitamin D intake exceeding the lowest observed adverse eff ect level. Am J Clin Nutr. 2001;73:288-294.
7. Barger-Lux MJ, et al. Vitamin D and its major metabolite: serum levels after graded oral dosing in healthy men. Osteoporos Int. 1998;8:222-230.
8. Sakuma M, et al. Vitamin D and intact PTH status in patients with hip fracture. Osteoporos Int. 2006;17:1608-1614.
9. Broe KE, et al. A higher dose of vitamin D reduces the risk of falls in nursing home residents. J Am Geriatr Soc. 2007;55:234-239.
10. Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly. Endocr Rev. 2001;22:477-501.
What’s best for your patients?
All these bisphosphonates have demonstrated efficacy for the secondary prevention of vertebral fracture. All except ibandronate have demonstrated efficacy for nonvertebral fracture, as well, and the evidence suggests that ibandronate will also be effective if adequate doses are given. Thus, for women at significant risk for fracture, it seems clear that the benefits of treatment outweigh the risks. The case is not so clearcut for women at lower risk. Evidence to support the use of bisphosphonates for primary prevention is limited, other than for alendronate—which has been shown to provide primary prevention of vertebral fracture.
Which bisphosphonate is best depends on patient preferences and individual profiles. (See “How would you treat these patients?”.) In the absence of head-to-head RCTs, it isn’t possible to comment on the relative efficacy of the various bisphosphonates or their adverse event profiles. Indeed, the authors of the 2 Cochrane reviews completed to date note that trial participants have been healthier, with fewer comorbidities, than many of the postmenopausal women seen by primary care physicians. Head-to-head studies conducted in family practice settings would be an important addition to the body of evidence for the prevention of osteoporotic fracture.
How would you treat these patients?
CASE 1 Mrs. A is an active 67-year-old in good health. On a recent hike, she lost her footing and sustained a Colles’ fracture when she fell, although her fall was only from standing height. Now, you are concerned that she might have osteoporosis.
A dual-energy x-ray absorptiometry (DXA) scan confirms this suspicion: Mrs. A’s lumbar spine T-score is –2.6. A dietary review reveals that she has a satisfactory calcium intake, and lab work shows that her serum vitamin D levels are normal. Mrs. A wants to discuss treatment options with you.
What immediate treatment do you consider?
Mrs. A has no contraindications to any FDA-approved treatment for osteoporosis; you suggest she begin taking bisphosphonates, explaining that they are first-line treatment to prevent subsequent osteoporotic fractures. You briefly discuss other options, but note that raloxifene only reduces the risk of vertebral fractures and parathyroid hormone is effective (but very expensive) and requires daily injections, and is therefore generally used for severe osteoporosis. Your patient asks about bisphosphonates’ side effects, particularly the serious jaw problems she’s heard about.
You explain that for the most part, oral bisphosphonates are well tolerated, but that there is a potential for upper gastrointestinal (GI) problems—which is why it’s important to remain upright for at least 30 minutes after taking the medication. You tell her that the risk of developing osteonecrosis of the jaw is very low when the medication is taken at the doses needed for osteoporosis treatment, but that the risk may increase after tooth extraction or dental surgery. Mrs. A has no current dental symptoms and at her usual yearly dental check-up 9 months ago, there were no problems noted, so dental review before starting treatment is not needed. Should she develop any jaw pain, however, she should see you or her dentist immediately.
You also advise her of the possible link between bisphosphonates and atypical femoral fracture, but point out that such fractures are extremely rare—and that the medication prevents far more fractures than it has the potential to cause. You tell her to contact you immediately if she develops pain in the groin or thigh or experiences GI distress.
Which bisphosphonate do you prescribe?
You inform Mrs. A that alendronate has the longest follow-up data of the oral bisphosphonates and has demonstrated efficacy for the secondary prevention of wrist fractures, that risedronate and ibandronate have the advantage of being able to be taken monthly rather than weekly, and that zoledronic acid can be administered in a yearly infusion. She opts for alendronate. You prescribe a weekly dose of 70 mg and ask her to return in 3 months, and to call before then if any problems arise.
CASE 2 Mrs. Y, age 82, recently sustained a fractured femoral neck, which was treated surgically at the local hospital. She was discharged with a prescription for alendronate to treat her osteoporosis and prevent further fractures; her husband has brought her in today to get a new prescription.
During the visit, he reminds you that Mrs. Y has problems with memory. He also says he’s finding it increasingly difficult to ensure that his wife remains upright for 30 minutes after taking alendronate, and that she has begun complaining of indigestion.
What do you decide to do?
An inability to stay upright for 30 minutes after drug administration is a contraindication to the use of oral bisphosphonates. The presence of upper GI symptoms is also a concern. You offer Mrs. Y the option of a once-yearly IV infusion of zoledronic acid instead, and she and her husband agree to this. Before scheduling a follow-up visit, you discuss the patient’s nutritional intake, and discover that she consumes only a moderate amount of calcium—at most 2 servings of dairy products per day. You also note that her serum vitamin D level was not checked in the hospital. You order lab work, with a view to correcting any deficiency before proceeding with a zoledronic infusion (due to the risk of tetany) and to maintaining her on an appropriate level of calcium and vitamin D intake, using supplements only if necessary.
CORRESPONDENCE Tania Winzenberg, MBBS, Menzies Research Institute, Private Bag 23, Hobart, Tasmania, Australia 7001; tania.winzenberg@utas.edu.au
1. National Osteoporosis Foundation. America’s bone health: the state of osteoporosis and low bone mass in our nation. Washington, DC: National Osteoporosis Foundation; 2002.
2. Burge R, Dawson-Hughes B, Solomon DH, et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res. 2007;22:465-475.
3. Wells GA, Cranney A, Peterson J, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 2008;(1):CD001155.-
4. Wells G, Cranney A, Peterson J, et al. Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 2008;(1):CD004523.-
5. Wang Q, Decai C. Ibandronate sodium for osteoporosis in post-menopausal women (Protocol). Cochrane Database Syst Rev. 2007;CD006514.-DOI:10.1002/14651858.
6. Albergaria BH, Gomes Silva BN, Atallah AN, et al. Intravenous zoledronate for postmenopausal osteoporosis (Protocol). Cochrane Database Syst Rev. 2010;(1):CD008332.-DOI:10.1002/14651858.
7. Anonymous. Australian Medicines Handbook. Adelaide, Australia: Australian Medicines Handbook Pty Ltd; 2007.
8. Silverman SL, Landesberg R. Osteonecrosis of the jaw and the role of bisphosphonates: a critical review. Am J Med. 2009;122 (suppl 2):S33-S45.
9. Reid IR. Osteonecrosis of the jaw: who gets it, and why? Bone. 2009;44:4-10.
10. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927-2938.
11. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280:2077-2082.
12. 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.
13. Mellstrom DD, Sorensen OH, Goemaere S, et al. Seven years of treatment with risedronate in women with postmenopausal osteoporosis. Calcif Tissue Int. 2004;75:462-468.
14. Cranney A, Wells GA, Yetisir E, et al. Ibandronate for the prevention of nonvertebral fractures: a pooled analysis of individual patient data. Osteoporos Int. 2009;20:291-297.
15. Chesnut IC, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241-1249.
16. Delmas PD, Recker RR, Chesnut CH, et al. Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study. Osteoporosis Int. 2004;15:792-798.
17. Recker R, Stakkestad JA, Chesnut CH, et al. Insufficiently dosed intravenous ibandronate injections are associated with suboptimal antifracture efficacy in postmenopausal osteoporosis. Bone. 2004;34:890-899.
18. Adami S, Felsenberg D, Christiansen C, et al. Efficacy and safety of ibandronate given by intravenous injection once every 3 months. Bone. 2004;34:881-889.
19. Delmas PD, Adami S, Strugala C, et al. Intravenous ibandronate injections in postmenopausal women with osteoporosis. One-year results from the dosing intravenous administration study. Arthritis Rheum. 2006;54:1838-1846.
20. Epstein S, Delmas PD, Emkey R, et al. Oral ibandronate in the management of postmenopausal osteoporosis: review of upper gastrointestinal safety. Maturitas. 2006;54:1-10.
21. Ettinger MP, Felsenberg D, Harris ST, et al. Safety and tolerability of oral daily and intermittent ibandronate are not influenced by age. J Rheumatol. 2005;32:1968-1974.
22. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809-1822.
23. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-1809.
24. Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010;25:2267-2294.
25. US Food and Drug Administration. FDA Drug Safety Communication: Safety update for osteoporosis drugs, bisphosphonates, and atypical fractures. October 13, 2010. Available at: http://www.fda.gov/drugs/drugsafety/ucm229009.htm. Accessed December 7, 2010.
26. Seeman E, Compston J, Adachi J, et al. Non-compliance: the Achilles’ heel of anti-fracture efficacy. Osteoporos Int. 2007;18:711-719.
27. Cramer JA, Gold DT, Silverman SL, et al. A systematic review of persistence and compliance with bisphosphonates for osteoporosis. Osteoporos Int. 2007;18:1023-1031.
28. Adami S, Giannini S, Bianchi G, et al. Vitamin D status and response to treatment in post-menopausal osteoporosis. Osteoporos Int. 2009;20:239-244.
An estimated 10 million US residents, most of them women over the age of 50, suffer from osteoporosis, and another 33 million have low bone mass.1 Together, they incur more than 2 million osteoporotic fractures annually.1,2 In addition to the high cost of a single osteoporotic fracture in terms of morbidity, mortality, and health care spending, individuals who sustain one such fracture are at high risk for another. That risk can be greatly reduced with appropriate treatment.
Bisphosphonates, which act on osteoclasts to inhibit bone resorption, are first-line therapy for prevention of osteoporotic fractures. Four bisphosphonates—alendronate, ibandronate, risedronate, and zoledronic acid—are approved by the US Food and Drug Administration (FDA) for the treatment of postmenopausal osteoporosis.
While menopause itself increases a woman’s risk for osteoporotic fracture, questions remain about when to initiate preventive therapy, which patients are candidates for bisphosphonates, and whether bisphosphonates are effective for primary as well as secondary prevention. This overview from the Cochrane Musculoskeletal Group (CMSG) addresses those questions.
To help you provide optimal treatment for postmenopausal patients, we present the findings of recently conducted systematic reviews of 2 bisphosphonates—alendronate and risedronate—from the Cochrane Database of Systematic Reviews,3,4 in context with the available evidence on the efficacy of ibandronate and zoledronic acid. Cochrane reviews of ibandronate and zoledronic acid are underway, but not yet completed.5,6
This is the second in a series of articles based on the findings of the Cochrane Musculoskeletal Group (CMSG), one of the largest review groups in the Cochrane Collaboration. The CMSG synthesizes the results of high-quality clinical trials to determine whether interventions for the prevention, treatment, and rehabilitation of musculoskeletal disorders are safe and effective. In this article and those that follow, CMSG’s aim is to bring its findings to the attention of family physicians in a context that is relevant to clinical practice.
Alendronate reduces vertebral fracture risk across the board
Wells et al identified 11 RCTs for the alendronate review (3 primary and 8 secondary prevention trials), representing a total of 12,068 women.3 (For definitions of what constituted a primary vs a secondary prevention trial, see the box.)
Doses of alendronate ranged from 1 to 20 mg daily, with most studies using doses of 5 or 10 mg. Treatment duration ranged from 1 to 4 years.
A look at the relative risk (RR) for primary and secondary prevention at different fracture sites (TABLE 1) highlights similarities and differences. The risk reduction for vertebral fractures was statistically significant—and about the same—for women being treated with alendronate for primary and secondary prevention (RR=0.55; 95% confidence interval [CI], 0.38-0.80; RR=0.55; 95% CI, 0.43-0.69, respectively). For all other (nonvertebral) fractures in patients being treated with alendronate, only the outcomes for secondary prevention were statistically significant.
The Cochrane reviewers studied the effects of alendronate and risedronate3,4 for both primary and secondary prevention of osteoporotic fractures in postmenopausal women, using the following definitions (with slight variations in definitions between trials):
Primary prevention. Randomized controlled trials were classified as primary prevention trials if the participants had baseline T-scores >–2.0 or a baseline prevalence of vertebral fracture <20%.
Secondary prevention. Studies were classified as secondary prevention trials if the women had baseline T-scores ≤–2.0 (ie, bone mineral density [BMD] ≥2 standard deviations below peak bone mass) or previous vertebral compression fractures. (In the ibandronate individual patient meta-analysis,14 secondary prevention was defined as lumbar spine T-score <–2.5 or baseline vertebral fracture prevalence >20% or mean age of participants >60 years.)
Age-based criterion. When data on T-scores and/or vertebral compression fractures were unavailable, age was the determinant: Trials were considered secondary prevention if the average age of the participants was >62 years, and primary prevention if the average age was ≤62.
Risedronate is effective only for secondary prevention
Seven RCTs, including 2 primary and 5 secondary prevention trials, were included in the Cochrane review of risedronate, representing a total of 14,049 women.4 Doses ranged from 2.5 to 5 mg daily, but also included cyclical dosing—for example, taking 5 mg/d for the first 2 weeks of every month. Treatment duration ranged from 2 to 3 years.
At doses of 5 mg/d, there were no statistically significant decreases in fracture risk at any site in the primary prevention trials (TABLE 1), although the quality of evidence assessed was low. For secondary prevention, however, the risk reduction for vertebral fracture was significant (RR=0.61; 95% CI, 0.50-0.76), as were the reductions in risk for nonvertebral and hip fractures.
TABLE 1
Fracture risk reduction: How the bisphosphonates compare*
| Study | Vertebral fracture RR (95% CI) | Nonvertebral fracture (hip, wrist, others) RR (95% CI) | Hip fracture RR (95% CI) | Wrist fracture RR (95% CI) |
|---|---|---|---|---|
| Primary prevention | ||||
| Alendronate3 | 0.55 (0.38-0.80) | 0.89 (0.76-1.04) | 0.79 (0.44-1.44) | 1.19 (0.87-1.62) |
| Risedronate4 | 0.97 (0.42-2.25) | 0.81 (0.25-2.58) | N/A | N/A |
| Secondary prevention | ||||
| Alendronate3 | 0.55 (0.43-0.69) | 0.77 (0.64-0.92) | 0.47 (0.26-0.85) | 0.50 (0.34-0.73) |
| Risedronate4 | 0.61 (0.50-0.76) | 0.80 (0.72-0.90) | 0.74 (0.59-0.94) | 0.67 (0.42-1.07)† |
| Ibandronate15,16 Oral daily Oral intermittent | 0.62 (0.42-0.75) 0.50 (0.26-0.66) | No effect)‡ No effect | N/A N/A | N/A N/A |
| Zoledronic acid22 | 0.30 (0.2-0.38) | 0.75)§ (N/A) | 0.59¶ (0.42-0.83) | N/A |
| CI, confidence interval; N/A, not available; RR, relative risk. *Bold type indicates statistical significance (P<.05). †P=.10. ‡RR of nonvertebral fracture was 0.69 (P=.013) for daily oral ibandronate in the subgroup with femoral neck BMD T-score <–3.0. §P<.001. ¶Hazard ratio. | ||||
What are the absolute benefits? A look at number needed to treat
In addition to looking at the RR, the authors of both the alendronate and risedronate reviews calculated the number needed to treat (NNT) to prevent one fracture (TABLE 2) in the trial participants;3,4 they focused on the secondary prevention outcomes, as these were statistically significant. The reviewers also estimated what the NNT would be if the risk reductions achieved with alendronate and risedronate in the reviews occurred when treating community-based samples of women at moderate compared with high fracture risk.
The biggest differences involved hip fracture: For alendronate, if a community-based sample of women at moderate risk of fracture were treated with the drug and the reduction in RR seen in the secondary prevention trials applied, the NNT would be 100. Thus, for every 100 women treated for 5 years with alendronate, 1 hip fracture would be prevented. However, if this same RR reduction were applied to women at high risk of fracture, the NNT would be only 22.3 For risedronate, the estimated NNT to prevent one hip fracture in women at moderate risk was 203, compared with only 45 for women at high risk.4 These estimates indicate that the benefits of bisphosphonate therapy in preventing fractures are greatest in women with a high underlying fracture risk.
TABLE 2
NNT analysis: Women at higher risk are most likely to benefit3,4
| NNT | |||
|---|---|---|---|
| Observed in secondary prevention trials in reviews | Estimated for community-based sample of women with | ||
| High fracture risk* | Moderate fracture risk* | ||
| Alendronate (10 mg/d) | |||
| Vertebral fracture | 19 | 20 | 42 |
| Nonvertebral fracture | 47 | 16 | 27 |
| Hip fracture | 146 | 22 | 100 |
| Wrist fracture | 69 | N/A | N/A |
| Risedronate (5 mg/d) | |||
| Vertebral fracture | 19 | 23 | 49 |
| Nonvertebral fracture | 49 | 19 | 31 |
| Hip fracture | 138 | 45 | 203 |
| Wrist fracture | N/A | N/A | N/A |
| N/A, not available; NNT, number needed to treat. *NNT calculated by applying the relative risk reduction observed in the reviews to published estimates of 5-year fracture risk in a community-based sample of women >50 years of age at moderate and high risk. | |||
Adverse effects do not increase with longer-term treatment
In both the alendronate and risedronate reviews, adverse effects and the risk of discontinuing treatment due to adverse events were similar in the intervention and control groups.3,4 Postmarketing data suggest that there is potential for upper gastrointestinal (GI) problems, however;7 osteonecrosis of the jaw has also been reported infrequently.8,9 More recently, there have been reports of a possible link between bisphosphonates and atypical femoral fractures, which we’ll say more about in a bit.
Some potential adverse events—eg, osteonecrosis of the jaw and atypical femoral fractures—may be related to treatment duration. The maximum duration of the trials included in these meta-analyses was 4 years for alendronate and 3 years for risedronate. However, additional published data do not appear to support a relation between adverse events and treatment duration.
For alendronate, researchers extended the Fracture Incidence Trial (FIT) for a 10-year follow-up,10,11 comparing women who took the drug for the first 5 years with women who took it for 10 years. Adverse effects were similar in both groups.
For risedronate, researchers followed a small subsample (n=164) of the participants in the Vertical Efficacy with Risedronate Therapy (VERT) Study Group for up to 7 years.12,13 For the first 5 years, half of the participants took 5 mg/d risedronate, while the other half took a placebo. During the final 2 years, all participants received 5 mg/d risedronate. The incidence of adverse events among those who took the drug for 7 years was similar to that reported in the first 3 years of the original trial.13
Ibandronate studies focus on dose
Nonvertebral fracture. The Cochrane systematic review examining ibandronate for postmenopausal osteoporosis is not yet completed.5 However, Cranney et al performed a pooled analysis of individual patient data from 8 RCTs to examine the efficacy of different doses of the drug for the secondary prevention of nonvertebral fracture.14 (No studies of the drug for primary prevention have been done.) After 2 years of treatment at higher doses of ibandronate (annual cumulative exposure ≥10.8 mg, equivalent to 150 mg orally/month, 3 mg IV quarterly, or 2 mg IV every 2 months), the hazard ratio was 0.62 (95% CI, 0.396-0.974), compared with those taking lower doses (annual cumulative exposure of 5.5 mg). The individual results of the 2 largest trials did not demonstrate an effect on nonvertebral fracture, except in the subgroup of women with very low femoral neck bone mineral density (BMD) (T-scores <–3.0). 15-17
Vertebral fracture. There is no meta-analysis available with vertebral fracture outcomes for ibandronate, so we present the results of individual secondary prevention trials.
One was a double-blind RCT with 2496 participants, comparing women taking either 2.5 mg/d of ibandronate or 20 mg on alternate days with a group on placebo.15,16 The results? Those in both the daily and the intermittent treatment arms had significant risk reductions (RR=0.62; 95% CI, 0.42-0.75; RR=0.50; 95% CI, 0.26-0.66, respectively), after taking the drug for 3 years (TABLE 1), compared with those on placebo.15,16 The other RCT—a trial in which 2862 women received either quarterly intravenous (IV) injections of 1 or 0.5 mg ibandronate or placebo—did not demonstrate a significant reduction in vertebral fracture.17 This was attributed to an insufficient dose of the drug, a supposition supported by improvements in BMD in patients receiving higher doses of ibandronate.18,19
Oral ibandronate has been well tolerated in clinical trials in terms of GI side effects.20,21 Injection site reactions have been reported in those receiving IV infusions,17 and both IV and monthly oral ibandronate may be associated with mild, self-limiting flu-like symptoms.
Zoledronic acid RCTs show reduced fracture, mortality risk
Black et al studied the efficacy of zoledronic acid in a randomized, double-blind, placebo-controlled trial of 7736 postmenopausal women between the ages of 65 and 89 years.22 The women, all of whom had osteoporosis, received an IV infusion of either zoledronic acid (5 mg) or placebo at baseline, and again at 12 and 24 months. Vertebral and nonvertebral fractures, as well as hip fracture, were significantly reduced in the treatment group compared with placebo (TABLE 1).
In another RCT with 2127 participants, Lyles et al examined the effectiveness of 5 mg zoledronic acid IV given within 90 days of surgical repair of a hip fracture. In the intervention group, there was a 35% risk reduction in new clinical fractures (8.6% vs 13.9% for those on placebo; P=.001); mortality was also lower in the zoledronic acid group (9.6% vs 13.3%; P=.01).23
In both trials, the number of patients who had serious adverse events or dropped out because of an adverse event was similar in the treatment and placebo groups. In both studies, too, a sizeable number of patients treated with zoledronic acid reported flu-like symptoms up to 3 days after receiving an infusion, particularly after the first one. Cardiovascular events were similar across intervention groups in both studies, with one exception: In Black’s study,22 there was an increased incidence of serious atrial fibrillation in the zoledronic acid group (1.3% vs 0.5% for the placebo group).
Other issues to keep in mind
Atypical femoral fractures. Published data suggest an association between bisphosphonate use and atypical femoral fractures, particularly with longer-term use,24 although whether there is a causal link is unclear. Atypical femoral fractures occur with little or no trauma along the femur from just distal to the lesser trochanter to just proximal to the supracondylar flare.
In 2010, the FDA announced requirements for a black box warning about a possible link,25 highlighting the uncertainty about both the optimal duration of bisphosphonate therapy and the cause of these fractures.
While concerns about such a link remain, it is important to note that atypical femoral fractures are very uncommon: Current estimates are that they account for less than 1% of hip/femoral fractures. What’s more, far more fractures are prevented by the use of bisphosphonates than are associated with their use, with an estimated ratio of up to 29:1.24
Dosing schedules. Adherence to treatment is of key importance in maximizing outcomes from osteoporosis treatments, and is frequently low.26,27 One way of improving adherence is to reduce the frequency of dosing required.27 With that in mind, researchers have tested intermittent dosing regimens, using noninferiority or bridging trials.
Such studies have led to a number of approved dosing regimens—70 mg weekly for alendronate; 150 mg monthly and 35 mg weekly for risedronate; and 150 mg PO monthly and 3 mg IV quarterly for ibandronate among them. In making decisions about dosing, family physicians should consider patient preferences, but be aware that there are no direct efficacy data from RCTs to support these dosing regimens.
Calcium and vitamin D. The major fracture prevention trials of bisphosphonates have featured women who are calcium- and vitamin D-replete. In a recent study of 1515 women undergoing treatment with alendronate, risedronate, or raloxifene, however, that wasn’t always the case. 28 After 13 months, 115 participants suffered from a new clinical fracture. The adjusted odds ratio for fractures in women with vitamin D deficiency compared with those with normal levels of vitamin D was 1.77 (95% CI, 1.20-2.59; P=.004), an indication of the importance of maintaining adequate vitamin D levels in patients taking bisphosphonates.
In clinical practice, it is important to ensure that patients being treated with bisphosphonates are not deficient in vitamin D. While direct evidence of poorer outcomes associated with low calcium levels is lacking, it is reasonable to also assess calcium intake and to ensure that patients have adequate intake of both. (For more on calcium and vitamin D requirements, see the Institute of Medicine’s recent report at http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Report-Brief.aspx) and “The IOM’s report on calcium and vitamin D: Should it change the way you practice?”.
“Dietary Reference Intakes for Calcium and Vitamin D,” the consensus report released by the Institute of Medicine (IOM) late last year (http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx) generated a great deal of attention because it concluded that postmenopausal women taking supplements may be getting too much calcium, and that few people need to take vitamin D. These findings, among others, left many physicians wondering how, or if, the IOM’s report should change the way they practice.
The Journal of Family Practice posed that question to Susan Williams, MD, MS, FACN, FACP, an internist at the Cleveland Clinic and a diplomate with the American Board of Physician Nutrition Specialists. Her response: The report probably shouldn’t change the way you practice.
Here, Dr. Williams explains why.
Recommended daily allowances are guidelines. The new dietary reference intakes (DRIs), like the recommended daily allowances (RDAs) they replace, are quantitative estimates of nutrient intakes intended for planning and assessing diets of healthy populations. They were never intended to be applied “across the board,” or used as a benchmark for the dietary adequacy of individual patients.
Testing is still advisable when there is clinical suspicion of a calcium or vitamin D deficiency. Because parathyroid hormone (PTH) compensates for calcium deficiency by drawing calcium from the bones, an adequate serum calcium level alone does not necessarily reflect an adequate calcium intake. In fact, a low serum calcium level is likely to be the result of abnormally low levels of vitamin D. Thus, the best way to get an accurate picture of a patient’s status is to simultaneously test serum calcium, vitamin D, and PTH levels.
Some patients require considerably larger doses of vitamin D than the recommended quantities.1,2 This is particularly true for obese individuals and patients who have undergone bariatric surgery, for example.3-5 The safety of daily dosing of vitamin D in far greater quantities has been established,6,7 and the risks of chronic undersupplementation8-10 outweigh the risks associated with hypervitaminosis D, particularly when D3 (cholecalciferol) supplements are recommended.
Calcium supplementation is safe for postmenopausal women. Many older women have poor dietary intake of calcium, and again, the consequences of a deficiency are far greater than those associated with an excess. The risk of kidney stones in women taking calcium supplements can be averted by advising patients to take calcium citrate, which tends to neutralize urine and has better fractional uptake into the bone than calcium carbonate.
The IOM report serves to remind us that getting adequate calcium and vitamin D is important for everyone. Age and gender-specific recommendations should be emphasized, remembering that in general, the IOM’s DRIs are likely to meet the actual needs of most healthy patients, but may well fall short in the presence of chronic illness and disease.
Remember, too, that while we should always emphasize the importance of eating foods that are rich in calcium and vitamin D, patients’ diets often fall short. In such cases—with the exception of patients with certain conditions (eg, renal failure or hyperparathyroidism)—supplements such as calcium citrate and vitamin D3 can be safely and confidently recommended.
Susan Williams, MD, MS, FACN, FACP, reported no potential conflict of interest relevant to this article.
References
1. Holick MF. The role of vitamin D for bone health and fracture prevention. Curr Osteoporos Rep. 2006;4:96-102.
2. Grant WB, Holick MF. Benefits and requirements of vitamin D for optimal health. Altern Med Rev. 2005;10:94-111.
3. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-281.
4. Bischoff-Ferrari HA, et al. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84:18-28.
5. Flores L, et al. Calcium and vitamin D supplementation after gastric bypass should be individualized to improve or avoid hyperparathyroidism. Obes Surg. 2010;20:738-743.
6. Vieth R, et al. Efficacy and safety of vitamin D intake exceeding the lowest observed adverse eff ect level. Am J Clin Nutr. 2001;73:288-294.
7. Barger-Lux MJ, et al. Vitamin D and its major metabolite: serum levels after graded oral dosing in healthy men. Osteoporos Int. 1998;8:222-230.
8. Sakuma M, et al. Vitamin D and intact PTH status in patients with hip fracture. Osteoporos Int. 2006;17:1608-1614.
9. Broe KE, et al. A higher dose of vitamin D reduces the risk of falls in nursing home residents. J Am Geriatr Soc. 2007;55:234-239.
10. Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly. Endocr Rev. 2001;22:477-501.
What’s best for your patients?
All these bisphosphonates have demonstrated efficacy for the secondary prevention of vertebral fracture. All except ibandronate have demonstrated efficacy for nonvertebral fracture, as well, and the evidence suggests that ibandronate will also be effective if adequate doses are given. Thus, for women at significant risk for fracture, it seems clear that the benefits of treatment outweigh the risks. The case is not so clearcut for women at lower risk. Evidence to support the use of bisphosphonates for primary prevention is limited, other than for alendronate—which has been shown to provide primary prevention of vertebral fracture.
Which bisphosphonate is best depends on patient preferences and individual profiles. (See “How would you treat these patients?”.) In the absence of head-to-head RCTs, it isn’t possible to comment on the relative efficacy of the various bisphosphonates or their adverse event profiles. Indeed, the authors of the 2 Cochrane reviews completed to date note that trial participants have been healthier, with fewer comorbidities, than many of the postmenopausal women seen by primary care physicians. Head-to-head studies conducted in family practice settings would be an important addition to the body of evidence for the prevention of osteoporotic fracture.
How would you treat these patients?
CASE 1 Mrs. A is an active 67-year-old in good health. On a recent hike, she lost her footing and sustained a Colles’ fracture when she fell, although her fall was only from standing height. Now, you are concerned that she might have osteoporosis.
A dual-energy x-ray absorptiometry (DXA) scan confirms this suspicion: Mrs. A’s lumbar spine T-score is –2.6. A dietary review reveals that she has a satisfactory calcium intake, and lab work shows that her serum vitamin D levels are normal. Mrs. A wants to discuss treatment options with you.
What immediate treatment do you consider?
Mrs. A has no contraindications to any FDA-approved treatment for osteoporosis; you suggest she begin taking bisphosphonates, explaining that they are first-line treatment to prevent subsequent osteoporotic fractures. You briefly discuss other options, but note that raloxifene only reduces the risk of vertebral fractures and parathyroid hormone is effective (but very expensive) and requires daily injections, and is therefore generally used for severe osteoporosis. Your patient asks about bisphosphonates’ side effects, particularly the serious jaw problems she’s heard about.
You explain that for the most part, oral bisphosphonates are well tolerated, but that there is a potential for upper gastrointestinal (GI) problems—which is why it’s important to remain upright for at least 30 minutes after taking the medication. You tell her that the risk of developing osteonecrosis of the jaw is very low when the medication is taken at the doses needed for osteoporosis treatment, but that the risk may increase after tooth extraction or dental surgery. Mrs. A has no current dental symptoms and at her usual yearly dental check-up 9 months ago, there were no problems noted, so dental review before starting treatment is not needed. Should she develop any jaw pain, however, she should see you or her dentist immediately.
You also advise her of the possible link between bisphosphonates and atypical femoral fracture, but point out that such fractures are extremely rare—and that the medication prevents far more fractures than it has the potential to cause. You tell her to contact you immediately if she develops pain in the groin or thigh or experiences GI distress.
Which bisphosphonate do you prescribe?
You inform Mrs. A that alendronate has the longest follow-up data of the oral bisphosphonates and has demonstrated efficacy for the secondary prevention of wrist fractures, that risedronate and ibandronate have the advantage of being able to be taken monthly rather than weekly, and that zoledronic acid can be administered in a yearly infusion. She opts for alendronate. You prescribe a weekly dose of 70 mg and ask her to return in 3 months, and to call before then if any problems arise.
CASE 2 Mrs. Y, age 82, recently sustained a fractured femoral neck, which was treated surgically at the local hospital. She was discharged with a prescription for alendronate to treat her osteoporosis and prevent further fractures; her husband has brought her in today to get a new prescription.
During the visit, he reminds you that Mrs. Y has problems with memory. He also says he’s finding it increasingly difficult to ensure that his wife remains upright for 30 minutes after taking alendronate, and that she has begun complaining of indigestion.
What do you decide to do?
An inability to stay upright for 30 minutes after drug administration is a contraindication to the use of oral bisphosphonates. The presence of upper GI symptoms is also a concern. You offer Mrs. Y the option of a once-yearly IV infusion of zoledronic acid instead, and she and her husband agree to this. Before scheduling a follow-up visit, you discuss the patient’s nutritional intake, and discover that she consumes only a moderate amount of calcium—at most 2 servings of dairy products per day. You also note that her serum vitamin D level was not checked in the hospital. You order lab work, with a view to correcting any deficiency before proceeding with a zoledronic infusion (due to the risk of tetany) and to maintaining her on an appropriate level of calcium and vitamin D intake, using supplements only if necessary.
CORRESPONDENCE Tania Winzenberg, MBBS, Menzies Research Institute, Private Bag 23, Hobart, Tasmania, Australia 7001; tania.winzenberg@utas.edu.au
An estimated 10 million US residents, most of them women over the age of 50, suffer from osteoporosis, and another 33 million have low bone mass.1 Together, they incur more than 2 million osteoporotic fractures annually.1,2 In addition to the high cost of a single osteoporotic fracture in terms of morbidity, mortality, and health care spending, individuals who sustain one such fracture are at high risk for another. That risk can be greatly reduced with appropriate treatment.
Bisphosphonates, which act on osteoclasts to inhibit bone resorption, are first-line therapy for prevention of osteoporotic fractures. Four bisphosphonates—alendronate, ibandronate, risedronate, and zoledronic acid—are approved by the US Food and Drug Administration (FDA) for the treatment of postmenopausal osteoporosis.
While menopause itself increases a woman’s risk for osteoporotic fracture, questions remain about when to initiate preventive therapy, which patients are candidates for bisphosphonates, and whether bisphosphonates are effective for primary as well as secondary prevention. This overview from the Cochrane Musculoskeletal Group (CMSG) addresses those questions.
To help you provide optimal treatment for postmenopausal patients, we present the findings of recently conducted systematic reviews of 2 bisphosphonates—alendronate and risedronate—from the Cochrane Database of Systematic Reviews,3,4 in context with the available evidence on the efficacy of ibandronate and zoledronic acid. Cochrane reviews of ibandronate and zoledronic acid are underway, but not yet completed.5,6
This is the second in a series of articles based on the findings of the Cochrane Musculoskeletal Group (CMSG), one of the largest review groups in the Cochrane Collaboration. The CMSG synthesizes the results of high-quality clinical trials to determine whether interventions for the prevention, treatment, and rehabilitation of musculoskeletal disorders are safe and effective. In this article and those that follow, CMSG’s aim is to bring its findings to the attention of family physicians in a context that is relevant to clinical practice.
Alendronate reduces vertebral fracture risk across the board
Wells et al identified 11 RCTs for the alendronate review (3 primary and 8 secondary prevention trials), representing a total of 12,068 women.3 (For definitions of what constituted a primary vs a secondary prevention trial, see the box.)
Doses of alendronate ranged from 1 to 20 mg daily, with most studies using doses of 5 or 10 mg. Treatment duration ranged from 1 to 4 years.
A look at the relative risk (RR) for primary and secondary prevention at different fracture sites (TABLE 1) highlights similarities and differences. The risk reduction for vertebral fractures was statistically significant—and about the same—for women being treated with alendronate for primary and secondary prevention (RR=0.55; 95% confidence interval [CI], 0.38-0.80; RR=0.55; 95% CI, 0.43-0.69, respectively). For all other (nonvertebral) fractures in patients being treated with alendronate, only the outcomes for secondary prevention were statistically significant.
The Cochrane reviewers studied the effects of alendronate and risedronate3,4 for both primary and secondary prevention of osteoporotic fractures in postmenopausal women, using the following definitions (with slight variations in definitions between trials):
Primary prevention. Randomized controlled trials were classified as primary prevention trials if the participants had baseline T-scores >–2.0 or a baseline prevalence of vertebral fracture <20%.
Secondary prevention. Studies were classified as secondary prevention trials if the women had baseline T-scores ≤–2.0 (ie, bone mineral density [BMD] ≥2 standard deviations below peak bone mass) or previous vertebral compression fractures. (In the ibandronate individual patient meta-analysis,14 secondary prevention was defined as lumbar spine T-score <–2.5 or baseline vertebral fracture prevalence >20% or mean age of participants >60 years.)
Age-based criterion. When data on T-scores and/or vertebral compression fractures were unavailable, age was the determinant: Trials were considered secondary prevention if the average age of the participants was >62 years, and primary prevention if the average age was ≤62.
Risedronate is effective only for secondary prevention
Seven RCTs, including 2 primary and 5 secondary prevention trials, were included in the Cochrane review of risedronate, representing a total of 14,049 women.4 Doses ranged from 2.5 to 5 mg daily, but also included cyclical dosing—for example, taking 5 mg/d for the first 2 weeks of every month. Treatment duration ranged from 2 to 3 years.
At doses of 5 mg/d, there were no statistically significant decreases in fracture risk at any site in the primary prevention trials (TABLE 1), although the quality of evidence assessed was low. For secondary prevention, however, the risk reduction for vertebral fracture was significant (RR=0.61; 95% CI, 0.50-0.76), as were the reductions in risk for nonvertebral and hip fractures.
TABLE 1
Fracture risk reduction: How the bisphosphonates compare*
| Study | Vertebral fracture RR (95% CI) | Nonvertebral fracture (hip, wrist, others) RR (95% CI) | Hip fracture RR (95% CI) | Wrist fracture RR (95% CI) |
|---|---|---|---|---|
| Primary prevention | ||||
| Alendronate3 | 0.55 (0.38-0.80) | 0.89 (0.76-1.04) | 0.79 (0.44-1.44) | 1.19 (0.87-1.62) |
| Risedronate4 | 0.97 (0.42-2.25) | 0.81 (0.25-2.58) | N/A | N/A |
| Secondary prevention | ||||
| Alendronate3 | 0.55 (0.43-0.69) | 0.77 (0.64-0.92) | 0.47 (0.26-0.85) | 0.50 (0.34-0.73) |
| Risedronate4 | 0.61 (0.50-0.76) | 0.80 (0.72-0.90) | 0.74 (0.59-0.94) | 0.67 (0.42-1.07)† |
| Ibandronate15,16 Oral daily Oral intermittent | 0.62 (0.42-0.75) 0.50 (0.26-0.66) | No effect)‡ No effect | N/A N/A | N/A N/A |
| Zoledronic acid22 | 0.30 (0.2-0.38) | 0.75)§ (N/A) | 0.59¶ (0.42-0.83) | N/A |
| CI, confidence interval; N/A, not available; RR, relative risk. *Bold type indicates statistical significance (P<.05). †P=.10. ‡RR of nonvertebral fracture was 0.69 (P=.013) for daily oral ibandronate in the subgroup with femoral neck BMD T-score <–3.0. §P<.001. ¶Hazard ratio. | ||||
What are the absolute benefits? A look at number needed to treat
In addition to looking at the RR, the authors of both the alendronate and risedronate reviews calculated the number needed to treat (NNT) to prevent one fracture (TABLE 2) in the trial participants;3,4 they focused on the secondary prevention outcomes, as these were statistically significant. The reviewers also estimated what the NNT would be if the risk reductions achieved with alendronate and risedronate in the reviews occurred when treating community-based samples of women at moderate compared with high fracture risk.
The biggest differences involved hip fracture: For alendronate, if a community-based sample of women at moderate risk of fracture were treated with the drug and the reduction in RR seen in the secondary prevention trials applied, the NNT would be 100. Thus, for every 100 women treated for 5 years with alendronate, 1 hip fracture would be prevented. However, if this same RR reduction were applied to women at high risk of fracture, the NNT would be only 22.3 For risedronate, the estimated NNT to prevent one hip fracture in women at moderate risk was 203, compared with only 45 for women at high risk.4 These estimates indicate that the benefits of bisphosphonate therapy in preventing fractures are greatest in women with a high underlying fracture risk.
TABLE 2
NNT analysis: Women at higher risk are most likely to benefit3,4
| NNT | |||
|---|---|---|---|
| Observed in secondary prevention trials in reviews | Estimated for community-based sample of women with | ||
| High fracture risk* | Moderate fracture risk* | ||
| Alendronate (10 mg/d) | |||
| Vertebral fracture | 19 | 20 | 42 |
| Nonvertebral fracture | 47 | 16 | 27 |
| Hip fracture | 146 | 22 | 100 |
| Wrist fracture | 69 | N/A | N/A |
| Risedronate (5 mg/d) | |||
| Vertebral fracture | 19 | 23 | 49 |
| Nonvertebral fracture | 49 | 19 | 31 |
| Hip fracture | 138 | 45 | 203 |
| Wrist fracture | N/A | N/A | N/A |
| N/A, not available; NNT, number needed to treat. *NNT calculated by applying the relative risk reduction observed in the reviews to published estimates of 5-year fracture risk in a community-based sample of women >50 years of age at moderate and high risk. | |||
Adverse effects do not increase with longer-term treatment
In both the alendronate and risedronate reviews, adverse effects and the risk of discontinuing treatment due to adverse events were similar in the intervention and control groups.3,4 Postmarketing data suggest that there is potential for upper gastrointestinal (GI) problems, however;7 osteonecrosis of the jaw has also been reported infrequently.8,9 More recently, there have been reports of a possible link between bisphosphonates and atypical femoral fractures, which we’ll say more about in a bit.
Some potential adverse events—eg, osteonecrosis of the jaw and atypical femoral fractures—may be related to treatment duration. The maximum duration of the trials included in these meta-analyses was 4 years for alendronate and 3 years for risedronate. However, additional published data do not appear to support a relation between adverse events and treatment duration.
For alendronate, researchers extended the Fracture Incidence Trial (FIT) for a 10-year follow-up,10,11 comparing women who took the drug for the first 5 years with women who took it for 10 years. Adverse effects were similar in both groups.
For risedronate, researchers followed a small subsample (n=164) of the participants in the Vertical Efficacy with Risedronate Therapy (VERT) Study Group for up to 7 years.12,13 For the first 5 years, half of the participants took 5 mg/d risedronate, while the other half took a placebo. During the final 2 years, all participants received 5 mg/d risedronate. The incidence of adverse events among those who took the drug for 7 years was similar to that reported in the first 3 years of the original trial.13
Ibandronate studies focus on dose
Nonvertebral fracture. The Cochrane systematic review examining ibandronate for postmenopausal osteoporosis is not yet completed.5 However, Cranney et al performed a pooled analysis of individual patient data from 8 RCTs to examine the efficacy of different doses of the drug for the secondary prevention of nonvertebral fracture.14 (No studies of the drug for primary prevention have been done.) After 2 years of treatment at higher doses of ibandronate (annual cumulative exposure ≥10.8 mg, equivalent to 150 mg orally/month, 3 mg IV quarterly, or 2 mg IV every 2 months), the hazard ratio was 0.62 (95% CI, 0.396-0.974), compared with those taking lower doses (annual cumulative exposure of 5.5 mg). The individual results of the 2 largest trials did not demonstrate an effect on nonvertebral fracture, except in the subgroup of women with very low femoral neck bone mineral density (BMD) (T-scores <–3.0). 15-17
Vertebral fracture. There is no meta-analysis available with vertebral fracture outcomes for ibandronate, so we present the results of individual secondary prevention trials.
One was a double-blind RCT with 2496 participants, comparing women taking either 2.5 mg/d of ibandronate or 20 mg on alternate days with a group on placebo.15,16 The results? Those in both the daily and the intermittent treatment arms had significant risk reductions (RR=0.62; 95% CI, 0.42-0.75; RR=0.50; 95% CI, 0.26-0.66, respectively), after taking the drug for 3 years (TABLE 1), compared with those on placebo.15,16 The other RCT—a trial in which 2862 women received either quarterly intravenous (IV) injections of 1 or 0.5 mg ibandronate or placebo—did not demonstrate a significant reduction in vertebral fracture.17 This was attributed to an insufficient dose of the drug, a supposition supported by improvements in BMD in patients receiving higher doses of ibandronate.18,19
Oral ibandronate has been well tolerated in clinical trials in terms of GI side effects.20,21 Injection site reactions have been reported in those receiving IV infusions,17 and both IV and monthly oral ibandronate may be associated with mild, self-limiting flu-like symptoms.
Zoledronic acid RCTs show reduced fracture, mortality risk
Black et al studied the efficacy of zoledronic acid in a randomized, double-blind, placebo-controlled trial of 7736 postmenopausal women between the ages of 65 and 89 years.22 The women, all of whom had osteoporosis, received an IV infusion of either zoledronic acid (5 mg) or placebo at baseline, and again at 12 and 24 months. Vertebral and nonvertebral fractures, as well as hip fracture, were significantly reduced in the treatment group compared with placebo (TABLE 1).
In another RCT with 2127 participants, Lyles et al examined the effectiveness of 5 mg zoledronic acid IV given within 90 days of surgical repair of a hip fracture. In the intervention group, there was a 35% risk reduction in new clinical fractures (8.6% vs 13.9% for those on placebo; P=.001); mortality was also lower in the zoledronic acid group (9.6% vs 13.3%; P=.01).23
In both trials, the number of patients who had serious adverse events or dropped out because of an adverse event was similar in the treatment and placebo groups. In both studies, too, a sizeable number of patients treated with zoledronic acid reported flu-like symptoms up to 3 days after receiving an infusion, particularly after the first one. Cardiovascular events were similar across intervention groups in both studies, with one exception: In Black’s study,22 there was an increased incidence of serious atrial fibrillation in the zoledronic acid group (1.3% vs 0.5% for the placebo group).
Other issues to keep in mind
Atypical femoral fractures. Published data suggest an association between bisphosphonate use and atypical femoral fractures, particularly with longer-term use,24 although whether there is a causal link is unclear. Atypical femoral fractures occur with little or no trauma along the femur from just distal to the lesser trochanter to just proximal to the supracondylar flare.
In 2010, the FDA announced requirements for a black box warning about a possible link,25 highlighting the uncertainty about both the optimal duration of bisphosphonate therapy and the cause of these fractures.
While concerns about such a link remain, it is important to note that atypical femoral fractures are very uncommon: Current estimates are that they account for less than 1% of hip/femoral fractures. What’s more, far more fractures are prevented by the use of bisphosphonates than are associated with their use, with an estimated ratio of up to 29:1.24
Dosing schedules. Adherence to treatment is of key importance in maximizing outcomes from osteoporosis treatments, and is frequently low.26,27 One way of improving adherence is to reduce the frequency of dosing required.27 With that in mind, researchers have tested intermittent dosing regimens, using noninferiority or bridging trials.
Such studies have led to a number of approved dosing regimens—70 mg weekly for alendronate; 150 mg monthly and 35 mg weekly for risedronate; and 150 mg PO monthly and 3 mg IV quarterly for ibandronate among them. In making decisions about dosing, family physicians should consider patient preferences, but be aware that there are no direct efficacy data from RCTs to support these dosing regimens.
Calcium and vitamin D. The major fracture prevention trials of bisphosphonates have featured women who are calcium- and vitamin D-replete. In a recent study of 1515 women undergoing treatment with alendronate, risedronate, or raloxifene, however, that wasn’t always the case. 28 After 13 months, 115 participants suffered from a new clinical fracture. The adjusted odds ratio for fractures in women with vitamin D deficiency compared with those with normal levels of vitamin D was 1.77 (95% CI, 1.20-2.59; P=.004), an indication of the importance of maintaining adequate vitamin D levels in patients taking bisphosphonates.
In clinical practice, it is important to ensure that patients being treated with bisphosphonates are not deficient in vitamin D. While direct evidence of poorer outcomes associated with low calcium levels is lacking, it is reasonable to also assess calcium intake and to ensure that patients have adequate intake of both. (For more on calcium and vitamin D requirements, see the Institute of Medicine’s recent report at http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Report-Brief.aspx) and “The IOM’s report on calcium and vitamin D: Should it change the way you practice?”.
“Dietary Reference Intakes for Calcium and Vitamin D,” the consensus report released by the Institute of Medicine (IOM) late last year (http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx) generated a great deal of attention because it concluded that postmenopausal women taking supplements may be getting too much calcium, and that few people need to take vitamin D. These findings, among others, left many physicians wondering how, or if, the IOM’s report should change the way they practice.
The Journal of Family Practice posed that question to Susan Williams, MD, MS, FACN, FACP, an internist at the Cleveland Clinic and a diplomate with the American Board of Physician Nutrition Specialists. Her response: The report probably shouldn’t change the way you practice.
Here, Dr. Williams explains why.
Recommended daily allowances are guidelines. The new dietary reference intakes (DRIs), like the recommended daily allowances (RDAs) they replace, are quantitative estimates of nutrient intakes intended for planning and assessing diets of healthy populations. They were never intended to be applied “across the board,” or used as a benchmark for the dietary adequacy of individual patients.
Testing is still advisable when there is clinical suspicion of a calcium or vitamin D deficiency. Because parathyroid hormone (PTH) compensates for calcium deficiency by drawing calcium from the bones, an adequate serum calcium level alone does not necessarily reflect an adequate calcium intake. In fact, a low serum calcium level is likely to be the result of abnormally low levels of vitamin D. Thus, the best way to get an accurate picture of a patient’s status is to simultaneously test serum calcium, vitamin D, and PTH levels.
Some patients require considerably larger doses of vitamin D than the recommended quantities.1,2 This is particularly true for obese individuals and patients who have undergone bariatric surgery, for example.3-5 The safety of daily dosing of vitamin D in far greater quantities has been established,6,7 and the risks of chronic undersupplementation8-10 outweigh the risks associated with hypervitaminosis D, particularly when D3 (cholecalciferol) supplements are recommended.
Calcium supplementation is safe for postmenopausal women. Many older women have poor dietary intake of calcium, and again, the consequences of a deficiency are far greater than those associated with an excess. The risk of kidney stones in women taking calcium supplements can be averted by advising patients to take calcium citrate, which tends to neutralize urine and has better fractional uptake into the bone than calcium carbonate.
The IOM report serves to remind us that getting adequate calcium and vitamin D is important for everyone. Age and gender-specific recommendations should be emphasized, remembering that in general, the IOM’s DRIs are likely to meet the actual needs of most healthy patients, but may well fall short in the presence of chronic illness and disease.
Remember, too, that while we should always emphasize the importance of eating foods that are rich in calcium and vitamin D, patients’ diets often fall short. In such cases—with the exception of patients with certain conditions (eg, renal failure or hyperparathyroidism)—supplements such as calcium citrate and vitamin D3 can be safely and confidently recommended.
Susan Williams, MD, MS, FACN, FACP, reported no potential conflict of interest relevant to this article.
References
1. Holick MF. The role of vitamin D for bone health and fracture prevention. Curr Osteoporos Rep. 2006;4:96-102.
2. Grant WB, Holick MF. Benefits and requirements of vitamin D for optimal health. Altern Med Rev. 2005;10:94-111.
3. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-281.
4. Bischoff-Ferrari HA, et al. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84:18-28.
5. Flores L, et al. Calcium and vitamin D supplementation after gastric bypass should be individualized to improve or avoid hyperparathyroidism. Obes Surg. 2010;20:738-743.
6. Vieth R, et al. Efficacy and safety of vitamin D intake exceeding the lowest observed adverse eff ect level. Am J Clin Nutr. 2001;73:288-294.
7. Barger-Lux MJ, et al. Vitamin D and its major metabolite: serum levels after graded oral dosing in healthy men. Osteoporos Int. 1998;8:222-230.
8. Sakuma M, et al. Vitamin D and intact PTH status in patients with hip fracture. Osteoporos Int. 2006;17:1608-1614.
9. Broe KE, et al. A higher dose of vitamin D reduces the risk of falls in nursing home residents. J Am Geriatr Soc. 2007;55:234-239.
10. Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly. Endocr Rev. 2001;22:477-501.
What’s best for your patients?
All these bisphosphonates have demonstrated efficacy for the secondary prevention of vertebral fracture. All except ibandronate have demonstrated efficacy for nonvertebral fracture, as well, and the evidence suggests that ibandronate will also be effective if adequate doses are given. Thus, for women at significant risk for fracture, it seems clear that the benefits of treatment outweigh the risks. The case is not so clearcut for women at lower risk. Evidence to support the use of bisphosphonates for primary prevention is limited, other than for alendronate—which has been shown to provide primary prevention of vertebral fracture.
Which bisphosphonate is best depends on patient preferences and individual profiles. (See “How would you treat these patients?”.) In the absence of head-to-head RCTs, it isn’t possible to comment on the relative efficacy of the various bisphosphonates or their adverse event profiles. Indeed, the authors of the 2 Cochrane reviews completed to date note that trial participants have been healthier, with fewer comorbidities, than many of the postmenopausal women seen by primary care physicians. Head-to-head studies conducted in family practice settings would be an important addition to the body of evidence for the prevention of osteoporotic fracture.
How would you treat these patients?
CASE 1 Mrs. A is an active 67-year-old in good health. On a recent hike, she lost her footing and sustained a Colles’ fracture when she fell, although her fall was only from standing height. Now, you are concerned that she might have osteoporosis.
A dual-energy x-ray absorptiometry (DXA) scan confirms this suspicion: Mrs. A’s lumbar spine T-score is –2.6. A dietary review reveals that she has a satisfactory calcium intake, and lab work shows that her serum vitamin D levels are normal. Mrs. A wants to discuss treatment options with you.
What immediate treatment do you consider?
Mrs. A has no contraindications to any FDA-approved treatment for osteoporosis; you suggest she begin taking bisphosphonates, explaining that they are first-line treatment to prevent subsequent osteoporotic fractures. You briefly discuss other options, but note that raloxifene only reduces the risk of vertebral fractures and parathyroid hormone is effective (but very expensive) and requires daily injections, and is therefore generally used for severe osteoporosis. Your patient asks about bisphosphonates’ side effects, particularly the serious jaw problems she’s heard about.
You explain that for the most part, oral bisphosphonates are well tolerated, but that there is a potential for upper gastrointestinal (GI) problems—which is why it’s important to remain upright for at least 30 minutes after taking the medication. You tell her that the risk of developing osteonecrosis of the jaw is very low when the medication is taken at the doses needed for osteoporosis treatment, but that the risk may increase after tooth extraction or dental surgery. Mrs. A has no current dental symptoms and at her usual yearly dental check-up 9 months ago, there were no problems noted, so dental review before starting treatment is not needed. Should she develop any jaw pain, however, she should see you or her dentist immediately.
You also advise her of the possible link between bisphosphonates and atypical femoral fracture, but point out that such fractures are extremely rare—and that the medication prevents far more fractures than it has the potential to cause. You tell her to contact you immediately if she develops pain in the groin or thigh or experiences GI distress.
Which bisphosphonate do you prescribe?
You inform Mrs. A that alendronate has the longest follow-up data of the oral bisphosphonates and has demonstrated efficacy for the secondary prevention of wrist fractures, that risedronate and ibandronate have the advantage of being able to be taken monthly rather than weekly, and that zoledronic acid can be administered in a yearly infusion. She opts for alendronate. You prescribe a weekly dose of 70 mg and ask her to return in 3 months, and to call before then if any problems arise.
CASE 2 Mrs. Y, age 82, recently sustained a fractured femoral neck, which was treated surgically at the local hospital. She was discharged with a prescription for alendronate to treat her osteoporosis and prevent further fractures; her husband has brought her in today to get a new prescription.
During the visit, he reminds you that Mrs. Y has problems with memory. He also says he’s finding it increasingly difficult to ensure that his wife remains upright for 30 minutes after taking alendronate, and that she has begun complaining of indigestion.
What do you decide to do?
An inability to stay upright for 30 minutes after drug administration is a contraindication to the use of oral bisphosphonates. The presence of upper GI symptoms is also a concern. You offer Mrs. Y the option of a once-yearly IV infusion of zoledronic acid instead, and she and her husband agree to this. Before scheduling a follow-up visit, you discuss the patient’s nutritional intake, and discover that she consumes only a moderate amount of calcium—at most 2 servings of dairy products per day. You also note that her serum vitamin D level was not checked in the hospital. You order lab work, with a view to correcting any deficiency before proceeding with a zoledronic infusion (due to the risk of tetany) and to maintaining her on an appropriate level of calcium and vitamin D intake, using supplements only if necessary.
CORRESPONDENCE Tania Winzenberg, MBBS, Menzies Research Institute, Private Bag 23, Hobart, Tasmania, Australia 7001; tania.winzenberg@utas.edu.au
1. National Osteoporosis Foundation. America’s bone health: the state of osteoporosis and low bone mass in our nation. Washington, DC: National Osteoporosis Foundation; 2002.
2. Burge R, Dawson-Hughes B, Solomon DH, et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res. 2007;22:465-475.
3. Wells GA, Cranney A, Peterson J, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 2008;(1):CD001155.-
4. Wells G, Cranney A, Peterson J, et al. Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 2008;(1):CD004523.-
5. Wang Q, Decai C. Ibandronate sodium for osteoporosis in post-menopausal women (Protocol). Cochrane Database Syst Rev. 2007;CD006514.-DOI:10.1002/14651858.
6. Albergaria BH, Gomes Silva BN, Atallah AN, et al. Intravenous zoledronate for postmenopausal osteoporosis (Protocol). Cochrane Database Syst Rev. 2010;(1):CD008332.-DOI:10.1002/14651858.
7. Anonymous. Australian Medicines Handbook. Adelaide, Australia: Australian Medicines Handbook Pty Ltd; 2007.
8. Silverman SL, Landesberg R. Osteonecrosis of the jaw and the role of bisphosphonates: a critical review. Am J Med. 2009;122 (suppl 2):S33-S45.
9. Reid IR. Osteonecrosis of the jaw: who gets it, and why? Bone. 2009;44:4-10.
10. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927-2938.
11. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280:2077-2082.
12. 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.
13. Mellstrom DD, Sorensen OH, Goemaere S, et al. Seven years of treatment with risedronate in women with postmenopausal osteoporosis. Calcif Tissue Int. 2004;75:462-468.
14. Cranney A, Wells GA, Yetisir E, et al. Ibandronate for the prevention of nonvertebral fractures: a pooled analysis of individual patient data. Osteoporos Int. 2009;20:291-297.
15. Chesnut IC, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241-1249.
16. Delmas PD, Recker RR, Chesnut CH, et al. Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study. Osteoporosis Int. 2004;15:792-798.
17. Recker R, Stakkestad JA, Chesnut CH, et al. Insufficiently dosed intravenous ibandronate injections are associated with suboptimal antifracture efficacy in postmenopausal osteoporosis. Bone. 2004;34:890-899.
18. Adami S, Felsenberg D, Christiansen C, et al. Efficacy and safety of ibandronate given by intravenous injection once every 3 months. Bone. 2004;34:881-889.
19. Delmas PD, Adami S, Strugala C, et al. Intravenous ibandronate injections in postmenopausal women with osteoporosis. One-year results from the dosing intravenous administration study. Arthritis Rheum. 2006;54:1838-1846.
20. Epstein S, Delmas PD, Emkey R, et al. Oral ibandronate in the management of postmenopausal osteoporosis: review of upper gastrointestinal safety. Maturitas. 2006;54:1-10.
21. Ettinger MP, Felsenberg D, Harris ST, et al. Safety and tolerability of oral daily and intermittent ibandronate are not influenced by age. J Rheumatol. 2005;32:1968-1974.
22. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809-1822.
23. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-1809.
24. Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010;25:2267-2294.
25. US Food and Drug Administration. FDA Drug Safety Communication: Safety update for osteoporosis drugs, bisphosphonates, and atypical fractures. October 13, 2010. Available at: http://www.fda.gov/drugs/drugsafety/ucm229009.htm. Accessed December 7, 2010.
26. Seeman E, Compston J, Adachi J, et al. Non-compliance: the Achilles’ heel of anti-fracture efficacy. Osteoporos Int. 2007;18:711-719.
27. Cramer JA, Gold DT, Silverman SL, et al. A systematic review of persistence and compliance with bisphosphonates for osteoporosis. Osteoporos Int. 2007;18:1023-1031.
28. Adami S, Giannini S, Bianchi G, et al. Vitamin D status and response to treatment in post-menopausal osteoporosis. Osteoporos Int. 2009;20:239-244.
1. National Osteoporosis Foundation. America’s bone health: the state of osteoporosis and low bone mass in our nation. Washington, DC: National Osteoporosis Foundation; 2002.
2. Burge R, Dawson-Hughes B, Solomon DH, et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res. 2007;22:465-475.
3. Wells GA, Cranney A, Peterson J, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 2008;(1):CD001155.-
4. Wells G, Cranney A, Peterson J, et al. Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 2008;(1):CD004523.-
5. Wang Q, Decai C. Ibandronate sodium for osteoporosis in post-menopausal women (Protocol). Cochrane Database Syst Rev. 2007;CD006514.-DOI:10.1002/14651858.
6. Albergaria BH, Gomes Silva BN, Atallah AN, et al. Intravenous zoledronate for postmenopausal osteoporosis (Protocol). Cochrane Database Syst Rev. 2010;(1):CD008332.-DOI:10.1002/14651858.
7. Anonymous. Australian Medicines Handbook. Adelaide, Australia: Australian Medicines Handbook Pty Ltd; 2007.
8. Silverman SL, Landesberg R. Osteonecrosis of the jaw and the role of bisphosphonates: a critical review. Am J Med. 2009;122 (suppl 2):S33-S45.
9. Reid IR. Osteonecrosis of the jaw: who gets it, and why? Bone. 2009;44:4-10.
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