Guideline

Pharmacologic approaches to prevention and treatment

Bisphosphonates

Osteoporosis management and fracture prevention in post-menopausal women and men > 50 years of age
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Bisphosphonates

Recommendation 21

Grade

Bisphosphonate therapy (alendronate, risedronate or zoledronate) should be considered for the primary prevention of vertebral fractures in women with osteopenia who are at least 10 years postmenopause.

B

Recommendation 22

Grade

Bisphosphonate therapy is recommended for reducing the risk of vertebral and non-vertebral fractures in postmenopausal women and men over the age of 50 years at high risk of fracture (those with osteoporosis by BMD criteria, or prior minimal trauma fracture).

A (women)
C (men)

Recommendation 23

Grade

Reconsider the need to continue bisphosphonate therapy after 5–10 years in postmenopausal women and men over the age of 50 years with osteoporosis who have responded well to treatment (T-score ≥–2.5 and no recent fractures). If BMD remains low (T-score ≤–2.5) and/or there are incident fragility fractures, continue treatment. Treatment should be restarted if there is bone loss, especially at the hip, or if a further minimal trauma fracture is sustained.

D

Bisphosphonates are potent inhibitors of bone-resorbing cells (osteoclasts). They work to inhibit bone resorption by interfering with normal osteoclast function and inducing osteoclast cell death (apoptosis). Because bisphosphonates are rapidly sequestered into bone (from where they are slowly released) and eliminated by the kidney, exposure to soft tissues, including bone marrow, is transient.

Alendronate and risedronate are taken orally once weekly. A monthly oral risedronate preparation (150 mg) is also available, although some patients find this too infrequent and may forget to take it. Intravenous (IV) bisphosphonates (once yearly; 5 mg zoledronate/zoledronic acid) can be used as first-line osteoporosis therapy and are often used in patients intolerant of oral preparations or likely to be non-adherent to oral medications. IV zoledronate has been shown to reduce mortality following hip fracture1 and to reduce fractures in the presence of osteopenia (hip T-scores between –1.0 and –2.5) without a fracture.2 Further analysis from the same study has intriguingly found that in women with osteopenia, zoledronate was associated with fewer myocardial infarcts (RaR 0.58; 95% CI: 0.35–0.94) and cancers (RaR 0.68; 95% CI: 0.52–0.89).3 Although these findings need to be confirmed in larger studies, they suggest potential non-skeletal benefits of zoledronate.

Bisphosphonates used in the management of osteoporosis are usually well tolerated. The most commonly reported adverse effects are gastrointestinal (gastric irritation, oesophageal erosions, gastric ulcers, perforations, and strictures). According to one meta-analysis,4 oral bisphosphonate therapy may be associated with oesophageal cancer risk; however, this has not been found in two other meta-analyses.5,6 Medication-related osteonecrosis of the jaw (MRONJ) is a rarely reported adverse effect (refer to Section 5.3). The incidence of MRONJ is in the range <1–10 cases per 10,000 patients treated with oral bisphosphonates7,8 and 1.7 cases per 10,000 patients treated with zoledronic acid.9

Atypical fracture of the femur (AFF) also appears to be a rare adverse event, occurring at a rate of 3.2–50 cases per 100,000 person-years of bisphosphonate treatment10 (refer to Section 5.4). In a recent North American study, 196,129 women aged >50 years receiving bisphosphonates were followed for 10 years.10 The risk of AFF increased with longer duration of bisphosphonate use – compared with a treatment duration of less than three months, the hazard ratio (HR) for treatment duration of three to less than five years was 8.86 (95% CI: 2.79–28.20), and this increased to 43.51 (95% CI: 13.70–138.15) for treatment for eight years or more.10 Other risk factors were race (HR for Asian versus White 4.84; 95% CI: 3.57–6.56), decreasing height (HR per 5-cm decrement 1.28; 95% CI: 1.15–1.43), increasing weight (HR per 5-kg increment 1.15; 95% CI: 1.11–1.19), age (HR for age 65–74 versus >85 years 2.76; 95% CI: 1.62–4.72) and glucocorticoid use for 1 year or more (HR versus no glucocorticoid use 2.28; 95% CI: 1.52–3.43). Reassuringly, bisphosphonate discontinuation was associated with a rapid reduction in AFF risk and the absolute risk of AFF remained very low (1.74 fractures per 10,000 patient-years) compared with reductions in the risk of hip and other fractures with bisphosphonate treatment. For example, after three years, there were two bisphosphonate-associated AFF, compared with 149 hip fractures prevented and 541 clinical fractures prevented.10 The benefit-to-risk ratio of bisphosphonate use for osteoporosis treatment is therefore very favourable.

Concern has been raised about bisphosphonate use around the time of fracture due to inhibition of bone remodelling. The Fracture and Bisphosphonates trial was a double-blind placebo-controlled trial involving 15 trauma centres in the UK that randomised 421 bisphosphonate-naïve patients aged >50 years with a distal radius fracture to alendronate 70 mg once weekly (n=215) or placebo (n=206) within 14 days of fracture. Reassuringly, there was no difference in fracture union at four weeks.

Evidence Statement

Several good-quality systematic reviews have found that bisphosphonates (alendronate, risedronate, and zoledronate) reduce fracture risk. Few studies have directly compared different agents or classes of agents used to treat osteoporosis, and hence data are insufficient to determine the relative efficacy or safety of these agents.

Primary prevention of osteoporotic fractures with bisphosphonates

A pivotal systematic review12 included two RCTs13,14 that reported the effect of alendronate 10–40 mg per day on fracture risk in postmenopausal women without osteoporosis. Alendronate was not associated with a reduction in the risk of vertebral fracture (RR 0.45; 95% CI: 0.06–3.15) or non-vertebral fractures (RR 0.79; 95% CI: 0.28–2.24) compared with placebo. In one RCT,13 the mean age was 51.8 years, the mean T-score –1.8, and no patients had prevalent vertebral fractures; in the other RCT,14 the mean age of participants was 53 years, the mean T-score was –1.8, and <10% of participants had prevalent vertebral fractures. A Cochrane systematic review and meta-analysis in 200815 reported a reduction in the risk of vertebral fractures (RR 0.55; 95% CI: 0.38–0.80), but no reduction in non-vertebral fracture risk (RR 0.89; 95% CI: 0.76–1.04) with alendronate therapy in one study (n=4432).16 In the Cochrane review, the mean T-score was –1.9, mean age was 67.6 years, and no patients had prevalent vertebral fractures.15 The fact that patients in the latter study16 were older by 15 years is likely to have contributed to the positive findings.

A meta-analysis of RCTs of risedronate17 in postmenopausal women (n=111 in one trial by Mortensen et al18) conducted in 2002 did not demonstrate reductions in either vertebral fractures (RR 2.44; 95% CI: 0.12–49.45) or non-vertebral fractures (RR 0.49; 95% CI: 0.12–2.03). A 2008 Cochrane review19 on the effectiveness of risedronate at doses of 2.5 and 5 mg per day for a duration of two years for the primary prevention of osteoporosis fractures included two RCTs (Mortensen et al18 and Hooper et al20) with 327 early postmenopausal women (mean age 52.6). The results were not significant compared with placebo for either vertebral fracture risk (RR 0.97; 95% CI: 0.42–2.25) or non-vertebral fracture risk (RR 0.81; 95% CI: 0.25–2.58).19 In the RCTs by Mortensen et al18 and Hooper et al,20 the respective mean age was 51.2 and 52.6 years, the mean T-score was –1.0 and –0.4, and 0% and 18% of subjects, respectively, had prevalent fractures.

Treatment of postmenopausal women at high risk of osteoporotic fracture

A good-quality meta-analysis including six treatment trials showed a reduction in the risk of vertebral fracture for alendronate compared with placebo (RR 0.53; 95% CI: 0.43–0.65), with no heterogeneity observed between trials.12 This translated to a number needed to treat (NNT) of 72 (95% CI: 61–99) to prevent one vertebral fracture over two years of treatment in women at high risk of vertebral fracture. The patients included were at high fracture risk, as indicated by a weighted mean age of 67.8 years (range 59.5–71 years), weighted mean FN T-score of –2.6 (range –3.3 to –2.3) and a prevalent vertebral fractures weighted mean of 29% (range 0–100%).12 Among five treatment trials included in the meta-analysis of non-vertebral fracture risk, the weighted mean age was 63.0 years (range 59.5–64 years), the weighted mean FN T-score was –2.7 (range –2.8 to –2.3) and the prevalent vertebral fractures weighted mean was 18% (range 0–21%). The pooled RR for non-vertebral fracture was 0.49 (95% CI: 0.36–0.67), with no heterogeneity between trials. The NNT to prevent one non-vertebral fracture over two years of treatment in women at high risk was 24 (95% CI: 19–37).12

A Cochrane review of RCTs in postmenopausal women compared risedronate 2.5 or 5 mg daily to placebo over 2–3 years.19 These trials were categorised as osteoporosis treatment (or secondary prevention) trials, based upon inclusion criteria of a T-score ≤–2.0 or the presence of a prevalent vertebral fracture. Pooled data from three RCTs showed a 39% reduction in vertebral fractures (RR 0.61; 95% CI: 0.50–0.76) for risedronate 5 mg per day with an estimated NNT of 48. The weighted mean age was 69.1 years (range 64.7–71 years), the weighted mean FN T-score was –2.7 (range –2.9 to –2.4) and the prevalent vertebral fractures weighted mean was 79% (range 30–100%).19 Pooled data from four RCTs showed a 20% reduction in non-vertebral fractures (RR 0.80; 95% CI: 0.72–0.90), with an estimated NNT of 30. The weighted mean age was 76.9 years (range 64.7–78 years), the weighted mean FN T-score was –3.6 (range –3.7 to –2.4) and the prevalent vertebral age: 42% to 100%. For hip fractures, there was a 26% reduction in risk (three RCTs; RR 0.74; 95% CI: 0.59–0.94), with an estimated NNT of 202. The weighted mean age was 77.3 years (range 69–78 years), the weighted mean FN T-score was –3.6 (range –3.7 to –2.4) and the prevalent vertebral fractures weighted mean was 47% (range 30–100%).19 The effect observed for 2.5 mg risedronate was not as large.19

The multicentre international Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON)–Pivotal Fracture Trial (PFT) followed the safety and efficacy of zoledronic acid in a cohort of postmenopausal women with osteoporosis for nine years. In the initial trial, 7765 patients (mean age 73 years) were randomised to receive either placebo or a single infusion (5 mg) of zoledronate/zoledronic acid at baseline, 12 months and 24 months. At 36 months from baseline, zoledronic acid treatment reduced the risk of morphometric vertebral fracture by 70% compared with placebo (3.3% versus 10.9%; RR 0.30; 95% CI: 0.24–0.38) and reduced the risk of hip fracture by 41% (1.4% versus 2.5%; HR 0.59; 95% CI: 0.42–0.83).21 A post hoc analysis of data from patients who received only one dose of zoledronic acid at baseline revealed a similar reduction in vertebral fracture risk (68%) at the 18-month follow-up compared with placebo.22

Treatment following hip fracture

An annual infusion of zoledronic acid within three months after a hip fracture was associated with a reduction in the rate of new clinical fractures and improved survival in women and men with an average age of 74.4 years, followed for a median of 1.9 years.1 In that randomised double-blind placebo-controlled trial, rates of any new clinical fracture were reduced by 35% (P=0.001) from 13.9% in the placebo group to 8.6% in the zoledronic acid group. The respective rates of a new clinical vertebral fracture in the zoledronic acid and placebo groups were 1.7% and 3.8% (P=0.02), and the respective rates of new non-vertebral fractures were 7.6% and 10.7% (P=0.03). There was also a reduction of 28% in deaths from any cause in the zoledronic acid group (P=0.01).1 No adverse effects on fracture healing were noted. The rates of renal and cardiovascular adverse events, including atrial fibrillation and stroke, were similar in the two groups.1 On the basis of that trial, the US Endocrine Society’s practice guideline for osteoporosis in men suggested treatment with IV zoledronic acid in men with a recent hip fracture.23

Duration of therapy

The Fracture Intervention Trial Long-term Extension (FLEX) trial demonstrated a reduction in clinical (not morphometric) vertebral fractures among those who continued alendronate for 10 years compared with those who discontinued after five years.24 A post hoc analysis revealed that among postmenopausal women without a vertebral fracture at FLEX baseline, an FN T-score of –2.5 or less at FLEX baseline was associated with non-vertebral fracture risk reduction (RR 0.50; 95% CI: 0.26–0.96).25 A further post hoc analysis of the FLEX trial showed that among women who discontinued alendronate after five years, the predictors of fracture were age (HR per five-year increase 1.54; 95% CI: 1.26–1.85) and FN T-score (lowest tertile of baseline FN DXA versus the other two tertiles relative HR 2.17; 95% CI: 1.38–3.41).26 Change in BMD after one year was not a predictor of further fracture.26

In an extension of the HORIZON–PFT study, 1233 women who had received three annual doses of zoledronic acid in the original trial were randomised to receive either zoledronic acid for another three years under the same annual, three-dose regimen or placebo.27 At the 36-month follow-up, the incidence of new vertebral fractures was lower in women who received six years of zoledronic acid than in those who had received the drug for only three years (14 versus 30 fractures; odds ratio [OR] 0.51; P=0.035), but there was no change in fracture rate in the placebo group.27 A further three-year extension of the trial did not show a significant difference in fracture rates between women taking zoledronic acid for a full nine years compared with those who had taken the drug for six years followed by three years on placebo.28 These results indicate that maximum benefit of zoledronic acid may be achieved in some patients after six years of therapy (for a reduction of vertebral fracture risk) and that for most patients the benefits are maintained for a further three years once therapy is stopped.

Treatment of osteoporosis in men

One RCT found a significant reduction (P=0.02) in the risk of vertebral fractures in older men with osteoporosis (n=241) for alendronate 10 mg per day for two years compared with placebo.29 The effect on non-vertebral fractures was not significant. An RCT to assess the effectiveness of risedronate 5 mg daily versus vitamin D/calcium in men with osteoporosis (n=316) with a baseline mean lumbar spine T-score of –3.3 and a prevalent vertebral fracture rate of 50% found a significant 60% reduction (P=0.028) in new morphometric vertebral fractures and statistically significant increases in lumbar spine and hip BMD at one year of follow-up.30 A placebo-controlled RCT of risedronate involving 284 men over two years with a baseline mean lumbar spine T-score of –3.2 and 25% of subjects with prevalent vertebral fractures demonstrated improved lumbar spine and hip BMD with risedronate.31 However, there was no significant effect on vertebral or non-vertebral fractures, although the study was underpowered to detect differences in fracture rates.31 Data on the efficacy of zoledronic acid in reducing fracture risk in men are rare. In a multicentre double-blinded trial of 1199 men with osteoporosis aged 50–85 years and randomised to receive either placebo or 5 mg zoledronic acid at baseline and at 12 months, zoledronic acid reduced the rate of morphometric vertebral fracture by 67% at the 24-month follow-up (RR 0.33; 95% CI: 0.16–0.70; P=0.002).32 The rate of non-vertebral fractures was also lower in the treatment group, but the difference did not reach statistical significance.32

  • The bisphosphonates approved in Australia for clinical use in osteoporosis are alendronate, risedronate and zoledronate/zoledronic acid. Alendronate and risedronate (all available preparations) are supported under the PBS for women and men with osteoporotic fracture independent of age, BMD or other clinical risk factors. It is important to note the PBS criteria for osteoporosis pharmacotherapy, namely ‘established osteoporosis with fracture due to minimal trauma’, means that an individual qualifies for subsidised treatment if a minimal trauma fracture has been sustained, regardless of BMD T-score. Assessment of absolute fracture risk and clinical judgement should guide individual decisions on osteoporosis pharmacotherapy.
  • Active upper gastrointestinal tract (GIT) disorders (current strictures, Barrett’s oesophagus and gastric, oesophageal or duodenal ulcers) are a contraindication to oral bisphosphonate use.
  • The oral bioavailability of bisphosphonates is very low (~1%), so dosing instructions are important. Taking oral therapy after fasting for several hours (usually overnight) and then remaining upright and avoiding food for at least 30 minutes will maximise medication absorption. Enteric-coated risedronate can be taken with or without food, making this formulation very convenient. This may assist with increasing patient medication adherence.
  • The incidence of GIT adverse events is low in patients without prior upper GIT disorders and minimised by taking the tablet with a large glass of water and remaining upright until after eating.
  • Calcium and vitamin D intake appropriate for gender, age and menopause status is recommended alongside bisphosphonate therapy (all the bisphosphonate intervention trials have occurred in vitamin D- and calcium-replete patients).
  • Oral bisphosphonates should not be taken together with other medications, particularly calcium, because they may affect bisphosphonate absorption. Calcium supplements should not be taken for at least 60 minutes after oral bisphosphonates.
  • Low serum vitamin D levels should be corrected to a serum concentration >50 nmol/L before commencing bisphosphonate therapy because low vitamin D levels increase the risk of hypocalcaemia, especially with parenteral bisphosphonates such as zoledronate.
  • IV zoledronate needs to be administered over at least 30 minutes because higher infusion rates can increase the risk of renal damage. Zoledronate acid is contraindicated in patients with a calculated creatinine clearance below 35 mL per minute.
  • The flu-like side effects from IV zoledronate tend to improve with subsequent infusions.
  • The combined use of bisphosphonates with other antiresorptive (eg raloxifene, hormone therapy) or anabolic (teriparatide) drugs is not recommended.
  • Good dental hygiene and care is recommended, particularly in those using long-term oral bisphosphonates, to reduce the risk of MRONJ (refer to Section 5.3).
  1. Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007;357(18):1799–809.
  2. Reid IR, Horne AM, Mihov B, et al. Fracture prevention with zoledronate in older women with osteopenia. N Engl J Med 2018;379(25):2407–16.
  3. Reid IR, Horne AM, Mihov B, et al. Effects of zoledronate on cancer, cardiac events, and mortality in osteopenic older women. J Bone Miner Res 2020;35(1):20–27.
  4. Andrici J, Tio M, Eslick GD. Meta-analysis: Oral bisphosphonates and the risk of oesophageal cancer. Aliment Pharmacol Ther 2012;36(8):708–16.
  5. Oh YH, Yoon C, Park SM. Bisphosphonate use and gastrointestinal tract cancer risk: Meta-analysis of observational studies. World J Gastroenterol 2012;18(40):5779–88.
  6. Sun K, Liu JM, Sun HX, Lu N, Ning G. Bisphosphonate treatment and risk of esophageal cancer: A meta-analysis of observational studies. Osteoporos Int 2013;24(1):279–86.
  7. Lo JC, O’Ryan FS, Gordon NP, et al. Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg 2010;68(2):243–53.
  8. Malden N, Lopes V. An epidemiological study of alendronate-related osteonecrosis of the jaws. A case series from the south-east of Scotland with attention given to case definition and prevalence. J Bone Miner Metab 2012;30(2):171–82.
  9. Grbic JT, Black DM, Lyles KW, et al. The incidence of osteonecrosis of the jaw in patients receiving 5 milligrams of zoledronic acid: Data from the health outcomes and reduced incidence with zoledronic acid once yearly clinical trials program. J Am Dent Assoc 2010;141(11):1365–70.
  10. Black DM, Geiger EJ, Eastell R, et al. Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. N Engl J Med 2020;383(8):743–53.
  11. Duckworth AD, McQueen MM, Tuck CE, et al. Effect of alendronic acid on fracture healing: A multicenter randomized placebo-controlled trial. J Bone Miner Res 2019;34(6):1025–32.
  12. Cranney A, Wells G, Willan A, et al. Meta-analyses of therapies for postmenopausal osteoporosis. II. Meta-analysis of alendronate for the treatment of postmenopausal women. Endocr Rev 2002;23(4):508–16.
  13. McClung M, Clemmesen B, Daifotis A, et al. Alendronate prevents postmenopausal bone loss in women without osteoporosis. A double-blind, randomized, controlled trial. Ann Intern Med 1998;128(4):253–61.
  14. Hosking D, Chilvers CE, Christiansen C, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. N Engl J Med 1998;338(8):485–92.
  15. 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.
  16. 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(24):2077–82.
  17. Cranney A, Tugwell P, Adachi J, et al. Meta-analyses of therapies for postmenopausal osteoporosis. III. Meta-analysis of risedronate for the treatment of postmenopausal osteoporosis. Endocr Rev 2002;23(4):517–23.
  18. Mortensen L, Charles P, Bekker PJ, Digennaro J, Johnston CC Jr. Risedronate increases bone mass in an early postmenopausal population: Two years of treatment plus one year of follow-up. J Clin Endocrinol Metab 1998;83(2):396–402.
  19. 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.
  20. Hooper MJ, Ebeling PR, Roberts AP, et al. Risedronate prevents bone loss in early postmenopausal women: A prospective randomized, placebo-controlled trial. Climacteric 2005;8(3):251–62.
  21. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356(18):1809–22.
  22. Reid IR, Black DM, Eastell R, et al. Reduction in the risk of clinical fractures after a single dose of zoledronic acid 5 milligrams. J Clin Endocrinol Metab 2013;98(2):557–63.
  23. Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97(6):1802–22.
  24. 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(24):2927–38.
  25. Schwartz AV, Bauer DC, Cummings SR, et al. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: The FLEX trial. J Bone Miner Res 2010;25(5):976–82.
  26. Bauer DC, Schwartz A, Palermo L, et al. Fracture prediction after discontinuation of 4 to 5 years of alendronate therapy: The FLEX study. JAMA Intern Med 2014;174(7):1126–34.
  27. Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: A randomized extension to the HORIZON–Pivotal Fracture Trial (PFT). J Bone Miner Res 2012;27(2):243–54.
  28. Black DM, Reid IR, Cauley JA, et al. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: A randomized second extension to the HORIZON–Pivotal Fracture Trial (PFT). J Bone Miner Res 2015;30(5):934–44.
  29. Orwoll E, Ettinger M, Weiss S, et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med 2000;343(9):604–10.
  30. Ringe JDFH, Faber H, Farahmand P, Dorst A. Efficacy of risedronate in men with primary and secondary osteoporosis: Results of a 1-year study. Rheumatol Int 2006;26(5):427–31.
  31. Boonen S, Orwoll ES, Wenderoth D, Stoner KJ, Eusebio R, Delmas PD. Once-weekly risedronate in men with osteoporosis: Results of a 2-year, placebo-controlled, double-blind, multicenter study. J Bone Miner Res 2009;24(4):719–25.
  32. Boonen S, Reginster JY, Kaufman JM, et al. Fracture risk and zoledronic acid therapy in men with osteoporosis. N Engl J Med 2012;367(18):1714–23.
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