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RECOMMENDATION 12 (Grade A)

There is excellent evidence to support the effectiveness of alendronate in reducing the risk of vertebral fractures and increasing BMD in postmenopausal women at risk of OP.

RECOMMENDATION 13 (Grade C)

There is evidence that bisphosphonates may reduce the risk of vertebral fractures and increase BMD in older men at risk of OP.

Currently, the only bisphosphonates approved in Australia for clinical use in OP are alendronate, etidronate, risedronate, and zoledronic acid. Other bisphosphonates such as ibandronate, clodronate and neridronate are in use outside Australia, or are currently under investigation for use for postmenopausal OP in Australia. The Therapeutic Goods Administration (TGA) approval for zoledronic acid restricts use to no more than three annual 5 mg doses due to the lack of clinical trial experience beyond 3 years for the treatment of OP. Alendronate and risedronate (all available preparations) are supported under the PBS for women and men with evidence of osteoporotic fractures independent of age, BMD or other clinical risk factors. This intervention depends on an individual’s absolute risk of fracture (see Absolute fracture risk nomograms). Alendronate and risedronate are also supported by the PBS in men and women 70 years or over, without prevalent fractures, but with a T-score of -3.0 or lower at the lumbar spine or femoral neck. Zoledronic acid is also available for women who meet these criteria.

Bisphosphonates are potent inhibitors of bone resorbing cells (osteoclasts). They work to inhibit bone resorption by interfering with normal osteoclast function and inducing osteoclast apoptosis. They are rapidly sequestered into bone (from where they are only slowly released) and eliminated by the kidney, therefore exposure to soft tissues, including bone marrow, is transient. Alendronate, one of the more commonly used bisphosphonates, has a half life of approximately 8 years.80

Alendronate and risedronate are usually taken orally on either a daily basis (alendronate 10 mg, risedronate 5 mg) or weekly (alendronate 70 mg, risedronate 35 mg). Intravenous bisphosphonates are often used in patients intolerant to oral preparations (eg. once yearly zoledronic acid) and this mode of delivery produces rapid anti-resorptive action in 24–48 hours.

There were no trials of alendronate or risedronate in older men and no trials on the effectiveness of zoledronic acid in preventive populations in the critically appraised studies. However, the Working Group found evidence in several studies81–83 _{to support the notion that bisphosphonates have been shown to} increase BMD and the risk of vertebral fractures in older men at risk of OP. These three studies have not been critically appraised.

Side effects and potential harms

Bisphosphonates used in the management of OP are usually well tolerated and the rate of adverse effects in every day clinical practice is low. The most frequent adverse effects observed with oral bisphosphonate treatment are gastrointestinal (GIT) symptoms (eg. gastric irritation, oesophageal erosions, gastric ulcers, perforations and strictures). Serious side effects have been observed when using very high doses (as in cancer indications) or when elimination is impaired.

Osteonecrosis of the jaw (ONJ) has recently been associated with long term and high dose bisphosphonate treatment. This is a very rare but potentially serious side effect seen mostly in patients with multiple myeloma or breast cancer bone metastases who receive frequent and high total doses of IV bisphosphonate treatment. While the aetiology is uncertain, a strong association with dental pathology and interventions highlights the need for close attention to dental health.84,85

Practical tips and precautions

• Active upper GIT disorders, including strictures, are a contraindication to oral bisphosphonate use • Taking oral therapy after fasting for several hours (usually overnight) and then remaining upright and

avoiding food or other medications for at least 30 minutes will maximise medication absorption

• The incidence of GIT adverse events is low and may be minimised by taking the tablet with a large glass of plain water and remaining upright until after eating

• Concurrent calcium and vitamin D supplementation is recommended alongside alendronate, risedronate or etidronate therapy

• To be absorbed properly, bisphosphonates should not be taken together with any other drug, particularly calcium. Calcium supplements should NOT be taken for at least 60 minutes after the administration of oral bisphosphonates

• Low serum levels of vitamin D should be corrected to a level above 50 nmol/L before commencing bisphosphonate therapy

• IV bisphosphonates need to be administered over at least 15–20 minutes as higher infusion rates can increase the risk of renal damage. Zoledronic acid is contraindicated in patients with a calculated creatinine clearance below 35 mL/min

• Combined use of bisphosphonates with other anti-resorptive (eg. raloxifene, hormone therapy) or anabolic drugs (teriparatide) is not recommended

• Good dental hygiene and care is recommended, particularly in those using long term IV bisphosphonates, to reduce the risk of ONJ. Treatment should be ceased in cases of confirmed ONJ. The dental practitioner should be made aware of bisphosphonate dosage and other risk factors, and extractions or other jaw bone surgery should be avoided. Where unavoidable, extractions should be performed under antibiotic prophylaxis with minimal trauma and suture socket.85_{The actual risk of ONJ with therapy for OP is} considered to be very low.

EVIDENCE STATEMENT Prevention of osteoporosis

A pivotal good quality SR86,87 _{included two good quality trials (n=1946) that reported the magnitude of effect}

of alendronate 10–40 mg/day on vertebral fractures in postmenopausal women without OP. Alendronate

was associated with a significant reduction in the risk of vertebral fracture (RR: 0.45; 95% CI: 0.06–3.15) and a non-significant reduction in the risk of non-vertebral fractures (RR: 0.79; 95% CI: 0.28–2.24) compared to placebo. There was also improvement in lumbar spine (WMD: 8.05; 95% CI: 7.06–9.05), total body and hip BMD. In comparing prevention and population trials, the review found no significant difference

in effect of therapy between postmenopausal women with or without confirmed OP, ie. similar relative risk

reduction, albeit with different absolute risk reduction.87

A recent Cochrane review88 _{on the effectiveness of risedronate at doses of 2.5 mg/day and 5.0 mg/day for}

a duration of 2 years for prevention of OP included one RCT with 381 early postmenopausal women (mean age 52.6 ± 3.3 years). Results were not significant compared to placebo for either vertebral (RR: 0.97; 95%

CI: 0.42–2.25) or non-vertebral fracture (RR: 0.81; 95% CI: 0.25–2.58) risk.88

Results of these SRs were supported by an additional MA that combined preventive and treatment trials.84

There are no trials of alendronate or risedronate in older men, and no trials on the effectiveness of zoledronic acid in preventive populations.

Duration of therapy

One moderate quality trial provided evidence that after 5 years of treatment with alendronate 10 mg the risk of fractures did not increase after 10 years, except in women with a high risk of fracture. Women who discontinued alendronate after 5 years therapy showed a small decline in BMD and a gradual rise in biochemical markers but no higher fracture risk, except for clinical vertebral fractures that did increase,

compared with those who continued alendronate.89 _{Given the lack of comparable evidence for duration}

of therapy for the other bisphosphonates used in Australia and the observed differences in return of bone turnover toward placebo after cessation with different bisphosphonates, the Working Group does NOT

suggest that the concept could be applied to all bisphosphonates or even to all oral bisphosphonates.

Safety

A number of good quality SRs found no significant differences between alendronate, risedronate, or

zoledronic acid compared to placebo for GIT effects84,87,88 _{or for rate of discontinuing medication as a result}

of adverse effects.87

One trial reported an increased risk compared to placebo for serious atrial fibrillation with zoledronic acid (1.3 vs. 0.5%; p<0.001) but another large trial found no significant increase in risk (1.1 vs. 1.3%; p<0.84).84

A recent SR84 _{reported that the only cases of ONJ have occurred in patients with cancer taking large IV doses}

of bisphosphonates. The reviewers noted that the American Society for Bone and Mineral Research had recently conducted a review and concluded that there appeared to be a low risk of ONJ in patients taking

oral bisphosphonates, but suggested that the incidence may be higher than reflected in current literature.84

The United States Food and Drug Administration has recently concluded that there are no data indicative of increased risk of ONJ with oral bisphosphonate therapy for OP.