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Three Part Question

In [patients with an acute osteoporotic vertebral compression fractures] do [bisphosphonates] reduce [pain]?

Clinical Scenario

A 72-year-old woman presents to the emergency department with severe back pain after a mechanical fall. Plain radiographs of her thoracic spine show osteopenic vertebrae with a wedge compression fracture of the body of T8. Her pain is controlled acutely with paracetamol, ibuprofen and oral morphine sulphate. She is mobilised and arrangements are made for her to have physiotherapy in the community. You are keen to discharge this patient but want to maintain pain control and, given the potential side effects, would prefer to avoid opiates and non-steroidals. You have heard that some bisphosphonates relieve the pain of pathological fractures and wonder whether they do so in vertebral compression fractures.

Search Strategy

MEDLINE 1950–November Week 2, 2010; EMBASE 1980–2010, Week 46 and the Cochrane Library November 2010.
MEDLINE and EMBASE: exp fractures, compression/OR exp spinal fractures/OR ((spinal or vertebrae) ADJ (osteoporosis OR compression) ADJ fractures).mp.) AND (exp bisphosphonates/OR bisphosphonates.mp. OR exp diphosphonates/OR exp alendronate/OR alendronate.mp. OR pamidronate.mp. OR exp pamidronate/) AND (exp pain/ OR exp analgesia/OR pain.mp. OR analgesia.mp.). Limit to human and English language.

Cochrane: (bisphosphonates OR diphosphonates OR alendronate OR pamidronate) AND (fracture*) AND (pain OR analgesia*).

Search Outcome

Eighty-three papers were identified in MEDLINE, 512 in EMBASE and 98 in the Cochrane Library. Of these, four papers were relevant to the three-part question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Armingeat et al, 2006, France	32 patients (30-85 years, 21 female, 11 male) with recent (<21 days) vertebral compression fractures (confirmed on X-rays) with pain rated 40-100mm on VAS randomised to IV pamidronate or placebo	Randomised, controlled, double-blind clinical trial	Improvement in standing pain on VAS at day 7	Statistically significant improvement in standing pain at day 7	Small patient numbers Six patients lost to follow-up No indication regarding whether or not this was an industry-sponsored trial
Laroche et al, 2006, France	27 patients (49-85 years, 22 female, 5 male) with painful, non-traumatic, benign vertebral compression fractures <4 months old randomised to IV pamidronate or placebo	Randomised, controlled, double-blind clinical trial	Improvement in pain on VAS at days 0, 4 and 30	No statistically significant reduction in pain with single dose IV pamidronate compared with IV calcitonin	Small patient numbers Calcitonin not administered via normal therapeutic route Subjects had varying analgaesic regimens No placebo control
Gangji and Appelboom, 1999, Belgium	26 patients (mean age 75 years, 16 female, 10 male) with chronic back pain secondary to osteoporotic vertebral fractures (≥2 months old). Received IV pamidronate every 3 months for a year.	Retrospective observational study	Improvements in pain/ mobility as scored by patients on five-point scales	Statistically significant improvement in pain/mobility scores at 48 hours	No control for comparison, no attempt made at blinding Non-validated scoring system No description of patient recruitment process
Abdulla, 2000, UK	Five female patients (59-88 years) admitted with acute vertebral compression fractures confirmed on X-rays. Received IV pamidronate 15 mg daily for 3 days	Case Series	Improvements in pain and mobility in first week of treatment	All patients reported improvements in pain and mobility	No statistical analysis Objective measures of pain (VAS) not used in all patients Small patient numbers No controls for comparison

Comment(s)

One randomised, masked, controlled trial examined pain relief from intravenous pamidronate for osteoporotic vertebral compression fractures less than 21 days old (Armingeat). Patients were randomised to receive either 30 mg intravenous pamidronate, or placebo, daily for a total of three days. The primary endpoint was the patients’ assessment of standing pain on a visual analogue scale (VAS) measured at day 7. There was a statistically significant decrease in VAS at day 7 with pamidronate compared to placebo (P=0.018). Previous studies have suggested that VAS decreases of 9 and 13 mm are clinically significant (Kelly, Todd): the mean VAS (on standing at day 7) in this study decreased by 23 mm with placebo and 42 mm with pamidronate. Significant improvements were also seen on standing pain at day 30 and patients' overall assessments at days 7 and 30. Another randomised, masked, controlled trial looked at the analgesic effect of a single infusion of intravenous pamidronate (1 mg/kg) against 1.5 mg synthetic human calcitonin, using VAS at days 0, 4 and 30 (Laroche). The authors found no significant difference in efficacy between the two: improvements were seen in patients' symptoms with both treatments but there was no placebo group to demonstrate that this was not simply the natural history of the condition. A third study involved 26 patients with vertebral compression fractures more than two months old, who received intravenous pamidronate (two doses of 30 mg, 48 hours apart) every three months for one year (Gangji). They were evaluated at 48 hours, one month, three months and one year and were asked to rate their pain and mobility on five-point scales. Mean pain and mobility scores were reported to have improved significantly 48 hours after the first infusion. Non-significant improvements were seen at one and three months and no further improvement was seen between three months and a year, although there was no worsening of symptoms, suggesting that the early benefits were sustained. No attempt was made at masking participants and there was no comparator. Finally, we identified a case series of five female patients who received three days of intravenous pamidronate (three had 15 mg daily for three days; two had 30 mg on day one, followed by two days of 15 mg doses)(Abdulla). All apparently had less pain and increased mobility in the ensuing days. However, there were no statistical analyses and there was no control group for comparison.

Editor Comment

VAS, visual analogue scale.

Clinical Bottom Line

There is some evidence that intravenous pamidronate is better than placebo in relieving pain associated with vertebral compression fractures in the acute phase. There is no evidence about the efficacy of any oral bisphosphonates. A larger, well designed clinical trial is still needed to demonstrate clear benefit.

References

1. Kelly AM. Does the clinically significant difference in VAS pain score differ with age, gender or cause of pain? Acad Emerg Med 1998;5:1086-1090.
2. Todd KH. Clinical versus statistical significance in the assessment of pain relief. Ann Emerg Med 1996;2:439-441.
3. Armingeat T, Brondino R, Pham T et al. Intravenous pamidronate for pain relief in recent osteoporotic vertebral compression fracture: a randomized double-blind controlled study. Osteoporosis International 2006;17(11):1659-1665 .
4. Laroche M, Cantogrel S, Jamard B et al. Comparison of the analgaesic efficacy of pamidronate and synthetic human calcitonin in osteoporotic vertebral fractures: a double-blind controlled study. Clin Rheumatol 2006;25:683-686.
5. Gangji V, Appelboom T. Analgaesic effect of intravenous pamidronate on chronic back pain due to osteoporotic vertebral fractures. Clin Rheumatol 1999;18:266-267.
6. Abdulla AJJ. Use of pamidronate for acute pain relief following osteoporotic vertebral fractures. Rheumatology 2000;39:567-568.