The use of bisphosphonate for patients on glucocorticoid therapy for the prevention of osteoporosis

1. The use of bisphosphonate for patients
on glucocorticoid therapy for the
prevention of osteoporosis
Prepared by: Sara Abudahab
Supervised by: Dr. Amal Akour
Department of Clinical Pharmacy
University of Jordan

2. Identifying the question
PICOT
• Population: adult patients who take long term glucocorticoid
therapy (for 3 months or more)
• Intervention: bisphosphonate as a prophylaxis therapy for
prevention of osteoporosis
• Comparison : patients on placebo or on VitD and Calcium therapy
• Outcome: Bone mineral density (BMD)and prevention of Fractures
• Time: up to 12-24 months follow-up

3. Introduction
• Glucocorticoids may effectively be used in the
management of many inflammatory
conditions but their use is associated with
significant morbidity and mortality.
• Osteoporosis, with resultant fractures,
constitutes one of these morbid complications
and is associated with significant pain and
disability.
• A rapid decline in bone mineral
density (BMD) begins within the first 3
months of glucocorticoid use and peaks at
6 months, followed by a slower steady loss
with continued use.

4. Introduction
• Bisphosphonates (BPs), a family of anti-osteoporosis drugs with
strong inhibitory effects on osteoclastic bone osteoporotic, acts as a
potential candidate for modifying bone loss
• There are four bisphosphonates currently approved for use in
Canada: Alendronate (Fosamax ®), Etidronate (Didrocal ®),
Risedronate (Actonel ®) and Zoledronic Acid (Aclasta®).

6. A Meta-Analysis of Prior Corticosteroid
Use and Fracture Risk
Materials and Methods: We studied 42,500 men and women from
seven prospectively studied cohorts followed for 176,000 patient-
years.
The effect of ever use of corticosteroids, BMD, age, and sex on all fracture,
osteoporotic fracture, and hip fracture risk alone was examined using
Poisson regression in each cohort and for each sex.
Conclusion: We conclude that prior and current exposure to
corticosteroids confers an increased risk of fracture that is of
substantial importance beyond that explained by the measurement of
BMD. Its identification on an international basis validates the use of this
risk factor in case-finding strategies.
Source: Journal of Bone and Mineral Research
Impact Factor: 5.622

7. Evidence used:
1- Z Feng, et al “Bisphosphonates for the Prevention and Treatment of
Osteoporosis in Patients with Rheumatic Diseases” (December 2013),
Plos One : 8 (12)
2- Allen CS, et al “Bisphosphonates for steroid-induced osteoporosis”,
(October 2016), Cochrane Library, Issue 10. Art. No.: CD001347

8. A meta analysis 2013

9. Study characteristics
Methodology:
We searched PubMed, EmBase, and
the Cochrane Central Register of
Controlled Trials for relevant
literatures with a time limit of Jan. 6,
2012.
All randomized clinical trials of
BPs for adult rheumatic patients
with a follow-up of 6 months or
more were included.
Total of 2o trials

10. Doses and route of administration used:
• Intervention: The intervention was the use of any generation
of BPs, alone or together with calcium and/or vitamin D,
irrespective of administered approach. The
intervention in control group was placebo, alone or
together with calcium, vitamin D, and calcitonin.
• Eight trials were prevention trials, defined as starting BPs
treatment in the first three months of GC therapy
• Eleven trials were classified as treatment trials because BPs
was given for long-term GC user.
▫ Of these 11 treatment trials, the mean dosage of GC
consumption was greater than 7.5 mg/day (prednisone
equivalent) in 6 trials,
▫ less than 7.5 mg/day in 5 trials
• No GC usage in 1 trial

11. Principal Findings:
• The RR in rheumatic patients treated with
BPs was 0.61 (95%CI [0.44, 0.83], P = 0.002) for
vertebral fractures, and 0.49 (95%CI [0.23,
1.02], P = 0.06) for non-vertebral fractures.
• The WMD of BMD change in the lumbar spine
was
3.72% (95%CI [2.72, 4.72], P,0.001) at 6 months,
3.67% (95%CI [2.84, 4.50], P,0.001) at 12 months,
3.64% (95%CI [2.59, 4.69], P,0.001) at 24 months,
and 5.87% (95%CI [4.59, 7.15], P,0.001) at 36
months in patients using BPs, as compared
with those treated with calcium, vitamin D
or calcitonin.
 In subgroup analyses, rheumatic patients using BPs for osteoporosis
prevention had greater WMD than those using BPs for treating
osteoporosis at 6 months (4.53% vs. 2.73%, P = 0.05) and 12 months
(4.93% vs. 2.91%, P = 0.01).

12. Biophosphonates for vertebral fracture of rheumatic patients. Pooled estimate for the
relative risk of vertebral fractures (a) and relative risk of vertebral fractures at 12 months (b)
Forest Plot for vertebral fracture

13. Forest Plot for vertebral fractures cont.
relative risk of vertebral fractures 24 months (c), and 36 months (d)

14. Forest Plot for non-vertebral fractures

15. Conclusions/Significance:
BPs can preserve bone mass and reduce the incidence
of vertebral fractures in rheumatic patients, mainly
for those who have GC consumption.
The efficacy of BPs is better when using BPs to
prevent rather than to treat osteoporosis in
rheumatic patients.
• Journal name: PLOS ONE
• Impact factor: 3.234

16. A meta analysis 2016

17. Study characteristics
Methodology:
• Initial search of the databases,
clinical trials registries and
handsearching provided 3934
records after the results were
merged and duplicate records
removed.
• 27 trials were included in the
review (25 studies from the updated
search and two studies from the
existing Cochrane Review).
• 3075 participants.

18. Principal Findings:
1. Analysis: benefits - fractures (Incident
radiographic vertebral fractures)
2. Analysis: benefits - fractures (Incident
radiographic non-vertebral fractures)
3. Analysis: benefits - bone mineral density (BMD) at
lumbar spine (LS)
4. Analysis: benefits - bone mineral density (BMD) at
femoral neck (FN)
5. Analysis: harms (Serious adverse events)

19. Dose and route of administration used:
• We included randomized controlled trials (RCTs)
satisfying the following criteria:
1) prevention or treatment of GIOP;
2) adults taking a mean steroid dose of 5.0 mg/day
or more;
3) active treatment including bisphosphonates of any type
alone or in combination with calcium or vitamin D;
4) comparator treatment including a control of calcium or
vitamin D, or both, alone or with placebo; and
4) reporting relevant outcomes. We excluded trials that
included people with transplant-associated steroid use.
Route used: IV and Oral (please check the next slide)

20. •Dose and route of administration used:

22. Principal Findings (vertebral fractures):
• Pooled analysis for incident vertebral fractures included 12
trials (1343 participants) with high-certainty evidence and low
risk of bias.
• In this analysis 46/597 (or 77 per 1000) people experienced new
vertebral fractures in the control group compared with 31/746 in
the bisphosphonate group
▫ relative improvement of 43% (9% to 65% better) with
bisphosphonates
▫ absolute increased benefit of 2% fewer people sustaining
fractures with bisphosphonates (5% fewer to 1% more)
▫ number needed to treat for an additional beneficial
outcome (NNTB) was 31 (20 to 145) meaning that
approximately 31 people would need to be treated with
bisphosphonates to prevent new vertebral fractures in one person.

23. Forest Plot for vertebral fractures

24. • Pooled analysis for incident non-vertebral fractures included
nine trials with 1245 participants with low-certainty
evidence (downgraded for imprecision and serious risk of
bias as a patient-reported outcome).
• In this analysis 30/546 (or 55 per 1000) people experienced
new nonvertebral fracture in the control group compared with
29/699 (or 42 per 1000; range 25 to 69) in the
bisphosphonate group;
• relative improvement of 21% with bisphosphonates (33%
worse to 53% better);
• absolute increased benefit of 1% fewer people with fractures
with bisphosphonates (4% fewer to 1% more).
Principal Findings (non-vertebral fractures):

25. Forest Plot for non-vertebral fractures

26. Principal Findings (BMD):
• Pooled analysis on BMD change at the lumbar
spine after 12 months included 23 trials with
2042 patients.
▫ Evidence for both outcomes was moderate-
certainty (downgraded for indirectness as
a surrogate marker for osteoporosis) with
low risk of bias.
• Overall, the bisphosphonate groups reported
stabilization or increase in BMD, while
the control groups showed decreased
BMD over the study period.

27. Forest Plot for BMD
Lumbar Spine Femoral Neck

28. Serious adverse events
• Pooled analysis on serious adverse events included 15
trials (1703 participants) with low-certainty evidence
(downgraded for imprecision and risk of bias).
• In this analysis 131/811 (or 162 per 1000) people
experienced serious adverse events in the control group
compared
• to 136/892 (or 147 per 1000; range 120 to 181) in the
bisphosphonate group;
• absolute increased harm of 0% more serious adverse
events (2% fewer to 2% more);
• a relative per cent change with 9% improvement (12%
worse to 26% better).

29. Forest Plot for serious adverse events

30. Conclusions/Significance:
• There was high-certainty evidence that bisphosphonates
are beneficial in reducing the risk of vertebral fractures with
data extending to 24 months of use.
• There was low-certainty evidence that bisphosphonates
may make little or no difference in preventing nonvertebral
fractures.
• There was moderate-certainty evidence that
bisphosphonates are beneficial in preventing
corticosteroid-induced bone loss at both the lumbar
spine and femoral neck.
• Regarding harm, there was low-certainty evidence that
bisphosphonates may make little or no difference in the
occurrence of serious adverse events or withdrawals due to
adverse events.

31. Conclusions/Significance:
• Overall, our review supports the use of
bisphosphonates to reduce the risk of vertebral
fractures and the prevention and treatment of
steroid-induced bone loss.
• Journal Name: Cochrane Database of Systematic
Reviews (CDSR)
• Impact factor: 6.103