Strontium Ranelate, sachet containing granules for oral suspension, 2g, Protos® , July 2005

Public Summary Document for Strontium Ranelate, sachet containing granules for oral suspension, 2g, Protos® , July 2005.

Page last updated: 24 October 2005

Public Summary Document
Product:Strontium Ranelate, sachet containing granules for oral suspension, 2g, Protos®
Sponsor:Servier Laboratories (Australia) Pty Ltd
Date of PBAC Consideration:July 2005

1. Purpose of Application


This application sought listing on the Pharmaceutical Benefits Scheme (PBS) as an authority required benefit for the treatment of post-menopausal osteoporosis.

2. Background


This was the first application to list this product on the PBS.

3. Registration Status


Strontium Ranelate was approved for marketing by the Therapeutic Goods Administration on 8 June 2005. The approved indication is: treatment of postmenopausal osteoporosis to reduce the risk of fracture.

4. Listing Requested and PBAC’s View


The application requested the following listing:

Authority required
Initial treatment for established postmenopausal osteoporosis in patients with fracture due to minimal trauma. The fracture must have been demonstrated radiologically and the year of plain x-ray or CT-scan or MRI scan must be included in the authority application.
A vertebral fracture is defined as a 20% or greater reduction in height of the anterior or mid portion of a vertebral body relative to the posterior height of that body, or, a 20% or greater reduction in any of these heights compared to the vertebral body above or below the affected vertebral body.

Continuing treatment for established osteoporosis in patients with fracture due to minimal trauma, where the patient has previously been issued with an authority prescription for this drug.

The Pharmaceutical Benefits Advisory Committee (PBAC) noted that, given the different mechanism of action of strontium compared to the currently listed antiresorptives, there is a potential for strontium to be added to, as well as to substitute for, current therapy and recommended that the restriction preclude PBS subsidisation of concomitant therapy with PBS listed antiresorptives.

5. Clinical Place for the Proposed Therapy


Osteoporosis affects the skeleton and is characterised by low bone mass and micro-architectural deterioration of bone tissue with a subsequent increase in bone fragility and susceptibility to fracture. Osteoporosis is defined by the measurement of bone mineral density, and is diagnosed in women when the BMD is 2.5 standard deviations or more below the average for young healthy women. Established osteoporosis denotes the presence of one of more fragility fractures. Strontium Ranelate can be used in the treatment of postmenopausal osteoporosis to reduce the risk of future fracture.

6. Comparator


The submission nominated alendronate as the comparator. This was accepted as appropriate by the PBAC.

7. Clinical Trials


The submission provided an indirect comparison of Strontium Ranelate and alendronate using placebo as the common comparator. One key long term placebo controlled study was included for each agent. Both studies had been published as follows.

Trial/first author

Protocol title

Publication citation

FIT-1/BlackRandomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet , Vol 348 (9041), pp 1535 – 1541, 1996
SOTI/MeunierThe effects of Strontium Ranelate on the risk of vertebral fracture in women with post-menopausal osteoporosis.NEJM, Vol 350 (5), pp 459 – 468, 2004

8. Results of Trials


The results of the indirect comparison of the two key trials on the rates of morphometric vertebral fractures are summarised in the table below.

Results of the indirect comparison: rates of morphometric vertebral fracture

Trial

Treatment effect RR
(95% CI)

Strontium

Placebo

Alendronate

Treatment effect RR
(95% CI)

Indirect estimate of effect
RR
(95% CI)

SOTI-strontium
0.59
(0.48, 0.73)
150/719
20.9%
237/723
32.8%
FIT-1-alendronate
145/965
15.0%
78/981
8.0%
0.53
(0.41, 0.68)
Indirect comparison
1.1
(0.8, 1.6) p=0.5

Both trials show significant risk reductions in morphometric vertebral outcomes and both show no difference in the indirect comparison.

In terms of comparative toxicity the submission only noted that Strontium Ranelate had not been reported to cause oesophageal irritation, ulceration, or perforation and can be administered without the need to remain upright for 30 minutes. The report for the strontium clinical trial noted a statistical increase for nausea and diarrhoea with strontium compared with placebo. No formal comparison of comparative toxicity was done. The PBAC accepted that there is no direct evidence to support major toxicity differences between these products, but there is indirect evidence of lesser oesophageal toxicity with strontium compared to alendronate.

9. Clinical Claim


The submission claimed that both Strontium Ranelate and alendronate significantly reduce the rate of incident vertebral fracture (morphometric) in the eligible patient population, with no significant difference in the indirect estimate of effect.

Strontium 2g daily was claimed by the submission to be equivalent to alendronate 70mg weekly. This is on the basis that the 70mg weekly regimen of alendronate was previously accepted as equivalent to the 10mg daily regimen of alendronate (as used in the clinical trial submitted) per the April 2004 Therapeutic Relativity Sheet.

These claims were accepted by the PBAC.

10. Economic Analysis


A cost-minimisation analysis of Strontium Ranelate against alendronate was presented in the submission. The resources included were drug costs only. A modelled economic evaluation was not presented. The PBAC considered this to be a valid approach.

11. Estimated PBS Usage and Financial Implications


The submission claimed that the listing of Strontium Ranelate would be cost-neutral as it will be substituted for the products currently PBS listed for osteoporosis.

The PBAC recognised that there was a potential for strontium to be added to, as well as substitute for current therapy with bisphosphonates or selective oestrogen receptor modulators, which would increase costs without corresponding evidence of a justifying increase in treatment effect. See also Listing Requested and PBAC’s view.

12. Recommendation and Reasons


The PBAC recommended listing on a cost-minimisation basis compared to alendronate for the outcome of morphometric vertebral fracture. The equi-effective doses are strontium 2 g daily and alendronate 70 mg weekly.

The PBAC recognised that, given the different mechanism of action of other listed antiresorptive drugs, there was a potential for strontium to be added to, as well as substitute for current therapy with bisphosphonates or selective oestrogen receptor modulators, which would increase costs without corresponding evidence of a justifying increase in treatment effect. Thus, the PBAC recommended that the restriction preclude PBS subsidisation of concomitant therapy with listed PBS antiresorptives.

Similarly, the PBAC recommended that the statement “…as the sole anti-resorptive agent…” be added to the PBS listings for the antiresorptives, alendronate, etidronate plus calcium, risedronate and raloxifene.

Recommendation:
List
Restriction:Authority required
Initial treatment as the sole anti-resorptive agent for established post-menopausal osteoporosis in patients with fracture due to minimal trauma. The fracture must have been demonstrated radiologically and the year of plain x-ray or CT-scan or MRI scan must be included in the authority application.
    A vertebral fracture is defined as a 20% or greater reduction in height of the anterior or mid portion of a vertebral body relative to the posterior height of that body, or, a 20% or greater reduction in any of these heights compared to the vertebral body above or below the affected vertebral body.

    Continuing treatment as the sole anti-resorptive agent for established post-menopausal osteoporosis in patients with fracture due to minimal trauma, where the patient has previously been issued with an authority prescription for this drug.
      NOTE:
      Anti-resorptive agents in established osteoporosis include alendronate sodium, risedronate sodium, disodium etidronate and raloxifene hydrochloride.
      Maximum Quantity:
      Repeats:
      28
      5


      13. Context for Decision


      The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia. It considers submissions in this context. A PBAC decision not to recommend listing or not to recommend changing a listing does not represent a final PBAC view about the merits of the medicine. A company can resubmit to the PBAC or seek independent review of the PBAC decision.

      14. Sponsor’s Comment



      Mechanism of Action:
      Strontium Ranelate has a dual effect on bone metabolism, both increasing bone formation (by increasing osteoblast precursors replication and collagen synthesis) and decreasing bone resorption (by decreasing osteoclasts differentiation and their resorbing activity).

      Efficacy:
      PROTOS has been shown by an indirect comparison to be equi-effective to the most commonly used product, alendronate, for the endpoints of:
      1. morphometric vertebral fractures
      2. clinical vertebral fractures.