NEWS - Strontium ranelate for osteoporosis launched in Europe

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Rheumawire

November 26, 2004

Strontium ranelate for osteoporosis launched in Europe

London, UK - A new drug for the treatment of osteoporosis,

strontium ranelate (Protelos, Servier), was launched this week in the

UK, and has also been launched in Ireland and Germany. Additional

launches in the European Community are expected soon following a

centralized approval for the product issued in September by the European

Medicines Agency (EMEA). However, there are no plans as yet for

marketing in the US as the French manufacturer is looking for a

partnership/licensing deal.

Strontium ranelate has a novel mechanism of action for an

osteoporosis drug as it acts both on bone resorption to reduce the rate

of bone growth (as do the bisphosphonates alendronate (Fosamax, Merck &

Co) and risedronate (Actonel, Procer & Gamble) but also acts on bone

formation promoting the growth of new bone (as does the parathyroid

hormone product, teriparatide (Forteo, Lilly).

" We have never had a medicine that combines the two processes, "

says Professor Tim Spector, consultant rheumatologist at St '

Hospital, London, and an investigator on clinical trials with the

product. " It's a very useful addition to existing treatments to enable

us to provide the best possible choice for our patients, " he comments in

a press release issued on behalf of Servier.

The product is licensed for the treatment of postmenopausal

osteoporosis to reduce the risk of vertebral and hip fractures. The

recommended dose is 2g daily, and comes in the form of granules to be

taken as a suspension in a glass of water. Given the slow absorption, it

should be taken at bedtime, preferably at least two hours after eating.

Food, milk and derivatives, and medicinal products containing calcium

may reduce bioavailability by 60-70%, so should be avoided for at least

two hours.

Strontium ranelate has been tested in two large phase 3 clinical

trials in postmenopausal women. The Spinal Osteoporosis Therapeutic

Intervention (SOTI) study involved 1649 patients with a previous

vertebral fracture, and was published earlier this year as reported at

the time by rheumawire.[1] The other study, the Treatment of Peripheral

Osteoporosis (TROPOS) trial, involved 5091 women with low hip bone

mineral density (BMD) and assessed the effect on peripheral fractures;

this study is still awaiting publication.

The SOTI trial showed that strontium ranelate reduced the risk of

vertebral fractures by 49% after a year, and by 41% over the three years

of the study. This " seems similar " to the reductions that have been

reported with existing agents, the researchers commented, citing results

from various separate trials as follows: alendronate (47%), risedronate

(49%), raloxifene 60mg (30%) and parathyroid hormone (65% after 21

months of treatment).

The TROPOS trial confirms the efficacy of strontium to reduce the

risk of new vertebral fractures, notes the product data sheet. It showed

a 39% relative risk reduction (p<0.001) calculated from rates of new

vertebral fractures over three years of 20% in 1823 patients on placebo

versus 12.5% in 1817 patients on the drug. An a-posteriori analysis

performed on a subgroup of patients in the TROPOS trial (n=1977, 40% of

the total) who had very low hip bone mineral density (BMD, T scores <3

SD) and who were aged >74 years shows a 36% reduction in the risk of hip

fracture for strontium compared to placebo, the data sheet adds.

A review of the SOTI study has recently been published online in

Osteoporosis International and concludes that strontium ranelate is " an

important new treatment option in the prevention of vertebral factures

in postmenopausal women with osteoporosis. " [2] The onset of treatment

was rapid, with significant protection against vertebral fractures

observed within one year and maintained over the three-year study.

Treated women experienced a reduction in new or worsening back pain and

in height loss, the review notes. The treatment was well tolerated, with

similar adverse events rates in the treatment and placebo groups,

although diarrhoea was seen more frequently with the drug than in

controls during the first few months.

The review was written by Dr t Compston (director of the

metabolic bone unit, Addenbrooke's Hospital, Cambridge), whom rheumawire

approached for an interview. Compston says she has served in an advisory

capacity for Servier as well as for many other pharmaceutical companies,

as " people in my position do. "

In the interview, Compston said that strontium might be

particularly useful in patients who cannot tolerate bisphosphonates or

who find it difficult to manage the dosing regimen (eg remaining upright

after taking the tablet). She also notes that a lot of the women

participating in the strontium trials were over 80 years old so there

are a lot more data in the very elderly patient population with this

drug than with some of the other agents that are available.

" Side-effects include an increased frequency of nausea, diarrhoea,

and headache in the first few months of treatment, not usually requiring

withdrawal of treatment, and there has also a very slight excess of

venous thromboembolism - the relative risk of 1.4, which in terms of

absolute risk is really very low, " she said. The cost of the product in

the UK (Pounds 25.60 for a four-week course) is " pretty similar " to

existing drugs like the bisphosphonates, and " much cheaper " than PTH,

which costs around Pounds 10 per daily injection.

When asked whether the novel mechanism of action of strontium

ranelate has been translated into any clinical differences for this drug

compared with other anti-osteoporosis therapies, Compston answered " not

obviously, no. The anti-fracture efficacy seems to be quite similar to

that of antiresorptive agents. " She adds that it's a " nice mechanism of

action because it addresses both of the things that go wrong in

age-related bone loss " but what it actually means in terms of clinical

effects is " a good question. "

" The mechanism of action of strontium needs further study and

remains an intriguing aspect of this agent, " says Dr Gurjit Singh Kaely,

a rheumatologist in private practice in Tacoma, Washington whom

rheumawire approached for comments. Kaeley has a particular interest in

bone disease and has received lecturing fees from Procter & Gamble,

Merck & Co, Aventis, Wyeth and Abbott. " Changes in markers of bone

turnover during therapy with strontium have suggested that there may be

a disconnect or an uncoupling of the bone formation unit, " he says.

The new drug adds another agent to the armamentarium for

osteoporosis, Kaely says, but he adds that physicians will have to learn

how to use it. Strontium is a bone-seeking element that is taken up by

bone, mainly by adsorption to the surface of the hydroxyapatite crystals

such as calcium. Kaely says: " practitioners will need to observe care

with following BMD, which is overestimated since strontium has a higher

molecular weight than calcium. Formulae were used to apply corrections

and estimate BMD related to calcium hydroxyapatite in the studies.

Clarification is needed to see if these corrections can be used on an

individual basis and on different densitometers. "

Zosia Chustecka

Sources

Meunier PJ, Roux C, Seeman E, et al. The effects

of strontium ranelate on the risk of vertebral fracture in women with

postmenopausal osteoporosis. N Engl J Med 2004; 350:459-468.

Compston J. Prevention of vertebral fractures by

strontium ranelate in postmenopausal women with osteoporosis.

Osteoporosis International; published online October 12, 2004.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org