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Therapy of osteoporosis: an update

Osteoporosis will affect one in three women over 50 and one in five men over 50. And as the elderly population grows worldwide, by 2050 the number of women and men that will suffer from osteoporosis-related hip fractures is set to increase by 240% and 310% respectively.

At the International Osteoporosis Foundation's World Congress on Osteoporosis, in Toronto, Canada, researchers reported on some newer and some older treatments for osteoporosis.

In three separate presentations, researchers report that Strontium ranelate, a relative newcomer to the clinic, strengthens bone architecture and continues to protect bones for at least five years.
Other researchers showed that bisphosphonates, the most widely prescribed treatment for osteoporosis, remain in the bone mineral and may continue to provide benefit for many years longer than previously thought.
For hormone therapy there is some mixed news. While back-to-back treatments with parathyroid hormone and an estrogen mimic helps protect against osteoporosis in postmenopausal women, a different type of hormone treatment, hormone replacement therapy, has been linked to a slightly increased risk for stroke.

Strontium ranelate

In previous clinical trials Strontium ranelate ( Protelos ) has proven effective in preventing fractures for up to three years. But according to new data the window of opportunity can now be extended to at least five years.

Jean-Yves Reginster, at the University of Liege, Belgium, reported that in the phase III Spinal Osteoporosis Therapeutic Intervention ( SOTI ) trial, Strontium ranelate reduced the risk of new vertebral fractures by about 30 percent over four years.
In the Treatment Of Peripheral Osteoporosis ( TROPOS ) trial, which has been running a little longer, those taking the drug for five years had about a 25 percent reduction in vertebral fractures and a 15 percent reduction in non-vertebral fractures, such as those of the thigh.

" These results demonstrate, uniquely for anti-osteoporotic treatments, that Strontium ranelate provides sustained efficacy over five years against both vertebral and non-vertebral fractures," said Reginster.

Because other existing treatments have not demonstrated such robust effects in prospective, pre-planned, double-blind, placebo-controlled studies, postmenopausal osteoporotic women stand to benefit from the proven efficacy and tolerability of Strontium treatment, according to Reginster.
In two other studies, Georges Boivin and colleagues at the INSERM, Universite Claude Bernard, Lyon, France and J. Yebin Jiang and colleagues at the University of California and the University of Michigan Osteoporosis and Arthritis Lab reported on just how Strontium ranelate contributes to bone strength.

Boivin reported that Strontium is incorporated into new bone but does not make its way into older bone, which remains virtually free of Strontium even after three years of treatment.
His findings, based on high resolution X-ray microanalysis, also suggests that Strontium does not affect the quality of the bone mineral, but it does affect the quantity.

" We believe that the microarchitecture of bone is improved in those taking Strontium ranelate. It appears that the bone mass is increased with a normal degree of mineralization," said Boivin.

That theory is supported by the findings of Jiang and colleagues, who reported that Strontium does, in fact, rearrange bone architecture.
Bone is made up of two different types of structure, a spongier honeycomb core and a harder outside layer called cortical bone.
Jiang reported that the bone making up the honeycomb appears as flatter, plate-like mineral in samples taken from patients treated with Strontium ranelate, whereas in control samples the bone appears as rod-like structures.
He also reported that the outer cortical bone becomes thicker. " The three-dimensional changes in trabecular and cortical bone may improve bone mechanical strength, explaining the decreased risk for fracture in those on Strontium ranelate treatment," said Jiang.

Both groups obtained their data by analyzing biopsies taken from those enrolled in the TROPOS, SOTI and also the STRATOS phase II clinical trials for Strontium ranelate.
Boivin and colleagues used high resolution X-ray microradiography to determine the degree of mineralization of pelvic bone samples. Jiang and colleagues used a sophisticated micro computerized tomography scanner, better known as a micro CAT scanner, to measure the three-dimensional structure of the bone, also taken from the pelvis.
Boivin compared 35 samples taken from patients treated with various doses of Strontium ranelate, with 22 samples taken from those given placebo. Jiang and colleagues measured similar numbers of samples, 20 from the treatment group and 21 controls.


Boivin's findings also suggest that because Strontium is laid down at the surface of newly formed bone mineral, it may be rapidly cleared from the bone once treatment is stopped.
Bisphosphonates, on the other hand, are released only very slowly from bone and continue to appear in the urine for years after treatment is stopped according to researchers from the Netherlands.
The finding should caution against prescribing the drugs for young girls who suffer from osteoporosis or brittle bone disorders such as osteogenesis imperfecta.

Bisphosphonates are the most widely prescribed treatment for those with, or at risk for, osteoporosis.
Like Strontium, bisphosphonates are incorporated into bone where they stop the bone mineral from being dissolved away. They are known to be slowly released from bone but just how long they remain imbedded in the mineral is uncertain.
However, Socrates Papapoulos and colleagues at Leiden University, report that the bisphosphonate Pamidronate ( Aredia ) can still be detected in urine eight years after treatment has stopped.

" Up to now it has been hypothesized in the literature that bisphosphonates trapped in the bone are slowly released once therapy is stopped, but now we show for the first time that that phenomenon is real," said Papapoulous.

The researchers tested urine samples from 6 children who had been given Pamidronate for 4-10 years. Urinary measurements were taken up to 13 years after treatment was suspended. Pamidronate was measurable in urine of all patients except one, who had received treatment for 6 years, and drug was measured 13 years after stopping treatment.

The long half-life of bone bisphosphonates probably explains why osteoporotic women who have taken bisphosphonates for a long time have reduced bone mineral loss after stopping treatment.
But there is a small cloud to this silver lining, " we need to be cautious about administering bisphosphonates to young girls because there is very little data on the effects of these drugs on embryonic development," said Papapoulous.

Sequential parathyroid/Raloxifene therapy

Silvano Adami, University of Verona, Italy, and colleagues reported that women who have completed a course of another hormone therapy, parathyroid hormone, maintain better bone strength if they begin taking the Selective Estrogen Receptor Modulator ( SERM ) Raloxifene ( Evista ) once the parathyroid treatment has ended.

" The results tell us that after a course of parathyroid treatment it is important to begin taking an anti-resorber, such as Raloxifene, as soon as possible," said Adami.

Parathyroid hormone is one of very few therapies that actually stimulates bone formation but the treatment is limited to two years or less in most countries. This has left doctors and patients wondering what the best course of action is once the hormone therapy has ended.
SERMs are compounds that mimic only some of the action of estrogen. As such, they have different efficacies and side effects to hormone replacement therapy ( HRT ).

Adami and colleagues measured bone mineral density in 329 women who had been on parathyroid for one year then switched to either Raloxifene or a placebo for a subsequent year.
The researchers found that at the end of the second year, women who followed the parathyroid therapy with the estrogen mimic had a 2.3% higher bone density at the hip than those who had taken a placebo after the hormone treatment.


In the LIFT trial to measure the efficacy of the estrogen hormone replacement therapy Tibolone ( Livial ).
Steve Cummings, lead investigator, reported that follow up analysis showed that women who had taken the drug had about half as many vertebral fractures as those who had taken placebo.

However, this trial was halted due to increased incidence of stroke. " The increased risk of stroke was unexpected and will limit the use of Tibolone for prevention of osteoporosis and fracture," said Cummings. He also suggested that women and physicians should weigh the benefits and risks and consider alternatives before prescribing Tibolone for any indication.

Source: International Osteoporosis Foundation, 2006