Strontium Ranelate

[pjoshea13]

Live2day began a thread on: "Strontium to preserve bone integrity" & milto27xabc responded with an informative post that is largely about Strontium ranelate. It is pasted below.

While strontium is freely available as a supplement, at least in the U.S., strontium ranelate is a prescription drug (Protelos or Protos) that has not been approved by the FDA.

Strontium ranelate has a mild dual effect, in that it stimulates osteoblastic creation of bone while inhibiting osteoclastic breakdown of bone. There are no PCa studies, & I'm guessing that, since PCa is invariably osteoblastic, strontium ranelate would not be an obvious PCa drug.

Although strontium ranelate has been used in Europe:

... begin 4/26/2013 press release ...

"The European Medicines Agency’s (EMA's) Committee for Medicinal Products for Human Use (CHMP) has recommended a restriction in the use of the osteoporosis medicine Protelos / Osseor, following an assessment of data showing an increased risk of serious heart problems. The CHMP recommended that Protelos / Osseor should only be used to treat severe osteoporosis in postmenopausal women at high risk of fracture and severe osteoporosis in men at increased risk of fracture. Additional measures, including restrictions in patients with heart or circulatory problems, were also recommended to minimise the heart risks of these medicines.

The CHMP recommendation is based on the advice of the Pharmacovigilance Risk Assessment Committee (PRAC), which evaluated Protelos / Osseor as part of a routine benefit-risk assessment. During the assessment, data from clinical studies in post-menopausal women were evaluated, showing a higher risk of heart attack with Protelos / Osseor than with placebo, with no observed increase in mortality risk. Given the other serious risks (blood clots and rare serious skin reactions) previously identified with the medicine, the PRAC concluded that certain restrictions in the use of the medicine should be in place for the benefit-risk balance to remain favourable and that a further in-depth evaluation of the benefits and risks of the medicine was needed.

The CHMP agreed with the PRAC’s recommendations and this opinion will be sent to the European Commission for a legally binding decision. A further wide-ranging evaluation of the benefits and risks of Protelos / Osseor will now be conducted by PRAC and CHMP. In the meantime, the current recommendations are intended to minimise the risk of serious heart problems.

Information to patients

Following an assessment of data showing an increased risk of heart problems with Protelos / Osseor, some changes in the way the medicine is used have been recommended:

Protelos / Osseor should only be used to treat severe osteoporosis in postmenopausal women at high risk of fracture and severe osteoporosis in men at increased risk of fracture. If you are taking Protelos / Osseor, your doctor will assess whether you have severe osteoporosis or are at high risk of fracture, and consider whether to stop your treatment.

Protelos / Osseor must not be used in patients with high blood pressure that is not properly controlled or in patients with a current or past history of any of the following:

ischaemic heart disease (such as angina or a heart attack);

peripheral arterial disease (obstruction of the blood flow in the arteries, usually in the legs);

cerebrovascular disease (diseases affecting the blood vessels in the brain, such as stroke).

If you continue to be treated with Protelos / Osseor, your doctor will check your risk of heart disease and high blood pressure at regular intervals during treatment.

If you have any questions, speak to your doctor or pharmacist.

Information to healthcare professionals

Healthcare professionals in the European Union Member States will receive a letter informing them of the updated recommendations on the use of Protelos / Osseor. The letter will advise them of the following:

Protelos / Osseor should only be used for the treatment of severe osteoporosis in postmenopausal women at high risk of fracture and severe osteoporosis in men at increased risk of fracture.

Protelos / Osseor is contraindicated in patients with a current or past history of ischaemic heart disease, peripheral arterial disease, or cerebrovascular disease, or in patients with uncontrolled hypertension.

Treatment with Protelos / Osseor should only be started by a physician experienced in the treatment of osteoporosis.

Physicians should base their decisions to prescribe Protelos / Osseor on an assessment of the individual patient’s risks. The patient’s risk of developing cardiovascular disease should be evaluated before and at regular intervals during treatment.

Treatment should be stopped if the patient develops ischaemic heart disease, peripheral arterial disease or cerebrovascular disease or if hypertension becomes uncontrolled.

The EMA’s recommendations are based on an analysis of pooled data from randomised studies in around 7,500 post-menopausal women with osteoporosis. The results showed an increase in the risk of heart attack with Protelos / Osseor as compared with placebo (1.7% versus 1.1 %), with a relative risk of 1.6 (95% confidence interval, 1.07 to 2.38). There was also an imbalance in the number of serious heart events seen with the medicine in two other studies, one in men with osteoporosis and another in patients with osteoarthritis. No increased risk in mortality was observed.

The EMA will keep healthcare professionals informed of the outcome of the further evaluation of the benefits and risks of Protelos / Osseor.

More about the medicine

Protelos / Osseor was authorised in the EU in 2004 for the treatment of osteoporosis (a disease that makes bones fragile) in women who have been through the menopause, to reduce the risk of fractures in the spine and the hip. In 2012, its authorisation was extended to include the treatment of osteoporosis in men at increased risk of fractures.

In March 2012, following concerns over the risks of blood clots in the veins (VTE, venous thromboembolism) and severe allergic skin reactions, the EMA completed a review of benefits and risks of Protelos / Osseor and recommended that the medicine must not be used in patients with blood clots or a history of blood clots, as well as in patients who were temporarily or permanently immobilised. In addition, warnings on the serious skin reactions were included in the product information.

More about this assessment

The assessment by the PRAC was a routine benefit-risk assessment, known as a periodic-safety-update-report (PSUR) assessment. PSURs are periodic reports on the benefit-risk balance of a medicine submitted by companies at defined time points after a medicine’s authorisation. During the assessment of PSURs, the Agency evaluates any new risks identified in order to determine whether the balance of benefits and risks of a medicine has changed and makes immediate proposals in relation to such risks.

Following the assessment by the PRAC, now endorsed by the CHMP, the CHMP opinion will be sent to the European Commission, which will issue a legally binding decision.

A further in-depth evaluation of all the benefits and risks of Protelos / Osseor will now be started."

... end 4/26/2013 press release ...

A problem I see is that while the risk is limited to those with a history of heart or circulatory problems, men with PCa are at greater risk for those conditions, whether pre-existing or not.

-Patrick

"I checked with the authors of the bone health diet I've been using on the use of strontium--the answer indicates that fracture s are much reduced using strontium--details are on strontium ranelate and women with breast cancer but should work with men with Pca.

We are not aware of any easy method to determine the deposition of strontium in vivo. The very real and impressive outcomes discussed in the literature on fracture rates with strontium, however, suggest that the ultimate aim of treatment – to diminish fractures - is significant.

In terms of efficacy, the results suggest that strontium diminishes fracture risk in many people. Large, multi-center human trials involving many postmenopausal women confirm that strontium greatly reduced the risk of vertebral, femur and hip fractures.

Some examples are:

Meunier PJ, Roux C, Ortolani S, et al. Effects of long-term strontium ranelate treatment on vertebral fracture risk in postmenopausal women with osteoporosis. Osteoporos Int. 2009 Oct;20(10):1663-73.

Reginster JY, Seeman E, De Vernejoul MC, et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab. 2005 May;90(5):2816-22.

Reginster JY, Felsenberg D, Boonen S, et al. Effects of long-term strontium ranelate treatment on the risk of nonvertebral and vertebral fractures in postmenopausal osteoporosis: Results of a five-year, randomized, placebo-controlled trial. Arthritis Rheum. 2008 Jun;58(6):1687-95.

In the SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment of Peripheral Osteoporosis Study) trials, some of the results were remarkable. Even in women older than 80 years, strontium produced a 55% reduction for vertebral fractures over the first year of treatment and a 32% reduction over 3 years.

In the SOTI trial, the risk of a clinically symptomatic vertebral fracture was 52% lower. After 3 years, the strontium group had a 41% lower risk of a new radiographic fracture, and the incidence of clinically symptomatic vertebral fractures was 38% lower. When the 4-year data were reported, they showed a 33% reduction in radiographic vertebral fractures.

In the large TROPOS trail, with 5,091 patients whose average age was 77 years, strontium produced a risk reduction of 16% in vertebral fractures and a 19% reduction in risk of non-vertebral fractures (e.g., hip, femur, wrist, ribs, etc.) In TROPOS, in the subgroup of women at highest risk of fracture (women 74 years of age or older who had a low femoral neck BMD score), strontium reduced the risk of hip fracture 36%. Over 3 years, the reduction in vertebral fracture risk was 39% and was similar even for patients who had already had a vertebral fracture when the study began. The 5-year data showed a 24% reduction in vertebral fracture risk.

A recent paper is of particular importance because of the prolonged use of strontium. (Reginster JY, Kaufman JM, Goemaere S, et al. Maintenance of antifracture efficacy over 10 years with strontium ranelate in postmenopausal osteoporosis. Osteoporos Int. 2011) They report the results of 10 years of strontium use in the postmenopausal osteoporotic women who, after participating in the SOTI and TROPOS studies for 5 years, were invited to enter a 5-year extension, during which they received strontium ranelate at a dose of 2 grams/day. The results: vertebral fracture risk was reduced by 31%, nonvertebral fracture risk by 27%, major nonvertebral fracture risk by 33%, and hip fracture risk by 24%.

There are a number of other articles which provide evidence for the safety and efficacy of strontium – which are referenced in the paper. As well, ongoing discussion in the literature of the safety issue appears to be reassuring with regards to bone mineralization.

For example:

Osteoporos Int. 2010 Apr;21(4):667-77. doi: 10.1007/s00198-009-1005-z.. In osteoporotic women treated with strontium ranelate, strontium is located in bone formed during treatment with a maintained degree of mineralization.

They conclude that “The quality of bone mineral was preserved after treatment with strontium ranelate, supporting the safety of this agent at the bone tissue level.”

and

J Bone Miner Res. 2008 Feb;23(2):215-22. Histomorphometric and microCT analysis of bone biopsies from postmenopausal osteoporotic women treated with strontium ranelate.

They conclude: Histomorphometry provided a 2D demonstration of the bone safety of strontium ranelate, with significantly higher mineral apposition rate (MAR) in cancellous bone (+9% versus control, p = 0.019) and borderline higher in cortical bone (+10%, p = 0.056). Osteoblast surfaces were significantly higher (+38% versus control, p = 0.047). 3D analysis of 3-yr biopsies with treatment (20 biopsies) and placebo (21 biopsies) using microCT showed significant changes in microarchitecture with, in the strontium ranelate group, higher cortical thickness (+18%, p = 0.008) and trabecular number (+14%, p = 0.05), and lower structure model index (-22%, p = 0.01) and trabecular separation (-16%, p = 0.04), with no change in cortical porosity. The changes in 3D microarchitecture may enhance bone biomechanical competence and explain the decreased fracture rate with strontium ranelate.

Furthermore, with millions of people taking strontium in close to 30 European countries, there has not been a lot of reports to my knowledge of strontium use causing problems. (Meunier et al. N Engl J Med. 2004 Jan 29;350(5):459-68.The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis.) They say “To date, no deleterious effects on the primary or secondary mineralization of bone in laboratory animals or humans have been reported.”

In addition, according to CDC’s Agency for Toxic Substances and Disease Registry report on the health effects of natural forms of strontium, (Centers for Disease Control’s Agency for Toxic Substances and Disease Registry Health Effects of Strontium report accessible @ atsdr.cdc.gov/ToxProfiles/t...}

“There is no direct evidence that strontium is toxic to humans, but there is suggestive epidemiological evidence that the oral toxicity observed at high doses in juvenile laboratory animals may pertain to humans under special circumstances… At low exposure levels, ingestion of stable strontium poses no harm to organisms with access to adequate calcium, phosphorus, and vitamin D. At higher exposure levels, especially under conditions of inadequate calcium, phosphorus, and vitamin D, stable strontium will interfere with normal bone development, causing ‘strontium rickets’ of variable severity.”

[Dan59]

Thanks Patrick