Strontium Abstracts 1

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A comparison of adverse event and fracture efficacy data for strontium ranelate in regulatory documents and the publication record.
            (Bolland and Grey, 2014) Download
OBJECTIVE:  Recently, the European Medicines Agency reported that strontium ranelate increases myocardial infarction risk in postmenopausal women, 8.5 years after it was registered for use in osteoporosis. Unreported serious adverse events in clinical trials for other pharmaceuticals have been described in recent years. We assessed reporting of adverse events and fracture efficacy of strontium. METHODS:  We compared data on adverse effects (myocardial infarction, venous thromboembolism and pulmonary embolism) and fracture efficacy of strontium in publicly available regulatory documents with data in publications retrieved from searching PubMed. RESULTS:  We identified 5 regulatory documents and 9 primary publications of 7 randomised, placebo-controlled trials of strontium that reported relevant data. We identified several areas of concern in these reports: the increased risk of myocardial infarction with strontium was not identified in a pivotal phase 3 clinical trial despite specific regulatory review of cardiovascular events; data on myocardial infarction were not included in any primary publication; increased risks of venous thromboembolism and pulmonary embolism with strontium were not reported in either of the phase 3 clinical trials; data on venous thromboembolism were reported in only 5 of 9 primary publications, data on pulmonary embolism in only 2 of 9 primary publications, and either was discussed in <50% of subsequent review articles. There were differences in participant numbers, fracture cases and venous thromboembolism cases between regulatory documents and primary publications. Based on all available data from primary publications and regulatory documents, the number of fractures prevented by strontium use is similar to the number of extra cases of venous thromboembolism, pulmonary embolism and myocardial infarction caused by strontium use. CONCLUSIONS:  The risks of strontium use are similar to the benefits. Full disclosure of the clinical trial data and regulatory documents would allow clinicians and their patients to decide whether use of the drug is worthwhile.


 

Osteoporosis and venous thromboembolism: a retrospective cohort study in the UK General Practice Research Database.
            (Breart et al., 2010) Download
In a retrospective cohort study using the General Practice Research Database (GPRD), there was a greater association of venous thromboembolism (VTE) in osteoporotic than in non-osteoporotic female patients. No greater association was shown in treated patients with strontium ranelate or alendronate compared to untreated osteoporotic female patients. INTRODUCTION: We explored the risk of VTE in usual practice in osteoporotic and non-osteoporotic women with and without anti-osteoporotic treatment. METHODS: A retrospective study was conducted using the GPRD in the UK. The cohorts consisted of untreated osteoporotic women (N = 11,546), osteoporotic women treated with alendronate (N = 20,084), or strontium ranelate (N = 2,408), and a sample of non-osteoporotic women (N = 115,009). Cohorts were compared using a Cox proportional hazards regression model. RESULTS: There was a significantly increased relative risk for VTE in untreated osteoporotic women versus non-osteoporotic women (annual incidence 5.6 and 3.2 per 1,000 patient-years, respectively; relative risk 1.75 [95% confidence interval (CI), 1.09-1.84]). Results were confirmed using adjusted models. The annual incidences of VTE in osteoporotic patients treated with strontium ranelate and alendronate were 7.0 and 7.2 per 1,000 patient-years, respectively, with no significant difference between untreated and treated patients whatever the treatment. Adjusted hazard ratios for treated versus untreated osteoporotic women were 1.09 (95% CI, 0.60-2.01) for strontium ranelate and 0.92 (95% CI, 0.63-1.33) for alendronate. CONCLUSION: This study shows a greater association of VTE in osteoporotic compared to non-osteoporotic patients, but does not show any greater association in treated patients with strontium ranelate or alendronate compared to untreated osteoporotic patients.

Ischaemic cardiac events and use of strontium ranelate in postmenopausal osteoporosis: a nested case-control study in the CPRD.
            (Cooper et al., 2014) Download
UNLABELLED:  We explored the cardiac safety of the osteoporosis treatment strontium ranelate in the UK Clinical Practice Research Datalink. While known cardiovascular risk factors like obesity and smoking were associated with increased cardiac risk, use of strontium ranelate was not associated with any increase in myocardial infarction or cardiovascular death. INTRODUCTION:  It has been suggested that strontium ranelate may increase risk for cardiac events in postmenopausal osteoporosis. We set out to explore the cardiac safety of strontium ranelate in the Clinical Practice Research Datalink (CPRD) and linked datasets. METHODS:  We performed a nested case-control study. Primary outcomes were first definite myocardial infarction, hospitalisation with myocardial infarction, and cardiovascular death. Cases and matched controls were nested in a cohort of women treated for osteoporosis. The association with exposure to strontium ranelate was analysed by multivariate conditional logistic regression. RESULTS:  Of the 112,445 women with treated postmenopausal osteoporosis, 6,487 received strontium ranelate. Annual incidence rates for first definite myocardial infarction (1,352 cases), myocardial infarction with hospitalisation (1,465 cases), and cardiovascular death (3,619 cases) were 3.24, 6.13, and 14.66 per 1,000 patient-years, respectively. Obesity, smoking, and cardiovascular treatments were associated with significant increases in risk for cardiac events. Current or past use of strontium ranelate was not associated with increased risk for first definite myocardial infarction (odds ratio [OR] 1.05, 95 % confidence interval [CI] 0.68-1.61 and OR 1.12, 95 % CI 0.79-1.58, respectively), hospitalisation with myocardial infarction (OR 0.84, 95 % CI 0.54-1.30 and OR 1.17, 95 % CI 0.83-1.66), or cardiovascular death (OR 0.96, 95 % CI 0.76-1.21 and OR 1.16, 95 % CI 0.94-1.43) versus patients who had never used strontium ranelate. CONCLUSIONS:  Analysis in the CPRD did not find evidence for a higher risk for cardiac events associated with the use of strontium ranelate in postmenopausal osteoporosis.

Cardiovascular safety of strontium ranelate: real-life assessment in clinical practice.
            (Donneau and Reginster, 2014) Download
The results of two new studies that recently became available are published together in this issue of Osteoporosis International. Both constitute retrospective observational studies conducted in databases of electronic healthcare records and were set up to analyse the cardiovascular risk associated with the prescription of strontium ranelate in real-life clinical practice in the UK and in Denmark.

[Adverse drug reactions of strontium ranelate(Protelos(®) in France].
            (Jonville-Bera and Autret-Leca, 2011) Download
OBJECTIVE:  Study of side effects (SE) associated with strontium ranelate required by the French Drug agency (Afssaps). METHOD:  SE associated with strontium ranelate and spontaneously reported until March 2009 to the manufacturer or to the French Regional Pharmacovigilance Centers and the periodic safety reports have been analyzed. Utilisation and sales data have been obtained from the manufacturer. RESULTS:  During the 3 years of the study, 844 SE have been reported in France in patients treated with strontium ranelate. The 199 severe SE are cardiovascular (52%), cutaneous (26%), hepatodigestive (6%), neurological (5%), haematological (3%), osteomuscular (3%) and various (3%). Venous thromboembolic events (VTEE) are the most frequent cardiovascular SE (93/104) with an incidence of 1/31,052 months of treatment. At least one VTEE risk factor is present in 26 (28%) patients. DRESS syndrome which median delay of advent is 35 days is the most frequent cutaneous SE (19/51 SE) with an incidence of 1/13,725 months of treatment. The 14 severe hepatodigestive SE are hepatitis (n=5), pancreatitis (n=2) and various others SE (n=7). The 10 severe neurological SE are confusion/amnesia (n=5), convulsions (n=4) and parenthesis (n=1). The seven severe haematological SE are pancytopenia (n=5), erythroblastopenia (n=1) and thrombocytopenic purpura (n=1). Among the seven deaths, only three (two pulmonary embolisms, one DRESS syndrome) are attributable to strontium ranelate. Apart from the severe SE, 685 SE have also been reported because strontium ranelate was the only drug with an imputability "suspect". DISCUSSION:  Anti-fractural effect of strontium ranelate is at least as equal as those of bisphosphonates. Its usual SE are benign but two severe risks of strontium ranelate i.e. VTEE and DRESS syndrome are confirmed. The profile of tolerability, different from the one of bisphosphonates makes strontium ranelate as an alternative when bisphosphonates are not recommended or contraindicated (renal insufficiency for example). CONCLUSION:  If DRESS syndrome is unpredictable, the one of VTEE could be reduced by a strontium ranelate contraindication for patients with a history of VTEE and by stopping the drug if a new VTEE risk situation happens.

Short-term toxicity of strontium chloride in rats.
            (Kroes et al., 1977) Download
A range-finding experiment with strontium chloride hexahydrate (0, 3, 30, 300 and 3000 ppm in the diet) and subsequently a 90-day test with the same compound at dose levels of 0, 75, 300, 1200 and 4800 ppm in a semipurified diet was carried out with SPF-derived Wistar-rats. The diet contained adequate levels of Ca, Mg, P and Vit.D3. Growth, food intake, behaviour and mortality were measured, extensive haematology and clinical biochemistry carried out, organ weights determined, X-ray photographs of the bones taken and complete histopathological examination was performed. In addition Sr-content of blood, bone and muscles was determined. Thyroid weights were significantly increased in the males of the 1200 and 4800 ppm group. Histological evidence for increased thyroid activity was noticed in the males of the 4800 ppm group. Pituitary weights were significantly decreased in the females of the 300 ppm and 4800 ppm group, but not of the 1200 ppm group. A histologically confirmed glycogen depletion of the liver was noted biochemically in the highest dose group (4800 ppm). Sr-content in bone was increased at all dose levels having a constant level from 4 weeks onwards, thus indicating that a no effect level cannot be established. If the increased Sr-concentration in the bone can be considered a non-toxic effect, the non-toxic effect level appears to be 309 ppm.


 

Strontium induced rickets: metabolic basis.
            (Omdahl and DeLuca, 1971) Download
Dietary strontium inhibits both the synthesis of 1,25-dihydroxycholecalciferol and intestinal calcium absorption in vitamin D(3)-repleted chicks. 1,25-Dihydroxycholecalciferol restores calcium absorption to normal, while 25-hydroxycholecalciferol is without effect in the strontium-fed chick. It is suggested that strontium induces rickets by blocking the biosynthesis of 1,25-dihydroxycholecalciferol, the metabolically active form of vitamin D in the intestine.

Rachitogenic activity of dietary strontium. I. Inhibition of intestinal calcium absorption and 1,25-dihydroxycholecalciferol synthesis.
            (Omdahl and DeLuca, 1972) Download
Inhibition of calcium absorption by dietary strontium is  the result of a block in the renal synthesis of 1,25-dihydroxy- cholecalciferol (1,25-(OH)2C) from 25-hydroxycholecal- ciferol (25-OHCC). The administration of 1,25-(OH)2C but not 25-OHCC restores to normal calcium absorption

Control of kidney 25-hydroxyvitamin D3 metabolism. Strontium and the involvement of parathyroid hormone.
            (Omdahl, 1977) Download
The action of parathyrdid extract (PTE) on the renal metabolism of 25hydroxyvitamin D, (25OHD,) was evaluated in rat models for strontium rickets and hypoparathyroid- ism. PTE elevated the production of la,25-(OH)2D, and suppressed the synthesis of 24,25-(OH12D3 in both animal models. Part of strontium’s action in suppressing la,25 (OH),D, and stimulating 24,25-(OH),D3 synthesis in strontium rickets appears to involve a decrease in parathyroid hormone (PTH) secretion and/or action. Calcitonin (CT) was not implicated in the cation’s action. Thyroparathyroidectomized rats showed a low level of la,25-(OH)2D3 production which increased four- to eightfold following chronic PTE treatment. PTH appears to be the major calcium regulatory hormone involved in modulation of renal 25-OHD, metabolism.

Cardiac concerns associated with strontium ranelate.
            (Reginster, 2014) Download
INTRODUCTION:  Strontium ranelate is proven to reduce vertebral and non-vertebral fracture risk in osteoporosis. Concerns about cardiac safety have led to a new contraindication to strontium ranelate in patients with uncontrolled hypertension and/or current or past history of ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease. AREAS COVERED:  A literature search was performed; data were also collected from the European Medicines Agency website. Randomised controlled trial (RCT) data indicate a higher incidence of non-adjudicated myocardial infarction (MI) with strontium ranelate versus placebo (1.7 vs 1.1%; odds ratio [OR]: 1.6; 95% CI: 1.07 - 2.38; p = 0.020) (Mantel-Haenzel estimate of the OR). There was no increase in cardiovascular mortality. MI risk was mitigated by excluding patients with cardiovascular contraindications (OR: 0.99; 95% CI: 0.48 - 2.04; p = 0.988). Three observational studies performed in the context of real-life medical practice in the UK and Denmark did not report a signal. EXPERT OPINION:  The increased risk for cardiac events with strontium ranelate has been detected in RCTs but not in real life. Excluding patients with cardiovascular contraindications appears to be an effective measure for controlling the risk of MI. Strontium ranelate remains a useful therapeutic alternative in patients with severe osteoporosis without cardiovascular contraindications who are unable to take another osteoporosis treatment.

Stereological studies on the epiphyseal growth plate in strontium-induced rickets. With special reference to the distribution of matrix vesicles.
            (Reinholt et al., 1984) Download
Applying stereological principles, we recently demonstrated a matrix-vesicle distribution between the zones of the epiphyseal growth plate that is at variance with the generally accepted distribution. In the present study of strontium-induced rickets we demonstrated a similar bimodal distribution, the highest matrix-vesicle volume fraction being found in the resting and hypertrophic zones and the lowest, in the proliferative zone. These volume-fraction differences are due to differences in the number of vesicles between zones, the variation in mean diameter being rather small. The disturbed mineralization in strontium-induced rickets is associated with a diminished reduction of the matrix-vesicle volume fraction in the lower part of the growth plate compared with normal animals. The findings may indicate that matrix-vesicle removal is a part of the mineralization process, but a causal connection cannot be proved on the basis of our results. Our findings are, however, compatible with the earlier-posed cell-debris theory for matrix-vesicle origin and distribution.

Studies on experimental rickets XX The effects of strontium administration on the histological structure of the growing bones.
            (Shipley, 1922b) Download
The therapeutic use of strontium bromide for epilepsy and kindred nervous disorders has stimulated pharmacologic studies of the toxicity of strontium salts. When strontium replaces calcium in an otherwise satisfactory diet, it stimulates growth, and stimulates the bone to develop the characteristic picture of rickets “strontium rickets.” The anatomical lesions described by Lehnerdt as induced by the administration of strontium to dogs, were not due to the strontium alone but to a diet very poor in calcium and high in phosphorous, and deficient in the factors fat-soluble vitamin A or a second dietary essential which we have shown to be associated with certain fats, notably cod-liver oil.

Studies On Experimental Rickets
            (Shipley, 1922a) Download
In the rat, then, there are two sorts of rickets, one of which results from a diet, caeteris paribus, low in phosphorus; one which fol lows the administration of a diet, caeteris paribus, low in calcium. It would seem as if the same thing might be true of children. Normal growth of bone depends on the maintenance of a normal ratio between the two ions, not on the absolute amount of either in the food. To sum up, (1) rickets is a disease of metabolism usually due to faulty food. 2. It may be produced in rats by certain diets containing an improper balance between calcium and phosphorus, when an uncharac terized substance associated with certain fats is absent or deficiently sup plied. 3. There are two sorts of rickets in rats, one a low calcium type, produced by diets relatively low in calcium, but containing an approxi mately normal amount of phosphorus, other things being equal, and second, a low phosphate type, produced by diets deficient in phosphorus, with a normal or high calcium content. 4. Some uncharacterized organic substance, which is present in abundance in cod-liver oil, enables the organism to compensate for a defective calcium-phosphate ratio in the food. 5. Exposure to sunlight or to the rays of the mercury vapor quartz lamp will do the same thing. 6. Either of these factors will induce healing in the bones of rachitic animals. 7. Starvation also will induce healing.

 


References

Bolland, MJ and A Grey (2014), ‘A comparison of adverse event and fracture efficacy data for strontium ranelate in regulatory documents and the publication record.’, BMJ Open, 4 (10), e005787. PubMed: 25293384
Breart, G, et al. (2010), ‘Osteoporosis and venous thromboembolism: a retrospective cohort study in the UK General Practice Research Database.’, Osteoporos Int, 21 (7), 1181-87. PubMed: 19806285
Cooper, C, KM Fox, and JS Borer (2014), ‘Ischaemic cardiac events and use of strontium ranelate in postmenopausal osteoporosis: a nested case-control study in the CPRD.’, Osteoporos Int, 25 (2), 737-45. PubMed: 24322476
Donneau, AF and JY Reginster (2014), ‘Cardiovascular safety of strontium ranelate: real-life assessment in clinical practice.’, Osteoporos Int, 25 (2), 397-98. PubMed: 24322477
Jonville-Bera, AP and E Autret-Leca (2011), ‘[Adverse drug reactions of strontium ranelate(Protelos(®) in France].’, Presse Med, 40 (10), e453-62. PubMed: 21885232
Kroes, R, et al. (1977), ‘Short-term toxicity of strontium chloride in rats.’, Toxicology, 7 (1), 11-21. PubMed: 841579
Omdahl, JL and HF DeLuca (1971), ‘Strontium induced rickets: metabolic basis.’, Science, 174 (4012), 949-51. PubMed: 4330835
——— (1972), ‘Rachitogenic activity of dietary strontium. I. Inhibition of intestinal calcium absorption and 1,25-dihydroxycholecalciferol synthesis.’, J Biol Chem, 247 (17), 5520-26. PubMed: 4341346
Omdahl, JL (1977), ‘Control of kidney 25-hydroxyvitamin D3 metabolism. Strontium and the involvement of parathyroid hormone.’, Arch Biochem Biophys, 184 (1), 172-78. PubMed: 200180
Reginster, JY (2014), ‘Cardiac concerns associated with strontium ranelate.’, Expert Opin Drug Saf, 13 (9), 1209-13. PubMed: 25020233
Reinholt, FP, et al. (1984), ‘Stereological studies on the epiphyseal growth plate in strontium-induced rickets. With special reference to the distribution of matrix vesicles.’, J Bone Joint Surg Am, 66 (8), 1274-80. PubMed: 6490703
Shipley, PG (1922a), ‘Studies On Experimental Rickets’, JBJS, 4 672-78. PubMed:
——— (1922b), ‘Studies on experimental rickets XX The effects of strontium administration on the histological structure of the growing bones.’, Bull Johns Hopkins Hosp, 33 216-20. PubMed: