Monthly Archives: May 2014

European Medicines Agency Recommends Restricting the use of Strontium Ranelate

In January 2014, the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) recommended that Protelos/Osseor (Strontium Ranelate) should no longer be used to treat osteoporosis. Then, in February 2014,  it concluded its review of Protelos/Osseor and recommended further restricting the use of the medicine to patients who cannot be treated with other medicines approved for osteoporosis.

The following is from their press release:

In addition these patients should continue to be evaluated regularly by their doctor and treatment should be stopped if patients develop heart or circulatory problems, such as uncontrolled high blood pressure or angina. As recommended in a previous review, patients who have a history of certain heart or circulatory problems, such as stroke and heart attack, must not use the medicine.

These final recommendations from the Agency’s Committee for Medicinal Products for Human Use (CHMP) come after initial advice from the Pharmacovigilance Risk Assessment Committee (PRAC) to suspend the medicine due to its cardiovascular risk.

‘The CHMP agreed with the PRAC’s overall assessment of the risks of Protelos/Osseor. Both committees worked in close collaboration and the PRAC’s recommendation was instrumental for us to fully assess the benefit-risk profile of the medicine’, said Tomas Salmonson, chair of the CHMP. ‘However, the CHMP considered that, for patients who have no alternative treatment, regular screening and monitoring to exclude cardiovascular disease will sufficiently reduce the risk identified by the PRAC so that these patients can continue to have access to the medicine.’

In arriving at its conclusions, the CHMP noted that study data showed a beneficial effect in preventing fractures, including in patients at high risk of fracture. In addition, available data do not show evidence of an increased cardiovascular risk with Protelos/Osseor in patients who did not have a history of heart or circulatory problems.

The CHMP considered that the cardiovascular risk in patients taking Protelos/Osseor can be managed by restricting its use to patients with no history of heart and circulatory problems and limiting its use to those who cannot take other medicines approved for the treatment of osteoporosis. In addition, patients treated with Protelos/Osseor should be screened and monitored regularly, every 6 to 12 months.

Additional risk minimisation measures include providing educational material to prescribers to ensure that only the appropriate patients are treated with the medicine. Importantly, the company is required to conduct further research to demonstrate the effectiveness of the new measures. The Committee concluded that given the benefits seen in preventing fractures in patients at high risk, Protelos/Osseor should remain an option for patients with no history of cardiovascular disease who cannot take other medicines.

In deciding on how Protelos/Osseor should be used, the CHMP took into account thePRAC’s analysis of its benefits and risks as well as advice from osteoporosis experts that there is a group of patients who could benefit from the medicine.

‘The PRAC has worked closely with the CHMP throughout the procedure and while we acknowledge that the recommendations of the two committees differed, our understanding of the medicine’s benefit-risk profile is closely aligned and we share a common view of the importance of effective monitoring of cardiovascular risk’, said June Raine, chair of the PRAC. ‘The PRAC will continue to monitor the safety of Protelos /Osseor and the effectiveness of risk minimisation in long term use.’

The CHMP’s recommendation will now be sent to the European Commission, which will then issue a final decision.

 Information to patients

  • Protelos/Osseor will only be prescribed for preventing fractures in post-menopausal women and men with severe osteoporosis who have a high risk of fracture and cannot be treated with other medicines approved for osteoporosis.
  • Before starting treatment, your doctor will assess your risk of heart disease and high blood pressure and continue to check your risk at regular intervals during treatment.
  • You should not take Protelos/Osseor if you have or have had heart or circulatory problems such as stroke, heart attack, or obstruction of the blood flow in the arteries.
  • Your treatment with Protelos/Osseor will be stopped if you develop heart or circulatory problems during treatment.
  • If you have any questions, speak to your doctor or pharmacist.

Information to healthcare professionals

Healthcare professionals in the EU 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 to treat severe osteoporosis in postmenopausal women and men at high risk of fracture, for whom treatment with other medicinal products approved for the treatment of osteoporosis is not possible due to, for example, contraindications or intolerance;
  • Protelos/Osseor must not be used in patients with established, current or past history of ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease, or those with uncontrolled hypertension;
  • Doctors should continue to base their decision 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 starting treatment and on a regular basis thereafter, generally every 6 to 12 months;
  • Protelos/Osseor should be stopped if the patient develops ischaemic heart disease, peripheral arterial disease or cerebrovascular disease, or if hypertension is uncontrolled;
  • Doctors should review their patients currently on Protelos/Osseor as necessary.

This final EMA recommendation on the use of Protelos/Osseor was based on an analysis of pooled data from randomised studies in around 7,500 post-menopausal women with osteoporosis. The results showed an increased risk of myocardial infarction with Protelos/Osseor as compared with placebo (1.7% versus 1.1 %), with a relative risk of 1.6 (95% CI, 1.07 to 2.38), and an increased risk of venous thrombotic and embolic events — 1.9% versus 1.3 % with a relative risk of 1.5 (95% CI, 1.04 to 2.19).

Available data do not show evidence of an increased cardiovascular risk in patients without established, current or past history of ischaemic heart disease, peripheral arterial disease or cerebrovascular disease, or in those without uncontrolled hypertension.

Regarding the benefits, the efficacy data showed an effect in preventing fractures, including in patients at high risk of fracture.

More about the medicine

Protelos/Osseor (strontium ranelate) is authorised in the EU to treat severe osteoporosis (a disease that makes bones fragile) in women who have been through the menopause and who are at high risk of fracture (broken bones) to reduce the risk of fractures of the spine and the hip. It is also used to treat severe osteoporosis in men who are at high risk of fracture.

The current recommendations add to EMA recommendations made in April 2013 not to use Protelos/Osseor in patients with known circulatory problems.

More about the procedure

The review of Protelos/Osseor was initiated in May 2013 at the request of European Commission under Article 20 of Regulation (EC) No 726/2004.

The first stage of this review was conducted by the Pharmacovigilance Risk Assessment Committee (PRAC), the committee responsible for the evaluation of safety issues for human medicines, which made a set of recommendations. The PRAC’s recommendations were then sent to the Committee for Medicinal Products for Human Use (CHMP) responsible for all questions concerning medicines for human use, which adopted the Agency’s final opinion.

Further information on the PRAC recommendation and the background to this review can be found on Agency’s website. The CHMP opinion will now be forwarded to the European Commission, which will issue a final decision in due course.

Gamma-Tocotrienol Inhibits Osteoclasts In Vitro


Direct inhibition of osteoclast formation and activity by the vitamin E isomer gamma-tocotrienol.

Vitamin E homologues, specifically tocotrienols, have been shown to have favorable effects on bone. They possess properties that are indicative of anti-resorptive activity, suggesting the potential for vitamin E in preventing bone loss. To investigate the anti-resorptive activity of the various vitamin E homologues, we cultured human osteoclasts from blood-derived CD14+ cells on collagen, dentin, and calcium phosphate substrates, with some samples supplemented with vitamin E homologues in their cell culture medium. These were compared to the clinically used bisphosphonate, pamidronate. Compounds were either added at the start of culture to study effects on osteoclast formation, or at the start of osteoclastic resorption to determine their effects on activity. The alpha- and gamma-tocotrienol isomers inhibited osteoclast formation without consequent reduction in total cell number. Only gamma-tocotrienol inhibited osteoclast activity without toxicity. Gamma-tocotrienol was the most potent inhibitor of both osteoclast formation and activity and requires further investigation into its anti-resorptive effects on bone.

Brooks R, Kalia P, Ireland DC, Beeton C…
Int J Vitam Nutr Res Nov 2011
PMID: 22673919

Icariin Inhibits Osteoclasts In Vitro


Icariin inhibits the osteoclast formation induced by RANKL and macrophage-colony stimulating factor in mouse bone marrow culture.

Icariin is a prenylated flavonol glycoside contained in the herb Epimedium, which has long been used to improve bone fracture healing or prevent osteoporosis because of the belief that the herb has bone-strengthening action. We have previously demonstrated that icariin enhances the osteogenic differentiation of rat bone marrow stromal cells, and partially explained the bone-strengthening mechanism of the herb. In the present study, the effect of icariin on osteoclastogenesis and bone resorption activity was investigated in mouse bone marrow culture. It was found that icariin dose-dependently inhibited the growth and differentiation of hemopoietic cells from which osteoclasts were formed. Far less TRAP+ multinuclear cells appeared in the 10 microM icariin group than in the control. The bone resorption pits formed in the 10 microM icariin group was also significantly less than that of the control. RT-PCR analysis showed that the gene expression of TRAP, RANK and CTR was obviously lower than that of the control. It can be concluded that icariin has the ability to inhibit the formation and bone resorption activity of osteoclasts, which suggests that icariin should be the effective component for the bone-strengthening action of herb Epimedium.

Chen KM, Ge BF, Liu XY, Ma PH…
Pharmazie May 2007
PMID: 17557750

Horny Goat Weed Icariin Metabolites Enhance Osteoblasts and Inhibit Osteoclasts In Vitro


Icaritin and its glycosides enhance osteoblastic, but suppress osteoclastic, differentiation and activity in vitro.

Icariin, a principal flavonoid glycoside in Herba Epimedii, is hypothesized to possess beneficial effects on bone mass. Icariin is metabolized to icariside II and then to icaritin in vivo. In the present study, we investigated the in vitro effects of icariin, icariside II and icaritin on both osteoblasts and osteoclasts. After treatment with these compounds at concentrations 10(-5)-10(-8) mol/l, osteoblasts were examined for proliferation, alkaline phosphatase activity, osteocalcin secretion and matrix mineralization, as well as expression levels of bone-related proteins. The formation of osteoclasts was assessed by counting the number of multinucleated TRAP-positive cells. The activity of isolated rat osteoclasts was evaluated by measuring pit area, actin rings and superoxide generation. Icariside II and icaritin increased the mRNA expression of ALP, OC, COL-1 and OPG, but suppressed that of RANKL. In addition, these compounds reduced the number of multinucleated TRAP-positive cells and the osteoclastic resorption area. Also decreases were observed in superoxide generation and actin ring formation that are required for osteoclast survival and bone resorption activity. These findings suggest that icaritin, which was more potent than icariin and icariside II, enhanced the differentiation and proliferation of osteoblasts, and facilitated matrix calcification; meanwhile it inhibited osteoclastic differentiation in both osteoblast-preosteoclast coculture and osteoclast progenitor cell culture, and reduced the motility and bone resorption activity of isolated osteoclasts.

Huang J, Yuan L, Wang X, Zhang TL…
Life Sci. Aug 2007
PMID: 17764702

Icariin, Anemarsaponin BII, and Berberine Benefit Bones


Antiosteoporotic chemical constituents from Er-Xian Decoction, a traditional Chinese herbal formula.

Er Xian Decoction (EXD), a traditional Chinese medicine formula, has long been used for the treatment of osteoporosis and menopausal syndrome in China. The present study was designed to investigate the antiosteoporotic constituents of EXD, and evaluate their antiosteoporotic effects in ovariectomized rats.
Osteoblasts in neonatal calvaria cultures and osteoclasts derived from rat marrow cells were used to bioactivity-guided screen the active constituents. The proliferation of osteoblast was assayed by MTT methods. The activity of ALP and TRAP was measured by p- nitrophenyl sodium phosphate assay. The antiosteoporotic effects of icariin (1), anemarsaponin B II (8) and berberine (6) were verified by using OVX rats model. The bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry using the small animal scan mode. The undecalcified longitudinal proximal tibial metaphysical (PTM) sections were cut and stained for the bone histomorphometric analysis.
Bioactivity-guided fractionation has led to the successful isolation of antiosteoporotic constituents, i.e., icariin (1), icariside I (2), baohuoside I (3), mangiferin (4), neomangiferin (5), berberine (6), anemarsaponin B (7), anemarsaponin BII (8), anemarsaponin C (9), anemarrhenasaponin I (10), rubiadin-1-methyl ether (11) and obaculactone (12) from EXD. Further study showed that icariin (1), anemarsaponin BII (8) and berberine (6) increased the BMD in ovariectomized rats, and icariin (1) not only increased the bone formation, but also inhibited bone resorption; anemarsaponin BII (8) mainly increased bone formation and berberine (6) only inhibited the bone resorption in ovariectomized rats.
Our findings demonstrate that multiple ingredients are responsible for antiosteoporotic activity in traditional Chinese medicine formula Er-Xian decoction.

Qin L, Han T, Zhang Q, Cao D…
J Ethnopharmacol Jul 2008
PMID: 18501540

Icariin Stimulates Proliferation and Differentiation of Human Osteoblasts In Vitro


Icariine stimulates proliferation and differentiation of human osteoblasts by increasing production of bone morphogenetic protein 2.

Icariine is a flavonoid isolated from a traditional Chinese medicine Epimedium pubescens and is the main active compound of it. Recently, Epimedium pubescens was found to have a therapeutic effect on osteoporosis. But the mechanism is unclear. The aim of the study was to research the effect of Icariine on the proliferation and differentiation of human osteoblasts.
Human osteoblasts were obtained by inducing human marrow mesenchymal stem cells (hMSCs) directionally and were cultured in the presence of various concentrations of Icariine. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) test was used to observe the effect of Icariine on cell proliferation. The activity of alkaline phosphatase (ALP) and the amount of calcified nodules were assayed to observe the effect on cell differentiation. The expression of bone morphogenetic protein 2 (BMP-2) mRNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR).
Icariine (20 microg/ml) increased significantly the proliferation of human osteoblasts. And, Icariine (10 microg/ml and 20 microg/ml) increased the activity of ALP and the amount of calcified nodules of human osteoblasts significantly (P < 0.05). BMP-2 mRNA synthesis was elevated significantly in response to Icariine (20 microg/ml).
Icariine has a direct stimulatory effect on the proliferation and differentiation of cultured human osteoblast cells in vitro, which may be mediated by increasing production of BMP-2 in osteoblasts.

Yin XX, Chen ZQ, Liu ZJ, Ma QJ…
Chin. Med. J. Feb 2007
PMID: 17355822 | Free Full Text

Horny Goat Weed Phytoestrogens Maintain Bone Density Over 2 Years in Women


Epimedium-derived phytoestrogen flavonoids exert beneficial effect on preventing bone loss in late postmenopausal women: a 24-month randomized, double-blind and placebo-controlled trial.

Epimedium brevicornum maxim, a nonleguminous medicinal plant, has been found to be rich in phytoestrogen flavonoids. Results from a 24-month randomized double-blind placebo-controlled clinical trial showed that Epimedium-derived phytoestrogen flavonoids were able to exert beneficial effects on preventing bone loss in late postmenopausal women, without resulting in a detectable hyperplasia effect on the endometrium.
We performed a 24-mo randomized double-blind placebo-controlled clinical trial for evaluating the effect of the Epimedium-derived phytoestrogen flavonoids (EPFs) on BMD, bone turnover biochemical markers, serum estradiol, and endometrial thickness in postmenopausal women.
One hundred healthy late postmenopausal women, with a natural menopausal history within 10 approximately 18 yr and with a BMD T-score at the lumbar spine between -2 and -2.5 SD, were randomized into EPF treatment group (n = 50; a daily dose of 60 mg Icariin, 15 mg Daidzein, and 3 mg Genistein) or placebo control group (n = 50). All participants received 300 mg element calcium daily. BMD, bone turnover biochemical markers, serum estradiol, and endometrial thickness were measured at baseline and 12 and 24 mo after intervention.
Eighty-five participants completed the trial. The patterns of BMD changes were significantly different between the EPF treatment group and placebo control group by repeated-measures ANOVA (p = 0.045 for interaction between time and group at femoral neck; p = 0.006 for interaction between time and group at lumbar spine). BMD was found with a decreased tendency in the placebo control group at 12 (femoral neck: -1.4%, p = 0.104; lumbar spine: -1.7%, p = 0.019) and 24 mo (femoral neck: -1.8%, p = 0.048; lumbar spine: -2.4%, p = 0.002), whereas EPF treatment maintained BMD at 12 (femoral neck: 1.1%, p = 0.285; lumbar spine:1.0%, p = 0.158) and 24 mo (femoral neck: 1.6%, p = 0.148; lumbar spine: 1.3%, p = 0.091). The difference in lumbar spine between the two groups was significant at both 12 (p = 0.044) and 24 mo (p = 0.006), whereas the difference in the femoral neck was marginal at 12 mo (p = 0.061) and significant at 24 mo (p = 0.008). Levels of bone biochemical markers did not change in the placebo control group. In contrast, EPF intervention significantly decreased levels of deoxypyrdinoline at 12 (-43%, p = 0.000) and 24 mo (-39%, p = 0.000), except for osteocalcin at 12 (5.6%, p = 0.530) and 24 mo (10.7%, p = 0.267). A significant difference in deoxypyrdinoline between the two groups was found at both 12 (p = 0.000) and 24 mo (p = 0.001). Furthermore, neither serum estradiol nor endometrial thickness was found to be changed in either groups during the clinical trial.
EPFs exert a beneficial effect on preventing bone loss in late postmenopausal women without resulting in a detectable hyperplasia effect on the endometrium.

Zhang G, Qin L, Shi Y
J. Bone Miner. Res. Jul 2007
PMID: 17419678

Horny Goat Weed and Icariin may Promote Osteoblasts In Vitro


Effects of total flavonoids and flavonol glycosides from Epimedium koreanum Nakai on the proliferation and differentiation of primary osteoblasts.

In a bioassay-guided drug screening for anti-osteoporosis activity, eight flavonol glycosides were isolated from Epimedium koreanum Nakai, which is traditionally widely used in China for the treatment of impotence and osteoporosis. The effects of total flavonoids and flavonol glycosides on the proliferation and differentiation of rat calvarial osteoblast-like cells were evaluated by the MTT method and measuring the activity of alkaline phosphatase (ALP activity). Total flavonoids (1.2 x10(-2) to 6.0 x10(-7) mg/ml) and flavonol glycosides (2.0 x10(-5) to 1.0 x10(-9) mol/l) exhibited a strong inhibition on the proliferation of primary osteoblasts at most concentrations. However, the total flavonoids and icariin significantly promoted the differentiation of primary osteoblasts. The results suggested that flavonoids from E. koreanum Nakai may improve the development of osteoblasts by promoting the ALP activity; and icariin might be one of the active constituents facilitating the differentiation of osteoblasts.

Zhang DW, Cheng Y, Wang NL, Zhang JC…
Phytomedicine Jan 2008
PMID: 17482445

Resveratrol Enhances Osteogenesis via Runx2 and SIRT1 In Vitro


Resveratrol mediated modulation of Sirt-1/Runx2 promotes osteogenic differentiation of mesenchymal stem cells: potential role of Runx2 deacetylation.

Osteogenic repair in response to bone injury is characterized by activation and differentiation of mesenchymal stem cells (MSCs) to osteoblasts. This study determined whether activation of Sirt-1 (a NAD(+)-dependent histone deacetylase) by the phytoestrogen resveratrol affects osteogenic differentiation.
Monolayer and high-density cultures of MSCs and pre-osteoblastic cells were treated with an osteogenic induction medium with/without the Sirt-1 inhibitor nicotinamide or/and resveratrol in a concentration dependent manner.
MSCs and pre-osteoblastic cells differentiated to osteoblasts when exposed to osteogenic-induction medium. The osteogenic response was blocked by nicotinamide, resulting in adipogenic differentiation and expression of the adipose transcription regulator PPAR-γ (peroxisome proliferator-activated receptor). However, in nicotinamide-treated cultures, pre-treatment with resveratrol significantly enhanced osteogenesis by increasing expression of Runx2 (bone specific transcription factor) and decreasing expression of PPAR-γ. Activation of Sirt-1 by resveratrol in MSCs increased its binding to PPAR-γ and repressed PPAR-γ activity by involving its cofactor NCoR (nuclear receptor co-repressor). The modulatory effects of resveratrol on nicotinamide-induced expression of PPAR-γ and its cofactor NCoR were found to be mediated, at least in part, by Sirt-1/Runx2 association and deacetylation of Runx2. Finally, knockdown of Sirt-1 by using antisense oligonucleotides downregulated the expression of Sirt-1 protein and abolished the inhibitory effects of resveratrol, namely nicotinamide-induced Sirt-1 suppression and Runx2 acetylation, suggesting that the acetylated content of Runx2 is related to downregulated Sirt-1 expression.
These data support a critical role for Runx2 acetylation/deacetylation during osteogenic differentiation in MSCs in vitro.

Shakibaei M, Shayan P, Busch F, Aldinger C…
PLoS ONE 2012
PMID: 22539994 | Free Full Text

From the introduction:

Resveratrol is a polyphenolic phytoestrogen (trans-3,5, 4′-trihydroxystilbene) found in the skin of red grapes, red vines, various other fruits, peanuts and root extracts of Polygonum cuspidatum [8]. Resveratrol acts as a mixed agonist/antagonist for the estrogen receptors alpha and beta [9]. Through binding to the estrogen receptor, resveratrol is thought to exert beneficial effects on the cardiovascular system and may reverse osteoporosis by a direct stimulatory effect on bone formation in osteoblastic cells [10]. Many of the biological effects of resveratrol have already been demonstrated in the literature; these include cardiovascular protection [11], anticancer activity [12] and stimulation of proliferation and osteoblastic differentiation in human and mouse MSCs [13], [14]. However, its effects on bone are less studied and are particularly relevant to this investigation.

From the discussion:

Resveratrol’s enhancement of osteogenesis was, at least in part regulated by Runx2 with additional contributions by Sirt-1. Resveratrol increases alkaline phosphatase activity in osteoblastic cells [10] an effect that is blocked by tamoxifen, an estrogen antagonist, suggesting that some of resveratrol’s stimulatory actions may be mediated through the estrogen receptor. Gehm et al. have reported that resveratrol acts as a phytoestrogen (i.e. activating the estrogen receptor) and decreases osteoporosis [43]. Moreover, resveratrol is one of the most potent Sirt-1 activators; through binding to a special binding site it induces a conformational change in Sirt-1, lowering the Km for both the acetylated substrate and NAD, thus resulting in increased enzymatic activity [18]. Sirt-1 facilitates the differentiation of MSCs to osteoblasts by directly regulating factors such as Runx2 and by modulation of nuclear receptor co-repressor NCoR and PPAR-γ.