Category Archives: Supplements

Review: Calcium Safety and New Recommendations

Abstract

Calcium builds strong bones, and more is better–correct? Well, maybe not.

Calcium supplementation has been considered the gold standard therapy for osteoporosis in the general population. It is given in both the placebo and treatment groups of trials evaluating antifracture efficacy of new therapies. Similarly, calcium-based phosphate binders have been considered the gold standard comparator for all new phosphate binders. However, large randomized trials demonstrate conflicting data on the antifracture efficacy of calcium supplementation, particularly in high doses, in patients with osteoporosis without CKD. In addition, recent data suggest an increased risk for cardiovascular events. These new studies raise safety concerns for the general approach with calcium supplementation and binders. This review describes recent data on the adverse effects of calcium supplementation for osteoporosis and how these new data should affect the strategy for phosphate binder use in CKD.

Jamal SA, Moe SM
Clin J Am Soc Nephrol Nov 2012
PMID: 22837272 | Free Full Text

It is important to note that some clinical practice guidelines have been modified on the basis of this new literature suggesting potential risk. For example, in its recently published evidence-based guidelines, Osteoporosis Canada recommended a total intake of calcium (from diet and supplement) of 1200 mg per day, a decrease from the previous recommendation of 1500 mg in supplements (32). The American Society for Bone and Mineral Research issued a statement regarding the potential risks of calcium supplements and suggested, among other points, that “the beneficial effects of calcium are found with relatively low doses. More is not necessarily better. Individuals should discuss the amount of their calcium intake with their healthcare provider” (33). The Institute of Medicine now recommends a daily dietary reference allowance of calcium of 1000–1200 mg per day in the form of diet and supplements (34,35). Finally, the draft United States Preventive Services Task Force statement, pending public comment (http://www.uspreventiveservicestaskforce.org/draftrec3.htm), currently states “the current evidence is insufficient to assess the balance of the benefits and harms of combined vitamin D and calcium supplementation for the primary prevention of fractures in premenopausal women or in men.” Thus, these authorities acknowledge that although some calcium supplements may be beneficial for bone health, too much calcium may be harmful.

Vitamin E Does Not Prevent Bone Loss in Rats

Abstract

Vitamin E does not prevent bone loss and induced anxiety in rats with ligature-induced periodontitis.

The purpose of this study was to investigate the effect of vitamin E on alveolar bone loss (ABL) and anxiety in rats with ligature-induced experimental periodontitis (EP).
Wistar rats were subjected to ligature-induced EP and treated with vitamin E (500mg/kg, orally) for 9 days. Then anxiety was tested using the elevated plus-maze (EPM) test. All of the animals were euthanised by cervical dislocation on day 11. ABL was analysed morphometrically and histopathologically. Lipid peroxidation quantification, activity of the enzyme superoxide dismutase and immunohistochemistry to tumour necrosis factor-alpha (TNF-α) and inducible isoform of nitric oxide synthases (iNOS) were also tested.
EP induced a marked inflammatory process and intense ABL. Treatment with vitamin E decreased inflammatory reaction, prevented malondialdehyde formation and reduced the immunoreactivity to iNOS, but did not decrease ABL. Vitamin E had an anxiogenic effect on rats with or without EP.
Vitamin E may have potential to reduce oxidative damage and inflammatory response in EP but does not prevent ABL. Attention should be given to indiscriminate use of vitamin E due to the risk of causing anxiety in patients.

Carvalho Rde S, de Souza CM, Neves JC, Holanda-Pinto SA…
Arch. Oral Biol. Jan 2013
PMID: 22664314

Vitamin D May Balance PTH to Improve Bone Density

Abstract

Impaired bone mineralization accompanied by low vitamin D and secondary hyperparathyroidism in patients with femoral neck fracture.

Although it is well established that a decrease in bone mass increases the risk of osteoporotic fractures, the proportion of fractures attributable to areal bone mineral density (BMD) is rather low. Here, we have identified bone mineralization defects together with low serum 25-hydroxyvitamin D (25-(OH) D) levels as additional factors associated with femoral neck fractures.
Osteoporotic fractures of the femoral neck are associated with increased morbidity and mortality. Although it is well established that a decrease in bone mass increases the risk of osteoporotic fractures, the proportion of fractures attributable to areal BMD is rather low. To identify possible additional factors influencing femur neck fragility, we analyzed patients with femoral neck fracture.
We performed a detailed clinical and histomorphometrical evaluation on 103 patients with femoral neck fracture including dual-energy X-ray absorptiometry, laboratory parameters, and histomorphometric and bone mineral density distribution (BMDD) analyses of undecalcified processed biopsies of the femoral head and set them in direct comparison to skeletal healthy control individuals.
Patients with femoral neck fracture displayed significantly lower serum 25-(OH) D levels and increased serum parathyroid hormone (PTH) compared to controls. Histomorphometric analysis revealed not only a decreased bone volume and trabecular thickness in the biopsies of the patients, but also a significant increase of osteoid indices. BMDD analysis showed increased heterogeneity of mineralization in patients with femoral neck fracture. Moreover, patients with femoral neck fracture and serum 25-(OH) D levels below 12 μg/l displayed significantly thinner trabecular bone.
Taken together, our data suggest that impaired bone mineralization accompanied by low serum 25-(OH) D levels is of major importance in the etiology of femoral neck fractures. Therefore, balancing serum 25-(OH) D levels and thereby normalizing PTH serum levels may counteract pronounced mineralization defects and might decrease the incidence of femoral neck fractures.

Seitz S, Koehne T, Ries C, De Novo Oliveira A…
Osteoporos Int Feb 2013
PMID: 22581296

Vitamin K2 (MK-4) + D + Calcium Reduces Lifetime Probability of Fracture by 25%

Abstract

Vitamin K supplementation for the primary prevention of osteoporotic fractures: is it cost-effective and is future research warranted?

Lifetime supplementation with vitamin K, vitamin D(3), and calcium is likely to reduce fractures and increase survival in postmenopausal women. It would be a cost-effective intervention at commonly used thresholds, but high uncertainty around the cost-effectiveness estimates persists. Further research on the effect of vitamin K on fractures is warranted.
Vitamin K might have a role in the primary prevention of fractures, but uncertainties about its effectiveness and cost-effectiveness persist.
We developed a state-transition probabilistic microsimulation model to quantify the cost-effectiveness of various interventions to prevent fractures in 50-year-old postmenopausal women without osteoporosis. We compared no supplementation, vitamin D(3) (800 IU/day) with calcium (1,200 mg/day), and vitamin K(2) (45 mg/day) with vitamin D(3) and calcium (at the same doses). An additional analysis explored replacing vitamin K(2) with vitamin K(1) (5 mg/day).
Adding vitamin K(2) to vitamin D(3) with calcium reduced the lifetime probability of at least one fracture by 25%, increased discounted survival by 0.7 quality-adjusted life-years (QALYs) (95% credible interval (CrI) 0.2; 1.3) and discounted costs by $8,956, yielding an incremental cost-effectiveness ratio (ICER) of $12,268/QALY. At a $50,000/QALY threshold, the probability of cost-effectiveness was 95% and the population expected value of perfect information (EVPI) was $28.9 billion. Adding vitamin K(1) to vitamin D and calcium reduced the lifetime probability of at least one fracture by 20%, increased discounted survival by 0.4 QALYs (95% CrI -1.9; 1.4) and discounted costs by $4,014, yielding an ICER of $9,557/QALY. At a $50,000/QALY threshold, the probability of cost-effectiveness was 80% while the EVPI was $414.9 billion. The efficacy of vitamin K was the most important parameter in sensitivity analyses.
Lifetime supplementation with vitamin K, vitamin D(3), and calcium is likely to reduce fractures and increase survival in postmenopausal women. Given high uncertainty around the cost-effectiveness estimates, further research on the efficacy of vitamin K on fractures is warranted.

Gajic-Veljanoski O, Bayoumi AM, Tomlinson G, Khan K…
Osteoporos Int Nov 2012
PMID: 22398856

Bisphosphonates Showed the Smallest Increase In Fracture Rate Over 10 Years

Abstract

Ten-year fracture risk in the assessment of osteoporosis management efficacy in postmenopausal women: a pilot study.

The aim of the reported longitudinal, retrospective pilot study was to establish changes in 10-year fracture risk in postmenopausal women with respect to applied fracture management.
A group of 191 postmenopausal women with a mean age of 68.76± 6.72 years was divided into subgroups. The subgroups were made up of untreated patients (n = 41), patients treated with vitamin D plus calcium (n = 46), and patients treated with bisphosphonates, vitamin D and calcium (n = 104). Repeated densitometric measurements and clinical data were taken into consideration (both baseline and follow-up). Ten-year fracture risk was established, using FRAX(TM) and Garvan nomograms. The mean follow-up period was 2.01±1.87 years.
Generally, the mean fracture probability increased in the studied women over the observation period. Patients on bisphosphonate therapy demonstrated the smallest increase in fracture probability. The probability rate for either any fractures or hip fractures decreased when the T-score increased. A diminished number of falls non-significantly decreased the probability for hip fractures and any fractures.
Ten-year fracture risk increased irrespective of applied management, while a decreased risk was observed only in women with improved bone status.

Pluskiewicz W, Drozdzowska B, Adamczyk P
Climacteric Feb 2013
PMID: 22335356

Genistein + EPA + DHA + Vitamin D + K1 Increases Bone Density in Postmenopausal Women

Abstract

Effect of a combination of genistein, polyunsaturated fatty acids and vitamins D3 and K1 on bone mineral density in postmenopausal women: a randomized, placebo-controlled, double-blind pilot study.

Many postmenopausal women desire non-pharmaceutical alternatives to hormone therapy for protection against osteoporosis. Soybean isoflavones, especially genistein, are being studied for this purpose. This study examined the effects of synthetic genistein in combination with other potential bone-protective dietary molecules on bone mineral density (BMD) in early postmenopausal women.
In this 6-month double-blind pilot study, 70 subjects were randomized to receive daily either calcium only or the geniVida™ bone blend (GBB), which consisted of genistein (30 mg/days), vitamin D3 (800 IU/days), vitamin K1 (150 μg/days) and polyunsaturated fatty acids (1 g polyunsaturated fatty acids as ethyl ester: eicosapentaenoic acid/docosahexaenoic acid ratio = ~2/1). Markers of bone resorption and formation and BMD at the femoral neck, lumbar spine, Ward’s triangle, trochanter and intertrochanter, total hip and whole body were assessed.
Subjects supplemented with the GBB (n = 30) maintained femoral neck BMD, whereas in the placebo group (n = 28), BMD significantly decreased (p = 0.007). There was also a significant difference (p < 0.05) in BMD between the groups at Ward’s triangle in favor of the GBB group. Bone-specific alkaline phosphatase and N-telopeptide significantly increased in the GBB group in comparison with those in baseline and in the placebo group. The GBB was well tolerated, and there were no significant differences in adverse events between groups.
The GBB may help to prevent osteoporosis and reduce fracture risk, at least at the hip, in postmenopausal women. Larger and longer-term clinical trials are warranted.

Lappe J, Kunz I, Bendik I, Prudence K…
Eur J Nutr Feb 2013
PMID: 22302614 | Free Full Text

Vitamin D Level Influences Bone Density in Saudi Men and Women

Abstract

Influence of vitamin D levels on bone mineral density and osteoporosis.

The effects of vitamin D on bone mass remain to be understood. This study was conducted with the objective of evaluating the influence of 25-hydroxyvitamin D (25OHD) levels on bone mineral density (BMD) among Saudi nationals.
Cross-sectional study carried out at university hospital from 1 February 2008 to 31 May 2008.
Healthy Saudi men and women in the peak bone mass (PBM) age group and those aged ≥ 50 years were recruited from the outpatient department of King Fahd University Hospital, Al Khobar, Saudi Arabia, between February 1, 2008, and May 31, 2008. Patient age and sex were documented, and body mass index was calculated. Hematological, biochemical, and serum 25OHD tests were performed. BMD was determined by dual-energy x-ray absorptiometry of the upper femur and lumbar spine. Patients were divided into three groups, based on their 25OHD level.
Data from 400 patients were analyzed. Among individuals with a normal 25OHD level, 50% of women and 7% of men in the PBM age group and 26.4% of women and 49.2% of men aged ≥ 50 years had low bone mass. In patients with 25OHD insufficiency, 84.2% of women and 88.9% of men in the PBM age group and 83.3% of women and 80% of men aged ≥ 50 years had low bone mass. Results for patients with 25OHD deficiency revealed that none of the men and women in the PBM age group or ≥ 50 years old had normal BMD. Significant positive correlations between 25OHD level and BMD and significant negative correlations with parathyroid hormone were shown in most of the groups.
This study showed that the vitamin D level significantly influences BMD reading among Saudi individuals. Evaluation and treatment of hypovitaminosis D should be considered during management of low bone mass.

Sadat-Ali M, Al Elq AH, Al-Turki HA, Al-Mulhim FA…
Ann Saudi Med
PMID: 22048506 | Free Full Text

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

Abstract

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