Corticosteroids even short term increase adverse events

Corticosteroids, prescribed for as many as one in five Americans in commercial insurance plans, can significantly increase the risk for adverse effects even when given short term, as found in a study recently published in BMJ (British Medical Journal). The authors note that though the severe adverse effects of longer term use or oral corticosteroids is well known, little has been understood about short term risks.

“…long term use of corticosteroids is generally avoided, given the risks of serious acute complications such as infection, venous thromboembolism, avascular necrosis, and fracture, as well as chronic diseases such as diabetes mellitus, hypertension, osteoporosis, and other features of iatrogenic Cushing’s syndrome…Indeed, corticosteroids are one of the most common reasons for admission to hospital for drug related adverse events…In contrast with long term use, however, the risk of complications from short term use is much less understood, and evidence is generally insufficient to guide clinicians.”

Corticosteroids often used where evidence is lacking

Until now little is know about the potential harms of short term use for the range of outpatient conditions for which they are often prescribed.

“…anecdotally corticosteroids are also used often in the short term to treat many other prevalent conditions where evidence is lacking, such as non-specific musculoskeletal pain and rashes. Despite such pervasive indications for use of oral corticosteroids, little is known about the prescribing patterns of short term use of these drugs in the general adult population, or their potential harm.”

Thus they set out to correlate short term use in an outpatient population and the risk of acute adverse events by analyzing data for 1,548,945 subjects who were prescribed oral corticosteroids for less than 30 days (non-oral forms were excluded from this study).

“We chose three acute events listed as adverse events on the Food and Drug Administration mandated drug label for oral corticosteroids (sepsis, venous thromboembolism, fracture). Given the inherent challenges related to confounding, we employed a self controlled case series (SCCS) design. This design has been used to examine drug and vaccine safety.”

The most common prescription was a six day methylprednisolone “dosepak”, most commonly given for upper respiratory tract infections, spinal conditions, and intervertebral disc disorders, allergies, bronchitis, and (non-bronchitic) lower respiratory tract disorders by family medicine and general internal medicine practitioners, but also by specialists in emergency medicine, otolaryngology, and orthopedics.

Significantly higher rates of sepsis, venous thromboembolism, and fracture

The authors identified a serious risk:

“Within 30 days of drug initiation, there was an increase in rates of sepsis (incidence rate ratio 5.30, 95% confidence interval 3.80 to 7.41), venous thromboembolism (3.33, 2.78 to 3.99), and fracture (1.87, 1.69 to 2.07), which diminished over the subsequent 31-90 days. The increased risk persisted at prednisone equivalent doses of less than 20 mg/day (incidence rate ratio 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P<0.001).”

It defies common sense to use an agent that suppresses the immune system during an infection in all but the rare cases of severe immune excess, especially when there are numerous, more benign alternatives.

Quoted in Medscape Family Medicine, lead author Akbar K. Waljee, MD, an assistant professor of gastroenterology at the University of Michigan in Ann Arbor, states:

“On the basis of these findings, Dr Waljee recommended prescribing the smallest possible amount of corticosteroids for treating the condition in question. “If there are alternatives to steroids, we should be use those when possible,” he said in the release. “Steroids may work faster, but they aren’t as risk-free as you might think.”

From the study:

  • This study of 1.5 million privately insured adults (18-64 years) in the US found that one in five patients in an outpatient setting used short term oral corticosteroid over a three year period (2012-14)

  • Within 30 days of corticosteroid initiation, the incidence of acute adverse events that result in major morbidity and mortality (sepsis, venous thromboembolism, fracture) increased by twofold, to fivefold above background rates

  • Greater attention to initiating prescriptions of these drugs and monitoring for adverse events may potentially improve patient safety

The authors conclude:

“Oral corticosteroids are frequently prescribed for short term use in the US for a variety of common conditions and by numerous provider specialties. Over a three year period, approximately one in five American adults in a commercially insured plan used oral corticosteroids for less than 30 days. The short term use of these drugs was associated with increased rates of sepsis, venous thromboembolism, and fracture; even at relatively low doses.”

Fracture healing requires intact nitric oxide production

BoneFracture healing gone awry can result in delayed or nonunion with significant morbidity. Useful research just published in the journal Bone shows that reduced nitric oxide production impairs fracture healing. The authors note:

“Between 5% and 10% of all fractures fail to heal adequately resulting in nonunion of the fracture fragments. This can significantly decrease a patient’s quality of life and create associated psychosocial and socio-economic problems.”

Nitric oxide synthase and fracture healing

Nitric oxide is known to be crucial for respiration, cardiovascular health, immune health and numerous other functions, and known to be involved in fracture healing. The authors take this a step further:

“Nitric oxide (NO) and nitric oxide synthases (NOS) have been found to be involved in fracture healing, but until now it is not known if disturbances in these mechanisms play a role in nonunion and delayed union development. In this study, we explored the role of endothelial and inducible NOS deficiency in a delayed union model in mice.”

They used femur osteotomy with periosteal damage for their model of fracture to observe the healing response in both normal (‘wild’) and NOS knockout (Nos2−/− and Nos3−/−) mice ‘engineered’ to not produce nitric oxide synthase and generate nitric oxide. Fracture healing completely stalled in the latter:

“With μCT [micro-computed tomography], delayed union was observed in wild type animals, whereas in both Nos2−/− and Nos3−/− mice nonunion development was evident. Both knock-out strains also showed a significantly increased influx of MPO [myeloperoxidase] when compared with wild type mice. Concentrations of amino acids and expression of enzymes related to the arginine-NO metabolism were aberrant in NOS deficient mice when compared to contralateral control femurs and wild type samples.”

Clinical note

Testing and for nitric oxide sufficiency and replenishment in the context of impaired NOS function is now very practical (see Neogenis Medical in Useful Links) and should be standard of care in fracture management, especially when there is a history of hypertension or other cardiovascular disorders. The authors conclude:

“In the present study we show for the first time that the absence of nitric oxide synthases results in a disturbed arginine-NO metabolism and inadequate fracture healing with the transition of delayed union into a nonunion in mice after a femur osteotomy. Based on these data we suggest that the arginine-NO metabolism may play a role in the prevention of delayed unions and nonunions.”

Increasing calcium intake does not prevent fractures

BMJCalcium is still, contrary to the best available evidence, often recommended to reduce fracture risk. Research just published in BMJ (British Medical Journal) adds more evidence that increasing calcium intake by diet or supplementation does not prevent fractures. The authors conducted a systematic review of randomized controlled trials and observational studies…

“To examine the evidence underpinning recommendations to increase calcium intake through dietary sources or calcium supplements to prevent fractures.”

Besides evaluating recommendations to increase dietary calcium intake to prevent fractures, they compared the anti-fracture effect of increasing calcium through dietary sources with the efficacy of calcium supplements by compiling data from randomized controlled trials or cohort studies of dietary calcium, milk or dairy intake, or calcium supplements (with or without vitamin D) with fracture as an outcome in subjects over 50.

No significant fracture reduction from dietary or supplemental calcium

When the data were thoroughly examined the evidence for efficacy of calcium intake vanished.

“There were only two eligible randomised controlled trials of dietary sources of calcium (n=262), but 50 reports from 44 cohort studies of relations between dietary calcium (n=37), milk (n=14), or dairy intake (n=8) and fracture outcomes. For dietary calcium, most studies reported no association between calcium intake and fracture (14/22 for total, 17/21 for hip, 7/8 for vertebral, and 5/7 for forearm fracture). For milk (25/28) and dairy intake (11/13), most studies also reported no associations. “

As for supplements…

“In randomised controlled trials at lowest risk of bias (four studies, n=44 505), there was no effect on risk of fracture at any site. Results were similar for trials of calcium monotherapy and co-administered calcium and vitamin D. Only one trial in frail elderly women in residential care with low dietary calcium intake and vitamin D concentrations showed significant reductions in risk of fracture.”

Osteoporosis is not a calcium deficiency disorder

Clinicians involved in case management of osteoporosis and osteopenia know (or should know) that these disorders are due to failure to maintain the protein matrix of the bone, the component that provides resilient strength and to which the minerals attach, not a deficiency of the minerals themselves, including calcium. (Calcium deficiency, or osteomalacia, is also known as ‘rickets.’) The authors comment further on their findings regarding diet:

“The recommended dietary calcium intake for older adults is 1200 mg/day.Most studies, however, did not report Creduced risk of fracture in individuals with this level of calcium intake compared with lower intakes. Thus, observational research does not support a hypothesis of dietary “calcium deficiency” in which there are reductions in fracture risk from increasing dietary calcium intake across the range of intakes (<300->1200 mg/day) in studies in this review.”


“There was no effect of calcium supplements on any fracture outcome in the largest trials at lowest risk of bias. …These results suggest that widespread untargeted use of calcium supplements in older individuals is unlikely to result in meaningful reductions in incidence of fracture.”

As the authors note:

“…it should not be assumed that short term changes in bone density will be sustained or translate into fracture prevention.”

Calcium and cardiovascular risk

Calcium supplementation has been associated with increased cardiovascular risk (see Calcium supplements increase risk of heart attack), probably by opposing the anti-inflammatory effects of magnesium. The authors comment on this and other risks:

“In our randomised controlled trial and subsequent meta-analyses, the cardiovascular risks of calcium were similar to or exceeded the benefits of calcium on fracture prevention. In addition, 10-20% of people experience gastrointestinal side effects such as constipation, which cause a considerable number to stop taking the supplements. Thus, because of the small benefits of use and unfavourable risk:benefit profile, calcium supplements should not be recommended for fracture prevention either at an individual or population level.”

Regarding the one study with elderly frail women…

“…it is possible that many participants had unrecognised osteomalacia, the treatment of which might have led to the benefits observed…Our analyses highlight that the results from this study of a frail population with marked vitamin D deficiency are so different to those from other large randomised controlled trials and so influential in any pooled analysis that they should probably not be combined in pooled analyses with studies that enrolled different patient groups. Furthermore, recommendation of use of calcium and vitamin D supplements generally for older adults to prevent fracture based on results heavily influenced by this study of frail women in residential care is inappropriate.”

Do not recommend calcium to patients for osteoporosis fracture risk

Medscape Medical News reports in regard to this research:

This is not the first recent review to find a lack of evidence for calcium supplements. The US Preventive Services Task Force reached similar conclusions in 2013.”The question is not so much why the guidelines were formed, but why is it, since there have been all these trials accumulated since 2000, they haven’t changed,” Dr Bolland [lead author] said.”

The authors conclude:

“On the basis of the trial data summarised here, we do not think further randomised controlled trials of calcium supplements with or without vitamin D with fracture as the endpoint in the general population are needed…our analyses indicate that dietary calcium intake is not associated with risk of fracture, and there is no evidence currently that increasing dietary calcium intake prevents fractures….There was no risk reduction in fracture at any site in pooled analyses of the randomised controlled trials of calcium supplements at lowest risk of bias, and there was evidence of publication bias in small-moderate sized trials. Collectively, these results suggest that clinicians, advocacy organisations, and health policymakers should not recommend increasing calcium intake for fracture prevention, either with calcium supplements or through dietary sources.”

No significant improvement through bone mineral density either

Additional research in the same issue of BMJ examined data for the effects of calcium intake on BMD (bone mineral density) and found no meaningful benefit.

“Increasing calcium intake from dietary sources increased BMD by 0.6-1.0% at the total hip and total body at one year and by 0.7-1.8% at these sites and the lumbar spine and femoral neck at two years. There was no effect on BMD in the forearm. Calcium supplements increased BMD by 0.7-1.8% at all five skeletal sites at one, two, and over two and a half years, but the size of the increase in BMD at later time points was similar to the increase at one year. Increases in BMD were similar in trials of dietary sources of calcium and calcium supplements (except at the forearm), in trials of calcium monotherapy versus co-administered calcium and vitamin D, in trials with calcium doses of ≥1000 versus <1000 mg/day and ≤500 versus >500 mg/day, and in trials where the baseline dietary calcium intake was <800 versus ≥800 mg/day.”

Based on this the authors of the BMD study conclude:

“In summary, increasing calcium intake from dietary sources increases BMD by a similar amount to increases in BMD from calcium supplements. In each case, the increases are small (1-2%) and non-progressive, with little further effect on BMD after a year. Subgroup analyses do not suggest greater benefits of increasing calcium intake on BMD in any subpopulation based on clinically relevant baseline characteristics. The small effects on BMD are unlikely to translate into clinically meaningful reductions in fractures. Therefore, for most individuals concerned about their bone density, increasing calcium intake is unlikely to be beneficial.”

Perverse influence of industry

In an accompanying editorial, the author comments on the use of guidelines that are contrary to the scientific evidence:

“By use of guidelines such as those by NOF and the International Osteoporosis Foundation (IOF), marketing now extends to all older people with dietary intakes below the recommended 1200 mg calcium and 800-1000 IU vitamin D daily. By this definition virtually the whole population aged over 50 is at risk.Most will not benefit from increasing their intakes and will be exposed instead to a higher risk of adverse events such as constipation, cardiovascular events, kidney stones, or admission for acute gastrointestinal symptoms.The weight of evidence against such mass medication of older people is now compelling, and it is surely time to reconsider these controversial recommendations…The profitability of the global supplements industry probably plays its part, encouraged by key opinion leaders from the academic and research communities. Manufacturers have deep pockets, and there is a tendency for research efforts to follow the money (with accompanying academic prestige), rather than a path defined only by the needs of patients and the public. The research agenda and recommendations can also be influenced by the conflicts of interest that arise when leading academics have shares or management positions in companies making and marketing supplements.”

NEJM Journal WatchA New England Journal of Medicine Journal Watch interview with lead author Dr. Mark Bolland can be heard here.

Interview on investigation into the flawed U.S. dietary guidelines


Oral bisphosphonates increase osteomyelitis of the jaw

Bisphosphonates are medications such as Fosamax®, Actonel®, Aredia®, Didronel®, Reclast® and Zometa® that are given to increase bone density. They have received much attention for a severe side effect, osteonecrosis of the jaw (ONJ), when given intravenously as part of a chemotherapy regimen. (ONJ refers to pockets of dead bone in the upper jaw and facial bones that can be very painful and prone to infection. Even surgery is rarely remedial.) There is also evidence bisphosphonates cause ‘brittle bones’ with an increased risk of fracture after five years of oral use. The authors of a study just published in the journal Bone offer evidence that bisphosphonates taken orally can also cause osteonecrosis of the jaw. Oral bisphosphonates are frequently used…

“However, several studies have reported osteonecrosis of the jaw (ONJ), also known as osteomyelitis of the jaw (OMJ), as a side effect of these drugs…Here, we estimated risk of oral BPs for OMJ in osteoporosis patients taking oral BPs compared with other osteoporosis drugs.”

They examined data on patients taking medications for osteoporosis between November 2000 and October 2010 to evaluate the relative risks of taking 4129 patients who were taking oral bisphosphonates for OMJ while 2794 subjects received other osteoporosis drugs. The data show that concern is justified:

“Absolute risk for OMJ was estimated to range from 0.46% to 0.99% (95% CIs: 0.25–0.66 to 0.69–1.2) among patients receiving oral BPs and 0.071% to 0.17% (95% CIs: 0–0.17 to 0.022–0.33) among patients receiving other osteoporosis drugs. The attributable risks of oral BPs for OMJ were estimated to range from 0.38% to 0.81% (95% CIs: 0.38–0.39 to 0.80–0.81). ORs (95% CIs) adjusted for confounding factors were 5.0 (1.9–12.9) to 6.0 (1.3–26.1) for confirmed cases only.”

OMJ/ONJ is a particularly severe side effect of bisphosphonates. ONJ and increase in brittleness and fracture after extended use of bisphosphonates are not surprising since bisphosphonates are a kind of chemotherapy that kills the osteoclasts—the special cells that break down old bone making way for its replacement by fresh new bone. When this cycle of tearing down to build anew is interrupted bone may appear more dense on scans but lacks the shock-absorbing elasticity of healthy bone, hence the increase in fractures. Since bones of the jaw receive a lot of pressure with chewing they are subject to localized foci of collapse in those most vulnerable. The authors conclude:

“In terms of absolute and attributable risks, the risk of oral BPs for OMJ is considered to be less than 1% in patients with osteoporosis. However, oral BPs may increase the risk of OMJ compared with patients treated with other osteoporosis medications and the risk of side effects should be kept in mind.”

The highest amounts of calcium intake increase the risk of fracture

Patients are often surprised to learn that osteoporosis is not a calcium deficiency disorder but rather a failure to maintain the microarchitecture of the bone of which the protein matrix is a critical component. Moreover, earlier posts on magnesium and calcium have document the pro-inflammatory potential of calcium supplementation. Now fascinating research just published in the British Medical Journal offers evidence that calcium above the lowest quintile does not improve the risk of fracture of any type, while the highest levels actually increase the risk of fracture. The authors set out to…

“……investigate associations between long term dietary intake of calcium and risk of fracture of any type, hip fractures, and osteoporosis.”

They note that confusion regarding the issue of calcium requirements has been…

“…reflected by the wide range of daily calcium recommendations for individuals older than 50 years: at present 700 mg in the UK, 800 mg in Scandinavia, 1200 mg in the United States, and 1300 mg in Australia and New Zealand.”

The authors investigated 61,433 women born between 1914 and 1948 for 19 years for correlations between dietary intake of calcium and fractures of any type, hip fractures, and osteoporosis. They took into consideration vitamin D consumption, hormonal status, and other pertinent biological and lifestyle factors including physical activity. Perhaps not surprisingly in light of other evidence that has emerged recently about calcium, their data challenges the conventional wisdom:

“These findings show an association between a low habitual dietary calcium intake (lowest quintile) and an increased risk of fractures and of osteoporosis. Above this base level, we observed only minor differences in risk. The rate of hip fracture was even increased in those with high dietary calcium intakes.

In others, amounts higher than the lowest level of calcium intake adequate to avoid gross insufficiency and compromised bone micoarchitecture there were not only no significant benefits, the highest levels of intake increased fracture risk. The authors comment:

“The present results may reflect a situation when a moderate intake of calcium* combined with adequate intake of other micronutrients is sufficient to meet the structural and functional demands of the skeleton. High levels of intake did not further decrease the rate of fracture, and might even increase the rate of hip fractures…Moreover, use of supplemental calcium has been associated with higher rates of hip fracture both in a cohort study and in randomised controlled trials…Furthermore, high calcium doses slow bone turnover and also reduce the number of active bone remodelling sites. This situation can lead to a delay of bone repair caused by fatigue, and thus increase the risk of fractures independent of bone mineral density.”

*Their data indicate that a total dietary intake of 700 mg of calcium per day is sufficient to prevent fracture and osteoporosis. The authors conclude:

“Incremental increases in calcium intake above the level corresponding to the first quintile of our female population were not associated with a further reduction of osteoporotic fracture rate.”

Considering that chronic inflammation can be a primary factor in causing loss of the protein ‘scaffolding’ of bone responsible for strength, resilience, and the matrix to which minerals attach, these findings invoke recollection of the recent evidence that calcium supplementation can increase the inflammation of  cardiovascular disease. In case you missed it, a recent research paper published in the British Medical Journal follows up on earlier reports of this association. The authors’ intent was…

“To investigate the effects of personal calcium supplement use on cardiovascular risk in the Women’s Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the recent meta-analysis of calcium supplements and cardiovascular risk.”

The examined the data from a randomised, placebo controlled trial of calcium alone or with vitamin D in 36,282 postmenopausal women over seven years for myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke. The data told an interesting story:

“In the WHI CaD Study there was an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events…Calcium or calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to 1.45), P=0.004) and the composite of myocardial infarction or stroke (1.15 (1.03 to 1.27), P=0.009).”

Clinicians and patients need to appreciate that inflammation, a fundamental causal factor in both osteoporosis and cardiovascular disease, can be made worse by calcium supplements. The authors conclude:

Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.


Proton pump inhibitors to suppress stomach acid increase risk of fracture and infection

Archives of Internal MedicineA collection of studies published in the latest edition of Archives of Internal Medicine highlights what you may already know about the dangers of powerfully suppressing digestion in the stomach by inhibiting the production of gastric acid with medications like Prilosec, Prevacid, Nexium, etc. As an accompanying editorial notes:

“A staggering 113.4 million prescriptions for proton pump inhibitors (PPIs) are filled each year, making this class of drugs, at $13.9 billion in sales, the third highest seller in the United States…it should come as no surprise that PPIs have been shown to be overprescribed; between 53% and 69% of PPI prescriptions are for inappropriate indications.”

What kind of damage can be done? Stomach acid is mandatory for the digestion of protein. Protein makes of the flexible matrix (“scaffolding”) of bone to which the minerals attach, so the first study that associates proton pump inhibitors with total fractures is not unexpected:

“Use of PPIs was…modestly associated with clinical spine, forearm or wrist, and total fractures.”

Stomach acid is also the body’s first line of defense against gastrointestinal infections. Two additional papers confirm that PPIs are associated with increased risk of Clostridium difficile infection. The authors of the first paper observe:

“Proton pump inhibitors (PPIs) are widely used gastric acid suppressants, but they are often prescribed without clear indications and may increase risk of Clostridium difficile infection (CDI). We sought to determine the association between PPI use and the risk of recurrent CDI.”

What did their data show?

“Proton pump inhibitor use during incident CDI treatment was associated with a 42% increased risk of recurrence.”

The authors of the second paper reached the same conclusion:

Increasing levels of pharmacologic acid suppression are associated with increased risks of nosocomial C difficile infection. This evidence of a dose-response effect provides further support for the potentially causal nature of iatrogenic acid suppression in the development of nosocomial C difficile infection.”

There is an important difference between treating the underlying causes of conditions like gastroesophageal reflux (which often occurs with stomach acid that is abnormally low) and just suppressing acid production. These studies only scratch the surface of the problems that can occur when the capacity to digest protein and protect the GI tract from infection is suppressed.