Testosterone Treatment and Fractures in Men with Hypogonadism


Abstract

Background

Testosterone treatment in men with hypogonadism improves bone density and quality, but trials with a sufficiently large sample and a sufficiently long duration to determine the effect of testosterone on the incidence of fractures are needed.

Methods

In a subtrial of a double-blind, randomized, placebo-controlled trial that assessed the cardiovascular safety of testosterone treatment in middle-aged and older men with hypogonadism, we examined the risk of clinical fracture in a time-to-event analysis. Eligible men were 45 to 80 years of age with preexisting, or high risk of, cardiovascular disease; one or more symptoms of hypogonadism; and two morning testosterone concentrations of less than 300 ng per deciliter (10.4 nmol per liter), in fasting plasma samples obtained at least 48 hours apart. Participants were randomly assigned to apply a testosterone or placebo gel daily. At every visit, participants were asked if they had had a fracture since the previous visit. If they had, medical records were obtained and adjudicated.

Results

The full-analysis population included 5204 participants (2601 in the testosterone group and 2603 in the placebo group). After a median follow-up of 3.19 years, a clinical fracture had occurred in 91 participants (3.50%) in the testosterone group and 64 participants (2.46%) in the placebo group (hazard ratio, 1.43; 95% confidence interval, 1.04 to 1.97). The fracture incidence also appeared to be higher in the testosterone group for all other fracture end points.

Conclusions

Among middle-aged and older men with hypogonadism, testosterone treatment did not result in a lower incidence of clinical fracture than placebo. The fracture incidence was numerically higher among men who received testosterone than among those who received placebo

Testosterone Treatment and Fractures in Men with Hypogonadism


Abstract

Background

Testosterone treatment in men with hypogonadism improves bone density and quality, but trials with a sufficiently large sample and a sufficiently long duration to determine the effect of testosterone on the incidence of fractures are needed.

Methods

In a subtrial of a double-blind, randomized, placebo-controlled trial that assessed the cardiovascular safety of testosterone treatment in middle-aged and older men with hypogonadism, we examined the risk of clinical fracture in a time-to-event analysis. Eligible men were 45 to 80 years of age with preexisting, or high risk of, cardiovascular disease; one or more symptoms of hypogonadism; and two morning testosterone concentrations of less than 300 ng per deciliter (10.4 nmol per liter), in fasting plasma samples obtained at least 48 hours apart. Participants were randomly assigned to apply a testosterone or placebo gel daily. At every visit, participants were asked if they had had a fracture since the previous visit. If they had, medical records were obtained and adjudicated.

Results

The full-analysis population included 5204 participants (2601 in the testosterone group and 2603 in the placebo group). After a median follow-up of 3.19 years, a clinical fracture had occurred in 91 participants (3.50%) in the testosterone group and 64 participants (2.46%) in the placebo group (hazard ratio, 1.43; 95% confidence interval, 1.04 to 1.97). The fracture incidence also appeared to be higher in the testosterone group for all other fracture end points.

Conclusions

Among middle-aged and older men with hypogonadism, testosterone treatment did not result in a lower incidence of clinical fracture than placebo. The fracture incidence was numerically higher among men who received testosterone than among those who received placebo.

Are Sleeping Pills Boosting Your Risk for Falls and Fractures?


(Billion Photos/Shutterstock)

(Billion Photos/Shutterstock)

Sleep is at a premium these days. The stress and anxiety of the holidays can make it tough to get a good night’s sleep. Toss a pandemic into the mix, and quality sleep becomes even more elusive.

Sleeping pills, also called “z-drugs,” can be an attractive option for those struggling with sleep. But they are not without risk. New research suggests high dose z-pills may increase the risk of falls or fractures in people with dementia.

The study appeared in BMC Medicine and looked at data on more than 27,000 patients in England diagnosed with dementia between 2000 and 2016. More than 3,500 were prescribed z-drugs.

Researcher Chris Fox from the University of East Anglia’s Norwich Medical School said up to 90 percent of people with dementia suffer sleep disturbances that can substantially impact physical and mental health.

Using high dose sleeping pills, however, might not be the safest way to treat it.

Of the patients who took z-drugs, 17 percent were given high doses (a high dose is 7.5 mg of zopiclone or an excess of 5 mg of Ativan).

Instead, finding other ways to address sleeping trouble might be in order. If you’re helping to care for someone with dementia, there are some other measures you could employ.

Improving sleep hygiene might be one way to help. Setting the mood for bed about an hour or two before the head goes down can help. This can include darkening the lights, turning off screens, or encouraging a low-stimulus activity.

Paying attention to caffeine and alcohol intake is also essential.

Getting some exercise during the day can also help, as can spending some time to ease nerves through relaxing conversation or mindfulness meditation.

If sleeping pills are still required, talk to the doctor about a lower dose. The study did not find an increased risk for falls and fractures in patients who were not taking high-dose sleeping pills.

Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults.


BACKGROUND: Vitamin D supplements are widely recommended for bone health in the general population, but data on whether they prevent fractures have been inconsistent.

METHODS: In an ancillary study of the Vitamin D and Omega-3 Trial (VITAL), we tested whether supplemental vitamin D3 would result in a lower risk of fractures than placebo. VITAL was a two-by-two factorial, randomized, controlled trial that investigated whether supplemental vitamin D3 (2000 IU per day), n-3 fatty acids (1 g per day), or both would prevent cancer and cardiovascular disease in men 50 years of age or older and women 55 years of age or older in the United States. Participants were not recruited on the basis of vitamin D deficiency, low bone mass, or osteoporosis. Incident fractures were reported by participants on annual questionnaires and adjudicated by centralized medical-record review. The primary end points were incident total, nonvertebral, and hip fractures. Proportional-hazards models were used to estimate the treatment effect in intention-to-treat analyses.

RESULTS: Among 25,871 participants (50.6% women [13,085 of 25,871] and 20.2% Black [5106 of 25,304]), we confirmed 1991 incident fractures in 1551 participants over a median follow-up of 5.3 years. Supplemental vitamin D3, as compared with placebo, did not have a significant effect on total fractures (which occurred in 769 of 12,927 participants in the vitamin D group and in 782 of 12,944 participants in the placebo group; hazard ratio, 0.98; 95% confidence interval [CI], 0.89 to 1.08; P = 0.70), nonvertebral fractures (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P = 0.50), or hip fractures (hazard ratio, 1.01; 95% CI, 0.70 to 1.47; P = 0.96). There was no modification of the treatment effect according to baseline characteristics, including age, sex, race or ethnic group, body-mass index, or serum 25-hydroxyvitamin D levels. There were no substantial between-group differences in adverse events as assessed in the parent trial.

CONCLUSIONS: Vitamin D3 supplementation did not result in a significantly lower risk of fractures than placebo among generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass, or osteoporosis.

Inadequate osteoporosis treatment persists after major fractures


Only 1 in 10 men and fewer than 2 in 10 women who did not receive osteoporosis therapy at the time of a fracture were prescribed adequate treatment during follow-up, increasing secondary fracture risks for those left untreated, according to an analysis of data from Austria published in Bone.

Oliver Malle

“The incidence of osteoporotic fractures in Austria is among the highest worldwide,” Oliver Malle, MD, of the division of endocrinology and diabetology at Medical University of Graz, Austria, and colleagues wrote in the study background. “However, so far, no sufficient data has been available on the incidence of osteoporosis treatment in patients suffering an osteoporotic fracture. Furthermore, due to substantial differences in health care systems, results from other countries in which treatment rate after major osteoporotic fractures has been investigated cannot be directly extrapolated to Austria.”

Malle and colleagues analyzed data from 915 adults recruited from eight trauma centers throughout Austria, as part of the International Costs and Utilities Related to Osteoporotic Fractures Study, a prospective observational study assessing data from patients who experienced a major osteoporotic fracture (78.3% women; mean age, 75 years). Researchers stratified participants into two groups: those with osteoporosis treatment at time of fracture (bisphosphonates, estrogens, parathyroid hormone, selective estrogen receptor modulators, or SERMS, and calcitonin) and those without treatment. A first interview was performed during inpatient care or no less than 2 weeks after fracture. Follow-up interviews were performed by phone call at 4, 12 and 18 months after fracture. All fractures were confirmed via X-ray.

Within the cohort, 624 patients (68.2%) were available at 4 months, 552 patients (60.3%) were available at 12 months and 495 patients (54.1%) were available at 18 months after the index fracture.

Fracture arm 3 2019

Only 1 in 10 men and fewer than 2 in 10 women who did not receive osteoporosis therapy at the time of a fracture were prescribed adequate treatment during follow-up, increasing secondary fracture risks for those left untreated.

Source: Adobe Stock

At the time of fracture, 184 patients (20.1%) received pharmacologic treatment and 731 (79.9%) did not. Compared with those who did not receive osteoporosis treatment, those who did were younger, more likely to have a prevalent fracture, and more likely to show two risk factors for osteoporosis (current corticosteroid therapy and parental history of proximal femur fracture) and intake of analgesic medication.

The researchers also observed large treatment disparities by sex. Among women with no osteoporosis treatment at the time of the index fracture, follow-up analysis revealed an osteoporosis treatment rate of 17.6%, 16% and 15.3% after 4, 12 and 18 months, respectively. Among men, the treatment rate was 8.1%, 12.1% and 10.4% at 4, 12 and 18 months, respectively.

Among participants initially treated for osteoporosis, the treatment rate was 65.4%, 54.2% and 60.4% for women, and 66.9%, 55.1% and 55.2% for men after 4, 12 and 18 months, respectively. At the time of fracture, the most frequently prescribed drugs were bisphosphonates (88%) and SERMs (4.3%). Additionally, osteoporosis treatment was lower among men vs. women 4 months after fracture (8% vs. 17.6%; P = .01).

“In those who did not receive osteoporosis treatment at the time of fracture, only 1 in 10 men and less than 2 in 10 women were prescribed an adequate osteoporosis treatment,” the researchers wrote. “In those who had received osteoporosis treatment at the time of fracture, roughly every second patient was deprived of his/her treatment.”

The researchers noted that the relatively short observation period of 18 months could further overestimate the adherence to osteoporosis treatment, so the treatment rate may decrease even further.

In a consensus statement spearheaded by the American Society for Bone and Mineral Research (ASBMR) and the Center for Medical Technology Policy and reported by Endocrine Today, a coalition of stakeholders wrote this month that older adults who sustain a hip or vertebral fracture should be appropriately evaluated and treated for osteoporosis to reduce the risk for secondary fracture, with clinicians utilizing fracture liaison services and offering pharmacotherapy. The coalition developed 13 recommendations, centered on an “overarching principle” that older adults with a hip or vertebral fracture optimally should be managed in the context of a multidisciplinary clinical system that includes case management, such as a fracture liaison service, to ensure patients are appropriately evaluated and treated.

Largest Ever Clinical Study on Vitamin D Shows We’re Wrong About a Crucial Benefit


We are still in love with vitamins a century after they were discovered, with half the US and UK population taking a supplement.

Vitamin D – the sunshine vitamin – is the favourite and is believed to have the most proven benefits.

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Governments, including the UK government, have said that the evidence for vitamin D’s health benefits is so overwhelming that every adult should take it as a supplement for at least six months of the year.

It was first used to cure rickets in Victorian children living in urban poverty and is now routinely given to prevent and treat brittle bone disease (osteoporosis) and fractures.

It has been associated with a reduced risk of over a hundred common diseases in observational studies, ranging from depression to cancer.

The largest ever clinical study on the benefits of vitamin D in preventing fractures has been reported in the BMJ, with over 500,000 people and around 188,000 fractures from 23 cohorts from many countries.

As vitamin D levels are strongly influenced by genes, the researchers used genetic markers for vitamin D blood levels (called Mendelian randomisation or MR) to avoid the normal biases of observational studies, such as confusing cause and consequence of disease and the effects of other related health behaviours (so-called “confounders”).

 

The results showed no association between vitamin D levels over a lifetime and the risk of fracture. This latest study contradicts the UK government’s recent view, but not a host of earlier clinical trials.

In 2014, a review and meta-analysis of 31 vitamin D supplement trials found no effect on all fractures. Much of our strong belief in the benefits of vitamin D came from studies of supplements in care homes in the 1980s, which were never replicated and were probably flawed.

In a more recent meta-analysis of 33 randomised trials of over 50,000 older adults, supplementation with calcium or vitamin D had no effect on the incidence of fractures. There were also no clear benefits on muscle strength or mobility.

So, if all the data points to vitamin D failing to prevent fractures, why worry about all the people with low blood levels of the vitamin? Vitamin D deficiency has become a modern epidemic with a fifth of the UK and US populations reported to have low levels. Will they be more susceptible to other diseases and cancer?

No consensus on deficiency

There is little agreement on what vitamin D deficiency is. Deficiency levels are arbitrary with no international consensus and confusion caused by different units in the US. A “normal” level can vary from 50 to 80 nanomole per litre of blood, but recent studies suggest 30nmol is quite enough.

While clinical deficiency (<10nmol) is often clear cut, wrongly labelling millions of people as vitamin D deficient causes stress and over-medicalisation. Most people assume calcium and vitamin D are safe, and the more you take the better. My clinical practice changed when studies showed calcium supplements, as well as being ineffective against fractures, may cause heart disease. Prescriptions are now dropping.

Vitamin D is fat soluble, so high levels can build up in the body. While recommendations for supplements are usually with modest doses (10 micrograms or 400 international units (IU)), these will inevitably be overdone by some people taking other sources in cod liver oil tablets or in fortified milk, orange juice or bread. More worrying, people increasingly buy high-dose supplements of 4,000-20,000IU on the internet.

Patients with very high vitamin D blood levels (over 100nmol) are becoming routine in my clinic and elsewhere, and toxic overdoses are increasingly being reported. Several randomised trials have shown that patients with high blood levels or taking large doses of vitamin D (above 800IU) had an unexpected increased risk of falls and fractures. Vitamin D is far from safe.

It can no longer be recommended for use in other conditions; the vast majority of the positive published studies in 137 diseases were reviewed as spurious. It was widely believed that vitamin D supplements prevented cardiovascular disease, but meta-analyses and large-scale genetic MR studies have ruled this out.

Pseudo-disease

We have created another pseudo-disease that is encouraged by vitamin companies, patient groups, food manufacturers public health departments and charities. Everyone likes to believe in a miracle vitamin pill and feels “they are doing something”.

Vitamin D, despite its star status, would not be called a vitamin today, as the doses needed are too large, the body can synthesise it from skin, and it is a steroid precursor. Instead of relying on this impostor, healthy people should get vitamin D from small doses of sunshine every day as well as from food, such as fish, oil, mushrooms and dairy products.

We should also trust that thousands of years of evolution would cope with a natural drop in vitamin D levels in winter without us snapping our limbs. About half the population take vitamins daily, despite zero benefits, with increasing evidence of harm. The worldwide trend of adding unregulated vitamins to processed food has now to be seriously questioned.

While vitamin D treatment still has a rare medical role in severe deficiency, or those bed bound, the rest of us should avoid being “treated” with this steroid for this pseudo-disease and focus on having a healthy lifestyle, sunshine and importantly save your money and energy on eating a rich diversity of real food.