Young Adult Childhood Cancer Survivors Have Higher Fracture Risk

Dutch adults aged 18 to 45 who had survived childhood cancer had a three- to fivefold higher risk of a first fracture than adults of the same age and sex in the general population in Sweden, according to the findings of a new study.

Among younger adult childhood cancer survivors who had bone mineral density (BMD) results, 36% had low BMD (Z-score ≤ –1) at any site and 9.6% had very low BMD (Z-score ≤ –2) at any site.

Several modifiable risk factors — growth hormone deficiency, hypogonadism, hyperthyroidism, low physical activity, low dietary calcium intake, severe vitamin D deficiency, vitamin B12 deficiency, and folic acid deficiency — were associated with low BMD or very low BMD in young adulthood or a first vertebral fracture ≥ 5 years after the childhood cancer diagnosis. Cancer treatment with high-dose carboplatin was a risk factor for low BMD. 

These findings, by Jenneke E. van Atteveld, MD, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands, and colleagues, were recently published online in The Lancet Diabetes & Endocrinology.

“Our findings highlight the importance of BMD surveillance in high-risk [childhood cancer] survivors (ie, treated with cranial, craniospinal, or total body irradiation),” the authors write.

Moreover, the data “suggest that more intensive surveillance for endocrine disorders might be advised, as recommended by the International Late Effects of Childhood Cancer Guideline Harmonization Group, because timely interventions for survivors of cancer with endocrine disorders (including hyperthyroidism), and supplementation of calcium, vitamin D, vitamin B12, and folic acid deficiencies could improve bone health.”

However, “this needs to be assessed in future prospective or interventional studies,” they conclude.

“A Highly Underrecognized Clinical Problem”

Developing bone surveillance recommendations for young adult childhood cancer survivors is “challenging for several reasons,” Cornelia S. Link-Rachner, PD, and Tilman D. Rachner, MD, Technische Universität Dresden, Germany, write in an accompanying editorial. Individuals may not be regularly seen by specialists once they become adults. Information related to bone health, such as radiation, chemotherapy, or corticosteroid regimen, might be lost.

Moreover, several of the modifiable risk factors for low BMD and fractures identified in the current study, including hypogonadism, growth hormone deficiency, thyroid disorders, vitamin D deficiency, vitamin B12 deficiency, and low physical activity, are typically managed by endocrinologists but might not be the focus of oncologists.

“In an ideal scenario, a childhood cancer survivor would be presented to an adult endocrinologist at the time they leave pediatric care with a current history that includes diagnosis, received treatment, and follow-ups, to allow the endocrinologist to make an individualized plan with the patient according to their risk profile (ie, baseline check-up and control every x years),” Rachner elaborated in an email to Medscape Medical News. “The same should be done on the oncology side, and the doctors should know about each other.”

“We would propose for all young adults that have survived childhood cancer to obtain one test for BMD to assess their baseline values and further tests depending on results and risk profile,” he continued.

“Again, as an endocrinologist myself,” Rachner said, “I would encourage each cancer survivor to have at least one endocrine check-up.”

Most if not all osteoporosis guidelines don’t adequately recognize childhood cancer as a risk factor for osteoporosis, says Rachner, and the current study underlines the need for updated guidelines to raise awareness for this population.

“I feel that this is a highly underrecognized clinical problem,” said Rachner. “I was also surprised to learn about the magnitude of risk increase depicted in the trial.”

“Integration into clinical guidelines may help to raise awareness,” he suggested. “In addition, educating oncologists who may not normally focus on this issue, standardizing patient follow-up programs, and educating patients about their increased risk may all be measures that could help.”

The findings “reinforce the need for well-conducted randomized controlled trials to verify which therapeutic interventions have a meaningful impact on fracture reduction in childhood cancer survivors,” the editorialists conclude.

BMD and Fracture Risk in Young Adult Childhood Cancer Survivors

Although low BMD is associated with fractures in older adults, this association is less well-established in younger adults, including childhood cancer survivors, the researchers note.

To investigate this, they analyzed data from 2003 individuals in the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort.

Participants had had a cancer diagnosis before age 19 and had been treated at one of seven Dutch pediatric oncology centers between 1963 and 2001.

They were 18-45 years old in 2016 (mean age 33) and 48% were female.

Just over three quarters had evaluable dual-energy X-ray absorptiometry (DXA) scans for assessment of BMD, 95% provided medical history of fractures that occurred at least 5 years after the cancer diagnosis, and 12% were assessed for vertebral fractures.

Male sex, underweight, high carboplatin dose, any dose of cranial radiotherapy, hypogonadism, hyperthyroidism, low physical activity, and severe vitamin D deficiency were associated with low BMD at any site.

Male sex, underweight, cranial radiotherapy, growth hormone deficiency, and severe vitamin D deficiency were associated with very low BMD at any site.

Male sex, former and current smoking, and very low lumbar spine BMD were associated with any fractures.

Older age at follow-up, previous treatment with platinum compounds, growth hormone deficiency, and low physical activity were specifically associated with vertebral fractures.

Vertebral fractures were prevalent in 33 (13.3%) of 249 evaluable participants, “impressively underpinning the clinical importance of stringent monitoring and early therapeutic interventions in high-risk individuals,” the editorialists note.

“Considering, that 31 (93.9%) of 33 individuals with vertebral fractures were unaware of their vertebral fracture and the young age of participants at the time of assessment, identification of individuals who do not reach an appropriate peak bone mass by age 25-30 years seems to be crucial,” they write.

The researchers compared the incidence of any first fracture that occurred between 1987 and 2014 in the Dutch childhood cancer survivors with population-level cancer incidence data from a Swedish national registry because Dutch population-level data are not available.

The study was supported by the Children Cancer-Free Foundation, KiKaRoW, and the ODAS foundation. van Atteveld and Link-Rachner have declared no competing interests. Rachner has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Amgen and UCB. Disclosures for the other study authors are listed with the article. 

Lancet Diabetes Endocrinol. Published online December 10, 2022. Abstract, Editorial

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