In this study, we analyzed the GIO in ITP patients aged ≥ 70 years according to femoral neck BMD T-scores < − 1.0 measured by DXA scan and their association with GIO prevalence during the initial loading of prednisolone treatment. We found that the FRAX® 10-year probabilities of major osteoporotic and hip fractures and probabilities defined by the Garvan tool were worse during the initial loading of prednisolone treatment compared with compared with the tapering phases, but there were no incidents of fracture, and no significant differences in BMD loss or probabilities defined by FRAX® and the Garvan tool between patients with and without bisphosphonate treatment, including women whose 25(OH)D levels were low. These results support our hypothesis that fractures in the early period of initial prednisolone treatment can be prevented by prescribing bisphosphonate and active vitamin D guided by femoral neck BMD T-score assessment.
Previous studies reported that 30–50% of adults receiving long term glucocorticoids developed fragility fractures . BMD loss is rapid in the first few months of glucocorticoid use but continues to decline at a slower rate with continued use . GIO is caused by multiple, complex mechanisms, including the suppression of bone formation by inhibiting osteoblast function, promoting osteoblast and osteocyte apoptosis , the inhibition of intestinal calcium absorption, and the reduction of gonadal hormones . In our institute, we assessed DXA and started GIO prevention guided by femoral neck BMD T-score assessment. Although the median observation period was much shorter than 10 years, which is the anticipated observation period for FRAX® and the Garvan tool, this early GIO prevention might reduce the risk of fragility fractures.
Our data show that changes in the lumbar BMD score, femoral neck BMD T-score, FRAX® 10-year probabilities of major osteoporotic and hip fractures, probabilities defined by the Garvan tool, and bisphosphonate prescription were associated with an increased femoral neck BMD T-score. However, there were no incidents of fracture and no significant differences in BMD loss. This was attributed to the fact that early bisphosphonate treatment for ITP patients receiving high-dose prednisolone was associated with an increased likelihood of BMD loss. In the United States, hip fracture rates among persons 65 years and older are declining, and comorbidities among patients with hip fractures have increased , but there are no data on GIO in ITP patients aged ≥ 70 years. Further study after prospective long-term observation is needed to assess the effect of bisphosphonate on preventing fragility fracture in elderly ITP patients undergoing high-dose prednisolone therapy.
Our study found that active vitamin D prescription was significantly associated with a low level of serum 25(OH)D at tapering phases during prednisolone treatment. In Japan, sufficient vitamin D status reflected by serum 25(OH)D levels is associated with low limb and vertebral fracture risk in community-dwelling elderly women . According to these data, we added active vitamin D for women, but not men. Our study did not show the importance of the additional prescription of active vitamin D for elderly women with ITP undergoing prednisolone treatment, but the need for active vitamin D prescription for men is also unknown.
In our patient cohort, 15 patients received TPO-RA and switching from prednisolone to TPO-RA had a positive effect on response and tolerability in patients aged ≥ 70 years. Prednisolone remains the initial treatment for newly diagnosed ITP patients . Prednisolone has multiple effects on platelets including decreasing platelet clearance , increasing platelet production , and reducing bleeding independent of the platelet count increase, via a direct effect on blood vessels [24, 25]. Although a consensus panel suggested that some patients were able to maintain a platelet response with a daily dose of < 5mg of prednisolone, the side effects of prednisolone outweigh their benefits over the long term . The most appropriate management of ITP patients refractory to the initial treatment remains controversial. Although many drugs are available for refractory ITP, including TPO-RA and rituximab, as well as treatments including splenectomy, immunosuppressants, and novel therapies, individualized management is usually based on patient preferences, side effects, previous treatment received, comorbidities, and cost associated with the treatment. Further studies are needed to assess the timing of switching from prednisolone to TPO-RA in elderly patients with refractory ITP according to the risk-adapted approach of GIO prevention.
This cohort study had some limitations, including its single-institute nature. Although serum 25(OH)D levels before prednisolone treatment and active vitamin D administration should be accurately measured, serum 25(OH)D measurements are only permitted according to the rules of the Japanese government and health authorities. We added active vitamin D for all women who received bisphosphonate and measured serum 25(OH)D levels in all patients to evaluate the treatment at the tapering phases of the course of prednisolone treatment. In addition, subjective data such as the assessment timing of BMD assessment were variable because this information depended on past medical records written by physicians before the study was planned. To minimize bias, we limited the inclusion criteria to patients who had at least one DXA assessment during the initial loading of prednisolone treatment at a single institution. The usage of FRAX® is limited for age 40 to 75 years old, but the FRAX® in patients over 75 years old did not seem to have significant difference in clinical practice compared to other tools . We assessed clinical, not determined morphometric vertebral fracture on the basis of the medical record. Furthermore, a decrease in the initial prednisolone treatment intensity may have caused poorer treatment outcomes in elderly patients. We selected patients who received TPO-RA at non-CR in the tapering phases of the course of prednisolone treatment because the effects of different second therapies for ITP according to the recommendations in the guidelines were unclear. Thus, there was potential for selection bias because no proper randomization could be achieved. Future research should apply standard prednisolone-dosing regimens, report patient-reported outcomes, and include cost-analysis evaluations. Finally, the sample size, selection bias, especially that related to the exclusion of patients without prednisolone treatment because of difficulties in evaluation, and short follow-up duration may have limited our ability to analyze the outcomes and the fracture of patients at tapering phases throughout prednisolone treatment.
In conclusion, we prevented GIO in elderly ITP patients using bisphosphonate treatment according to < − 1.0 femoral neck BMD T-score measured by DXA scan. Prescribing bisphosphonate during the initial loading of prednisolone treatment might prevent the reduction of BMD and the additional prescription of active vitamin D for women might prevent fragility fractures. It is important to prioritize clinical trials of current and new anti-osteoporotic drugs. Preventing fragility fractures might maintain the activities of daily living at tapering phases throughout prednisolone treatment and allow the identification of individuals suitable for novel ITP therapies.