The main finding of this nationwide retrospective cohort study is that the patients with PD using continuous BPs medication for one year after initial diagnosis of osteoporosis were associated with a lower risk of osteoporotic fracture than the patients with PD whose BPs use were not continued through 1 year after initial diagnosis of osteoporosis. The effectiveness of BPs in preventing osteoporotic fractures was consistent throughout the regression models and survival analyses.
Osteoporosis is a bone disease characterized by the deterioration of bone tissues in which bones become progressively less dense and more fragile34. When bones are severely weakened by osteoporosis, they can be fractured easily even from minimal trauma such as falling from standing position34.
BPs function as an antiresorptive drug by inhibiting osteoclast activity. They have been shown in numerous clinical trials to promote increase in bone mineral density and reduce the risk of osteoporotic fractures35. The BPs are considered as the mainstay of a wide range of anti-osteoporotic drugs36. Alendronate and risedronate, both bisphosphonates, have shown their preventive effects against osteoporotic vertebral and hip fractures in previous randomized clinical trials37,38. Zoledronic acids, an intravenous bisphosphonate, have been reported to be slightly more effective than oral bisphosphonate in preventing vertebral fracture in a previous study39. In addition, according to a previous meta-analysis that studied the efficacy of bisphosphonates in osteoporotic fracture prevention, the effectiveness of bisphosphonates varied between the included studies and also varied between different types of bisphosphonates40.
However, several previous studies elucidated that the most important factor in the efficacy of bisphosphonate for the prevention of osteoporotic fracture is the compliance with the bisphosphonate rather than the type of bisphosphonate41–44. According to previous studies, older age, lack of awareness of osteoporosis, poor socioeconomic status, complex intake methods, and side effects such as gastrointestinal irritation were major risk factors for poor bisphosphonate compliance45–47. Due to these factors, unlike randomized controlled trials, compliance with bisphosphonate cannot be a 100% in the real world41.
In the current study, risk factors and prevention factors for osteoporotic fractures were also investigated in a large population of PD patients with osteoporosis. The risk factors found in this study were older age, larger waist circumference, smoking, and presence of tumor as comorbidity. The preventive factors for osteoporotic fracture were higher body weight and higher physical activity score. Common risk factors identified in literature include older age, female sex, smoking, low body weight, waist circumference, immobilization, and inadequate activity48–50, which are generally consistent with the results of this study.
However, our study also showed some differences from previously known sociodemographic risk factors for fractures in PD patients. According to a previous study, the risk of femur fracture with parkinsonism decreased as subjects aged51. In that study, PD patients younger than 70 years of age reported a higher hazard ratio than those of PD patients older than 70 years51. On the contrary, in the current study, the risk of osteoporotic fracture in patients with PD accompanying osteoporosis increased as subjects aged. Furthermore, the female sex was considered a sociodemographic risk factor for fracture among patients with PD in a previous study52, but the current study did not find the female sex as a significant risk factor for osteoporotic fracture.
Thus, some results of the current study may seem contradictory to literature on fractures in patients with PD. To that matter, we presume that the difference in study subjects themselves between studies is the main reason behind the different results between this study and the previous studies. Specifically, we only included patients with PD accompanying osteoporosis, rather than the entire PD patient group.
In general, bone mass decreases with age53, and it is known that vertebral fractures occur in more than 50% of people over 80 years of age54. Therefore, we speculate that the current study results also converge on the biological risk of age in the risk of osteoporotic fractures55. In addition, since the subjects were PD patients diagnosed with osteoporosis, it is possible that the effect of the risk factor of an older woman, whose bone mass is rapidly decreasing due to hormonal changes after menopause, has been offset. Moreover, a previous study that analyzed the risk factors of femur fracture in PD patients reported that males with PD had a higher risk of femur fracture than the females with PD, suggesting the possibility that PD can be a risk factor for femur fracture in men24,51.
In current study, in line with previous studies on osteoporotic fractures, the risk of osteoporotic fractures decreased as the body weight increased. Lower body weight may be explained as a general risk factor for fractures in osteoporosis patients, but can also be viewed as interlinked with PD. As PD progresses, appetite decreases due to hypothalamus dysfunction, weight loss occurs as a result of unnecessary energy consumption due to movement disorder13, and body weight tends to decline due to decreased physical activity and sarcopenia22. Therefore, the effect of body weight on the risk of fracture might be in part a product of the progression of PD.
The results of the current study have clinical impacts on several points. First, to our best knowledge, the current study is the first investigational finding using large population data that patients with PD could take advantage of prevention of osteoporotic fracture with bisphosphonate after initial diagnosis of osteoporosis. In particular, the KNHIS database is not limited to a specific region or patient cohort as it is a highly representative database of the national population. Second, the results of this study were derived from multivariate adjustment for sociodemographics and coexisting multiple confounding medical conditions, providing valuable, statistically meaningful insights. The third strength of this study is its cohort study design using a large population.
This study has some limitations. First, we could not evaluate the prevention efficacy of BPs for osteoporotic fracture under the long-term compliance of bisphosphonate. According to the clinical guidelines for taking bisphosphonates, a regular patient monitoring including bone mineral density (BMD) is warranted56,57. In South Korea, insurance coverage of osteoporotic medication is valid for 1-year period after diagnosis of osteoporosis with BMD test, and we routinely perform BMD follow-up every 1-year after the initial diagnosis of osteoporosis. If a patient shows improved BMD results, prescription of osteoporosis medication is stopped. Therefore, at 2-years after initial diagnosis of osteoporosis, if use of osteoporosis drug is discontinued, the reason could be due to improved BMD, not due to patient incompliance. To avoid this bias, we included a landmark analysis58 time spot of 1-year period after initial diagnosis of osteoporosis for our statistical model. To gain more insights on the long-term effects of BPs, more detailed clinical database including BMD values for patients is warranted for future studies. However, we thought that the large population of specific patient group with PD, and strict patient selection criteria make the current study clinically relevant. The second limitation of this study is that the history of diagnoses and procedures were from the Korean National Health Insurance Service (KNHIS) data, not from the hospital medical records. To amend the limitation, we included the prescription of osteoporosis drugs simultaneously with diagnosis of osteoporosis to increase diagnostic accuracy. Lastly, because KNHIS database did not include hospital medical records, we could not examine the severity of PD in each patient. Still, the extensive study population with the long-term follow-up period might lend significant potential to the clinical meaning of the current study.