Risk of Bone Fracture Assessed Using Modified Creatinine Index

Individuals with chronic kidney disease (CKD) are at increased risk for bone fracture compared with the general population. Part of the reason for the increase in risk for patients with CKD is bone fragility, mediated by various complex pathologic states including CKD-mineral bone disorder and uremic osteoporosis. Previous epidemiologic studies have clarified the risk factors for bone fracture in this patient population; however, a preventive strategy has not been established and therapeutics are promising but limited.

Other studies have demonstrated a strong link between bone and muscle health. Bone and skeletal muscle are connected anatomically and mechanistically and they develop interactively. In addition, results of recent studies have shown that bone and muscle are secretory organs that share humoral mediators and interact in paracrine and endocrine manners.

Shunsuke Yamada, MD, PhD, and colleagues recently conducted a cross-sectional and prospective longitudinal cohort study to determine the association between skeletal muscle mass and bone fracture risk in patients undergoing hemodialysis. The researchers utilized data from the Q-Cohort Study to examine the association between modified creatinine index and incidence of bone fracture. They used modified creatinine index as a surrogate marker of skeletal muscle mass because it has been shown to be a good estimation of skeletal muscle mass. The study was also designed to test the validity of using modified creatinine index as an estimate of skeletal muscle mass measured by bioelectric impedance analysis (BIA) through analysis of data from a small independent hemodialysis cohort. Study results were reported in the American Journal of Kidney Diseases [2017;70(2):270-280].

Data were stratified according to sex-specific quartiles of modified creatinine index. Participants with a lower modified creatinine index were significantly older, had shorter median dialysis vintage, higher prevalence of diabetes mellitus, higher prevalence of history of cardiovascular events and bone fracture, lower mean body mass index, higher cardiothoracic ratio, and lower hemoglobin level. Patients with lower modified creatinine indexes also had significantly higher mean levels of serum C-reactive protein and alkaline phosphate levels, and significantly lower levels of serum albumin, urea nitrogen, creatinine, phosphate, and parathyroid hormone. Those with lower modified creatinine indexes used calcium-containing phosphate binders and vitamin D receptor activators significantly less frequently.

There were 140 patients who had newly developed bone fracture over a mean observational period of 3.9 years. The crude fracture rate in men was 3.4% (61/1793) and in women the crude fracture rate was 6.4% (79/1237). In both sex groups, the fracture rate was highest in the lowest modified creatinine index quartile when incidence rates of bone fracture were stratified by sex-specific modified creatinine index quartile (P for trend <.001).

In both sex groups, unadjusted Kaplan-Meier curves showed a significantly higher incidence rate of bone fracture in lower modified creatinine index quartiles than in higher modified creatinine index quartiles (Gray test, P<.01). In models that set all-cause death as a competing risk, patients with lower modified creatinine indexes (quartiles 1 and 2) were associated with higher adjusted hazard ratios (HRs) for the incidence of bone fracture compared with the reference group (quartile 4) in both sex groups. HRs for a decrease of 1 mg/kg/d in modified creatinine index were 1.25 (95% confidence interval [CI], 1.11-1.40; P<.001) overall, 1.28 (95% CI, 1.07-1.52; P=.008) in men, and 1.16 (95% CI, 0.96-1.39; P=.2) in women.

In models to determine the effects of dialysis vintage on the association between modified creatinine index and the risk for bone fracture, patients were divided into three subgroups based on dialysis vintage at enrollment: <2 years, 2-<5 years, and ≥5 years. Following multiple adjustment, results of Fine-Gray Proportional hazard analysis demonstrated a significant association between a decrease in modified creatinine index and the risk for bone fracture in patients with a dialysis vintage of ≥5 years (P=.04). There was a marginally associated risk for bone fracture in patients with a dialysis of 2 to <5 years (P=.09). In patients with dialysis vintage <2 years, there was no association between decrease in modified creatinine index and risk of bone fracture (P=.3).

The researchers also examined baseline risk factors of bone fracture. There were significant associations between female sex, the presence of diabetes mellitus, a history of bone fracture, and higher serum PTH level and an increased risk for bone fracture (P<.05 for all).

The researchers cited some limitations to the study, including not using skeletal muscle mass by methods such as magnetic resonance imaging and dual-energy x-ray absorptiometry, noting that their results should be confirmed using those methods. Other limitations were one-time measurement of serum creatinine, lack of data for residual kidney function, and not measuring other known risk factors for bone fracture, such as current smoking or history of smoking; use of glucocorticoids, antiosteoporosis drugs, and medications that affect neuromuscular function; family history of bone fracture; and bone mineral density.

The researchers said, “We demonstrated that modified creatinine index in the independent cohort was closely correlated with skeletal muscle mass measured by BIA. Furthermore, lower modified creatinine index was associated with increased risk for bone fracture in both male and female patients undergoing maintenance hemodialysis, even after adjustment for potential confounding factors. These results suggest that lower skeletal muscle mass plays a role in the pathogenesis of bone fracture and may become a potential therapeutic target in this hemodialysis population. However, because modified creatinine index uses a simplified method of estimating skeletal muscle mass, our observation should be cautiously interpreted and confirmed by more robust methods, such as magnetic resonance imaging. Also, further studies are necessary to elucidate whether interventions that increase or maintain skeletal muscle mass reduce the incidence of bone fracture in hemodialysis patients.”

Takeaway Points

  1. It is unclear whether lower skeletal muscle mass increases the risk for bone fracture in patients on maintenance hemodialysis, a population at increase for bone fracture and sarcopenia.
  2. In a cross-sectional study, there was significant correlation between modified creatinine index and skeletal muscle mass measured by bioelectrical impedance analysis. During a medial follow-up of 3.9 years, 140 patients had bone fracture.
  3. In patients with dialysis vintage of ≥5 years, a decrease in modified creatinine index was significantly associated with the risk of bone fracture; risk of bone fracture in patients with a dialysis vintage of 2 to <5 years was marginally associated with a decrease in modified creatinine index.