Thiazide diuretic may decrease the risk of fracture, indicating the protective effect of this class in clinical practice.

Osteoporosis is a major chronic condition worldwide, and the major health issue in the USA especially in the aging population. About 300,000 people aged 65 and older are hospitalized each year due to hip fracture, a situation which often leads to decreased quality of life. It is estimated that there will be 50% increase in the annual fracture and the medical expenses associated with it by 2025 as compared to 2005.

Hypertension is also a common chronic condition that often is present in patients with osteoporosis. The prevalence of hypertension had increased about 33.5% from the past 20 years. Thiazide diuretics have been the most recommended drugs for hypertension treatment. Thiazide diuretic being used in several heart conditions such as stroke, heart attack, and heart failure. It acts by lowering the blood pressure on the kidneys and the intestines and reduce the urinary excretion of calcium. Besides, thiazide diuretic also reported being beneficial in decreasing the risk of osteoporotic fractures.

Due to the association of hypertension and osteoporosis and the extensive use of thiazide diuretics for antihypertensive treatment, understanding the effect of thiazide diuretics on bone structure, especially concerning fracture, becomes extremely important.

Rationale behind the research:

A comprehensive review and meta-analysis of prospective cohort studies in order to investigate the association of between thiazide diuretic use and fracture risk is not available.

Therefore, Xiao X et al conducted a meta-analysis to quantitatively assess all eligible prospective cohort studies that have examined the effect of using thiazide diuretics on the risk of fracture.

Objective:

To examine the association between the use of thiazide diuretics and the risk of fracture.

Study outcome measures:

• Relative Risk and Hazard ratio: used as a measure of the association between thiazide diuretic use and fracture risk
• The morbidity benefit associated with thiazide diuretic use was further examined in the following pre-specified subgroups
• By plotting the logarithms of individual study effects against their standard errors, a funnel plot was constructed to examine the potential publication bias
• The trimand-fill method to estimate and adjust for the potential effects that unpublished studies might have had on the estimates

Time period: NA

Study Outcomes:

Meta-analysis:

• The Cochran Q statistic (p = 0.009) and the Higgins’s I2 index (57.8%) indicated heterogeneity among the 11 studies. Compared to non-users, thiazide diuretic users had a significant 14% reduction in the risk of fracture (RR, 0.86; 95%CI, 0.80– 0.93; p = 0.009).
• The pooled estimates varied a little and remained significant when they included studies with different eligibility criteria for the analysis. When hip fracture was included as the only outcome measure, the overall RR decreased slightly (RR, 0.82; 95%CI, 0.72–0.93). When the analysis was restricted to the six studies that included only participants over 65 years of age, the overall RR decreased to 0.82 (95%CI, 0.81–0.84).

Subgroup analysis:

• The risk of fracture was substantially lower in studies with smaller size (< 10,000) (RR, 0.83; 95%CI, 0.68–0.98) compared to studies with larger sample size (> 10,000) (RR, 0.95; 95%CI, 0.85–1.05). In the six studies conducted after 2007, the association between thiazide diuretic use and risk of fracture was not significant (RR, 0.92; 95%CI, 0.82–1.02), whereas the risk of fracture was significantly lower among thiazide users compared to non-users in the studies carried out before 2007 (RR, 0.77; 95%CI, 0.63–0.90).

Publication bias:

• Publication bias was examined by plotting the log RRs between thiazide diuretic users and non-users, against their standard errors for each study. By visual inspection of the funnel plot, no publication bias was suspected. The Egger test for publication bias was not significant (p=0.12). Additionally, the use of a trim and fill correction procedure did not alter the results.

The Xiao et al. included data from 11 qualified prospective cohort studies that investigated the relationship between thiazide diuretics use and the risk of fracture. The results showed 14% decrease in fracture risk in thiazide diuretic users compared to that in nonusers. The combined meta-analysis also showed a significant association between thiazides use and lower risk of fracture. A pooled study in 2011 fluctuated little after four recent reviews were added, suggesting that the addition of further investigations would have limited impact on the overall estimate.

Additionally, when the studies were arranged chronologically, the 95% CIs were also found to be increasingly narrower. Which further demonstrated the robustness and accuracy of our overall finding.

The results of this meta-analysis were consistent with prior meta-analyses. Results of sensitivity analysis also suggest a stronger negative association between thiazide diuretic use and risk of hip fracture. The rates of bone loss differ between the anatomic regions. For example, the hip is less affected by degenerative changes and is thus more sensitive to bone loss. Therefore, thiazide diuretic use may convey a more protective effect in increasing BMD at the hip and hence lower the risk of hip fracture.

Hormone replacement therapy is a common choice for fracture prevention because the treatment inhibits bone resorption. Related research has demonstrated that women using both thiazides and estrogen have higher BMD when compared to women using the only thiazide. In this meta-analysis, after adjusting the protective effect from hormone replacement therapy, a lower effect size of thiazide diuretics was observed, compared to the pooled effect size of studies that did not control for hormone replacement therapy.

Two main physiological explanations for the beneficial effect of thiazide diuretics on fracture risk were; thiazide diuretics slowed bone loss and thiazide diuretics facilitate intestinal calcium absorption and skeletal retention of calcium. In addition, the beneficial effect of thiazide diuretics on bone density to decrease fracture risk could also potentially be offset by the increased incidence of falls caused by the medicine’s side effects, which include dizziness, blurred vision, and weakness, especially in the elderly.

The use of thiazide diuretics can decrease the risk of fracture. However, since the variance was observed in the subgroup analysis, further investigation is warranted.