The Effect on Bone Mineral Density in Patients with Osteoporosis and Obesity of Once-weekly Treatment with Risedronate/Vitamin D3 Combined in a Single Pill for 12 Months: A Post-marketing Study

  

    
 
    
AR (95% CI)
    
RR (95% CI)
    
RRI (95% CI)
    
ARI (95% CI)
    
NNTh
  
  

    
Control    group
    
0.04    (0.00-0.09)
    
1 reference
    
1 reference
    
1 reference
    
1 reference
  
  

    
Overweight
    
0.10    (0.05-0.15)
    
2.26    (0.66-7.74)
    
1.26    (-0.34-6.74)
    
0.05    (-0.02-0.13)
    
20
  
  

    
Obesity
    
0.07    (0.02-0.12)
    
1.59    (0.43-5.95)
    
0.59    (-0.57-4.95)
    
0.03    (-0.04-0.09)
    
33
  

Table 4: Absolute Risk, Relative Risk, Relative Risk Reductions, Absolute Risk Reductions and values of Number needed to treat for patients with osteoporosis and no effect on BMD after one year of treatment, according to body mass index.

Discussion

Osteoporosis is a global public health problem that mainly affects the female population: women experience a 40% risk of fractures compared to 13% in males [25]. The prevalence of osteoporosis in Mexico is 16% in women older than 50 years. This prevalence increases with age, affecting up to 80% of women over 80 years of age [25]. In 2005 the rates of osteoporotic fractures were 169 females and 98 males per 10,000 inhabitants [26].

Osteoporosis is the main factor leading to the increased incidence of hip fractures after the fifth decade of life [27]. Approximately 12 to 20% of females who suffer a hip fracture die during the first year of fracture evolution [25,28]. Osteoporotic fractures are responsible for most of the morbidity, mortality and cost of illness due to surgical complications and comorbid conditions [25,28]. Approximately 50% of patients lose their ability to walk independently and 30% are totally dependent on a family member or caregiver [28]. This renders many elderly patients disabled despite having their higher brain functions intact [25].

In the present study, we did not find a significant difference in baseline T-scores across the three groups despite substantial differences in body size. Furthermore, we did not find a correlation between BMD and baseline BMI. Our data on BMD in the distal radius and BMI are consistent with those from a previous study in females from Israel [29], but are different from data found in females from Japan [30] and Northern Thailand [31]. However, in these latter populations a low positive correlation has been reported between BMD in the distal radius with BMI [30, 31]. These results suggest that regions free of body weight as a load are only weakly influenced by tissue weight. This hypothesis is supported by the fact that regions such as the femoral neck or lumbar spine are directly influenced by tissue weight [29-33], which varies depending on the genetic background of each population. In addition to these results, several studies in Thai females [34] and Caucasian women from England [35], USA and Denmark [36,37] have described a significant correlation between BMD of the distal radius with BMD of the hip [34], lumbar spine, femoral neck [31] and Ward’s triangle [38]. The lowest mean BMD values are often observed at the distal forearm, as compared to BMD values in the hip and lumbar spine [37,39].

We did not observe correlations between baseline BMI and both clinical outcomes on BMD at the end of treatment, as determined by logistic regression analysis (Table 2). Moreover, no statistically significant difference was observed between the absolute and relative risks. Nevertheless, we observed higher bone mass densities after treatment compared to baseline densities. This effect of bisphosphonates on bone density has been widely studied by clinical trials. Several studies have shown that bisphosphonates are safe and effective for the treatment and prevention of postmenopausal and glucocorticoid-induced osteoporosis [13-18,40-52]. However, clinical trials do not evaluate the effectiveness of a therapeutic intervention under the usual conditions of clinical practice through outpatient consultations. The number needed to treat enables the measurement of the effectiveness of any given intervention. This statistical method could be used not only to describe the difference between the treatment and control groups but also to distinguish differences between several clinical outcomes. Number needed to treat can thus be used to describe any outcome where event rates are available for both a treatment and a control. On the other hand, post-marketing surveillance studies play important roles for the discovery of undesirable effects and can provide additional information on the benefits or risks of a drug. Such studies may also be used to identify whether treatment leads to a positive clinical effect or fails to induce the desired effect in different clinical conditions observed through outpatient consultation services. The primary objective of this analysis was to assess efficacy according to BMI.

Our results indicate that to prevent one case of worsening bone mass density, a clinician must treat 50 overweight patients once-weekly with Risedronate 35 mg and vitamin D 2800 UI for 12 months. However, 20 obese patients must be similarly treated to obtain the same outcome. We also observed that for every 20 overweight subjects treated with the study drug, one additional case of unchanged BMD will occur. A clinician would need to treat 33 patients, more than twice as many obese patients as compared to overweight subjects. These data suggest that females with osteoporosis and obesity respond better than overweight patients to treatment with Risedronate (35 mg) and vitamin D3 (2800UI), combined in a single pill, once-weekly for one year. Obese patients thus will have better prognoses. The prevalence of patients with improved BMD is greater in the obesity group as compared to the overweight group and even to those with normal BMI. These data are consistent with the observation that the incidence of osteoporosis and fracture is lower in obese patients [53].

Several factors can influence and increase osteoblast activity. These factors include physical activity, muscle, fat tissue level or simply increased weight and, therefore, increased bone mass. Additional weight can increase the mechanical load on the skeleton, particularly in the cortical elements. In response to this stress, the body promotes bone formation [1,5,25]. It has been suggested that leptin may directly promote the differentiation of osteoblasts and that it affects bone resorption [53].

Bisphosphonates are pyrophosphate analogue drugs that can bind to hydroxyapatite and inhibit bone resorption by inducing apoptosis in osteoclasts [13-16]. These drugs are considered to be highly potent antiresorptive agents and can bind to bone and remain there for many years [13]. Several studies have shown that Risedronate 5 mg, dosed once daily, can increase BMD after 2 to 3 years of treatment [14-16] and is effective in reducing the risk of vertebral and non-vertebral fractures [16,17,54].

In this study, we found that the changes generated by, or attributed to, Risedronate and vitamin D can be observed from the first year of treatment and that the response is different among patients with lower values of body mass index. Overall, we observed that a higher proportion of patients showed improvement (79%, 74-83), but we also observed a group of patients who did not show changes in BMD at the end of the treatment (6%, 4-9). However, the percentage of patients with decreased BMD (15%, 11-19) was higher than in the previous group. These findings are similar to the results observed by Chiodini I. et al., who reported 25.8 % of primary osteoporosis postmenopausal women inadequately responds to bisphosphonates, and showed that current smoking and baseline alkaline phosphatase total activity levels ≥ 66.5 U/L are associated with the inadequate response to bisphosphonates [55].

We thus suggest that health authorities and clinicians should focus on implementing a clinical algorithm to include screening and monitoring of osteoporotic patients with different body mass index values during treatment. Our data suggests that studies along this line of research will contribute to substantial changes in the way that patients with osteoporosis are managed. However, several studies report mono therapy administration of Risedronate (5 mg) every 24 hours or once-weekly doses increase bone mass in several parts of the body and reduce bone turnover and the risk of vertebral and non-vertebral bone fractures [13-17,54]. We can assume, by considering the high prevalence of patients with an increase on BMD after treatment it would have positive effects on reduction in the risk of fracture.

This study by its design includes information of several clinical co-morbidities that may associate and independently affects the response to the study drug. For instance, systolic arterial hypertension, type 2 diabetes mellitus, dyslipidemia as components of metabolic syndrome, and degenerative joint disease and peripheral vascular disease. Another factors may be affect the response of patients to risedronate, into these factors we may include hypothyroidism, peptic ulcer disease, systemic lupus erythematosus, but its prevalence was very low (≤ 10%). Vestergaard P demonstrated that the antiresorptive effect of alendronate, etidronate, and raloxifene do not seem associated with an increased risk of type 2 diabetes and postulated these three drugs may provide a protective effect related to the suppression of bone turnover [56]. By other hand, there are evidence that visceral adiposity and the metabolic syndrome have detrimental effects on bone health, such as a higher incidence of osteoporotic fractures and an impaired bone structure [57-59]. In addition Giustina A. et al., suggests that hyperglycemia is an important factor that has direct and indirect deleterious effects on osteoblast function and bone formation [59,60]. Even some animal’s models show that insulin resistance might associate with osteoporosis [61,62]. Moreover, the genetic background could to explain at least a part the response of patients to the study drug. Several studies have identified polymorphisms in some candidate genes that have been associated with bone mass or osteoporotic fracture, including the Vitamin D receptor, and the estrogen receptor or the collagen type I alpha-1 gene [63,64]. However, there are several genes and transcription factors involving with the bone formation and bone resorption in relation to the regulation of several cellular and molecular mechanisms that could to explain or elucidate the response of patients to the drugs, because they play an important role like regulators of biological process and gene expression, respectively.

Limits

The present study had the limitation than we did not include the comparative interventional group (placebo controlled group). In addition, we only described the changes on BMD before and after treatment with bone densitometer. Therefore, we could not ascertain the direct relationship between drug efficacy and fracture reduction. However, our results are similar of a post-marketing surveillance study in Korean postmenopausal women with osteoporosis [65].

In conclusion, our data suggest that under the usual conditions of outpatient family medicine consultation, a reasonable number of patients treated once-weekly with Risedronate (35 mg) and vitamin D3 (2800 IU) combined in a single pill will experience increased bone mineral density during the first year of treatment. We further conclude that a more favorable response can be expected in obese patients.

Acknowledgment

To Dr. Leticia Brito Aranda for reviewing the manuscript.

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