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

Research Article

Austin J Endocrinol Diabetes. 2014;1(4): 1017.

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

Luis Beltrán-Lagunes1, Silvia Munguía-Lozano1 and Daniel López-Hernández1,2*

1Clinic of Family Medicine “Gustavo A Madero”, Institute of Security and Social Services for State Workers, Mexico

2Department of Biostatistical, Centro de Investigación y de Educación Continua, Mexico

*Corresponding author: Daniel López Hernández, Department of Biostatistical, Centro de Investigación y de Educación Continua (CENINVEC), Oyameles No. 30, Postal code 57820, Nezahualcóyotl, Mexico State, Mexico,

Received: June 24, 2014; Accepted: July 28, 2014; Published: July 29, 2014

Abstract

Several health authorities around the world propose conducting additional observational studies after controlled clinical trials as a part of the regulatory approval process of a drug for marketing. These studies, known as post-marketing surveillance studies, are intended give further insight into the safety, efficacy, and/or optimal use of the drug under the usual conditions of clinical practice. Limited post-marketing studies have been conducted on Risedronate. Therefore, the aim of this study was to evaluate and compare the effect of recent treatment with Risedronate (35 mg) and vitamin D3 (2800 IU) combined in a single pill on bone mineral density in female patients with postmenopausal osteoporosis. Patients were classified according to body mass index criteria. An open-label, observational, post-marketing surveillance study was conducted in a sample group of 345 osteoporosis patients. All patients were allocated according to CONSORT recommendations and treated for 12 months with the study drug. We considered overweight (144) and obese (116) patients as the intervention group and patients with normal weight (84) as the reference group. We excluded one underweight patient from the statistical analysis. Osteoporosis was detected using peripheral bone mineral densitometry. We calculated the number needed to treat for both improvement and no effect on bone mineral density, and we conducted the appropriate statistical analysis. In obese patients, the number needed to treat was 20 and 33, and for overweight patients, the corresponding number was 50 and 20. In conclusion, treatment with Risedronate (35 mg) and vitamin D3 (2800 IU) combined in a single pill showed the most favorable antiresorptive effect in obese osteoporotic patients. These data suggest that health authorities and clinicians should focus on implementing a clinical algorithm that includes screening and monitoring of osteoporotic patients with different body mass indices during treatment.

Introduction

Obesity and osteoporosis are considered to be public health problems worldwide [1], affecting approximately 130 or 500 million people according to the International Osteoporosis Foundation [2] and the World Health Organization [3] (WHO), respectively. Osteoporosis leads to more than 8.9 million fractures annually, of which over 4.5 million occur in Europe and America [4], and this disease is the most common metabolic bone disease in the United States and Mexico. A significant economic cost is associated with osteoporosis [5].

Obesity is the result of chronic excessive storage of body fat due to an imbalance between the intake and expenditure of energy [6]. Osteoporosis is characterized by decreased bone tissue per unit volume of bone [7] and the consequent microarchitectural deterioration of the bone [6-10]. This is associated with increased osteoclast activity, decreased osteoblast activity, or both [11]. Osteoporosis leads to excessive bone fragility and increased susceptibility to future bone fractures [6,8].

Bone remodeling is regulated locally by various hormonal factors, including estrogens, androgens and parathyroid hormone. This latter agent stimulates the hydroxylation of vitamin D in the kidneys and increases the absorption of calcium [11]. Some medical organizations have recommended that bone mineral density (BMD) should be determined in subjects with osteoporotic risk factors because the increase in bone fragility is asymptomatic [4,12]. Osteoporosis risk factors related to weight include a body mass index (BMI) between 20 and 25 kg/m2, body weight less than 40 kg, weight loss greater than 10% of usual body weight in young or adult subjects, or recent weight loss [12]. Bone densitometry (BD) is recognized by WHO as the reference method for the diagnosis of osteoporosis in postmenopausal women because it can be used to quantify BMD with acceptable accuracy and reproducibility [13]. Medical treatment for osteoporosis around the world recommends the use of bisphosphonates as the first-line agents [13]. Administration of Risedronate (5 mg) in postmenopausal women [13-16] every 24 hours for two or three years has been shown to reduce bone turnover [13-15] and increase bone mass in the lumbar spine, femoral neck and trochanter, and to increase diaphysis of the radius [16]. Compared to placebo, Risedronate reduces the risk of vertebral and non-vertebral bone fractures by 33- 65% [16,17]. Moreover, once-weekly doses of Risedronate at 35 mg once provide the same efficacy and safety [18]. All drugs used to treat postmenopausal osteoporosis must be accompanied by an adequate intake of calcium (1500 mg/day) and vitamin D (800 U/day) to prevent the accompanying increase in bone remodeling, bone loss and fractures [11].

The effectiveness of a medical drug is initially evaluated in controlled clinical trials, but these studies do not assess the drug under the usual conditions of clinical practice [19]. Several health authorities around the world propose conducting additional observational studies after controlled clinical trials as part of the regulatory approval process for a drug to be marketed. These studies, known as post-marketing surveillance studies, are intended to further understand the safety, efficacy, and/or optimal use of the drug [19]. Limited post-marketing studies of Risedronate have been conducted. Therefore, the aim of this study was to evaluate and compare the effect on BMD of recent, once-weekly treatment with Risedronate and vitamin D3 (35 mg/2800 IU) combined in a single pill in osteoporotic female patients from Mexico compared to BMI at the level of primary care.

Materials and Methods

Study design and patient enrollment

We conducted an open-label, observational, post-marketing surveillance study at the Clinic of Family Medicine (CFM) “Gustavo A. Madero” of the Institute of Security and Social Services for State Workers (ISSSTE: Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, for its acronym in Spanish) in Mexico City. The study was conducted in accordance with Good Clinical Practices of our laws and the Helsinki Declaration. The protocol was approved by the appropriate ethics committee and an investigational review board (IRB). A total of 345 women (aged 40-99 years) were recruited between March 10, 2008 and April 2, 2009. All females were enrolled after osteoporosis was detected through outpatient services of family medical consultations. Patients were monitored through outpatient family medicine consultations. We also determined systolic and diastolic blood pressure (based on the 2007 recommendations of the European Society of Hypertension-European Society of Cardiology) and the Quetelet index (kg/m2) [20,21]. Serum concentration of glucose, total cholesterol (TC), low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL) and triglycerides (TG) were determined after 8-12 hours of fasting due to the higher prevalence of comorbidities. Exclusion criteria were: lacking a second BMD measurement or possible failure to complete one year of treatment.

Bone mineral density measurements and operational definitions

Bone mineral density was performed using the Omnisense 7000S device (Sunlight, Germany) according to the manufacturer’s recommendations. Baseline BMD was determined in the distal portion of the radius bone using an Omnisense 7000S bone densitometer. Subsequent BD was measured one year after starting treatment. Osteoporosis was defined according to the operational definition of WHO as a BMD value 2.5 standard deviations (SD) or more below that of the maximum density average value for a young normal adult (T score at or below 2.5 SD) [4]. Patients were considered to be overweight if they had BMI between 25 and 29.9 kg/m2 and were considered to be obese if they had BMI of 30 kg/m2 or higher [21]. We defined clinical improvement outcomes (increase in BMD) as T scores higher than the previous baseline densitometry values or changes in clinical diagnoses (from osteoporosis to osteopenia). Similarly, we considered worsening to be a clinical adverse outcome (decrease in BMD). Worsening was defined as a T score lower than the baseline densitometry value.

Drug information, dosage and administration

All patients received Risedronate (35 mg) and vitamin D3 (2800 IU) combined in a single pill and administered once-weekly for 12 months. Patients were instructed to take the study drug with at least 120mL of water, on an empty stomach, at least 30 minutes before breakfast. Patients were also to remain upright (sitting or standing) for at least 1 h, according to the recommendations of the data sheet [22]. Risedronate (35 mg) and vitamin D3 (2800 IU) combined in a single pill is a new drug approved and registered (Reg. Núm. 188 M2007, SSA IV) according to our laws with the Secretaria de Salud (SS; by its acronym in Spanish).

Analysis of clinical outcomes

We used the Graphical Appraisal Tool for Epidemiology (GATE) frame to compare the effectiveness of treatment with Risedronate and vitamin D3 relative to BMI classification [23,24]. We then estimated: 1) absolute risk, 2) relative risk, 3) the number needed to treat (NNT), and 4) the number needed to harm (NNH). Therefore, we stratified patients based on the WHO criteria for BMI classification (Figure 1). To study the effect on bone mineral density of Risedronate and vitamin D combined in a single pill, we divided all patients into three subgroups (according to BMI) and two categories (depending clinical outcomes). Study subgroups included patients with osteoporosis and normal BMI as a reference group and osteoporotic females who were overweight or obese as study groups. Clinical outcomes were stratified to assess the effect of treatment on BMD in two categories. To prevent a decrease (worsening) in BMD, we evaluated the number needed to treat (NNT) to achieve improvement in patients. To determine the number of patients who showed no effect on BMD after one year of treatment, data were analyzed under the assumption that a persistent unchanged value of BMD was an adverse event (NNH). We thus analyzed four groups (Figure 2a-d).