The effects of daily alendronate, daily calcitonin and alendronate every other day on bone mineral density in osteoporotic men

Abstract

Objectives. Biphosphonates have been widely used in the treatment of osteoporosis, but there is not enough data on their use in men. The aim of this study is to investigate the effects of twelve months' treatment with daily 10 mg alendronate, every other day 10 mg alendronate and daily 200 IU calcitonin on bone mineral density (BMD) in men with osteoporosis.

Materials and methods. 46 men with osteoporosis were randomly allocated to three groups: 15 patients in the first group received daily 10 mg alendronate and calcium (1000 mg/day), 14 patients in the second group used every other day 10 mg alendronate and calcium and 17 patients in the third group were given intranasal salmon calcitonin and calcium. At the baseline, sixth and twelfth months, BMD was measured at lumbar spine (L_2–4), femoral neck and Ward's triangle zone by means of dual energy X-ray absorptiometry (LUNAR).

Results. In daily and every other day alendronate and calcitonin groups there was a significant increase in BMD at lumbar spine (p = 0.004, p = 0.001, p = 0.04), but no difference at the femoral neck (p > 0.05) at the end of twelve months. When the groups were compared with each other, no significant differences in BMD levels at lumbar spine, femoral neck and Ward's triangle were found (p > 0.05).

Keywords:

• Male osteoporosis
• alendronate
• calcitonin
• bone mineral density

Introduction

Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality [1]. It is more often considered as a disease affecting women. A greater bone size with a greater peak bone mass, shorter life span and no equivalence of menopause are the major reasons for lower incidence of osteoporosis in the male [2]. However, 4–6% of men older than 50 years of age have osteoporosis and 33–47% have osteopenia according to WHO criteria, and about one third of all hip fractures occur in men [2]. Prevalence of vertebral deformities appears to be similar in men and women and also vertebral fractures in males are becoming more frequent than had been thought [3]. Under these circumstances, osteoporosis in men is estimated to be an important health and economic problem in near future.

Alendronate is the first bisphosphonate studied extensively in men [2]. It is a potent inhibitor of osteoclast-mediated bone resorption and has been shown to reduce the incidence in both vertebral and non-vertebral fractures [3]. Nasal salmon calcitonin is also a well known agent used in osteoporosis with inhibitory action on osteoclasts. Although calcitonin reduces the incidence of vertebral fracture, not enough data has been gathered about hip fractures [4]. Also it is an alternative in the treatment of osteoporosis in men with gastro-oesophageal reflux and dyspeptic symptoms.

The aim of this study is to investigate the effects of twelve months of treatment with daily 10 mg alendronate, every other day 10 mg alendronate and daily 200 IU nasal calcitonin on bone mineral density (BMD) scores in osteoporotic men.

Patients and methods

Forty-six men with primary osteoporosis were enrolled in this single-centred, open label, prospective study. The inclusion criteria for individuals were: (1) low BMD scores of at least one of the lumbar spine, femoral neck or femoral Ward's triangle region (corresponding to T scores of ≤−2.5 SD); (2) no specific risk factors for secondary osteoporosis. No patient had ever previously received bisphosphonate, nasal calcitonin or medications known to affect bone metabolism (thyroid hormone therapy, glucocorticoids, anabolic hormones, diuretics and anticonvulsants for more than one month within the previous six months).

Forty-six men with primary osteoporosis were randomly allocated to three groups. fifteen patients in the first group received daily 10 mg alendronate (Fosamax®, MSD), 14 patients in the second group used every other day 10 mg alendronate and 17 patients in the third group were given intranasal salmon calcitonin at a dosage of 200 IU/day (Miacalcic®, Novartis). All patients received a daily supplement of 1000 mg calcium. BMD was measured at lumbar spine (L_2–4), femoral neck and femoral Ward's triangle zone by means of dual energy X-ray absorptiometry (DEXA, LUNAR) at the baseline, sixth and twelfth months. Medical history and physical examination were also obtained in each visit.

The local hospital ethics committee had approved the study proposal and informed consent was obtained from each subjects.

Subjects were instructed to take alendronate with a full glass of water while in an upright position and on an empty stomach in the morning at least 30 minutes before the first food or drink of the day. Calcitonin was given daily in the morning as a nasal spray with one puff in one nostril.

At baseline all patients' fasting blood glucose, blood urea nitrogen (BUN), creatinin, liver function tests (ALT, AST), calcium, phosphorus, alkaline phosphotase, total blood count and thyroid functions were evaluated by laboratory tests. Routine biochemical tests were repeated at the end of twelve months' treatment.

Patients' back pain and depression levels were evaluated respectively by using visual analogue scale (VAS) and Beck depression scale (BDS) at baseline, sixth and twelfth months.

Statistical analysis

Within each group, differences in BMD were compared by using Friedman test and between groups differences in BMD over time were analysed by using Kruskal-Wallis analysis of variance. Statistical significance is defined by p values less than 0.05. All analyses were performed using SPSS 10 for Windows.

Results

Forty-six men enrolled in the study were randomly assigned to three groups. There were 15, 14 and 17 patients in the groups respectively.

The baseline demographic and pretreatment laboratory values are shown in Table I and II respectively. No statistical significance was found between groups (p > 0.05).

Table I.  Demographic characteristics of patients.

	Group 1 (n = 15)	Group 2 (n = 14)	Group 3 (n = 17)
Age (years)	63 ± 11	61 ± 11	65 ± 10
Height (cm)	165 ± 4.8	165 ± 4.9	169 ± 4.6
Weight (kg)	65.6 ± 7.2	64.6 ± 7.3	69.9 ± 8.6
BMD (g/cm^2)
Lumbar (L2–4)	0.89 ± 0.12	0.88 ± 0.18	0.96 ± 0.12
Femoral neck	0.77 ± 0.08	0.78 ± 0.1	0.76 ± 0.1
Ward's triangle	0.63 ± 0.1	0.64 ± 0.12	0.64 ± 0.08

Table II.  Biochemical parameters.

	Group 1 (n = 15)	Group 2 (n = 14)	Group 3 (n = 17)
Glucose (mg/dl)	128 ± 10	134 ± 15	124 ± 8
BUN (mg/dl)	13.8 ± 7	14 ± 2.8	15.3 ± 3.6
Creatinine (mg/dl)	0.7 ± 0.2	0.6 ± 0.1	0.7
AST (U/l)	20.7 ± 5	23 ± 6	21 ± 4
ALT (U/l)	19.7 ± 7.3	20 ± 8.2	20 ± 7
Ca (mg/dl)	9.3 ± 0.3	9.5 ± 0.5	9.6 ± 0.5
P (mg/dl)	3.1 ± 0.3	3.3 ± 0.4	3.1 ± 0.4
ALP (U/l)	234 ± 18	250 ± 24	246 ± 14
Haemoglobin (g/dl)	12.8 ± 3	13 ± 4	13.1 ± 4

At the end of six months there was a statistically significant increase in BMD of the lumbar spine in daily and every other day alendronate groups (p = 0.01, p = 0.008 respectively), however, no significant difference in the calcitonin group (p = 0.225). At the sixth month, no significant difference was seen in femoral neck BMD levels of all groups (p > 0.05).

At the end of twelve months, there were a statistically significant increase in lumbar spine BMD values in all groups compared to their baseline (group 1: p = 0.004, group 2: p = 0.001, group 3: p = 0.04) (Figure 1). Patients on daily and every other day alendronate showed an increase in spine BMD 4.3% and 4.9% compared with 4% in the calcitonin group. In the calcitonin group, statistical significance in lumbar BMD levels was not as prominent as the daily and every other day alendronate groups. Femoral neck BMD values showed no difference at the end of twelve months in all groups (p = 0.42, p = 0.67, p = 0.056). Overall there was no statistical difference in BMD values at lumbar spine, neck of femur and Ward's triangle between groups (Tables III, IV, and V).

Figure 1. Bone mineral density level of lumbar spine.

Table III.  BMD and T score levels in the daily alendronate group.

	Baseline	Sixth month	Twelfth month	p
BMD (g/cm^2)
Lumbar	0.89 ± 0.12	0.9 ± 0.14	0.9 ± 0.15	0.004
Femoral neck	0.7 ± 0.08	0.7 ± 0.09	0.7 ± 0.09	>0.05
Ward's	0.63 ± 0.1	0.6 ± 0.11	0.6 ± 0.11	>0.05
T scores
Lumbar	−2.6 ± 0.9	−2.2 ± 1	−2 ± 1	<0.001
Femoral neck	−2.2 ± 0.5	−2.2 ± 0.8	−2.2 ± 0.9	>0.05
Ward's	−2.3 ± 0.7	−2.3 ± 0.7	−2.2 ± 0.9	>0.05

Table IV.  BMD and T score levels in the every other day alendronate group.

	Baseline	Sixth month	Twelfth month	p
BMD (g/cm^2)
Lumbar	0.88 ± 0.18	0.9 ± 0.14	0.9 ± 0.15	0.001
Femoral neck	0.78 ± 0.1	0.7 ± 0.09	0.7 ± 0.09	>0.05
Ward's	0.64 ± 0.12	0.6 ± 0.11	0.6 ± 0.11	>0.05
T scores
Lumbar	−2.6 ± 0.9	−2.2 ± 1	−2 ± 1	<0.001
Femoral neck	−2.2 ± 0.5	−2.2 ± 0.8	−2.2 ± 0.9	>0.05
Ward's	−2.3 ± 0.7	−2.3 ± 0.7	−2.2 ± 0.9	>0.05

Table V.  BMD and T score levels in calcitonin group.

	Baseline	Sixth month	Twelfth month	p
BMD (g/cm^2)
Lumbar	0.96 ± 0.1	0.97 ± 0.1	1 ± 0.7	0.04
Femoral neck	0.76 ± 0.1	0.77 ± 0.9	0.79 ± 0.9	>0.05
Ward's	0.64 ± 0.08	0.65 ± 0.8	0.68 ± 0.1	0.002
T scores
Lumbar	−2.1 ± 0.9	−1.8 ± 0.9	−1.7 ± 0.7	<0.05
Femoral neck	−2.1 ± 0.5	−2 ± 0.7	−1.9 ± 0.5	>0.05
Ward's	−2.2 ± 0.5	−2.1 ± 0.2	−2 ± 0.5	<0.01

Visual analogue and Beck depression scale scores revealed pronounced difference at the sixth and twelfth months compared to their baseline within each group (p < 0.001). Significant improvement was also observed between the sixth and twelfth months within each group (p < 0.05) (Table VI).

Table VI.  Beck depression scale scores.

	Group 1	Group 2	Group 3	p value
Baseline	12.6 ± 5.9	9.7 ± 5.3	12.5 ± 3.5	0.81
Sixth month	11.4 ± 5.6	8.7 ± 5.1	11.7 ± 3.4	0.81
Twelfth month	10.1 ± 5.2	7.7 ± 4.2	11.2 ± 3.5	0.51
p value	<0.001	<0.001	<0.001

Oral alendronate and nasal calcitonin treatments were both well tolerated by the patients. Three patients in the 10 mg/day alendronate group and one patient in the every other day alendronate group had mild dyspepsia. Two patients in the nasal calcitonin group reported mild flushing on the face. None of these adverse effects necessitated patients to give up the treatment.

Routine biochemical testing performed at the end of the treatment revealed no abnormal values in all groups.

Discussion

Although osteoporosis is increasingly recognized as an important health and socioeconomic issue, male osteoporosis is an underdiagnosed and undertreated problem worldwide. Prevalence of vertebral deformities appears to be similar in men and women [3],[5] and about one third of all hip fractures occur in men [3]. Moreover morbidity and mortality from hip fractures is higher in men than in women [6] In the FIT study, alendronate at the end of the first year reduced vertebral fracture by 59% (p = 0.03 versus placebo), hip fracture by 63% at 18 months in women with or without prior fractures (p = 0.014 versus placebo) and multiple vertebral fractures by 90% at three years in women with prior fractures (p < 0.001 versus placebo). The increase in BMD in lumbar vertebra, femoral neck and trochanter were respectively 6.2%, 4.1% and 6.1% (p < 0.001 for all) [7]. In the PROOF study, intranasal calcitonin with the 200 IU dose only increased BMD by 1–2% compared to placebo, but the risk of new vertebral fractures was decreased by 33%[4].

While a number of drugs have been widely available in the clinical management of postmenopausal osteoporosis, relatively few studies have examined the effectiveness of different antiresorptive agents in male osteoporosis. Alendronate is the first and most extensively studied bisphosphonate in men [1],[8],[9]. It has been shown to increase bone mineral density and decrease the incidence of vertebral fractures in osteoporotic men [8]. Ringe et al., in an alendronate treatment study of 134 men with osteoporosis, found a mean increase of 11.5% in lumbar spine BMD with daily 10 mg alendronate at the end of 3 years [10].

Nasal salmon calcitonin is an inhibitor of osteoclastic activity used in treatment of metabolic bone diseases. It has been extensively used in treatment of osteoporosis; nowadays its place in treatment protocols has been changed. Data about its use in male osteoporosis are quite few. Trovas et al., in a twelve-month double blind, placebo controlled trial, examined the effects of nasal salmon calcitonin in 28 men with primary osteoporosis. They showed suppression of bone resorption markers with twelve months' nasal calcitonin use and concluded that nasal salmon calcitonin is effective in increasing lumbar BMD (7%) and reducing bone turnover in men with osteoporosis [11].

In the present study, the effects of daily 10 mg alendronate, every other day 10 mg alendronate and daily 200 IU nasal salmon calcitonin treatment on BMD scores were investigated in osteoporotic men. In agreement with previous studies [10],[12],[13] there was statistically significant progression in lumbar spine BMD levels of both alendronate groups (daily 10 mg alendronate and every other day 10 mg alendronate) compared to their baseline. Although in lesser degree than both alendronate groups statistically significant increase in lumbar BMD is also observed in the nasal calcitonin group compared to its baseline. None of the daily 10 mg alendronate, every other day 10 mg alendronate and daily 200 IU nasal salmon calcitonin treatment regimens resulted in a change in femoral neck BMD. Concerning the effects of alendronate on femoral neck our results were similar to Weber et al. [12], who found no increase in femoral neck BMD. Trovas et al. [11] also found no change in femoral neck BMD with nasal salmon calcitonin in men. On the other hand, Toth et al. showed that 200 IU of intranasal calcitonin daily for one year produced an increase in BMD at lumbar spine and femoral neck [14]. Some osteoporotic patients may report pain, particularly in their back. Rarely, it is associated with depression due to changes in body image and reduced survival rates due to fractures. We recorded decreased back pain in both alendronate and salmon calcitonin treatment groups pronounced from the sixth month of treatment and continuing at the twelfth month.

Both alendronate regimens (daily 10 mg alendronate and every other day 10 mg alendronate) and nasal calcitonin (200 IU/day) treatments were well tolerated by the patients. Any side effect necessitating cessation of treatment was not recorded during twelve months in all groups.

In conclusion, our study revealed that daily 10 mg alendronate, every other day 10 mg alendronate and 200 IU/day calcitonin all increased BMD scores of the lumbar spine (4.3%, 4.9% and 4% respectively), in osteoporotic men at the end of one year of treatment. However femoral neck BMD scores did not change significantly with any of the medications above. Since most of the studies in osteoporotic women investigating the effects of alendronate and calcitonin on BMD reveal an increase in both spinal and femoral region. Our findings on hip BMD can be explained with the small amount of patients investigated or different mechanisms in men. Long term follow-up studies are necessary to evaluate the effects of antiresorptive agents on BMD, fracture reduction rate and bone quality in men.