Isosorbide mononitrate versus alendronate for postmenopausal osteoporosis

1. Introduction 

Postmenopausal osteoporosis is a worldwide health problem, particularly in low-income countries where there may be a lack of public health awareness and inadequate provision of care. Osteoporosis-related vertebral and hip fractures result in an increased risk for morbidity and mortality in menopausal women [1]. It is therefore important to prevent these adverse health outcomes using suitable interventions that are effective, safe, and affordable [2], [3].

Antiresorptive therapy with bisphosphonates is used in the prevention and treatment of osteoporosis. Bisphosphonates include alendronate, risedronate, and ibandronate, and have been shown to increase bone mineral density, decrease bone resorption, and reduce fracture risk [4], [5], [6]. Systematic reviews and randomized controlled trials have shown that alendronate increases bone density in both early postmenopausal women and those with established osteoporosis. It has also been shown to reduce the risk of fractures [7], [8], [9].

Nitric oxide (NO) is a short-lived free radical. It is involved in several biological processes as a bioregulator and as a second messenger [10], and has important effects on the functioning of bone cells. Endothelial nitric oxide synthase (eNOS or NOS3) is the predominant isoform expressed in bone [11], [12]. This isoform seems to play a role in bone formation [10], [13]. It has been speculated that NO, derived from the eNOS (NOS3) pathway, mediates the beneficial effects of estrogen [14], raloxifen [15], and mechanical loading [16] to promote bone formation and reduce resorption. Furthermore, NO probably decreases bone resorption by decreasing osteoclast formation, motility, and function in vitro. In addition, it has been speculated that NO regulates bone remodeling in vivo [17].

Animal studies have shown that nitric oxide donors prevent ovariectomy-induced osteoporosis in rats [18], [19]. Preliminary studies suggest that these agents may also influence bone turnover in humans [20], [21], [22]. However, to our knowledge, the effectiveness of NO donors has not been compared to an established and approved antiresorptive agent in a clinical trial to treat postmenopausal osteoporosis.

The aim of the present study was to compare the effectiveness of a nitric oxide donor with a bisphosphonate in the management of postmenopausal osteoporosis.

3. Results 

The baseline characteristics of the study groups are shown in Table 1. There were no significant differences between the 2 groups regarding age, time since menopause, body mass index, bone mineral density, and T-score.

Table 1. Baseline characteristics of the two study groupsa

	Characteristics	Isosorbide mononitrate (n=30)	Alendronate (n=30)	P value
	Age, y	54.7±6.51	53.07±6.69	0.34
	Duration of menopause, y	8.07±3.6	7.2±3.84	0.37
	Body mass indexb	30.64±2.24	30.71±2.22	0.91
	Parity	3.07±1.6	3.93±1.48	0.03
	Average bone mineral density, g/cm2	0.213±0.05	0.215±0.05	0.53
	T-score	–3.23±0.78	–3.14±0.66	0.60

a Values are given as mean±SD. b Body mass index calculated as weight in kilograms divided by height in meters squared.

Isosorbide mononitrate was comparable to alendronate regarding the effect on bone mineral density and T-score shown by DXA at the 12-month follow-up. For BMD and T-score the mean differences were –0.005 (95% CI, –0.02 to 0.03) and 0.31 (95% CI, –0.03 to 0.64), respectively (Table 2). Bone mineral density significantly improved with isosorbide mononitrate (P=0.027) and alendronate (P<0.001), as did T-score (P=0.047 and P<0.001) (Table 3). The percentage change in BMD was 10.8% and 12.1% for isosorbide mononitrate and alendronate, respectively.

Table 2. Isosorbide mononitrate versus alendronate after 12 months

	Value	Nitrate (n=30)	Alendronate (n=30)	Mean difference	95% CI	P value
	Mean BMD, g/cm2	0.24±0.05	0.24±0.05	–0.005	–0.02 to 0.03	0.73
	T Score	–2.89±0.69	–2.58±0.59	0.31	–0.03 to 0.64	0.07

Table 3. Effect of the two interventions on postmenopausal osteoporosisa

		Baseline	After therapy	Paired difference	95% CI	% change in BMD	P value
	ISMO
	BMD, g/cm2	0.21±0.05	0.24±0.05	0.02	0.002–0.044	10.8%	0.027
	T score	–3.23±0.78	–2.89±0.69	0.34	0.215–0.472		<0.001
	Alendronate
	BMD, g/cm2	0.22±0.05	0.24±0.05	0.03	0.000–0.051	12.1%	0.047
	T score	–3.14±0.66	–2.58±0.59	0.55	0.458–0.649		<0.001

Abbreviations: ISMO, isosorbide mononitrate; BMD, bone mineral density.

a Values are given as mean±SD unless otherwise indicated.

There were no fractures during the follow-up period. Seven women (23.3%) in the isosorbide mononitrate group complained of mild headaches that were relieved by paracetamol. The women were reassured that this complaint was not an indication to stop medication. There were no reported adverse events in the alendronate group. The cost of alendronate for 12 months was EGP 2470 (approximately US $450). The cost of isosorbide mononitrate for 12 months was EGP 108 (approximately US $20).

4. Discussion 

Postmenopausal osteoporosis is a serious and well known health problem for women, and efforts to find a safe and affordable treatment with, at least, comparable effectiveness to standard therapy are underway to identify potential alternatives. New data suggest that nitric oxide donors may influence bone turnover in humans [21], [22].

The aim of the present study was to compare the effectiveness, safety, and affordability of isosorbide mononitrate (an NO donor) with alendronate, which is an established and approved antiresorptive agent used in the treatment of postmenopausal osteoporosis. The results of the present study showed that daily oral administration of isosorbide mononitrate is comparable to alendronate in terms of effects on BMD and T-score in postmenopausal women with osteoporosis.

Alendronate is an effective intervention used to treat osteoporosis. In the most recent meta-analysis, alendronate was associated with clinically important and statistically significant reductions in vertebral, nonvertebral, hip, and wrist fractures; these were observed for secondary prevention. For primary prevention, a reduction in vertebral fractures was clinically important [9].

The present study has demonstrated a small yet statistically significant improvement in BMD and T-score in postmenopausal osteoporotic women. It should be noted that the lower limit of the 95% CI for BMD in the women who received isosorbide mononitrate was 0.002. This effect may be explained by a reduction in bone resorption or an enhancement of bone formation. The molecular targets for NO action in bone cells are still not fully understood, but cGMP dependent pathways have been proposed [14].

NO seems to play a role in bone formation, evidenced by reduced bone density observed in mice with eNOS deficiency [13]. It has been speculated that there is an important interaction between eNOS and the molecular pathways involved in osteoblast differentiation and function [13]. In humans a randomized placebo controlled trial showed that mononitrate improved the biochemical marker of bone formation [22].

The effect of NO on bone resorption may involve decreasing osteoclast formation, motility, and function in vitro and regulating bone remodeling in vivo. The molecular targets for the effect of NO on osteoclasts may be through an interaction between the receptor activator of nuclear factor-kappa-B ligand (RANKL) and osteoprotegerin (OPG) [11], [12], [17]. The reduction in bone resorption is a key factor in reducing fracture risk by decreasing the rate of bone loss, by reducing the disruption in trabecular connectivity, or by decreasing the number of sites that could act as areas of weakness and enable fracture propagation.

The results of the present study show improved BMD and T-score, which can be translated clinically as a reduction in fracture risk. The results of a population-based pharmacoepidemiological case-control study demonstrated a reduced risk of fractures in users of organic nitrates. The use of nitrates was associated with an 11% reduced risk of any fracture (OR 0.89; 95% CI, 0.86–0.92) and a 15% reduced risk of hip fracture (OR 0.85; 95% CI, 0.79–0.92) [24]. However, it should be noted that the results of this nationwide study must be viewed with caution because the upper limit of the CI for the risk of any fracture or hip fracture is 0.92. Therefore, the results of both this study and the present study do not show a major impact of this intervention for the treatment of postmenopausal osteoporosis.

Alendronate has been criticized for causing upper gastrointestinal adverse events. In addition, the cost of alendronate in many low-income countries, such as Egypt, is another factor that may preclude its use. It is obvious that in a setting where the annual income of individuals is less than US $1000 per year, a therapy that costs half the annual income is not affordable. Women may not be willing to receive such an expensive medication, particularly for primary prevention of fracture. On the other hand, an affordable alternative with comparable effectiveness might improve patients' adherence to therapy.

Data from the cardiovascular literature suggest that the long-term use of nitrates (up to 20 years) is safe and not associated with any adverse long-term effects [25]. The mononitrate was well tolerated in the present study. The prevalence of headache in the study group (23%) was not a reason for discontinuing the intervention.

The effect of oral administration of a nitric oxide donor, isosorbide mononitrate, on BMD in postmenopausal osteoporotic women is comparable to alendronate. Oral nitric oxide donors may be a promising intervention, particularly in low income countries, and larger trials are needed to further investigate this finding.