Osteoporosis is a leading cause of disability and death among elderly women which imposes huge economic costs on the society.12 Estrogens are integral to skeletal homeostasis, with ovarian hormone deficiency acting as critical risk factors of osteoporosis. There are strong evidences on bone-related benefits of raloxifene and hormone replacement therapy (HRT).34 However, short-term estrogen use can lead to vaginal bleeding, while long-term use can increase the risk of breast cancer, stroke and cardiovascular disease.5 The main side effects of raloxifene are vein thromboses and pulmonary embolism. As a result, many postmenopausal women favor compounds that contain non-hormonal materials like phytoestrogens as a safer option.6789 Phytoestrogens are plant substances with a structure and function similar to estradiol, which is responsible for estrogenic effect.10 Phytoestrogens have been the subject of growing attention for their bone-sparing properties.3 Foeniculum vulgare is used to treat liver obstruction, spleen and gall bladder, to alleviate digestive problems such as indigestion, colic, nausea, flatulence and bronchodilation, and to enhance memory.1112 It also includes phenolic compounds such as flavonoids (flavonoid glycosides and flavonoid aglycones), phenolic acids, hydroxycinnamic acids, coumarins and tannins.13 The results of in vitro studies have revealed the osteoprotective effect of Foeniculum vulgare extract.14 Another recent in vitro cell culture demonstrated that Foeniculum vulgare Miller seed (FvMs) could potentially prevent bone loss in postmenopausal osteoporosis by mitigating osteoclast differentiation and function.15 Nonetheless, to the best of our knowledge, the effect of Foeniculum vulgare on bone mineral content (BMC) and bone mineral density (BMD) has not been examined in human studies.

This is part of a study that assessed the effect of fennel on lipid profile and bone density in Iranian postmenopausal women. It is a randomized, double-blind, placebo-controlled clinical trial intended to compare the effectiveness of Foeniculum vulgare on bone density in menopausal women. The study was conducted in accordance with the principles of Declaration of Helsinki and approved by Ethics Committee of the Mashhad University of Medical Science.

All participants were recruited in the medical center of Imam Reza Hospital in Mashhad, Iran. Inclusion criteria were: 1) postmenopausal status, which was defined as an age of over 40 years with no vaginal bleeding for one year; 2) no regular ingestion of phytoestrogen or soy-based products (which was defined as consumption more than once a week) and 3) a normal mammogram in the last year. Exclusion criteria were: 1) use of any fluoride or bisphosphonates; 2) diseases or medications affecting bone metabolism; 3) current (or over past 6 months) use of estrogen or calcitonin; 4) history of endometrial or breast cancer; 5) any fracture, and 6) regular physical exercise or allergy to Foeniculum vulgare.

In the next step, informed consent forms were signed by participants along with verbal reassurance that participation was on a voluntary basis and that they could abandon the trial at any time. In addition, all participants were ensured about the confidentiality of information during and after the study. Sixty participants were randomly assigned to Foeniculum vulgare or placebo groups at the baseline. All participants were asked to take soft capsule three times a day - (in the morning, in the midday, and at night). Each 100-mg fennel soft capsule contained 30% fennel (Standardized to 21-27 mg anethole) combined with sunflower oil. Active ingredients of each capsule were Trans-anthol, Methyl chavicol, fenchone and stragol. Placebos were in identical shape and size, but filled with sunflower oil. These capsules were provided by Barij Essence Company. The sequence of allocation was based on a random number table. For the purpose of allocation concealment, a numbered sealed opaque plastic bottle was used, which contained enough treatment for 30 days. The allocation sequencing and packing was implemented by an employee of Barij Essence Pharmaceutical Company, who was not directly engaged in the study. In this study, participants and research team were blind to the treatment assignment.

Then, dual-energy X-ray absorptiometry (DXA; Hologic QDR-2000 Inc., Bedford, MA, USA) was utilized to measure BMD and BMC of the spine, femoral neck, intertrochanteric, and trochanter at the baseline and after three months.16 The subject screening was performed every 4 weeks to check for any side effect and compliance. To ensure compliance, patients were asked to bring their medication bottle to each visit to count the pills.

The two groups were similar in variables such as age, history of hysterectomy, body weight, body mass index (BMI) and duration of menopause at the baseline, as shown in Table 1. Side effects were observed in 6 subjects in the fennel group and 3 subjects in the placebo group. In the fennel group, subjects complained of allergic rash (n = 1), weight gain (n = 1), hypertension (n = 1) and vaginal bleeding (n = 2). Only one patient in placebo group complained of stomachache. The fennel was different from placebo in term of the mean BMD and BMC at lumbar spine (P = 0.14, P = 0.504), total hip femoral (P = 0.427, P = 0.471), trochanter (P = 0.075, P = 0.07), intertrochanter (P = 0.864, P = 0.932) and femoral neck (P = 0.439, P = 0.641) (Table 2). Also, no significant difference was observed in both groups at the baseline and three-month follow-up in terms of mean BMD and BMC at lumbar spine, total hip femoral, trochanter and intertrochanter (the data is not shown in the Table)

To the best of our knowledge, this is the first study to assess the effects of Foeniculum vulgare on BMC and BMD at the lumbar spine, femoral neck, trochanter, intertrochanter and hip femoral in post-menopausal women. According to results, Foeniculum vulgare did not have any significant positive effect on BMD and BMC over a three-month period.

Despite our efforts, no human study about the effects of Foeniculum vulgare on bone density was found. Nevertheless, considering that phytoestrogen is an active biological compound in fennel, we referred to studies that evaluated the effect of phytoestrogen on BMC and BMD. Phytoestrogens are plant compounds with properties that resemble those of estrogen. There are four main groups of phytoestrogens: isoflavones, lignans, flavonoids and coumestans.10 Isoflavones are found in soy and red clover extracts; soy isoflavones are mainly composed of genistein and daidzein, but red clover isoflavones consist of formononetin and biochanin.2 Lignans are commonly found in flaxseed11 and Foeniculum vulgare is considered as a major source of flavonoids. 13 Although the positive effect of soy isoflavone has been demonstrated in a number of studies1718 other studies have not reported any beneficial effect (Table 3).18192021 We found three studies assessing the effect of red clover on bone density. The first study was by Atkinson according to which red clover isoflavones enriched with biochanin had a beneficial effect on spine BMD and BMC, but not on hip BMD and BMC over a 24-month follow-up.3 In the second study by Clifton-Bligh, no significant difference was observed in BMD loss in the spine, hip and forearm after 24 months of treatment with red clover isoflavones enriched with formononetin.22 The third trial by Thorup showed that 150 mL/day red clover could improve bone status.23

A systematic review of five trials by Abdi revealed an increase in BMD and bone turnover after genistein administration in postmenopausal women. They also found that it was impossible to make conclusive statements about the effect of soy on BMD in postmenopausal women due to heterogeneity in formulation, phytoestrogen content, and dosage of supplement.24

The results of an in vitro study showed that Foeniculum vulgare extract in the range of 5 to 50 µg/mL might have a positive effect on cell proliferation and mineralization. In another study on the effects of FvMs on the femurs bone, 32 female mice were randomly assigned to four groups as follows: Group 1 (n = 8) was sham; Group 2 (n = 8) was ovariectomized and treated with water; Group 3 (n = 8) was ovariectomized and treated with low-dose of FvMs 30 mg/kg, and Group 4 (n = 8) ovariectomized and treated with high dose of FvMs 100 mg/kg. Compared to the control group, the group treated with low and high doses of FvMs demonstrated improved BMD and BMC in the trabecular bone.15 This is inconsistent with the findings of this study.

Foeniculum vulgare did not have any significant effect on BMC and BMD at lumbar spine and total hip in post-menopausal women. Further studies with longer durations and larger sample sizes are recommended to validate the results of this study.