Fluoride in Postmenopausal Osteopenia
Abstract & Commentary
By Michael A. Thomas, MD
Professor, Reproductive Endocrinology and Infertility,
Director, Division of Reproductive Endocrinology and
Infertility, University of Cincinnati College of Medicine
Dr. Thomas reports no financial relationships relevant to this field of study.
Synopsis: In this randomized, controlled trial, three low doses of fluoride demonstrated no significant positive effect on bone mineral density or markers of bone turnover over placebo.
Source: Grey A, et al. Low-dose fluoride in postmenopausal women: A randomized controlled trial. J Clin Endocrinol Metab 2013;98:2301-2307.
Over 12 months, these authors performed a randomized, controlled, double-blind trial where 180 postmenopausal women with osteopenia were randomized to receive either oral placebo or one of three oral fluoride (FL) tablets (2.5 mg, 5 mg, or 10 mg). To be enrolled in the study, subjects had to be postmenopausal for > 5 years and have a bone mineral density (BMD) T-score between -1 and -2.5 at either the lumbar spine, total hip, or femoral neck or they could have a BMD T-score < -2.5 at any site. Women who were actively treating their osteopenia or osteoporosis were not included. The primary endpoint was a change in lumbar spine BMD at baseline, 6 months, and 12 months. Secondary endpoints included changes in BMD in the total hip or total body as well as changes in the bone turnover markers serum procollagen type I N-terminal propeptide (P1NP) and beta-C-terminal telopeptide of type I collagen (beta-CTX). The bone turnover markers were collected at baseline, then 1, 3, and 12 months.
Of the 394 women who received study material, 180 were evenly randomized into four groups (45 subjects in each group to receive either placebo, 2.5 mg FL, 5 mg FL, or 10 mg FL). A total of 173 women completed the 12 months of study, but all 180 were included in the analysis of BMD and bone turnover. At the study’s conclusion, all four groups demonstrated no differences in change in total body weight or compliance with study drug. There was no statistical difference in the change in BMD in the lumbar spine between placebo and any of the FL doses (-0.4% with placebo, -0.7% with 2.5 mg FL, 0.0% with 5 mg FL, and 0.2% with 10 mg FL). No differences were noted in BMD at the total hip or total body with any of the FL doses compared to placebo. The bone turnover markers showed mixed results. Beta-CTX showed no differences between the four groups, but the P1NP was significantly greater in groups taking the 5 mg and 10 mg doses when compared to placebo. However, despite the P1NP findings, the authors concluded that fluoride at 2.5, 5, and 10 mg was unlikely to be an effective treatment option for women with osteopenia or osteoporosis.
The primary purpose of this study was to investigate if FL could potentially serve as a less-expensive option for the prevention and treatment of osteopenia and osteoporosis. Drugs used for these conditions act either by decreasing bone resorption, which slows bone loss, or by increasing the formation of bone. Pharmacologic agents that decrease the rate of bone resorption include calcium, vitamin D and calcitrol, estrogen, selective estrogen receptor modulators, calcitonin, bisphosphonates, and RANK-ligand inhibitors (denosumab).1 However, medications that decrease bone resorption may eventually decrease the rate of bone formation. Therefore, BMD values in bone resorptive drugs may actually plateau after a year or two of therapy, but their reduction in fracture risk may still be the same as a woman who shows a continued increase in BMD. Bisphosphonates are commonly used bone resorption agents and have been known, depending on the skeletal site, to reduce fracture risk by 50-60%. Though gastrointestinal issues are common with these medications, recent reports of bisphosphate-related osteonecrosis of the jaw has caused some patients and physicians to seek alternatives for treatment of osteopenia and osteoporosis.2
Bone-forming or anabolic agents include FL, androgens, parathyroid hormone (PTH), and strontium ranelate. PTH is an anabolic daily injection that has proven efficacy in this patient population.3 Studies have demonstrated that PTH, when given for approximately 21 months, can reduce the incidence of vertebral fractures by 60% and nonvertebral fractures by 50%. However, some have argued that PTH may be unacceptable because of its high cost. Additionally, it is has to be given subcutaneously on a daily basis for almost 2 years to see these positive effects. Therefore, FL offers a more cost-effective option and is also an anabolic alternative.
Elemental FL is plentiful and has previously been shown to stimulate osteoblast growth, increase bone formation, and increase BMD in trabecular bone.4 Other investigators have found FL to show no improvement in cortical BMD and actually increase risk of fracture in a daily dose of 34 mg. Lower doses of FL ranging from 13-27 mg showed mixed results with either protective or no effect on bone.5-7 But these lower-dose FL studies were not designed appropriately or not powered to give clear results.
The current study by Grey and colleagues offered a randomized, placebo-controlled design and was powered appropriately. And if FL was found to work at 2.5, 5, or 10 mg, it would offer a nonhormonal option without the high costs and side effects that limit use of PTH or bisphosphonates.
However, low-dose FL was not shown to have a consistent beneficial effect for the treatment of osteopenia or osteoporosis. This study clearly points out that doses of 10 mg or below should not be administered. Higher doses of FL (≥ 10 mg) are even suspect and may cause bone deminerialization in some subjects. In my opinion, low-dose FL should not be given for the prevention or treatment of osteoporosis because the data do not support its use for this condition. Also, studies using higher doses have been inconsistent and may actually cause harm. It is my hope that the door is now closed on FL as an alternative treatment for osteopenia and osteoporosis.
- Chen JS, Sambrook PN. Antiresorptive therapies for osteoporosis: A clinical overview. Nat Rev Endocrinol 2011;8:81-91.
- Khosla S, et al. Bisphosphonate-associated osteonecrosis of the jaw: Report of a task force of the American Society for Bone and Mineral Research. J Bone Min Res 2007;22:1479-1491.
- Pleiner-Duxneuner J, et al. Treatment of osteoporosis with parathyroid hormone and teriparatide. Calcif Tiss Int 2009;84:159-170.
- Farley JR, et al. Fluoride directly stimulates proliferation and alkaline phosphatase activity of bone-forming cells. Science 1983;222:330-332.
- Pak CY, et al. Slow-release sodium fluoride in the management of postmenopausal osteoporosis. A randomized controlled trial. Ann Intern Med 1994;120:625-632.
- Reginster JY, et al. The effect of sodium monfluorophosphate plus calcium on vertebral fracture rate in postmenopausal women with moderate osteoporosis. A randomized, controlled trial. Ann Intern Med 1998;129:1-8.
- Reid IR, et al. Addition of monofluorophosphate to estrogen therapy in postmenopausal osteoporosis: A randomized controlled trial. J Clin Endocrinol Metab 2007;92:2446-2452.