Skeletal fluorosis secondary to methoxyflurane use for chronic pain

Abstract

 

Skeletal fluorosis is rare and occurs secondary to chronic high amounts of fluoride consumption, manifesting as diffuse osteosclerosis, skeletal pain, connective tissue calcification, and increased fracture risk. Methoxyflurane is a volatile, fluorinated hydrocarbon-inhaled analgesic, and the maximum recommended dose is 15 mL (99.9 % w/w) per wk. A rodent study found increased skeletal fluoride after methoxyflurane exposure. However, skeletal fluorosis secondary to methoxyflurane use in humans has rarely been reported. We present the case of a 47-yr-old female with diffuse osteosclerosis secondary to fluorosis from methoxyflurane use for chronic pain, presenting with 3 yr of generalized bony pain and multiple fragility fractures. Lumbar spine BMD was elevated. CT and radiographs demonstrated new-onset marked diffuse osteosclerosis, with calcification of interosseous membranes and ligaments, and a bone scan demonstrated a grossly increased uptake throughout the skeleton. Biochemistry revealed an elevated alkaline phosphatase and bone turnover markers, mild secondary hyperparathyroidism with vitamin D deficiency, and mild renal impairment. Zoledronic acid, prescribed for presumed Paget’s disease, severely exacerbated bony pain. Urinary fluoride was elevated (7.3 mg/L; reference range < 3.0 mg/L) and the patient revealed using methoxyflurane 9 mL per wk for 8 yr for chronic pain. A decalcified bone biopsy revealed haphazardly arranged cement lines and osteocytes lacunae and canaliculi, which was consistent with an osteosclerotic process. Focal subtle basophilic stippling around osteocyte lacunae was suggestive of fluorosis. Although fluorosis is not a histological diagnosis, the presence of compatible histology features was supportive of the diagnosis in this case with clinical–radiological–pathological correlation. Skeletal fluorosis should be considered as a cause of acquired diffuse osteosclerosis. Methoxyflurane should not be recommended for chronic pain. The risk of repeated low-dose exposure to fluoride from methoxyflurane use as analgesia may be greater than expected, and the maximum recommended dose for methoxyflurane may require re-evaluation to minimize skeletal complications.

Abbreviated abstract

Skeletal fluorosis is rare and occurs secondary to chronic high amounts of fluoride consumption, manifesting as diffuse osteosclerosis, skeletal pain, connective tissue calcification, and increased fracture risk. We present the case of a 47-yr-old female with skeletal fluorosis secondary to long-term methoxyflurane for chronic pain. The risk of repeated low-dose exposure to fluoride from methoxyflurane use for analgesia may be greater than expected, and the maximum recommended dose for methoxyflurane may require re-evaluation to minimize skeletal complications.

Introduction

Skeletal fluorosis is rare and occurs secondary to chronic high fluoride consumption, ^1,2 manifesting as diffuse osteosclerosis, skeletal pain limiting mobility,³ connective tissue calcification, and increased fracture risk.⁴ Fluoride undergoes rapid gastrointestinal absorption, subsequently integrating into calcified tissues in the crystal lattice and acting as an anabolic agent uncoupled from bone resorption.^5,6 Endemics of skeletal fluorosis have been reported secondary to toxic levels of fluoride in water, such as industrial exposure or wells.³ We report a rare case of skeletal fluorosis secondary to methoxyflurane, a fluorinated hydrocarbon inhalational analgesic.⁷

Case description

A 47-yr-old female presented with 3 yr of generalized bony pain involving the axial and appendicular skeleton on a background of migraines, seizures, depression, and endometriosis. The patient had recently experienced bilateral low-trauma foot and acetabulum fractures; however, BMD was elevated in the lumbar spine (Table 1). Her height was 154 cm, with a BMI of 22.3. There was no family history of skeletal abnormalities. Biochemistry revealed elevated alkaline phosphatase and bone turnover markers, with normocalcemia and mild secondary hyperparathyroidism due to vitamin D insufficiency and an estimated glomerular filtration rate of 78 mL/min/1.73 m² (Table 2). No gastrointestinal symptoms were present.

Table 1.

Dual-energy X-ray absorptiometry results of our patient.

	BMD (g/cm 2 )	T-score	Z-score
Lumbar spine	1.435	+3.5	+4.0
Left femoral neck	0.767	−0.7	−0.3
Right femoral neck	0.792	−0.5	−0.1
Left distal 1/3 forearm	0.626	−1.1	−0.6

Table 2.

Biochemistry results.

	Patient’s results	Reference range
Corrected calcium	2.34 mmol/L (9.38 mg/dL)	2.15–2.55 mmol/L (8.62–10.22 mg/dL)
Phosphate	1.41 mmol/L (4.37 mg/dL)	0.8–1.5 mmol/L (2.48–4.65 mg/dL)
Magnesium	0.88 mmol/L (2.14 mg/dL)	0.70–1.10 mmol/L (1.70–2.67 mg/dL)
Estimated glomerular filtration function	78 mL/min/1.73m2	>90 mL/min/1.73m2
Alkaline phosphatase	5467 nkat/L (328 U/L)	333–1750 nkat/L (20–105 U/L)
Parathyroid hormone	18.2 pmol/L (172 pg/mL)	1.7–10.0 pmol/L (16–94 pg/mL)
25-hydroxyvitamin D	42 nmol/L (17 ng/mL)	>50 nmol/L (>20 ng/mL)
Thyroid stimulating hormone	1.9 mU/L (1.9 uU/mL)	0.35–4.94 mU/L (0.35–4. 94 uU/mL)
C-terminal telopeptide of type I collagen	3.6 ng/mL (3600 ng/L)	0.15–0.8 ng/mL (150–800 ng/L)
Procollagen type 1 amino-terminal peptide	480 ng/mL (480 μg/L)	15–70 ng/mL (15–70 μg/L)
Serum lead	0.02 μmol/L (0.414 μg/dL)	0–0.24 μmol/L (0–4.97 μg/dL)
24 h urine fluoride	7.3 mg/L	<2.0 mg/L pre-shift and < 3.0 mg/L post-shift16
Creatinine-adjusted urinary fluoride	19.2 mg/g	<4 mg/g post-shift.17

The CT of the spine demonstrated marked diffuse osteosclerosis with focal ossification and thickening at the junctions of trabeculae, which was not evident 10 yr prior (Figure 1). Furthermore, there was connective tissue calcification with focal new bone formation at the vertebral insertion of the anterior longitudinal ligament and ossification along ligamentum flavum (Figure 1B). A technetium-99 m hydroxy diphosphonate bone scan demonstrated generalized markedly increased uptake (Figure 2). Forearm radiograph revealed ossification of the interosseous membrane (Figure 3). A sand-like granular pattern of the medullary cavity due to bone deposition and thickening at the junctions of trabeculae was seen on the foot radiograph (Figure 4). In addition, the patient experienced connective tissue calcification with focal new bone formation at the vertebral insertion of the anterior longitudinal ligament and ossification along the ligamentum flavum (Figure 1B).

Figure 1.

Comparison of sagittal CT image of the spine from 2010 and 2023. (A) Lumbar spine from 2010. Normal bone density and architecture with preserved corticomedullary differentiation. (B) Thoracic and lumbar spine from 2023. Marked diffuse osteosclerosis. Note focal new bone formation at the vertebral insertion of the anterior longitudinal ligament (arrow), and ossification along the ligamentum flavum (star).

Figure 2.

Whole-body technetium-99 m hydroxy diphosphonate bone scan. Uniform diffuse uptake throughout the axial and appendicular skeleton with no activity in the urinary tract or soft tissues compatible with a “super scan.”

Figure 3.

Anteroposterior radiograph of the right forearm. Ossification of the interosseous membrane is a common feature of fluorosis and usually occurs on the radial side³⁰ (arrow).

Figure 4.

Lateral radiograph of the foot. Bone deposition and thickening at the junctions of trabeculae lead to a sand-like granular pattern of the medullary cavity (arrow).

Zoledronic acid infusions for presumed Paget’s disease severely exacerbated pain. Although there was mild secondary hyperparathyroidism, this was thought to be insufficient to cause marked diffuse osteosclerosis. Her serum lead level and a BM aspirate were unremarkable, however, urinary fluoride was more than double the reference range (Table 2). The patient revealed using methoxyflurane for migraines and post-ictal muscle cramps in an attempt to avoid hospitalization and manage chronic pain, while she resided in a remote area with limited health-care access; initially, 3 mL once per month for 1 yr, then 3 t a wk (9 mL/wk) for the past 8 yr. Notably, she consumed bottled water and other potential sources of fluoride were excluded.

A thoracic spine decalcified bone biopsy obtained at decompression laminectomy for an intercurrent symptomatic arachnoid cyst and adhesions revealed thickened lamellar bony trabeculae (Figure 5A). Haphazardly arranged hematoxylin-positive cement lines and osteocytes lacunae and canaliculi were consistent with an osteosclerotic process (Figure 5B). Focal subtle basophilic stippling around osteocyte lacunae was suggestive of fluorosis (Figure 5C). Although this could be consistent with Paget’s disease, overall, the bone biopsy was supportive of the clinical–radiological impression of diffuse skeletal fluorosis. The patient was advised to cease methoxyflurane and was referred to a pain specialist. One month post-fluoride cessation, she represented with an exacerbation of back pain, with imaging revealing 3 new thoracic vertebral minimal trauma fractures and no nephrolithiasis. The patient has planned follow-up with repeat urine fluoride levels, urinary calcium levels, and renal tract ultrasound.

Figure 5.

Histopathology of the decalcified thoracic spine bone biopsy. (A) Low power shows marked thickening of bony trabeculae with haphazard cement lines (H&E, 40×). (B) Haphazard hematoxylin-positive cement lines and osteocytes lacunae and canaliculi (H&E, 100×). (C) Subtle basophilic stippling around osteocyte lacunae (H&E, 200×).

Discussion

Methoxyflurane is a volatile fluorinated hydrocarbon⁷ inhalational analgesic that is predominantly used for emergency pre-hospital settings and is administered by a handheld device.⁴ Methoxyflurane was previously utilized for anesthesia at higher doses, however, since 2005, methoxyflurane is no longer approved by the US Food and Drug Administration due to nephrotoxicity and hepatotoxicity.⁸ Outside the United States, methoxyflurane is still utilized as an analgesic agent at lower doses for its rapid action and short-term pain relief.⁴ Methoxyflurane is available in 1.5- and 3-mL bottles, which consist of 99.9% methoxyflurane w/w.⁹ The maximum recommended methoxyflurane dose is 6 mL/d; however, consecutive days of administration are not recommended, and the maximum total weekly dose is 15 mL.⁹ Currently, in Australia, the prescription of methoxyflurane is limited to emergency treatment supply only (doctor’s bag) with a limit of 1 × 3 mL vial per mo by the Pharmaceuticals Benefits Scheme. A rodent study found increased skeletal fluoride after methoxyflurane exposure^10,11; however, skeletal fluorosis secondary to methoxyflurane in humans has been rarely reported.¹²

Fluoride biomarkers include blood, urine, saliva, nails, and bone surface.¹³ Urine fluoride is considered as the most useful biomarker of daily contemporary fluoride exposure,¹⁴ as the concentration of fluoride is expected to be the highest in the urine due to its primarily renal excretion.¹⁵ Urine collection over 24 h is recommended to account for diurnal variations.¹³ The American Conference of Governmental Industrial Hygienists recommends urine fluoride Biological Exposure Index of <2 mg/L (105 μmol/L) pre-shift and 3 mg/L (158 μmol/L) post-shift for the prevention of skeletal fluorosis,¹⁶ which our patient greatly exceeded. Additionally, a creatinine-adjusted urine fluoride level of <4 mg/g post-shift has been suggested by the Deutsche Forschungsgemeinschaft to prevent osteosclerosis.¹⁷ The US Environmental Protection Agency suggested a fluoride reference dose of 0.06 mg/kg/d to develop fluorosis,¹⁸ and fluoride consumption of >10 mg/d for at least 10 yr have been associated with skeletal fluorosis.^1,2

Various methodologies have been suggested to evaluate fluoride exposure from methoxyflurane. Serum concentrations of methoxyflurane, when used as an analgesic, have been reported to vary between 0.6 and 2.6 mg/100 mL.⁷ The prescribing information reports that a 3 mL methoxyflurane dose leads to serum inorganic fluoride ion levels <10 μmol/L.¹⁹ The maximum recommended dose led to a minimum alveolar concentration (MAC) of 0.59 MAC-hours, and exposure to methoxyflurane ≤2.0 MAC-hours resulted in serum fluoride ≤40 μmol/L.⁷ A urine fluoride concentration of 43.13 μmol/L has been described in neonates of women receiving methoxyflurane for analgesia during labor.²⁰ Although serum and urine fluoride concentrations resulting from methoxyflurane use have been reported, direct quantification of fluoride exposure from methoxyflurane is lacking, perhaps due to its vaporized form limiting its assessment.

Although our patient utilized methoxyflurane 9 mL per wk, which is well below the maximum recommended dose of 15 mL per wk, our patient’s prolonged regular use for 9 yr may have contributed to the significant cumulative fluoride exposure. Our patient experienced skeletal fluorosis with diffuse osteosclerosis, connective tissue calcifications, and mild renal impairment without hepatotoxicity. The patient’s lumbar spine BMD was elevated, but not that of the total hip or the femoral neck, which is consistent with previous literature demonstrating elevated lumbar spine but variable femoral neck and total hip BMD.²¹ This has been hypothesized due to the cancellous bone having greater osteosclerosis from fluoride compared to cortical bone.²¹ The current recommended maximum dose of methoxyflurane use as an analgesic is significantly lower than the doses associated with nephrotoxicity.⁷ However, the risk of repeated low-dose exposure to fluoride from methoxyflurane use as analgesia may be greater than expected, given (i) one-third of the methoxyflurane metabolite after hepatic metabolism remains in the body for 9 d following exposure,²² (ii) fluoride integrates into the skeletal framework with a stable crystal lattice prolonging its presence,⁵ and (iii) iatrogenic hepatic enzyme induction may amplify fluoride exposure.²³

Skeletal fluorosis is prolonged with variable reversibility after fluoride cessation. Serum fluoride normalized after 8 mo and urine fluoride normalized after 9 yr in 1 case,²⁴ while serum fluoride level plateaued at double the upper limit of normal after 8–11.5 yr in 2 other cases.²⁵ Regression of radiographic ossification has been reported after 9 yr of fluoride cessation²⁴; however, significantly elevated bone fluoride content after 8.5 yr, although improved, has been demonstrated in an iliac crest bone biopsy.²⁴ A decline in BMD has been reported after 1 yr of fluoride cessation.^26,27 Improvements of joint pain^24,25 and bone pain²⁸ have been observed shortly after fluoride cessation before radiological improvements. Monitoring for nephrolithiasis is recommended as urinary calcium excretion can increase to reduce the excess skeleton mineral post-fluoride cessation.²⁴

In conclusion, skeletal fluorosis is a rare cause of acquired diffuse osteosclerosis, and inhaled methoxyflurane exposure should be considered as a potentially reversible cause. Chronic excessive fluoride exposure should be considered for individuals with diffuse osteosclerosis, skeletal pain, connective tissue calcification, insufficiency fractures, nephrotoxicity, and hepatotoxicity. Reported histological features of fluorosis include thickened trabeculae, increased cement lines, and basophilic mottling around osteocyte lacunae²⁹ as seen in this case. Although fluorosis is not a histological diagnosis, the presence of compatible histology features was supportive of the diagnosis in this case. Our case highlights the importance of a detailed drug history and clinical–radiological–pathological correlation. Furthermore, our case demonstrates clinically significant adverse events of skeletal fluorosis with chronic methoxyflurane use at doses below the current maximum recommended dose, warranting re-evaluation of the current maximum recommended dose. Use of methoxyflurane for the treatment of chronic pain should be avoided.

Author contributions

Yeung-Ae Park (Writing—original draft [lead], Writing—review & editing [equal]), Walter E. Plehwe (Writing—review & editing [supporting], Investigation [lead]), Kapilan Varatharajah (Writing—review & editing [supporting], Investigation [supporting]), Sophie Hale (Writing—review & editing [supporting], Investigation [supporting]), Michael Christie (Writing—review & editing [supporting], Investigation [supporting]), and Christopher J. Yates (Writing—review & editing [equal], Investigation [supporting])

Funding

None declared.

Conflicts of interest

None declared.

Data availability statement

Data available on request.

Informed patient consent for publication

Completed.