Elevated Bone Resorption Markers in Patients With Migraine: A Case Series

Dear Editor,

Migraine is a debilitating headache characterized by pulsating quality, and is often on one side of the head and aggravated by movement. Excessive bone resorption due to osteoclast activity can lead to diminished bone strength. Although it may appear ambiguous, a recent study by Wu et al.¹ suggested a pathophysiological link between osteoporosis and migraine.

Magnesium and vitamin D levels are known to be vital for proper bone function, while they may regulate the frequency of migraines² by shaping nociceptive processes in unmyelinated calcitonin gene-related peptide (CGRP)-positive neurons, a process also influenced by ovarian hormones.³ Inflammatory mediators such as certain interleukins and tumor necrosis factor-α contribute to endothelial dysfunction and pain pathways in migraine,⁴ and exerts a significant influence on bone turnover that induces osteoporosis. Moreover, inflammatory mediators play roles in activating the trigeminovascular system, which in turn releases proinflammatory substances, particularly CGRP. Elevated CGRP levels have also been found in subjects with osteoporosis and may indirectly regulate osteoclast activity.⁵ Furthermore, both of these diseases include high prevalence rates of migraine and osteoporosis in patients with inflammatory bowel disease,⁶ possibly due to multiple factors such as gut microbiota profile, stress hormones, nutrients, and neuropeptides that affect different intestinal bacterial strains.⁷ Finally, migraine causes social withdrawal with a consequent reduction in motor activity, and less exposure to light due to a reaction from photophobia.

We present 19 patients with migraine who presented pathological bone turnover. In our private clinic, we evaluated 19 Italian adult patients (15 fertile females and 4 males) aged between 20 and 40 years over the course of 1 year. These patients were suffering from migraine with aura or migraine without aura according to the third edition of the International Classification of Headache Disorders (ICHD-3), or one or more migraine attacks per month for at least 6 months. All subjects did not show associated comorbidities or present a history of fragility fracture. All patients were not sedentary, followed a Mediterranean diet, and had body mass indices of 18.42–25.12 kg/m² (Table 1). However, we did not further detail exercise capacity, smoking, or alcohol consumption in detail. None of the patients had taken prophylactic or contraceptive therapies within the past 5 years, and they utilized nonsteroidal anti-inflammatory drugs or triptans for symptomatic therapy. The sex, age, and migraine frequency distributions are listed in Table 1.

Table 1. Demographics and clinical characteristics of patients with migraine with pathological bone turnover.

No.	Sex	Age (yr)	Age at diagnosis (yr)	Days with migraine per month	Medication, days/month (NSAIDs or triptans)	Prophylaxis therapy or contraceptive pills	Body mass index (kg/m2)	Vitamin D level, (ng/mL)†	C-terminal telopeptide (ng/mL)‡
1	f	20	15	8	8	No	20.86	Normal	0.677
2*	f	29	24	5	4	No	18.42	19.2	0.691
3	f	36	34	10	10	No	19.26	14.2	0.686
4	f	25	24	3	3	No	20.51	19.3	0.691
5*	m	20	19	30	30	No	22.53	24.4	0.780
6*	f	20	18	4	4	No	21.35	Normal	0.676
7	f	40	37	10	10	No	22.67	22	0.584
8	f	20	18	1	1	No	19.43	19.1	1.201
9*	f	31	21	6	5	No	21.68	27.6	1.300
10	m	25	18	12	12	No	18.78	11.4	0.586
11	m	20	19	25	20	No	24.58	Normal	0.827
12	f	40	14	10	10	No	23.38	16.7	0.930
13	m	26	21	10	10	No	23.69	17	0.639
14	f	27	21	4	4	No	22.31	Normal	0.593
15	f	37	26	5	3	No	19.32	Normal	1.030
16	f	26	23	7	6	No	25.12	18.26	0.721
17	f	23	19	2	2	No	21.60	Normal	0.632
18	f	24	22	7	7	No	22.76	19.43	0.589
19	f	25	20	3	3	No	21.87	Normal	0.598

^*Patients who received DEXA (see main text for details); ^†Normal >30 ng/mL; ^‡Normal <0.573 ng/mL.

DEXA, dual energy X-ray absorptiometry; f, female; m, male; NSAIDs, non-steroidal anti-inflammatory drugs.

The findings of physical and neurological examinations were unremarkable for all patients. Considering the frequent vitamin D deficiency in patients with migraine, we also performed bone profile laboratory tests. Serological tests were performed under fasting conditions and without taking into account the menstrual cycle for females. Complete blood count, calcium, phosphate, creatinine, alkaline phosphatase, aminotransferases, thyroid-stimulating hormone, and parathyroid hormone levels were within their respective normal ranges. Vitamin D deficiency or insufficiency (defined as <20, and ≥20 and <30 ng/mL 25[OH]D, respectively) was present in 12 patients. All patients presented high serum levels of C-terminal telopeptide (CTX), defined as pathological at >0.573 ng/mL in males and premenopausal females. This value was established in accordance with the reference intervals of our laboratories and similar cohorts in other studies.⁸

We collected samples throughout 1 year without any particular seasonal differentiation. Vitamin D deficiency and pathological CTX were slightly more common in spring and winter than in summer and fall (86%, 83%, 71%, and 57%, respectively). Among the patients with elevated CTX levels, four received a dual energy X-ray absorptiometry (DEXA) scan to measure the bone mineral density, which revealed pathological levels in three (20-year-old male, and 20- and 29-year-old females) and a normal level in the fourth (31-year-old female).

The observed alteration of bone resorption biomarkers in our patients and pathological bone mineral density scan in three patients with migraine highlight a possible relationship between osteopenia and migraine, as indicated by Wu et al.¹

Future studies should attempt to clarify the association between bone turnover and migraine, and further evaluate the possible effect of vitamin D treatment for patients affected by migraine, even if it does not yet have a clear impact on migraine attacks. Moreover, clinicians should consider possible consequences from prophylaxis therapies with topiramate⁹ and anti-CGRP¹⁰ in regulating the bone mass.

Availability of Data and Material

The datasets generated or analyzed during the study are available from the corresponding author on reasonable request.