INTRODUCTION

Osteomalacia (OM), a curable disease, is unfortunately underdiagnosed,¹ and can be mistaken as fibromyalgia (FM). Although there are overlapping symptoms (e.g. widespread musculoskeletal pain), these 2 conditions have different causes, diagnostic clues, and treatment approaches. However, OM is often not included in the differential when FM is considered, thereby leading to potential misdiagnosis.²

OM is a metabolic bone disease due to deficiency of vitamin D that leads to bone softening.³ This, in turn, can cause pain, with accompanying sleep disturbance/fatigue/cognitive difficulties, weakness, and fracture. OM is best confirmed by bone biops; however, the presence of specific laboratory and imaging findings can form the basis for diagnosis.⁴

FM is a chronic condition characterized by prolonged (minimum of 3 months) widespread muscle and soft tissue pain and often includes fatigue, sleep disturbances, headaches, cognitive difficulties and mood disorders. It is diagnosed by the exclusion of other diseases and via the Widespread Pain Index (WPI) and Symptom Severity Scale (SS).^5–8

The purpose of this paper is to compare and contrast FM and OM. FM is regularly used as a diagnosis but, given the “not otherwise specified” etiology and lack of objective diagnostic criteria, OM may, in fact, be the correct explanation for many of the nonspecific symptoms often attributed to FM.

METHODS

Literature searches using PubMed and Google Scholar were performed using the following key words: osteomalacia, vitamin D, vitamin D deficiency, fibromyalgia, bone quality.

RESULTS

In total, 56 human intervention trials and basic science articles were included. Articles published post-2000 were favored. All animal trials and editorials were excluded.

DISCUSSION

Osteomalacia

The possible etiologies of OM include vitamin D deficiency, calcium deficiency, and various cancers. Of these, vitamin D deficiency is the most common.⁹ Vitamin D deficiency, believed to be the most under-diagnosed nutritional deficiency,^10,11 is defined as blood levels of <20 ng/ml (equal to 50 nmol/L).¹² Rates of deficiency are estimated to be >50% of many populations.^10,11,13,14 The causes are several and include: avoidance of sunshine, frequent use of sunscreen, living at higher latitudes, cultural/religious practices of full cover clothing, having dark skin, aging, a history of bariatric surgery, and medications.

A number of drugs are known to interfere with vitamin D metabolism.¹⁵ Table 1 is arranged with greatest to least impact on vitamin D.

The natural compounds, kava kava and St. John’s wort, can similarly decrease vitamin D levels.¹⁵

Interruptions in vitamin D metabolism are not trivial. During long-term glucocorticoid therapy, 30 to 50% of patients develop osteoporosis increasing with greater dose or duration.¹⁶ 91% of HIV positive patients taking antiretrovirals who were studied had suboptimal vitamin D levels, 1/3 having severe deficiency.^17,18 Up to 50% of patients taking long term antiseizure medications will develop bone disease with fracture risk increasing 2-6 times higher compared with the average population.^19,20

Symptoms of osteomalacia include:

• Vague muscle and bone aches

• Muscle weakness

• Increased susceptibility to fracture

As with FM, the symptoms of OM are non-specific and often go unnoticed at the early stages of disease.²¹ From a mechanical viewpoint, poorly mineralized bone is weaker, more flexible and may result in bowing of the lower extremity long bones in a manner similar to rickets in children.

The reduced mineral content increases fracture risk at both the axial and appendicular skeleton. Patients with OM often display proximal muscle weakness in the lower extremity leading to a characteristic waddling gait. In severe cases, mobility can be limited. In the most extreme cases, patients become bedridden.^22,23

Vitamin D insufficiency and deficiency are prevalent worldwideTable 2 provides deficiency levels.

Osteomalacia and osteoporosis may occur alone or together. The normal human skeleton is composed of mineral components including calcium hydroxyapatite (60%), and organic material, mainly collagen protein (40%).^4,24 With osteoporosis, the collagen:mineral ratio remains in the normal reference range. The reduction of both bone quantity and quality (compromised microarchitecture) lead to brittleness and increased fracture risk. With OM, the collagen:mineral ratio is increased (less mineral relative to collagen) yielding bone softening.²⁵ OM and osteoporosis may co-occur with both contributing to fracture risk.^26,27

Unlike FM, there are objective signs of OM.^4,24 These include:

• Low serum 25-hydroxycholecalciferol

• Hypocalcemia

• Elevated alkaline phosphatase

• Decreased bone mineral density on a DXA examination

• Pseudofractures

The most accurate test for OM is a bone biopsy, a painful procedure. If OM is suspected, it is best to pursue a comprehensive metabolic panel, 25-hydroxycholecalciferol level, and a DXA (bone density test).²⁴ Anyone with a vitamin D level <20 ng/ml (the definition of deficiency) will have impaired mineralization, which is OM.

Given that vitamin D levels fluctuate between winter and summer months, noting the time of year for testing is important. For example, if a given patient’s test result is 31ng/ml at the end of summer, the levels will likely decrease to approximately 18 ng/ml at the end of winter.¹¹ This patient would be deficient for a portion of the year and insufficient most months in spite of a test result in the normal range.

Regarding DXA testing, the use of the trabecular bone score (TBS) may be an additional diagnostic clue. In severe cases of OM, alterations in bone microarchitecture will be reflected in the TBS. The current capabilities of TBS may demonstrate poor bone quality but alone is not sufficient to diagnose or monitor OM.²⁸

OM is not a uniform nor static disease. With OM due to vitamin D deficiency, the initial stage is characterized by normal serum calcium and phosphate levels and elevated alkaline phosphatase and parathyroid hormone (PTH). If the disease progresses, hypocalcemia and hypophosphatemia are seen as well as further increases in both alkaline phosphatase and PTH. In addition to low bone density, the classic radiologic findings are “codfish” vertebrae and/or a pseudofracture that most commonly occur at the ribs, scapulae, proximal femur, or pubic rami.²⁹ Pseudofractures (aka Looser’s zone) are typically bilateral and symmetrical representing areas of poor mineralization (not an actual fracture) and are asymptomatic.³⁰

With a demonstrated deficiency, the combined vitamin D sources of sunshine, food, and supplements should add at least 5000 IUs (125 mcg) per day. Because vitamin D is fat soluble, obese patients will require 2-3 times the suggested amount.³¹ Other protocols call for 50,000 IU/week/12 weeks.³² All interventions should include a retest at 12-20 weeks.

The quantities necessary to overcome deficiency will vary with individuals; however, the more important consideration is blood levels with a target of >30ng/ml of 25-hydroxycholecalciferol during all months of the year. In addition to the prescription of vitamin D, calcium should be supplemented at 500-1000 mg/day.²⁹ Although a blood level of 30 ng/ml will be sufficient to prevent or represent a target minimum level for treating OM, a 2021 consensus of researchers concluded that optimal levels be maintained above 50 ng/ml (125 nmol/L).³³

Fibromyalgia

The etiology of FM is not understood. Several partial mechanisms have been suggested such as central nervous system sensitization,³⁴ dysfunction of the hypothalamic-pituitary-adrenal axis (HPA),^35–39 and sleep disturbances.⁴⁰

Central nervous system sensitization is considered the main mechanism by some researchers. This is described as spontaneous nerve activity, enlarged receptor fields, and augmented responses to stimulus. Each of the above are difficult to measure objectively and can be a consequence of various external or psychiatric stressors leading to widespread pain and fatigue.^34,41

These same stressors also affect the HPA. FM-diagnosed patients often show elevated cortisol and adrenocorticotropic hormone levels associated with circadian rhythm disruption.⁴⁰ This is directly linked to sleep disturbances. The prevalence of FM ranged from 1.7% to 5.4% of studied populations.⁴²

The 3 main symptoms of FM are pain, fatigue, and sleep disturbances.^5,43,44 These non-specific symptoms can, and have been, associated with numerous disease states that include mental health disorders, hypothyroidism, rheumatoid arthritis, adrenal dysfunction, and multiple myeloma.⁴⁵ Given that the symptoms are vague, misdiagnosis is a genuine risk.

The symptoms of FM may include some or all of the following^7,8,46,47:

• Widespread musculoskeletal pain that lasts for more than 3 months (not explained by other illness)

• Fatigue

• Muscular tender points

• Sleep disturbances

• Morning stiffness

• Headaches

• Restless legs syndrome

• Cognitive difficulties, including memory problems and poor concentration

• Mood disorders, such as depression and anxiety

The first 2 symptoms are necessary for the diagnosis of FM.

In addition to the above-listed symptoms, the combined scores of the Widespread Pain Index (WPI) and Symptoms Severity Scale (SS) are needed for FM diagnosis.^5–8 The WPI is a questionnaire that helps assess the extent and severity of pain, while the SS evaluates other symptoms (fatigue, sleep disturbances, etc.) associated with FM. The diagnosis of FM is derived by ruling out diseases with similar symptoms and meeting specific criteria, accompanied by various other symptoms listed above.^48–50 The lack of abnormal objective measurements is important to note.

One could speculate that widespread pain would cause sleep disturbances that, in turn, would lead to fatigue, memory impairment, and/or depression. Alternatively, depression can yield fatigue, sleep disturbance, and increased pain sensitivity.

Treatment for FM typically involves a multidisciplinary approach to symptoms that are often difficult to manage. It may include medications, lifestyle changes, exercise, stress management, sleep hygiene, and counseling.⁵⁰

The medications that are often used are from the following classes: antidepressants, antiseizure, pain relievers, muscle relaxants, and sleep aids.⁵⁰ Numerous natural compounds that have been suggested for the treatment of FM. These include agmatine,⁵¹ arginine,⁵² coenzyme Q-10,⁵³ magnesium,⁵⁴ and thiamine.⁵⁵ It is important to note that just as OM is omitted from the differential diagnosis, vitamin D is not included among the list of treatment options.²⁷

CONCLUSION

FM and OM are distinct conditions with different causes and treatment approaches; however, the symptoms often overlap. (Figure 1) Some of the diagnostic confusion can be attributed to the important consideration of time-of-year testing of vitamin D. Given the substantial and predictable seasonal variability of vitamin D blood levels, a patient testing as normal in summer months may be insufficient or deficient levels for much of the year.

Figure 1.Overlapping symptoms.

• As there are no identifying lab or imaging tests; FM is a diagnosis of exclusion.

• OM can be suspected in a symptomatic patient with low serum 25-hydroxycholecalciferol, low serum calcium, and/or high alkaline phosphatase.

• OM can be directly attributed to vitamin D deficiency.

OM, a curable disease, is unfortunately underdiagnosed and too often labeled as FM. OM is often the source of widespread pain that, in turn, causes sleep disturbances and mood changes. Intervention with large doses of vitamin D to objectively increase blood levels is treating the cause as opposed to continual management of FM.

If OM is suspected, the steps to take include:

1. Refer for laboratory studies (comprehensive metabolic panel and 25-hydroxycholecalciferol).

2. Refer for DXA.

3. If confirmed, begin vitamin D treatment.

4. Retest vitamin D in 12-20 weeks.

OM is currently underdiagnosed. Given the widespread vitamin D deficiency, the confusion associated with time of year testing for 25-hydroxycholecalciferol, and the non-specific symptom overlap shared with FM, many patients currently diagnosed with FM may, in fact, be unrecognized cases of OM.