Osteomalacia (OM) is frequently confused with various musculoskeletal or other rheumatic diseases, especially in patients with adult-onset widespread musculoskeletal pain because of its low prevalence and non-specific manifestations.

To facilitate the early diagnosis and etiology-specific treatment of adult-onset hypophosphatemic OM.

A retrospective review of medical records was performed to screen adult patients who visited a physiatry locomotive medicine clinic (spine and musculoskeletal pain clinic) primarily presenting with widespread musculoskeletal pain at a single tertiary hospital between January 2011 and December 2019. We enrolled patients with hypophosphatemia, high serum bone-specific alkaline phosphatase levels, and at least one imaging finding suggestive of OM.

Eight patients with adult-onset hypophosphatemic OM were included. The back was the most common site of pain. Proximal dominant symmetric muscle weakness was observed in more than half of the patients. Bone scintigraphy was the most useful imaging modality for diagnosing OM because radiotracer uptake in OM showed characteristic patterns. Six patients were diagnosed with adefovir (ADV)-induced Fanconi syndrome, and the other two patients were diagnosed with tumor-induced OM and light-chain nephropathy, respectively. After phosphorus and vitamin D supplementation and treatment for the underlying etiologies, improvements in pain, muscle strength, and gait were observed in all patients.

Mechanical pain characteristics, hypophosphatemia, and distinctive bone scintigraphy patterns are the initial diagnostic indicators of adult-onset hypophosphatemic OM. ADV-induced Fanconi syndrome is the most common etiology of hypophosphatemic OM in hepatitis B virus-endemic countries.

Osteomalacia (OM) is characterized by bone matrix hypomineralization, and its histological hallmarks include hyperosteoidosis and delayed mineralization[1]. The symptoms of OM include widespread musculoskeletal pain due to multiple bone fractures, arthralgia, skeletal deformities, height loss, and muscle weakness[2-4]. Most patients complain of generalized or localized bone pain, which usually occurs in the axial skeleton, rib cage, shoulder/pelvic girdle, and weight-bearing bones, particularly patients with adult-onset disease. Hence, patients with adult-onset OM commonly visit physiatric or musculoskeletal pain clinics rather than endocrinology or rheumatology clinics. Owing to variable clinical manifestations, non-specific radiological findings, and non-characteristic routine biochemical changes, adult-onset OM is often confused with various musculoskeletal diseases or other rheumatic diseases, and a high clinical index of suspicion is essential for diagnosing OM[4-7].

The etiologies of OM include vitamin D deficiency or resistance, calcium deficiency, hypophosphatemic disorders, and mineralization inhibitors. Although the most common cause of OM is vitamin D deficiency due to lack of exposure to the sun and inadequate intake, which results in secondary hyperparathyroidism, hypophosphatemic OM of various etiologies other than vitamin D deficiency is yet another important cause of OM[2,3,8-11].

This study assessed the clinical manifestations and laboratory and imaging findings of patients with adult-onset hypophosphatemic OM and summarized the points differentiating this disease from other musculoskeletal or rheumatic diseases. We focused on the imaging findings of the skeletal system and etiologies of hypophosphatemia to facilitate the early diagnosis of this rare, but treatable and, even curable cause of widespread musculoskeletal pain.

Eight patients with adult-onset hypophosphatemic OM, comprising three men and five women, were identified. Of the eight patients, one and seven patients were classified as having possible and definite OM, respectively, according to the Japanese diagnostic criteria[8]. The average age at diagnosis was 62 years (range, 52-76 years), and the average interval between symptom onset and diagnosis of OM was 23.8 mo (range, 6-61 mo). Two cases (patients #2 and #7) had been described in our previous case report, and these cases provided insights on the suspicion and diagnosis of OM in adult patients presenting with widespread musculoskeletal pain[15].

Imaging studies of the skeletal system

On bone scintigraphy, multiple hot uptakes were observed in all patients (Table 2). The most common sites of involvement were the thoracic vertebrae, costochondral junctions, costovertebral/costotransverse process joints, and arc of the ribs. The uptakes were not necessarily symmetric. Multiple hot uptakes at the bilateral costochondral junctions revealed a characteristic “adult rachitic rosary” appearance in five patients (Figure 1A). Pseudoreactivation of the growth plate was observed in the distal femur (two patients) and proximal tibia (three patients) (Figure 1B). None of the patients showed the “tie sign” of the sternum. Chest CT in patient #2 confirmed the fractures of the neck and tubercle of the ribs, where multiple hot radiotracer uptakes of the costovertebral/costotransverse process joints were observed on bone scintigraphy (Figure 1C). CT in patient #8 confirmed an insufficiency fracture at the sites of pseudo-reactivation of the growth plate on bone scintigraphy and the calcaneus (Figures 1D and E). Looser’s zones (pseudo-fractures) or overt fractures on plain radiographs or CT scans were observed in all patients, which correlated with the hot-uptake sites on bone scintigraphy (Figures 1F and G). Typical “codfish vertebrae” findings due to multiple compression fractures of the vertebrae were observed in only one patient. According to the DEXA scans of the lumbar spine and femoral neck, four patients were in the osteoporotic range, whereas the other four were in the osteopenic range.

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Figure 1 Bone scintigraphic and radiologic findings of adult-onset hypophosphatemic osteomalacia. A: Bone scintigraphy of patient #5 shows multiple foci of increased radiotracer uptake in multiple costovertebral/costotransverse joints, bilateral costochondral junctions (blue thin arrows: Costochondral beading or “adult rachitic rosary” appearance), arc of the ribs, cervicothoracolumbar vertebral bodies, sacrum, right humerus, left calcaneus, and right midtarsal bone; B: Bone scintigraphy of patient #8 shows multiple foci of increased radiotracer uptake in the thoracolumbar vertebral bodies, costovertebral junctions, costochondral junctions, posterior arc of the ribs, bilateral scapula, sacrum, pelvic bone, bilateral distal femur and proximal tibia (blue arrows and arrowheads: Pseudo-reactivation of the growth plate), bilateral calcaneus, right distal tibia, and right midtarsal bone; C: Axial computed tomography (CT) image of patient #2 shows insufficiency fracture of the neck and tubercle of the ribs (thick orange arrows); D and E: Coronal and sagittal CT images of patient #8 reveals insufficiency fracture of bilateral distal femur (thick orange arrows in D, proximal tibia (orange arrowheads in D), and left calcaneus (thick orange arrow in E); F: CT of patient #1 shows transverse linear radiolucency on the lateral aspects of the subtrochanteric area of both femurs (Looser’s zone or pseudo-fracture) (thick orange arrows); G: Magnetic resonance imaging of the shoulder of patient #4 shows overt fracture of the right scapula (thick orange arrow); H: Axial image of ⁶⁸Ga-DOTATOC positron emission tomography/CT of patient #1 shows small, focal increased radiotracer uptake on the inner surface of the right temporal bone (thick orange arrow).

	Spine				Girdles		Long bone (focal)				Long bone (pseudo-reactivation of the growth plate)		Hand and Foot				Rib cage				Others
	C	T	L	S	Scapula	Pelvis	Humerus	Femur	Tibia	Patella	Femur	Tibia	Carpals	Calcaneus	Mid tarsals	Meta tarsals	CV/CT JT	CC jnc	Rosary	Arc	Mandible	Sternum
1		●	●		●		●	●	●	●				●			●	●	●	●	●
2	●	●		●								●	●	●		●	●	●	●	●	●	●
3		●		●														●
4		●	●		●			●	●		●	●		●	●		●	●		●
5	●	●	●	●		●	●							●	●	●	●	●	●	●
6	●	●	●		●		●	●	●	●				●			●	●	●	●	●
7		●	●	●	●	●		●	●						●		●	●		●		●
8		●	●		●	●		●	●		●	●	●	●	●		●	●	●	●

C: Cervical; T: Thoracic; L: Lumbar; S: Sacral; CV/CT JT: Costovertebral/costotransverse joint; CC jnc: Costochondral junction.

We summarized the characteristics of eight patients with adult-onset hypophosphatemic OM of various etiologies. The most common cause was ADV-induced Fanconi syndrome, whereas the other two rare causes of renal tubular phosphate wasting were PMT and light-chain nephropathy. The most important indicators of OM suspected as a cause of widespread musculoskeletal pain are low serum phosphate levels and characteristic findings on bone scintigraphy.

Since the most common symptom of OM is widespread skeletal pain, it can mimic various musculoskeletal or rheumatic diseases, such as osteoporosis, myofascial pain syndrome, degenerative spondylosis, fibromyalgia, polymyalgia rheumatica (PMR), spondyloarthritis (SpA), and inflammatory myositis; hence, it may be easily misdiagnosed or underdiagnosed[3,5-7,16]. Adult-onset OM should be differentiated from inflammatory rheumatic diseases, such as PMR or SpA. Two of our patients were initially suspected of having PMR before visiting our clinic. As the prominent features of PMR and SpA are periarticular and articular inflammation, their pain presented with inflammatory pain characteristics[17]. In contrast, pain in OM presents with mechanical pain characteristics because fractures due to weak bone strength are the source of pain. Thus, pain characteristics in a patient’s history are vital for differentiating between OM and inflammatory rheumatic diseases. OM may also be misdiagnosed as osteoporosis owing to the accompanying multiple fractures. Unlike osteoporotic fractures, which usually involve the neck of the femur, vertebral bodies, and wrists, OM fractures mainly involve the ribs, shoulder/pelvic girdle, spine, and long bones[3,4]. In our case series, insufficiency fractures occurred mainly in the neck/tubercle of the ribs, long bones of the lower extremities, sacral ala, calcaneus, and vertebral bodies. The accompanying muscle weakness and biochemical abnormalities in OM, especially hypophosphatemia and alkaline phosphatase elevation, could also be crucial for differential diagnoses.

More than half of the patients in this study showed evidence of proximal muscle weakness in the lower extremities. Osteomalacic myopathy usually involves the proximal muscles around the shoulder and pelvic girdles, causing gait disturbance, difficulty in sit-to-stand, and difficulty in climbing up and down stairs; when properly treated, it has a good prognosis and is rapidly reversible[1,3,4,18-20]. Although proximal muscle weakness in OM may lead to misdiagnosis as a primary muscle disease, such as inflammatory myositis, normal CK levels and characteristic findings on bone scintigraphy can easily differentiate OM from inflammatory myositis. The pathophysiological mechanism of proximal weakness in OM is assumed to be multifactorial; however, no clear mechanism for muscle weakness has been identified in OM[20]. In our patient, electromyography did not reveal evidence of denervation or myopathic motor unit action potential, and serum CK levels were within the normal range. These findings suggest that muscle weakness in OM is not caused by denervation or muscle cell death but by disturbed energy metabolism of muscle cell contraction, probably due to phosphorus deficiency. In an animal study, significant muscle force reduction occurred only when vitamin D deficiency was accompanied by hypophosphatemia[21]. Thus, muscle weakness in OM can be reversed with appropriate treatments. The early improvement (within 3 mo after treatment) in muscle strength and disappearance of the waddling gait in our cases support this hypothesis.

Bone scintigraphy is the most useful imaging modality for diagnosing OM, or at least one type of metabolic bone disease. This is because it permits the examination of the whole skeleton at a glance, and the patterns of uptake in OM are distinct from those of other skeletal diseases, such as metastatic bone disease and osteoporosis. In our cases, “adult rachitic rosary” appearance at the chest cage or pseudo-reactivation of the growth plate at the distal femur/proximal tibia was noted in all patients, except two. Thus, these two characteristics are highly suggestive of, but not specific to OM. A characteristic finding of OM on plain radiographs is a pseudofracture or Looser’s zone, which is a radiolucent line through one cortical plate, often with sclerosis at the margins. This insufficiency fracture is usually observed prior to the occurrence of other radiologic changes in OM[22]. In the present case series, it was commonly observed in the long bones, pelvic rami, scapula, and posterior arcs of the ribs. However, standard plain radiography did not reveal definite cortical disruption at any site.

Previously, vitamin D deficiency was considered the most common cause of OM. However, with improvements in the nutritional status, hypophosphatemic OM due to other causes has become more common. There have been several reports of adult-onset hypophosphatemic OM and renal Fanconi syndrome induced by regular doses (10 mg/d) of ADV after long-term use (mostly for 2-7 years) since 2000, especially in HBV-endemic areas[15,16,23]. In the present case series, ADV-induced Fanconi syndrome was the most common cause of hypophosphatemic OM. Therefore, when hypophosphatemic OM is suspected to be the cause of widespread musculoskeletal pain, careful history taking for the use of anti-HBV medications is imperative. Regular monitoring of serum phosphate levels is also recommended for the early detection of hypophosphatemia in patients taking ADV for hepatitis B.

Although rare, light-chain nephropathy or PMT can cause adult-onset hypophosphatemic OM when there is no history of causative medications that induce OM. Light-chain nephropathy causes hypophosphatemic OM due to proximal tubular dysfunction caused by crystal deposition in the proximal tubule cells[24,25]. Therefore, latent MM should be considered in patients with acquired hypophosphatemic OM. In TIO, the tumor secretes a factor called phosphatonin, which causes phosphaturia and hypophosphatemia. The tumors were morphologically distinct and classified as a single histopathological entity named PMT[26]. As PMTs are often small and exist within the bone, they are difficult to locate. The recent development of somatostatin-receptor functional scintigraphy and PET/CT using ⁶⁸Ga-radiolabeled DOTA-conjugated peptides has helped in diagnosis[6,10,13]. Although serum FGF23 levels in blood samples from the antecubital vein of one patient with TIO in this case series were within the normal range, ⁶⁸Ga-DOTATOC PET/CT detected the culprit lesion for PMT. Although autosomal dominant hypophosphatemic rickets (ADHR) is one of the causes of adult-onset hypophosphatemic OM because it is characterized by variability in the age of the clinically evident disease, genetic studies for ADHR were not performed because other causes of hypophosphatemia were clearly identified in our cases.

The treatment of OM requires the management of the underlying disease or drugs that cause it, along with simultaneous phosphate and vitamin D supplementation. In our cases, the bone pain improved within a short period when appropriate treatment was administered. In some of our patients, the symptoms tended to improve even if the phosphorus level was not completely normalized. This can be explained by the inaccuracy of serum phosphate levels in predicting total phosphorus levels in the body[27]. The favorable prognosis in our cases emphasizes the importance of the early diagnosis of hypophosphatemic OM in adult-onset patients presenting with multiple musculoskeletal pain.

Our study had some limitations. The most crucial limitation was the lack of a pathological diagnosis of OM. However, a bone biopsy is rarely performed at our institute for the diagnosis of OM because of its invasiveness. We attempted to include highly compatible patients using the criteria set by a thorough review of the literature. All patients presented with a clear etiology of OM. Another limitation was the inherent bias due to the retrospective nature of the study and the relatively small number of patients recruited in a single center. Larger prospective multi-centered cohort studies are needed to establish a more precise clinical picture of the disease entity. Additionally, ADV has been used as a drug of choice for treating HBV infection for years. However, after the introduction of other anti-HBV medications with better efficacy including entecavir and tenofovir, ADV is not recommended for the treatment of chronic HBV infection in European and Korean clinical guidelines[28,29]. Thus, our conclusion that ADV-induced Fanconi syndrome is the most common etiology of adult-onset hypophosphatemic OM in HBV-endemic countries may have little clinical significance in the future. However, as a considerable number of patients continue to receive ADV for their long-term maintenance therapy, physicians in HBV-endemic countries should be aware of this clinical entity.

Therefore, physicians should consider the possibility of adult-onset hypophosphatemic OM as a cause of widespread musculoskeletal pain. Although it is not a common disease, the quality of life of affected patients can be severely compromised if the diagnosis is delayed. Once the correct diagnosis is made, there is dramatic improvement with proper treatment. The mechanical pain characteristics, hypophosphatemia, and distinctive patterns on bone scintigraphy may be initial diagnostic indicators. When hypophosphatemic OM is confirmed, a diagnostic work-up based on the proposed diagnostic algorithm is necessary. Drugs, such as antiviral agents for hepatitis B, may be the most common etiology of adult-onset hypophosphatemic OM in HBV-endemic countries.