Sarcoidosis of bone

INTRODUCTION — Sarcoidosis, a multisystem disorder of unknown etiology, commonly presents clinically with bilateral hilar adenopathy, pulmonary infiltrates, skin and/or eye lesions, or a combination of these features. Bone and joint manifestations occur less commonly. Sarcoid is characterized pathologically by the presence of noncaseating granulomas in affected organs. It typically affects young adults, and any organ may be affected.

Although musculoskeletal disease, which is estimated to occur in 4 to 38 percent of patients, is less common than the characteristic pulmonary features, joint manifestations may be clinically significant, especially in patients with acute disease, and involvement of muscle, bone, and other organs and tissues may also occur [1,2].

Sarcoid involvement of the bone will be reviewed here. Sarcoid arthropathy and myopathy, other extrapulmonary manifestations of sarcoidosis, pulmonary sarcoidosis, and general issues related to sarcoidosis and its pathogenesis are discussed separately. (See "Sarcoid arthropathy" and "Sarcoid myopathy" and "Clinical manifestations and diagnosis of sarcoidosis" and "Pathology and pathogenesis of sarcoidosis".)

FOCAL LESIONS (OSSEOUS SARCOIDOSIS) IN BONE — Bone involvement in sarcoidosis typically involves focal, usually multiple, osseous lesions in the appendicular and/or axial skeleton.

Pathology and pathogenesis — The pathology of sarcoidosis is described in detail separately; the histologic findings of sarcoidosis in the bone are the same as in other tissues of the body. (See "Pathology and pathogenesis of sarcoidosis", section on 'Pathology'.)

The steps involved in the formation of sarcoid granulomas involve a complex interplay of immune cells, including macrophages, dendritic cells, T helper lymphocytes, T regulatory cells, and their mediators. The pathogenesis of sarcoidosis is described in detail separately. (See "Pathology and pathogenesis of sarcoidosis", section on 'Immunopathogenesis'.)

The pathogenesis of sarcoid specifically involving bone is uncertain; it has been postulated that antigenic particles are spread hematogenously or through the lymphatics, creating granulomas within the bone, bone marrow, and other organs [3]. This hypothesis may help to explain the greater frequency of liver, spleen, and extrathoracic lymph node involvement in patients with bone sarcoidosis [3].

Epidemiology — Sarcoidosis of bone occurs in approximately 5 percent of patients with sarcoidosis (range of 1 to 13 percent), although its frequency is likely to be underestimated as it is often asymptomatic [4]. It is more common in middle-aged (30 to 50 years of age) female and African American patients and usually presents later in the course of the disease than many of the other common manifestations of sarcoidosis.

Imaging modalities such as magnetic resonance imaging (MRI) or positron emission tomography (PET)/computed tomography (CT) scans, which are used to characterize organ involvement in systemic sarcoidosis or discovered incidentally for other indications, appear to identify more patients with bone involvement than historically appreciated using conventional radiography [5]. (See 'Imaging' below.)

Clinical manifestations — Osseous sarcoidosis can involve focal areas of both the appendicular and axial skeleton; it is symptomatic in over half of patients, with pain, tenderness, and sometimes swelling. The hands are frequently involved; the findings are often bilateral but asymmetric [6-8]. Other appendicular and axial skeletal sites are also often affected, including the feet, extremities, skull, vertebrae, pelvis, ribs, sternum, clavicle, maxilla, and nasal bones [9-12]. (See 'Appendicular involvement' below and 'Spinal and other axial involvement' below.)

Osseous sarcoid is frequently identified in asymptomatic patients incidentally on imaging studies, usually MRI or PET/CT done for other reasons, such as evaluating fever of unknown origin or for metastatic cancer [6]. Bone lesions typically appear lytic and on imaging can be difficult to distinguish from malignancy. (See 'Imaging' below.)

Osseous sarcoidosis is rarely the presenting symptom or finding of sarcoidosis but is commonly detected during initial evaluation of systemic sarcoidosis, which is usually present when bone lesions are initially noted [13]. As an example, in one report, 70 percent of patients with osseous sarcoid had other involvement, such as pulmonary disease or hilar adenopathy [6]; and in addition to pulmonary manifestations, patients with bone involvement have multiple organs affected with higher incidence of liver, spleen, and extrathoracic lymph node involvement than patients without bone lesions [3].

Appendicular involvement — The most frequently affected appendicular skeletal sites are the proximal and middle phalanges of the hands. With phalangeal involvement, patients can experience local pain and tenderness in the affected region, which can exhibit swelling, reduced function, distortion of fingers, and overlying erythema. The findings are often bilateral but asymmetric [6-8]. There is also frequent involvement of the feet and in the extremities (eg, humerus and femur) [3,6]. Hand lesions were more common in African Americans in one study [3,6], but bone involvement overall was more frequent in White Americans [3].

Dactylitis, manifested by fusiform, sausage-like swelling of a digit due to destructive bone lesion and soft tissue infiltration and swelling, similar to findings that can be seen in patients with spondyloarthritis (SpA) and gout, may occur in association with phalangeal bone involvement in patients with sarcoidosis but can also occur without apparent bone involvement [14,15]. In one series, it was seen in 17 percent of patients with sarcoidosis (2 of 12 patients) who were seen in an arthritis center [14]. (See "Sarcoid arthropathy", section on 'Chronic arthritis'.)

Conventional radiographic changes include lesions that appear punched out, permeative or reticular, and least often, sclerotic (see 'Imaging' below and 'Conventional (plain) radiography' below). A combination of such findings is often present.

Spinal and other axial involvement — Bony involvement in the spine is common in patients with osseous sarcoidosis but is mostly asymptomatic and underdiagnosed [6]. With symptomatic axial involvement, pain is a prominent feature, especially at the thoracolumbar region [3]. The disease most commonly affects the lower dorsal and upper lumbar vertebrae, but the cervical spine including the atlantoaxial (C1-C2) joint may also be involved [16,17]. Sternal and pelvic involvement associated with diffuse spinal sarcoid has also been reported [18,19]. The skull, ribs, clavicle, maxilla, and nasal bones can also be affected [9-12,19].

On imaging, lesions are typically lytic in appearance, with peripheral sclerosis most commonly affecting vertebral bodies and pedicles [6,19-22]. Multiple lesions can occur at different levels. Widespread lytic lesions of the spine can mimic metastatic disease on imaging [23,24]. Vertebral sarcoidosis is best imaged by use of MRI. (See 'MRI' below.)

Although bone sarcoidosis can involve the skull, it is generally a rare and isolated finding [19]. However, its incidence might be underestimated due to being less symptomatic compared with other sites. Changes in the skull are often detected on plain radiographs as lytic lesions throughout the thickness of the cranium without peripheral sclerosis.

With the more frequent use of advanced imaging (MRI, PET/CT) to evaluate sarcoidosis, there has been increasing recognition of the greater relative frequency of axial involvement. In one series of 20 patients with osseous sarcoid, involvement of the axial skeleton, especially the pelvis and lumbar spine, was seen in 90 percent of patients but was often asymptomatic [6]. In another study, 3.5 percent of patients (64 out of 1802) with sarcoidosis had bone involvement [3]; the bones of the axial skeleton were more frequently involved than the bones of the appendicular skeleton.

An association between vertebral sarcoidosis and paravertebral ossification simulating ankylosing spondylitis and reactive arthritis has also been described [25]. Six of 42 patients in this series, predominantly female patients with sarcoidosis, had human leukocyte antigen (HLA)-B27-negative sacroiliitis.

Laboratory findings — Laboratory findings in bone sarcoidosis are nonspecific and similar to those seen in other forms of systemic sarcoidosis without bony involvement [3] (see "Clinical manifestations and diagnosis of sarcoidosis", section on 'Laboratory testing'). Erythrocyte sedimentation rate (ESR), alkaline phosphatase, and serum calcium are frequently normal but may be elevated in 5 to 10 percent of patients [6]. Hypercalcemia occurs in 10 percent of patients with normal or elevated 1,25-dihydroxyvitamin D (calcitriol), a marker associated with disease activity [26]. The angiotensin-converting enzyme (ACE) level has been found to be elevated in up to 60 to 70 percent of the osseous sarcoid patients but has limited specificity [6,26].

Imaging — A number of changes can be seen using conventional radiographs, MRI, and PET/CT in patients with osseous sarcoidosis [3]. Conventional radiographs are usually sufficient for evaluation of the hands and feet, but MRI and PET/CT are more sensitive for the detection of changes in other parts of the skeleton. (See 'Conventional (plain) radiography' below and 'Nuclear scintigraphy and positron emission tomography' below and 'CT scan' below and 'MRI' below.)

Conventional (plain) radiography — Conventional radiography can demonstrate sarcoid bone lesions in small bones of the hands and feet [6,19-22,27,28]. The bony lesions are usually lytic; they are also called cystic bone lesions, but this is a misnomer as bony lesions are a result of osteolysis. These multiple small lytic or cystic lesions sometimes result in a "lacy pattern," which is a typical description of a lesion seen in sarcoid bone disease (image 1). These cystic lesions have also been referred to as Perthes-Jüngling osteitis, and a similar pattern has been seen of mycobacteria infection. Bone lesions on conventional radiography are less common in other areas and are less characteristic in appearance.

These changes, most often seen in the head of the proximal or middle phalanx of the hands, are typically detected by plain film radiography, but in some patients may only be detected by MRI (image 2) [27,28]. These findings are sufficiently characteristic of sarcoidosis that the presence of these findings should prompt further evaluation for underlying sarcoidosis if the diagnosis has not been previously established.

The following findings have been described in a study of 136 osseous radiographic lesions of hands and feet [29]:

●Punched-out lesions – This is the most common pattern, which is caused by small cortical defects surrounded by normal bone [30].

●Permeative or reticular lesions – These findings are caused by tunneling in the cortex of the shafts of small bones, followed by remodeling of the cortical and trabecular architecture to give a reticular pattern.

●Sclerotic lesions – This is a rare noncystic pattern resulting from marrow infiltration. Sclerotic lesions commonly affect the axial skeleton, with the bones of the pelvis, spine, and ribs being most often involved [31]. These lesions appear to occur exclusively in middle-aged Black patients [32].

Clinical dactylitis is due to rare destructive lesions from rapidly advancing bone involvement with multiple fractures and severe soft tissue swelling and can be observed on plain radiography as well.

A combination of two or more types of lesions is commonly seen in the same patient. Complete resolution of an osseous lesion is very rare. The osseous lesions are sometimes associated with cutaneous changes as well. (See 'Associated skin and nail findings' below.)

Nuclear scintigraphy and positron emission tomography — Nuclear medicine studies are more sensitive techniques for osseous sarcoidosis than plain radiography [33,34]. However, the findings of osseous sarcoidosis either by conventional radiographic methods or nuclear medicine studies are nonspecific and cannot reliably distinguish osseous sarcoid from other pathology, including tumor (eg, bony metastasis) and infections (eg, osteomyelitis) [24,35].

Nuclear medicine imaging includes nuclear scintigraphy, such as technetium-99m methylene diphosphonate (Tc-99m MDP) bone scanning and gallium-67 (GA-67) scanning, and also includes PET scanning with 18-fluoro-2-deoxyglucose (¹⁸F-FDG; ¹⁸F-FDG-PET). All three imaging techniques, which rely upon the detection of gamma rays, have been used in the staging of sarcoidosis, including assessment of extrapulmonary involvement.

Bone scintigraphy is more sensitive than gallium scanning, but gallium scans have the advantage of identifying pulmonary and extrapulmonary involvement in other tissues.

¹⁸F-FDG-PET is the most sensitive and accurate for extrapulmonary involvement, including bone, of all the nuclear imaging techniques; however, the findings closely mimic widespread skeletal metastases [36]. A study from the Netherlands of 122 patients with biopsy-proven severe sarcoidosis (defined as persistent, unexplained disease-related disabling symptoms) revealed focal bone uptake and/or more diffuse bone marrow involvement in more than one-third of patients by use of PET/CT scanning, although 94 percent of the lesions were not evident on low-dose bone CT [5].

MRI — MRI is a highly sensitive technique for detecting bony lesions in sarcoidosis, including those in the axial skeleton and large tubular bones, as well as bone marrow involvement, and MRI can reveal bone involvement that is not evident by conventional radiography. On MRI, changes from osseous sarcoidosis commonly appear as multiple focal intramedullary lesions that are typically hypointense on T1 and hyperintense on T2, which shows variable enhancement on contrast [23,37,38]. Unlike small-bone involvement (eg, in the hands), cortical destruction or extraosseous extension is not seen by MRI in large tubular bones, possibly explaining why large-bone involvement can be radiographically occult and clinically silent. Granulomatous infiltration of the bone marrow also results in an abnormal signal on MRI (image 3).

Despite the sensitivity of MRI compared with conventional radiography, osseous sarcoidosis lesions cannot be reliably distinguished from metastatic lesions on routine MRI [7,39]. However, MRI can be useful to exclude tophaceous gout lesions; tophi, unlike the bone lesions in sarcoidosis, are mostly hypointense on T2-weighted images. In a comparison of osseous sarcoidosis with osseous metastatic lesions, the presence of intra- or perilesional fat, lesional border characteristics (ie, sharply defined, brush-like, or poorly defined), and the presence of an extraosseous soft tissue mass, as well as posterior element involvement of spinal changes, were indicative of osseous sarcoidosis, but overall had only moderate sensitivity for the diagnosis, despite relatively high specificity [39].

CT scan — CT scanning is often used to evaluate pulmonary or lymph node involvement in sarcoidosis, and bony lesions can be detected on these scans. However, CT scan is nonspecific, as is conventional radiography, and the sensitivity of CT for osseous sarcoid is lower than MRI or PET/CT [3]. Lesions may be osteolytic or osteosclerotic on CT scan.

Associated skin and nail findings — Several types of dermatologic abnormalities affecting the skin and nails may be seen in patients with osseous sarcoid. The cutaneous manifestations of sarcoidosis are described in detail separately (see "Cutaneous manifestations of sarcoidosis"), but these associations are described here briefly:

●Cutaneous findings – Bone disease is often accompanied by infiltrative skin lesions, and patients with bone lesions often experience more chronic and severe disease (see 'Prognosis' below). Examples of associated skin changes include:

•Lupus pernio, a manifestation of cutaneous sarcoid, which can present with nodular skin lesions of the nose and malar areas, as well as the hands and feet. Lupus pernio skin lesions are associated with sarcoid of the flat bones. They may be observed with lesions of the nasal bones and hard palate; in the hands and feet, cystic or lytic underlying bone lesions may be present. (See "Cutaneous manifestations of sarcoidosis", section on 'Lupus pernio'.)

•Painless nodules of the scalp may be present in patients with involvement of the skull.

●Clubbing and other nail changes – Underlying bone disease, especially distal phalangeal involvement, is often present in patients with sarcoid nail disease (ie, nail striations), and nail clubbing is one of the nonspecific cutaneous and bone manifestations that may infrequently occur in sarcoidosis (see "Cutaneous manifestations of sarcoidosis", section on 'Nail sarcoidosis'). True clubbing is rare in sarcoidosis, although nail bed thickening is common (figure 1) [40].

As an example, in one study, clubbing was observed in only 2 of 136 patients at disease presentation and in only two more at follow-up [41]. Unilateral clubbing and localized periostitis without clubbing have also been described [42,43].

Dystrophic nails frequently accompany bony abnormalities; however, there are two reports in which the diagnosis was made with nailfold biopsy in patients without bone disease [44].

Diagnosis — The diagnosis of sarcoidosis affecting bone can generally be made in a patient with an established diagnosis of sarcoidosis affecting organs and tissues other than bone (eg, pulmonary sarcoid) and radiographic features that are typical for this disease (eg, cystic bone lesions with well-defined margins). In patients with classic bony lesions, either on conventional hand radiographs or with characteristic lesions detected on MRI or PET/CT, and biopsy-proven sarcoidosis in another organ, additional studies, such as a biopsy of affected bone, are often unnecessary, depending upon the clinical context. (See "Clinical manifestations and diagnosis of sarcoidosis" and "Overview of extrapulmonary manifestations of sarcoidosis", section on 'Extrapulmonary disease in initial diagnosis'.)

However, several findings may indicate the need for a biopsy of a bone lesion. In patients with sclerotic bone lesions, extension of an infiltrative lesion that encroaches on nearby structures (eg, spinal vertebral disease with extradural compression of the spinal cord or spinal nerves), or concurrent involvement of the disc and spine, a biopsy is often required to exclude other conditions (see 'Differential diagnosis' below). This is because it is not possible to reliably distinguish granulomatous bone involvement of sarcoidosis from other causes by MRI or other imaging studies in these cases.

A site appropriate for biopsy should be readily identifiable. As an example, in one study, imaging or symptoms identified the site of a biopsy that was positive in all but 1 of 53 patients [3].

Differential diagnosis — Other disorders may cause changes in bone that mimic osseous sarcoidosis. These include metastatic disease of the breast or prostate, lymphoma, multiple myeloma, osseous hemangioma, disseminated granulomatous infection, Paget disease of bone, osteopetrosis, and mastocytosis [32]. The differential diagnosis of vertebral sarcoidosis, in particular, includes vertebral infection (eg, tuberculosis [Pott's spine]) or tumor (metastasis, plasmacytoma, lymphoma, etc) and requires biopsy for confirmation of the etiology.

In one study, among the 57 bone marrow biopsies demonstrating granulomas that were identified in over six years in a French university hospital, the most common etiology was infection (33 percent), which was followed by sarcoidosis (21 percent), unknown (21 percent), malignancy (19 percent), and therapy-induced granulomas (6 percent) [45].

Major conditions that should be considered in the differential diagnosis of sarcoidosis include:

●Metastatic cancer or hematopoietic malignancy – The bone lesions in sarcoid can mimic those of metastatic cancer (eg, of the breast or prostate), lymphoma, multiple myeloma, or osseous hemangioma [32,34,39]. In patients with sarcoidosis documented in other organs and tissues and without any evidence otherwise of malignancy, it may be possible to infer that bone lesions, particularly with characteristic imaging changes, are due to sarcoid rather than malignancy. However, malignancy and sarcoid cannot be reliably distinguished on plain radiographs, by MRI [39], or on PET/CT; thus, biopsy is often required to make this distinction if there is any clinical uncertainty. Additionally, there is a sarcoid-like reaction most often described with lymphoma [46]; it has also been described with solid tumors [47,48]. (See 'Imaging' above and 'Diagnosis' above and "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults".)

●Paget disease of bone – Sarcoidosis of the long bones may resemble Paget disease since both disorders are associated with increased uptake on bone scans and with lytic and sclerotic lesions on radiography. Unlike Paget disease, however, the serum alkaline phosphatase concentration is usually normal or only mildly elevated in patients with sarcoidosis. (See "Clinical manifestations and diagnosis of Paget disease of bone".)

●Spondyloarthritis – Musculoskeletal manifestations seen in both sarcoidosis and SpA, as well as psoriatic arthritis (PsA), can include back pain, oligoarthritis, and fusiform digital swelling suggestive of dactylitis. These conditions can usually be distinguished by the other clinical findings of systemic sarcoidosis, SpA, and PsA, but if the diagnosis remains uncertain it can be determined by additional imaging or biopsy, if necessary. (See "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults" and "Clinical manifestations and diagnosis of psoriatic arthritis".)

●Infection – Disseminated granulomatous infections like tuberculosis involving bone can result in focal or multifocal bone lesions. Infectious discitis can result in similar imaging abnormalities to sarcoid of the spine. Ruling out granulomatous infection by serologic testing and/or biopsy and culture of the affected area can be performed to exclude infection [49]. (See "Vertebral osteomyelitis and discitis in adults", section on 'Diagnosis'.)

●Other conditions – Additional conditions, such as osteopetrosis and systemic mastocytosis, may also have an appearance similar to sarcoid on imaging studies, and a biopsy may be required to identify or exclude these conditions or to confirm the diagnosis of sarcoidosis. (See "Skeletal dysplasias: Specific disorders", section on 'High bone density' and "Skeletal dysplasias: Approach to evaluation" and "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis" and "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Unusual initial presentations'.)

Treatment — The presence of osseous sarcoidosis does not influence the choice of therapy in most patients with this manifestation, because treatment is usually determined by the type, severity, and frequency of other organ and tissue involvement; the management of systemic sarcoidosis requires collaboration among treating clinicians. Most patients with osseous sarcoidosis will already be receiving treatment for other disease manifestations, such as pulmonary disease or other organ involvement, when bone disease is identified or will require therapy for these manifestations if they are newly diagnosed [3,6]. Treatment in patients with symptomatic bone disease should be individualized depending upon the patient's treatment program and comorbidities. Asymptomatic bone disease does not generally require systemic immunosuppressive treatment. Some patients with spontaneous remission of osseous sarcoid have been reported [50-52]. (See 'Clinical manifestations' above and "Clinical manifestations and diagnosis of sarcoidosis" and "Overview of extrapulmonary manifestations of sarcoidosis".)

Treatment guidelines for extrapulmonary sarcoidosis are lacking and evidence for benefit in patients with osseous sarcoid comes primarily from retrospective case series and individual case reports [3,6,53,54].

The approach to therapy, including drug choice, dosing, and duration of therapy, is thus based largely upon the treatment of pulmonary sarcoidosis and the evidence supporting such treatment. Details of this approach are described separately (see "Treatment of pulmonary sarcoidosis: Initial approach" and "Treatment of pulmonary sarcoidosis refractory to initial therapy"). As examples:

●For patients with symptomatic bone involvement despite ongoing treatment of the patients' other disease manifestations, we suggest glucocorticoids (prednisone 20 to 40 mg daily or equivalent) rather than nonsteroidal antiinflammatory drugs. We gradually taper the dose as tolerated to 5 to 10 mg daily with the goal of discontinuing therapy over 6 to 12 months. Glucocorticoids improve pain and soft tissue swelling but do not normalize the bone abnormalities seen on imaging [3]. (See "Treatment of pulmonary sarcoidosis: Initial approach".)

●In patients who do not respond adequately to glucocorticoids or cannot be tapered to ≤10 mg daily after three months of treatment, we add a conventional immunosuppressive agent (eg, methotrexate, azathioprine, or leflunomide) [6]. An alternative agent that has been used in patients with mild disease is hydroxychloroquine [3]. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy", section on 'Patients who progress on or do not tolerate glucocorticoids' and "Treatment of pulmonary sarcoidosis refractory to initial therapy", section on 'Azathioprine' and "Treatment of pulmonary sarcoidosis refractory to initial therapy", section on 'Leflunomide' and "Treatment of pulmonary sarcoidosis refractory to initial therapy", section on 'Hydroxychloroquine and chloroquine'.)

●In patients with symptomatic bone disease who respond inadequately or are intolerant to acceptable doses of glucocorticoids and either methotrexate, azathioprine, or leflunomide after three months of treatment, another alternative that may be effective is a monoclonal tumor necrosis factor inhibitor, such as infliximab or adalimumab, which have been reported as effective in case reports, series, and uncontrolled studies [6,53-56]. We generally avoid use of etanercept in patients with sarcoidosis since it may not be effective and can rarely have a sarcoidal-like reaction. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy", section on 'Tumor necrosis factor-alpha antagonists'.)

Prognosis — The presence of bone lesions generally implies a more advanced, chronic, and severe disorder overall, with more organs and tissues affected by sarcoidosis [4,57]. Prognosis in patients with asymptomatic bone sarcoidosis largely depends upon other organ manifestation and disease severity. Hand deformities may become permanent, leading to loss of function, if not treated early for bone involvement. Rare patients with spontaneous remission of osseous sarcoid have been described in case reports [51,52]. In a report of a patient with multifocal vertebral sarcoid followed by MRI over four years of glucocorticoid treatment, gradual fatty involution and a good outcome were noted [58]. Osteoporosis, avascular necrosis, and fracture risk are important complications of sarcoidosis and treatment.

OSTEOPENIA AND OSTEOPOROSIS — Bone density may be normal or high in early sarcoidosis, but due to several factors, including treatment with glucocorticoids and the inflammatory state of the illness, osteoporosis and/or osteopenia may gradually develop, with up to a quarter of patients developing vertebral fractures [59-62]. The risk of fracture is increased and may be greater than expected based upon bone density measurement alone. (See 'Mechanism of low bone mass' below and 'Risk of low bone mass and fracture prevalence' below.)

The prevention and treatment of bone loss in patients with sarcoidosis is complicated by potential excess production of vitamin D and increased risk for hypercalciuria and hypercalcemia, which may be worsened by calcium and/or vitamin D supplementation [26,63]. (See 'Mechanism of low bone mass' below and 'Risk of low bone mass and fracture prevalence' below and 'Prevention and treatment' below.)

Hypercalcemia in patients with sarcoidosis results in large part from the effects of activated mononuclear cells (particularly macrophages) in the lung and lymph nodes, which produce 1,25-dihydroxyvitamin D (calcitriol) from 25-hydroxyvitamin D (calcidiol) independently of regulation by parathyroid hormone (PTH). The mechanisms of hypercalcemia and hypercalciuria in sarcoidosis are discussed in detail separately. (See "Hypercalcemia in granulomatous diseases", section on 'Sarcoidosis'.)

Mechanism of low bone mass — Osteopenia in sarcoid may be caused by one or more of the following factors:

●Diffuse skeletal granulomatosis [64].

●Interferon-gamma production by activated T cells, which stimulates macrophage-derived 1,25-dihydroxyvitamin D production and the resultant release of osteoblast-derived resorption factors. These factors stimulate osteoclast activity; there may also be other factors secreted by T cells that have a role as well. In addition, high levels of 1,25-dihydroxyvitamin D can stimulate osteoclastogenesis both in vitro and in vivo [63,65].

●Treatment with glucocorticoids, particularly in the postmenopausal patient [66]. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)

Although metabolic derangements in vitamin D and hypercalcemia could potentially affect bone health in patients with sarcoidosis, many patients with sarcoidosis of bone have normal serum levels of calcium, vitamin D, and alkaline phosphatase.

Risk of low bone mass and fracture prevalence — A number of studies have shown that bone mineral density (BMD) in patients with sarcoid is generally comparable and sometimes increased compared with the general population [67], but that bone fragility and fracture risk may be increased, particularly in patients who are receiving glucocorticoid therapy and in postmenopausal female patients, as well as patients who receive excess vitamin D supplementation [59,60,68]. The most affected anatomic regions differ between studies. The following range of findings largely support these conclusions:

●In a study involving 64 patients with sarcoidosis, baseline BMD was normal or mildly increased for age, depending upon the region studied, and regardless of baseline 25-hydroxyvitamin D status there was no evidence of accelerated bone loss over one to two years of follow-up [67]. Vitamin D supplementation, used in a subset of patients, did not improve BMD.

●A retrospective study that compared 5722 patients with sarcoidosis (mean age of 48 years) with nearly 29,000 matched controls also found an increased risk of symptomatic vertebral fractures but a mildly reduced risk of nonvertebral fractures (relative risk [RR] 1.77, 95% CI 1.06-2.96, and 0.87, 95% CI 0.77-0.99, respectively). Recent use of glucocorticoids increased risk of any fracture and of osteoporotic fracture. Despite the increased risk, the absolute number of symptomatic vertebral fractures was low (37 events over 6.7 years of follow-up).

●Another study found an association between 25-hydroxyvitamin D serum levels, BMD, and risk of fractures, suggesting a U-shaped range of the association of vitamin D levels with fracture risk, with relatively lower and higher levels conveying increased risk compared with a midrange, and suggesting that excessive vitamin D supplementation can be deleterious with respect not only to risk of hypercalcemia but to fracture risk as well [60]. This study, involving 142 consecutive patients with histologically proven sarcoidosis in a specialty clinic, found a high risk of vertebral fragility fractures and that 23.5 percent of the patients had either a vertebral or peripheral fracture, despite a normal mean BMD in the study population. The factors associated with a higher fracture risk were not only greater glucocorticoid exposure and low dietary calcium, but also serum 25-hydroxyvitamin D levels that were either very low (<10 ng/mL) or normal to high (>20 ng/mL). Levels of 25-hydroxyvitamin D between 10 and 20 ng/mL were associated with higher BMD, but levels above 20 ng/mL were not associated with a higher BMD and were associated with higher fracture risk.

The association of high levels of vitamin D or vitamin D supplementation with lower bone mass and fracture are also supported by studies in patients without sarcoidosis [69,70]. (See "Overview of vitamin D", section on 'Excess'.)

●Other studies have had similar findings:

•One cross-sectional study showed vertebral fracture risk of 21 percent, despite mean age of the cohort of less than 45 years; one-half of these patients were taking glucocorticoid therapy [71]. Risk of vertebral osteoporotic deformities increased up to 32 percent in a four-year follow-up study [61].

•A population-based study in Minnesota of a cohort of 345 patients with sarcoid found that fragility fractures were increased compared with age- and sex-matched comparators, but that the main contributor to such risk was a higher rate of distal forearm fractures [72].

•Another study found that increased fracture risk in sarcoidosis was associated with current glucocorticoid use, but risk was otherwise not increased compared with controls, and the risk with glucocorticoid use did not differ from that seen in patients without sarcoidosis [73].

Prevention and treatment — The prevention and treatment of bone loss in patients with sarcoidosis is challenging, and the prevention of glucocorticoid-induced bone loss is complicated in patients with sarcoidosis compared with other glucocorticoid-treated diseases by production of vitamin D by sarcoid granulomas and the risk of hypercalcemia and hypercalciuria with calcium supplementation. (See 'Osteopenia and osteoporosis' above and 'Mechanism of low bone mass' above and 'Risk of low bone mass and fracture prevalence' above and "Hypercalcemia in granulomatous diseases", section on 'Sarcoidosis' and "Hypercalcemia in granulomatous diseases", section on 'Treatment'.)

We take the following steps to guide preventive therapy and management of low bone mass:

●Patients receiving glucocorticoids or with a history of osteoporotic fracture – In the absence of prior hypercalcemia or hypercalciuria, both in patients being treated with glucocorticoids and in patients with osteoporotic fractures who are not receiving these medications, we suggest calcium-vitamin D supplements to achieve a total calcium intake of 1200 mg/day and a vitamin D intake of 800 international units/day. Goal levels of serum vitamin D should be between 15 and 20 ng/mL We prefer that calcium come from dietary sources (table 1) as much as possible (at least half), to reduce the risk of nephrolithiasis. At the completion of glucocorticoid therapy, calcium and vitamin D supplements should be stopped to prevent subsequent hypercalcemia, but supplements should be continued in patients with a history of osteoporotic fracture. (See "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Calcium and vitamin D' and "Calcium and vitamin D supplementation in osteoporosis", section on 'Dietary sources'.)

●Pretreatment assessment and monitoring

•Serum and urine calcium levels during calcium therapy – In patients receiving calcium supplementation (beyond dietary), serum and urine calcium should be measured before starting supplements and carefully monitored during therapy. We typically check these levels more frequently at the initiation of supplements (monthly for two to three months), then every three to six months thereafter; although the risk of hypercalcemia or hypercalciuria with calcium-vitamin D supplements is elevated in sarcoidosis, it is relatively low, especially if patients are being concomitantly treated with glucocorticoids for active sarcoidosis. Supplementation should be stopped if levels increase to the upper limit of normal to prevent further escalation. Urinary calcium excretion is best assessed by measuring calcium in a 24-hour urine specimen (normal <250 mg/day). Alternatively, a spot urinary calcium-creatinine ratio can be obtained, although it is less accurate. A ratio >0.2 suggests hypercalciuria.

•Vitamin D levels during vitamin D therapy – Serum 25-hydroxyvitamin D can be low in sarcoidosis because of enhanced conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D due to increased 1-alpha-hydroxylase activity in macrophages. Therefore, 25-hydroxyvitamin D levels may not accurately reflect calcium absorption nor the nutritional status of vitamin D, and one must measure 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D prior to adding supplemental vitamin D and recheck them periodically. Vitamin D should be measured more frequently at the start of supplementation (monthly for two to three months) and subsequently every three to six months during therapy. This should be scheduled to include monitoring during the summer, when cutaneous production of vitamin D might enhance 1,25-dihydroxyvitamin D production. We check the 25-hydroxyvitamin D level every six months.

We advise supplementing if 25-hydroxyvitamin D is lower than 15 ng/mL, with the goal of replacement to achieve a level of 15 to 20 ng/mL, if 1,25-dihydroxyvitamin D levels are low or normal as well. In patients with elevated 1,25-dihydroxyvitamin D levels, vitamin D supplementation should not be given due to risk of hypercalcemia [26]. In one retrospective study of a cohort of patients with sarcoidosis, patients who were prescribed vitamin D developed moderate to severe hypercalcemia more frequently than those who were not (12.8 versus 3.6 percent); renal failure also increased the risk [63]. (See "Hypercalcemia in granulomatous diseases", section on 'Sarcoidosis'.)

•Baseline fracture risk assessment – The presence of any clinical risk factors for fragility fracture (table 2) should be assessed in patients with sarcoidosis. Those with risk factors may need a more formal assessment of fracture risk (eg, FRAX analysis and bone density testing with dual-energy x-ray absorptiometry [DXA]) to determine whether additional therapy, such as bisphosphonates, is needed. DXA should be obtained every two years for monitoring. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis", section on 'Fracture risk assessment'.)

●Role of bisphosphonates – In general, bisphosphonates are prescribed for prevention of bone loss and fractures in postmenopausal females and in males ≥50 years old who require systemic glucocorticoids ≥7.5 mg/day for longer than three months and are considered at high risk for bone fragility. For younger patients, bisphosphonates are reserved for those who have had a fragility fracture or who have accelerated bone loss. The approach to bisphosphonate use is the same as in patients without sarcoidosis. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)

There is limited direct evidence that supports the use of antiresorptive therapy for glucocorticoid-induced bone loss in patients with sarcoidosis [74,75]. In addition, bisphosphonates may be helpful for treatment of refractory hypercalcemia secondary to sarcoidosis. (See "Hypercalcemia in granulomatous diseases", section on 'Treatment'.)

The effect of vitamin D supplementation on BMD in sarcoidosis patients has been reported in a few different studies. One study showed strong association of low BMD with low calcium intake and serum 25-hydroxyvitamin D lower than 10 ng/mL or higher than 20 ng/mL [60]. However, another study supported the notion that vitamin D supplementation does not improve BMD [76]; the risk of significant hypercalcemia was very low.

By contrast, a randomized trial of 25-hydroxyvitamin D supplementation without calcium in sarcoidosis patients with low serum 25-hydroxyvitamin D (<50 nmol/L) showed no benefit on surrogate markers of bone health (bone turnover markers, PTH, or BMD over 12 months) [77]. However, except for one patient (out of 13), there was no change in average serum calcium or urinary calcium with such supplementation. Only one patient was on glucocorticoids.

Excessive 1,25-dihydroxyvitamin D levels, which increase risk of hypercalcemia and hypercalciuria, are due to extrarenal 1-alpha-hydroxylation within sarcoid granulomas. The biggest concern in giving calcium and vitamin D supplementation in sarcoidosis is hypercalcemia, which has been reported after vitamin D supplementation in patients with sarcoidosis [78]. However, calcium with vitamin D supplementation was not associated with hypercalcemia in several studies [79]. This was especially true if patients are being treated with glucocorticoids [67,77].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sarcoidosis".)

SUMMARY AND RECOMMENDATIONS

●Bone lesions are uncommonly identified in patients with sarcoidosis. They may be detected by imaging studies in approximately 5 percent of patients but are symptomatic in only approximately one-half of the affected patients. Studies with MRI or positron emission tomography (PET)/CT suggest a higher prevalence of asymptomatic bone lesions than was historically appreciated based upon conventional radiography alone. (See 'Epidemiology' above and 'Imaging' above.)

●Cystic lesions of the phalanges are the most typical symptomatic bone lesion, but osseous sarcoid may also be found in the pelvic bones, vertebral bodies, flat bones, and elsewhere. Clubbing has also been reported in patients with sarcoid. (See 'Clinical manifestations' above and 'Associated skin and nail findings' above.)

●The diagnosis of sarcoidosis affecting bone can generally be made in a patient with an established diagnosis of sarcoidosis affecting organs and tissues other than bone and radiographic features that are typical for this disease (eg, cystic bone lesions with well-defined margins). In patients with classic bony lesions, either on conventional hand radiographs or with characteristic lesions detected on MRI or PET/CT, and biopsy-proven sarcoidosis in another organ, additional studies, such as a biopsy of affected bone, are often unnecessary. However, bone biopsy is needed in patients in whom the diagnosis is uncertain, particularly in patients with sclerotic bone lesions, since these are rarely seen in sarcoidosis, and other causes of sclerotic/blastic bone lesions, such as metastatic cancer, should be excluded. (See 'Diagnosis' above.)

●In patients with symptoms of osseous sarcoid that are not controlled by therapies for other disease manifestations, we suggest glucocorticoids rather than nonsteroidal antiinflammatory drugs. We typically use prednisone (20 to 40 mg daily or equivalent), then gradually taper the dose as tolerated to 5 to 10 mg daily with the goal of discontinuing therapy over 6 to 12 months. (See 'Treatment' above.)

●In patients who do not respond adequately to glucocorticoids or cannot be tapered to ≤10 mg daily after three months of treatment, we add a conventional immunosuppressive agent (eg, methotrexate, azathioprine, or leflunomide). In patients with symptomatic bone disease who respond inadequately or are intolerant to acceptable doses of glucocorticoids and either methotrexate, azathioprine, or leflunomide after three months of treatment, another alternative that may be effective is a tumor necrosis factor inhibitor, such as infliximab or adalimumab. (See 'Treatment' above.)

●Osteopenia and osteoporosis in patients with sarcoidosis may be due to the disease itself or to glucocorticoid treatment. We use bisphosphonates for prevention and treatment of glucocorticoid-induced bone mineral loss, as in patients without sarcoid. (See 'Prevention and treatment' above and "Prevention and treatment of glucocorticoid-induced osteoporosis".)

●In patients receiving glucocorticoids or with a history of osteoporotic fracture, we suggest calcium and vitamin D supplementation, with monitoring of serum and urine calcium and of vitamin D levels. We otherwise avoid use of calcium supplements and vitamin D because of the risk of hypercalcemia. (See 'Prevention and treatment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Winston Sequeira, MD, who contributed to an earlier version of this topic review.