bubble_chart Overview

Although medical scientists have long recognized that the deposition of calcified substances in periarticular tissues, particularly in tendons, can cause recurrent inflammation, the nomenclature for such conditions has varied. It has been referred to as peritendinous calcification, hydroxyapatite Bi disease, calcific periarthritis, or calcific tendinitis. The most common site of calcified deposition is the shoulder, especially at the supraspinatus ligament, hence it is often termed calcific tendinitis. However, calcifications can also deposit in many other locations. Basic calcium phosphate crystals can deposit in periarticular tissues, forming typical clinical and radiographic features. The most common radiographic finding is calcific deposits in the shoulder joint, but similar changes can also be observed in other areas.

bubble_chart Pathogenesis

The pathogenesis of calcium hydroxyapatite deposition disease (CALD) remains incompletely understood, though several hypotheses have been proposed:

1. Codman suggested that initial injury results from abnormal stress causing tendon degeneration, followed by calcium deposition in the degenerated tendon. Pain arises from abnormal pressure due to tissue inflammation or calcium deposits.

2. Pederson and Key proposed that calcium deposits occur in necrotic tissue or hypovascular areas, possibly related to local pH changes. This is supported by the "critical zone of relative hypovascularity" theory, identifying an avascular region approximately 1cm from the supraspinatus tendon insertion – though this isn't the most common calcification site.

3. Gondos observed that highly mobile joints are prone to calcification, concluding that injury is one initiating factor.

4. Amor et al. performed HLA typing on 38 patients compared with 591 controls, finding higher frequencies of HLA-A₂ and HLA-Bw₃₅. Since dialysis patients show systemic calcifications, some suggest genetic and metabolic abnormalities contribute to pathogenesis.

5. Uhthoff's 1970s theory proposed that peritendinous calcification begins with hypoxia-induced fibrocartilaginous metaplasia, followed by secondary calcium deposition. Histological studies revealed chondrocyte-like cells near deposits but no inflammatory cells. He proposed calcification occurs in living cells (not necrotic tissue), resembling endochondral ossification in tendons/ligaments – except tendon calcification lacks vascularization. However, this theory remains unproven, and the true mechanism of disease requires further investigation.

bubble_chart Pathological Changes

Moseley observed that calcific deposits can undergo the following evolutionary processes.

1. Resting phase

The calcific material is completely deposited within the tendon, and this stage does not cause any clinical symptoms. At this time, X-rays show calcific deposits with clearly defined edges. If surgically removed, the calcific material appears as concentrated granules or caseous matter.

2. Mechanical phase

The deposits enlarge and compress the subacromial bursa, leading to varying degrees of shoulder pain. The subbursal vessels become congested, and X-rays reveal indistinct edges of the calcific deposits, which may appear dispersed in a linear pattern or even disappear completely.

⑴ Subbursal rupture: Part of the deposit is expelled from the tendon into the subbursal space. This process may repeat until all the deposits are expelled from the tendon.

⑵ Intrabursal rupture: The deposit ruptures and is expelled into the bursa, sometimes causing severe pain and inflammation.

3. Adhesive periarthritis phase

In this phase, calcific deposits within the tendon coexist with adhesive bursitis. Patients experience pain, general weakness, and restricted joint movement.

4. Intraosseous loculation

Occasionally, calcific deposits may extend into the nearby greater tuberosity, forming variably sized cystic structures within the tuberosity.

5. Dumbbell-shaped loculation

In rare cases, due to compression by the coracoacromial ligament, the deposits beneath the acromial bursa assume a dumbbell shape. Although these processes are not very pronounced, they indicate that shoulder calcific deposits can take various forms, and their location depends on which tendon is affected by the calcification.

bubble_chart Clinical Manifestations

1. Calcific Periarthritis

As early as 1870, calcific periarthritis was described as most commonly occurring in the shoulder, but it was not systematically reviewed until 1938. An insurance company surveyed 5,061 employees and found that 138 had calcium deposits in one or both shoulder joints. Over 70% of these patients were under 40 years old, and most were asymptomatic. However, follow-up studies revealed that larger calcium deposits often led to acute inflammatory episodes, while smaller deposits could sometimes resolve spontaneously. In 1992, Dr. Chan Yik-fung and colleagues at Taipei Veterans General Hospital investigated 81 cases of calcific tendinitis of the shoulder, with an average age of 61.2 years. Joint arthrography revealed rotator cuff tears in 22 of these cases.

Most cases of acute calcific periarthritis occur in a single joint and are accompanied by redness, swelling, heat, and pain, which can persist for several weeks. X-ray detection of calcium deposits is the best diagnostic criterion.

Recurrent multifocal calcific periarthritis suggests that this condition is not merely localized but rather a systemic disease. Some reports also indicate a familial clustering tendency.

2. Intra-articular Basic Calcium Phosphate Crystal Deposition Arthropathy

Basic calcium phosphate (BCP) crystals are now considered the third type of intra-articular crystals, alongside urate and calcium pyrophosphate dihydrate (CPPD) crystals. Schumacher et al. described acute and chronic arthritis in young individuals, often presenting with acute redness, swelling, and pain, closely resembling acute gout. Scanning electron microscopy can identify BCP crystals in synovial fluid, where leukocyte counts are also significantly elevated. Direct injection of BCP crystals into animal joints can induce acute arthritis.

In 1976, Dippe et al. found that crystals in the synovial fluid of degenerative arthritis, analyzed by X-ray energy dispersion, were BCP crystals. Other reports indicate that BCP crystals can be detected in 30–60% of degenerative arthritis patients. BCP and CPPD crystals often coexist, and studies suggest that BCP crystals are closely associated with the degree of joint destruction, whereas CPPD deposition correlates with patient age.

3. Milwaukee Shoulder/Knee Syndrome

McCarty studied 30 patients with a unique form of arthritis and named it Milwaukee shoulder/knee syndrome. This syndrome exhibits distinctive clinical, radiographic, and synovial fluid characteristics.

1. Clinical Manifestations

80% of patients are female, with the shoulder being the primary site of involvement, accompanied by glenohumeral joint degeneration and significant rotator cuff tears. Patient ages range from 53 to 90 years, with an average of 72.5 years. The onset is insidious, lasting from 1 to 10 years. Most patients experience mild to moderate (grade II) pain, especially after shoulder movement, while a few report severe pain even at rest. Other symptoms include limited joint mobility, stiffness, and nocturnal pain. Physical examination reveals restricted joint motion, instability, and crepitus with pain when the humeral head is pressed against the glenoid. Synovial fluid aspiration often yields bloody fluid, typically 30–40 ml, but sometimes as much as 130 ml.

2. Associated Factors

Contributing factors include: ① Trauma and overuse (e.g., falls, motorcycle accidents, professional wrestlers, recurrent shoulder dislocation); ② Congenital shoulder dysplasia; ③ Neuropathic conditions (e.g., cervical radiculopathy or syringomyelia); ④ Long-term dialysis patients; ⑤ Idiopathic causes (accounting for about one-third of cases).

Milwaukee shoulder/knee syndrome is likely the result of multiple contributing factors. It closely resembles the rotator cuff tear arthropathy described by Neer et al. and may represent the same condition.

3. Radiographic Features

X-rays can reveal degenerative changes in the glenohumeral joint, soft tissue calcification, and upward subluxation of the humeral head. Arthrography demonstrates rotator cuff tears. In most patients, the distance between the superior margin of the humeral head and the inferior margin of the acromion is less than 2mm. Injuries to the coracoid process, inferior surface of the acromion, and acromioclavicular joint are commonly observed. A pseudojoint often forms between the humeral head, acromion, and clavicle. Destruction of the humeral head is frequently seen, but osteophyte formation is not severe. These radiographic findings differ from those of degenerative arthritis of the shoulder joint. So far, no such cases have been reported domestically.

4. Characteristics of Synovial Fluid

The white blood cell count in synovial fluid is often less than 1×10⁹/L. Alkaline calcium phosphate crystals and granular collagen can be found in most synovial fluids, along with increased collagenase and protease activity.

5. Knee Joint Manifestations

In McCarty's report of 30 cases, 16 patients had knee joint involvement, with lateral tibiofemoral joint space narrowing accounting for approximately 30%. This form of knee joint degeneration differs from typical knee osteoarthritis.

IV. Secondary Alkaline Calcium Phosphate Crystal Arthropathy

Certain diseases, including chronic renal failure, autoimmune diseases, and nerve damage, can lead to calcification deposits. Alkaline calcium phosphate crystals may deposit in periarticular soft tissues, bursae, and joints, often accompanied by symptoms of wind-dampness diseases.

Some reports describe calcification in the joints of scleroderma patients, with synovial fluid resembling chalk dust. Others have noted multiple calcification deposits in patients with overlap syndrome.

Intra-articular injections of corticosteroids have been observed to cause periarticular calcification along the needle tract, which may develop months after injection. These calcifications can gradually resolve over months or years.

Tumoral calcinosis involves massive, progressive calcification deposits in or around single or multiple joints, more common in Africa and rare in North America and Europe. For patients with hyperphosphatemia, definitive treatment involves phosphate restriction. The disease often has a familial tendency.

Uremia can also be associated with alkaline calcium phosphate crystal deposits in or around joint soft tissues. Uremic patients frequently exhibit metastatic soft tissue calcification, often accompanied by joint or periarticular inflammation. Crystal-induced arthritis is not uncommon in uremic patients; these crystals may be urate or alkaline calcium phosphate crystals, while calcium pyrophosphate dihydrate crystals are often associated with secondary hyperparathyroidism.

bubble_chart Auxiliary Examination

Studying calcium phosphate crystal deposition disease is a diagnostically challenging task, as there is currently no simple and reliable examination method available. Faure et al. used high-resolution transmission electron microscopy to directly measure apatite crystals and found that the crystal composition is not uniform. McCarty et al. employed infrared spectroscopy to study crystals in synovial fluid, identifying the presence of at least hydroxyapatite, octacalcium phosphate (OCP), tricalcium phosphate (TCP), and particulate collagen. While these methods serve as excellent research tools, they are not practical for clinical use.

Clinically, diagnosis is typically made indirectly using radiology and synovial fluid analysis.

Radiology: Deposited calcium phosphate crystals may appear as round or fluffy calcifications on X-rays, ranging in size from a few millimeters to several centimeters, and can present as single or multiple calcifications. Although X-rays are a useful diagnostic tool, their sensitivity and specificity for diagnosing calcium phosphate crystal-associated arthropathy are not high. Clinically, asymptomatic periarticular calcifications are often observed.

Synovial fluid: While polarized light microscopy is a valuable tool for diagnosing gout and pseudogout, it cannot be used to identify calcium phosphate crystals because the size of individual crystals (75–250 nm) falls below the resolution limit of optical microscopy. Although crystals may occasionally aggregate, their random arrangement prevents them from exhibiting birefringence. In rare cases, when thousands of crystals align along the same axis, birefringence may occur. When large aggregates of calcium phosphate crystals form, shiny, coin-like crystals may be visible under optical microscopy. Some have suggested using Alizarin red S stain on synovial fluid as a screening method for calcium phosphate crystals. While this method has high sensitivity, its specificity is low, leading to false positives. Currently, there is no simple, highly specific method for identifying calcium phosphate crystals. Despite diagnostic challenges, the relationship between calcium phosphate crystals and periarticular or intra-articular lesions can often be established.

Regardless of the deposition site, calcium phosphate crystals share certain radiographic features that allow radiologists to distinguish them from other conditions. On X-rays, calcium phosphate crystal deposits appear as homogeneous but irregularly shaped masses without trabeculation, making them easily distinguishable from heterotopic ossification or sesamoid bones. The deposits vary in size, with most being slightly rounded, though linear or triangular shapes with sharp or indistinct margins are also possible. Tendon deposits are typically located near tendon insertion points. While periarticular regions are the most common sites, deposits can also occur farther from joints, such as at the insertion points of the gluteus maximus, adductor muscles, and pectoralis major.

bubble_chart Diagnosis

(1) Identification of Crystals

(2) The periarticular synovial membrane, tendons, ligaments, and bursae of the shoulder joint are the most common sites for calcific deposits. Bosworth found that deposits are more frequent in the right shoulder than the left, and approximately 50% of patients exhibit bilateral deposits simultaneously. Basic calcium phosphate can deposit in almost any joint or tendon throughout the body. Gondos observed that joints with greater mobility are more prone to basic calcium phosphate deposition, with shoulder calcifications accounting for about 69% of cases, followed by the hip, elbow, wrist, and knee joints. Within the shoulder, the most common site of deposition is the supraspinatus ligament, particularly within approximately 1 cm of its attachment to the greater tubercle of the humerus. When the shoulder is in internal or external rotation, calcific deposits in the supraspinatus ligament can be clearly visualized. Calcifications at the attachment site of the supraspinatus ligament to the greater tubercle are secondary degenerative calcifications, which are irreversible and differ from the primary periarticular calcifications described earlier. The calcifications in calcific periarthritis may enlarge, shrink, disperse, or completely disappear over time.

(3) Clinical Manifestations

(4) Typical Radiographic Findings

bubble_chart Treatment Measures

Acute inflammation of joints or periarticular tissues caused by calcium pyrophosphate deposition can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) at the same dosage as for acute gout. Oral or intravenous colchicine is also beneficial. As with other crystal deposition diseases, joint aspiration followed by corticosteroid injection is effective.

For patients in the chronic phase, low-dose daily NSAID therapy also yields good results. As with all subacute and chronic arthritis, physical therapy—including heat therapy and exercise—is important for maintaining joint mobility and alleviating symptoms. For large periarticular crystal deposits, surgical removal may be considered if conservative treatment fails.

bubble_chart Differentiation

Calcific tendinitis and bursitis must be differentiated from the following three major categories of diseases. The first category is metastatic calcification, which is caused by abnormal calcium and phosphorus metabolism, such as renal osteodystrophy, hypoparathyroidism, vitamin D excess, and {|###|}fleshy tumor{|###|} disease. The second category is calcium salt deposition {|###|}abdominal mass disease{|###|} (calcinosis): calcification occurs in the skin or subcutaneous interstitial tissue, but calcium metabolism is normal, such as generalized interstitial calcinosis, scleroderma, dermatomyositis, and tumoral calcinosis. The third category is dystrophic calcification, where calcium deposits in nonviable tissues, which can be localized or systemic, such as deposits in degenerated or necrotic tissues, tumor inflammation, trauma, or even tissues infected by {|###|}Chinese Taxillus Herb{|###|} parasites.

Calcific tendinitis and bursitis must be differentiated from soft tissue ossification. Ossified tissue may have trabecular bone formation, whereas calcification does not. Soft tissue ossification is commonly seen in traumatic myositis ossificans, nerve {|###|}injury{|###|}, burns, soft tissue {|###|}fleshy tumor{|###|}, postoperative scars, varicose veins, or even progressive myositis ossificans.

Osteophytes at tendon and ligament attachment sites may exhibit trabecular bone formation and extend toward the tendon attachment, making them easily distinguishable from tendon calcification.

Calcific tendinitis can also occur in {|###|}abdominal mass disease{|###|} caused by calcium pyrophosphate dihydrate crystal deposition. This condition may present with chondrocalcinosis and tendon calcification, often appearing diffuse and elongated. Alkaline calcium phosphate deposits typically appear round.

{|###|}Pain wind{|###|} and calcific tendinitis can sometimes be difficult to distinguish clinically, as both present with inflammation, and X-rays may show soft tissue swelling and calcification. Both also respond to colchicine treatment. {|###|}Pain wind{|###|} may sometimes be accompanied by bone erosion, whereas calcific tendinitis is not.

The radiographic findings of intra-articular alkaline phosphate crystal deposition {|###|}abdominal mass disease{|###|} resemble those of degenerative arthritis and calcium pyrophosphate dihydrate crystal deposition {|###|}abdominal mass disease{|###|}. In the knee joint, joint destruction caused by alkaline calcium phosphate crystals is often more severe than degenerative arthritis and tends to occur in the lateral femorotibial or femoropatellar joints, whereas degenerative arthritis typically affects the medial femorotibial or femoropatellar joints. Radiographic manifestations of degenerative arthritis in the glenohumeral joint are often mild, unlike the severe joint destruction seen in alkaline calcium phosphate crystal arthropathy.

The condition most similar to alkaline calcium phosphate crystal arthropathy is calcium pyrophosphate dihydrate crystal arthropathy, and these two diseases can often coexist in the same individual or even the same joint. Generally, alkaline calcium phosphate crystal deposition does not cause chondrocalcinosis. It forms uniform, cloud-like intra-articular opacities, which may or may not be accompanied by joint capsule calcification. Both can lead to severe progressive joint degeneration.

It is important to emphasize that alkaline calcium phosphate crystals can deposit in joints affected by other diseases, such as degenerative arthritis and {|###|}wind-dampness{|###|} arthritis. Once deposited, these crystals can accelerate the progression of the underlying disease, causing severe damage to cartilage, bone, and soft tissues.