Basic calcium phosphate crystal deposition diseases

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Basic calcium phosphate (BCP) crystal deposition diseases are an uncommon form of crystalline arthropathy. BCP crystals include several different types of calcium phosphate crystals, such as partially carbonate-substituted hydroxyapatite, octacalcium phosphate, and tricalcium phosphate. These crystals are deposited in joints or in periarticular structures, causing BCP-associated arthritis (including Milwaukee shoulder syndrome) and calcific tendinitis. The underlying etiology of articular and periarticular BCP crystal deposition is unknown, but risk factors include female sex, joint trauma, and various metabolic abnormalities. The presentation and management of BCP-associated osteoarthritis are similar to that of age-related osteoarthritis. Milwaukee shoulder syndrome and acute calcific tendinitis manifest with joint pain and swelling, most commonly of the shoulder or other large joints. Diagnosis is based on clinical and radiological findings. Synovial fluid analysis may be helpful in excluding differential diagnoses (e.g., acute gout, pseudogout, septic arthritis) but rarely identifies the small, nonbirefringent BCP crystals. Management is primarily supportive and includes pain relief for acute episodes, physical dissolution of crystals by various methods (e.g., needle aspiration, ultrasound therapy), and surgery in severe cases.

The underlying etiology that results in BCP crystal deposition within joints and periarticular tissue remains poorly understood. The following factors are associated with an increased risk of developing BCP crystal deposition diseases: ^[2][3][4]

• Female sex
• Mild trauma or joint overuse
• Gout and acute CPP crystal arthritis
• Renal disease ^[5]
• Metabolic abnormalities including hypercalcemia, hyperphosphatemia, and hypophosphatasia (in calcific tendinitis) ^[6]

The pathophysiology of BCP crystal deposition diseases is complex and not yet fully understood. BCP crystals appear to cause joint degeneration by inducing both inflammatory and catabolic processes. ^[2][7]

• Inflammatory processes: e.g., BCP crystals act on local fibroblasts, chondrocytes, and synovial macrophages to upregulate the expression of inflammatory cytokines and prostaglandins
• Catabolic processes: e.g., BCP crystals act on chondrocytes to upregulate the expression of enzymes that degrade cartilage, and they also inhibit antiosteoclastogenic factors → osteoclast formation

There are three main subtypes of BCP crystal deposition disease, all of which vary in their clinical presentation and diagnosis.

BCP-associated osteoarthritis (OA) is osteoarthritis associated with the intraarticular deposition of BCP crystals. ^[7]

• Epidemiology: BCP-associated OA is widely prevalent. ^[3][8]
• Clinical features
  • Similar to clinical features of osteoarthritis
  • The degree of calcification appears to correlate to the severity of OA seen on imaging. ^[3]
• Diagnostics
  • Imaging: See “Diagnosis of osteoarthritis” for modalities and findings.
  • Additional diagnostics: not routinely required

BCP-associated arthropathies typically affect large joints. ^[2]

Milwaukee shoulder syndrome is a subtype of BCP-associated OA characterized by a noninflammatory osteoclast-mediated destructive arthritis of the shoulder joint and commonly accompanied by non-inflammatory joint effusion and rotator cuff deficits. ^[3][7][9]

• Epidemiology ^[4]
  • Sex: ♀ > ♂ (4:1)
  • Age of onset: adults ≥ 60 years
• Clinical features ^[2][4][10]
  • Joint pain and swelling ^[11]
  • Restricted range of motion
  • Crepitus with joint movement
  • Location
    • Typically affects the shoulder
    • May frequently involve joints other than the glenohumeral joint (e.g., knees, hips, elbows, wrists)
  • Symptoms may diminish after 1–2 years. ^[8]
• Diagnostics ^[2]
  • Synovial fluid analysis
    • Typically shows fewer WBCs (effusions are noninflammatory) and many RBCs
    • Nonspecific for BCP crystals; detects CPP crystals in approx. 50% of patients ^[2][3]
    • Special stains (e.g., alizarin red S stain) may detect clumps of crystals but have poor specificity for BCP crystals. ^[2][4]
  • Imaging
    • X-ray shoulder: may show signs of rotator cuff damage
    • MRI shoulder: may show large joint effusion, significant rotator cuff tears, synovial hypertrophy, and calcification and destruction of cartilage at the articular surface

Milwaukee shoulder syndrome is associated with an extensive loss of articular cartilage, destruction of the humeral head, rotator cuff defects, large effusion, and small osteophytes. Conversely, OA is typically associated with prominent osteophytes, an intact rotator cuff, and humeral head sclerosis. ^[9]

Calcific tendinitis is an inflammatory tendinopathy and periarticular soft tissue inflammation associated with periarticular deposition of BCP crystals. ^[12]

• Epidemiology ^[7][8]
  • Sex: ♀ > ♂
  • Age of onset: adults aged 30–60 years; relatively uncommon in older adults ^[12]
• Clinical features ^[2][12]
  • Acute calcific tendinitis
    • Rapid onset of severe pain, with mild swelling and erythema
    • Range of motion may be restricted.
    • Possible low-grade fever
    • Location
      • Most commonly the rotator cuff (supraspinatus or infraspinatus tendons)
      • Can also affect the hip, spine, hand/wrist, and other joints ^[3][12]
    • Symptoms are typically self-limiting, with clinical and radiological resolution in 2–3 weeks (or less, with treatment). ^[2]
    • Recurrences are common. ^[3]
  • Chronic calcific tendinitis: a chronic pain syndrome that may develop after recurrent acute attacks ^[8]
• Diagnostics ^[2][12]
  • Laboratory studies: WBC and inflammatory markers (e.g., CRP, ESR) may show mild elevations.
  • Imaging ^[12]
    • X-ray of the affected joint ^[3]
      • Initial imaging modality of choice
      • Large deposits of calcifications within the articular cartilage
    • MRI: can be useful to exclude other diagnoses
    • Arthrography: can be useful to confirm a rotator cuff tear

Periarticular calcium deposits may be asymptomatic and detected incidentally. ^[2]

The diagnosis of BCP crystal deposition diseases is primarily based on clinical and radiological findings. See “Subtypes and variants” section for specific diagnostic studies. ^[2]

• Assess the pretest probability of the underlying etiology based on clinical features and patient risk factors.
• Moderate or high clinical suspicion for possible septic arthritis, gout, acute CPPD disease: Perform synovial fluid analysis, as the interpretation of SFA will help narrow the diagnosis.
• Low suspicion for septic arthritis or gout: Perform imaging (beginning with x-ray of the affected joint) to evaluate for calcifications and, if the shoulder is affected, rotator cuff damage.
• If the diagnosis remains uncertain, consult rheumatology.

• Septic arthritis
• Inflammatory arthritis (other types): See “Differential diagnoses of inflammatory arthritis.”
  • Gout and CPPD disease
  • Rheumatoid arthritis
  • Seronegative spondyloarthropathy (e.g., psoriatic arthritis, reactive arthritis)
• Charcot joint ^[9]
• Avascular necrosis
• Traumatic soft tissue or bony injury ^[12]
• Dialysis arthropathy

References: ^[4][10]

The differential diagnoses listed here are not exhaustive.

General principles

• The management of BCP crystal deposition diseases is primarily supportive.
• Treatment for BCP-associated OA is the same as for general OA (see “Treatment of osteoarthritis”).
• Treatment for other BCP crystal deposition diseases should involve consultation with a rheumatologist.
  • Acute episodes: Treatment is focused on achieving pain relief.
  • Chronic disease: The aim is to physically dissolve the crystals using a variety of modalities.
  • Surgical intervention is a last resort.

Initial management (acute episodes) ^[2][3]

• Joint rest: Consider immobilization with a splint.
• NSAIDs (see “Oral analgesics”)
• Glucocorticoid injections ^[2]
• Needle aspiration :
  • Of large joint effusions in Milwaukee shoulder syndrome
  • Of crystal deposits in calcific tendinitis (combined with lavage; known as barbotage) ^[3]
• Physical therapy

Subsequent management ^[2][3]

• Chronic calcific tendinitis: Various physical modalities may be used to attempt to break up large crystal deposits.
  • Ultrasound therapy
  • Barbotage
  • EDTA injections
  • High-energy extracorporeal shockwave therapy
• Advanced disease: Surgery may be considered.
  • Milwaukee shoulder syndrome: acromioplasty, hemiarthroplasty, total arthroplasty
  • Calcific tendinitis: arthroscopic surgery