Hydroxyapatite Crystal-Induced

Does this patient have basic calcium phosphate crystal/hydroxyapatite deposition disease?

Basic calcium phosphate (BCP) crystals encompass three different types of calcium crystals: carbonate-substituted hydroxyapatite, octacalcium phosphate, and tricalcium phosphate.

Hydroxyapatite (HA) is the most common component of BCP crystals.

BCP crystals are usually inert and asymptomatic, but can cause several syndromes due to deposition in and around the joints and soft-tissues:

Calcific periarthritis

Associated with BCP deposits in tendons and bursae, most commonly around the shoulder (particularly rotator cuff), but can occur around almost any joint. Acute calcific periarthritis presents with sudden onset of severe pain, swelling, tenderness, and restricted motion, with overlying redness and warmth.

At the glenohumeral joint, pain is most prominent at the subacromial region, radiating down the lateral arm. Due to rupture of the calcific deposits into adjacent soft tissues, BCP crystals elicit an intense inflammation in subacromial bursa.

Symptoms usually resolve over 2-3 weeks, but may result in a “frozen shoulder”. Hip, knee, elbow, wrist, ankle joint involvement can occur, while hands and feet are less commonly affected. Most cases occur spontaneously, but can occur after mild trauma or overuse injuries.

Acute neck pain can occur from calcifications around the odontoid process (“Crowned dens syndrome”, which can be composed of apatite, CPP crystals, or both).

Damage to rotator cuff apparatus may lead to partial/complete total tears.

Most periarticular BCP deposits are asymptomatic and most commonly discovered as an incidental finding on plain film radiography.

Articular disease

Intra-articular BCP crystal deposits may be found in synovial joint fluid, synovium, and articular cartilage. Co-occurrence of BCP crystals and osteoarthritis (OA) is well-established.

In mild-moderate-stage OA of the hip and knee (radiographic Kellgren stages two and three) mineralization of the articular cartilage by BCP, particularly apatite, was strongly associated with OA development; whereas, cartilage calcification with CPP crystal was found less infrequently. The association between BCP crystals and OA is much stronger, since their presence correlated significantly with severity of cartilage degeneration.

Acute bouts of arthritis related to intra-articular BCP deposits have been described in the knee, resembling gout. Chronic, sometimes erosive monoarthritis can occur rarely, particularly in finger joint arthropathies such as erosive or inflammatory OA. The severity of radiographic changes of OA tends to correlate with the incidence of apatite deposition, with some data supporting the role of BCP crystals in cartilage degeneration.

Milwaukee shoulder syndrome

BCP crystal-associated destructive arthritis of the shoulder. It has been described in elderly individuals (usually >70 years old); 90% females, and is associated with rotator cuff defects and numerous BCP crystals in joint fluids. Rotator cuff is usually completely destroyed.

Presents with increasing pain, swelling, functional loss over months to years. Pain is most severe at night and on joint use, with reduced range of motion, and sometimes with joint instability. Marked crepitation is typical, and joint effusion may be massive. Destructive arthritis predominantly affects the shoulder but can also occur in knees, hips, elbows, and other joints.

Calcinosis (soft tissue dystrophic calcification with BCP crystals)

Subcutaneous deposits can occur in scleroderma, and fascial deposits in dermatomyositis. Tumoral calcinosis is a rare, progressive deposition of BCP masses in cutaneous and subcutaneous tissue, typically associated with chronic renal failure and hyperparathyroidism.

Calciphylaxis is a severe complication of renal failure characterized by nodular subcutaneous calcifications that may lead to painful tissue necrosis, ulceration, and secondary infection.

Differential diagnosis

Acute calcific periarthritis or arthritis attacks may mimic gout, pseudogout, and sepsis. BCP crystal deposition should be considered in erosive arthritis, particularly in the wrist and fingers. BCP crystals are often detected in osteoarthritic joints, and thus should be considered as a cause of cartilage damage, although controversy exists as to BCP being the result, rather than the cause, of joint damage.

Multifocal deposits may be present, and development of symptoms at several sites may simulate a seronegative polyarthritis.

The differentials for destructive arthropathies in the elderly include: neuropathic arthropathy or Charcot joints, chronic sepsis, advanced rheumatoid arthritis, osteonecrosis, CPPD deposition disease.

What tests to perform?

Imaging

Plain radiographs should be performed, which is the easiest method to detect calcific material in periarticular tissues. These appear dense, homogenous, with well-defined borders.

During acute attacks of periarthritis, deposits may appear fluffy with poorly-defined margins radiographically, with decrease in size or even disappearance. This is presumably due to rupture of the calcific deposit into adjacent soft tissue or bursa inciting an acute inflammatory response. Subsequently, sharp calcifications reappear.

Intra-articular BCP deposits are rarely visible on radiographs. In the shoulder, deposits are usually seen by x-ray in the rotator cuff, particularly the supraspinatus tendon, or the subacromial bursa (Figure 1). CT or MRI may help demonstrate small deposits or other soft tissue changes around the calcifications, and MRI can define rotator cuff tears.

Figure 1.

In the Milwaukee shoulder syndrome, the radiographs strikingly demonstrate upward subluxation of the humeral head as evidence of rotator cuff defects and degenerative changes in the majority of the cases.

The use of high-resolution ultrasound (US) with power-Doppler imaging potentially could differentiate the formative and resorptive phases of the calcification and could be used as a follow-up modality in calcific tendonitis of the shoulder.

In a study, positive power-Doppler signal within the calcific deposit and widening of the subacromial bursa were US features strongly associated with pain. Larger calcifications are also more symptomatic, suggesting that US can help physicians confirm that calcification is responsible for shoulder pain.

Identification of basic calcium phosphate crystals

Intra-articular BCP crystals are infrequently recognized due to lack of simple, reliable tests for its detection. These crystals are not birefringent, thus compensated polarized light microscopy is not useful, unlike MSU or CPP crystals of gout or pseudogout respectively. Individual BCP crystals are too small to be resolved by light microscopy. They tend to aggregate into globular clumps and can appear as refractile “shiny coins” on light microscopy (Figure 1 A).

Larger BCP aggregates can be detected by Alizarin red S stain which is highly sensitive but lack specificity (Figure 1 B). Clumps of crystals show a “halo” of this stain. Tetracyclines stain calcium phosphate mineral has been used to identify BCP crystals in synovial fluid based on its avidity to bind hydroxyapatite mineral and its fluorescence. In a small trial, the use of oxytetracycline binding assay appeared to perform better than Alizarin red S, with lower false-positive results. However, additional studies are required. Both of these staining methods are performed in specialized Rheumatology laboratories.

Definitive methods of BCP identification such as x-ray diffraction, scanning or transmission electron microscopy are typically unavailable or too costly for routine use. It is sometimes possible to aspirate material from periarticular tissues, appearing like toothpaste, chalk, or creamy fluid.

Synovial or bursal fluid findings vary, but should be sent for analysis including cell count, to rule out other causes of inflammatory arthritis, along with gram stain and culture if septic arthritis or bursitis is being considered. Synovial fluid that contains BCP is typically viscous with low, predominantly mononuclear cell count, similar to findings in OA. In destructive arthropathies/Milwaukee shoulder syndrome, synovial fluid is frequently blood-stained. In synovial fluid samples, BCP crystals frequently coexist with calcium pyrophosphate dihydrate crystals.

Identification of BCP/hydroxyapatite crystals is less crucial because there is no drug therapy yet that alters BCP effects in vivo, compared with monosodium urate crystal deposition.

How should patients with basic calcium phosphate crystal/hydroxyapatite deposition disease be managed?

Calcific periarthritis

Asymptomatic calcific deposits require no treatment. Acute periarthritis can be managed with immobilization, nonsteroidal anti-inflammatory drugs (NSAIDs), or colchicine. Most patients improve within 5 days and may completely resolve by 1-3 weeks.

Use of local corticosteroid injection is controversial as it may help resolve acute attacks, but may be associated with further calcification or recurrent attacks. Thus, this should be used with caution.

Shock-wave lithotripsy has been suggested as a method of breaking up calcific deposits. In acute periarthritis, tenotomy with needle aspiration of toothpaste-like calcific deposits, with or without irrigation, followed by steroid injection may be helpful.

In chronic, refractory periarthritis, arthroscopic or surgical removal of calcific deposits may provide permanent symptomatic relief.

BCP/Hydroxyapatite-associated arthritis

Patients with OA complicated by BCP crystal deposition should be treated as in primary OA. In destructive arthritis/Milwaukee shoulder syndrome, advanced destructive changes are usually present; treatment of symptomatic disease is unsatisfactory. Conservative management with analgesics, NSAIDs, joint aspirations, temporary immobilization may sometimes control symptoms.

Theoretically, non-selective COX inhibitors would be more effective because BCP crystals induce both COX-1 and COX-2 pathways.

Surgical therapy may be necessary for pain relief and restoration of function, but may be challenging due to extent of damage and age of the patient. This may involve arthroscopic lavage, arthroplasty, but ultimately joint replacement may be necessary for advanced degenerative disease.

What happens to patients with basic calcium phosphate crystal/hydroxyapatite deposition disease?

Etiology is unknown. Frequent occurrence of bilateral and multifocal deposits suggests a systemic predisposition, although no local, metabolic cause for calcification is found. No genetic defects are identified, although there are several reports of familial occurrences of calcific periarthritis. Relationship between repetitive shoulder use and the formation of calcific deposits have not been established.

Females are affected more frequently with calcific periarthritis than males, and prevalence was highest in ages 31-40.

Prevalence of intra-articular BCP crystal deposition is not clearly established; up to 60% of synovial fluid samples from patients with knee joint OA contain apatite crystals, and in a study of 53 preoperative OA knees, prevalence of BCP was around 50%.

The Milwaukee shoulder syndrome and other BCP crystal-associated destructive arthropathies are rare with unknown prevalence; these tend to occur in elderly females.

Natural history of large joint destructive arthropathies is unclear, but many cases seem to stabilize over 2 years, with reduction of symptoms and joint effusions, with no further radiographic changes.

Recurrent acute attacks of periarthritis or arthritis can occur, and may be followed by development of chronic pain. Pain may subside over time.

There remains no specific treatment to modify the effects of BCP crystals.

How to utilize team care?

Specialty consultation with Rheumatology.

Orthopedic surgery for severe or refractory symptoms.

Physical therapy and occupational therapy as adjunctive management of periarthritis syndromes or for mobilization/strengthening exercises.

Are there clinical practice guidelines to inform decision making?

None.

What is the evidence?

Schumacher, HR, Cherian, PV, Reginato, AJ. “Intra-articular apatite crystal deposition”. Ann Rheum Dis. vol. 42. 1983 Aug. pp. 54-9.

McCarthy, G, Hochberg, MC, Silman, AJ, Smolen, JS. “Basic calcium phosphate crystal deposition disease”. Rheumatology. 2011. pp. 1889-1897.

Bouvet, -J-P, le Parc, J-M, Michalski, B. “Acute neck pain due to calcifications surrounding the odontoid process: the crowned dens syndrome”. Arthritis Rheum. vol. 28. 1985. pp. 1417-1420.

MacMullan, P, McMahon, G, McCarthy, G, Terkeltaub, R. “Basic Calcium Phosphate Crystal Arthropathy”. Gout and Other Crystal Arthropathies. 2012.

O’Shea, FD, McCarthy, GM. “Basic calcium phosphate crystal deposition in the joint—a potential therapeutic target in osteoarthritis”. Curr Opin Rheumatol. vol. 16. 2004. pp. 273-278.

McCarty, DJ, Halverson, PB, Carrera, GF. “Milwaukee shoulder: association of microspheroids containing hydroxyapatite crystals, active collagenase, and neutral protease with rotator cuff defects, I: clinical aspects”. Arthritis Rheum. vol. 24. 1981. pp. 464-473.

Fuerst, M, Bertrand, J, Lammers, L. “Calcification of articular cartilage in human osteoarthritis”. Arthritis Rheum. vol. 60. 2009 Sep. pp. 2694-703.

Fuerst, M, Niggemeyer, O, Lammers, L. “Articular cartilage mineralization in osteoarthritis of the hip”. BMC Musculoskelet Disord. vol. 10. 2009 Dec 29. pp. 166

Chiou, HJ, Chou, YH, Wu, JJ. “Evaluation of calcific tendonitis of the rotator cuff. Role of color Doppler ultrasonography”. J Ultrasound Med. vol. 21. 2002. pp. 289-95.

Le Goff, B, Berthelot, JM, Guillot, P. “Assessment of calcific tendonitis of rotator cuff by ultrasonography: comparison between symptomatic and asymptomatic shoulders”. Joint Bone Spine. vol. 77. 2010 May. pp. 258-63.

Paul, H, Reginato, AJ, Schumacher, HR. “Alizarin red S staining as a screening test to detect calcium compounds in synovial fluid”. Arthritis Rheum. vol. 26. 1983. pp. 247-251.

Gibilisco, PA, Schumacher, HR, Hollander, JL. “Synovial fluid crystals in osteoarthritis”. Arthritis Rheum. vol. 28. 1985. pp. 511-515.

MacMullan, P, McMahon, G, McCarthy, G. “Detection of basic calcium phosphate crystals in osteoarthritis”. Joint Bone Spine.. vol. 78. 2011 Jul. pp. 358-63.

Rosenthal, AK, Fahey, M, Gohr, C. “Feasibility of a tetracycline-binding method for detecting synovial fluid basic calcium phosphate crystals”. Arthritis Rheum. vol. 58. 2008 Oct. pp. 3270-4.

Ebenbichler, GR, Erdogmus, CB, Resch, KL. “Ultrasound therapy for calcific tendinitis of the shoulder”. N. Engl. J. Med. vol. 340. 1999. pp. 1533-8.

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