Hydroxyapatite deposition disease (HADD), also known as calcific tendinosis, is a condition characterized by the accumulation of hydroxyapatite crystals in tendons, joints, and other soft tissues. These crystals, a form of calcium phosphate, are normally found in bones and teeth, providing their rigidity. HADD can be asymptomatic, but when associated with an inflammatory process, it can mimic trauma, infection, or neoplasm, leading to misdiagnosis and unnecessary interventions.
Understanding Hydroxyapatite Deposition Disease
HADD is one of several types of crystal-induced arthropathies, which also include gout (caused by uric acid crystals) and pseudogout (caused by calcium pyrophosphate dihydrate crystals). While these conditions share the commonality of inflammation resulting from the body's reaction to crystals, the type of crystal differs in each case.
- Gout: Caused by the deposition of monosodium urate crystals in the joints, most commonly affecting the big toe.
- Pseudogout (Calcium Pyrophosphate Deposition Disease - CPPD): Characterized by the deposition of calcium pyrophosphate dihydrate crystals in the joints, often affecting the knees and wrists.
- Hydroxyapatite Deposition Disease (HADD): Involves the buildup of hydroxyapatite crystals in soft tissues such as tendons, ligaments, and bursae.
This review aims to delve into the etiology, highlight the critical role of radiological findings in diagnosis, and explore current and emerging treatment strategies for HADD.
Etiology and Pathogenesis of HADD
The precise etiology of HADD remains elusive and is an ongoing subject of investigation. The deposition of hydroxyapatite crystals can occur intra- or periarticularly. Several theories attempt to explain the development of HADD.
Proposed Pathogenic Mechanisms
Four main hypotheses have been proposed for the development of HADD:
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Degenerative Calcification: This theory suggests that HADD is a response to physical stress or injury, involving tissue degeneration followed by calcification. Vascular ischemia, resulting from factors such as physical injury or repetitive strain, can lead to insufficient oxygen and glucose for cellular metabolism in tendons. Repetitive trauma can cause microtears in the tendon, leading to inflammation and subsequent tissue degeneration. This process results in hydroxyapatite crystal formation, inducing pain and inflammation.
Reactive or Cell-Mediated Calcification: This mechanism proposes that chondrocytes, the cells maintaining the cartilaginous matrix, mediate calcium deposition. Chondrocytes, residing in cartilage, synthesize and maintain the cartilaginous matrix, a network of proteins and molecules that provide structure and support to the tissue. In the context of HADD, chondrocytes may contribute to calcium deposition, potentially in response to injury or inflammation. Phagocytosing cells, which absorb harmful foreign particles, bacteria, and dead or dying cells, aid in the resorption of calcified material, implying that the body’s cells play a part in both HADD development and resolution.
Endochondral Ossification: This fundamental bodily process is responsible for long bone formation and natural growth. In HADD, this process deviates pathologically, resulting in abnormal calcium deposition within the soft tissues rather than the standard transformation of cartilage into bone. This deviant calcification can occur in tendons, ligaments, and other periarticular soft tissues, leading to HADD’s clinical manifestations. The specific trigger for this abnormal ossification remains elusive but is conjectured to be a response to tissue damage or stress, similar to the physiological injury response where bone forms to repair and strengthen the damaged area.
Faulty Differentiation of Tendon-Derived Stem Cells: This hypothesis involves the faulty differentiation of tendon-derived stem cells into calcium-depositing chondrocytes or osteoblasts. In the context of HADD, these tendon-derived stem cells are hypothesized to mis-differentiate into calcium-depositing chondrocytes or osteoblasts, contributing to disease development. This implies a dysregulation in the stem cell differentiation process, possibly due to genetic or environmental factors.
Predisposing Factors
Several predisposing factors augment the likelihood of HADD onset, including metabolic and genetic influences.
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Metabolic Factors: Diabetes is a substantial risk factor associated with HADD, though the exact contribution remains to be fully delineated. Disorders pertaining to thyroid and estrogen metabolism have also been associated with HADD.
Genetic Factors: Certain genetic factors, such as the HLA-A1 genotype (part of the human leukocyte antigen (HLA) system), are linked with an increased HADD risk.
The etiology of HADD is likely influenced by a complex interplay between metabolic and genetic components, which may interact with the proposed pathogenic pathways, potentially instigating the disease in susceptible individuals. Metabolic disorders like diabetes, and disorders of thyroid and estrogen metabolism, might induce cellular stress or damage, triggering the degenerative calcification pathway.
Stages of HADD
The progression of HADD involves distinct stages:
Precalcific Stage: Characterized by reduced perfusion and resultant localized hypoxia, triggering fibrocartilaginous transformation at the prospective calcification site.
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Calcific Stage: This stage is marked by calcium crystal deposition and is further divided into formative, resting, and resorptive phases.
- Formative Phase: Fibrocartilage is replaced by a calcific deposit. Hydroxyapatite crystals begin to accumulate within the previously formed cartilaginous matrix.
- Resting Phase: The calcific deposit resides without associated vascularity or inflammation for a variable duration. The deposit becomes more stable and is often well-delineated.
- Resorptive Phase: The calcium deposit is invaded by macrophages, polymorphonuclear cells, and fibroblasts that phagocytose and remove the calcium, giving the calcification an ill-defined, irregular appearance. The calcifications begin to break down and liquefy, which can lead to leakage out of the tendon. Acute pain typically coincides with this phase, wherein the calcific deposit may rupture into nearby tissues, inciting an acute inflammatory response.
Postcalcific Stage: The body initiates the repair of calcification-induced damage. Granulation tissue, comprising new connective tissue and microscopic blood vessels, replaces the void left by the resorptive phase. This tissue matures into scar tissue over time, indicating the termination of the active disease phase. However, this does not always indicate a cessation of symptoms or treatment requirement, as the scar tissue can induce discomfort and restrict function depending on its location. The tissue where the deposit was located is remodeled, often leaving behind a fibrocartilaginous scar.
The progression of HADD is dynamic and individualized, varying in duration and severity among individuals. Symptom severity does not necessarily align with the disease stage; the resorptive phase, despite being part of the calcific stage, is often the most acutely painful.
Radiological Findings in HADD
Radiological imaging plays an instrumental role in the diagnosis and management of HADD. Hydroxyapatite deposition disease showcases a broad spectrum of radiological findings discernible in multiple imaging modalities. Hydroxyapatite crystals are predominantly radiopaque, translating to augmented density zones on radiographs.
Imaging Modalities
Plain Radiographs: Regarded as the first line of imaging modality for HADD diagnosis, plain radiographs capture the hallmark feature of HADD: amorphous, nebulous densities in soft tissues. Advanced cases of HADD might exhibit these deposits in conjunction with bone erosion or cortical irregularities. The scattered distribution of the calcified material accounts for the nebulous appearance of these deposits on radiographs, setting HADD apart from other conditions with similar radiographic findings. The location of these deposits could provide valuable insights for diagnosing HADD. Progressed HADD stages might show hydroxyapatite deposits accompanied by bone erosion or cortical irregularities. Bone erosion, the dissolution of bone tissue, might occur due to the pressure exerted by the hydroxyapatite deposits on the neighboring bone tissue. Cortical irregularities, anomalies in the bone’s outer layer, could be due to various factors, including HADD. The appearance will vary based on the calcific stage, broken into the formative, resting and resorptive phases. The formative and resting phases will appear as round-to-ovoid calcification in the soft tissue with well-defined borders. The resorptive phase will appear ill-defined with a comet tail-like appearance. The resorptive phase may mimic a periosteal reaction.
Computed Tomography (CT): CT offers an in-depth visualization of hydroxyapatite deposits, elucidating their size, shape, and location. CT scans reveal these deposits as high-density zones within soft tissues, often associated with the inflammation around them, apparent as increased attenuation in adjacent soft tissues. The high-density portrayal of hydroxyapatite deposits on CT scans stems from hydroxyapatite’s high calcium content, which absorbs more X-rays than the surrounding soft tissues. The detailed information offered by CT scans can shape treatment strategies for HADD patients, such as by guiding surgical interventions. The hydroxyapatite deposits’ association with surrounding inflammation can be gauged on a CT as decreased attenuation in adjacent soft tissues from the soft tissue edema. CT is most sensitive in the detection of hydroxyapatite deposits as well as in analyzing the shape and consistency of deposits.
Magnetic Resonance Imaging (MRI): MRI constitutes an essential imaging modality for diagnosing soft tissue modifications linked to HADD. MRI images display hydroxyapatite deposits as regions with low signal intensity across both T1- and T2-weighted images, attributable to the high mineral content of hydroxyapatite. Concurrently, MRI also reveals inflammation signs within the surrounding soft tissues, such as edema and increased signal intensity on T2-weighted images. On all MRI sequences, calcific deposits show up as focal areas of low signal, usually close to tendon insertions. MRI is the best modality for assessing inflammatory changes and other causes of hip pain. Edema that is connected with the acute resorptive phase may be severe and mimic an infection or injury. A malignant or infectious process may be mistaken for cortical erosion, periosteal response, and marrow involvement, which have all been described.
Ultrasound: Calcifications typically appear hyperechoic with or without acoustic shadowing. Four morphologies of tendon calcification have been described on ultrasound: arc-shaped (echogenic arc of calcification with deep acoustic shadowing), nodular (single echogenic focus of calcification without acoustic shadowing), fragmented (two or more echogenic foci of calcification with or without acoustic shadowing), and cystic (hyperechoic wall with anechoic region, weakly hypoechoic region, or layering content). The nodular, fragmented, and cystic morphologies on ultrasound are associated with the acute, symptomatic phase of calcific tendinitis while the arc morphology is more suggestive of the chronic or asymptomatic phase. Increased flow on power Doppler is strongly associated with acute symptomatic calcific tendinopathy but is present in only about one-third of cases.
Differential Diagnosis
HADD can mimic other conditions, posing diagnostic challenges. It is often mistaken for acute bacterial infection, malignancy, or other crystal arthropathies (gout and pseudogout). The primary differential diagnosis for calcific periarthritis is gout. Gout typically presents as a monoarticular condition, commonly involving the first metatarsophalangeal joint. Radiographically, it displays well-defined “punched-out” erosions with sclerotic margins and overhanging edges (known as rat bite erosions). Periarticular soft-tissue swelling occurs due to monosodium urate crystal deposition around the joints.
Treatment Strategies for HADD
The treatment of HADD aims to alleviate symptoms, reduce inflammation, and facilitate the reabsorption of calcium deposits. The choice of treatment depends on the severity of symptoms, the location and size of the calcium deposits, and the patient's overall health and preferences. Often, a combination of therapies is used to achieve the best outcome.
Conservative Treatments
Rest and Cold Application: Resting the affected area and applying ice packs can help reduce inflammation and numb pain.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Oral NSAIDs, such as ibuprofen or naproxen, are commonly used to manage pain and inflammation for short-term relief during acute flare-ups.
Physical Therapy: A physical therapist can provide exercises to improve range of motion, strengthen the affected muscles, and reduce stiffness. Therapy may include stretching, strengthening exercises, and modalities such as ultrasound therapy to break up calcifications.
Corticosteroid Injections: Local injection of corticosteroids can provide significant pain relief by reducing inflammation.
Fluid Aspiration: A minimally invasive procedure where needles are used under ultrasound guidance to break up and aspirate calcium deposits. This technique helps remove calcium crystals and reduce symptoms.
Interventional Treatments
Extracorporeal Shock Wave Therapy (ESWT): ESWT involves the application of shock waves to the affected area to break down calcium deposits. The shock waves promote reabsorption of calcium deposits and stimulate healing.
Surgical Removal: Surgical removal of calcifications may be appropriate for cases refractory to other attempts of conservative treatment.
Additional Pain Management Strategies
In addition to NSAIDs and corticosteroids, other pain management strategies such as acetaminophen or opioid analgesics (for short-term use) may be employed. Educating patients about the nature of HADD, potential triggers, and self-management strategies is important for long-term management.
Prognosis and Long-Term Management
While HADD can be painful and debilitating, it often resolves on its own over time. The size and location of the deposits play a significant role in the disease's course. Individual variability in the body's response to the crystals also affects the resolution. Most calcifications will decrease in size, or pain will resolve within three months, and roughly 70% of cases will improve with conservative measures within one year. Regular follow-up with health care providers is crucial to monitor progress and adjust the treatment plan as necessary.
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