Hyperostosis

Hyperostosis is a medical condition characterized by the excessive growth or abnormal thickening of bone tissue, typically involving subperiosteal or endochondral bone deposition on the outer (periosteal) or inner (endosteal) surfaces of bones.^[1][2] This non-inflammatory process can lead to increased bone volume and density, often without pain, though symptoms vary depending on the extent and location of the bone overgrowth.^[2] Hyperostosis manifests in various forms, broadly classified as primary (genetic or idiopathic) or secondary (associated with underlying diseases such as malignancies, infections, or metabolic disorders like vitamin A excess).^[2] Among the most notable types is diffuse idiopathic skeletal hyperostosis (DISH), also known as Forestier disease, a common musculoskeletal disorder primarily affecting individuals over age 50, characterized by calcification and ossification of ligaments and entheses, especially along the anterior longitudinal ligament of the spine, leading to spinal stiffness and reduced mobility.^[3][4] Another prominent variant is hyperostosis frontalis interna, a benign thickening of the inner table of the frontal bone of the skull, often incidental and more prevalent in postmenopausal women, with unclear etiology but potential links to hormonal factors.^[5] Less common but significant forms include infantile cortical hyperostosis (Caffey disease), a rare genetic disorder in infants under 4 months old, featuring painful swelling of the long bones, mandible, and clavicles, accompanied by fever and irritability, which typically resolves spontaneously but can recur.^[2] Hypertrophic osteoarthropathy involves periosteal new bone formation along the shafts of long bones, often secondary to lung diseases or malignancies, presenting with digital clubbing, joint pain, and skin changes.^[2] Pachydermoperiostosis and diaphyseal dysplasia (Camurati-Engelmann disease) are rare inherited conditions causing progressive bone thickening and associated soft tissue hypertrophy.^[2] Diagnosis generally relies on radiographic imaging, with treatment focusing on managing symptoms through nonsteroidal anti-inflammatory drugs (NSAIDs) or addressing underlying causes, as many cases do not require intervention.^[2][3]

Definition and Overview

Definition

Hyperostosis refers to an abnormal increase in bone volume or quantity, characterized by excessive growth or thickening of bone tissue, often involving subperiosteal or endochondral deposition of new bone. This process typically manifests as the apposition of new bone along the shafts of long bones or other skeletal structures, potentially leading to the formation of exostoses (bony projections) or enthesophytes (bony spurs at ligament or tendon attachments).^[2][6] Unlike osteosclerosis, which denotes an increase in bone density without significant alteration in bone shape or volume, hyperostosis specifically involves hypertrophic changes that modify the bone's architecture. Similarly, it differs from osteophytosis, a term reserved for the development of osteophytes—bony outgrowths primarily at joint margins in response to degenerative processes such as osteoarthritis—rather than generalized bone thickening.^[2][7] The term "hyperostosis" originates from Greek roots, with "hyper-" meaning excessive or over, and "ostosis" derived from "osteon" (bone) combined with the suffix "-osis" indicating a pathological condition. First appearing in medical literature around 1836, it gained prominence in early 20th-century radiology through descriptions of spinal column hyperostosis by various authors, laying the groundwork for later characterizations of related disorders.^[8][9][10] Hyperostosis is commonly associated with musculoskeletal conditions like diffuse idiopathic skeletal hyperostosis (DISH).^[11]

Epidemiology

Hyperostosis refers to a group of conditions characterized by abnormal bone overgrowth, with prevalence varying significantly by type and population studied. Diffuse idiopathic skeletal hyperostosis (DISH), a common skeletal form, affects approximately 10-30% of individuals over age 50 in various populations, with rates increasing to over 25% in those aged 65 and older.^[3] Cranial hyperostosis frontalis interna (HFI) is reported in 5-12% of adults based on imaging and autopsy studies, though it may be underdiagnosed in asymptomatic cases.^[12] Infantile cortical hyperostosis (Caffey disease), a rare genetic form, has no established prevalence due to underdiagnosis, with no more than a few hundred cases reported in the literature.^[13] Demographic patterns show sex-specific differences across hyperostosis types. Skeletal forms like DISH exhibit a male predominance, with a male-to-female ratio of approximately 2:1, particularly in older adults.^[10] In contrast, cranial HFI is predominantly observed in females, with a female-to-male ratio of approximately 9:1, and is most common in postmenopausal women, with prevalence rising sharply after age 50.^[5] Age is a universal risk factor, as all major forms increase in frequency with advancing age, rarely occurring before 40 years.^[14] Geographic variations are notable, especially for DISH, which shows higher incidence in Mediterranean and Middle Eastern populations compared to Asian or Northern European groups, with prevalence rates up to 42% in certain high-risk cohorts versus 2-3% in others.^[10] Caffey disease appears globally without strong ethnic bias but is likely underreported in low-resource settings.^[15] Key risk factors for hyperostosis, particularly DISH, include age over 50 years, obesity (with higher body mass index correlating to increased odds), and diabetes mellitus (odds ratio 2-3).^[16] Metabolic syndrome components such as hypertension, hyperlipidemia, and hyperuricemia further elevate risk, while for HFI, hormonal changes in postmenopausal women are implicated.^[3]

Classification and Types

Cranial Hyperostosis

Cranial hyperostosis refers to the abnormal thickening of the calvarial bones, particularly involving the inner table of the frontal bone or other skull regions, often resulting from benign proliferative processes.^[17] A primary example is hyperostosis frontalis interna (HFI), characterized by thickening of the inner table of the frontal bone, which can exceed 1 cm in advanced cases and is predominantly observed in postmenopausal women.^[18] HFI is classified into four types (A-D) based on morphological and histopathological features, as described by Hershkovitz et al.: Type A consists of small, unilateral or bilateral elevations less than 10 mm in height; Type B features nodular formations covering less than 25% of the endocranial surface; Type C involves irregular, nodular overgrowth covering 25-80% of the surface with defined borders; and Type D exhibits extensive, nearly complete coverage exceeding 80% of the surface, often with smooth or irregular borders.^[17][19] Other forms of cranial hyperostosis include focal reactive bone overgrowth of the calvarium associated with meningioma, typically seen in 4.5% of cases and more frequently with meningioma en plaque subtypes, where tumor-induced osteoblastic activity leads to localized thickening.^[20] Another variant is leontiasis ossea, which presents as diffuse craniofacial hyperostosis resembling a lion-like facies, primarily due to polyostotic fibrous dysplasia involving the skull bones and causing expansive, sclerotic bone proliferation.^[21][22] Clinically, cranial hyperostosis is often asymptomatic and discovered incidentally on imaging, but severe cases may lead to headaches from dural tension or neurological compression, potentially causing cerebral atrophy, cognitive impairment, or cranial nerve deficits such as vision loss or facial weakness.^[18][23]

Skeletal Hyperostosis

Skeletal hyperostosis primarily manifests as abnormal bone formation along the spine and at peripheral entheseal sites, with diffuse idiopathic skeletal hyperostosis (DISH), also known as Forestier disease, serving as the most common systemic form.^[11] DISH is characterized by flowing ossification of the anterior longitudinal ligament along the anterolateral aspect of the spine, typically involving at least four contiguous thoracic vertebral levels, with preservation of intervertebral disc height and absence of sacroiliac joint erosions or ankylosis, as defined by the Resnick criteria. This condition predominantly affects older adults, leading to progressive spinal stiffness due to ligamentous bridging.^[11] The progression of DISH usually begins in the thoracic spine, where ossification is most pronounced, before extending to the cervical and lumbar regions in advanced cases.^[24] Radiographically, it presents a distinctive "candle-wax" appearance, with smooth, flowing hyperostosis projecting horizontally from the vertebral bodies without involving the posterior elements.^[11] Peripheral manifestations in DISH include enthesopathies such as heel spurs, Achilles tendon ossification, and plantar fasciitis, which can contribute to localized pain and reduced mobility.^[11] Ossification at pelvic entheses, including the iliac crests and ischial tuberosities, may also occur, forming bony excrescences that mimic ossicles.^[3] Another notable form of skeletal hyperostosis is infantile cortical hyperostosis, or Caffey disease, a rare genetic disorder affecting infants under six months of age.^[15] It involves subperiosteal bone proliferation primarily in the mandible, clavicles, and diaphyses of long bones such as the ulna, tibia, and femur, often accompanied by soft tissue swelling and fever.^[13] Unlike DISH, Caffey disease is self-limiting, with hyperostosis typically resolving by age two, though residual deformities may persist.^[15] Metabolic factors, such as diabetes mellitus, are associated with increased risk of DISH.^[11]

Other Forms

Hyperostosis manifests in several rare genetic forms that involve abnormal bone overgrowth due to specific genetic mutations. Camurati-Engelmann disease, also known as progressive diaphyseal dysplasia, is an autosomal dominant disorder characterized by hyperostosis primarily affecting the diaphyses of long bones, leading to cortical thickening and narrowing of the medullary cavities.^[25] This condition results from heterozygous mutations in the TGFB1 gene, which encodes transforming growth factor beta-1, disrupting normal bone remodeling and promoting excessive osteoblast activity.^[26] Affected individuals often experience progressive skeletal deformities, muscle weakness, and gait abnormalities starting in childhood.^[27] Sclerosteosis and Van Buchem disease represent another pair of related genetic sclerosing bone dysplasias involving endosteal hyperostosis, with progressive thickening of the skull base, facial bones, and long bone cortices.^[28] Sclerosteosis is caused by loss-of-function mutations in the SOST gene, which encodes sclerostin, a protein that inhibits bone formation by osteoblasts, resulting in syndactyly, tall stature, and potential cranial nerve compression.^[29] In contrast, Van Buchem disease arises from a homozygous 52-kb deletion downstream of the SOST gene, leading to reduced sclerostin expression and similar hyperostotic features but typically without syndactyly.^[30] Both conditions predominantly affect individuals of Dutch ancestry for Van Buchem disease and South African origin for sclerosteosis, with hyperostosis contributing to mandibular enlargement and hearing loss.^[31] Iatrogenic causes of hyperostosis include drug-induced bone changes from prolonged exposure to certain medications. Retinoid therapy, such as isotretinoin used for severe acne vulgaris, can induce periosteal hyperostosis, particularly in the spine, pelvis, and long bones, with radiographic evidence of ligamentous ossification resembling diffuse idiopathic skeletal hyperostosis.^[32] This adverse effect is dose- and duration-dependent, often becoming apparent after years of intermittent treatment, and may progress even after discontinuation.^[33] Similarly, chronic fluoride excess from environmental or occupational sources leads to skeletal fluorosis, a condition marked by osteosclerosis and hyperostosis of the axial skeleton, including ligament calcification and vertebral fusion.^[34] In non-endemic cases, such as inhalant abuse of fluoride-containing products, this results in symmetric periosteal reactions and joint stiffness.^[35] Hypertrophic osteoarthropathy (HOA) is another significant form, characterized by periosteal new bone formation (hyperostosis) along the diaphyses and metaphyses of long bones, often accompanied by digital clubbing, joint effusions, and skin changes. It is classified into primary and secondary types. The primary form, also known as pachydermoperiostosis, is a rare autosomal dominant genetic disorder linked to mutations in genes such as HPGD or SLCO2A1, typically onset in adolescence with more severe effects in males, leading to pachydermia, painful joint swelling, and cosmetic concerns from facial coarsening.^[36] The secondary form, which is more common, arises from underlying conditions including pulmonary malignancies (e.g., non-small cell lung cancer), chronic infections (e.g., tuberculosis), cyanotic congenital heart disease, or inflammatory bowel disease; it involves similar skeletal and soft tissue changes but resolves upon treatment of the primary cause.^[37] Among miscellaneous forms, hyperostosis in variants of Paget's disease of bone, such as juvenile Paget disease, involves excessive bone formation and resorption imbalance, causing hyperostotic expansion of the skull, limbs, and vertebrae with deformities and fractures.^[38] This rare form stems from mutations in TNFRSF11B (encoding osteoprotegerin), resulting in accelerated bone turnover and elevated alkaline phosphatase levels.^[39]

Causes and Pathophysiology

Etiology

Hyperostosis encompasses a range of conditions with diverse etiologies, including genetic, metabolic, inflammatory, neoplastic, and iatrogenic factors. Genetic forms often arise from specific mutations affecting bone remodeling pathways. For instance, Camurati-Engelmann disease, a rare autosomal dominant disorder, results from gain-of-function mutations in the TGFB1 gene, leading to progressive diaphyseal hyperostosis of long bones and the skull.^[25] Sclerosteosis, an autosomal recessive sclerosing bone dysplasia, is caused by loss-of-function mutations in the SOST gene, which encodes sclerostin, resulting in generalized hyperostosis and syndactyly.^[40] Additionally, infantile cortical hyperostosis, or Caffey disease, has been linked to specific mutations in the COL1A1 gene, such as c.3040C>T, causing episodic hyperostosis primarily in the mandible, clavicles, and long bones during infancy.^[41] Acquired metabolic causes are frequently associated with systemic conditions that promote ectopic ossification. Type 2 diabetes mellitus, particularly through insulin resistance and hyperinsulinemia, correlates with increased risk of diffuse idiopathic skeletal hyperostosis (DISH), where metabolic dysregulation may enhance ligamentous ossification along the anterolateral spine.^[42] Obesity contributes similarly, with elevated levels of adipokines such as leptin implicated in stimulating osteoblast activity and entheseal ossification in DISH and related hyperostotic states.^[43] Hypervitaminosis A, from excessive intake of vitamin A or its derivatives, induces periosteal hyperostosis and exostoses, often affecting the spine and peripheral skeleton in chronic cases.^[44] Inflammatory and neoplastic etiologies involve reactive bone overgrowth. Hyperostosis can occur secondary to meningiomas, especially those invading the skull base, where tumor-secreted factors like vascular endothelial growth factor (VEGF) promote periosteal proliferation and bony thickening.^[45] Certain seronegative spondyloarthropathies, such as SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), feature hyperostosis as a core component, often affecting the anterior chest wall and spine through chronic inflammatory enthesopathy.^[46] Iatrogenic causes stem from therapeutic exposures that stimulate bone formation. Synthetic retinoids, including isotretinoin and etretinate, used in dermatological treatments, frequently induce skeletal hyperostosis via periosteal activation, with radiographic changes like ligamentous ossification appearing after prolonged high-dose administration.^[47] Rare cases of chronic fluoride exposure, such as in skeletal fluorosis from occupational or environmental sources, lead to dense periosteal hyperostosis and osteosclerosis, particularly in the spine and pelvis.^[35] In many instances, particularly with DISH—the most common form of spinal hyperostosis—the etiology remains idiopathic, lacking identifiable genetic or secondary triggers despite strong associations with metabolic syndrome.^[11]

Pathophysiological Mechanisms

Hyperostosis arises from an imbalance in bone remodeling processes, where osteoblast-mediated bone formation predominates over osteoclast-driven resorption, leading to excessive subperiosteal bone apposition and ossification at entheseal sites.^[11] This dysregulation results in the characteristic flowing ossifications along ligamentous attachments, particularly in conditions like diffuse idiopathic skeletal hyperostosis (DISH).^[11] At the molecular level, upregulation of bone morphogenetic protein (BMP) signaling contributes to enhanced osteogenesis in genetic forms of hyperostosis, as evidenced by reduced expression of BMP inhibitors such as CHRDL2 and NOG, which normally restrain osteoblast differentiation.^[48] Similarly, transforming growth factor-β (TGF-β) pathways, through regulators like RUNX2, promote mesenchymal cell commitment to osteoblastic lineages, fostering abnormal bone growth.^[48] In metabolic variants like DISH, elevated insulin-like growth factor-1 (IGF-1) levels drive the differentiation of entheseal mesenchymal stem cells into osteoblasts, amplifying new bone formation at tendon and ligament insertions.^[49] Histologically, hyperostotic lesions exhibit new woven bone formation with prominent vascular proliferation, reflecting active osteogenesis.^[50] In DISH specifically, ligamentous calcification often precedes ossification, with focal or diffuse deposition along structures like the anterior longitudinal ligament, transitioning to mature lamellar bone over time.^[51] The progression of hyperostosis typically begins with chronic low-grade entheseal inflammation or mechanical stress, which initiates enthesophyte development as a reparative response.^[50] This evolves through progressive ossification, potentially leading to bridging enthesophytes and ankylosis in severe cases, with the process accelerating in the presence of metabolic factors such as diabetes.^[50]

Clinical Features

Symptoms and Signs

Hyperostosis manifests through a variety of symptoms depending on the affected region, though many cases remain asymptomatic and are discovered incidentally during imaging for unrelated issues.^[52] In diffuse idiopathic skeletal hyperostosis (DISH), a common form of spinal hyperostosis, patients often experience stiffness and pain, particularly in the back and neck, which is typically more pronounced in the morning or evening. Reduced range of motion in the spine is also frequent, alongside occasional involvement of peripheral joints leading to shoulder, elbow, or knee discomfort.^[53][54] Cervical involvement in DISH can lead to dysphagia due to compression of the esophagus by anterior osteophytes, while rare cases may present with myelopathy from spinal cord compression.^[55][56] General physical signs across hyperostotic conditions include palpable bony prominences at sites of entheseal ossification and crepitus in affected joints from irregular bone overgrowth.^[11] In cranial hyperostosis frontalis interna (HFI), symptoms are often absent, but when present, they include headaches and, in cases of significant compression, seizures or cognitive impairment.^[5][57] Peripheral forms, such as Caffey disease (infantile cortical hyperostosis), typically affect infants and cause painful soft tissue swelling over involved bones like the mandible or long bones, accompanied by irritability, fever, and tenderness.^[58][15] In pachydermoperiostosis, a hereditary peripheral hyperostosis, key signs include digital clubbing and thickening of the facial skin (pachydermia), often with hyperhidrosis and joint pain.^[59] Hyperostosis, particularly DISH, has been associated with metabolic syndrome, potentially contributing to symptom severity in symptomatic individuals.^[60]

Associated Syndromes

Hyperostosis is associated with several metabolic conditions, particularly in the context of diffuse idiopathic skeletal hyperostosis (DISH), where patients exhibit an increased risk of cardiovascular disease due to higher prevalence of coronary artery calcifications and atherosclerosis.^[61] This association persists even after adjusting for traditional risk factors, suggesting a direct link between the ossification processes in DISH and vascular pathology.^[62] Additionally, DISH is associated with an apparent paradox where elevated bone mineral density coexists with increased fracture risk, particularly vertebral fractures, due to altered bone quality and biomechanics in affected areas.^[63] Genetic syndromes involving hyperostosis include Camurati-Engelmann disease, an autosomal dominant disorder caused by TGFB1 mutations leading to diaphyseal hyperostosis of long bones and the skull base, often accompanied by proximal limb weakness, waddling gait, and cranial nerve palsies from foraminal narrowing.^[25] Sclerosteosis, another rare sclerosing bone dysplasia resulting from SOST gene mutations, features progressive hyperostosis of the skull and long bones, syndactyly, and facial paralysis due to cranial nerve entrapment, with mandibular overgrowth and potential hearing loss.^[28][64] Neoplastic processes can induce hyperostosis, as seen in spheno-orbital meningiomas, where tumor invasion causes reactive bone overgrowth along the sphenoid wing, resulting in proptosis and progressive vision loss from optic nerve compression.^[65][66] Comorbidities of hyperostosis include elevated fracture risk during or after surgery owing to the brittle nature of hyperostotic bone, which predisposes to spinal cord injury in thoracic and lumbar fractures.^[67] Spinal rigidity from extensive ossification in DISH can also lead to gastrointestinal complications, such as dysphagia or esophageal obstruction from anterior cervical bridging.^[68][24]

Diagnosis

Imaging Techniques

Imaging techniques play a crucial role in diagnosing hyperostosis by visualizing abnormal bone growth, distinguishing it from other conditions, and assessing extent and complications. Radiography remains the initial and often sufficient modality for many forms, while advanced imaging like computed tomography (CT) and magnetic resonance imaging (MRI) provides detailed evaluation when needed. Bone scintigraphy can detect increased uptake at metabolically active sites but is not routinely used due to nonspecific findings.^[11] Radiography serves as the gold standard for diagnosing diffuse idiopathic skeletal hyperostosis (DISH), a common skeletal form, where it reveals characteristic flowing ossification along the anterolateral aspects of at least four contiguous thoracic vertebral bodies without associated erosions or sacroiliitis.^[11] In DISH, lateral spine radiographs show preserved intervertebral disc heights and lack of ankylosis of posterior elements, aiding differentiation from inflammatory spondyloarthropathies.^[69] For cranial hyperostosis, such as hyperostosis frontalis interna (HFI), skull X-rays demonstrate bilateral thickening of the inner table of the frontal bone, typically exceeding 10 mm in postmenopausal women, confirming the benign overgrowth without invading the brain parenchyma.^[18] Computed tomography (CT) offers superior detail for cortical and endosteal bone changes in hyperostosis, enabling precise measurement of ossification thickness and identification of enthesophytes at ligamentous attachments.^[70] In DISH, CT is more sensitive than radiography for detecting subtle bony proliferations and peripheral enthesopathies, including sacroiliac joint alterations.^[71] Three-dimensional CT reconstructions are valuable for preoperative planning in symptomatic hyperostosis causing mass effect, such as dysphagia from cervical DISH or cosmetic concerns in HFI.^[72] Magnetic resonance imaging (MRI) is less effective for assessing bone density in hyperostosis but is essential for evaluating associated soft tissue involvement and potential neural compression.^[11] In spinal DISH, MRI can depict ligamentous ossification encroaching on the spinal cord or nerve roots, revealing edema or stenosis that may contribute to myelopathy.^[73] For HFI, MRI occasionally shows mild frontal lobe compression but primarily rules out secondary causes like meningiomas mimicking hyperostosis.^[18] Bone scintigraphy may highlight increased radiotracer uptake at entheses or skull margins in conditions like HFI or DISH-related hyperostosis, aiding in assessing extent when symptoms suggest multifocal involvement.^[74] This modality can briefly aid in differential diagnosis by confirming non-malignant, non-inflammatory bone turnover patterns.^[11] For infantile cortical hyperostosis (Caffey disease), radiography shows characteristic periosteal new bone formation in affected bones like the mandible and long bones, often with soft tissue swelling; ultrasound can assess early changes, and genetic testing confirms COL1A1 mutations in familial cases.^[75] In hypertrophic osteoarthropathy, radiography or CT reveals symmetric periosteal reactions along long bone shafts, frequently with digital clubbing; secondary causes like lung pathology are evaluated via chest imaging.^[76] Rare hereditary forms such as pachydermoperiostosis (primary hypertrophic osteoarthropathy) and Camurati-Engelmann disease are diagnosed via radiography showing diffuse diaphyseal sclerosis, supported by genetic testing for SLCO2A1 or TGFB1 mutations, respectively.^[77]

Differential Diagnosis

The differential diagnosis of hyperostosis, particularly diffuse idiopathic skeletal hyperostosis (DISH), primarily involves distinguishing it from other spondyloarthropathies and degenerative bone conditions based on clinical presentation and laboratory findings. Ankylosing spondylitis (AS) is a key mimic, but it typically presents with earlier onset (under 40 years) and more inflammatory symptoms such as morning stiffness and back pain, whereas DISH commonly affects individuals over 50 years with milder or asymptomatic progression.^[11] Unlike DISH, AS features sacroiliitis with erosions and is strongly associated with HLA-B27 positivity in about 90% of cases, which is absent in DISH.^[78] Psoriatic arthritis, another inflammatory differential, often shows asymmetric joint involvement, dactylitis, and skin psoriasis, which are not seen in DISH, along with potential elevation of inflammatory markers.^[11] For cranial forms of hyperostosis, such as hyperostosis frontalis interna, mimics include Paget's disease of bone, which involves a lytic phase with bone pain, deformities, and elevated alkaline phosphatase (ALP) levels, contrasting with the normal ALP in idiopathic hyperostosis.^[78] Fibrous dysplasia presents with monostotic or polyostotic lesions leading to fractures and deformities, often diagnosed in younger individuals, and lacks the specific entheseal ossification of hyperostosis; ALP may be elevated but inflammatory markers remain normal.^[11] Laboratory tests play a crucial role in differentiation: idiopathic hyperostosis shows normal C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), unlike the elevated levels in inflammatory arthritides such as AS or psoriatic arthritis.^[78] For suspected hereditary types, such as Camurati-Engelmann disease or sclerosteosis, genetic testing identifies mutations in genes like TGFB1 or SOST, confirming the diagnosis and excluding idiopathic forms.^[28] Clinical clues, including the absence of HLA-B27 in DISH and later age of onset compared to AS, further aid in narrowing the differential.^[11]

Management and Prognosis

Treatment Approaches

Treatment of hyperostosis varies by underlying type and clinical severity, focusing on symptom relief, progression management, and complication prevention rather than cure, as most forms are chronic or self-limited.^[11][79] Conservative measures form the cornerstone for managing pain and stiffness in conditions like diffuse idiopathic skeletal hyperostosis (DISH). Nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin at doses of 25-50 mg two to three times daily (50-150 mg total daily), effectively alleviate inflammatory symptoms and improve quality of life.^[80][11] Physical therapy emphasizes exercises to enhance spinal mobility and reduce rigidity, often combined with lifestyle modifications like weight loss and glycemic control in DISH patients to potentially slow disease advancement.^[53][54] For iatrogenic hyperostosis induced by prolonged retinoid therapy, the primary intervention is immediate discontinuation of the offending agent, such as isotretinoin or acitretin, which typically halts further progression and resolves milder symptoms.^[81] In active genetic or sclerosing forms, such as melorheostosis, targeted therapies like bisphosphonates (e.g., pamidronate infusions) have shown efficacy in reducing pain and hyperostotic growth by inhibiting bone resorption.^[82][83] Surgical options are reserved for severe, symptomatic cases impairing function. Anterior cervical osteophytectomy provides decompression and relieves dysphagia or myelopathy caused by large osteophytes in DISH, with high success rates in restoring swallowing and neurological function.^[84][85] For symptomatic hyperostosis frontalis interna (HFI) or hyperostosis associated with meningiomas, craniotomy enables bone removal to alleviate intracranial pressure or neurological deficits, though such procedures are infrequent due to the often benign course of HFI.^[86][87] Supportive care includes orthotic devices to stabilize deformities and prevent further strain in conditions like infantile cortical hyperostosis or melorheostosis, alongside regular monitoring via imaging for asymptomatic individuals to detect progression early without routine intervention.^[88][15]

Prognosis and Complications

The prognosis of hyperostosis varies significantly depending on the specific type and underlying etiology, but it is generally benign in most acquired forms with minimal impact on life expectancy. In hyperostosis frontalis interna (HFI), the condition is typically incidental and non-progressive, discovered during imaging for unrelated issues, and does not substantially affect overall health or longevity in the absence of compressive symptoms.^[89] Diffuse idiopathic skeletal hyperostosis (DISH) follows a slowly progressive course characterized by increasing spinal stiffness and reduced flexibility, yet it carries a low mortality risk and is rarely life-threatening, allowing most patients to maintain functional independence with appropriate management.^[3] In contrast, genetic forms such as sclerosteosis present a more guarded outlook due to relentless cranial hyperostosis leading to cranial nerve entrapment, increased intracranial pressure, and potential brain herniation; affected individuals often experience stabilization of skeletal overgrowth by the third decade, but life expectancy is reduced to approximately 33 years on average, primarily from neurological complications.^[90][28] Complications of hyperostosis arise mainly from mechanical effects of bone overgrowth and can significantly impair function if untreated. In DISH, the rigid ankylosed spine predisposes patients to vertebral fractures following even minor trauma, with a pooled prevalence of such fractures estimated at 22.6% among diagnosed individuals, often resulting in greater instability, delayed healing, and heightened risk of spinal cord injury compared to fractures in non-DISH spines.^[91] Cervical hyperostosis in DISH or related forms can compress the esophagus, causing dysphagia that leads to recurrent aspiration pneumonia, a potentially life-threatening sequela reported in multiple cases where bony protrusions mechanically obstruct swallowing.^[92] Cranial variants, including HFI and sclerosteosis, may produce hearing loss through encroachment on the auditory nerve or internal acoustic canal stenosis, with sensorineural deficits noted in up to 19% of symptomatic patients in associated sclerosing dysplasias.^[23][93] Quality of life in hyperostosis is predominantly affected by progressive musculoskeletal limitations rather than direct mortality, though severe cases can lead to notable disability. Advanced skeletal involvement in DISH often results in chronic pain, restricted mobility, and challenges with daily activities, contributing to reduced physical function and overall well-being in approximately 20-30% of patients with longstanding disease.^[94] Despite these impacts, 10-year survival rates exceed 90% in uncomplicated DISH, though specific complications like pyogenic vertebral osteomyelitis can elevate mortality to 62% in affected subgroups.^[95] In genetic hyperostoses, facial distortion, syndactyly, and neurological deficits further diminish quality of life, emphasizing the need for multidisciplinary support. Ongoing monitoring is essential for high-risk cases to mitigate progression and complications, particularly in genetic or symptomatic forms. Annual imaging, such as CT or MRI, is recommended for patients with cranial involvement or spinal ankylosis to detect early nerve compression or fracture risk, enabling timely intervention.^[18] For hereditary types like sclerosteosis, genetic counseling is advised to inform family planning, assess carrier status, and discuss inheritance patterns, given the autosomal recessive transmission and potential for severe outcomes in offspring.^[28]