The name osteopetrosis is derived from the Greek language. ‘Osteo’ means bone and ‘petrosis,’ meaning stone. Therefore, the disease is often referred to colloquially as “marble bone disease.” The disease was originally described by a radiologist in Germany, Dr. Albers-Schonberg, in 1904. Bone with abnormally increased density is the key radiographic finding. This increased density is secondary to osteoclast dysfunction and leads to the affected bones being abnormally brittle.
The name osteopetrosis encompasses a group of hereditary metabolic bone diseases, all of which detrimentally affect bone growth and remodeling leading to generalized osteosclerosis and the potential of pathologic fractures, pancytopenia, and even cranial neuropathies and hepatosplenomegaly in severe cases.
Four disease forms are known. The malignant autosomal recessive form, not named malignant due to any relation to oncology but rather due to the degree of condition severity, is very severe and often leads to mortality in early childhood. The intermediate autosomal recessive form usually becomes clinically significant during the first decade of life. These patients will often suffer pathologic fractures and progressive cranial nerve compression neuropathies but typically live into adulthood. There are two subclassifications of autosomal dominant osteopetrosis, and these patients are often asymptomatic into adulthood. Type I typically does not have increased fracture risk and presents with isolated osteosclerotic thickening of the cranial vault. Patients with type II often present in adulthood with anemia, pathologic fracture, or early arthritis.
Genetic research has found this disease of osteoclastic dysfunction to have an association with at least 8 gene mutations.
Six of these eight genes are associated with a malignant, autosomal recessive form of the disease. Loss of function mutations in TCIRG1, CLCN7, OSTM1, PLEKHM1, AND SNX10 lead to an osteoclast rich version of autosomal recessive osteopetrosis. In this version, osteoclasts are plentiful. However, the osteoclasts that are present are unable to resorb bone due to defective ruffled border formation effectively. Loss of function mutations in TNFSF11 and TNFRSF11A lead to disrupted osteoclast development and a condition of osteoclast poor osteopetrosis.
Intermediate autosomal recessive osteopetrosis is the result of a loss of function mutation in CAII, the gene responsible for the production of the carbonic anhydrase II protein.
Autosomal dominant osteopetrosis is the result of the dysfunction of chloride channel 7 secondary to a dominant-negative mutation of CLCN7.
The autosomal recessive form of the disease, fortunately, has an incidence far less than the autosomal dominant form.
The autosomal recessive form occurs in approximately 1 out of every 250,000 births. Of note, in Costa Rica, the incidence has been found to be significantly higher, with a rate of approximately 3.4 out of every 100,000 births.
The autosomal dominant form of the disease occurs at an approximate frequency of 1:20,000.
Bone is in a dynamic state and is dependent upon a healthy balance between osteoclast-mediated resorption and osteoblast-mediated deposition. In osteopetrosis, defective osteoclast development or function leads to a disruption in normal bone homeostasis. Osteoclasts that have defective proton pumps, chloride channels, or carbonic anhydrase II proteins are unable to resorb bone effectively. Consequently, the unorganized, overly dense bone that is prone to fracture develops unchecked.
Histological evaluation of bone in a patient with osteopetrosis will likely show empty lacunae with plugged Haversian canals, calcified cartilage dispersed within bony trabeculae, and defective osteoclasts that lack a clear zone and ruffled border. These clear zone and ruffled border structures are the trademark findings in osteoclasts undergoing active resorption, and their absence corresponds perfectly with the findings of osteopetrosis.
History and physical exam findings differ drastically depending on which type of osteopetrosis the patient presents.
Malignant, autosomal recessive osteopetrosis presents in the infant within a few months of delivery. Symptoms include frequent infections, abnormal bruising, and bleeding abnormalities. These symptoms are secondary to the bone that is no longer being correctly resorbed by osteoclasts and is consequently encroaching into the medullary space. These patients also have frequent pathologic fractures. Additional symptoms that can occur include macrocephaly, hepatosplenomegaly because of the body’s extramedullary hematopoiesis response, nasal congestion due to sinus malformations, and dental abscess or osteomyelitis of the mandible due to the predilection of the mandible to develop significantly reduced medullary canal diameter with disrupted vascularity. Diseased bone has a tendency to narrow cranial nerve foramina in these children leading to progressive deafness and blindness along with possible facial palsies. The most frequently involved cranial nerve is the optic nerve, followed by the auditory nerve, trigeminal nerve, and the facial nerve.
The history and physical exams of patients with intermediate autosomal recessive osteopetrosis are highly variable. Symptoms resemble but are not as severe and do not present as early as the symptoms present in the malignant form of the autosomal recessive disease. Due to the fact this variety of osteopetrosis can be secondary to carbonic anhydrase II dysfunction, renal tubular acidosis can be present in these patients.
Type 1 autosomal dominant osteopetrosis tends to have a very mild clinical presentation. Unlike other forms of osteopetrosis, type 1 autosomal dominant osteopetrosis has been found to be due to an error in increased bony formation rather than a defect in osteoclast function. Consequently, these patients do not have increased fracture risk like other patients with osteopetrosis. This form tends to have osteosclerosis most focused in the cranial vault, and cranial nerve compression neuropathies are common.
Type 2 autosomal dominant osteopetrosis is the most common form managed by orthopedic surgeons, and it has a very heterogeneous course. Most patients with this form of the disease lead relatively normal lives with generally normal life span, overall health, and physique. Patients will often discover that they have this disease after the clinical presentation for evaluation of either fracture determined radiographically to be pathologic or early-onset osteoarthritis. Fractures occur in approximately 4 out of 5 of these patients. The average number of fractures per affected individual is 3, and the bone that experiences the most pathologic fractures is the femur. While arthritis can affect these patients in a variety of locations, the hip is the most reported location, with approximately 50% of patients having early-onset hip pain. Fatigue secondary to anemia and cranial nerve neuropathies can affect these patients as well but occurs less frequently than in other forms of the disease with optic and/or auditory nerve damage only in approximately 1 out of 20 patients.
Osteopetrosis is most frequently diagnosed based on the patient having the typical clinical and radiographic findings of the disease.
Radiographs will show diffuse osteosclerosis throughout the skeleton with a “marble bone” appearance. There will generally be increased cortical thickness with associated decreased medullary canal diameter. The “Erlenmeyer flask” deformity can be found at the metaphyses of long bones, particularly at the proximal humerus and the distal femur. A “bone-in-bone” or “endobone” appearance most frequently is noted in the bones of the spine or the hand phalanges. “Rugger jersey spine” is another axial skeleton radiographic finding that can occur secondary to excessive sclerosis of the vertebral endplates.
If clinical and radiographic findings do not yield a diagnosis, laboratory findings of increased creatinine kinase BB and tartrate-resistant acid phosphatase can aid in diagnosis.
Genetic testing can also be performed to evaluate for the presence of the gene mutations associated with the condition.
Management of patients with osteopetrosis must be tailored to the individual patient. Treatment is predominantly supportive with no known cure, and interprofessional care and surveillance are treatment mainstays.
Fractures and arthritis associated with osteopetrosis are best managed by an experienced orthopedic surgeon since fracture treatment, and arthroplasty in these patients is frequently plagued by the following complications: non-union, delayed union, and osteomyelitis.
Due to the frequency of cranial nerve compression neuropathies, most frequently of the optic nerve, routine ophthalmologic evaluation is needed, and in some patients, surgical decompression of the optic nerve may be required to preserve eye-sight.
Routine dental evaluation is needed in these patients to prevent the complications of abscesses, cysts, and osteomyelitis that can occur more frequently in these patients due to altered bone anatomy of the mandible .
Bone marrow transplantation of hematopoietic stem cells (HSC) is reserved for the malignant, autosomal recessive form of osteopetrosis due to the risk of rejection and other possible complications. HSC therapy from HLA matched donors does not necessarily reverse disease complications but has been found to have 73% 5-year disease-free survival.
Interferon-gamma 1b therapy has been used in some patients found unfit for bone marrow transplantation or as bridging therapy until HSC therapy can be used. It shows benefit in increasing immune function and bone resorption. High dose calcitriol has also been used to attempt the stimulation of host osteoclasts.
While osteopetrosis is a disease of primary bone sclerosis, there are many conditions that can lead to similar osteosclerosis in a secondary way. The following conditions must be considered when evaluating a patient with osteosclerotic bone noted on radiographic evaluation:
The malignant, autosomal recessive form of osteopetrosis is frequently fatal in the first years of life without successful bone marrow transplantation treatment. Many patients may undergo multiple attempts at bone marrow transplant without long-lasting success. The other disease forms typically allow patients to live into adulthood with the autosomal dominant form of the disease, having typically very little effect on life span and overall health.
Complications include a high risk of refracture in patients with pathologic fractures due to the brittle nature of their sclerotic bone. Hardware failure is a common problem in osteopetrosis patients requiring fracture fixation. Peri-prosthetic fractures around previously reinforced bone can further complicate care. Also, these patients can require specialized orthopedic tools intraoperatively as the hard, brittle bone can cause failure in some tools such as bone drill bits and Kirschner wires. Bone infections secondary to disrupted bone vascularity are common as well as malunion and non-union of pathologic fractures.
Patients and their families should be educated about the natural history and common complications of the disease. Referrals should be made if needed for orthopedic surgery and ophthalmology or neurosurgery if the patient has neuro-deficits. The patient should be encouraged to receive routine dental and ophthalmologic surveillance and maintenance care.
Optimal care for patients with osteopetrosis is best delivered by an interprofessional team consisting of nurses, pharmacists, physical therapists, and physicians of a variety of specialties. This interprofessional team design allows for these sometimes complex patients to have patient-centered care that hopefully leads to improved outcomes.
Diagnosis is often made by clinical and radiographic assessment by a primary care physician, pediatrician, emergency medicine physician, or orthopedic surgeon depending on age and symptoms at initial presentation. These patients will almost all require hospitalization at some point in their life secondary, either medical or orthopedic complications. The nursing staff must have an understanding of these patients and the physiologic mechanism that makes them prone to fracture to provide optimal care. The same applies to physical therapists when performing physical activity with these patients during rehab. Pharmacists guide complex medical treatment in patients with the malignant, autosomal recessive form of the disease.
Regardless of the specialty of the provider that initially discovers this condition, they must communicate with the other specialties needed to provide optimal care for these patients. These patients will almost all require orthopedic care. In addition, neurosurgeons may be required for worsening cranial compression neuropathies, and ophthalmologists and dentists are needed to provide maintenance and surveillance care for these at-risk patients. Care for these patients with osteopetrosis is truly a team effort, and interprofessional communication is a must.
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