Osteopetrosis

                                DR KS Dhillon

Introduction

The term osteopetrosis is derived from the Greek language. In the Greek language ‘osteo’ means bone, and ‘petrosis,’ means stone. Hence, the disease is colloquially often referred to as “marble bone disease.” The disease was originally described by Dr. Albers-Schonberg, a German radiologist in 1904 (1). Increased bone density is the key radiographic finding. The increased density is secondary to osteoclast dysfunction. This leads to the affected bones being abnormally brittle (1). 

The term osteopetrosis encompasses a group of hereditary metabolic bone diseases. All these diseases detrimentally affect bone growth and remodeling leading to generalized osteosclerosis. With osteosclerosis, there is a potential for pathologic fractures, pancytopenia, and even cranial neuropathies and hepatosplenomegaly in severe cases (2-4).

There are 4 known disease forms. One is the malignant autosomal recessive form. It is not named malignant due to any relation to oncology. It is rather due to the degree of condition severity which is very severe and often leads to mortality in early childhood (5,6). The other is the intermediate autosomal recessive form. This usually becomes clinically significant during the first decade of life. Patients with this form often suffer pathologic fractures and progressive cranial nerve compression neuropathies. They however typically live into adulthood. For autosomal dominant osteopetrosis, there are two subclassifications, and these patients are often asymptomatic into adulthood. The type I does not have increased fracture risk. It presents with isolated osteosclerotic thickening of the cranial vault. Patients with type II usually present in adulthood with pathologic fracture, anemia, or early arthritis (7).

Etiology

Genetic studies have found that this disease of osteoclastic dysfunction has an association with at least 8 gene mutations (3). Six of these 8 genes are associated with a malignant, autosomal recessive form of the disease. Loss of function mutations in CLCN7, OSTM1, TCIRG1, PLEKHM1, AND SNX10 lead to an osteoclast rich version of autosomal recessive osteopetrosis. In this version, there are a lot of osteoclasts. However, these osteoclasts are unable to resorb bone effectively due to defective ruffled border formation. Loss of function mutations in TNFRSF11A and TNFSF11 leads to disrupted osteoclast development and osteoclast poor osteopetrosis (8).

Intermediate autosomal recessive osteopetrosis is the result of a loss of function mutation in CAII. This gene is responsible for the production of the carbonic anhydrase II protein (3).

Autosomal dominant osteopetrosis results from dysfunction of chloride channel 7 secondary to a dominant-negative mutation of CLCN7 (3).

Epidemiology

The autosomal recessive form of the disease is far less common than the autosomal dominant form. The autosomal recessive form occurs in about 1 out of every 250,000 births. In Costa Rica, the incidence is significantly higher, with a rate of approximately 3.4 out of every 100,000 births (5). 

The frequency of the autosomal dominant form of the disease is about 1:20,000 (9).

Pathophysiology

Bone is in a dynamic state. It is dependent upon a healthy balance between osteoclast-mediated resorption and osteoblast-mediated deposition of bone. In osteopetrosis, there is defective osteoclast development or function that leads to a disruption in normal bone homeostasis (8,1). Osteoclasts with defective proton pumps, chloride channels, or carbonic anhydrase II proteins are unable to resorb bone effectively. This leads to the formation of unorganized, overly dense bone that is prone to fractures.

Histopathology

Histological examination of bone in patients with osteopetrosis usually shows 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 classical findings in osteoclasts undergoing active resorption, and their absence corresponds with the findings of osteopetrosis (10).

Clinical Presentation

The history and physical examination findings differ drastically depending on the type of osteopetrosis the patient has. The malignant, autosomal recessive osteopetrosis presents in infants within a few months following birth. They present with symptoms that include frequent infections, abnormal bruising, and bleeding abnormalities. These symptoms occur due to the bone that is no longer being correctly resorbed by osteoclasts and is consequently encroaching into the medullary space (3). Pathologic fractures are common among these patients. There are additional symptoms that can occur. These include macrocephaly, nasal congestion, hepatosplenomegaly, and dental abscess or osteomyelitis of the mandible (2). Diseased bone tends to narrow cranial nerve foramina in children leading to progressive deafness and blindness along with possible facial palsies. The most frequently involved cranial nerve is the optic nerve. This is followed by the auditory nerve, trigeminal nerve, and the facial nerve (11,1). 

The history and physical examination of patients with intermediate autosomal recessive osteopetrosis are very variable. Symptoms are similar but are not as severe and do not present as early as the symptoms present in the malignant form of the autosomal recessive disease. Since this variety of osteopetrosis can be secondary to carbonic anhydrase II dysfunction, renal tubular acidosis can be present in these patients (12).

Type 1 autosomal dominant osteopetrosis usually has a very mild clinical presentation. Unlike other forms of osteopetrosis, type 1 autosomal dominant osteopetrosis is due to an error in increased bony formation rather than a defect in osteoclast function (13,14). Hence these patients do not have increased fracture risk as in other patients with osteopetrosis (9). In this form, osteosclerosis is most focused in the cranial vault, and cranial nerve compression neuropathies are common (15). 

Type 2 autosomal dominant osteopetrosis is the most common form that doctors treat, and it has a very heterogeneous course. Most patients with this form of the disease lead a relatively normal life. They generally have a normal life span, physique, and overall health. Patients often discover that they have this disease after they present for evaluation of a pathological fracture or early-onset osteoarthritis. Fractures occur in about 4 out of 5  patients. The average number of fractures per affected individual is three. Most pathological fractures occur in the femur (16). Arthritis can occur in a variety of locations. The hip is the most common location, with about 50% of patients having early-onset hip pain (16). Fatigue due to anemia and cranial nerve neuropathies can affect these patients as well but occurs less frequently than in other forms of the disease. Optic and/or auditory nerve damage occurs in approximately 1 out of 20 patients (17).

Evaluation

Osteopetrosis is usually diagnosed based on the presence of typical clinical and radiographic findings of the disease. The radiographs usually show diffuse osteosclerosis throughout the skeleton with a “marble bone” appearance. There is increased cortical thickness with associated decrease in medullary canal diameter. There will be an “Erlenmeyer flask” deformity at the metaphyses of long bones, especially at the proximal humerus and the distal femur. A “bone-in-bone” appearance is frequently noted in the bones of the spine or phalanges of the hand. “Rugger jersey spine” is another axial skeleton radiographic finding. It can occur due to excessive sclerosis of the vertebral endplates (1).

If radiographic and clinical findings do not lead to a diagnosis, laboratory findings of increased creatinine kinase BB and tartrate-resistant acid phosphatase can help in the diagnosis (18). Genetic testing can also be done to evaluate the presence of the gene mutations associated with the condition.

Management

Treatment of patients with osteopetrosis should be tailored to the individual patient. Treatment is predominantly supportive. There is no known cure. Interprofessional care and surveillance are the mainstays of treatment. 

Fractures and arthritis associated with osteopetrosis are treated by orthopedic surgeons. Fracture treatment, and arthroplasty in these patients can frequently be associated with the following complications: delayed union, non-union, and osteomyelitis (19).

Routine ophthalmologic evaluation is needed since cranial nerve compression neuropathies are common. The optic nerve is frequently involved. In some patients, surgical decompression of the optic nerve may be required to preserve eyesight (20).

Routine dental evaluation is needed in these patients to look for complications such as cysts, abscesses, and osteomyelitis that can occur due to altered bony anatomy of the mandible (1).

Bone marrow transplantation of hematopoietic stem cells (HSC) is reserved for the malignant, autosomal recessive form of osteopetrosis. There are risk of rejection and other possible complications. HSC therapy from HLA-matched donors does not necessarily reverse disease complications. It has been found to have a 73% 5-year disease-free survival (21).

In some patients who are unfit for bone marrow transplantation, interferon-gamma 1b therapy has been used. It can also be used as bridging therapy until HSC therapy can be used. It increases immune function and bone resorption (22). High-dose calcitriol has also been used to stimulate host osteoclasts (23).

Differential Diagnosis

Osteopetrosis is a disease of primary bone sclerosis. Many conditions can lead to similar osteosclerosis. The following conditions must be kept in mind when evaluating a patient with osteosclerotic bone seen on radiographic evaluation:

• Fluorosis

• Myelofibrosis

• Beryllium, lead, and bismuth poisoning

• Paget disease

• Cancer (lymphoma or osteoblastic bony metastases)

Prognosis

Without successful bone marrow transplantation treatment, the malignant autosomal recessive form of osteopetrosis is frequently fatal in the first years of life. Many patients undergo multiple attempts at bone marrow transplants without long-lasting success. The other disease forms usually allow patients to live into adulthood. The autosomal dominant form of the disease has very little effect on life span and overall health.

Complications

Complications include refracture in patients with pathologic fractures. Refractures occur due to the brittle nature of sclerotic bone. Hardware failure is also a common problem in patients with osteopetrosis who require fracture fixation. Peri-prosthetic fractures can further complicate care. These patients may require specialized orthopedic tools intraoperatively since the hard, brittle bone can cause failure in some tools. Bone infections are common due to disrupted bone vascularity. Malunion and non-union of pathologic fractures can occur.

Conclusion

Treatment for patients with osteopetrosis is best delivered by an interprofessional team that consists of pharmacists, nurses, physical therapists, and physicians. This team design allows for complex patients to have patient-centered care that leads to improved outcomes.

Diagnosis is usually made by clinical and radiographic assessment. These patients will require hospitalization at some point in their life to treat complications that occur. 

These patients will invariably require orthopedic care. Neurosurgeons may be required to treat cranial compression neuropathies. Ophthalmologists and dentists are required to provide maintenance and surveillance care for at-risk patients. Care for these patients with osteopetrosis is truly a team effort. 

References

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22. Key LL, Ries WL, Rodriguiz RM, Hatcher HC. Recombinant human interferon gamma therapy for osteopetrosis. J Pediatr. 1992 Jul;121(1):119-24. 

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