Osteopetrosis

What is Osteopetrosis?

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Osteopetrosis, often called “marble bone disease,” originates from Greek words where ‘osteo’ means bone and ‘petrosis’ means stone. This condition was first identified by a German radiologist named Dr. Albers-Schonberg in 1904. The hallmark of this disease is an unusually high density in the bones, which is caused by a malfunction in osteoclasts – the cells that normally break down bone. Oddly enough, this results in the affected bones being extremely fragile.

Osteopetrosis refers to a set of inherited metabolic bone diseases that unfavorably affect the growth and rebuilding of the bones, creating a widespread thickening of the bones (osteosclerosis). This can potentially lead to pathological fractures, which are breaks in bones that occur because the bone is weakened by disease. It can also cause pancytopenia (a decrease in all types of blood cells), and in severe cases, dysfunction of the cranial nerves and enlarged liver and spleen (hepatosplenomegaly).

There are four known types of osteopetrosis. The most severe type, known as the malignant autosomal recessive form, isn’t malignant because it is related to cancer, but because of the serious nature of the condition. It often results in death at an early age. The intermediate autosomal recessive type often shows symptoms during the first ten years of life. Patients with this type commonly suffer from pathological fractures and progressive pressure on the cranial nerves, but they can usually live into adulthood. The two types of autosomal dominant osteopetrosis usually do not show signs until adulthood. One subtype does not have an increased risk of fractures and typically presents with thickening of the cranial vault (the space inside the skull). The other subtype often shows symptoms in adulthood such as anemia (low red blood cells), pathological fractures, or early onset of arthritis.

What Causes Osteopetrosis?

Scientists have found that this disease, which messes with the function of osteoclasts (cells that break down bone), is linked to at least 8 gene changes.

Six out of these eight gene changes are connected to a harmful form of the disease which is passed down through families. In this case, if a person has a certain malfunction in the genes called TCIRG1, CLCN7, OSTM1, PLEKHM1, or SNX10, they could have a form of the disease where there are a lot of osteoclasts, but these cells are unable to break down bone effectively because of a structural defect.

If there are gene malfunctions in TNFSF11 and TNFRSF11A, osteoclast development gets disrupted, leading to a form of the disease where there are not enough osteoclasts.

Another form of the disease, known as intermediate form, occurs due to a malfunction in the CAII gene. This gene is responsible for making a protein called carbonic anhydrase II.

And lastly, there is a form of the disease that can be passed down if one parent carries the altered gene. This is caused by a malfunction in the CLCN7 gene, leading to the dysfunction of something called a chloride channel 7.

Risk Factors and Frequency for Osteopetrosis

The two types of a certain disease can get passed down differently through families. One kind is autosomal recessive – it happens less frequently than the other kind, which is autosomal dominant.

• The autosomal recessive form occurs in roughly 1 out of every 250,000 births. Interestingly, in Costa Rica, this rate is much higher, at about 3.4 out of every 100,000 births.
• The autosomal dominant form happens more frequently, with a usual rate of about 1 in every 20,000 births.

Signs and Symptoms of Osteopetrosis

Osteopetrosis is a bone disease that has different types, each with unique symptoms. The type of osteopetrosis determines the patient’s health history and physical findings.

The first type of osteopetrosis, malignant autosomal recessive, usually becomes apparent within a few months of a child’s birth. Symptoms for this include frequent infections, abnormal bruising, and abnormal bleeding because the bone isn’t properly absorbed by bone-dissolving cells, leading to inward growth. This may cause frequent bone fractures and other symptoms such as:

• Big head size
• Enlarged liver and spleen due to the body responding to the disease
• Nasal congestion due to malformations in the sinus
• Teeth abscess or jawbone infection because of decreased blood supply to the jaw

The affected bone in these children can also narrow the holes through which the cranial nerves pass, potentially leading to hearing and vision loss, or facial muscle weakness. The optic nerve, which is responsible for vision, is most often affected.

The second type, intermediate autosomal recessive osteopetrosis, has varying symptoms. These symptoms resemble the first type but are less severe and don’t manifest as early. If this is associated with an enzyme problem in the kidneys, these patients may also manifest with renal tubular acidosis.

The third type, Type 1 autosomal dominant osteopetrosis, usually presents mildly. Unlike the other types, it’s caused by increased bone formation rather than a defect in the bone-dissolving process, so they don’t have an increased risk of fractures. However, increased bone density can put pressure on the cranial nerves, resulting in neuropathies.

The last type, Type 2 autosomal dominant osteopetrosis, has various courses but is most commonly treated by orthopedic surgeons. Patients with this type often live relatively normal lives, with normal lifespan and overall health. They often discover their condition when evaluated for pathologic fractures or early-onset osteoarthritis. Anemia-related fatigue and nerve damage can also occur but not as frequently as in other forms of the disease.

Testing for Osteopetrosis

Osteopetrosis, a disease that affects the bones, is often diagnosed through physical exams and specific types of X-ray pictures, which can show distinct changes in the bones that are characteristic of this disease.

X-ray images might reveal a “marble bone” look where the bones appear overly dense and solid all over. There could be increased thickness of the outer layer of the bone, accompanied by a narrowing of the marrow channel inside the bone. Some patients may present with an “Erlenmeyer flask” deformity, more commonly seen at the ends of long bones like the upper arm bone (humerus) or the thigh bone (femur). The bones may show a unique “bone-in-bone” or “endobone” pattern, usually seen in the spine or the finger bones. Another key feature is the “Rugger jersey spine,” where excessive denseness can be seen on the ends of the spine’s bones.

If physical exams and X-ray findings don’t confirm a diagnosis, blood tests for specific chemicals like creatinine kinase BB and tartrate-resistant acid phosphatase – which can increase with this condition – may help with the diagnosis.

Lastly, for definitive diagnosis, a genetic test can be conducted. This helps determine if you have the gene mutations that are linked with osteopetrosis.

Treatment Options for Osteopetrosis

Osteopetrosis is a health condition without a known cure, so the treatment is usually centered on providing support and care to the patient, rather than trying to cure the disease. Because of this, the treatment should be customized to the needs of each individual patient. Teamwork between different health professionals is vital to monitor the patient’s condition and provide the best care.

One common problem for patients with osteopetrosis is fractures and arthritis. Since treating fractures in these cases can be challenging with possible issues such as non-healing fractures, slow-to-heal fractures, and bone infection (osteomyelitis), it’s best for an experienced orthopedic surgeon to handle these situations.

Eye issues are also common in osteopetrosis patients, especially problems with the optic nerve, which is responsible for vision. Regular eye exams are necessary, and in some cases, a surgical procedure may be required to relieve pressure on the optic nerve to prevent vision loss.

Because of changes in bone structure in the lower jaw (mandible), patients with osteopetrosis may experience more dental problems such as abscesses, cysts, and osteomyelitis. So, regular dental check-ups are also important in managing this condition.

For more severe cases, especially the kind of osteopetrosis that is inherited and can cause malignancies, a treatment option is to replace the patient’s bone marrow cells with healthy cells (hematopoietic stem cells or HSC) from a well-matched donor. Although this treatment doesn’t always ease all symptoms of the disease, it has shown positive results, with about 73% of patients remaining disease-free after 5 years.

Two other therapies also exist. One employs a medicine called Interferon-gamma 1b for patients who aren’t good candidates for bone marrow transplants or are waiting for HSC therapy. This medicine has shown potential to boost immune function and promote bone absorption. Another treatment uses a high dose of a medication called calcitriol, which is thought to stimulate the body’s own bone-dissolving cells (osteoclasts).

What else can Osteopetrosis be?

Osteopetrosis is a disease that causes bones to become overly dense. However, there are several other conditions that can also make the bones denser in a secondary manner. When a doctor sees overly dense bones on an X-ray or other medical imaging, they need to consider these other possibilities:

• Poisoning from substances like beryllium, lead, or bismuth
• Fluorosis, a condition that comes from consuming too much fluoride
• Myelofibrosis, a serious bone marrow disorder
• Paget’s disease, a condition that interferes with your body’s ability to replace old bone tissue
• Cancer, specifically lymphoma or types that cause bone to grow excessively (osteoblastic bony metastases)

What to expect with Osteopetrosis

Osteopetrosis is a serious condition that can be life-threatening, especially if it is a particular type called “malignant autosomal recessive.” This form of the disease often leads to death in early childhood without successful treatment, which typically involves a procedure known as bone marrow transplantation. However, the treatment doesn’t always work on the first try, and many patients may need multiple attempts.

On the other hand, there are other forms of osteopetrosis that are less severe. Patients with these types of the disease usually live into adulthood. One such form is called “autosomal dominant osteopetrosis.” This type doesn’t typically have a significant impact on a person’s overall health or lifespan.

Possible Complications When Diagnosed with Osteopetrosis

Patients with osteopetrosis, a condition that makes the bones harder and more brittle, face several potential complications. One of these is a high risk of the bone breaking again after a fracture. This is especially true for people who already had a bone fracture due to disease, as their bones are more brittle.

Another frequent issue is that the hardware used to fix the fractures can fail. Additionally, fractures around previously reinforced bones can complicate care even further. Performing surgery on these patients can also require specialized orthopedic equipment as regular tools, like bone drill bits and Kirschner wires, can break due to the hardness of the bone.

Moreover, infections in the bone, caused by disturbed blood flow to the bone, are quite common in osteopetrosis patients. As a result, bones may not heal properly or completely after a fracture, leading to malunion or non-union of the fracture.

Potential Complications:

• High risk of the bone breaking again especially in patients with disease-related fractures
• Failure of the hardware used to fix the fractures
• Fractures around previously reinforced bones complicating care
• Requirement of specialized orthopedic tools due to hardness of the bones
• Common infections in the bone due to disturbed blood flow
• Improper or incomplete healing after a fracture (malunion or non-union)

Preventing Osteopetrosis

Patients and their families need to learn about the usual progress and common issues that can come up with this illness. If needed, arrangements should be made to see a specialist in bone and joint surgery or in eye and brain surgery if the patient has problems related to their nervous system. It’s also crucial for the patient to regularly go for dental and eye check-ups, to keep their teeth and vision healthy and well-maintained.