In the animal kingdom there also exists a non-pathological form of osteosclerosis, resulting in unusually solid bone structure with little to no marrow. It is often seen in aquatic vertebrates, especially those living in shallow waters, providing ballast as an adaptation for an aquatic lifestyle. It makes bones heavier, but also more fragile. In those animal groups osteosclerosis often occurs together with bone thickening (pachyostosis). This joint occurrence is called pachyosteosclerosis.

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

Osteosclerosis is a disorder that is characterized by abnormal hardening of bone and an elevation in bone density. It may predominantly affect the medullary portion and/or cortex of bone. Plain radiographs are a valuable tool for detecting and classifying osteosclerotic disorders. It can manifest in localized or generalized osteosclerosis. Localized osteosclerosis can be caused by Legg–Calvé–Perthes disease, sickle-cell disease and osteoarthritis among others. Osteosclerosis can be classified in accordance with the causative factor into acquired and hereditary.

The only effective line of treatment for malignant infantile osteopetrosis is hematopoietic stem cell transplantation. It has been shown to provide long-term disease-free periods for a significant percentage of those treated; can impact both hematologic and skeletal abnormalities; and has been used successfully to reverse the associated skeletal abnormalities.

Radiographs of at least one case with malignant infantile osteopetrosis have demonstrated bone remodeling and recanalization of medullar canals following hematopoietic stem cell transplantation. This favorable radiographic response could be expected within one year following the procedure - nevertheless, primary graft failure can prove fatal.

The differential diagnosis of malignant infantile osteopetrosis includes other genetic skeletal dysplasias that cause osteosclerosis. They are collectively known as osteosclerosing dysplasias. The differential diagnosis of genetic osteosclerosing dysplasias including infantile osteopetrosis has been tabulated and illustrated in literature citations.

- Neuropathic infantile osteopetrosis

- Infantile osteopetrosis with renal tubular acidosis

- Infantile osteopetrosis with immunodeficiency

- IO with leukocyte adhesion deficiency syndrome (LAD-III)

- Intermediate osteopetrosis

- Autosomal dominant osteopetrosis (Albers-Schonberg)

- Pyknodysostosis (osteopetrosis acro-osteolytica)

- Osteopoikilosis (Buschke–Ollendorff syndrome)

- Osteopathia striata with cranial sclerosis

- Mixed sclerosing bone dysplasia

- Progressive diaphyseal dysplasia (Camurati–Engelmann disease)

- SOST-related sclerosing bone dysplasias

Usual diagnosis is via radiograph, patient history, biopsy is rarely needed. Periodic follow ups should included additional radiographs that show minimal growth or regression.

The disorder is progressive, with the ultimate severity of symptoms often depending on age of onset. In severe cases amputation has been performed when conservative measures such as physical therapy and regional anesthetics have been ineffective.

Approximately eight to 40 children are born in the United States each year with the malignant infantile type of osteopetrosis. One in every 100,000 to 500,000 individuals is born with this form of osteopetrosis. Higher rates have been found in Denmark and Costa Rica. Males and females are affected in equal numbers.

The adult type of osteopetrosis affects about 1,250 individuals in the United States. One in every 200,000 individuals is affected by the adult type of osteopetrosis. Higher rates have been found in Brazil. Males and females are affected in equal numbers.

The odds are greater in the Russian region of Mari El (1 of every 14,000 newborns) and much greater in Chuvashia (1 of every 3,500—4,000 newborns) due to genetic features of the Mari people and Chuvash people, respectively.

Pachyosteosclerosis is a combination of thickening (pachyostosis) and densification (osteosclerosis) of bones. It makes bones more heavy, but also more fragile. The condition often occurs in aquatic vertebrates, especially those living in shallow waters, creating ballast as an adaptation for maintaining neutral buoyancy and horizontal trim. It is in no way pathological. To resist roll, it frequently is found especially in ventral bones, whereas concentration near the lungs helps in maintaining trim.

Examples of animals showing pachyosteosclerosis are seacows (dugongs and manatees), the extinct Plesiosauria and Mesosauria and extinct aquatic sloths.

"Osteosclerosis", an elevation in bone density, is normally detected on an X-ray as an area of whiteness, and is where the bone density has significantly increased. Localized osteosclerosis can be caused by injuries that compress the bone, by osteoarthritis, and osteoma.

Osteogenesis imperfecta is a rare condition in which bones break easily. There are multiple genetic mutations in different genes for collagen that may result in this condition. It can be treated with some drugs to promote bone growth, by surgically implanting metal rods in long bones to strengthen them, and through physical therapy and medical devices to improve mobility.

Melorheostosis is a medical developmental disorder and mesenchymal dysplasia in which the bony cortex widens and becomes hyperdense in a sclerotomal distribution. The condition begins in childhood and is characterized by thickening of the bones. Pain is a frequent symptom and the bone can have the appearance of dripping candle wax.

It is phenotypically difficult to diagnose between TDO and Amelogenesis imperfecta of the hypomaturation-hypoplasia type with taurodontism (AIHHT) as they are very closely linked phenotypically during adulthood, and the only distinguishing characteristic is found during genetic analysis by Polymerase Chain Reaction (PCR) amplification. This type of test in diagnosis of TDO is only used during research or if there is a concern of genetic issue to a particular individual whose family member has been diagnosed with TDO.

Well defined, rounded or triangular radiodensity, that is uniformly opaque. There is no lucent component. Found near the root apex or in the inter-radicular area. Root resorption and tooth movement are rare.

TDO is a genetic based disorder it is diagnosed based on radiographic imaging, physical characteristics of the disease, and genetic testing if necessary. PCR amplification is used to check for normal and deletion allele, found in the 141 base pair allele. A four base pair deletion in exon 3 is also noted in patients with TDO; deletion in two transcription factor genes DLX-3 and DLX-7 gene (distal-less gene) that occurs by a frameshift mutation, makes this gene shorter than its normal length and non-functional. Radiographs such as cephalometric analysis or panoramic radiograph are used to detect skeletal abnormalities in TDO cases; these radiographs along with the phenotypic effects of the disease are often enough evidence for proper diagnosis. In TDO, radiologic imaging almost always shows evidence of hardening of bone tissue (sclerosis), lesions on the bone structures surrounding the teeth due to decay or trauma, or hard tissue mass. The radiographic testing is non-invasive, and involves the patient to be able to sit or stand in front of the radiographic device with their mouth closed and lips relaxed for approximately one minute. Oral abnormalities are diagnosed by a visual dental examination. A normal oral evaluation would show no signs of broken or fractured teeth, attrition of tooth enamel, no spacing between teeth, no soft tissue mass or sign of dental abscess, and a bite relationship where the mandibular (bottom) teeth interdigitate within a normal plane of 1-2mm behind and underneath the maxillary (top) teeth.

Radiologic osteosclerosis and histology are the main diagnostic features. Diagnosis can often be difficult because of the rareness of ECD as well as the need to differentiate it from LCH. A diagnosis from neurological imaging may not be definitive. The presence of symmetrical cerebellar and pontine signal changes on T2-weighted images seem to be typical of ECD, however, multiple sclerosis and metabolic diseases must also be considered in the differential diagnosis. ECD is not a common cause of exophthalmos but can be diagnosed by biopsy. However, like all biopsies, this may be inconclusive. Video-assisted thoracoscopic surgery may be used for diagnostic confirmation and also for therapeutic relief of recurrent pericardial fluid drainage.

Histologically, ECD differs from Langerhans cell histiocytosis (LCH) in a number of ways. Unlike LCH, ECD does not stain positive for S-100 proteins or Group 1 CD1a glycoproteins, and electron microscopy of cell cytoplasm does not disclose Birbeck granules. Tissue samples show xanthomatous or xanthogranulomatous infiltration by lipid-laden or foamy histiocytes, and are usually surrounded by fibrosis. Bone biopsy is said to offer the greatest likelihood of reaching a diagnosis. In some, there is histiocyte proliferation, and on staining, the section is CD68+ and CD1a-.

Epidemiologically, the disorder usually develops slowly and is mainly observed in people over the age of 50. It may also develop as a side-effect of treatment with some drugs that target hematological disorders, such as polycythemia vera or chronic myelogenous leukemia.

Diagnosis of myelofibrosis is made on the basis of bone marrow biopsy. A physical exam of the abdomen may reveal enlargement of the spleen, the liver, or both.

Blood tests are also used in diagnosis. Primary myelofibrosis can begin with a blood picture similar to that found in polycythemia vera or chronic myelogenous leukemia. Most people with myelofibrosis have moderate to severe anemia. Eventually thrombocytopenia, a decrease of blood platelets develops. When viewed through a microscope, a blood smear will appear markedly abnormal, with presentation of pancytopenia, which is a reduction in the number of all blood cell types: red blood cells, white blood cells, and platelets. Red blood cells may show abnormalities including bizarre shapes, such as teardrop-shaped cells, and nucleated red blood cell precursors may appear in the blood smear. (Normally, mature red blood cells in adults do not have a cell nucleus, and the presence of nucleated red blood cells suggests that immature cells are being released into the bloodstream in response to a very high demand for the bone marrow to produce new red blood cells.) Immature white cells are also seen in blood samples, and basophil counts are increased.

When late in the disease progression an attempt is made to take a sample of bone marrow by aspiration, it may result in a dry tap, meaning that where the needle can normally suck out a sample of semi-liquid bone marrow, it produces no sample because the marrow has been replaced with collagen fibers. A bone marrow biopsy will reveal collagen fibrosis, replacing the marrow that would normally occupy the space.

The process is usually asymptomatic and benign, in which case the tooth does not require endodontic treatment.

The offending tooth should be tested for vitality of the pulp, if inflamed or necrotic, then endodontic treatment is required, while hopeless teeth should be extracted.

The prognosis is excellent, as no treatment is usually required.

If the offending tooth is extracted, the area of condensing osteitis may remain in the jaws indefinitely, which is termed osteosclerosis or bone scar.

Worth syndrome, also known as benign form of Worth hyperostosis corticalis generalisata with torus platinus, autosomal dominant osteosclerosis, autosomal dominant endosteal hyperostosis or Worth disease, is a rare autosomal dominant congenital disorder that is caused by a mutation in the LRP5 gene. It is characterized by increased bone density and benign bony structures on the palate.

Worth syndrome is caused by a mutation in the LRP5 gene, located on human chromosome 11q13.4. The disorder is inherited in an autosomal dominant fashion. This indicates that the defective gene responsible for a disorder is located on an autosome (chromosome 11 is an autosome), and only one copy of the defective gene is sufficient to cause the disorder, when inherited from a parent who has the disorder.

The one known curative treatment is allogeneic stem cell transplantation, but this approach involves significant risks.

Other treatment options are largely supportive, and do not alter the course of the disorder (with the possible exception of ruxolitinib, as discussed below). These options may include regular folic acid, allopurinol or blood transfusions. Dexamethasone, alpha-interferon and hydroxyurea (also known as hydroxycarbamide) may play a role.

Lenalidomide and thalidomide may be used in its treatment, though peripheral neuropathy is a common troublesome side-effect.

Frequent blood transfusions may also be required. If the patient is diabetic and is taking a sulfonylurea, this should be stopped periodically to rule out drug-induced thrombocytopenia.

Splenectomy is sometimes considered as a treatment option for patients with myelofibrosis in whom massive splenomegaly is contributing to anaemia because of hypersplenism, particularly if they have a heavy requirement for blood transfusions. However, splenectomy in the presence of massive splenomegaly is a high-risk procedure, with a mortality risk as high as 3% in some studies.

In November 2011, the FDA approved ruxolitinib (Jakafi) as a treatment for intermediate or high-risk myelofibrosis. Ruxolitinib serves as an inhibitor of JAK 1 and 2.

The "New England Journal of Medicine" (NEJM) published results from two Phase III studies of ruxolitinib. These data showed that the treatment significantly reduced spleen volume, improved symptoms of myelofibrosis, and was associated with improved overall survival compared to placebo.

A lipodystrophy can be a lump or small dent in the skin that forms when a person performs injections repeatedly in the same spot. These types of lipodystrophies are harmless and can be avoided by changing (rotating) the locations of injections. For those with diabetes, using purified insulins may also help.

One of the side-effects of lipodystrophy is the rejection of the injected medication, the slowing down of the absorption of the medication, or trauma that can cause bleeding that, in turn, will reject the medication. In any of these scenarios, the dosage of the medication, such as insulin for diabetics, becomes impossible to gauge correctly and the treatment of the disease for which the medication is administered is impaired, thereby allowing the medical condition to worsen.

In some cases, rotation of the injection sites may not be enough to prevent lipodystrophy.

Doctors can diagnose "urticaria pigmentosa" (cutaneous mastocytosis, see above) by seeing the characteristic lesions that are dark-brown and fixed. A small skin sample (biopsy) may help confirm the diagnosis.. To check whether the mastocytosis is cutaneous only or systemic, the level of serum tryptase in the blood is also checked. If the level is elevated, this most probably implies that the mastocytosis is systemic and can only be confirmed by undergoing a bone marrow biopsy.

By taking a biopsy from a different organ, such as the bone marrow, the doctor can diagnose systemic mastocytosis. Using special techniques on a bone marrow sample, the doctor looks for an increase in mast cells. Another sign of this disorder is high levels of certain mast-cell chemicals and proteins in a person's blood and sometimes in the urine. Serum tryptase level is the initial screening test for suspected systemic mastocytosis.