Rare skeletal diseases

Genetic abnormalities related to the skeletal system arise due to disorders that occur in complex processes during skeletal development, growth and homeostasis, and remain a diagnostic challenge due to the variety they present. To date, nearly 400 different types of skeletal dysplasia have been described. With the advancement of molecular genetics, it has been shown that different phenotypes can be caused by gene mutations, depending on the type of mutation and the place where it will take place within the gene.

The International Organization for Osteoporosis (IOF) has set up a group that deals primarily with rare skeletal diseases (SRD-WG). The purpose of this group is to investigate rare skeletal diseases and to inform the public about them.


Advises Mr. George Trovas, Endocrinologist Partner of EEPMS.

Hypoparathyroidism is a rare endocrine disorder, which is caused by chronic insufficiency or complete absence of parathyroid hormone and occurs with a frequency of one case per 200,000 people. Low levels of calcium and parathyroid hormone are the hallmarks of hypoparathyroidism.

Under normal conditions, low calcium levels stimulate the parathyroid glands to produce and secrete parathyroid hormone, which in turn acts on the bones and kidneys to increase calcium levels. In the case of hypoparathyroidism, the parathyroid glands do not function well enough to produce parathyroid hormone, leading to low calcium levels, along with the risks involved.

One of the most common causes of reversible hypoparathyroidism is high levels of magnesium, which inhibit parathyroid hormone secretion. With the correction of the magnesium levels, the function of the parathyroid glands returns to normal. The most common cause that can lead to hypoparathyroidism, which accounts for 75% of all cases of hypoparathyroidism, is injury or complete removal of the parathyroid glands during surgery on the cervix. 75% of these cases of hypoparathyroidism are transient and usually resolve within the first six months after surgery, eventually leaving less than 2% of patients with permanent hypoparathyroidism.

The greatest risk for developing hypoparathyroidism postoperatively has been identified:

  • in the case of complete removal of the thyroid gland
  • in extensive surgery in the cervical region
  • in recurrent surgery in the cervical region
  • in the case of Graves’ disease

If the surgeon is unable to recognize more than two parathyroid glands during surgery, the occurrence of postoperative complications such as bleeding, and low calcium levels (below 7.5mg/dl) 24 hours after surgery. Autoimmune parathyroid destruction is the second most common cause of hypoparathyroidism. Finally, less common causes are genetic causes, invasive diseases such as iron deficiency or Wilson’s disease, which are characterized by iron and copper deposition in various tissues, including the parathyroid glands and exposure to ionizing radiation.

Clinical manifestations of hypoparathyroidism include:

Manifestations from the musculoskeletal system: Low calcium levels can cause muscle cramps, numbness, especially in the extremities and around the mouth, and in more severe cases can even lead to airway spasm with impaired ventilation even at epileptic seizures.

In addition, low levels of parathyroid hormone appear to adversely affect the skeleton, leading to disturbances in bone density and bone strength. Hypoparathyroidism appears to be associated with increased bone density in both the lumbar region of the spine and the hip. However, this increase in bone density appears to be accompanied by decreased bone strength, as a result of a disturbance in bone microarchitecture.

-Neuro/psychiatric manifestations: Depression appears to be twice as common in patients with hypoparathyroidism. Also, disorders in mental functions can occur, and in fact seem to be related to the duration of the disease and phosphorus levels. Finally, as previously mentioned, seizures can occur in more severe forms of the disease.

-Kidneys: are another target organ of the disease. Kidney function may be affected and stones may develop

-Cardiovascular: low calcium levels can lead to severe arrhythmias and death

-Other: cataract and appearance of skin lesions less often, such as dry skin, dry hair, psoriasis, etc.

In the treatment of hypoparathyroidism, timely and urgent treatment of acute hypocalcaemia is very important, especially when it is symptomatic and life-threatening. In this case, urgent hospitalization and immediate intravenous calcium administration is required to restore normal calcium levels. Once the patient has stabilized, the next goal is to treat chronic hypoparathyroidism.

The purpose of this treatment is to restore calcium levels by administering calcium and vitamin D supplements, while in case the phosphorus levels are particularly high, special preparations are used that bind phosphorus and reduce its levels. This medication is always given by a specialized and properly trained physician, as specialized knowledge is required for the proper guidance and proper monitoring of the patient suffering from hypoparathyroidism.

In conclusion, in case the above measures do not work as expected, alternatively the administration of parathormone can be used. In fact, this treatment seems to improve the bone strength that is observed in patients with hypoparathyroidism, but always, as already mentioned, the administration of such drugs requires monitoring by a specialist and should be done with the proper guidance of a specialist.


Pseudo-hypoparathyroidism is a rare inherited disease characterized by hypocalcaemia and hyperphosphataemia. Pseudo-hypoparathyroidism has many features in common with Hypoparathyroidism. In contrast, however, in Pseudo-hypothyroidism there is resistance of the end organs to the administration of PTH (parathyroid hormone). The disease seems to affect people of all ages, from infancy to old age.

There are two types: type I (divided into Iα and Iβ) and type II. Type Ia is the most common type, it is inherited and is due to a genetic abnormality. Finally, patients with Type Iβ show renal resistance to PTH.


Advises Mr. George Trovas, Endocrinologist, Scientific Associate of the Laboratory of Musculoskeletal Diseases Research


It is a chronic skeletal disorder characterized by swollen and deformed bones in one or more bony areas.


The cause of Paget’s disease has not been clarified. Genetic and environmental factors have been implicated and some disease-related genes have been found. The fact that there is heredity also follows from the fact that it can occur in more than one member of a family. Some researchers claim that the disease is due to a chronic mild viral infection but this is also a controversial theory.


It is a rare disease with a prevalence of 1.5-8% depending on age and country. It rarely occurs in people under the age of 40 and affects women and men equally.


It is asymptomatic in many people and is suspected of being elevated alkaline phosphatase, an enzyme that can be measured in a routine blood test. The most common symptom is pain, usually in the area of the affected bone. There may also be headache or hearing loss when the skull is affected. In advanced disease, bone deformities such as enlargement of the skull, curvature of the limbs and spine can occur. Arthritis of the affected areas also coexists with age.


Any bone can be affected but most often the bones of the pelvis, skull, spine and lower extremities are affected. Some patients have a bone injury while others have two, three or more.


With imaging methods such as:

X-rays of the affected areas, which have a characteristic appearance.

Bone scintigraphy, which is a very sensitive examination.

Also, blood alkaline phosphatase, an enzyme that is characteristic of the disease, is usually elevated. However, when the affected area is very small, alkaline phosphatase may be normal.


Although they may coexist in the same patient, these are two completely different conditions.


Paget’s disease increases the volume and deformity of the bones resulting in wear out of the joints of the affected areas.


DIET: No special diet is needed but patients need 1000mg of calcium per day and 800 units of vitamin D for good skeletal health.

EXERCISE: Exercise is recommended for patients with Paget’s disease after first discussing with their doctor what is the appropriate form of exercise for their case.

DRUGS: Drugs used in Paget’s disease belong to the group of bisphosphonates mainly risedronate and zolendronic acid in doses different from those used in osteoporosis, in order to keep the disease in long-term downturn.

SURGERY: There are 3 cases in which surgery is recommended:

  • Firsty, when a fracture occurs in the bone suffering from the disease.
  • Secondly, when severe degenerative arthropathy develops.
  • Thirdly, for the correction of serious deformations

Advises Mr. George Trovas, Endocrinologist, Scientific Associate of Musculoskeletal Diseases Research Laboratory


Incomplete osteogenesis (IO) is a genetic disease characterized by brittle bones.

Who is at risk of Incomplete Osteogenesis

Anyone can be born with incomplete osteogenesis but people who have relatives in the family with the disease are at greater risk. It is a rare disease with a reported prevalence in two Nordic countries Sweden and Denmark 1/13500 and 1/9700 respectively.


Incomplete osteogenesis is due to genetic defects that are primarily related to the production or quality of type 1 collagen, an important connective tissue protein that results in bones breaking easily. Specific genetic tests detect type 1 collagen mutations in about 90% of cases but when the test is negative the disease may be due to other mutations not related to type 1 collagen which can also be detected.

Clinical features

The severity of IO varies and some people do not know it until they break a bone.

The main features are:

  • fragile bones that break easily with minimal injury
  • Bone algae
  • Bone deformities (Scoliosis – lower extremities)
  • Low height
  • Fragile teeth
  • Blue or gray hard linings of the eyes
  • Triangular face shape
  • Hearing loss
  • Relaxation of the joints

To date, with the help of genetics, at least 15 types of IO have been described, with the most common being the first 4 types.

How Incomplete Osteogenesis is diagnosed

In addition to the family history, a check is made for unexpected fractures, dental problems, blue hard linings of the eyes, short stature, etc.

The laboratory test includes:

  • X-rays
  • Genetic testing for mutations
  • Blood and urine tests to rule out other conditions.


There is no cure for patients with IO but treatment aims to treat the symptoms, as much independent mobility as possible and the development of optimal bone and muscle mass.

People with IO are encouraged to exercise through swimming and hydrotherapy. For those who can walk, walking is a very good choice.

Children and adults with IO benefit from a balanced diet, which maintains normal body weight, is rich in calcium, vitamin D and protein. Of course, special mention is made of smoking avoidance and alcohol abuse.

Various oral or intravenous drugs (bisphosphonates) have been used to prevent and treat fractures, as well as in some cases teriparatide (adults only).

Finally, in many cases, surgical correction of skeletal deformities is needed.


Advisors: Aikaterini Deli, doctor Georgia Karachristou, doctor Susana Gazi, MD, doctor, Rheumatologist

Osteoid Osteoma: What is it and how is it treated?

Osteoid osteoma is a benign bone tumor. It occurs most often in the long bones of the lower limbs (legs) and mainly in the femur, but can occur in the bones of the hand and sometimes in the lower vertebrae. It occurs extremely rarely in the bones of the head and face.

Osteoid osteomas are very small tumors that are no larger than 1.5 cm in diameter. They usually occur in adolescence or young adulthood and are more common in men than women. These tumors, while causing pain locally in the bone, do not worsen the bone.

Osteoid osteomas in children can deform or stimulate the bone and make it larger or longer if they are located in areas of the bone growth zone. If they are close to joints they can lead to swelling of the joint or collection of fluid in the joint. They do not extend beyond the bone and do not metastasize.

What is the cause of osteoid osteoma?

Osteoid osteoma is caused when certain cells divide uncontrollably resulting in a small mass. This mass is poor quality bone, which replaces healthy bone. However, it is not known why this disorder occurs.

What are the symptoms of osteoid osteoma?

The most common symptoms are the following:

  • Mild or acute pain, worsening at night
  • The pain usually goes away with an anti-inflammatory drug
  • Lameness (i.e. difficulty walking)
  • If the tumor is in the spine, scoliosis and pain from muscle spasm or sciatica may occur.
  • If the tumor is in the bone growth zone, growth may be affected
  • Near muscle atrophy
  • Bone curvature

The symptoms may be similar to those of other illnesses, so you should always consult your doctor.

How is osteoid osteoma diagnosed?

  • The patient’s history is needed
  • Clinical examination by the doctor
  • Blood tests: General blood and biochemical test
  • X-rays of the diseased bone
  • X-ray computed tomography
  • Brain scans
  • Bone scan

How is osteoid osteoma treated?

The treatment is determined by the Orthopedist and depends on:

  • Age
  • The general health of the body
  • The extent of the tumor
  • The patient’s resistance to various drugs or therapeutic techniques
  • Traditionally the osteoid osteoma is surgically removed by the Orthopedist with various surgical techniques, depending on the case.

Recently, the ablation of the tumor with transdermal radiofrequency is being performed by a radiotherapist. This technique is applied under general anesthesia and with simultaneous computed tomography. With this method, radio frequencies are injected under the skin with a needle, in order to destroy the tumor cells. This method is minimally invasive and has successfully replaced surgery, but does not apply to tumors in the spine.

What is the long-term prognosis of a patient with osteoid osteoma?

The prognosis is generally excellent, although it varies from person to person and depends on:

  • How active the tumor is
  • Tumor’s behavior in treatment
  • The age and state of health of the patient

Most of these tumors are successfully treated. They may, however, recur, which requires regular monitoring of the patient with osteoid osteoma. The manner and frequency of monitoring should be determined by the physician.


Advises Mr. George Trovas, Endocrinologist Partner of EEPMS.

Fibrous dysplasia / McCune – Albright syndrome (MAS) is a rare disorder characterized by skeletal lesions, skin lesions (café-au-lait spots) and overactive endocrine glands. The disease resulting from this mechanism is a mosaic of diseases with variety in its clinical manifestation, ranging from accidental discovery to random radiological examination to manifestation as a serious disease that adversely affects the quality of life. Fibrous dysplasia may be unifocal or multifocal located in the bone and may be associated with or without extraoskeletal manifestations. While Mc Cune-Albright fibrous dysplasia / syndrome is classically described as a disease involving the skeleton, skin, and endocrine glands, multiple tissues and organs may be affected. Skeletal lesions appear in the first years of life and worsen during adolescence, reaching the final clinical picture of the disease around the age of 15 years.

Around the age of 5 years, 95% of clinically significant lesions of fibrous dysplasia are apparent and a bone scintigraphy should be performed in all patients of this age for the initial evaluation / staging of the patient’s disease. The lesions of fibrous dysplasia become less active in adulthood.

Disease management is demanding, with multiple barriers to diagnosis and management. The involvement of multiple systems and the rarity of the disease, makes its management difficult, with the participation of multiple specialties necessary. It is therefore necessary to establish general guidelines for its diagnostic approach and treatment and to properly inform patients and their relatives.

How is the disease manifested in the skeleton and outside the skeleton?

Diagnosis of fibrous dysplasia / Mc Cune-Albright syndrome can only be made after extensive evaluation:

1) Skeletal disease (unifocal/multifocal localization)


2) The presence of extraoskeletal manifestations.

Unifocal fibrous dysplasia is characterized by the presence of fibrous dysplasia lesions in one part of the skeleton and multifocal fibrous dysplasia is described by the presence of fibrous dysplasia in more than one skeletal location without extracoskeletal manifestations. Mc Cune-Albright syndrome is characterized by a combination of fibrous malformations’ damages and exoskeletal manifestations.

Other exoskeletal manifestations of the disease include:

1) café-au-lait spots on the skin with characteristically blurred and irregularly defined borders and distribution such that the lesions do not penetrate the midline of the body.

2) Hypersecretion of sex steroid hormones leading to premature puberty, recurrent ovarian cysts in girls / women, autonomous testosterone production in boys / men, which may coexist with testicular damage, usually lithiasis.

3) Thyroid damage with or without hyperthyroidism.

4) Growth hormone hypersecretion

5) Hypercortisolemia

How is the diagnosis made?

In most cases, the diagnosis of Mc Cune-Albright fibrous dysplasia / syndrome can be made clinically after evaluating the patient, skeleton, endocrine system, soft tissues and skin lesions. Sometimes a biopsy may be needed for histological confirmation of the disease, while in other cases the molecular diagnosis of the disease by examination of the affected tissue may be required if clinical, radiological and histological analysis fails to confirm the diagnosis of fibrosis dysplasia.

General radiological features of fibrous dysplasia/MAS in conventional radiography are radiolucent lesions, cystic lesions, sclerosing lesions, or mixed sclerosing/cystic lesions with well-defined boundaries. Damage may extend with a thin or thickened housing and/or with small infiltrations around the lesion.

Computed tomography is useful for the evaluation of lesions in areas with complex anatomy e.g. face, pelvis, spine, and for the detection of non-displaced fractures. Also, MRI, photon emission tomography and positron emission tomography help to locate the lesions.

Biopsy for histological confirmation of the disease is required in case of inability to diagnose the disease or on suspicion of malignancy. Genetic testing is recommended when the clinical diagnosis of the disease is not certain.

For the evaluation of skeletal lesions, a complete personal reminder, physical examination, laboratory examination and radiological examination are recommended. Skeletal evaluation includes a recording / marking of areas of symptoms, such as bone pain, joint pain, deformities, fracture history (location, date, severity of injury) and degree of fracture healing (complete, incomplete, no healing), previous orthopedic procedures (type of surgery and date), history of taking drugs related to bone metabolism (name of drug, duration of treatment, start and end of treatment). The presence of pain at night is a warning symptom of possible complications such as impending fracture, bleeding inside the bladder or very rarely malignant change.

Physical examination of the musculoskeletal system includes gait, check for the presence of limb deformities, areas of sensitivity and range of motion of adjacent joints, and check for the presence of kyphosis and scoliosis in the spine.

Laboratory tests include renal function, total alkaline phosphatase, bicarbonate, total calcium, albumin, phosphorus, 25 (OH) vitamin D, parathormone.

Radiological examination is recommended for further investigation in case of clinical symptoms. Bone scintigraphy is required to assess the extent of fibrous dysplasia, which should be avoided in asymptomatic children, especially those under 5 years of age, as the results may be false negative, so it is advisable to expect the child to reach an older age. In case of a positive scintigraphy, localized radiological examination or computed tomography is recommended to check nerve entrapment.

For the evaluation of exoskeletal lesions, dermatological lesions such as cafe au lait spots that do not penetrate the midline of the body as well as the function of the endocrine system are evaluated.

Ovarian function test: individual reminder, physical examination, history of vaginal bleeding, ovarian cysts, irregular menstruation (duration less than 21 days or more than 35 days), breast growth test. Measurement of FSH, LH, estradiol and genital ultrasound is required.

Testation of testicles: individual reminder, physical examination, testicular test, testicular ultrasound. Measurement of FSH, LH, and free testosterone is required.

Thyroid examination: individual reminder, clinical examination, measurement of TSH, fT4, fT3, ultrasound of the thyroid gland.

Pituitary examination: individual history, physical examination, height measurement. Measurement

IGF-1, GH. Pituitary MRI is recommended.

Adrenal control: hypercortisolemia occurs in the first year of life and may progressively subside. Individual history, history of growth retardation, severe weight gain, clinical examination. In case of clinical suspicion of hypercortisolemia, measurement of 24-hour urinary cortisol free, low-dose dexamethasone suppression test, blood cortisol measurement and adrenal computed tomography are recommended.

What is the treatment to be followed?

Proper information of patients and relatives is very important, especially when the disease is manifested with severe disability that cannot be clinically improved with any treatment. The goal is the psychological support of the patient. There must be information about the non-heredity of the disease and the low probability of malignant recurrence of the lesions of fibrous dysplasia. Also, there are no known environmental risk factors associated with the onset of the disease. It is recommended to be informed through publications, social media, and participation in patients’ associations.

What advice could we give to improve patients’ quality of life?

Adequate dietary intake of calcium and vitamin D is recommended, especially if there is a possibility of starting treatment with anti-osteoporotic treatment. Smoking cessation, reduction of alcohol consumption to 3 units/day and maintaining a healthy body weight, and proper physical exercise are essential. Regular dental monitoring to reduce the risk of oral infections and reduce the risk of osteonecrosis as a result of receiving anti-osteoporotic treatment. Psychological support is especially useful in patients with moderate to severe disease, especially when accompanied by craniofacial localization/deformity.

In some cases we have to follow special treatment. Treatment may include analogues or active metabolites of vitamin D and phosphorus supplements. Bone pain is treated with paracetamol/acetaminophen as a first-line drug, followed by NSAIDs. Bisphosphonates are recommended for persistent, moderate to severe pain without it being clear whether bisphosphonates reduce the extent of fibrous dysplasia lesions and/or its progression. Also, the management of endocrine diseases that accompany McCune-Albright syndrome is considered necessary, such as the regulation of ovarian function, testicular function, thyroid function, pituitary gland and adrenal glands.

Exercise is also recommended to improve the cardiovascular system. Physiotherapy to improve functionality and mobility. Physiotherapy is recommended to improve limb function / mobility and reduce pain.

Finally, in case of fracture, tumor or deformity of the limb, surgery is required accompanied by postoperative physiotherapy, in order to improve the mobility/functionality of the limb.


Advises  Mr. Konstantinos Dion. Stathopoulos, Orthopedic Surgeon. Member of the Hellenic Society of Orthopedic Surgery and Traumatology, of the Hellenic Society for the Study of Bone Metabolism, and of the International Society of Musculoskeletal & Neuronal Interactions (ISMNI), associate of the Medical School of the University of Athens “Metabolic Diseases of Bones” and the Research Laboratory of Research and Education “Th. Garofalidis”.

What is osteopoikilosis?

Osteopoikilosis is a rare, usually asymptomatic, benign bone malformation that is usually found on random radiological examination. In most cases, the patient sees a doctor for another cause related to skeletal pain, and the radiological examination that follows reveals multiple foci of osteosclerosis, usually circular in shape, resembling osteoblastic lesions (Figure 1).

The most common location is in the pelvic bones, as well as in short bones such as the bones of the wrist and tarsus, while it can also occur in the metaphyses of the long bones. The foci consist of mature bone tissue with normal osteoclasts and osteoblasts. The picture is sometimes striking because of the multiple foci that may occur, and is confused with secondary metastatic foci, initially creating confusion and sometimes panic in the patient. In these cases, the examination with bone scintigraphy clarifies the real nature of the foci, because in osteo-diversification the lesions do not give a pathological signal to the scintigraphy, while the metastatic foci are clearly displayed and allow the diagnosis with absolute safety. Therefore, care is needed on the part of doctors who may encounter this unexpected image on plain radiography, in order to immediately request further examination to clarify the cause.

Is this condition inherited?

Indeed, it is a disease inherited with the autosomal dominant character and today we believe that it is due to the neutralizing mutation of a gene called LEMD3. It occurs with the same frequency in both sexes, is estimated at 1 in 50,000 births, and can be diagnosed at any age. Also, in some cases it can coexist with autoimmune diseases such as Systemic Lupus Erythematosus (SLE), systemic scleroderma, and others, and in some cases it is associated with cutaneous warts (cutaneous osteoporosis or Buschke-Ollendorff syndrome). Usually in these cases the warts are soft, pressed and painless, while symptoms of bone pain are unusual (15-20% of patients).

What should we keep in mind when it comes to osteopoikilosis?

The important thing in any case is to remember that this is a benign bone dysplasia for which we do not expect any development over time. Osteoblastic foci remain for life without usually changing in size.

Osteopoikilosis does not require treatment and in the few cases where pain occurs, anti-inflammatory drugs are administered with good results.

Patients with osteopoikilosis do not have fractures more often than the general population and this condition does not require anti-osteoporotic medication.


Advises Mr. Konstantinos Dion. Stathopoulos, Orthopedic Surgeon

Member of the Hellenic Society of Orthopedic Surgery and Traumatology, of the Hellenic Society for the Study of Bone Metabolism, and of the International Society of Musculoskeletal & Neuronal Interactions (ISMNI), associate of the Medical School of the University of Athens “Metabolic Diseases of Bones” and the Research Laboratory of Research and Education “Th. Garofalidis”.

What is osteopetrosis?

Osteopetrosis belongs to a family of rare genetic disorders that are manifested by an increase in bone mass due to impaired osteoclast function. Osteoclasts are the basic cells that break down bones in places that are mechanically aged to create new and durable bone tissue at every point in our lives through the process of bone remodeling.

In patients with osteopetrosis, the function of osteoclasts is defective, with the result that there is no bone resorption, and these people have very dense and heavy bones with abnormally increased bone mass. However, despite their increased bone mass, the bones are abnormal due to their poor quality and often show fractures.

What are the types of osteopetrosis?

Osteopetrosis was first described about 100 years ago by the German radiologist Albers-Schonberg and based on its latest classification it includes 4 different types depending on the method of inheritance:

Autosomal recessive osteopetrosis: It usually occurs in 1 in 200,000-300,000 births. It is an extremely rare condition that is perceived in infancy or childhood and in severe cases is accompanied by severe deformities and high mortality. Children suffer from multiple fractures even with simple injuries inside the home, while the increase in bone mass in the skull can cause cranial nerve entrapment with loss of vision, hearing or facial deformity.

These children may also have anemia, frequent infections and a predisposition to bleeding. They usually have growth disorders and short stature, teething disorders, increased liver and spleen size or seizures. If there is a suspicion from the family history it is necessary to have a genetic prenatal test. The most common mutations are in the TCIRG1 and CLCN7 genes.

Intermediate autosomal recessive osteopetrosis: Appears with a much milder clinical picture than the autosomal recessive form. This type of osteopetrosis presents with symptoms in childhood and in particular usually anemia and low energy fractures. Some of these children usually have some form of mental retardation, and calcium deposits have been found in the brains of affected children.

Autosomal dominant osteoporosis (Albers-Schonberg disease): This form is the most common form of osteopetrosis (1: 20,000 births) and is usually the least severe, as some children have no symptoms at all. The most severe forms are characterized by fractures, skeletal deformities such as scoliosis, while osteomyelitis can be particularly common in these individuals.

The diagnosis is usually made by random radiological examination and sometimes patients do not show any symptoms or deformities in the skeleton (adult osteopetrosis). Most individuals (> 75%) carry mutations in the gene X-linked form of osteopetrosis: It is the rarest form of the disease and in addition to increased bone mass is characterized by abnormal lymphedema as well as disorders of the skin, teeth and sweat glands. Often these people also suffer from recurrent episodes of infections due to a deficiency of their immune system. In this form the responsible gene is the IKBKG located on the X chromosome, which is why the disease occurs in its vast majority in boys.

Typical radiological findings for all forms of osteopetrosis:

On plain X-ray we see a diffuse symmetrical increase in bone mass of all bones with thickening of both cortical and spongy bone. In the infant-specific form, the metaphyses are broad with a characteristic deformity like an Erlenmeyer bottle”. The bones of the skull are thickened and the pneumatosis of the sinuses is reduced.

In some cases, in addition to the sclerosing lesions, there are also lucent focis, as well as the image as if one sees a bone being enclosed within a bone (bone within bone), which is not pathognomonic.

The hallmark of increased bone mass may coexist with fractures or a picture of osteomyelitis. “Rugger-jersey” imaging is common on the spine.

In some cases of osteopetrosis where there may be doubts, selective bone biopsy in combination with genetic testing is the sure choice to clarify the patient’s condition.

Special care is needed in asymptomatic adults who experience excessive bone density with the DXA method to be referred to a specialist for examination for osteopetrosis.

Ways to Treat Osteopetrosis:

Proper treatment: We need to understand that there is no specific treatment with a drug to treat the disease. Given the lack of appropriate medication, great care is needed especially in patients who have suffered fractures, so that they are NEVER and under NO circumstances given drugs for osteoporosis, such as anti-osteoclastic drugs which are mainly bisphosphonates and denosumab. In particular, these drugs do not allow osteoclasts to function. Therefore, if one accidentally gives these drugs to patients who have osteopetrosis, then it greatly aggravates the existing condition, especially in the intermediate form.

Fracture prevention: Care must be taken to avoid falls and general injuries that can lead to a fracture. We pay special attention to the treatment of fractures in these patients, in order to prevent deformities and to prevent osteomyelitis

Special treatment depending on age: It should be done only by specialized doctors and especially in infants and children. A team of specialists is required, long-term care and monitoring and correction of threatening disorders such as hypocalcaemia (with calcium and in some cases calcitriol can be given). In cases where there is hepatomegaly or splenomegaly, cortisone treatment is often indicated, while in the most severe form of osteopetrosis a bone marrow transplant could be the solution.

We should be aware that there is unfortunately no definitive cure for genetic diseases. However, there are hopes that in the next 30-40 years we will be able to do gene therapies.

Attention! If the doctor sees an increase in bone mass by 3-4 statistical deviations greater than that of healthy young adults in measuring bone density in patients with fractures, he/she should be mobilized immediately, as this finding may in some cases obscure osteopetrosis. We recommend that the treatment be undertaken only by a specialist as the wrong treatment will harm the patients, because osteopetrosis is DIFFERENT from osteoporosis.


Advises Mr. George Trovas, Endocrinologist Partner of EEPMS.

Alkaline phosphatase is an enzyme that exists in humans in different forms and each form is encoded by a different gene. Thus, there is the gene encoding intestinal alkaline phosphatase, another gene encoding alkaline phosphatase produced by the placenta and another gene encoding alkaline phosphatase associated with germ cells.

Finally, in humans there is another gene that encodes tissue non-specific alkaline phosphatase (TNSALP), which predominates in bones, kidneys, liver and growing teeth.

What is hypophosphatasia?

Hypophosphatasia is an inherited disease characterized by impaired alkaline phosphatase enzyme activity. More than 260 different alkaline phosphatase gene mutations have been described, as well as a wide variety of clinical manifestations of the disease, ranging from isolated early tooth loss to intrauterine death. An attempt has been made to classify the forms of hypophosphatase which include:

  • dental hypophosphatasia: when the manifestations of the disease are limited to the teeth, without manifestations from the bones. Early tooth loss before the age of five occurs painlessly. Otherwise, the sufferers are in good health.
  • And depending on the severity and age of manifestation of skeletal abnormalities and complications, the other forms of hypophosphatasia include the adult, childhood, infant and perinatal form. Finally, benign prenatal hypophosphatasia refers to the form of hypophosphatasia in which skeletal abnormalities occur during intrauterine life or at birth and improve in ectopic life.
  • The adult form of hypophosphatasia is manifested in adulthood. However, some patients report early tooth loss or a history of rachitis at a younger age. Tooth loss is quite common in sufferers. There is also an inability of adequate healing of recurrent fractures in the metatarsal bones (in the extremity of the foot). Pain in the hip area may be indicative of a fracture. In addition, calcification may occur in other tissues such as ligaments and joints leading to periarthritis. Eventually, the adult form of the disease can lead to severe disability due to recurrent fractures, musculoskeletal pain, joint pain, and muscle weakness.
  • Childhood hypophosphatemia occurs after the first six months of life and can vary in severity from mild to severe. Tooth loss occurs in all sufferers. Picture of rachitis, with deformities of the bones of the skull, swelling of the joints, deformities of the knees and lower limbs are common. Also, musculoskeletal pain is quite common, while due to the deformities the patient may end up with short stature. Accompanying muscle weakness can lead to gait disturbance. The clinical manifestations of the pediatric form of hypophosphatasia occur and persist during skeletal development, but in some cases the symptoms improve later, during adulthood.
  • The infantile form of hypophosphatasia manifests itself during the first six months of life. The infant gradually begins to not develop properly, to show muscle weakness without being able to develop kinetically, showing at the same time manifestations of rachitis. The baby may have a short head, which can lead to increased intracranial pressure and seizures. Also, as calcium cannot be used in the bones, it accumulates in other tissues such as the kidneys leading to nephrolithiasis and impaired renal function. Also, deformities in the chest and ribs increase the tendency to respiratory infections. Unfortunately, 50% of babies die within the first year.
  • The perinatal form of hypophosphatia, which is the most extreme form of hypophosphatasia, manifests itself clinically already from intrauterine life and soon after birth leads to death. Short and deformed edges are a typical finding. Seizures, transient apneas leading to cyanosis and bradycardia, as well as hypoplastic lungs may also occur.
  • Finally, the carriers of the disease carry a mutation in the alkaline phosphatase gene but without clinical manifestations from the bones or teeth.

The diagnosis of hypophosphatasia is based on history, clinical examination, laboratory and radiological findings. Low levels of alkaline phosphatase activity and elevated levels of pyridoxal phosphate guide us to the diagnosis of hypophosphatasia. Elevated levels of inorganic pyrophosphate are measured in research studies.

X-rays may show osteopenia, fractures of the limb and hip, and calcification of ligaments that can lead to periarthritis. Although the diagnosis of hypophosphatasia can be made with the above, genetic analysis to detect a mutation in the alkaline phosphatase gene helps to identify the risk of recurrence in the next pregnancy and genetic programming and control.

As for the treatment of the disease it is mainly supportive. Close monitoring is needed in infancy for the occurrence of neurological complications, treatment of dental disorders and supportive respiratory treatment. In adults, fractures are treated with appropriate supportive care with appropriate orthoses. Finally, in recent years, efforts have been made to address life-threatening forms of hypophosphatasia by providing appropriate enzyme replacement therapy.


Advises Mr. George Trovas, Endocrinologist, Scientific Associate of the Laboratory of Musculoskeletal Diseases Research.

What is histiocytosis?

Histiocytosis is a rare malignancy, resulting from abnormal proliferation of dendritic cells or Langerhans cells, that express specific markers, CD1a+/CD207+.

Histiocytosis is most commonly caused by a mutation in the BRAF gene that is involved in the proliferation and function of various cells in the human body. These pathological Langerhans cells activate other cells, such as eosinophils, neutrophils, and lymphocytes that accumulate in the affected organs leading to a variety of clinical manifestations.

Histiocytosis can affect people of all ages, although younger children usually develop the so-called multisystemic form of the disease.

How does histiocytosis manifest?

Histiocytosis is divided into three clinical forms including eosinophilic granuloma, Hand-Schuller-Christian disease and Abt-Letterer-Siwe disease. Eosinophilic granuloma, whether localized or multifocal, occurs mainly in childhood, between five and ten years, but also in adults. It is the most common form of histiocytosis and affects 60% to 80% of all cases of the disease. It usually occurs with individual lesions in the bones, skin or with lymphadenopathy.

Hand-Schuller-Christian disease is described as the typical clinical triad of lytic bone lesions, ocular and diabetes mellitus and is usually described between the ages of four and seven years. Finally, Abt-Letterer-Siwe disease is the rarest but also the most severe form of histiocytosis. Typically patients are under the age of two and present with skin rashes, discharge from the ear and a picture of multisystemic infection with cytopenia, respiratory failure, lymphadenopathy and/or hepatosplenomegaly.

Histiocytosis can affect all systems. The main clinical manifestations include:

-Bones: they are the most commonly affected system. Bone lesions are present in 80% of patients with histiocytosis. Most commonly, bone lesions are located in the skull, femur, lower jaw, pelvis, and spine and appear as lytic lesions. Bone pain is a common clinical manifestation of histiocytosis.

-Skin: the most common clinical manifestation is the image of eczema, which typically appears in childhood, while in newborns diffuse brown and erythematous papules are characteristic, which may show ulceration in their center. The involvement of only the skin in the clinical manifestations of the disease is associated with a good prognosis. However, even in the case of individual skin involvement, frequent monitoring is needed, as in 40% of cases the disease can develop into multisystemic.

Neuro-endocrine manifestations: the onset of diabetes can occur in 25% of cases, usually when there is an attack of the hypothalamus-pituitary gland of the brain. Infection of the anterior pituitary gland can lead to growth hormone deficiency, which is why endocrinological monitoring of these patients is important. Also, cranial bone involvement may be accompanied by neurodegeneration, of unknown etiology, characterized by brain dysfunction and cognitive impairment, with symptoms of gait disturbances, dysarthria, behavioral disorders, learning disabilities, and psychiatric problems, with depression being the most common.

-Respiratory: manifestations of lung infection include cough, shortness of breath, and is more common in adult smokers.

-Hematopoietic: the presence of pancytopenia is a poor prognostic sign. It usually occurs in the context of multisystemic disease at a young age.

Liver/Gallbladder: typically affects young people with multiple systemic infection and is associated with poor prognosis. Hepatic fibrosis and sclerosing cholangitis may occur, with elevated bilirubin levels and hepatic impairment which may result in the need for a liver transplant.

With regard to histiocytosis in adults, atypical symptoms of the disease usually lead to a delayed diagnosis, which usually occurs after the fourth decade of life and usually with multisystemic involvement. Lung involvement is particularly common in adults, especially smokers. It usually presents with a dry cough and abnormal findings on the chest x-ray and CT scan, while the final diagnosis is made by biopsy.

Patients with an organ infection can be treated surgically and generally have a good prognosis. On the other hand, patients with multiple organ systems need multifaceted treatment and have a varied prognosis, while the neurodegeneration that may accompany the disease is a major clinical challenge that we have to deal with.


Treatment options are varied and depend on the extent and severity of the disease. In cases where only one system is affected, local treatment or follow-up is usually needed. In cases of multisystemic infection, various treatments with specialized drugs have been used such as vinblastine, etoposide, methotrexate, bisphosphonates, corticosteroids, BRAF inhibitors and others.


Advises Mr. George Trovas, Endocrinologist, Supervisor Partner of EEPMS.

One of the most important diseases of phosphorus metabolism is FGF23-related hypophosphatemia. FGF23 is a hormone produced by bone cells that induces renal excretion of phosphorus in the urine, while also reducing the levels of vitamin D in the body. Diseases characterized by elevated FGF23 levels can either be inherited or acquired.

Oncogenic osteomalacia is an acquired disease, in which autonomic secretion of FGF23 by the cells of a tumor is observed. Patients present muscle weakness, myalgias and bone pain, while laboratory findings include low phosphorus levels and loss of phosphorus in the urine. Tumors that may be accompanied by oncogenic osteomalacia are usually small in size and often quite difficult to detect and remove surgically.

X-linked hypophosphataemic rachitis (XLH) is the most commonly inherited phosphorus renal impairment disorder. It usually occurs in childhood, and is due to inactivating mutations in the PHEX gene on the X chromosome, which encodes a peptidase whose interaction with FGF23 is unclear.

Autosomal dominant hypophosphatemic rachitis (ADHR) is caused by mutations in the FGF23 gene, which lead to elevated levels of FGF23. The clinical picture of the disease is characterized by a wide variety of symptoms that can vary from simple asymptomatic disease or the manifestation of rachitis in childhood.

Autosomal recessive hypophosphataemic rachitis (ARHR) is divided into type 1, which is caused by mutations in the DMP1 gene, and type 2, which is caused by mutations in the ENPP1 gene. ARHR typically occurs during childhood with hypophosphatemia, elevated FGF23 levels, and radiographic images typical of rachitis.

The only way to differentiate between these diseases is genetic testing to determine if there are mutations in the genes mentioned.

There are also renal causes of loss of phosphorus in the urine, leading to low levels of phosphorus in the blood, causing skeletal damage.

There are two conditions that cause hypophosphatemia due to renal phosphorus loss:

  • hereditary hypophosphataemic rachitis with hypercalciuria (HHRH) and
  • Fanconi syndrome

HHRH is caused by autosomal recessive mutations in the SLC34A3 gene, which encodes the NPT2c transporter. Loss of function of this transporter leads to renal loss of phosphorus in the urine. Fanconi syndrome is an inherited and acquired form of proximal tubular dysfunction in the kidney, characterized by increased urinary loss of phosphorus and calcium, among others. Urinary phosphorus loss in Fanconi syndrome, causes hypophosphatemia and osteomalacia that responds well to calcium, phosphorus and vitamin D.

Other conditions that can lead to low phosphorus levels and bone problems include:

  • Drugs and Toxins, such as anticoagulants, phosphorus-binding antacids, such as magnesium and aluminum salts, etc.
  • Hypophosphatase, which is an inherited disease characterized by impaired alkaline phosphatase enzyme activity. More than 260 different alkaline phosphatase gene mutations have been described, as well as a wide variety of clinical manifestations of the disease.
  • Fibrous dysplasia – Mc Cune-Albright syndrome due to activating mutations of the α-subunit of G proteins, and may be accompanied by hypophosphoramic rachitis.
  • Reduced absorption from the gastrointestinal tract such as reduced phosphorus uptake, vomiting, diarrhea, malabsorption syndromes
  • Alcoholism, pancreatitis, burns, etc.

Rachitis in children, osteomalacia in adults

The clinical picture of these conditions is our well-known rachitis in children and osteomalacia in adults. It can manifest from infancy where the bones of the skull show soft areas, giving it the image of a ping-pong ball. After the first year of life, rachitis manifests itself as swellings in the area of the wrists and ankles, as well as in the chest, creating the well-known “rachitic rosary”.

In older children, deformities of the lower extremities, curvature of the long bones and knees may occur, while in severe cases of rachitis, fractures may occur. Short stature, tooth abnormalities, as well as muscle weakness can coexist. Osteomalacia in adults can be asymptomatic or present with symptoms such as bone pain, muscle weakness, fractures and gait disturbance. A characteristic gait disorder is the so-called “goose gait”, i.e. walking like a duck.

Finally, manifestations of co-occurring hypocalcaemia may coexist, such as numbness, cramps in mild cases, and in more severe cases, contraction of the muscles of the face and airway, creating a problem in the patient’s ventilation. As for the findings on the X-rays, there may be widening of the ends of the bones, a rachitic rosary on the chest and a diffuse image of osteopenia. In addition, the vertebral bodies are deformed and can suffer fractures, as fractures can also occur in the pelvis, ribs, shoulder and hip.

The diagnosis of these conditions is based on the clinical picture, laboratory and imaging findings, which must be evaluated by a properly trained, specialized physician.

The goals of treating these diseases are to treat short stature and deformities in the case of rachitis.

In the case of osteomalacia, the relief of bone pain and the reduction of the risk of fracture. Calcium, phosphorus and vitamin D supplements are required, with measurement of calcium, phosphorus, parathormone, vitamin D, as well as calcium levels in a 24-hour urine collection and then careful monitoring of the patient’s response to treatment.

We usually expect improvement in symptoms and x-ray findings in three to six months. We should be aware that the most severe cases require hospitalization and intravenous administration of drugs, as well as that in many cases, such as in malabsorption syndromes or in the case of obesity, etc. Large doses of vitamin D may be needed for a longer period of time in order to show the patient’s response to treatment.

Finally, in various hypophosphatemia syndromes, phosphorus salts are administered orally, in combination with vitamin D in order to normalize phosphorus levels. The above treatment improves children’s development, bone pain and the risk of bone deformities but has poor compliance due to the intolerance caused by phosphorus formulations. It is clearly understood that patient monitoring by a properly trained and specialized physician is crucial for the management of these rare diseases.


Advises Mr. George Trovas, Endocrinologist Partner of EEPMS.

Fibrous duplication is a set of skeletal diseases with extremely significant complexity. Normal bone tissue and bone marrow are replaced by fibrous tissue, leading to bone damage that presents clinically with fractures, pain, and disability.

Fibrous dysplasia can affect one bone (unifocal) or many bones (multifocal) and can be solitary or occur in combination with exoskeletal manifestations (skin blemishes, overactive endocrine glands), known as McCune-Albright syndrome. The clinical manifestations of the syndrome are wide-ranging and the differences between patients can make it quite difficult to treat.

Fibrous dysplasia is due to activating mutations in the α subunit of G proteins, which play an important role in cell function. Depending on the type of tissue that has the mutation and the roles played by the activation of the Ga subunit in tissue function, the clinical manifestations of fibrous dysplasia vary.

In the case of bone, the clinical manifestations of the disease depend on the area of the skeleton that is affected. In the skull, the lesions of fibrous dysplasia tend to extend, leading to facial deformity and rarely to neurological complications, such as vision or hearing impairment. Fibrous dysplasia tends to deform bones, which are mechanically loaded by body weight, such as the lower extremities, leading to fractures and impaired mobility.

Also, fibrous dysplasia in the trunk can lead to scoliosis, which in some cases can be severe. Skeletal lesions appear in the first years of life and worsen during adolescence, reaching the final clinical picture of the disease around the age of 15 years. The lesions of fibrous dysplasia become less active in adulthood, and in bone biopsies in older patients, the mutated cells appear to fall off.


Investigation and treatment of any co-existing endocrine diseases is equally important, as unregulated endocrine diseases are a cause of deteriorating skeletal health. Hyperthyroidism can have a detrimental effect on bone density, increasing the risk of skeletal deformity in patients with fibrous dysplasia.

Growth hormone overexpression increases the extent of fibrous dysplasia lesions, while early puberty can affect the final height of the adult, leading to short stature. Finally, FGF-23-mediated hypophosphoraemia may have a significant effect on the severity of fibrous dysplasia. Patients with fibrous dysplasia who have unregulated low phosphorus levels are at greater risk for fractures, deformities, and bone pain.

The treatment of fibrous dysplasia focuses on the prevention of fractures, improved function and mobility of the patient and the treatment of pain. Bone pain is common in fibrous duplication, and its management is an important aspect of treatment.

In patients presenting with pain, it is important to rule out the existence of an injury, a possible fracture, or other causes that may require orthopedic intervention. If the pain does not respond to preservatives and simple painkillers, even intravenous medications may be required. In general, these drugs should be administered according to the symptoms, using the lowest and most effective dose.

Finally, orthopedic surgeries are important components of treatment, however surgeons should be aware that conventional surgical techniques used in other skeletal conditions may be unsuccessful in fibrous dysplasia, and that aggressive surgeries may exacerbate patient’s condition. Unfortunately, there are no specific treatments that can improve the course of bone disease in fibrous dysplasia, so studies related to this disease will contribute to new discoveries that will significantly help these patients.


Advises Mr. George Trovas, Endocrinologist Partner of EEPMS.

Tumor calcification is a rare disease in which calcium deposits are observed in soft tissues, especially in the periarticular positions, i.e. around joints.

There are several theories that have been proposed to explain the mechanism of development of tumor calcification. Among them are trauma, infection, parasites as well as disruption in the synthesis and deconstruction of collagen. In fact, disorders in phosphorus metabolism have been considered as one of the most important causes for the development of tumor calcification.

In the case of phosphorus metabolism disorders, there may be an inherited disorder in the renal response to parathormone action or a disturbance in renal phosphorus excretion and renal vitamin D production.

Elevated phosphorus levels may stimulate the formation of extracellular calcium phosphate deposits, which in turn lead to the clinical picture of oncogenic calcification.

Classification of tumor calcification:

An attempt has been made to classify tumor calcification, which includes three main forms:

  • Primary oncogenic calcification with normal phosphorus levels: Concerns 42% of cases of oncogenic calcification. It usually occurs before the second decade of life with a free family history, and there may be a history of injury. The most common location of lesions is in the hip area. Phosphorus and vitamin D levels are normal, and in a small percentage of patients the lesions may recur after their initial surgical removal.
  • Primary hyperphosphatic oncogenic calcification: It affects less than 30% of cases of oncogenic calcification. It usually appears before the second decade of life, with a positive family history. There are multiple calcifications, usually in the hips, elbows and shoulders. Phosphorus and vitamin D levels are elevated, and in most cases the lesions reappear after their initial surgical removal.
  • Secondary oncogenic calcification: It affects about 35% of cases of oncogenic calcification. Most patients suffer from chronic renal failure with concomitant secondary hyperparathyroidism. There is an increase in renal phosphorus reabsorption and increased levels of vitamin D. Other conditions that can lead to secondary oncogenic calcification are scleroderma, primary hyperparathyroidism, various malignancies, sarcoidosis, hypervitaminosis D etc.

Calcium deposits in the soft tissues, especially around the joints, are the hallmark of tumor calcification. The most common locations are the shoulder, hip and elbow joints. These calcium deposits can expand significantly and compress adjacent muscles, nerves, and blood vessels leading to a variety of clinical manifestations. It can also cause significant swelling of the joints and overlying skin, creating ulcers that can be painful.

Characteristic is the imaging of lesions of tumor calcification on X-rays, bone scintigraphy, computed tomography and magnetic resonance imaging, imaging techniques that help to locate and identify the extent of damage to the surrounding tissues. Treatment of the disease includes surgical removal of the lesion as well as normalization of phosphorus levels with appropriate phosphorus-binding drugs as well as by limiting the dietary intake of calcium and phosphorus.

Finally, we must always keep in mind that there is a significant potential for recurrence, especially in the case of the hyperphosphoraemic form of the disease, a risk that exists even with proper management of phosphorus levels.


Advises Mr. George Kalogirou, Obstetrician – gynecologist

Osteoporosis during pregnancy and lactation is a rare condition, which can be accompanied by fractures. The mechanism of their provocation is not fully understood.

The data we know so far, is that during pregnancy the skeleton of the fetus contains 30g of calcium and that about 80% of this calcium is obtained during the third trimester of pregnancy.

Therefore, in order for the pregnant woman to be able to respond to these needs of the fetus, as well as her own, it is required to take 1000 mg of calcium per day. Especially during the third trimester of pregnancy.

Trying to adapt the pregnant woman’s body to these increased needs, increases the absorption of calcium in the intestine, so that as much of it as possible, be available to the fetus. In addition, another mechanism to provide the calcium needed by the fetus is to increase bone resorption in the pregnant woman’s skeleton.

This is done mainly through the secretion of a hormone, PTHrp, from the placenta and the mammary gland of the pregnant woman. In fact, it seems that this increase in bone resorption occurs to a greater extent when the dietary intake of calcium by the pregnant woman is insufficient, thus highlighting the importance of adequate calcium intake by the pregnant woman, to protect her skeleton.

Neonatal age – breastfeeding

These increased calcium needs continue throughout infancy, as the infant receives 30-40mg of calcium per day during breastfeeding. If all of a baby’s diet comes exclusively from breastfeeding, as may be the case during the first six months of life, it means that the baby needs four times more calcium than he or she receives during the nine months of pregnancy.

While, as previously stated, the basic mechanism for securing the required calcium in the fetus during pregnancy is to increase the intestinal absorption of calcium, in the case of breastfeeding, the basic mechanism for securing the required calcium in the newborn is through increase of bone resorption to the mother’s skeleton.

This increase in bone resorption during breastfeeding, is mainly due to the low levels of estrogen, present in the breastfeeding woman and the high levels of PTHrp secreted by the mammary gland.

Studies show a significant reduction in bone density and disruption of bone microarchitecture in breastfeeding women, leading to a loss of approximately 5-10% of bone during the first three to six months of lactation.

However, after the lactation period, the skeleton undergoes reconstruction, correcting the loss of bone mass and strength, which is observed during lactation. Complete restoration of the skeleton appears to be achieved six to twelve months after cessation of breastfeeding.

Under normal circumstances, the complete restoration of bone mass after cessation of breastfeeding, results in women not having an increased fracture risk due to pregnancy and lactation in the long run.

Pregnancy, lactation and vertebral fractures

However, there are some studies that show that skeletal repair may not be complete in some women, for reasons unknown until now, thus leading to an increased risk of fracture. In these cases, the most common fractures that occur are vertebral fractures. Weight gain and lordosis that occur during pregnancy can increase the risk of vertebral fracture in these women. Other co-occurring conditions that may be associated with an increased risk of fractures include inadequate dietary intake of calcium and vitamin D, anorexia nervosa, low body weight, prolonged oligoamenorrhea, or use of medications that can induce bone loss, etc.

During breastfeeding, as mentioned before, the loss of bone mass in the skeleton is significant, and occurs mainly in the area of the spongy bone, a type of bone that dominates the vertebrae and therefore, the risk of vertebral fractures in these cases is higher.


Proper management of the patient is very important in these cases. Adequate intake of calcium and vitamin D is very important. It is also important to recognize and treat any coexisting conditions such as endocrine disorders, malabsorption syndromes, etc. which may worsen the condition of the skeleton.

In the case of vertebral fractures, weight lifting should be avoided, while the placement of a torso splint can relieve the patient from pain. Gradually, starting gentle physical activity can help heal the fracture. Finally, a number of specialized drugs may need to be administered individually, always under the guidance of a specialist. Finally, it is equally important to reassure the woman and inform her that the risk of recurrence of osteoporosis and vertebral fracture in the next pregnancy is extremely rare.

Transient osteoporosis of the hip

It is a rare disorder that can occur during pregnancy. It is also called reflex sympathetic dystrophy, and can affect other bone areas besides the hip. It usually appears in the third trimester of pregnancy or during childbirth, as pain in the hip, lower extremity or with a hip fracture, while it can occasionally affect both hips.

The exact mechanism of its cause is not known. There are various theories, such as what can happen in the context of bone loss observed during pregnancy, either due to the venous stasis observed in the hip due to local pressure from the pregnant uterus, or due to pressure of the thyroid nerve from the fetus, etc. We must keep in mind that, unlike the pregnancy and lactation osteoporosis mentioned earlier, transient hip osteoporosis can recur in future pregnancies.

In terms of treatment, the administration of painkillers is necessary to treat the pain, while in the case of a fracture, surgery may be necessary.


Advises Mr. George Trovas, Endocrinologist, Scientific Associate of the Laboratory of Musculoskeletal Diseases Research

Mastocytosis is a rare disease characterized by the proliferation of mast cells that accumulate in the skin, bone marrow and other organs. The majority of cases are usually due to an inherited mutation in the C-kit gene, which causes increased proliferation and activation of mast cells.

This abnormal activation of mast cells leads to the release of factors contained in their granules and which are responsible for the clinical manifestations of the disease such as itching, skin rashes, allergic life threatening manifestations, etc.

Mast cells are cells that play an important role in the body’s defenses, while also being involved in allergic reactions. The activation of mast cells by various factors such as drugs, food, etc. lead to the release from their granules of factors such as prostaglandins, cytokines, serotonin, tryptase, growth factors, etc., leading to the known allergies. In fact, tryptase is produced almost exclusively by mast cells and is used as a diagnostic indicator of the disease. There are two main forms of mastocytosis, cutaneous and systemic mastocytosis. Cutaneous mastocytosis is usually benign and affects the skin, while systemic mastocytosis affects organs other than the skin and can develop into an aggressive disease.

How does mastocytosis occur?

The clinical manifestations of mastocytosis vary depending on the form of the disease and the age of onset. A common feature of all forms of the disease is the increased risk of anaphylaxis/allergy, with pruritus being the most common symptom. Also, children tend to show more benign forms of the disease while adults more aggressive. Thus, the clinical picture of the disease can vary from completely asymptomatic to showing a variety of systemic manifestations depending on the tissues affected.

Cutaneous mastocytosis is limited to the skin and is characterized mainly by itching, swelling, blisters, etc. in the affected area of skin. On the other hand, systemic mastocytosis can occur with more general and atypical symptoms, such as weight loss. Skin manifestations can often coexist, similar to those that appear in the dermal form, while the absence of dermal manifestations in the case of systemic mastocytosis is associated with a more aggressive course of the disease.

The most common clinical manifestations of systemic mastocytosis include:

-General manifestations: weight loss, fatigue, lethargy, weakness, sweating, chills

-Skin manifestations: itching, swelling, erythema, blisters, angioedema

-Neurological/Psychiatric manifestations: headache, concentration disorders, dizziness, depression, anxiety disorder, sleep disorders

-Respiratory manifestations: difficulty breathing, bronchospasm, nasal congestion, itchy nose

-Cardiovascular manifestations: hypotension, palpitations, tachycardia, seizures

-Gastrointestinal manifestations: diarrhea, nausea, vomiting, abdominal pain, flatulence, epigastric pain, ulcer, gastritis, hepatosplenomegaly

-Musculoskeletal manifestations: myalgias, arthralgias, osteoporosis, pathological fractures

-Hematological manifestations: lymphadenopathy, hemostasis disorders, cytopenias, recurrent infections

The diagnosis of mastocytosis is made on the basis of special criteria which are beyond the scope of this information. However, it is useful to note that bone marrow biopsy is useful in diagnosing systemic mastocytosis and skin biopsy is useful in diagnosing cutaneous mastocytosis. Also, the measurement of tryptase levels helps in the diagnosis mainly of systemic mastocytosis, as its levels are usually normal in the case of cutaneous mastocytosis. Finally, the measurement of bone density indicates the presence of osteopenia or osteoporosis in patients with systemic mastocytosis.


The treatment of mastocytosis initially concerns the avoidance of allergens such as alcohol, food allergens, drugs, insect bites, etc. and treating any allergic reactions. There is no specific treatment for mastocytosis. Its treatment is limited to the symptomatic treatment of the clinical manifestations of the disease.

Corticosteroids, antihistamines, montelukast, etc. can be used for cutaneous manifestations of the disease. Vitamin D and calcium can be given to people with osteopenia and osteoporosis. Also, antidepressants in patients with depressive symptoms can help significantly.

A more detailed reference to the treatment of more specific forms of systemic mastocytosis takes us away from the essence of this information, which aims to inform us about the rare disease of mastocytosis, the effect it can have on our skeleton and the importance of addressing properly trained specialists to deal with it.