At some point in the last month I had found an article talking about children and adults who develop into short stature from tumor induced osteomalacia. This post is not going to have anything to do with height increase but is more of a study on the mechanism behind one of the more common causes for short stature. I am hoping that through learning more about dwarfism and the many causes, we can figure out the entire mechanism for human growth.

For us to understnd tumor induced osteomalacia, we first have to study the general form of osteomalacia. Let’s first to a very quick intro on osteomalacia.

From the Wikipedia article on Osteomalacia (HERE)…

Osteomalacia is the softening of the bones caused by defective bone mineralization secondary to inadequate amounts of available phosphorus and calcium, or because of overactive resorption of calcium from the bone as a result of hyperparathyroidism (which causes hypercalcemia, in contrast to other aetiologies). Osteomalacia in children is known as rickets, and because of this, use of the term osteomalacia is often restricted to the milder, adult form of the disease. It may show signs as diffuse body pains, muscle weakness, and fragility of the bones. The most common cause of the disease is a deficiency in vitamin D, which is normally obtained from the diet and/or from sunlight exposure.

Osteomalacia is a generalized bone condition in which there is inadequate mineralization of the bone. Many of the effects of the disease overlap with the more common osteoporosis, but the two diseases are significantly different. There are two main causes of osteomalacia: (1) insufficient calcium absorption from the intestine because of lack of dietary calcium or a deficiency of or resistance to the action of vitamin D; and (2) Phosphate deficiency caused by increased renal losses.[edit]General characteristics

Osteomalacia is derived from Greek: osteo- which means “bone”, and malacia which means “softness”. In the past, the disease was also known as malacosteon and its Latin-derived equivalent, mollities ossium.

Causes

The causes of adult osteomalacia are varied, but ultimately result in a vitamin D deficiency:

• Insufficient nutritional quantities or faulty metabolism of vitamin D or phosphorus
• Renal tubular acidosis
• Malnutrition during pregnancy
• Malabsorption syndrome
• Hypophosphatemia
• Chronic renal failure
• Tumor-induced osteomalacia
• Long-term anticonvulsant therapy
• Coeliac disease

Clinical features

Osteomalacia in adults starts insidiously as aches and pains in the lumbar (lower back) region and thighs, spreading later to the arms and ribs. The pain is symmetrical, non-radiating and is accompanied by sensitivity in the involved bones. Proximal muscles are weak, and there is difficulty in climbing up stairs and getting up from a squatting position.

Due to demineralization bones become less rigid. Physical signs include deformities like triradiate pelvis^[6] and lordosis. The patient has a typical “waddling” gait. However, those physical signs may derive from a previous osteomalacial state, since bones do not regain their original shape after they become deformed.

Pathologic fractures due to weight bearing may develop. Most of the time, the only alleged symptom is chronic fatigue, while bone aches are not spontaneous but only revealed by pressure or shocks.

It differs from renal osteodystrophy, where the latter shows hyperphosphatemia

Biochemical findings

Biochemical features are similar to those of rickets. The major factor is an abnormally low vitamin D concentration in blood serum.

Major typical biochemical findings are:

• The serum calcium is low
• Urinary calcium is low
• Serum phosphate is low except in cases of renal osteodystrophy
• Serum alkaline phosphatase is high

Furthermore, a technetium bone scan will show increased activity.

Radiological appearances include:

Radiographic characteristics

• Pseudofractures, also called Looser’s zones.
• Protrusio acetabuli, a hip joint disorder

Treatment

Nutritional osteomalacia responds well to administration of 10,000 IU weekly of vitamin D for four to six weeks. Osteomalacia due to malabsorption may require treatment by injection or daily oral dosing of significant amounts of vitamin D.

Me: What is to be taken away is that the disorder of Osteomalacia is a general term used to describe the condition that develops from most often Vitamin D and/or Calcium diffeciency. Osteomalacia in children is known as rickets. Rickets in children leads to limbs and bones being bent or twisted, causing bow legs, knock knees, and cranial, pelvic, and spinal deformities. The cause of this disorder is most often from a lifestyle where the person is not getting enough Vitamin D and Calcium. Being out in the sun, taking around 10,000 IU of Vitamin D for up to 8 weeks, and drinking more milk would help keep the bones from loosing more strength  and density. Osteomalacia and Rickets are often found in places which suffer through famine. It is important to note that Calcium creates the crystals that gets embedded into the matrix of the bone giving it its strength from increased density. If the bone matrix can not absorb the Calcium, it is because the lack of Vitamin D that allow the Calcium to be absorbed.

The other major cause of Osteomalacia is phosphate deficiency caused by increased renal losses. This is where we will look into tumor induced osteomalacia

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From Wikipedia (Here)…

Tumor-induced osteomalacia, also known as oncogenic hypophosphatemic osteomalacia or oncogenic osteomalacia, is an uncommon disorder resulting in increased renal phosphate excretion, hypophosphatemia and osteomalacia.

Signs and symptoms

Adult patients have worsening myalgias, bone pains and fatigue which are followed by recurrent fractures. Children present with difficulty in walking, stunted growth and deformities of the skeleton (features ofrickets).^[1]

Diagnosis

Biochemical studies reveal hypophosphatemia, elevated alkaline phosphatase and low serum 1, 25 dihydroxyvitamin D levels. Routine laboratory tests do not include serum phosphate levels and this can result in considerable delay in diagnosis.

Pathogenesis

FGF23 (fibroblast growth factor 23) inhibits phosphate transport in the renal tubule and reduces calcitriol production by the kidney. Tumor production of FGF23, frizzled-related protein 4  and matrix extracellular phosphoglycoprotein (MEPE) have all been identified as possible causative agents for the hypophosphatemia.

Causative tumors

Tumor-induced osteomalacia is usually referred to as a paraneoplastic phenomenon, however, the tumors are usually benign and the symptomatology is due to osteomalacia or rickets. A benign mesenchymalor mixed connective tissue tumor (usually phosphaturic mesenchymal tumor and hemangiopericytoma) are the commonest associated tumors. Association with mesenchymal malignant tumors, such asosteosarcoma and fibrosarcoma, has also been reported.^[6] Locating the tumor can prove to be difficult and may require whole body MRI. Some of the tumors express somatostatin receptors and may be located by octreotide scanning.

Differential diagnosis

Serum chemistries are identical in tumor-induced osteomalacia, X-linked hypophosphatemic rickets (XHR) and autosomal dominant hypophosphatemic rickets (ADHR). A negative family history can be useful in distinguishing tumor induced osteomalacia from XHR and ADHR. If necessary, genetic testing for PHEX (phosphate regulating gene with homologies to endopepetidase on the X-chromosome) can be used to conclusively diagnose XHR and testing for the FGF-23 gene will identify patients with ADHR.

Treatment

Resection of the tumor is the ideal treatment and results in correction of hypophosphatemia (and low calcitriol levels) within hours of resection. Resolution of skeletal abnormalities may take many months.

If the tumor cannot be located, treatment with calcitriol (1-3 µg/day) and phosphorus (1-4 g/day in divided doses) is instituted. Tumors which secrete somatostatin receptors may respond to treatment with octreotide. If hypophosphatemia persists despite calcitriol and phosphate supplementation, administration of cinacalcet has been shown to be useful

Me: For me, the major take away of learning about tumor induced osteomalacia for height increase application is that “the FGF23 (fibroblast growth factor 23) inhibits phosphate transport in the renal tubule and reduces calcitriol production by the kidney. ” This is seems to be the main cause of hypophosphatemia

I haven’t really talked about the family of proteins the FGFs but they are critical in the process of cell differentiaton and prolliferation, which is what causes all type sof tissue growth including bone growth.