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XLH and Bone Formation
By:
Scott Schmitz
Authorship Information; XLH and Bones Introduction (Normal bone formation) Minerals are required for good bone formation Effect of exercise on dynamic bone growth XLH Rickets and the role of Vitamin D The primary gene issue in XLH is with a protein called PHEX The XLH Network is eager to learn more! Authorship Information; XLH and Bones This information has been compiled by members of the XLH Network with special reference to medical textbooks, discussions within the F-HYPDRR mailing list, and valuable professional comment and criticism, but normal disclaimers apply. X-Linked Hypophosphatemia is a metabolic disorder that often causes a bone disease called rickets. In this disorder, as a result of the low phosphorus in the blood, the mechanism by which bone is formed can be disrupted from its normal operation. Although some five percent of people with XLH do not develop any bone disease, often the weight of a growing, walking child with this syndrome causes their lower limbs to bow or bend because the bone is too soft. In adults, this condition of soft bones is called osteomalacia. To understand XLH and its effects on bones, we must first understand how normal bones are formed. Introduction (Normal bone formation) Bones are formed in three basic steps. First, cells called osteoblasts create a protein scaffolding. Next, these osteoblasts mineralize the spaces between the scaffolding primarily with calcium and phosphorus. The osteoblasts end up in minute canals called canaliculi surrounded by this matrix of protein and minerals. The canals permit circulation of tissue fluids and allow the osteoblasts, now called osteocytes, to continue to function. The last stage in bone formation is that of bone remodeling and reabsorption. Cells called osteoclasts work with osteocytes to break down the bone scaffolding and reabsorb the mineral deposits. Osteoclasts lie in depressions called reabsorption bays located on the surface of the bone. Bones are in a constant state of being built, broken down and being rebuilt. This process is controlled by a number of factors, but it's by this 'dynamic equilibrium' that bones grow, mend themselves and retain their strength. Minerals are required for good bone formation The construction of bones requires a precise combination of amino acids which are used to create the proteins for the scaffolding. Specific levels of phosphorus and calcium are also required for mineralization. An imbalance in the specific combination of any of these elements can result in incorrect bone formation. The body uses several mechanisms (sometimes called biofeedback loops) to regulate the delivery of these necessary building blocks for bones. Vitamin D helps the intestine absorb calcium from food into the bloodstream, and from there to the bones of the body. PTH, the hormone which the parathyroid glands secrete, also helps to control calcium levels so that sufficient resources of this mineral are available for bone formation. The kidney tubules are responsible for keeping phosphorus in the blood from where it can be used for bone construction, and Vitamin D is also important in helping to regulate this phosphorus level. Effect of exercise on dynamic bone growth Exercise is also an important factor in normal bone growth and development. It is believed that a piezo-electric effect due to exercise within the intercellular matrix of bones acts as a stimulus for bone reabsorption and creation. Exercise can accelerate knitting of broken bones, and extended heavy exertion can increase bone density and mass. In dietary rickets, insufficient Vitamin D, or calcium in the diet may mean that normal calcium and phosphorus maintenance in the blood, and therefore in the bone, does not occur. Bone formation is slowed; additionally, bone density and strength is compromised because the resulting mineralization is deficient in phosphorus or calcium. When a proper diet is restored, or when sufficient sunlight exposure means that the body can make its own Vitamin D, then the calcium and phosphorus levels can return to normal and bones can resume proper growth. In X-Linked Hypophosphatemic rickets, neither the dietary intake nor the body's manufacture of Vitamin D is at fault. Instead, it seems that the kidney tubules in people with XLH do not reabsorb the necessary amount of phosphorus before it is lost in urine, and thus the level of phosphorus in their bloodstream is very low. For some reason, people with XLH cannot get the benefit of normal Vitamin D to help regulate this phosphorus reabsorption by the kidney. It was because the Vitamin D that helps normal people grow strong bones just doesn't do anything for people with XLH, that this disorder was originally called Vitamin D Resistant Rickets. This syndrome is now more accurately called hypophosphatemic rickets, because the primary problem experienced by people with this syndrome is low phosphorus in the blood. It became clear, however, that many people with XLH could respond to a combination of an active Vitamin D (usually 1,25 dihydroxyVitamin D also known as calcitriol, or alternatively the 1alpha or DHT forms) and large supplements of phosphorus, taken by mouth. Current treatment techniques concentrate on balancing these two medications so that useful phosphorus levels can be reached without overstimulating the parathyroid glands, ensuring that normal calcium levels are not overshot. Treatment is best undertaken by specialists in bone metabolism, and requires good monitoring of the kidneys to ensure that the tubules are not compromised by too much deposition of calcium. It's not clear just how, or whether, exercise can be particularly beneficial to people with XLH. But many people with XLH lead very active lives, and it's common good sense to enjoy non-percussive exercise like swimming to keep heart and lungs healthy, as well as possibly strengthening bones. The primary gene issue in XLH is with a protein called PHEX Recent research indicates that the gene responsible for XLH is not in fact in the kidney, but instead is an important component of the osteoblast bone cells. This gene, now called PHEX, is believed to affect yet another important control mechanism in bone formation. It seems that the product of the PHEX gene interacts with, or processes, a hormone tentatively called 'phosphatonin', which is directly responsible for the maintenance of the body's phosphorus levels. It's believed that when this phosphatonin is not processed correctly, it is unable to instruct the kidney to reabsorb phosphorus before it gets passed into the voided urine. Interestingly, not everybody with XLH has a bone disorder you can see, but everybody with XLH has low phosphorus in their blood. All people with XLH have a mutation in their PHEX gene, which can usually be confirmed by a molecular genetics test if there is a particular concern about the diagnosis that conventional blood chemistry tests cannot resolve. XLH research has made great strides in the past few years, and these advancements have resulted in a better understanding both of XLH and the mechanisms responsible for bone growth and formation. Advances in research hold great promise for better treatment options for XLH as well as for a host of other metabolic bone disorders including osteoporosis. The XLH Network Inc. is eager to learn more! Members of The XLH Network Inc. are particularly interested in the latest research news. The field is advancing rapidly, and new potential treatments based on the new models of bone development and maintenance that have grown out of research on PHEX and phosphatonin, are being explored. These models and possible treatments will need to be assessed in an animal model before they can be considered in human subjects. Fortunately, the so-called hyp mouse, which has a mutation in its Phex gene, the exact equivalent of the human PHEX gene, is a good model in which to explore these sorts of pre-clinical questions. The XLH Network Inc. is warmly receptive to questions and enquiries from anyone interested in familial rickets. We would be delighted to hear from you if you have a particular interest in this syndrome, or any questions about this website for The XLH Network Inc. Last modified Aug 8, 2007 XLH is also known as X-Linked Hypophosphatemia (sometimes also spelled as hypophosphataemia), X-Linked Hypophosphatemic Rickets, Familial Hypophosphatemia, Vitamin D-Resistant Rickets (VDRR) Rickets and even Genetic Rickets. Its notable characteristics are bowed legs, short stature, poor teeth formation causing spotaneous dental abscesses, and low blood phosphorus levels.
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