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Metabolic bone disease
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Metabolic bone disease
In addition, Parathyroid Hormone Related Peptide (PTHrP) is important in fetal life to maintain calcium transport across the placenta and as a paracrine factor in cartilage formation. In postnatal life it is usually undetectable in serum but may be of importance in certain malignant conditions. Clinically apparent metabolic bone disease usually only occurs in the presence of considerable hyperparathyroidism which will only be mentioned in this context.
Jeremy Allgrove
Abstract Bone is a complex organ that is highly metabolically active, particularly in children. Normal metabolism is dependent upon the three main elements, matrix, mineral and cells that are integral components of bone. In addition, there are several humoral factors that also influence bone. Abnormalities in any of these components can give rise to metabolic bone disease. Abnormalities of mineralisation are the commonest manifestation of metabolic bone disease although some are ultimately derived from problems within the supporting cellular components. On the one hand these present themselves as osteomalacic conditions that principally show themselves as mineralisation defects within the growth plates, a condition that is known as rickets, whilst more generalised mineralisation defects, known as osteoporosis are principally caused by Osteogenesis Imperfecta but can also present as a secondary phenomenon following, for instance, prolonged steroid therapy. Conversely, there are several rarer conditions that cause an increase in bone density, some of which cause a decrease in bone fragility but some which, paradoxically are associated with increased tendency to fracture. Many of these conditions have a genetic origin. This article summarises these conditions.
Disorders of mineralisation Bone mineral is made up mainly of calcium and pyrophosphate. The latter consists of two phosphate molecules bound to an oxygen atom. Mineral is laid down by osteoblasts and removed by osteoblasts. Normal mineralisation depends upon a regular and sufficient supply of both calcium and phosphate. The principal role of vitamin D is to promote absorption of calcium by the gut and, in the absence of sufficient vitamin D, calcium absorption is impaired. This leads to one or other of the forms of calciopaenic osteomalacia which, in children, is manifest as rickets. In contrast, phosphate is easily absorbed by the gut. Renal excretion of both calcium and phosphate is closely regulated, the latter mainly by another hormone, FGF23, and, in the presence of excessive urinary renal losses of phosphate, the supply of phosphate is limited and this results in phosphopaenic rickets. The principal causes of rickets are shown in Table 1. PTH has a physiological role in promoting bone formation by an action on osteoblasts. However, under circumstances of calcium deficiency, PTH acts to resorb calcium and phosphate from bone to maintain a normal calcium level in plasma. If severe hyperparathyroidism occurs, metabolic bone disease may supervene. This can manifest itself in undermineralisation and features very similar to those of rickets. Indeed, many of the radiological features of rickets can be attributed to hyperparathyroidism.
Keywords Bone density; Bone matrix; Bone mineral; Fibroblast growth factor 23; Osteoblast; Osteoclast; Osteocyte; Osteogenesis Imperfecta; Osteomalacia; Osteoporosis; Parathyroid hormone; Rickets; Vitamin D
Introduction Bone consists of three principal elements e matrix, mineral and cells. Defects in any of these components can give rise to metabolic bone disease (MBD). Of these, defects in mineralisation are the commonest cause of MBD and most frequently manifest themselves as rickets, of which the commonest cause is vitamin D deficiency. Matrix abnormalities most frequently cause one or other of the forms of Osteogenesis Imperfecta (OI) whilst the least common forms of MBD are those associated with abnormalities in the cellular components. MBD is usually associated with a variable degree of reduced bone density which is often associated with an increased tendency to bone fragility. However, increased bone density is sometimes seen in MBD. This may be associated with increased bone strength or, paradoxically, sometimes with increased bone fragility as in Osteopetrosis. Since osteoporosis or osteomalacia are the most important clinical manifestations this article will summarise disorders of bone matrix and of mineralisation separately, regardless of the specific aetiology. Calcium and phosphate homeostasis is maintained by several factors, principally parathyroid hormone (PTH) and vitamin D for calcium and Fibroblast Growth Factor 23 (FGF23) for phosphate.
Calciopaenic rickets and vitamin D deficiency Vitamin D deficiency is widespread, particularly in the UK. It occurs more frequently in some ethnic minority groups, particularly those from south Asia or Africa. Skin colour and the extent of skin exposure to ultraviolet light are important factors in its aetiology. Estimates of the prevalence of vitamin D deficiency are difficult to ascertain but, in some parts of the population, may be as high as 90%. However, not all people with vitamin D deficiency develop rickets or osteomalacia and other factors, such as milk intake, may also play an important role. Rarely, inborn errors of metabolism, particularly a failure of conversion of 25-hydroxyvitamin D (25OHD) to its active metabolite, 1,25-dihydroxyvitamin D (1,25(OH)2D) by low 1a-hydroxylase activity, or end-organ resistance to 1,25(OH)2D due to abnormal vitamin D receptors, can give rise to a similar syndrome. Clinical manifestations of vitamin D deficiency range from the very severe, sometimes fatal, syndrome of dilated cardiomyopathy or congenital rickets, via classical rickets and hypocalcaemic convulsions to generalised aches and pains, which is the most common manifestation. If the diagnosis is suspected, investigations should include measurement of bone profile (calcium, phosphate, alkaline phosphatase (ALP), albumin and creatinine),
Jeremy Allgrove MD MA FRCP (UK) FRCOCH is a Consultant Paediatric Endocrinologist in the Department of Paediatric Endocrinology, Royal London Hospital, Whitechapel, London E1 1BB, UK. Conflict of interest: none.
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if the rickets has been severe, a longer period may be required. Young children with rickets usually recover completely although they may be left with some degree of motor delay and diminished intellectual function if the rickets was severe at diagnosis. Prevention of vitamin D deficiency is straightforward as vitamin D supplementation, if undertaken correctly, can be very effective. Unfortunately in the UK, this often does not happen. Treatment of mild rickets or asymptomatic vitamin D deficiency can be undertaken in the community although the rarer forms of rickets require follow-up in secondary care.
Principal causes of rickets All treatments correspond with causes A. Calciopaenic rickets Vitamin D deficiency Poor sunlight exposure Dark skin Malabsorption (e.g. coeliac disease) Lack of adequate supplementation Impaired 25-hydroxylation of Vitamin D (very rare but may be a factor in severe liver disease) Impaired 1a-hydroxylation of 25OHD Intrinsic defect As part of the spectrum of renal disease Calcium deficiency (mainly described in West Africa) Distal Renal Tubular Acidosis B. Phosphopaenic rickets Hypophosphataemic rickets X-linked dominant (PHEX gene mutations) Autosomal dominant (FGF23 mutations) Autosomal recessive (DMP1 mutations) Sodium/phosphate cotransporter mutations Miscellaneous causes McCuneeAlbright syndrome
Fanconi syndrome (various causes)
Malignancy (inappropriate FGF23 synthesis) Neurocutaneous abnormalities (Epidermal Naevus Syndrome) Other renal tubular abnormalities
Treatment
Vitamin Vitamin Vitamin Vitamin Vitamin
D D D þ GFD D D
Phosphopaenic rickets Hypophosphataemic rickets most commonly occurs as a result of a defect in the metabolism of FGF23, usually as a result of mutations in the PHEX gene, which determines the cleavage (and hence the inactivation) of FGF23. This is an X-linked dominant condition that usually manifests itself more severely in boys than in girls. A similar syndrome can result from other metabolic abnormalities that result in higher than normal circulating levels of FGF23. Diagnosis of hypophosphataemic rickets is made by simultaneously measuring plasma and urine phosphate and creatinine and calculating the Fractional Excretion (FE) and, if necessary, the Tubular Maximal Reabsorption of Phosphate (TmPO4/GFR) (see Recommended Reading for details of the methodology), together with appropriate radiology. Treatment of hypophosphataemic rickets consists of a combination of oral phosphate supplements and, in most instances, alfacalcidol. The prognosis is variable and depends on the severity of the condition. Conventional treatment, as indicated above, does not cause the bones to heal completely although considerable improvement can often be achieved. Growth impairment may be manifest and orthopaedic intervention may also be required in order to facilitate walking. It is possible that newer treatments, particularly those aimed at reducing levels of FGF23, may improve the prognosis if, as expected, they become available in the future. These patients do require long term follow-up in secondary care.
Alfacalcidol Vitamin D and alfacalcidol Calcium supplementation Bicarbonate
Phosphate supplements and alfacalcidol Phosphate supplements and alfacalcidol Phosphate supplements and alfacalcidol Phosphate supplements Phosphate supplements and alfacalcidol Phosphate supplements and alfacalcidol Remove malignancy if possible Remove cutaneous lesions if possible Depends on precise diagnosis
Hyperparathyroidism Hyperparathyroidism in children most commonly occurs as a secondary consequence of vitamin D deficiency. Chronic kidney disease (CKD) may also be a factor. Primary hyperparathyroidism is less common but is associated with a variety of symptoms including thirst, polyuria and polydipsia and muscle weakness. Infants may have a hoarse cry because of paralysis of the vocal cords. In severe cases, bone density may be so reduced that fractures occur and, if the ribs are affected, respiratory compromise may be such that respiratory support is required. This is most likely to occur in infants who are either born very vitamin D deficient or because of neonatal severe hyperparathyroidism (NSHPT). The clinical and radiological features of these two conditions are very similar although the biochemistry is different in that hypercalcaemia is a prominent feature of the latter. Investigations include a measurement of bone profile with PTH and of urinary excretion of calcium. This is low in severe rickets and raised in NSHPT which is caused by inactivating mutations of the calcium sensing receptor. In many cases this is homozygous but it may also be a feature of heterozygous
Table 1
urine calcium and creatinine, 25OHD (the major circulating metabolite of vitamin D) and PTH if the clinical picture is severe. Treatment of vitamin D deficiency is with vitamin D (either ergo or colecalciferol) and this should always be corrected before considering an alternative diagnosis. In the rare cases of 1a-hydroxylase activity, treatment with a 1a-hydroxylated vitamin D metabolite (e.g. alfacalcidol) is required and end-organ resistance usually requires calcium and phosphate infusions, at least in the first instance. Treatment needs to be continued for 3 months during which time healing will usually occur although,
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mutations especially if the mother is unaffected. Treatment of the severe neonatal rickets consists of correcting the vitamin D deficiency whereas that of NSHPT is directed at reducing the PTH levels as soon as possible whilst reducing the effects of the hypercalcaemia. In many instances vitamin D deficiency may be an additional factor that exacerbates the hyperparathyroidism and needs to be corrected. Some authors recommend the use of bisphosphonates to reduce the plasma calcium but this does have the effect of raising PTH levels further. In many cases, parathyroidectomy is required but occasionally it is possible to alter the clinical picture with the calcimimetic agent, cinacalcet, to allow the clinical picture to improve.
is available. Renal ultrasonography is the most reliable way of assessing nephrocalcinosis. Bone biochemistry is usually normal but should always be undertaken, particularly prior to treatment as vitamin D deficiency must be excluded and, if necessary, corrected prior to commencing treatment. Genetic analysis of the COL1A1 and COL1A2 genes is not always undertaken if the diagnosis is straightforward. In more difficult cases, particularly if there are medico-legal issues where NAI is suspected or if one of the rarer forms of OI such as those involving the crosslinking genes is suspected, mutations may be sought as appropriate. However, genetic analysis of COL1A1 and COL1A2 is time consuming and expensive and is often not recommended by the geneticists except in doubtful cases. Follow-up of patients with OI, particularly in severe cases, should be undertaken by a multidisciplinary team in a specialist centre where there is access to paediatricians, endocrinologists, nurses, occupational and physiotherapists, dentists and orthopaedic surgeons. Genetic advice may also be desirable in difficult cases. Treatment depends on the severity of the disease and any or all of the above personnel may need to be involved. The mainstay of medical treatment is bisphosphonates. These have now been in routine use for OI for about 15 years and have improved the outlook for these patients quite considerably. The principal effects are a reduction in bone pain, fewer fractures and, if present, remodelling of vertebral crush fractures. The most commonly used drug is pamidronate given in a dose of 1 mg/kg/d daily for 3 days every 3e4 months. Young infants may be given it in half the dose at 6 weekly intervals and toddlers often receive it every 2 months in an intermediate dose. It is given by intravenous infusion. Patients should be warned that the first cycle of treatment is often accompanied by an acute phase reaction with pyrexia and ‘flu’-like symptoms which can usually be controlled with antipyretic analgesics. These symptoms do not usually recur with subsequent cycles. Acute iritis can also occur and rashes are occasionally seen. More recently, another bisphosphonate, risedronate, has been used in trials and seems promising and is more convenient as it only needs to be administered weekly and does not require hospital admission. However, oral preparations are not well absorbed and may be more useful for maintenance therapy than initiation. Zoledronate is a fourth generation bisphosphonate that is considerably more potent than pamidronate but is little used in children as its long term effects are less well understood but has the advantage of only requiring a single infusion every 6e12 months. Mobilisation, which is made more possible by bisphosphonate therapy, is encouraged as it helps to improve bone health. This can be effected by a combination of physiotherapy, orthopaedic surgery and walking aids, hence the need for a multidisciplinary approach to care.
Disorders of matrix Primary osteoporosis Matrix consists principally of collagen, together with a number of other bone proteins that interact with it. Collagen, of which more than 20 types are described, is the main protein of connective tissue. All types of collagen consist of three fibrils which are wound round each other in the manner of a rope to form fibres. These fibres are then joined together by crosslinks. Qualitative or quantitative abnormalities in the structure of the collagen fibrils result in weakening of the fibres. In addition, disruption of the crosslinking may also result in weakened collagen. The most abundant form of collagen in bone is Type I which consists of two fibrils of A1 and one of A2 collagen bound together. These two fibrils are coded for by genes known as COL1A1 and COL1A2 respectively. Mutations in either of these genes result in Osteogenesis Imperfecta (OI). OI is a rare disease and very variable in its manifestations. Mild forms (Type I) may cause a slight increase in tendency to fracture but little else. The more severe forms can sometimes be incompatible with post-natal life (Type II) or may cause children to be wheelchair-bound with multiple low trauma fractures and bony deformity (Type III) or a more intermediate form with multiple fractures and some growth impairment (Type IV). Other rare forms, usually affecting the crosslinking proteins, are also described. The different forms of OI, together with the principal clinical features, are shown in Table 2. Diagnosis of OI is principally clinical. A history of low trauma or apparently spontaneous fractures is suggestive although it can sometimes be difficult to distinguish from non-accidental injury (NAI). The pattern of injuries can often be useful in distinguishing the two. Poor growth is often present in the more severe forms. There is an increased incidence of scoliosis and poor muscle tone in some cases. The presence of blue sclerae, easy bruising, skin fragility and a tendency to sweating excessively are also suggestive. Dental development may be abnormal and manifest as Dentinogenesis Imperfecta (DI). Hearing may be impaired and a family history of progressive deafness may be relevant. In severe cases, nephrocalcinosis caused by hypercalciuria can occur. Alterations in the shape of the skull base may occur and the possibility of platybasia and herniation of the vermix should be considered. Radiological investigations consist of plain X-rays as necessary. However, assessment of bone density on plain X-ray is very unreliable and DXA scanning provides a better solution to this problem. The results of DXA scans should be interpreted with caution and these patients should only be seen in centres where appropriate expertise
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Secondary osteoporosis Osteoporosis may occur as a consequence of a number of other conditions, the commonest of which is chronic steroid exposure, either endogenous or, more commonly, exogenous. Immobilisation is a second factor that may contribute considerably to secondary osteoporosis and, if the two are combined, such as in Duchenne Muscular Dystrophy, the effects can be seen in vertebral collapse and fractures.
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Classification and principal features of Primary Osteoporosis
OI Type
Phenotype (during childhood)
I
Mild motor delay. Bowing of long bones. Vertebral crush fractures. Ligamentous laxity, hernias, mixed conductive/sensorineural deafness, blue sclerae. Subdivided on the basis of the presence or absence of dentinogenesis imperfecta (A¼absent, B¼present) Lethal. Subdivided by appearance of ribs Lethal. Similar to Type IIA Severe, progressively deforming. Typically have fractures in utero, very poor post-natal growth. Characteristic facies with small mid face and pointed chin. Triangular facial appearance less noticeable with bisphosphonate treatment. Very delayed motor development. Almost all need intramedullary rodding. Blue sclerae remain. All have dentinogenesis imperfecta. Moderately severe. May have fractures in utero, but better post-natal growth than Type III. Blue sclerae fade with age; may have dentinogenesis imperfecta Moderately severe. Metaphyseal sclerosis in early life, followed by calcification of interosseous membranes in the forearm and lower leg. Characteristic bowing of the forearms. Hypertrophic callus formation following fractures and surgery Severe, progressively deforming. Osteomalacic on bone biopsy, possibly as a result of abnormal matrix deposition e normal lamellar structure is disrupted Moderately severe. Rhizomelic in both arms and legs; femurs and humeri are very bowed. White sclerae Very severe/lethal. Round face, white sclerae, thin ribs (may be beaded). Most cases are reported in children whose families originate from West Africa, Pakistan and Ireland Severe. May be lethal at or soon after birth. Resembles Type III in living individuals Contractures. White sclerae, mild DI. Moderatelysevere bone disease Clinical phenotype as for Bruck 1 Normal at birth; develop craniosynostosis, ocular proptosis, hydrocephalus and diaphyseal fractures Decreased bone mineralisation and increased tendency to fractures. Usually improves at adolescence Decreased bone mineralisation and increased tendency to fractures. Congenital blindness
IIA IIB III
IV
V
VI
VII VIII
IX Bruck 1 Bruck 2 ColeeCarpenter Idiopathic juvenile osteoporosis Osteoporosis Pseudoglioma Syndrome (OPS) Juvenile Paget’s disease Geroderma osteodysplasticum Hypophosphatasia Perinatal lethal
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Genetic origin Typically null allele of COL1A1, resulting from stop, frameshift or splice site mutations Missense mutations in COL1A1 or COL1A2
Complete loss of CRTAP Missense mutations in COL1A1, COL1A2; null allele of COL1A2
Missense mutations in COL1A1 or COL1A2
Unknown
Mutations in FKBP10
Cryptic splice site in intron 1 of CRTAP Deletion of LEPRE1
Mutations in PPIB causing overproduction PLOD2; bone-specific telopeptide lysyl hydroxylase Unknown Unknown Some cases associated with heterozygous mutations of LRP5 Heterozygous mutations in LRP5
Debilitating bone pain, short stature, long bone and vertebral fractures Prematurely aged skin, osteoporosis, increased joint laxity, kyphoscoliosis
Homozygous mutations in Osteoprotegerin gene Mapped to chromosome 1q24
Congenital. Usually incompatible with post-natal life
Liver alkaline phosphatase (tissue non-specific alkaline phosphatase)
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Table 2 (continued ) Infantile
Presents during infancy with osteoporosis and fractures
Liver alkaline phosphatase (tissue non-specific alkaline phosphatase)
Childhood
Osteoporosis and early tooth loss
Adult
May only be diagnosed following another family member Tooth problems only
Liver alkaline phosphatase (tissue non-specific alkaline phosphatase) Liver alkaline phosphatase (tissue non-specific alkaline phosphatase) Liver alkaline phosphatase (tissue non-specific alkaline phosphatase)
Odontohypophosphatasia
Table 2
Several chronic conditions such as cystic fibrosis, b-thalassaemia major, idiopathic juvenile arthritis and other chronic inflammatory diseases, may result in secondary osteoporosis either because of the steroid usage that is frequently needed in some of these conditions or probably also as a direct result of the inflammatory agents that are responsible for the disease in the first place. It is not generally regarded as good practice to treat any of these conditions prophylactically but rather to wait until such time as symptoms, either bone pain or fractures, occur and then to treat appropriately under supervision of a bone specialist. Initial treatment should consist, if possible, of removing the underlying cause or, if this is not possible, of minimising any therapy that may be contributing to the osteoporosis. Mobilisation of the patient as much as possible may also help to improve bone health. If delayed puberty is present, treatment with appropriate sex steroids may improve matters. If, however, none of these measures is effective, there may be a need to use bisphosphonates, in a similar regimen to that of OI, to improve bone density, reduce fracture risk and ease pain. DXA scanning should only be used as an adjunct to monitoring and not as an indication for treatment.
important factors that enable mineralisation is the enzyme, alkaline phosphatase (ALP). Mutations within the genes for this enzyme result in hypophosphatasia, an osteoporotic condition of variable severity that ranges from incompatibility with post-natal survival to mild osteoporosis and dental abnormalities. In its most severe (homozygous) form, infants are born with little bone mineralisation and usually succumb rapidly to respiratory difficulties because of poor rib compliance. Currently, however, a trial is being conducted of the use of recombinant ALP which is proving promising in these infants. Older children may present with an increased fracture tendency and rachitic changes on X-ray and have a tendency to early tooth loss that is atypical in that the roots remain intact. Diagnosis is confirmed by the presence of low ALP in plasma and raised phosphoethanolamine/creatinine ratio in urine. Phosphoethanolamine is also a substrate for ALP. There is no definitive treatment and bisphosphonates are ineffective. Osteoclasts Osteoclasts are multinucleated cells of haematopoietic origin. Differentiation from their precursors occurs under the influence of several factors. Final differentiation of osteoclasts from preosteoclasts is determined by the action of RANK Ligand (RANKL) on RANK, its receptor on the cell surface. RANKL is a product of osteoblasts which thus control the function of osteoclasts. A second protein, osteoprotegerin (OPG), is also produced by osteoblasts. This is a soluble inhibitor of RANKL and acts as a ‘brake’ on osteoclast activity. At times of increased need for bone resorption (such as when hypocalcaemia is present), OPG production is limited and bone resorption can proceed unhindered whilst when calcium is plentiful, larger quantities of OPG inhibit bone resorption. Mutations within the OPG gene result in Juvenile Paget’s Disease in which bone resorption is unrestricted and osteoporosis results. Treatment with either bisphosphonates or, more logically, recombinant OPG, has proved promising. Defects within the osteoclasts themselves give rise to the spectrum of conditions known as Osteopetrosis (OP). There are two main types, osteoclast poor OP, in which differentiation of osteoclasts is impaired by mutations either in RANKL or RANK, and osteoclast rich OP in which osteoclasts are plentiful but do not function normally because of mutations in one or other of the genes controlling the production of the acid environment created by osteoclasts that is necessary for bone resorption. The severity of OP varies depending on which gene is mutated and varies from malignant to benign forms some of which may only be diagnosed
Disorders of bone cells Osteoblasts Osteoblasts, together with osteocytes, are derived from multipotent mesenchymal precursor cells which also give rise to chondrocytes, adipocytes, myocytes and fibroblasts. A complex series of transcription factors determines the destination of these cells. Once these cells have differentiated into osteoblasts, the activity is regulated principally via the Wnt signalling pathway which consists of a number of proteins which, by a complex series of interactions, determine osteoblast function. One of these, Low Density Lipoprotein Receptor Related Protein 5 (LRP5), has an important regulatory function. Inactivating mutations in the gene responsible for it may cause osteoporosis if heterozygous but may also cause the rare but serious Osteoporosis Pseudoglioma Syndrome if homozygous. The latter presents with severe osteoporosis, which clinically resembles OI, but is associated with visual impairment as LRP5 is also involved in development of retinal vasculature. In contrast, activating mutations of LRP5 are associated with a syndrome of increased bone density and decreased fracture risk. The principal function of osteoblasts is to facilitate bone formation both by laying down matrix and depositing calcium and pyrophosphate onto this matrix. Matrix abnormalities have already been discussed as a principal cause of OI. One of the more
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Conditions associated with increased bone density Osteopetrosis Autosomal recessive 1 (OPTB1)
Osteoclast rich
Malignant
Failure of acidification
Autosomal recessive 2 (OPTB2)
Osteoclast poor
Benign
Autosomal recessive 3 (OPTB3)
Osteoclast rich
Intermediate
Autosomal recessive 4 (OPTB4)
Osteoclast rich
Autosomal recessive 5 (OPTB5)
Osteoclast rich
Malignant/ intermediate Malignant
Failure of osteoclast transformation Failure of acidification; RTA Failure of acidification
Autosomal recessive 6 (OPTB6)
Osteoclast rich
Intermediate
Autosomal recessive 7 (OPTB7)
Osteoclast poor
Malignant
Autosomal dominant 2 (OPTA2) Other bone sclerosing conditions Pyknodysostosis
Osteoclast rich
Benign
Hyperostosis corticalis generalisata (van Buchem Disease) Sclerosteosis (SOST)
Osteoclast rich Osteoclast rich
Activating LRP5 mutations (OPTA1)
Osteoclast rich
Osteoclast rich
Benign
Failure of acidification Abnormal vesicular transport Failure of osteoclast transformation Failure of acidification Failure of bone matrix resorption Increased osteoblast signalling Increased osteoblast signalling Increased osteoblast signalling
CamuratieEngelmann disease (PPD) Fibrodysplasia Ossificans Progressiva (FOP) Progressive Osseous Heteroplasia (POH) Caffey’s disease
T-cell immune regulator subunit of the vacuolar proton pump Tumour necrosis factor superfamily 11 Carbonic anhydrase II Chloride channel-7 protein Osteopetrosis-associated transmembrane protein-1 Plekstrin homology domain-containing protein, family M member 1 Tumour necrosis factor receptor superfamily, member 11a Chloride channel-7 protein Cathepsin K Sclerostin Sclerostin Low density lipoprotein receptor protein 5 Transforming growth factor, beta-1 Activin receptor I/activin-like kinase 2 GNAS complex e paternally inherited COL1A!, Exon 42
Table 3
incidentally or as a result of diagnosis in another family member. In all cases, increased bone density is present although this bone is of poor quality and is accompanied by an increased tendency to fracture. Malignant forms have been treated with some success with bone marrow transplantation but this must be carried out early before the effects of bone overgrowth (e.g. on hearing) have occurred. A similar condition, known as Pyknodysostosis, is caused by inactivating mutations of cathepsin K, the enzyme responsible for resorption of collagen. Bone mineral is resorbed but bone density remains high but with fractures and delayed skull suture closure. Treatment is symptomatic only. The principal causes of increased bone density are shown in Table 3.
They synthesise a number of proteins that contribute to the maintenance of bone health. Amongst these is FGF23, defects in which are responsible for hypophosphataemic rickets (see above). In addition, a number of Bone Matrix Proteins are also made that help to maintain the integrity of bone and to fill the spaces between collagen fibrils. Another protein, Dentin Matrix Protein (DMP1), also has an inhibitory effect on FGF23 production. Homozygous mutations in this protein cause a very rare form of hypophosphataemic rickets.
Renal tubular abnormalities Abnormalities of renal tubular function may also cause metabolic bone disease. Phosphate reabsorption may be impaired as a result of intrinsic renal tubular dysfunction which can occur either in connection with one or other form of the Fanconi syndrome in which impaired reabsorption of phosphate is associated with glycosuria, aminoaciduria and bicarbonaturia, or secondary to mutations in the gene for the sodium/phosphate cotransporter in the distal renal tubule. The rickets is treated in a similar fashion to other forms of hypophosphataemic rickets
Osteocytes Osteocytes are derived from osteoblasts that become embedded in bone. They communicate with each other via fine dendritic processes that lie within canaliculae. They are principally responsible for maintaining bone health and respond to mechanical stresses within bone, the so-called mechanostat.
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FURTHER READING Allgrove J, Shaw NJ, eds. Calcium and bone disorders in children and adolescents. Basel, Freiburg, Paris, London, New York, Bangalore, Bangkok, Shanghai, Singapore, Tokyo, Sydney: Karger, 2009. Glorieux F, Pettifor JM, J} uppner H, eds. Pediatric bone: biology and diseases. Amsterdam, Boston, Heidelberg, London, New York, Oxford, Paris, San Diego, San Francisco, Singapore, Sydney, Tokyo: Academic Press, 2003.
although in the latter case alfacalcidol should not be used as it tends to worsen nephrocalcinosis. Distal Renal Tubular Acidosis, in which excretion of hydrogen ions within the renal tubule leads to metabolic acidosis, also causes rickets. This is also associated with nephrocalcinosis and is treated principally with bicarbonate to counteract the metabolic acidosis.
Summary and conclusions Metabolic bone disease results from a wide variety of causes, some of which, such as vitamin D deficiency, are both preventable and easily treatable, whilst others are more problematic. Apart from vitamin D deficiency and secondary osteoporosis, most conditions resulting in MBD are genetic in origin. Some of these are amenable to treatment quite easily whilst therapy for others is either directed at symptomatic relief or palliative care only. In any case, it is imperative that a correct diagnosis is made and that, where necessary, ongoing care is undertaken by a suitably experienced multidisciplinary team. A
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Practice points C
C
C
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Vitamin D deficiency is the commonest cause of rickets and should be excluded before considering any other diagnosis. A diagnosis relating to rickets or hypocalcaemia cannot be made until vitamin D deficiency has been excluded or treated. The treatment of vitamin D deficiency is vitamin D and NOT a vitamin D analogue.
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Metabolic bone disease
In addition, Parathyroid Hormone Related Peptide (PTHrP) is important in fetal life to maintain calcium transport across the placenta and as a paracrine factor in cartilage formation. In postnatal life it is usually undetectable in serum but may be of importance in certain malignant conditions. Clinically apparent metabolic bone disease usually only occurs in the presence of considerable hyperparathyroidism which will only be mentioned in this context.
Jeremy Allgrove
Abstract Bone is a complex organ that is highly metabolically active, particularly in children. Normal metabolism is dependent upon the three main elements, matrix, mineral and cells that are integral components of bone. In addition, there are several humoral factors that also influence bone. Abnormalities in any of these components can give rise to metabolic bone disease. Abnormalities of mineralisation are the commonest manifestation of metabolic bone disease although some are ultimately derived from problems within the supporting cellular components. On the one hand these present themselves as osteomalacic conditions that principally show themselves as mineralisation defects within the growth plates, a condition that is known as rickets, whilst more generalised mineralisation defects, known as osteoporosis are principally caused by Osteogenesis Imperfecta but can also present as a secondary phenomenon following, for instance, prolonged steroid therapy. Conversely, there are several rarer conditions that cause an increase in bone density, some of which cause a decrease in bone fragility but some which, paradoxically are associated with increased tendency to fracture. Many of these conditions have a genetic origin. This article summarises these conditions.
Disorders of mineralisation Bone mineral is made up mainly of calcium and pyrophosphate. The latter consists of two phosphate molecules bound to an oxygen atom. Mineral is laid down by osteoblasts and removed by osteoblasts. Normal mineralisation depends upon a regular and sufficient supply of both calcium and phosphate. The principal role of vitamin D is to promote absorption of calcium by the gut and, in the absence of sufficient vitamin D, calcium absorption is impaired. This leads to one or other of the forms of calciopaenic osteomalacia which, in children, is manifest as rickets. In contrast, phosphate is easily absorbed by the gut. Renal excretion of both calcium and phosphate is closely regulated, the latter mainly by another hormone, FGF23, and, in the presence of excessive urinary renal losses of phosphate, the supply of phosphate is limited and this results in phosphopaenic rickets. The principal causes of rickets are shown in Table 1. PTH has a physiological role in promoting bone formation by an action on osteoblasts. However, under circumstances of calcium deficiency, PTH acts to resorb calcium and phosphate from bone to maintain a normal calcium level in plasma. If severe hyperparathyroidism occurs, metabolic bone disease may supervene. This can manifest itself in undermineralisation and features very similar to those of rickets. Indeed, many of the radiological features of rickets can be attributed to hyperparathyroidism.
Keywords Bone density; Bone matrix; Bone mineral; Fibroblast growth factor 23; Osteoblast; Osteoclast; Osteocyte; Osteogenesis Imperfecta; Osteomalacia; Osteoporosis; Parathyroid hormone; Rickets; Vitamin D
Introduction Bone consists of three principal elements e matrix, mineral and cells. Defects in any of these components can give rise to metabolic bone disease (MBD). Of these, defects in mineralisation are the commonest cause of MBD and most frequently manifest themselves as rickets, of which the commonest cause is vitamin D deficiency. Matrix abnormalities most frequently cause one or other of the forms of Osteogenesis Imperfecta (OI) whilst the least common forms of MBD are those associated with abnormalities in the cellular components. MBD is usually associated with a variable degree of reduced bone density which is often associated with an increased tendency to bone fragility. However, increased bone density is sometimes seen in MBD. This may be associated with increased bone strength or, paradoxically, sometimes with increased bone fragility as in Osteopetrosis. Since osteoporosis or osteomalacia are the most important clinical manifestations this article will summarise disorders of bone matrix and of mineralisation separately, regardless of the specific aetiology. Calcium and phosphate homeostasis is maintained by several factors, principally parathyroid hormone (PTH) and vitamin D for calcium and Fibroblast Growth Factor 23 (FGF23) for phosphate.
Calciopaenic rickets and vitamin D deficiency Vitamin D deficiency is widespread, particularly in the UK. It occurs more frequently in some ethnic minority groups, particularly those from south Asia or Africa. Skin colour and the extent of skin exposure to ultraviolet light are important factors in its aetiology. Estimates of the prevalence of vitamin D deficiency are difficult to ascertain but, in some parts of the population, may be as high as 90%. However, not all people with vitamin D deficiency develop rickets or osteomalacia and other factors, such as milk intake, may also play an important role. Rarely, inborn errors of metabolism, particularly a failure of conversion of 25-hydroxyvitamin D (25OHD) to its active metabolite, 1,25-dihydroxyvitamin D (1,25(OH)2D) by low 1a-hydroxylase activity, or end-organ resistance to 1,25(OH)2D due to abnormal vitamin D receptors, can give rise to a similar syndrome. Clinical manifestations of vitamin D deficiency range from the very severe, sometimes fatal, syndrome of dilated cardiomyopathy or congenital rickets, via classical rickets and hypocalcaemic convulsions to generalised aches and pains, which is the most common manifestation. If the diagnosis is suspected, investigations should include measurement of bone profile (calcium, phosphate, alkaline phosphatase (ALP), albumin and creatinine),
Jeremy Allgrove MD MA FRCP (UK) FRCOCH is a Consultant Paediatric Endocrinologist in the Department of Paediatric Endocrinology, Royal London Hospital, Whitechapel, London E1 1BB, UK. Conflict of interest: none.
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if the rickets has been severe, a longer period may be required. Young children with rickets usually recover completely although they may be left with some degree of motor delay and diminished intellectual function if the rickets was severe at diagnosis. Prevention of vitamin D deficiency is straightforward as vitamin D supplementation, if undertaken correctly, can be very effective. Unfortunately in the UK, this often does not happen. Treatment of mild rickets or asymptomatic vitamin D deficiency can be undertaken in the community although the rarer forms of rickets require follow-up in secondary care.
Principal causes of rickets All treatments correspond with causes A. Calciopaenic rickets Vitamin D deficiency Poor sunlight exposure Dark skin Malabsorption (e.g. coeliac disease) Lack of adequate supplementation Impaired 25-hydroxylation of Vitamin D (very rare but may be a factor in severe liver disease) Impaired 1a-hydroxylation of 25OHD Intrinsic defect As part of the spectrum of renal disease Calcium deficiency (mainly described in West Africa) Distal Renal Tubular Acidosis B. Phosphopaenic rickets Hypophosphataemic rickets X-linked dominant (PHEX gene mutations) Autosomal dominant (FGF23 mutations) Autosomal recessive (DMP1 mutations) Sodium/phosphate cotransporter mutations Miscellaneous causes McCuneeAlbright syndrome
Fanconi syndrome (various causes)
Malignancy (inappropriate FGF23 synthesis) Neurocutaneous abnormalities (Epidermal Naevus Syndrome) Other renal tubular abnormalities
Treatment
Vitamin Vitamin Vitamin Vitamin Vitamin
D D D þ GFD D D
Phosphopaenic rickets Hypophosphataemic rickets most commonly occurs as a result of a defect in the metabolism of FGF23, usually as a result of mutations in the PHEX gene, which determines the cleavage (and hence the inactivation) of FGF23. This is an X-linked dominant condition that usually manifests itself more severely in boys than in girls. A similar syndrome can result from other metabolic abnormalities that result in higher than normal circulating levels of FGF23. Diagnosis of hypophosphataemic rickets is made by simultaneously measuring plasma and urine phosphate and creatinine and calculating the Fractional Excretion (FE) and, if necessary, the Tubular Maximal Reabsorption of Phosphate (TmPO4/GFR) (see Recommended Reading for details of the methodology), together with appropriate radiology. Treatment of hypophosphataemic rickets consists of a combination of oral phosphate supplements and, in most instances, alfacalcidol. The prognosis is variable and depends on the severity of the condition. Conventional treatment, as indicated above, does not cause the bones to heal completely although considerable improvement can often be achieved. Growth impairment may be manifest and orthopaedic intervention may also be required in order to facilitate walking. It is possible that newer treatments, particularly those aimed at reducing levels of FGF23, may improve the prognosis if, as expected, they become available in the future. These patients do require long term follow-up in secondary care.
Alfacalcidol Vitamin D and alfacalcidol Calcium supplementation Bicarbonate
Phosphate supplements and alfacalcidol Phosphate supplements and alfacalcidol Phosphate supplements and alfacalcidol Phosphate supplements Phosphate supplements and alfacalcidol Phosphate supplements and alfacalcidol Remove malignancy if possible Remove cutaneous lesions if possible Depends on precise diagnosis
Hyperparathyroidism Hyperparathyroidism in children most commonly occurs as a secondary consequence of vitamin D deficiency. Chronic kidney disease (CKD) may also be a factor. Primary hyperparathyroidism is less common but is associated with a variety of symptoms including thirst, polyuria and polydipsia and muscle weakness. Infants may have a hoarse cry because of paralysis of the vocal cords. In severe cases, bone density may be so reduced that fractures occur and, if the ribs are affected, respiratory compromise may be such that respiratory support is required. This is most likely to occur in infants who are either born very vitamin D deficient or because of neonatal severe hyperparathyroidism (NSHPT). The clinical and radiological features of these two conditions are very similar although the biochemistry is different in that hypercalcaemia is a prominent feature of the latter. Investigations include a measurement of bone profile with PTH and of urinary excretion of calcium. This is low in severe rickets and raised in NSHPT which is caused by inactivating mutations of the calcium sensing receptor. In many cases this is homozygous but it may also be a feature of heterozygous
Table 1
urine calcium and creatinine, 25OHD (the major circulating metabolite of vitamin D) and PTH if the clinical picture is severe. Treatment of vitamin D deficiency is with vitamin D (either ergo or colecalciferol) and this should always be corrected before considering an alternative diagnosis. In the rare cases of 1a-hydroxylase activity, treatment with a 1a-hydroxylated vitamin D metabolite (e.g. alfacalcidol) is required and end-organ resistance usually requires calcium and phosphate infusions, at least in the first instance. Treatment needs to be continued for 3 months during which time healing will usually occur although,
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mutations especially if the mother is unaffected. Treatment of the severe neonatal rickets consists of correcting the vitamin D deficiency whereas that of NSHPT is directed at reducing the PTH levels as soon as possible whilst reducing the effects of the hypercalcaemia. In many instances vitamin D deficiency may be an additional factor that exacerbates the hyperparathyroidism and needs to be corrected. Some authors recommend the use of bisphosphonates to reduce the plasma calcium but this does have the effect of raising PTH levels further. In many cases, parathyroidectomy is required but occasionally it is possible to alter the clinical picture with the calcimimetic agent, cinacalcet, to allow the clinical picture to improve.
is available. Renal ultrasonography is the most reliable way of assessing nephrocalcinosis. Bone biochemistry is usually normal but should always be undertaken, particularly prior to treatment as vitamin D deficiency must be excluded and, if necessary, corrected prior to commencing treatment. Genetic analysis of the COL1A1 and COL1A2 genes is not always undertaken if the diagnosis is straightforward. In more difficult cases, particularly if there are medico-legal issues where NAI is suspected or if one of the rarer forms of OI such as those involving the crosslinking genes is suspected, mutations may be sought as appropriate. However, genetic analysis of COL1A1 and COL1A2 is time consuming and expensive and is often not recommended by the geneticists except in doubtful cases. Follow-up of patients with OI, particularly in severe cases, should be undertaken by a multidisciplinary team in a specialist centre where there is access to paediatricians, endocrinologists, nurses, occupational and physiotherapists, dentists and orthopaedic surgeons. Genetic advice may also be desirable in difficult cases. Treatment depends on the severity of the disease and any or all of the above personnel may need to be involved. The mainstay of medical treatment is bisphosphonates. These have now been in routine use for OI for about 15 years and have improved the outlook for these patients quite considerably. The principal effects are a reduction in bone pain, fewer fractures and, if present, remodelling of vertebral crush fractures. The most commonly used drug is pamidronate given in a dose of 1 mg/kg/d daily for 3 days every 3e4 months. Young infants may be given it in half the dose at 6 weekly intervals and toddlers often receive it every 2 months in an intermediate dose. It is given by intravenous infusion. Patients should be warned that the first cycle of treatment is often accompanied by an acute phase reaction with pyrexia and ‘flu’-like symptoms which can usually be controlled with antipyretic analgesics. These symptoms do not usually recur with subsequent cycles. Acute iritis can also occur and rashes are occasionally seen. More recently, another bisphosphonate, risedronate, has been used in trials and seems promising and is more convenient as it only needs to be administered weekly and does not require hospital admission. However, oral preparations are not well absorbed and may be more useful for maintenance therapy than initiation. Zoledronate is a fourth generation bisphosphonate that is considerably more potent than pamidronate but is little used in children as its long term effects are less well understood but has the advantage of only requiring a single infusion every 6e12 months. Mobilisation, which is made more possible by bisphosphonate therapy, is encouraged as it helps to improve bone health. This can be effected by a combination of physiotherapy, orthopaedic surgery and walking aids, hence the need for a multidisciplinary approach to care.
Disorders of matrix Primary osteoporosis Matrix consists principally of collagen, together with a number of other bone proteins that interact with it. Collagen, of which more than 20 types are described, is the main protein of connective tissue. All types of collagen consist of three fibrils which are wound round each other in the manner of a rope to form fibres. These fibres are then joined together by crosslinks. Qualitative or quantitative abnormalities in the structure of the collagen fibrils result in weakening of the fibres. In addition, disruption of the crosslinking may also result in weakened collagen. The most abundant form of collagen in bone is Type I which consists of two fibrils of A1 and one of A2 collagen bound together. These two fibrils are coded for by genes known as COL1A1 and COL1A2 respectively. Mutations in either of these genes result in Osteogenesis Imperfecta (OI). OI is a rare disease and very variable in its manifestations. Mild forms (Type I) may cause a slight increase in tendency to fracture but little else. The more severe forms can sometimes be incompatible with post-natal life (Type II) or may cause children to be wheelchair-bound with multiple low trauma fractures and bony deformity (Type III) or a more intermediate form with multiple fractures and some growth impairment (Type IV). Other rare forms, usually affecting the crosslinking proteins, are also described. The different forms of OI, together with the principal clinical features, are shown in Table 2. Diagnosis of OI is principally clinical. A history of low trauma or apparently spontaneous fractures is suggestive although it can sometimes be difficult to distinguish from non-accidental injury (NAI). The pattern of injuries can often be useful in distinguishing the two. Poor growth is often present in the more severe forms. There is an increased incidence of scoliosis and poor muscle tone in some cases. The presence of blue sclerae, easy bruising, skin fragility and a tendency to sweating excessively are also suggestive. Dental development may be abnormal and manifest as Dentinogenesis Imperfecta (DI). Hearing may be impaired and a family history of progressive deafness may be relevant. In severe cases, nephrocalcinosis caused by hypercalciuria can occur. Alterations in the shape of the skull base may occur and the possibility of platybasia and herniation of the vermix should be considered. Radiological investigations consist of plain X-rays as necessary. However, assessment of bone density on plain X-ray is very unreliable and DXA scanning provides a better solution to this problem. The results of DXA scans should be interpreted with caution and these patients should only be seen in centres where appropriate expertise
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Secondary osteoporosis Osteoporosis may occur as a consequence of a number of other conditions, the commonest of which is chronic steroid exposure, either endogenous or, more commonly, exogenous. Immobilisation is a second factor that may contribute considerably to secondary osteoporosis and, if the two are combined, such as in Duchenne Muscular Dystrophy, the effects can be seen in vertebral collapse and fractures.
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Classification and principal features of Primary Osteoporosis
OI Type
Phenotype (during childhood)
I
Mild motor delay. Bowing of long bones. Vertebral crush fractures. Ligamentous laxity, hernias, mixed conductive/sensorineural deafness, blue sclerae. Subdivided on the basis of the presence or absence of dentinogenesis imperfecta (A¼absent, B¼present) Lethal. Subdivided by appearance of ribs Lethal. Similar to Type IIA Severe, progressively deforming. Typically have fractures in utero, very poor post-natal growth. Characteristic facies with small mid face and pointed chin. Triangular facial appearance less noticeable with bisphosphonate treatment. Very delayed motor development. Almost all need intramedullary rodding. Blue sclerae remain. All have dentinogenesis imperfecta. Moderately severe. May have fractures in utero, but better post-natal growth than Type III. Blue sclerae fade with age; may have dentinogenesis imperfecta Moderately severe. Metaphyseal sclerosis in early life, followed by calcification of interosseous membranes in the forearm and lower leg. Characteristic bowing of the forearms. Hypertrophic callus formation following fractures and surgery Severe, progressively deforming. Osteomalacic on bone biopsy, possibly as a result of abnormal matrix deposition e normal lamellar structure is disrupted Moderately severe. Rhizomelic in both arms and legs; femurs and humeri are very bowed. White sclerae Very severe/lethal. Round face, white sclerae, thin ribs (may be beaded). Most cases are reported in children whose families originate from West Africa, Pakistan and Ireland Severe. May be lethal at or soon after birth. Resembles Type III in living individuals Contractures. White sclerae, mild DI. Moderatelysevere bone disease Clinical phenotype as for Bruck 1 Normal at birth; develop craniosynostosis, ocular proptosis, hydrocephalus and diaphyseal fractures Decreased bone mineralisation and increased tendency to fractures. Usually improves at adolescence Decreased bone mineralisation and increased tendency to fractures. Congenital blindness
IIA IIB III
IV
V
VI
VII VIII
IX Bruck 1 Bruck 2 ColeeCarpenter Idiopathic juvenile osteoporosis Osteoporosis Pseudoglioma Syndrome (OPS) Juvenile Paget’s disease Geroderma osteodysplasticum Hypophosphatasia Perinatal lethal
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Genetic origin Typically null allele of COL1A1, resulting from stop, frameshift or splice site mutations Missense mutations in COL1A1 or COL1A2
Complete loss of CRTAP Missense mutations in COL1A1, COL1A2; null allele of COL1A2
Missense mutations in COL1A1 or COL1A2
Unknown
Mutations in FKBP10
Cryptic splice site in intron 1 of CRTAP Deletion of LEPRE1
Mutations in PPIB causing overproduction PLOD2; bone-specific telopeptide lysyl hydroxylase Unknown Unknown Some cases associated with heterozygous mutations of LRP5 Heterozygous mutations in LRP5
Debilitating bone pain, short stature, long bone and vertebral fractures Prematurely aged skin, osteoporosis, increased joint laxity, kyphoscoliosis
Homozygous mutations in Osteoprotegerin gene Mapped to chromosome 1q24
Congenital. Usually incompatible with post-natal life
Liver alkaline phosphatase (tissue non-specific alkaline phosphatase)
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Table 2 (continued ) Infantile
Presents during infancy with osteoporosis and fractures
Liver alkaline phosphatase (tissue non-specific alkaline phosphatase)
Childhood
Osteoporosis and early tooth loss
Adult
May only be diagnosed following another family member Tooth problems only
Liver alkaline phosphatase (tissue non-specific alkaline phosphatase) Liver alkaline phosphatase (tissue non-specific alkaline phosphatase) Liver alkaline phosphatase (tissue non-specific alkaline phosphatase)
Odontohypophosphatasia
Table 2
Several chronic conditions such as cystic fibrosis, b-thalassaemia major, idiopathic juvenile arthritis and other chronic inflammatory diseases, may result in secondary osteoporosis either because of the steroid usage that is frequently needed in some of these conditions or probably also as a direct result of the inflammatory agents that are responsible for the disease in the first place. It is not generally regarded as good practice to treat any of these conditions prophylactically but rather to wait until such time as symptoms, either bone pain or fractures, occur and then to treat appropriately under supervision of a bone specialist. Initial treatment should consist, if possible, of removing the underlying cause or, if this is not possible, of minimising any therapy that may be contributing to the osteoporosis. Mobilisation of the patient as much as possible may also help to improve bone health. If delayed puberty is present, treatment with appropriate sex steroids may improve matters. If, however, none of these measures is effective, there may be a need to use bisphosphonates, in a similar regimen to that of OI, to improve bone density, reduce fracture risk and ease pain. DXA scanning should only be used as an adjunct to monitoring and not as an indication for treatment.
important factors that enable mineralisation is the enzyme, alkaline phosphatase (ALP). Mutations within the genes for this enzyme result in hypophosphatasia, an osteoporotic condition of variable severity that ranges from incompatibility with post-natal survival to mild osteoporosis and dental abnormalities. In its most severe (homozygous) form, infants are born with little bone mineralisation and usually succumb rapidly to respiratory difficulties because of poor rib compliance. Currently, however, a trial is being conducted of the use of recombinant ALP which is proving promising in these infants. Older children may present with an increased fracture tendency and rachitic changes on X-ray and have a tendency to early tooth loss that is atypical in that the roots remain intact. Diagnosis is confirmed by the presence of low ALP in plasma and raised phosphoethanolamine/creatinine ratio in urine. Phosphoethanolamine is also a substrate for ALP. There is no definitive treatment and bisphosphonates are ineffective. Osteoclasts Osteoclasts are multinucleated cells of haematopoietic origin. Differentiation from their precursors occurs under the influence of several factors. Final differentiation of osteoclasts from preosteoclasts is determined by the action of RANK Ligand (RANKL) on RANK, its receptor on the cell surface. RANKL is a product of osteoblasts which thus control the function of osteoclasts. A second protein, osteoprotegerin (OPG), is also produced by osteoblasts. This is a soluble inhibitor of RANKL and acts as a ‘brake’ on osteoclast activity. At times of increased need for bone resorption (such as when hypocalcaemia is present), OPG production is limited and bone resorption can proceed unhindered whilst when calcium is plentiful, larger quantities of OPG inhibit bone resorption. Mutations within the OPG gene result in Juvenile Paget’s Disease in which bone resorption is unrestricted and osteoporosis results. Treatment with either bisphosphonates or, more logically, recombinant OPG, has proved promising. Defects within the osteoclasts themselves give rise to the spectrum of conditions known as Osteopetrosis (OP). There are two main types, osteoclast poor OP, in which differentiation of osteoclasts is impaired by mutations either in RANKL or RANK, and osteoclast rich OP in which osteoclasts are plentiful but do not function normally because of mutations in one or other of the genes controlling the production of the acid environment created by osteoclasts that is necessary for bone resorption. The severity of OP varies depending on which gene is mutated and varies from malignant to benign forms some of which may only be diagnosed
Disorders of bone cells Osteoblasts Osteoblasts, together with osteocytes, are derived from multipotent mesenchymal precursor cells which also give rise to chondrocytes, adipocytes, myocytes and fibroblasts. A complex series of transcription factors determines the destination of these cells. Once these cells have differentiated into osteoblasts, the activity is regulated principally via the Wnt signalling pathway which consists of a number of proteins which, by a complex series of interactions, determine osteoblast function. One of these, Low Density Lipoprotein Receptor Related Protein 5 (LRP5), has an important regulatory function. Inactivating mutations in the gene responsible for it may cause osteoporosis if heterozygous but may also cause the rare but serious Osteoporosis Pseudoglioma Syndrome if homozygous. The latter presents with severe osteoporosis, which clinically resembles OI, but is associated with visual impairment as LRP5 is also involved in development of retinal vasculature. In contrast, activating mutations of LRP5 are associated with a syndrome of increased bone density and decreased fracture risk. The principal function of osteoblasts is to facilitate bone formation both by laying down matrix and depositing calcium and pyrophosphate onto this matrix. Matrix abnormalities have already been discussed as a principal cause of OI. One of the more
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Conditions associated with increased bone density Osteopetrosis Autosomal recessive 1 (OPTB1)
Osteoclast rich
Malignant
Failure of acidification
Autosomal recessive 2 (OPTB2)
Osteoclast poor
Benign
Autosomal recessive 3 (OPTB3)
Osteoclast rich
Intermediate
Autosomal recessive 4 (OPTB4)
Osteoclast rich
Autosomal recessive 5 (OPTB5)
Osteoclast rich
Malignant/ intermediate Malignant
Failure of osteoclast transformation Failure of acidification; RTA Failure of acidification
Autosomal recessive 6 (OPTB6)
Osteoclast rich
Intermediate
Autosomal recessive 7 (OPTB7)
Osteoclast poor
Malignant
Autosomal dominant 2 (OPTA2) Other bone sclerosing conditions Pyknodysostosis
Osteoclast rich
Benign
Hyperostosis corticalis generalisata (van Buchem Disease) Sclerosteosis (SOST)
Osteoclast rich Osteoclast rich
Activating LRP5 mutations (OPTA1)
Osteoclast rich
Osteoclast rich
Benign
Failure of acidification Abnormal vesicular transport Failure of osteoclast transformation Failure of acidification Failure of bone matrix resorption Increased osteoblast signalling Increased osteoblast signalling Increased osteoblast signalling
CamuratieEngelmann disease (PPD) Fibrodysplasia Ossificans Progressiva (FOP) Progressive Osseous Heteroplasia (POH) Caffey’s disease
T-cell immune regulator subunit of the vacuolar proton pump Tumour necrosis factor superfamily 11 Carbonic anhydrase II Chloride channel-7 protein Osteopetrosis-associated transmembrane protein-1 Plekstrin homology domain-containing protein, family M member 1 Tumour necrosis factor receptor superfamily, member 11a Chloride channel-7 protein Cathepsin K Sclerostin Sclerostin Low density lipoprotein receptor protein 5 Transforming growth factor, beta-1 Activin receptor I/activin-like kinase 2 GNAS complex e paternally inherited COL1A!, Exon 42
Table 3
incidentally or as a result of diagnosis in another family member. In all cases, increased bone density is present although this bone is of poor quality and is accompanied by an increased tendency to fracture. Malignant forms have been treated with some success with bone marrow transplantation but this must be carried out early before the effects of bone overgrowth (e.g. on hearing) have occurred. A similar condition, known as Pyknodysostosis, is caused by inactivating mutations of cathepsin K, the enzyme responsible for resorption of collagen. Bone mineral is resorbed but bone density remains high but with fractures and delayed skull suture closure. Treatment is symptomatic only. The principal causes of increased bone density are shown in Table 3.
They synthesise a number of proteins that contribute to the maintenance of bone health. Amongst these is FGF23, defects in which are responsible for hypophosphataemic rickets (see above). In addition, a number of Bone Matrix Proteins are also made that help to maintain the integrity of bone and to fill the spaces between collagen fibrils. Another protein, Dentin Matrix Protein (DMP1), also has an inhibitory effect on FGF23 production. Homozygous mutations in this protein cause a very rare form of hypophosphataemic rickets.
Renal tubular abnormalities Abnormalities of renal tubular function may also cause metabolic bone disease. Phosphate reabsorption may be impaired as a result of intrinsic renal tubular dysfunction which can occur either in connection with one or other form of the Fanconi syndrome in which impaired reabsorption of phosphate is associated with glycosuria, aminoaciduria and bicarbonaturia, or secondary to mutations in the gene for the sodium/phosphate cotransporter in the distal renal tubule. The rickets is treated in a similar fashion to other forms of hypophosphataemic rickets
Osteocytes Osteocytes are derived from osteoblasts that become embedded in bone. They communicate with each other via fine dendritic processes that lie within canaliculae. They are principally responsible for maintaining bone health and respond to mechanical stresses within bone, the so-called mechanostat.
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FURTHER READING Allgrove J, Shaw NJ, eds. Calcium and bone disorders in children and adolescents. Basel, Freiburg, Paris, London, New York, Bangalore, Bangkok, Shanghai, Singapore, Tokyo, Sydney: Karger, 2009. Glorieux F, Pettifor JM, J} uppner H, eds. Pediatric bone: biology and diseases. Amsterdam, Boston, Heidelberg, London, New York, Oxford, Paris, San Diego, San Francisco, Singapore, Sydney, Tokyo: Academic Press, 2003.
although in the latter case alfacalcidol should not be used as it tends to worsen nephrocalcinosis. Distal Renal Tubular Acidosis, in which excretion of hydrogen ions within the renal tubule leads to metabolic acidosis, also causes rickets. This is also associated with nephrocalcinosis and is treated principally with bicarbonate to counteract the metabolic acidosis.
Summary and conclusions Metabolic bone disease results from a wide variety of causes, some of which, such as vitamin D deficiency, are both preventable and easily treatable, whilst others are more problematic. Apart from vitamin D deficiency and secondary osteoporosis, most conditions resulting in MBD are genetic in origin. Some of these are amenable to treatment quite easily whilst therapy for others is either directed at symptomatic relief or palliative care only. In any case, it is imperative that a correct diagnosis is made and that, where necessary, ongoing care is undertaken by a suitably experienced multidisciplinary team. A
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Practice points C
C
C
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Vitamin D deficiency is the commonest cause of rickets and should be excluded before considering any other diagnosis. A diagnosis relating to rickets or hypocalcaemia cannot be made until vitamin D deficiency has been excluded or treated. The treatment of vitamin D deficiency is vitamin D and NOT a vitamin D analogue.
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