Metabolic and congenital bone disease in adults

• Metabolic and congenital bone disease is an umbrella for disorders that weaken, deform or deaden bone in adults through defective matrix, minerals or remodeling. Osteogenesis imperfecta, achondroplasia, fibrous dysplasia, avascular necrosis of bone, osteopetrosis and hypophosphatasia are the core examples here.
• Each condition has a different mechanism (collagen defect, cartilage signaling defect, mosaic GNAS mutation, vascular interruption, osteoclast failure, alkaline phosphatase deficiency), so the same symptom, such as fracture or pain, needs different reasoning.
• Most adults who fracture repeatedly are not osteoporotic; low-trauma fractures in a young or apparently healthy adult should prompt a search for these disorders and for secondary causes.
• Investigation is directed: genetics and family history, specific radiographic patterns, biochemistry (alkaline phosphatase, phosphate, vitamin B6) and, when relevant, MRI or biopsy.
• Management is mostly supportive and fracture prevention; a few conditions have specific therapy such as surgical decompression in achondroplasia, and bisphosphonates help some disorders but can harm others.

By the end of this page you should be able to:

1. Recognise the main metabolic and congenital bone disorders that present in adult life and explain why they are missed.
2. Link clinical and radiographic findings to their mechanism for osteogenesis imperfecta, achondroplasia, fibrous dysplasia, avascular necrosis, osteopetrosis and hypophosphatasia.
3. Plan appropriate investigations, including which biochemical tests protect against misdiagnosis as osteoporosis.
4. Decide when bisphosphonates, surgery or specialist referral are appropriate, and when they are dangerous.
5. Distinguish benign familial and sporadic disease and counsel families using published inheritance patterns.

It is useful to classify the conditions covered here by mechanism:

• Collagen matrix defects. Osteogenesis imperfecta results from abnormalities of type I collagen synthesis or processing. Defects directly in type I collagen structure or quantity cause 80 to 85 percent of cases.^[1]
• Cartilage signaling defects. Achondroplasia is caused by a gain-of-function mutation in the fibroblast growth factor receptor 3 gene, inherited in an autosomal dominant pattern; most cases are new mutations.^[2]
• Mosaic activating mutations. Fibrous dysplasia arises from post-zygotic activating GNAS mutations and is never inherited. It can be monostotic (about 70 to 80 percent of cases) or polyostotic, and may occur as part of McCune-Albright syndrome.^[4]
• Vascular interruption. Avascular necrosis of bone is osteocyte death after loss of subchondral blood supply.
• Osteoclast failure. Osteopetrosis is a spectrum of heritable disorders in which osteoclasts fail to resorb immature bone.
• Enzyme deficiency. Hypophosphatasia is caused by loss-of-function mutations in the gene for tissue-nonspecific alkaline phosphatase.

Several of these diseases are classified by age of onset (for example perinatal, infantile, childhood, adult and odontohypophosphatasia), and the adult form is often mild and dominated by fractures or pain.

• Osteogenesis imperfecta is rare, with an incidence of 1 in 15,000 to 20,000 live births.^[1]
• Achondroplasia has a birth prevalence of about 1 in 26,000 to 28,000, affects roughly 250,000 people worldwide, and occurs in 1 in 10,000 to 30,000 live births; 80 to 90 percent of cases are new mutations.^[2][3]
• Fibrous dysplasia accounts for about 2.5 percent of all bone lesions and 7 percent of benign skeletal dysplasias.^[4]
• Osteonecrosis of the femoral head is estimated at 20,000 to 30,000 new cases per year in the United States, mostly in adults aged 20 to 40 years, and 20 to 40 percent of cases are idiopathic.^[6]
• Osteopetrosis is rare: autosomal recessive osteopetrosis occurs in about 1 in 250,000 births and autosomal dominant osteopetrosis in about 1 in 20,000 births.^[5]
• Hypophosphatasia severe forms occur in about 1 in 100,000 to 300,000 births, with moderate forms far more frequent, and at least 388 ALPL mutations have been described.^[7]

Osteogenesis imperfecta usually results from mutations in COL1A1 or COL1A2; recessive and X-linked variants involve post-translational modification, folding and cross-linking of collagen.^[1] There is no modifiable risk factor; severity ranges from mild to perinatal lethal.

Achondroplasia follows an autosomal dominant pattern and about 80 percent of cases are de novo, associated with increased paternal age.^[2] Heterozygotes who survive have normal cognition and near-normal life span, but several complications are common.^[3]

Fibrous dysplasia is non-inherited. Post-zygotic GNAS mutations produce mosaicism, which explains why disease extent ranges from one bone to extensive polyostotic involvement with extraskeletal features.^[4] Because the mutation is somatic, germline testing of blood or saliva is not recommended.^[4]

Avascular necrosis is multifactorial. The commonest causes are trauma (femoral neck fracture or hip dislocation), systemic glucocorticoid use (a cumulative dose exceeding 10 g doubles risk), excess alcohol consumption (more than 400 mL per day carries an about 11-fold higher risk), sickle cell disease, Gaucher disease, systemic lupus erythematosus, hyperlipidaemia, dysbaric injury, acute lymphoblastic leukaemia, transplantation and HIV.^[6] Twenty to forty percent of cases have no identifiable cause.^[6]

Osteopetrosis is autosomal recessive in severe infantile forms and autosomal dominant in the mild adult-onset Albers-Schonberg disease; mutations in more than 10 genes impair osteoclast development or function.^[5]

Hypophosphatasia may be autosomal dominant or recessive with variable penetrance. Adult disease usually presents in middle age and is often misdiagnosed as osteoporosis.^[7]

In osteogenesis imperfecta the underlying problem is collagen: misfolded or deficient type I collagen weakens bone, increases brittleness and produces high-turnover, hypermineralised bone that fractures at low loads.^[1] Bisphosphonates increase bone mass in affected children and some adults but have equivocal effects on fracture incidence.^[1]

In achondroplasia the FGFR3 gain-of-function mutation disturbs endochondral ossification by slowing chondrocyte proliferation and hypertrophy, producing rhizomelic shortening, a narrow spinal canal and a small foramen magnum.^[3]

In fibrous dysplasia the GNAS mutation raises cyclic AMP continuously in bone cells, producing fibro-osseous replacement of normal bone with expansion, deformity and fracture. Lesions also overproduce fibroblast growth factor 23, which can cause renal phosphate wasting and osteomalacia.^[4]

In avascular necrosis the sequence is ischaemia, osteocyte death and failed repair: bone formation does not keep pace with resorption and the necrotic segment collapses. Spontaneous regression is rare.^[6]

In osteopetrosis the basic defect is failure of acidification or function of the osteoclast; immature bone accumulates, marrow space is obliterated and bone becomes brittle despite being dense.^[5]

In hypophosphatasia tissue-nonspecific alkaline phosphatase (TNSAP) activity is low, so inorganic pyrophosphate accumulates and inhibits hydroxyapatite propagation; mineralisation fails and bone remains soft. The raised plasma pyridoxal 5'-phosphate also explains the seizures of severe infantile disease.^[7]

Adults with the mild form (type I) may have a history of childhood fractures, blue or grey sclerae, dentinogenesis imperfecta, hearing loss, joint laxity and short stature.^[1] They can present with fractures not recognised until adolescence or adult life. Osteogenesis imperfecta can overlap radiologically and biochemically with osteoporosis, and type I is an important differential of "young osteoporosis".^[1]

Short stature (about 131 cm in men and 124 cm in women), rhizomelic shortening, macrocephaly with frontal bossing and trident hands are present from birth.^[3] The adult complication that matters most is lumbar spinal stenosis between L1 and L4 from a congenitally narrow canal; it affects about 10 percent of adults and may require surgical decompression in young adults.^[3] Adults also develop thoracolumbar kyphosis, genu varum, obesity (more than half) and sleep apnoea.^[3] Intellect and life span are normal.^[3]

Lesions produce pain, deformity, pathologic fracture and sometimes nerve compression. Craniofacial disease presents with facial asymmetry, vision or hearing impairment and dental anomalies.^[4] Pain is reported by 46 to 67 percent of patients and is more common in adults than children (81 versus 49 percent).^[4] Polyostotic disease in McCune-Albright syndrome adds cafe-au-lait skin macules with irregular margins, precocious puberty, hyperthyroidism, growth hormone excess, Cushing syndrome and renal phosphate wasting.^[4]

The typical patient is a young adult with groin or hip pain that is worse on weight-bearing and better at rest, plus limited internal rotation.^[6] The femoral head is most often affected; other sites include the humeral head, knee and small bones of the hand and foot.^[6] Patients with sickle cell disease, alcohol excess or glucocorticoid exposure are at risk and the disease is frequently bilateral in atraumatic cases.^[6]

Autosomal dominant (Albers-Schonberg) disease usually begins in late childhood or adolescence. Adults may have fractures (paradoxically because bone is brittle), osteomyelitis of the mandible, scoliosis and hip osteoarthritis. Cranial nerve compression with hearing or visual loss affects around 5 percent.^[5]

Adult disease becomes apparent in middle age with recurrent metatarsal fractures that heal poorly, bilateral femoral pseudofractures that originate from the lateral cortex of the subtrochanteric region, CPPD crystal arthritis, predisposition to atypical femoral fracture, and premature loss of teeth.^[7] It is commonly misdiagnosed as osteoporosis.^[7]

Biochemistry. Check serum alkaline phosphatase carefully (use age-adjusted ranges; remember that ALP rises after fracture and can mask hypophosphatasia), phosphate, calcium, 25-hydroxyvitamin D, parathyroid hormone and liver function. In hypophosphatasia, plasma pyridoxal 5'-phosphate is high and is the most sensitive companion test.^[7] In osteopetrosis, creatine kinase BB and tartrate-resistant acid phosphatase can support the diagnosis.^[5] In fibrous dysplasia, test for endocrinopathy (thyroid, growth hormone, cortisol, gonadotrophins, phosphate wasting via tubular reabsorption of phosphate) because McCune-Albright syndrome may be present.^[4]

Genetics. Achondroplasia and osteogenesis imperfecta require genetic confirmation for counselling; fibrous dysplasia is diagnosed on lesion tissue because the mutation is somatic. Hypophosphatasia can be confirmed by ALPL sequencing.^[2][1][4][7]

Imaging. Plain radiographs show the signature patterns: diffuse osteosclerosis and sandwich vertebrae in osteopetrosis, ground-glass lesions in fibrous dysplasia, beaking and transverse lucency in atypical femoral fracture. MRI is the benchmark for early avascular necrosis and is sensitive for bone marrow oedema and stress fracture. CT is the imaging modality of choice for fibrous dysplasia lesions.^[6][4] Radionuclide bone scintigraphy helps map metabolically active Paget disease and polyostotic fibrous dysplasia.^[8]

First-line test by suspected diagnosis. Suspected avascular necrosis: MRI of the affected bone. Suspected fibrous dysplasia: CT with staging bone scan. Suspected hypophosphatasia: repeat alkaline phosphatase when healed, plus pyridoxal 5'-phosphate and ALPL testing. Suspected achondroplasia: skeletal survey and FGFR3 testing. Suspected osteogenesis imperfecta: collagen or gene studies plus DXA in an experienced centre.

Osteogenesis imperfecta is classified by phenotype and genetics. Types I, IV and III are the common forms ranging from mild to severe, with perinatal lethal type II; recurrence and inheritance depend on the specific mutation.^[1]

Achondroplasia is diagnosed clinically and radiologically, then confirmed by FGFR3 mutation testing; about 94 percent of genetically confirmed cases carry the common G380R substitution.^[2]

Fibrous dysplasia is diagnosed by characteristic imaging (ground-glass intramedullary lesion) plus, when needed, histology and GNAS testing.^[4]

Avascular necrosis is staged by imaging as precollapse or collapsed disease (Ficat/ARCO/University of Pennsylvania schema); the distinction governs conservative versus arthroplasty options.^[6]

Osteopetrosis is classified by inheritance and severity (autosomal recessive infantile, intermediate, and autosomal dominant adult forms) and by the underlying gene.^[5]

Hypophosphatasia has six subtypes: perinatal lethal, prenatal benign, infantile, childhood, adult and odontohypophosphatasia, each defined by age and severity.^[7]

Bisphosphonates (commonly intravenous zoledronate or pamidronate) increase bone mineral density. They are most effective in the first year and do not reliably improve bone material properties or connectivity; oral bisphosphonates may cause gastrointestinal problems.^[1] Teriparatide is an option for type I osteogenesis imperfecta in adults because it has an anabolic effect.^[1] Surgical rodding, physiotherapy and occupational support remain important. Families need prenatal and preimplantation options discussed when mutations are known.

Management is supportive and preventative. Lumbar spinal stenosis is treated with surgical decompression when symptomatic; foramen magnum and craniocervical disease is managed in specialist centres. Obesity, sleep apnoea and ENT complications should be screened for. New pharmacologic strategies targeting FGFR3 are under investigation and are not standard care.^[3]

Pain is managed multimodally. Intravenous bisphosphonates (zoledronic acid 5 mg intravenously monthly for up to three doses then yearly, or pamidronate 90 mg per day intravenously for 2 consecutive days every 6 months) may improve pain in more than 50 percent of adults.^[4] Denosumab can reduce lesion volume and pain but carries a significant rebound risk on stopping and should only be started after expert consultation.^[4] Surgery is reserved for fracture, deformity and refractory pain; phosphate wasting is treated with active vitamin D analogues and, in trials, burosumab. Craniofacial lesions are monitored with CT no more frequently than every 5 years in asymptomatic adults.^[4]

Joint-preserving options include core decompression, bone grafting, osteotomy and adjunctive stem cells, with best results in precollapse disease. Total hip arthroplasty is the only definitive treatment for collapse.^[6] Bisphosphonates have mixed evidence and are not a reliable primary therapy.^[6] Address risk factors where possible.

There is no curative medical therapy. Supportive care includes orthopaedic management of brittle bone fractures by experienced surgeons, dental surveillance, and management of osteomyelitis. Haematopoietic stem cell transplantation is reserved for severe recessive forms and improves survival but not necessarily vision.^[5]

Avoid bisphosphonates. They may worsen hypomineralisation and can precipitate atypical femoral fracture.^[7] Femoral fractures and pseudofractures are stabilised with intramedullary rods rather than plates or screws.^[7] Teriparatide has been reported to aid fracture healing (20 micrograms subcutaneously daily) but evidence is case-report level.^[7] Asfotase alfa is licensed for paediatric-onset disease, not for adult-onset hypophosphatasia.^[7]

Osteoporosis and Paget disease of bone are covered in the Endocrinology musculoskeletal topics and only need flagging here. Osteoporosis pharmacotherapy is guideline-led: the Endocrine Society (2019 guideline, 2020 romosozumab update) recommends bisphosphonates as first-line for postmenopausal women at high risk of fracture, reassessment after 3 to 5 years, a bisphosphonate holiday for low-to-moderate risk, and anabolic therapy (teriparatide or abaloparatide) for very high risk; monitor bone mineral density every 1 to 3 years.^[9] Any adult with a low-trauma fracture should also be checked for hypophosphatasia before antiresorptives are prescribed, because bisphosphonates can be harmful there.^[7]

Paget disease is usually focal, driven by osteoclast activation, most often in adults over 55, with a prevalence of about 1 percent in the United Kingdom. The Ralston guideline (2019) recommends total alkaline phosphatase as first-line screening, bisphosphonates for bone pain (zoledronic acid 5 mg intravenously as a single dose is more likely to give relief than risedronate 30 mg daily for 2 months), and symptom-targeted rather than alkaline phosphatase normalising treatment.^[8] Bisphosphonates in atypical femoral fracture are handled according to the ASBMR 2014 second task force report: discontinue the antiresorptive, ensure calcium and vitamin D, consider teriparatide for non-healing disease, and operate on complete or symptomatic incomplete fractures.^[10][11]

• Osteogenesis imperfecta: repeated fractures, deformity, basilar invagination, hearing loss, cardiorespiratory impairment, and challenges in anaesthesia and surgery.^[1]
• Achondroplasia: spinal stenosis requiring decompression, hydrocephalus, sleep apnoea, cervical myelopathy, genu varum and joint arthritis.^[3]
• Fibrous dysplasia: pathologic fracture, severe deformity, cranial nerve compression, phosphate wasting, and rare malignant transformation; pain is common.^[4]
• Avascular necrosis: collapse, secondary osteoarthritis, prosthetic surgery; contralateral disease is common.^[6]
• Osteopetrosis: fractures with delayed union or non-union, osteomyelitis, cranial nerve palsies, bone marrow failure in recessive forms.^[5]
• Hypophosphatasia: non-healing fractures, pseudofractures, CPPD attacks, dental loss and atypical femoral fracture, especially with bisphosphonates.^[7]

Osteogenesis imperfecta ranges from normal life expectancy in mild disease to perinatal lethality in the most severe forms; many adults function well with support.^[1] Achondroplasia is compatible with near-normal life expectancy.^[3] Fibrous dysplasia lesion activity often plateaus after puberty but pain may persist. Avascular necrosis tends to progress without intervention, and many patients need arthroplasty. Adult-onset osteopetrosis (Albers-Schonberg) has normal life expectancy with skeletal complications.^[5] Adult hypophosphatasia is chronic but manageable if recognised.^[7]

The ASBMR defines an atypical femoral fracture by five major criteria: low or no trauma, a transverse fracture line starting at the lateral cortex, non-comminuted or minimally comminuted, complete through both cortices (or incomplete involving lateral cortex only), and localised periosteal or endosteal thickening ("beaking") at the site.^[10] Additional minor features (generalised cortical thickening, prodromal thigh or groin pain, bilateral disease, delayed healing) may be present but are not required.^[10] Such fractures are associated with prolonged antiresorptive therapy and also occur in hypophosphatasia, which is another reason to check the alkaline phosphatase.^[11]

• Family history and genetic counselling for osteogenesis imperfecta and hypophosphatasia; parental testing where appropriate.^[1][7]
• In achondroplasia, monitor head growth, sleep, spinal alignment and ENT health from infancy; adults need proactive assessment for stenosis.^[3]
• In fibrous dysplasia, stage lesions at diagnosis and screen for endocrinopathy.^[4]
• Avoid unnecessary high-dose glucocorticoids and unmanaged alcohol use for avascular necrosis prevention.^[6]
• In osteoporosis-risk patients, ensure vitamin D and calcium status before starting antiresorptives, and revisit the alkaline phosphatase.^[9][7]

• Pregnancy. Bisphosphonates are generally avoided in pregnancy; management of maternal osteoporosis in pregnancy is individualised. Fibrous dysplasia and osteogenesis imperfecta pregnancies need multidisciplinary input.
• Children. Several of these disorders are lethal or severe in infancy (osteogenesis imperfecta type II, infantile osteopetrosis, perinatal hypophosphatasia). Hypophosphatasia diagnosed in childhood may enter remission then relapse in adulthood.^[7]
• Older adults. Do not assume all low bone mass in older adults is osteoporosis; hypophosphatasia can present with low bone mineral density and normal or raised alkaline phosphatase after fracture.^[7]

• Plain radiography remains the most useful single test: osteosclerosis, ground-glass lesions, Erlenmeyer flask deformity and pseudofractures are all visible without advanced imaging.^[5][4]
• Basic biochemistry (alkaline phosphatase, calcium, phosphate, vitamin D) distinguishes many of these disorders and is inexpensive.^[7]
• Bisphosphonates (the backbone of osteoporosis care) should be given only after hypophosphatasia has been excluded, and teriparatide is usually unavailable.^[7][9]
• Surgical correction of stenosis or joint replacement and specialist genetics may require referral to centres with experience.

• Endocrinology osteoporosis topics (cross-check): pharmacologic management of osteoporosis in postmenopausal women (Endocrine Society).
• Endocrinology Paget disease of bone (cross-check): diagnosis and management of Paget's disease in adults.
• Musculoskeletal rheumatology: inflammatory arthritis and bone pain differential.
• Genetics: skeletal dysplasia counselling and inheritance patterns.
• Orthopaedic surgery: femoral neck fracture, atypical femoral fracture and hip arthroplasty.