PRINCIPLES OF ORTHOPAEDICS

World Health Organization definition
Metabolic bone disease
Jonathan Peters
Alastair Robertson
Charles Godavitarne
Benedict Rogers
Abstract
Metabolic bone disease encompasses a diverse group of disorders
associated with altered calcium and phosphorous homoeostasis.
Although many of these disorders are quite common, they may be diffi-
cult to distinguish on the basis of history, physical examination and im-
aging studies. In clinical practice, metabolic bone disease is often silent
until the patient presents with a fracture which is the ultimate complica-
tion of many metabolic bone disorders. However, other patients present
with a clinical history of back pain and non-specific radiological findings
of osteopenia. It is at this stage, that thorough understanding of these
diverse manifestations and an accurate diagnosis is crucial to provide
the best outcomes for patients with these potentially debilitating disor-
ders. This article aims to give a thorough and succinct review of more
relatively common of these diseases.
Keywords idiopathic transient osteoporosis of the hip (ITOH);
metabolic bone disease; osteomalacia; osteopetrosis; osteoporosis;
renal osteodystrophy; rickets
Introduction
Metabolic bone disease includes a diverse group of disorders of
skeletal homeostasis. Although many of these are relatively
common, they can be difficult to distinguish. A sound compre-
hension of the metabolic diseases that cause intrinsic biome-
chanical alterations and damage to the skeletal system is an
essential part of orthopaedic knowledge. This article will sys-
tematically review the pertinent facts of the more relatively
common of these diseases.
Conditions of bone mineral density
Osteoporosis
Osteoporosis is defined as an age-related decrease in bone mass
secondary to uncoupling of osteoclasteosteoblast activity, with
disruption of the bone micro-architecture.
Jonathan Peters BMBS BMedSci (Hons) MRCS (Eng) Core Surgical
Trainee, Royal Sussex County Hospital, Brighton, UK. Conflicts of
interest: none declared.
Alastair Robertson BMBS BMedSci (Hons) MRCS (Eng) Specialist
Orthopaedic Registrar, Royal Sussex County Hospital, Brighton, UK.
Conflicts of interest: none declared.
Charles Godavitarne BMBS BSc(Hons) MRCS(Eng) Specialist
Orthopaedic Registrar, Royal Sussex County Hospital, Brighton, UK.
Conflicts of interest: none declared.
Benedict Rogers MA (Oxon) Msc MRCGP DipIMC DipSEM FRCS (Orth)
Consultant Trauma and Orthopaedic Surgeon, Royal Sussex County
Hospital, Brighton, UK. Conflicts of interest: none declared.
ORTHOPAEDICS AND TRAUMA --:-
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 L2e4 lumbar vertebral density >2.5 standard deviations
(T score <2.5) below the peak bone mass of a 25-year-
old sex-matched individual.

Epidemiology:1
 Incidence: 20 million people worldwide have
osteoporosis
 Male:female ratio is 1:4
 Associated with fragility fractures
 Wrist fractures occur most commonly at age 50e60
years
 Vertebral fractures occur most commonly at age 60e70
years
 Hip fractures occur most commonly at age 70e80 years

Risk factors are listed in Table 1.

Histology
 Bone resorption is greater than bone formation:
e Cancellous bone: trabeculae are thinned and
decreased in number. Some are lost completely.
This loss of bony struts leaves adjacent areas un-
supported and therefore significantly weakened.
e Cortical bone: decreased size of osteons and
enlargement of marrow space. The cortices of long
bones become thinner with age, while the overall
bone diameter expands.

Management
 History: to include risk factors and symptoms
 Examination
 Blood tests:
e Full blood count, erythrocyte sedimentation rate
(ESR), biochemistry, thyroid function, bone profile
e Prostate-specific antigen, testosterone, gonadotro-
phin levels (men)
e Serum parathyroid hormone (hyperparathyroidism)
e Plasma electrophoresis (multiple myeloma)
e Urinary free cortisol (Cushing’s disease)
e Serum bone-specific alkaline phosphatase (osteo-
blast activity).
 Plain X-ray:
e Thinned cortices, loss of trabecular bone, kyphosis,
codfish vertebra
e >30% bone loss required to be seen on X-ray,
making it an insensitive test.
 DEXA scan (dual-energy X-ray absorptiometry):
- Measures bone mineral density commonly in lum-
bar spine or hip areas and compiles scores.

Treatment is outlined in Table 2.
Osteopetrosis (marble bone disease)
A group of bone disorders characterized by increased sclerosis
and loss of the medullary canal, caused by impaired osteoclast
function, leading to failure of bone resorption. This is associated
with a mutation the causes a loss of function of the carbonic
anhydrase II gene.

Histology
 Osteoclasts lack ruffled border required for effective
bone resorption
 Marrow spaces are filled with necrotic calcified cartilage
 Empty lacunae and plugging of Haversian canals2
1 Ó 2017 Published by Elsevier Ltd.
 PRINCIPLES OF ORTHOPAEDICS

Osteoporosis risk factors1 Treatment options for osteoporosis2

Lifestyle Bone loss Y Halt loss / Bone gain [
C Sedentary lifestyle C Phosphate C Calcium C Fluoride þ
C Caucasian women of European descent C Bisphosphonates C Vitamin D C Calcium
C Smokers C Alendronate C Vitamin D

C Low body mass index C Calcitonin C Calcitonin

C Low protein intake C Mild exercise C Extensive exercise

C Heavy drinkers (biomechanical- (biomechanical-

C Positive family history electrical coupling) electrical coupling)
C Premature menopause C Pamidronate

C Breastfeeders with low vitamin D diets C Raloxifene

C Tamoxifen

Medications
C Phenytoin therapy Table 2
C Reduces vitamin D metabolism
C Cytotoxic/antineoplastic drugs €nberg
 ‘Tarda’ (benign) form (also known as Albers-Scho
C Selective serotonin reuptake inhibitors (SSRIs) disease)
C Antiretroviral therapy e Autosomal dominant
C Cyclosporine, furosemide e generalized osteosclerosis
C Methotrexate e Radiograph: typical ‘rugger jersey’ spine4
C Omeprazole
Paget’s disease of bone (osteitis deformans)
C Unfractionated heparin and low-molecular-weight heparin
Figure 1 shows Paget’s disease of bone affecting the femur.
C Glucocorticoids

Epidemiology
 High prevalence in the UK and USA
Genetic polymorphisms
 Family history 15e30% cases
C Calcitonin receptor  No racial difference in incidence
C Oestrogen receptor-1  Slight male predominance
C Type 1 collagen a-1 chain (COL1A1)  Increased incidence HLA-DQwl
C Vitamin D receptor
Aetiology
C Low-density lipoprotein receptor-related protein (LRP5)  Likely viral (paramyxovirus) as osteoclasts contain
virus-like inclusion bodies causing abnormal function.
Diseases  Genetic predisposition: chromosome focus for familial
C Malabsorption syndromes expansile osteolysis
C Liver disease
Pathophysiology
C Hyperthyroidism  Increased osteoclast size and number, leading to raised
C Type 1 diabetes mellitus bone resorption
C Cancer  Following this, a compensatory increase in disorganized
C Chronic renal failure osteoblastic bone formation occurs
C Chronic obstructive pulmonary disease
C Rheumatoid arthritis
C Sarcoidosis

Table 1

Types
 Infantile (malignant) form
e Autosomal recessive (TCIRG1 gene mutations cause
about 50% of cases of autosomal recessive
osteopetrosis)3
e Most severe form
e Clinical features: aplastic anaemia,
hepatosplenomegaly
e Radiograph: ‘bone within a bone’ appearance
e Treatments:
e bone marrow transplantation can be lifesaving
e calcitriol  steroids can be helpful Figure 1 Paget’s disease of bone affecting the femur.

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Please cite this article in press as: Peters J, et al., Metabolic bone disease, Orthopaedics and Trauma (2017), http://dx.doi.org/10.1016/
j.mporth.2017.07.008
 PRINCIPLES OF ORTHOPAEDICS

 Three phases
Malignant sarcomatous change

e Lytic phase: intense osteoclastic bone resorption  1e6% of all patients with Paget’s
e Mixed phase: both osteoclastic resorption and  Up to 30 times increased risk of osteogenic sarcoma
osteoblastic formation occur in same area of bone.  Commonly diffuse, long-standing disease
This laying down of bone in chaotic fashion, leads  Prognosis very poor4
to relevant sclerotic and osteopenic areas
e Burn-out phase: dense mosaic pattern of bone, with Conditions of bone mineralization
minimal cellular activity
Rickets

Histology
Rickets is deficient or impaired mineralization of cartilage matrix
 Multiple resorbing and forming surfaces with charac-
(chondroid). Osteomalacia is the adult form occurring after
teristic mosaic appearance
physis closure, with impaired mineralization of cartilage matrix
 Chaotic process produces disorganized collagen fibrils,
(chondroid).
making the matrix brittle and susceptible to pathological

Orthopaedic manifestations
fractures
 Physeal cupping/widening and brittle bones

Diagnosis
 Ligamentous laxity
 Laboratory tests
 Long bone bowing
e High alkaline phosphatase (ALP)
 Skull flattening
e High acid phosphatase
Figure 2 illustrates rickets in a child.5
e High urine hydroxyproline and collagen-derived

Radiograph findings
cross-linked peptides (marker of collagen turnover)
 Physeal widening, metaphyseal cupping
 Clinical
 Looser’s zones (compression side of bone
e 95% asymptomatic
pseudofracture)
e Bone pain, worse at night and unrelated to activity
 Rachitic rosary (rib head prominence at osteochondral
e Deformity (long bone bowing, skull enlargement)
junction)
e Secondary osteoarthritis
 Bowing (commonly genu varum)
e Osteosarcoma

Classification
e Pathological fracture
 Familial hypophosphataemic (vitamin D-resistant)
e Vascular shunting, causing high-output cardiac
 Vitamin D-dependent (Type I þ II)
failure
 Vitamin D-deficient (nutritional)
e Nerve compression:
 Renal osteodystrophy
e Conductive hearing loss due to temporal bone
 Hypophosphatasia
enlargement

Familial hypophosphataemic rickets (vitamin D-resistant
e Spinal stenosis or cauda equine syndrome
rickets)
e Basilar invagination
 Commonest form of heritable rickets
 Radiographs
e Early:
e Lytic areas of bone
e Osteoporosis circumscripta of the skull
e Late:
e Thickened and sclerotic cortices
e Loss of bony architecture
e Widened, bowing bones
e Loss of corticomedullary differentiation
e Fissure fracture on convex side of long bones
 Bone scintigraphy
e Hot spots seen in active areas of Paget’s disease
e Only 65% bone scan lesions visible on X-ray

Treatment
 Indications for medical treatment
e Bone deformity and pain
e Nerve entrapment of spinal stenosis due to Paget’s
e Prevention of fracture
e Secondary high output cardiac failure
 Bisphosphonates: taken 2e3 months prior to elective
surgery
 Open reduction internal fixation of fractures
 Osteotomy/arthroplasty for secondary joint Figure 2 Radiograph illustrating rickets in a child.5 Case courtesy of Dr
osteoarthritis Angela Byrne, Radiopaedia.org, rID: 8116.

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 PRINCIPLES OF ORTHOPAEDICS

 Caused by inability of renal tubules to absorb e Type I: joint deformity/pain, muscle weakness,
phosphate growth failure, hypocalcaemic seizures/fractures
 X-linked dominant e Type II: Same as type I teeth  hypoplasia or severe
 Clinical findings dental caries
e tibial bowing, secondary to widened tibia physis  Treatment
 Investigations e Type I: 1,25-(OH)2-vitamin D
e Low phosphorus e Type II: vitamin D þ calcium
e High ALP Biochemical markers of rickets are shown in Table 3.
e Normal/low calcium
 Treatment Osteomalacia
e Medical: Defective mineralization resulting in excessive unmineralised
e calcitriol (standard therapy) osteoid formation. Unlike osteoporosis this is a qualitative pro-
e phosphate replacement cess, not quantitative.
e Surgical:
Risk factors
e corrective surgery of tibial bowing  Vitamin D-deficient diets

Vitamin D deficiency rickets (nutritional)  Malabsorption (e.g. coeliac disease)
 Associated with reduced dietary intake of vitamin D  Hypophosphataemia
 Clinical findings  Chronic alcoholism
e Rachitic rosary  Drugs
e Knee bowing - Associated with vitamin D deficiency
e Codfish vertebrae - Affecting phosphate haemostasis
e Pathological fractures - Affecting bone mineralization
e Muscle hypotonia
Clinical findings
 Investigations  Bone/muscle pain
e Low/normal calcium  Fractures of vertebrae, long bones and ribs
e Low phosphate  Proximal muscle weakness
e High ALP  Waddling gait
e High PTH
Imaging
e Low vitamin D  Bone scan
 Treatment e Increased activity
e Vitamin D  Radiographs

Hereditary vitamin D-dependent rickets (Type I þ II) e Looser’s zones (insufficiency fractures)
 Similar clinical features to vitamin D-deficient rickets but e Trefoil pelvis
more severe e Biconcave vertebral bodies7
 Autosomal recessive
Treatment
 Pathophysiology  Oral vitamin D þ treat underlying cause
e Type I: defect in renal 25-(OH)-vitamin D1 a-hy-
droxylase prevents conversion of the inactive form Renal osteodystrophy
of vitamin D to the active form A group of disorders of bone mineral metabolism, seen in chronic
e Type II: defect in receptor for 1,25-(OH)2-vitamin D renal failure.
e TI is distinguished from TII by elevated levels of
Pathophysiology
1,25-(OH)2-vitamin D  Hypocalcaemia, hyperparathyroidism and secondary
 Clinical features hyperphosphataemia

Biochemical markers for types of rickets6

Condition Genetics Ca Phos ALP PTH VitD 1,25(OH)VitD

Vitamin D-resistant rickets X-linked dominant - Y [ -

(hypophosphataemic)
Vitamin D deficiency rickets (nutritional) Nutritional -Y Y [ [ Y
Type I vitamin D-dependent Autosomal recessive Y Y [ [ YY
Type II vitamin D-dependent Autosomal recessive Y Y [ [[
Hypophosphatasia Autosomal recessive [ [ YY - -
Renal osteodystrophy Renal disease Y [ [ [
Hyperparathyroidism 90% adenoma [ Y [ [

Ca, calcium; Phos, phosphate; ALP, alkaline phosphatase; PTH, parathyroid hormone; VitD, vitamin D.

Table 3

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 PRINCIPLES OF ORTHOPAEDICS

e Damaged kidney unable to convert vitamin D3 to

the active form, calcitriol, due to phosphate reten-
tion (hyperphosphataemia)

Classification
 Low turnover renal bone disease (normal PTH)
e Lack of secondary hyperparathyroidism
e Normal PTH levels with bone lesions marked by
low bone formation levels
e Raised deposition of aluminium into bone affects
mineralization
 High turnover renal bone disease (high PTH)
e Secondary hyperparathyroidism as a result of
chronically elevated phosphate8

Clinical findings
 Weakness
 Bone pain
 Pathological fractures
 Hypocalcaemic symptoms

Orthopaedic manifestations Figure 3 Coronal MRI short T1 inversion recovery (STIR) illustrating
 avascular necrosis bone marrow oedema pattern of idiopathic transient osteoporosis of
the hip.9 Case courtesy of Dr Laughlin Dawes, Radiopaedia.org, rID:
 Growth retardation (children), osteomalacia (adults)
35805.
 Carpal tunnel syndrome (amyloid deposits)
 Pathological fracture (brown tumours and amyloid
deposits) e X-ray findings in femoral head and neck occur 4e8
 Osteomyelitis and septic arthritis weeks after clinical signs

Imaging e Joint effusion
 Radiographs e Joint space is preserved
e Looser’s zones  Bone scan
e Brown tumour e Raised femoral head uptake
e Widened growth plate (children)
Treatment
e Osteosclerosis  Avoidance of weight bearing
 CT  Symptomatic10
e Osseous resorption

Treatment Conclusion
 Treat underlying renal condition
Overall, metabolic bones diseases remain a major challenge for
Idiopathic transient osteoporosis of the hip (ITOH) patients and physicians, despite the advances in medicine over
See Figure 3 for a coronal MRI short T1 inversion recovery (STIR) the past few decades. These conditions can be difficult to di-
illustrating bone marrow oedema pattern of ITOH. agnose and treat. To orthopaedic surgeons, metabolic bone dis-
Local hyperaemia and impaired venous return with raised ease is often silent until the patients present with deformities or
intramedullary pressure and marrow oedema. Resolves sponta- fractures. Other patients, however, present with a history of bone
neously in 6e8 months. pain or non-specific radiological findings. It is at this stage that

Epidemiology thorough understanding of these diverse manifestations and an
 Location accurate diagnosis are crucial to provide the best outcomes for
e Unilateral patients with these potentially debilitating disorders.11,12 A
 Demographics
e Males > females (3:1)
e Middle-aged men REFERENCES

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j.mporth.2017.07.008
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