Key Points
Disease summary:
Osteoporosis is a common disease characterized by low bone mass, microarchitectural disruption, and skeletal fragility resulting in an increased risk for fracture. Osteoporosis results from the interactions of multiple genetic loci, physiologic changes across the lifecycle, and disorders that secondarily influence bone mass and strength as well as environmental factors.
Primary osteoporosis includes juvenile osteoporosis (affects children or young adults with normal gonadal function), type 1 osteoporosis (postmenopausal women), or type 2 (age-associated or senile) osteoporosis.
Type 1 osteoporosis develops in postmenopausal women, typically aged 50 to 65 years, and is characterized by a phase of accelerated loss of bone mass especially from trabecular sites with an increased risk of fractures of the distal forearm and vertebral bodies.
Type 2 osteoporosis occurs in men and women older than 70 years and represents bone loss associated with aging and other factors such as nutritional deficiencies. Fractures usually occur in cortical and trabecular bone, including hip, wrist, and vertebral fractures.
Secondary osteoporosis refers to bone loss that occurs as a result of an underlying disease, hormone deficiency, or medication (Table 65-1). Many patients have overlap in these designations as well. For example, elderly postmenopausal women may have vitamin D deficiency in addition to chronic estrogen deficiency.
Differential diagnosis:
This includes renal osteodystrophy, osteomalacia, and many secondary causes for loss of bone mass including those in Table 65-1.
Monogenic forms:
There are several monogenic causes of osteoporosis as described in Table 65-2. There is no single genetic etiology for postmenopausal or for senile osteoporosis. Bone mineral density (BMD) is likely a complex polygenic trait.
Family history:
Studies on the genetics of osteoporosis have shown that BMD and other skeletal characteristics such as the ultrasound properties of bone, skeletal geometry, and bone turnover have significant heritable components. Heredity and genetics may determine as much as 60% to 70% of an individual’s peak bone mass. Affected first-degree relatives and a strong family history confer a higher risk for osteoporosis. It is not clear, however, to what extent the relative risk of osteoporosis is increased in an individual with an affected first-degree relative.
Twin studies:
Twin studies have demonstrated that BMD is highly heritable with estimates from a cohort study in the United Kingdom demonstrating 50% to 80% heritability for BMD; another study showed heritability at the lumbar spine was 78% and at the femoral neck was 84%. These figures are consistent with other twin studies.
Environmental factors:
Multiple lifestyle factors have been shown to contribute to the pathogenesis of osteoporosis (Tables 65-1 and 65-3).
Genome-wide associations:
Although previous linkage and candidate gene studies have provided few replicated loci for osteoporosis, genome-wide association studies (GWAS) have produced multiple candidate genes. To date, several GWAS for osteoporosis and related traits have been conducted.
Pharmacogenetics:
Genetic variants of osteoporosis that may be more or less responsive to certain forms of therapy have not been identified thus far. As a result, pharmacogenetics does not currently play a role in selecting the treatment of osteoporosis.
| Lifestyle factors | Systemic mastocytosis |
| Alcohol abuse | Thalassemia |
| Chronic low calcium intake | Rheumatologic and autoimmune diseases |
| Inadequate physical activity and immobilization | Ankylosing spondylitis |
| Vitamin D insufficiency | Systemic lupus |
| Tobacco use | Rheumatoid arthritis |
| Genetic disorders (discussed in this chapter) | Central nervous system disorders |
| Hypogonadism | Parkinson disease |
| Androgen insensitivity | Stroke |
| Hyperprolactinemia | Multiple sclerosis |
| Premature ovarian failure and menopause | Spinal cord injury |
| Anorexia nervosa and bulimia | Miscellaneous conditions and diseases |
| Turner syndrome | Post-organ transplantation bone disease |
| Klinefelter syndrome | End stage renal disease |
| Hypopituitarism | Chronic metabolic acidosis |
| Endocrine disorders | Hypercalciuria |
| Hypercortisolism | Weight loss |
| Type 1 and 2 diabetes mellitus | Chronic obstructive lung disease |
| Primary hyperparathyroidism | Medications |
| Thyrotoxicosis | Aluminum (in antacids) |
| Gastrointestinal disorders | Cyclosporine A and tacrolimus |
| Celiac disease | Proton pump inhibitors |
| Inflammatory bowel disease | Heparin |
| Primary biliary cirrhosis | Depo-medroxyprogesterone |
| Malabsorption | Glucocorticoids (≥ 5 mg/d prednisone or equivalent for ≥ 3 months) |
| Chronic pancreatic disease | Aromatase inhibitors |
| Hematologic disorders | Gonadotropin releasing hormone antagonists and agonists |
| Multiple myeloma | Thiazolidinediones |
| Monoclonal gammopathies | Thyroid hormones (in excess) |
| Sickle cell disease |
| Syndrome | Gene Name & Symbol | Associated Findings | Inheritance |
|---|---|---|---|
| Cystic fibrosis | Cystic fibrosis transmembrane conductance regulator (CFTR) | Multisystem disease affecting primarily the lungs but also the digestive, endocrine, reproductive systems. Osteoporosis is mainly secondary to pancreatic insufficiency leading to fat malabsorption and vitamin D deficiency | Autosomal recessive |
| Ehlers-Danlos syndrome | Many, but most commonly caused by defects in the fibrous proteins: COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, TNXB or the enzymes: ADAMTS2, PLOD1a | Group of inherited connective tissue disorders caused by a defect in the synthesis of collagen type I or III | Various (see below) |
| *Types I and II (classical) | COL5A1, COL5A2, COL1A1 | Affects type I and V collagen. Type 1 presents with severe skin involvement and type 2 presents with mild-moderate skin involvement | Autosomal dominant |
| *Type III and due to tenascin X deficiency (hypermobility) | COL3A1, TNXB | Characterized by extreme hypermobility | Autosomal recessive or autosomal dominant |
| *Type IV (vascular) | COL3A1 | Defect in type III collagen synthesis. One of the more serious types of EDS as blood vessels and organs are more prone to tearing (rupture). Many patients have characteristic facial appearance (large eyes, small chin, thin nose & lips, lobeless ears), small stature with slim build with thin, pale, translucent skin | Autosomal dominant |
| *Type VI (kyphoscoliosis) | PLOD1 | Deficiency of enzyme lysyl hydroxylase. Progressive curvature of the spine (scoliosis), fragile eyes, severe muscle weakness | Autosomal recessive |
| *Types VIIA & VIIB (arthrochalasis) | COL1A1, COL1A2 | Affects type I collagen. Very loose joints, dislocations involving both hips. | Autosomal dominant |
| *Type VIIC (dermatosparaxis) | ADAMTS2 | Extremely fragile and sagging skin | Autosomal recessive |
| Marfan syndrome | Fibrillin-1 gene (FBN1); a minority have mutations in the TGF-beta receptor 2 (TGFBR2) or TGF-beta receptor 1 (TGFBR1) gene | Characterized by aortic root dilatation, ectopia lentis, joint hypermobility, lumbosacral dural ectasia | Autosomal dominant |
| Gaucher disease (type 1) | Glucocerebrosidase gene (GBA) | Characterized by splenomegaly, hepatomegaly, anemia, thrombocytopenia, osteopenia and pathologic fractures, bone pain, growth retardation | Autosomal recessive |
| Hemochromatosis | Majority have HFE gene mutation. Other types include mutations in hemojuvelin, hepcidin, transferrin receptor 2, ferroportin 1, H-ferritin, L-ferritin | Mutations in the HFE gene cause increased intestinal iron absorption. The clinical manifestations are related to excess iron deposition in tissues such as the liver, heart, pancreas, pituitary (leading to hypogonadism which causes low bone mass). | Autosomal recessive |
| Homocystinuria | Cystathionine beta synthase gene (CBS). May also involve the MTHFR, MTR, MTRR, MMADHC genes (play a role in converting homocysteine to methionine) | Increased risk of mental retardation, nearsightedness, scoliosis, megaloblastic anemia, osteoporosis. | Autosomal recessive |
| Osteogenesis imperfecta | Most have autosomal dominant mutation in COL1A1 or COL1A2. In 10% of cases, patients have alternate mutations (usually autosomal recessive): FK506-binding protein 10 (FKBP10 or FKBP65 gene), CRTAP, LEPRE1, PPIB, SERPINH1, SERPINF1, SP7/OSX | 9 subtypes identified. Characterized by multiple fractures, short stature, occasionally blue sclerae and hearing loss.2 | Mixed |
| Osteoporosis- pseudoglioma syndrome | Low-density lipoprotein receptor-related protein 5 gene (LRP5) | Characterized by congenital or infancy-onset visual loss and skeletal fragility recognized during childhood. | Autosomal Recessive |
| Neurofibromatosis type 1 | Neurofibromin (NF1) | Café-au-lait macules, neurofibromas, freckling in the axillary or inguinal regions, optic glioma, Lisch nodules (iris hamartomas), bony lesions and osteoporosis | Autosomal Dominant |
| Menkes steely hair syndrome | ATPase, Cu++ transporting, alpha polypeptide gene (ATP7A) | Inability to regulate copper levels in the body. Mutations in ATP7A gene result in poor distribution of copper to the body’s cells, causing accumulation in some tissues (small intestine & kidney) while other tissues (brain) have unusually low levels of copper. Those affected are characterized by sparse, kinky hair, failure to thrive and deterioration of the nervous system as well as osteoporosis. Children often do not live past age 3. | X-linked recessive |
| Age > 50 years |
| Female sex |
| Caucasian or Asian ethnicity |
| Family history of osteoporosis |
| Thin build or small stature (eg, body weight <58 kg or 127 lb) |
| Amenorrhea |
| Late menarche |
| Early menopause |
| Postmenopausal state |
| Physical inactivity or immobilization |
| Use of medications (such as anticonvulsants, corticosteroids, thyroid hormone supplementation, heparin, chemotherapeutic agents, androgen deprivation therapy) |
| Alcohol and tobacco use |
| Androgen or estrogen deficiency |
| Calcium or vitamin D deficiency |
Diagnostic Criteria and Clinical Characteristics
The World Health Organization (WHO) has provided a densitometric definition of osteoporosis for postmenopausal women based on dual-energy x-ray absorptiometry (DXA) measurements of BMD.
Normal BMD is characterized by a value above 1 standard deviation below the reference mean for young adult females (T-score ≥−1 SD).
Low bone mass or osteopenia is characterized by a value greater than 1 but less than 2.5 standard deviations below the young adult female reference mean (T-score <−1 and >−2.5 SD).
Osteoporosis is characterized by a value 2.5 standard deviations or more below the young adult female reference mean (T-score ≤−2.5).
Severe osteoporosis is characterized by a value greater than 2.5 standard deviations below the young adult female reference mean in the presence of one or more fragility fractures.
In premenopausal women, men less than 50 years of age and children, the WHO BMD diagnostic classification should not be applied. In these groups, the diagnosis of osteoporosis should not be made on the basis of densitometric criteria alone. The International Society for Clinical Densitometry (ISCD) recommends that instead of T-scores, ethnic or race adjusted Z-scores should be used, with Z-scores of −2 or lower defined as either “low BMD for chronologic age” or “below the expected range for age.”
The relative risk of fracture increases as BMD decreases.
Fragility fractures are defined as fractures that occur following a fall from standing height or less or with minimal to no trauma.
