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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, ...

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