Osteoporosis (Secondary)


Article Author:
Kavitha Ganesan


Article Editor:
Douglas Roane


Editors In Chief:
Timothy Craig
Yoon Kim
Robert Hostoffer


Managing Editors:
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Scott Dulebohn
Sobhan Daneshfar
William Gossman
Pritesh Sheth
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Richard Ciresi
Hajira Basit
Phillip Hynes


Updated:
3/2/2019 8:20:36 AM

Introduction

Osteoporosis is a bone disorder which is characterized by a decrease in bone strength, resulting from reduced bone mineral density, microarchitectural disruption, and skeletal fragility, thereby causing an increased risk of fracture. Secondary osteoporosis, which occurs due to the presence of underlying disease or medications, can also lead to low bone mass, resulting in increased risk of fractures.[1][2][3]

Etiology

The most common causes of secondary osteoporosis include:

  1. Endocrinopathies (hyperthyroidism, hypogonadism, hypopituitarism, primary hyperparathyroidism, diabetes mellitus, eating disorders, growth hormone deficiency and acromegaly)
  2. Gastrointestinal disorders (celiac disease, inflammatory bowel disease, gastric bypass surgery, hemochromatosis and chronic liver diseases)
  3. Hematological disorders (monoclonal gammopathy of uncertain significance, multiple myeloma, systemic mastocytosis, beta thalassemia major)
  4. Autoimmune Disorders (rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, multiple sclerosis) 
  5. Renal disease (renal tubular acidosis, chronic kidney disease)
  6. Medications (corticosteroids, thyroid hormone, aromatase inhibitors, medroxyprogesterone acetate, GnRH agonists and antagonists, selective serotonin reuptake inhibitors, carbamazepine, phenytoin, cyclosporine, tacrolimus, antiretroviral therapy, lithium, heparin, furosemide and proton pump inhibitors).[4][5][6]

Epidemiology

The Literature indicates that around 30% of women in post-menopausal age and 50% to 80% of men are reported to have factors contributing to secondary osteoporosis. Studies based on United States population indicate that about 20 to 25 million people might be affected by osteoporosis. Roughly two million fractures per year can be attributed to osteoporosis.[7][8]

Pathophysiology

Bone remodeling involves three consecutive phases: osteoclast-mediated bone resorption, reversal phase in which osteoblast precursor cells appears on the bone surface, and finally, osteoblast-mediated bone formation and mineralization. Major systemic regulators of bone remodeling include parathyroid hormone, vitamin D, glucocorticoids, growth hormone, thyroid hormones and sex hormones. Cytokines such as interleukin-1, interleukin-6, tumor necrosis factor (TNF), and bone morphogenic protein stimulate the osteoclast formation. However, interleukin-4, transforming factor-beta and gamma-interferon inhibits the formation and activity of osteoclasts. When parathyroid hormones stimulate osteoblasts, there is an upregulation of expression of RANKL which is present on osteoblasts. RANKL binds to RANK present on osteoclasts and promotes osteoclast differentiation, thereby promoting bone resorption. Wnt signaling promotes differentiation of osteoblast precursor cells into mature osteoblasts, promoting bone formation.

Secondary causes of osteoporosis have differing pathophysiology, depending on the condition. For example, glucocorticoids cause inhibition of osteoblast replication and differentiation, increased osteoblast apoptosis and enhanced bone resorption. They also lead to induction of RANK ligand and macrophage stimulating factor. Glucocorticoids also cause a decrease in growth hormone secretion and inhibition of gonadotropin release, which in turn leads to a reduction of estrogen and testosterone production, thus causing hypogonadism as well as bone loss. Glucocorticoids also inhibit calcium absorption mediated by vitamin D, cause a decrease in serum calcium, and cause an increase in the serum levels of parathyroid hormone.

Inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus, on the other hand, cause a systemic release of inflammatory cytokines such as IL-1, IL-6, and TNF-alpha, thus promoting osteoclastic activity. Vitamin D deficiency occurs in patients with SLE with avoidance sun exposure and can lead to bone loss. Ankylosing spondylitis causes osteoclast-mediated bone resorption and dysregulated bone formation by RANK ligand induction with an increase in TNF-alpha and decrease in Wnt signaling. Hyperthyroidism causes increased in bone turnover, with shortening and uncoupling of the bone remodeling cycle. Primary hyperparathyroidism causes an increase in RANK ligand expression by cells of the osteoblast precursors thereby increasing osteoclast-mediated bone resorption.

Celiac disease is associated with a decrease in calcium and vitamin D absorption and an increase in the levels of TNF-alpha, IL-1, and IL-6, which might be responsible for an increase in bone resorption and bone metabolism alteration. Hypogonadism in men and women results in a decrease in circulating testosterone and estradiol, leading to inhibition of proliferation and differentiation of osteoblasts and inhibition of recruitment and signaling of osteoclasts resulting in increased bone resorption.[9][10]

Histopathology

Essential compounds such as calcium, phosphate, sodium, and magnesium are stored mainly in bone tissue. Histopathologic changes of secondary osteoporosis include trabecular and sinus capillary disorganization, enlarged marrow spaces, fibroblast proliferation, loss of trabeculae, and thinning of the outer supportive cortex which leads to reduced bone mass.

History and Physical

Osteoporosis does not show any clinical manifestations until a fracture occurs, which most commonly occur in the spine, hips, and forearm. Other clinical manifestations include height loss, thoracic kyphosis, and backache with varying degrees of severity.  However, many vertebral compression fractures are asymptomatic. A careful history and physical exam are important when treating or screening patients with/for secondary causes of osteoporosis.

Evaluation

Evaluation of secondary osteoporosis may include:

  • Complete blood count (CBC)
  • Complete metabolic panel (CMP)
  • Serum testosterone
  • Estradiol
  • LH and prolactin
  • Serum ferritin
  • Calcium
  • Phosphate
  • Albumin
  • Alkaline phosphatase
  • 25-hydroxyvitamin D
  • Twenty-four-hour urine calcium
  • Serum  and urine protein electrophoresis
  • Parathyroid hormone
  • Thyroid-stimulating hormone (TSH)
  • Tissue transglutaminase antibodies
  • Dexamethasone suppression test or a 24-hour urinary free cortisol
  • Bone resorption and formation markers
  • X-rays (lumbar and thoracic spine) to look for vertebral fractures.

The diagnosis of osteoporosis can be made by dual-energy x-ray absorptiometry (DXA), if the T-score less than or equal to -2.5 or if the individual has had low-trauma fractures.[11][1][12]

Treatment / Management

The effective treatment of secondary osteoporosis should, first and foremost, address any underlying reversible causes. This would include vitamin D replacement in deficient individuals, testosterone replacement in hypogonadal men, lowering the dose of corticosteroids, if possible, in steroid-induced osteoporosis, and correction of metabolic disorders or malabsorption if possible. FDA-approved indications for the treatment of glucocorticoid-induced osteoporosis are oral bisphosphonates, intravenous bisphosphonates, and teriparatide.[13][14][15]

Weight-bearing exercise is helpful in stimulating the bone formation. There is an association between reduced physical activity and bone fracture in elderly men along with the positive influence of exercise in women who had osteoporosis. In addition, smoking cessation and avoidance of alcohol intake should be encouraged.

Once reversible causes are addressed, if pharmacologic therapy is needed, bisphosphonates such as alendronate, zoledronic acid, ibandronate and risedronate are often used in patients with adequate renal function (GFR greater than 30ml/min to -35 ml/min). Before starting bisphosphonates, vitamin D should be replaced, and, during treatment, adequate intake of calcium and vitamin D intake is important.

Teriparatide is a recombinant human parathyroid hormone which is given as a 20 micrograms daily subcutaneous injection. Teriparatide is not the first line drug line drug used in the treatment of secondary osteoporosis, but it is used in glucocorticoid-induced osteoporosis in patients who have severe osteoporosis, those who are unable to tolerate or have contraindications to bisphosphonates, or those who have failed other modalities of treatment.

Denosumab is a human monoclonal antibody, and it is given as 60 mg subcutaneous injection for the treatment of osteoporosis secondary to malignancies, especially prostate cancer or other malignancies with metastasis to the bone.

Differential Diagnosis

Differential diagnosis of secondary osteoporosis includes osteomalacia, renal osteodystrophy, lymphoma, mastocytosis, sickle cell anemia, multiple myeloma, Paget disease, osteonecrosis, infection, homocystinuria, scurvy, homocysteinemia, and metastatic bone disease.

Prognosis

Patients with secondary osteoporosis have a mild increase in overall morbidity due to the vertebral and hip fractures and its complications, such as pulmonary embolism, deep vein thrombosis, and pneumonia. Compression fractures may also lead to reduced quality of life, chronic neurogenic pain, impaired ventilation, and deformities of the spine.

Pearls and Other Issues

Increased awareness in avoiding the risk factors of secondary osteoporosis and increased vigilance in the workup for the causes of secondary osteoporosis and its treatment are essential to improve bone health in all patients.

Enhancing Healthcare Team Outcomes

Today a multidisciplinary approach is being recommended to establish measures to prevent fractures in patients with osteoporosis. The multidisciplinary team should include physicians, nurses, physical and occupation therapists, social workers and other allied healthcare workers like the pharmacist. Evidence shows that a multidisciplinary approach can help improve post-fracture osteoporosis by early identification of patients, documenting their disease state, and making appropriate referrals. Such an approach has been shown to be cost-effective in avoiding the cost of secondary fractures. In addition, patient referral to the endocrinologist, nurse, geriatrician or rheumatologist can increase the number of patients who get treated with medications and thus, improve outcomes. Unfortunately, there are still a significant number of patients who do not get such treatment because they are lost to follow up. Today, prior to the discharge of a patient with a fracture, the nurse should ensure that the patient has the appropriate referrals, resources, and a dedicated social worker to follow up with. [16][17][18](Level III)

Outcomes

There continue to be significant deficiencies in the healthcare system with respect to communication and follow up of patients with fractures. Although there is a clear focus on preventing fractures and falls, this has not translated into better care for patients with osteoporosis. Thus, today many healthcare institutions have created a dedicated fracture liaison nurse to ensure that no patient with a fracture is missed. Without dedicated personnel, secondary prevention of osteoporosis still remains a major challenge in the US. [19][20](Level III) 


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Osteoporosis (Secondary) - Questions

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Which of the following statements correctly describes the mechanism of steroid hormone-induced osteoporosis?



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Which of the following drugs can cause osteoporosis?



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Which of the following drugs is not associated with increased risk of osteoporosis?



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Which central nervous system disorder does not contribute to osteoporosis?



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A 46-year old female who has been treated with high dose corticosteroids for sarcoidosis comes for a follow-up visit. The latest DEXA scan reveals a T score of -2.5. What treatment should she be offered?



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A female with systemic lupus erythematosus is started on high dose corticosteroids. According to the guidelines by the American College of Rheumatology, when should the initial risk for fracture be assessed in such patients?



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In men who are treated for long periods with glucocorticoids where is the majority of the bone loss is seen?



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Which of the following is not helpful in postmenopausal osteoporosis?



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Which of the following is not used in the treatment of osteoporosis or osteopenia?



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Which of the following is the responsible for osteoporosis in patients with thyrotoxicosis?



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Osteoporosis (Secondary) - References

References

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