Secondary Osteoporosis

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Continuing Education Activity

Osteoporosis is a bone disorder that 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 an increased risk of fractures. The most common causes of secondary osteoporosis include endocrinopathies, gastrointestinal disorders, hematological disorders, autoimmune disorders, renal disease, and medications. This activity highlight the role of the interprofessional team in the assessment and management of patients with secondary osteoporosis.

Objectives:

  • Outline the causes of secondary osteoporosis.
  • Describe the pathophysiology of secondary osteoporosis.
  • Summarize the treatment options for secondary osteoporosis.
  • Review the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by secondary osteoporosis.

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

There are several common causes of secondary osteoporosis.[4] These include:

  1. Endocrinopathies (hyperthyroidism, Cushing syndrome, 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, HIV)
  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).[5][6][7]

Epidemiology

The Literature indicates that around 30% of women in post-menopausal age and 50% to 80% of men are reported to have additional factors contributing to secondary osteoporosis.[8][9] Studies based on the United States population indicate that about 20 to 25 million people might be affected by osteoporosis.[10] Roughly two million fractures per year can be attributed to osteoporosis.[11][12]

Pathophysiology

Bone remodeling involves three consecutive phases: osteoclast-mediated bone resorption, reversal phase in which osteoblast precursor cells appear on the bone surface, and finally, osteoblast-mediated bone formation and mineralization. Major system 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 osteoclast formation. However, interleukin-4, transforming factor-beta, and gamma-interferon inhibit the formation and activity of osteoclasts. When parathyroid hormones stimulate osteoblasts, there is an upregulation of the expression of RANKL, which is present in osteoblasts. RANKL binds to RANK that is present on osteoclasts and promotes osteoclast differentiation, thereby promoting bone resorption. Wnt signaling promotes the differentiation of osteoblast precursor cells into mature osteoblasts, promoting bone formation.[13]

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.[8] They also lead to the induction of RANK ligand and macrophage-stimulating factors. 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 that causes bone loss. Additionally, glucocorticoids may inhibit calcium absorption mediated by vitamin D, causing a decrease in serum calcium and a subsequent increase in the serum levels of parathyroid hormone.

Inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus (SLE), 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 of sun exposure and can lead to bone loss. Ankylosing spondylitis causes osteoclast-mediated bone resorption and dysregulated bone formation by RANK ligand induction with increased TNF-alpha and decreased Wnt signaling. Hyperthyroidism causes an increase 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.[14][15]

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 reduces bone mass.

History and Physical

Osteoporosis is a silent disease that does not show any clinical manifestations until a fracture occurs, most commonly in the spine, hips, or 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 for secondary causes of osteoporosis. Men are also affected by secondary osteoporosis, not just women. In a recent study, it was shown that men might be affected by secondary causes of osteoporosis more frequently than women.[16][17]

Evaluation

Evaluation of secondary osteoporosis may include:

  • Complete blood count (CBC)
  • Comprehensive metabolic panel (CMP)
  • Serum testosterone (in men)
  • Estradiol (in women)
  • LH and prolactin
  • Serum ferritin
  • Calcium
  • Phosphate
  • Albumin
  • Alkaline phosphatase
  • 25-hydroxyvitamin D
  • 24-hour urine calcium
  • Serum and urine protein electrophoresis
  • Parathyroid hormone, intact (PTH)
  • 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 is less than or equal to -2.5 or if the individual has had low-trauma fractures.[18][1][19] Treatment decisions can also be based on FRAX scores that calculate the 10-year risk for major osteoporotic fracture as well as the 10-year risk of hip fracture.[20] The assessment of the trabecular bone score (TBS), another way of looking into bone microarchitecture, can also help evaluate the fracture risk, especially in cases of normal bone mass. One of the most indicative examples would be diabetes, where patients fracture their bones while they are shown to have higher bone mass (as measured with a DXA scan) but lower TBS scores.[21]

Treatment / Management

The effective treatment of secondary osteoporosis should, first and foremost, address any underlying reversible causes.[22] This should include vitamin D replacement in deficient individuals[23], testosterone replacement in hypogonadal men, lowering to the minimal needed 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.[24][25][26][27]

Weight-bearing exercise helps stimulate bone formation. There is an association between reduced physical activity and bone fracture in older 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 30-35ml/min). Before starting bisphosphonates, vitamin D should be replaced, and adequate calcium and vitamin D intake should be provided during the treatment.

Teriparatide is a recombinant human parathyroid hormone that is given as a 20 mcg daily subcutaneous injection. Teriparatide is not the first-line drug used in the treatment of secondary osteoporosis, but it is used in glucocorticoid-induced osteoporosis in patients with severe osteoporosis, those who are unable to tolerate or have contraindications to bisphosphonates, or those who have failed other modalities of treatment. Abaloparatide is a parathyroid hormone-related peptide molecule that has also been shown to have an anabolic effect and stimulate bone formation.[28] It is given as an 80 mg daily subcutaneous injection as well, and it is approved for use in women with osteoporosis but not in men.

Denosumab is a human monoclonal antibody given as a 60 mg subcutaneous injection to treat osteoporosis due to secondary causes. It has been proven effective in treating bone loss due 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 vertebral and hip fractures and their 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 spine deformities.

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.[29]

Enhancing Healthcare Team Outcomes

Today an interprofessional team approach is being recommended to establish measures to prevent fractures in patients with osteoporosis. This interprofessional team should include clinicians (MDs, DOs, NPs, and PAs), nurses, physical and occupational therapists,  pharmacists, and other allied healthcare workers such as social workers. Evidence shows that an interprofessional 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, geriatrician, or rheumatologist can increase the number of patients treated with medications and, thus, improve outcomes. Unfortunately, there is 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 with whom they can follow up.[30][31][32] [Level 3]

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.[29][22] Without dedicated personnel, secondary prevention of osteoporosis remains a major challenge in the US.[33][34] [Level 3]


Article Details

Article Author

Kavitha Ganesan

Article Author

Jagmohan S. Jandu

Article Author

Catherine Anastasopoulou

Article Author

Sana Ahsun

Article Editor:

Douglas Roane

Updated:

10/19/2022 12:03:39 PM

References

[1]

Czerwiński E,Czubak J,Synder M,Warzecha M,Berwecka M, Contemporary Management of Osteoporotic Fractures. Ortopedia, traumatologia, rehabilitacja. 2018 Apr 16     [PubMed PMID: 30152776]

[2]

Barton DW,Behrend CJ,Carmouche JJ, Rates of osteoporosis screening and treatment following vertebral fracture. The spine journal : official journal of the North American Spine Society. 2019 Mar     [PubMed PMID: 30142455]

[3]

Di Iorgi N,Maruca K,Patti G,Mora S, Update on bone density measurements and their interpretation in children and adolescents. Best practice & research. Clinical endocrinology & metabolism. 2018 Aug     [PubMed PMID: 30086870]

[4]

Sobh MM,Abdalbary M,Elnagar S,Nagy E,Elshabrawy N,Abdelsalam M,Asadipooya K,El-Husseini A, Secondary Osteoporosis and Metabolic Bone Diseases. Journal of clinical medicine. 2022 Apr 24     [PubMed PMID: 35566509]

[5]

Kempisty A,Lewandowska A,Kuś J, [Disturbances of calcium metabolism and vitamin D supplementation in sarcoidosis - two-way street]. Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego. 2018 Mar 27     [PubMed PMID: 29601566]

[6]

Wool NK,Wilson S,Chong AC,Dart BR, Bone Health Improvement Protocol. Kansas journal of medicine. 2017 Aug     [PubMed PMID: 29472972]

[7]

Lüftner D,Niepel D,Steger GG, Therapeutic approaches for protecting bone health in patients with breast cancer. Breast (Edinburgh, Scotland). 2018 Feb     [PubMed PMID: 29073497]

[8]

Kobza AO,Herman D,Papaioannou A,Lau AN,Adachi JD, Understanding and Managing Corticosteroid-Induced Osteoporosis. Open access rheumatology : research and reviews. 2021     [PubMed PMID: 34239333]

[9]

Ebeling PR,Nguyen HH,Aleksova J,Vincent AJ,Wong P,Milat F, Secondary Osteoporosis. Endocrine reviews. 2022 Mar 9     [PubMed PMID: 34476488]

[10]

Salari N,Ghasemi H,Mohammadi L,Behzadi MH,Rabieenia E,Shohaimi S,Mohammadi M, The global prevalence of osteoporosis in the world: a comprehensive systematic review and meta-analysis. Journal of orthopaedic surgery and research. 2021 Oct 17;     [PubMed PMID: 34657598]

[11]

Lewiecki EM,Wright NC,Curtis JR,Siris E,Gagel RF,Saag KG,Singer AJ,Steven PM,Adler RA, Correction to: Hip fracture trends in the United States, 2002 to 2015. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2018 Nov     [PubMed PMID: 30151621]

[12]

Albergaria BH,Chalem M,Clark P,Messina OD,Pereira RMR,Vidal LF, Consensus statement: osteoporosis prevention and treatment in Latin America-current structure and future directions. Archives of osteoporosis. 2018 Aug 24     [PubMed PMID: 30143914]

[13]

Peng CH,Lin WY,Yeh KT,Chen IH,Wu WT,Lin MD, The molecular etiology and treatment of glucocorticoid-induced osteoporosis. Tzu chi medical journal. 2021 Jul-Sep;     [PubMed PMID: 34386357]

[14]

Parva NR,Tadepalli S,Singh P,Qian A,Joshi R,Kandala H,Nookala VK,Cheriyath P, Prevalence of Vitamin D Deficiency and Associated Risk Factors in the US Population (2011-2012). Cureus. 2018 Jun 5     [PubMed PMID: 30087817]

[15]

Starr J,Tay YKD,Shane E, Current Understanding of Epidemiology, Pathophysiology, and Management of Atypical Femur Fractures. Current osteoporosis reports. 2018 Aug     [PubMed PMID: 29951870]

[16]

De Martinis M,Sirufo MM,Polsinelli M,Placidi G,Di Silvestre D,Ginaldi L, Gender Differences in Osteoporosis: A Single-Center Observational Study. The world journal of men's health. 2021 Oct     [PubMed PMID: 33474849]

[17]

Adami G,Gatti D,Rossini M,Giollo A,Bertoldo E,Viapiana O,Olivi P,Fassio A, Factors associated with referral for osteoporosis care in men: a real-life study of a nationwide dataset. Archives of osteoporosis. 2021 Mar 15     [PubMed PMID: 33723677]

[18]

Schultz K,Wolf JM, Emerging Technologies in Osteoporosis Diagnosis. The Journal of hand surgery. 2019 Mar     [PubMed PMID: 30177358]

[19]

He QF,Sun H,Shu LY,Zhu Y,Xie XT,Zhan Y,Luo CF, Radiographic predictors for bone mineral loss: Cortical thickness and index of the distal femur. Bone & joint research. 2018 Jul     [PubMed PMID: 30123496]

[20]

Ayub N,Faraj M,Ghatan S,Reijers JAA,Napoli N,Oei L, The Treatment Gap in Osteoporosis. Journal of clinical medicine. 2021 Jul 5     [PubMed PMID: 34279485]

[21]

Shevroja E,Cafarelli FP,Guglielmi G,Hans D, DXA parameters, Trabecular Bone Score (TBS) and Bone Mineral Density (BMD), in fracture risk prediction in endocrine-mediated secondary osteoporosis. Endocrine. 2021 Oct;     [PubMed PMID: 34245432]

[22]

Anderson PA,Freedman BA,Brox WT,Shaffer WO, Osteoporosis: Recent Recommendations and Positions of the American Society for Bone and Mineral Research and the International Society for Clinical Densitometry. The Journal of bone and joint surgery. American volume. 2021 Apr 21     [PubMed PMID: 33587517]

[23]

Pan SL,Li CC,Cui HW,Wang WX,Li CH, Evaluation of the efficiency of calcium and vitamin D in treating adults with corticosteroid-induced osteoporosis: A protocol for systematic review and meta-analysis. Medicine. 2021 Oct 1;     [PubMed PMID: 34596117]

[24]

Nuti R,Brandi ML,Checchia G,Di Munno O,Dominguez L,Falaschi P,Fiore CE,Iolascon G,Maggi S,Michieli R,Migliaccio S,Minisola S,Rossini M,Sessa G,Tarantino U,Toselli A,Isaia GC, Guidelines for the management of osteoporosis and fragility fractures. Internal and emergency medicine. 2018 Jun 13     [PubMed PMID: 29948835]

[25]

Henault D,Westley T,Dumitra S,Chang SL,Kremer R,Tamblyn R,Mayo N,Meguerditchian AN, Divergence from osteoporosis screening guidelines in older breast cancer patients treated with anti-estrogen therapy: A population-based cohort study. Bone. 2018 Jul 5     [PubMed PMID: 29981903]

[26]

Curry SJ,Krist AH,Owens DK,Barry MJ,Caughey AB,Davidson KW,Doubeni CA,Epling JW Jr,Kemper AR,Kubik M,Landefeld CS,Mangione CM,Phipps MG,Pignone M,Silverstein M,Simon MA,Tseng CW,Wong JB, Screening for Osteoporosis to Prevent Fractures: US Preventive Services Task Force Recommendation Statement. JAMA. 2018 Jun 26     [PubMed PMID: 29946735]

[27]

Migliorini F,Colarossi G,Eschweiler J,Oliva F,Driessen A,Maffulli N, Antiresorptive treatments for corticosteroid-induced osteoporosis: a Bayesian network meta-analysis. British medical bulletin. 2022 Sep 22     [PubMed PMID: 35641234]

[28]

Brent MB, Abaloparatide: A review of preclinical and clinical studies. European journal of pharmacology. 2021 Oct 15;     [PubMed PMID: 34364879]

[29]

Vaughn N,Akelman M,Marenghi N,Lake AF,Graves BR, Patients undergoing surgical treatment for low-energy distal radius fractures are more likely to receive a referral and participate in a fracture liaison service program. Archives of osteoporosis. 2022 Jul 19     [PubMed PMID: 35854058]

[30]

Agostini D,Zeppa Donati S,Lucertini F,Annibalini G,Gervasi M,Ferri Marini C,Piccoli G,Stocchi V,Barbieri E,Sestili P, Muscle and Bone Health in Postmenopausal Women: Role of Protein and Vitamin D Supplementation Combined with Exercise Training. Nutrients. 2018 Aug 16     [PubMed PMID: 30115856]

[31]

Cohn MR,Gianakos AL,Grueter K,Rosen N,Cong GT,Lane JM, Update on the Comprehensive Approach to Fragility Fractures. Journal of orthopaedic trauma. 2018 Sep     [PubMed PMID: 30036208]

[32]

Tsang DS,Jones JM,Samadi O,Shah S,Mitsakakis N,Catton CN,Jeon W,To J,Breunis H,Alibhai SMH, Healthy Bones Study: can a prescription coupled with education improve bone health for patients receiving androgen deprivation therapy?-a before/after study. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2018 Aug     [PubMed PMID: 29532243]

[33]

Rotondi NK,Beaton DE,Sujic R,Sale JEM,Ansari H,Elliot-Gibson V,Bogoch ER,Cullen J,Jain R,Slater M, Identifying and Addressing Barriers to Osteoporosis Treatment Associated with Improved Outcomes: An Observational Cohort Study. The Journal of rheumatology. 2018 Sep 1     [PubMed PMID: 30173147]

[34]

Giangregorio LM,Gibbs JC,Templeton JA,Adachi JD,Ashe MC,Bleakney RR,Cheung AM,Hill KD,Kendler DL,Khan AA,Kim S,McArthur C,Mittmann N,Papaioannou A,Prasad S,Scherer SC,Thabane L,Wark JD, Build better bones with exercise (B3E pilot trial): results of a feasibility study of a multicenter randomized controlled trial of 12 months of home exercise in older women with vertebral fracture. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2018 Nov     [PubMed PMID: 30091064]