Secondary Osteoporosis

Etiology

Conditions causing secondary osteoporosis include:

Endocrine Problems

a. Primary Hyperparathyroidism (PHPT): Generally presents in individuals over 50 years of age. It has a high prevalence of 233 cases per 100,000 women and 85 cases per 100,000 men. PHPT can result from a single gland adenoma, parathyroid gland hyperplasia, double adenoma, or rarely parathyroid carcinoma. There is also familial PHPT condition in the setting of MEN 1, MEN 4, MEN 2A and hereditary hyperparathyroidism like in jaw tumor syndrome or nonsyndromic familial isolated primary hyperparathyroidism.[3]

b. Cushing's Syndrome: Patients with Cushing syndrome have a higher risk for osteoporosis-related fractures. Bone resorption is increased, and there is decreased bone synthesis. [4]

c. Hyperthyroidism: Von Recklinghausen, in 1891, described the appearance of long bones from a young woman who died of hyperthyroidism as "worm-eaten." Thyroid hormones act through the thyroid nuclear receptor. [5]

d. Hypogonadism and Premature Ovarian Insufficiency (POI), also referred to as primary ovarian insufficiency or premature menopause: It describes the loss of ovarian function younger than 40 years of age. POI has a prevalence of almost 3 to 4%. Osteoporosis is a major health concern in this population. Other risk factors for bone loss also play an important role in determining the final bone quality in this population. Turner syndrome is the most common genetic cause of POI, which affects 1 in 2,000 female births. Male hypogonadism can affect men of all ages and can be of primary or secondary etiology in males younger than age 50. Z-scores instead of T-scores should be used in bone density evaluation for this age bracket. The National Osteoporosis Foundation (NOF) recommends using a T-score of less than -2.5 for the diagnosis of osteoporosis in both men and women and a Z-score of -2.0 or lower for a younger age. [6][7]

e. Diabetes Mellitus: Patients with type 1 diabetes have increased fracture risk. The review of the literature suggests that there is a 3-fold increased risk for any fracture and a 7-fold increased risk for hip fracture in patients with type 1 diabetes as compared to the general population. Patients with type 2 diabetes have a higher risk than the general population, with a relative risk of 1.17-2.03 in anterior sites. Although this risk is less than in patients with type 1 diabetes, the higher prevalence of type 2 diabetes makes it an important secondary cause of osteoporosis. Certain medications for diabetes, including thiazolidinediones and SGLT-2 inhibitors, have shown an increased risk in studies for osteoporosis.[8][9][10]

Chronic Inflammatory Conditions

a. Rheumatoid arthritis: Almost one-third of patients with rheumatoid arthritis have osteoporosis. The presence of fragility fractures in this population is close to double that of the age-matched general population. [11]

b. Cystic fibrosis: Cystic fibrosis-related bone disease involves osteomalacia as well as osteoporosis. Patients with cystic fibrosis have a high prevalence of vertebral and non-vertebral fractures. Thoracic vertebral and rib fractures are more common in this population. HRpQCT in cystic fibrosis-affected young adults shows compromised trabecular and cortical microarchitecture.[12]

c. Chronic Obstructive pulmonary disease: Osteoporosis affects about one-third of the patients with COPD worldwide. The most common fragility fractures in this population are vertebral, femoral, and rib fractures.[13]

Chronic Kidney Disease

Chronic kidney bone disease prevalence has increased lately and is described as chronic kidney disease–mineral bone disorders (CKD-MB). The spectrum involves osteomalacia, adynamic bone disease, osteitis fibrosis cystic, and mixed bone disease.[14]

Idiopathic Hypercalciuria

Idiopathic hypercalciuria is a prevalent cause of calcium-containing renal stones and involves almost 1/5 of a healthy population and up to 40% of postmenopausal women with fractures. Urinary calcium of more than 200 mg/day is associated with an increased risk for calcium stone formation. These patients have lower BMD than the general population and increased fracture risk.[15]

Neuromuscular Diseases

a. Cerebral palsy: Cerebral palsy involves defects in the motor component of the central nervous system. Patients with cerebral palsy have improved survival resulting in a higher population with increased risk for skeletal conditions, including contractures, spasticity, and osteoporosis.[16]

b. Spina Bifida: In multiple studies, patients with spina bifida have been found to have a higher risk for osteoporosis and fractures than the general population, with a prevalence of almost 30% in this population.[17]

c. Duchenne's muscular dystrophy (DMD): DMD is an X-linked recessive progressive muscular disease resulting from mutations in the dystrophin gene. Boys with DMD have a significantly higher risk for osteoporosis, with a prevalence of almost 20 to 60% in this population.[18]

d. Multiple Sclerosis: Studies have suggested that patients with multiple sclerosis have a twofold increased risk for osteoporosis and osteoporotic fractures compared to the general population.[19]

e. Parkinson disease: Patients with Parkinson disease have higher fracture-related mortality than the general population.[20]f.  Post stroke: Stroke survivors have a higher risk of osteoporosis and fractures related to bone loss from immobilization and neurological disability.[21]

Gastrointestinal Diseases

a. Inflammatory Bowel Disease: Patients suffering from inflammatory bowel disease with either Crohn disease or ulcerative colitis have a significantly higher risk for osteoporosis and fractures than the general population.[22]b. Celiac disease: Gluten enteropathy results in malabsorption and diarrhea with weight loss, ultimately leading to an increased risk of bone loss and osteoporosis.[23]c. Chronic liver disease:(+/- hepatitis): There is a higher prevalence of fractures and osteoporosis reported in patients awaiting a liver transplant.[24]d. Cholestatic liver disease: Cholestatic liver disease has a high risk for fractures and osteoporosis.[25] e. Non-cholestatic liver disease: Chronic viral hepatitis, including chronic hepatitis B and C, is the most common type of non-cholestatic liver disease, and there is a high prevalence of osteoporosis reported in this population.

Nutritional Conditions

a. Anorexia nervosa: Patients with anorexia nervosa have decreased peak bone mass, impaired bone microarchitecture, and a high risk for osteoporosis.[26]b. Obesity: Although BMD and BMI are positively correlated, there are still patients with a BMI of more than 30 that are found to have a higher loss of BMD at the femoral neck as compared to adults with normal BMI.c. Bariatric surgery: Patients with a history of bariatric surgery have a significantly higher risk for osteoporosis. The bone loss is also related to the type of procedure done, with the gastric bypass resulting in a higher bone loss compared to the rest of the procedures. Wrist fracture was the most common site of fracture overall.

Glucocorticoid Induced Osteoporosis

Glucocorticoids, even at low doses of 2.5 mg of prednisone per day or inhaled corticosteroids for bronchial asthma, can lead to increased bone loss. The bone loss with glucocorticoids is maximum during the first 2 to 3 months of therapy. Glucocorticoids are not only involved with excessive bone resorption but also cause decreased bone formation. Guidelines from the American College of Rheumatology suggest treating patients with a higher risk for osteoporosis fractures when they are on a glucocorticoid dose of around 2.5 mg of prednisone, or more, per day for over three months.[27][28]

Post-transplant Osteoporosis

With the advancement of medical therapy and an increasing number of patients who are benefiting from transplants, there is a need to evaluate bone health in these patients as well. All patients awaiting transplants should have a baseline DXA scan.a. Stem cell transplant: Almost half of the patients with stem cell transplants have osteopenia and osteoporosis, which are more prominent at the proximal femur.b. Heart/lung transplants: Higher bone loss has been observed in these patients.c. Liver transplant: Bone loss and fractures are highest in patients with liver transplants in the first 6 to 12 months.d. Kidney transplant: In this patient population, bone loss is reported that is more significant in the first 6 to 8 months.[29]

HIV Infection

HIV infection and antiretroviral therapy increase the risk of bone loss and osteoporosis. Patients should have a baseline DXA for evaluation of bone health.[30]

Medications/Adverse Lifestyle Factors

Depot medroxyprogesterone acetate, antiepileptic drugs (like phenobarbitone, phenytoin, topiramate), SSRIs, PPIs, alcohol, PPAR gamma, glucocorticoids, smoking are all accused of causing bone loss in various degrees, so patients receiving those medications on a chronic basis should be evaluated with a bone density measurement.[31]

Cancer and Bone

Monoclonal gammopathy of uncertain significance MGUS: These patients have a high risk for pathological fractures and osteoporosis. Multiple myeloma patients can present with lytic bone lesions as a result of plasma cell infiltration. Adjuvant endocrine therapies: Therapies for prostate cancer and breast cancer involving androgen deprivation therapy, tamoxifen, and aromatase inhibitors have all been associated with increased bone loss.[32]

Genetic Diseases

Thalassemia: This is an autosomal recessive disorder of red cells due to mutations in either alpha or beta globin chain of the hemoglobin molecule. Patients with thalassemia have reduced BMD and increased fracture risk and bone pain.Ehlers-Danlos syndrome (EDS): Osteoporosis has been recognized as a complication of EDS.[33]

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.[2] Studies based on the United States population indicate that about 20 to 25 million people might be affected by osteoporosis, and roughly two million fractures per year can be attributed to osteoporosis.

Osteoporosis is a worldwide problem causing more than 8 million fractures annually, resulting in one osteoporosis fracture occurring every 3 seconds. If we use the WHO definition of osteoporosis, this disease affects 6% of men and 21% of women above the age of 50. With these statistics, approximately 500 million people may be affected worldwide.[2]

Pathophysiology

Endocrine Disorders

a. Primary Hyperparathyroidism: PTH (parathyroid hormone) is the main regulator of calcium by its effects on the kidney and bone. In primary hyperparathyroidism, there is excessive bone turnover where the bone resorption exceeds the bone formation. The elevated PTH levels can increase the release of RANKL, which stimulates the receptors on osteoclastic precursor cells. The increased resorption is seen in both trabecular and cortical bone.

b. Cushing's Syndrome: Glucocorticoids exert their effects on bones through glucocorticoid receptors. The activity of the 11 B-HSD1 enzyme in osteoblasts determines the degree of reduced bone formation and glucocorticoid-induced osteoporosis (GIO). There is also disruption of the Wnt signaling pathway. Glucocorticoid administration results in a decrease in osteoprotegerin (OPG) and osteocalcin levels with an unopposed RANKL activity. There is also increased osteoblastic apoptosis.[34][35]

c. Hyperthyroidism: The net effects of thyroid hormone are brought about by the changes it causes in the expression of T3-responsive genes in the target tissues. The normal bone remodeling cycle lasts for approximately less than seven months, but in the hyperthyroid state, its duration is half which is almost 2-3 months.  Since bone resorption requires much less time than bone formation, this rapid bone turnover results in net bone loss.[5]

d. Hypogonadism:

Premature ovarian insufficiency (POI): Mechanisms for low BMD in patients with POI include insufficient attainment of peak bone mass, excessive bone resorption with estrogen deficiency, and the presence of other comorbidities. 

Male Hypogonadism: High risk for osteoporosis results from a deficiency of both estrogen and testosterone since there is also decreased aromatization of testosterone to estrogen, and both hormones play an important role in bone health.[36]

e. Diabetes Mellitus: Excessive bone fragility in T1DM results from various factors, including defective attainment of peak bone mass, as a result of insulin deficiency or decreased IGF-I. Hypercalciuria occurring as a result of hyperglycemia can cause impaired bone mineralization. Hyperglycemia also leads to excessive accumulation of advanced glycation end products (AGEs), which can accumulate in osteoblasts and impair their function. Growth factors and cytokines released from adipocytes can adversely affect bone remodeling commonly seen in obesity and insulin resistance.[37]

Chronic Inflammatory Conditions

a. Rheumatoid arthritis: Rheumatoid arthritis affects bone health through a multitude of factors involving excess inflammatory mediators. Autoantibodies can stimulate inflammatory cytokines by upregulating RANKL/OPG pathway.  There is also a down-regulation of the Wnt signaling pathway. The use of glucocorticoids in the treatment of the disease can affect bone health as well.  Various studies have shown that patients who are on glucocorticoids for the management of rheumatoid arthritis have higher bone loss as compared to patients with RA without glucocorticoids.[38]

b. Cystic fibrosis: Patients with cystic fibrosis have compromised trabecular and cortical microarchitecture from the poor attainment of peak bone mass.  This decreased peak bone mass is multifactorial, resulting from malabsorption due to pancreatic insufficiency, pubertal delay, and hypogonadism. Direct effects of CFTR dysfunction on bone have also been described. Guidelines suggest screening for low BMD with DXA from age 18 years old and above in all patients with cystic fibrosis or earlier if the patients have increased risk factors for further bone loss.[12]

c. Chronic Obstructive pulmonary disease (COPD): Inflammatory state and COPD drive excessive RANKL activity with decreasing OPG activity, ultimately resulting in low BMD.[13]

Chronic Kidney Disease–Mineral Bone Disorders (CKD-MBD)

a. Osteomalacia: Inadequate bone mineralization is seen in early CKD. As early as stage 2 CKD, there is increased FGF23 and a decline in its co-receptor alpha Klotho. FGF23 has a phosphaturic effect and also inhibits the 1 alpha-hydroxylase action resulting in decreased calcitriol levels.[39]b. Adynamic bone disease: This results from reduced osteoclastic and osteoblastic selectivity due to skeletal PTH resistance or PTH suppression. It is mostly seen in patients with advanced CKD and in patients on dialysis. Dickopf-1 (DKK-1) and sclerostin are upregulated in CKD-MBD and are prominent inhibitors of bone formation. c. Osteitis fibrosis cystica: It results from high bone turnover from secondary or tertiary hyperparathyroidism.[39]d. Mixed bone disease: This is usually involving features of both high and low bone turnover. e. Age-related osteoporosis is also increasingly seen in patients with CKD.

Idiopathic Hypercalciuria

Idiopathic hypercalciuria has increased calcium reabsorption from the gut, but at the same time, there is decreased calcium reabsorption from the kidneys resulting in increased calcium loss from the urine. The calciuria exceeds GI calcium absorption, resulting in a net negative calcium balance. Patients are at increased risk for osteoporosis and fractures.These patients should have an adequate calcium intake of at least 1200 mg/day and a high fluid intake. They should avoid dehydration and excessive sodium intake.[40]

Neuromuscular Disease

Neuromuscular disorders have an excessive risk for osteoporosis due to several factors, with the most common being immobility, malnutrition, vitamin D deficiency, and the use of medications like steroids and anticonvulsants.  In patients with Parkinson disease, levodopa dosage is inversely associated with BMD.[20]

Gastrointestinal Diseases

a. Inflammatory Bowel Disease (IBD): Bone health is affected in patients with IBD due to an inflammatory state with osteoclastogenic cytokines, including TNF alpha, interleukin-1, and interleukin-6. Malabsorption and a nutrient-deficient state resulting from reduced nutrient intake and decreased nutrient absorption may also affect bone health. IBD treatment using glucocorticoids combined with bowel resection contributes to poor bone health. [41]These patients are at specific risk for vitamin D deficiency and deficiency of essential nutrients like magnesium, potassium, and phosphorus. Physical inactivity also plays a role. Additional risk factors for excessive bone loss in these patients include increasing age, female sex, smoking, alcohol consumption, and positive family history of fractures.

b. Celiac disease: Calcium and vitamin D malabsorption have been implicated to play a significant role in bone loss in patients with celiac disease.c. Cholestatic liver disease: Primary biliary cirrhosis has been associated with decreased osteoblastic activity due to decreased osteoblastic factors, including vitamin K and IGF-I.d. Noncholestatic liver disease: Inflammatory cytokines, including TNF alpha and interleukins- 1, 6, 13, 17, upregulation of RANKL, and decreased OPG activity stimulate osteoclastogenesis resulting in bone loss. Fracture risk is also increased in patients treated with tenofovir disoproxil fumarate (TDF), which can induce renal tubulopathy (Fanconi syndrome), resulting in hypophosphatemia, hyperphosphaturIa, and osteomalacia. Bone loss from TDF involves the hip and spine and occurs mostly in the first year after the initiation of therapy.Patients with NASH and NAFLD also have lower BMD as a result of increased inflammation compared to healthy subjects.[42]

Nutritional Conditions 

a. Anorexia nervosa: Fracture risk in anorexia nervosa is multifactorial, resulting from hypogonadism with an estrogen-deficient state, energy deficiency, altered gut microbiota, and vitamin D deficiency.  Other potential factors involved also include low levels of IGF-I and elevated cortisol levels.[26]b. Obesity: The mechanisms that cause bone loss include a pro-inflammatory state and obesity-induced hypogonadism.c. Bariatric surgery: Potential factors resulting in osteoporosis from bariatric surgery include malabsorption, weight loss, secondary hyperparathyroidism from deficiency of calcium and vitamin D, decreased protein intake, decreased muscle mass, and bone marrow fat changes.

d. Smoking and alcohol consumption: Tobacco smoking affects bone through both direct and indirect effects. The direct effect is through decreased osteogenesis and angiogenesis, and the indirect effect is through increased oxidative stress and decreased calcium absorption from decreased vitamin D activation to 1,25 form. There is also an increase in RANKL/OPG. Heavy alcohol consumption in the early years of life has been shown to affect osteogenesis and the attainment of peak bone mass while the effects are not reversed by stopping alcohol consumption. 

Glucocorticoid Induced Osteoporosis

The mechanism of bone loss is described above.

Bone loss from glucocorticoids is maximum in the first three months of therapy.[27]

Post-transplant Osteoporosis

Post-transplant osteoporosis results from using immune modulators and immunosuppressive drugs like cyclosporin, mycophenolate, tacrolimus, and glucocorticoids. As in glucocorticoid-induced osteoporosis, the bone loss in posttransplant osteoporosis is maximum in the first couple of months to a year after transplant. Preventive therapy in these patients should be administered to avoid this rapid bone loss.[43]

HIV/Infections

Patients living with HIV infection are at high risk for bone loss from antiretroviral therapy and other coexisting conditions, including high-risk behavior like drug and alcohol use.  Also, low BMI, frailty, hypogonadism, and DM type 2 are more common in patients with HIV. Antiretroviral therapy, especially with protease inhibitors and tenofovir disoproxil fumarate (TDF), increases bone loss. The newer agent tenofovir alafenamide (TAF) results in less bone loss than TDF. Newer integrase inhibitors have the least osteoporotic effect.[44]

Cancer and Bone

Osteolytic lesions in multiple myeloma result from bone marrow infiltration with the plasma cells and excessive RANKL activity and inhibition of the Wnt signaling pathway. Monoclonal Gammopathy of Undetermined Significance (MGUS) is associated with increased fracture risk and osteoporosis, even in the absence of lytic lesions.[45] Certain cancer treatments like aromatase inhibitors and androgen deprivation therapy may also increase bone loss. 

Genetic Diseases

Thalassemia: Mechanisms for bone loss include hypogonadism, iron overload, renal dysfunction from a transfusion-dependent state, and renal calculi formation. Deferasirox, the major iron-chelating agent, has also been associated with calciuria.[46]

Other genetic diseases causing bone loss include Ehlers-Danlos syndrome and osteogenesis imperfecta.[47]

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.[48]

History and Physical

Osteoporosis is, in general, a silent disease until there is a fragility fracture, and the high suspicion of the disease is what should drive the request for testing. 

It has been linked with low bone mass and reduced bone mass index.

In the physical exam, there may also be thoracic kyphosis and loss of height from vertebral compression fractures, but more frequently, osteoporosis is initially completely asymptomatic, and it is usually detected either by a DXA scan or by a fragility fracture.[49]

Evaluation

Workup for secondary causes of osteoporosis is indicated for premenopausal women with osteoporosis, as well as men aged less than 50 years old who present with fragility fractures or osteopenia. 

Bone mineral density should be evaluated using a DXA scan. Spine x-rays should also be obtained, including vertebral fracture assessment (VFA) if needed. Bone microarchitecture can be assessed using HRp QCT. A bone biopsy can also be helpful in certain select situations for severe secondary osteoporosis where the exact cause cannot be established with the rest of the workup, as it happens in some select cases of adynamic bone disease. 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.

FRAX score calculation involves ages 40 to 90 years old, so it has a limited value for patients less than 40 years of age. It also only involves femoral neck BMD and can underestimate the osteoporosis risk in patients with a worse spinal BMD. FRAX score calculates the 10-year risk for major osteoporotic fracture as well as the 10-year risk of hip fracture. Assessing the trabecular bone score (TBS) is another way of looking into the bone microarchitecture that 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.

A comprehensive list of investigations to work up for secondary causes of osteoporosis may include:

General Screening

• Complete blood count to screen for inflammatory conditions, including myeloproliferative and other hematological disorders.
• ESR or CRP helps in assisting and supplementing the diagnosis of inflammatory conditions.
• Serum calcium, phosphate, magnesium, and renal function to look for PHPT and renal disease. 
• iPTH levels also help with Primary hyperparathyroidism and understanding the nature of CKD-MBD.
• 25 OH vitamin D: Vitamin D deficiency or malabsorption.
• Alkaline phosphatase: Osteomalacia, Paget's disease of bone, renal disease, metastatic bone disease.
• Liver function tests: Chronic liver disease.
• TSH and FT4 to look for clinical or subclinical hyperthyroidism.
• Hemoglobin A1c to diagnose diabetes mellitus.
• SPEP/UPEP, free light chains in older men and women >40 years to look for Multiple myeloma or MGUS.
• Testosterone levels, LH, and FSH in men and estradiol levels in premenopausal women to evaluate for the hypogonadal state.
• Transglutaminase IgA and Deamidated gliadin peptide IgG to diagnose Celiac disease.
• 24-hour urinary calcium excretion to evaluate for idiopathic hypercalciuria and also malabsorption. 

Selected Conditions

• HIV testing
• Hep B and hep C testing
• Ferritin levels to assess for hemochromatosis
• Alkaline phosphatase and pyridoxal 5-phosphate levels to assess for hypophosphatasia
• Tryptase and IgE to assess for mastocytosis
• 24-hour urinary free cortisol, overnight dexamethasone suppression, or midnight salivary cortisol to assess for Cushing syndrome
• EDSCL 1 and other gene tests for Ehlers-Danlos.[2]

Others

• Bone resorption and formation markers
• Plain X-rays (lumbar and thoracic spine) to look for vertebral fractures.

Treatment / Management

The effective treatment of secondary osteoporosis should, first and foremost, address any underlying reversible causes. The response of secondary osteoporosis to conventional therapy is always suboptimal unless the underlying condition is addressed. 

Adequate calcium and vitamin D supplementation should be maintained in all patients.[50](A1)

Weight-bearing exercise helps stimulate bone formation. There is an association between reduced physical activity and bone fracture in older men and the positive influence of exercise in women who have osteoporosis. In addition, smoking cessation and avoidance of alcohol intake should be encouraged.[51]

Antiresorptive agents: Once reversible causes are addressed, if pharmacologic therapy is needed, antiresorptive agents like bisphosphonates such as alendronate, zoledronic acid, ibandronate, and risedronate are the first line and can be used in patients with adequate renal function.[52] Denosumab is also an antiresorptive agent, a human monoclonal antibody against RANKL, and is given as a subcutaneous injection. It has been proven effective in treating bone loss due to malignancies, especially prostate cancer or other malignancies with metastasis to the bone.[53] It can also be given in cases of renal dysfunction since it does not require renal clearance, and it is most likely cleared by the reticuloendothelial system. (A1)

Anabolic agents, including Teriparatide and Abaloparatide: Teriparatide is a recombinant human parathyroid hormone given as a 20 mcg daily subcutaneous injection. Teriparatide is not the first-line drug used in the treatment of secondary osteoporosis, but it can be used in glucocorticoid-induced osteoporosis, in patients with severe osteoporosis, in those who have contraindications to bisphosphonates and 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. It is given as an 80 mcg daily subcutaneous injection as well. Recent studies have shown beneficial results and BMD gains in men using abaloparatide, and the medication has recently been approved for treating male osteoporosis.[54][55](A1)

Romosozumab has been studied and approved for treating postmenopausal osteoporosis but not yet for secondary osteoporosis.[56][57][58](A1)

Management of some of the secondary causes is discussed below:

Endocrine Disorders

a. Primary Hyperparathyroidism: If osteoporosis is present, the management of the disease includes parathyroidectomy, which usually results in the reversal of bone loss in 1 to 2 years.

b. Cushing's Syndrome: Bone loss in patients with Cushing's syndrome improves once the cause for hypercortisolism is addressed.  

c. Hyperthyroidism: Bone loss as a result of hyperthyroidism also is reversed by the treatment with antithyroid drugs and controlling the hyperthyroid state.

d. Hypogonadism: Women with premature ovarian insufficiency will benefit from hormone replacement therapy and will have an improvement in their BMD due to estrogen replacement. Testosterone supplementation has been shown to improve BMD in men with hypogonadism. If there is significant osteoporosis with osteoporotic fractures, they may need treatment with osteoporotic medications.

e. Diabetes Mellitus: Good glycemic control has been shown to improve BMD in patients with diabetes. Also, general measures, including weight-bearing and calcium and vitamin D supplementation, have been shown to be of help. [2]

Chronic Inflammatory Conditions

a. Rheumatoid arthritis: Patients with rheumatoid arthritis might benefit from treatment with osteoporosis medications, including bisphosphonates. Teriparatide has also been seen to improve BMD and reduce vertebral and nonvertebral fractures in patients with rheumatoid arthritis. Lastly, denosumab can also prevent periarticular bone erosions in these patients. 

b. Cystic fibrosis: Management of patients with cystic fibrosis-associated bone loss should include optimizing nutrition and ensuring adequate caloric intake. 25 OH vitamin D level of at least 50 should be maintained at all times, but when presenting with Z scores of < -2 and significant bone loss of > 4 %/year, in cases with significant bone loss, bisphosphonates should be commenced.

c.  Obstructive pulmonary disease: Treatment should include addressing the underlying health condition. Also, optimizing general bone health with calcium and vitamin D supplementation and weight-bearing exercises helps. All patients should be evaluated for osteoporosis treatment if they meet the criteria based on the general guidelines of osteoporosis and GIO.[36]

Chronic Kidney Disease

Management of bone disease with CKD is extensive. The patients should maintain their phosphate levels in the normal range using phosphate binders. Noncalcium phosphate binders are encouraged to be used. Also, bone markers should be used to differentiate between adynamic bone disease versus other bone mineral disorders. Calcium levels should be maintained in the low normal range. Parathyroidectomy may be considered in patients with severe secondary or tertiary hyperparathyroidism. Excess use of calcimimetics should be discouraged. Hypogonadal patients may also benefit from hormone replacement therapy.[36]

Idiopathic Hypercalciuria

Thiazide diuretics have been shown to improve calciuria in these patients. Potassium citrate, which increases urinary pH, has also been shown to improve idiopathic calcium nephrolithiasis. Bisphosphonate use should be assessed on a case-by-case basis. [59]

Neuromuscular Disease

Management in patients with neuromuscular disease involves addressing the underlying disease status. Also, maintaining optimal levels of calcium and vitamin D is crucial. Patients with severe bone loss or use of higher-dose glucocorticoids usually meet the criteria for osteoporosis treatment. Testosterone supplementation in case of hypogonadism will help with BMD as well.

Weight-bearing exercises and physical therapy should be provided in all these cases. 

Gastrointestinal Diseases

General measures to prevent bone loss can help in all of these patients, with a special focus on nutrition counseling, including calcium and vitamin D supplementation. In cases of malabsorption, higher doses of supplementation are required. Patients on glucocorticoids or immunosuppressive medications may benefit from osteoporosis treatment. 

Nutritional Conditions

Patients with bariatric surgery should have a DXA scan done. In case of low BMD, they should be on treatment for osteoporosis. These patients should never stop their nutritional supplements and continue following up with bariatric clinics. Higher doses of calcium and vitamin D levels may be required to maintain normal levels in these patients as well. 

Glucocorticoid Induced Osteoporosis

Patients with glucocorticoid-induced osteoporosis who need continued treatment with steroids might need prophylaxis with bisphosphonates based on the available guidelines, which suggest prophylaxis when the prednisone is 7.5 mg or higher for more than three months duration.

Post-transplant Osteoporosis

Post-transplant patients should always have a baseline BMD checked. In cases of significant risk factors and low BMD, there is a documented benefit from bisphosphonates and other osteoporosis treatments, including anabolic agents. Denosumab has also been under investigation for patients with transplant osteoporosis.[29]

HIV/Infections

Antiretroviral agents with decreased risk for bone loss should be preferred in patients with HIV. Also, optimal management of HIV infection and maintaining optimal general health will help with overall skeletal health and decrease the risk of osteoporosis. There should be a baseline DXA evaluation in patients with increased risk, and these patients should be treated with osteoporosis medications.

Cancer and Bone

Bisphosphonates have been studied and are being used in various malignancies, including multiple myeloma.[60] Denosumab has been studied in mastocytosis.[60] In addition to lifestyle measures, both denosumab and bisphosphonates have been successfully used in breast and prostate cancer, even in cases with bone metastasis.[2](B2)

Genetic Diseases

Optimal levels of calcium and vitamin D should be maintained. Physical activity should be encouraged. In cases of worse bone health and decreased BMD, patients will benefit from osteoporosis treatment to prevent fragility fractures.

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
• 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.

Complications

Secondary causes of osteoporosis should be addressed in the early stages to prevent complications, including fractures and reduced quality of life. 

Osteoporotic fractures can result in limited mobility and occasionally chronic pain that can ultimately result in psychological issues, including depression. 

Patients may have affected their quality of life and physical dependence even at a young age.