Osteoporosis in Females

Etiology

Osteoporosis is commonly encountered in older women with no underlying risk factors. However, this does not necessarily mean that it is attributed only to old age.

Many diseases have strong evidence to be considered as risk factors attributing to the development of osteoporosis, even in the young female population. These include conditions like hyperthyroidism, hyperparathyroidism, celiac disease, chronic kidney disease, and autoimmune disorders like rheumatoid arthritis, SLE (systemic lupus erythematosus), ankylosing spondylosis. Smoking is an important modifiable risk factor besides high alcohol intake.[1]

It is always a good clinical practice to advise women to quit smoking and reduce their alcohol intake.

Vitamin D is essential for managing bone strength and calcium absorption. It is a significant factor considered as an additional risk for osteoporosis in countries lacking tropical weather, which is vital for vitamin D synthesis.

Other contributing factors to the development of osteoporosis are the judicious use of certain medications, known as secondary risk factors for osteoporosis. Important to mention are corticosteroids, thyroxine, antacids, and chemotherapies, especially aromatase inhibitors.[2]

Epidemiology

One of the critical health hazards is osteoporosis, with over 200 million affected people worldwide. It has more prevalence in postmenopausal women with around 25 to 30 percent of its prevalence in the United States and equally in Europe. Besides the actual prevalence, there has been a tremendous impact due to increased life expectancy and a more aged population.[3]

A previous history of fracture is, by itself, a very significant risk factor for future fractures. Those already sustained a low trauma fracture in the past have over 80 percent probability for a new one. Similarly, those who had a history of vertebral fracture have over two-fold increased risk of hip fracture and roughly 1.5 fold distal forearm fracture risk.[4][5]

Ethnicity also has a strong influence on the prevalence of osteoporosis, with co-relation to bone mineral density (BMD).

• African American women have the highest BMD as compared to Asian women of the same age group.
• The most prevalent risk of osteoporosis has been found in Native Americans with 11.9 %, followed by Asians 10%, Hispanics 9.8%, Whites 7.2%, and blacks 4%.
• Interestingly even though BMD has been recorded highest in African Americans, they are most like to die from hip fractures because of increased hospital stay.

Pathophysiology

Bone metabolism is a complex mechanism that revolves around the needful bone turnover involving bone formation (osteoblastic activity) and resorption (osteoclastic activity). This cycle continues throughout life and has phases of rapid bone formation to phases of increased resorption. This complex process takes weeks to months. It can be simplified for the purpose of a better understanding of bone mineralization and formation.

The whole process goes through a continuous phase of activation, resorption, formation, mineralization, followed by a period of quiescency. These five factors are called stages of bone modeling.

• For better conceptual understanding, let us describe things from the quiescent phase, which describes the inactive phase of bone before initiation of remodeling.

• As a result of mechanical loading, low calcium from primary or secondary causes leads to microfractures beginning the activation phase. In this phase, pre-osteoclasts are attracted to remodeling sites that fuse to form multinucleated osteoclasts.

• These are subsequently activated by RANKL and M-CSF to help them attach to the bone surface. This begins the resorption phase with so formed osteoclasts degrading the bone resulting in releasing of trapped growth factors within the matrix, before entering in apoptosis that is the programmed cell death.

• As a result of all this, a resorption pit is formed, followed by clearance of debris from activated macrophages and a transition to the formation phase. A collagenous matrix (osteoid) is deposited to fill the void of the cavity or pit.

• The complete mineralization of this matrix takes roughly 3-6 months and is helped by secreting vesicles from osteoblasts in an environment helped by increased calcium and phosphorous ion concentrations.

For successful remodeling, the existing bone matrix should be completely removed prior to new bone formation. The other molecular details to mention are beyond the scope of this learning module.

Factors that contribute to osteoporosis are as follows:

• Osteoporosis has significant hormonal influence, especially in postmenopausal women, where decreased estrogen levels have a negative impact on bone formation by increasing the sensitivity to the bone resorption effect of parathyroid hormone. This can lead to rapid bone loss as compared to bone formation leading to osteoporosis.

• There are other risks and environmental factors that can potentiate this bone loss, including smoking, diet, lifestyle, and climate.[6][7][8]

• At the molecular level, the RANK (Receptor activator of nuclear factor-κB) pathway and its role in the pathogenesis of osteoporosis can be a potential target for new therapies.RANK is a receptor expressed by osteoclasts and its precursors.RANKL is the ligand that binds to the RANK receptor, which acts as a common final pathway in controlling osteoclast differentiation, proliferation, and survival.

Current challenges in treatment with judicious use of oral corticosteroids had led to a very increased surge of osteoporosis from prolonged use of these medications. Steroids decrease the peripheral calcium ion concentration resulting in PTH release and very rapid bone loss, especially in the first three months of steroid use. This also results in impairing bone quality because of increased osteoblastic activity, not able to measure or quantify by normal bone measuring techniques like DEXA scan.

Histopathology

The main histopathological abnormality of an osteoporotic bone is trabecular thinning with defects in the trabeculae, in the form of irregularity, reflecting the role of osteoclastic overactivity in most of the bone samples (from osteoporotic bones).[9]

History and Physical

Osteoporosis has no specific clinical signs and symptoms unless there is a fracture. Some patients may complain of bone aches (hips and feet), but the pain is more of a symptom of osteomalacia. Fracture Risk Assessment Tool (FRAX) is available for evaluating 10-year fracture risk probability, especially hip and other major osteoporotic fractures. FRAX assessment takes into consideration of age, family history, smoking status, steroid use, arthritis, and femoral neck bone density. Common manifestations of osteoporosis include vertebral fracture, hip fracture (about 15% of women), and distal radial fractures.[10] Vertebral fractures are typically incidentally noted on imaging as a majority of them are asymptomatic.

Unfortunately, the screening of women for osteoporosis doesn't have an international following, although, in the United States and Canada, Bone Mineral Density in postmenopausal women greater than 65 years is recommended for screening even without risk factors. There are various risk factors for osteoporosis classified under modifiable and non-modifiable. 

In General, the causes of osteoporosis can be simply classified into Primary and Secondary. Primary is generally age-related influenced by hormonal and dietary elements, while secondary osteoporosis is a result of various medical conditions and medications.

Primary: Primary causes of osteoporosis can be further subclassed into Type 1 and Type 2.

• Primary type 1 osteoporosis is a result of hormonal changes occurring in postmenopausal women, influenced by the change of balance in estrogen and progesterone levels, which are responsible for the symbiosis of osteoblastic and osteoclastic activity. Estrogen regulates in osteoclastic activity and progesterone in osteoblastic. This is common after 10-15 years after menopause, usually in the age group of 50-70. Because of decreased estrogen levels in postmenopausal women, there is more bone loss than significant bone formation.

• Primary type 2 osteoporosis is also termed as senile osteoporosis and is generally as a result of chronic low dietary calcium or sometimes factors that influence calcium metabolism like hyperparathyroidism. This is also called low turn over osteoporosis, because the rate of bone turnover is much lower than osteoporosis, and is more common in women with a high rate of hip fractures seen in this type.

Secondary: Certain Medical conditions increase bone remodeling leading to interference or disruption of bone reformation. There is a resultant bone loss as a consequence of imbalance from new bone production and loss. Some of the common conditions promoting osteoporosis are hyperparathyroidism, hyperthyroidism, diabetes, thalassemia, multiple myeloma, intestinal malabsorption, leukemia, Liver disease, metastatic bone disease, Cushing's syndrome, acromegaly, scurvy, and Marfan's syndrome.

In addition to medical conditions, medications that can cause osteoporosis are antacids containing aluminum, heparin, anticonvulsants, thyroxine, and steroid use(cortisone therapy).

Apart from the above-mentioned causes, modifiable risk factors are listed below.

 Non-modifiable risk factors include but are not limited to:

1) History of fracture as an adult or in a first-degree relative

2) White race

3) Advanced age/Dementia/Fragility

4) Female sex

Modifiable risk factors include

1) Current cigarette smoking

2) Low BMI

3) Early menopause (less than 45-year-old) or bilateral oophorectomy and prolonged premenopausal amenorrhea (for more than a year) 

4) Low dietary calcium intake

5) Alcoholism

6) Recurrent falls

7) Inadequate physical activity[11][12]

A thorough history is mandatory to identify known risk factors for osteoporosis and osteoporotic fracture, as listed above. Conditions including COPD (chronic obstructive pulmonary disease), asthma, and other rheumatological disorders like giant cell arteritis, polymyalgia, and others with judicious use of steroids for years predispose patients for secondary osteoporotic risk. Risk factors for falls in older patients include poor balance, weakness of muscles and deconditioning, medications with sedative effects, poor vision, or hearing.[13][14]

Some fractures are picked on incident x-ray findings, especially vertebral. However, there can be associated features of pain, a decrease in height, cord compression features of severe disability in weight-bearing moments from hip fractures. Gait disturbances could also occur as a result of an abnormal pattern of walking and occasional loss of muscle tone and sarcopenia (muscle mass loss)

Evaluation

Laboratory Analysis

The initial evaluation should include basic labs to access levels of complete blood count, serum electrolytes, calcium, phosphorus, albumin, total protein, renal, and liver function. Also, thyroid function and 25-hydroxyvitamin D levels should be obtained. Based on the abnormalities detected in basic labs, patients should have additional tests to evaluate for diseases like celiac disease, malignancies, and multiple myeloma. Disorders of calcium and vitamin D malabsorption should be considered. Hormone imbalances like Cushing syndrome and parathyroid hormone abnormalities are also very important in the evaluation of osteoporosis.

X-ray

Plain X-ray report of low bone density is a strong predictor of osteopenia or osteoporosis but not diagnostic. Changes in plain radiograph showing osteopenia, wedging in vertebrae can be a clue of underlying fracture risk.

DEXA Bone Density Scan

The most common test used for the measurement of bone health and osteoporosis is the DEXA bone density scan (Dual-energy x-ray Absorptiometry). It is a radiological diagnostic test and is universally classified by T and Z scores. T score is the measurement of bone density compared to younger people and estimates the risk of fracture, whereas Z score measures the bone density of the comparable age group. Most guidelines use T score as a standard approach for estimating fracture risk assessment and treatment. T score above -1 is Normal, a score of -1.0 to -2.5 is classified as osteopenia, and anything less than -2.5 is osteoporosis. These numerical values are the standard deviations of comparison.[15] It is important to mention that T-scores are just a clinical guide for treatment and can sometimes vary from case to case basis, e.g., a patient on steroid use for more than six months and expected to be on that for a while is offered treatment with T score of only -1.5, whereas a young female with underlying celiac disease and vitamin D malabsorption with T score of -2.8 might not be offered bisphosphonates before correcting the reversible causes.

Imaging

Besides the DEXA scan, other radiological tests could be used to support and differentiate the cause of fracture, including pathological and secondary fractures from malignancies. These include conventional radiography, CT (computed tomography (CT) scans, MRI, and bone scan (scintigraphy). Recently, the use of bone turnover markers was introduced as part of monitoring treatment failures or responses. They are not used in isolation as some results are nonspecific, but they could be helpful in complex patient assessments where DEXA scans alone might not be sufficient for decision making. These include serum alkaline phosphatase (ALP) and bone-specific ALP. Serum osteocalcin (a specific marker for osteoblastic function), serum type 1 procollagen, or serum carboxy-terminal collagen crosslinks (CTX) (a marker for bone resorption) are used as treatment response markers.[16] Besides these, there are other bone resorption markers like urinary hydroxyproline, urinary pyridinoline, bone sialoprotein, and few others.

Biopsy

Bone Biopsy, although very specific in identifying the mineralization and microarchitecture of the bone is rarely used for diagnosis of osteoporosis, but are nevertheless included when determining the effects of treatment, bone structure, and turnover in certain clinical contexts. They can establish the safety and efficacy of new treatment modalities if clinically appropriate.

Treatment / Management

Management of osteoporosis in women could be approached with two aspects, namely lifestyle modifications, and pharmacological therapy. The recommended guidelines are based on fracture risk assessment,co-morbidities, and any history of fragility fractures.

Non-Pharmacological Therapy

• Smoking cessation is strongly recommended, as smoking has been strongly associated with bone loss.

• Routine exercise of about 30 minutes per day three to four times a week is recommended and shown to improve Bone Mineral density (BMD).[17] But the positive effects fo exercise on BMD could be reversible on stopping the exercise, so longterm adherence is also equally important. A variety of exercises have shown benefit for improving bone health, but the most effective type of exercise to improved BMD of femur neck is non-weight bearing high force exercise like progressive resistance strength training for the lower extremities, and the most effective exercise for the spine is a combination exercise program.[17]
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• One of the mainstays of treatment of osteoporosis is an adequate dietary intake of calcium and vitamin D. If a woman is not getting about 1200 mg of calcium per day in regular diet intake, she should be supplemented with daily calcium or encouraged to eat calcium-rich foods. Calcium is available mainly dairy products, including milk, cheese yogurt, etc. Calcium supplementation dose is usually 500 mg to 1000 mg per day in single or divided doses. Along with calcium, Vitamin D supplements are also very essential typically given in the form of Vitamin D3 ranging from 400 IU to 800 IU per day, but various dosing regimens are available based on the patient vitamin D levels and other risk factors. Another important aspect of the management of osteoporosis is fall prevention. All patients at risk should be educated and provided adequate help to prevent falls and subsequent fractures.

Pharmacological Therapy: After replacing and supplementing adequate calcium and vitamin D, specific medications for osteoporosis could be initiated based on fracture risk assessment using FRAX as suggested by WHO.

As per the National Osteoporosis Foundation (NOF) guidelines, pharmacological therapy is initiated in any of the three scenarios:

1. Patient with a history of hip or a vertebral fracture

2. T-score less than or equal to -2.5 at femoral neck or spine

3. T-score between -1 and -2.5 with a 10-year probability of more than 3 percent hip fracture or more than 20 percent probability of osteoporosis-related major fracture. 

First-line Therapy

Bisphosphonates are still considered to be the first-line treatment of osteoporosis, which ranges from oral to intravenous use, the commonest ones include Alendronic acid, risedronate, etidronate, ibandronate, pamidronate, and zoledronate.

Although a precise mechanism of action is unsure, the evidence so far with their use is based on two facts. One, its affinity for hydroxyapatite (an essential constituent of the bone mineral matrix) and second, targeting FPP inhibition (farnesyl pyrophosphate synthase), an important enzyme which eventually prevents the formation of essential signaling proteins for osteoclastic activity reducing bone resorption and overall turnover.

Dosing and route of administration of bisphosphonates depend on the specific medication and the formulation, whether it is an immediate release or delayed-release.

• The most commonly used oral bisphosphonates, alendronate, is typically dosed 70 mg once weekly and Risedronate 35 mg weekly.

• Multiple regimens ranging from daily to monthly dosing are available, but most patients prefer to take oral bisphosphonates once-weekly dosing.

• Oral bisphosphonates should be taken on an empty stomach at least half-hour before the first meal of the day with at least 8 oz of water to prevent the pills from getting stuck in the esophagus.

• Zoledronic acid is given intravenous route 5 mg either once yearly or once in two years. Duration of treatment is usually a minimum of three to five years and, after which patients should be closely evaluated for further need and should be considered for a drug-free interval, called “bisphosphonate holiday.”

• For women who remain at high risk of fractures should continue therapy for a maximum of ten years.[18]
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Patients with esophageal motility disorders, including severe hiatal hernia and patients with a history of certain Roux-en-Y gastric bypass surgery, oral bisphosphonates are contraindicated, but intravenous zoledronic acid could be considered.

As the drug has a half-life of over ten years, it can remain for a few years in the body tissues even after stopping. Side effects of bisphosphonate therapy include transient hypocalcemia, bone pain, rare ocular, and renal effects, but few critical side effects of note are osteonecrosis of the jaw and atypical femur fractures after prolonged use.[19](B2)

Other Pharmacological Therapies

• Patients intolerant or contraindicated to bisphosphonates can be offered denosumab, which is preferred in patients with poor renal function. [20] Denosumab is a fully human monoclonal antibody that binds RANKL, preventing RANKL from activating RANK, its receptor on the osteoclast surface. This decreases bone resorption and strengthens bone mass.[21] Denosumab can be given subcutaneously 60 mg once every six months and has shown an advantage over bisphosphonate in increasing the bone density without reaching a plateau level, which happens with bisphosphonates. The disadvantage is that once stopped. There is a paradoxical decline in bone density that can alarm within a short time. This limits its use if considering treatment for a short period.

• Anabolic agents like teriparatide, abaloparatide, (parathyroid hormone or parathyroid hormone-related protein analog) and romosozumab (monoclonal anti-sclerostin antibody) are considered for postmenopausal women who are at very high risk of fracture with a T-score of less than -3.5 or T-score of less than -2.5 plus history of multiple osteoporotic fractures. Teriparatide and abaloparatide must be injected subcutaneously daily, whereas romosozumab is injected once monthly. Also, given in patients who failed other treatment options or hormonal disturbances, especially parathyroid oversecretion. This treatment is given from eighteen months to two years only.[22]

• Raloxifene (selective estrogen receptor modulators - SERMs) is less effective than bisphosphonates, usually considered in less severe osteoporotic postmenopausal women who cannot tolerate bisphosphonates or denosumab and have an increased risk of invasive breast cancer.

• Hormone replacement therapy with estrogen may be advised to postmenopausal women less than ten years from menopause, at low risk of deep vein thrombosis, especially in those who can not take or are intolerant to bisphosphonates or denosumab.[18]
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• Intranasal calcitonin is another option in patients who are not candidates for all the above-mentioned therapies. Calcitonin has shown to significantly reduce vertebral fractures, but long term safety is a concern.[23]
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Surgical Treatment

Few numbers of patients where the pharmacological treatment has not been helpful, especially in at-risk vertebral fractures, well-known procedures from orthopedics can be helpful for stabilization of fractures and pain relief as well. The two commonest one used is

• Kyphoplasty: Baloon is inflated and introduced surgically, and then after the approximation of fractured bone pieces, a material to harden and stabilize the bone is introduced.

• Vertebroplasty: This involves inserting low viscosity cement material directly into the collapsed vertebral body for unstable fractures, to prevent further deformities and loss of height. It is different from kyphoplasty as it does not involve any manipulation of fractured bone pieces before injecting.

As with all surgical procedures, they are not risk-free and can lead to bone cement leak, the persistence of pain, allergic reaction to bone cement, infection, paralysis, or rarely pulmonary embolism.

Differential Diagnosis

Fractures, especially vertebral and atypical fractures, have wide differentials, particularly in the younger age group, and it needs careful evaluation before considering osteoporosis as a primary diagnosis. Important conditions to rule out are leukemias, lymphomas, melanomas, any metastatic malignancy, especially breasts and ovaries.

Other diseases worth considering are some inborn metabolic, genetic disorders, acquired one's like homocystinuria, sickle cell anemia, mastocytosis, Paget disease, hyperparathyroidism, and scurvy.

Prognosis

Prognosis of this disease is good if detected in early phases of bone loss, which can improve with early initiation of treatment with bisphosphonates. However, if detected after hip fracture, the mortality rate increases significantly by 10 to 15 percent, especially in women aged 80 years or older. Because of high disease prevalence, we need to implement early recognition of this condition with proper efforts for prevention and treatment. The commonest fractures are the hip, followed by vertebral fractures.

The incidence of fractures worldwide is, 80% of the forearm, 75% of humerus, 70% of hip, and 58% of spinal fractures. Hip fractures can be debilitating and associated with chronic pain, disability, reduced mobility, and impaired independence as a result of the same with poor quality of life.

Compared with hip fractures, vertebral fractures are associated with an eight-fold increase with age-related mortality. It can lead to intense back pain with chronicity, a decrease in height, deformity, kyphosis, and even reduced lung function as a result of the same. The presence of vertebral fractures increases the risk of further vertebral and non-vertebral fractures. Women having sustained a vertebral fracture are at risk of additional fracture in 1 to 2 years.

Complications

Osteoporotic fractures are associated with high morbidity, increased mortality risk, and significant economic impact. Multiple fractures can severely impair the quality of life in females and can be a severe complication of osteoporosis. Fractures of the hip and spine can limit and disable the patients. Some might have to undergo surgical interventions, including neurosurgical, if fractures cause any spinal canal stenosis or cord compression. Patients with hip fractures have an increased risk of mortality in first-year post fractures.[24]