Bones

Age Changes

Bone structure changes throughout life owing to ongoing bone resorption by osteoclasts and bone growth by osteoblasts. With increasing age, the balance is lost, leading to a net increase in bone resorption. This in turn leads to gradual and progressive loss of bone from the age of 35 onwards. This process affects trabecular bone more than cortical bone. In osteoporosis, the molecular composition is similar to normal bone, but the microarchitecture is disorganized so that the bone is fragile and at increased risk of fractures.

Bone loss per year is 0.2% of the total from the age of 35. This rate of loss increases to 1% after the menopause in women. Therefore, on average, by the age of 80 a woman will have lost 30% of her bone mass, whilst a man of the same age will have lost 10%.

The shape of long bones changes with increasing age; the internal cavity increases in diameter, the outer cortical layer becomes thinner and the total bone diameter becomes expanded. These changes result in weaker bones.

Osteoporosis

Risk Factors

Age > 65.
Female sex.
Family history, especially maternal hip fracture.
Failure to maximize by early adulthood because of poor nutrition or oestrogen deficits, e.g. secondary to anorexia nervosa.
Hormonal changes at the menopause: the fall in oestrogen causes a marked acceleration of bone loss. Fractures secondary to osteoporosis affect one in two post-menopausal women.
Previous fragility fractures.
Low body weight (BMI < 19 kg/m²).
Physical inactivity, e.g. following a stroke.
Use of corticosteroids for 3 or more months.
Other drugs especially antiepileptics, aromatase inhibitors for breast carcinoma, anti-androgen treatment and caffeine.
Alcohol intake > 3 units/day.
Smoking.
Endocrine disorders, e.g. thyrotoxicosis, Cushing’s disease, hyperparathyroidism and hypopituitarism.
Chronic disease: CKD, liver disease and COPD.
Malabsorption.
Falls are not a cause of osteoporosis but are strongly predictive of osteoporotic fractures.
Older people often have vitamin D deficiency and secondary hyperparathyroidism, and these are likely to contribute.
The reduction of insulin-like growth factor production is also being investigated as a risk factor.

Osteoporosis in men

• Affects 20% of men over 70.

• One in five men over the age of 50 will sustain a fracture.

• Fifty percent of men affected have idiopathic osteoporosis.

• Of the remaining 50% with secondary osteoporosis, the most common causes are:

hypogonadotrophic hypogonadism;

steroids;

alcohol;

hyperparathyroidism;

malabsorption, e.g. secondary to Crohn’s disease, gastric surgery and coeliac disease.

Clinical Features

Osteoporosis is usually asymptomatic until there has been a fracture:

Fractured neck of femur

• Increasingly common in the ageing population.

• The number predicted worldwide in 2050 is 6.26 million.

• Presents as pain in the hip with inability to weight bear; however, if the fracture is impacted, the patient may still be able to walk.

• The affected leg is shortened because the hip is flexed and externally rotated.

• The fracture is surgically fixed according to its site.

• Evidence suggests that patients should have their surgery within 48 h of admission, during the normal working day. Pre-operative delay leads to a longer length of stay which in turn leads to a higher risk of nosocomial adverse events.

• The patient does best if mobilized early.

• The reasons for the fall should be sought and treated.

• Women over 75 who sustain a fracture should be treated for osteoporosis (NICE).

• The mortality rate at 1 month post fracture is 10%.

• At 1 year, the mortality rate is 25%.

• Twenty percent of people with hip fractures require institutional care.

• Forty percent never regain their full premorbid function.

Fractured pelvis

• Usually the pubic rami. As the pelvis is a ring it is likely to fracture in two places. See Figure 6.2.

• Often caused by trivial trauma.

• Produces pain in the groin that is worse on getting up from sitting and walking.

• Treatment is conservative with analgesia and early mobilization.

• Most heal within 6–8 weeks.

• The mortality rate at 1 year is 15–20%.

• Sadly, patients who have sustained a pelvic fracture are less likely to be considered for treatment of osteoporosis than those with hip fractures.

Often the first presentation is a Colles’ wrist fracture in women aged 50–65.
Vertebral fractures may present as severe mid-thoracic or low back pain often with no history of trauma.
Loss of height and dorsal kyphosis secondary to multiple vertebral fractures. A loss of > 4 cm suggests at least one vertebral fracture.
Contact between ribs and iliac crests.
Hip fractures: rising incidence with increasing age. See Figure 6.1 showing a comminuted fracture of the left hip. The incidence is rising faster than expected from demographic changes. There are now 57,000 cases per annum in the UK – 75% of which are aged over 75.
Other fractures associated with osteoporosis include neck of humerus, pelvis and distal tibia/fibula.

Figure 6.1 Radiograph of a comminuted intertrochanteric fracture of the left hip.

Figure 6.2 X-ray of fractured pelvis.

Investigations

The WHO Fracture Risk Assessment Tool (FRAX) collates clinical information and risk factors to stratify the patient’s risk and determine whether a dual-energy X-ray absorptiometry (DXA) scan would give extra information.

Bone Mineral Density

The DXA scanner measures bone density usually at the proximal femur and lumbar vertebrae (because these are clinically important fragility fractures). Osteoporosis is defined as a bone mineral density (BMD) of greater than 2.5 standard deviations below that of a normal pre-menopausal woman and is expressed as a T score (i.e. T –2.5 SD).

Ultrasound of the Calcaneum

This has the advantage of being inexpensive and portable so that it can be used in the primary-care setting, but it has not been fully validated. It is probably most useful for risk stratification; if the result suggests low bone density, the patient should have DXA scan.

Excluding Causes of Secondary Osteoporosis

If serum calcium is raised, check PTH level to exclude primary hyperparathyroidism (see later).

Thyroid function tests to exclude thyrotoxicosis (see Chapter 12).
Liver and renal function tests.
Bone function tests.
Testosterone: in men with suspected hypogonadotrophic hypogonadism.
ESR, serum immunoglobulins and urinary Bence–Jones protein to exclude myeloma.
Dexamethasone suppression test to exclude Cushing’s disease.

Complications

Fractures, as above.
Pain and reduced mobility.
Deformity: kyphosis, loss of height, abdominal protrusion. Cord compression is very uncommon in this context.
Loss of independence and increased risk of being admitted to a care home.
Use of resources: 25% of UK orthopaedic beds are occupied by patients with fractured hips. The average cost is £25,000 per patient. Fractures in osteoporotic bones now account for over 1 million bed-days annually in the NHS. The cost of treatment of these patients is now more than £5 million per week.

Prevention

Adequate nutrition.
Calcium and vitamin D.
Hormone replacement therapy is most useful in women in early menopause.
Exercise: should be regular and weight-bearing, e.g. brisk walking, Tai Chi.
Stop smoking and moderate alcohol intake.
Prophylactic use of bisphosphonates: if treating with steroids at > 7.5 mg prednisolone for three or more months.

Treatments

Calcium and Vitamin D

The debate regarding the role of calcium and vitamin D in the treatment of osteoporosis rages on. Questions surround the efficacy of both elements and the optimum dose. It has been shown that treatment with calcium and vitamin D prevented hip fractures in older people living in care homes. There is controversy about the role in other populations; research is ongoing. A large meta-analysis of women given calcium and vitamin D demonstrated a modest increase in cardiovascular events. The Scientific Advisory Committee on Nutrition is undertaking a new review of this controversial area.

What is certain is that all the trials demonstrating the efficacy of bisphosphonates, strontium and teriparatide have co-prescribed calcium and vitamin D preparations.

Bisphosphonates

Bisphosphonates, e.g. risedronate and alendronate, work by binding to hydroxyapatite in the bone, which inhibits recruitment of osteoclasts and apoptosis, thus inhibiting bone resorption. Effects are seen in the first 12–18 months of use. Both are shown to increase bone mass of the spine and the hip and to reduce fractures and are indicated in women and men. Weekly preparations are available. This is an advantage because bisphosphonates have to be taken on an empty stomach to ensure absorption. Thus, patients only miss their early morning cup of tea once a week! The patient also has to remain upright for 30 min to reduce the risk of oesophageal ulceration. Ibandronate has the added advantage of being a monthly oral preparation or a 3-monthly injection.

Intravenous zoledronate is given annually. The infusion is usually given in hospital because a few patients developed atrial fibrillation in the drug trials. More common side-effects include flu-like symptoms, fever, headache, diarrhoea and vomiting. Zoledronate is more potent than the other bisphosphonates.

Osteonecrosis of the jaw is a rare complication that seems more likely in patients on high-dose bisphosphonates for carcinoma; however, it is sensible to warn patients to inform their dentists if they are planning any invasive dental treatment.

There is also concern that bisphosphonates may be the cause of atypical subtrochanteric fractures below the neck of femur which produce a characteristic ‘beak’ appearance on the radiograph of the fracture site. Current advice is to reassess the patient’s risk-benefit after 5 years of treatment and consider stopping the bisphosphonate. Bisphosphonates are not recommended if the creatinine clearance is less than 35 ml/h.

Strontium Ranelate

This is thought to increase bone growth and reduce bone loss, although the precise mode of action is unknown. It comes in a sachet to be mixed with water and usually is taken at bedtime. It is an alternative for women over 75 years old who do not tolerate bisphosphonates. Side-effects include diarrhoea, nausea and increased thromboembolic risk.

Teriparatide, Recombinant 1-34 PTH

This is given daily by subcutaneous injection for 18 months. Given intermittently, PTH is anabolic and stimulates osteoblast activity (contrary to the effect of endogenous PTH which is catabolic). Use of teriparatide is restricted to patients with severe disease who have not tolerated or responded to other treatments because it is extremely expensive. Side-effects include gastrointestinal upset. It is contraindicated in renal impairment.

Selective Oestrogen Modulators (SERMs)

SERMS, e.g. raloxifene, act as oestrogen agonists in the bone and liver, but as oestrogen antagonists in the breast and uterus, and therefore increase bone density without increasing the risk of breast or uterine cancer. It reduces the risk of vertebral fractures only. HRT is now only used second line because of the high risk of cancer and heart disease in older women.

Synthetic Analogues of Calcitonin

Given as intramuscular injections, synthetic analogues of calcitonin also inhibit bone resorption. They are not as effective as other agents, so are used as second line. However, they may be a useful adjunct in pain control following an acute vertebral wedge fracture.

Denosumab

A monoclonal antibody to RANK ligand (receptor activator of nuclear factor kappa-B), denosumab is given by subcutaneous injections 6 monthly to post-menopausal women. The mechanism of action is shown in Figure 6.3.

Figure 6.3 The mechanism of action of denusomab. Osteoblasts build bone and have a role in bone resorption by producing RANK ligand (RANKL) and osteoprotegerin. RANKL binds to its receptor RANK and mediates osteoclast differentiation, activation and survival. The protein osteoprotegerin binds to RANKL and functions as an endogenous inhibitor of this pathway. Denosumab is a monoclonal antibody to RANKL and functions like osteoprotegerin, mopping up RANKL and reducing osteoclast activity and decreasing bone resorption.

Side-effects include cellulitis, eczema and a few reports of osteonecrosis of the jaw. Denosumab must not be given without correcting calcium and vitamin D levels. If denosumab is discontinued, the patient must be treated with another preparation, e.g. IV zoledronate, or there is profound rebound bone-remodelling.

Analgesia

This is essential for all osteoporotic fractures.

Secondary Osteoporosis

Treat causes of secondary osteoporosis.

Internal Fixation of Hip Fractures

The most appropriate type of fixation depends on the fracture site.

Balloon Kyphoplasty

This is a treatment for vertebral collapse; it restores the vertebral body height, reduces pain rapidly and thus enables the patient to mobilize early.

Concordance

Concordance with calcium and vitamin D preparations and bisphosphonates is extremely poor even 3 months after they are first prescribed. Explaining the rationale to patients may improve this. Different preparations of vitamin D and calcium are available including soluble and capsule forms as well as the familiar chalky tablets, so it is worth trying to find the most palatable for an individual. It may be worth considering monthly or yearly bisphosphonates or denosumab injections; as expensive as these treatments are, they are cheaper than hospital admissions following fractures.

Patient Education

Encourage patients to stop smoking, reduce their alcohol intake and increase their weight-bearing activity.

Prevention of Further Fractures

Treatment of osteoporosis.
Exercise programmes.
Falls prevention strategies (see Chapter 5).
The benefit of hip protector pads is controversial (see Chapter 5).

Osteomalacia

This is reduced calcification of the osteoid matrix due to vitamin D deficiency. The amount of bone is normal, but it is soft and weak compared with normal bone.

Incidence

Incidence is uncertain and depends on the population studied:

Admissions to Scottish departments of geriatric medicine, 4%.
Post-mortem study of elderly patients, 12%.
Biopsies on fractured neck of femur patients, 25%.

Causes

Reduced Vitamin D Availability

Deficient diet.
Reduced sun exposure: most common in Muslim and Hindu cultures (where women cover their heads) and in institutionalized elderly people. Ultraviolet light converts 7-dehydrocholesterol to previtamin D₃ and then to vitamin D₃ (cholecalciferol).
Ten to fifteen minutes’ exposure to sunlight is sufficient to replenish the body’s stores.
Vitamin D binding protein carries D₂ and D₃ to the liver which converts it to 25-hydroxyvitamin D. Then 1-alpha-hydroxylase in the proximal tubule of the kidney converts it to 1, 25-dihydroxycholecalciferol.
Malabsorption of vitamin D in food and medications occurs in coeliac disease, diverticular disease of the small bowel and post-gastrectomy.

Impaired Vitamin D Metabolism

Chronic kidney disease (reduced activity of 1-hydroxylation).
Drugs that induce liver enzymes, e.g. phenytoin and carbamazepine.