Editors

Anna-MariKoski

Osteoporosis

Essentials

Bone health is important throughout a person's life.
Before fracture, osteoporosis can only be diagnosed by bone mineral density (BMD) measurement.
A fracture risk assessment should be carried out and bone-protective medication started if indicated in the presence of co-existing medical conditions or medication associated with bone loss, or a history of a low-trauma fracture. The FRAX (Fracture Risk Assessment Tool) calculator can be used for assessing the fracture risk http://frax.shef.ac.uk/FRAX/.
All units treating fractures should arrange osteoporosis screening in order to prevent further fractures, using osteoporosis specialist nurses, for instance.

Definitions

Osteoporosis is characterised by a decrease in bone strength so that the risk of fracture is increased. Bone strength is influenced both by the quantity (density) and quality of bone.
In osteoporosis without fracture the bone mineral density is reduced to the osteoporotic level (T score ≤ -2.5) but the patient has no fracture history.
A low-energy fracture is caused by an amount of energy equivalent to falling from standing height or from a height of less than one metre.

Diagnosis

Osteoporosis is diagnosed by measurement of bone mineral density (BMD). In some cases, treatment may be started without the BMD test.
In osteoporosis the bone density is 2.5 SD or more below the mean bone density value in women aged 20-40 years (T score ≤ -2.5). Osteoporosis can be diagnosed according to the lowest T score either from the lumbar spine (L1-L4 or L2-L4) or the proximal femur (femoral neck or total femur).
The BMD test indicates osteopenia if bone mineral density is 1-2.5 SD below the above mean density (-2.5 < T score < -1).

Assessment of fracture risk

Clinical risk factors can be used in combination with a BMD to assess the fracture risk. A fracture risk assessment tool (FRAX) is available http://frax.shef.ac.uk/FRAX/. The FRAX tool uses the patient's risk factors to calculate the 10-year probability of fracture.

Aetiology and differential diagnosis

Osteoporosis may be primary (advancing age, idiopathic) or secondary. Principal causes of secondary osteoporosis are listed in table T1. Moreover, general risk factors for a fracture must be considered: age, low levels of physical activity, vitamin D deficiency, low body weight, family history, increased propensity to fall, smoking, excessive alcohol intake (≥ 3 units/day), a history of a fracture or height loss (≥ 4 cm).
After osteoporosis has been diagnosed, secondary osteoporosis should be excluded with the following laboratory tests:
- ESR and basic blood count with platelet count
- ionized or albumin-corrected Calcium and ALP
- for men, serum testosterone (morning sample), as considered clinically appropriate
- plasma creatinine and eGFR (calculator Gfr Calculator)
- 25-OH vitamin D
- screening for coeliac disease (such as anti-transglutaminase antibodies)
- as necessary, thyroid function tests, parathyroid hormone, PTH, short 1-1.5 mg dexamethasone test to exclude Cushing's syndrome, serum and urine protein electrophoresis to exclude myeloma.

Risk factors for secondary osteoporosis. Modified from: Current Care Guideline on Osteoporosis, 2021 (referenced on 3.3.2021).

Drugs	Glucocorticoids Heparin Antiepileptic drugs Calcineurin inhibitors GnRH agonists Aromatase inhibitors
Endocrine disorders	Hypogonadism Hypercortisolism Hyperthyroidism Growth hormone deficiency Diabetes Primary hyperparathyroidism
Neuromuscular disorders	Cerebral palsy Duchenne´s muscular dystrophy and spinal muscular atrophy (SMA)
Haematological disorders	Leukaemia Thalassaemia Myeloma Stem cell transplantation
Bowel and eating disorders	Coeliac disease Inflammatory bowel diseases Eating disorders Malnutrition Short-bowel syndrome Sequela of gastrectomy
Other chronic disorders	Kidney or liver failure Rheumatic diseases Cystic fibrosis Cyanotic heart diseases Metabolic diseases
Organ transplantation

Treatment of osteoporosis

Basic treatment , Exercise for Osteoporosis in Postmenopausal Women, Vitamin D with or Without Calcium Supplement for Preventing Fractures, Exercise after Osteoporotic Vertebral Fracture

Exercise, adequate calcium and vitamin D intake, stopping smoking and prevention of falls
Calcium should primarily be obtained from diet: 2 dl of milk contains about 250 mg and a small slice of cheese (5 g) about 50 mg of calcium. An average of 300 mg of calcium/day is derived from food sources other than dairy. Dietary calcium intake can be assessed using a calcium calculator. Use a calculator relevant for locally available foods and drinks. The aim is 1 000-1 500 mg/day.
The requirement for vitamin D varies. The target level for serum 25-OH vitamin D in patients with osteoporosis is 75-120 nmol/l. For patients over 75 years of age the recommended minimum dose is 20 μg/day, the maximum dose is 100 μg/day.

Pharmacological intervention Inhaled Corticosteroids and Risk of Fractures, Menopausal Hormone Therapy in the Prevention Fractures

Aims

The aim of treatment in osteoporosis is to prevent fractures, especially vertebral and hip fractures.

Indications for pharmacological intervention

History of a low-trauma vertebral or hip fracture
- BMD measurement is recommended but medication may be started without it, provided that a cancer-induced pathological fracture and other secondary causes of osteoporosis have been excluded.
- In the case of vertebral fracture, the radiological fracture severity must be moderate or severe (Genant 2-3) but how recent the fracture is is of no consequence for the treatment decision. In the case of a milder vertebral fracture, the patient's symptoms and clinical examination must suggest a recent vertebral fracture (see picture 1).
- BMD measurement is recommended particularly if life expectancy is over 5 years.
Other low-trauma fracture (for example, wrist, upper arm)
- Osteoporosis should be confirmed with a BMD measurement before treatment is started.
- If BMD measurement indicates osteopenia, see section 4.
- If BMD measurement is not available, see section 5.
A BMD test indicating osteoporosis (T score ≤ -2.5 SD).
- The patient's overall situation and fracture risk must be taken into account.
A BMD test indicating osteopenia (-2.5 SD < T score < -1 SD) in a patient with many clinical risk factors for a fracture. The FRAX risk calculator, for instance, should be used to assess the risk of fracture http://frax.shef.ac.uk/FRAX/. If the patient's fracture risk is high, pharmacotherapy may be considered. The NOGG guideline included in the FRAX risk calculator can be used to assess pharmacotherapy. (Notice that the calculator gives different results depending on the country selected and that guidelines are associated with only some countries. The NOGG is also available at http://www.sheffield.ac.uk/NOGG/result-nobmd.html without association to a specific result.)
If the patient's fracture risk is high but bone densitometry is difficult to arrange, pharmacotherapy may be regarded as indicated if recommended by the NOGG guideline (see above).
Patients on glucocorticoids
- See below for the treatment of glucocorticoid-induced osteoporosis here

Pharmacotherapy in practice

Pharmacotherapeutic alternatives
- Oral medication
  - Alendronate and risedronate once weekly
  - Ibandronate once monthly
- Denosumab administered subcutaneously twice yearly
- Zoledronic acid (zoledronate) administered intravenously once yearly
- Parathyroid hormone (teriparatide) for the management of severe osteoporosis, administered subcutaneously daily for 24 months
- Romosozumab for the management of severe osteoporosis, administered subcutaneously once a month for 12 months
Oestrogen and testosterone correct bone problems caused by their deficiency.

Bisphosphonates Alendronate for the Primary and Secondary Prevention of Osteoporotic Fractures in Postmenopausal Women, Effects of Continuing or Stopping Alendronate after 5 Years of Treatment, Risedronate for the Prevention of Osteoporotic Fractures in Postmenopausal Women, Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis

Bisphosphonates inhibit the functioning of osteoclasts and reduce their numbers. The functioning of osteoblasts is also inhibited.
The most important adverse effects are gastrointestinal symptoms. Osteonecrosis of the jaw and atypical femoral fracture are rare adverse effects.
Contraindications: hypocalcaemia, abnormalities of the oesophagus, inability to be in an upright position for ≥ 30 minutes. Bisphosphonates are not recommended for patients with severe renal insufficiency (eGFR < 30-35 ml/min) or ones who are pregnant or breast-feeding.
Regular dental check-ups and appropriate preventive dental care are recommended with bisphosphonate treatment. Bone-protective medication, when indicated, is started right away and the patient is referred for a dental check-up according to the local procedure.
Intravenously administered zoledronate may be used where oral medicines are not suitable, their absorption is impaired or in patients with poor treatment compliance. Adverse effects associated with the infusion may include a febrile reaction, flu-like symptoms, muscular and joint pains as well as headaches, which can be relieved with paracetamol or NSAIDs. Adequate hydration as well as calcium and vitamin D intake must be ensured with the infusion.
Treatment period
- 3-5 years, after which a bone densitometry is carried out and the fracture risk is evaluated. A pause of 1-2 years in medication should be considered. After ta medication pause bone densitometry should be repeated.
- If the fracture risk is still high after 3-5 years of treatment, the therapy should either be continued or intensified by changing the drug to another one.
- In special cases, bisphosphonate treatment may continue for 10 years (prevention of vertebral fracture).

Denosumab

Denosumab (a monoclonal antibody that binds to RANK ligand) inhibits the functioning of osteoclasts and shortens their lifespan.
The most important adverse effects: hypocalcaemia, dermatitis, atypical femoral fracture, osteonecrosis of the jaw
Regular dental check-ups and appropriate preventive dental care are recommended with denosumab treatment. Bone-protective medication, when indicated, is started right away and the patient is referred for a dental check-up according to the local procedure.
Contraindications: hypocalcaemia. The product is not recommended for pregnant or breast-feeding patients.
No limitation regarding the treatment period. The length of treatment should be considered for each patient on an individual basis. In most cases the first treatment period lasts 3-5 years.
Stopping denosumab treatment may sometimes provoke a vertebral fracture. It is therefore recommended that when denosumab is discontinued it should be followed by a bisphosphonate for one year, at least, and the basic treatment of the skeletal system should be revisited and follow-up organised.

Teriparatide Teriparatide for the Prevention of Fractures in Postmenopausal Women

The parathyroid hormone analogue is an anabolic (bone growing) agent that stimulates the functioning of osteoblasts
Reimbursement may require a medical statement by a specialist.
Duration of treatment 24 months.
The most important adverse effects: nausea, limb pain, dizziness, hypercalcaemia
Contraindications: hypercalcaemia, unexplained elevation of alkaline phosphatase, metabolic bone disease (including hyperparathyroidism and Paget's disease of bone) or a malignant bone tumour, radiation therapy to the skeleton, severe renal insufficiency (GFR < 30 ml/min), pregnancy and breast-feeding

Romosozumab

Romosozumab is a humanized IgG2 anti-sclerostin antibody. Sclerostin inhibits the functioning of osteblasts.
Romosozumab increases bone formation (anabolic effect) by increasing the number and activity of osteoblasts and simultaneously inhibits bone breakdown (antiresorptive effect) by reducing osteoclast activity.
Romozozumab is indicated in postmenopausal women at high risk of bone fracture.
Romozumab is more effective than alendronate in preventing fractures and more effective than teriparatide in increasing bone density.
Check local policies concerning reimbursement of the drug.
Romozozumab is administered in two subcutaneous injections of 105 mg (210 mg in total) once a month. The duration of treatment is 1 year.
The most important adverse effects: hypocalcaemia, myocardial infarction, stroke. Atypical femur fracture and osteonecrosis of the jawbone have also been described as rare cases.
Regular dental check-ups and appropriate preventive dental care are recommended with romozozumab treatment. Bone-protective medication, when indicated, is started right away and the patient is referred for a dental check-up according to the local procedure.
Contraindications: hypocalcaemia, hypersensitivity to the active substance, history of myocardial infarction or stroke

Monitoring and duration of treatment

The treatment plan should be drawn up together with the patient with osteoporosis.
Treatment usually lasts for several years and requires a motivated patient as well as the monitoring of the patient for possible adverse effects and the occurrence of treatment endpoints (fractures). The effect of the pharmaceutical intervention may be monitored with a BMD test roughly every 2-3 years.
The duration of the pharmaceutical therapy is individual and dependent on clinical parameters and the agent chosen (see above).

Glucocorticoid-induced osteoporosis Calcium and Vitamin D for Corticosteroid-Induced Osteoporosis, Bisphosphonates for Steroid Induced Osteoporosis

Systemic glucocorticoid treatment is associated with a significant reduction in bone density and an increased fracture risk.
Specific bone-protective medication should be considered if the planned duration of glucocorticoid treatment is more than 3 months and the prednisolone dose at least 2.5 mg/day. See picture 2.
- Bone-protective medication is started for persons over 40 years of age if their fracture risk is estimated as high e.g with FRAX calculator http://frax.shef.ac.uk/FRAX/, and the NOGG guidance of the risk calculator recommends pharmacotherapy (see note about NOGG above). A high fracture risk is also indicated by osteoporotic-level bone density. In certain patient groups, the risk of fracture in association with glucocorticoid treatment is so high that bone-protective medication should be considered even if such further examinations (DXA, FRAX) would not be available. Such groups include patients
  - of 70 or more years of age
  - with a history of low-energy fracture in adulthood
  - with glucocorticoid therapy at a dose of at least 7.5 mg prednisolone/day.
- In persons below 40 years of age the FRAX calculator cannot be used to assess fracture risk and need for pharmacotherapy. In this group, fracture risk should be assessed by the presence of an earlier fracture, bone density and clinical parameters.
The fracture risk is high even during a shorter course of glucocorticoids if the patient has several other risk factors.
The bone-protective treatment should be started at the onset of glucocorticoid therapy in patients at an increased risk of fracture. The bone-protective therapy is withdrawn when glucocorticoid therapy is stopped, unless the fracture risk is high for other reasons.
- Drugs indicated for glucocorticoid-induced osteoporosis include bisphosphonates, denosumab and teriparatide. The levels of sex hormones should be determined and replacement therapy considered.
- Discontinuation of denosumab is associated with a rebound phenomenon due to a strong activation of osteoclasts. Therefore, a 1-2 year bisphosphonate treatment is always recommended as a follow-up after discontinuation of denosumab. If denosumab treatment has lasted at least 2.5 years or the patient is otherwise at high risk of fracture, the use of zoledronate is recommended.

Osteoporosis in patients with age-related frailty syndrome

There are several meters available for assessing age-related frailty, such as the Clinical Frailty Scale (CFS) http://www.mdcalc.com/csha-clinical-frailty-scale-cfs.
There is no reliable evidence on pharmacotherapy of osteoporosis in this patient group because patients of very advanced age, with multiple diseases, impaired functional capacity or age-related frailty are usually excluded from therapeutic trials.
In patients with age-related frailty, it is important to guarantee sufficient intake of calcium, vitamin D and proteins and to take care of reducing a multifactorial risk of falling. Weight loss should be stopped. The decision to start medication for osteoporosis should be made after ensuring that its probable advantages for preserving functional capacity and quality of life are greater than its disadvantages.

Osteoporosis in children

In children, the Z score is used instead of the T score in bone density measurement.
Compression fracture of the spine without high-energy injury or local vertebral abnormality is sufficient to diagnose osteoporosis in children regardless of bone density.
A referral to specialist care is indicated if a child presents with a vertebral fracture or a child under 10 years has at least 2, or a child not older than 19 years has at least 3, long bone fractures.

References

Black DM, Rosen CJ. Clinical Practice. Postmenopausal Osteoporosis. N Engl J Med 2016;374(3):254-62. [PubMed]
Buckley L, Guyatt G, Fink HA ym. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol 2017;69(8):1521-1537. [PubMed]