Secondary causes of osteoporosis should be considered in patients who suffer a fragility fracture when ‘traditional’ risk factors are insufficient to explain the injury. People with a bone mineral density Z-score –2.5 or less may also have secondary osteoporosis. (The Z-score is a comparison to age-matched, sex-matched individuals.)
Clues to an underlying secondary cause include an atypical fracture, the severity of osteoporosis and the presence of clinical features found through history and clinical examination (e.g. anaemia, malabsorption, amenorrhoea, constitutional symptoms or specific endocrinopathies) (see Table). A careful drug history may identify possible causes. While corticosteroids are well known to cause osteoporosis and fragility fractures, a number of other drugs also increase fracture risk (see Box). However, not all patients with secondary osteoporosis will present with the classic signs of the underlying condition. They may have subclinical disease at the time of their fracture or when the low bone mineral density is detected, with osteoporosis being the first manifestation of their underlying condition.
Table Secondary causes of osteoporosis
Disorder
|
Most common fracture site
|
Primary mechanism
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Inflammatory conditions
|
Rheumatoid arthritis, systemic lupus erythematosus
|
Hip
|
High bone turnover due to pro-inflammatory cytokines
|
Crohn’s disease, ulcerative colitis
|
Vertebrae
|
High bone turnover due to pro-inflammatory cytokines, malnutrition and malabsorption
|
Hypogonadism
|
Premature menopause (auto-immune, surgical, drugs)
|
Distal radius (Colles), vertebrae
|
High bone turnover from low oestrogen or low testosterone
|
Hypopituitarism (structural or functional)
|
Distal radius (Colles), vertebrae
|
High bone turnover from low oestrogen or low testosterone
|
Endocrinopathies
|
Hypercortisolaemia (Cushing’s syndrome)
|
Vertebrae, ribs
|
Low bone turnover from impaired bone formation and mineralisation
|
Hyperthyroidism
|
Hip
|
High bone turnover from increased bone resorption
|
Primary hyperparathyroidism
|
Distal radius, vertebrae
|
High bone turnover from increased bone resorption
|
Hyperprolactinaemia
|
Distal radius, vertebrae
|
High bone turnover from oestrogen deficiency
|
Acromegaly
|
Vertebrae
|
High bone turnover, increase in bone size and co-existing secondary hypogonadism
|
Diabetes mellitus
|
Hip
|
Low bone turnover from insulinopenia in type 1, mechanism not well understood in type 2
|
Malabsorption
|
Pernicious anaemia
|
Vertebrae
|
Low bone turnover from impaired osteoblast recruitment
|
Coeliac disease
|
Distal radius, vertebrae
|
High bone turnover due to malnutrition and malabsorption
|
Gastrectomy
|
Vertebrae
|
High bone turnover due to malnutrition and malabsorption
|
Haematological conditions
|
Multiple myeloma and monoclonal gammopathy of unknown significance
|
Vertebrae
|
Uncoupling in bone turnover (high bone resorption and low bone formation) from pro-inflammatory cytokines
|
Myeloproliferative disorders
|
Vertebrae
|
Direct marrow effects on bone
|
Systemic mastocytosis
|
Vertebrae
|
High bone turnover from mast cell mediators
|
Abnormal bone architecture
|
Paget’s disease
|
Long bones
|
High bone turnover from overactive bone resorption
|
Osteopetrosis
|
Hip, long bones
|
Low bone turnover due to defective bone resorption
|
Malignancy (primary or secondary)
|
Affected bones
|
High bone turnover from paraneoplastic effects
|
Other conditions
|
Chronic liver disease
|
Vertebrae
|
Low bone turnover from liver disease and increased bone resorption due to malabsorption, vitamin D deficiency and hypogonadism
|
Chronic kidney disease
|
Hip, vertebrae
|
High bone turnover from osteomalacia, secondary hyperparathyroidism or mixed bone disease, or low bone turnover from adynamic bone disease (from aluminium or iron)
|
Kidney transplantation
|
Vertebrae, small bones
|
High bone turnover and tertiary hyperparathyroidism
|
Box Drugs that increase fracture risk
Corticosteroids (≥5 mg prednisolone daily or equivalent for ≥3 months)
Antiepileptics: carbamazepine, phenytoin, phenobarbitone
Hypoglycaemics: thiazolidinediones, empagliflozin
Selective serotonin reuptake inhibitors
Excess thyroxine
Aromatase inhibitors
Tamoxifen (when used in pre-menopausal women)
Gonadotropin-releasing hormone
Chemotherapy
Immunosuppressants: cyclosporine, tacrolimus, methotrexate
Lithium
Heparin
Proton pump inhibitors
Aluminium-containing antacids
Depot medroxyprogesterone acetate
Antipsychotics
|
Identifying the cause
When a patient has clinical evidence of an underlying cause of osteoporosis, the necessary investigations may be straightforward. In an otherwise healthy patient with no specific clinical signs, a range of investigations may be required to identify a secondary cause of osteoporosis.
The prevalence of undiagnosed secondary causes of osteoporosis is unknown and there are no guidelines regarding appropriate laboratory tests for the otherwise healthy patient. In any patient suspected of having secondary osteoporosis, most experts recommend evaluation of bone and mineral metabolism with blood tests for calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D, parathyroid hormone, liver and kidney function, full blood count and thyroid-stimulating hormone.
In those with severe osteoporosis (multiple fractures or bone mineral density T-score <–3.0) without specific clinical findings, additional tests should be performed. These tests include serum protein electrophoresis, free light chain assay, markers of inflammation, coeliac serology and total IgA, sex steroids (testosterone in men and oestradiol in women) and 24-hour urinary free cortisol.3-7 A 24-hour urinary calcium collection is indicated if there are abnormalities of serum calcium or parathyroid hormone.
The role of bone turnover markers, such as telopeptides, in the diagnosis of osteoporosis is controversial. Currently, in specialists’ clinics, their clinical role is in monitoring treatment efficacy.8
Several small cross-sectional studies have evaluated the yield of combined laboratory investigations in identifying an underlying cause of osteoporosis in otherwise asymptomatic patients. In studies of 1739
and 2044 postmenopausal women, the three most common findings were hypercalciuria, malabsorption (vitamin D deficiency) and hyperparathyroidism.
In the study of 204 women, hyperparathyroidism was detected in 35%, although less than 10% had primary hyperparathyroidism with hypercalcaemia.4 A cost-benefit analysis of the investigations was not performed in either of these studies.4,9 There are no large studies assessing the frequency and cost–benefit of investigations for secondary osteoporosis.
Bone biopsy
In the past, bone histomorphometry was commonly used to assess the severity of osteoporosis before the advent of dual energy X-ray absorptiometry.
Bone biopsies are now rarely performed. In a highly select group of patients, bone biopsy performed and interpreted by an experienced specialist is useful in establishing the underlying aetiology and appropriate therapy of atypical cases if non-invasive methods have been inconclusive. Bone histomorphometry is a specialist tool to diagnose and assess:
- osteomalacia
- renal bone disease
- bone turnover (to differentiate between low- and high-turnover osteoporosis) with potential impact on therapeutic options.
In one specialist centre, 99 transiliac bone biopsies were performed over 14 years on ‘atypical’ cases of osteoporosis.
This represented 0.003% of patients reviewed for bone-related consultations.
Bone marrow and trephine biopsy is only required to exclude an underlying haematological cause for osteoporosis such as plasma cell dyscrasia, lymphoma or mastocyte disorders which will require specific therapies.