Glucocorticoid-Induced & Secondary Osteoporosis

The index of suspicion. Most osteoporosis in older women is primary (postmenopausal). You must actively look for a secondary cause when the picture is atypical, because identifying and treating the cause is often more effective than adding another bone drug:

• Men, premenopausal women and children with osteoporosis
• Very low BMD or a fragility fracture out of proportion to age
• Osteoporosis in someone on a culprit drug, especially long-term glucocorticoids
• A relevant systemic disease
• Ongoing bone loss or fracture despite treatment

Glucocorticoids. GIOP is the commonest form of secondary osteoporosis and the commonest iatrogenic cause, with an estimated annual fracture rate of around 5% in treated patients (Saag, 2018). A steroid-treated patient is therefore a standing fracture-risk problem, not an incidental one.

The causes to screen for. The table is the list to run through in the history and the screen that follows.

View larger

Density and quality. Osteoporosis is defined operationally on DXA as a T-score of −2.5 or lower (osteopenia −1 to −2.5), but strength depends on microarchitecture, the number, connectivity and thickness of the trabeculae, not on density alone. GIOP degrades quality more than quantity, which is why glucocorticoid-treated patients fracture at a higher BMD than in postmenopausal osteoporosis and why the T-score under-reads their risk. A 'not that low' T-score is falsely reassuring, so clinical risk is assessed and treatment started early.

View larger

Formation down. Glucocorticoids inhibit Wnt/β-catenin and BMP signalling, diverting mesenchymal precursors to adipocytes rather than osteoblasts, and they cause osteoblast and osteocyte apoptosis. Suppressed formation, alongside increased resorption, is what makes GIOP behave differently from postmenopausal osteoporosis.

Resorption up, early. They also raise the RANKL:OPG ratio, enhancing osteoclast maturation and activity in a relatively early, transient phase.

Indirect effects. Reduced intestinal calcium absorption, increased renal calcium loss and hypogonadism from sex-steroid suppression add to the loss.

The time course. The net result is a rapid early phase of bone loss followed by ongoing formation suppression: loss is fastest in the first months of treatment and partly dose-dependent.

View larger

The screen. Before attributing osteoporosis to age, screen for the common, treatable secondary causes, tailored to the patient. Finding one changes management, because you treat the cause.

• Serum calcium and phosphate, renal and liver function
• 25-hydroxy vitamin D, PTH, TSH
• Testosterone in men
• Coeliac serology
• A myeloma screen (FBC/ESR, protein electrophoresis) where indicated
• Consider 24-hour urinary calcium, cortisol testing and others as the history directs

Reading the screen. In uncomplicated osteoporosis, primary or glucocorticoid-induced, the routine bone biochemistry (serum calcium, phosphate, alkaline phosphatase and PTH) is characteristically normal. The panel is therefore aimed at unmasking the mimics whose biochemistry is abnormal, and an abnormal result moves you off the osteoporosis pathway and onto treating that disease, which is exactly why it is worth sending even when osteoporosis seems obvious.

• Osteomalacia - low or normal calcium, low phosphate, high alkaline phosphatase, high PTH, low vitamin D
• Primary hyperparathyroidism - high calcium with a high PTH
• Paget's disease - an isolated high alkaline phosphatase with normal calcium and phosphate
• Multiple myeloma - high calcium, high ESR and a paraprotein on electrophoresis
• Renal osteodystrophy (CKD) - high phosphate, high PTH, abnormal calcium

Who is assessed. ≥2.5 mg/dprednisolone, ≥3 months is the ACR threshold. For adults starting or continuing glucocorticoids at ≥2.5 mg/day prednisolone-equivalent for ≥3 months, fracture risk is assessed as soon as possible after starting, and the assessment is a triad rather than a T-score:

1. Clinical fracture-risk assessment
2. BMD with vertebral fracture assessment, or a spinal X-ray
3. FRAX if 40 years or older, adjusted for glucocorticoid dose

Adjusting FRAX. For high-dose glucocorticoids, over about 7.5 mg/day, FRAX can be adjusted upward, because standard FRAX underestimates risk at higher steroid doses.

Stratifying. Patients are placed into low, medium, high or very-high fracture risk. A prior fragility fracture, very low BMD and a high FRAX score push them into the higher categories, and the category is what the treatment algorithm acts on.

View larger

View larger

Silent until the first fracture. GIOP is usually asymptomatic until a fragility fracture, characteristically a vertebral compression fracture, the commonest and often the first, with back pain, height loss and kyphosis, but also hip and other low-trauma fractures. Because loss is early and the fracture comes at a higher BMD, the first presentation can be a fracture in someone whose DXA looked only mildly reduced. The practical lesson is to identify the at-risk steroid patient before the fracture, not after it.

View larger

Not steroid osteonecrosis. Glucocorticoids cause two distinct bone problems: generalised osteoporosis, this topic, and focal osteonecrosis (avascular necrosis), classically of the femoral head, through a different mechanism (marrow fat, vascular and apoptotic effects). A steroid-treated patient with new hip or groin pain is worked up for osteonecrosis with MRI, not just sent for a DXA on the assumption that this is osteoporosis.

View larger

Everyone on long-term glucocorticoids. Optimise calcium and vitamin D, apply the lifestyle measures (weight-bearing exercise, stopping smoking, limiting alcohol, falls reduction) and use the lowest effective glucocorticoid dose for the shortest time. These apply regardless of risk category, and throughout treatment the lowest effective dose and treatment of the underlying disease remain the single most effective bone-protective move.

Medium, high and very-high risk. Pharmacological treatment is strongly recommended. The choice among oral or IV bisphosphonates, denosumab or a PTH analogue (teriparatide or abaloparatide) is made by shared decision-making; anabolic agents are conditionally recommended as initial therapy for high and very-high risk, teriparatide having given greater BMD gains and fewer vertebral fractures than alendronate (Saag 2009).

Special populations and sequencing. Children, organ-transplant recipients, those who may become pregnant and very-high-dose glucocorticoid patients have specific recommendations, as do discontinuation and sequential therapy.

Algorithm

View larger

Do not wait. The time course in the pathophysiology is the reason not to delay assessment and treatment until a follow-up DXA shows loss.

Monitoring and duration. Reassess fracture risk and repeat DXA periodically, commonly every 1-2 years while on glucocorticoids or sooner if the steroid dose is high. Re-evaluate when glucocorticoids stop: bone partly recovers, so treatment can sometimes be stepped down once the steroid and its risk are withdrawn, provided the patient is no longer high-risk.

View larger

Prognosis. The fragility fracture is the endpoint GIOP treatment exists to prevent, and it is largely preventable: bone loss is partly reversible, and fracture risk falls with early calcium and vitamin D plus an effective agent and the lowest glucocorticoid dose.

Atypical femoral fracture. The antiresorptives the algorithm recommends carry rare but important long-term complications you should counsel about. An atypical femoral fracture (AFF) is a transverse or short-oblique fracture of the subtrochanteric or diaphyseal femur with minimal trauma, often with prodromal thigh or groin pain, localised lateral cortical thickening ('beaking') and a medial spike, and it is frequently bilateral. It is associated with prolonged bisphosphonate (and also denosumab) use, and it warrants stopping the drug, imaging the contralateral femur and prophylactic fixation of a painful incomplete lesion.

Osteonecrosis of the jaw. Exposed necrotic jaw bone, rare at osteoporosis doses (commoner at oncology dosing) and reduced by dental assessment before and during therapy.

Reviewing therapy. These risks are why therapy is reviewed periodically and a drug holiday considered for bisphosphonates, but not a simple stop for denosumab, for the rebound reason above.