Bone Disease: Screening and Diagnosis

Osteoporosis

• Postmenopausal women and men age ≥ 50 years with BMD T-score ≤ -2.5 at hip or lumbar spine
• Premenopausal women and men age < 50 years with BMD Z-score ≤ -2 at hip or lumbar spine and fragility fracture

Characteristics

• Reduced bone mineral density (BMD), altered bone quality and reduced bone strength
• Increased risk of fractures
• Asymptomatic until fractures occur
• Aetiology is multifactorial
• Loss of BMD is observed with ART initiation (mainly during the 1st year)
• Greater loss of BMD with initiation of certain ARVs⁽ⁱ⁾

Risk factors

1. Postmenopausal women 
2. Men ≥ 50 years 
3. High risk for falls^(iv)
4. Those with high fracture risk (>20% 10-year major osteoporotic fracture risk based on FRAX assessment, including bone dual energy X-ray absorptiometry (DXA) in the FRAX assessment, when possible)
5. History of low impact fracture
6. Clinical hypogonadism (symptomatic, see Sexual Dysfunction)
7. Oral glucocorticoid use (minimum 5 mg/day prednisone equivalent for >3 months) 

Diagnostic tests

• Consider classic risk factors⁽ⁱⁱ⁾ and estimate fracture risk using FRAX in people ≥ 40 years
• Consider DXA in any person if ≥ 1 of the risk factors above⁽ⁱⁱⁱ⁾:
• DXA scan:
  • In those with classic risk factors who require DXA, where feasible consider DXA scan prior to ART initiation or soon after initiation
  • Add DXA result to FRAX^® to refine fracture risk prediction (https://frax.shef.ac.uk/FRAX/)
    - May underestimate risk in persons with HIV
    - Consider using HIV as a cause of secondary osteoporosis^(v)
    - Trabecular Bone Score (TBS: derived from DXA scan result) may also be added to FRAX^® risk prediction.

Rule out causes of secondary osteoporosis if history of fracture and/or low BMD^(vi)

• Assess for vertebral fracture on lateral DXA images or lateral spine X-rays (lumbar and thoracic) if low BMD, significant height loss (≥4 cm), kyphosis or age ≥70 years. 

Osteomalacia

Characteristics

• Defective bone mineralisation
• Associated with vitamin D deficiency
• Increased risk of fractures and bone pain
• Vitamin D deficiency may cause proximal muscle weakness

Risk factors

• Dark skin
• Dietary deficiency
• Avoidance of sun exposure
• Malabsorption
• Chronic kidney disease
• Renal phosphate wasting^(vii)

Diagnostic tests

• Measure serum calcium, phosphate, alkaline phosphatase and 25 (OH) vitamin D, see Vitamin D Deficiency. If deficient or insufficient, check PTH levels and consider vitamin D replacement if clinically indicated, see Vitamin D Deficiency

Osteonecrosis

Characteristics

• Infarct of epiphyseal plate of long bones resulting in acute bone pain
• Rare but increased prevalence in persons with HIV

Risk factors

• Low CD4 count
• Glucocorticoid exposure 
• IVDU
• Alcohol
• Blood coagulation disorders

Diagnostic tests

• MRI

Footnotes:

1. Greater loss of BMD observed with initiation of regimens containing TDF and some PIs. * Additional loss and gains in BMD observed with switch to and away from TDF-containing ARV regimens, respectively. Clinical relevance to fracture risk not determined. TAF is associated with less bone loss than TDF.
   * There are limited data on use of PIs and changes after their replacement. Consider replacing TDF if:
   - Osteoporosis / progressive bone loss
   - History of fragility fracture 
2. Classic risk factors: older age, female gender, hypogonadism, family history of hip fracture, low BMI (≤ 19 kg/m2), smoking, physical inactivity, history of low trauma fracture, alcohol excess (> 3 units/day), glucocorticoid exposure (minimum prednisone 5 mg/qd or equivalent for > 3 months)
3. If BMD T-score normal (≥ -1), repeat DXA after 3-5 years in risk groups 1, 2 and 3; no need for re-screening with DXA in risk groups 4, 5 and 6 unless risk factors change and only rescreen group 7 if glucocorticoid use is ongoing:
   Risk groups:
   1. Postmenopausal women 
   2. Men ≥ 50 years 
   3. High risk for falls^(iv)
   4. Those with high fracture risk (>20% 10-year major osteoporotic fracture risk based on FRAX assessment, including bone dual energy X-ray absorptiometry (DXA) in the FRAX assessment, when possible)
   5. History of low impact fracture
   6. Clinical hypogonadism (symptomatic, see Sexual Dysfunction)
   7. Oral glucocorticoid use (minimum 5 mg/day prednisone equivalent for >3 months)
4. See Falls
5. If including BMD within FRAX, entering yes in the ‘secondary cause’ box will not be considered in the FRAX algorithms, as it is assumed that secondary osteoporosis affects fracture risk solely through BMD. However, if the contribution of HIV infection to fracture risk is partially independent of BMD, fracture probability may be underestimated by FRAX
6. Causes of secondary osteoporosis include hyperparathyroidism, vitamin D deficiency, hyperthyroidism, malabsorption, hypogonadism or amenorrhoea, diabetes mellitus, chronic liver disease and chronic kidney disease
7. Use of TDF is associated with cases of renal phosphate wasting. For diagnosis and management of renal phosphate wasting, see Indications and Tests for Proximal Renal Tubulopathy (PRT)

Approach to Reducing Risk of Fracture

Approach to Fracture Reduction

Persons at high risk of fractures: • Frail or sarcopenic persons • Previous fracture, particularly if recent • Low BMD • High FRAX score (refer to national guidelines) • High falls risk

• Aim to decrease falls by addressing frailty and fall risks(i) • Consider bisphosphonate(ii)    - Treatment based on fracture history and FRAX score (see section on Bone Disease: Screening and Diagnosis)    - Ensure adequate calcium and vitamin D intake(iii) • Consider choice of ARV in those at high risk of fractures(iv)    - No significant interactions between bisphosphonates and ARVs • Optimal management of frailty includes optimising nutrition, exercise (aerobic and resistance training), see section on Frailty • In complicated cases (e.g. young men, premenopausal women, recurrent fracture despite bone protective therapy), refer to osteoporosis specialist • If on bisphosphonate treatment, repeat DXA after 2 years. Persons without response to treatment refer to osteoporosis specialist for second line treatment. Re-assess need for continued treatment after 3-5 years

1. See Falls and Diagnosis and management of vitamin D deficiency
2. Bisphosphonate treatment with either of oral alendronate 70 mg once weekly; oral risedronate 35 mg once weekly; oral ibandronate 150 mg once a month or 3 mg intravenously every 3 months; zoledronate 5 mg intravenously once yearly
3. See Diagnosis and management of Vitamin D deficiency
4. See Bone Disease: Screening and Diagnosis; some ARVs can affect BMD but relationship to increased fractures are not well defined. Consider relative risk/benefit of using these agents in persons with high fracture risk

Vitamin D Deficiency

Diagnosis and Management

Vitamin D	Test	Therapy(i)
Deficiency: < 10 ng/mL (< 25 nmol/L)(ii)   Insufficiency: < 20 ng/mL (< 50 nmol/L)	Serum 25-hydroxy vitamin D (25[OH]D). If deficient, consider checking parathyroid hormone (PTH), calcium, phosphate(iii), alkaline phosphatase	If vitamin D deficient, replacement recommended. Various regimens suggested(iv) Supplementation with vitamin D may reduce bone loss with initiation of ART, see Bone Disease: Screening and Diagnosis Consider re-checking 25(OH) vitamin D levels 3 months after replacement. After replacement, maintenance with 800-2000 IU vitamin D daily
Factors associated with lower vitamin D: Dark skin Dietary deficiency Avoidance of sun exposure Malabsorption Obesity Chronic kidney disease Some ARVs(v)	Check vitamin D status in persons with history of: low BMD and/or fracture high risk for fracture Consider assessment of vitamin D status in persons with other factors associated with lower vitamin D levels (see left column)	Replacement and/or supplementation of vitamin D is recommended for persons with both vitamin D insufficiency(vi) and one of the following: osteoporosis osteomalacia increased PTH (once the cause has been identified) Consider re-testing after 6 months of vitamin D intake

 

1. Can be provided according to national recommendations/availability of preparations (oral and parenteral formulations). Combine with calcium where there is insufficient dietary calcium intake. Consider that in some countries food is artificially fortified with vitamin D
2. Vitamin D insufficiency has a prevalence of up to 80% in HIV cohorts and was associated with increased risk for osteoporosis, type 2 diabetes, mortality and AIDS events. However, causal association not proven for all outcomes. Consider seasonal differences (in winter approximately 20% lower than in summer)
3. Consider that hypophosphataemia can be associated with TDF therapy. This phosphate loss through proximal renal tubulopathy may be independent of low vitamin D, see Indication and Tests for Proximal Renal Tubulopathy. A combination of low calcium + low phosphate +/- high alkaline phosphatase may indicate osteomalacia and vitamin D deficiency
4. Expect that 100 IU vitamin D daily leads to an increase in serum 25(OH) vitamin D of approximately 1 ng/mL. Some experts prefer a loading dose of e.g. 10,000 IU vitamin D daily for 8-10 weeks in persons with vitamin D deficiency. The principal goal is to achieve a serum level > 20 ng/ mL (50 nmol/L) and to maintain normal serum PTH levels. Combine with calcium where potential for insufficient dietary calcium intake. The therapeutic aim is to maintain skeletal health; vitamin D supplementation has not been proven to prevent other co-morbidities in persons with HIV
5. The role of HIV-therapy or specific drugs remains unclear. Some studies suggest an association of EFV with reductions in 25(OH)D but not 1,25(OH)D. PIs may also affect vitamin D status by inhibiting conversion of 25(OH)D to 1,25(OH)D
6. The implications of vitamin D levels that are below the physiological reference range but not markedly reduced and the value of supplementation in that situation are not completely understood