The enzyme lysosomal acid lipase is responsible for triacylglycerol and cholesteryl ester hydrolysis in the lysosome. Without it functioning optimally, ectopic lipid accumulation begins to occur in the liver, spleen, small intestine, blood, and adrenal glands. 

This is what makes lysosomal acid lipase deficiency (LAL-D) such a rare and devastating disease. Besides the damage it can do to the body, its presentation is usually vague enough for some physicians to miss. According to Strebinger and colleagues, “While the severe form manifests as a rapidly progressive disease with near-universal mortality within the first 6 months of life, milder forms frequently go undiagnosed for prolonged periods and typically present with progressive fatty liver disease, enlarged spleen, atherogenic dyslipidemia, and premature atherosclerosis.”

This means that even if the patient with LAL-D survives beyond childhood, the patient likely has to deal with a number of diseases relating to toxic lipid accumulation. 

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Read more about LAL-D etiology

Helderman et al considered looking at LAL-D beyond the typical symptoms that characterize the disease and wanted to examine its effects on bone growth. Despite the list of diseases mentioned above that are known to be associated with LAL-D, “skeletal phenotyping has not been reported,” observed Helderman and colleagues.

In fact, it seems that the impact of LAL-D on healthy bone growth has almost been missed completely. The researchers continued, “To date, there has been no documented skeletal phenotype associated with LAL-D. This is particularly interesting because epidemiologic data indicate that high concentrations of circulating cholesterol and accelerated atherosclerosis are linked to low bone mass and osteoporosis.” 

We are all well aware that unesterified cholesterol and fatty acids are essential for bone metabolism. Therefore, it is no stretch to imagine that LAL plays an important role in the formation of bone and the maintenance of skeletal health. Helderman et al wanted to investigate how far LAL-D impacts osteoblastogenesis and whether the disease carries with it an increased risk of fractures in adults. They designed a clinical study for this purpose. 

Osteoporosis and Fractures

We will talk briefly about the methodology of this clinical study and spend more time looking at the results. Helderman and his team used a few methods to study the effects of LAL-D on bone homeostasis, including studying mice that had LAL-D, as well as gleaning clinical data from patients with LAL-D. 

As for the mice that had LAL-D, the researchers discovered the following: 

  • An analysis of the distal femur metaphysis showed lower trabecular bone in the LAL-D mice compared to wild-type mice. In addition, the LAL-D mice had decreased trabecular number and thickness, with increased trabecular separation. 
  • LAL-D mice had a weaker, ‘rod-like’ bone morphometry. 
  • LAL-D mice had significantly decreased connectivity density compared to wild-type mice. 
  • LAL-D mice had femurs that were mildly reduced in length. 
  • The cortical bone followed the trabecular bone in its presentation: LAL-D mice had reduced cortical parameters compared to wild-type mice. 
  • Mice with LAL-D demonstrated reduced biomechemical strength. 

As for the clinical data gleaned from human subjects, the researchers found that adults with LAL-D had a higher unadjusted prevalence of osteoporosis and fracture for all measures (except for stress fracture) when compared to adults without the disease. Even after adjusting for other factors that might influence bone health such as age, sex, race, and place of residence, patients with LAL-D had higher odds of developing LAL-D compared to patients without the disease (OR=1.23; 95% CI=1.05–1.43).

With the factor of osteoporosis removed, patients with LAL-D still had higher odds of developing fractures compared to the normal population (OR=1.21; 95% CI=1.03–1.41), meaning that patients with LAL-D are vulnerable to fractures independent of osteoporosis. 

Implications on Care 

In the discussion section of the study, Helderman et al stated, “The current study establishes, for the first time, that LAL is essential for skeletal health as it supports osteoblast differentiation in a cell-autonomous manner via modulation of lipid metabolism. Moreover, our innovative clinical analyses provide strong evidence that adults with LAL-D suffer from heightened fracture susceptibility, especially in the lower extremities.” 

Read more about LAL-D therapies

Because this is the first study to look into such detail regarding the impact of LAL-D on bone health, its full implications for clinical care are yet to be fully untangled. The study did a masterful job at describing how LAL-D is associated with osteoblast function and bone formation. Certainly, it adds to the list of things that physicians need to monitor when caring for patients with LAL-D. Multidisciplinary dialogue that includes orthopedic surgeons should be considered if beneficial for the patient. 

Perhaps one of the best things we can do for our patients with LAL-D is to ensure a speedy and accurate diagnosis. Strebinger et al commented, “LAL-D is a rare disease that may go unnoticed or be diagnosed late if not suspected” because “the clinical signs and symptoms are common.”

The widespread availability of blood spot tests should make it easier for physicians to test for LAL-D. The partial success of enzyme replacement therapy has also improved the quality of life of LAL-D patients. If we can suspect and detect LAL-D early, a whole host of interventions can be introduced on a personalized basis, including an emphasis on bone care.


Helderman RC, Whitney DG, Duta-Mare M, et al. Loss of function of lysosomal acid lipase (LAL) profoundly impacts osteoblastogenesis and increases fracture risk in humansBone. Published online April 7, 2021. doi:10.1016/j.bone.2021.115946

Strebinger G, Müller E, Feldman A, Aigner E. Lysosomal acid lipase deficiency – early diagnosis is the keyHepat Med. Published online May 23, 2019. doi:10.2147/HMER.S201630