Lysosomal acid lipase deficiency (LAL-D) is a rare disease that results in ectopic lipid accumulation in the body, especially in the liver, spleen, small intestine, blood, and adrenal glands. Given that unesterified cholesterol and fatty acids play an important role in bone metabolism, a team of scientists has proposed that LAL-D also significantly disrupts skeletal homeostasis. 

The impact that LAL-D has on bone metabolism has not received as much attention as its impact on other organs. Helderman and colleagues, in their study on the relationship between LAL-D and skeletal health, wrote, “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.”  

Let’s take a closer look into the relationship between LAL-D and skeletal homeostasis. 


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A Close Connection With the Brain 

Skeletal homeostasis is an area in which the disciplines of endocrinology and orthopedics overlap. Zaidi and colleagues, in their study on skeletal homeostasis, wrote, “Bone is a highly dynamic and purposefully organized composite consisting of a protein matrix, mainly comprising type 1 collagen, mineral, and cells of multiple lineages.” 

Recent studies have demonstrated that the bone is a vital organ that possesses both endocrine and paracrine functions. During bone remodeling, molecular crosstalk occurs between bone cells; osteoblasts, osteoclasts, and osteocytes communicate among themselves and with other cells in the bone marrow, such as macrophages, adipocytes, as well as T and B cells. 

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Osteoblastic bone formation is controlled epigenetically through three pathways: Notch, Wingless-integration-1 (WNT), and bone morphogenetic protein (BMP). Osteoblasts are responsible for modulating both erythropoiesis and the formation of blood vessels in the bone.

In addition, scientists have discovered a close connection between brain and bone. Zaidi et al wrote, “Neural surveillance of the skeleton comprises a neural arm driven mainly by sympathetic discharges and a neuroendocrine arm wherein pituitary hormones act directly to regulate bone remodeling.” 

The Critical Role of the LAL Enzyme 

Given the complex biological interactions involved in maintaining bone homeostasis, it should come as no surprise that deficiency in the LAL enzyme can potentially impact bone health in a negative way. 

Helderman and colleagues decided to further investigate the relationship between LAL-D and bone health because their lab has previously reported that intracellular lipid droplets play a crucial role in osteoblast differentiation. They had also previously discovered that peripheral adipose depots contribute fatty acid energy sources that support the function of osteoblasts. 

To investigate the relationship between LAL-D and skeletal homeostasis, Helderman et al conducted studies on mice with the global deletion of the LIPA gene. Nonmutated, wild-type mice were used as controls. At 16 weeks of age, the mice were sacrificed and their femora and tibiae extracted for analysis. 

The research team discovered that LAL−/− mice had lower trabecular bone parameters in the distal femur, reduced femur length, and less cortical bone area and thickness than the control. Histological studies have demonstrated these mice also have fewer osteoblasts than wild-type mice. 

Importantly, Helderman and colleagues discovered that LAL plays a critical role in generating osteoblasts and maintaining their function. They wrote, “We indeed confirmed that LAL protein is expressed in osteoblasts and the flushed femoral cortex. Next, we demonstrate that calvariae osteoblasts from LAL−/− mice exhibit impaired differentiation potential.” 

Aside from studies conducted on mice models, Helderman et al also used data from Clinformatics Data Mart Database, a national insurance claims database, to determine if LAL-D patients suffer from impairments in skeletal health. They discovered that adults with LAL-D had a higher unadjusted prevalence of osteoporosis and fracture for all measures (except stress fracture).

“After adjusting for age, sex, race, and U.S. region of residence, adults with LAL-D had higher odds of any fracture compared to adults without LAL-D,” Helderman et al wrote. 

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“By utilizing the LAL−/− mice we were able to investigate the skeletal phenotype caused by loss of functional LAL, which previous characterizations have failed to mention,” they explained. “Along these same lines, the multisystemic disorder of LAL-D, which is similarly observed in LAL−/− mice, it is logical that the skeletal phenotype might be an indirect consequence of such confounders including vitamin deficiencies, chronic inflammation, altered mineral homeostasis, and/or the profound perturbations in whole-body metabolism.”

A Reminder for Clinical Practice

The significance of this study is that it serves as a reminder that LAL-D is a systemic disease that affects multiple organs in the body, and equal attention and care should be afforded to its pathological effects on each one.

Now that a biological association between LAL-D and bone health has been proposed, physicians should avoid making the mistake of identifying LAL-D and bone pathology as 2 separate medical issues. Rather, clinicians should include bone health in the routine monitoring of LAL-D disease progression.

References

Zaidi M, Yuen T, Sun L, Rosen CJ. Regulation of skeletal homeostasisEndocr Rev. 2018;39(5):701-718. doi:10.1210/er.2018-00050

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. 2021;148:115946. doi:10.1016/j.bone.2021.115946